Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline.

Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline.
Stuenkel CA1, Davis SR1, Gompel A1, Lumsden MA1, Murad MH1, Pinkerton JV1, Santen RJ1.
J Clin Endocrinol Metab. 2015 Nov;100(11):3975-4011.
Menopausal hormone therapy (MHT) is the most effective treatment for vasomotor symptoms and other symptoms of the climacteric. Benefits may exceed risks for the majority of symptomatic postmenopausal women who are under age 60 or under 10 years since the onset of menopause. Health care professionals should individualize therapy based on clinical factors and patient preference. They should screen women before initiating MHT for cardiovascular and breast cancer risk and recommend the most appropriate therapy depending on risk/benefit considerations. Current evidence does not justify the use of MHT to prevent coronary heart disease, breast cancer, or dementia. Other options are available for those with vasomotor symptoms who prefer not to use MHT or who have contraindications because these patients should not use MHT. Low-dose vaginal estrogen and ospemifene provide effective therapy for the genitourinary syndrome of menopause, and vaginal moisturizers and lubricants are available for those not choosing hormonal therapy. All postmenopausal women should embrace appropriate lifestyle measures.
COMMENT-A very important and thorough study that basically rewrites much of medical advice given for a couple of decades, and that will have enormous impact on treatment menopasal women


Evaluation of 451 danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. Lawaetz JG1, Hagen CP, Mieritz MG, Blomberg Jensen M, Petersen JH, Juul A. J Clin Endocrinol Metab. 2015 Apr;100(4):1376-85.

Few data exist on the diagnostic criteria, and on the effects of puberty induction, in boys with constitutional delay in growth and puberty (CDGP). To evaluate the different diagnostic criteria and the effect of oral testosterone undecanoate (TU) in boys with CDGP. The authors performed a cross-sectional and longitudinal study of Danish boys with normal pubertal development and a retrospective observational study of 451 boys evaluated for delayed puberty between 1990 and 2013.
Seventy-eight (27%) of the 287 boys had delayed pubertal onset according to the classical criteria, whereas 173 (60%) of the 287 boys had impaired pubertal progression according to the puberty nomogram. Ninety-six (56%) of these 173 boys were treated with oral TU for 0.8 years (0.5; 1.3) [median (25th; 75th percentiles)], which resulted in beneficial effects on pubertal progression. Height increased from -1.9 SD (-2.5; -1.2) to -1.5 SD (-2.1; -0.7) (P < .001), and PAH increased from 172.3 cm (170.3; 182.8) to 178.1 cm (171.4; 191.7) (P = .001) following one year of treatment.

The puberty nomogram evaluates both delayed pubertal onset as well as delayed pubertal progression and allows separation of normal versus abnormal pubertal development. Oral TU treatment was followed by pubertal induction and progression and short-term growth without  compromising final height.

Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement

Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the fourth international workshop. Bilezikian JP 1, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9.
In view of new findings since the last International Workshop on the Management of Asymptomatic PHPT, guidelines for management have been revised. The revised guidelines include: 1) recommendations for more extensive evaluation of the skeletal and renal systems; 2) skeletal and/or renal involvement as determined by further evaluation to become part of the guidelines for surgery; and 3) more specific guidelines for monitoring those who do not meet guidelines for parathyroid surgery.

Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. Eastell R 1, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV. J Clin Endocrinol Metab. 2014 Oct;99(10):3570-9
We conclude that: 1) reference ranges should be established for serum PTH in vitamin D-replete healthy individuals; 2) second- and third-generation PTH assays are both helpful in the diagnosis of PHPT; 3) normocalcemic PHPT is a variant of the more common presentation of PHPT with hypercalcemia; 4) serum 25-hydroxyvitamin D concentrations should be measured and, if vitamin D insufficiency is present, it should be treated as part of any management course; 5) genetic testing has the potential to be useful in the differential diagnosis of familial hyperparathyroidism or hypercalcemia.

