Hyperaldosteronism??  1/6/2018

Hyperaldosteronism??
QUESTION--I have a question about a patient who is showing abnormal lab values. She is 36 y/o female with history of hypertension postpartum at age 34 with no other past history. Her BP were ranging 160/70's-180/100s. She was put on Labetolol 200mg twice daily and her blood pressure are now ranging 115/60-130/70's. She does not have a significant family history of hypertension, early stroke or CAD. She had her Renin concentration and Aldosterone levels checked while on labetolol and came to me with following numbers:

1st check) Renin Concentration (not activity):  <2.0 microIU/mL  (2.8-39.9 )
Aldosterone Concentration:  308 pmol/L ( 118-946)

2nd Check) Renin: 2.5 microIU/mL  (2.8-46.1)
Aldosterone: 150 pmol/L (118-946)
A/R ratio: 60 pmol/L/microIU/mL (normal 90.99)

3rd check)  Renin: 2.7 microIU/mL (2.8-46.1)
Aldosterone: 313 pmol/L (118-946)
A/R ratio: 115 pmol/L/microIU/mL (normal 90.99)

4th Check) different lab, performed during follicular phase of menses
Renin 1.0 ng/L (2.8-46.1 )   Aldosterone 221 pmol/L (118-946 )
A/R ratio 221 pmol/ng (normal <53) Her K ranges in 4.5-5.0 and catecholamines and metanephrines are normal.

She has low renin, normal aldosterone, and elevated AR ratio each check and I am trying to figure out the next step?Should I try taking her off Labetolol as I read this can interfere with the hormone assay causing false elevation of AR ratio due to beta-adrenergic effect, switch to a non interfering BP medication, then check aldosterone and renin levels again?  Or should I just go straight for the salt loading test and check the urine Aldosterone and Na levels?

RESPONSE- Labetalol has beta 1/2 and alpha 1 receptor (ratio approx. 3:1) blocking effects.. In general, betablockers can reduce the concentrations of aldosterone and renin and may lead to a false elevation of the ARR. Central alpha blocking agents may also lead to an elevation of the ARR.
Taking a look at the Endocrine Society Guideline from 2016 on “The management of primary aldosteronism: case detection, diagnosis, and treatment. The Journal of Clinical Endocrinology & Metabolism, Volume 101, Issue 5, 1 May 2016, Pages 1889–1916’--
Tables 3, 4, and 5 nicely summarize important points in evaluating patients with possible primary aldosteronism. Table 3 depicts factors that may lead to false positive or false negative ARR results. Table 4 suggests an approach how to best measure the ARR including which medications to withdraw before measuring aldosterone and renin concentrations. Table 5 lists medications with minimal effects on plasma aldosterone levels that can control hypertension during case finding and confirmatory testing for primary aldosteronism.

Regarding the 4 checks on aldosterone and renin levels in this patient, the absolute aldosterone level certainly should be taken into account as well as the menstrual cycle. Plasma aldosterone concentrations measured during the menses or the proliferative phase are similar to those in men but rise briskly in the luteal phase. Renin levels are typically lower in premenopausal women, therefore the ARR higher than in men for all phases of the menstrual cycle. False positives can occur during the luteal phase if renin is measured as DirectRC and not PRActivity. To screen women at risk for primary aldo in the follicular phase is reasonable.

Looking at the absolute plasma aldosterone level in all 4 blood checks, the highest one was "only" approx. 11 ng/dL and the lowest one approx. 5 ng/dL, all measured while K was above 4 mmol.

I assume this patient did not have any clinical features of hypercortisolism and that a 1 mg dexamethasone suppression test had not been performed. Certainly, there could be mineralocorticoids other than aldosterone alone, i.e. DOC etc. which could stimulate the MR. However, I doubt that this patient does have "true" / pure primary aldosteronism / aldosterone excess. Obviously, the BP is controlled with the current antihypertensive and certainly, there are forms of "normotensive" PA in the spectrum of patients with PA.

One could certainly look at Table 4 of the Endocrine Society Guidelines and consider point 4a and then recheck the ARR. From a practical standpoint, my recommendation would be to perform the salt loading test and see if plasma / urinary aldosterone is suppressible (considering urinary Na).
Christian Koch, MD

 

 

 

HEALTHY  YOUNG  MAN WITH  ”LOWISH  FREE  T”,  NEEDING  TREATMENT?? 1/5/2018

HEALTHY  YOUNG  MAN WITH  ”LOWISH  FREE  T”,  NEEDING  TREATMENT??

