ENDOTEXT---ASK AN EXPERT The aut

The Authors and Editors of WWW.ENDOTEXT.ORG will attempt to answer questions from physicians about diagnosis and management of endocrine problems. Physicians who wish to submit questions should provide information identifying their place of practice. Responses will be sent by return Email, and questions with general application will be published in this column. Names of correspondents will be included unless we are specifically requested not to do so. Questions may be addressed to any author or editor, and sent to ldegroot@earthlink.net

MANAGING MENOPAUSE IN A TRANSGENDER MALE -- 16 May 2013
QUESTION--I request your opinion on a patient of mine. He is new to my practice and is a very delightful 65 yrs male to female transgender. He underwent surgery inThailand for genital transformation . She is a very productive musician and a pilot. She looks feminine and is not sexually active. She has been on Premarin 0.625 since the surgery in 2004 . Her lipid profile is normal and has no underling medical problems or family h/o any chronic illness. I have ordered a Dexa and she has been screened by Pcp for prostate surveillance .
My question is that would you recommend discontinuing Premarin ? I appreciate your opinion and enjoy reading ENDOTEXT !
Deepa T=
RESPONSE--I usually discontinue estrogen in women after age 60-65 unless they are miserably symptomatic and nothing else works. If she is not sexually active (and therefore not struggling with vaginal dryness, not sure if that is an issue with transgendered people) and her DEXA is OK, the risk of VTE is probably increased a bit and for sure the background rate is higher at his age than it was when he started the Premarin. In the WHI stroke risk was also higher in the women who took postmenopausal estrogen only. So assuming the physiology is similar I would suspect that these are the two biggest risks of continuing hormones. The risk of breast cancer is likely to be low because it is estrogen only but I don't know when in life your patient had the sex change. So overall I would favor discontinuing the estrogen if she can do it without much inconvenience.
The interesting question that this raises is what to do if her DEXA is low? That would tip the scales on balance to favor continuing the Premarin, and monitoring BP and risk factors for thromboembolic disease. Nanette Santoro, MD

POSSIBLE TREATMENT OF ACANTHOSIS NIGRICANS---27 March 2013
QUESTION-Gracias por su pregunta interesante. Por desgracia, yo no hablo español, y han utilizado un programa translatioon. Espero que sea lo adecuado.
He conocido de ningún tratamiento establecido para esta afección. Representa una respuesta hipertrófica piel a niveles altos de insulina, y la única terapia eficaz es reducir insulinemia través de la dieta a largo plazo y programas de ejercicios. No he visto un impacto beneficioso de los fármacos sensibilizantes a la insulina como la metformina o tiazolidinedionas ni sé de estudios en ese sentido. Hay información anecdótica sobre el uso de Retin-A, 20% de urea, alfa hidroxiácidos, ácido salicílico y recetas. Pero nunca he hecho eso y no puedo comentar directamente. También sitios web dermatología han sugerido la dermoabrasión o la terapia láser. Una vez más no tengo experiencia. En general, la mejor recomendación para sus pacientes es trabajar duro en los esfuerzos de estilo de vida - con énfasis en los muchos beneficios potenciales para la salud. Dra. María del Pilar Sánchez.
RESONSE- Thank you for your interesting question. Unfortunately, I do not speak Spanish, and have used a translatioon program. I hope its adequate.
I known of no established therapy for acanthosis nigricans. It represents a hypertrophic skin response to high insulin levels, and the only effective therapy is to reduce insulinemia through longterm diet and exercise programs. I have not seen a beneficial impact of insulin sensitizing drugs such as metformin or thiazolidinediones nor do I know of studies in that regard. There is some anecdotal information about using Retin-A, 20% urea, alpha hydroxyacids, and salicylic acid prescriptions. But I've never done that and cannot directly comment. Also dermatology web sites have suggested dermabrasion or laser therapy. Again I have no experience. Overall the best recommendation for your patients is to work hard on lifestyle efforts - with emphasizing the many potential health benefits. Jack Leahy, MD

HOMOGENTISIC ACID AND URINARY CATECHOLAMINE TEST-18Feb2013
QUESTION - Dear Dr. Koch- A patient referred to test Urinary Catecholamines has been advised to avoid Homogentisic acid containg drugs prior to the test. Please could you provide me a reference for such drugs since the Pathologists too are unaware of such a reference. ASB Wijekoon (MD, MRCP, DCH),Teaching Hospital, Peradeniya, Sri Lanka
RESPONSE-As you know, homogentisic acid usually is not present in plasma or urine in healthy people. In people with alkaptonuria, however, it is.
If homogentisic acid cannot be fully metabolized, it is conceivable that there might be an accumulation of tyrosine with subsequent metabolism of tyrosine into various substances. As you know tyrosine hydroxylase is the key enzyme for catecholamine synthesis. Perhaps that was the consideration of the pathologists at your hospital.
I myself have not come across such a case and have searched a bit in the literature all the way back into the "old days", please take a look at the references attached below my name.
I would suggest to measure homogentisic acid and urinary catecholamines in this patient....if he has not taken any herbs etc. which might contain homogentisic acid, and if the patient does not have alkaptonuria, then the urine homogentisic acid specimen should be normal = negative.
Of course, it is important to remember other medications that might interfere with urinary catecholamine determinations, i.e. I had encountered several patients who referred to me for elevated urinary dopamine etc. who were treated with carbidopa for restless leg syndrome (or Parkinson). These patients did not have a pheochromocytoma or paraganglioma. Best regards, Christian A. Koch, MD, PhD

Arch Pharm Res. 2012 Oct;35(10):1785-91. doi: 10.1007/s12272-012-1011-0. Epub 2012 Nov 9.Qualitative and quantitative simultaneous determination of six marker compounds in Soshiho-tang by HPLC-DAD-ESI-MS.Yang HJ, Ma JY, Weon JB, Lee B, Ma CJ.
Soshiho-tang, one of the herbal prescriptions, has been used in treatment of chronic liver disease. In this study, the efficient high-performance liquid chromatography coupled with diode array detection and electrospray ionization tandem mass spectrometry (HPLC-DAD-ESI-MS) method was developed and validated for simultaneous determination of six marker compounds, namely homogentisic acid, baicalin, glycyrrhizin, saikosaponin A, 6-gingerol and ginsenoside Rg3 in Soshiho-tang. The analysis of six marker compounds was carried out using a C(18) column (SHISEIDO S-5 μm, 4.6 mm I.D. × 250 mm) and gradient elution with water - 0.1% trifluoroacetic acid and acetonitrile. The analytical method was validated for linearity, precision and accuracy. Calibration curve for six marker compounds showed good linear regression (r(2) > 0.9996). The limits of detection (LOD) and limits of quantification (LOQ) for analytes were ranged from 0.04 to 0.16 μg/mL and 0.12 to 0.47 μg/mL, respectively. The relative standard deviations (RSD%) of the precision test, intra- and inter-day, were less than 0.32% and 0.10%, respectively. All recoveries of the six marker compounds were ranged from 100.05% to 102.25% with RSD less than 0.63%. These results have shown that this developed method was efficient for the quality evaluation of Soshiho-tang.

J Mol Biol. 2009 May 8;388(3):597-610. doi: 10.1016/j.jmb.2009.03.053. Epub 2009 Mar 25.At low concentrations, 3,4-dihydroxyphenylacetic acid (DOPAC) binds non-covalently to alpha-synuclein and prevents its fibrillation.Zhou W, Gallagher A, Hong DP, Long C, Fink AL, Uversky VN.
Several studies have shown that catecholamines can inhibit the fibrillation of alpha-synuclein (alpha-Syn), a small presynaptic protein whose aggregation is believed to be a critical step in the etiology of Parkinson's disease and several other neurodegenerative disorders. However, the mechanism of this inhibition is uncertain. We show here that substoichiometric concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC), a normal product of the metabolism of dopamine, can inhibit the fibrillation of alpha-Syn, due to non-covalent binding of DOPAC to alpha-Syn monomer. Intriguingly, the presence of alpha-Syn accelerates the spontaneous oxidation of DOPAC, and the oxidized form of DOPAC (the quinone) is responsible for the fibrillation inhibition. In addition, the presence of DOPAC leads to the oxidation of the methionine residues of alpha-Syn, probably due to the H(2)O(2) production as a by-product of DOPAC oxidation. The lack of fibrillation results from the formation of stable oligomers, which are very similar to those observed transiently at early stages of the alpha-Syn fibrillation. A possible explanation for this phenomenon is that DOPAC stabilizes the normally transient oligomers and prevents them from subsequent fibril formation. The analysis of the alpha-Syn Y39W variant suggests that DOPAC binds non-covalently to the same N-terminal region of alpha-Syn as lipid vesicles, probably in the vicinity of residue 39. In contrast to the compounds with 1,2-dihydroxyphenyl groups (DOPAC and catechol), their 1,4-dihydroxyphenyl isomers (hydroquinone and homogentisic acid) are able to modify alpha-Syn covalently, probably due to the less steric hindrance in the Michael addition.

Arch Int Physiol Biochim Biophys. 1993 Nov-Dec;101(6):417-23.Renal excretion of plasma soluble melanins by healthy human adults.Hegedus ZL, Nayak U.
The soluble melanins of blood plasma form in vivo and in vitro from dopa, catecholamines, catechol, hydroquinone, homogentisic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, p-aminophenol, p-phenylenediamine and other structurally related end(ex)ogenous compounds by oxidative polymerization. The mean quantity of natural melanins in normal plasma is 1.61 +/- 0.10 (standard deviation) mg/ml, (n = 20) and in uraemic plasma 2.72 +/- 0.38 mg/ml, (n = 16). The plasma melanins (approximately 3%), are associated with proteins (approximately 85%), mucoproteins (approximately 0.25%), lipids (approximately 0.4%), as soluble lipofuscins, and probably are associated with proteins without lipids as soluble melanoproteins. Fluorescence, UV-VIS and IR spectroscopies and the melanin isolation method show the presence of soluble melanins in the urine of healthy people. Soluble melanins can also be formed in vitro in the urine by oxidative polymerization of the precursors. In most of the urine samples we studied, melanins were present in larger amounts than the urinary proteins, indicating that the kidneys can selectively excrete the melanin components of the lipofuscins, and that the solubility of melanins does not depend upon combination with proteins. The quantities of purified melanins precipitated with 6 N HCl at 110 degrees C during 72 h from urine samples collected during 24 h periods ranged from 0.1460 g to 3.7627 g (mean 1.1303 +/- 1.1739 g, n = 8) and the plasma clearance rates ranged from 0.06 ml/min to 1.56 ml/min (mean 0.48 +/- 0.48 ml/min, n = 8). From the individual 24 h urine samples we obtained from 9 to 216 mg/dl of precipitated melanins while the individual plasma samples contained from 145 to 175 mg/dl.

Clin Chem. 1973 May;19(5):459-62.Urinary homogentisic acid: determination by thin-layer chromatography.Feldman JM, Bowman J.
Catecholaminescomprise of dopamine , noradrenaline (norepinephrine), and adrenaline (epinephrine). Metanephrines are metabolites of catecholamines which comprise of metanephrine and normetanephrine.Analysis of these hormones/metabolites ishelpful in diagnosis or ruling out the presence of pheochromocytoma or other neuroendocrine tumor. Measurement of their levels in urine is influenced by chocolate, cocoa, coffee, tea, bananas, and other vanillin compounds in the diet. Such interference occurs only with colorimetric assay methods. HPLC methods are not subject to this interference. Catecholamine and metanephrine levels are also affected by emotional and physical stress and vigorous exercise and can be increased by medications including lithium, insulin, tetracycline, and nitroglycerin. Levels of catecholamines may be decreased in patients receiving salicylates and imipramine22. 22Skobe C. Preanalytical variables in urine testing. BD LabNotes 2006; 16(3):1-7

Yale J Biol Med. 1978 Nov-Dec;51(6):625-33.Deranged tyrosine metabolism in cirrhosis.
Fulenwider JT, Nordlinger BM, Faraj BA, Ivey GL, Rudman D.
In normal individuals, the main route for tyrosine degradation is the hepatic pathway tyrosine→4-hydroxyphenylpyruvic acid→homogentisic acid→CO(2). Quantitatively minor pathways, in large part extrahepatic, are: tyrosine→tyramine→octopamine and tyrosine→dopa→catecholamines.In cirrhosis, the main hepatic pathway is blocked to varying degrees at the first three stages. This appears to be due to lack of activity of the enzymes tyrosine transaminase, PHPA oxidase, and HGA oxidase, the first step being rate limiting. Hypertyrosinemia and tyrosine intolerance result.With the main hepatic pathway partially blocked, an abnormally large amount of tyrosine passes into the normally minor extrahepatic pathway leading to the false neurotransmitters tyramine and octopamine. Overproduction of these amines ensues and they accumulate in the body fluid.The false neurotransmitters can displace catecholamines from their storage sites in the peripheral and central nervous system, and thereby disrupt adrenergic processes in arterioles, kidneys, and brain. Their accumulation in cirrhotic patients may play a role in the pathogenesis of hepatic encephalopathy, hepatorenal syndrome, and hyperdynamic circulation.

CONTROL OF DIABETES RESISTANT TO INSULIN TREATMENT? 7 Decemb er 2012
QUESTION-Presently I am treating a lady, 65 yrs of age, suffering from Type 2 Diabetes for the last 15 yrs. Earlier on she used to be treated with oral hypoglycaemic agents but presently she is on insulin, since 2007. Her body weight is 70 kg, BMI 28.5, renal profile within normal limits. Urine Albumin creatinine ratio mildly raised.She is on basal bolus regime with Insulin Glargine 60 units, and Insulin aspart 24 for breakfast, 30 for lunch and 30 for dinner, along with Sitagliptin and metformin combination ( 50/1000 mg) twice daily. Her SMBG is in the
range of 180 -320 . Despite increasing the insulin dosage, her blood sugars do not respond
adequately. She is compliant with her diet and medications.
I had once admitted her to a local hospital to improve the glycaemic control. She had iv insulin aspart as per sliding scale for 4 days and required about 60 units of insulin in each 24 hrs. On switching over from iv to subcut insulin, her glycaemic control became poor and she required quite heavy dose of insulin as mentioned above.
What else can I give her to improve her glycaemic control ? Insulin pump may not be an option due to financial strains. Dr Sagarika Mukherjee, AMRI Hospitals, Kolkata, India.
RESPONSE-The first thing to do is rule out syndromic insulin resistance. While most of these are rare, most are also not identified when they are present. I would encourage this patient to be considered for all of these.
For the more common insulin resistance associated with obesity and/or metabolic syndrome, the first thing to appreciate is there are little data to support a glycemic benefit when using over 1 u/kg of the most commonly used basal insulin, insulin glargine. Furthermore, there are data to suggest for a basal insulin, NPH may be preferred. From a cost basis, this is a potential major advantage. Finally, it has been shown that NPH may work better in these patients when administered in two injections (two depots). The thought is there is better absorption from two than one depot. It should be noted gold standard clamp studies have not been preformed to prove this, but clinically this is how many of us have been managing these patients for years.

For the prandial insulin, larger doses result in longer durations of action. While this is true for basal insulins also, the goal with prandial insulin is to match the insulin with the food. For this reason, my preference is to continue to use rapid acting analogues but there are no controlled trials showing in this insulin resistant population one is better than the other. The other point: timing of the meal time insulin is critical-the longer "lag time" (time between giving the insulin and eating) will have a tremendous impact on postprandial hyperglycemia, especially with the higher doses of insulin. Fifteen to 20 min with a rapid-acting analogue should be the rule for these patients.

Many of these patients will not be controlled with these tools. There have been initial reports of dramatic benefits with the use of the GLP-1 analogue liraglutide, but this needs to be confirmed with controlled studies. Most of these patients have already been tried on metformin and that should be continued if tolerated and there are no contraindications. The real issue at this point is moving to U500 regular insulin, which has been available for decades in the US, but is not available in many countries. In the US, we tend to move to U500 regular insulin when the insulin dose is > 2 units/kg or > 200 units/day AND the HbA1c is > 8%. U-500 regular insulin is used as both a prandial and basal insulin. The fine points on how to best use this are beyond the scope of this discussion, but there are excellent reviews noted in the references. There are currently other higher concentrated insulin now in development which should assist in the management of patients like this. Irl B. Hirsch, M.D.
References:
1. Bota VM Hirsch IB: Insulin glargine or neutral protamine Hagedorn in patients with severe insulin resistance: Is there a benefit? Endocrine Practice 2012;18:e49-51 2. Crasto W. Jarvis J, Hackett E, et al: Insulin U-500 in severe insulin resistance in type 2 diabetes mellitus. Postgrad Med J 2009;85:219-22 3. Chukwu JF, Hirsch IB, Trence D: Use of liraglutide in severely insulin resistant patients with type 2 diabetes. Presented Endocrine Society 4. Annual Meeting, 2012 4. Gagnon-Auger M, du Souich P, Baillargeon JP et al: Dose dependent delay of the hypoglycemic effect of short-acting insulin analogs in obese subjects with type 2 diabetes: a pharmacokinetic and pharmacodynamic study. Diabetes Care 2010;33:2502-2507 5. Lane WS, Cochran EK, Jackson JA, et al: High-dose insulin therapy: is it time for U-500 insulin? Endocrine Practice 2009;15:71-79 6. Lane W, Weinrib S, Rappaport J: The effect of liraglutide added to U-500 insluin in patients with type 2 diabetes and high insulin requirements. Diabetes Technol Ther 2011;13:592-5.
7. Wang Z, Hedrington MS, Joy NG, et al: Dose -response of insulin glargine in type 2 diabetes. Diabetes Care 2010 33:1555-1560 8. Wolska A: One vs. two depots for NPH insulin in severely insulin resistant patients with type 2 diabetes. Presented at the European Associatio for the Study of Diabetes, 2011

HYPOPARATHYROIDISM AND DIFFICULT TO CONTROL HYPOCALCEMIA 1 Jun 2012
QUESTION: I am taking care of a 47 woman with PMH of RA and Hep B s/p thyroid lobectomy in 1994 for thyroid nodules with completion thyroidectomy in 2008 because of dysphagia in the Philippines. She reports that she did not have a history of cancer but her medical records are not available. She has had post-operative hypoparathyroidism. She is post-menopausal as of May 2011 and has osteopenia.
Her previous physicians had her on 1950mg of elemental Calcium TID for a total daily dose of 5850mg. She was also taking vitamin D3 600 IU daily and one-alpha (alfacalcidiol) 0.5mcg-1mcg daily . However, she was having significant diarrhea, and her calculated her fractional excretion of calcium = (6.11mmol/d x 0.107mmol/L)/(2.05mmol/L x 9.6mmol/d)=3.3% and so I slowly reduced her dose to 650mg QID, increased Vit D3 to 2000 IU daily and changed her one-alpha to Rocaltrol 1mcg BID. I also added a thiazide diurectic (HCTZ) at 12.5mg daily at a low dose considering her BP of 110/66 to reduce calciuria. I made these changes in February 2012.
She continues to be biochemically hypocalcemic with symptoms of parasthesias. an you please advise how to correct her hypocalcemia. Her labs are as below (reference ranges are in brackets).
Recent labs:
May 26 2012
Mg 0.69 (ref 0.65-1.05)
Cr 111 (ref 60-115)
Ca 1.76 mmol/L (ref 2.15-2.6)
Phos 1.88 (ref 0.8-152)
Feb 23 2012
Hgb 129
CK 337 (ref 29-165)
Ca 2.05 mmol/L
Albumin 45
TSH 6.66
FT3 3.3 (REF 3.5-6.5)
FT4 17 (REF 9-23)
iCA 1.06 (REF 1.15-1.35)
25OH VIT D 75
1,25 VIT D 51 (REF 30-120)

Dec 22 2011
Hgb 117
Cr 105
AST 24
ALT 19
CK 265
Ca 1.83 (ref 2.15-2.6)
iCa 0.91 (ref 1.15-1.35)
Phos 2.38 (ref 0.80-1.45)
Mg 0.77 (ref 0.7-1.0)
PTH < 0.3
FT3 4.3 (REF 3.5-6.5)
FT4 26 (REF 9-23)
TSH 0.05
25OH vit D 77
TTG Ab 6 (ref <20)
ACR 6.6

Dec 1 2011
Ca 1.64 (REF 2.15-2.60)
PHOS 2.6 (REF 0.8-1.45)
FT3 3.9 (REF 3.5-6.5)
FT4 22 (REF 9-23)
Cr 105
GFR 49

OCT 31 2011
PTH < 0.03
CA 1.68 (REF 2.15-2.60)
PHOSPHATE 2.28 (REF 0.8-1.45)
ALBUMIN 43
FT3 4.8 (REF 3.5-6.5)
FT4 34 (REF 9-23)
TSH < 0.05
ionizeD ca 0.82 (ref 1.15-1.35)
HGB 121
CR 98
AST 25
ALT 18
ALK PHOS 52
25 OH VIT D 80

OCT 6 2011
L FEMORAL NECK T -0.9, Z -0.5
L TOTAL FEMUR -1.1, Z -0.9
L SPINE T 0.6 T 0.9

RESPONSE-From the above it is not clear what Ca salt she was taking at the time she manifested diarrhea. My guess would be that the Ca was not giving her diarrhea but that she was malabsorbing the Ca due to diarrhea and rapid GI transit. Therefore if she still has significant diarrhea, I would recommend an evaluation for it. If it is due to a parasitic process or celiac disease for example, it can be addressed. Diarrhea and malabsorption are very important issues in the treatment of hypoparathyroidism. Important electrolytes can be lost as well as important nutritional factors (protein, fat, etc). These include K+ and Mg2+ as well as the Ca2+ supplements she is taking. I would recommend a gastroenterologist evaluate the patient if there is ongoing diarrhea.

Regarding her current supplements:
(1) vitamin D3: I think the amount of vitamin D3 at the current dose is sufficient (2000 IU/day). I would not recommend changes there. Serum levels are 75 and 80 with no units mentioned and no normal range. If the units are “nM”, then her levels are more than sufficient. If they are “ng/ml”, then you have her at the top of the desired “normal” range. With an undetectable PTH and high serum phosphate, it is doubtful she will be doing significant conversion of 25 OH vitamin D to 1,25 (OH)2 vitamin D.

(2) Rocaltrol: She is now taking a substantial dose of this medication. If she is malabsorbing in general, she should still be able to absorb most of this least of the polar vitamin D metabolites. I have seen patients taking more than 2 micrograms per day to treat hypoparathyroidism, but I have never been convinced that doses above this level were needed to restore gi absorption of Ca. The dose can be increased and spread out from bid to tidn(e.g., 1 ug tid), but I doubt that that alone will bring the serum Ca to the desired low normal range 8.0-9.0 mg/dL. You have a 1,25 D level showing she is in the middle of the normal range. Those levels are hard to interpret in this context.