Medical management of primary hyperparathyroidism: proceedings of the fourth international workshop on the management of asymptomatic primary hyperparathyroidism. Marcocci C 1, Bollerslev J, Khan AA, Shoback DM  J Clin Endocrinol Metab. 2014 Oct;99(10):3607-18
The recommended calcium intake in patients with PHPT should follow guidelines established for all individuals. It is not recommended to limit calcium intake in patients with PHPT who do not undergo surgery. Patients with low serum 25-hydroxyvitamin D should be repleted with doses of vitamin D aiming to bring serum 25-hydroxyvitamin D levels to ≥ 50 nmol/L (20 ng/mL) at a minimum, but a goal of ≥75 nmol/L (30 ng/mL) also is reasonable. Pharmacological approaches are available and should be reserved for those patients in whom it is desirable to lower the serum calcium, increase BMD, or both. For the control of hypercalcemia, cinacalcet is the treatment of choice. Cinacalcet reduces serum calcium concentrations to normal in many cases, but has only a modest effect on serum PTH levels. However, bone mineral density (BMD) does not change. To improve BMD, bisphosphonate therapy is recommended. The best evidence is for the use of alendronate, which improves BMD at the lumbar spine without altering the serum calcium concentration. To reduce the serum calcium and improve BMD, combination therapy with both agents is reasonable, but strong evidence for the efficacy of that approach is lacking

Androgen therapy in women: a reappraisal: an endocrine society clinical practice guideline.

Androgen therapy in women: a reappraisal: an endocrine society clinical practice guideline. Wierman ME 1, Arlt W, Basson R, Davis SR, Miller KK, Murad MH, Rosner W, Santoro N. J Clin Endocrinol Metab. 2014 Oct;99(10):3489-510
We continue to recommend against making a diagnosis of androgen deficiency syndrome in healthy women because there is a lack of a well-defined syndrome, and data correlating androgen levels with specific signs or symptoms are unavailable. We recommend against the general use of T for the following indications: infertility; sexual dysfunction other than hypoactive sexual desire disorder; cognitive, cardiovascular, metabolic, or bone health; or general well-being. We recommend against the routine use of dehydroepiandrosterone due to limited data concerning its effectiveness and safety in normal women or those with adrenal insufficiency. We recommend against the routine prescription of T or dehydroepiandrosterone for the treatment of women with low androgen levels due to hypopituitarism, adrenal insufficiency, surgical menopause, pharmacological glucocorticoid administration, or other conditions associated with low androgen levels because there are limited data supporting improvement in signs and symptoms with therapy and no long-term studies of risk. Evidence supports the short-term efficacy and safety of high physiological doses of T treatment of postmenopausal women with sexual dysfunction due to hypoactive sexual desire disorder. Importantly, endogenous T levels did not predict response to therapy. At present, physiological T preparations for use in women are not available in many countries including the United States, and long-term safety data are lacking. We recommend that any woman receiving T therapy be monitored for signs and symptoms of androgen excess.
Ongoing improvement in androgen assays will allow a redefinition of normal ranges across the lifespan; this may help to clarify the impact of varying concentrations of plasma androgens on the biology, physiology, and psychology in women and lead to indications for therapeutic interventions.

The Benefits and Harms of Systemic Testosterone Therapy in Postmenopausal Women With Normal Adrenal Function: A Systematic Review and Meta-analysis.Elraiyah T 1, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Firwana B, Altayar O, Prokop L, Montori VM, Murad MH. J Clin Endocrinol Metab. 2014 Oct;99(10):3543-50
T use was associated with statistically significant improvement in various domains of sexual function and personal distress in postmenopausal women, although the majority of the trials did not have specific or contemporary diagnostic criteria for androgen deficiency in women. T use was also associated with a reduction in total cholesterol, triglyceride, and high-density lipoprotein and an increase in low-density lipoprotein and in the incidence of acne and hirsutism. No significant effect was noted on anthropometric measures and bone density. Long-term safety data were sparse, and the quality of such evidence was low.

The Benefits and Harms of Systemic Dehydroepiandrosterone (DHEA) in Postmenopausal Women With Normal Adrenal Function: A Systematic Review and Meta-analysis.Elraiyah T 1, Sonbol MB, Wang Z, Khairalseed T, Asi N, Undavalli C, Nabhan M, Altayar O, Prokop L, Montori VM, Murad MH. J Clin Endocrinol
In 23 RCTs with moderate to high risk of bias enrolling 1188 women, DHEA use was not associated with significant improvement in libido or sexual function (standardized mean difference, 0.35; 95% confidence interval, -0.02 to 0.73; P value = .06; I(2) = 62%). There was also no significant effect of DHEA on serious adverse effects, serum lipids, serum glucose, weight, body mass index, or bone mineral density.
Evidence warranting low confidence suggests that DHEA administration does not significantly impact sexual symptoms or selected metabolic markers in postmenopausal women with normal adrenal function.