QUESTION- I am an endocrinologist working in a small hospital in Somerset, UK. We are coming up against a testosterone related clinical issue as follows –
We are seeing a number of younger men who are requesting investigation for hypogonadism and coming up with low-ish testosterone levels. The issue relates to how to interpret the results in the context of our local assay. We use the Beckman Access Testosterone Assay that quotes a normal range (from the manufacturer and not age related) of 6.07-27nmol/l.
The case that I am struggling with at present illustrates the issue:  29 year old referred because of fertility issues and is requesting a testosterone prescription. He has non-specific symptoms such as tiredness, but no sweats and only occasional ED(possibly a slightly reduced libido).

Clinically he has no features of hypogonadism and has normal sized testes (25ml bilaterally).

His blood results are:
Total testosterones (9am samples) 6.7nmol/l, 6.9nmol/l and 5.1nmol/l
SHBG 10nmol/l (NR in the lab we use 10-50nml/l)
Albumin 46g/l
Calculated free testosterones 0.201nmol/l, 0.208nmol/l and 0.152nmol/l (using http://www.issam.ch/freetesto.htm )

The relevant pituitary function results are:  LH 7.4u/l, FSH 5.2u/l, PRL 178miu/l

Between appointments his partner has fallen pregnant(!). His semen analysis was 25- 30mill/ml but with 95% abnormal morphology.

My questions are:
1. Generally - the combined guidelines from the ASA, EAA, EAU, ISA, and ISSAM recommend obtaining free testosterone levels in men with total testosterone 8–12 nmol/L, with a suggested threshold of 225.4 pmol/L established as the lower range of normal. However, given our assay has a quoted normal range down to 6.07nmol/l, which is likely to be a reflection of a mixed age population of normals, we will not infrequently encounter men with low calculated free testosterone - are they really testosterone deficient?

  1. For the case above – Is the fact that he has fathered a child enough biological evidence to say that he does not need testosterone, or does the abnormal sperm morphology with the other softer features mean that a trial of therapy with close monitoring of testosterone would be the way forward?

I look forward to hearing from you.  Dr Alex Bickerton BM FRCP DPhil (Oxon),Yeovil District Hospital NHS Foundation Trust

RESPONSE--A 29-year-old man is referred because of fertility issues and was requesting a testosterone prescription. He has non-specific symptoms including tiredness, slightly reduced libido and occasional erectile dysfunction. Clinically he has no significant co-morbidities or features of hypogonadism. He is not obese and has 25ml testes bilaterally.

His morning serum hormone results are:

  • Total testosterone (9am samples) 6.7, 6.9 and 5.1nmol/l (1.93, 1.99, 1.48ng/ml)
    [Beckman Access Testosterone Assay, ref range 6.1-27nmol/l. = 1.76- 7.79 ng/ml]
  • SHBG 10nmol/l (Ref range 10-50nmol/l)
  • Albumin 46g/l
  • Calculated free testosterones 0.201, 0.208 and 0.152nmol/l (calculated using http://www.issam.ch/freetesto.htm )

Selected pituitary function tests are normal  LH 7.4 IU/l, FSH 5.2 IU/L, PRL 178 IU/L
Semen analysis: Sperm concentration was 30 million/ml with 5% normal morphology.

Between appointments his partner conceived has naturally!

 QUESTIONS RAISED:
Generally - the combined guidelines from the ASA, EAA, EAU, ISA, and ISSAM recommend obtaining free testosterone levels in men with total testosterone 8–12 nmol/L, with a suggested threshold of 225.4 pmol/L established as the lower range of normal. However, given our assay has a quoted normal range down to 6.07nmol/l, which is likely to be a reflection of a mixed age population of normal, we will not infrequently encounter men with low calculated free testosterone - are they really testosterone deficient?

 Comments
“Total T is the key’: All guidelines direct that the diagnosis of androgen deficiency (AD) be based on a synthesis of clinical features and confirmatory biochemistry, and rely on total testosterone (TT) as the key measure. One must take into account all these aspects and cannot use a parameter, such as free T, to exercise a ‘casting vote’. This measure is not analogous to free thyroid hormones and its place in clinical decision making is limited (underscoring the vague references to its use in the guidelines) and some would argue, non-existent. It can be well argued that the free T measure does not provide a better measure of androgen status than TT. Nonetheless its use has become widespread and it is now often provided without specific request and without validates reference ranges – this is extremely problematic as discussed below.

