Hormonal Control of Reproduction in the Female

Ovarian function is driven by the two pituitary gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) which stimulate: ovarian steroid production growth of the follicle Ovulation and development of the corpus luteum

Ovarian Hormones The principal hormones secreted by the ovary are: estrogens (estradiol and estrone) and progesterone These hormones are steroids and are derived from cholesterol by the series of reactions Their biosynthesis is complexly linked with the events of the ovarian cycle In addition, the ovary produces a large number of biologically active peptides, most of which act within the ovary as paracrine growth factors But at least two, inhibin and relaxin, are produced in sufficient amounts to enter the blood and produce effects in distant cells

Estrogens Estrogens are compounds that promote intense desire and originally were isolated from follicular fluid of sow ovaries Characteristic of steroid-secreting tissues, little hormone is stored within the secretory cells themselves Estrogens circulate in blood loosely bound to albumin and tightly bound to the testosterone-estrogen-binding globulin (TeBG), which is also called the sex hormone-binding globulin

Estrogens Plasma concentrations of estradiol are considerably lower than those of other gonadal steroids and vary over an almost 20-fold range during the cycle Liver is the principal site of metabolic destruction of the estrogens Estradiol and estrone are completely cleared from the blood by a single passage through the liver and are inactivated by hydroxylation and conjugation with sulfate and glucuronide The kidney is the chief route of excretion of estrogenic metabolites the conversion of chemical compounds to glucuronides, is a method that animals use to assist in the excretion of toxic substances

Progesterone Pregnancy requires the presence of another ovarian steroid hormone, progesterone In the nonpregnant woman progesterone secretion is limited largely to cells of the corpus luteum But because it is an intermediate in the biosynthesis of all steroid hormones, small amounts may also be released from the adrenal cortex Some progesterone also is produced by granulosa cells just before ovulation The rate of progesterone production varies widely Its concentration in blood ranges from virtually nil during the early preovulatory part of the ovarian cycle to as much as 2 mg/dL after the corpus luteum has formed

Progesterone Progesterone circulates in blood in association with plasma proteins and has a high affinity for the corticosteroid-binding globulin (CBG) Liver is the principal site of progesterone inactivation, which is achieved by reduction of the A ring and the keto groups at carbons 3 and 20 to give pregnanediol, which is the chief metabolite found in urine Considerable degradation also occurs in the uterus Transcortin = corticosteroid-binding globulin

Inhibin Inhibin is a 32 kDa disulfide linked dimer of an α subunit and either of two β subunits, βA or βB , and enters the circulation as either inhibin A (α/βA) or inhibin B (α/βB) Expression of the βA subunit is greatest in luteal cells blood levels of inhibin A are highest during peak luteal cell function and expression of the βB subunit is a product of granulosa cells blood levels of inhibin B are highest during the periods of preovulatory growth and expansion of granulosa cells

Relaxin The corpus luteum secretes a second peptide hormone called relaxin (6 kDa) In humans it relaxes the myometrium and plays an important role in parturition by causing softening of the uterine cervix Relaxin is encoded in two genes (H1 and H2) on chromosome 9 Although both relaxin genes are expressed in the prostate, only the H2 gene is expressed in the ovary A physiological role for relaxin in the nonpregnant woman has not been established In males, relaxin enhances motility of sperm in semen

Control Of Ovarian Function Follicular development beyond the antral stage depends on two gonadotropic hormones secreted by the anterior pituitary gland: FSH and LH In addition to stimulating follicular growth, FSH and LH are required for ovulation, luteinization, and steroid hormone formation by both the follicle and the corpus luteum Follicular growth and function also depend on paracrine effects of estrogens, androgens, possibly progesterone as well as peptide paracrine factors including IGF-II and others The sequence of rapid follicular growth, ovulation, and the subsequent formation and degeneration of the corpus luteum is repeated about every 28 days and constitutes the ovarian cycle Luteinization: The transformation of the mature ovarian follicle into a corpus luteum. Follicle: small secretory cavity

