Control of hypothalamic–pituitary–ovarian function

CHAPTER 15 Control of hypothalamic–pituitary–ovarian function






Anatomy of the Hypothalamic–Pituitary Axis


The portion of the hypothalamus of special interest in the control of reproductive function is the neurohypophysis, which can be divided into three regions:






The adenohypophysis consists of:





The anterior pituitary does not normally receive an arterial vasculature but receives blood through portal vessels. The arteries supplying the median eminence and infundibular stalk empty into a dense network of capillaries, which are heavily innervated and drain into the portal venous plexus. In the human, these are present on all sides of the infundibular stalk, particularly posteriorly. These lead to the anterior pituitary formed by vessels from the median eminence and upper stalk joined ventrally by the short portal vessels arising in the lower infundibular stalk. Some 80–90% of the blood supply to the anterior pituitary is provided by the long portal vessels; the remainder comes from the short portal veins. The sinusoids of the adenohypophysis thus receive blood that has first traversed capillaries residing in the neurohypophyseal complex, and this unique relationship provides the basis for the view that the hypothalamus regulates the secretion of adenohypophyseal hormones through neurohormonal mechanisms involving hypothalamic-releasing and -inhibiting factors.


In contrast, the neurohypophysis — posterior pituitary — is an extension of the hypothalamus and the neurosecretory neurones of the supraoptic and paraventricular nuclei. These neurones release vasopressin, oxytocin and their associated neurophysins.



Neural connections


There are numerous and extensive neural pathways connecting the hypothalamus with the rest of the brain. The majority of afferent hypothalamic nerve fibres run in the lateral hypothalamic areas, whilst efferent pathways are more medially placed. One important efferent connection is the supraopticohypophyseal nerve tract carrying fibres from the supraoptic and paraventricular nuclei to the infundibular process of the pituitary, whilst other fibres carry hypothalamic-releasing or -inhibiting factors from the medial and basal parts of the hypothalamus to the anterior pituitary (Figure 15.2).



Gonadotrophin-releasing hormone (GnRH)-secreting neurones appear in the medial olfactory placode and enter the brain with the nervus terminalis, a cranial nerve that projects from the nose to the septal preoptic nuclei in the brain. By migration during embryogenesis, the cells, between 1000 and 3000 GnRH-producing neurones, predominantly settle in the arcuate nucleus of the hypothalamus (Schwanzel-Fukunda et al 1989). Failure of this migration has been shown to result in Kallmann’s syndrome; a disorder associated with an absence of GnRH secretion and a defect of smell-anosmia (a failure of both olfactory axonal and GnRH neuronal migration from the olfactory placode). A 5–7-fold increased frequency of this condition is found in males, indicating that an X-linked transmission is the most common, although autosomal-dominant and autosomal-recessive modes of transmission have also been established (Waldstreicher et al 1996).


The mutations responsible for this syndrome result in the failure to produce a protein, homologous to members of the fibronectin family, responsible for cell adhesion and protease inhibition that is necessary for migration of these neurones (Bick et al 1992). GnRH neurones have cilia — as do olfactory epithelial cells in the nose — and the olfactory origin and structural similarity of these cells suggest an evolution from reproduction controlled by pheromones.



Hypothalamic Regulation of Pituitary Secretion


Considerable efforts have been made in the past 25 years to identify, characterize and synthesize the substances thought to be produced in the neural elements of the infundibulum. Several substances which can either stimulate or suppress the rate of release of one or more hormones from the pituitary gland have been found in the infundibular complex. These can be classified into hypophysiotrophic, neurohypophyseal and pituitary peptide hormones and are listed in Table 15.1. Other substances will probably be added to this list in the future.


