Pulsatile subcutaneous low-dose gonadotropin-releasing hormone treatment of anovulatory infertility

Subcutaneous pulsatile long-term administration of low doses of gonadotropin-releasing hormone (GnRH) was given for induction of ovulation to 14 infertile amenorrheic women who did not respond to clomiphene citrate. A small peristaltic pump was used to deliver 1, 5, or 20 micrograms of GnRH every 90 minutes. Nineteen treatment courses with a duration of 26 to 187 days were given. Thirty-six ovulatory cycles were induced in 12 of the 14 women; 8 of the women conceived. Five healthy children have been born. Three early spontaneous abortions occurred. The subcutaneous GnRH therapy was given with the same pulse frequency until menstruation or pregnancy occurred. The treatment could be given without interruption to induce repeated ovulatory menstrual cycles. No serious adverse effects occurred. Subcutaneous pulsatile administration of low doses of GnRH is a promising new treatment of women with anovulatory infertility.     

Life table analysis of fecundity in intravenously gonadotropin-releasing hormone-treated patients with normogonadotropic and hypogonadotropic amenorrhea

The success of pulsatile intravenous (IV) gonadotropin-releasing hormone (GnRH) treatment in patients with normogonadotropic and hypogonadotropic amenorrhea was studied retrospectively using life table analysis. Two hundred forty-four ovulatory cycles in 48 normogonadotropic and hypogonadotropic patients were evaluated. The cumulative conception rate after 12 cycles was 93%, with a mean conception rate of 22.5% per cycle. Comparing cycles 1 to 6 with cycles 7 to 12, no significant difference in conception rate was observed. Subdivisions were made relative to the presence of additional infertility factors, history of weight loss, actual weight, estrogenic status, and primary versus secondary amenorrhea. The life table curves of patients either with or without other infertility factors were significantly different. No statistically significant differences were found in the other subdivisions. It is concluded that IV GnRH therapy is highly successful in patients with normogonadotropic and hypogonadotropic amenorrhea, especially if no other infertility factors are present.     

Ovulation induction in clomiphene nonresponsive patients: the place of pulsatile gonadotropin-releasing hormone in clinical practice

Seventy-three treatment courses of pulsatile gonadotropin-releasing hormone (GnRH) were given to 19 patients with clomiphene nonresponsive anovulatory infertility. Fifty cycles were given by the subcutaneous route, and 23 were given intravenously. Doses varied between 1 and 40 micrograms per pulse given at 60- or 90-minute intervals. Luteal support was either by continuation of the pulsatile GnRH or by human chorionic gonadotropin injections. In 16 cycles, potentially fertile ovulation occurred, and three pregnancies resulted, of which one continues normally. Only one of the three pregnancies occurred during intravenous GnRH treatment, and it is likely that this patient would have responded to subcutaneous treatment. The optimum dosage to induce ovulation ranged between 10 and 20 micrograms per pulse at a frequency of 60 to 90 minutes. Those patients who responded to treatment were all of normal or low body weight for their age and frame. Conversely, those who failed to respond to pulsatile GnRH with ovulation were obese except for one patient with the polycystic ovary syndrome. Because pulsatile GnRH treatment is simple and potentially safe to administer, a therapeutic trial is indicated in patients of low to normal body weight who fail to respond to clomiphene. Where patients are responsive to pulsatile GnRH, the ovulations produced are likely to be fertile, possibly because of the endogenous nature of the ovulatory luteinizing hormone surge.     

Pulsatile administration of gonadotropin-releasing hormone for induction of ovulation

Chronic pulsatile administration of gonadotropin-releasing hormone (GnRH) was used to induce ovulation in 12 women with various ovulatory disorders. In the first group of eight patients with normal to low baseline levels of gonadotropin, seven responded favorably to the treatment. Follicular maturation was observed in 57% of the treated cycles, and normal ovulatory cycles were induced in 24% of the patients. Two patients became pregnant. The intravenous route of administration was more effective than the subcutaneous one, possibly in response to the GnRH profile after each pulse. (The amplitude of GnRH peaks after an intravenous pulse was four times that seen after a subcutaneous one.) In contrast, follicular maturation and ovulation could not be induced in four women of a second group of patients with normal baseline levels of follicle-stimulating hormone but with high and frequent pulses of luteinizing hormone. The conclusion reached was that pulsatile administration of GnRH can be a new therapeutic tool in the treatment of ovulatory disorders in women who have an insufficient endogenous release of GnRH.     