(3) Ca supplements: With possible diarrhea and RA in the picture, one must think of a possible underlying process such as atrophic gastritis. I would check CBC, mcv, vitamin B12 level. I tend to favor the use of calcium citrate instead of carbonate in my patients with hypoparathyroidism. Citrate does not require gastric acid for absorption and does not need to be taken in conjunction with a meal for ideal absorption. So the type of supplement is not specified and I would convert the main Ca supplement to citrate to see if that allows for better control of the serum Ca. Clearly the doses of elemental Ca for this patient have gone as high as nearly 6 grams per day. With the undetectable PTH this is not surprising, since those with low to no residual PTH secretion are the most difficult patients to control. If you are switching her from her current Ca dosing to citrate, I would start with 1 Gm elemental Ca (as Ca citrate) tid and rocaltrol 1 ug tid and follow closely. Incrementally, she can be up-titrated with Ca 1.25 Gm tid, 1.5 Gm tid, 1.75 Gm tid, 2 Gm tid etc. Option #7 might be a consideration at these higher levels.

(4) Mg supplements: I see 2 borderline low normal serum Mg levels. In my experience, patients with hypoparathyroidism often need Mg supplements especially in light of the prior or ongoing problems with diarrhea. I would check a 24 hour urinary Mg and creatinine level to see if there is detectable Mg being excreted. If there was I would probably still try a gentle amount of supplementation, I say gentle because of the possible baseline diarrhea and the diarrhea that can come from oral Mg supplements. If the urinary level of Mg is very low or undetectable, then for sure, your patient is Mg depleted. This can happen even with a “normal” serum Mg level. I would supplement more vigorously in that case. Since Mg is an intracellular ion, serum levels do not reflect the degree of total body Mg depletion.

(5) I don’t see basic chemistries here, with ongoing diarrhea, K depletion is a concern and must be supplemented. Hypocalcemia, hypomagnesemia/Mg depletion, and hypokalemia all can present with tetany and muscle symptomatology. I would monitor the serum electrolytes periodically.

(6)Thiazide diuretics: Unfortunately at the dose the patient is taking, there may be little urinary Ca lowering effects ongoing. I would try to increase to at least 25 mg/day. If that is not tolerated, you could try giving an additional dose of 12.5 mg before going to bed as she might tolerate it then. I would follow the 24 hour urinary Ca level with creatinine. I am aiming to achieve a level less than 300 or 350 mg/24 hours (with an adequate urinary creatinine assuring a good collection). I am not familiar with the clinical application of the excretion assessment the doctor is using and just monitor the 24 hour urinary Ca and creatinine totals.

(7) Replacement with PTH: At present in the US, human recombinant PTH (1-34) is available for the treatment of patients with osteoporosis. I would consider it in this patient, as an off-label use if I up-titrated to 1-2 micrograms rocaltrol, added Mg supplements, added additional thiazide, and got the Ca supplements to 1.5-2 Gm tid without reaching at least a serum Ca of 8.0 mg/dl and controlled symptoms. Conversion to SI units would be about 2.00 mM Ca and relative control of symptoms. I have used PTH (1-34) 20 mcg once daily and even twice daily. It is reported sometimes that patients may be titrated down once they have improved. Outside the US, both recombinant PTH 1-34 and PTH 1-84 (the full-length authentic secreted form of the hormone) are available and could be considered in the context of an off-label use. There are several papers that report on the use of PTH 1-34 and PTH 1-84 in the treatment of hypoparathyroidism. They are listed below, but at least in the US, this is still an off-label use of the hormone and PTH 1-84 is not available in the US.

(8)Diet: No mention is made of this but I would encourage the patient to consume a diet with at least 1000 mg of absorbable Ca in it.
Dr Dolores Shoback

Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism. J Clin Endocrinol Metab. 2012 Feb;97(2):391-9. Epub 2011 Nov 16.

Winer KK, Sinaii N, Reynolds J, Peterson D, Dowdy K, Cutler GB Jr. Long-term treatment of 12 children with chronic hypoparathyroidism: arandomized trial comparing synthetic human parathyroid hormone 1-34 versus calcitriol and calcium. J Clin Endocrinol Metab. 2010 Jun;95(6):2680-8. Epub 2010 Apr 14.

Winer KK, Sinaii N, Peterson D, Sainz B Jr, Cutler GB Jr. Effects of once versus twice-daily parathyroid hormone 1-34 therapy in children with poparathyroidism. J Clin Endocrinol Metab. 2008 Sep;93(9):3389-95. Epub 2008 May 20.

Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, Gerber LH, McGarvey C, Cutler GB Jr. Long-term treatment of hypoparathyroidism: a randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin Endocrinol Metab. 2003 Sep;88(9):4214-20.

Winer KK, Yanovski JA, Sarani B, Cutler GB Jr. A randomized, cross-over trial of once-daily versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol Metab. 1998 Oct;83(10):3480-6.

Winer KK, Yanovski JA, Cutler GB Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol and calcium in the treatment of hypoparathyroidism. JAMA. 1996 Aug 28;276(8):631-6.

Rubin MR, Dempster DW, Sliney J Jr, Zhou H, Nickolas TL, Stein EM, Dworakowski E, Dellabadia M, Ives R, McMahon DJ, Zhang C, Silverberg SJ, Shane E, Cremers S, Bilezikian JP. PTH(1-84) administration reverses abnormal bone-remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res. 2011 Nov;26(11):2727-36.

Rubin MR, Sliney J Jr, McMahon DJ, Silverberg SJ, Bilezikian JP. Therapy of hypoparathyroidism with intact parathyroid hormone. Osteoporos Int. 2010 Nov;21(11):1927-34. Epub 2010 Jan 22.

Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L; Hypoparathyroid Study Group. The effect of adding PTH(1-84) to conventional treatment of hypoparathyroidism: a randomized, placebo-controlled study. J Bone Miner Res. 2011 Oct;26(10):2358-70.

Thank you Drs. Shoback for this detailed and informative response. I will try some of these suggestions to see if it helps with her hypocalcemia. Tharsan Sivakumar, MD, MPH, FRCPC

CUSHING’S PROBABLY DUE TO ECTOPIC ACTH-- SOURCE-UNCLEAR -- 9 May 2012
QUESTION-I have a patient who I believe has Cushing's syndrome secondary to ectopic ACTH, but have been unable to find a source and have had difficulty managing her profound hypercortisolism.
The patient is a 28 year old female, who was diagnosed with Cushing’s syndrome in February 2012. Work-up revealed ACTH-dependent hypercortisolemia. 24-hour urine cortisol was markedly elevated (> 600 mcg) and 1-mg dexamethasone suppression test revealed a non-suppressed cortisol level of > 60 mcg/dL. ACTH has ranged from 150 to 250 pg/mL. MRI (02/23/12) revealed just a prominent pituitary, but no adenoma. Subsequent 03/21/12 IPSS revealed central-to-peripheral ACTH gradient < 2:1 before and < 3:1 after CRH, with ACTH increase < 50% (actual data from the IPSS is attached), suggestive of ectopic ACTH. An 8-mg overnight dexamethasone suppression test on 04/09/12, also suggested ectopic ACTH with cortisol > 60 (ACTH not run by the lab) prior to the dose and ACTH 173.5 and cortisol 51 after the dose.
Work-up for the source of the ectopic ACTH has thus far been negative. CT of the abdomen/pelvis on 02/22/12, was unremarkable. CT of the neck/chest on 03/26/12, revealed thyroid nodules only, but no other masses. An ultrasound of the thyroid on 02/22/12, revealed two subcentimeter nodules in the right lobe, but calcitonin level on 03/26/12, was negative. Additional labs checked on 03/26/12, were also normal, including normal 24-hour urine metanephrines, 24-hour urine 5-HIAA, and gastrin (only mildly elevated at 103 [N < 100], but while non-fasting). MRI was repeated again on 04/03/12, during a hospitalization for hypertension and headache, which also revealed a prominent pituitary, but no clear adenoma. Chromogranin A checked on 04/16/12, was negative. Octreotide scan on 04/23/12, was normal.
She started ketoconazole at 200 mg BID on 04/11/12. I increased the dose to 400 mg BID after two weeks, and just yesterday increased her to 400 mg TID. Prior to her most recent dose change, her serum cortisol remained > 60 (24 hour urine cortisol is pending).
My questions for the expert would include:
1) Do you have any suggestions regarding the next step in localizing the ACTH source?
2) Do you have recommendations regarding the medical management of her hypercortisolism at this time? I am thinking about adding metyrapone to her ketoconazole therapy, but was wondering if you have additional suggestions? Brandon Chock, M.D Ontario, California
RESPONSE- Thanks, all the right things seem to have been done, and it certainly looks very like an ectopic source.My own plan in such cases is to get the chest CT reviewed by a real expert (that worked with our last patient; a 'negative' CT was reviewed by our local Head of Dept., a source found, and then video-thorascopically removed).
However, in terms of therapy I would now move towards bilateral adrenalectomy. In the short-term I would add metyrapone up to 1g 4x/daily, with careful assessments of cortisol levels as these may fall abruptly. A block-and-replace regime may be required. Then book for adrenalectomy in the near future. These patientrs are at significant risk of overwhelming sepsis or pulmonary embolism and effective therapy should not be delayed. Ashley Grossman, MD

HYPERCALCEMIA 26 March 2012
QUESTION-I have a patient who presented with severe hypercalcemia at 15.6mg/dl. With rehydration her calcium lowered to 12.3 mg/dl.
Concomitant intact PTH was 15 and 12.7 respectively. D-25 and 1, 25 were 56.3 ng/ml and 95 pg/ml with a gfr of 26 on no vit d supplement for months. 24 hour urine calcium was 438 mg/dl . She had normal thyroid function tests and normal cosyntropin stim test. She had negative malignancy work-up including bone marrow biopsy. ACE level was elevated at 157 so presuming increased 1,25 vitamin d production in sarcoid I placed her on prednisone 10 # 4 a day with taper. Her calcemia normalized in 1week. Pulmonary was consulted and felt that she did not have sarcoid and sent her back to me. I do not see and endocrine problem here and I am not sure where to go from here. Dr. Mary Lynn Kemick
RESPONSE-Your patient had increased serum 1,25(OH)2D with a somewhat high 25OHD(especially for someone not taking supplements) and 24 hr urine calcium that was also on the high side. The increased 1,25(OH)2D seemed to be the culprit in causing the hypercalcemia because PTH was low (although not suppressed—but this may be an assay problem) and the patient`s hypercalcemia responded well to steroids. This is all consistent with increased 1,25(OH)2D production either due to a non-infectious granuloma, an infectious granuloma or a lymphoma. (Does she have fever or weight loss?)The increased ACE level is consistent with sarcoid but not diagnostic. Although there is pulmonary involvement in over 90% of cases of sarcoid, there may not be hilar adenopathy and sometimes the alveolitis needs special imaging(eg high resolution CT) for diagnosis. Diagnosing sarcoid therefore may depend on how hard the pulmonary physician looked. Were there any skin or eye manifestations of sarcoid? As you know sarcoid may involve just about any system. I don`t know the age of your patient, but the GFR of 26 is quite low for any age and makes one wonder what the underlying renal pathology is. Interestingly the 1,25(OH)2D was elevated and the PTH was suppressed (presumably by the hypercalcemia) despite the low GFR. You may wish to consult a nephrologist if the low GFR is reproducible, and the nephrologist may decide a biopsy is warranted which could reveal non-caseating granulomas.
Overall therefore the most likely diagnoses, I would say are 1 Sarcoidosis 2 Lymphoma3 Other granulomatous disease. While she is being worked up you might recommend that she not take supplements that contain vitamin D, and stay out of the sun or use sunscreen. If she does have another episode of hypercalcemia, clearly rehydration and prednisone would be indicated until the underlying disease can be treated. David Goltzman, MD

FOLLOW-UP TESTING NEEDED AFTER BILATERAL ADRENALECTOMY IN MEN 12/10/2011
QUESTION-A 62 yo male patient with multiple endocrine neoplasia had bilateral adrenalectomy- one in 2003, the other in 2004. The man also had 4 gland parathyroidectomy and thyroidectomy. He is on synthroid and hydrocortisone. I am trying to locate the operative reports to see if both adrenalectomy surgeries were complete, but my question in general is in patients who have undergone bilateral adrenalectomy for pheochromocytoma, do you recommend annual biochemical profile work up such as 24 hour urine studies or is it unnecessary since in theory the patient should be cured due to bilateral adrenal removal? Does it depend on the genetic cause of the pheochromocytoma ? This patient is not currently having any typical symptoms of pheochromocytoma and the lesions were nonmalignant at the time of surgery based on pathology, but just was wondering about long term follow up. Gay Story, MD, , Baton Rouge Clinic
RESPONSE- Patients with MEN2-associated pheochromocytomas rarely (< 4%, see Lenders J et al., Lancet 2005) develop malignant disease / metastases. Also, such patients almost never develop extra-adrenal tumors (Neumann HP et al., NEJM 2002; 346:1459). In contrast, patients with germline mutations in the VHL gene or SDHD, SDHB gene, may present with extra-adrenal pheochromocytomas in 13% (VHL), 36% (SDHD), and 50% (SDHB), respectively. Certainly, one big problem with pheochromocytoma recurrence, similar to recurrence of thyroid cancer, is the extent / completion of primary surgery. In other words, if microscopic tumors cells were left behind in the adrenal bed (for instance, by performing adrenal sparing adrenalectomy or alike), it is very conceivable that over time pheochromocytoma regrowth might occur (I actually myself encountered such a patient in whom MEN2A-pheochromocytoma reappeared 11 years after the initial bilateral adrenalectomies). As symptoms in such patients may develop very slowly and are predominantly related to the epinephrine / metanephrine biochemical phenotype in MEN2-pheochromocytomas, it may take a while before the diagnosis is clinically (BP rise, tachycardia) suspected. For longterm follow-up, it is recommended to follow BP, annual plasma free and urinary fractionated metanephrines, and an adrenal MRI every 3 years. Depending on MEN2A or MEN2B status, serum calcium and PTH (MEN2A) as well as plasma calcitonin (and CEA) levels should be checked annually (Armstrong R et al., Arch Dis Child 2008). One might argue that this longterm follow-up approach is not costeffective and more longterm data are needed to help decide which is best for the future patient. However, one thing is clear: each patient should be assessed individually based on her/his individual history (surgeon, pathology report, interfering medications, etc.). Sources of variable interferences with measuring catecholamines and catecholamine metabolites including tricyclic antidepressants with false elevations of plasma and urine norepinephrine and normetanephrine should be considered (Lenders J et al., Lancet 2005). Patients with asymptomatic pheochromocytoma have been reported in up to 35% of pts with von Hippel-Lindau disease (Walther MM et al., J Urology 1999), in 19 of 33 pts with adrenal pheochromocytoma incidentalomas (Motta-Ramirez et al., AJR Am J Roentgenol 2005), and 15 of 150 patients seen at the Mayo Clinic (Kudva et al., The Endocrinologist 1999). The patient here seems to not require fludrocortisone which raises the question if complete (or adrenal sparing) bilateral adrenalectomies had been performed. Christian A. Koch, MD, PhD,

PITUITARY TUMOR NEITHER SHRINKING NOR GROWING 16 Oct 2011
QUESTION: I would appreciate suggestions regarding treatment for the following case.
Patient is Male age 44.
June 2010 – Prolactin level at 251 ng/ml with total testosterone 197 ng/dl and TSH 6.65 ulU/ml normal T3 and T4 . Subsequent MRI revealed tumor 1.9 x 1.8 x 1.5 cm with extension into the left cavernous sinus and rightward displacement of the pituitary gland and stalk deviation. Cortisol and other hormones for pituitary reserve were normal. Initial diagnosis of Prolactinoma with treatment of .5mg of Cabergoline in addition to Levothyroxine, and Testosterone replacement therapy.
July 2010 – Prolactin levels dropped to 12.3, testosterone and TSH normal.
Dec 2010 – Prolactin 10.8, testosterone and TSH normal. MRI results – no gross change in lesion, measurement 2.0 x 1.5 x 1.6 cm.
April 2011 – Prolactin 11.2, testosterone and TSH normal.
Patient came under my care in Sept 2011.
Sept 2011 – Prolactin 8.3 ng/mL. MRI shows no change in size of the tumor. Complete MRI text.. “Pituitary: Stable size and morphology of the sella turcica. Intrasellar lesion is reidentified resulting in some expansion of the sella turcica. Gross stability in height and morphology of this intrasellar lesion relative to 12/30/2010. Again, portions of the lesion extend into the suprasellar cistern on the left side. Deviation of the pituitary stalk to the right is noted. Probable involvement of the medial aspect of the left cavernous sinus again noted, stable. Preserved flow voids of the cavernous and supraclinoid segments of the bilateral internal carotid arteries. Stable signal characteristics of this lesion. Soft tissue signal intensity noted on the unenhanced coronal T1 images. The T2 signal characteristics are also stable. Avid enhancement following contrast administration. This lesion currently measures 2.0 x 1.6 x 1.5 cm in the respective craniocaudal, AP and transverse dimensions. Suprasellar Cistern: No impingement on the optic chiasm present.Hypothalamus: No mass, signal abnormality, or abnormal enhancement.Cavernous Sinus: Signal voids of cavernous internal carotid arteries present. Meckel cave is bilaterally fluid filled.Brain: Ventricles and sulci are age appropriate. Midline and basal cisterns are preserved. No focal signal abnormality, mass effect, or abnormal enhancement present. No change.Skull/Extracranial Structures: No mass, signal abnormality, or abnormal enhancement.Impression: 1. No change from 12/30/2010. 2. Intrasellar solid mass reidentified with some stable extension into the suprasellar cistern on the left side in the medial aspect of the left cavernous sinus. 3. Routine whole brain MRI images unremarkable. Negative for acute CVA or enhancing intra-axial mass.”
At this point  prolactin levels are normal on cabergoline0.5mg twice weekly dosage, the tumor is stable at 2 cm in its maximal dimension wit normal thyroid and testosterone levels on replacement . He had normal visual fields examination. He came to me looking for a third opinion. My diagnoses is  a non functioning pituitary adenoma that caused elevation of the prolactin level by compression; since the tumor is not shrinking with normal prolactin level and therefore my recommendation will be surgery.
Would you consider a prolactin producing tumor that is resistant to treatment ? even though his prolactin level is now normal.
would increasing dosage present any chance of reducing the size of the tumor? Is surgery the best path of treatment at this time?
Thank you again for your support. M. Montoya , M.D.
RESPONSE- Based on pre-treatment data, your patient could most likely harbor a macroprolactinoma, as hyperprolactinemia secondary to pituitary stalk disconnection very seldom is above 100 ng/mL 1, unless associated with macroprolatinemia2. Furthermore, in the case of nonfunctioning pituitary macroadenomas we should expect very low or even undetectable serum prolactin levels during cabergoline therapy instead of normal values, even in low doses.
Concerning treatment, first of all I would suggest to withdraw testosterone therapy and, if still low, introduce clomiphene instead 3. As neurophtalmologic evaluation and MRI ruled out chiasma compression, medical treatment with cabergoline (in the same dose, as no clear data on the benefits of increasing doses in tumor shrinkage is available when prolactin is already within the normal range). Some prolactinomas may exhibit shrinkage in the long-term treatment. Of course surgery can be performed at any time. I also would advice to follow the patient with echocardiograms, as the issue of cardiac valvular disease in prolactinoma patients on cabergoline is still under debate 4.
Marc ello Bronstein, MD|
Wass JA, Karavitaki N. Nonfunctioning pituitary adenomas: the Oxford experience. Nonfunctioning pituitary adenomas: the Oxford experience. Nat Rev Endocrinol. 2009 Sep;5(9):519-22
Glezer A, Soares CR, Vieira JG, Giannella-Neto D, Ribela MT, Goffin V, Bronstein MD.Human macroprolactin displays low biological activity via its homologous receptor in a new sensitive bioassay.J Clin Endocrinol Metab. 2006 Mar;91(3):1048-55
Ribeiro RS, Abucham J.Recovery of persistent hypogonadism by clomiphene in males with prolactinomas under dopamine agonist treatment. Eur J Endocrinol. 2009 Jul;161(1):163-9

PREGNANCY COMPLICATED BY AUTOIMMUNE THYROID DISEASE 26 Aug 2011
QUESTION-. I would appreciate if I can get your valuable suggestions on a case of autoimmune thyroid disease in pregnancy that I am dealing with.The lady is 25 years old married Indian Muslim. Her husband is her first cousin as well. She is primigravida. Her first presentation was at 8 weeks of gestation with the following abnormal TFT results-
24.05.2011 (at 6 weeks gestation)-TSH 0.15 microIU/ml (0.35-5.5)
27.05.2011 TSH- 0.06 µIU/ml (0.35-5.5), FT4- 2.07 ng/dl (0.8-1.8), FT3- 5.78 pg/ml (1.4-4.4)
05.06.2011- TSH 0.078 (0.27-4.2).
She attended my clinic on 11.06.2011. She had US done on 08.06.2011 which showed single live fetus 8 weeks & 3 days size.On enquiry & physical examination she had no goitre and no other signs & symptoms suggestive of hyperthyroidism.There was no history of thyroid disorder in her or her husband's family. She gave history of persistent nausea and a few episodes of vomiting from the beginning of her pregnancy, which was gradually settling down. I made a diagnosis of Hyperemesis gravidarum & gestational thyrotoxicosis and informed her that her TFT were likely to go back to normal over the next 4 to 8 weeks time and she did not require any treatment.
On 08.07.2011 she visited another endocrinologist. He did the following tests on her-
11.07.2011 TSH- 0.046 µIU/m l (0.27-4.2) , FT4- 11.87 pmol/L(12-22),AntiTPO antibody 85.95 IU/ml (<34)
Ultrasound thyroids normal morphology with no increased blood flow on doppler..On full examination he also did not find any abnormal features suggestive of hyperthyroidism and agreed with my diagnosis of gestational thyrotoxicosis.
I examined her on 22.08.2011 with the following TFT results-
19.08.2011;TSH 7.41 µIU/ml (0.27-4.2),FT4 10.08 pmol/L (12-22),AntiTPO antibody 90.51 IU/ml (<34).
23.08.2011 TSH 12.919 microIU/ml (0.35-5.5),FT4 0.85 ng/dl (0.89-1.76), AntiTPO antibody 84.4 U/ml (<60).
I have started her on LT4 50 micrograms per day and plan to review her at 4 weeks with repeat TSH & FT4.I suspect she has Graves' disease with changing nature of TSH receptor antibody.
I plan to measure her TSH receptor antibody at 6 weeks postpartum. Praveen Shankar, Ranchi, India
RESPONSE-I believe your patient started with the normal suppression of TSH caused by hCG in early pregnancy, and minimal increase in thyroid hormone levels. In the second trimester as hCG subsided, her endogenous thyroid function driven by TSH took over. She certainly has autoimmune thyroid disease, and seems intrinsically hypothyroid.. Whether she has Graves disease and blocking antibodies is unknown, and perhaps unlikely.. Most likely she has Hashimoto's thyroiditis, and is now mildly hypothyroid, needing supplementation, as you have done. She needs close follow to get her TSH quickly and consistently into the 2.5-3 range. Best regards, L De Groot, MD

