Physiology of the Menstrual Cycle: Understanding the Principles of Ovarian Stimulation

Published on 09/05/2017 by admin

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Last modified 09/05/2017

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FIGURE 1.1 Graphic representation of variation in pituitary and ovarian hormonal levels during menstrual cycle (not to scale).

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FIGURE 1.2 Graphic representation of inhibin A and B levels during menstrual cycle (not to scale) (2,3).

The LH Surge and the Luteal Phase

Rising levels of E2, produced by the granulosa cells of the preovulatory dominant follicle, cause the release of fast pulse frequencies (>1 pulse per hour) and high amplitude GnRH, favoring increased LH production (2). This causes a switch from a negative to positive feedback effect, resulting in a rapid rise in LH release and the so-called LH surge. The initial onset of the LH surge (not the peak level, which is reached 10–12 hours before ovulation) induces the ovulation about 34–36 hours later. The mean duration of the LH surge is 48 hours. Besides triggering ovulation, the LH surge induces the formation of the corpus luteum, for which an adequate amplitude and duration of LH surge is essential. The wall of the follicle collapses, and capillaries invade the developing corpus luteum probably under the influence of angiogenic and mitogenic factors. The differentiated granulosa cells in the corpus luteum will produce progesterone (P) in increasing amounts, E2, and inhibin A (1,2).

In some species, such as rodents, prolactin-like hormones play a principal role in the luteotropic process, and luteal regression involves a uterine signal such as prostaglandin F2 alpha (1). In contrast to this, in humans, LH is the principle hormone responsible for the following events. First, the mid-cycle surge of gonadotropins (notably, LH) stimulates the resumption of oocyte meiotic maturation; rupture of the dominant follicle, allowing the release of oocyte (ovulation), and corpus luteum formation (i.e., luteinization). Second, the pulsatile secretion of pituitary LH during the luteal phase of the menstrual cycle promotes the continued development and normal functional lifespan of the corpus luteum (1,2).

And finally, the exponential rise in circulating levels of the LH-like hormone, chorionic gonadotropin (CG), secreted by the implanting blastocyst and syncytiotrophoblast of the developing placenta, extends the functional lifespan of the corpus luteum in early pregnancy until luteal activities are assumed by the placenta, that is, at the luteal–placental shift (1,4).

Studies during the 1970s and 1980s and more recent experiments using GnRH antagonists and pure recombinant human LH or human CG (hCG) have strengthened the critical role of LH/CG in regulating primate luteal structure–function and is increasingly being applied in ovarian stimulation for IVF (1).

Although the maturing dominant follicle may be less sensitive to acute LH withdrawal at mid-cycle, a GnRH-induced LH surge of substantial length is required for ovulation and development of normal luteal function. What remains unclear is how duration and/or amplitude of the mid-cycle LH surge influences peri-ovulatory events. Initial monkey and human studies on GnRH-induced LH surges or administering exogenous LH/CG suggest that surges of lesser duration (<24 hours) and amplitude are sufficient to reinitiate oocyte meiosis and granulosa cell luteinization, but surges of greater duration (>24 hours) and amplitude improve oocyte recovery, fertilization, and corpus luteum development (1,2). Although the LH surge is believed to be the physiological signal for peri-ovulatory events, studies in rodents showed that a mid-cycle bolus of FSH can replace LH and elicit oocyte maturation, ovulation, and successful pregnancy (1). The clinical relevance of these physiological observations has recently been brought into sharper focus by the use of GnRHa agonists to induce a mid-cycle LH surge in IVF cycles. Although the short period of stimulation reduces the risk of developing ovarian hyperstimulation syndrome, it is clear that it may impact detrimentally on the luteal phase, compared with the use of hCG as a trigger, which remains bioactive for a longer period. These clinical issues are addressed elsewhere.

The LH-stimulated luteinization of granulosa cells around ovulation includes enhanced vascular endothelial growth factor (VEGF) production, which is likely essential for the angiogenic process within the corpus luteum. With regards to hCG, a mid-cycle bolus in ovarian stimulation cycles increased expression of the endogenous angiopoietin agonist, Ang-1, without altering that of the endogenous antagonist, Ang-2, in macaque granulosa cells. These factors control not only the development or maintenance of the vasculature in developing tissue beds, but also vascular integrity, maturity, and permeability (1

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