Ovulation induction with pulsatile gonadotropin-releasing hormone administration in patients with polycystic ovarian syndrome

Gonadotropin-releasing hormone (0.025 microgram/kg) was administered intravenously in a pulsatile fashion to four subjects with polycystic ovary syndrome for a total of six cycles. Five of the six cycles culminated in ovulation, although in one course the response occurred too early to be attributed to the therapy alone. No pregnancies resulted. All luteal phases were of normal duration, but progesterone production as manifested by serum progesterone determination was deficient in some. If additional investigation confirms these preliminary findings, this form of therapy may offer a safe and economic alternative for anovulatory patients refractory to clomiphene citrate therapy. The response of the four subjects suggests that pulsatile gonadotropin-releasing hormone administration may override hypothalamic-pituitary dysfunction and result in ovulatory menstrual cycles.     

Alternative indications for pulsatile gonadotropin-releasing hormone therapy in infertile women

Three groups of women with different types of ovulatory dysfunction who had failed to conceive on conventional therapy were treated with pulsatile gonadotropin-releasing hormone (GnRH). Group A consisted of nine patients with luteal phase defect; group B included four patients with apparently normal menstrual cycles but disordered folliculogenesis seen by serial ultrasound examinations; and group C consisted of eight patients who exhibited anovulation or irregular ovulation. GnRH was administered subcutaneously or intravenously in dosages varying from 5 micrograms to 20 micrograms, with pulse frequency of 2 to 3 hours in 53 cycles. Forty-one cycles were ovulatory. Four pregnancies resulted, one ending in miscarriage at 12 weeks' gestation. Our results indicate that GnRH may be used as an alternative to the prevalent therapeutic methods for ovulatory dysfunction. Only those women who had anovulation and abnormal basal levels of serum luteinizing hormone were resistant to GnRH therapy.     

Plasma luteinizing hormone during clomiphene-induced ovulatory cycles

Seven oligoovulatory or anovulatory women were studied during a clomiphene-induced ovulatory cycle. Plasma luteinizing hormone determinations by radioimmunoassay showed an elevation after only 2 to 3 days of therapy. In each ovulatory cycle there was a second and greater peak in plasma LH occurring 6 to 10 days following completion of the 5 day course of therapy. Plasma LH levels during the luteal phase and following the ovulatory menses averaged lower than control levels. Ovulatory status in 3 subjects was confirmed by culdoscopic biopsy and subsequent histologic examination of the corpus hemorrhagicum. The initial mode of action of clomiphene was considered to be on the hypothalamic-pituitary axis. Criteria for predicting responsiveness to clomiphene and the correlation of the early LH rise with subsequent ovulation were considered.     

Effects of gonadotropin-releasing hormone (GnRH) agonist on pituitary and ovarian responses to pulsatile GnRH therapy in polycystic ovarian disease

Nine clomiphene citrate-resistant polycystic ovarian disease (PCOD) patients received intravenous gonadotropin-releasing hormone (GnRH) pulses before and immediately after 1 month of GnRH agonist (GnRH-a) therapy. Circulating gonadotropin and ovarian steroid levels, as well as follicular development, were measured throughout therapy. Results were compared with those obtained from five hypogonadotropic patients treated with GnRH pulses only who ovulated during six of seven treatment cycles. Only two PCOD patients ovulated normally with GnRH pulses before GnRH-a therapy. Aberrant gonadotropin and ovarian steroid secretory patterns were noted in the others. After GnRH-a, gonadotropin and ovarian steroid hormone levels were similar to those of the hypogonadotropic patients. Subsequent secretory responses to GnRH pulses were partially normalized. However, only two additional PCOD patients ovulated.     

Clinical studies with d-Trp 6-luteinizing hormone-releasing hormone in anovulatory women.

Nine anovulatory patients with hypothalamic-pituitary dysfunction were treated with d-Trp6-luteinizing hormone-releasing hormone, an analog with far greater gonadotropin-releasing activity than luteinizing hormone-releasing hormone. Four of eight patients, who were formerly unsuccessfully treated with clomiphene, human chorionic gonadotropin, and human menopausal gonadotropin, ovulated after treatment with the peptide alone or with peptide preceded by clomiphene, and three became pregnant. The ninth patient, who had amenorrhea and anovulation due to excessive loss of weight caused by anorexia nervosa, also ovulated after treatment with the analog. These results demonstrate the effectiveness of this potent analog for induction of ovulation and pregnancy and point favorably toward clinical applications.     

