1. Control of the Menstrual Cycle
Chapter 28
Control of the Menstrual Cycle
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2. FIGURE 28.1 Profiles of the concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and inhibins throughout the human menstrual cycle. Source: Redrawn from Ref. 47 with permission, Copyright 1996, The Endocrine Society.
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3. FIGURE 28.2 Multiunit electrical activity (MUA) recorded from the mediobasal hypothalamus in a normal monkey on day 5 of the follicular phase of the menstrual cycle (A) and in an ovariectomized animal (B). Note the association of the MUA volleys with the initiation of luteinizing hormone (LH) pulses and the shorter duration of the volleys in the presence of the ovary. Source: Reproduced from Ref. 52 with permission, Copyright 1991, S. Karger AG, Basel.
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4. FIGURE 28.3 A hemi-coronal section through the mediobasal hypothalamus of a castrated rhesus monkey at the level of the arcuate nucleus (Arc), the posited site of the gonadotropin-releasing hormone (GnRH) pulse generator. This figure is reproduced in color in the color plate sec­tion. The section was doubled labeled by immu- nofluorescence for GnRH and kisspeptin. Top panel, a confocal image of the distribution of GnRH cell bodies and fibers; middle panel, also a confocal image of the same section showing the corresponding dis- tribution of kisspeptin cell bodies and fibers. The lower panel shows the merged image. Castration results in an upregulation of kisspeptin expression that is associated with robust GnRH pulse generator activ- ity. Note that GnRH cell bodies at this level of the hypothalamus are found lateral to the kisspeptin perikarya in Arc: both sets of neurons send projections to the median eminence (ME) where they closely intermingle. The ependymal lining of the third ventricle (V) may be seen on the right-hand side of the section. Scale bar 100μm. Source: Rearranged from Ref. 57, with permission, Copyright 2008, The Endocrine Society.
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5. FIGURE 28. 4 Pattern of human follicular development
FIGURE 28.4 Pattern of human follicular development. Growth of follicles from the primordial (approximately 0.03 mm diameter) to the small antral stage (4–5 mm diam- eter) is characterized principally by proliferation of granu- losa cells and takes greater than 120 days to complete. The maturation of a small antral follicle to a preovulatory fol- licle (approximately 20 mm diameter) takes approximately 15 days. See Ref. 98 for more details.
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6. FIGURE 28.5 Ovarian responses in a cynomolgus monkey that received hourly pulses of purified human follicle-stimulating hor- mone (FSH) and human luteinizing hormone (LH). The concentra- tion of FSH in the infusate was increased every 4–5 days until estrogen secretion became evident; thereafter, the concentration of FSH in the infusate was reduced by 12.5% per day for 5 days. Estrogen secretion, reflecting the presence of a maturing follicle, was stimulated when plasma concentrations reached ∼20 mIU/ml. When plasma FSH con- centrations were reduced to levels that were unable to initiate estrogen secretion (10–15 mIU/ml), the production of estrogen by the stimu- lated follicle continued to increase in an exponential manner. Source: Reproduced from Ref. 200, with permission, Copyright 1986, The Endocrine Society.
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7. FIGURE 28.6 Induction of ovulatory menstrual cycles in women with primary hypothalamic amenorrhea with an unvarying pulsatile gonadotropin-releasing hormone (GnRH) treatment (5.0 μg GnRH pulse IV every 60 min). Note the close similarities in hormonal profiles of the women with amenorrhea and treated with GnRH and normal controls depicted by the area between the broken lines. Day 0, day of the preovulatory luteinizing hormone (LH) surge. Source: Reproduced from Ref. 225, with permission, Copyright 1991, The Endocrine Society.
