Female Reproductive Physiology

PITUITARY GLAND

The pituitary gland lies below the hypothalamus at the base of the brain within a bony cavity (sella turcica) and is separated from the cranial cavity by a condensation of dura mater overlying the sella turcica (diaphragma sellae). The pituitary gland is divided into two major portions (Figure 4-1). The neurohypophysis, which consists of the posterior lobe (pars nervosa), the neural stalk (infundibulum), and the median eminence, is derived from neural tissue and is in direct continuity with the hypothalamus and central nervous system. The adenohypophysis, which consists of the pars distalis (anterior lobe), pars intermedia (intermediate lobe), and pars tuberalis—which surrounds the neural stalk—is derived from ectoderm.

FIGURE 4-1 Hypophyseal-pituitary portal circulatory system.

The arterial blood supply to the median eminence and the neural stalk (pituitary portal system) represents a major avenue of transport for hypothalamic secretions to the anterior pituitary.

The neurohypophysis serves primarily to transport oxytocin and vasopressin (antidiuretic hormone) along neuronal projections from the supraoptic and paraventricular nuclei of the hypothalamus to their release into the circulation.

The anterior pituitary contains different cell types that produce six protein hormones: follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), prolactin, growth hormone (GH), and adrenocorticotropic hormone (ACTH).

The gonadotropins, FSH and LH, are synthesized and stored in cells called gonadotrophs, whereas TSH is produced by thyrotrophs. FSH, LH, and TSH are glycoproteins, consisting of α and β subunits. The α subunits of FSH, LH, and TSH are identical. The same α subunit is also present in human chorionic gonadotropin (hCG). The β subunits are individual for each hormone. The half-life for circulating LH is about 30 minutes, whereas that of FSH is several hours. The difference in half-lives may account, at least in part, for the differential secretion patterns of these two gonadotropins.

Prolactin is secreted by lactotrophs. Unlike the case with other peptide hormones produced by the adenohypophysis, pituitary release of prolactin is under tonic inhibition by the hypothalamus. The half-life for circulating prolactin is about 20 to 30 minutes. In addition to its lactogenic effect, prolactin may directly or indirectly influence hypothalamic, pituitary, and ovarian functions in relation to the ovulatory cycle, particularly in the pathologic state of chronic hyperprolactinemia (see Chapter 32).

GONADOTROPIN SECRETORY PATTERNS

A normal ovulatory cycle can be divided into a follicular and a luteal phase (Figure 4-2). The follicular phase begins with the onset of menses and culminates in the preovulatory surge of LH. The luteal phase begins with the onset of the preovulatory LH surge and ends with the first day of menses.

FIGURE 4-2 Hormone levels during a normal menstrual cycle.

Decreasing levels of estradiol and progesterone from the regressing corpus luteum of the preceding cycle initiate an increase in FSH by a negative feedback mechanism, which stimulates follicular growth and estradiol secretion. A major characteristic of follicular growth and estradiol secretion is explained by the two-gonadotropin (LH and FSH), two-cell (theca cell and granulosa cell) theory of ovarian follicular development. According to this theory, there are separate cellular functions in the ovarian follicle wherein LH stimulates the theca cells to produce androgens (androstenedione and testosterone) and FSH then stimulates the granulosa cells to convert these androgens into estrogens (androstenedione to estrone and testosterone to estradiol), as depicted in Figure 4-3. Initially, at lower levels of estradiol, there is a negative feedback effect on the ready-release form of LH from the pool of gonadotropins in the pituitary gonadotrophs. As estradiol levels rise later in the follicular phase, there is a positive feedback on the release of storage gonadotropins, resulting in the LH surge and ovulation. The latter occurs 36 to 44 hours after the onset of this midcycle LH surge. With pharmacologic doses of progestins contained in contraceptive pills, there is a profound negative feedback effect on gonadotropin-releasing hormone (GnRH) so that none of the gonadotropin pool (ready-release or storage) is released. Hence, ovulation is (generally) blocked (see Chapter 26).

FIGURE 4-3 The two-gonadotropin (LH and FSH), two-cell (theca cell on top and granulosa cell below) theory of follicular development. Each cell is theorized to perform separate functions; LH stimulates the production of androgens (androstenedione and testosterone) in the theca cell, and FSH stimulates the aromatization of these androgens to estrogens, estrone, and estradiol in the granulosa cell.

During the luteal phase, both LH and FSH are significantly suppressed through the negative feedback effect of elevated circulating estradiol and progesterone. This inhibition persists until progesterone and estradiol levels decline near the end of the luteal phase as a result of corpus luteal regression, should pregnancy fail to occur. The net effect is a slight rise in serum FSH, which initiates new follicular growth for the next cycle. The duration of the corpus luteum’s functional regression is such that menstruation generally occurs 14 days after the LH surge in the absence of pregnancy.

HYPOTHALAMUS

Five different small peptides or biogenic amines that affect the reproductive cycle have been isolated from the hypothalamus. All exert specific effects on the hormonal secretion of the anterior pituitary gland. They are GnRH, thyrotropin-releasing hormone (TRH), somatotropin release-inhibiting factor (SRIF) or somatostatin, corticotropin-releasing factor (CRF), and prolactin release-inhibiting factor (PIF). Only GnRH and PIF are discussed in this chapter.