MEDULLARY THYROID CARCINOMA AND CUSHINGS’ SYNDROME 15Aug 2011
QUESTION-I have a pt with mets. medullary CA of the thyroid. He is to undergo chemo per oncology, however, his potassium is low(2.2) and we suspect ectopic acth production. He is on IV potassium and Aldactone. 4AM cortisol in hospital was 46. ACTH and mid. sal. cort. is pending. Clinically, he is cushingoid with wt gain, full facies, hypertension, and low K. Will addition of ketoconazole help with the potassium? What dose? When should we see a response? When do we add metyrapone? What dose? Thank you for your help. J. Molinary,DO
RESPONSE-Ketokonazole slowly increased up to 2g a day over two weeks can be beneficial. Follow plasma cortisol.If the pt cannot take per os iv etomidate can be a good altrenative.
Metyrapone can be added as a second drug if ketokonazole cannot block steroidogenesis.
George P. Chrousos, MD

OSTEOPOROSIS AND MARFAN’S SYNDROME 26 MAY 2011
QUESTION-I am writing in hopes of obtaining your expert opinion on a particular patient I am following.
The patient is a 49 year-old gentleman with a history of Marfan's Syndrome and osteoporosis. He has a remote history of a growth-hormone producing pituitary tumor resected 14 years ago (no evidence of any active acromegaly). His anterior pituitary function tests are currently all within normal limits. There is no evidence of diabetes insipidus.
This man has only had one DEXA performed in December 2010, with the following results:
Anatomic Location: AP LUMBAR SPINE (L4 excluded)
BMD (gm/cm2): 0.703
SD above (+)/below, (-) T score: -3.3
SD above (+)/below, (-) Z score: -3.0
Anatomic Location: LEFT FEMORAL NECK
BMD (gm/cm2): 0.440
SD above (+)/below, (-) T score: -3.6
SD above (+)/below, (-) Z score: -2.9
He has had compression fractures of T12, L2, and L4 without any specific trauma that he recalls; there have been no other fragility fractures. He has had a negative work-up for hyperthyroidism, hypogonadism, hyperparathyroidism, Vitamin D deficiency, and multiple myeloma. There is no significant history of glucocorticoid use. He has significant scoliosis. A 24 hour urine collection for calcium was not elevated. He has normal renal function.
With respect to the treatment for his osteoporosis (beyond the 1,000 mg of elemental calcium and 1,000 units of Vitamin D supplements he takes daily), I was considering teriparatide.
Do you have any experience treating patients with osteoporosis and Marfan's Syndrome with teriparatide? Would you recommend bisphosphonate use instead for such an individual? Thank you so much for your time..-William Amess, MD
RESPONSE-Thank you for the note and your great workup; I don’t have experience treating the osteoporosis of Marfan's syndrome but as you know its more a qualitative defect, than quantitative. Although you can use PTH, and it has recently been trialed in OI, I think you are safer using a bisphosphonate. The fracture risk reduction remains substantial among OI patients treated with these agents.-I hope this helps. Cliff Rosen, MD

MANY POSSIBLE PROBLEMS, INCLUDING OSTEOPOROSIS 14 January 2011
QUESTION--I have a limited consultative practice in integrative medicine. This case involves a 57 yo physically active, lean male with some interesting problems including recent diabetes, elevated somatomedin-C, osteoporosis and other health issues.
Elevated Somatomedin-C: 243 ng/mL (ref range: 81-225); no obvious signs of acromegaly. (Pt has congenital short stature (62")). (pt asked for this test because of fatigue and his concern that it might be related to decreased growth hormone with aging).
Recent onset diabetes: Both parents had type 2 diabetes and obesity - because of this pt has tried to eat healthy, maintain nl weight and exercise. Wt is stable at 125#, Ht 62". His fasting glucose historically was between 90-100, but 7 mos ago had a level of 120 on a routine blood chem. Pt began to follow his AM fasting glucose and found it to be consistently in that range. He asked that I start Metformin and is currently on 500 mg bid. Despite that, his FG has remain elevated in the range of 120-150 and has crept upward . Hb A1C was initially 5.8, last level was 5.4. Fasting insulin was 38.8 uIU/mL.
Osteoporosis: DXA Bone Density from 1 yr ago -- LS: .892, T-score -2.7, Z-score -1.8; Hips: .983, T-score -.8, Z-score 0.
Recent N-Telopeptide/Creat Ratio 73 (Ref Range: 3-51); Pt takes Vit D and has a Vit D 25-Hydrox of 76.3 ng/mL. Ca is nl. Parathyroid hormone 51 (RR: 14-72). The patient has lost 2" in height over the last decade or so -- that prompted the DXA scan.
Possible Hypothyroidism: Has been seen by an FP who told pt he was hypothyroid and placed pt on natural porcine thyroid (30) and iodine (225 mcg). Most recent lab results from this FP: Free T4 - 1.32 (had been .79), Free T3 - 2.7, TSH 3.5, Reverse T3 elevated at 363 (RR 90-350).
Recent increase in H/H: Historically Hct has been 41-44. In last 18 mos has increased from 41 to 49. Indices unchanged. Does not take Fe.
Pt's other history includes mild atherosclerosis, longstanding well-controlled hypertension, atherogenic lipid profile controlled with Niaspan, elevated homocysteine (13), recent elevation of HS CRP, prior low levels of albumin, total protein, copper and zinc (now nl after supplementation); previous hx of lymes 18 yrs ago (CDC diagnosis), prior Hep B (non-active).
Other labs: Total testosterone (305, 475 on two occasions), Free testosterone 16.6 (RR 7.2-24), Estradiol 17 Beta 18.5 (RR 7.6-42), DHEA 118 (RR 52-295)
The patient has tremendous vitality but states he has felt fatigued compared to his baseline energy and dates this decline back to a flulike illness 3 yrs ago -- immediately after recovery from what was probably influenza, he had engaged in a brief winter camping/backcountry ski trip and upon his return home was profoundly fatigued and felt chilled for several weeks. This episode prompted his first medical evaluation in many years. While the patient's energy has increased, he still feels it is abnormal for him. He believes this may be due to chronic Lyme disease.
The patient has a fair degree of medical knowledge. Given the range of potential endocrine abnormalities, I referred him to an endocrinologist at our local medical school but he has decided instead to be seen by an endocrinologist at Mayo Medical Clinic. I don't have a problem with that approach, but it will be several months before he can get that evaluation. In the meantime, I wonder what your experts think. David Moss, MD
RESPONSE-Assuming that this is a valid DXA study, a diagnostic classification of osteoporosis is correct. Considering his historical height loss of 2 inches, I would also suggest that lateral imaging of the spine be done to evaluate for prevalent vertebral fractures. If he has any type of fracture, including an asymptomatic vertebral fracture, then his diagnosis becomes severe osteoporosis; more importantly, it suggests that the future risk of fracture is very high. He should have a thorough evaluation for secondary causes of osteoporosis, much of which has already been done. It would be helpful to include a 24-hour urine for calcium to evaluate for hypo- or hypercalciuria, both of which could have important implications regarding the pathogenesis of his osteoporosis. A serum protein electrophoresis and kappa/lamda light chains would assess the possibility of multiple myeloma. Note that diabetes mellitus type 1 and type 2 are considered risk factors for osteoporosis, and that treatment of diabetes with a TZD may be associated with increased risk of fracture. Any treatable secondary causes that are identified should be managed appropriately. He meets the National Osteoporosis Foundation guidelines for initiation of pharmacological therapy to reduce fracture risk. A follow-up DXA 1-2 years after starting treatment would be helpful to evaluate for treatment effect. E. Michael Lewiecki, MD, FACP, FACE

We also offered a note that Niospan has been reported to lower T4 and T3 levels without affecting TSH, and that treatment with desiccated thyroid typically is associated with a lower T4 and normal T3 when the TSH is normal. L De Groot, MD

ABNORMAL THYROID FUNCTION TESTS AND HYPERCORTISOLEMIA IN THE SETTING OF PREGNANCY 10 Jan 2011
(SEE FOLLOW-UP BELOW)
QUESTION-21 year old patient with single intrauterine pregnancy, gravida 1, para 0 found to have abnormal thyroid function tests at presentation for pregnancy care at 13 weeks in November 2010. TSH 0.644uIU/ml (reference range - 0.270-4.2) and free T4 0.56 ng/dl (0.65 -2).
2 weeks later - TSH 0.836uIU/ml, total T4 4 ug/dl (5.1-14.1). She had no complaints except mild fatigue which she attributed to pregnancy. Her only medication was an herbal supplement for the last 4-5 months(Spanish Black Radish). She had started to take this supplement for cleansing after a UTI, around the same time she also developed an itchy, erythematous rash on her back which she attributed to UTI, she was not really concerned about this rash even though it had not improved over time. She had coarse, black hair growth over face, chin, sideburns, back, chest, abdomen and thighs which she reported having for several years and was not concerned, but denied having a similar pattern in the family. She did not have acne, clitoromegaly, purple striae, or goiter.
Levothyroxine was recommended at that time but she did not want to start treatment and failed to follow up. At 20 weeks of gestation she presented with hypertension, increasing edema, rapid weight gain. Found to have hypokalemia and proteinuria. Free T4 was 0.36 and TSH was 0.476.(reference ranges same as above). At 7p.m. plasma cortisol was 37.9 ug/dl (3-23) and ACTH <2 pg/ml (6-58). 24 hour urine cortisol 1860 ug/dl (<45) volume 2500, creatinine 1025 mg/d (weight 168 lbs at the time of collection so appears to be an adequate collection) (cortisol was eighteen hundred sixty). Pituitary MRI was normal. Blood pressure ranged between 129-140/ 80-90 mmHg without medications. Abdominal ultrasound to assess adrenal glands and to repeat 24 hour urine collection are planned but not complete yet. She agreed to start levothyroxine.
Is this central hypothyroidism? What additional work up would you suggest to evaluate for Cushing's syndrome? Is there a way to differentiate hypercortisolemia caused by pregnancy? Could the abnormality in the thyroid function tests be related to the cortisol elevation? I would appreciate any help you can offer in further evaluation and treatment of this patient. Thank you very much in advance. Ebru Sulanc, MD
RESPONSE-This is a very interesting case with lots of problems.
I am more worried about her Cushing’s syndrome than the thyroid, albeit both are important. With the rapid onset of symptoms, the hirsutism, the very high cortisol levels, and the completely suppressed ACTH, I am quite concerned that she might have an adrenal carcinoma rather than just an adenoma as the cause of her Cushing’s. Adrenal carcinomas occur during pregnancy as a cause of Cushing’s syndrome more commonly than outside of pregnancy (Lindsay & Nieman, 2005). I think that you need to proceed fairly quickly to the adrenal ultrasound and, if she has a tumor, proceed with surgery even during the pregnancy. Depending upon the size, this might be able to be done via laparoscopy but you should alert the surgeon that this might be an adrenal carcinoma and this may have to be handled differently if surgery is to be curative. Treatment for all types of Cushing’s syndrome during pregnancy is indicated, as it improves pregnancy outcomes with respect to fetal mortality and prematurity (Lindsay & Nieman, 2005).
The thyroid levels are very interesting. Early in pregnancy, there may be a suppression of TSH levels due to high thyroid hormone levels stimulated by hCG. However, in this patient the TSH is normal but the T4 levels are low. You do not give the T3 levels, which might be normal or even highish, allowing her to maintain the euthyroid state. This would be certainly unusual in this setting, as high cortisol levels tend to decrease T4 to T3 conversion. It has been known for many years that high cortisol levels can suppress TSH secretion as well (Re et al., 1976) and in patients with Cushing’s syndrome TSH and often free T4 levels tend to be decreased but not to abnormally low levels (Colao et al., 2000; Niepomniszcze et al., 2002; Roelfsema et al., 2009). However, reversible very significant decreases in both TSH and Free T4 have also been reported (Kurata et al., 1981). Another possibility might be that the high cortisol is preventing the normal rise in TSH that might be seen with primary hypothyroidism. Years ago, it was shown that high doses of dexamethasone could acutely lower TSH levels in patients with primary hypothyroidism (Wilber & Utiger, 1969) and in patients with Cushing’s syndrome with evidence of autoimmune thyroid disease and subclinical hypothyroidism, TSH levels rise after cure of the Cushing’s syndrome (Niepomniszcze et al., 2002). However, I have been unable to find any reports of what happens to free T4 and TSH levels in patients with overt hypothyroidism before and after cure of Cushing’s syndrome when thyroxine has not also been administered.
In your patient, therefore, hypothyroidism is a distinct possibility. Given the adverse consequences of even mild hypothyroidism on the developing fetus (Reviewed in Abalovich et al., 2007) and the absence of overt consequences of giving thyroxine, she should be treated with thyroxine. However, because of the effects of the high cortisol levels in suppressing TSH, you probably cannot use the TSH levels to titrate the thyroxine dosage and will need to use total T4 levels (there may be problems with analog free T4 measurements during pregnancy) with an adjustment for stage of pregnancy. With either free T4 or total T4 monitoring (normal range multiplied x 1.5), levels should be brought into the upper part of the normal range. As she is young and speed is of the essence with respect to the fetus, it is reasonable to start her on a full replacement dose of thyroxine. Because of the increased metabolism of thyroxine, a dose of 2.0 – 2.4 mcg/kg is recommended rather than the usual 1.7 – 2.0 mcg/kg (Abalovich et al., 2007).
I hope you find these suggestions useful. Please give us follow-up on what happens with this patient. Mark Molitch, MD
Refs.
Lindsay JR, Nieman LK. The hypothalamic-pituitary-adrenal axis in pregnancy: challenges in disease detection and treatment. Endocrine Reviews 2005;26:775-799.
Re RN, Kourides IA, Ridgway EC, Weintraub BD, Maloor F. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J Clin Endocrinol Metab 1976;43:338-346.
Colao A, Pivonello R, Fagginao A, Filippella M, Ferone D, DiSomma C, Cerbone G, Marzullo P, Fenzi G, Lombardi G. Increased prevalence of thyroid autoimmunity in patients successfully treated for Cushing’s disease. Clin Endocrinol 2000;53:13-19.
Niepomniszcze H, Pitoia F, Katz SB, Chervin R, Bruno OD. Primary thyroid disorders in endogenous Cushing’s syndrome. Eur J Endocrinol 2002;147:305-311.
Roelfsema F, Pereira AM, Biermasz NR, Frolich M, Keenan DM, Veldhuis JD, Romijn JA. Diminished and irregular TASH secretion with delayed acrophase in patients with Cushing’s syndrome. Eur J Endocrinol 2009;161:695-703.
Inada M, Kurata S, Nishikawa M, Oishi M, Mashio Y, Tanaka K, Ishi H, Nato K, Imura H. Cushing’s syndrome associated with corticogenic hypothyroidism: a case study. Endocrinol Jpn 1981;28:225-230.
Wilber, JE, Utiger RD. The effect of glucocorticoids on thyrotropin secretion. J Clin Invest 1969;48:2096-2103.
Abalovich M, Amino N, Barbour LA, Cobin RH, DeGroot LJ, Glinoer D, Mandel SJ, Stagnaro-Green A. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2007;92:S1-S47.
NOTE ON FOLLOW-UP ---She had an adrenal ultrasound that reported no adrenal mass but commented on
limitations of the study. This was followed by an abdominal MRI that showed a left adrenal mass (3.7x3.6x3.2cm) She had a left adrenalectomy in
January, pathologic diagnosis was consistent with a 4 cm adrenal cortical adenoma. She was started on steroid replacement. 2 weeks ago she delivered a 2100 gm baby at 34 weeks due to premature rupture of membranes. She remains on hydrocortisone and levothyroxine.
Thank you once again for your assistance and sharing your opinions on this case.

TSH-SECRETING ADENOMA   10 December 2010
QUESTION-I recently saw a 16-year-old lady referred for abnormal thyroid function tests. A year ago, she noticed increasing hair loss off the top of her head. She was also complaining of fatigue and cold intolerance. No weight loss, no loose stools. She noticed an increased frequency of parietal headaches, 2-3 times weekly. She has regular menses with no breast discharge. She is on Depo-Provera every 90 days. She has had 3 "blackout spells", periods of sudden LOC, lasting < 1 minute, with slight confusion on waking. Neurologic workup and EEG negative. Brain MRI negative. Initial TSH (12/16/2009) = 1.55 (range = 0.35-5.50).
     Went back to her PCP and repeat labs in 11/27 showed TSH = 1.750, Free T4 = 1.990 (range = 0.930-1.700). I saw her 2 days after these labs were drawn. I ordered labs on 11/29 with the following results:
Free T3 = 480 pg/dL (range = 230-420)
Thyroid binding Globulin = 24.1 ug/ml (range = 10.0-23.8)
T3 uptake = 35% (range = 22-35)
Total T4 = 11.8 mcg/dL (range = 4.5 - 12.5)
Free T4 by direct dialysis = 3.0 ng/dl (range = 1.0-2.4)
Thyroid-Stimulating Immunoglobulin = <89% (range <140%)
Thyroid US = Right lobe 5.5 cm, left lobe 5.2 cm. Small 1.1 cm nodule on the right. 6 mm hypoechoic nodule in the isthmus.
Pituitary MRI = Within the sella and extending superiorly toward the suprasellae cistern with an upwardly convex margin is a 9 x 10 x 9 mm homogeneously enhancing mass in the anterior aspect of the sella, essentially replacing the normal anterior lobe of the pituitary. On the sagittal images, there is a thin crescentic focus of decreased enhancement which likely separates this lesion from normal pituitary gland.
      The high free T4 and free T3, with an inappropriately normal TSH, and a pituitary macroadenoma would suggest TSH-secreting tumor. I will be doing the pituitary hormonal workup. I will also do an FNA of the thyroid nodule. Given the relatively small size of the tumor, would this still be amenable to trans-sphenoidal resection?
Is differentiation from Resistance to Thyroid Hormone required in this case? Would you recommend a T3 suppression test? Are there any other labs you would recommend to confirm the diagnosis? Sincerely, Patrick Litonjua, MD
RESPONSE-There are no doubts that the patient has a TSHoma. To confirm the diagnosis we usually ask for the measurement of FT4 and TSH in the closer relatives and we perform a TRH test (no TSH response definitely confirm the presence of TSHoma). Unfortunately TRH is no longer available in the States. I suggest, therefore, to send the young lady to the neurosurgeon. Alternatively, you can treat her with long acting somatostatin analogs that are effective in blocking TSH secretion in more than 90% of cases and may cause tumor shrinkage in more than 50% of cases. Let me know of your decision. Paolo Beck-Peccoz, MD

HYPERALSOSTERONISM- ADRENAL / RENAL VEIN SAMPLING Nov 2010
QUESTION-I have a patient with a 1.2 right adrenal mass, hypertension and hypokalemia. Chemistries were consistent with a diagnosis of primary hyperaldosteronism and I had radiology do AVS. The results are puzzling to me:
          Left adrenal                   Left renal            Right adrenal           Right renal          IVC
PRA:              0.12                   0.25                     0.1                           0.92                    0.22
Aldo:             204                     50                        36                            42                        45
Cort:             15.1                    3                            3.3                          2.8                     3.4
Aldo/Cort:     13.5                   16.7                       10.9                         15                      13.2
It appears that this is a bilateral situation. Is that your reading?   The mass is again on the right but must be an “incidentaloma” Thank you for your help.   Ann Ward
RESPONSE-Thank you for your case and your thoughtful questions. From the information you have provided, we gather that your patient presented with hypertension, hypokalemia, and a 1.2 cm right adrenal mass on CT scan. There was biochemical evidence of primary hyperaldosteronism, although we do not have the primary data. The patient underwent AVS. From the information provided, it looks as though ACTH was not used in the sampling protocol. The data generated from the procedure are listed above.:
            If ACTH is not used during AVS, a side-to-side ratio of more than 2:1 (comparing cortisol-corrected aldosterone ratios) is considered consistent with unilateral disease. This is clearly not the case in the numbers you have provided, so we agree that these data are most consistent with bilateral disease. However, we note that the right adrenal sample looks very similar biochemically to the right renal sample, and so the right adrenal may not have been successfully cannulated (sometimes the radiologist who performed the procedure can tell you if it was technically challenging). But given that there is also no evidence of suppression of the contralateral (left) adrenal (the left cortisol-corrected aldosterone ratio compared to the IVC is about 1), this also supports the lack of unilateral disease.
As you know, non-functioning adrenal ‘incidentalomas’ are not rare, especially in patients above the age of 40 . We know that adrenal anatomy determined by CT scanning may wrongly predict etiology (or lateralization) of hyperaldosteronism in a significant proportion of patients, and that may be the case here from the information you have presented us.
We hope this is helpful in the management of your case. Florencia Halperin, MD, Erik K. Alexander, MD, Robert D. Dluhy, MD

ELEVATED IGF-1, PARTIALLY SUPPRESSIBLE HGH, ? ACROMEGALY—11/15/2010
QUESTION-I have a 35 year old female patient complaining of fatigue, night-sweats, joint pains. Was on the b-HCG diet four month ago, has been off that drug for the past 2 months (and has regained all her weight). BMI = 27. Her only other past medical history is of a nontoxic thyroid nodule, herniated disk in 1991, and rheumatoid arthritis for which she takes Lyrica. Complaining of hirsutism on the face (which she lasers.) Has menses monthly although the character has changed.
IGF-1 was measured several times and has been elevated between 350 - 450 ng/mL (about 2 - 2.5 times normal). Prolactin, TSH, FSH, LH normal. I sent for a 75 gram OGTT.
GH at time 0 = 1.3 ng/mL
GH at 1 hour = 6.2 ng/mL
GH at 2 hours = 0.9 ng/mL
GH DID supress to less that 1.0 at two hours, but after a paradoxal climb to 6.2? And, the assay for GH was the newer ICMA...some authorities suggest that with the newer assay GH should suppress to > 0.3 ng/mL, but I'm not seeing that in any guidelines yet.
Pituitary MRI shows a 5 mm microadenoma.
Do you send her to the neurosurgeon? Is the suggestion that GH should suppress to less that 0.3 ng/mL using ICMA in normal practice yet? Patient is anxious and wants something done, she's convinced she has Acromegaly.
RESPONSE-I think there are several issues here which might complicate matters:

POSSIBLE TREATMENT OF HETEROTOPIC OSSIFICATION 3 November 2010
QUESTION- The patient is a 65 year-old male with h/o stage II adenocarcinoma of the colon who underwent partial colectomy 3/2010. The surgery was uneventful. His post-operative course has been complicated by heterotopic ossification in the midline incision. The ossification was first noted approximately 4 months after the surgery and CT scan of the abdomen demonstrated an area of heterotopic ossification within the scar tissue starting just inferior to the xyphoid process an dextending 12 cm inferiorly. The abnormal bone is slightly tender to palpation but is causing no significant symptoms other than generalized distress regarding its presence. The patient has no other metabolic abnormalities. Calcium level is normal, kidney function normal. He takes no medications.
The key findings from my review of the literature are that the cause of heterotopic ossification is unclear, removal of the abnormal bone prior to bone maturation might lead to a higher risk of recurrence, that there may be a benefit to prophylactic use of NSAIDs just after excisional sugery to try to reduce that risk, and that there is no clear role for bisphosphonates in this setting.
I'm wondering if there are any experts who might comment on this condition, and if there are any other suggestions for timing/indications for surgical resection and prophylaxis to prevent recurrence. Joyce Leary, MD
RESPONSE-You have done an excellent review of the literature. Other than removing the heterotopic bone there is no proven and safe way to treat the problem. I also think prophylactic treatments to prevent recurrence are unproven and radiation is potentially dangerous. NSAIDs would be reasonably safe in trying to prevent recurrence after surgery but there is little evidence of efficacy. Frederick R. Singer, M.D.

