Induction of ovulation with pulsatile gonadotropin releasing hormone (GnRH) in anovulatory women

In this study we employed pulsatile GnRH therapy in different anovulatory disorders to test its real efficacy on ovulation induction. Ten adult women, 25-35 years old with primary or secondary infertility, underwent our study; all women showed anovulatory disorders such as Secondary Amenorrhea (n. 4), PCOD (n. 3) or Oligomenorrhea resistant to Clomiphene Citrate (n. 3). Pulsatile gonadotropin releasing hormone (GnRH) was given intravenously via automatic micropump, with a pulse interval of 90' and a pulse dose of 5 mcg/day. Ovulation was achieved in 7 cases (70%), whereas the failure of therapy was observed in 3 patients (30%), all affected by PCOD. The mean duration of follicular phase was 15 days and the ovulatory cycles did not need the luteal phase support. The maximum length of infusional therapy was 20 days with a low incidence of adverse side effects such as phlebitis; only in one patient a mild ovarian hyperstimulation was observed. Our results confirm that infusional pulsatile GnRH therapy is a very important tool to ovulation induction and it is more successful in primary or secondary amenorrhea and in hypothalamic disorders than in PCOD.     

Value of subcutaneous and intravenous pulsatile gonadotropin releasing hormone in polycystic ovary disease.

Nine patients with clomiphene-resistant polycystic ovary disease (PCOD) were treated with pulsatile gonadotropin releasing hormone (GnRH). The patients were started on subcutaneous (SC) GnRH. If they failed to ovulate on SC therapy, intravenous (IV) therapy was administered. Nine patients were treated for a total of 22 cycles; 13 were SC and 9, IV. There were nine ovulatory cycles (41%); four were SC (31%) and five, IV (56%). Two conceptions occurred, both among the IV cycles. One conception was a singleton; the infant was delivered uneventfully at term. The second conception was quadruplets, with the delivery of four healthy infants at 36 weeks. These data suggest that ovulation and conception in clomiphene-resistant PCOD patients using pulsatile GnRH are more likely to occur after IV than SC administration. However, the overall pregnancy rate was not greater than with gonadotropin treatment, and the risk of multiple births after IV administration is potentially high.     

Ovulation induction and pregnancy in women with hypothalamic amenorrhea treated with intermittent gonadotropin-releasing hormone

We induced ovulation in 34 cycles in 16 women following the administration of gonadotropin-releasing hormone (GnRH). In two patients two control cycles were induced. The patients self-administered GnRH through an indwelling intravenous catheter every 2 hours for 18 hours per day. In subsequent cycles the dose interval, dosage and infusion site, intravenous or subcutaneous, were varied. In all patients the estradiol, follicle-stimulating hormone and luteinizing hormone were measured, and follicular development was assessed ultrasonographically. Based on this preliminary study, a total of 34 cycles were studied in 16 women treated with 10 mg of self-administered GnRH intravenously every two hours during the day. Apparent ovulation was documented in all 34 cycles, and 11 pregnancies occurred. It appears that self-administered GnRH is economical and safe and achieves satisfactory results with respect to both ovulation and pregnancy.     

The induction of ovulation by pulsatile administration of GnRH: an appropriate method in hypothalamic amenorrhea

The induction of ovulation by the means of a pump which assures the pulsatile administration of GnRH is a well-known method that applies to women suffering from amenorrhea of hypothalamic origin. Although a simple and efficient method to establish fertility, it is underused. Twelve patients suffering from this condition, 1 Kallmann syndrome, 4 normosmic isolated hypogonadotropic hypogonadism, and 7 functional hypothalamic amenorrhea desiring pregnancy were treated. They underwent one or more cycles of pulsatile GnRH, at a frequency of 90?minutes, either by the intravenous or the subcutaneous route. An initial dose of 5?μg per pulse in the intravenous route was administered and of 15?μg per pulse in the subcutaneous route. The treatment was monitored by regular dosing of gonadotropins, estradiol and progesterone, and the development of follicles and ovulation was monitored by intra-vaginal ultrasonography. All the patients had documented ovulation, after a mean of 17?days on pump stimulation. Single ovulation occurred in 30 of 33 treatment cycles, irrespective of the route of administration. Ovulation resulted in 10 pregnancies over 7 patients (2 pregnancies in 3 of them), distributed in the 3 diagnostic categories. For comparison, a patient with PCOS treated similarly, disclosed premature LH surge without ovulation.     

