Abstract | Context: Vitamin D deficiency disproportionately affects nonwhite individuals. Controversy persists over how to best restore low 25D levels, and how to best define vitamin D status [total (protein bound plus free) vs free 25D].

Objective: To assess the effects of vitamin D3 (cholecalciferol, or D3) vs 25-hydroxyvitamin D3 (calcifediol, or 25D3) on total and free 25D in a multiethnic cohort of adults, and whether change in parathyroid hormone (PTH) is more strongly associated with total vs free 25D.

Design: Sixteen-week randomized controlled trial. Biochemistries at 0, 4, 8, and 16 weeks.

Setting: Academic medical center.

Participants: Thirty-five adults ≥18 years of age with 25D levels <20 ng/mL.

Intervention: Sixty micrograms (2400 IU)/d of D3 or 20 μg/d of 25D3.

Main Outcome Measures: Total and free 25D, and PTH.

Results: Baseline total (16.2 ± 3.7 vs 17.0 ± 2.5 ng/mL; P = 0.4) and free (4.2 ± 0.8 vs 4.7 ± 1.0 pg/mL; P = 0.2) 25D were similar between D3 and 25D3 groups, respectively; 25D3 increased total (+25.5 vs +13.8 ng/mL; P = 0.001) and free (+6.6 vs +3.5 pg/mL; P = 0.03) 25D more than D3. By 4 weeks, 87.5% of 25D3 participants had total 25D levels ≥30 ng/mL, compared with 23.1% of D3 participants (P = 0.001). Change in PTH was associated with both total (P = 0.01) and free 25D (P = 0.04).

Conclusions: 25D3 increased total and free 25D levels more rapidly than D3, regardless of race/ethnicity. Free and total 25D were similarly associated with change in PTH.

Albert Shieh Christina Ma Rene F. Chun Sten Witzel Brandon Rafison Hannah T. M. Contreras Jonas Wittwer-Schegg Leon Swinkels Tonnie Huijs Martin Hewison John S. Adams

J Clin Endocrinol Metab (2017) 102 (4): 1133-1140. DOI: https://doi.org/10.1210/jc.2016-3919
Published: 10 February 2017

Abstract | Context: Menstrual cycle hormone patterns in women approaching menopause are inadequately studied.

Objective: To describe day-to-day menstrual cycle hormones in women as they approach menopause from the Study of Women’s Health Across the Nation (SWAN) Daily Hormone Study (DHS).

Design: DHS enrollees collected daily urine for one entire menstrual cycle or up to 50 days, whichever came first, annually, up to the final menstrual period (FMP) or for up to 10 years.

Setting: 7 sites across the US.

Participants: 511 premenopausal or early perimenopausal women at enrollment, within 10 years before menopause.

Intervention: time-to-FMP measurement.

Main Outcome Measures: Evidence of luteal activity (ELA), determined using objective algorithms. Menstrual cycle/segment length; whole cycle and segment integrated urinary LH, FSH, estrone conjugates (E1c) and pregnanediol glucuronide (Pdg) for each year, organized around the FMP.

Results: Mean menstrual cycle length was remarkably preserved at 26-27 days in ELA cycles; non-ELA cycles had greater variability. The % cycles that were ELA remained high until 5 years before the FMP (87.9%); only 22.8% of cycles within 1 year of the FMP were ELA. Whole cycle hormones remained relatively stable up to 3 years before the FMP, when gonadotropins began to increase. Pdg excretion declined slowly with progress to the FMP, but Pdg patterns of ELA cycles remained distinguishable from non-ELA.

Conclusions: Menstrual cycle hormone patterns in perimenopausal women resemble those of midreproductive aged women until 5 years before menopause and presumably ovulatory cycles retain a potentially fertile pattern up to the end of reproductive life.

