Female Reproduction Parturition and l Actation
Parturition and lactation
The factors that stimulate parturition (birth) in humans are complex, and reflect a synchronized set of endocrine-related events (Fig. 28a). As estrogen levels rise during pregnancy, they stimulate an increase in uterine oxytocin receptors. The fetus grows rapidly near to the time of birth; its hypothalamus–pituitary system matures and activates the adrenal system, resulting in increased secretion of cortisol, and there is evidence that the fetus produces the oxytocin necessary for the onset of labour.
Cortisol is known to be important in the initiation of labour in some mammals, for example the sheep, but it is not known if fetal cortisol plays a similarly pivotal role in human parturi- tion. The distension of the uterus caused by fetal growth may also contribute to increased oxytocin receptor synthesis. Oxytocin, through its receptors, may also stimulate prostaglandin (Pg) synthesis, particularly of PgF2 and PgE2. The prostaglandins are a group of oxygenated, unsaturated, long-chain fatty acids with profound effects on virtually all tissues, and PgE2 and PgF2 appear to act through the cAMP second messenger system to increase cytosolic Ca2+ and thus uterine contractility.
These two have a therapeutic role in the induction of labour. During parturition, there is a profound fall in maternal plasma estrogen and progesterone concentrations, but it is not known what causes the rapid and sudden changes in the secretion of the female sex hormones during labour.
There is evidence that nitric acid donors ripen the human uterine cervix and the enzyme nitric oxide synthase is upregulated during spontaneous human cervical ripening. Inflammatory mediators may play an important role as well. The onset of labour is associated with a large influx of leukocytes, mainly T lymphocytes, neutrophils and macrophages, into the myometrium.
Lactation and the suckling reflex Although maternal prolactin (PRL) plasma levels rise well before birth, their role in pregnancy is unknown. During pregnancy the breast enlarges, due to the combined effects of PRL, placental lactogen, cortisol, growth hormone, estrogens and progesterone on the growth of the mammary lobular–alveolar system, but lactogenesis is virtually absent. Estrogen and progesterone actually inhibit milk production through a direct inhibitory effect on PRL receptor synthesis.
After birth, however, the concentrations of these two sex hormones are relatively low, and PRL is allowed to play its key role in promoting lactogenesis. Lactogenesis and milk secretion begin very soon after birth. Milk is produced in the cells which line the alveoli, and is composed of lactose (produced from glucose), milk proteins, the most important of which are casein and whey, lipids, divalent cations, and also antibodies, through which the mother temporarily transfers certain forms of immunity to the baby. In humans, certain drugs are also carried in breast milk and this may be an important consideration for women on long-term medication such as antiepileptics or those using, for example, drugs of addiction.
There is evidence that PRL stimulates milk production through stimulation of the phospholipase A2 second messenger system and increased prostaglandin synthesis, resulting in increased mRNA for casein. Cortisol and insulin are essential for this action of PRL. PRL has also been shown to activate the transport of K+ and Na+ through an action on the Na+/Ka+– ATPase pump, which in mammary tissue is confined mainly to the basolateral membranes of the mammary epithelial cells.
The suckling reflex. PRL secretion from the anterior pituitary lactotroph cell is controlled by a reflex, the neuroendocrine suckling reflex (Fig. 28b). The secretion of prolactin is normally under the inhibitory control of dopamine (called prolactininhibitory factor, or PIF) from the hypothalamus. The neurotransmitter gamma-aminobutyric acid (GABA) may mediate the release of PIF (Fig. 28c). When a mother begins nursing, or suckling the baby, the mechanical stimulation of the nipple sends afferent impulses through the anterolateral columns of the spinal cord, some of which converge, eventually, in the supraoptic (SON) and paraventricular (PVN) nuclei in the hypothalamus. Oxytocin is released from neurosecretory terminals in the posterior pituitary, and travels in the bloodstream to the mammary gland, where it contracts the mammary myoepithelial cells, resulting in an explosive discharge of milk. The same reflex somehow lessens or removes the inhibitory influence of dopamine, resulting in PRL release from the anterior pituitary. The control of prolactin release by the brain is complex and not fully understood. A novel prolactin-releasing peptide has been described in the hypothalamus, but its role as a specific PRL-releasing factor is not established. Thyrotrophin-releasing hormone (TRH), vasoinhibitory peptide (VIP) and angiotensin II act in the hypothalamus to stimulate PRL secretion from the anterior pituitary. Milk production is maintained for as long as nursing is continued. In some poorer societies, a mother may lactate for up to 3 years, during which time she is relatively infertile. During nursing, gonadotrophin secretion from the pituitary is inhibited, and sex hormone production remains low. This results in a form of natural contraception. Non-lactating women will return to normal cyclic activity within about 4–5 weeks after birth, whereas in lactating women there will be no ovarian follicular development while plasma PRL levels remain elevated. After weaning, or the cessation of suckling, the secretion of estradiol and of LH increases, reflecting the resumption of normal ovarian function.
Prolactin has many other actions in both males and females, many of which are still poorly understood. It is released in stress, sleep, during eating and exercise, and is involved in hair growth. During the normal menstrual cycle it appears to maintain LH receptor production, and also to maintain LH receptors during pregnancy.