Which hormone is released from the anterior pituitary and stimulates the ovaries?

I Introduction

Follicle-stimulating hormone (FSH) is named for its ability to stimulate follicle growth in females, as depicted in Fig. 1. Follicle-stimulating hormone stimulates the division and function of granulosa cells that surround and nurture the developing oocyte (egg) in the follicle.

Spermatogenesis also relies heavily on FSH, which induces Sertoli cell division in early life. In later life, both FSH and testosterone stimulate Sertoli cells to nurture B spermatogonia as they develop into sperm. A number of hormones from the hypothalamus, the gonads, and the pituitary itself help regulate FSH. This article first deals with the effect(s) of FSH on sperm and egg maturation (including the use of FSH to solve infertility problems in the female) and then it outlines the complex nature of FSH regulation in mammals.

Follicle-Stimulating Hormone

FSH varies less than LH over time, and so the number of animals needed to power an experiment sufficiently for LH will be more than sufficient for FSH. While the main feedback regulator of LH is testosterone, the feedback partner for FSH is thought to be inhibin B, a hormone whose response to toxicity is much less certain. Nonetheless, it is easy to measure FSH with confidence. Often FSH will be increased when there is substantial damage in the testis, but it is almost never a leading or concurrent indicator and is much more often a trailing marker of damage. The rodent testis can apparently function quite well on very low levels of FSH, but FSH appears to have a much more important role in the dog and primate, where it regulates the entry of stem cell spermatogonia into differentiation. Therefore, species differences would be expected in response to treatments that suppress FSH levels.

Follicle-Stimulating Hormone

FSH is produced and exported from the pituitary to act principally on the Sertoli cells. It is secreted in a pulsatile manner in response to GnRH, also referred to as luteinizing-hormone releasing hormone (LHRH), from the hypothalamus. Inhibin, secreted by the Sertoli cell, is believed to be involved in a feedback loop from the testis to the pituitary to inhibit FSH production. The action of FSH on immature and mature animals is profoundly different. FSH is often considered to be the hormone of puberty, as rising levels of FSH act as a trigger for testicular growth, junction formation between adjacent Sertoli cells and ABP secretion from the Sertoli cells, and generally initiates spermatogenesis and the expansion of the seminiferous tubules. Once this has occurred, the Sertoli cell switches its responsiveness from FSH to testosterone as many of the FSH-regulated functions in the immature animal are taken over by testosterone in the adult.

The primary impact and effects of FSH in the adult are poorly understood, although its importance seems to vary between species. Suppression of FSH in the adult rat has a negligible effect on spermatogenesis, whereas in nonhuman primates, it results in considerable suppression of spermatogenesis and sperm output.

V FSH dependency

FSH plays a key role in the development of the immature testis, particularly by controlling the size of the Sertoli cell population, which is set early in postnatal life. This is of particular importance for the adult animal because Sertoli cell number dictates sperm output. After debating many conflicting data from animal models, there is agreement that some degree of complete spermatogenesis can be initiated and maintained in the absence of FSH; however, quantitatively normal spermatogenesis depends on FSH. FSH acts at multiple sites in the spermatogenic pathway by promoting spermatogonial proliferation and survival and viability of later germ cell types by presumably maintaining structures and proteins involved in attachment of the germ cell to the Sertoli cell. More specifically, rat and monkey studies have shown that FSH plays a major role in supporting spermatogonial development, with FSH having more pronounced effects on certain subpopulations. FSH has been shown to play a role in later germ cell types, supporting spermatocytes and round spermatid development presumably by supporting cell survival. The specialized Sertoli cell junctional apparatus has been shown to be a hormone-sensitive structure; the structures are found between Sertoli cells and at stages from mature round spermatids to mature sperm before spermiation. This specialized apparatus has been shown to be disorganized in long-term gonadotropin-deplete rats and can be restored by FSH treatment, suggesting that FSH is important for the maintenance of the junctional apparatus. In vitro experiments on Sertoli and round spermatid cultures suggest that FSH is important for adherence of the round spermatids to the Sertoli cells. Finally, FSH may be involved in the release of mature sperm from the epithelium, based on reports that more sperm are retained within the seminiferous epithelium following acute FSH withdrawal. Another way that FSH can support germ cell development is via the Leydig cells. FSH has been shown to regulate Leydig cell products that play a role in spermatogenesis and promote maturation of the Leydig cell population.

