Neuroendocrinology is an interdisciplinary discipline formed by neuroscience and endocrinology, aiming at studying the regulation of the central nervous system-pituitary-peripheral endocrine system and its feedback mechanisms, in order to understand and elucidate the relationship between central and peripheral neurohumoral homeostasis and its derangements with diseases. Peripheral endocrine glands mainly include gonads, adrenal glands and thyroid glands. The central nervous-pituitary, ovarian and peripheral endocrine glands exert extremely complex and sophisticated regulation of the physiological processes of development, growth, maturation, reproduction and aging in the female individual.
I. Neuroendocrine structure of the hypothalamus
(I) Hypothalamus
The hypothalamus is a very important component of the central nervous system. The hypothalamus is usually divided into three zones (medial, lateral and periventricular), among which the medial and periventricular zones contain most of the structures related to the central regulation of the endocrine system.
The neural connections reaching the hypothalamic nucleus are divided into ascending afferent branches and descending afferent branches. Ascending afferent branches originate from the caudal medulla to different levels of the anterior brainstem of the midbrain, while descending afferent branches originate from the basal structures of the forebrain, the olfactory nodes, the septum, the pyriform cortex, the amygdala and the hippocampus. Direct projections from the retina to the supraoptic nucleus of the hypothalamus are involved in the day-night regulation of neuroendocrine rhythms by light stimulation, mainly the regulation of melatonin synthesis and secretion from the pineal gland.
The efferent neural connections of the hypothalamus are the projections of hypothalamic neurons to the pituitary gland, including the median eminence, the funnel stalk of the pituitary gland, and the neurohypophyseal lobes of the pituitary gland. Most of the large-cell neurosecretory system originates from the hypothalamic supraoptic and paraventricular nuclei, which produce oxytocin and pressor hormone; the small-cell neurosecretory system mainly originates from the medial basal hypothalamus, which includes gonadotropin-releasing hormone neurons and nodal pituitary dopamine neurons, two reproduction-related components.
Hypothalamic tissue is composed of neurons and glial cells, which are highly differentiated and store large amounts of information, performing coordinated precision reception and rapid transmission functions through their specialized dendritic and axonal structures. Glial cells, previously thought to be only support cells, have been found to secrete a variety of cytokines that play an important regulatory role on neurons through a paracrine mechanism.
(II) Steroid hormones and neurosteroids
1.steroid hormone
Steroid hormones in blood transport can bind to specific receptors in the central nervous system, proving that central neurons receive feedback regulation from peripheral steroid hormones. Recent studies have found that central nervous tissue itself can also synthesize steroid hormone molecules, and the binding of these steroid molecules to neurons is the same as that of peripheral organizers, and both are involved in the regulation of neuronal gene transcription and expression.
(1) Estrogen: The target cells are mainly concentrated in the preoptic and hypothalamic regions. It has been found that estrogen has two types of receptors, ERα and ERβ, which bind to ligands as complexes with opposite effects, i.e. estrogen binds to its ERα receptor to activate gene transcription and to its ERβ receptor to inhibit gene transcription. This demonstrates that in gene regulation, the two receptors trigger distinct effects. In addition, the distribution of the two receptors in the brain is different, with ERα in the arcuate nucleus and ERβ in the paraventricular nucleus.
(2) Progesterone: Progesterone receptors are present in the medial base of the hypothalamus around the median bulge of the brain, but the density of progesterone receptors is influenced by estrogen stimulation, and estrogen can upregulate their expression levels.
(3) Androgens: Similar to estradiol distribution, their density is highest in the hypothalamus and amygdala, and lower in the septum and hippocampus.
(4) Adrenal glucocorticoid hormone: The expression density is higher in hippocampus, septum and amygdala, and very low in hypothalamus including preoptic area and midbrain.
2.Neurosteroids
In 1975, it was found that estrogen could be produced in the hypothalamus by itself, and later it was reported that there were many kinds of progesterone and androstenedione in the brain of male rats, the content of which was 10 times that of peripheral blood, indicating that there is a mechanism of steroid synthesis in the brain. Neurosteroids can regulate the activity of GABAA and glutamate receptors, which may include the effect on memory and recall, as well as the regulation of neuronal activity.