Effects of FSH and LH on the developing follicle Estradiol production Follicular Development Effects on ovulation Effects on corpus luteal function Effects on ovarian blood flow

Proliferative phase

Effects of FSH and LH on the developing follicle: 1- Estradiol production Granulosa cells in follicles are the only targets for FSH Granulosa cells of the ovulatory follicle are the major and virtually only source of estradiol in the follicular phase of the ovarian cycle and secrete estrogens in response to FSH Aromatase, also called estrogen synthetase or estrogen synthase, is an enzyme responsible for a key step in the biosynthesis of estrogens. LH stimulates thecal cells to produce androstenedione which is converted to estradiol by the action of Aromatase 17β-hydroxysteroid dehydrogenase in granulosa cells

Effects of FSH and LH on the developing follicle: 2- Follicular Development By about the middle of the follicular phase granulosa cells begin to express increasing amounts of LH receptors, which become quite abundant just prior to ovulation Acquisition of LH receptors in response to FSH enables these cells to respond to both FSH and LH In response to FSH, granulosa cells secrets different growth factors including IGF-II and vascular endothelial growth factor (VEG-F), which greatly increases vascularization around the theca

Effects of FSH and LH on the developing follicle: 2- Follicular Development IGF-II not only stimulates the growth and secretory capacity of granulosa cells, but also acts synergistically with LH to increase synthesis of androgens by cells of the theca interna However, some mechanism must exist to maintain balance between androgen production and their aromatization as accumulation of androgens prevents ovulation

Effects of FSH and LH on the developing follicle: 3- Effects on ovulation Luteinizing hormone is the physiological signal for ovulation Its concentration in blood rises sharply and reaches a peak about 16 hours before ovulation The events that lead to follicular rupture and expulsion of the ovum are complex and not fully understood But the process is known to be initiated by increased production of cyclic AMP in theca and granulosa cells in response to LH This is followed by the release of paracrine factors and enzymes To date more that 88 ovulation-related genes are known to be activated by LH at this time

Effects of FSH and LH on the developing follicle: 3- Effects on ovulation Granulosa cells of the preovulatory follicle respond to LH by secreting progesterone just prior to ovulation In response to progesterone granulosa cells secrete plasminogen activator, which activates the proteolytic enzyme plasmin that has accumulated in follicular fluid in the form of its inactive precursor, plasminogen together with stimulation of other proteases

Effects of FSH and LH on the developing follicle: 3- Effects on ovulation Granulosa cells of the preovulatory follicle respond to LH by secreting progesterone just prior to ovulation In response to progesterone granulosa cells secrete plasminogen activator, which activates the proteolytic enzyme plasmin that has accumulated in follicular fluid in the form of its inactive precursor, plasminogen together with stimulation of other proteases Plasmin weakens the wall of the Graafian follicle (leading toovulation).

Effects of FSH and LH on the developing follicle: 4- Effects on corpus luteal function Maintenance of steroid production by the corpus luteum depends on continued stimulation with LH The corpus luteum has a finite lifespan, however, and about a week after ovulation becomes progressively less sensitive to LH and finally regresses despite continued stimulation with LH 5- Effects on ovarian blood flow Increased ovarian blood flow increases the opportunity for: delivery of steroid hormones to the general circulation and for delivery to the ovary of cholesterol-laden LDL needed to support high rates of steroidogenesis

Physiological Actions Of Ovarian Steroid Hormones Intraovarian actions of estradiol and progesterone are closely connected to: ovulation and formation of the corpus luteum In general, extraovarian actions of these hormones ensure that the ovum reaches its potential to develop into a new individual Ovarian steroids act on the reproductive tract to prepare it for fulfilling its role in fertilization, implantation, and development of the embryo and they induce changes elsewhere that equip the female physically and behaviorally for conceiving, giving birth, and rearing the child

