Psychoneuroendocrinology, Vol. 17, No. 4, pp. 385-390, 1992 0306-4530/92 $5.00+0.00 Printed in Great Britain 1992 Pergamon Press Ltd.

THE BRAIN AS A TARGET ORGAN OF GONADAL STEROIDS

A. R. GENAZZANI, M. GASTALDI, B. BIDZINSKA, N. MERCURI, A. D. GENAZZANI, R. E. NAPPI, A. SEGRE and F. PETRAGLIA

Department of Obstetrics and Gynecology, University of Modena School of Medicine, Modena, Italy

(Received in final form 18 March 1992)

SUMMARY

Gonadal steroids have many effects in the central nervous system. Through a feedback mecha- nism, they influence the synthesis and release of hypothalamic gonadotropin-releasing hormone (GnRH) and/or pituitary gonadotropic hormones (luteinizing hormone, LH, and follicle stimulating hormone, FSH). Endogenous opioid peptides (EOPs) represent one of the key factors modulating the activity of sex steroids on the hypothalamus-pituitary-gonadal (HPG) axis. In particular, these peptides control the secretion of LH by inhibiting the activity of the hypothalamic neurons which produce GnRH. The EOP effect is dependent on the steroid hormone milieu, as shown by different responses to naloxone administration, both in animals and in humans. For the naloxone-induced increase in LH secretion to occur, relatively high levels of sex steroids are required. In humans, LH release is absent before sexual maturation. In fertile women, naloxone administration increases LH levels in the luteal phase but not in the follicular phase. In the postmenopausal period, naloxone has no effect on LH release; estrogen/progestin therapy does restore the LH response.

INTRODUCTION

GONADAL STEROIDS play an important role in the regulation of the neuroendocrine mechanisms which form the basis of reproductive function. The effects of these hormones appear to be mediated by neurotransmitters and neuropeptides. In particular, endogenous opioid peptides (EOPs) have a key function in inhibiting the activity of hypothalamic neurons which produce gonadotropin-releasing hormone (GnRH). Several data indicate that the EOPs are involved, both in animals and humans, in the feedback effect exerted by sex steroids on GnRH secretion. The central opioid suppression of luteinizing hormone (LH) is in part dependent on the steroid hormone milieu.

GONADAL STEROIDS, OPIOIDS AND SEXUAL MATURATION

It is well known that, in the prepubertal period, there are low plasma sex steroids levels. The secretion of LH is not pulsatile and plasma follicle-stimulating hormone (FSH) levels are higher than those of LH. During puberty, this secretory pattern undergoes important changes, which reflect the maturation of the hypothalamo-pituitary-gonadal (HPG) axis. In prepubertal

Address correspondence and reprint requests to: Prof. A. R. Genazzani, Department of Obstetrics and Gyne- cology, University of Modena School of Medicine, Via del Pozzo 71, 1-41100 Modena, ITALY.

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children, naloxone administration does not significantly change plasma LH levels (Fraioli et al., 1984; Petraglia et al., 1985a). On the other hand, at advanced stages of pubertal maturation, an increase in LH occurs after naloxone administration (Petraglia et al., 1985a), in parallel with the beginning of the pulsatile secretion of LH. It has been suggested that EOPs represent the bio- chemical basis of the so-called "gonadostat", the central mechanism that seems to maintain the high sensitivity to the negative feedback by gonadal steroids before puberty (Bhanot & Wilkinson, 1983).

The beginning of pubertal maturation may be linked to a reduced activity of opioid systems. This hypothesis has been supported by the observation that in children with gonadal dysgenesis or delayed puberty, naloxone does not induce a significant rise in plasma LH levels (Petraglia et al., 1988). Similarly, studies in rats lead to the conclusion that pubertal maturation is character- ized by a functional change in the central opioidergic pathways (Bhanot & Wilkinson, 1988). However, this neuroendocrine change does not seem to be linked to increased plasma sex steroid levels: Administration of exogenous estrogen-progestin does not result in any modifi- cation of central opioidergic activity.