Nanette Santoro Sybil L. Crawford Samar R. El Khoudary Amanda A. Allshouse Sherri-Ann Burnett-Bowie Joel Finkelstein Carol Derby Karen Matthews Howard M. Kravitz Sioban D. Harlow Gail A. Greendale Ellen B. Gold Rasa Kazlauskaite Dan McConnell Genevieve Neal-Perry Jelena Pavlovic John Randolph Gerson Weiss Hsiang-Yu Chen Bill Lasley

J Clin Endocrinol Metab jc.2016-4017. DOI: https://doi.org/10.1210/jc.2016-4017
Published: 22 March 2017

Middle-aged and older men (≥50 years), especially those who are obese and suffer from comorbidities, not uncommonly present with clinical features consistent with androgen deficiency and modestly reduced testosterone levels. Commonly, such men do not demonstrate anatomical hypothalamic-pituitary-testicular axis pathology but have functional hypogonadism that is potentially reversible.

Literature review from 1970 to October 2016.

Although definitive randomized controlled trials are lacking, evidence suggests that in such men, lifestyle measures to achieve weight loss and optimization of comorbidities, including discontinuation of offending medications, lead to clinical improvement and a modest increase in testosterone. Also, androgen deficiency-like symptoms and end-organ deficits respond to targeted treatments (such as phosphodiesterase-5 inhibitors for erectile dysfunction) without evidence that hypogonadal men are refractory. Unfortunately, lifestyle interventions remain difficult and may be insufficient even if successful. Testosterone therapy should be considered primarily for men who have significant clinical features of androgen deficiency and unequivocally low testosterone levels. Testosterone should be initiated either concomitantly with a trial of lifestyle measures, or after such a trial fails, after a tailored diagnostic work-up, exclusion of contraindications, and appropriate counseling.

There is modest evidence that functional hypogonadism responds to lifestyle measures and optimization of comorbidities. If achievable, these interventions may have demonstrable health benefits beyond the potential for increasing testosterone levels. Therefore, treatment of underlying causes of functional hypogonadism and of symptoms should be used either as an initial or adjunctive approach to testosterone therapy.

The Journal of clinical endocrinology and metabolism. 2017 Mar 01 [Epub]

Mathis Grossmann, Alvin M Matsumoto

Department of Medicine, Austin Health, University of Melbourne, Heidelberg, Victoria 3081, Australia., Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, Washington 98195; and.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/28359097

Abstract | Context: Physical activity (PA) is associated with 25-hydroxyvitamin D [25(OH)D] levels. Both are associated with atherosclerotic cardiovascular disease (ASCVD), but their joint association with ASCVD risk is unknown.

Objective: To examine the relationship between PA and 25(OH)D, and assess effect modification of 25(OH)D and PA with ASCVD.

Design: Cross-sectional and prospective study.

Setting: Community-dwelling cohort.

Participants: A total of 10,342 participants free of ASCVD, with moderate- to vigorous-intensity PA assessed (1987 to 1989) and categorized per American Heart Association (AHA) guidelines (recommended, intermediate, or poor).

Main Outcome Measures: Serum 25(OH)D levels (1990 to 1992) and ASCVD events (i.e., incident myocardial infarction, fatal coronary disease, or stroke) through 2013.

Results: Participants had mean age of 54 years, and were 57% women, 21% black, 30% 25(OH)D deficient [<20 ng/mL (<50 nmol/L)], and <40% meeting AHA-recommended PA. PA was linearly associated with 25(OH)D levels in whites. Whites meeting recommended PA were 37% less likely to have 25(OH)D deficiency [relative risk, 0.63 (95% confidence interval [CI], 0.56, 0.71)]; there was no significant association in blacks. Over 19.3 years of follow-up, 1800 incident ASCVD events occurred. Recommended PA was associated with reduced ASCVD risk [hazard ratio [HR], 0.78 (95% CI, 0.65, 0.93) and 0.76 (95% CI, 0.62, 0.93)] among participants with intermediate [20 to <30 ng/mL (50 to <75 nmol/L)] and optimal [≥30 ng/mL (≥75 nmol/L)] 25(OH)D, respectively, but not among those with deficient 25(OH)D (P for interaction = 0.04).

