Clinical Aspects

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Damage can occur to the fragile structures connecting the hypothalamus to the anterior pituitary, the stalk, and the connecting blood portal system, often by trauma to the head. This can happen in automobile accidents and the like. Tumors, of course, can decrease the transport from the hypothalamus to the pituitary or disconnect it altogether. In any case, such damage has far-reaching effects and these conditions can be collectively listed under panhypopituitarism or hypothalamic hypofunction. Many of the releasing hormones will fail to arrive at their receptors on the plasma membranes of the specific anterior pituitary cell, and the hypothalamic-pituitary-end organ axis will be broken. Diagnosis is now possible through the availability of the releasing hormones, and often patients with these syndromes are treated with the hormone of the terminal gland in the pathway, such as the adrenal hormones, sex hormones, thyroid hormones, etc. The releasing hormones have come into prominence in the clinic. The function of the hypothalamic-pituitary-end organ axis is now possible to define in terms of the affected organ by the availability of releasing hormones that can be injected into the bloodstream. These hormones can gain access to the pituitary gland by this route, and therefore it becomes possible to elicit the function of the pituitary. If the pituitary is malfunctioning, the level of pituitary hormone released in the bloodstream in response to the stimulus of a specific releasing hormone will be subnormal, and it becomes possible to pinpoint the cause of disease in a malfunctioning hypothalamic-pituitary-end organ axis by measuring the level of the blood pituitary hormone, usually with a radioimmunoassay.

Short stature in children requires treatment with growth hormone. Some work also demonstrates that treatment with GHRH instead of growth hormone may be useful in some cases and may also be more economical. However, the regimen for this treatment to obtain the most satisfactory results has not been concluded. Release of GHRH is stimulated by inter-leukin-1/3, while thyroid hormone decreases the secretion of GHRH. Research indicates that GHRH is produced by human lymphocytes, and lymphocytes from rats have also been shown to contain GHRH receptors. These may prove to be useful indicators of the status of GHRH function. The response to GHRH may be greater in women than in men, and GHRH appears to be located in human gonads (corpora lutea) and in Leydig cells in the testes of prepubertal men.

Gonadotropin Release

Gonadotropin Release

FIGURE 3-15 Mechanism of action of GnRH in the pituitary gonadotroph. GnRH interactions with the plasma membrane receptor. This interaction provokes receptor-receptor interaction (microaggregation, patching, capping, and internalization), activates the mobilization of calcium, and, through a transducing G protein, activates a phospholipase C enzyme. Calcium accumulation activates calmodulin, which appears to mediate the release of gonadotropins. In combination with diacylglycerol (DAG), calcium activates protein kinase C (PKC), which appears to mediate the synthesis of gonadotropins (gene expression). LHp denotes the /3-subunit of luteinizing hormone. Other abbreviations: mRNA, messenger RNA; PI, phosphatidylinositol; IP, inositol phosphate; PA, phosphatidic acid. This figure is reproduced with permission from Conn, P. M„ and Crowley, W. F. (1991). New Engl. }. Med. 324, 93-103.

FIGURE 3-15 Mechanism of action of GnRH in the pituitary gonadotroph. GnRH interactions with the plasma membrane receptor. This interaction provokes receptor-receptor interaction (microaggregation, patching, capping, and internalization), activates the mobilization of calcium, and, through a transducing G protein, activates a phospholipase C enzyme. Calcium accumulation activates calmodulin, which appears to mediate the release of gonadotropins. In combination with diacylglycerol (DAG), calcium activates protein kinase C (PKC), which appears to mediate the synthesis of gonadotropins (gene expression). LHp denotes the /3-subunit of luteinizing hormone. Other abbreviations: mRNA, messenger RNA; PI, phosphatidylinositol; IP, inositol phosphate; PA, phosphatidic acid. This figure is reproduced with permission from Conn, P. M„ and Crowley, W. F. (1991). New Engl. }. Med. 324, 93-103.

TRH, as well as CRH, has been found to stimulate respiration independent of activation of the pituitary-adrenal axis. CRH acts in the brain to activate the sympathetic nervous system and reduce cellular immune function. Also, the central administration of CRH leads to a reduction in natural killer cell activity in the spleen. Interestingly, there has been a report of the existence of a specific binding protein for human CRH in human plasma. This may indicate that the binding protein can inactivate CRH and may involve as much as one-half of the CRH in the blood. The induction of CRH mRNA by ligands in the PKC mechanism may be blocked more effectively by glucocorticoids than message induction by ligands operating through the PKA pathway. This may explain abnormal CRH production in clinical conditions, such as anorexia nervosa and major depression. Stress is known to disturb reproductive function. Stress causes the output of CRH and ^-endorphin, which lower the secretion of gonadotropins, oxytocin, and vasopressin. Opioids increase during puberty and fall at menopause. /3-Endorphin is elevated by estradiol and progesterone in the luteal phase of the menstrual cycle. Thus, the rapid decline in these steroids and the fall of ¡3-endorphin at menstruation may lead to symptoms of premenstrual syndrome. Conversely, it may be possible to counteract the deleterious effects of stress on reproductive function by the use of opiate antagonists.

Hypothalamic GnRH is secreted in a pulsatile fashion at puberty and not prior to that time. Some evidence suggests that N-methyl-D-aspartate (NMDA) receptors, through excitatory amino acids, may facilitate the initiation of puberty. In immature male rats (15 days), there is an inhibitory control of pulsatile GnRH secretion presumably mediated by NMDA receptors, and specific antagonists of NMDA receptors can cause early pubertal development. This inhibitory effect on

GHRH GHRH Somatoststin

FIGURE 3-16 Speculative scheme for the action of GHRH and somatostatin. Abbreviations: R, receptor; G, GTP-binding protein; C, catalytic subunit of adenylate cyclase; s, stimulatory; i, inhibitory; ? indicates that this phosphatidylinositol (PI) pathway, either through the established GHRH receptor (Gs) or through another receptor and G protein, is highly speculative.

FIGURE 3-16 Speculative scheme for the action of GHRH and somatostatin. Abbreviations: R, receptor; G, GTP-binding protein; C, catalytic subunit of adenylate cyclase; s, stimulatory; i, inhibitory; ? indicates that this phosphatidylinositol (PI) pathway, either through the established GHRH receptor (Gs) or through another receptor and G protein, is highly speculative.

Somatostatin neuron (periventricular nucleus)

FIGURE 3-17 Hypothalamic peptidergic neurons of the GH neuroendocrine axis. Direct synaptic communication between somatostatin neurons and GHRH-containing arcuate neurons within the hypothalamus is postulated. Ill indicates the third ventricle. Reproduced from Tannenbaum, G. S. (1991). Neuroendocrine control of growth hormone secretion. Acta Paediatr. Scand. 372[Suppl.], 5-16.

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