Human Reproduction vol.10 no. 11 pp.2868-2871, 1995 Naltrexone administration modulates the neuroendocrine control of luteinizing hormone secretion in hypothalamic amenorrhoea Alessandro D.Genazzani 1 , Mario Gastaldi, Felice Petraglia, Cesare Battaglia, Nicola Surico 2 , Annibale Volpe and Andrea R.Genazzani 3 Department of Physiopathology of Human Reproduction, University of Modena, 2 Department of Obstetrics and Gynecology, University of Novara and department of Obstetrics and Gynecology, University of Pisa, Italy 'To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, University of Modena, Via del Pozzo 71, 41100 Modena, Italy Because endogenous opioids have been considered to be deeply involved as a causal factor of hypothalamic amenor- rhoea, this study was designed to evaluate the efficacy of the administration of naltrexone, an antagonist of opioid receptors, on luteinizing hormone (LH) secretion in patients with hypothalamic amenorrhoea. A total of 30 patients with hypothalamic amenorrhoea were studied. Patients were divided into two groups: group A, hypogonadotrophic (» = 15), and group B, normogonadotrophic (n = 15). All patients were administered naltrexone at a dose of 50 mg/ day per os for 6 months. A third group of 10 amenorrhoeic patients was treated with placebo per os with the same schedule. All patients were evaluated for LH spontaneous pulsatile release in baseline conditions and after 3 and 6 months of treatment. Plasma gonadal steroid concentra- tions increased significantly in all patients after 3 months of naltrexone therapy, but only hypogonadotrophic patients showed a sharp increase in both LH plasma concentrations and LH pulse amplitude within the first 3 months of treatment which remained unchanged until the sixth month of treatment. Plasma follicle stimulating hormone concen- trations did not change significantly in any patient. Menstrual bleeding occurred within 90 days of the begin- ning of treatment in 24 out of the 30 patients. Patients treated with placebo did not show a significant change in gonadotrophin and gonadal steroid plasma concentrations. The results of our study support the efficacy of naltrexone administration on neuroendocrine pathways controlling LH secretion in patients with hypothalamic amenorrhoea. Key words: endogenous opioid peptides/gonadotrophins/hypo- thalamic amenorrhoea/naltrexone Introduction Hypothalamic amenorrhoea is a model of hypogonadism characterized by neuroendocrine aberrations affecting hypo- thalamic control (Vigersky et al, 1977) and the modulation 2868 of the release of hypophyseal hormones (Berga et al., 1989; Genazzani er al., 1990, 1991, 1993a, 1994a,b). Amenorrhoeic patients have altered luteinizing hormone (LH; Genazzani et al., 1990), growth hormone (Genazzani et al., 1993a) and prolactin (Berga etai, 1989; Genazzani etal., 1994a) secretory patterns and a deregulation of some central neuromodulators has been suggested. In particular, an alteration in the activity of the opioidergic system has been proposed because an acute injection of naloxone, an opioid receptor blocker, increases LH pulse frequency and amplitude in healthy women but not in amenorrhoeic patients (Quigley et al., 1980; Lightman et al., 1981; Khoury et al., 1987). However, when naltrexone, a long- acting specific blocker of opioidergic receptors, was used to restore menstrual cyclicity in patients with hypothalamic amenorrhoea, conflicting results were reported. Remorgida et al. (1990) showed no difference between placebo and naltrexone, while Armeanu et al. (1992a,b) reported a moderate effect of naltrexone on LH episodic release in patients with weight loss-related amenorrhoea but not in those suffering from anorexia nervosa (Armeanu et al., 1992a). Conversely, the restoration of normal cyclicity in hypothalamic amenor- rhoea was reported using naltrexone at the standard dose of 50 mg/day (Wildt and Leyendecker, 1987) or higher (Wildt etal., 1993). On the basis of these data, our study aimed to evaluate the efficacy of chronic naltrexone administration on the spontan- eous LH episodic secretion in hypo- and normogonadotrophic patients with hypothalamic amenorrhoea. Materials and methods Subjects From among all the patients with menstrual cycle disturbances attending our department (Department of Physiopathology of Human Reproduction, University of Modena, Italy), 40 patients affected by hypothalamic amenorrhoea and reduced body mass index (BMI) were enrolled for this study. All subjects gave informed consent and the study protocol was approved by the Human Investigation Committee of the University of Modena (Italy). Criteria for inclusion were: (i) an absence of menstrual cycles for at least 6 months prior to the study; (ii) normal plasma concentrations of adrenal cortex, thyroid hormones, prolactin and androgens; (iii) an absence of depression or psychiatric diseases assessed according to Diagnostic and Statistical Manual—/// (revised) criteria (Spitzer et al., 1986) ; (iv) the presence of weight loss in the last 12-18 months prior this study; and (v) a BMI <20 and no weight gain in the 6 weeks preceding the study. Subjects undergoing intense training for agonistic purposes were excluded from our study. Patients were divided into two groups according to their plasma LH concentrations: group A (n = 15) comprised hypogonadotrophic © Oxford University Press