24.10: Hormones can affect health and longevity.

Sometimes the links between cause and effect in biological systems appear straightforward. Take, for example, the results from one of the most appalling “experiments” ever conducted. In the early 1900s, many men committed to sanitariums were castrated. In a case-controlled study, the castrated men were compared with non-castrated, institutionalized men, born in the same year and with the same estimated IQ. It turned out that the median longevity of the 297 castrated men, at 69.3 years, was almost 14 years longer than that of the 735 men in the control group. Similarly, data from analyses of more than 1,000 cats (male and female) showed that sterilized cats live significantly longer than those not sterilized. Among males, for example, those not castrated lived a mean of 5.3 years, while castrated males had a mean life span of 8.1 years (FIGURE 24-24).

Laboratory mice also have significantly lengthened life spans when sterilized. And in similar experiments, female fruit flies exposed to high temperature or X rays experienced a dramatic reduction in ovary size, a severe drop in egg-laying rate, and an accompanying 73% increase in life span. Other researchers found that the amounts of reproductive hormones in the bloodstream of mice were significantly reduced among calorie-restricted males and females compared with controls—animals given access to as much food as they wanted. Mice on the low-calorie diet lived more than 40% longer than those with unlimited access to food. All of these results suggest that reducing the levels of circulating reproductive hormones increases longevity.

Hormones probably have their significant impact on longevity because the rate of cancer occurrence—in rodents as well as in humans—is closely related to the concentrations of circulating reproductive hormones, such as estrogen.

• Increased lifelong exposure to estrogen is associated with increased rates of cell division and, consequently, increased cancer risk.
• High concentrations of estrogen in the bloodstream are associated with an increased incidence of endometrial cancer.
• Women taking oral contraceptives and women giving birth to higher numbers of children—both of which reduce a woman’s lifetime exposure to estrogen and other hormones produced by developing follicles—have decreased incidences of ovarian cancer. An analysis of 20 studies reported that five years of taking oral contraceptives reduced women’s lifetime risk of ovarian cancer by approximately 50% (FIGURE 24-25).

There is similar evidence of increased cancer risk linked to circulating levels of progesterone and testosterone.

These seemingly straightforward results, however, lead us to an example that illustrates the extreme complexity and interrelatedness of the body’s physiological systems. It would seem, given the results above, that longevity should be decreased by hormone replacement therapy, which generally involves supplementation of estrogen (or estrogen and progesterone), following menopause—which, typically beginning in the late forties to early fifties, is characterized by the cessation of monthly ovulation and reduced production of estrogen and progesterone by the ovaries. In fact, though, almost all studies of hormone replacement have found that the treatment reduces the annual risk of death by about 25% and leads to increased longevity.

How can this increased longevity be reconciled with observations on the adverse effects of estrogen? It turns out that estrogen reduces circulating levels of cholesterol, which can reduce the risk of death from heart disease, the top killer of elderly women. Heart disease kills significantly more women than do breast cancer and cancers of the reproductive system, so any treatment that reduces heart disease is likely to increase longevity, even if it increases the risk of breast cancer and reproductive system cancers.

Nonetheless, as a consequence of the complex nature of these results, there is still confusion and concern when it comes to hormone replacement therapy, and the debate continues. In 2013, a review of studies on the mortality risks of hormone replacement therapy concluded that for younger post-menopausal women (under 60 years of age), there is a significant reduction in mortality risk associated with hormone therapy, but that the benefit is reduced or absent among older women (over 70 years of age). And so, while there are several strong links between hormones and health and longevity, the complex and myriad ways in which hormones can affect health make it difficult to make simple predictions about the influence of any hormone on health and longevity.