CLINICAL RESEARCH

that supports the optimization of hormones in men and women using bio-identical hormone replacement therapies.

1. Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions

PUBLISHED by Mayo Clinic Proceedings, Diagnosis and Treatment Guidelines, 2016.
AUTHORS: Abraham Morgentaler, MD (Chairman); Michael Zitzmann, MD (Cochairman)

An international panel of experts met in October 2015 and made consensus statements on the benefits and safety of testosterone therapy. (1) Testosterone (T) Deficiency (TD) is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes.

2. No VTE Risk Seen With Testosterone Therapy

PUBLISHED on MedPage and Mayo Clinic Proceedings, July 2015.
AUTHORS: Jacques Baillargeon, PhD, Randall J. Urban, MD, Abraham Morgentaler, MD, Charles J. Glueck, MD, Gwen Baillargeon, MS, Gulshan Sharma, MD, MPH, Yong-Fang Kuo, PhD

The findings of this study fly directly against the recent FDA mandate changes to testosterone drug labels regarding a potential increased risk of VTE, with good retrospective data across a very large sample size. The study acknowledges its numerous limitations, and the only definitive way to truly determine the relationship between VTE and testosterone use would be to perform a prospective, controlled study. No one has directly examined the anti-inflammatory properties of testosterone, which might lower the risk of thrombosis.

3. Study Finds No Convincing Evidence of Increased Cardiovascular Risk with Testosterone Therapy

Fears of a link between testosterone replacement therapy and cardiovascular risk are misplaced, according to a review published in this month’s Mayo Clinic Proceedings. The therapy has come under widespread scrutiny in recent months, including by a federal Food and Drug Administration (FDA) panel convened last fall. “There’s no good evidence that we could find that testosterone therapy increases cardiovascular risk,” says lead author Abraham Morgentaler, MD, of Director of Men’s Health Boston and a urologist on staff at Beth Israel Deaconess Medical Center. “That’s not to say it’s perfectly safe. But we cannot find evidence and the headlines that jumped out on recent retrospective studies appear to be too strong.”

Importantly, and under-recognized among physicians, Morgentaler adds, “review of the literature clearly reveals a strong relationship between higher serum testosterone concentrations … as being beneficial for reduction in cardiovascular disease and cardiovascular risk factors.”

4. Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

PUBLISHED on Mayo Clinic Proceedings,, 2015.
AUTHORS: Abraham Morgentaler, MD, Martin M. Miner, MD, Monica Caliber, MSc, Andre T. Guay, MD, Mohit Khera, MD, Abdulmaged M. Traish, PhD.
ABSTRACT: Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

5. Study Finds No Convincing Evidence of Increased Cardiovascular Risk with Testosterone Therapy

PUBLISHED on Wiley Online Library by AlphaMed Press, 2014.
AUTHORS: Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS.

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

6. New VA study demonstrates cardiovascular benefits of testosterone replacement therapy

A Veterans Affairs database study of more than 83,000 patients found that men whose low testosterone was restored to normal through gels, patches, or injections had a lower risk of heart attack, stroke, or death from any cause, versus similar men who were not treated.

The study also found that men who were treated but did not attain normal levels did not see the same benefits as those whose levels did reach normal. The study was published online Aug. 6, 2015, in the European Heart Journal.
The findings may sway the ongoing debate over testosterone therapy’s benefits and risks, especially for the heart. Studies over the past few years have yielded mixed results, although part of that might stem from differing patient populations and research methods.

7. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men

Conclusion: In this large observational cohort with extended follow-up, normalization of TT levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.

8. Testosterone’s Impact on Cardiovascular Health

Author: Gary Huber, D.O.

The research of the past 20 years is pointing towards the conclusion that androgens are a key piece of the cardiovascular repair and recovery cycle. Low twstostywerone levles open the door for inflammation and vascular compromise. When this defixciency is corrected there is a pattern of decreased inflammation, atherosclerosis and resultant Coronary Artery Disease. Optimal testosterone levels play an integral role in the process of good cardiovascular health. “If we are not measuring testosterone levels and treating low T, we are not offering our patients every available avenue for cardiovascular health.”

9. Testosterone Keeps Women’s Brains Sharp

PUBLISHED on MedPage Today, 2013.
AUTHORS: Todd Neale

Summary: Testosterone supplementation may improve cognitive performance in postmenopausal women, a randomized trial suggested.

Among women who were not cognitively impaired, those who received testosterone performed an average of 1.57 points better on the International Shopping List Task — a measure of verbal learning and memory in which scores can range from 0 to 48 — than those who received placebo after 26 weeks (P=0.037), according to Susan Davis, MBBS, PhD, of Monash University in Melbourne, Australia.