Second, the hypothalamus regulation of pituitary hormone secretion in relation to reproduction
The hypothalamus and the pituitary gland constitute the central link of neuroendocrinology. The former releases the integrated information from the brain in the form of chemical products to the anterior pituitary gland to promote or inhibit the production and secretion of pituitary hormones, thus regulating the growth, differentiation process and physiological functions of the cells of the relevant peripheral target organs. To date, five neurohormones have been purified to act on the pituitary gland, namely: pituitary gonadotropin-releasing hormone (GnRH), growth hormone-releasing hormone (GHRH), corticotropin-releasing factor (CRF), growth hormone-releasing inhibitory hormone (somatostatin) and thyrotropin-releasing hormone (TRH). In addition to hypothalamic neurons, they are also present in the brainstem, spinal cord, central and peripheral autonomic nervous system, some exocrine and endocrine glands, gastrointestinal tract, respiratory tract, reproductive tract, and placenta, among other tissues.
(i) Hypothalamic GnRH-pituitary gonadotropin system
The cluster of GnRH neurons is networked and located mainly in the medial base of the hypothalamus and the preoptic area, and its axons project to many parts of the brain, transporting GnRH to gonadotropic cells. Its projections to the limbic system and periventricular organs have neurotransmitter-like or modulatory effects and thus regulate reproductive function. gnRH is encoded by a single gene located on the short arm of chromosome 8.
GnRH is released rhythmically from the medial basal neurons of the hypothalamus, and there is a significant synchronization between GnRH pulses in portal blood and LH pulses in peripheral blood, suggesting that the mechanisms controlling the rhythm of GnRH release are key to the regulation of pituitary gonadotropin secretion and the entire reproductive process. minutes.
Gonadotropin levels rise after birth, gradually reaching a peak and then progressively decreasing; they remain at a steady low level at 6-8 years of age, after which GnRH secretion rises again, thus stimulating the initiation of puberty. This process is regulated by a decrease in hypothalamic inhibitory factors or an increase in stimulatory factors. The increase in GnRH/LH pulses due to pubertal sleep is essential for the activation of pituitary-gonadal function.
Natural GnRH has a half-life of only 2-4 minutes. Synthetic GnRH analogs, which are not easily degraded by peptide hydrolases and have high affinity for GnRH receptors, have much longer half-lives. clinically, GnRH agonists are used to treat ovulation disorders and induce ovulation and pregnancy. continuous use of GnRH agonists has a pituitary-gonadal inhibitory effect and can be used to treat precocious puberty and endometriosis.
(ii) Hypothalamic CRF/ACTH system
CRF is an important neuropeptide that induces ACTH-cortisol secretion during stress, and the human CRF gene is localized on the long arm of chromosome 8. The CRF neuronal system is widespread in the hypothalamus and outside the brain.
CRF affects reproductive function by inhibiting the release of GnRH. Administration of CRF attenuates ACTH response in the presence of anorexia nervosa, depression, psychogenic hypothalamic amenorrhea, and exercise-related amenorrhea due to excess cortisol.
(iii) Hypothalamic GHRH/growth hormone releasing inhibitory factor/growth hormone system
GH is a single-chain polypeptide molecule synthesized, stored, and secreted by anterior pituitary flanking growth hormone cells, and its secretion is influenced by various exogenous stimuli and endogenous neural rhythms. GH is secreted in a pulsatile manner, occurring 4-8 times in a 24-hour period during puberty, with the highest peak seen 1 hour after the onset of slow sleep waves. The daily secretion rate is age-dependent, ranging from about 9ug in prepubertal children to about 700ug during puberty, decreasing to 380ug in young adults and even more in postmenopausal women. The decrease is mainly due to changes in pulse amplitude. In blood, GH has a half-life of 17-45 minutes. Pituitary GH secretion increases during exercise, physical stress, emotional stress and sepsis; estrogen, testosterone and thyroid hormones all increase GH secretion, but free fatty acids and other factors associated with obesity inhibit its secretion.
