For the second year in a row, Endocrine News talks to editors from Endocrine Society journals to get the scoop on the top endocrine discoveries of 2016.
The life work of a scientist requires an enormous amount of patience. “Eureka moments” take years of tireless experimentation and iteration to achieve, which is why impactful discoveries deserve celebration. Over the past year, many important papers have been published in the field of endocrinology — from confirming the essential role of ESR1 in male reproductive health to uncovering the therapeutic potential of corticosterone for congenital adrenal hyperplasia.
This article is a sampling of the research achievements of our community in 2016, as picked by five editors from the journals Endocrinology and The Journal of Clinical Endocrinology & Metabolism (JCEM). While not intended as a comprehensive overview of all major studies, it instead aims to encourage reflection on this year’s successes and recognize a few important publications across a handful of endocrine specialties.
Testosterone Under the Microscope
In last year’s “Top Endocrinology Discoveries of 2015” article in Endocrine News, two reproductive specialists underscored the revelation that testosterone therapy, which is widely prescribed in aging men, lacks solid evidence of beneficial effects. They described the need for more concrete literature on the subject.
Fortunately, the call for more research is leading to important publications in this area. Alvin M. Matsumoto, MD, professor at the University of Washington and an associate editor of JCEM, points to the initial publication of The Testosterone Trials in the New England Journal of Medicine as a critical step forward.
“In the area of male reproductive endocrinology, I think that this is the most impactful report in the last year,” Matsumoto says.
The publication, “Effects of Testosterone Treatment in Older Men” by Snyder, PJ, et al, followed 790 men over the age of 65 with unequivocally low serum testosterone levels for one year as they participated in at least one of three trials: The Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. Half of the participants received testosterone gel, and half received a placebo.
“Versus placebo, testosterone treatment for one year moderately improved sexual function and slightly improved depressive symptoms and mood, but did not improve fatigue or walking distance,” Matsumoto explains.
The sample size was not large enough to draw conclusions about possible negative effects, implying that the jury is still out on testosterone supplementation. The moderately positive effects are not enough to make the case for continued use. Still, there are four additional studies in the queue for publication from The Testosterone Trials — relating to bone health, cognition, anemia, and coronary artery plaque formation — that could sway recommendations for or against the therapy.
The Fairer Sex Steroid
While testosterone supplementation remains under scrutiny, estrogen as a part of male reproductive health is receiving more attention. Gail S. Prins, PhD, professor at the University of Illinois at Chicago and an associate editor for Endocrinology, sees the study published in the July issue of that journal, “Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice” by Nanjappa, M, et al, as a top discovery in the field of steroids and male reproduction.
These are the research trends that we expected to see more of in 2016, based on interviews with editors of Endocrine Reviews. Have you seen these topics emerge in your reading? Let us know by submitting your feedback online: endocrinenews.endocrine.org/contact-us/
- Metabolic reprogramming and its importance for understanding hormone action
- Stress hormones in regulating cardiovascular function
- Sex differences in metabolic homeostasis, diabetes, and obesity.
- Genotype-phenotype correlation and inherited predisposition for developing pituitary adenomas
- Epigenetic effects during pregnancy and in offspring
- Importance of local control of thyroid hormone levels by the types 2 and 3 deiodinases
- Mutations that underlie thyroid cancer and development of targeted therapies
- Bone’s role in the homeostatic mechanisms of the whole body
- Chronic exercise and the recently discovered protein, irisin, on skeletal turnover
- Free vitamin D rather than total vitamin D evaluations
- Treatments for hypophosphatasia
- X-linked hypophosphatemia and hypoparathyroidism
- Crescent application of new methods for genetic diagnosis, such as gene panel and whole genomic/exomic sequencing
- Tools for investigating epigenetic factors, such as DNA methylation and microRNA
- Effects of testosterone (and its metabolites) on bone, muscle, brain, prostate, and the cardiovascular system
- Male hormonal contraceptives
- Relationship between body weight and male gonadal function
“Nearly 20 years ago, Nature published an important study about ER (ESR1) and estrogen, identifying for the first time that ERalpha possesses an essential physiologic role in male reproduction by controlling fluid resorption in the rete testis and influencing the fertilization capacity of spermatozoa,” Prins says. “Since that time, the molecular pathways involved in ESR1 actions have been shown to be numerous and include membrane-initiated signaling due to ERa localized to the membrane.”