Evaluation of techniques for induction of ovulation in outpatients employing pulsatile gonadotropin releasing hormone

The efficacy, safety, and patient's acceptance of intravenous and subcutaneous therapy with gonadotropin releasing hormone (GnRH) with the use of either an autoinfusion pump or a smaller manual pen pump delivery system have been evaluated during the induction of ovulation in outpatients with hypothalamic hypogonadotropic amenorrhea. An ovulatory response to intravenous GnRH was highly reproducible, even at low doses, and complications associated with the intravenous route of delivery were infrequent and readily treated. Although no complications were observed during subcutaneous GnRH therapy, the response to the subcutaneous route of delivery was unpredictable over a wide range of dosages and delivery schedules. The pen pump was rated more highly by subjects than the autoinfusion pump, because the pen pump was both light and inconspicuous.     

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 intravenous gonadotropin-releasing hormone

The efficacy of ovulation induction with the use of pulsatile gonadotropin-releasing hormone (GnRH) therapy was examined in 21 infertile women. Seventeen had hypothalamic amenorrhea (HA) and 4 polycystic ovary syndrome (PCO). All patients were treated as outpatients. GnRH was infused in a pulsatile mode by means of portable auto-infusion pumps connected to an indwelling intravenous catheter inserted into a forearm vein. The doses varied from 1.8 to 5 micrograms/pulse with a frequency of 90 minutes. Ovulation occurred in 52 out of 64 cycles (81.2%). Ten (47.6%) of the 21 patients became pregnant. Seven patients had normal term deliveries and 3 aborted spontaneously. With regard to the 17 patients with HA, ovulation occurred in 93.7% of treatment cycles and 6 women became pregnant. In the case of the PCO patients, ovulation was achieved in 6 out of 15 cycles (40%) and 2 women became pregnant. There was no overstimulation or any other serious complication. In conclusion, therapy with GnRH provides an elevated probability of therapeutic success, especially in HA.     

Ovulation induction with intravenous gonadotropin-releasing hormone

The efficacy of ovulation induction with the use of pulsatile gonado- tropin-releasing hormone (GnRH) therapy was examined in 21 infertile women. Seventeen had hypothalamic amenorrhea (HA) and 4 poly-cystic ovary syndrome (PCO). All patients were treated as outpatients. GnRH was infused in a pulsatile mode by means of portable auto-infusion pumps connected to an indwelling intravenous catheter inserted into a forearm vein. The doses varied from 1.8 to 5 μ;g/pulse with a frequency of 90 minutes. Ovulation occurred in 52 out of 64 cycles (81.2%). Ten (47.6%) ofthe 21 patients became pregnant. Seven patients had normal term deliveries and 3 aborted spontaneously. With regard to the 17 patients with HA, ovulation occurred in 93.7% of treatment cycles and 6 women became pregnant. In the case ofthe PCO patients, ovulation was achieved in 6 out of 15 cycles (40%) and 2 women became pregnant. There was no overstirnulation or any other serious complication. In conclusion, therapy with GnRH provides an elevated probability of therapeutic success, especially in HA.     

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.     