The difference is clinically relevant and equal to the reduction in performance expected in 1 year among patients with Alzheimer’s disease and to the average increase seen in studies of an investigational histamine H3 antagonist — GSK239512 — that is being developed for patients with mild-to-moderate Alzheimer’s disease, she reported at the Endocrine Society meeting here.

The current study suggests that the women are performing suboptimally even though it’s normal for their age group and that we can really have women performing more optimally in terms of cognitive performance if they have testosterone therapy.

10. Testosterone Therapy May Improve Sexual Function for Women

PUBLISHED on Inquisitr.com, 2013.
SUMMARY: High doses of testosterone significantly improve sexual function among women who have had their uterus and ovaries surgically removed, a clinical study demonstrates. The results were presented Sunday at The Endocrine Society’s 95th Annual Meeting in San Francisco.

There has been emerging interest in supplemental hormonal treatment with the primary male sex hormone, testosterone for disrupted sexual functioning in postmenopausal women.

To determine whether testosterone therapy increases sexual functioning among patients who have had hysterectomy and oophorectomy, study investigators recruited 71 women who had undergone these procedures. For the first 12 weeks of the study, participants received estrogen replacement. Investigators then randomly assigned them to one of five groups for weekly injections of placebo, or 3, 6.25, 12.5, or 25 milligrams (mg) of an intramuscular testosterone medication, called testosterone enanthate, for 24 weeks.

They found that sexual functioning significantly improved among the group of women who received 25 mg of testosterone compared to placebo. In addition, the weekly number of sexual encounters among this group increased by 2.7 encounters. These improvements were related to greater blood concentrations of free testosterone, which means that the hormone is more active because it is not bound to proteins in the blood. The groups receiving lower doses of the hormone, however, did not have improvement in sexual functioning.

A primary concern with testosterone replacement therapy is that it can cause symptoms of masculinization among women. These symptoms include unwanted hair growth, lower voice tone, and increased muscle mass. Few of these side effects were reported in this study.

11. Effect of testosterone on abdominal adipose tissue in men.

Int J Obes. 1991 Nov;15(11):791-5.
Authors: Rebuffé-Scrive M1, Mårin P, Björntorp P.
Abstract: Recent studies in men have shown that abdominal fat increases with age and decreasing testosterone concentrations. Furthermore, in cell culture, testosterone expresses an increased lipolytic potential and depresses lipoprotein lipase activity (LPL) in adipose cells. These metabolic characteristics are found in abdominal adipose tissue in young men. In order to see whether abdominal fat masses in moderately obese middle-aged men might be diminished by testosterone, this hormone was given either as a single injection (500 mg) or in moderate doses (40 mg X 4) for 6 weeks in an oral preparation, bypassing the liver. When measured 1 week after the single dose, abdominal LPL tended to decrease. After 6 weeks a dramatic decrease of abdominal LPL was found, as well as an increase in the lipolytic responsiveness to norepinephrine, both changes confined solely to the abdominal, and not femoral adipose tissue regions. The waist/hip circumference decreased in 9 out of the 11 examined men. No untoward effects were seen in behavioural variables, blood pressure, triglyceride or cholesterol values, and liver function tests. These preliminary results suggest that administration of testosterone in moderate doses to middle-aged men lead to adaptations of the metabolism of adipose tissue expected to be followed by a diminution of this mass.

12. Testosterone Therapy Does Not Hike Risk of Aggressive Prostate Cancer

PUBLISHED on Renal and Urology News, September 2013.
AUTHORS: Jody Charnow
SUMMARY: Despite the high prevalence of hypogonadism in older men and well-established health benefits of TRT, use of TRT is markedly low. The concern of increasing prostate cancer risk or cancer severity by administering TRT has been widely disproved. This population-based study adds to the growing body of evidence that TRT does not confer worse prostate cancer outcomes.

13. The Mortality Toll of Estrogen Avoidance: An Analysis of Excess Deaths Among Hysterectomized Women Aged 50 to 59 Years

PUBLISHED on American Journal of Public Health, February 2013.
AUTHORS: Philip M. Sarrel MD, Valentine Y. Njike MD MPH, Valentina Vinante MD, David L. Katz MD MPH
Results. Over a 10-year span, starting in 2002, a minimum of 18 601 and as many as 91 610 postmenopausal women died prematurely because of the avoidance of estrogen therapy (ET).
Conclusions. Estrogen therapy in younger postmenopausal women is associated with a decisive reduction in all-cause mortality, but estrogen use in this population is low and continuing to fall. Our data indicate an associated annual mortality toll in the thousands of women aged 50 to 59 years. Informed discussion between these women and their health care providers about the effects of ET is a matter of considerable urgency.

