Naltrexone treatment restores menstrual cycles in patients with weight loss-related amenorrhea.

OBJECTIVE: To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test. DESIGN: Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. RESULTS: Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. CONCLUSIONS: The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.

Evidence suggesting an additional control mechanism regulating episodic secretion of luteinizing hormone and follicle stimulating hormone in pre-pubertal children and post-menopausal women.

The possible differential regulation of pulsatile follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertal children and in post-menopausal women was investigated. Children were studied for 4 h and post-menopausal women for 6 h; blood samples were taken every 10 min. Post-menopausal women were studied before and 21 days after administration of a single i.m. dose of gonadotrophin-releasing hormone (GnRH) analogue. Eight post-menopausal women and 18 children (nine boys and nine girls) were enrolled. The children were divided into two groups: A, at Tanner stages 0-1 (four boys and three girls); B, at Tanner stage 2-3 (five boys and six girls). Plasma LH and FSH concentrations were determined using an immunofluorimetric assay. Time series were analysed and the specific concordance (SC) index was computed to determine the degree of concordance between episodes of LH and FSH secretion. While children of group A had LH concentrations below the minimal detectable dose of 0.1 IU/l, group B showed measurable LH plasma concentrations (1.4 +/- 0.3 IU/l, mean +/- SEM). Plasma FSH concentrations were detectable in both groups. Group A showed FSH plasma concentrations significantly lower than those of group B (0.75 +/- 0.2 and 1.95 +/- 0.4 IU/l respectively; P < 0.05), but FSH pulse frequency was higher in group A (P < 0.05). Children of group B showed significant concomitance of LH and FSH secretory events at time 0 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Episodic release of prolactin in women with weight loss-related amenorrhea.

Amenorrhea associated with weight loss is characterized by several neuroendocrine aberrations. The aim of the present study was to define the characteristics of episodic secretion of prolactin in women with weight loss-related amenorrhea. To evaluate whether hypoestrogenism was responsible for the changes in prolactin secretion in amenorrheic women, the pulsatile secretory pattern was also studied during hormone replacement therapy (HRT). Fifteen patients were studied by blood sampling every 10 min for 8 h. Four normally cycling women were studied as a reference group, during both the midfollicular and midluteal phases. Mean plasma prolactin levels and pulse amplitude were lower in amenorrheic patients than in controls. The prolactin pulse frequency was higher than that in controls during the follicular phase, but lower than controls during the luteal phase of the menstrual cycle. During HRT, mean plasma prolactin levels significantly increased, pulse frequency decreased and pulse amplitude significantly increased both during estradiol and estradiol plus medroxyprogesterone acetate administration. In conclusion, in amenorrhea associated with weight loss the chronobiological organization of prolactin secretion is deranged, both as a result of a neuroendocrine alteration and as a result of low plasma levels of gonadal steroids.

The duration of prolactin secretory bursts from the pituitary is independent from both prolactin and gonadal steroid plasma levels in women and in men.

The intrinsic secretory characteristics of prolactin (PRL) have been investigated using newly developed algorhythms for instantaneous secretory rate (ISR) computation. PRL secretory rate, its intrinsic pulsatile characteristics and their possible dependance from gonadal steroids were investigated in five groups of subjects: a) 11 women during the follicular and luteal phase of the same menstrual cycle; b) 5 healthy postmenopausal women; c) 6 women affected by functional hyperprolactinemia; d) 5 normal men; e) 4 agonadal subjects before and during testosterone replacement therapy. All subjects underwent a 6 hours pulsatility study, from 08:00 to 14:00, sampling every 10 minutes. PRL plasma concentrations were determined using a RIA system and the presence of PRL secretory pulses was evaluated with program DETECT, both on plasma time series and after ISR computation. A distinct PRL episodic release was observed in all groups (follicular phase: 5.5 +/- 0.5, luteal phase: 6.5 +/- 0.6, postmenopause: 5 +/- 1, hyperprolactinemic women: 4.2 +/- 0.8, men: 4.8 +/- 0.4, agonadal before testosterone: 6 +/- 1, agonadal during testosterone administration: 5.3 +/- 0.3 peaks/6h), but mainly the computation of ISR allowed to demonstrate that the duration of the lactotropes secretory events was constant in all groups studied. PRL secretory bursts duration ranged between 23.1 +/- 1.8 and 25.4 +/- 2.5 minutes independently both on PRL or on sex steroid plasma levels. In conclusion, the present report shows that in different physiological conditions the intrinsic secretory bursts from lactotropes are constant in duration independently from the functional state, sex and the steroid hormone levels.

Opioid control of gonadotrophin secretion in humans.

Hypothalamus-pituitary-axis (HPA) is constantly under the modulatory effect of many substances, such as neurotransmitters, neuromodulators and steroid hormones. Recently, the involvement of endogenous opioid peptides (EOP) in the control of the neuroendocrine mechanism modulating gonadotrophin secretion has been supported by several authors. It has been demonstrated that acute morphine administration decreases luteinizing hormone (LH) plasma levels and this is due to an inhibitory modulation on gonadotrophin releasing hormone discharge from the hypothalamic neurons. EOP are usually increased by stressful situations. In stress-induced amenorrhoea, the presence of low LH plasma levels and an abnormal LH pulsatile secretion has been related to an increased opioid activity, thus supporting the integrative role of opioids between hormonal and neuronal afferences of brain.

Growth hormone treatment affects plasma LH pulsatile release in women with secondary amenorrhoea.