This new publication proves that the pathway is vital for ESR1 actions. “Deletion of the membrane component with retention of the nuclear ESR1 signaling results in many similar phenotypes in sperm maturation, rete testis fluid absorption, and so on as observed with the total ESR1 knockout mouse,” she continues.
The results indicate that new therapeutic tools could be on the horizon, taking advantage of “a previously underappreciated pathway.” The possibilities are far-reaching, and may even include a male contraceptive approach. Further research will determine the clinical potential of tapping into these rapid signaling pathways in the male reproductive tract.
Male Birth Control Shots Show Promise
As Endocrine News reported in June, the ongoing search for the ever-elusive male hormonal birth control method seems to be many years away. However, a new study published in The Journal of Clinical Endocrinology & Metabolism this fall revealed that new shots that men can take have been shown to prevent pregnancy in their female partners.
According to Mario Philip Reyes Festin, MD, of the World Health Organization and one of the study’s authors, “it is possible to have a hormonal contraceptive for men that reduces the risk of unplanned pregnancies in the partners of men who use it,” adding that the findings confirmed the efficacy of this contraceptive method previously seen only in small studies.
The prospective Phase II single arm, multi-center study tested the safety and effectiveness of injectable contraceptives in 320 healthy men ages 18 to 45 who were all in monogamous relationships for at least a year. The men underwent testing to ensure they had a normal sperm count at the start of the study.
The men received injections of 200 milligrams of a long-acting progestogen called norethisterone enanthate (NET-EN) and 1,000 milligrams of a long-acting androgen called testosterone undecanoate (TU) for up to 26 weeks to suppress their sperm counts. The men received two injections every eight weeks. Participants initially provided semen samples after eight and 12 weeks in the suppression phase and then every 2 weeks until they met the criteria for the next phase. During this time, the couples were instructed to use other non-hormonal birth control methods.
Once a participant’s sperm count was lowered to less than 1 million/ml in two consecutive tests, the couple was asked to rely on the injections for birth control. During this period known as the efficacy phase of the study, the men continued to receive injections every eight weeks for up to 56 weeks. Participants provided semen samples every eight weeks to ensure their sperm counts stayed low.
The hormones were effective in reducing the sperm count to 1 million/ml or less within 24 weeks in 274 of the participants. The contraceptive method was effective in nearly 96% of continuing users. Only four pregnancies occurred among the men’s partners during the efficacy phase of the study.
However, side effects such as depression, acne, injection site pain, muscle pain, and others caused 20 subjects to drop out. Festin says that more research is needed to advance this method so that it can be made widely available as a contraception option. “Although the injections were effective in reducing the rate of pregnancy,” he says, “the combination of hormones needs to be studied more to consider a good balance between efficacy and safety.”
The Heart and the Hormone
Two articles stand out to Robert H. Eckel, MD, professor at the University of Colorado Denver and an associate editor for JCEM. With a background in both endocrinology and cardiology, he pays close attention to scientific developments that overlap across both fields.
The first paper that Eckel highlights is “Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease” by Yusuf, S, et al. The study, which was published in the New England Journal of Medicine in May 2016, set out to evaluate the potential benefits of statins in groups that have been underrepresented in previous trials, such as ethnic minorities and patients with intermediate cardiovascular risk.
After collecting data from 12,705 participants across 21 countries, the authors discovered, “Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events (26.5% lower) than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease.”