30.4.4.2 Control of follicle-stimulating hormone β-subunit expression

FSH β subunit is expressed in pituitary gland but also in the hypothalamus, ovary, and oviduct and in all four organs, expression is increased as birds start egg production (domestic goose: Huang et al., 2015). Pituitary expression of FSH β-subunit changes with developmental stage by feedback from the gonadal hormones, and it seems to be affected by the hypothalamus. Chicken embryos as early as day 11 express the FSH β-subunit in their anterior pituitary glands (Grzegorzewska et al., 2009). Pituitary expression of FSH β-subunit is increased during sexual maturation (chicken: Han et al., 2017) but decreased with aging (chicken: Avital-Cohen et al., 2013). Inhibin exerts a negative feedback effect on the expression of the FSH β-subunit in birds. Turkeys immunized against inhibin show increased pituitary FSH β-subunit expression and more small yellow follicles, presumably due to elevated FSH (Ahn et al., 2001).

There is stimulatory central nervous control of FSH β-subunit expression, but the hypothalamic factors participating in birds have not been definitively identified. Evidence for the hypothalamic control comes from the following. Photostimulation is accompanied by increased FSH β-subunit expression (chickens: Li et al., 2009). Early puberty is induced by sulfamethazine with increased pituitary expression of the FSH β-subunit (chickens: Li et al., 2009). Similarly, exposure of two-week-old chickens to long daylengths is followed by increases in the expression of FSH β subunit in the pituitary gland with this effect much greater in birds receiving sulfamethazine treatment (Kang and Kuenzel, 2015). Expression of FSH β-subunits is reduced by starvation in Japanese quail (Kobayashi et al., 2002). Restraint stress is reported to be followed by reduced pituitary expression of FSH β-subunit (zebra finch: Ernst et al., 2016). Administration of the serotonin synthesis inhibitor, PCPA to old male chickens increased pituitary expression of FSH β subunit (old male chickens: Avital-Cohen et al., 2015).

Follicle-Stimulating Hormone

Follicle-stimulating hormone (FSH) is administered to mares to advance the first ovulation of the year in seasonally anestrous mares, stimulate follicular development in postpartum acyclic mares, and induce ovulation of multiple follicles in cycling mares. Multiple FSH products have been tested, including porcine FSH, recombinant human FSH, equine pituitary extract, purified equine FSH, and recombinant equine FSH. Porcine and recombinant human FSH have limited efficacy in the horse.

Administration of recombinant equine FSH (reFSH) to mares in seasonal anestrus or postpartum anestrus usually stimulates follicular development if mares are in transition rather than deep anestrus, and FSH is administered twice rather than once daily. Administration of reFSH (0.65 mg, IM, every 12 hours) will stimulate follicular development in approximately 80% to 90% of anestrous mares within 7 to 10 days, but administration of hCG (1500 to 2500 units, IV or IM) is required to induce ovulation. Mares initially treated during deep anestrus that respond and ovulate may revert to anestrus following a normal luteal phase.

Superovulation of cycling mares can be accomplished by administration of 0.65 mg of reFSH twice daily for 3 to 7 days. Superovulation therapy for cycling mares will be most successful if (1) endogenous FSH initially stimulates a cohort of follicles to develop before the onset of exogenous FSH therapy (this reduces the number of FSH treatments required), (2) twice-daily FSH therapy is used, and (3) there is a 36-hour interval between the last FSH treatment and hCG administration. This interval may be beneficial in allowing the follicle or follicles to mature and likely improves the ovulation rate.

Follicle-stimulating hormone

FSH prolongs ventricular repolarization and has a positive correlation to QTc in women [17]. The presence of FSH receptors in the myocardium supports these findings [17]. Therefore, it is speculated that the FSH peak in the ovulatory phase increases the susceptibility to drug-induced QT prolongation [14]. In men with hypogonadism, the QTc interval is longer than in healthy men, but this does not apply to hypogonadotropic hypogonadism with low FSH [18–20]. Therefore, it is thought that QTc prolongation is not present while FSH values are low in these patients (Table 19.2).

Table 19.2. ECG parameter changes with the menstrual cycle.

DOB, double autonomic blockade, QTc, corrected QT interval.

Gonadotropin Physiology

FSH and LH are produced and released by the gonadotrophs of the adenohypophysis to regulate ovarian and testicular function (Fig. 40.16). In women, FSH stimulates growth of the granulosa cells of the ovarian follicle and controls their estrogen secretion. At the midpoint of the menstrual cycle, the increasing level of estradiol stimulates a surge of LH secretion, which then triggers ovulation. After ovulation, LH supports the formation of the corpus luteum. Exposure of the ovary to FSH is required for expression of the LH receptors. In men, LH is responsible for the production of testosterone by Leydig cells in the testes. The combined effects of FSH and testosterone on the seminiferous tubule stimulate sperm production.