ACROMEGALY?? –ELEVATED IGF AND GH WITH DIABETES AND CRF 9 4 2010
QUESTION-65 yr old man underwent tests for acromegaly because of his facial
features. IGF1 was elevated 3 times upper limit of normal for age.
GH failed to suppress on OGTT. MRI pituitary normal. No abnormality
of the rest of the pituitary functions. This case was discussed by another physician.
The questions: are these results compatible with false positive
elevation of GH as this pt has underlying type 2 diabetes and CRF
with GFR 25. Can IGF1 level be falsely elevated in pts with low GFR? < jshakher@aol.com>
RESPONSE- Failure of GH suppression to an OGTT is recognised in patients with
severe renal impairment. However in CRF serum IGF-I levels tend to be
normal or only slightly raised. The 3-fold elevation in this patient
together with his clinical symptoms would point towards the diagnosis
of acromegaly. A normal MRI is not uncommon although it would be
prudent to have it reviewed by a specialist neuroradiologist if not
already done.
A theraputic trial of somatostatin analogue might be considered both
in terms of biochemical and clinical response. Paul Jenkins, MD

MANAGEMENT OF HYPERCALCEMIC HYPERPARATHYROIDISM 11 AUG 2010
QUESTION-I have a puzzling hypercalcemia case which I have not been able to solve. This is her story below - also please find attached a spread sheet with all her bone metabolic parameters over the past 2 years. It is my impression that she has primary hyperparathyroidism with PTH now 18-20. PTH should be suppressed however given her degree of hypercalcemia.
The patient has now had significant bone loss (3 % in spine) and is getting more and more symptomatic with hypercalciuria.

51-year-old female with presumed primary hyperparathyroidism (PTH 59, Ca 10.8)- s/p neck exploration and removal of the right upper parathyroid gland in 2008 , which per pathology report measured 7 mm. No intraoperative PTH drop.
       Since her surgery her calcium levels have been between 10.1 with a iPTH of 25, and 11.0, iPTH 51, albumin of 4.9. Hypercalciuria between 413 to 508 mg in 24 hours (2008- mid 2009). 25-OH D level have always been greater than 32.
     Calcium levels have been rising since please see spreadsheet - PTH levels have been coming down- but never suppressed.  I considered granulomatous disease (when one PTH came back as low as 12 ) and evaluated the patient further. 1,25 dihydroxy vitamin D 44 pg/ml, ACE level 6 U/l, normal serum and urine protein electrophoresis, PTH related peptide 14, calcium 11.2, albumin 4.8, ionized calcium 5.8, iPTH 47. The case was discussed with Michael Hollick ( I used to be a fellow at BUMC) who recommended prednisone 10 mg for one week to see if her calcium comes down. Calcium measurements were unchanged after 10 mg of prednisone for one week. I then sent the patient for a venous neck localization study, which did not identify any clear cut PTH elevation, but localization mainly performed on the left side of the neck as the right thyroidal vein was not clearly identified ( difficult postop neck!)
The patient had a repeat dual isotope, dual phase subtraction 99 technetium/I 123 sestamibi scan which identified mild increased activity at 15 minutes on right inferior pole on subtraction imaging. Neck ultrasound in 1/2010 showed two hypoechoic lesions inferior to the right thyroid lobe. The more superior lesion was hypoechoic, measured 5.8 x 3.0 x 4.1 cm, was difficult to compress, did not have a central fatty hilum, but a small pole artery. The inferior lesion was hypoechoic, measured 4.9 x 3.7 x 6.1 mm, was difficult to compress, did not have a central fatty hilum and also appeared to have a pole artery. These two lesions look like 2 small parathyroid adenomas in the classical position. I was planning on doing a PTH washout,but was hesitant as lesions are small, neck is scarred and patient a little worried.
The patient feels unchanged, with extreme fatigue, polyuria and polydipsia. She denies any fractures, bone aches or bone pain. She takes calcium 2000 units daily along with 2000 units of cholecalciferol . The patient is very frustrated because she does not know what to do. She's was considering consulting Dr. Norman in Florida who would charge her $2500 for consultation, however does not have the money to go ahead.
Bone density in June 2009 in the osteopenic range, with nonsignificant changes from 2006 to 2002. BMD in 2010 with 3.5 % decrease in spine, normal value in 1/3 radius
12/09 : PTH 45, calcium 10.8, albumin 4.6 (corrected calcium 10.4) 25-OH D 66, urine n-Tx 35
1/10 : PTH 37, Ca 11.1, Alb 4.5, corrected calcium 10.7. Ionized calcium 6.0.
4/10: PTH 29, albumin 4.2, calcium 9.6, ionized calcium 5.7, 25OH-D level wrr.
please see attached sheet for all labs
Can you please help me with this case.. Am I correct thinking that her PTH is inappropriately normal for her hypercalcemia ( upper end of ref range for 40-50 year old more around 40-50 pg/ and not 65 pg/ml as given by lab? What else should I do?.Claudia Panzer, M.D.

RESPONSE--: Dr. DeGroot asked me to respond to your request as I have extensive experience with primary hyperparathyroidism. I assume the parathyroid gland which was removed was abnormal and that the patient has parathyroid hyperplasia. About 10% of our surgically proven hyperparathyroid patients have a normal serum PTH, as low as 20 pg/ml. I don't know why your patient had 18 and 14 pg/ml levels recently. Possibly magnesium deficiency could do this. Assuming further PTH levels are not fully suppressed the patient could be treated either with cinecalcet 30 mg every 12 hours or with surgery by a very experienced parathyroid surgeon. At least 2 other glands will need to be removed and intraoperative PTH would be desirable to decide the adequacy of the surgery. If the patient is presently symptomatic it would be worthwhile to start her on cinecalcet to see if she feels better. It lowers serum calcium immediately. Unfortunately it would have to be used off-label but I usually can persuade insurance companies to approve its use. I hope this is helpful.   Frederick R. Singer, M.D.

HYPERCALCEMIA- vitamin D deficiency in possible hyperparathyroidism 1Aug 2010
QUESTION-I have 66 year old lady with PHM Diabetes type II, obesity and hypertension. Referred by her GP with corrected Calcium mildly high at 2.68nmol/l (2.2-2.6), phosphate 1.07nmol/L , ALP normal PTH 6.2(1.1-6.9) as query hyperparathyroidism. Patient is completely asymptomatic and no weight loss.
No medication causing hypercalcemia. 24 hour urine for Cacium was non detectable 0.00 and Ca/Creatinine was 0.0. Vitamine D was defient at D2 <1.3 nmom/L D316.3 nmol/L.
U/S parathyroid showed thyroid nodule but no parathyroind nodule .
My question is is this primary hyperparathyroidims or secondary to vitamin D defiency ? how would i confirm this ? and would i have to treat with Vitamin D replacement despite teh hypercalcemia ?
Appreciate your help. Dr Yahya Mahgoub
RESPONSE-As the urinary calcium is very low, the diagnosis of FHH (Familial Hypocalciuric Hypercalcemic) should be considered. Conclusively diagnosed only by genetic testing, FHH may be diagnosed clinically if there is also a strong (autosomal dominant) family history of hypercalcemia. The vitamin D deficiency should be treated cautiously to avoid further increase in serum calcium. Primary hyperparathyroidism is still possible if the very low urinary calcium can not be confirmed; the absence of creatinine in the urine makes the test suspect. Secondary hyperparathyroidism is inconsistent with an elevated serum calcium, and there is no information regarding renal function. To be diagnostically useful, the serum phosphate must be done in the fasting state. Bone DXA would also be useful, and a 1, 25 dihydroxyvitamin D-mediated cause of hypercalcemia needs to be ruled out. Leonard J Deftos, MD

HYDOXYLASE DEFICIENCY AND ANTI-ANDROGEN USE? 7 June 2010
QUESTION--I have a 6 y old boy with 11 hydroxylase deficiency growing steady on the 90th percentile with no growth acceleration though with unfortunate bone advancement to 13 y.
His physical exam has been stable with regards to his tanner stage ( pubic hair III) has not changed over the last one year with his penile length of 6 cm. His testis though is at 3 ml bilaterally with no palpable masses to suggest adrenal rests.
He is maintained on hydrocortisone almost 14 mg / day and his 17OHP is in 248 range ng/dl but his androstenidione is significantly elevated at 600 ng/dl. I am admitting him to ensure that he has no central puberty neither adrenal rest and my question is in the absence of the above; is there a good indication of using anti androgen to slow down his bone age to improve his height potential. If so which one and what is the recommended dosing please. Suzan Mushcab, MD suzan.mushcab@aramco.com
RESPONSE--There are no reported levels of 11 desoxyhormones such as DOC or compound S, which would be diagnostic of 11-hydroxylase deficiency. In addition, we measure renin and aldosterone in every patient with 11 hydroxylase deficiency as a suppressed renin indicates poor control. We would never treat patients with Florinef who have this form of CAH. Indeed I don’t see any evidence that this patient has 11 hydroxylase deficiency as there is neither hormonal nor genetic evidence for it. We sequence every patient to determine the genetic mutation. He also has not been tested for 21-hydroxylase deficiency, which is more frequent that 11 hydroxylase deficiency, by DNA analysis. His advanced bone age and pubertal stage are very disturbing, indicating he will have final height that is below his target height (calculated from his parental heights). As the predicted height is probably significantly below his target, he is probably a candidate for growth hormone treatment and LHRH analogue to delay his puberty (if he is in fact in central puberty). If he is indeed in central puberty, he may also be a candidate for an aromatase inhibitor to delay bone age maturation.
Until you know whether his androgens are suppressible with Dexamethasone, I would not treat with an anti-androgen. Maria New, MD

PCOS or ADRENAL TUMOR? 24 MAY 2010
QUESTION-I would be grateful for you assistance regarding the following case: A 14-year-old female referred to me with the diagnosis of PCOs with high S.Testosterone of 6 nmol/l ( X3 ULN), high DHEA-S of 17 ( x2 ULN) and slightly raised s.PRL.Her Androstendione is slightly elevated with low SHBG and CT abdomen revealed a nodular Lt adrenal (the Rt looks normal ).I have ruled out cushings as well as late onset CAH.She has been on OCP with Aldactone for the last one year with no much improvement.worth. mentioning is the pelvic US which reveals multiple cysts mainly in the rt ovary. How should I proceed? where do this androgens come from? Ovaries or the Lt nodular adrenal?
Regards, Dr.Yahya Al Zaman, Salmaniya Medical Hospital, Kingdom of Bahrain

RETARDED GROWTH, AND NORMAL GH 24 Jan 2010
QUESTION-I have a case of a female child (7.5 yr-old) with short stature relative to familial channel (channel 3%, ht 115cm) without low weight (10-25%, wt 20.5kg) with severe bone age retardation (2yr at chronological age of 6yr and 3yr at chronological age of 7.5 yr).
She was born with ht 49cm and wt 3250g. She shifted her growth channel from 90% at age of two yr to 25% at 4-5yr and then stabilized in the 3% channel between 6 to 7.5yr old. She had a well-registered low growth velocity from 4 to 5yr of age (4cm/yr, channel <3%) but current normal velocity (6cm/yr, channel 25%).
Medical history and physical examination did not suggest chronic illness, malnourishment or congenital syndromes.
She had normal response of GH to clonidine test (0.1 to 10.78) and normal basal evaluation: RBC, WBC, AST, ALT, creatinine, stool fat, IGF-1 163; IGFBP3 3.8; TSH 1.8; FT4 1.27; anti-endomisium IgA and IgG (-). Calcium was evaluated when she was 6yr old and was normal. Alkaline phosphatase and karyotype were not analyzed.
What do you suggest for differential diagnosis and workout on such a severe bone age retardation? Dr. Marcelo Miranda O. Lima, Campinas - SP - Brazil

RESPONSE-Regarding her evaluation, it seems that you have been quite thorough. In the laboratory analyses, did you obtain an ESR? Did you measure total IgA to ensure that the negative endomesial IgA is reliable? Additionally, I would like to see a normal urinalysis, normal liver functions, including albumin. On the CBC, did you have a normal MCV? You did not obtain a karyotype, and I would consider one if the above tests are all negative—although I think that the likelihood of Turner syndrome is quite low. Is there a family history of similar growth ? Of medical problems ? Is she taking any medication now—or in the past ? Have physical and cognitive development been normal since birth ?
The fairly realistic differential at this point includes the iron deficiency, zinc deficiency, skeletal dysplasias, pseudohypoparathyroidism (or pseudopseudo), psychosocial dwarfism and constitutional delay of growth.
The early growth pattern suggests that this is not GH deficiency, and your lab work clearly supports this. Over how long a period has her growth velocity been 6 cm/yr ? If sustained, and IF this is without pubertal/sex hormone influence, then this is very reassuring—and supports an extremely exaggerated constitutional delay of growth as the cause.
An assessment of her growth curve--normal in utero/early growth followed by poor growth after the infancy, and now normal—suggests that she had some type of abnormality from age 2-6 years, and that she has (mostly or completely) recovered; note that her bone age advanced two years in the first six years of her life, and then one year from chronological age 6 to 7.5 years.
In addition to the above, I would continue to follow her closely, to ensure that her growth stays normal, and that puberty does not occur early. I would not suggest treating her at this time (e.g. with growth hormone) as her current growth velocity may indicate some degree of spontaneous catch-up growth. I suspect that most height prediction algorithms will overestimate her adult height (due to her severe bone age delay), and I would caution against excessively optimistic height predictions. Michael P. Wajnrajch, MD

PRECOCIOUS PUBERTY 15 December 2009
QUESTION-I have an 18 month old Caucasian boy presenting with 8cm penis, 8ml testes, advanced bone age of 4.5 yrs, LH stimmed to 35, high FT4 of 2.5, normal TSH, ACTH baseline 44, cortisol 7.5 random. MRI normal. Growth hormone 10.5, IGF-1 470 (very high for him), IGF-BP3 3.2. What does he have?
How do I proceed? Can you please send reply to sachinbendre@yahoo.com.
Thank you, Sachin Bendre MD
RESPONSE-your patient looks like he has gonadotropin-dependent (stimulated LH 25!) precocious puberty, and I assume his testosterone levels are in the pubertal range. For the differential diagnosis, the head MRI ruled out all congenital anomalies and tumors, so we are left with the forms secondary to chronic exposure to sex steroids. I would measure baseline 17OHP levels to rule out congenital adrenal hyperplasia, and repeat TSH and FT4 (normal TSH with high FT4 is odd). The GH and IGFI, and IGFBP3 levels are consistent with the stage of pubertal development. Regardless of the cause of his precocious puberty, he needs to be treated with GnRH analogues.I look forward to hearing more about your patient. Lucia Ghizzoni, M.D., Ph.D

POSSIBLE PSEUDOHYPOPARATHYROIDISM (2 December 2009)
QUESTION-I wonder if you could help us with a lady who is now 27 years old initially presented to hospital in 2005 with seizures. CT brain at that time showed bilateral symmetrical calcification of basal ganglia. Corrected serum calcium at that time was 1.79 mmol/l(2.20-2.54), phosphate 1.82 mmol/l(0.75-1.40) with normal albumin and alkaline phosphatase. She was lost to follow up.
     Presented again in 2009 with seizures and low calcium and was seen by endocrinology team. She had short statute ( height 150.8 cm), BMI of 25.5, no ectopic calcification normal metacarpals and metatarsals. She was clinically euthyroid and had normal TSH and T4 levels. Periods normal, delivered normal baby 6 months ago.Her adjusted calcium was 1.75 mmol/l, parathyroid hormone level 27.2 pmol/l(1.1-4.2), vitamin D level 13.7 mcg/l(10-60). Dexa scan showed osteopenia of spine only. Urine calcium was 0.01 mmol/l, urine creatinine 32.5 mmol/l. Genetic testing for GNAS1 did not detect any mutations.
    The corrected serum calcium has improved to 1.84 on 1alphahydroxy cholecalciferol and calcium supplements. We are increasing the doses depending on the levels. However there is no confirmed diagnosis for genetic counselling and prognostic assesment.
    I would be grateful for your opinion regarding further investigations. Dr Subash Sivaraman,
University hospital, Coventry, UK.
RESPONSE- Your patient has some classical features of pseudohypoparathyroidism type 1. She lacks heterotopic ossification of the skin, abnormal fingers and toes and, of course, no definable genetic mutation. I think that she can be successfully treated without full knowledge of her underlying problem. Some hypocalcemic patients need higher doses of calcitriol or 1 alpha hydoxycholecalciferol than others. I would not hesitate to raise the dose quickly so that a normocalcemic state can be achieved. A calcium intake of 1000-1500mg daily should be appropriate and if the vitamin D level is 25OHD I believe the patient should also be treated with cholecalciferol or ergocalciferol to raise the level to at least 30 ug/L. If serum 25OHD has not been measured, it should be as vitamin D deficiency is common and would influence the clinical course of the patient. The response to treatment with vitamin D metabolites is rapid so that within about a week you should achieve normocalcemia. If you produce hypercalcemia inadvertently this should be reversible within a few days after lowering the dose. As to the etiology of this case I would suggest you communicate with Michael Whyte in Saint Louis, Mo. for his opinion. He has a very large experience of genetic disorders affecting mineral metabolism. His email address is mwhyte@Shrinenet.org. Let me know if I can answer any other questions. Frederick R. Singer, M.D.

OSTEOGENESIS IMPERFECT AND ITS Therapy 22Sep 2009
QUESTION- The patient is a 64 yo woman with osteogenesis imperfecta and presumably, postmenopausal osteoporosis. She started having fractures at age 5 and has had many low-trauma fractures since that time. Her last fractures were 2002, vertebral compression fractures for which she had vertebroplasty of T5-T9. She underwent menarche at age 11. She had a partial hysterectomy with one ovary removed at 33 and was started on Premarin at 40, 0.625mcg daily. Her dose of HRT has been gradually reduced over the years and she is now on Menostar 14mcg patch daily.

She started on alendronate in 1995 and over the years, gradually developed worsening in bony pain until the alendronate was stopped in 2007. The pain then resolved over the course of a few months. She was put on monthly ibandronate 4/08 and took it without a problem for 15 months until she developed similar bone pain. The pain was severe, requiring IV analgesic at her PCP's office, but resolved after one month. Finally, 2 weeks ago, she was tried on risedronate 35mg weekly, but developed the same bone pain within 36 hrs of taking her first dose. She also has been on calcitonin in the past, for an unclear number of years, but it was stopped at least 5 years ago.

The question is what to do for her. She continues on the estrogen, but she is very nervous being off a bisphosphonate completely. Given the OI, Forteo does not really make sense. The literature on OI supports use of bisphosphonates, but the data is in children, not adults, and certainly not in women who likely also have a component of postmenopausal osteoporosis. She has now exhausted the most commonly used PO FDA-approved bisphosphonate regimens. Reclast seems a poor option as the bone pain then might last a very long should it occur.

I'm thinking we should switch her to either the low daily dose (2.5mg) of ibandronate, reduce her monthly dose to 100mg, or extend her dosing interval of 150mg to 6 weeks. I do not know if any of these regimens would be better tolerated. Perhaps she will have the same symptoms. We would be doing this knowing, of course, that reducing her to 100mg monthly will likely have lower efficacy than the 150mg monthly dose.

A related question is whether or not she should come off the estrogen patch if she is started back on a bisphosphonate. My reading would suggest the risk of adynamic bone is mostly theoretical, not established, but perhaps I am wrong.