The other top study, in Eckel’s opinion, is “Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial” by Nissen, S, et al., published in the Journal of the American Medical Association (JAMA) in April.
Between 5% and 20% of patients on statins report muscle-related intolerance, meaning a significant population requires an alternative therapy for lowering lipids. This study investigated the effectiveness of two nonstatin therapies—ezetimibe and evolocumab—in adult patients with a history of statin intolerance.
Of the many major studies to be released in 2016, these are the six that editors from JCEM and Endocrinology selected as their personal picks:
- “Effects of Testosterone Treatment in Older Men.” Snyder et al; N Engl J Med 2016; 374:611–624.
- “Membrane-Localized Estrogen Receptor 1 Is Required for Normal Male Reproductive Development and Function in Mice.” Nanjappa, M, et al; Endocrinology 2016; 157:7 2909-2919.
- “Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease.” Yusuf, S, et al; N Engl J Med 2016; 374:2021-2031.
- “Efficacy and Tolerability of Evolocumab vs Ezetimibe in Patients With Muscle-Related Statin Intolerance: The GAUSS-3 Randomized Clinical Trial.” Nissen, S, et al; JAMA 2016; 315(15):1580-1590.
- “Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore.” Lyon, J, et al; Endocrinology 2016; 157(2):560-9.
- “ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy.” Nixon, M, et al; Sci Transl Med 2016; 8(352):352ra109.
Results demonstrated that evolocumab led to a significantly greater reduction in LDL-C levels after 24 weeks than ezetimibe. However, both drugs saw muscle symptoms in over 20% of participants, and the authors concluded that further testing of long-term effects and safety are needed.
A Bigger Biobank
According to Patricia Brubaker, PhD, FRSC, professor at the University of Toronto and an associate editor for Endocrinology, one particular paper from this past year comes to mind — a study that could lead to a greater number of human islet samples for diabetes research.
Generally, the world of research faces more restrictions now than ever, but there are exceptions to the rule. Every so often a finding indicates that the rules can be loosened, which is what Lyon, J, et al, discovered with “Research-Focused Isolation of Human Islets From Donors With and Without Diabetes at the Alberta Diabetes Institute IsletCore” published in the February issue.
This study uncovered that human islet isolation for science may be able to accept tissue from donors with a wider cold ischemia time (CIT) window.
“Through 142 isolations over approximately five years, we confirm that CIT and glycated hemoglobin each have weak negative impacts on isolation purity and yield, and extending CIT beyond the typical clinical isolation cutoff of 12 hours (to ≥ 18 h) had only a modest impact on islet function,” the authors state.
With more acceptable samples to work with, scientists may be able to further diabetes researcher at a faster rate.
Avoiding Adverse Metabolic Effects
Richard Auchus, MD, professor at the University of Michigan and an associate editor for Endocrinology, cites “ABCC1 confers tissue-specific sensitivity to cortisol versus corticosterone: A rationale for safer glucocorticoid replacement therapy” by Nixon, M, et al., published in the journal Science Translational Medicine in August as one of the most impactful studies of 2016.
“This paper could be revolutionary,” Auchus says.
In treating congenital adrenal hyperplasia, the challenge is keeping excess adrenal androgens at bay while attaining sufficient physiological glucocorticoid replacement. The glucocorticoid replacement therapies currently in place — namely cortisol infusions — almost always come with adverse metabolic effects.
This study indicates that corticosterone is a preferable alternative to cortisol. In patients with Addison’s disease, adrenal androgens were suppressed at similar levels when treated with cortisol or corticosterone, but corticosterone resulted in fewer negative metabolic outcomes. Thus, development of a pharmaceutical therapy using corticosterone could mean better health for people with congenital adrenal hyperplasia.
The past year has brought endocrinology closer than ever to solving some of the most complex diseases and disorders on the planet, as the studies highlighted in this article clearly demonstrate. Though the journey to discovery is often a long one, the achievements of researchers in 2016 show that the field of endocrine science is not slowing down.