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Ovarian Cycle

 

The ovarian cycle is driven by the changes in the concentrations of a few hormones. GnRH, produced by the hypothalamus, stimulates the glandular cells of the anterior pituitary to synthesize and release luteinizing hormone (LH) and follicle stimulating hormone (FSH). GnRH is released in a pulsatile manner, with peak concentrations at 60-90 minute intervals. LH and FSH act on thecal and granulosa cells, inducing them to produce progesterone, estrogen and some androgens. The thecal cells synthesize progesterone and androgens, whereas the granulosa cells synthesize estrogen. The reason for the difference in the location of these steroid hormones is that the thecal cells lack the enzyme aromatase, which means that they cannot convert androgens to estrogens, and the granulosa cells lack the enzyme 17a-hydroxylase, which means that granulosa cells cannot convert progesterone to androgens. Also, the thecal cells only have LH receptors. The LH receptor is a 7 transmembrane receptor, which acts through Gs proteins. The resulting increase in cytosolic cAMP activates protein kinase A, which acts on enzymes that catalyze progesterone and androgen synthesis. Cholesterol is converted to progesterone and androgens. The androgens diffuse through the basement membrane and go into the granulosa cells, where they are converted to estrogens by aromatase. This conversion is stimulated by FSH, which also has a 7 transmembrane receptor and uses Gs proteins. The estrogens diffuse through the basement membrane and go into the blood stream. This is called the "Two Cell Theory."

The ovarian cycle has two phases, follicular phase and luteal phase. Follicular phase is the period between the first day of menses and ovulation (usually the first 15 days of ovarian cycle). During early follicular phase the developing follicle has a small number of granulosa cells. GnRH stimulates the anterior pituitary to releases FSH and LH but due to the small number of granulosa cells, estrogen is produced in low amounts. Somehow, low estrogen concentration stimulates cells in the hypothalamus to produce dopamine, which acts on the hypothalamus and inhibits GnRH synthesis and release. At the same time, estrogen also decreases the activity of gonadotrophs, particularly the ones that produce FSH. There are three other proteins produced by the ovaries during early follicular phase. One of them is called inhibin, a heterodimer, which acts on the gonadotrophs and inhibits FSH synthesis and release. Inhibin is made up of alpha and beta subunits. The alpha subunit is identical in all inhibin molecules. There are two types of beta subunits, bA and bB. In other words, inhibin is found in two different forms, abA or abB. The other protein produced by the granulosa cells is activin, which is also a heterodimer and is composed of two b subunits which are identical to the b subunits of inhibin. There are three types of activin molecules, bAbA, bAbB and bBbB. Activin inhibits inhibin by binding to the inhibin receptors. The third protein is follistatin, which is an activin inhibitor. It actually binds to the b subunit of activin and inhibin, however, since activin has two b subunits, its effects are more prominent on activin. During late follicular phase, estrogen concentration is much higher, because there are a lot more granulosa cells in the follicle. Also, the negative feedback of estrogen on the hypothalamus and the anterior pituitary gland switches to positive feedback. This is done by increasing the number of GnRH receptors and GnRH receptor sensitivity on gonadotrophs (up regulation).

Around day 15 of the ovarian cycle the LH and FSH concentrations spike, triggering ovulation. This marks the end of the follicular phase and the beginning of the luteal phase. The LH spike also triggers luteinization, in other words, it causes the granulosa and the thecal cells to become corpus luteum (yellow body). During early luteal phase, the corpus luteum synthesizes progesterone and estrogen. The corpus luteum is maintained by high LH concentrations. Due to high concentrations of progesterone and estrogen, FSH and LH synthesis and release is inhibited. During late luteal phase, the low LH concentrations trigger luteolysis (luteal degeneration). This means that the estrogen and progesterone levels also decrease which causes an increase in FSH and LH, triggering a new cohort of follicles to develop and start over the whole cycle. The luteal phase takes about 14 days.

Hormone concentrations during ovarian cycle



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