Abstract: The Mediterranean Diet (MD) has been associated with reduced mortality and risk of cardiovascular diseases, but there is only limited evidence on cancer. We investigated the relationship between adherence to MD and risk of postmenopausal breast cancer (and estrogen/progesterone receptor subtypes, ER/PR). In the Netherlands Cohort Study, 62,573 women aged 55–69 years provided information on dietary and lifestyle habits in 1986. Follow-up for cancer incidence until 2007 (20.3 years) consisted of record linkages with the Netherlands Cancer Registry and the Dutch Pathology Registry PALGA. Adherence to MD was estimated through the alternate Mediterranean Diet Score excluding alcohol. Multivariate case–cohort analyses were based on 2,321 incident breast cancer cases and 1,665 subcohort members with complete data on diet and potential confounders. We also conducted meta-analyses of our results with those of other published cohort studies. We found a statistically significant inverse association between MD adherence and risk of ER negative (ER−) breast cancer, with a hazard ratio of 0.60 (95% Confidence Interval, 0.39–0.93) for high versus low MD adherence (ptrend = 0.032). MD adherence showed only nonsignificant weak inverse associations with ER positive (ER+) or total breast cancer risk. In meta-analyses, summary HRs for high versus low MD adherence were 0.94 for total postmenopausal breast cancer, 0.98 for ER+, 0.73 for ER− and 0.77 for ER − PR− breast cancer. Our findings support an inverse association between MD adherence and, particularly, receptor negative breast cancer. This may have important implications for prevention because of the poorer prognosis of these breast cancer subtypes.

Piet A. van den Brandt, Maya Schulpen

First published: 5 March 2017

DOI: 10.1002/ijc.30654


Controversy exists regarding the safety of testosterone replacement therapy (TRT) following recent reports of an increased risk of adverse cardiovascular events.

To investigate the association between TRT and cardiovascular outcomes in men with androgen deficiency.

A retrospective cohort study was conducted within an integrated health care delivery system. Men at least 40 years old with evidence of androgen deficiency either by a coded diagnosis and/or a morning serum total testosterone level of less than 300 ng/dL were included. The eligibility window was January 1, 1999, to December 31, 2010, with follow-up through December 31, 2012.

Any prescribed TRT given by injection, orally, or topically.

The primary outcome was a composite of cardiovascular end points that included acute myocardial infarction (AMI), coronary revascularization, unstable angina, stroke, transient ischemic attack (TIA), and sudden cardiac death (SCD). Multivariable Cox proportional hazards models were used to investigate the association between TRT and cardiovascular outcomes. An inverse probability of treatment weight, propensity score methodology, was used to balance baseline characteristics.

The cohorts consisted of 8808 men (19.8%) ever dispensed testosterone (ever-TRT) (mean age, 58.4 years; 1.4% with prior cardiovascular events) and 35 527 men (80.2%) never dispensed testosterone (never-TRT) (mean age, 59.8 years; 2.0% with prior cardiovascular events). Median follow was 3.2 years (interquartile range [IQR], 1.7-6.6 years) in the never-TRT group vs 4.2 (IQR, 2.1-7.8) years in the ever-TRT group. The rates of the composite cardiovascular end point were 23.9 vs 16.9 per 1000 person-years in the never-TRT and ever-TRT groups, respectively. The adjusted hazard ratio (HR) for the composite cardiovascular end point in the ever-TRT group was 0.67 (95% CI, 0.62-0.73. Similar results were seen when the outcome was restricted to combined stroke events (stroke and TIA) (HR, 0.72; 95% CI, 0.62-0.84) and combined cardiac events (AMI, SCD, unstable angina, revascularization procedures) (HR, 0.66; 95% CI, 0.60-0.72).

Among men with androgen deficiency, dispensed testosterone prescriptions were associated with a lower risk of cardiovascular outcomes over a median follow-up of 3.4 years.

JAMA internal medicine. 2017 Feb 21 [Epub ahead of print]

T Craig Cheetham, JaeJin An, Steven J Jacobsen, Fang Niu, Stephen Sidney, Charles P Quesenberry, Stephen K VanDenEeden

Southern California Permanente Medical Group, Department of Research & Evaluation, Pasadena., Western University of Health Sciences, Pharmacy Practice and Administration, Pomona, California., Kaiser Permanente Southern California, Drug Information Service, Downey., Kaiser Permanente Northern California, Division of Research, Oakland.