A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

OBJECTIVE: To establish whether initial screening characteristics of normogonadotropic anovulatory infertile women can aid in predicting live birth after induction of ovulation with clomiphene citrate (CC). DESIGN: Prospective longitudinal single-center study. SETTING: Specialist academic fertility unit. PATIENT(S): Two hundred fifty-nine couples with a history of infertility, oligoamenorrhea, and normal follicle-stimulating hormone (FSH) concentrations who have not been previously treated with any ovulation-induction medication. INTERVENTION(S): 50, 100, or 150 mg of oral CC per day, for 5 subsequent days per cycle. MAIN OUTCOME MEASURE(S): Conception leading to live birth after CC administration. RESULT(S): After receiving CC, 98 (38%) women conceived, leading to live birth. The cumulative live birth rate within 12 months was 42% for the total study population and 56% for the ovulatory women who had received CC. Factors predicting the chances for live birth included free androgen index (testosterone/sex hormone-binding globulin ratio), body mass index, cycle history (oligomenorrhea versus amenorrhea), and the woman's age. CONCLUSION(S): It is possible to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a nomogram. Applying this nomogram in the clinic may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulatory infertility. Alternative first line of treatment options could be considered for some women who have limited chances for success.     

The response of patients with organic hypothalamic-pituitary disease to pulsatile gonadotropin-releasing hormone therapy

Treatment with pulsatile gonadotropin-releasing hormone (GnRH) therapy has been attempted in 13 women and 5 men with hypogonadotropic hypogonadism caused by structural lesions of the hypothalamic-pituitary axis. Ten patients responded to treatment with induction of ovulation or spermatogenesis. Of these subjects, seven had primary suprasellar lesions, and one had an apparently empty pituitary fossa on reconstructive computerized tomographic scanning. The eight patients who failed to respond to treatment all had extensive intrafossa damage, as a result of either surgery, irradiation, or infarction. Pulsatile GnRH therapy is not effective in patients with extensive intrafossa lesions.     

The effects of superovulatory doses of clomiphene citrate on spontaneous luteinizing hormone peaks in regularly ovulating women

The effects of superovulatory doses of clomiphene citrate (150 mg orally every day for 5 days) on normal spontaneous menstrual cycles were studied in 16 women. Eight-eight percent of treatment cycles had clearly defined, timely luteinizing hormone (LH) peaks indistinguishable from those observed in normal cycles. Eight percent of treatment cycles did not have clearly defined LH peaks but were ovulatory. One cycle (4%) was anovulatory. Treated cycles were 2.1 days longer than previous control cycles (p less than 0.005). The follicular phase was significantly longer than control cycles (p less than 0.025) whereas the luteal phase was not (p greater than 0.05). There was a direct positive correlation between previous menstrual cycle length and follicular phase length in the treated cycle (r = 0.730, 0.01 less than p less than 0.05). The conclusion was that 96% of menstrual cycles of normally ovulating women remained ovulatory when the women were given superovulatory doses of clomiphene and that 88% of the cycles had clearly defined LH peaks.     

Hormonal responses to a first course of clomiphene citrate in women with amenorrhoea.

The hormonal criteria of a "normal" or "ovulatory" response, and three grades of subnormal anovulatory responses, were defined during a first course of treatment with clomiphene citrate in twenty patients with amenorrhoea for which no organic cause could be found. The hormonal responses were estimated by frequent serum measurements and by the menstrual response. Seven patients had a normal or ovulatory response with a late rise of serum progesterone and subsequent menses. Their serum luteinizing hormone (LH) and oestradiol (E2) responses were greater than in spontaneous menstrual cycles. Five patients gave only partial responses, with menstruation and no prior rise of progesterone, Their serum LH and E2 responses were generally lower than in the normal group but had the same pattern except for an absence of the luteal phase rise in E2. Five patients who did not menstruate showed smaller and more variable responses. The remaining five showed no hormonal responses. The second and third groups had ovulatory responses on subsequent clomiphene courses, whereas no improvement was shown by the last group. The serum E2 responses offered the most sensitive index of the responsiveness to clomiphene. Response values in our normal group suggested that higher progesterone levels need to be reached after clomiphene administration than in spontaneous cycles for ovulation to be inferred. The serum prolactin showed no consistent response during the clomiphene test; three patients with moderately raised basal prolactin levels had "normal" responses.     

