Reproduction and Development: Proceedings of the 28th International Congress of Physiological Sciences, Budapest, 1980

1980

The role of the hypothalamus in the regulation of LH and FSH secretion

NEW FINDINGS IN REPRODUCTIVE NEUROENDOCRINOLOGY

L. Martini,     Department of Endocrinology, University of Milano, Italy

Publisher Summary

This chapter discusses the new findings in reproductive neuroendocrinology. Hypothalamus influences anterior pituitary function by releasing specific polypeptidic hormones into the pituitary portal vessels. These hormones activate or inhibit the activity of the various components of the gland. Three hypothalamic releasing or inhibiting hormones have been identified so far. These are thyroid-stimulating hormone-releasing hormone (TSHRH), which stimulates the release of thyroid stimulating hormone (TSH) and of prolactin; luteinizing hormone-releasing hormone (LH–RH), which activates the secretion of LH and follicle-stimulating hormone (FSH); and Somatostatin, which inhibits the release of growth hormone and of TSH. The hypothalamic–pituitary unit receives important inputs from several extra-hypothalamic structures and from different types of feedback signals. The sertoli cells in the male and the granulosa cells in the female produce a principle of proteic nature, which specifically inhibits the release of FSH. The activity of the hypothalamic–pituitary complex can be modified by nervous signals, originating either in extra-hypothalamic structures or in the hypothalamus itself.

INTRODUCTION

It is universally accepted that the hypothalamus influences anterior pituitary function by releasing into the pituitary portal vessels specific polypeptidic hormones which activate or inhibit the activity of the various components of the gland. Three hypothalamic releasing or inhibiting hormones have been identified so far (Burgus et al., 1969; Matsuo et al., 1971; Brazeau et al., 1973). These are TSHRH, which stimulates the release of TSH and of prolactin; LHRH which activates the secretion of LH and FSH; and Somatostatin which inhibits the release of growth hormone and of TSH. This last principle exerts also several peripheral activities (e.g., inhibition of insulin and glucagone release, inhibition of the secretion of gastric enzymes, etc.) (Prange Hansen et al., 1975). Evidence accumulated in the last decade indicates that dopamine is probably the most important hypothalamic factor involved in the inhibitory control of prolactin secretion (Mac Leod, 1976). However, several data suggest the existence of a Prolactin Inhibiting Factor (PIF) different from dopamine, and of a Prolactin Releasing Factor (PRF) which cannot be identified with TSHRH.

The hypothalamic-pituitary unit receives important inputs from several extrahypothalamic structures, as well as different types of feedback signals. In addition to the classical long feedback systems (which operate via steroids produced by the ovary and by the testis), short and ultrashort feedback mechanisms have been described (see Piva et al., 1979a for references). In these last two systems, the stimulatory or inhibitory signals are provided respectively by anterior pituitary or hypothalamic hormones. A further complication has been added by the recent demonstration that the Sertoli cells in the male and the granulosa cells in the female produce a principle of proteic nature (called inhibin or folliculostatin) which specifically inhibits the release of FSH (Schwartz and Channing, 1977; Franchimont et al., 1980; Shander et al., 1980).

For obvious reasons, only a few aspects of the complicated mechanisms underlying the control of gonadotropin and prolactin secretion will be selected for presentation.