Abstract | Introduction: The female sexual response is complex and influenced by several biological, psychological, and social factors. Testosterone is believed to modulate a woman’s sexual response and desire, because low levels are considered a risk factor for impaired sexual function, but previous studies have been inconclusive.

Aim: To investigate how androgen levels and psychosocial factors are associated with female sexual dysfunction (FSD), including hypoactive sexual desire disorder (HSDD).

Methods: The cross-sectional study included 428 premenopausal women 19 to 58 years old who completed a questionnaire on psychosocial factors and had blood sampled at days 6 to 10 in their menstrual cycle. Logistic regression models were built to test the association among hormone levels, psychosocial factors, and sexual end points.

Main Outcome Measures: Five different sexual end points were measured using the Female Sexual Function Index and the Female Sexual Distress Scale: impaired sexual function, sexual distress, FSD, low sexual desire, and HSDD. Serum levels of total and free testosterone, androstenedione, dehydroepiandrosterone sulfate, and androsterone glucuronide were analyzed using mass spectrometry.

Results: After adjusting for psychosocial factors, women with low sexual desire had significantly lower mean levels of free testosterone and androstenedione compared with women without low sexual desire. None of the androgens were associated with FSD in general or with HSDD in particular. Relationship duration longer than 2 years and mild depressive symptoms increased the risk of having all the sexual end points, including FSD in general and HSDD in particular in multivariate analyses.

Conclusion: In this large cross-sectional study, low sexual desire was significantly associated with levels of free testosterone and androstenedione, but FSD in general and HSDD in particular were not associated with androgen levels. Length of relationship and depression were associated with FSD including HSDD.

Wåhlin-Jacobsen S, Kristensen E, Tønnes Pedersen A, et al. Androgens and Psychosocial Factors Related to Sexual Dysfunctions in Premenopausal Women. J Sex Med 2017;14:366–379.

Sarah Wåhlin-Jacobsen, MD’Correspondence information about the author MD Sarah Wåhlin-JacobsenEmail the author MD Sarah Wåhlin-Jacobsen, Ellids Kristensen, MD, Anette Tønnes Pedersen, MD, PhD, Nanna Cassandra Laessøe, MD, Arieh S. Cohen, PhD, David M. Hougaard, MD, DMSc, Marika Lundqvist, MSc, Annamaria Giraldi, MD, PhD



Abstract | Context: Findings of studies of testosterone’s effects on muscle strength and physical function in older men have been inconsistent; its effects on muscle power and fatigability have not been studied.

Objective: To determine the effects of testosterone administration for 3 years in older men on muscle strength, power, fatigability, and physical function.

Design, Setting, and Participants: This was a double-blind, placebo-controlled, randomized trial of healthy men ≥60 years old with total testosterone levels of 100 to 400 ng/dL or free testosterone levels <50 pg/mL.

Interventions: Random assignment to 7.5 g of 1% testosterone or placebo gel daily for 3 years.

Outcome Measures: Loaded and unloaded stair-climbing power, muscle strength, power, and fatigability in leg press and chest press exercises, and lean mass at baseline, 6, 18, and 36 months.

Results: The groups were similar at baseline. Testosterone administration for 3 years was associated with significantly greater performance in unloaded and loaded stair-climbing power than placebo (mean estimated between-group difference, 10.7 W [95% confidence interval (CI), −4.0 to 25.5], P = 0.026; and 22.4 W [95% CI, 4.6 to 40.3], P = 0.027), respectively. Changes in chest-press strength (estimated mean difference, 16.3 N; 95% CI, 5.5 to 27.1; P < 0.001) and power (mean difference 22.5 W; 95% CI, 7.5 to 37.5; P < 0.001), and leg-press power were significantly greater in men randomized to testosterone than in those randomized to placebo. Lean body mass significantly increased more in the testosterone group.

