What the HPT Axis Tells Us About Aging in Men

Study looks at super-agers for clues.

with Sandra Aleksic MD

senior man with a subtle smile

People are living longer, and largely aging better, but what drives aging and how can extremely old men inform us about the role the hypothalamic-pituitary-testicular (HPT) axis plays in healthy aging? A recent study has looked at the masculine axis in exceptionally old men to study the age-related function of male reproductive hormones (1).

While men don’t age out of reproduction the way women do, they do see a decline in:

  • sex hormones (testosterone, androgen)
  • sperm production
  • fertility

Between the ages of 20 and 80, testosterone decreases by as much as half (2).

A study from 2013 explored the potential explanations for declining hormone levels in men as they age (3). It studied more than 3,200 men aged 40-79 based in 8 European countries. The authors found four potential reasons for declining sex hormones:

  • Aging resulted in lower free testosterone and increased luteinizing hormone (LH)
  • Obesity resulted in lower total and free testosterone levels
  • Co-morbidities resulted in lower total testosterone with unchanged LH
  • Smokers had higher sex hormone binding globulin (SHBG), LH, and total testosterone, but not free testosterone.

Higher LH can be problematic as some studies show it can predict higher ischemic heart events (4).

Following up on the European Male Aging study, a group of researchers in 2013 wanted to see if lifestyle changes could alter sex hormone levels in aging men (5). They found that weight loss could influence the HPT axis positively, and weight gain negatively. Adverse changes were reversible with weight loss, but not with co-morbidity status.

What about very old men?

Most early work, including the studies above, often focused on men younger than 90, but an ENDO2021 presentation by Aleksic et al. included men up to the age of 106. It also looked at the relationship of the HPT axis with metabolic dysfunction which was missing in many other studies.

The researchers looked at 427 Eastern European Jewish men aged 50-106. Those over the age of 88 had their total testosterone (TT), LH, and SHBG measured, as well as lipids, glucose and body mass index (BMI).

The authors looked at the trend of testosterone levels and any association between the metabolic data and total testosterone. They found that:

  • Total testosterone dropped significantly in men older than 88
  • Primary and secondary hypogonadism increased over age 88
  • There was an inverse association between TT and BMI, serum triglycerides, and random glucose levels
  • There was a positive association between HDL cholesterol and TT
  • TT was not associated with any of the metabolic data or overall survival

Ultimately, for men over 88, it appeared that the lower testosterone levels were probably a result of age-related testicular decline, whereas in younger men, it was a result of HPT dysfunction and was associated with “metabolic derangements.”

“The HPT axis is regulated like a thermostat – if there is too much testosterone produced, this will signal to the hypothalamus and pituitary to reduce production of LH, which will then bring testosterone production down to normal,” says lead author Sandra Aleksic MD, an assistant professor in the department of medicine (endocrinology and geriatrics) at the Albert Einstein College of Medicine in the Bronx.

Flow chart illustrating the function of the HPT axis

The opposite is also true. If the testes don’t make enough testosterone, it signals the hypothalamus and pituitary gland to produce more LH, which brings testosterone back up to normal.

In those who were obese or had diabetes, the hypothalamus was adversely affected, she says, and it doesn’t sense low testosterone levels or send the appropriate signals to manufacture more. “The HPT axis which is dysregulated at the level of the hypothalamus can be viewed as a marker of poor health and unhealthy aging in men,” says Dr. Aleksic. “On the other hand, our work showed that in men who experience healthy aging, like our participants with exceptional longevity, the hypothalamus remains functioning. So if these men develop low testosterone from failure of the aging testes, they will also have elevated LH levels. Properly functioning HPT can be viewed as a marker of healthy aging.”

Aleksic and her team initially hypothesized that low testosterone alone was not the main culprit in unhealthy aging. “But the way the hypothalamus responds to low testosterone levels is more important,” she says. “If it can’t respond properly to low testosterone, that may be a signal that men are not having a healthy aging process.”

Additionally, Dr. Aleksic says that very old men with low testosterone but a normally functioning hypothalamus don’t have the negative survival repercussions that those under 90 have when they have low testosterone because it is often associated with poor metabolic health, including obesity, high blood sugar and high triglycerides.

Some men do, it seems, experience a menopause-like condition, Aleksic adds. “It just occurs about 40 or so years later than in women.” Women have low estrogen production from failing ovaries with a compensatory rise in LH. Men have a low testosterone due to failing testes with a similar rise in LH. She says more than half of men over 100 years experience “male menopause” also referred to as “andropause.”

All Aging Men or an Ethnic Curiosity?

Aleksic suspects these findings can be extrapolated to men who are not of Eastern European Jewish descent, in part because many other findings from the Jewish cohort have been confirmed by other longevity studies that look at more diverse subjects.

Her advice to endocrinologists? Think before starting testosterone replacement therapy in the oldest patients in their practice. Lower testosterone in that group “could be a part of normal aging for them, and not something that requires correction.” As we live longer lives and the number of super-agers increases, it will become more important to correctly determine who should get supplemental testosterone. “Future studies will be critical to establish if testosterone treatments in these men may be more harmful than beneficial.”

This study, which is being prepared for publication, is the largest study of the HPT axis in aging men and the first to find that a large proportion of very old men experience a kind of menopause, Aleksic says. What she wants to see next is longitudinal studies to confirm and expand the findings. “We hope that this will motivate more studies to understand what constitutes normal aging of the endocrine system, with a goal of avoiding potentially harmful interventions targeted at artificially correcting hormone levels that normally change with healthy aging.”

Continue Reading:
Case Break: Low Testosterone Caused by Which Endocrine Condition?
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