EUREKA! The Top Endocrine Discoveries of 2018

For the fourth year running, Endocrine News talks to editors from Endocrine Society publications to get the scoop on the top endocrine discoveries of 2018.

Progress, as they say, is slow, an axiom perhaps nowhere truer than in the field of medicine.  Achieving major breakthroughs can take decades of research and scientific effort. But when that “Eureka!” moment does come, it should be duly recognized. This article compiles highlights from what stood out to eight editors from The Journal of Clinical Endocrinology & Metabolism (JCEM), Endocrine Reviews, and Journal of the Endocrine Society as the most important endocrinology studies of 2018.

Although remaking the field in a single swoop is not likely to happen, it is hard to overstate the enormous leaps forward that endocrinologists made this year, publishing vital research that will ultimately improve peoples’ lives. From developing new clinical tools, to unmasking health threats, to elucidating new intracellular communication pathways, to clarifying disease mechanisms, taken together, these important breakthroughs provide a snapshot of this year’s unalloyed endocrinology gold.

Testosterone Therapy Explained

As reported in Endocrine News’ 2017 “Eureka!” article, Alvin M. Matsumoto, MD, professor at the University of Washington, associate director of the VA Puget Sound Geriatric Research, Education and Clinical Center and an associate editor for JCEM, cited several male reproductive endocrinology papers from The Testosterone Trials as well as one reporting on a harmonized reference range for testosterone levels as landmark achievements. This year, he highlights new guidelines that provided important clinical implications of those collective findings.

“The revised Endocrine Society guideline on testosterone treatment of men with hypogonadism is an important ongoing clinical contribution to the field,” Matsumoto says. “Testosterone Therapy in Men with Hypogonadism: An Endocrine Society Clinical Practice Guideline,” by Bhasin, S, et al. (an Endocrine Society–appointed task force of 10 medical content experts including Matsumoto and a clinical practice guideline methodologist) and published in JCEM in March, updates 2010 guidelines with graded, evidence-based differences regarding how hypogonadism is diagnosed and managed. In short, the diagnosis is made in men who demonstrate signs and symptoms of testosterone deficiency as well as “unequivocally and consistently low serum T concentrations.” Relatedly, using accurate assays for measuring testosterone and repeating those measurements is essential, which is now possible in part owing to “Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe,” by Travison, TG, et al., one of the studies Matsumoto cited for last year’s wrap up.

In men meeting the criteria, testosterone therapy is recommended, particularly in men with diseases of the hypothalamic–pituitary–testicular system; however, in men planning fertility or with certain cancers or other enumerated conditions, testosterone therapy is not recommended. Additionally, for men ages 65 years and older, testosterone therapy should not be routinely prescribed; rather, its appropriateness should be gauged on a case-by-case basis after explanation of the uncertainties of the long-term risks and benefits of treatment.

One of the most significant aspects of the new guideline is its emphasis on patient education and shared decision making between patient and provider. In “Ungraded Good Practice Statements,” the task force underscores the importance of explaining potential risks and benefits of therapy and any associated concerns to the patient in order to keep these fundamental good practices front-of-mind for clinicians.  “Like most areas of medicine, hypogonadism and testosterone treatment is an area where evidence is incomplete,” Matsumoto says. “The Endocrine Society clinical practice guideline provides an ongoing, up-to-date summary of evidence and the quality of evidence that clinicians can use to inform their practice. Guidelines are not cookbooks; they can only supplement, not be a substitute for, good clinical judgment.”

Three More Reasons to Stay Heart Healthy (and a Cautionary Tale on Aspirin)

Also an associate editor for JCEM as well as professor at the University of Colorado Anschutz Medical Campus in Aurora, Robert H. Eckel, MD, selected four cardiovascular papers, two published in JAMA, and two from the New England Journal of Medicine as the studies he found most impactful in endocrinology this year.

From the April issue of JAMA, “Association Between Baseline LDL-C Level and Total and Cardiovascular Mortality After LDL-C Lowering: A Systematic Review and Meta-analysis,” by Navarese, EP, et al., showed that lowering low-density-lipoprotein cholesterol (LDL-C) in patients with higher baseline LDL-C levels reduced mortality from cardiovascular events as well as of total mortality. Nearly 300,000 patients from 34 trials were treated with either intensive or less-intensive LDL-C lowering therapy consisting of statin only (less intensive) or some combination of higher-dose statins, ezetimibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9)-inhibiting monoclonal antibodies (intensive). Meta-regression showed that the intensive LDL-C lowering therapy reduced mortality as well as the secondary end points of myocardial infarction (MI), cerebrovascular events, revascularization procedures, and major cardiovascular events.