Ovulation induction with pulsatile intravenous GnRH

Human menopausal gonadotropin has been the treatment of choice for hypogonadotropic hypogonadism patients who fail ovulation induction with clomiphene citrate. Several authors have reported successful ovulation induction with the use of gonadotropin releasing hormone (GnRH). We used commercially available GnRH (Factrel, Ayerst Laboratories) and the Auto Syringe AS6H Infusion Pump for ovulation induction in such patients. Eight patients completed 15 cycles of pulsatile intravenous GnRH therapy. A mean of 12.2 days of therapy was required per cycle. Basal body temperatures and ultrasound documented ovulation of a single, dominant follicle in 12 cycles (80%). There were four singleton pregnancies. The overall corrected pregnancy rate was four pregnancies for ten cycles (40%) in six patients (67%). No complications were observed, and the cost of care was one-third that of human menopausal gonadotropin at our institution.     

Ovulation induction with subcutaneous pulsatile gonadotropin-releasing hormone: singleton pregnancies in patients with previous multiple pregnancies after gonadotropin therapy

Three patients with hypothalamic amenorrhea who had previously had multiple pregnancies following gonadotropin therapy were treated with subcutaneous pulsatile gonadotropin-releasing hormone (GnRH), administered by a portable pump. After treatment with lower doses in some cases, pulses of 5 to 10 micrograms were given at 90-minute intervals, resulting in ovulation on six occasions. Ovarian steroid profiles closely resembled those of normal ovulatory cycles, and spontaneous ovulation of a single ovarian follicle was consistently demonstrated by ultrasound. Singleton pregnancy was confirmed in each patient. The results imply normal operation of the ovarian-pituitary feedback loop and suggest that subcutaneous pulsatile GnRH therapy is a safe and effective means of ovulation induction in clomiphene-resistant cases of hypothalamic amenorrhea and may possibly become the preferred method of treatment.     

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.     

Ovulation induction with pulsatile gonadotropin-releasing hormone: a study of the subcutaneous route of administration

The efficacy of ovulation induction with the use of intermittent gonadotropin-releasing hormone (GnRH) therapy was examined in seven infertile women with hypothalamic amenorrhea. GnRH was administered every 90 minutes via the subcutaneous route in doses ranging from 50 to 300 ng/kg. Analysis of the induced gonadotropin pulse pattern revealed normal to modestly increased luteinizing hormone secretory parameters (e.g., pulse amplitude) in six of the seven patients. Six of seven women and 15 of 16 treatment cycles (94%) were ovulatory. The conception rate was 43% per woman and 19% per cycle. However, detailed hormonal analysis of 13 treatment cycles revealed that only 1 cycle was entirely normal in terms of duration and/or steroid secretion.     

Successful induction of ovulation with synthetic luteinizing hormone-releasing hormone in anovulatoy infertility

13 women with suspected hypothalamic anovulation were treated with l uteinizing hormone-releasing hormone (LH-RH) by a variety of regimens. 3 women received LH-RH by continuous intravenous infusion equal to 100 mcg LH-RH for 8 hours, followed by an acute injection of LH-RH 100 mcg. 10 days later the infusion was repeated without the supplemental injecti on and coitus advised immediately after the end of the 2nd infusion. 10 patients were given LH-RH by injection of 50 mch/day for 10 days. Coitus was indicated every other day from Day 8 of therapy. Presumptive ovulation was determined on each mode of therapy. 2 of the 3 intravenous patients had presumptive ovulation responses wihtout conception. 4 of the 10 injection patients had presumptive ovulation signs and 2 conceived. The 6 remaining injection patients responded with increased estrogens and estrogenic effect on cervical mucus. The results confirm the therapeutic role of LH-RH in certain cases of sterility.     