Peripheral monocytes of obese women display increased chemokine receptor expression and migration capacity. Krinninger P1, Ensenauer R, Ehlers K, Rauh K, Stoll J, Krauss-Etschmann S, Hauner H, Laumen H. J Clin Endocrinol Metab. 2014 Jul;99(7):2500-9
The activation of peripheral immune cells and the infiltration of immune cells into adipose tissue in obesity are implicated in the development of type 2 diabetes mellitus. In this study peripheral immune cells from obese and normal-weight women were compared with regard to composition of immune cell subpopulations, surface expression of the chemokine receptors (CCRs) CCR2, CCR3, CCR5, and CXCR3 (chemokine (C-X-C motif) receptor 3) and cell-intrinsic migration capacity. Obese females and normal-weight females were included for fluorescence-activated cell sorting analysis and migration assays. Peripheral blood mononuclear cells were prepared from fasting blood samples. An increase in the percentages of CD14(+)CD16(+) monocytes was observed in obese subjects compared with controls. The CCR profile of monocytes differed significantly in the obese state; in particular, CCR2 levels were increased. In addition, a higher chemotactic activity of monocytes from obese subjects was observed in a migration assay, which was associated with both insulin resistance and CCR2 expression. Conclusion: The results suggest that the enhanced intrinsic migratory capacity of peripheral monocytes in obese women may be due to the increased CCR expression, further supporting a link between peripheral immune cell dysfunction and obesity.
COMMENT-The obese subjects had an increased proportion of CD14+CD16+ circulating monocytes, that can secrete pro-inflammatory cytokines on activation. This, along with other evidence, supports a role for general immune activation as part of the low-grade inflammatory process seen in adipose tissue in obesity.

Bacterial DNA translocation holds increased insulin resistance and systemic inflammatory levels in morbid obese patients.Ortiz S1, Zapater P, Estrada JL, Enriquez P, Rey M, Abad A, Such J, Lluis F, Francés R. J Clin Endocrinol Metab. 2014 Jul;99(7):2575-83
Morbidly obese patients show several common comorbidities associated with immunological alterations such as a sustained low-level proinflammatory profile. Bacterial product translocation is frequent in inflammation-related diseases and may aggravate patients' clinical outcome. Consecutively admitted morbidly obese patients who presented indications for bariatric surgery were studied. Before surgery, patients were subjected to a modified fasting diet. Patients (58) underwent surgery by sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass. Blood samples were collected at baseline, at the end of a 3-month modified fasting period, and 3, 6, and 12 months after surgery. Serum cytokine and endotoxin levels were evaluated by flow cytometry and ELISA, respectively. Bacterial DNA was identified in blood by broad-range PCR of prokaryote 16SrRNA gene and partial sequencing analysis.
All patients showed a significantly reduced weight and body mass index at each time-point. Postoperative mortality was null. Bacterial DNA translocation rate was 32.8% (19 of 58) at baseline; 13.8% (8 of 58) after the modified fasting period; and 13.8% (8 of 58), 1.8% (1 of 58), and 5.2% (3 of 58) at 3, 6, and 12 months after surgery. Proinflammatory cytokines, serum endotoxin levels, and insulin resistance remained increased in patients with bacterial DNA despite weight loss and were individually affected by the appearance/clearance of bacterial DNA in blood. Multivariate analyses revealed bacterial DNA as an independent significant factor, explaining the systemic cytokine response and the insulin resistance levels in the studied population. Bacterial DNA translocation “holds” increased insulin resistance and systemic inflammatory levels in morbidly obese patients despite significant weight loss.
COMMENT- This study indicates that gut bacterial DNA is at least transiently present in blood of 30% of obese indiviuals, and is related to the low-grade inflammatory state of morbid obesity. While inflammatory markers generally declined after surgery, their persistence was associatecd with maintenance of the inflammatory state.