“All-cause mortality reduction is what we all want,” Eckel says. “LDL-C being higher before lowering is the best predictor.”

“Association of Cardiovascular Health Level in Older Age with Cognitive Decline and Incident Dementia,” from the August issue of JAMA, by Samieri, C, et al., definitively answered the question many have long wanted to know: Does the suspected association really exist?

“Like most areas of medicine, hypogonadism and testosterone treatment is an area where evidence is incomplete. The Endocrine Society clinical practice guideline provides an ongoing, up-to-date summary of evidence and the quality of evidence that clinicians can use to inform their practice. Guidelines are not cookbooks; they can only supplement, not be a substitute for, good clinical judgment.” – Alvin M. Matsumoto, MD, professor, University of Washington; associate director, VA Puget Sound Geriatric Research, Education and Clinical Center, Seattle; associate editor, JCEM

In a French cohort study, 6,626 individuals ages 65 years or older without history of cardiovascular disease (CVD) or dementia at baseline in 1999 had systematic in-person neuropsychological testing through 2016. Using the American Heart Association’s “My Life’s Simple 7” tool, researchers scored participants with a total derived from values assigned to each of the tool’s seven metrics. Optimally, these are being a nonsmoker; having a body mass index <25; regularly engaging in physical activity; eating fish twice a week or more and fruits and vegetables at least three times a day; and maintaining cholesterol <200 mg/dL, fasting glucose <100 mg/dL, and blood pressure <120/80 mm Hg. Participants were also given a global cardiovascular health score. The more optimal cardiovascular health metrics a person exhibited correlated with lower risk of cognitive decline.

“CVD risk factor control is among the best things we can do to stave off what we all do not want–loss of memory as we age,” Eckel says.” Also stay active and use your brain.”

The two studies from NEJM, published in August and October, respectively, concern type 2 diabetes and cardiovascular health. In “Effects of Aspirin for Primary Prevention in Persons with Diabetes Mellitus,” by the ASCEND Study Collaborative Group, 15,480 adults with diabetes but without CVD were randomized to receive 100 mg of aspirin daily or matching placebo. Over the course of about seven years, those in the aspirin group experienced significantly fewer vascular events, including MI, stroke or transient ischemic attack, or death from any vascular cause than those in the placebo group; however, they experienced significantly more major bleeding events, such as intracranial hemorrhage, sight-threatening bleeding event in the eye, gastrointestinal bleeding, or other serious bleeding.

The upshot, according to Eckel is: “Aspirin may work in reducing CVD events in high-risk patients with diabetes without known CVD disease, but not without more risk of serious bleeding; so, in general, don’t go there.”

“Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes,” by Rawshani, A, et al., investigated whether reducing type 2 diabetes patients’ high risk of death and cardiovascular events is possible. The researchers matched up 271,174 Swedish patients with type 2 diabetes with 1,355,870 controls according to age, sex, and county. They then assessed the type 2 diabetes group for the presence of five risk factors–elevated glycated hemoglobin and LDL-C levels, albuminuria, smoking, and high blood pressure — and followed-up for about five years to quantify the risk for adverse outcomes including death, MI, stroke, and hospitalization for heart failure) as well as to explore how each of the five risk factors is linked with those outcomes. They found that a high glycated hemoglobin level was the strongest predictor of stroke and MI, and smoking was the strongest predictor of death in patients with type 2 diabetes. On the upside, patients with type 2 diabetes whose five risk-factor variables were within target ranges demonstrated the same degree of risk of death, MI, and stroke as that of the control group.

“No surprise,” Eckel says, “but fewer CVD risk factors with diabetes leads to better outcomes than more risk factors.”

What Does Your Gut Say?

Endocrine Reviews editor-in-chief Daniel J. Drucker, MD and senior scientist at the Lunenfeld Tanenbaum Research Institute of the Mt. Sinai Hospital in Toronto, Ontario, points to a paper that establishes a direct connection between our guts and our brains. “A Neural Circuit for Gut-Induced Reward,” by Han, W, et al., and published in Cell in September showed that optogenetic stimulation of vagal sensory neurons that innervate the gut induced dopamine release in mice and motivated them to sustain the resulting reward sensations.

“Gut enteroendocrine cells (EECs) have been classically viewed as sensors of the local nutritional and microbial environment that communicate information via the synthesis and release of circulating peptide hormones,” Drucker says. “The current study expands the versatility of EECs to encompass direct and rapid communication with the enteric, peripheral, and central nervous systems via synthesis and release of neurotransmitters and highlights how EECs serve as central cellular relays for transmission of information from the external environment to convey information about nutrient availability, mucosal integrity, and luminal inflammation, to distal organs and the peripheral and central nervous systems.”

