Neuroendocrinology of Aging

Perimenopause

Characteristics inherent to the perimenopausal transition have been extensively documented and chronicled. The Stages of Reproductive Aging Workshop (STRAW) criteria, an international collaborative effort, along with the Study of Women Across the Nation (SWAN), based on an ethnically diverse U.S. population, have contributed to the classification of the perimenopausal transition while simultaneously identifying the complexity of symptoms and ethnic diversity of perimenopausal phenotypes. Normal reproductive aging in women is characterized by three distinct phases that can span years—perimenopause (also known as the menopause transition), menopause, and postmenopause. According to STRAW, reproductive senescence can be subdivided into three distinct stages—perimenopause, menopause, and postmenopause. Variable cycle length, variable intervals between cycles, vasomotor symptoms (hot flushes), and wide variations in steroid hormone levels characterize the menopausal transition. One year of amenorrhea is considered to be the end of the perimenopause stage and onset of menopause. The end of the amenorrheic year commences the onset of the postmenopausal stage, which is also subdivided into early and late components. Early postmenopause is defined as 4 years since the last menstrual period and is followed by late-stage postmenopause, which thereafter defines the neuroendocrine state.

Perimenopause is characterized by menstrual and endocrine changes in the hypothalamic-pituitary-ovarian-uterine axis that lead inexorably to reproductive senescence. During perimenopause, ovulation occurs irregularly as a result of fluctuations in hypothalamic and pituitary hormones. In late-phase perimenopause, nearly half of the cycles are anovulatory. In the ovulatory cycles, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and 17β-estradiol levels increase with progression of the stage of reproductive aging and, in the luteal phase, the serum progesterone level is decreased. The early-cycle (ovulatory and anovulatory) inhibin B level decreases steadily across the STRAW stages and is largely undetectable during elongated ovulatory and anovulatory cycles during the transition. The decline of inhibin B levels during early perimenopause results in an increase in follicle-stimulating hormone (FSH) levels, with no significant change in inhibin A or estradiol levels. FSH levels may rise during some cycles but return to premenopausal levels in subsequent cycles. Further complicating the determination of FSH concentration is the pulsatile pattern of secretion. The variability in hormone levels creates difficulties in interpreting a single laboratory test result but an increase in FSH levels continues to be a clinical marker of ensuing menopause and postmenopause.

In late-stage perimenopause, concentrations of 17β-estradiol are highly variable; levels can be persistently low, as might be expected, but can also be abnormally high. A high 17β-estradiol concentration is associated with increased vulnerability to neurodegenerative insults and neuronal cell death, but does not reduce the persistently high FSH and LH levels. Remarkably, the cyclicity of progesterone appears to remain generally intact, whereas the level of progesterone can vary from a normal value to a high spike of progesterone to an undetectable level. When considering relationship between steroid exposure and neurologic symptoms of menopausal transition, plasma levels of ovarian hormones are not predictive of brain concentrations of steroids.

The hallmark symptom of the menopausal transition is the hot flush, also referred to as hot flashes. Although the hot flush is evidenced by vasodilation, the signal to vasodilate is neurologic. The neural mechanisms underlying the signature symptom of menopause remain unclear. Hot flushes are most likely to occur during late-stage perimenopause and early-stage postmenopause. The prevalence of hot flushes increases substantially in early perimenopause, reaches a maximum in late-stage perimenopause, remains high into the early postmenopausal stage, and returns to a low but persistent prevalence in late-stage postmenopause. The prevalence of hot flushes can range from 30% to 80%, depending on ethnicity, with African American women experiencing the greatest frequency and longest duration. Women aged 40 to 60 years who have had a hysterectomy and oophorectomy are at high risk for hot flushes. In most women, hot flushes are transient. Hot flush frequency and severity abate within a few months in 30% to 50% of women and resolve in 85% to 90% of women within 4 to 5 years. However, 10% to 15% of women continue to have hot flashes into late-stage postmenopause.

Although the mechanism underlying hot flushes remains unknown, the resemblance to heat dissipation responses has led to a focus on thermoregulation by the anterior hypothalamus. However, the exact role of estrogen in the pathogenesis of hot flushes remains unresolved. Increasingly, evidence has linked metabolic dysregulation to the occurrence of hot flashes. Estrogen levels do not differ substantially between postmenopausal women who have hot flushes and those who do not, but the withdrawal of estrogen can induce hot flushes in women with gonadal dysgenesis who have undergone estrogen therapy that was subsequently discontinued, suggesting that estrogen withdrawal plays a role in the cause of hot flashes. In SWAN, a large U.S. multicenter cohort study, higher levels of FSH were the only hormonal measure independently associated with flushing after adjustment for levels of estradiol and other hormones. Women undergoing pharmacologic therapy to antagonize estrogen receptor activation by selective estrogen receptor modulators (SERMs) or inhibit estrogen synthesis using 5α-reductase inhibitors for breast cancer experience a significant increase in the frequency of hot flashes.

Postmenopause

Like perimenopause, postmenopause is separated into early and late stages. Early postmenopause is defined as 4 years since the final menstrual cycle. Levels of FSH continue to be high during early menopause and remain elevated throughout the late stage of postmenopause. During the early postmenopause phase, there is a significant decline in ovarian hormones to a permanently low level, which is associated with accelerated bone loss. Postmenopausal women undergo two phases of bone loss, whereas aging men undergo only one. In women, menopause initiates an accelerated phase of predominantly trabecular bone (also known as cancellous and spongy bone) loss that declines over 4 to 8 years; this is followed by a slow phase that disappears after 15 to 20 years, when severe depletion of trabecular bone stimulates counterregulatory forces that limit further loss. The accelerated phase results from the loss of the direct repressive effects of estrogen on bone turnover, which is mediated by estrogen receptors in osteoblasts and osteoclasts. During menopause, bone resorption increases by 90%, whereas bone formation markers increase by only 45%. In the ensuing slow phase, the rate of trabecular bone loss is reduced, but the rate of cortical bone loss can be increased. Bioavailable serum estrogen and testosterone levels decline in aging men, and bioavailable estrogen is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but estrogen deficiency is the major determinant of age-related bone loss in both genders. Trabecular bone has low density and strength but a very high surface area and fills the inner cavity of long bones. The external layer of trabecular bone contains red bone marrow, in which hematopoiesis occurs and most of the arteries and veins of bone organs are found.

A wide range of pharmacologic agents are available to prevent and treat osteoporosis, including antiresorptive estrogen, SERMs, bisphosphonates, calcitonin, and anabolic therapies, including parathyroid hormone (PTH—PTH1-34 or PTH 1-84) and agents with an as yet undetermined mechanism of action, such as strontium ranelate. Corrections in general deficiencies in calcium, vitamin D, or both are first-line therapeutic interventions.