OBJECTIVE: Since growth hormone (GH) is administered as a co-gonadotrophic factor in ovulation induction, this study aimed to assess the action of GH on the episodic pulsatile release of LH and FSH in amenorrhoeic patients. PATIENTS AND DESIGN: Nineteen patients affected by hypothalamic amenorrhoea were enrolled for this study: group A, 9 patients with normal gonadotrophins; group B, 10 patients with low gonadotrophins. Both groups were studied during GH infusion (0.015 IU/min for 4 hours) and after 7 days of GH administration (0.1 IU/kg/day). Patients underwent a 4-hour pulsatility study, with blood sampling every 10 minutes. A standard GnRH test (10 micrograms i.v. bolus) was performed immediately after the pulsatility evaluation. MEASUREMENTS: LH and FSH were assayed with an IFMA method; oestradiol and IGF-I were assayed by RIA and IRMA, respectively. PULSE DETECTION: Time series were analysed with Detect program. RESULTS: All patients showed similar LH and FSH pulsatile characteristics both under baseline conditions and during GH infusion. After 7 days of GH administration, episodic FSH release showed no change in either group. On the contrary, LH pulse frequency (mean +/- SE) significantly increased in group A (4.0 +/- 0.2 peaks/4h, P < 0.05), while pulse amplitude (baseline, 3.9 +/- 0.6 IU/l; after 7 days, 2.9 +/- 0.3 IU/l, P < 0.05), and integrated LH plasma concentrations (baseline, 7.6 +/- 1.1 IU/l; after 7 days, 5 +/- 0.8 IU/l, P < 0.05) were significantly decreased. No significant changes were observed for LH pulse frequency, amplitude or integrated LH plasma concentrations in hypogonadotrophinaemic patients (group B). Plasma oestradiol levels were significantly increased only in group A (baseline, 154.18 +/- 23.8 pmol/l; after 7 days, 380.3 +/- 110.1 pmol/l, P < 0.05), while IGF-I levels were significantly increased in both groups after 7 days of GH administration (P < 0.05). No significant differences were observed in the gonadotrophin responses to GnRH test before and after GH administration. CONCLUSIONS: The present study showed that the administration of GH in amenorrhoeic patients determines the significant changes in episodic LH release in those subjects with normal LH plasma levels and suggests that the action of GH may be dependent upon the ovarian-pituitary feedback action.

Modulatory role of estrogens and progestins on growth hormone episodic release in women with hypothalamic amenorrhea.

OBJECTIVE: To define the characteristics of spontaneous GH episodic secretion and the modulatory role of gonadal steroids in patients with hypothalamic amenorrhea associated with weight loss. DESIGN: Women were studied for 8 hours, sampling every 10 minutes, and plasma GH levels were measured by RIA. SUBJECTS: Fifteen patients with weight-loss-related amenorrhea were studied in baseline conditions. Five out of 15 patients underwent two cycles of hormonal replacement therapy with E2 patches (100 micrograms every 3 days for 24 days) and medroxyprogesterone acetate (MPA) (10 mg/d, from day 12 to day 24). On the second cycle of therapy, the pulsatility study was repeated twice: after only estrogen (day 11) and after E2 plus progestin (day 22). Four normally cycling women were studied as a reference group during midfollicular and midluteal phases. RESULTS: Amenorrheic patients showed mean plasma GH levels similar to healthy women during the follicular phase but significantly lower than those observed during the luteal phase. GH pulse frequency was higher in patients than in controls, whereas pulse amplitude was comparable with the follicular phase but lower during the luteal phase. During the hormonal replacement therapy, when only E2 was administered, GH pulse frequency decreased, whereas GH integrated plasma concentrations and GH pulse amplitude increased significantly. After MPA and E2 administration, GH pulse amplitude and GH plasma levels decreased, which was similar to pretreatment condition. CONCLUSIONS: The present study demonstrated that in amenorrhea associated with weight loss the frequency of GH episodic release is significantly higher than in normally cycling women. Moreover, a different modulatory role of estrogen (increased amplitude) and P (decreased amplitude) on the episodic release of GH in amenorrheic women undergoing a replacement treatment was shown by the present data.

FSH secretory pattern and degree of concordance with LH in amenorrheic, fertile, and postmenopausal women.

Pulsatile secretion of gonadotropin was investigated in amenorrheic patients and in fertile and postmenopausal women to assess both follicle-stimulating hormone (FSH) episodic secretion and its temporal coupling with luteinizing hormone (LH). Three groups of amenorrheic patients were studied: hyperandrogenic (n = 20), hypogonadotropic (n = 51), and normogonadotropic (n = 31). Nineteen fertile women (during the follicular and luteal phases of the cycle) and sixteen postmenopausal women were investigated as reference groups. All subjects demonstrated the presence of a distinct pulsatile pattern with LH and FSH pulses/4 h as follows: hyperandrogenic 3.95 +/- 0.26 and 3.85 +/- 0.2, hypogonadotropic 3.76 +/- 0.26 and 3.9 +/- 0.16, normogonadotropic 3.5 +/- 0.2 and 3.9 +/- 0.17 LH and FSH pulses/4 h, respectively (means +/- SE). Normal controls showed 4.1 +/- 0.2 and 3.1 +/- 0.2 pulses/4 h for LH (P < 0.05) and 3.2 +/- 0.1 and 3.6 +/- 0.3 pulses/4 h for FSH, during follicular and luteal phases, respectively. Postmenopausal women showed 3.6 +/- 0.2 and 3.0 +/- 0.3 pulses/4 h for LH and FSH, respectively. Specific concordance (SC) index demonstrated that LH and FSH were significantly and simultaneously secreted in all groups. Conversely, LH and FSH were not temporally related during the luteal phase. In conclusion, we report a distinct FSH episodic secretion and its temporal linkage with LH pulses irrespective of plasma concentrations of gonadal steroids in secondary amenorrhea.

The concomitant release of androstenedione with cortisol and luteinizing hormone pulsatile releases distinguishes adrenal from ovarian hyperandrogenism.

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p < 0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)