Exercise Tissue Talk

Also from Endocrine Reviews, associate editor Gregory R. Steinberg, PhD, and Professor of Medicine at McMaster University in Hamilton, Ontario gives “Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise” top billing. By Whitham, M, et al., and published in Cell Metabolism in January, this study lends further credence to the notion that tissues communicate via signaling proteins circulating in extracellular vesicles (EVs).

“It’s now well established that exercise elicits beneficial effects across the entire body but how a contracting muscle communicated directly with other organs to exert these effects was not understood,” Steinberg says. In the current study, Whitham and colleagues used high-performance liquid chromatography tandem mass spectrometry to identify muscle-derived cytokines (myokines) that are packaged within EVs and released from contracting muscles during cycling.

“…Researchers have revealed an important correlation of tuberculosis (TB) and diabetes in the U.S. compared to previous reports in different places globally. The authors have provided a cross-sectional comparison of tuberculosis cases with and without diabetes in a TB clinic.” – Takashi Kadowaki, MD, PhD, principal investigator, Kadowaki Lab, University of Tokyo Hospital, Japan

They found more than 300 proteins were increased with cycling and that the EVs tend to cluster in the liver. More research to identify their function is planned. In the meantime, the existence of an exercise-induced EV proteome suggests that inter-tissue communication during exercise stimulates essential biologic processes at the cellular level. “These may be important for mediating the beneficial effects of exercise across the body,” Steinberg says.

High Plasma Leptin and Frailty in Older Adults

Four associate editors for the Journal of the Endocrine Society weighed in with their selections, each taken from JES.

Takashi Kadowaki, MD, PhD, and principal investigator at the Kadowaki Lab at the University of Tokyo Hospital in Japan chose two articles. In “Plasma Leptin Concentration and Sympathetic Nervous Activity in Older Adults with Physical Dysfunction,” by Shibasaki, et al., published in September, researchers examined the relationship between plasma leptin concentration, physical function, and sympathetic nervous system activity in 69 frail Japanese adults 75 years old and older. They found that a higher plasma leptin level is significantly negatively associated with physical function, independent of age, sex, and body mass index. No correlation was found, however, between plasma leptin levels and the sympathetic nervous system, possibly due to the participants’ older ages.

Furthermore, leptin concentration was higher in obese subjects with muscle wasting, suggesting a failure of the sympathetic nervous system’s feedback system. “This study represents an interesting contribution to the knowledge about the relationships between leptin and autonomic cardiovascular regulations and metabolic status in obese sarcopenia,” Kadowaki says.

Diabetes Exacerbates Tuberculosis

Kadowaki also mentioned “The Negative Clinical Impact of Diabetes on Tuberculosis: A Cross-Sectional Study in New Jersey,” by Lardizabal, A et al. “In this article, researchers have revealed an important correlation of tuberculosis (TB) and diabetes in the U.S. compared to previous reports in different places globally,” Kadowaki says. “The authors have provided a cross-sectional comparison of tuberculosis cases with and without diabetes in a TB clinic,” he says. After excluding TB patients with HIV infection, they reviewed 73 cases of TB and found that extent of disease on chest x-ray was higher for diabetes-positive cases compared to diabetes-negative cases and that diabetes-positive cases had higher evidence of cavitation on chest x-ray and were slightly more likely to have positive sputum cultures than diabetes-negative cases.

“The paper offers a clinical look at tuberculosis in the United States that might otherwise be overlooked,” Kadowaki says.

Transgender Population Health

Another JES associate editor, Ana Claudia Latronico, MD, PhD, and professor at Sao Paulo University in Brazil, selected “Health and Cardiometabolic Disease in Transgender Adults in the United States: Behavioral Risk Factor Surveillance System 2015,” by Nokoff, NJ, et al., and published in April. In an effort to fill an information gap on a burgeoning population, this study used national survey data to look at differences in cardiometabolic disease among subgroups of transgender adults including female-to-male (FTM), male-to-female (MTF), and gender nonconforming (GNC) as well as compared these differences with the health status of cisgender adults in the U.S.

Researchers found that, compared to cisgender adults, the FTM subgroup was less likely to be insured. They also found that GNC-F adults were more likely to have poor mental and physical health than cisgender women. Although they expected to find that the MTF subgroup would have higher rates of MI than both cisgender women and men, they found instead that MTF had more MI than only cisgender women.

These findings expose an urgent need for additional study on how best to support the health of the growing transgender population as well as to learn more about the effects of hormone therapy, which a large segment of transgender people use, on cardiovascular health.

