Pituitary responsiveness after administration of a GnRH agonist depot formulation: Decapeptyl CR.

OBJECTIVE: This study was focused on the pattern of LH release from the pituitary during the initial response to high dose GnRH agonist administration. Secondly, the pattern of LH release and the pituitary responsiveness to physiological and pharmacological stimulation during long-term pituitary suppression by a high dose GnRH agonist was studied. In addition, the relation between serum agonist levels and pituitary function and responsiveness was investigated. DESIGN: DTrp6GnRH in microcapsules (Decapeptyl CR) was administered i.m. to 12 women on the third day of the cycle. High-rate blood sampling was carried out during the first 48 hours after the injection. Secondly, high-rate blood sampling for 6 hours and a GnRH challenge were performed before and weekly after administration, from week 4 till week 9. All samples were assayed for LH and FSH. LH patterns were analysed by applying a computerized pulse detection program. In the second or third week an oestradiol benzoate test was performed. Finally, triptorelin levels were measured before and weekly after administration. PATIENTS: Twelve patients, suffering from tubal infertility and recruited from the waiting list for in-vitro fertilization/embryo transfer (IVF/ET) participated in the study. RESULTS: During the first 48-hour period, LH and FSH levels demonstrated a rapid rise to peak values after 4 hours, subsequently declining to nearly normal levels. E2 rose to peak values at 12 hours and returned to the follicular range thereafter. LH pulse patterns showed a rapid increase in pulse intervals leading to a near absence of LH pulses at the end of the 48-hour period. From the fourth till the seventh week after agonist administration, LH pulse patterns showed a markedly increased pulse interval, decreased pulse amplitude, and a severely decreased mean LH level. In the same period, LH responses to GnRH were severely blunted or absent. Restoration of the pre-injection LH pulse pattern and the LH response to GnRH was observed during the eighth and ninth week. Oestradiol benzoate challenges showed an E2 rise to preovulatory levels in response to the injections. However, no changes were observed in LH and FSH concentrations. Triptorelin levels showed a peak within 48 hours and gradual decline towards pretreatment values in week eight. CONCLUSIONS: It is concluded from the study, that after administration of triptorelin depot in the early follicular phase, desensitization of the pituitary starts to develop within 24 hours. Pituitary responsiveness is completely absent in the second week and continues to exist until the eighth week after injection, when the agonist has disappeared from the circulation. These findings suggest profound alterations in GnRH receptor availability and post-receptor pathways, that prevent the pituitary from responding to physiological stimuli.

Pituitary and ovarian suppression after early follicular and mid-luteal administration of a LHRH agonist in a depot formulation: decapeptyl CR.

In order to study its effect on pituitary and ovarian function, a single dose of triptorelin depot (Decapeptyl CR, Ferring) was administered to 12 women in the early follicular (EF,n = 6) or mid-luteal phase (ML,n = 6) of a normal cycle. In all 12 women the initial pituitary and ovarian responses were similar. Luteinizing hormone (LH) and follicle stimulating hormone (FSH) rose to peak values within 48 h, and declined to hypogonadotropic levels within 2 weeks' time. Steroid levels showed a slight to marked rise after injection and fell to hypogonadal values within 1 week. LH suppression was maintained until the 8th week after the injection, while FSH levels rose to normal between the 3rd and 4th week. Estrogen secretion started to be restored in the course of the 7th and 8th week. Menses occurred between the 11th and 13th week after the injection of the drug. This study demonstrates the possibility of rapid induction of a hypogonadotropic and hypogonadal condition in regularly cycling women by administration of a single triptorelin depot. Suppression of pituitary and ovarian function appears to be continued until the 8th week after the injection.

Induction of multiple follicular growth by pulsatile gonadotrophin-releasing hormone (GnRH) treatment in women with normal cycles: the role of the route of administration.