FSH and LH secretion occur in a pulsatile fashion in response to pulses of secretion of GnRH from the hypothalamus. GnRH is also known as LH-releasing hormone (LHRH) because of its potent stimulation of LH secretion. Levels of FSH and LH are regulated by a balance of GnRH stimulation, negative feedback regulation from the inhibin peptide secreted by the ovaries and the testes, and the effect of the sex steroids on the pituitary and the hypothalamus. Appropriate concentrations of FSH and LH are required for normal sexual development and reproductive function in both women and men. LH and FSH circulate in blood predominantly in the monomeric form found in the pituitary. FSH has a half-life of 3 to 5 hours, so serum levels are more stable than are those of LH, which has a half-life of 30 to 60 minutes.

GnRH stimulates gonadotropin secretion from the pituitary for the first few months of life. Then the pituitary becomes unresponsive to GnRH until puberty, when pulsatile secretion of FSH and LH occur in response to pulses of GnRH. At menopause, when gonadal failure occurs, the negative feedback provided by the hormonal products of the gonads is eliminated so serum levels of FSH and LH increase.

Role of Follicle-Stimulating Hormone in Ovarian Function.

FSH is the main promoter of follicular maturation. Given that FSH receptors have been exclusively localized to granulosa cells, it is presumed that FSH action in the ovary involves the granulosa cells. The ability of FSH to orchestrate follicular growth and differentiation depends on its ability to exert multiple actions concurrently.

Phenotypes of women with mutations that disrupt the function of the FSH β-subunit gene are in good agreement and demonstrate that FSH is necessary for normal follicular development, ovulation, and fertility. Pubertal development is hampered in the absence of sufficient numbers of later-stage follicles with the granulosa cells needed for adequate estrogen production. Treatment of affected patients with exogenous FSH has resulted in follicular maturation, ovulation, and normal pregnancy.43 The presenting phenotype of FSH β-subunit deficiency is practically identical to that caused by inactivating mutations of the FSH receptor.43

Women with FSH receptor mutations are clinically similar to patients with gonadal dysgenesis; they have absent or poorly developed secondary sexual characteristics and high serum levels of FSH and LH. The notable difference is the presence of ovarian follicles in women with mutated FSH receptors, consistent with the FSH independence of primordial follicle recruitment and early follicular growth and development. Total absence of any follicles, including those in the primordial stage, occurs in women in whom FSH receptor mutations cannot be demonstrated.43 The ovarian phenotype of FSH receptor deficiency is distinct from the common form of gonadal dysgenesis (Turner syndrome), which is characterized by streak gonads and an absence of growing follicles.43

In vivo rodent studies suggest that FSH is capable of increasing the number of its own receptors in the granulosa cell. Whereas estradiol by itself may be without effect on the distribution, number, or affinity of granulosa cell FSH receptors, estrogens synergize with FSH to enhance the overall number of granulosa cell FSH receptors.86 Changes in the production of estradiol by preantral follicles can increase their response to FSH through regulation of granulosa cell surface FSH receptors. This interaction between FSH and estradiol in follicular development has been well established in rodents. It appears that ERα and ERβ mediate the estrogenic effect on ovarian development and follicular maturation in mice.87 However, it is not clear whether a similar relationship exists in the human ovary. ERα is not detected in the human ovary in significant quantities. Nevertheless, the demonstration of ERβ in the human ovary suggests an interaction between FSH and estrogen in the regulation of normal follicle development and ovulation in women.88

One of the major actions of FSH is induction of granulosa cell aromatase activity.89 Little or no estrogen can be produced by FSH-unprimed granulosa cells even if they are supplied with aromatizable androgen precursors. Treatment with FSH enhances the aromatization capability of granulosa cells, an effect related to enhancement of the granulosa cell aromatase content.89

Treatment with FSH has also been shown to induce LH receptors in granulosa cells. The ability of FSH to induce LH receptors is augmented by the concomitant presence of estrogens.90 Progestins, androgens, and LH itself may also induce LH receptors. After induction, the granulosa cell LH receptor requires the continued presence of FSH for its maintenance.

Circumstantial evidence, deduced from studies of women with disrupting mutations of the genes that encode FSH and LH receptors and aromatase (CYP19A1), indicates that FSH action, but not estrogen or LH action, is essential for follicular growth in humans.43,90 Follicular growth and development up to the antral stage were observed in women with deficient LH action or estrogen biosynthesis, although these individuals were anovulatory.43,90 Women with mutations of the FSH β-subunit or FSH receptor have only primordial follicles in their ovaries.43 These data indicate that estrogen and LH are not critical for follicular development at least until the tertiary stage (see Figs. 17-11 and 17-12). However, FSH by itself is not sufficient to achieve normal follicular development and ovulation.