Discuss the hormonal regulation of the menstrual cycle.

Outline:

·        Hormones involved: LH, FSH, estrogen, progesterone, inhibin

·        Follicular phase:

- growth of follicles

- synthesis and release of hormones

·        Ovulatory phase: actions of LH and FSH

·        Luteal phase: role of corpus luteum

·        Menstruation

Essay:

            The menstrual cycle involves a sequence of events in the ovary and in the uterine endometrium. It is divided physiologically into three sequential phases. The follicular phase begins with the onset of menstrual bleeding and averages 15 days. The ovulatory phase lasts 1 to 3 days and culminates in ovulation. The luteal phase lasts 13 days and ends with the onset of menstrual bleeding. The overall duration of a normal menstrual cycle averages 28 days, but it can vary from 21 to 35 days.

            The changes that occur during a menstrual cycle is mediated by gonadotropins from the anterior pituitary and hormones produced by the ovary itself. These serve to stimulate the growth and development of follicles, the release of the oocyte into the uterine tubes and preparation of the uterine endothelium for implantation of the embryo should fertilization occurs.

            After menstruation, plasma FSH levels begin to rise, followed somewhat later by a rise in LH levels. FSH acts on the granulosa cells to stimulate the growth of follicular cells and to increase its aromatase activity hence estrogen synthesis from androgen precursors is enhanced. The increased local estradiol levels causes proliferation of its receptors and those of growth factors. It reinforces FSH actions by increasing FSH receptors and by synergizing with the gonadotropins to stimulate further granulosa cell hyperplasia and hypertrophy. FSH, along with estradiol, induces LH receptors of granulosa cells. Slowly rising estradiol levels condition the hypothalamic gonadotropin axis, which maintains or slightly increases plasma LH while plasma FSH is decreasing.

            Under the influence of estrogens from the developing follicle, the uterine endometrium increases rapidly in thickness. As the thickness increases, the uterine glands are drawn out so that they lengthen, but they do not become convoluted or secrete to any degree. The spiral arteries that supply the endometrium also elongate.

            The rising LH level stimulates theca cells to produce increasing amount of androgens, which serves as substrates for granulosa aromatase and sustain the augmented estradiol production. LH also stimulates granulosa cells to produce progesterone. Inhibin from granulosa cells inhibit FSH secretion and together with IGF-1, augments androgen production by theca cells.

            Under normal conditions, only one follicle reaches full maturity while the others degenerate and become atretic. The dominant follicle has more FSH receptors and therefore it is able to obtain enough FSH to sustain its growth and development when FSH levels is waning.

The sharply increasing estradiol release from the dominant follicle triggers the ovulatory surge of gonadotropins. A critical plasma level of at least 200 pg/ml, sustained for at least 2 days, is required to elicit this positive feedback on LH.  The loci of this positive feedback on gonadotropin secretion are both the pituitary and the hypothalamus. The mechanism involves decreasing the inhibitory activity of dopaminergic and endorphinergic neurons on GnRH neurons.

            LH stimulation of granulosa cell leads to completion of meiosis I. The LH surge induces the enzyme prostaglandin endoperoxidase synthase in granulosa cells. This enzyme increases the synthesis of prostaglandins, thromboxanes, and leukotrienes, causing a pseudoinflammatory response that leads to follicular rupture. Plasminogen activator, stimulated by FSH, generates the proteolytic enzyme plasma, which catalyzes the breakdown of follicular wall. FSH also stimulates the detachment of the oocyte-cumulus complex.

            Following ovulation, the follicle undergoes luteinization, forming the corpus luteum. The corpus luteum is formed from both granulosa cells and theca interna cells. LH is essential for the luteinization of the granulosa cells. Estrogens and progesterone produced by the corpus luteum causes the uterine endometrium to become more vascularized. The glands become coiled and tortuous and they begin to secrete a clear fluid. These two hormones, together with inhibin exerts a negative feedback on the pituitary, decreasing the levels of FSH and LH. As LH declines, the corpus luteum regresses and its secretion of progesterone and estrogen ceases completely in 14 days. The abrupt loss of estradiol and progesterone causes spasmodic contractions of the spiral arteries and uterine muscles. The resultant ischemia produces necrosis, the stroma condenses and degenerates, and the superficial endometrial cells are sloughed together with the sludged blood, marking the onset of menstruation.

            About 12-13 days after ovulation, progesterone, estradiol and inhibin levels have fallen to levels low enough to release the pituitary gland from negative feedback inhibition. FSH then begins to rise, ushering another menstrual cycle.