In case you would like the info, here are her last 2 DXAs:
EXAM DATE: 05/16/2006
Anatomic Location: AP LUMBAR SPINE
BMD (gm/cm2): 0.659
SD above (+)/below, (-) T score: -3.5
SD above (+)/below, (-) Z score: -2.0
Percent Change From Previous: -1.5%

Anatomic Location: LEFT FEMORAL NECK
BMD (gm/cm2): 0.540
SD above (+)/below, (-) T score: -2.8
SD above (+)/below, (-) Z score: -1.4
EXAM DATE: 05/08/2008
Anatomic Location: AP LUMBAR SPINE
BMD (gm/cm2): 0.670
SD above (+)/below, (-) T score: -3.4
SD above (+)/below, (-) Z score: -1.8
Percent Change From 05/16/06: 1.7%

Anatomic Location: LEFT FEMORAL NECK
BMD (gm/cm2): 0.469
SD above (+)/below, (-) T score: -3.4
SD above (+)/below, (-) Z score: -2.0
Percent Change From Previous:
Thank you for any help you can provide. Please let me know if there is additional information that would be helpful. Thank you, LJ, MD

Answer-: This is an adult OI patient age 64. The clinical type of OI is not specified, I guess it might be type I (mild) Her last fractures were in 2002 (vertebral). She tolerated vertebroplasty ! She has had consistent estrogen replacement which is good. Her total bisphosphonate exposure is approximately 12 years of alendronate plus recently ibandronate for 15 months and the residronate for one dose. She has been on calcitonin "in the past" that was stopped 5 years ago but when she was also taking alendronate. She has developed bone pain (generalized ?) at some point "over the years" that has become increasingly frequent and severe on any bisphosphonate.
Her last two DXA values are provided: May '06 and April ' O8. The spine did not change, the femur neck T score went from -2.8 to -3.4.
    1. Calcitonin and bisphosphonates should not be administered at the same time. They have the same target cell and the calcitonin does not add anything to the more effective bisphosphonate.
    1. Bone pain (see FDA MedAlert about 1 year ago) is difficult to characterize. It occurs in a small number of bisphosphonate-treated patients. It stops when the bisphosphonate wears down over a month or so. We do not push bisphosphonate when this happens, I'm not sure why it occurs but it maybe due to a periosteal response or a change in bone turnover.
    2. Do you have bone biomarkers: Are they significantly suppressed ? What is her CTx (C-telopeptide) serum phosphorus ?
    3. What do her x-rays show (femur, humerus) at this time. Over time has she gained bone or is the demineralization basically unchanged. Is the cortex thinner ?
    4. Is she Vit. D replete ?
    5. An isotope bone scan may be informative re: sites contributing to the pain. I don't know this has been done in "bone pain" patients.
We are in the midst of the Adult OI Forteo study with Oregon and Baylor at this time. No hard results as yet. I agree using teriparatide might not offer much with all that bisphosphonate in bone.   We do not use ibandronate pending hard data that shows that it will decrease hip fracture rate as alendronate and pamidronate and residronate do. Our adult data submitted for publication shows no effect of pamidronate or orals (alendronate/residronate) on fracture rate in type I OI and a p=0.05 effect in type III/IV patients. That is for 5 years after treatment, average age 34 years. .
A consideration regarding more bisphosphonate in this patient are the reports of femur shaft fractures in patients on long term treatment. The more useful determination at this point would be a bone biopsy after tetracycline labeling to show what her bone turnover actually is. . I can't see where zoledronic acid would add to what she has already gotten and it could provoke bone pain. In the absence of hard data, and depending on the biopsy she might receive teriparatide as shown effective sequentially after bisphosphonate in osteoporosis (not yet done for OI). I can't comment on pain with teriparatide.
Sorry, no good answers for this patient. I do not recommend more bisphosphonate at this time.
  Jay R. Shapiro, MD, Director, the OI Program, Kennedy Krieger Institute and Johns Hopkins, Baltimore.

POSSIBLE GASTRINOMA -9/1/2009
QUESTION-A physician writes in to say that he has a problem case and would like some help. He has a female patient who is 48 years old. Since 1996 she was diagnosed with gastric ulcer - for the next 5 years , multiple episodes and different ulcers , patient states she had the acid test at that time and was told that she produces too much acid . test not available . she is a heavy smoker and she currently smokes 1 to 3 ppd .
she takes about 10 excedrin a day. Her BMI is 15 ( unable to gain weight )
she takes misoprostol and zegerid .
when she does not take those medication she is not able to tolerate the pain
she was refer for gastrectomy and since her gastrin level was 198 was refer to me .
I stopped her medication and gave her proper instructions to measure her gastrin level again and was over 200 .
I gave her instructions about smoking cessation and no t to use excedrin .
I requested secretin stimulation test , I was told that secretin is not available .
what is your advise with this patient .
Is secretin available ??
she is refusing to do the acid test again and an attempt to get prior results had been unsuccessful. No records of it .
Thank you
I will appreciate your recommendations Dr MM
RESPONSE-You do have a problem case indeed . With this background of a +10 year of gastric ulcer disease superimposed on heavy smoking, anorexia, low body weight and the excessive use of aspirin, a prostaglandin analog and a proton pump inhibitor it is not easy to make the diagnosis with the information available.
Firstly, we need to distinguish an elevated gastrin due to a tumor from secondary causes of hypergastrinemeia. Under the circumstances it would be mandatory to obtain a gastric pH. She is thin, smokes heavily, uses aspirin, prostaglandin and a proton pump inhibitor all of which contrive to produce a pseudo gastrinoma syndrome with reduction of gastric output, loss of the restraint on gastrin secretion and therefore an increase of gastrin leading one to make the tentative diagnosis of a gastrinoma. Misoprostol is approved for use in the prevention of NSAID-induced gastric ulcers. It acts upon gastric parietal cells, inhibiting the secretion of gastric acid via G-protein coupled receptor-mediated inhibition of adenylate cyclase, which leads to decreased intracellular cyclic AMP levels and decreased proton pump activity at the apical surface of the parietal cell. Because other classes of drugs, especially H2-receptor antagonists and proton pump inhibitors, are more effective for the treatment of acute peptic ulcers, Misoprostol is only indicated for use by people who are both taking NSAIDs and are at high risk for NSAID-induced ulcers, including the elderly and people with ulcer complications. Misoprostol is sometimes co-prescribed with NSAIDs to prevent their common adverse effect of gastric ulceration (e.g. with Diclofenac in Arthrotec)..It can also induce proliferation of gastric mucosal folds and induce a resemblance to the rugae found in gastrinoma syndrome. The ph would be <2 in contrast to gastrinoma in which case it would be >2. The situation is similar for the PPIs and one would have to have stopped both drugs for at least a week or longer and obtained a repeat gastrin level-preferably with an acid measurement to be confident that the parietal cells had been unbridled. With he asthenia one might also consider other factors and antibodies to gastric parietal mucosa and a B12 level would exclude pernicious anemia. Incidentally with the difficulty in weight gain, if antibodies were found one ought to check her thyroid function.
Now say we thought that she did have a gastrinoma. It would have been helpful to know the family history as well as know the Pth, ionized calcium and prolactin and pancreatic polypeptide values since they would point in the direction of MEN syndrome in which case the treatment would still be conservative (<10% are malignant). And then to the final question would it be useful to do a secretin test. Yes if all these other variables are controlled for. Secretin is available again ( a different company) so it can be done-but the drugs being used and the possibilities of alternate diagnoses raise the issue of a false positive secretin test!!
Now for a few words of prognostication. This has gone for 10 years with pure medical therapy so it does not seem to be behaving in an aggressive manner. I would measure her Chromogranin A ( again after stopping the medications), pancreastatin and NeurokininA. , the first as an indicator of the general presence of a neuroendocrine tumor and the latter as indicators of prognosis and the need to be aggressive or conservative in management. Hope this helps.

Aaron Vinik MD PhD, FCP, MACP
Professor Internal Medicine, Pathology/Neurobiology
Director Research

QUESTION-I was hoping for some assistance with a case: 25 year old student of chinese descent. Presents with probably thyrotoxic periodic paralysis and TSH 10, FT4 40, FT3 12. Goitre noted, intermittent tachycardia and tremor. Patient well and no aware of symptoms. Pit MRI incl sinus views normal Alpha subunit elevated x 4 ULN. SHBG 2x ULN. Uptake scan increased at 15%
TRH stimulation: increase from 10 to 16 mIU/L
T3 suppression: no signficant change on doppler or TSH value (10 to 9)
Questions:
1. Should we image this patient further or just observe with plans for repeat MRI?
2. Should we treat this patient with a somatostatin analogue (he has no had further episode of weakness at 3 months and is very well)?
3. Do you interpret the TRH stimulation as positive, borderline or negative?
4. Please tell me where I can get advise on how I can calculate the alpha subunit to TSH molar ratio

LOW SOMATOMEDIN C LEVEL 27Jul 2009
QUESTION-I enjoyed "endotext" and hope to stay in touch with you. Right now I have a question. A 48 y/o man with hepatitis C, HTN, probable bipolar, had for a while consistently lower hemoglobin A1C values. No certain history of hypoglycemic episodes. TSH 0.64, repeated 2.13 (?), somatomedin C 63 (normal range 94-252), glucagon 56 (40-130), BUN and creatinine tend to be low.
Should we consider somatomedin-C value relevant, is his lower HgB A1C explainable by liver damage with hepatitis C? <edkorkut@hotmail.com>
RESPONSE-The relatively low IGF-I (Somatomedin C) is fully explained by the patients Hepatitis C, and should not give rise to further endocrine tests.Low HbA1c cannot be used as a diagnostic measure for hypoglycaemia. Only a fasting test will be helpful here. Low HbA1c is most likely associated with a short lifespan of erythrocytes. Best regards, Jens Sandahl Christiansen, MD

DOMPERIDONE AND VAGINA BLEEDING? 27 Jul 2009
QUESTION-I need to know the effect of motilium ( Domperidone) Dopamine agonist on postmenopausal women. Could it be a cause of abmnormal vaginal bleeding in this group?Thanks .Fatma Almarashi M.D. F.A.C.E. Medical Director, Dubai Healthcare City
RESPONSE-Domperidone is not used in the U.S. It is a dopamine receptor antagonist (D2 and D3). It has been used to induce lactation by increasing circulating prolactin and does not cross the blood brain barrier. Other uses are similar to metaclopramide. Since the ovaries are inactive in the menopause domperidone should not cause bleeding as it does not have estrogenic activity based on its structure to the best of my knowledge. James H. Liu, M.D.

QUESTION-In the new institution that I joined 1 month ago, I have already had multiple consults for osteoporosis. I have discovered that the department that does all of the DXAs at this institution routinely measures the lateral spine BMD. This was not done at any of the other institutions where I trained, and was not mentioned during my ISCD certifcation training at Endocrine University. In my brief review of up-to-date, endotext, the ISCD website, and the published medical literature, I do not see adequate information regarding the use of lateral BMD. If my impression is correct, lateral BMD measurements may be useful for interpreting and following changes in BMD in patients who have aortic calcifcations or osteophytic changes, but should not be used for the diagnosis of osteoporosis. I assume the recommendation to not use it for diagnosis is because there is no fracture risk data regarding BMD measurements using the lateral spine (is this true?). However, at this institution, I have already seen multiple patients diagnosed with osteoporosis on the basis of the lateral spine, with normal or much more mild decrements in BMD at the AP spine and hip. My concern is that primary care physicians and others who have not been trained to read DXAs or understand fracture risk assessment may be overtreating patients because of these lateral spine measurements.
If you could please give me a quick overview of the current "state of the art" and guidelines regarding the use of lateral spine BMD, I would appreciate it. Furthermore, if there is data to either support or refute the use of lateral DXA in the evaluation and/or diagnosis of osteoporosis that would be greatly appreciated as well.
RESPONSE-Sorry for the delay in responding, as I was out of town. You are correct in that one cannot use the lateral spine DXA for making a diagnosis of osteoporosis, which should be based on femoral neck (or total femur) BMD and/or the AP spine BMD. In my practice, I rely on this measure, combined with the AP spine.

TO USE AVANDIA AND/OR LANTUS, OR NOT? 1 Jul 2009
QUESTIONS-I really would like to have your advice regarding two issues: first, as you know the RECORD study has reassuring results regarding the use of rosiglitazone. Do you think that it would be better if we replace it with pioglitazone as we have an offer to supply the hospital with Actos with comparable price to that of Avandia, given the adverse publicity of Avandia?
The second issue is again regarding the recent observational studies about the possible association between Lantus and some cancer. Do you think switching to Detemir would be safer or shall we continue with lantus till we get more information. what is the NICE and the UK standpoint of this issue.
Dr.Yahya Al Zaman,MD,FRCP(UK) ,Cert.(RCP)(Endocrinology&Diabetes), Salmaniya Medical Hospital, Ministry of Health, Kingdom of Bahrain.
RESPONSE-Thank you for your email.
1. I think that Actos and Avandia are equivalent and you can use either. If you feel that your patients will be more comfortable taking Actos, then I would use it.
2. I think that the data concerning Lantus and cancer are weak at best and there are no data on Detemir and cancer. At my institution we are making no changes in the treatment of our diabetics. Sincerely, Ira D. Goldfine MD

BILATERAL NODULAR ADRENAL HYPERPLASIA-- 6/25/2009
QUESTION- I have a patient with bilateral nodular adrenal hyperplasia,.mildly elevated cortisol,but well apart from well controlled diabetes. What do I do ?
Surgery,medical therapy eg ketoconazole, nothing? Thanks. Steven Harris
RESPONSE- Just having slightly enlarged nodular adrenals is not in itself a disease, and has to be seen in biochemical context. I would perform a dexamethasone suppression test for cortisol, preferably the full 2-day test, and measure plasma ACTH and 17-OH-progesterone. Assuming the patient suppresses their serum cortisol to <50 nmol/l and the 17-OH-P is normal, then I would do nothing. If the patient fails to suppress and the ACTH is readily detectable they will need a work-up for Cushing's disease. If the ACTH is undetectable then this may be a form of primary nodular adrenal disease and should be considered for medical-blocking therapy in the first instance followed by consideration of adrenalectomy. In general, if the patient is 'well' I would be more inclined to do less rather than more. Ashley Grossman, MD

POSSIBLE PRECOCIOUS PUBERTY IN AN INFANT 15 June 2009
QUESTION- I have 7 months girl with a history of monthly vaginal bleeding for the last 3 months, without other signs of precocious puberty. pelvic US revealed multiple follicular appearance in both ovaries with following diameters of the ovaries : 0.9*1*1.5 cm. estradiol= 5 pg/ml. there are no other sources of the bleeding ( anal or others ) . how to manage this case/
thank you. Dr rasha ghazi ,Damascus,Syria
RESPONSE-Dear Dr. Ghazi, Infrequently, an endocrine cause may pose as a local cause because of an absence of physical signs of puberty when bleeding starts as an apparently isolated phenomenon. Once you have ruled out malignant and benign lesions of the vagina, uterus and ovaries as well as foreign bodies in the vagina, traumatic lesions, and child abuse, specific causes include the following examples:

The newborn may have physiological vaginal (uterine estrogen withdrawal bleeding) bleeding and discharge (from the estrogenic vagina)
The first clinical sign of McCune-Albright syndrome is often vaginal bleeding. The diagnosis requires the characteristic cafè-au-lait pigmentation and radiological bone disease. Eventually secondary sexual development occurs. Careful follow-up is necessary because fibrous dysplasia may become apparent later in life.
Patients with isolated premature menarche may have isolated or recurrent vaginal bleeding without other signs of precocious puberty. This entity is usually benign and self-limiting and is thought to be the result of either a partial, transient activation of true precocious puberty or of an increased sensitivity of the endometrium to circulating levels of oestrogens which are too low to produce breast development. Careful evaluation and follow-up are required.
Prepubertal vaginal bleeding without signs of precocious puberty may be infrequently caused by prolonged, untreated hypothyroidism. I doubt this is the case in an infant with negative screening for congenital hypothyroidism.
Accidental estrogen ingestion, through maternal milk also, may set off vaginal bleeding without puberty development.
Sometimes, precocious puberty caused by a central nervous system lesion may have bleeding before secondary sexual development. Brain imaging is necessary for diagnosis. Let me know how the clinical picture evolve.
Dr Lucia Ghizzoni, Division of Endocrinology and Metabolism, Department of Internal Medicine
University of Turin,Corso Dogliotti 14, 10126 Turin, Italy

SEVERE HYPOCALCEMIA DURING TREATMENT FOR OSTEOMALACIA, WITH COELIAC DISEASE 5 March 2009
QUESTION-can hungry bone syndrome occurs in severe osteomalacia with immediate large dose replacement of Vitamin D.
Patient has low calcium raised alkaline phosphatase and high level of PTH, twice the upper limit of normal. Also, found to have underlying coeliac disease with low hemoglobin.
should the primary aim be to replenish the calcium with Vitamin D in lower dose to avoid potential risk of hungry bone. Calcium level were as low as 1.3 before being seen by endocrinologist and had treatment by IV with calcium by acute physician and subsequently remained low at 1.7. She is now on gluten free diet.
Once the calcium replete with fall in AlKphos and normalization of calcium, then to consider higher doses upto 5000 IU day or weekly equivalent dose? Dr J Shakher, Consultant Physician, Birmingham, UK
RESPONSE-Hungry bone syndrome, or a decrease in serum calcium levels as one promotes a rapid mineralization process in bone that has been chronically aberrant, is not uncommon in the setting of chronic osteomalacia as treatment with vitamin D is being initiated. This complication of therapy can be usually prevented, or at least considerably tempered, by providing generous calcium supplementation during the healing process. If severe malabsorption exists, then parenteral calcium administration may be required.

In your patient, the low calcium, elevations in serum alkaline phosphatase activity, and secondary hyperparathyroidism are typical biochemical findings of severe osteomalacia or rickets. The very low serum calcium values may represent further calcium malabsorption as a consequence of the intestinal disease, as well as the rapid shift of calcium into the mineralizing skeleton. Indeed, the underlying coeliac disease can affect intestinal absorption of both calcium and vitamin D.

To heal rickets or osteomalacia, we usually recommend vitamin D together with calcium to prevent hungry bone syndrome. For vitamin D, this is in the range of 1000- 2000 IU daily in children; in an adult I would suggest 50,000 units twice weekly for 3-4 weeks and then lower to maintenance therapy of 1000 units daily, monitoring the chemistry values indicated. Given that there is coeliac disease you may need to increase this dose, based on resultant 25-OHD levels. However, the critical piece for prevention of hungry bone syndrome is the provision of sufficient calcium. We usually are successful providing this orally, but you will need to employ a product compatible with a gluten-free diet. You can adjust calcium supplementation upwards as to make sure you correct the hypocalcemia. Your severe case may require the use of intravenous calcium, as you have been doing. We generally do not decrease the dose of vitamin D to manage this problem, with the idea of later increases in dose. Thomas Carpenter, MD

POSSIBLE HYPOPITUITARISM- 12 JAN 2009
QUESTION-I have a 29 year old female with secondary amenorrhea for 4 years.It appears to be hypothalamic amenorrhea by workup. However, her F T4 and Ft3 were low with a TSH of 1.78. I suspect central hypothyroidism. Her Mri showed a possible microadenoma,. Could a Microadenoma be responsible for selective hypogonadism and hypothyroidism? Alan Terlinsky MD
RESPONSE- Thank you for your enquiry. Your patient has amenorrhoea with hormonal features of secondary hypogonadism and hypopituitary hypothyroidism; the pituitary MRI may indicate a microadenoma. It would be helpful to know the dimensions of the putative pituitary lesion and also whether there is any evidence of hyperprolactinaemia. It would be unusual for a small intrasellar lesion to cause overt hypothyroidism but the gonadotrophin-ovarian axis is more vulnerable. Is there any other clinical factor which might predispose to a sick euthyroid picture and
thus simulate secondary hypothyroidism? Weight related amenorrhoea, which may persist after weight regain in a significant proportion of
patients, will give a picture of gonadotrophin deficiency and may be associated with secondary and reversible thyroid function changes -
worth exploring this aspect. On present evidence I would suggest a full dynamic pituitary function test (insulin or glucagon) for ACTH/cortisol and GH secretion. I would be pleased to advise further with some additional information as indicated above. Prof John Monson

POSSIBLE NORMOCALCEMIC HYPERPARATHYROIDISM 5 JAN 2009
QUESTION-I have a 57 year old female with an elevated intact PTH. Initally the PTH was in the 200 range associated with nml calcium , phosphorous and cr but with a decreased vit D-OH. We then replaced vit d with 50000 u D2. Now 6 to 7 months later her calcium is nml @9.3 mg/dl; phos= 4.4 mg/dl; Vit d-25 total is 144 ng ml (vit D-25-OH-D2) and creatinine is slightly elevated at 1.11 mg/ dl but her PTH intact is staying in the 68 to 109.4 pg/ml at last check with the afore mentioned labs ....why? Dr. Mary Lynn Kemick, mskemick@lexhealth.org
RESPONSE-This sounds like a case of normocalcemic primary hyperparathyroidism. These patients are characterized by a persistently normal serum calcium but an elevated PTH. In your patient, the vitamin D deficiency could have been responsible for the elevated PTH, but with replacement, the PTH continues to be elevated. This rules out a secondary hyperparathyroidism due to vitamin D deficiency. It is remotely possible that the creatinine of 1.1 mg/dL could reflect a creatinine clearance that is diminished, but I would doubt it would be in the range (i.e. <40 cc/min) that could explain an elevation of PTH to this magnitude. The entity, 'normocalcemic primary hyperparathyroidism' is being seen with increasing frequency, but guidelines as to how to manage these patients are not clear. The upcoming report of the International Workshop on the management of asymptomatic primary hyperparthyroidism (J Clin Endocrinol & Metab, February, 2009) will give you more information on this variant of primary hyperparathyroidism.John Bilezikian, MD

SWITCH PATIENT FROM ROSIGLITAZONE? 18 Dec 2008
QUESTION-I am a consultant Endocrinologist from the Kingdom of Bahrain.I would be grateful for your assistance regarging the issues related to the use of Rosiglitazone(Avandia).Is it safe to continue using this drug for my patients?Dr. Yahya Al-Zaman,BSc,MD,FRCP(UK), Bahrain
RESPONSE-If a patient without heart disease is on Avandia and is doing well, I would leave them on it, unless they insist on being changed to Actos. In my opinion, the data, when are looked at as a whole, do not show a significant increase in cardiac risk with Avandia. However, given the adverse publicity, I probably would not start any new patient on Avandia - rather I would use Actos. Another question concerns the increased fracture rate with both drugs in post menopausal women. How to deal this problem remains an unanswered question.Ira Goldfine,MD

Possible Carcinoid Tumor 14 December 2008
Question-I have recently seen an Indian man, aged 48 years,smoker and social drinker, suffering with hypertension for a long time. Over the last few months, he develops flushing on and off, aggravated during times of anxiety, specially when work pressure escalates.Physical examination reveals, BMI 25, BP 180/100 (both arms), all pulses palpable, systoliv flow murmur at apex. Labs show--- raised urea and high creatinine ( 2.6 mmol/l), fasting glucose 115 mg/dl, and 2 hrs post prandial glucose 166 mg/dl. 24 hrs urinary adrenaline and nor adrenaline and total catecholamine levels normal. 5 HIAA markedly raised. He complained of symptoms of gastritis ---an upper GI endoscopy showed mild antral gastritis. My working diagnosis is Carcinoid tumour
My questions are?
Is the hypertension related to Carcinoid , or is this a separate problem?