Conclusion: Compared with placebo, testosterone replacement in older men for 3 years was associated with modest but significantly greater improvements in stair-climbing power, muscle mass, and power. Clinical meaningfulness of these treatment effects and their impact on disability in older adults with functional limitations remains to be studied.

Topic: testosterone testosterone measurement chest lean body mass elderly muscle power muscle strength ascending stairs physical function leg press
Issue Section: Clinical Research Article

Thomas W. Storer Shehzad Basaria Tinna Traustadottir S. Mitchell Harman Karol Pencina Zhuoying Li Thomas G. Travison Renee Miciek Panayiotis Tsitouras Kathleen Hally … Show more

(2017) 102 (2): 583-593. DOI:
Published: 18 October 2016


Abstract | Context: Common concerns when using low-calorie diets as a treatment for obesity are the reduction in fat-free mass, mostly muscular mass, that occurs together with the fat mass (FM) loss, and determining the best methodologies to evaluate body composition changes.

Objective: This study aimed to evaluate the very-low-calorie ketogenic (VLCK) diet-induced changes in body composition of obese patients and to compare 3 different methodologies used to evaluate those changes.

Design: Twenty obese patients followed a VLCK diet for 4 months. Body composition assessment was performed by dual-energy X-ray absorptiometry (DXA), multifrequency bioelectrical impedance (MF-BIA), and air displacement plethysmography (ADP) techniques. Muscular strength was also assessed. Measurements were performed at 4 points matched with the ketotic phases (basal, maximum ketosis, ketosis declining, and out of ketosis).

Results: After 4 months the VLCK diet induced a −20.2 ± 4.5 kg weight loss, at expenses of reductions in fat mass (FM) of −16.5 ± 5.1 kg (DXA), −18.2 ± 5.8 kg (MF-BIA), and −17.7 ± 9.9 kg (ADP). A substantial decrease was also observed in the visceral FM. The mild but marked reduction in fat-free mass occurred at maximum ketosis, primarily as a result of changes in total body water, and was recovered thereafter. No changes in muscle strength were observed. A strong correlation was evidenced between the 3 methods of assessing body composition.

Conclusion: The VLCK diet-induced weight loss was mainly at the expense of FM and visceral mass; muscle mass and strength were preserved. Of the 3 body composition techniques used, the MF-BIA method seems more convenient in the clinical setting.

Topic: obesity weight reduction calories diet body composition ketosis fat-free mass ketogenic diet visceral fat muscle strength benefit incidence analysis
Issue Section: Clinical Research Article

Diego Gomez-Arbelaez Diego Bellido Ana I. Castro Lucia Ordoñez-Mayan Jose Carreira Cristobal Galban Miguel A. Martinez-Olmos Ana B. Crujeiras Ignacio Sajoux Felipe F. Casanueva

(2017) 102 (2): 488-498. DOI:
Published: 18 October 2016


Abstract | Context: Endothelial microRNA 126 (miR-126) attenuates the development of atherosclerosis (AS). However, there is no evidence showing the role of miR-126 in estrogen’s antiatherogenic effects.

Objective: We hypothesized that 17β-estradiol (E2) modulates miR-126 expression and thus may improve endothelial function and retard AS development.

Design/Setting/Participants: This was a prospective cohort study of 12 healthy regularly menstruating female volunteers. ApoE−/− mice were used as the atherosclerosis model and human umbilical vascular endothelial cells (HUVECs) were cultured as the cell model.

Main Outcome Measures: Serum hormones and miR-126-3p levels were measured up to 3 times for 1 cycle. Real-time polymerase chain reaction, histology for atherosclerotic lesions, immunofluorescence, luciferase assay, transfection experiments, cell proliferation, migration and tube formation assay, and western blot were performed.

Results: Serum concentrations of miR-126-3p in cycling women were higher at the ovulatory and luteal phases than in the follicular phase, and they were positively correlated with E2 values. Administration of miR-126-3p mimics to ApoE−/− mice-attenuated atherogenesis, and antagomir-126-3p partially reversed the protective effect of E2 on atherogenesis. In HUVECs, E2 increased miR-126-3p expression via upregulation of Ets-1 (a transcription factor for miR-126). c-Src/Akt signaling was important for E2-mediated expression of Ets-1/miR-126. E2 decreased expression of miR-126-3p target Spred1 (a protein that inhibits mitogenic signaling). Overexpression of Spred1 partially blocked enhancement of endothelial cell proliferation, migration, and tube formation by E2. Additionally, E2 regulates miR-126-3p–mediated expression of vascular cell adhesion molecule-1 to inhibit monocyte adhesion into HUVECs.