Consideration of free T measures is suggested when changes in SHBG are marked and in turn affect total testosterone levels and their interpretation. Mild elevation in SHBG levels is seen with ageing, but marked elevation is seen hyperthyroidism, liver disease and anti-epileptic therapies that are accompanied by elevated TT without evidence of androgen excess. Conversely SHBG levels are low in obesity, insulin resistance, and exposure to exogenous androgens, in which setting serum TT levels fall below the reference range, especially with normal serum LH and FSH, but do not confirm a diagnosis of androgen deficiency (1). An intrinsically low normal SHBG in this case probably accounts for the low range TT level but does not inform the diagnosis of AD and thus treatment.

 

There are different approaches to assessing free T with direct measure by equilibrium dialysis (EQ) being the most scientifically valid yet rarely available in practice. Estimated (calculated) free T measures are based on various formulae that use TT, SHBG and albumen levels along with assumptions about binding affinities. Close examination shows that the correlate reasonably well with EQ free T yet generate significantly different values using the same primary data (2).

In all formulae, the TT estimate has the major effect on the calculated free T readout; this raises the next problem, of how well are TT assays standardised?  The news here is not good; there is considerable variability in TT levels between immunoassay platforms when applied to identical samples. As a demonstration, we studied reproductively normal young men (normal testes and semen analysis), the reference range for TT using mass spectrometry was 10.4-30.1 nmol/L but the lower limit of the reference ranges across 7 commercial immunoassay methods ranged from 7.3 to 12.1nM! (3)  There is inherent variability between immunoassay platforms (3,4) yet they dominate commercial laboratories due to their high throughput and low cost. There is a global movement toward quantitative approaches, specifically mass spectroscopy [MS] and these are becoming more available, despite the high set up costs.  Given that calculated free T is highly dependent upon the TT values, any attempt at a consensus lower limit figure, [such as 225pmol/L] is a ‘rubbery’ figure indeed!

Perhaps it is also worth reflecting on TT reference intervals: what is a healthy normal TT?  Currently laboratories report a ‘one size fits all’ interval for normal men, irrespective of age, adiposity and co-morbidities. While this patient is young, issue often arise in middle aged and older men.  It is becoming clear that the age-related decline in serum testosterone is primarily a result of the accumulation of co-morbidities with age, especially obesity which is the major determinant of serum T within population.  No decline was seen in serum TT of healthy aging men (5) and there is little objective support for an intrinsic decline in the HPT axis function in male ageing (the so called ‘andropause’).  The European Male Ageing Study (EMAS) shows this impact if obesity: across middle aged and older men, obese men (BMI > 30) have serum T level ~ 6 nM lower than their lean peers (6). One encounters many obese and/or diabetic men with TT below the reference range; a low SHBG may result in a normal, or at least somewhat higher, calculated free T. There is no way of knowing but the inclusion of older men with co-morbidities may account for the low end reference value of 6.07nmol/L in the questioner’s lab although a recent study very healthy men aged 70-89 years, provided a reference range using mass spectrometry of 6.4-25.7 nmol/L (7).

It is clear that in are many men presenting for evaluation of possible androgen deficiency, TT levels will be below that provided in the kit manufacturer package insert emphasising the need for clinical judgment and not simply to rely on a numerical threshold.

In this particular case, there seems no evidence of androgen deficiency. He is clinically well virilised, demonstrably fertile and has normal testes. Objective tissue markers of androgen action include haemoglogin and bone density would likely confirm eugonadism.  His SHBG falls in the lower end of normal and appears not to reflect any pathological process but substantially explains his low range TT. The calculated free TT value of ~200pmol/L which is around the lower range of normal and does not add to the clinical management.  His symptoms may reflect an entirely different process.

  1. Is the fact that he has fathered a child enough biological evidence to say that he does not need testosterone, or does the abnormal sperm morphology with the other softer features mean that a trial of therapy with close monitoring of testosterone would be the way forward?

This question has two components:
2.1   No, infertile men with subnormal semen quality may have normal or low TT levels: an elevated serum LH being indicative of primary AD due to testicular failure. Conversely, many men with poor semen quality may conceive naturally; around 30% of couples get pregnant with sperm concentration in the 1-5 million/ml range. Thus one cannot conflate the issues of androgen deficiency (Leydig cell function) and fertility (spermatogenesis).  Although making it much less likely, the fact that he caused a natural conception does not mean he could not have been androgen deficient. But in this case, he has normal semen, normal sized testes, mid normal gonadotropins and low-normal TT, SHBG and free T.

2.1   I don’t exactly follow this proposition. I do not see any indication for a ‘trial’ of testosterone therapy as this man does not have demonstrated testicular or pituitary problems and is clinically eugonadal. Also, testosterone is a potent contraceptive and is contraindicated in men seeking fertility. One does not know the outcome of the current pregnancy nor whether subsequent ones are planned.  Exogenous testosterone will suppress LH, FSH and sperm output and testis size will fall.  His sperm morphology is of no importance and ‘softer testes’ (noting they are 25 ml in volume) is a subjective parameter which would not direct management. Thus I would re assure him re his male hormonal status and see no need for treatment or ongoing review in this regard.

