Sex steroid hormone production declines during reproductive aging
Reproductive aging is defined as the gradual decline in fertility during the aging process. It is accompanied by decreasing levels of circulating sex steroid hormones estrogen, progesterone, and testosterone [
1,
2]. In women, the end of reproductive aging occurs when ovarian follicles drop below a threshold (approximately < 1,000 follicles), resulting in cessation of the menstrual cycle which is termed menopause [
3]. The stock of non-renewing ovarian follicle reserves begins to decline from birth as a result of continuous maturation, ovulation, and atresia [
4]. Ovarian follicles eventually become exhausted by the age of 51, which corresponds to the median age of menopause in the general population [
5]. Because granulosa cells and theca cells of the ovarian follicles are the major sources of sex steroid biosynthesis in women, reproductive aging eventually leads to reduced estrogen and progesterone production [
6], although the drop in progesterone levels surpasses the drop in estrogen levels during the menopausal transition [
7].
In men, reproductive aging is accompanied by a decline in the ability of the testes to produce testosterone [
8]. Leydig cells of the testes provide a significant source of testosterone in males. Reduced number of Leydig cells and decreased ability to respond to intracellular signaling during aging may contribute to low testosterone levels in aging men [
9‐
11]. Testosterone production gradually decreases by approximately 1%–3% per year, beginning around the age of 35–40 years [
12], and can eventually result in hypogonadism (<325 ng/dL of total serum testosterone) in older men. Partial androgen deficiency (sometimes referred as andropause) occurs in ~20% of men by age 60 and ~50% of men by age 80 [
13].
Sex steroid hormone replacement may extend healthspan but not lifespan
The decline in sex steroid hormones with age is thought to reduce healthspan. In women, menopause correlates with several age-related diseases, such as hot flashes, bone loss, weight gain, vaginal atrophy, night sweats, sleep problems, mood changes, and skin atrophy [
14,
15]. Estrogen replacement alleviates some of these menopausal symptoms, resulting in lowered frequency and severity of hot flashes, decreased bone loss and vertebral fractures, and increased bone mass [
16]. Estrogen can also provide many beneficial effects to skin physiology and protects against skin aging [
17]. In female mice, loss of sex steroid hormones by ovariectomy also presents numerous age-related diseases similar to those found in humans, such as accelerated bone loss, decreased uterine weight, increased fat mass, and impaired wound healing, which can all be alleviated by estrogen replacement [
18‐
20].
Because estrogen increases the risk of endometrial cancers to women, progesterone supplements were added to estrogen replacement therapies to inhibit the proliferative effects of estrogen in the uterus. Estrogen plus progesterone replacement therapy provides many beneficial effects similar to those of estrogen alone treatment, but it also seems to increase the risk for other types of diseases, such as breast cancer [
16]. Findings from the Women’s Health Initiative show a high risk-to-benefit ratio of using hormone replacement therapies. However, criticisms of the regimens used suggest that health status or age at initiation of treatment may contribute to severity of the side effects associated with hormone replacement therapy [
21,
22]. Analysis of the current Kronos Early Estrogen Prevention Study (KEEPS) [
23] and the Early versus Late Intervention Trial with Estradiol (ELITE) will hopefully address whether hormone replacement therapy is beneficial within a critical window of time [
24,
25].
In men, hypogonadism at old age is correlated with age-related symptoms, such as impotence, decreased virility, decreased libido, and limited physical vigor [
26]. However, it remains debatable whether these age-related phenotypes are mainly due to the decline in testosterone levels. In fact, while testosterone replacement can alleviate some of the aging characteristics associated with partial androgen deficiency [
27‐
31], testosterone supplementation in aged men does not always seem to improve physical function [
32]. Moreover, increased skeletal muscle mass due to testosterone does not seem to be specific to aged men [
33]. In male mice, testosterone can increase skeletal muscle regeneration [
34], but it may also accelerate aging phenotypes in other tissues, such as heart and kidneys [
35]. Hence, the overall impact of testosterone on healthspan needs further investigation. The current Testosterone Trial will hopefully address the benefit and risk of testosterone replacement in hypogonadal men above the age of 65.
While sex steroid hormones may potentially extend healthspan, the effect of sex steroid hormones on lifespan is less clear. For example, while increasing age at menopause in women is associated with an overall increased lifespan [
36], menopausal age does not seem to predict lifespan in non-human primates, as chimpanzees rarely reach menopause whether in captivity or in the wild [
37,
38]. Moreover, the length of postmenopausal years (that is, period of reduced sex steroid hormones) does not seem to be proportionally correlated with age at death [
39]. In males, castration in rats and dogs increases lifespan [
40,
41]. However, while some studies show that castration in humans (that is, eunuchs) extends lifespan [
42,
43], another report mentions no change in lifespan [
44]. Nevertheless, several studies have linked reduced sex steroid hormones to many age-related diseases. Hence, while loss of sex steroid hormones may not significantly influence longevity and lifespan, reduced sex steroid hormones can potentially shorten overall healthspan.