Pathophysiology of Ovarian Function in the Human Female Chapter 29 Pathophysiology of Ovarian Function in the Human Female © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.1 The decline in follicle number in the human ovary with age. Source: Data compiled from various sources. 48–51 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.2 Stages of human follicle development. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.3 Possible mechanisms to provide inhibition of activation of primordial follicles in the mammalian ovary. (A) Inhibitory signal from grow- ing follicles; (B) primordial follicles produce a local factor (or factors) that inhibits their neighbors from activating; (C) an inhibitory factor produced by the ovarian surface epithelium. 60 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.4 Neighboring primordial follicles inhibit activa- tion of follicle growth. The proportion of follicles that are growing is inversely related to the number of primordial follicles within a 10 μm radius, suggesting that neighboring primordial follicles inhibit each other from initiating growth (juvenile mouse ovary day P8). 60 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.5 The human menstrual cycle. Source: From Ref. 66. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.6 Mathematical modeling of growth trajec- tory of follicles in (A) ovulatory and (B) anovulatory poly- cystic ovary. Time and maturity are in arbitrary units. By applying Lacker’s model, 74 it is suggested that in anovula- tory PCOS: (1) the primary cause of follicular dysfunction is at the level of the ovary, rather than the pituitary, and is characterized by variable responsiveness of follicles to FSH; (2) arrested follicles have different properties from healthy follicles; (3) the abnormal response to gonadotropins is best characterized by enhanced sensitivity to FSH (and LH) in a subpopulation of follicles; and (4) those follicles that are hyperresponsive to gonadotropins produce a high enough concentration of circulating estradiol to suppress FSH to a level that is too low to encourage further development of healthy follicles in the cohort. See also the section Etiology and Pathogenesis of PCOS: Anovulation, Androgen Excess, and Disordered Follicle Development. Source: Data are from Ref. 73 and Ref. 63. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.7 LH secretory patterns in (A) a normal woman with regular menses, studied in the midfollicular phase; (B) a woman with partially recovered weight loss-related amenorrhea; and (C) a woman with a persistently low BMI. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.8 Heterogeneity of pulsatile LH secretion in women with PCOS showing (A) elevated mean LH and high-amplitude pulses; (B) levels of LH that fall into the normal range (2–12 U/L) (although still above the mean level in normal subjects), with occa- sional high-amplitude pulses; and (C) normal mean LH and normal pulse amplitude. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.9 Proposed developmental etiol- ogy of polycystic ovary syndrome (PCOS). 162,163 It is suggested that the ovary is genetically predis- posed to hypersecrete androgens, perhaps as early as intrauterine life but certainly during the activa- tion of the hypothalamic–pituitary–ovarian axis that occurs transiently in infancy and in a sustained manner at puberty. Higher than normal circulat- ing levels of testosterone “program” the hypotha- lamic–pituitary unit to produce high tonic levels of luteinizing hormone (LH), and also amplify the physiological insulin resistance of puberty. Higher than normal concentrations of LH and insulin fur- ther enhance ovarian androgen production and may contribute to the mechanism of anovulation. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.10 Production of androstenedione (median, range) by human theca cells in primary culture. Greatly increased androgen production by cells from women with polycystic ovaries is shown. Note the logarithmic scale of the Y-axis. LH stimulated androstene- dione production by both normal (1.7-fold) and PCO theca (1.8-fold, p < 0.005). Source: Adapted from Ref. 182. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.11 Serum LH concentrations in women with poly- cystic ovaries on ultrasound who were studied in the follicular phase of spontaneous cycles or whilst taking the combined oral contracep- tive (COC). Note the reduced suppression of LH (p < 0.05) in women with PCOS during COC treatment. Source: Data adapted from a study of the prevalence of PCOS in women in the general population by Ref. 196. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.12 Proposed mechanisms for increased density of preantral follicles in women with PCOS. (A) Possible mechanisms for increased initial density are (i) more cell division in PGCs leading to (ii) increased endowment of primordial; and/or (B) increased survival of preantral follicles. Source: Adapted from Ref. 200. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.13 Granulosa cell proliferation is increased in pren- tral follicles of women with PCOS. Proportion of preantral ovarian follicles expressing the proliferation marker mini-chromosome main- tenance protein 2 (MCM2) in women with normal ovaries, and two groups of women with PCOS—those with regular ovulatory cycles (ovPCO) and those with anovulation (anovPCO) (*p = 0.03). Source: Data from Ref. 207. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.14 Relationship between granulosa cell number and oocyte diameter in preantral follicles from normal and polycys- tic ovaries. Note the discordant pattern in follicles from women with anovulation and PCOS. 207 © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.15 Sum of serum insulin concentrations during a standard 75 gm oral glucose tolerance test (median and interquartile range), and insulin sensitivity (mean ± SEM) in three groups of weight- matched subjects: women with normal ovaries and regular cycles; women with polycystic ovaries, androgen excess, and regular cycles (ovPCO); and women androgen excess and anovulation (anovPCO). Hyperinsulinemia and insulin resistance are features of anovPCO but not ovPCO. Source: Data from Ref. 190. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition

FIGURE 29.16 Mean serum LH (filled circles, day −20) and FSH (filled squares, day −20) concentrations before treatment; and LH (filled circles with dashed lines), FSH (filled squares with solid line), and estra- diol (filled triangles with dotted line) during induced mono-ovulatory cycles in women with anovulatory PCOS treated with low-dose FSH. Serum FSH levels are raised to the normal early follicular phase range but show a fall toward day 0 (days normalized to start of the LH surge or injection with human chorionic gonadotropin), indicating preserva- tion of the normal negative feedback control of FSH in the late follicular phase despite a fixed dose of exogenous FSH from day 10 onward. Note also the suppression of high LH levels during the late follicular phase. © 2015, Elsevier, Inc., Plant and Zeleznik, Knobil and Neill's Physiology of Reproduction, Fourth Edition