Influence of the frequency of gonadotropin-releasing hormone (GnRH) administration on ovulatory responses in women with anovulation

In attempt to optimize gonadotropin-releasing hormone (GnRH) treatment of anovulation, we compared the effect of intravenous GnRH administration at three pulse intervals (PI) during 63 cycles in 30 anovulatory patients who had: (1) amenorrhea secondary to anorexia nervosa (group I: 10 patients, 21 cycles); (2) unexplained anovulation with normal to high luteinizing hormone plasma levels (group II: 12 patients, 24 cycles); and (3) polycystic ovarian disease (PCOD) (group III: 8 patients, 18 cycles). Ovulation was achieved more frequently in group I (85%) than in group II (41%) or in group III (50%). In both groups I and II, the frequency of ovulatory responses was not different with the PI used, and 6 of the 17 women treated for infertility conceived; 3 with 90-minute PIs, 2 with 64-minute PIs, and 1 with 128-minute PIs. In women with PCOD, seven of the nine ovulatory responses and three pregnancies were obtained with 128-minute PIs. The overweight women with PCOD did not respond reliably to GnRH at the doses used, i.e., 4 to 15 micrograms per pulse. In all groups, the urinary estrone and estradiol preovulatory peak, duration of luteal phase, progesterone levels, and preovulatory follicle diameter were unrelated to the frequency of GnRH administration.     

New trends in combined use of gonadotropin-releasing hormone antagonists with gonadotropins or pulsatile gonadotropin-releasing hormone in ovulation induction and assisted reproductive technologies.

The use of gonadotropin-releasing hormone agonists as adjunctive therapy with gonadotropins for ovulation induction in in vitro fertilization and other assisted reproductive technologies has become common clinical practice. With the recent advent of potent gonadotropin-releasing hormone antagonists free from the marked histamine-release effects that stymied earlier compounds, an attractive alternative method may be available. We have established the feasibility of combining gonadotropin-releasing hormone antagonist-induced inhibition of endogenous gonadotropins with exogenous gonadotropin therapy for ovulation induction in a nonhuman primate model. Here, the principal benefits to be gained from using the gonadotropin-releasing hormone antagonist rather than the gonadotropin-releasing hormone agonist are the immediate inhibition of pituitary gonadotropin secretion without the "flare effect," which brings greater safety and convenience for patients and the medical team and saves time and money. We have also recently demonstrated the feasibility of combining gonadotropin-releasing hormone antagonist with pulsatile gonadotropin-releasing hormone therapy for the controlled restoration of gonadotropin secretion and gonadal steroidogenesis culminating in apparently normal (singleton) ovulatory cycles. This is feasible only with gonadotropin-releasing hormone antagonists because, unlike gonadotropin-releasing hormone agonists, they achieve control of the pituitary-ovarian axis without down regulation of the gonadotropin-releasing hormone receptor system. This capacity to override gonadotropin-releasing hormone antagonist-induced suppression of pituitary-ovarian function may allow new treatment modalities to be employed for women who suffer from chronic hyperandrogenemia with polycystic ovarian disease.     

Pulsatile luteinizing hormone secretion and clomiphene and bromocriptine response in amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding

This study was carried out to determine whether the ovulatory response with clomiphene citrate and bromocriptine in 20 amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding is influenced by the pretreatment pattern of pulsatile luteinizing hormone (LH) secretion. Two patients who had no LH pulse for 3-5 h failed to respond to clomiphene. One of them was treated with bromocriptine, but ovulation did not occur. Eleven of 12 patients who had one or more LH pulses and LH pulse/h ratios of less than 1 for 3-5 h ovulated with clomiphene. One clomiphene nonresponsive patient ovulated with combined therapy of bromocriptine and clomiphene. All 6 patients who had LH pulse/h ratios of greater than or equal to 1 for 3-5 h failed to ovulate with clomiphene. Three of them were treated with bromocriptine. Two of 3 patients ovulated with bromocriptine alone and 1 ovulated with combined therapy of bromocriptine and clomiphene. These results suggest that the pretreatment pattern of pulsatile LH secretion may predict the clinical response to clomiphene and bromocriptine treatment in amenorrheic women with normoprolactinemia and gestagen withdrawal bleeding.     