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8. FIGURE Frequency of gonadotropin-releasing hormone (GnRH) pulse generator activity (MUA volleys per hour) monitored by radiotelemetry during the menstrual cycle of unrestrained rhesus monkeys, with accompanying time courses of luteinizing hormone (LH), estradiol, and progesterone. Data are normalized to the day of the mid-cycle LH peak (day 0). Each point represents the mean ± stan- dard error of the mean (N = 5–12 observations). Note the slower fre- quency of the GnRH pulse generator at night during the follicular phase, the abrupt reduction in pulse generator activity with the onset of the LH surge, and the slower frequency of the pulse generator dur- ing the luteal phase in comparison with its activity during the follicular phase. (MUA, multiunit electrical activity.) Source: Reproduced with per- mission from Ref. 53, Copyright 1991, The Endocrine Society.
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9. FIGURE The follicle-stimulating hormone (FSH) threshold model for the selection of the preovulatory follicle. During the luteal phase of the menstrual cycle, circulating FSH concentrations are held below the FSH threshold by secretions of estrogen, progesterone, and inhibin by the corpus luteum and growing follicles do not advance beyond the preantral stage and undergo atresia. Upon the regression of the corpus luteum at the end of the menstrual cycle, the negative feedback restraint on FSH secretion is released and FSH concentrations rise above threshold levels. One (or occasionally more) of the matur- ing preantral follicles is stimulated in response to the elevation of FSH and develops both the P450arom enzyme and luteinizing hormone (LH) receptors. The acquisition of P450arom produces a rise in sys- temic levels of estradiol that results in the suppression of FSH secre- tion, which, in turn, prevents the maturation of less mature follicles. The FSH-stimulated induction of LH receptors and the acquisition of LH responsiveness of granulosa cells of the stimulated follicle permit the FSH-stimulated follicle to mature in the presence of FSH concen- trations that are insufficient to stimulate the maturation of other less mature follicles that undergo atresia due to the lack of sufficient FSH stimulation.
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10. FIGURE 28. 9 Conventional controlled ovarian stimulation pro- tocol
FIGURE 28.9 Conventional controlled ovarian stimulation pro- tocol. Recombinant FSH or human menopausal gonadotropins are administered to elevate blood follicle-stimulating hormone (FSH) con- centrations above the threshold level, which results in the stimulation of preovulatory follicular development. Prolonged treatment with FSH may result in asynchronous recruitment and maturation of follicles, which may lead to recovery of suboptimal oocytes from less mature follicles as well as increasing the number of smaller follicles, which could result in ovarian hyperstimulation.
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11. FIGURE A model of the neuroendocrine mechanisms underlying the positive and negative feedback actions of ovarian estradiol (E2) on luteinizing hormone (LH) secretion during the men- strual cycle. In this model, the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator is located in the arcuate nucleus, which contains one of the two major hypothalamic populations of kisspeptin neurons (the second population of kisspeptin neurons is found in the anteroventroperiventricular nucleus (AVPV) in the pre- optic area). The negative feedback action of E2 that regulates tonic LH secretion during the follicular phase and luteal phase (in combi- nation with progesterone) is exerted on the GnRH pulse generator to primarily suppress GnRH pulse amplitude and on the pituitary to inhibit responsiveness to pulsatile GnRH stimulation. In the mon- key, the positive feedback action of E2, which triggers the preovula- tory LH surge, is also exerted within the medial basal hypothalamus (MBH) and at the pituitary. In the human female, the significance of the MBH in mediating the positive feedback action of estradiol is less clear: in both species positive and negative feedback actions of E2 solely at the pituitary level are sufficient for menstrual cyclicity and ovulation.
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12. FIGURE Serum luteinizing hormone (LH) and progester- one concentrations in medial basal hypothalamus (MBH)-lesioned rhesus monkeys whose menstrual cycles were restored by a pulsa- tile infusion of synthetic gonadotropin-releasing hormone (GnRH). The top panel illustrates serum LH and progesterone concentrations of animals that received GnRH at a frequency of 1 pulse/h throughout the menstrual cycle. Note that these animals have luteal phases of nor- mal duration. The bottom panel illustrates data from animals in which the infusions of GnRH were terminated on day 8 of the luteal phase. Serum LH and progesterone concentrations fell rapidly upon the ces- sation of GnRH treatment and premature menses were observed in all animals. Source: Reproduced with permission from Ref. 341, Copyright 1984, The Endocrine Society.
