A gradual alteration in the mechanisms underlying reproduction and fertility characterizes the aging process in human females. These changes culminate in menopause, conventionally defined as a cessation of menstrual cycles that marks the end of reproductive capacity. In fact, a central and defining event in menopause is the discontinuation of ovulation, which is correlated with a number of structural and functional changes in the reproductive axis. Despite several decades of research, a degree of uncertainty remains as to whether nonhuman primates undergo menopause, and whether they are suitable models of human reproductive senescence. We review some of the controversies that have clouded our understanding of reproductive aging in nonhuman primates, including issues of definition, timing, comparability of data from wild versus captive populations, and cross-species comparisons. The existing data support the view that menopause occurs in a number of primate species, and is not unique to humans.

Fifteen female rhesus monkeys (Macaca mulatta), ranging in age from 8 to 34 years, were studied for one year to characterize the endocrine and menstrual changes associated with menopause in this species. Five monkeys were premenopausal; these younger monkeys, ages 8-1 1 years, menstruated and showed cyclic ovarian activity during the 12-month study period, as evidenced by menses and periodic elevations of serum estradiol (E,) and luteinizing hormone (LH) concentrations. Four females, ages 24-26 years, were in transition to menopause. Two of these perimenopausal females menstruated and secreted E, and LH in a periodic fashion; the other two females showed elevated LH concentrations, consistently low E, levels, and no evidence of menstruation. Six females, ages 27-34 years, were clearly postmenopausal; LH concentrations were high, whereas E, concentrations were uniformly low. There was a significant inverse correlation between basal E, concentrations and age, and a significant positive correlation between age and LH concentrations across all 15 animals. Hormonal changes indicative of ovulation, when they occurred, were generally restricted to the winter and early spring months. Histological analysis of ovaries from four postmenopausal females revealed little or no evidence of active folliculogenesis. These data indicate that menopause in female rhesus monkeys does not occur until the second half of the third decade of life. o 1995 Wiley-Liss, Inc.

Introduction We and collaborators discovered that flickering lights and sound at gamma frequency (40 Hz) reduce Alzheimer's disease (AD) pathology and alter immune cells and signaling in mice. To determine the feasibility of this intervention in humans we tested the safety, tolerability, and daily adherence to extended audiovisual gamma flicker stimulation. Methods Ten patients with mild cognitive impairment due to underlying AD received 1‐hour daily gamma flicker using audiovisual stimulation for 4 or 8 weeks at home with a delayed start design. Results Gamma flicker was safe, tolerable, and adherable. Participants’ neural activity entrained to stimulation. Magnetic resonance imaging and cerebral spinal fluid proteomics show preliminary evidence that prolonged flicker affects neural networks and immune factors in the nervous system. Discussion These findings show that prolonged gamma sensory flicker is safe, tolerable, and feasible with preliminary indications of immune and network effects, supporting further study of gamma stimulation in AD.

In female rhesus monkeys (n = 12) housed in a seminatural environment, serum gonadotropin and steroid levels fluctuated annually in a pattern indicative of a seasonally restricted period of ovulatory cycles in the fall and winter and anovulatory cycles in the spring and summer. This seasonal endocrine rhythm occurred independent of pregnancy and lactation, although the presence of a suckling infant delayed the onset of ovulation in the fall by 81 +/- 3.7 days (Dec. 4 vs. Sept 14). Except for serum PRL, levels of gonadotropin and ovarian hormones were similar in lactating and nonlactating females during the spring and summer anovulatory months. Serum levels of LH (less than 10 ng/ml), FSH (less than 4 micrograms/ml), and 17 beta-estradiol (E2; less than 30 pg/ml) were low throughout the summer anovulatory period, exhibiting a significant rise approximately 20 days before first ovulation. Serum progesterone levels were low throughout the 100 days before ovulation (less than 0.5 ng/ml) and did not rise until ovulation occurred. PRL levels remained elevated (greater than 20 ng/ml) in lactating females until 50 days before the first ovulation of the breeding season, but were low throughout the ovulatory, anovulatory, and ensuing ovulatory periods (less than 10 ng/ml). During the breeding period, females exhibited from two to six ovulations. Although the first ovulation of the breeding season occurred within a 40-day period for all females, a subset (n = 6) ceased ovulations significantly earlier than the remaining six females (Jan. 26 vs. March 3). The early cessation of ovulation for these females was associated with significantly lower body weight. After the last ovulation, FSH and E2 fell and remained low, at levels indistinguishable from those of the ensuing spring-summer anovulatory period. In contrast, in females who ceased ovulations later in the breeding season, the period following the luteal phase of the last ovulation was characterized by E2 and gonadotropin levels that were intermediate between those of the anovulatory months and normal follicular phase values. Serum progesterone levels were slightly but significantly elevated following the last ovulation for both groups of females. These data indicate that low basal levels of gonadotropin secretion during the seasonal anovulatory period may result from diminished GnRH secretion or from an alteration in pituitary sensitivity to GnRH stimulation. These data further suggest that the timing of ovulations and associated changes in the neuroendocrine system controlling gonadotropin secretion may be mediated by an environmental variable.

Rhesus monkeys in seminatural environments exhibit a distinct seasonal mating cycle with conceptions restricted to the fall and winter months. In the present study, the characteristics of menstrual cycles were examined during a 1-year period in twelve rhesus monkeys in whom pregnancy was prevented. Menses occurred throughout the year, but ovulations were observed only in the fall and winter months. Menses in the spring and summer months occurred irregularly and were associated exclusively with anovulatory cycles. The total number of ovulations exhibited by these females during the breeding season ranged from two to six and was positively related to body weight, mean luteal phase progesterone (P) levels of normal cycles and social dominance rank. Ovulations with a short luteal phase were exhibited by four females (seven cycles), with the likelihood of occurrence increasing as the breeding season progressed. The incidence of abnormal cycles was predicted from the linear combination of parity, body weight and luteal phase P of normal ovulatory cycles. These results suggest that during the seasonally delimited period of ovulation, females exhibit a range in the quality and quantity of ovulations which may be predicted by certain idiosyncratic physical and behavioral traits.