GONADAL STEROIDS, OPIOIDS AND THE MENSTRUAL CYCLE

Many studies, both in vivo and in vitro, suggest a close relationship between EOPs and gonadal steroids during fertile life. The arcuate nucleus of the hypothalamus contains estradiol- concentrating neurons as well as 13-endorphin (13-EP)-producing neurons, and a subpopulation of the arcuate nucleus ~-EP neurons is receptive to the influence of estradiol (Jirikowski et al., 1986). POMC mRNA is found mostly in the rostral 1/4 of the arcuate nucleus, and here there are neurons highly responsive to gonadal steroids (Chowen et al., 1990). Moreover, a small population of hypothalamic 13-EP-producing neurons contains progesterone. It also has been reported that estrogen reduces hypothalamic proopiomelanocortin (POMC) mRNA (Wilcox & Roberts, 1985). Other studies indicate that testosterone replacement in castrated male rats significantly increases POMC mRNA levels in the arcuate nucleus (Chowen-Breed et al., 1989).

In normally menstruating women, the opioid influence on LH secretion undergoes changes during the menstrual cycle. The effect of naloxone is evident during the luteal phase, but not during the follicular phase. The stimulatory effect of naloxone on LH is present from the pre- ovulatory days, and the increase in LH is related to circulating estradiol levels (Quigley & Yen, 1980). It also has been suggested that differential LH pulsatile secretion is in part determined by a synergistic effect between the high levels of progesterone and opioids (Ferin et al., 1984).

Dynamic changes in LH release are closely related to the sex steroid environment through the menstrual cycle. During the early and late follicular phases, the frequency of the LH pulses is higher than during the luteal phase of the cycle, when LH episodic release shows a reduced frequency and an increased amplitude of the secretory bursts (Filicori et al., 1986). It may be proposed that steroids affect LH pulsatile secretion by modulating the level of activity of opioid systems on hypothalamic GnRH release. The changes in opioid activity during the menstrual cycle are not evident from challenges with opiate agonists. Morphine injection, for example, inhibits plasma LH levels in all subjects, irrespective of phase of the menstrual cycle (Petraglia et al., 1986). The correlation between opioids and gonadal steroids in modulating LH release is further confirmed by the lack of plasma LH increase after naloxone administration in patients with hypothalamic amenorrhea (Petraglia et al., 1985b) and by the restoring of a normal response to naloxone after pulsatile GnRH or gonad0tropin therapies (Nappi et al., 1987).

The administration of the long-acting opioid receptor antagonist, naltrexone, induces ovula-

GONADAL STEROIDS AND THE BRAIN 387

tory cycles (Wildt & Leyendecker, 1987). In particular, patients affected by hypothalamic amenorrhea show a LH pulse frequency similar to that of normal cycling women in the follicu- lar phase. However, naltrexone treatment is not effective in all amenorrheic subjects in restor- ing the menstrual cycle (Remorgida et al., 1990). A hyperactivity of central opioids also may be a factor in other menstrual disorders, such as hyperprolactinemia and polycystic ovary disease (Sarkar & Yen, 1985; Lobo, 1988).

GONADAL STEROIDS, OPIOIDS AND THE MENOPAUSE

During the postmenopausal period, with the decrease of plasma estradiol levels, opioid activity on LH secretion is again modified. Evidence for ovarian steroid mediation is the failure of opioid receptor blockade by naloxone, which does not increase LH levels both in physiologi- cal and in surgical postmenopausal women treated with steroid hormone replacement therapy (Petraglia et al., 1985c). This may explain the presence of high plasma gonadotropin levels and the high frequency and amplitude of LH pulses (Reid et al., 1983). Even the injection of ~-EP or dermorphine does not alter the high plasma LH levels; this suggests an impairment of endogenous opioid tone in postmenopausal women. Estrogen and/or progestin therapies restore EOP action in modulating gonadotropin secretion (Shoupe et al., 1985).