Pulsatile luteinizing hormone-releasing hormone therapy in women with polycystic ovary syndrome

Induction of ovulation with pulsatile luteinizing hormone-releasing hormone (LH-RH) therapy was attempted in 48 women with polycystic ovary disease (PCOD) and clomiphene citrate (CC) resistant anovulation. Fourteen women ovulated regularly, 23 ovulated variably, but 11 did not ovulate at all. Fifty-two of the 108 cycles of pulsatile LH-RH therapy alone (15 mu gm per pulse, one pulse every 90 minutes) administered through the subcutaneous route were ovulatory. In patients who did not ovulate on subcutaneous LH-RH, treatment with CC (100 mg per day for 5 days) was added to the LH-RH therapy in an additional 33 cycles, of which 21 were ovulatory. In those who did not respond to the combination of treatments, the same dose of LH-RH was administered intravenously: 14 of 29 cycles of intravenous therapy were ovulatory. The overall cumulative conception rate after 6 months of therapy was 60%. When recalculated for ovulatory cycles alone it was 90%, indicating that failure of ovulation was the only cause of the failure of conception. Analysis of the clinical and endocrine findings indicated that failure to ovulate was associated with obesity and hyperandrogenization. Ten of the 23 conceptions ended in miscarriage, 8 within 4 weeks of ovulation. The authors conclude that infertility in patients with PCOD is not optimally corrected by pulsatile LH-RH therapy.     

Endocrine dynamics during pulsatile GnRH administration in patients with hypothalamic amenorrhea and polycystic ovarian disease

The LH secretory patterns and ovarian endocrine responses have been determined during pulsatile gonadotropin-releasing hormone (GnRH) administration for induction of ovulation in patients with hypothalamic amenorrhea (HA). However, until now these endocrine dynamics during GnRH therapy have not been thoroughly investigated in patients with polycystic ovarian disease (PCOD). Seven patients with HA and 4 patients with PCOD have therefore been studied to determine changes in LH pulsatile activity and in serum sex steroid levels in response to chronic intermittent GnRH stimulation. GnRH was administered intravenously (5-10 micrograms/90 minutes) by means of a portable infusion pump. Blood samples were obtained at 15-minute intervals for 4 hours on the day before the start of GnRH stimulation (control day) and on treatment days 5, 10 and 15. LH was determined in all samples and FSH, serum androgens and estrogens were measured in baseline samples by RIA. While 8 (62%) ovulations and 5 conceptions were observed in 13 treatment cycles in patients with HA, no ovulations were achieved during 9 treatment cycles in patients with PCOD. On the control day significantly (p less than 0.05) higher basal LH and testosterone (T) levels and significantly (p less than 0.05) lower FSH levels were found in the PCOD patients. The LH pulsatile profiles of the PCOD patients showed significantly (p less than 0.05) higher pulse amplitudes and areas under the curve (integrated responses). Pulsatile GnRH administration induced a significant (p less than 0.05) increase in LH pulse amplitudes in both HA and PCOD patients, and also increased (p less than 0.05) the integrated responses in patients with HA. During the GnRH stimulation, the LH interpulse intervals of both HA and PCOD patients were found to be similar to the frequency in which exogenous GnRH was administered. FSH levels rose continuously (p less than 0.001) during stimulation in patients with HA, but remained unchanged in patients with PCOD. In HA patients, T, androstenedione (AD) and estrone (E1) did not change during the GnRH treatment, but estradiol (E2) rose so that the ratios of aromatized estrogens to non-aromatized androgens (E1/AD, E2/T) increased. In contrast, T and AD increased significantly (p less than 0.05 or less) and E2 remained unchanged during stimulations in PCOD patients, which resulted in decreasing ratios of estrogens to androgens. These observations confirm that pulsatile GnRH administration can successfully induce ovulation in patients with HA by restoring the ovarian physiology. The data also demonstrate that pulsatile GnRH administration can influence the LH secretory patterns in PCOD patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Prospective,randomized comparison between pulsatile GnRH therapy and combined gonadotropin (FSH + LH) treatment for ovulation induction in women with hypothalamic amenorrhea and underlying polycystic ovary syndrome

Objective(s)

To compare the efficacy of pulsatile GnRH therapy versus combined gonadotropins for ovulation induction in women with both hypothalamic amenorrhoea and polycystic ovarian syndrome (HA/PCOS) according to their current hypothalamic status.