Physiological Actions Of Ovarian Steroid Hormones: 1- Effects on the reproductive tract At puberty estrogens promote growth and development of the Fallopian tubes, uterus, vagina, and external genitalia Estrogens stimulate cellular proliferation in the mucosal linings as well as in the muscular coats of these structures Even after they have matured, maintenance of size and function of internal reproductive organs requires continued stimulation by estrogen and progesterone

Physiological Actions Of Ovarian Steroid Hormones: 2- Menstruation The follicular phase (Proliferative phase): Estradiol secreted by the developing follicle increases the thickness of the endometrium Follicles in the ovary grow and form an egg Endometrial glands form and elongate Endometrial growth is accompanied by increased blood flow The Secretory phase (luteal phase): After the follicle ruptures as it releases its egg, it closes and forms a corpus luteum Progesterone secreted by the corpus luteum causes the newly proliferated endometrial lining to differentiate and become secretory

Proliferative phase

Physiological Actions Of Ovarian Steroid Hormones: Menstruation Maintaining the thickened endometrium depends on the continued presence of the ovarian steroid hormones After the regressing corpus luteum loses its ability to produce adequate amounts of estradiol and progesterone, the outer portion of the endometrium degenerates and is sloughed into the uterine cavity In the myometrium, estradiol increases expression of contractile proteins and spontaneous contractions Progesterone counteracts these effects and decreases both the amplitude and frequency of spontaneous contractions

Physiological Actions Of Ovarian Steroid Hormones: 3- Effects on the mammary glands Development of the breasts begins early in puberty and is due primarily to estrogens which promote development of the duct system and growth and pigmentation of the nipples and areolar portions of the breast Estrogens also stimulate stromal proliferation and fat deposition It is important to recognize that the ovaries are not the only source of the estradiol that is available to the breast Aromatization of abundant adrenal androgens, dihydroepiandrosterone and androstenedione by breast tissues is a major source of estrogens, particularly in postmenopausal women stromal cells are connective tissue cells of any organ. They are cells that support the function of the parenchymal cells of that organ

Regulation of FSH and LH secretion During most of the cycle gonadotropin secretion is under negative feedback control similar to that seen for the gonadotropins in men The ovulatory burst of FSH and LH secretion is brought about by a positive feedback mechanism unlike any we have considered Secretion of FSH and LH also is controlled by GnRH, which is released in synchronized pulsatile bursts from the hypothalamus

Regulation of FSH and LH secretion Negative feedback aspects FSH and LH stimulate production of ovarian hormones In the absence of ovarian hormones, after ovariectomy or menopause, concentrations of FSH and LH in blood may increase as much as five- to tenfold Progesterone alone, unlike estrogen, is ineffective in lowering high levels of FSH and LH in the blood of postmenopausal women, but it can synergize with estrogen to suppress gonadotropin secretion

Regulation of FSH and LH secretion Positive feedback aspects The sustained increase in estradiol in the late follicular phase triggers the massive burst of LH secretion that just precedes ovulation It can be considered positive feedback because LH stimulates estrogen secretion, which in turn stimulates more LH secretion in a self-generating explosive pattern

Regulation of FSH and LH secretion It is significant that when given in large doses progesterone blocks the estrogen induced surge of LH, which may account for the absence of repeated LH surges during the luteal phase This action of progesterone, which may contribute to the decline in the LH surge, also contributes to its effectiveness as an oral contraceptive agent In this regard, progesterone also inhibits follicular growth

Ovarian-pituitary interactions at various phases of the menstrual cycle Green arrows represent stimulation, red arrows indicate inhibitory effects

Hormonal Contraceptives Synthetic progestins are the basic ingredient of hormonal contraceptives and may be administered alone or in combination with estrogens Synthetic compounds devised for this use bind to progesterone receptors, but are considerably more resistant to hepatic degradation than their natural counterparts In addition to blocking the LH surge, progestins stimulate production of a thick cervical mucus, which provides a barrier to the entry of sperm into the uterine cavity