LOCALIZATION OF LHRH IN THE BRAIN

In 1967, Mess et al. have shown that the electrolytic lesion of two different hypothalamic regions (the arcuate ventro-medial area and the suprachiasmatic area) was followed by a decrease of the amounts of LHRH stored in the median eminence. Consequently, they have proposed that LHRH might be synthesized in these two neural regions. This interpretation has been subsequently supported by Schneider et al (1969) who used a similar technique, and by Motta and co-workers (1971), who utilized either different types of hypothalamic deafferentation or the implantation of blockers of protein synthesis into these two hypothalamic areas. More recently, the presence of LHRH in these two areas has been confirmed using the direct evaluation of the hormone by radioimmunological (Wheaton et al., 1975) or immunocytochemical procedures (Brownstein et al., 1976; Zimmerman, 1976; Elde and Hökfelt, 1978). It has now been demonstrated that, in the most frontal region of the hypothalamus, the bulk of LHRH activity is associated with one of the circumventricular organs, the organum vasculosum of the lamina terminalis (OVLT) (Zimmerman, 1976; Wenger et al., 1978; Ajika, 1980). Like in the median eminence, the LHRH of the OVLT is mainly localized in the granulated vesicles of the nerve endings which imping on the blood vessels of this structure on the ependyma of the third ventricle (Flerko’ et al., 1978). The origin of the LHRH-containing axons ending in the OVLT of the rat is still an open question, since LHRH-containing cell bodies have not been identified so far in the rat OVLT. LHRH positive perikarya have been shown in the preoptic region and in the bed nucleus of the stria terminalis (Silverman et al., 1979). The presence of LHRH in the OVLT has suggested that this structure might participate in the control of gonadotropin secretion. Piva et al. (1979b) have recently found that radiofrequency lesions placed in the OVLT of regularly cycling female rats induce a status of prolonged diestrus and abolish (or significantly depress) the LH and FSH surges normally occurring on the day of proestrus. On the contrary, OVLT lesions performed in adult castrated female rats do not influence the high serum levels of the two gonadotropins typical of the post-castration situation. These findings suggest that the OVLT plays a major role in the regulation of the cyclic but not of the tonic release of the two gonadotropins. A similar conclusion has been recently reached by Samson and McCann (1979); they have found that, in estradiol-primed ovariectomized rats, OVLT lesions significantly decrease the positive feedback effect of progesterone on gonadotropin release. A role for the OVLT in the control of estrous cyclicity is also suggested by the fact that the LHRH content of this structure fluctuates during the estrous cycle (Sétalo et al., 1976) and by the observation that the electrical stimulation of the OVLT induces gonadotropin secretion and ovulation in female rats in which these processes have been blocked by Nembutal (Kawakami et al., 1973). LHRH is present also in other circumventricular organs (such as the subcommissural organ, the subfornical organ and the area postrema) (Kizer et al., 1976). Recent results of Limonta and Piva (1980) suggest that also the subcommissural organ may participate in the control of cyclic release of LH and FSH.

According to some authors, LHRH is also present in the pineal gland (Zimmerman, 1976). This finding, if confirmed, would be relevant, since it is known that the pineal gland and its indolic and peptidic hormones exert important functions in the control of the secretion of pituitary gonadotropins (Martini et al., 1968). It must be added at this point that the fact that LHRH may be detected outside the hypothalamus has led to the suggestion that this hormone might exert, in addition to its effect on anterior pituitary function, some neurotransmitter-like activity in the brain and participate in the control of non-endocrine phenomena (e.g., sex behavior) (see Martini, 1978 a for references).

INPUTS TO LHRH SYNTHESIZING NEURONS

It is currently believed that the activity of the hypothalamic-pituitary complex may be modified by nervous signals originating either in extra-hypothalamic structures or in the hypothalamus itself. It is generally accepted that this information is transferred to the LHRH producing system through the release, at neuronal junctions, of different classes of classical or putative neurotransmitters. The pertinent evidence cannot be reviewed here, but it has been shown that catecholamines, acetylcholine, serotonin, prostaglandins, histamine, gamma-aminobutyric -acid, substance P, neurotensin and several peptides common to the brain and to the gastrointestinal tract may participate in the control of gonadotropin and prolactin secretion (Batta et al., 1974; Simonovic et al., 1974; Fiorindo and Martini, 1975; Justo et al., 1975; Fioretti et al., 1978; Sawyer, 1979; Vijayan and McCann, 1979; Vijayan et al., 1979 a, b; see also Müller et al., 1977 for additional references). Figure 1 shows, for example, the effects of neurotensin on gonadotropin secretion in the rat. It is apparent that the intraventricular injection of minute amounts of this peptide inhibits LH but not FSH release in long-term castrated females (Motta and Martini, unpublished). A similar finding has been reported by Vijayan and McCann (1979).

