Female Sex Hormones
Physiology Review
Research shows that fluctuating levels of estradiol, progesterone, and testosterone play a key role in shaping the course of a woman’s menstruation cycle, affecting changes in mood, sleep patterns, appetite, sexual drive, and PMS symptoms. Because hormones work together and influence each other in complex ways, an analysis of melatonin, DHEA, and cortisol can give a more complete picture of how endocrine function may be influencing female reproductive health.
Estrogens
Three steroid hormones — estrone (E1), ß-estradiol (E2), and estriol (E3) — are known collectively by their function as estrogens. Estradiol is the most physiologically active estrogen in non-pregnant women. Its potency is 12 times that of estrone and 80 times that of estriol. In non-pregnant women, estrogens are mainly produced in the ovaries and adrenal cortex. In pregnant women, estrogens are also produced in the placenta. ß-estradiol is produced in the ovaries; estrone is synthesized in the ovaries and adrenal cortices from ß-estradiol and androstenedione; and estriol is formed in the liver by conversion of either ß-estradiol or estrone.
During puberty, estrogens play a significant role in the maturation of such female reproductive organs as the vagina, uterus, fallopian tubes, and ovaries. Estrogens also trigger secondary sexual characteristics, namely the development of breasts and increased osteoblastic activity, resulting in characteristically feminine skeletal development.
Estrogens stimulate an increase in total body protein, promoting body development during puberty. These hormones also stimulate deposition of fat in subcutaneous tissues, particularly breasts, buttocks, and thighs. Estrogens influence development of vascular function and soft textured skin and have a minor effect on pubic and underarm hair growth. Furthermore, estrogens cause a slight retention of sodium and water by the kidneys and more pronounced retention during pregnancy.
Progesterones
Progesterone is present as progesterone and 17-a hydroxyprogesterone. They exhibit similar potency. Because 17-a hydroxyprogesterone is produced in minute quantities compared to progesterone, the latter is considered the most significant progesterone. As is the case with estrogen, progesterone is produced in the ovaries and adrenal cortex in non-pregnant women, while in pregnant women it is also secreted in the placenta.
Both progesterone and estradiol are formed from cholesterol. In the luteal phase progesterone levels increase dramatically, in spite of a portion of available steroids still being converted to estrogens. Conversion of ß-estradiol to the less potent estrone or estriol diminishes circulating ß-estradiol, and further functional degradation occurs as formation of glucuronides and sulfates in the liver takes place. Similarly, progesterone is functionally degraded to less potent steroids in the liver.
Like estrogen, progesterone plays a role in increasing the size of breasts by stimulating the development of lobules and alveoli. During the menstrual cycle, progesterone promotes secretory changes in the endometrium preparatory to the implantation of a fertilized ovum. Progesterone also has a minor effect on the retention of sodium, chloride, and water by the kidneys.
Testosterone
In the adult female, testosterone plays an important role in maintaining lean body mass, bone density, skin elasticity, and libido. In addition, testosterone is involved in blood cell production. Low testosterone levels have been linked to increased risk for osteoporosis, decreased lean body mass, and decreased libido, and may suggest ovarian insufficiency and/or adrenal insufficiency. Elevated testosterone levels have been linked to masculinization, hirsutism, and increased risk of insulin resistance. Elevated testosterone levels have been noted in polycystic ovary disease and adrenal hyperplasia and suggest the presence of ovarian dysfunction or adrenal dysfunction.
Menstrual Cycle
The average menstrual cycle takes about 28 days (25-35 days) to complete and falls into three phases: follicular, ovulatory, and luteal phases.
Follicular Phase
In the follicular phase ovarian follicular growth, the uterine endometrium develops in preparation for the implantation of fertilized ovum. The growing follicles themselves produce high amounts of estrogen, which stimulates the uterine endometrium to proliferate and to synthesize cytosolic receptors for progesterone. Progesterone levels during this phase remain low.
The follicular phase can be divided into two stages. In the periantral stage of follicular growth, luteinizing hormone (LH) stimulates theca interna cells to produce androgens (mainly androstenedione), which diffuse through the basal lamina into the granulosa cell compartment to stimulate proliferation. The follicle grows, accumulates fluid, and forms an antrum. Estradiol levels are not high enough to diffuse into general circulation, so follicle stimulating hormone (FSH) and LH are not inhibited.
In the antral stage of follicular growth, the combined effects of FSH and estradiol induce LH receptors on the granulosa cells. This enables them to begin producing estradiol from pregnenolone (de novo estradiol synthesis). Spillage of estradiol into the general circulation results from this increased estradiol pool and accelerated follicle growth. Subsequently, a relatively rapid increase in circulating estradiol level is seen during the last 5 or 6 days of the follicular phase.
Initially this rise in estradiol exerts a negative feedback on FSH release. Continued high levels (about a three-fold increase) presented over a 2- to 3-day period exert a positive feedback effect, resulting in a large surge of LH and FSH. The large bolus of LH (preovulatory LH surge) released induces ovulation in about 1 day. The follicular phase lasts for about 9 to15 days, and its duration determines the period of the menstrual cycle itself, since the length of the two subsequent phases remains fairly constant.
Ovulatory Phase
The ovulatory phase involves the release of the ovum or egg (ovulation) from the follicles and lasts about 36 hours. Ovulation is probably induced when LH stimulates the production of granulosa plasminogen activator, triggering the formation of plasmin, an enzyme responsible for digesting the basal lamina, and thus the rupture of the follicle Women generally experience an increase in the basal body temperature of 0.5º to 1.0º F following ovulation. This increase is due to the thermogenic effect of pregnanediol, a metabolite of progesterone.
After ovulation, granulosa cells proliferate in response to the preovulatory LH surge, while theca interna cells and perifollicular blood vessels invade the cavity of the collapsed follicle. Under the influence of LH, the granulosa and evasive theca cells differentiate into luteal cells.
Luteal Phase
During the luteal phase the ruptured follicles in the ovary form a corpus luteum. Luteal cells are steroidogenic and produce large amounts of progesterone and moderate amounts of estradiol.
The increase of estrogen and progesterone during the first 4 to 5 days of the luteal phase promotes endometrium and fallopian tube secretions that allow for proper nourishment and implantation of the fertilized ovum. During this time, circulating levels of estradiol are reduced, a decrease necessary for the proper transport of the ovum through the fallopian tube into the uterus. Exposure to high levels of estrogen during this interval would lead to expulsion of the ovum or to blockage of ovum transport.
The corpus luteum has a life span of about 12 days. If fertilization and implantation do not occur, the corpus luteum degenerates (luteolysis), and its production of progesterone and estradiol rapidly declines. Since progesterone inhibits FSH and folliculogenesis, withdrawal of progesterone and estradiol during luteolysis results in deterioration of the endometrium and its shedding (menstruation). The first day of menstruation is the first day of the menstrual cycle.
The endometrium is most conducive to implantation during the progesterone peak secretion period, about the fifth day into the luteal phase. If fertilization of the ovum occurs, secretion of chorionic gonadotropin (hCG) by the implanted blastocyst stimulates the corpus luteum to continue producing progesterone and luteolysin is prevented.47