Follicle-stimulating hormone bioactivity in idiopathic normogonadotropic oligoasthenozoospermia: double-blind trial with gonadotropin-releasing hormone.

OBJECTIVE: To identify, among patients with idiopathic normogonadotropic oligoasthenozoospermia, those with low bioactive follicle-stimulating hormone (FSH), possibly because of inadequate gonadotropin-releasing hormone (GnRH) pulsatility, whose bioactive FSH and sperm could be improved by GnRH treatment. DESIGN: Randomized, double-blind, placebo-controlled trial with intranasal (IN) GnRH, followed by open GnRH treatment. SETTING: Outpatient endocrinology clinic. PATIENTS: Twenty-eight infertile men with idiopathic normogonadotropic oligoasthenozoospermia. INTERVENTIONS: Gonadotropin-releasing hormone or placebo was self-administered IN every 2 hours. MAIN OUTCOME MEASURES: Serum immunoreactive and bioactive FSH and semen analyses. RESULTS: Ten men showed a low basal FSH bioactive/immunoreactive ratio, which increased in 5 of them under GnRH without parallel sperm modification. Sperm improvements were observed in 10 patients with no parallel evolution of FSH bioactive/immunoreactive ratio. Unpredicted by sperm changes, three pregnancies developed on placebo and 5 on GnRH. CONCLUSIONS: Low bioactive FSH was not the cause of idiopathic normogonadotropic oligoasthenozoospermia in our patients and could not predict response to GnRH. Pulsatile GnRH did not improve sperm beyond random fluctuations.     

Improvement of spontaneous pregnancy rate after stopping gonadotropin therapy for anovulatory infertility

In a prospective study, 140 patients with infertility because of ovulatory factors (group A) were followed up for 6 months after failure to achieve pregnancy using human menopausal gonadotropin (hMG) therapy. They included cases of oligomenorrhea, polycystic ovarian disease (PCOD), and hypogonadotropic amenorrhea. They were treated with hMG alone or in combination with clomiphene citrate or gonadotropin-releasing hormone agonist analog. The control group (B) included 83 infertile patients because of similar ovulatory factors. They were followed up for 6 months not preceded by ovulation induction. The overall pregnancy rate (PR) in group A (20.7%) was significantly higher than group B (7.2%). The PR was significantly higher in oligomenorrhea and PCOD patients when compared with the control group. There was no significant difference in the hypogonadotropic group.     

Treatment of cryptorchidism with pernasal gonadotropin-releasing hormone therapy.

Twenty-five boys between 1 and 10 years of age with unilateral or bilateral cryptorchidism were treated with 200 microgram of gonadotropin-releasing hormone (GnRH) pernasally six times daily until descensus was completed, or for 10 weeks at most. Complete descent of the tests occurred in 16 patients, usually after 2 to 5 weeks of treatment. No adverse side effects have been observed. Radioimmunologic measurements of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and prolactin, carried out before treatment, at the end of treatment, and 6 months after treatment, showed a transitory increase of the LH responsiveness to GnRH in only four of the patients and in the group as a whole a slight but significant decrease of FSH responsiveness. There were no signs of precocious puberty. GnRH antibodies were not found.     

Ovulation induction in anovulatory women

Ovulation induction therapy is administered to stimulate follicular growth and induce ovulation in anovulatory infertile women. In anovulatory women with polycystic ovary syndrome, the treatment of choice is clomiphene citrate, whereas in clomiphene nonresponders, gonadotrophins are given as secondary therapy. Currently, insulin-sensitizing agents are used in the treatment of polycystic ovary syndrome to restore menstrual cyclicity. In selected patients, laparoscopic drilling has also been suggested. In anovulatory patients affected with hypogonadotropic hypogonadism, treatment is based on gonadotrophin replacement therapy or pulsatile gonadotrophin-releasing hormone infusion. In ovulation induction therapy the clinician's attention should be directed at restoring normal ovary function. When pharmacotherapy is required, monofollicular growth should be induced to reduce the risk of multiple pregnancy.