Estrogen deficiency results in bone mass reduction of largely varying extent in postmenopausal females, indicating that additional mechanisms influence the response of bone. They are by no ways identified in either the animal experiment or under clinical conditions. In search for factors, conditioning the response of bone to estrogen deficiency, we have conducted a study in females under treatment with the GnRH agonist decapeptyl (D-Trp6-LHRH). This drug blocks ovarian function and was administered for treatment of endometriosis or uterine leiomyoma. We determined spinal (dual photon absorptiometry) and forearm (single photon absorptiometry) bone mineral density before and 3 and 6 months after the onset of therapy and measured biochemical parameters of bone metabolism. Our results showed an increase in bone turnover after initiation of estrogen deficiency, as indicated by the elevation of alkaline phosphatase and osteocalcin. This resulted in a secondary decrease in serum intact PTH and 1,25-dihydroxy-vitamin D3. Furthermore, we found a positive correlation between pretreatment values of serum 1,25-dihydroxyvitamin D3 as well as its decrease and the reduction in bone mass during GnRH agonist treatment. This demonstrates that the patients' metabolic conditions predict their response to estrogen deficiency.

One-hundred-and-thirty-eight women suffering from hypothalamic or hyperandrogenic ovarian failure were treated with daily doses of 25-150 mg of the opiate antagonist naltrexone for 4-100 weeks. In patients with hypothalamic ovarian failure, treatment with naltrexone alone was followed by an increase of gonadotrophins and by normalization of the menstrual cycle in approximately 70% of patients. Eight of 10 patients who did not respond to naltrexone and had not previously ovulated in response to clomiphene administration exhibited ovulatory cycles when both compounds were administered. Twenty-four pregnancies were achieved in 22 women, corresponding to an overall pregnancy rate of 26%, with a cumulative pregnancy rate closely resembling that of a normal population. In contrast, in hyperandrogenic insulin-resistant patients, the pattern of gonadotrophin secretion did not seem to change dramatically during naltrexone treatment. However, the rise of insulin in plasma following an oral load of glucose (oGTT) was blunted considerably, resulting in normalization of previously elevated circulating insulin levels. Since the time course of plasma glucose after oGTT did not appear to be affected by treatment, this indicates an increase in insulin sensitivity (or a decrease in insulin resistance) during naltrexone therapy. Side-effects of naltrexone treatment were negligible in patients with hypothalamic ovarian failure. Hyperandrogenic patients, however, did experience more intense and prolonged side-effects, such as nausea and dizziness.(ABSTRACT TRUNCATED AT 250 WORDS)

Sixty-six women suffering from various grades of hypothalamic ovarian failure were treated with the opiate antagonist naltrexone at doses ranging from 25 to 150 mg per day. This treatment resulted in complete normalization of the menstrual cycle in 49 of 66 patients, as indicated by the pattern of circulating levels of gonadotrophins and ovarian steroids. Five patients failed to respond, three of whom were suffering from primary hypothalamic amenorrhoea. In patients who responded to the administration of naltrexone, there was a dramatic increase in the amplitude and frequency of gonadotrophin pulses, reflecting disinhibition of the hypothalamic gonadotrophin-releasing hormone (GnRH) pulse generator. Eighteen pregnancies were achieved in 16 women who were also treated for infertility, resulting in a cumulative pregnancy rate closely resembling that of a normal population. There were only minor side-effects that could be attributed to the drug. These data demonstrate that chronic administration of an opiate antagonist will normalize ovarian function in women suffering from different grades of hypothalamic ovarian failure. The data therefore support the view that suppression of the activity of the hypothalamic pulse generator, that directs GnRH release, is mediated by endogenous opioids. Also, that hypothalamic ovarian failure is the consequence of an inappropriate increase in opioid tone impinging on neurons that release GnRH in a pulsatile manner into the pituitary portal circulation.

Oestrogen deficiency at the menopause is associated with changes in calcium and bone metabolism. Hypo-oestrogenism induced by the use of GnRH-agonists is clinically useful in the treatment of oestrogen-dependent diseases. This study was done to investigate calcium homeostasis and bone metabolism of pre-menopausal women in a GnRH-agonist-induced pseudo-menopause. Eighteen patients with endometriosis or uterine leiomyoma received monthly i.m. injections of 3.2 mg of long-acting D-Trp-6-LHRH over a 6-month period. Plasma oestradiol-17 beta and progesterone levels under treatment were significantly decreased to the levels of the early follicular phase. Plasma total calcium, serum osteocalcin and plasma alkaline phosphatase concentrations increased, while plasma phosphate levels did not change. Levels of 1,25-dihydroxyvitamin D3 decreased significantly, but 25-hydroxyvitamin D3 values remained constant. Trabecular bone mineral density of lumbar spine decreased continuously during the 6-month period. Nine women completed 6-9 months follow-up. In these women bone loss was reversible. Cortical bone measurements at the proximal radius showed no change during oestrogen deficiency. In conclusion, our findings demonstrate that GnRH-agonist-induced bone loss is reversible. Furthermore, they suggest that the state of pseudo-menopause induced by GnRH-agonist may serve as a model for further pathophysiological studies on calcium homeostasis and bone metabolism in the post-menopause.

Between 1979 and 1990, 73 patients suffering from hypothalamic amenorrhoea were treated by pulsatile administration of gonadotrophin releasing hormone (GnRH) in 359 treatment cycles. Seventy-two pregnancies were achieved. In 64 favourable patients in whom hypothalamic amenorrhoea constituted the only reason for infertility, a pregnancy rate of 29% per cycle could be obtained. Patients who conceived during pulsatile GnRH required an average of only 2.4 cycles per conception. Twelve out of 24 patients with hypothalamic amenorrhoea who exhibited an ovulatory response to pulsatile GnRH, ovulated during oral administration of naltrexone; such responsiveness to opioid antagonism was, however, restricted to the less serious grades. In conclusion, pulsatile administration of GnRH continues to be a highly effective mode of treatment of infertility due to hypothalamic amenorrhoea of various aetiologies. A subgroup of these patients may be successfully treated by the oral administration of naltrexone.