I shall be very much obliged if you kindly enlighten me about this computer software engineer please Thanking you in anticipation.Dr Sagarika Mukherjee MRCP(UK), MRCP(Ireland), CCST(UK), AMRI Hospital, Calcutta, India

Response-
1. It is not clear than this is carcinoid-you say the 5HIAA is very high but of course one would like to see the numbers and be sure there has been adequate preparation such as avoiding serotonin containing foods before doing the urine collection. It would also be wise to get blood serotonin values at the same time.
2. Your patient seem to be evolving diabetes and has IGT by your numbers, These people may have autonomic dysfunction and then get gustatory sweating associated with flushing of the upper half of the body while the lower half remains dry. An autonomic function test would help. Simply the measurement of heart rate variability
3. The gastritis may then be due to altered gastric emptying, but alternatively could be due to atrophic gastritis with the possibility of pernicious anemia. You need a gastrin and gastric pH to determine if this is so. These people then get secondary carcinoid s of the gastric mucosa.
4. up to 50% of patients with carcinoid have hypertension in the absence of Pheochromocytoma. You need to obtain fractionated urine or plasma metanephrines to make this diagnosis and the best measure today for a pheo is the plasma chromogranin A level. The chromgranin molecule is processed to pancreastatin and Vasostatin and the latter is a potent vasoconstrictor so you may not nee to postulate a pheo but simply a carcinoid
5. MIBG scans are usually only helpful if the metanephrine levels are markedly elevated and you need the high affinity tracer 123I MIBG to obtain useful pictures.
Hope this helps, AIV Aaron Vinik, MD

PROLACTINOMA UNRESPONSIVE TO CONVENTIONAL THERAPY- 8/18/2008
QUESTION-a 21 yr old man ,presented with headache for 6 monhs and RT eye decreased vision for 6 months .on ophthalmological evalutation found to have both eyes temporal pallor,bitemporal field defect more in the rt eye.MRI brain was done suggestive of a sellar and suprasellar mass measuring 4.2x3.4x2.5cm isointense to hypointense on T1WI and hyperintese on T2WI ,with heterogenous enhancement with contrast with subfrontal cyctic component on rt side and lt parasellar extension ,optic chaismatic compression present - suggestive of pituitary macroadenoma.hormonal profiles LH/FSH,FT4,TSH,TESTOSTERONE-NORMAL LEVELS.only PRL was >470ng/dl above the detectable levels.
Pt undewent endoscopic transphenoidal excision of tumour on 1/9/2006,the histopathological diagnosis was pituitary macroadenoma,immunochemistry was s/o prolactinoma.
The present problem is he ,after post operative scan after 1yrs and 2yrs was only minimal decrease in tumour size & the mass is surrounding the internal carotid in the rt side,mass is abutting the stalk. and the prolactin levels were in the range of (1350-700ng/dl) after maximum dose of t.cabergoline therapy 2mg thrice a week for almonst 6-8 months of therapy.Presently his testo is 2.5ng/ml(just below the normal),prl-752.he is only on cabergoline therapy.his HP axis,thyroid axis is normal.his present visual fields are stable. Question is
1.how to further manage this case?
2.if to plan for Radio Therapy he is 21 yrs -the chance of hypopit after RT?
3.if surgery ?difficult surgery because the mass is encasing the carotid?
thnaks. dr arun kannan
RESPONSE-You really are dealing with a difficult case ! I would like to see his MRI�s, but in fact it seems to be a giant, invasive prolactinoma with neurological and visual complaints. Loss of libido was nor described in your report, but it seems to be likely due to the high prolactin and low testosterone levels presented by the patient. Endoscopic transsphenoidal approach improved headache and visual impairment but serum prolactin persisted high, paralleled by low testosterone levels. Treatment with high dose cabergoline did not improve his hormonal profile and, albeit not clear in your report, probably the tumor size was not reduced. This scenario points to a resistant macroprolactinoma. Response to another dopamine agonist would be highly improbable, as cabergoline is currently considered the gold standard drug. Radiotherapy, besides the induction of hypopituitarism, brings the potential risk of neurologic, neuropsychiatric and visual impairment. Moreover, prolactin control, if occurs, usually takes a considerable time. I could suggest the following options:

1. A second surgery, either by extended endoscopic transsphenoidal approach or by transscranial route. Even considering that this particular case probably will not be cured even with sophisticated techniques performed by skilled surgeons, evidences from our group suggest that an extensive tumor debulking can improve the response to dopamine agonist drugs in partially resistant prolactinomas.

2. If sexual impairment is the main clinical complaint, testosterone replacement would be a reasonably approach. Nevertheless, androgen treatment often is less effective in the presence of hyperprolactinemia. Additionally, testosterone aromatization to estradiol may increase prolactin levels and tumor size, a complication that may be lessened by the concomitant use of an aromatase inhibitor.

3. Some reports point to temozolamide effectiveness in aggressive prolactinomas and in pituitary carcinomas. This drug is an alkilating agent used for the treatment of brain tumors as gliomas. Of course you need to evaluate in this particular case if the side-effects of temozolamide do not overcome its potential therapeutic effectiveness.

POSSIBLE CUSHING�S DISEASE WITH HIGH CORTISOLS 8/128/08
QUESTION I'm Dr. Noor Lita Adam currently doing my endocrine fellowship in University Malaya Medical Center, Kuala Lumpur. I really hope that somebody may help me and give their opinion on this patient that I saw recently. He's a 32 years old Chinese man who was investigated earlier for secondary cause of hypertension in one of private medical center. He is obese with BMI of 32 kg/m2 and has positive family history of hypertension ( mother at age 50+). He is not diabetic. He has no cushingoid features. His 24 H urine cortisol was markely elevated at 8550 nmol/24H ( 79-590). However his overnight dexamethasone test was suppressed < 50 nmol/L. ACTH level was 42 pg/ml ( < 46). MRI pituitary revealed 3mm R adenoma. We performed a low dose dexamethasone suppression test, baseline cortisol was 646 nmol/l and ACTH was 125 pg/ml. His cortisol suppressed to 12 nmol/l and ACTH 10 pg/ml after LDDST. Is it possible to have Cushing's despite a negative LDDST?
Would inferior petrosal sinus sampling helps in getting a right diagnosis?
I appreciate any opinion on this. Thank you, Dr. Noor Lita Adam
RESPONSE-Your patient has a urine free cortisol that is 14-fold higher than the upper limit of normal; normal suppression with overnight dexamethasone, however you don�t mention the dose of dexamethasone used. The LDDST suggests a normal HPA axis and suggests �pseudocushings�. The possible reasons for discrepancies between a high urine free cortisol and normal dexamethasone suppression testing are medications which decrease the metabolism of dexamethasone or substances that interefere with the measurement of cortisol. Furthermore the absence of stigmata on clinical presentation with such a high cortisol makes one suspicious of a false reading in the cortisol � or rapid onset of disease. I would do the following:

1.clarify the medications the patient is taking (rule out: carbamazepine, fenofibrate, licorice, carbenoxolone, exogenous hydrocortisone)

2.Repeat a basal urine free cortisol by HPLC to determine if intermediates are elevated.

4.If still elevated urine free cortisol perform a low dose dexamethasone suppression/CRF stimulation test (0.5 mg q6h for 2 days and on the morning of the 3rd day do CRF stimulation test). Measure dexamethasone level in the blood to confirm levels.
To answer your specific questions:

5.Is it possible to have CD despite a negative LDDST � unlikely, but possible.

6.IPSS would not be helpful here. First you need to confirm there is hypercortisolism and that it is ACTH dependent.

I look forward to hearing more about your patient. Thank you for allowing me to comment.
Roy Weiss ,MD, PhD, FACP, FACE

15 YEAR OLD GIRL WITH HIRSUTISM 8/1/2008
QUESTION- Here I send my question about the girl with hirsutism once more, now with the units of the laboratory tests. . She is 15-years old.Her problem is hirsutism. She has a beard, hair on chest, back and lower abdomen and limbs. She has developed and grown up normally, menarche at age of 13. Last menstrual periods 7 months ago. With dydrogesterone 10 mg for 10 days, one day uternal bleedinq. No family history of hirsutism. Hirsutism started two years ago. Height 160 cm, weight, 58 kg. No signs of Cushing syndrome. Blood pressure normal. On abdominal ultrasound scan, uterus and ovaries normal. Here are her laboratory test results: Prolaktin 55.76 ng/ml ( 3.26-29.12 ng/ml) TSH 2,1 mU/l T4 1,37 pmol/l Testosterone 4.2 nmol/l (0.3-1.4 nmol/l) DHEAS 418 mikrog/dl (39-288 mikrog/dl) 17-Hydroksiprogesteron 0.3 ng/ml ( 0.3-1 ng/ml) There are Prolactin, testosteron and DHEAS elevated. 17-hydroksi progesterone was normal so it not CAH? Is this PCOS? What do you advice? Thank you for your help! Dr. Heli Efendi

DIFFICULT PROBLEMS WITH OSTEOPENIA 28 Jul 2008
QUESTIONS-I practice (general endocrinology) in Tupelo, MS (the birthplace of elvis presley). I was wondering if you could share your thoughts regarding these 2 cases.

Ms. Owen is a 48 year old white female with a diagnosis of clinical osteoporosis, osteomalacia with multiple fractures. tolerated pamidronate IV infusion (although with some nausea) in 10-05. also had zometa injection 4 mg 02-20-06 and 05-07. has missed dose of zometa this year. had allergic reaction of boniva IV. continues to have leg cramps and bone pains. +pain hips r>left, radicular pain to right leg. stopped smoking in 2007 after taking chantix (took for 5 months). h/o Mild to moderate mitral regurgitation in 05-07 - requires prophylaxis for endocarditis.

h/o osteogenesis imperfecta. sees hematology for hypercoagulopathy due to factor XIII deficiency, h/o pulmonary emobolism, h/o hyperhomocystinemia, osteoporosis. h/o multiple fractures even with trivial trauma. pt is shortest in the family. +decreased hearing left, teeth loss. no kidney stones. did not tolerate fosamax, actonel, miacalcin spray. h/o hypercoagulopathy. h/o pulmonary emboli s/p filter placement. MRI 06-15-06: mild canal stenosis C5-6 due to endplate osteophyte. complains of neck and upper back pain and also lower back pain. decreased hearing left ear

CHLORIDE [H] 111 MEQ/L (98-107) CO2 25.0 MEQ/L (22-30) GLUCOSE SERUM 82 MG/DL (70-110)

ALBUMIN 4.0 GM/DL (3.2-5.0) TOTAL PROTEIN 6.5 G/DL (6.3-8.2) CALCIUM 9.6 MG/DL (8.7-10.4)

Bone mineral density (BMD) of the femoral neck is 0.632 g/cm2. The value is 2.0 standard deviations below the mean for young normal control subjects (T-score) and 1.2 standard deviations below for age and sex-matched control subjects (Z-score). The relative risk for future hip fracture is 7.

Bone mineral density (BMD) of the distal ulna and radius is 0.426g/cm2. This value is 2.7 standard deviations below the mean for young normal control subjects (T-score)and 1.9 standard deviations below the mean for age and sex- matched control subjects (Z-score).The relative risk for future fracture is 10.

Based on a minimal detectable change of 0.01 g/cm2 in this bone densitometry unit, there is a statistically significant change -3.2% in the BMD of the femoral/neck compared to 10-06-05.

RESPONSE-- Patient #1: There is very little data regarding the use of Forteo in patients with OGI. Also, I generally do not use Forteo in the setting of osteomalacia. If you are comfortable that the osteomalacia has been adequately treated (not sure what the underlying cause for that was), I think it would be ok to treat with Forteo for 2 years followed by IV zolendronate, if she can tolerate that. Sundeep Khosla, MD

QUESTION Patient #2: What do you think about this case? Only mild osteopenia of forearm. Does she need bone biopsy to confirm osteoporosis or go ahead tx with forteo?

55 y/o white lady with h/o stress fracture 1994 of both hips s/p percutaneous screw fixation. a right hip recurrent stress fracture - s/p surgery 05-05-08. G1P1. hysterectomy 09-2007 due to DUB (ovaries intact) - been on estradiol since then. h/o ruptured disc in 2006 - no surgery. mother has osteoporosis 92 y/o with kyphosis. no loss of height. no kidneys stones. BMD 7 years ago - normal as per pt. does not smoke or drink ETOH. no intake of anti-seizure meds. hearing ok.

XR note from orthopdeic surgery dated 04-08: no sign of avascular necrosis. There is some DJD of right hip. right hip sill has suggestion of an incomplete femoral neck fracture on inferior aspect of the neck. normal appearance of left hip with percutaneous screws.

Bone mineral density (BMD) of the distal ulna and radius is 0.511g/cm2. This value is 1.0 standard deviations below the mean for young normal control subjects (T-score)and 0 standard deviations above the mean for age and sex- matched control subjects (Z-score).The relative risk for future fracture is 2.

SODIUM 139 MEQ/L (136-145) POTASSIUM 4.7 MEQ/L (3.6-5.0) CHLORIDE 104 MEQ/L (98-107)

CO2 26.0 MEQ/L (22-30) GLUCOSE SERUM 88 MG/DL (70-110) BLOOD UREA NITROGEN 15 MG/DL (6-20)

CREATININE SERUM 0.8 MG/DL (0.6-1.0) ALBUMIN 4.3 GM/DL (3.2-5.0) TOTAL PROTEIN 7.3 G/DL (6.3-8.2)

CALCIUM 9.5 MG/DL (8.7-10.4) BILIRUBIN TOTAL 0.2 MG/DL (0.2-1.3) ALKALINE PHOSPHATASE 96 IU/L (38-126)

Patient #2: Puzzling situation, and the cause of her fractures is somewhat unclear to me. I would prefer in a relatively young patient such as this to obtain a tetracycline labelled bone biopsy (to evaulate bone volume, exclude osteomalacia, or other marrow dyscarasia) before initiating treatment. If the biopsy is unrevealing, then at least you have done what you can to uncover an explanation. Sundeep Khosla, MD

STATIN TREATMENT FOR ATHEROSCLEROSIS IN THE ELDERLY 20 May 2008
QUESTION- I have a lipid problem that I would be grateful for your
consultant's opinion on. I saw her originally in 1984 with Graves' hyperthyroidism and treated her with 10.6 mCi of I131, after which, she became   hypothyroid and has since then been on an appropriate dose of Thyroxine. She is completely asymptomatic at the present time, and there are no abnormal findings on physical examination. She is a nonsmoker, and on March 28, 2008, her blood pressure was 120/70 mm Hg.
Her mother died at age 91 of a stroke. She has ten siblings,  >> neither of whom has ischemic heart disease.
On February 1, 2008, she had a total cholesterol of 4.61 mmol/L (4 - 5.2 mmol/L), triglycerides 1.55 mmol/L (0.40 - 1.9 mmol/L), HDL   cholesterol 1.52 mmol/L (0.9 - 2.0 mmol/L), LDL Cholesterol 2.39 mmol/L (1.68 - 3.4 mmol/L), and cholesterol/HDL ratio 3.03 (0 - 4). Her Apo-B is low at 0.68 g/L. Her fasting blood glucose is 4.5 mmol/L and other routine blood   work is normal.
Sonographic evaluation of the abdominal aorta shows no evidence of aneurysm. There is mild atheromatous change with early   calcification in the distal abdominal aorta.
On chest X-ray, there is evidence of calcification in the aortic arch.
Echocardiogram shows mild aortic valve sclerosis with minimal   stenosis and mild aortic insufficiency.
Bilateral cerebrovascular duplex scan of the carotid arteries shows a small amount of heterogeneous plaque in the bulb and bifurcation.   There is no evidence of flow restriction or
turbulent flow. There   is no evidence of stenosis.
Two of our cardiologists, on the basis of these findings of early   plaque formation in the carotid arteries, have advised her to have statin therapy and daily Aspirin therapy. They have referred me to   the Canadian Cardiovascular Society Position Statement for the    Diagnosis and Treatment of Dyslipidemia and Prevention of   Cardiovascular Disease published in September 2006 in the Canadian Journal of Cardiology, Volume 22, Number 11, Page 913.
On page 920 the statement is made, "Although intimal medial   thickness quantification is not yet a standard measure, evidence of early carotid atherosclerosis by routine carotid ultrasonography is   an indication for statin therapy."
I would be grateful if your consultant could express an opinion as to the validity of these recommendations. Yours sincerely, D. W. Ingram, MB, FRCPC, FACP
RESPONSE- The question raised by Dr Ingram is very interesting and of course
there is no straight answer to it. In summary, his patient is a
healthy 71 year old woman with no family history of cardiovascular
disease and with no cardiovascular risk factors who was found to have
aortic arch calcifications and carotid plaques. The question is
whether statin therapy should be initiated or not. To make matters
more complicated, her LDL cholesterol is below the NCEP target level
for all dyslipidemia patients with the exception of those at "very
high risk" (documented coronary artery disease AND diabetes or
uncontrolled risk factors).

No clinical endpoint cholesterol lowering study has ever enrolled a
patient with these characteristics, therefore an evidence based answer
can not be directly provided. Most family physicians faced with such
findings on a routine physical examination would probably not
recommend statin therapy. Cardiologists who are usually consulted
because of patient concern will respond to it by recommending statin
therapy on the grounds that the risk of such therapy is low and
statins have been shown to decrease cardiovascular risk in most
situations. A third solution which I would favor is to make
recommendations for additional testing which might enable an evidence
based answer.

1. The mere presence of aortic calcifications is a qualitative rather
than a quantitative result. The quantitative approach to this finding
is electron bean computer tomography (EBCT). This test is relatively
affordable and considered an acceptable method of evaluation of the
atherosclerosis burden. It determines the amount of calcium deposited
on the coronary arteries and it is graded according to age adjusted
standards. There is evidence that its results provide information
concerning cardiovascular risk prediction which is additive to
Framingham risk factors. The finding of a high coronary calcium score
in this patient would justify a therapeutic approach equivalent to
that reserved to a patient with higher levels of traditional risk
factors. To note is that five different studies have showed that
statins do not prevent the progression of calcifications and
consequently the method could be used for the evaluation of risk but
not for the evaluation of the results of therapy.
2. The mere presence of carotid plaques is a qualitative rather than a
quantitative result. Carotid plaques are found at autopsy in North
American children and adolescents. The guidelines quoted by Dr Ingram
are probably referring to a quantitative test, the determination by
ultrasound of carotid intima-media thickness (CIMT). CIMT is
frequently used as a surrogate outcome for interventions aimed at
reducing cardiovascular risk. . There is evidence that its results
provide information concerning cardiovascular risk prediction which is
additive to Framingham risk factors. An estimate of CIMT in this
patient could also refine the evaluation of cardiovascular risk and
justify the intervention.
3. Finally, the estimate of C reactive protein (CRP) is very
inexpensive and could be ordered. CRP level correlates with carotid
plaques and with EBCT. Should it found to be high it could directly
justify the intervention based on the recently completed (but not
published) JUPITER trial. This trial which was stopped because of
overwhelming success enrolled patients with elevated CRP of which a
quarter had LDL cholesterol lower than Dr Ingram 's patient.

I hope this answer will satisfy Dr Ingram. I would be delighted to
add additional information or provide references. DAN STREJA, M.D., FRCPC, FACP.

MANAGEMENT OF RECURRENT ONCOGENIC OSTEOMALACIA-24 APR 2008
QUESTION- I would be most grateful for help with a very difficult problem of oncogenic osteomalacia. The patient is a 62-year-woman who presented to me in 2001 with multiple rib fractures resulting in severe pain. Her serum phosphate was low at 0.56 mmol/L, and she had an undetectable 1,25 Dihydroxy Vitamin D and a low 25 Hydroxy Vitamin D at 29.8 nmol/L. She had an ovoid tumor between the metacarpals in her right hand, and this was removed in March 2002 (unfortunately incompletely removed). This was read at the Armed Forces Institute of Pathology as an atypical fibrochondo-osseous neoplasm of uncertain malignant potential with features suggestive of a phosphaturic mesenchymal tumor (mixed connective tissue variant).
    After this first operation on March 1, 2002, there was remarkable improvement, and by March 27, 2002, the serum phosphate was 1.30 mmol/L and her 1,25 Dihydroxy Vitamin D was normal. At this time she was asymptomatic, and her fractures appear to have healed. Her serum phosphate gradually fell after that, and during 2002 and 2003, it was approximately 0.89 mmol/L � at the lower end of the normal range, but by February 2005, it was low at 0.42 mmo/L. She was being treated, at this time, with Rocaltrol 0.5 �g t.i.d., Calcium Citrate 500 mg t.i.d., and Phosphate Novartis 500 mg q.i.d.
    She had a second operation on August 12, 2004, for the removal of residual tumor, but after this, there was little improvement in the phosphate level. She also had a course of radiation to her hand consisting of 6200 rads in 26 fractions in 2004 and early 2005, but this did not help. Her serum phosphate remained low. In addition, we had been able to send off her FGF-23 to the reference lab in Indiana, and it was high at the beginning and fell back to normal after the first operation. Unfortunately, we have not been able to get it assayed since.On April 5, 2005, she started Octreotide 100 �g t.i.d. subcutaneously, and by June of that year, she was 50% improved in symptoms. Because of expense, this was changed to the long-acting form of Sandostatin LAR 20 mg IM every four weeks. In March 2006, this was increased to Sandostatin LAR 30 mg.
    The phosphate did not normalize after starting the Octreotide; although, her symptoms were somewhat better. At the beginning the tumor was visualized on a Somatostatin scan, and this was true also of the situation before the second operation but since then a Somatostatin scan after being off Sandostatin LAR for a month was negative. Recently her serum phosphate has become very low again, and her symptoms of pain have recurred, and she has multiple fractures again. We are restarting Octreotide 100 mg t.i.d. subcutaneously. I presume that we have either residual tumor in the arm or metastatic tumor, which so far has not been located by imaging investigations.D. W. Ingram, MB, FRCPC, FACP
RESPONSE-Your case is very convincing for a diagnosis of oncogenic osteomalacia. The biochemistry, location, and response to initial therapy are all very typical. The case also presents the difficult management challenges in the disorder. I think you have to assume that there is either residual/recurrent tumor or metastases. I would suggest you try alternate imaging techniques to try and localize this. In addition to octreotide scans, sestamibi and MRI have been used. Most recently the PET scan using CT coregistration has been fruitful and I would suggest this approach. You may also wish to attempt regional venous sampling for FGF23 levels to try and focus the area of concentration of CT scanning, if possible. In addition to the standard therapeutic maneuvers you have tried, another potential therapy could be used (radiofrequency ablation) if the tumor is in a difficult location (see Hesse E et al, NEJM 357: 422, 2007).Thomas Carpenter, MD

IS GROWTH HORMONE THERAPY SAFE WITH RESIDUAL PITUITARY TUMOR? 4 Apr 08
QUESTION- I have a 60 year old patient who is post transsphenoidal resection of a large macroadenoma. He has growth hormone deficiency and hypogonadism and I am weaning him off of steroids. He is much better symptomatically on growth hormone, but a post-op MRI reveals
some residual tumor. Is growth hormone contraindicated here because of the residual tumor? Thank you very much. Ann Ward>
RESPONSE- This is an interesting question. There are two parts to this: firstly, the value of replacing GH in an older age group, and secondly, its safety when there is residual tumour. The answer to both is positive. There is published evidence that GH replacement should be considered regardless of age, although of course the normal range in which one would like to get circulating IGF-1 falls with age; we try and place the IGF-1 in the normal age- and sex-adjusted range but above the median. In terms of safety, there have now been numerous reports which can reference if you are interested in which GH has been shown not to be a risk factor for tumour regrowth or recurrence. However, you should bear in mind that when there is residual tumour postoperativey, the 10-year recurrence rate is pretty high in the absence of external beam radiotherapy regardless as to whether GH is administered. Regards, Ashley Grossman, MD

ALPHA SUBUNITS IN RENAL FAILURE February 26, 2008
QUESTION-Are apha subunit results elevated in premenopausal women with renal failure?Thank you for your reply.Dr MG Endocrinologist, Australia
RESPONSE-They are extremely elevated since they come from hypersecretion of both gonadotropins as well as from already elevated alpha-subunit concentration that are usually found in renal failure. Paolo Beck-Peccoz, M.D.

