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.
Hormonal contraceptives
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.