Prof  Robert McLachlan   1/5/2018

 References
1 Yeap BB, Grossmann M, McLachlan RI et al Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy. Med J Aust. 2016 ;205:173-8.
2   Ly LP, Sartorius G, Hull L, et al. Accuracy of calculated free testosterone formulae in men. Clin Endocrinol 2010; 73(3): 382-388.

3   Sikaris K, McLachlan RI, Kazlauskas R, et al. Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays. J Clin Endocrinol Metab 2005; 90(11): 5928-5936.

4   Taieb J, Mathian B, Millot F, et al. Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children. Clin Chem 2003; 49(8): 1381-1395.

5   Sartorius G, Spasevska S, Idan A, et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin Endocrinol 2012; 77(5): 755-763.

6   Wu FC1, Tajar A, Pye SR et al   Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab. 2008;93(7):2737-45

7   Yeap BB, Alfonso H, Chubb SA, et al. Reference ranges and determinants of testosterone, dihydrotestosterone, and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men. J Clin Endocrinol Metab 2012; 97(11): 4030-4039.

26 YEAR OLD WOMAN WITH THREE YEARS OF AMENNORRHEA 1/2/2018

26 year-old woman with three years of amennorrhea

QUESTION-26 year-old woman presents with three years of amenorrhea. Menarche was at age 13 with initially irregular menses that ultimately normalized by late teens. Her cycles lengthened over a period of one year, around age 22-23 and she has been completely amenorrheic since, without any irregular bleeding. She has had eight negative progesterone withdrawal challenges, but did bleed on OCPs, which she did not tolerate due to side effects.

Patient complains of vaginal dryness, marked reduction in breast volume, and loss of libido. Denies hot flashes. Patient has normal BMI of 21, albeit with some weight fluctuation of approximately 6 kg. She does not do any vigorous exercise and denies mood symptoms. No family history of infertility, irregular menses, hirsutism, male-pattern baldness. Family history of hyper- and hypothyroidism.

Physical exam shows healthy Tanner stage 5 female of normal stature (161 cm) without any notable abnormalities. Normal breast morphology.

Labs obtained at various timepoints over the past three years have shown undetectable and low estradiol (20 to 32) with generous LH at 27.8, FSH 10.3. Repeat showed LH of 15.6, FSH 8.8 with estradiol undetectable throughout. Progesterone 0.14 ng/mL. DHEA-S mildly elevated at 391, repeat was 377. Androstenedione mildly elevated at 346. Total testosterone 41 ng/dL. AMH is elevated to 12 ng/mL. Inhibin B 80 pg/mL. SHBG 57 nmol/L. 17-OH-P normal at 70 ng/dL. TSH normal. AM cortisol 10.5. Normal prolactin. Negative 21-hydroxylase antibodies. Normal 2-hr OGTT.

TVUS showed an endometrial lining of 7 mm and normal ovarian volume showing multiple nondominant follicles.

Patient was given a diagnosis of PCOS. However, it does not seem fitting that her gonadotropins are relatively high given her level of estradiol and symptomatic hypoestrogenemia. POF does not fit with her normal inhibin B and elevated AMH, but could this be a partial gonadotropin resistance? Her timeline seems consistent with cases of resistant ovary syndrome in the literature. Can aromatase deficiency be acquired? Are there any other autoimmune etiologies that might be reasonable to work up? She has been started on HRT for her symptoms. Lilly Chan,MD, MA,

RESPONSE-Because I have not seen a case such as this, I consulted some of my colleagues. My thoughts coincide with theirs, and one told me that he has seen a few similar patients.

Basically it is probable that this patient has PCOS with an overlying hypothalamic component. Thus it would make sense to explore her emotional and social situations, her diet, and her exercise patterns in more detail. It makes sense to provide estrogen in some form with the recognition that she will still have PCOS with any resolution of the hypothalamic disturbance. There is often an overlap between PCOS and functional hypothalamic amenorrhea (FHA). As she recovers her axis, she may or may not develop more features of PCOS as several patients have - some have not (as reported to me).

For now I would just treat her as an FHA patient with lower dose HT. I would stop the estrogen with unscheduled bleeding or after 6 months to a year just to retest the axis.

I always worry that the overlying condition may be a physical abnormality of the hypothalamus and the least expensive form of imaging available to you may well be warranted to rule out an actual lesion. The chances of such a lesion are probably remote.   Robert Rebar, MD