Conclusions: E2 protection against atherogenesis is possibly mediated by Ets-1/miR-126.
Topic: atherosclerosis polymerase chain reaction signal transduction western blotting cell proliferation endothelial cells estradiol adhesions apolipoprotein e endothelium fluorescent antibody technique menstrual cycle, proliferative phase luciferases monocytes vascular cell adhesion molecule-1 mice transcription factor atherogenesis protein overexpression proto-oncogene proteins c-akt micro rna spred-1 protein attenuation antagomirs
Issue Section: Clinical Research Article

Ping Li Jinzhi Wei Xiaosa Li Yang Cheng Weiyu Chen Yuhong Cui Tommaso Simoncini Zhengtian Gu Jun Yang Xiaodong Fu
(2017) 102 (2): 594-603. DOI:

shutterstock_462824650 (1)

Summary: Recently, it has been reported that treatment with testosterone (T) could have favorable effects on prostate inflammation; however, the data appear inconsistent. The main evidences concern experimental studies, and there is lower information obtainable from clinical studies. This study was conducted on patients with diagnosis of male accessory gland infection (MAGI) and a concomitant hormonal condition of acquired hypergonadotropic hypogonadism and has evaluated the effects on sperm parameters of the administration of a transdermal formulation of T gel for 3 months. The treated patients showed a significantly increased percentage of spermatozoa with normal form and progressive motility (p < .05 vs baseline), a significant reduction of CD45pos leucocytes in the semen (p < .05 vs baseline) and finally a significant increase of the seminal concentrations of zinc, fructose and alpha-glucosidase (p < .05 vs baseline) identified as key parameters associated to secretory function of the male accessory glands. The results of this study suggest the use of transdermal T in hypogonadal patients with MAGI for favorable effects on sperm parameters.

S. La Vignera, R. A. Condorelli, L. M. Mongioi, S. G. Vitale, G. I. Russo, A. S. Laganà, A. E. Calogero

First published: 24 November 2016
DOI: 10.1111/and.12745


To determine the degree of transparency of health insurer policies regarding coverage of male sexual health conditions, we examined the publicly available policy coverage documents of the largest US medical insurance plans.

We selected two index patients across the male sexual health spectrum: (1) a PDE5 refractory erectile dysfunction patient requiring intracavernosal injection therapy or penile prosthesis, (2) a 50 yo male patient with laboratory-confirmed, symptomatic hypogonadism requiring testosterone replacement therapy as defined by endocrine society criteria. We researched the policy documents regarding coverage for standard therapies. We used breast reconstruction after mastectomy as a control.

We queried the publicly available policy statements for 84 of the largest health care plans in the United States. While breast reconstruction policies are publicly available for 94% of plans examined, policies of only 39% of plans for advanced ED treatment options and 62% for hypogonadism are publicly available. Of the plans that had publicly accessible data for erectile dysfunction coverage, 85% viewed penile prosthesis and intracavernosal injection as medically necessary, while 91% of viewed androgen replacement as medically necessary for our index patient.

There is a lack of transparency among medical insurers regarding coverage of ED and hypogonadism in stark contrast to reconstructive breast surgery.

Urology. 2016 Dec 23 [Epub ahead of print]

Brian V Le, Sarah McAchran, David Paolone, Daniel R Gralneck, Daniel Williams, Wade Bushman

Department of Urology, University of Wisconsin-Madison, Madison, WI. Electronic address:, Department of Urology, University of Wisconsin-Madison, Madison, WI.



Abstract | CONTEXT: We hypothesize that endogenous sex steroids are associated with fracture risk independent of race/ethnicity.