Conclusion: PA is linearly associated with higher 25(OH)D levels in whites. PA and 25(OH)D may have synergistic beneficial effects on ASCVD risk.

Kathleen Chin, Di Zhao, Martin Tibuakuu, Seth S. Martin, Chiadi E. Ndumele …

Published: 17 February 2017

Abstract | Context: Evidence supports a protective effect of menopausal hormone therapy (HT) on bone. However, whether genetic susceptibility modifies the association of HT and fracture risk is not sufficiently explored.

Objective: The objective was to test an interaction between genetic susceptibility and HT on fracture risk.

Design: We constructed two weighted genetic risk scores (GRSs) based on 16 fracture-associated variants (Fx-GRS) and 50 bone mineral density (BMD) variants (BMD-GRS). We used Cox regression to estimate the main effects of GRSs and their interactions with HT on fracture risk. We estimated the relative excess risk due to interaction (RERI) as a measure of additive interaction. We also utilized the case-only approach to test for a multiplicative interaction.

Setting: 40 US clinical centers

Participants: 9,922 genotyped white postmenopausal women (age 50-79) from the Women’s Health Initiative HT randomized trials

Main outcome: Adjudicated fracture incidence

Results: Both GRSs were associated with fracture risk (hazard ratio (HR) (95% CI) per one-unit increment in GRS, 1.04 (1.02-1.06) for Fx-GRS and 1.03 (1.02-1.04) for BMD-GRS). We found no evidence for multiplicative interaction for either of the GRS. However, we observed a significant additive interaction, where the highest quartile of both GRSs and randomization to placebo have excess fracture risk: Fx-GRS p-for-RERI=0.047, BMD-GRS p-for-RERI=0.046.

Conclusions: These results suggest that HT reduces fracture risk in postmenopausal women especially in those at highest genetic risk of fracture and low BMD.

Youjin Wang Jean Wactawski-Wende Lara E. Sucheston-Campbell Leah Preus Kathleen M. Hovey Jing Nie Rebecca D. Jackson Samuel K. Handelman Rami Nassir Carolyn J. Crandall

J Clin Endocrinol Metab jc.2016-2936. DOI: https://doi.org/10.1210/jc.2016-2936

Published: 06 March 2017

Written by: Rakesh Saini, PhD

The alarming rate of increase in gluten sensitivity in recent times is due to genetic modifications of grains, like wheat, resulting in an increase in gluten content by as much as 500 times in last about 110 years, and a change in molecular structure of gluten added to some foods from water extracted to alcohol extracted. Human genetics has not evolved yet to accommodate these changes.
Two distinct forms of gluten sensitivity / intolerance are NCGS (Non-Celiac Gluten Sensitivity – Not a disease – symptoms are gas/bloating/cramping/abdominal pain/ etc.) and an immune disease – CELIAC. Since there is no prescription medication for either, the only option available to MD’s until now was to ask the patients to go Gluten Free. This is not fool proof though, because patients not only get ill from gluten but also from “hidden” gluten*, cross-reactors*, FODMAPS*, and cross-contamination* (definition of each of these *irritants is provided at end of this write-up). Strictly avoiding each of these is extremely difficult, if not impossible. Therefore, patients get hit or miss relief from gluten sensitivity, causing anxiety, stress, disappointment and frustration.
Root cause of gluten sensitivity is a high concentration of gluten in intestines (>20 PPM, Parts Per Million) and/or other irritants stated above. Therefore, a solution to the problem is to break down the gluten and irritants, to zero or near zero BEFORE FOOD LEAVES THE STOMACH.

Based upon this fundamental understanding the dietary supplement ZyGluten™ was created. This development required a gastroenterologist to work with 6 PhDs for 7 years at a total cost of about $15 million, conducting most of the Research and Development in a stomach stimulator. They first discovered the root cause of gluten sensitivity and then developed a science based product to take care of it.