The main function of GH is to cause muscle and bone growth, which is achieved indirectly through insulin-like growth factors (IGF-I and IGF-II), and IGF-I has a negative feedback effect on GH. GH gene is located on the long arm of chromosome 17, q22-24.
Pituitary GH is doubly regulated by two hypothalamic peptide factors. Growth hormone release inhibitory factor inhibits its secretion and GH release factor (GHRH) stimulates its release. Recently, a new group of GH secretagogues, including GH-releasing peptide 6 and several synthetic peptides, has been identified, which have a role in stimulating GH release from the pituitary and hypothalamus in vivo.
It also has a physiological role as a thyroid stimulating hormone (TSH) release inhibitor. It is the first hypothalamic hormone found outside the hypothalamus of the central nervous system and has a wide distribution, being present in the gastrointestinal tract, pancreas, and placenta in addition to the center, and showing different functions. It acts as a neurotransmitter in CNS neurons, inhibits the secretion of pituitary and gastrointestinal hormones and inhibits intestinal motility and nutrient absorption, and may also have a suppressive effect on the immune system.
(iv) Hypothalamic TRH/TSH system
The hypothalamus regulates the pituitary TSH-thyroid axis through the excitatory effect of TRH and the inhibitory effect of growth hormone-releasing inhibitory factor. The human TRH gene is localized on chromosome 3. Thyroid hormone plays a negative feedback role in regulating TRH mRNA expression and secretion, and is probably the most important regulator of TRH biosynthesis.
The regulation of the pituitary system by the hypothalamus
(A) Oxytocin, arginine pressor and pituitary hormone
Oxytocin and arginine pressor hormone are secreted by the axon terminals of the pituitary gland (posterior pituitary). The peripheral target of oxytocin is the reproductive system and the peripheral target of arginine pressor hormone is the kidney.
In the reproductive system, oxytocin and arginine pressor are present in the human ovaries, follicular fluid and fallopian tubes. Oxytocin induces the release of uterine prostaglandin F2α, which in turn causes an increase in ovarian oxytocin levels.
(II) Major homeostatic functions of arginine pressor (AVP)
AVP responds to elevated blood osmolarity and decreased hydrostatic pressure through certain mechanisms. As a strong vasoconstrictor and antidiuretic hormone (ADH), it acts on the kidney through the mediation of tissue-specific G protein-coupled receptors, which increase water retention. Release is rapidly increased in response to a rise in plasma osmolality; it is inhibited in response to water loading, thus leading to antidiuretic or diuretic effects, respectively. A decrease in blood volume from any cause can cause AVP release, and AVP release and water retention occur when intravascular volume falls sharply by more than 10%.
(C) Oxytocin has effects on childbirth, lactation, sexual behavior and learning and behavior
1. Labor: Human oxytocin is an important stimulating factor for uterine contractions during late labor. During labor, vaginal distension or neurological reflexes stimulate the release of oxytocin from the mother. In pregnant women, estrogen induces an increase in oxytocin receptors in the myometrium and meconium, with the highest receptor concentration at term. Changes in the receptors may explain the increase in spontaneous contractions and increased sensitivity to oxytocin in late pregnancy in the absence of an increase in plasma oxytocin levels. In the second stage of labor, oxytocin and the prostaglandins stimulated by it have a synergistic effect on the delivery of the fetus.
2. Lactation: oxytocin causes contraction of myoepithelial cells of the mammary gland and smooth muscle of the mammary ducts through binding sites; when breastfeeding, the nipple nerve endings are stimulated and the neuronal reflexes are transmitted through the spinal cord, midbrain, and hypothalamus to induce the release of oxytocin from the pituitary gland. Due to the psychological reflex, oxytocin can be released before breastfeeding, while oxytocin release is inhibited during fear, anger or mental tension, and lactation is thus inhibited.
3. Sexual behavior: Tactile stimulation of the vulva causes the release of oxytocin, and orgasm is further increased which may be related to the contraction of vaginal smooth muscle.
Learning and behavior: AVP and oxytocin affect memory, with the former reinforcing memory and enhancing recall and the latter the opposite, thus oxytocin is thought to be an endogenous amnesic peptide. Maternal behavior is also associated with the central action of oxytocin.