DESIGN AND SETTING: We performed a nested case-control study within the prospective Women’s Health Initiative Observational Study (WHI-OS). Incident non-spine fractures were identified in 381 Black, 192 Hispanic, 112 Asian, and 46 Native American women over an average of 8.6 years. A random sample of 400 White women who experienced an incident fracture was chosen. One control was selected per case and matched on age, race/ethnicity, and blood draw date. Bioavailable estradiol (BioE2), testosterone (BioT) and sex hormone-binding globulin (SHBG) were measured using baseline fasting serum. Conditional logistic regression models calculated the odds ratio (OR) and 95% confidence interval (CI) of fracture across tertiles of hormone.

RESULTS: In multivariable and race/ethnicity adjusted models, higher BioE2 (>8.25 pg/ml) and higher BioT (>13.3 pg/ml) were associated with decreased risk of fracture, OR=0.65 (0.50-0.85), p trend=0.001 and OR=0.76 (0.60-0.96), p trend=0.02, respectively. The interaction term between race/ethnicity and either BioE2 or BioT was not significant. There was no association between SHBG and fracture risk. In models stratifying by race/ethnicity, higher BioE2 was associated with a lower risk of fracture in both White women, OR=0.56 (0.36-0.87) and Black women, OR=0.61 (0.39, 0.96). Higher BioT was associated with a significantly lower fracture risk in only Black women, OR=0.65 (0.43-0.97).

CONCLUSION: Serum BioE2 and BioT are associated with fracture risk in older women irrespective of race/ethnicity, independent of established risk factors for fracture.

Jane A. Cauley Michelle E. Danielson Guru Rajesh Jammy Doug C. Bauer Rebecca Jackson Jean Wactawski-Wende Rowan T. Chlebowski Kristine E. Ensrud Robert Boudreau

(2017) jc.2016-3589. DOI:

Published: 25 January 2017


Abstract | Objective: Sex hormone-binding globulin (SHBG) binds and transports testosterone and estradiol in plasma. The possibility that SHBG is a mixture of transporting proteins has been postulated. We analyzed in parallel the effects of obesity status on the levels and binding capacity of circulating SHBG and their relationship with testosterone and estradiol.

Design: Anthropometric measures and plasma were obtained from apparently healthy young (i.e. 35 ± 7 years) premenopausal women (n=32) and men (n=30), with normal weight and obesity (BMI>30 kg·m-2).

Methods: SHBG protein (Western blot), as well as the plasma levels of testosterone, estradiol, cortisol and insulin (ELISA) were measured. Specific binding of estradiol and testosterone to plasma SHBG was analyzed using tritium-labelled hormones.

Results: Significant differences in SHBG were observed within the obesity status and gender, with discordant patterns of change in testosterone and estradiol. In men, testosterone occupied most of the binding sites. Estrogen binding was much lower in all subjects. Lower SHBG of morbidly obese (BMI>40 kg·m-2) subjects affected testosterone but not estradiol. The ratio of binding sites to SHBG protein levels, was constant for testosterone, but not for estradiol. The impact of gender was maximal in morbid obesity, with men showing the highest binding / SHBG ratios.

Conclusions: The results reported here are compatible with SHBG being a mixture of at least two functionally different hormone-binding globulins, being affected by obesity and gender, and showing different structure, affinities for testosterone and estradiol, and also different immunoreactivity.

Maria del Mar Grasa, José Gulfo, Núria Camps, Rosa Alcalá, Laura Monserrat, José María Moreno-Navarrete, F Ortega, Montserrat Esteve, Xavier Remesar, José Antonio Fernández-López, José Manuel Fernández-Real and Marià Alemany⇑

– Author Affiliations

M Grasa, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Gulfo, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
N Camps, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
R Alcalá, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
L Monserrat, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Moreno-Navarrete, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
F Ortega, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
M Esteve, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
X Remesar, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Fernández-López, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain
J Fernández-Real, Endocrinology and Diabetes, Girona Institute of Biomedical Research and Hospital of Girona "Dr. Trueta", Girona, Spain
M Alemany, Department of Biochemistry and Molecular Biomedicine, University of Barcelona, Faculty of Biology, Barcelona, Spain

Correspondence: Marià Alemany, Email:

Published online before print January 11, 2017, doi: 10.1530/EJE-16-0834
Eur J Endocrinol January 11, 2017 EJE-16-0834