Table 15.1 Hypothalamic and pituitary hormones




























































Hypothalamic hormones  
Gonadotrophin-releasing hormone GnRH
Thyrotrophin-releasing hormone TRH
Corticotrophin-releasing factor CRF
Growth-hormone-releasing hormone GHRH
Somatostatin  
Prolactin-inhibiting factor PIF
Growth hormone secretagone receptor Ghrelin
Posterior pituitary products  
Vasopressin  
Oxytocin  
Neurophysin I and II  
Anterior pituitary peptide hormones  
Adrenocorticotrophic hormone ACTH
Prolactin PRL
Luteinizing hormone LH
Follicle-stimulating hormone FSH
Growth hormone GH
Thyroid-stimulating hormone TSH

Disorders of hypothalamic control of metabolic as well as reproductive hormones can influence the hypothalamic–pituitary–ovarian axis. For example, reproductive dysfunction may be associated with thyroid deficiency or excess, adrenocorticotropic hormone (ACTH) excess (Cushing’s syndrome) or growth hormone excess (acromegaly).


Further discussion in this chapter will be restricted to the roles played by GnRH, prolactin, dopamine and other neurotransmitters controlling the rates of release and synthesis of the gonadotrophins.



GnRH


In 1971, Schally et al isolated pure preparations of porcine LH-releasing hormone (LHRH) from hypothalamic extracts. Subsequently, its structure was discovered and synthesis was achieved (Matsuo et al 1971a, b). The finding of FSH-releasing activity of this LHRH led to the hypothesis of a single hypothalamic-releasing hormone, GnRH, controlling secretion of both LH and FSH from the pituitary gland, with the suggestion that sex steroids might play a role in modulating the proportions of LH and FSH released. The amino acid sequence of GnRH is shown in Figure 15.3; it is a decapeptide secreted with a large pre- and postprecursor molecule.




GnRH neurone system


The GnRH neurone system has been mapped in detail using primarily immunocytochemical methods. The GnRH neurones are not grouped into specific nuclei but form a loose network in several anatomical divisions. However, GnRH neurone bodies are found principally in two areas: the preoptic anterior hypothalamic area and the tuberal hypothalamus, particularly the arcuate nucleus and periventricular nucleus. Axons from GnRH neurones project to many sites in the brain; the most distinct tract is from the medial basal hypothalamus to the median eminence, where extensive plexuses of boutons are found on the primary portal vessels. GnRH, then, has ready and direct access to the anterior pituitary gonadotroph cells via the portal capillary plexus (see Figure 15.2). There are also numerous projections of GnRH-secreting neurones to the limbic system and the circumventricular organ, other than the median eminence. The role of these connections is currently unknown, but they may connect with other cells or GnRH may bind to different receptors (type II) which may modulate sexual behaviour or sexual arousal.


The GnRH terminals in the median eminence remain outside the blood–brain barrier and can therefore be exposed to chemical agents within the general circulation. The GnRH neurones themselves have receptors for a number of neurotransmitters, in common with other neurones, and release them in their contacts with other neurones. In addition, their activity and release of GnRH can be influenced by GnRH agonists and antagonists. Exposure to GnRH agonists causes a greater release of GnRH but at less frequent pulse intervals. Exposure to GnRH antagonists induces a slower and non-pulsatile release of GnRH. Hence, GnRH neurones have an internal feedback loop for control of GnRH release through receptors for their own secretory product.


It has been estimated that there may be as few as 2000–3000 GnRH neurones dispersed within the hypothalamus, located predominantly in the preoptic and mediobasal areas. Considerable reduction in number can occur without affecting the pulsatile release of gonadotrophins. The pulsatile nature of gonadotrophin release is dependent upon small numbers of GnRH neurones working in synergy; the so-called ‘pulse generators’.



Regulation of gonadotrophin secretion by GnRH


The GnRH gene sequence was first isolated by Seeburg and Adelman in 1984. The GnRH decapeptide is derived from the post-translational processing of a larger precursor molecule that has been termed ‘pre–pro-GnRH’. This appears to be a tripartite structure with a preceding 23-amino acid sequence joined to the decapeptide GnRH, which is then attached via a 3-amino acid sequence, glycine–lycine–arginine (GLY–LYS–ARG), to a 56-amino acid terminal peptide, which is termed the ‘gonadotrophin-associated peptide’ (GAP). The post-GnRH-decapeptide GLY–LYS–ARG 3-amino acid section is an important site for proteolytic processing. GAP itself is thought to have some prolactin-inhibiting properties (Figure 15.3). GnRH genes are encoded from a single gene located on the shorter arm of chromosome 8.