13 YEAR OLD WITH OVARIAN AND THYROID DYSFUNCTION   18 December 2007
QUESTION- This is a 13 year old Asian girl who came to the clinic with her mother bec of short stature (4ft 4 inches, mother 5ft 2, father 5 ft 8 ). A week prior , they did US of pelvis , reported as possible uterine agenesis.We are doing MRI now to confirm findings. Bone age: 105 months(vs her chronological age of 162 months).difference is >2SD based on the patients age and sex. epiphyseal plates open.
LH 24.01ml/uml, FSH 90.46 ml/uml, estradiol 7 pg/ml tsh irma 18 ;freet4 ria 17;8am cortisol 199.
NO signs of thelarche, no onset yet of secondary sex characteristics.
Will she benifit from GH? Can we immediately start T4? Thanks so much for your input. Lynn Bilar, MD
RESPONSE- Unfortunately, this sounds like a much more complex case than I can handle adequately by e-mail. An initial question is whether or not this patient has Turner syndrome, which would explain the high gonadotropin levels, and short stature, but not the uterine agenesis. She certainly needs a Karyotype done to look not only for XO Turner's but for the rarer variants as well. If, indeed, she has Turner syndrome, then she qualifies for growth hormone therapy and you need do no further testing.
     As far as her thyroid status is concerned, I would want to know why she has an elevated TSH and so would do anti-thyroglobulin Abs, and anti-thyroid peroxidase Abs. I am assuming that the free T4 is in
pmoL/dL and is normal- what is the normal range for your lab? As you may know, there is an increased risk of autoimmune thyroid disease in patients with Turner syndrome. I would see no reason not to treat her for this- it could certainly be contributing to her short stature and delayed bone age.
     Should she have Turner syndrome, then there are many other aspects that need to be explored- cardiac, renal, learning, etc and she needs counselling. Patients with Turner syndrome can die from rupture of an aortic aneurysm, particularly those with undiagnosed coarctation of the aorta. They are also at risk of horseshoe kidney. If she does not have Turner syndrome and she, indeed, has neither a uterus or gonads, she needs renal fx evaluated. She may have a rare genetic abnormality in one
of the transcription factors necessary for genito-urinary development. In either case, it sounds like she needs a sophisticated pediatric endocrine and/or genetic evaluation, and not one that is best handled by
e-mail. I hope that this is helpful to you. I would be most interested in learning about what you find. Rosalind S. Brown MD,

PREMATURE TELARCHE OR PRECOCIOUS PUBERTY 3 December 2007
QUESTION-I am a physician in Romania and I want to ask you about the case of 1 years and 3 months old girl who came in to my office in September 2007. She had breast development on stage 3, noticed by her mother about 6 months. I recommend: estradiol=20pg/ml, FSH=2,4mui/ml, LH=o,o . Because in Romania we don�t have access to LHRH I couldn�t practice THE stimulation test. The skeletal age had no advance And the pelvic ultrasound shows a cyst of 4mm on left ovary. I recommend to avoid food possible contaminated by estrogens and cosmeticals products and ask her to come back after 1 months.
In October 2007 she had no different on her breast, LH=0,1mui/ml, estradiol=80pg/ml, FSH=2,1mui/ml. I found a LHRH agonist (Leuprolid) and I administrated half of 3,75. The basal results were similar with the previous except the estradiol which was again 24 pg/ml. after 1 hour LH=6,7mui/ml, FSH=24mui/ml and after 24 hours LH=7,4 and FSH= 20mui/ml.
How should I interpret the results ? I have an argue with my collaborators about the diagnosis and treatment . So I need your superior opinion to decide what to do next?
RESPONSE-The problem you have been faced with, i.e. the differential diagnosis between precocious puberty and premature telarche in the first 2-3 years of life, is a very controversial one. In this age group, in fact, the hormonal findings are not so helpful in distinguishing between these two clinical entities because both baseline and stimulated gonadotropin and estradiol blood levels can be physiologically increased with values highly variable and inconstant. Therefore, what we should mostly rely on to make a diagnosis, are the clinical findings. In your specific case, there is a 1.5 yr old girl with a 6 months history of breast development, a bone age appropriate for chronologic age, pelvic US showing what presumably is a follicle normally present at this age. It is crucial to know the height velocity in the previous months, and the uterine and ovarian measurements at US. In the presence of a height velocity within normal limits in the previous 6 months, uterine and ovarian measurements appropriate for age, no other signs of pubertal development, and absence of neurological findings, I would go for a diagnosis of premature telarche and follow carefully the patient clinically. In case of precocious puberty I would expect a fast advancement of pubertal signs and ovarian and uterine dimensions, an advanced bone age, and increased height velocity. If this would be the case, I would repeat the GnRh agonist stimulation test and expect to find a further increase in LH and decrease in FSH blood levels, and perform a head MRI to rule out intracranial pathology present in 8% of girls with precocious puberty without neurological findings or neurofibromatosis (Chalumeau, M., et al., Selecting girls with precocious puberty for brain imaging: validation of European evidence-based diagnosis rule. J Pediatr, 2003. 143(4): p. 445-50). Lucia Ghizzoni, M.D.

POLYGLANDULAR AUTOIMMUNITY, HYPOPARATHYROIDISM, AND RESISTANCE TO VITAMIN D THERAPY
QUESTION-I am ibrahim mokhtar endocrinologist working in king khalid hospital , najran , saudi arabia. I have 18 years old female patient . She is a known case with famlial primary hypoparathyroidism and gonadal failure ( APGS ).Her serum calcium was well maintained with one alpha 1 microgram tab.daily and calcium carbonate tab. 1 gram tid . For the last few months it is difficult to maintain her serum calcium . She was admitted to our hospital 10 days back with recurrent carpal spasms .Her serum calcum was low  0.4 mmol and magnisum low 0.5 mmmol , serum albumin is normal . She was treated with I.V CALCIUM GLUCONATE and MG. SULPHATE infusion with symptomatic improvement , however her serum calcium hardly exceeds 1.6 mmol . I increased her dose of one alpha to 2 microgram daily and calcium carbonate t. to 2 g. tid . Upon stopping calcium and magnesium infusion her serum calcium and mag. dropped again with recurrence of carpal spasms . For the last 2 days I am keeping her on calcium (50 ml. cal. gluc. 10% IN 500 ml NS 12 hourly and mag. sulphate ( 3g 12 hourly ) IV infusion. her latest serum cal . is 1.55 mml and mg. is 0.7 mmol . How I can further manage this case. Thank you very much
To Dr. Moktar --One unusual feature of your patient that needs further explanation is the low magnesium, and it would be important to document the degree of hypercalcIuria and hypermagnesuria, as fractional excretions. This should usually be done by 24 hour urines with matching serum that measures calcium, magnesium, and creatinine.
Further information-My patient had familial primary hypoparathyroidism diagnosed about 10 years back with low serum calcium and low serum parathormone level. Her younger sister has the same condition.
(autoimmune polyglandular syndrome) manifested with primary hypoparathyroidism and primary gonadal failure. Her urinary calcium excretion is normal for her body weight and her renal function is normal Her urinary magnesiun not measured , assuming that hypomagnesemia is due to hypoparathyroidism
RESPONSE-Your additional information is very helpful. Has your patient shown any signs or do her laboratory tests suggest any adrenal abnormalities? It would not be uncommon for the exacerbation of the hypoparathyroidism-induced hypocalcemia to be complicated by mild hypoadrenalism.
This would not explain the sudden need for intravenous therapy. In this case, I wonder whether your patient has developed a sprue-like or celiac-related malabsorption syndrome described occasionally in APECED. This would account for the failure of the oral vitamin D metabolite therapy, and has been known to affect oral magnesium absorption.   The key transepithelial transporter for magnesium in gut and kidney is not dependent on PTH for its activity, and hypomagnesemia of the severity you describe is likely due to malabsorption or to a renal leak. In this case, it would be the hypomagnesemia exacerbating the hypoparathyroidism not the converse.
            Before committing to a change in therapy at this point, I would think it important to know that there is no hypermagnesuria when the magnesium is low/normal (between 0.5 and 0.7 mmol/L). Other tests should be directed at establishing adrenal in/sufficiency and ruling out malabsorption. In the meantime, you may require IV support for calcium and magnesium, with aim of maintaining them in the low/normal range (0.6 mM for Mg and enough to stop the Chvostek's ).You may want to consider long-term therapeutic options now: If there is malabsorption, then a celiac type of diet may be effective in the long run. Because magnesium is laxative at doses that overcome its malabsorption, we initiated night-time slow-rate nasogastric infusions to escape the parenteral routes (Cole et al. Eur J Pediatr 2000;159:38). If available you may wish to initiate a trial of recombinant PTH, which we have found to be of benefit in autosomal dominant hypoparathyroidism (see Mittelman et al. J Clin Endocrinol Metab 2006;91:2474).I hope these considerations are helpful. David E. C. Cole MD PhD

PROLACTINEMIA WITH ANTI-PSYCHOTIC MEDS
QUESTION-This case is an 50 year old postmenopausal female who presented with galactorhea and headache. She is also a diabetic on drug control. she is a known case of psychiatric disorder on amitryptiline and sertaline. Her prolactin was 170 ng/ml. Her thyroid function test is normal. No visual field defect. MRI pituitary was normal. our diagnosis was Hyperprolactinemia-Drug induced. But the problem is we were not able to wean her off from the psychiatric medicines and she does not do well with other alternate psychiatric medicine and we are forced to continue the above psychiatric meds. In view of persistant galactorehea and high prolactin, can we go ahead with bromocriptine or cabergoline(with continuation of amitryptiline and sertaline)? Expecting your valuable feedback. Thanking you, Dr.Kumaravel kumaravel velayutham
RESPONSE-Regarding your clinical case, a serum prolactin of 170 ng/mL is an unusual level for aminotryptiline/sertaline induced hyperprolactinemia (was macroprolactinemia excluded?). Generally, drugs which induce such a high prolactin levels are the dopamine antagonist neuroleptic/antipsychotic drugs as sulpiride, haloperidol or chlorpromazine, and, no so commonly, GI drugs as metoclopramide or domperidone. Anyway, if MRI, thyroid and renal function are normal, and galactorrhea is not troublesome for this postmenopausal woman, I would keep the patient on her medication. Otherwise, if galactorrhea is bothering, and the drugs cannot be withdrawal or switched to other medications, I would try a small dose of cabergoline, keeping in mind that in principle the dopaminergic effect of this dopamine agonist may interfere in the anti-depressive effect of the drugs she is taking. Sincerely, Marcello D. Bronstein, MD Sao Paulo, SP, Brazil

Rokitansky-Kuster-Hauser Syndrome (Inadequate Mullerian development) � 12 Jun 2007
QUESTION-I am an endocrinology intern form india,this my second case to the ask the expert section.firstly i would thank u for the advice given for the last case.
The case is 18/F, h/o primary amenorrhoea,Fourth child of a nonconsanguinus marriage,family history- Elder sister had periods at 16 yrs, normal pernatal events,normal developmental milestones,normal intelligence.No history of growth spurt but was growing normally. Thelarche at 12 yrs and pubarche at 14 yrs.No history of virilization at pubertal age.Normal prenatal events.Normal developmental milestones.Normal intelligence. No history of growth spurt but was growing nornally.Thelarche at 12 yrs and pubarche at 14 yrs.No history of virilization at pubertal age.No history of inguinal hernia.H/O infertility in paternal aunt. No history of acne,hirsutism.No history of maternal abortions or neonatal deaths.No history of short stature.
H/o attempted withdrawal to progesterone : no bleeding,. Mother's height: 158 cm. Father is short. Height : 153cm Weight : 48.5kg Height is at 5 th centile.Upper segment : 74 cm Lower segment: 78 cm. Arm span : 153 cm
Thyroid:Normal. Other findings:Smell normal. Pubic hair stage 4, Breast stage 4 Axillary hair has been shaved off.
Local Examination : Labia Majora - normal, labia minora - fused together. Small blind vagianal opening / pouch. P/R - could not get Uterus. Systems :Normal
Investigations: TSH/FT4,PROLACTIN,-NORMAL LEVELS. Testosterone; total 0.097 (ng/ml)(F-< 0.1). FSH-2.43 (mIU/ml)(1-8). LH-<0.1(mIU/ml). Estradiol 154.8 pg/ml. Sonogram of pelvis: Uterus Measures 32.6x8.2mm (CC x AP). Endometrium not visualised. Bilateral ovaries :Not visualised. No obvious pelvic mass seen. : Hypoplastic uterus.No obvious pelvic mass
The question is how to further proceed about the case? any further investigations? management? Arun Kannan:, India <mailto:drarunkannan@gmail.com>
RESPONSE- This 18 year old has genital outflow tract obstruction and perhaps uterine abnormalities and probably represents a variant of Rokitansky-Kuster-Hauser Syndrome.The workup of this patients indicates:
1. Normal progression of pubertal events including thelarche and adrenarche.
2. Adequate growth given the history of short stature in the father.
3. Normal thyroid and prolactin function.
4. Low or normal FSH with ovulatory levels of estradiol.
5. Failure to withdraw bleed with progesterone due to no endometrial compartment.
Thus, this individual has proceeded through puberty, has adequate secondary sex characteristics that are estrogen driven, has a normal XX karyotype but is unable to respond to estrogens due to inadequate development of the Mullerian system and the upper parts of the vagina with a blind vaginal pouch.
To complete her workup, I would probably perform a transrectal ultrasound which may provide further anatomic details such as an absence of a cervix and no endometrium and the presence of ovaries (I disagree that there are absent ovaries since the estradiol levels are too high for peripheral conversion of estradiol).
She can be treated with vaginal dilators to achieve a functional vagina using the approach proposed by Frank.
James H. Liu, M.D. Case School of Medicine, Cleveland, OH

DETECTING OVULATION BY PROGESTERONE LEVEL--- 7 Jun 2007
QUESTION-Traditionally (often a euphemism for "We've always done it though we don't have the evidence") serum progesterone has been used in the UK to assess the likelihood of ovulation having occurred on day 21 of a day 28 day cycle (or 7 days before next period if cycle >28 days). A cut-off of >30 nmol/L ( = 943 ng/dL) is quoted as indicating a likely ovulatory cycle by some. My own response has been that this indicates "evidence of adequate luteal activity".
My understanding of the events leading to ovulation is that an ovarian follicle matures, and that if ovulation occurs, a corpus luteum develops which is responsible for progesterone production. If pregnancy ensues, the placenta takes over. If fertilisation does not occur, the CL regresses and progesterone falls.
I therefore have a question as follows:
If a serum progesterone is measured on day 21, and the result is <30 nmol/L, but, say, in double figures - 10-15 nmol/L - the UK perspcetive in many quarters would be that ovulation had not occurred. However, that being the case, where is the progesterone coming from ? Is it the case that ovulation has occurred but that the ovum is produced, is non-viable with rapid "failure" ensuing, and thus a brief burst of progesterone occurs but which peaks below 30 nmol/L ? Philip Hyde, Pilgrim Hospital, Lincolnshire, United Kingdom
RESPONSEProgesterone is produced from both the adrenal gland and the corpus lutuem. Progesterone production from the adrenal gland is fairly stable and contributes approximately 1-1.5 ng/mL when measured in the serum of women during the follicular phase. Following ovulation, there is increasing production of progesterone from the corpus luteum and the progesterone levels gradually rises from a baseline of 1.5 to 3 ng/mL by the first day after ovulation. Levels then continue to rise until it reaches a peak 7 days after ovulation reaching levels of approximately 10-20 ng/mL. Levels of progesterone are secreted in a pulsatile pattern during the luteal phase and thus levels can vary depending on the timing of the blood draw. (See Filicori et al. J Clin Invest 1984;73(6):1638-47).
In this case, where progesterone is lower than the normal D21 peak probably suggests that the timing of the blood draw was either 3 or 4 days before the peak (i.e. the ovulation was occurring later) or 3 or 4 days after the peak ( i.e. the ovulation was occurring earlier). In the U.S. a level of 4 ng/mL is considered ovulatory. However, the most reliable clinical indicator for ovulation is regular menstrual cycles between 25-35 day intervals. Thus, reproductive endocrinologists seldom measure progesterone levels to confirm ovulation. James H. Liu, M.D. Case School of Medicine

MARKED DROP IN BONE DENSITY IN ONE AREA 20 May 2007
QUESTION-I would like to request an expert opinion on a bone and mineral metabolism case, and ask for your assistance in directing my question to an expert you feel would be most appropriate in addressing this case. 60 year old man with osteoporosis, with unremarkable evaluation for secondary causes of decreased BMD (normal CBC, TSH, testosterone, ESR, PTH/calcium, creatinine, serum protein electrophoresis, 25 OH vit.D), treated with Actonel 35 mg weekly with calcium 1000 mg/day and vit. D 400-800 u/day. Follow-up DXA scan 2 years later showed decrease in BMD of 8% for lumbar spine, and stable proximal femur BMD. Why was there a signficant "disconnect" between lumbar spine and proximal femur BMD on follow up scan, and what would you advise for further diagnostic/therapeutic interventions? Thank you.Bill Jou, M.D.Arcadia, CA
RESPONSE-The most likely explanation here is instrument error, since this much of a disconnect is unusual. If that is not the explanation, then one would need to look harder for an underlying process. You have appropriately excluded significant vitamin D deficiency, hyperparathyroidism, etc. However, if you are convinced that this is not due to some type of instrument error (ie either the initial or f/u spine BMD is erroneous), I would recommend obtaining a bone marrow aspirate and biopsy to be sure there is not an underlying marrow dyscrasia (plasma cell disorder, mast cell disease, etc) that may be causing this. Sundeep Khosla MD,Mayo Clinic College of Medicine

ELEVATED PROLACTIN AND TINY ? TUMOR 12 May 2007
QUESTION-. This is a 27 year old female patient G1P1 who has been having persistent galactorrhea since 2005.She has regular monthly cycles. Her prolactin levels are all normal except for one taken in 2005. Lately she also complains of dizziness and tolerable headaches.MRI done showed a 2-3 mm pit mass.The galactorrhea though very scanty is bothering her. How do we proceed? Thanks a lot again for your time and inputs. Lynn f.w.Bilar.MD
RESPONSE- Regarding your clinical case, certainly the dizziness and headaches are not related to the 2-3 mm pit mass depicted by MRI: more probably the image refers to a pituitary incidentaloma. As most of serum prolactin measurements were normal, probably the patient has normoprolactinemic galactorrhea, a non rare event in women that already delivered and nursed a baby. I suggest to perform prolactin and progesterone measurements at her supposed luteal phase just to assess ovulation. Anyway, if the galactorrhea bothers her (and secondary causes such as dopamine antagonist drugs or hypothyroidism are discarded), I suggest a course of cabergoline treatment. Sincerely, Marcello D. Bronstein, MD

SHORT STATURE AND HYPOCALCURIA 12 May 2007
QUESTION- I would like to ask about non-identical twin sisters, 20 yrs old, with "osteopenia" on DXA. However, their lower Z score (-2,0) is very likely due to their short stature (150 cm). They both have absolute and relative hypocalciuria (1,49 mmol urinary calcium per day, CCa/CCr 0,0048) with normal serum calcium, phosphorus, potassium, magnesium, creatinine, PTH, TSH and 25OH vitamin D levels. The pubertal development was normal and they both have regular menses.
Is there any link between "isolated" hypocalciuria and short stature? What else could be examined in adulthood? Best regards, K. Zajickova Institute of Endocrinology, Prague, Czech republic.
RESPONSE-- I would agree that the small height (4'11") may have a significant impact on the DEXA Z-score. It is somewhat difficult to assess the urinary calcium excretion in this setting. I assume the clearance values are in mmol/mmol. We often normalize 24-hr urine excretion to kg body weight, and I assume that she may also be of a relatively low weight. It would also be of use to know her dietary calcium intake as the value may be accounted for by a relatively low calcium diet. Rare disorders such as Gitelman's syndrome can present with hypocalciuria and decreased bone mass; hypomagnesemia and hypermagnesiuria are usually present. I also assume that such a patient may also be short because of chronic disease, alkalosis, and other electrolyte abnormalities. I am not aware of a specific syndrome of an otherwise healthy child with short stature and low dietary calcium excretion. Tom Carpenter, MD

MANAGEMENT OF ACROMEGALY 10 MAY 2007
QUESTION-I am an Endocrinologist in private practice in Tucson. I was asked to see a patient for hyperthyroidism on Tapazole, he is a 64 year old male. He also has diabetes. When I evaluated him he appeared to be acromegalic, all of his testing confirmed acromegaly, including failure to suppress with glucose. Initial pituitary MRI demonstrated a small left sided pit. micro adenoma, 3x2 mm however when he was ready to undergo surgery he arrested with intubation. He has had 3 subsequent MRI's ,that fail to demonstrate a micro adenoma I suspect that the adenoma involuted. I have evaluated him for ectopic GH secretion with ct scans, octreoscan scan which have been normal. My question is whether I should continue to pursue an ectopic source of GH secretion or treat . I was planning on treating him with Sandostatin Lar. IGF-1 504, IgF Binding protein-3 6.6 TFT wnl. Of interest his IGF-1 level has remained elevated. The neurosurgeon is strongly suggesting pursuing ectopic eval. I was planning on treating him and following the IGF-1 levels. Your help with this case is appreciated, as far as any further testing that I may peruse Thank you very much, M Garcia MD
RESPONSE-thank you for your recent interesting question sent to EndoText. I presume that the GH and IGF-I levels have remained elevated after the initial attempted surgery with failure of suppression of GH after a glucose load, and with detectable GH levels in multiple testingover 12 hour period. If this is the case, it seems unlikely that there has been a spontaneous invlution of the microadenoma asthe biochemistry would indicate on-going active disease.
I would recommend measureing GHRH levels to determine if there is an ectopic source of the hypothalamic hormone. The important issue would be to initiate treatment and to assess the GH and IGF-I response to a somatostatin analogue such as you suggest. I trust you find these suggestions helpful in this interesting case. With kind regards. Paul J Jenkins

LOW PLASMA METANEPHRINE VALUES---STEROIDS, HYPOTENSION- 3 May 2007
QUESTION-I am a practicing clinical endocrinologist. i was asked to see a patient with cns lymphoma who had been treated with high dose steroids and chemotherapy. when the steroids were tapered he developed severe postural hypotension that responded partially to mitodrine and florinef. when steroids were restarted due to cns symptoms without evidence of definite anatomic recurrence of lyphoma the postural hypotension improved significantly. an acth stimulation teat while on steroids showed a normal serum cortisol response. however, plasma metanephrines were below detection limit. can you explain the low metanephrines? George Gewirtz, MD,
RESPONSE- Very interesting. Metanephrines reflect epinephrine secretion from the medulla, and need adrenal cortisol to be methylated from norepinephrine. I suspect there may be pituitary involvement by the lymphoma (we reported a couple of cases in "Pituitary" a few years back) and he is now ACTH deficient (this will not show up acutely in the ACTH stimulation test). If so, he should have replacement therapy with hydrocortisone. In time, I would anticipate the metanephrines will normalise. However, I frequently see patients who are normal with very low urinary catecholamines (we are not currently using metanephrines). Ashley Grossman, MD

PROBABLE HYPOPITUITARISM IN AN INFANT�2 May 2007
QUESTION-I need your help in managing one of my patients.

