Endocrine Control Of Reproduction
Reproductive function in males and females is controlled by common hormonal systems based on the hypothalamic control of the pituitary gonadotrophins, individually known as luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These glycoproteins are released from the gonadotrophs of the anterior pituitary gland under the influence of gonadotrophin-releasing hormone (GnRH; Chapter
44) (Fig. 50a,b). Failure of GnRH release is one cause of infertility. It is released in pulses at intervals of 1–3 h in both males and females, a pattern that is accurately reflected in plasma levels of LH. The pulsatile pattern of GnRH secretion is essential for normal reproductive activity, as continuous exposure of gonadotrophs to the hormone leads to a rapid desensitization of the gonadotrophs and a reduction in the release of gonadotrophins. The releasing hormone acts through receptors coupled to Gq (Chapter 3) to stimulate the release and manufacture of the gonadotrophins.
Actions of gonadotrophins
The gonadotrophins produce their effects via interactions with guanosine triphosphate-binding protein (G-protein)-coupled receptors that activate the intracellular production of cyclic adenosine monophosphate (cAMP) (Chapter 3). In the male, LH acts on the Leydig cells of the testes to stimulate the production of the steroid testosterone, which acts in concert with FSH on Sertoli cells of the seminiferous tubules to support spermatogenesis (Fig. 50a). Sperm are generated in a two-stage meiosis from spermatocytes via spermatids. Spermatogenesis proceeds most efficiently at a temperature of 34 °C, which is why the testes are located outside the body cavity. A normal adult male produces some 2 × 108 sperm per day, a process that carries on from puberty until the end of life. Sertoli cells also produce inhibin, a peptide feedback signal that specifically inhibits the release of FSH from the anterior pituitary.
The situation in females varies over time according to the menstrual cycle (Fig. 50b,c), which lasts for around 28 days but is also ultimately driven by the activity of the hypothalamic GnRH neurones. After puberty, the ovaries contain about 400 000 primordial follicles, each of which contains an ovum (or oocyte) in an arrested state of meiosis. All follicles are present at birth and no new gametes are formed after this time. Small groups of follicles begin to mature spontaneously throughout reproductive life, but only those for which development coincides with the appropriate phase of the cycle reach the stage of ovulation. In the first part of the cycle (the follicular phase), LH acts on theca interna cells in developing follicles to stimulate the production of testosterone, which is converted to oestrogens (mainly oestradiol; Fig. 50b) by aromatase enzymes in follicular granulosa cells under the influence of FSH. Granulosa cells also produce inhibin, which suppresses FSH release. In the follicular phase, oestrogens promote the growth of the uterine endometrial lining and the release of watery secretions at the cervix that enhance the transit of sperm into the uterus. Oestrogens also stimulate the production of
LH receptors in granulosa cells. During this time, the actions of FSH and oestrogens stimulate maturing follicles within the ovary, only the largest of which will normally undergo ovulation. The remainder wither away by the process of atresia. Ovulation occurs at about day 14 of the cycle (Fig. 50c). It is initiated by a large increase in the release of oestradiol from the granulosa cells, stimulated by their newly developed LH receptors. Normally, oestrogens act as a negative feedback signal, inhibiting LH release (Fig. 50b), but the large amounts secreted by the mature follicle stimulate LH release, i.e. the system switches from negative to positive feedback. This leads to a massive increase in the release of LH, which causes the wall of the most developed follicle to rupture and releases the ovum into the nearest oviduct to await fertilization (Chapter 52). Following ovulation, the granulosa cells undergo hypertrophy (growth) and the ruptured follicle develops into the corpus luteum, and the cycle enters the luteal phase. The corpus luteum produces progesterone (Fig. 50b), as well as oestrogens, in response to stimulation by LH. Progesterone prepares the reproductive tract for pregnancy, stimulating further growth of the uterine endometrium and altering the nature of cervical secretions to discourage the entry of sperm into the uterus. If fertilization does not occur, the corpus luteum undergoes luteolysis after roughly 14 days, a process that results from the reduced ability of LH to support the corpus luteum. In the absence of progesterone and oestradiol, the endometrial lining degenerates and is shed in the process of menstruation, followed by the onset of a new cycle. After 30–40 years of menstrual activity, the exhaustion of ovarian follicles causes the female system to enter the menopause, after which reproduction is no longer possible. Circulating levels of sex steroids are greatly reduced, leading to drying of the secretory glands in the reproductive tract and other symptoms, including circulatory changes that cause hot flushes. The most pernicious outcome of the menopause is osteoporosis (Chapter 48).
All sex steroids exert their effects by interacting with intracellular receptors that bind to deoxyribonucleic acid (DNA) response elements, and thus induce changes in gene expression. Some of the actions of testosterone are actually mediated by its conversion to the more active dihydrotestosterone, produced within the target cells by the action of the enzyme 5-α-reductase.
Human fertility control currently rests firmly on the use by women of hormonal contraceptives. These agents can contain a mixture of synthetic oestrogens and progestogens (analogues of progesterone), or progestogens only, and are administered as daily tablets, depot injections that last for several months, or as long-term (5 years) uterine implants. They probably have multiple sites of action, affecting negative feedback signals to suppress gonadotrophins, the consistency of cervical mucus to prevent sperm penetration, and the sensitivity of the uterine lining to prevent implantation of the embryo.