Current and Evolving Approaches to Individualizing Estrogen Receptor-Based Therapy for Menopausal Women

Santen RJ1,Kagan R, Altomare CJ,Komm B, Mirkin S,Taylor HS. J Clin Endocrinol Metab. 2014 Jan 1:jc20133680 PMID:24423357
Adding progestogens to estrogens changes the risk profile of hormonal therapy for menopausal women, and recent data support the need for progestogen-free options. Several current
and evolving approaches to managing estrogen deficiency allow for progestogen
omission. We review the mechanisms of estrogen activity and provide an overview
of emerging and available estrogen receptor (ER)-based therapies. Advances in
our understanding of ER pharmacology have led to therapies designed to optimize
ER activity, including selective-estrogen receptor modulators (SERMs) and
tissue-selective estrogen complexes (TSECs). Each estrogen, SERM, and TSEC
exhibits a unique profile of tissue-specific activity, spanning the spectrum
from ER agonism to antagonism. Systemic estrogens unopposed by progestogens
effectively manage menopausal symptoms in hysterectomized postmenopausal women
but require progestogen use in postmenopausal women with a uterus. SERMs are
effective for managing certain aspects of estrogen deficiency in postmenopausal
women, but data suggest pairing a SERM with estrogens to form a TSEC provides a
more optimal therapeutic profile for women with a uterus. Treating signs and
symptoms of estrogen deficiency requires an individualized approach based on a
woman's goals and the purported risks of different therapies. New and emerging
agents have demonstrated efficacy in postmenopausal women with a uterus, while
allowing these women to avoid progestogens and their possible adverse effects.
Comment- This review offers an extensive contemporary analysis of approaches to
treating menopausal symptoms, and is valuable read for anyone managing such


ARMC5 mutations in macronodular adrenal hyperplasia with Cushing's syndrome.
Assié G, Libé R, Espiard S, Rizk-Rabin M, Guimier A, Luscap W, Barreau O, Lefèvre L, Sibony M, Guignat L, Rodriguez S, Perlemoine K, René-Corail F, Letourneur F, Trabulsi B, Poussier A, Chabbert-Buffet N, Borson-Chazot F, Groussin L, Bertagna X, Stratakis CA, Ragazzon B, Bertherat . N Engl J Med. 2013 Nov 28;369(22):2105-14.
Corticotropin-independent macronodular adrenal hyperplasia may be an incidental finding or it may be identified during evaluation for Cushing's syndrome. Reports of familial cases and the involvement of both adrenal glands suggest a genetic origin of this condition.
We genotyped blood and tumor DNA obtained from 33 patients with corticotropin-independent macronodular adrenal hyperplasia (12 men and 21 women who were 30 to 73 years of age), using single-nucleotide polymorphism arrays, microsatellite markers, and whole-genome and Sanger sequencing. The effects of armadillo-repeat-containing-5 (ARMC5) inactivation and overexpression were tested in cell-culture models.
The most frequent somatic chromosome alteration was loss of heterozygosity at 16p (in 8 of 33 patients for whom data were available [24%]). The most frequent mutation identified by means of whole-genome sequencing was in ARMC5, located at 16p11.2. ARMC5 mutations were detected in tumors obtained from 18 of 33 patients (55%). In all cases, both alleles of ARMC5 carried mutations: one germline and the other somatic. In 4 patients with a germline ARMC5 mutation, different nodules from the affected adrenals harbored different secondary ARMC5 alterations. Transcriptome-based classification of corticotropin-independent macronodular adrenal hyperplasia indicated that ARMC5 mutations influenced gene expression, since all cases with mutations clustered together. ARMC5 inactivation decreased steroidogenesis in vitro, and its overexpression altered cell survival.Some cases of corticotropin-independent macronodular adrenal hyperplasia appear to be genetic, most often with inactivating mutations of ARMC5, a putative tumor-suppressor gene. Genetic testing for this condition, which often has a long and insidious prediagnostic course, might result in earlier identification and better management.