Fig. 1

It must be recognized that, in the last few years, the most interesting results have been obtained while exploring the role of the opioid system and of the opioid-related peptides. The evidence available indicates that the opioid system certainly plays a major role in the control of prolactin release. Morphine and other opioids exert a strong stimulatory effect on prolactin secretion, while opioid antagonists (e.g., naloxone) inhibit the secretion of these two hormones (Meites et al., 1979; Collu and Taché, 1979). An example is provided in figure 2, which shows that the administration of naloxone to lactating rats strongly inhibits the release of prolactin induced by suckling (Sirinathsinghji and Martini, unpublished). The participation of the opioid system in the control of gonadotropin secretion is still unclear.

Fig. 2

In the pioneer studies of Bruni et al. (1977), naloxone was shown to stimulate LH and FSH secretion in male rats, while morphine and Methionine-Enkephalin (Met-Enk) (following systemic injections of large doses) have been reported to have the opposite effect. On the basis of these and similar findings (Blank et al., 1980), it has been suggested that opioid peptides exert an inhibitory effect on gonadotropin secretion. However, Motta and Martini (unpublished) have recently found that Met-Enk, in the dose of 25μg/rat, increases LH release if injected intraventricularly into castrated female rats (Fig. 3). Identical results have been obtained utilizing a Met-Enk analogue (Fig. 4). Similar data have been reported by Takahara et al. (1978) following the intraventricular infusion of β -endorphin. These results seem to imply that there are opioid receptors in the brain whose activation is followed by a stimulation rather than by an inhibition of LH secretion. Several hypotheses may be put forward for explaining the discrepancy between these results and those obtained following the peripheral administration of naloxone, morphine and of high doses of opioid peptides. First of all the existence of two types of opioid receptors has been demonstrated (Della Bella et al., 1978). Secondly, one may suggest that, in the brain, there are different opioid systems, one inhibiting and the other activating the LHRH system. The inhibiting system would be usually prevailing, as shown by the effects of naloxone. However, depending on the doses and especially on the way of the administration, opioids might reach only the stimulatory system and bring consequently to the release of LH. With regard to the mode of action of the opioids, evidence which is rapidly accumulating indicates that they may interact with hypothalamic dopamine storage, turnover and release (Ferland et al., 1977; Gudelsky and Porter, 1979; Van Vugt et al., 1979; Van Loon et al., 1980). Evidence is also available suggesting that they may also affect serotoninergic (Ieiri et al., 1980) and cholinergic (Casanueva et al., 1980) mechanisms. Further work is obviously needed to fully clarify the intricacies of these interrelationships.

Fig. 3

Fig. 4

Old and recent evidence suggests that the amygdala may participate in the control of gonadotropin secretion by sending to the hypothalamic-pituitary axis modulatory influences via the stria terminalis and the ventral amygdalofugal pathway. It has also been demonstrated that the amygdala is richly innervated by fibers originating in the brain-stem and that catecholamines and acetylcholine are present within nerve terminalis arriving at the amygdala. Recently Borrell et al. (1979) and Piva et al. (1980) have tried to interrupt, using a pharmacological approach, inputs reaching the amygdala from the brain-stem. They have bilaterally implanted into the basomedial portion of the amygdala of castrated female rats drugs which exert agonistic or antagonistic effects on adrenergic or cholinergic receptors. The data obtained have indicated, among others, that the implantation of either propranolol (a β -adrenergic receptor blocker) or of atropine (a muscarinic receptor blocker) is followed by a very significant increase of LH but not of FSH release (Fig. 5 and 6). On the basis of these and other findings, it has been concluded: a) that the amygdala is certainly involved in the nérvous processes which control gonadotropin secretion; b) that the amygdala is not autonomous in exerting such a control, since its function seems to depend largely on cholinergic and adrenergic inputs arriving from other regions of the brain; c) that the activity of these different structures (brain-stem-amygdala-hypothalamus) is essential for the neuroendocrine control of gonadotropin secretion; and d) that the amygdala represents one of the major stations for the differential regulation of the secretion of LH and