The synergistic negative effect of estrogen and progesterone on gonadotropins may be func- tionally linked to an increase in the opioidergic effect on GnRH secretion. Many studies, both in vivo and in vitro, confirm that hypothalamic 13-EP content varies in rats administered gonadal steroids. The diurnal rhythm of the hypothalamic ~-EP concentration in female rats - - charac- terized by a significant nocturnal increase - - is modulated by estrogens, as demonstrated by the disappearance of the night-related changes in hypothalamic ]3-EP after ovariectomy, and by the restoring effect of acute or chronic treatment with estradiol benzoate (Genazzani et al., 1990a). Also, progesterone and noretisterone significantly increase the ]3-EP content of the medial basal hypothalamus in ovariectomized rats (Genazzani et al., 1987). Administration of progesterone or progestins together with estradiol benzoate in ovariectomized rats reduces the estradiol benzoate effect on central [3-EP content. It thus seems that gestagens have a modula- tory role on the estradiol benzoate effect in the medial basal hypothalamus.

Androgens also influence central 13-EP concentrations. The administration of dihydrotestos- terone to ovariectomized or intact female rats causes a decrease in medial basal hypothalamus ]3-EP concentrations (Genazzani et al., 1990b), suggesting a central action of androgens in the regulation of the HPG axis in female rats. This could help explain the effects of androgens on sexual behavior.

THE FUNCTIONAL IMPACT OF SEX STEROIDS ON OPIOID-RELATED EFFECTS IN REPRODUCTIVE LIFE

The responsiveness of the central nervous system (CNS) as a target for circulating steroid levels represents a fundamental link in the coordinated regulation of neuroendocrine systems. Gonadal steroids can regulate the secretion of EOPs in the hypothalamus probably by direct genomic activation (Kalra & Kalra, 1991). EOPs are widely distributed through the body and are implicated in a wide variety of biological functions (Fig.). There are roles for ~-EP in relation to analgesia, feeding and drinking behavior, temperature regulation, mood and social behavior, learning and memory processes, sexual behavior, psychic disturbances, and immune regulation. A large body of evidence suggests that opioid peptides exert a modulatory influence

388 A.R. GENAZZANI et al.

sexualbehavior mood behavior l learning memory

~jw thermoregulation. GnRH "- I beta-endorphin I feeding

estrogens ~ / immune system progesterone,,~' androgens /

Roles for ~-endorphin in biological functions of the CNS.

on all these functions mediated by the interaction between circulating hormones and brain physiology (Rodgers & Cooper, 1988).

By considering the close relationship between endogenous opioid peptides and the repro- ductive system we can explain some of the functional manifestations associated with the hormonal changes during reproductive life. Emotional and physical changes such as depres- sion, irritability, headache, elevation of basal body temperature, sexual behavior, and fluctua- tions in food intake and body weight normally occur under the influence of central opioids. For example, patients suffering from premenstrual syndrome show increased somatic, affective, cognitive and behavioral symptomatology during the luteal phase of the menstrual cycle (Reid & Yen, 1981). A change in hypothalamic opioidergic control in premenstrual syndrome is sup- ported by the lack of LH response to naloxone administration in the luteal phase (Facchinetti et al., 1988).

Similarly, at menopause, a group of symptoms including nervousness, anxiety, irritability, and depression are related to a series of biochemical events involving EOPs, neurotransmitters, and neuropeptides. These findings might be explained by the effects of progesterone and estra- diol on opioidergic tone at the hypothalamic level.

CONCLUSIONS

By modifying central f3-EP activity, gonadal steroids act on the HPG axis, modulating GnRH secretion and, moreover, possibly influencing mood and behavior. Some neurochemical studies have indicated that opioids have an effect on several other neuronal pathways (GABAergic, noradrenergic, serotoninergic, dopaminergic and cholinergic pathways). The complex interac- tions among steroid hormones, opioids and neurotransmitters appear to regulate the central events involved in reproductive function.

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