Intraadrenal corticotropin in bilateral macronodular adrenal hyperplasia
Louiset E, Duparc C, Young J, Renouf S, Tetsi Nomigni M, Boutelet I, Libé R, Bram Z, Groussin L, Caron P, Tabarin A, Grunenberger F, Christin-Maitre S, Bertagna X, Kuhn JM, Anouar Y, Bertherat J, Lefebvre H. N Engl J Med. 2013 Nov 28;369(22):2115-25
Bilateral macronodular adrenal hyperplasia is a rare cause of primary adrenal Cushing's syndrome. In this form of hyperplasia, hypersecretion of cortisol suppresses the release of corticotropin by pituitary corticotrophs, which results in low plasma corticotropin levels. Thus, the disease has been termed corticotropin-independent macronodular adrenal hyperplasia. We examined the abnormal production of corticotropin in these hyperplastic adrenal glands.
We obtained specimens of hyperplastic macronodular adrenal tissue from 30 patients with primary adrenal disease. The corticotropin precursor proopiomelanocortin and corticotropin expression were assessed by means of a polymerase-chain-reaction assay and immunohistochemical analysis. The production of corticotropin and cortisol was assessed in 11 specimens with the use of incubated explants and cell cultures coupled with hormone assays. Corticotropin levels were measured in adrenal and peripheral venous blood samples from 2 patients.
The expression of proopiomelanocortin messenger RNA (mRNA) was detected in all samples of hyperplastic adrenal tissue. Corticotropin was detected in steroidogenic cells arranged in clusters that were disseminated throughout the adrenal specimens. Adrenal corticotropin levels were higher in adrenal venous blood samples than in peripheral venous samples, a finding that was consistent with local production of the peptide within the hyperplastic adrenals. The release of adrenal corticotropin was stimulated by ligands of aberrant membrane receptors but not by corticotropin-releasing hormone or dexamethasone. A semiquantitative score for corticotropin immunostaining in the samples correlated with basal plasma cortisol levels. Corticotropin-receptor antagonists significantly inhibited in vitro cortisol secretion.Cortisol secretion by the adrenals in patients with macronodular hyperplasia and Cushing's syndrome appears to be regulated by corticotropin, which is produced by a subpopulation of steroidogenic cells in the hyperplastic adrenals.
The hypercortisolism associated with bilateral acronodular adrenal hyperplasia appears to be corticotropin-dependent.


Bariatric Surgery versus Conventional Medical Therapy for Type 2 Diabetes

Mingrone G, Panunzi S, De Gaetano A, Guidone C, Iaconelli A, Leccesi L, Nanni G, Pomp A, Castagneto M, Ghirlanda G, Rubino F. N Engl J Med. 2012 Mar 26. [Epub ahead of print]

Background Roux-en-Y gastric bypass and biliopancreatic diversion can markedly ameliorate diabetes in morbidly obese patients, often resulting in disease remission. Prospective, randomized trials comparing these procedures with medical therapy for the treatment of diabetes are needed. Methods In this single-center, nonblinded, randomized, controlled trial, 60 patients between the ages of 30 and 60 years with a body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) of 35 or more, a history of at least 5 years of diabetes, and a glycated hemoglobin level of 7.0% or more were randomly assigned to receive conventional medical therapy or undergo either gastric bypass or biliopancreatic diversion. The primary end point was the rate of diabetes remission at 2 years (defined as a fasting glucose level of

Comment-While the side effects of bariatric surgery are not insignificant (see chapter 20 in OBESITEXT) the dramatic results of this randomized trial are sure to send many more patients to surgery.

Update in hormone therapy use in menopause

J Clin Endocrinol Metab. 2011 Feb;96(2):255-64. Taylor HS, Manson JE.

Division of Reproductive Endocrinology and Infertility, Yale University School of Medicine, New Haven, Connecticut06520,.

The original report from the Women's Health Initiative (WHI) changed our understanding of the benefits and risks of hormone therapy. Since that time, reanalysis of the WHI and additional data from other studies have further refined these concepts. Here we provide an update on recent advances in the field. Menopausal hormone therapy continues to have a clinical role in the management of vasomotor symptoms. However, our understanding of the role of hormones in cardiovascular disease and breast cancer continues to evolve. Further analyses of the effect of age and proximity to menopause at the time of initiation of therapy, duration of treatment, dose, route of administration, and the persistence of risks and benefits after stopping hormone therapy are described. In addition, recent data have emerged suggesting that there may be a link between hormone therapy and cancers of the lung and ovary. Finally, we discuss new advances in hormone therapy that will likely lead to a more favorable benefit-to-risk ratio, enabling safer effective menopausal symptom relief.

This is an extensive review of all pros and cons of menopausal hormonal therapy.