Safety and efficacy of ZyGluten™ has been proven beyond doubt in a clinical trial conducted under the supervision of a physician on an unpaid patient population. The study has been published in Journal of Gluten Sensitivity, 2015, Volume 14, Page 17. Safety and efficacy got further validated via post marketing data (repeat purchases, return of symptoms if use is stopped, no negative side effects or adverse events) since product was introduced about six months ago.
ZyGluten™ is a mixture of twenty enzymes of high potency, two probiotic type microbes with gluten digesting capability, and two herbs to soothe the digestive system, all together at a high concentration of enzymes in a capsule made of tapioca. Each of the twenty enzymes, within the categories of Proteases, Lipases, Amylases, and Cellulases, in reality, contains hundreds of enzymes, some that have not been even discovered yet. Before marketing, the product was tested on following foods, using twice the concentration of gluten expected in a typical American meal: Pizza, Pasta, Bread, Bagels with cream cheese, Hamburger/fries/coke, pancakes, sandwiches, etc. An example from one of these experiments in the graph shows ZYGLUTEN is extremely fast acting, bringing the concentration of gluten from 3525 PPM to <20 PPM in < 30 minutes.
ZyGluten’s™ efficacy is 7 times to 231 times higher relative to competitive products because of high concentration of high potency ingredients. It is almost a misnomer to say ZyGluten™ has a competitor. Many products are designed to breakdown gluten only, whereas ZyGluten™ ingredients start with breaking down the protective matrix surrounding the polymer of gluten. Once this shield has been removed, gluten breaks down quickly because it is now exposed and ready to be attacked by specific enzymes (diphenyl peptidases) in the product. Moreover, the capsule is made of tapioca, dissolves much faster than gelatin allowing more time for the biological natural catalysts to do their job in achieving gluten/irritant level of zero / near zero BEFORE FOOD LEAVES THE STOMACH.

Healthcare professionals can purchase ZyGluten™ from our exclusive distributor:

Medaus Pharmacy
6801 Cahaba Valley Road
Birmingham, AL 35244

Healthcare Professionals

ABSTRACT | Objective: To explore the association between postmenopausal hormone therapy (HT) and Alzheimer disease (AD).

Methods: Twenty-year follow-up data from the Kuopio Osteoporosis Risk Factor and Prevention study cohort were used. Self-administered questionnaires were sent to all women aged 47–56 years, residing in Kuopio Province starting in 1989 until 2009, every 5th year. Register-based information on HT prescriptions was available since 1995. Probable AD cases, based on DSM-IV and National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria, were identified from the special reimbursement register (1999–2009). The study population included 8,195 women (227 cases of incident AD).

Results: Postmenopausal estrogen use was not associated with AD risk in register-based or self-reported data (hazard ratio/95% confidence interval 0.92/0.68–1.2, 0.99/0.75–1.3, respectively). Long-term self-reported postmenopausal HT was associated with reduced AD risk (0.53/0.31–0.91). Similar results were obtained with any dementia diagnosis in the hospital discharge register as an outcome.

Conclusions: Our results do not provide strong evidence for a protective association between postmenopausal HT use and AD or dementia, although we observed a reduced AD risk among those with long-term self-reported HT use.

Received May 6, 2016.
Accepted in final form December 21, 2016.
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

A prospective cohort study

Bushra Imtiaz, MD, MPH, Marjo Tuppurainen, MD, PhD, Toni Rikkonen, PhD, Miia Kivipelto, MD, PhD, Hilkka Soininen, MD, PhD, Heikki Kröger, MD, PhD and Anna-Maija Tolppanen, PhD

Correspondence to Dr. Imtiaz: bushra.imtiaz@uef.fi
Published online before print February 15, 2017, doi: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0000000000003696

Neurology 10.1212/WNL.0000000000003696

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.

PubMed http://www.ncbi.nlm.nih.gov/pubmed/28241244

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

DOI: http://dx.doi.org/10.1016/j.jsxm.2016.12.237