ACTIONS OF ESTROGENS AND PROGESTINS IN FEMALES
Secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus stimulates the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the anterior pituitary. FSH and LH regulate the production of estrogen and progesterone by the ovary. Ovarian estrogen and progesterone secretion proceed in a cyclical manner. It is this cyclical release of estrogen and progesterone that determines the regular hormonal changes in the uterus, vagina, and cervix as-sociated with the menstrual cycle. Cyclical changes in blood levels of estrogen and progesterone, together with FSH and LH, modulate the development of ova, ovulation, and the corpus luteum in the ovary.
During the first, or follicular, phase of the menstrual cycle, estradiol blood levels rise slowly and then fall quite rapidly. Estradiol blood levels peak around mid-cycle (days 12–14). The midcycle estrogen peak is thought to be important in triggering a midcycle surge of LH and FSH secretion. Estrogens have a biphasic ef-fect on LH and FSH release, with high levels of estro-gen at midcycle triggering LH and FSH release; subse-quently they suppress LH and FSH secretion. This suppression is mediated by inhibition of GnRH release from the hypothalamus.
The luteal phase of the menstrual cycle follows the LH and FSH surge (days 14–28). The brief elevation of the LH level stimulates production of the ovarian cor-pus luteum. The high levels of estradiol and the FSH surge at midcycle inhibit estradiol biosynthesis by the ovarian granulosa cells. As a consequence, during the luteal phase, estrogen production is reduced and andro-gens produced by the ovarian thecal cells accumulate. Androgens, together with low levels of FSH, stimulate the production of progesterone by the granulosa cells in the corpus luteum. The menstrual cycle ends about 14 days later with the regression of the corpus luteum and a concomitant fall in estrogen and progesterone pro-duction. The triggering mechanism for this regression may involve both estrogens and prostaglandins. In the event that pregnancy occurs, human chorionic go-nadotropin secretion by the embryo maintains the cor-pus luteum through stimulation of progesterone and es-trogen synthesis.
During the follicular phase of the menstrual cycle, one or more follicles are prepared for ovulation. FSH and estrogens are the most important hormones for this de-velopmental process. Complete follicular maturation cannot occur in the absence of LH. Rupture of a mature follicle follows the midcycle peak of LH and FSH by about 24 hours. In humans, usually one mature ovum is released per cycle. During the luteal phase of the men-strual cycle and under the influence of LH, the ovarian granulosa cells of the corpus luteum become vacuolated and accumulate a yellow pigment called lutein.
The lining of the uterus, that is, the endometrium, is crit-ical for implantation of the fertilized ovum. The en-dometrium consists of a layer of epithelial cells overly-ing a layer of vascularized stromal cells. Under the influence of estrogen and progesterone, the endome-trium undergoes cyclical changes that prepare it for the implantation of a fertilized ovum. The follicular phase of the menstrual cycle also may be called the prolifera-tive phase when referring to changes that occur in the uterus. Estrogens induce endometrial cell division and growth.
During the luteal phase, when the uterus is exposed to high concentrations of progesterone and moderate estradiol levels, the mitotic activity in the endometrial cells is suppressed. The action of progesterone on the endometrium converts it from a proliferative state to a secretory state. The epithelial cell structure assumes a more glandular appearance. Vascularization of the stroma increases, and some stromal cells begin to look like the decidual cells of early pregnancy. Estrogens and progesterone are key hormones in the maintenance of pregnancy. Estriol is produced in high concentrations by the placenta in pregnant women.
Cervical mucus is secreted by the endocervical glands and is regulated by estrogens and progestins. Under the influence of high levels of estrogen or pro-gesterone, the physicochemical composition of cervical mucus may reduce sperm motility and provide a barrier to fertilization.
When implantation of the ovum does not occur, es-trogen and progesterone levels fall and menstrual bleeding ensues. The endometrial lining, but for a single layer of epithelial cells, is shed.
Estrogens cause the growth of the uterus, fallopian tubes, and vagina. Stimulation of proliferation of the vaginal epithelium is checked by the cyclical exposure to progesterone during the luteal phase in the mature female. Estrogens also are responsible for the expres-sion of female secondary sex characteristics during pu-berty. These include breast enlargement, the distribu-tion of body hair, body contours as determined by subcutaneous fat deposition, and skin texture. During development, estrogens stimulate proliferation of the ductal epithelial cells in breast tissue. Progesterone me-diates lobuloalveolar development at the ends of these mammary ducts. In women, cyclical changes in the breast cell proliferation occur during the menstrual cy-cle, with the highest levels of proliferation occurring during the luteal phase, when circulating levels of both estrogen and progesterone are high. This has led to the idea that progesterone, as well as estrogens, exerts mi-totic effects in adult human breast tissue. The effects of estrogens and progesterone on breast development are most noticeable during puberty and pregnancy.
Estrogens can stimulate the release of growth hor-mone and exert a positive effect on nitrogen balance. These effects contribute to the growth spurt during pu-berty. Closure of the bone epiphyses signaling the end of long bone growth is also estrogen mediated.
Bone remodeling occurs throughout adult life. Osteoblasts are the bone cells that are responsible for increasing bone mass. Bone loss occurs through the ac-tivity of other bone cells, called osteoclasts. Normal bone remodeling takes place when there is a balance between osteoblast and osteoclast activities. Estrogens maintain bone mass by inhibiting bone resorption by the osteoclasts. Estrogens inhibit the production of cy-tokines by peripheral blood cells and the osteoblasts that stimulate osteoclast activity. In postmenopausal women, declining estrogen levels give rise to a net in-crease in osteoclast activity and loss of bone mass re-sulting in the serious condition osteoporosis. Also, pro-gestins antagonize loss of bone.
The high levels of estrogens and progesterone associ-ated with pregnancy may alter liver function and glu-cose metabolism. High circulating levels of estrogen can cause mild glucose intolerance. Estrogens increase the synthesis of many liver proteins, including transferrin, SHBG, corticosteroid-binding globulin, thyroid-binding globulin, and proteins involved in blood clotting.
Estrogens lower serum cholesterol levels by stimulating the formation of high-density lipoproteins and reducing low-density lipoproteins. Reductions in serum albumin and antithrombin III synthesis can occur in the pres-ence of elevated female sex steroids.
In males, estrogens stimulate the growth of the stro-mal cells in the accessory sex organs.