14. The Bio-identical Hormone Debate: are Bio-identical Hormones (estradiol, estriol, and Progesterone) safer or More efficacious than Commonly used synthetic Versions in Hormone replacement therapy?

PUBLISHED in The Journal of the North American Menopause Society, July 2003, Volume 10, Issue 4, pp 277-285.
AUTHORS: Decker, David A. MD; Pettinga, Jane E. MD; VanderVelde, Nancy MD; Huang, Raywin R. PhD; Kestin, Larry MD; Burdakin, John H. MD
CONCLUSIONS: In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.

Abstract: Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bio-identical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone. Conclusion: Physiological data and clinical outcomes demonstrate that bio-identical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animalderived counterparts. Until evidence is found to the contrary, bio-identical hormones remain the preferred method of HRT.
Estrogen Replacement Therapy in Breast Cancer Survivors: a Matched-Controlled Series

15. Estrogen Replacement Therapy After Breast Cancer: A 12-Year Follow-Up

PUBLISHED on Annals of Surgical Oncology, Dec 2001, Volume 8, Issue 10, pp 828-832.
AUTHORS: George N. Peters MD, Tomasina Fodera MD, Jennifer Sabol MD, Stephen Jones MD, David Euhus MD
Conclusions: Use of ERT in a cohort of breast cancer survivors with tumors of generally good prognosis was not associated with increased breast cancer events compared with non-ERT users, even over a long follow-up period.

16. Early Initiation of HRT ‘Halves Risk of Death or CVD’

PUBLISHED on Pulse – Atthe Heart of General Practice, 2012
AUTHOR: David Swan
SUMMARY: GPs should aim to initiate hormone replacement therapy as early as possible after menopause, as it can halve a woman’s risk of death or a serious cardiovascular event, say researchers.

The ten-year study found that initiating HRT less than two years after women have stopped menstruating resulted in a significant 52% reduction in death, heart failure or myocardial infarction compared to women not receiving treatment.

The study adds support to the ‘timing hypothesis’ for HRT – a theory that differences in cardiovascular outcome are explained by the time between menopause and the start of HRT.

Danish researchers followed 502 women aged 45-58 whose last menstrual bleed was three to 24 months prior to study entry or had perimenopausal symptoms in combination with recorded postmenopausal serum FSH values for ten years.

They compared them with 504 controls who were randomised to no hormone therapy.

They found a 43% decreased risk of death, an 86% decrease in heart failure risk and a 75% reduced likelihood of myocardial infarction in the HRT group compared with those not receiving treatment, though these were non-significant.

There was no significant difference between the two groups for cancer occurrence – 36 cases in the HRT group compared with 39 in the control group. Breast cancer rates were also non-significant between the two groups – 10 in the intervention arm compared with 17 in the controls.

The results from the Danish Osteoporosis Prevention Study conflict with the Women’s Health Initiative study published in 2010.

17. Estrogen Is a New Weapon Against Urinary Tract Infection in Post Menopausal Woman

PUBLISHED on Science Daily, 2013.
AUTHOR: Karolinska Institutet
SUMMARY: Estrogen replacement therapy stimulates the production of the body’s own antibiotic and strengthens the cells in the urinary tract, according to a new study from Karolinska Institutet in Sweden. The results, which are published in the journal Science Translational Medicine, show that estrogen supplements may help menopausal women to ward off recurrent urinary tract infections.

In the current study, the researchers treated post-menopausal women with estrogen for 14 days, and then analyzed cells excreted in the urine. They found that estrogen acts on the epithelium in a way that the gaps between the cells lining the bladder lumen are healed, i.e. estrogen is gluing them together. This makes it more difficult for bacteria to break this protecting shield and reach the underlying cells.

18. Estrogen Can Reduce Risk of Liver and Heart Disease in Women

PUBLISHED on BioOptics World, 2013.
AUTHOR: Lee Mather
SUMMARY: The research shows the beneficial effect that estrogen (the female hormone) has on liver metabolism by revealing a new type of estrogen receptor, which controls estrogen-responsive genes that regulate cholesterol and fatty acid production.

Professor Brian Harvey, RCSI Principal Investigator, says that estrogen tends to protect women against high cholesterol and heart disease during the child-bearing years. “Our research has allowed us to gain important insights into how estrogen may suppress some genes and prevent excessive accumulation of cholesterol and triglycerides in the blood that can progress to heart disease and liver cancers. This leaves the door open for the development of drugs that can decrease the incidence of liver and heart disease in women.”

This female-specific study showed that estrogen binds to a new type of estrogen receptor at the cell membrane and not in the nucleus of the cell. This activates a network of enzymes that slows down a regulator of genes (SREB), which usually drive the build-up of cholesterol in the liver. Estrogen was also found to suppress lipid metabolism in general, including the accumulation of fatty acids and harmful triglycerides.

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