It was an interesting set up: FT NB baby boy had somewhat complicated delivery, few self -resolved hypoglycemias and was kind of too sleepy/ uninterested in feeding for about 10 days -longer then looked appropriate for the degree of his birth stress, so brain MRI was done. Ectopic small pituitary gland with no visualized pituitary stalk and partial absence of anterior falx were seen. Initial labs at age of 2 weeks showed TSH-5.6, T4 -QNS, LH/FSH <0.2, prolactin 30.1, IGF-1<25, bili 9.2/0.9 (high for 2 weeks), cortisol 1.3.
I was concerned about low cortisol, so ACTH test was done. The samples for 0 and 60' were combined by lab(!!!), so there was no repeat cortisol level at all.I could not r/out panhypopit as well as confirm it for sure, so, as soon as baby was doing better and had no hypoglycemias, he was d/c home with teaching about emergency Solu-Cortef injection and F/up.Meanwhile, abnormal NB screen with low TT4 and normal TSH came, suggestive of central hypothyroidism.Repeat TFT at 3 weeks of age again did not have thyroxin (QNS), and TSH was normal -4.6.
Repeat TFT's showed low FT4 of 0.65 (No TSH in this set because of inability to get enough blood, previous TSH of 4.6 was 3 days ago) Also we found very low Testosterone-7.3, IGF-1 of 17 (mean 55, range 15-109), IGF-BP-3 -1.1 (range 0.7-3.6)
I started this baby on Levoxyl 25 mcg, thinking of possible central hypothyroidism in the light of previous events/findings. Baby was close to 4 weeks old and still had some mild jaundice, supporting my concerns about hypothyroidism.I saw the baby at age of 7 weeks (in 3 weeks after starting Levoxyl) and found well looking active infant boy growing at 90% for Wt and Ht, gaining 700gm (wt-5.4kg) and 4 cm (L-60cm) I repeated TFT's in 3 weeks after starting on Levoxyl 25 mcg: TSH-0.015, FT4-1.69 (0.76-2.00). I wanted the repeat Testosterone to assess the minipuberty, but it was QNS again.
I contacted the mother and while discussing the results, figured out that she thinks that the baby is eating too much and is kind of too active.I decreased the dose to 12.5 mcg, mentioned to her that we will check the levels in 2 weeks. Also I mentioned that I would ask your opinion.
Now are my questions about thyroid aspect of this difficult patient:
Is this an iatrogenic suppression of TSH by too high Levoxyl dose(although it is 5mcg/kg only)? I tend to think so, because we had 3 previous normal levels of TSH before treatment.Or this is a declined function of the thyreotrops of the displaced pituitary?Have no answer for this, as soon as low IGF, low T are suggestive of loss of function. But clinically baby is doing and growing fine, so no data for growth failure and GH deficiency though.
What is my next action if TSH is still suppressed/low and FT4 is still in the high normal? Ignore it or d/c Levoxyl completely?
Does it look like central CH? I would value you opinions and suggestions a lot.I will inform you about future tests and events if you are interested.Thank you so much in advance. Irina Kazachkova, MD, Maimonides Medical Center,
RESPONSE-I think that your patient almost certainly is GH, ACTH and TSH ( and probably LH/FSH) deficient- based on the exceedingly low IGF-1, and low free T4 and random cortisol values. As you know babies with GH (and ACTH) deficiency are at risk of hypoglycemia, but often the blood glucose is only low after fasting, so the fact that you have not documented it does not necessarily rule it out. You need to check a blood sugar prior to the next feed, and be particularly concerned as the baby sleeps longer and longer during the night.
In my opinion, this baby should be started on GH, and cortisol (in addition to T4) ASAP. If it is that difficult to obtain blood and you cannot do either a GH stimulation test (arginine/glucagon) or ACTH test, I would just treat speculatively. Note that with a glucagon stimulation test you can also assess cortisol. With the evidence you have, there is not too much doubt about the dx and many insurance companies will not require formal stimulation tests. I would use a low cortisol replacement dose (<10 mg/kg/day) because of the growth-suppressive effect of cortisol. I would probably use 0.15-2 mg/kg/wk of GH given daily and titrate the dose thereafter according to the growth response, although initially one treats because of the adverse metabolic consequences rather than the growth effects of GH deficiency.
As far as the suppressed TSH is concerned, if the baby is TSH deficient then the TSH is not very helpful in monitoring the adequacy of thyroid hormone replacement and I would follow the free T4. I would not reduce the L-T4 dose (unless the free T4 is elevated using age-appropriate norms).Sincerely,Rosalind S. Brown, M.D.,

HAIR LOSS IN A 30 YEAR OLD, LOW TESTOSTERONE- 26 March 2007
QUESTION-I am an endocrinology intern from Brazil. The case is: Female, 30yrs. She presents with concern for losing hairs and low testosterone, sent by a dermatologist. Menses are normal, no changes in desire or muscle mass or body hair (only alopecia). Hormone profiles: thyroid functions normal , prolactin normal, DHEA normal, LH/FSH/estrogen in normal range. Testosterone = 12,2 (range 15-80) and repeated testosterone=6,9.
The questions: 1) what do I have to think about it (hypothesis)? 2) which are the tests that I have to ask in this case? 3) management? Thanks.A Rubin, Sao Paulo
RESPONSE- First, I cannot offer specific advice in the absence of seeing a specific patient so all I can do is comment about alopecia in general. As you know, most causes of alopecia are not endocrine -- having said that, it clearly can occur as a result of low estrogen (without a concomitant decrease in testosterone) after the menopause. For postmenopausal hair loss estrogen therapy is somewhat effective. Testosterone measurements in laboratories are so poorly performed that I am never confident about any values, low or normal or high. About 25% of testosterone comes from the ovary, 25% from the adrenal, and 50% from peripheral conversion from inactive precursors. So have you considered any adrenal abnormality here? If there is no evidence of this either, I would not think that her hair loss is primarily endocrine. Robert W. Rebar, M.D.

MASCULINIZATION AND HIGH TESTOSTERONE IN A 63 YR OLD WOMAN 24 March 2007
QUESTION-I am an endocrinologist from India. I have an interesting case. I will be happy if you could help me in the management of this case. Case is a 63 year old female, who presented to us with history of hirsutism of 8 years duration and complaints of hair loss in the temperoparietal and frontal area (Male pattern baldness) of 2 years duration.Past issues in this case: 1.She undervent hysterectomy with Bilateral salphingo oopherectomy 8 yeras before (Indication not known). 2.Total thyroidectomy for MNG 1 year before. Now euthyroid on thyroxine replacement.(HPE: MNG, No evidence of malignancy) No history of drug intake or other co-morbidities.On examination she had Hirsutism(FG score>30), masculanizing features and voice change were present. She also had clitoromegaly. No evidence of cushings syndrome.
Investigations:
TSH-3.2mIU/l(0.3 to 4) on thyroxine 150mcg/day
RFT, LFT,Calcium, sodium, potassium-normal
Testosterone-6.14ng/ml
17 hydroxy progesterone-1.3ng/ml
DHEAS-259.2mcg/dl (normal: 80-390)
CT scan Abdomen: Adrenals normal. No abnormal pathology.
MRI of neck and chest to r/o germinoma was normal.
We had treated the patient with aldactone 100mg/day and finasteride� 5mg/day for 3 months and still her testosterone is 5.1ng/ml and not much of clinical improvement.The question of concern is: 1. What is the probable diagnosis and how do we proceed further? 2.How do we treat her? Dr.Kumaravel Amrita Institute of Medical Sciences, Cochin, India
RESPONSE- It is again difficult to address a specific problem in the absence of seeing a specific patient.All I can do is make some general comments.It would appear that the testosterone values are about 10 times the upper limit of the normal range for women. If this is the case, then a source must be identified. Generally speaking, testosterone is produced by ovarian androgen producing tumors (generally benign). These tumors can be quite small. Ovarian tissue can remain in the pelvis even if a BSO is produced. It would be reasonable to search for a source of androgen excess. IF there is a skilled interventional radiologist samples could be obtained from near the origins of the ovarian vessels and from other sites in the abdomen and measured for testosterone. This might help determine if surgery is warranted.It would not be unreasonable to determine if the testosterone is suppressible during a dexamethasone suppression test -- but this can occur with ovarian as opposed to adrenal lesions. Robert W. Rebar, M.D.

HYPOCALCEMIA FOLLOWING THYROID SURGERY  FOR HYPERTHYROIDISM 20 Mar 2007
QUESTION-I have a patient who has had thyroidectomy for Graves 3 weeks back. He was admitted initially with fast AF and high output cardiac failure. He had treatment with high dose PTU, propranolol, Potassium Iodide and Warfarin.He was adequately prepared and proceeded to total thyroidectomy.
      He developed severe hypocalcaemia ( corrected Ca 1.53 mmol/L), and has required continous infusion of Calciem gluconate and 8 gm elemental cacim orally to keep his Calcium around 1.9 mmol/L and symptom free, for 3 weeks post operatively. His Mg initially was low and is now in the normal range on oral Mg replacement. Phosphate has been high between 1.55 to 1.93 mmol/L.. His 24 hour urine Ca with a paired serum Ca of 1.9 mmol/L was low at 2.2mmol/24 hrs (NR 2.5 -7.5). He has been receiving 2 micrograms a day of alpha calcidol.
      It seems as though he has hungry bone syndrome. Serum PTH is awaited. He was non compliant with ATD for about 4 years prior to developing high output heart failure and AF. I am not entirely sure what to do next. Is it just a question of time before his calcium normalises or is there any other modalities of treatment? Dr S.P., England
RESPONSE- While it is always important to avoid coming to premature closure and to fully consider the differential diagnosis of hypocalcemia, in this instance the described clinical situation is classic for surgically-induced hypoparathyroidism. Most likely the parathyroids were inadvertendly removed or traumatized during neck surgery. As such, I would expect the pending PTH level to be low, or inappropriately 'low-normal' in the face of hypocalcemia. Treatment would typically involve calcitriol and calcium, with related issues more fully described in the Endotext chapter. In followup, one should consider the possibility that traumatized parathyroid tissue can sometimes recover function over a period of weeks or months. Andrew Arnold, MD

TREATMENT OF ALOPECIA WITH PROPECIA 9 March 2007
QUESTION-. I am treating a 21 years old male with androgenic alopecia pattern. His hormone profile is normal. For the last 6 months he received Propecia (A selective 5 alpha reductase inhibitor) showing a nice improvement. How long do I have to continue the treatment? What will happen once I stopped the treatment? Shilo, Shmuel M.D
RESPONSE-Androgenetic Alopecia is a chronically progressive condition that occurs in people with an inherited susceptibility and is mediated by the action of androgens and, in particular, dihydrotestosterone in the hair follicle androgen receptor. Blocking the synthesis of dihydrotestosterone will arrest progression of hair loss but will not change the natural history of androgenetic alopecia in people who are genetically pre-disposed. As such, the treatment will continue to arrest the hair loss for as long as the treatment is continued. When the treatment is stopped then the hair loss will resume. In answer to your question, the treatment needs to be continued for as long as he needs to keep his hair. Professor Rodney Sinclair, University of Melbourne

FINAL HEIGHT FOLLOWING �EARLY� PUBERTY? 5 Feb 2007
QUESTION- I am an endocrinology intern from india,the case is a 12yrs 8month old boy
presents with concern for short stature and puberty advancement,(voice broken
at 11yrs, axillary hair 111/2 yrs), when comparing with the peers. ht
145cm/wt38.5,axillary hair stage 3/pubic hair stage 3/testis 20ml on both
sides/phallus length 8cm/bone age 13-14yrs,
Hormone profiles thyroid functions normal , prolactin normal,17OHP
normal,LH/FSH are in pubertal range. sr.testosterone slightly lower than the
normal range.
The question 1) his concern is how tall he will grow? (mother and father ht
152cm/155cm)
2) Is there any way his mild advancement in puberty can be slowed or delayed?
3) management? Dr.Arun Kannan, Amrita Institute of Medical Sciences, Cochin, India
RESPONSE- I believe that your patient had a normal, or sligthly anticipated pubertal
development. Despite a testicular volume of 20cc, his predicted height with
a bone age of 13.5 yrs is 160cm (BA 13: 165 cm; BA 14:156 cm) which is
exactly the same as his target height that is 160 cm. I don't think is worth
doing anything, and I believe that slowing the pubertal process at this
point might either harm his growth pattern by eventually stopping his
pubertal spurt, if he he has not been through it yet, or just be useless. I
would just continue a clinical follow-up reassuring him that he will
probably achieve his father's height. Keep me updated on your patient's follow-up.
Lucia Ghizzoni M.D., Ph.D

AHO, PSEUDOHYPOPARATHYROIDISM, AND BICUSPID AORTIC VALVE 20 Nov 2006
QUESTION- I�m caring for an patient with AHO and Pseudohypoparathyreoidism. Also she
is suffering from aortic stenosis caused by a bicuspid aortic valve. Is there any known linkage between AHO and bicuspid aortic valve ? Sincerely yours, Dr P.Matheiowetz
RESPONSE-Thanks for your query. I recommend you contact Dr. David Cole in Toronto and he would have further insights. Patients with 2q37 deletion have been reported with an Albright hereditary osteodystrophy (AHO)-like phenotype and ductus arteriosus and possible bicuspid aortic valve (see Reddy KS et al 1999 Microdeletion of chromosome sub-band 2q37.3 in two patients with abnormal situs viscerum. Am J Med Genet 84: 460-468 and references therein � see Table 1). Yours sincerely, Geoff Hendy, MD

DIAGNOSING AND MANAGING HYPERNATREMIA 8 Nov 2006
QUESTION-Could you pl write how to differentiate if hypernatremia is from hypo or adypsia versus reset osmostat in an individual with hx of head injury in the past and if the history about thirst is limited because of mental retardation. Also pl let me know how to manage hypernatremia from reset osmostat. padmalatha berikai
RESPONSE- This is a difficult problem, and in principle it may not be possible to differentiate hypodipsia from a reset osmostat (indeed, they may be pathophysiologically the same process). Managing patients with adipsia is one of the most challenging to neuroendocrinologists, and this is especially the case with patients less mentally astute. I generally admit them for a few days and get a baseline weight and fluid intake which keeps the serum osmolality in the normal range, and then instruct their carers to keep them to this input with at least weekly weighing. If their weight departs from the determined set-point then the fluid intake can be adapted accordingly. If possible, a check on the osmolality at intervals will allow them to see if the balance is working out. This means a lot of input from the carer, but the only patients who do well long-term are those with good home input. Ashley Grossman, MD

�

RELIABILITY OF CORTROSYN TEST 7 Nov 2006
QUESTION-I did a CST on a young male, aged 16, because he had been given some compounded steroids by a "fibromyalgia clinic" because of diagnoses adrenal insufficiency. The early AM cortisol level was low at 2.1 ug/dl and the one hour was normal at 25.9 ug/dl. What is the significance of the low 8 AM value and do I need to do anything else? Clinically, he had hyperthyroidism due to compounded T3 from the same clinic and, of course, the T3 has been discontinued and further evaluation will be done in a few weeks after being off of the T3. Thanks for your help with this. Ann Ward, MD Taylorsville, GA

HYPOGLYCEMIA, PULMONARY AND PERIPHERAL EDEMA 9/17/2006
QUESTION-I am an IM doc in Yuma, AZ. I recently had a patient, 31y/o WF, hospitalized after showing up in the ER semi-comatose, with a glucose of 40 and pulmonary and peripheral edema. Only PMH is depression for which she takes Cymbalta with good results.
Her fasting (12hr) insulin was <2, her pro-insulin <5 and c-peptide was 1.0. Her CMP/CBC/TSH were normal. I thought maybe insulinoma before I drew the labs, and now I'm thoroughly confused. Any ideas? Thank you. RSmythe MD
RESPONSE-Since I do not have much clinical information I will answer this based on several different assumptions.
Assumption 1. The glucose was from a venous sample, not a finger stick. If this patient was in cardiac failure and in a degree of cardiovascular collapse, it is possible that there was peripheral vasoconstriction. When this occurs, it has been shown to lead to a false low glucose level on a finger stick test.
Assumption 2 -The Patient Did Not Have Cardiac Failure
In 2000, Ortega et al in Diabetes care (Ortega et al. 23 (7): 1023. (2000) published their observation of the relationship of hypoglycemia and pulmonary edema. This occurred in a diabetic patient who had a hypoglycemic seizure. In a follow-up letter, Matz (Diabetes Care 23 (11): 1715. (2000)), pointed out a long forgotten association of non cardiac pulmonary edema as a consequence of grandmal seizures.
Thus in this case, given that the finding of hypoglycemia was real (see above), then hypoglycemia and seizure could still be underlying this.
Assumption 3. The Patient Did Have Cardiac Failure
In this case, the cardiovascular issues raised above again must be satisfied. If the glucose level was "real," then one can rarely see severe hypoglycemia with severe hepatic congestion and dysfunction. One always would be concerned about the possibility of ethanol with hypoglycemia and cardiac problems.
So given all the above, where does that leave us. At this point, the data you present does not help. Insulin levels, proinsulin and c-peptide will only help if they are drawn at the time of hypoglycemia. In addition, testing for sulfonylureas would need to be done, with specific request that glimepiride and meglitinides be tested as these are not checked for on the routine screening tests of the past.
Proactive testing at this point can be done with a formal 72 hour fast that would require hospitalization. 99% of patients with an insulinoma will reveal themselves during this time. Other tests, such as a 72 hour continuous glucose monitor can be done, but given the history here, it is unclear if that test would be as helpful.
After these tests, if hypoglycemia is found, the concurrent insulin, c-peptide, proinsulin, and cortisol levels should lead to a correct diagnosis.Robert J. Rushakoff, MD
Note added- Cymbalta has been associated with the �inappropriate ADH syndrome� which might be part of this problem but could not explain it all. What was her serum sodium? L DeG

ESTROGEN THERAPY IN GENDER DYSPHORIA 9/1/2006
QUESTION-I am an endocrinologist in private practice. I have a transgender pt (male to female) who received hormone therapy in Florida, as per the pt. Could you advise me in regards to the dose of E2 the pt is maintained on and what we specifically need to monitor. I understand the mammo should be done but is there anything I need to follow? I would very much appreciate your information. Thank you. Elise Kwon, M.D.
RESPONSE-I have done this for approximately 40-50 individuals. Before starting estrogen treatment, I get a Leiden V and a prothrombin G20210A gene screen. I will usually use a 0.1 mg estradiol transdermal patch which should give a 100-150 pg/mL estradiol level. This will be easy to measure if you want and will detect any cheating or overdosing by the patient. (This group often thinks that more estrogen is better). I also get a psychology consult with a clinician experienced in gender dysphoria evaluation before starting on estrogen therapy. James H. Liu, M.D. .

TESTING FOR ADRENAL INSUFFICIENCY
QUESTION-I am a first year Internal Medicine Resident at Rio de Janeiro, Brazil. In my ward there is a patient with Paracoccidioidomycosis which is a deep mycosis present predominantly in South American countries (around 80% of the cases report described in Brazil). Current recommendations support the screening for adrenal insuficciency in all patients since the adrenal gland is the third organ most involved in this disease. Our patient has severe symptomatic disease in the lungs, oral cavity and larynx but has no symptoms/signs or laboratory evidence of Addison's Disease (electrolyte disturbances, etc). Unfortunately our poor public resources do not allow us to use the high-dose short synacthen test (SST). My question is: in the absence of the SST what is the applicability of the Insulin Tolerance Test in diagnosing subclinical primary adrenal insufficiency or even manifest disease? Is it a valid test? And the other question is: is the low-dose SST a reliable test for the diagnosis of primary adrenal insufficiency or should it be reserved only for diagnosing secondary and tertiary adrenal failure? I have read this topic in a few places and I have not things clear in my mind yet. Andre Faria, MD
RESPONSE-The standard ACTH test is the best. The low dose ACTH would not be helpful. It should be used in research studies looking for subtle changes in adrenal function. The ITT is as good as the standard test but has risks. You might also contact Prof. Ayrton Moreira, University of Riberao Preto, on this topic. Best regards!
Dr George Chrousos

ELEVATED PROLACTIN NON-REPONSIVE TO CABERGOLINE 5 May 2006
QUESTION-I'm an argentine endocinologIst. I have a patient 18 years old young woman. She had her first menstruation at 14 y/o and was regular for 2 years. Then she started a secondary amenorrhea with PRL over 120 ng/ml. She consulted me on September 2005. I didn't find galactorrhea, the weight was normal (BMI 24), the genetic study was normal, the MRI in September showed a normal pituitary gland, except for a very little image suspicious, but not clear. The fractionated PRL was elevated in all the fragments. We start with cabergoline in crescent dose. At the present time, with 4mg of cabergoline, the MRI shows a decrease of pitutary size, PRLis 100 ng/ml and she is still amenorrheic as the only symptom. She shows some sign of emotional stress but refuses psychotherapy. How do I best manage this patient? Thank you for your attention and your advice. Forgive my poor english. Susana Nemas, MD. La Plata. Rep Argentina

RESPONSE-Thank you. This is a difficult problem. The initial prolactin with only a suspicion of a microprolactinoma raises the possibility of macroprolactin
interference in the assay, but I take your point on the 'prolactin fractions' to have excluded this possibility. If not, retesting the current prolactin after polyethylene glycol precipitation may reveal whether this all all monomeric prolactin. If it is, then the dose of cabergoline is already very high, so you could switch to an alternative drug such as quinagolide, although my experiece is that there is usually cross-resistance to all drugs. If the only problem is lack of menstruation then simply starting the oral contaceptive pill will provide regular menses and avoid the risk of osteoporosis, but regular rescanning is mandatory. Alternatively, a new high quality MRI should be discussed with an experienced transsphenoidal surgeon with a view to microadenomectomy. Ashley Grossman, MD