In a prospective study, seven patients with normal menstrual cycles were treated with pulsatile gonadotrophin-releasing hormone. They received one cycle of intravenous (i.v.) therapy and one cycle of subcutaneous (s.c.) therapy. Another four volunteers with normal cycles were treated for one s.c. cycle only. Cycles were compared to each other and to the normal unstimulated cycles of 14 other volunteers. Multiple follicular development could be achieved using both the i.v. and the s.c. routes. However, the i.v. route showed significantly higher luteinizing hormone (LH) and luteal steroid levels. Comparing s.c. cycles to controls, significantly lower LH levels were observed, resulting in significantly lower steroid production if calculated per large follicle. We conclude that the i.v. route is superior to the s.c. route in inducing multiple follicular growth in women with normal cycles.

Pulsatile luteinizing hormone secretion in hypothalamic amenorrhea, anorexia nervosa, and polycystic ovarian disease during naltrexone treatment.

OBJECTIVE: To determine if chronic treatment with the long-acting oral opioid antagonist naltrexone can increase luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion in women with secondary amenorrhea. DESIGN: Prospective. SETTING: Large reproductive endocrinology unit of an academic hospital. PATIENTS: Three groups of women with oligomenorrhea or amenorrhea: (1) hypothalamic amenorrhea; (2) anorexia nervosa; and (3) polycystic ovarian disease (PCOD). INTERVENTION: Naltrexone 50 mg every day for 4 days. MAIN OUTCOME MEASURES: Luteinizing hormone pulse pattern, frequency and amplitude, mean LH and FSH levels, measured by serial blood sampling over a 6-hour period before and after naltrexone. RESULTS: Naltrexone caused a significant increase (P less than 0.05) of the LH pulse frequency in patients with hypothalamic amenorrhea and in PCOD but not in anorexia nervosa. The mean levels of LH and FSH and LH pulse amplitudes were not significantly changed by naltrexone. The naltrexone nonresponders were underweight either because of simple weight loss or anorexia nervosa and had low levels of estradiol and an LH pulse pattern similar to the luteal one. CONCLUSION: The luteal LH pulse pattern in weight loss-related amenorrhea is caused by a nonopioid, undernutrition-linked factor.

Effects of opioid antagonism with naltrexone on pulsatile luteinizing hormone secretion in women with hypothalamic amenorrhea in basal conditions and after discontinuation of treatment with pulsatile LHRH.

Although endogenous opioids seem to play an important role in the inhibition of luteinizing hormone releasing hormone (LHRH) secretion in women with hypothalamic amenorrhea, opioid antagonism does not always cause an increase of pituitary luteinizing hormone (LH) secretion. The effect of the long-acting oral opiate antagonist naltrexone on pulsatile LH secretion was studied in eight women with weight loss and exercise-related hypothalamic amenorrhea. LH pulse studies and LHRH tests were performed in basal conditions and after 4 days of naltrexone treatment, 50 mg q.d. Naltrexone caused a slight, but significant increase of LH pulse frequency. Six weeks later, a second experiment was performed. The response to naltrexone was studied after enhancement of the pituitary sensitivity. Patients were pretreated with pulsatile LHRH during 4 days, followed by naltrexone 50 mg q.d. during 4 days. An increased LH response to LHRH, but no response to naltrexone, were seen after discontinuation of pulsatile LHRH. It is concluded that the limited pituitary response to opioid antagonism, observed in weight loss-related forms of hypothalamic amenorrhea, is not caused by pituitary insensitivity to LHRH.

Multiple follicular development in women with normal menstrual cycles treated with pulsatile gonadotrophin-releasing hormone.

In a prospective study, 15 patients with normal menstrual cycles were treated with pulsatile gonadotrophin-releasing hormone (GnRH) for one to four cycles. These cycles were compared to unstimulated cycles of 14 volunteers. There was a surprisingly stable number of large (greater than or equal to 14 mm diameter) follicles per patient. The number of large follicles in induction cycles was significantly greater than in controls (2.4 versus 1.07). This was due to significantly higher follicle stimulating hormone levels during the first days of treatment. Our data provide a rationale for the use of pulsatile GnRH for a safe and mild form of stimulation in assisted reproductive therapies.