GnRH is a decapeptide that is synthesized primarily in the arcuate nucleus. It is responsible for the synthesis and release of both LH and FSH. Because it usually causes the release of more LH than FSH, it is less commonly called LH-releasing hormone (LH-RH) or LH-releasing factor (LRF). Both FSH and LH appear to be present in two different forms within the pituitary gonadotrophs. One is a releasable form and the other a storage form. GnRH reaches the anterior pituitary through the hypophyseal portal vessels and stimulates the synthesis of both FSH and LH, which are stored within gonadotrophs. Subsequently, GnRH activates and transforms these molecules into releasable forms. GnRH can also induce immediate release of both LH and FSH into the circulation. Some recent research that found receptors for GnRH in other tissues including the ovary suggests that GnRH may have a direct effect on ovarian function as well.

GnRH is secreted in a pulsatile fashion throughout the menstrual cycle as depicted in Figure 4-4. The frequency of GnRH release, as assessed indirectly by measurement of LH pulses, varies from about every 90 minutes in the early follicular phase to every 60 to 70 minutes in the immediate preovulatory period. During the luteal phase, pulse frequency decreases while pulse amplitude increases. A considerable variation among individuals has been identified.

FIGURE 4-4 The pulsatile release of GnRH during the normal menstrual cycle.

Intravenous and subcutaneous administration of exogenous pulsatile GnRH has been used to induce ovulation in selected women who are not ovulating as a result of hypothalamic dysfunction. A continuous (nonpulsatile) infusion of GnRH results in a reversible inhibition of gonadotropin secretion through a process of “downregulation” or desensitization of pituitary gonadotrophs. This represents the basic mechanism of action for the GnRH agonists (nonapeptides, containing only nine amino acids) that have been successfully used in the therapy of such ovarian hormone–dependent disorders as endometriosis, leiomyomas, hirsutism, and precocious puberty.

Several mechanisms control the secretion of GnRH. Estradiol appears to enhance hypothalamic release of GnRH and may help induce the midcycle LH surge by increasing GnRH release or by enhancing pituitary responsiveness to the decapeptide. Gonadotropins have an inhibitory effect on GnRH release. Catecholamines may play a major regulatory role as well. Dopamine is synthesized in the arcuate and periventricular nuclei and may have a direct inhibitory effect on GnRH secretion through the tuberoinfundibular tract that projects onto the median eminence. Serotonin also appears to inhibit GnRH pulsatile release, whereas norepinephrine stimulates it. Endogenous opioids suppress release of GnRH from the hypothalamus in a manner that may be partially regulated by ovarian steroids.

The hypothalamus produces PIF, which exerts chronic inhibition of prolactin release from the lactotrophs. A number of pharmacologic agents (e.g., chlorpromazine) that affect dopaminergic mechanisms influence prolactin release. Dopamine itself is secreted by hypothalamic neurons into the hypophyseal portal vessels and inhibits prolactin release directly within the adenohypophysis. Based on these observations, it has been proposed that hypothalamic dopamine may be the major PIF. In addition to the regulation of prolactin release by PIF, the hypothalamus may also produce prolactin-releasing factors (PRFs) that can elicit large and rapid increases in prolactin release under certain conditions, such as breast stimulation during nursing. All PIFs and PRFs have not been clearly characterized biochemically as of 2008. TRH serves to stimulate prolactin release as well. This phenomenon may explain the association between primary hypothyroidism (with secondary TRH elevation) and hyperprolactinemia. The precursor protein for GnRH, called GnRH-associated peptide (GAP), has been identified to be both a potent inhibitor of prolactin secretion and an enhancer of gonadotropin release. These findings suggest that this GnRH-associated peptide may also be a physiologic PIF and could explain the inverse relationship between gonadotropin and prolactin secretions seen in many reproductive states.

ESTROGENS

During early follicular development, circulating estradiol levels are relatively low. About 1 week before ovulation, levels begin to increase, at first slowly, then rapidly. The conversion of testosterone to estradiol in the granulosa cell of the follicle occurs through an enzymatic process called aromatization and is depicted in Figure 4-3. The levels generally reach a maximum 1 day before the midcycle LH peak. After this peak and before ovulation, there is a marked and precipitous fall. During the luteal phase, estradiol rises to a maximum 5 to 7 days after ovulation and returns to baseline shortly before menstruation. Estrone secretion by the ovary is considerably less than secretion of estradiol but follows a similar pattern. Estrone is largely derived from the conversion of androstenedione through the action of the enzyme aromatase (Figure 4-5).

FIGURE 4-5 Steroidogenic pathways showing aromatization in red. Cmpd B, corticosterone; cmpd S, II-deoxycortisol; DOC, desoxycorticosterone; OH, hydroxylase.

PROGESTINS

During follicular development, the ovary secretes only very small amounts of progesterone and 17α-hydroxyprogesterone. The bulk of the progesterone comes from the peripheral conversion of adrenal pregnenolone and pregnenolone sulfate. Just before ovulation, the unruptured but luteinizing graafian follicle begins to produce increasing amounts of progesterone. At about this time, a marked increase also occurs in serum 17α-hydroxyprogesterone. The elevation of basal body temperature is temporally related to the central effect of progesterone. As with estradiol, secretion of progestins by the corpus luteum reaches a maximum 5 to 7 days after ovulation and returns to baseline shortly before menstruation. Should pregnancy occur, progesterone levels and therefore basal body temperature remain elevated.

ANDROGENS

Both the ovary and the adrenal glands secrete small amounts of testosterone, but most of the testosterone is derived from the metabolism of androstenedione, which is also secreted by both the ovary and the adrenal gland.