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13. FIGURE The primate corpus luteum is capable of recover- ing from a transient withdrawal of pituitary gonadotropin support. Medial basal hypothalamus (MBH)-lesioned rhesus monkeys whose menstrual cycles were driven by exogenous gonadotropin-releasing hormone (GnRH) were deprived of the GnRH infusion from days 8–11 of the luteal phase of the menstrual cycle. During the interval of deprivation of gonadotropins, serum progesterone concentrations fell to nondetectable levels and premature menstruations occurred. However, when luteinizing hormone (LH) secretion was restored by reinstating the GnRH infusions, progesterone production recom- menced, and the corpus luteum regressed at its normal time, 16 days after ovulation. The shaded areas show data from animals in which GnRH was provided at a frequency of 1 pulse/h throughout the luteal phase. Source: Reproduced with permission from Ref. 370, Copyright 1985, The Endocrine Society.
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14. FIGURE Expression of mRNAs for P P450 scc and 3β-HSD throughout the luteal phase of cynomolgus monkeys. Corpora lutea were collected at defined stages of the luteal phase, as defined on the x axis. The top panel illustrates serum progesterone concentrations of the animals immediately before removal of the corpora lutea. The bottom panel illustrates levels of mRNAs for P450scc (open bars) and 3β-HSD (solid bars). Source: Reproduced with permission from Ref. 379, Copyright 1991, The Endocrine Society.
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15. FIGURE Response of the macaque corpus luteum to a decrease in the frequency of luteinizing hormone (LH) pulses. Medial basal hypothalamus (MBH)-lesioned rhesus monkeys received exogenous gonadotropin-releasing hormone (GnRH) at a frequency of 1 pulse/h to restore follicular development and ovulation. Shortly after ovulation, on days 2–3 of the luteal phase, the frequency of GnRH pulses was changed to one pulse every eight hours, which is typical of the mid through late luteal phase. The individual bars over each day, beginning on day 3, reflect plasma progesterone concentrations obtained 30, 60, 120, and 240 min after a GnRH pulse. Despite the reduced LH pulse frequency, normal luteal function was observed in three of four animals. Source: Reproduced with permission from Ref. 387, Copyright 1986, The Endocrine Society.
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16. FIGURE Patterns of serum chorionic gonadotropin (CG), progesterone, and estrogen concentrations during early pregnancy in the rhesus monkey. Results are standardized to the time of rescue of the corpus luteum (day 0) that occurs on average 10–11 days after ovu- lation. Note the decline in serum progesterone that occurs after the first week of pregnancy despite rising concentrations of CG. By contrast, estrogen concentrations parallel the temporal pattern of CG. Source: Reproduced with permission from Ref. 467, Copyright 1975, The Society for the Study of Reproduction.
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17. FIGURE Responses of the primate corpus luteum to exogenous luteinizing hormone (LH) and human chorionic gonadotropin (hCG). The duration of each gonadotropin treatment is shown by the shaded rectangle at the top of each panel. The left panels illustrate serum progesterone in animals that received intravenous infusions of LH and hCG at a constant rate. The right panels illustrate serum progesterone in animals that received intravenous infusions of LH and hCG at an exponentially increasing rate. The dark shaded area encompasses the means +/− 1 standard error of the mean (SEM) of serum progesterone concentrations during luteal phases of three control monkeys, and the light shaded area encompasses the means +/− 1 SEM of serum progesterone concentrations during luteal phases of three pregnant monkeys. Source: Redrawn with permission from Ref. 494, Copyright 1999, National Academy of Sciences USA.
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