Aging and Reproduction Chapter 37 Aging and Reproduction © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.1 The hormonal, follicular, and endometrial dynamics of the normal menstrual cycle from the late luteal phase through menses and the beginning of a new cycle of follicle development, ovulation, and corpus luteum function and decline. Dynamic changes in the frequency of pulsatile gonadotropin-releasing hormone (GnRH) stimulate the integrated actions of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which are responsible for: (1) follicular development with secretion of estradiol (E2), inhibin B (InhB), and inhibin A (InhA); (2) the preovulatory LH surge and ovulation; and (3) secretion of progesterone (Prog), E2, and InhA from the corpus luteum. Secretion of E2 and Prog result in proliferative and secretory changes in the endometrium (Endo), preparing it for implantation should conception occur. If conception does not occur, endometrial shedding follows the decline in hormone secretion, which accompanies demise of the corpus luteum. From Hall JE.19 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.2 Relationships between estradiol (E2), progesterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) over the course of a normal menstrual cycle in midreproductive women aged 18–38 (open symbols) and older reproductive women aged 43–53 (closed symbols). Hormones are standardized to the day of the LH surge (cycle day 0). Note that FSH concentrations in older women are elevated in the presence of comparable (or slightly elevated) levels of estradiol. Inhibin B levels (not shown in this figure) were lower during the follicular phase in older women. Reprinted with permission from Santoro N et al.28 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.3 In early reproductive aging, the decrease in ovarian follicle number results in a decrease in inhibin B feedback on follicle-stimulating hormone (FSH) secretion from the pituitary and increased FSH levels. The decrease in follicle number is also associated with lower levels of anti-Mullerian hormone (AMH), increasing the ovarian response to FSH with: (1) increased recruitment of follicles into the growing pool from which the dominant follicle will be chosen and accelerated follicle depletion; and (2) an increase in aromatase activity, which also helps to maintain estradiol levels. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.4 Daily urine samples over 6 months in a perimenopausal woman indicate marked variability in the pattern of LH, FSH, estrone conjugates (E1C), and progesterone diglucuronide (PDG). The dashed line in the upper panel indicates the upper limit of normal for FSH in young women, while the dotted line in the lower panel indicates the upper limit of normal E1C in young women. Shaded bars indicate cycles in which levels of PDG are consistent with ovulatory cycles. Adapted from Santoro et al.102 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.5 The transition to menopause is characterized by marked variability in the ability to recruit growing follicles from the aging ovary. Combined with the potential independent effects of aging on hypothalamus and pituitary, this variability results in three distinct patterns of hormonal changes and clinical symptoms: (1) the inability of follicle-stimulating hormone (FSH) to stimulate follicle recruitment results in low levels of both estradiol and inhibin B. These primary ovarian changes may be associated with vasomotor symptoms and sleep disturbance and result in the loss of gonadal hormone and peptide feedback at the pituitary. Combined with the possible age-related changes in hypothalamic gonadotropinreleasing hormone (GnRH) secretion (decreased pulse frequency and increased GnRH pulse amplitude), decreased negative feedback results in increased FSH secretion that is augmented by prolongation of the half-life of FSH secondary to low estradiol levels. The black arrows represent mechanistic changes that result in markedly elevated FSH levels; (2) markedly elevated FSH levels stimulate the remaining follicles, often resulting in extremely high levels of estradiol (gray arrows). Prolonged elevations in estradiol are frequently associated with marked breast tenderness, endometrial proliferation, and dysfunctional bleeding; (3) despite follicle development, abnormal patterns of estradiol, combined with the age-related loss of pituitary sensitivity to GnRH, results in inadequate LH surges and anovulation, further increasing the risk of irregular and heavy vaginal bleeding. These events repeat at irregular intervals before the complete loss of ovarian function following the final menstrual period and persistent hypoestrogenism. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.6 Standardization of Menopausal Terminology: The Stages of Reproductive Aging Workshop +10 (STRAW+10) system for reproductive aging in women. FMP, final menstrual period; FSH, follicle-stimulating hormone; AMH, anti-Mullerian hormone. From Harlow et al.10 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.7 Schematic diagram showing age-related changes to hypothalamic regulators of gonadotropin-releasing hormone (GnRH) neurons, from the female rodent literature. In young adults (left), GnRH neurons receive excitatory inputs from kisspeptinergic (KiISS1) neurons from the anteroventral periventricular nucleus (AVPV). GnRH release is also strongly affected by excitatory glutamatergic (GLU) inputs, acting upon N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Pharmacological studies suggest that GABAergic inputs are relatively modest at that age. In addition, glial cells produce neurotrophic factors through ERBB1, ERBB4, insulin-like growth factor 1 (IGF1), and transforming growth factor α (TGFα). In aging adults (right), the balance of these neurotransmitters and neurotrophic factors shifts, with the relative size of inputs to GnRH neurons shown smaller or larger compared to the young adult. GABA, gammaaminobutyric acid. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 37.8 Changes in the hypothalamic-pituitary-gonadal axis with aging in the male. The arrows indicate that the amount of gonadotropin- releasing hormone (GnRH) secreted from the hypothalamus decreases with age as evidenced by frequent sampling studies showing lower luteinizing hormone (LH) pulse amplitude, where LH is used as a surrogate marker of GnRH,276 a more disorderly pattern of release,277 and greater LH suppression after administration of a submaximal GnRH antagonist dose.278 In contrast, there is evidence of heightened pituitary responsiveness to GnRH Kaufman.279–281 Functional studies demonstrate an age-related reduction in the amount of testosterone secreted per LH bolus,282,283 which correlates with the histological demonstration of a reduction in Leydig cell number with aging.284 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition