ABSTRACT

The roles of dopamine and the endogenous opiate peptides in the mediation of the inverse relationship between prolactin and gonadotrophin secretion during lactation were studied by comparing the effects of bromocriptine and naloxone on plasma levels of prolactin, LH and FSH during suckling in the female rat. The effects of exogenous gonadotrophin releasing hormone (GnRH) on the LH and FSH responses to bromocriptine and naloxone were also assessed. In control animals (saline), there was a marked fall in LH levels and a large increase in prolactin levels within 15 min of suckling. In response to GnRH (25 ng) there was a small progressive increase in LH levels reaching a maximum at 45 min. Both bromocriptine (500 μg) and naloxone (500 μg) markedly suppressed the suckling-induced prolactin surge when administered in two separate groups of animals. However, despite the bromocriptine-induced suppression of prolactin levels, there was no increase in LH levels which remained low throughout the suckling period. Naloxone (500 μg), however, induced a twofold increase in LH levels within 15 min suggesting that an enhanced opiate rather than dopaminergic activity may be responsible for the suppression of GnRH and hence gonadotrophin secretion during suckling. This is supported by the finding that whereas combined bromocriptine (500 μg) and GnRH (25 ng) treatment suppressed the suckling-induced prolactin rise and also induced only a small progressive increase in LH (similar to GnRH alone), combined naloxone (500 μg) and GnRH (25 ng) treatment induced a sharp sixfold increase in LH levels within 15 min while at the same time markedly suppressing prolactin levels. None of these drug treatments affected the levels of FSH.

The results of this study may thus indicate that (1) the suckling stimulus itself rather than the high prolactin levels may be responsible for the suppression of gonadotrophin secretion during lactation, (2) although dopamine may be an important physiological factor controlling prolactin secretion, it may not be involved in the regulation of LH during lactation and (3) the suckling stimulus may enhance the release of endogenous opiates within the central nervous system which could then stimulate prolactin and at the same time inhibit gonadotrophin secretion by inhibiting GnRH release. This opiate-mediated mechanism may explain the reciprocal nature of prolactin and LH secretion during lactation.

J. Endocr. (1984) 100, 175–182

It is well recognized that during pregnancy the placenta develops into a highly active endocrine organ and elaborates a variety of peptide hormones similar or identical to those synthesized and secreted by the hypothalamic-pituitary system. These include chorionic gonadotrophin, the prolactin family of peptides (prolactin, placental lactogen and growth hormone) and gonadotrophin-releasing hormone (Stewart, Jones, Pascall et al. 1988). In addition, studies based on radioimmunoassay of placental extracts and immunocytochemical examination of placental tissue have demonstrated that the human placenta contains immunoreactive (ir) corticotrophin-releasing factor (CRF) (Shibasaki, Odagiri, Shizume & Ling, 1982; Petraglia, Sawchenko, Rivier & Vale, 1987), pro-opiomelanocortin (POMC)-derived peptides namely β-endorphin and corticotrophin (ACTH) (Rees, Burke, Chard et al. 1975; Liotta, Osathanondh, Ryan & Krieger, 1977; Odagiri, Sherell, Mount et al. 1979), enkephalin and dynorphin (Tan & Yu, 1981) and neuropeptide Y (NPY) (Petraglia, Calza, Coukos et al. 1988) all of which are intimately involved in the regulation

Human pituitary LH (1200 i.u.) was infused for 4 h (from 10.00 to 14.00 h) into six women with anorexia nervosa and into five women with polycystic ovarian disease (PCO). Plasma dehydroepiandrosterone sulphate (DHAS), androstenediol sulphate, dehydroepiandrosterone (DHA), androstenediol and testosterone were estimated by gas–liquid chromatography in blood samples taken every 2 h from 10.00 to 20.00 h. The values were compared with those obtained at the same times on the previous control day. There were no significant changes in the plasma levels of DHAS and androstenediol sulphate in response to LH at any of the sampling times in either the anorexia nervosa or the PCO patients. In the anorexia nervosa women, plasma DHA levels were significantly increased at 16.00 (P<0·001), 18.00 (P<0·001) and 20.00 h (P<0·05) after LH infusion. In the PCO women, DHA levels increased significantly at 14.00 (P<0·01), 16.00 (P<0·001), 18.00 (P<0·001) and 20.00 h (P<0·001) in response to LH infusion. Plasma androstenediol levels increased significantly in the anorexia nervosa patients at 12.00 (P<0·001), 14.00 (P<0·01) and 16.00 h (P<0·01) in response to LH. Similar increases were also found in the PCO patients at 12.00 (P<0·01), 14.00 (P<0·001) and 16.00 h (P<0·01). Plasma testosterone decreased progressively in the anorexic women in response to LH, becoming significant at 16.00 (P<0·05), 18.00 (P<0·05) and 20.00 h (P<0·01). A similar progressive decrease in plasma testosterone was seen in the PCO women, the levels being significantly lower than controls at 16.00 (P<0·05), 18.00 (P<0·05) and 20.00 h (P<0·05).

The results represent the first experimental evidence for a direct regulatory role for LH on androgen secretion in women. In addition, the data have a significant bearing on the pathogenesis of the PCO syndrome and the development of hirsutism which may be directly related to the high androgen levels in PCO women in whom the levels of LH are normally raised. The data may also offer an explanation for the mechanisms responsible for the low androgen levels in anorexia nervosa patients in whom there is a gonadotrophin deficiency.

ABSTRACT

Studies were undertaken using the opiate receptor antagonist naloxone to examine the hypothesis that endogenous opiates may have a restraining effect on prepubertal gonadotrophin secretion and may be involved in the maturation of the central nervous system mechanisms regulating the onset of puberty in the female rat. Naloxone (2·5 mg/kg) administered intraperitoneally every 6 h to female rats from day 1 to day 10 of postnatal life significantly (P <0·001) advanced the age of onset of puberty assessed in terms of the day of vaginal opening and first oestrus (32·3 ± 0·2 vs 40·8 ± 0·4 days in control saline-treated animals). Animals so treated with naloxone showed significantly (P < 0·001) higher levels of FSH (761·4 ± 87·6 vs 483·8± 57·2 μg/l in control animals) and LH (562·8 ± 57·4 vs 351·3 ± 43·3 μg/l in control animals) at the first late pro-oestrus and a significantly (P < 0·001) higher number of ova released at first oestrus (12·4 ± 0·4 vs 8·1±0·3 in controls). Body weight at first oestrus was significantly (P <0·001) lower in the naloxone-treated animals, an indication that these animals were much younger. The weights (per 100 g body wt) of the ovaries and uteri at the first oestrus were significantly (P <0·01) higher in the naloxone-treated rats than in the controls. However, there were no significant differences in the weights of the adrenals and anterior pituitary glands between the two groups of animals. A study of the cyclic patterns of the neonatally naloxone-treated animals performed for 15 consecutive cycles after the first oestrus showed normal 4- or 5-day cycles similar to those occurring in the saline-treated animals. The lengths of the first and second cycles in the naloxone-treated animals were not significantly different from controls. No significant differences in body weight or in organ weights at oestrus or in the levels of LH and FSH determined during the various stages of the oestrous cycle were found between naloxone- and saline-treated animals when these parameters were examined at 3 months of age. Naloxone had no effect on onset of puberty when administered during the other stages of prepubertal life. The mechanisms by which naloxone acts specifically during the neonatal period to induce precocious puberty are at present not known but are being investigated; they may be related to naloxone-induced alterations in the inhibitory synaptic arrangements between opiatergic and gonadotrophin-releasing hormone (GnRH) neurones, with a resulting decrease in the inhibitory influence exerted by endogenous opioids on GnRH neurones during this period of intense neurological development. The results suggest that the endogenous opiate peptides could play a key role in the central mechanisms which trigger the onset of puberty in the female rat.

J. Endocr. (1985) 104, 299–307