Using radioimmunoassays, GnRH has been demonstrated in the hypophyseal portal blood from a number of animal species (Carmel et al 1976). Electrical stimulation of the preoptic area of the brain in female rats on the day of pro-oestrus increases the GnRH concentration in portal blood, and the stimulus induces a marked release of LH from the anterior pituitary. In contrast, administration of antibodies against GnRH prevents this electrically stimulated LH release. These data provide evidence favouring a cause-and-effect relationship between GnRH release by the hypothalamus and LH release by the anterior pituitary.


It is now firmly established that GnRH can stimulate the secretion of both LH and FSH in animals and humans. Following intravenous administration of synthetic GnRH, a significant rise in serum LH, and sometimes FSH, will be seen within 5 min, reaching a peak within approximately 30 min, but FSH peaks are often delayed further. LH release has a linear log-dose relationship up to doses of 250 µg but no such relationship can be found for FSH.


In the female, the magnitude of gonadotrophin release, particularly LH, in individuals varies with the stage of the menstrual cycle, being greatest in the preovulatory phase, less marked in the luteal phase and least in the follicular phase of any individual cycle (Yen et al 1972, Shaw et al 1974) (Figure 15.4).



GnRH is thus the humoral link between the neural and endocrine components controlling LH and FSH release.



Mechanism of action of GnRH on pituitary cells


The first step in the action of GnRH on the pituitary gonadotroph is recognition of a specific receptor. GnRH receptor complexes often form clusters and become internalized, then undergo degradation in the lysosomes. The receptor fragments then pass back rapidly to the surface of the cell. This recycling process is causally related to upregulation of the receptor by GnRH. GnRH receptors tend to be of 60 kDa, to be glycoproteins and to have a transmembrane character of a complex nature with seven transmembrane domains. A negatively charged domain interacts predominantly with ARG in position 8 of the GnRH molecule.


The transmembrane domains have many formats which are common to humans and other species, and ligand-binding sites are fairly superficial within the receptor. In the human, the C-terminal tail is lost on the type 1 receptor (as found in the pituitary). Thus, once GnRH binds to the receptor, decoupling does not occur rapidly. This may be beneficial in allowing protracted LH release to occur.


Various GnRH agonists and antagonists have different binding ligands. An understanding of the site and mechanisms of binding to the GnRH receptor have allowed specific structural changes to be made to GnRH analogues to produce more potent pharmacological agents and to attempt to develop non-peptide antagonists.


Prolonged exposure to GnRH leads to suppression of LH release, called ‘downregulation’, which is associated with reduced numbers of GnRH receptors. This phenomenon is vitally important in understanding the mechanism of action of the GnRH analogues.


There are three principal positive actions of GnRH on gonadotrophin secretion:





The binding of GnRH to its receptor induces a complex series of intracellular responses, which result in hormone secretion and biosynthesis of the α and β subunits of LH and FSH. In addition, dimerization of α and β subunits and the glycosylation processes are induced. The mechanism of action of GnRH is depicted in Figure 15.5. Within seconds of GnRH binding to and activating GnRH receptors on the pituitary gonadotrophs, intracellular free Ca2+ concentrations increase. This Ca2+ is initially mobilized from intracellular stores (e.g. endoplasmic reticulum) but also, to maintain sustained LH release, extracellular Ca2+ enters the gonadotroph through receptor-regulated voltage-dependent Ca2+ channels.



The initial mobilization of intracellular Ca2+ is induced by inositol triphosphate, released as a consequence of receptor activation of the membrane-bound phospholipase-C enzyme. Diacylglycerol is also released by the action of phospholipase-C and in turn activates the phosphorylating enzyme protein kinase C. The adenyl cyclase complex is also stimulated and cyclic adenosine monophosphate (cAMP) is generated. Ca2+, protein kinase C and cAMP then interact to stimulate release of stored LH and FSH and subsequent biosynthesis (for review, see Clayton 1989).



Jun 4, 2016 | Posted by in GYNECOLOGY | Comments Off on Control of hypothalamic–pituitary–ovarian function

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