Novel Indian Hedgehog (IHH) Gene Mutations Implicated in Growth Disorders

Latronico also mentioned a JCEM paper in pediatric endocrinology from February. “IHH Gene Mutations Causing Short Stature with Nonspecific Skeletal Abnormalities and Response to Growth Hormone Therapy,” by Vasque, GA, et al. “It is an excellent paper with novel findings in the genetic of short stature,” Latronico says. Among 290 patients with autosomal-dominant short stature, researchers performed whole exome sequencing to screen for defects in the IHH gene that regulates endochondral ossification. They uncovered 10 variants that were present in higher numbers than in cohorts without a growth disorder. Some phenotypes had a good response to recombinant human growth hormone therapy.

Detection Bias in Adrenal Adenoma

JES associate editor Paul M. Stewart, MD, FRCP, FMedSci, executive dean and professor at the University of Leeds School of Medicine in the United Kingdom, chose “The Lateralizing Asymmetry of Adrenal Adenomas,” by Hao M, et al., from March.

In cross-sectional and longitudinal studies of 1,376 patients, Hao et al., found that left-sided adenomas were discovered in 65% of patients, right-sided adenomas in 21%, and bilateral adenomas in 14%. Among unilateral adenomas, 75% were left-sided. Notably, left-sided adenomas were significantly more prevalent than right-sided adenomas in each size except the largest, at ≥30 mm, which suggests that right-sided adenomas may be harder to find, rather than being rarer.

“Aspirin may work in reducing CVD events in high-risk patients with diabetes without known CVD disease, but not without more risk of serious bleeding; so, in general, don’t go there.” – Robert H. Eckel, MD, professor, University of Colorado Anschutz Medical Campus, Aurora; associate editor, JCEM

“This study has a surprising outcome and highlighted the predominance of left-sided adrenal adenoma diagnosis, something that many endocrinologists (including myself) had not even thought about,” Stewart says. “One would expect a 50:50 split in adrenal adenomas across the right and left glands as in, for example, in other bilateral organs such as breast and testicular cancer, but this is not been the case and has important clinical consequences.”

Apart from raising the obvious question of “why,” the implications are that adenomas may be getting missed by clinicians. In the case of right-sided disease, this could mean that the tumor has progressed to a large size by the time of diagnosis. Additionally, when bilateral disease is unrecognized, associated conditions will be more difficult to identify and treat. Hao and team urge clinicians to be aware of the lateralizing detection asymmetry while evaluating imaging of patients with adrenal adenomas.

BPA—Stay Away!

Finally, “Experimental BPA Exposure and Glucose-Stimulated Insulin Response in Adult Men and Women,” by Stahlhut, RW, et al., published in October, was chosen by JES associate editor Bülent O. Yildiz, MD, professor at Hacettepe University School of Medicine in Ankara, Turkey, as his top JES pick of 2018. On the basis of findings from animal studies as well as cross-sectional and epidemiological studies in humans that demonstrated disrupted glucose homeostasis on exposure to bisphenol A (BPA), researchers investigated whether BPA alters insulin/C-peptide secretion in humans, using a dose of 50 µg/kg body weight, the amount considered the maximum safe daily dose by both the U.S. Food and Drug Administration and the Environmental Protection Agency.

In two exploratory cross-over studies, non-diabetic participants were tested with and without oral BPA exposure (and thus served as their own controls). In the first experiment, eight healthy young men took the oral glucose tolerance test so that researchers could measure early and late-phase insulin response. Serum HbA1c demonstrated marked within-subject differences in insulin and C-peptide levels between BPA and control sessions. In the second, five men and three postmenopausal women (including a study author) were tested with the hyperglycemic clamp, which allowed glucose to be stabilized prior to dosing of BPA or control, and only late response measured. These results did not replicate the strong positive relationship between HbA1c and the change in insulin response between BPA and control sessions from the first experiment, but they did show the opposite — a significant percentage decrease between control and BPA sessions in late-phase insulin and the maximum concentration of C-peptide as well as an inverse relationship between the percentage change in later-phase C-peptide with HbA1c.

Although this study created some controversy, its implications for U.S. regulatory entities are quite clear. What has been considered a safe dose of exposure, in fact, alters the insulin/C-peptide response to a glucose challenge (by at least a couple of different mechanisms), which may suggest that BPA plays a role in triggering insulin resistance. Clinically, this suggests that anyone predisposed to insulin resistance might consider finding ways to reduce BPA exposure.

— Horvath is a freelance writer in Baltimore, Md., and a frequent Endocrine News contributor. She wrote about the link between obesity and breastfeeding in the October issue.

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