Study design

This single-centre, prospective, randomized study was conducted in the Nantes University Hospital, France. Thirty consecutive patients were treated for ovulation induction with either pulsatile GnRH therapy or combined gonadotropins (rFSH + rLH). Frequency of adequate ovarian response (mono- or bi-follicular) and clinical pregnancy rate were then compared between both groups.

Results

Ovarian response was similar in both groups with comparable frequency of adequate ovarian response (73% vs 60%), but the clinical pregnancy rate was significantly higher in the pulsatile GnRH therapy group than in the combined gonadotropin group (46% vs 0%).

Conclusions

HA/PCOS is a specific subgroup of infertile women. Pulsatile GnRH therapy is an effective and safe method of ovulation induction that can be used successfully in these patients.     

Induction of ovulation with pulsatile subcutaneous administration of human menopausal gonadotropin in anovulatory infertile women

Pulsatile administration of human menopausal gonadotropin (hMG) via the subcutaneous route was evaluated in 15 patients with various ovulatory disorders. Administration of hMG was started at a dose of 4.6875 IU (75 IU/day) or 9.375 IU (150 IU/day) per pulse every 90 minutes. Ovulation was observed in 26 (92.9%) of 28 treatment cycles, and two singleton pregnancies were confirmed. Ovarian hyperstimulation was observed in 1 to 26 ovulatory cycles; however, no other side effects were observed during treatment. A regimen of 75 IU/day resulted in a significant increase (P less than 0.0001) of the total dose and prolongation of the treatment period for induction of ovulation, as compared with that of 150 IU/day. Shortened luteal phases occurred in ovulatory cycles induced by pulsatile subcutaneous treatment. Human chorionic gonadotropin administration given every other day until the midluteal phase significantly prolonged the duration of the luteal phase (P less than 0.05). This treatment in patients with the polycystic ovary syndrome was followed by a normalization of luteinizing hormone/follicle-stimulating hormone ratio and resulted in a successful induction of ovulation in 8 to 10 cycles. The present data demonstrated that pulsatile subcutaneous administration of hMG was effective in inducing follicular maturation and ovulation in patients with various types of anovulatory infertility.     

Ovulation induction with a combination of LHRH analogue and hMG pulsatile subcutaneous administration in PCO patients

The pulsatile subcutaneous administration of hMG (hMG therapy) and treatment with a combination of luteinizing hormone releasing hormone analogue (Buserelin) and hMG (combined therapy) were used to induce ovulation in 9 patients with polycystic ovary syndrome (PCO). Ovulation was observed in all twelve treatment cycles in the combined therapy, and two cases (delivery at term, and abortion) of pregnancy were confirmed. In the hMG therapy, ovulation occurred in 22 cycles of 26 treatment cycles. Ovarian hyperstimulation occurred in one cycle in the combined therapy and in 5 cycles (3 ovulated patients) in the 26 hMG therapy. The total dose per cycle of hMG required to induce ovulation in the combined therapy (1,700 +/- 203IU) was significantly lower than in the hMG therapy (2,344 +/- 223IU). In response to Buserelin administration, LH and FSH increased transiently and then declined to the normal range observed in the early follicular phase. The reduced LH level was sustained throughout the hMG administration. The concentration of FSH increased in response to hMG administration, resulting in a change in the LH/FSH ratio. The LH/FSH ratio in the combined therapy was significantly lower than in the hMG therapy. The present data demonstrated that pulsatile subcutaneous administration of hMG associated with Buserelin was effective in inducing ovulation in patients with PCO with a low incidence of serious side effects.     

Serum tobramycin levels in low- and very low-birthweight infants

This study was designed to evaluate the serum concentration of tobramycin sulfate following a 2.5-mg/kg intravenous infusion in 43 premature infants on days 1, 3, and 5 of age (therapy). Twenty premature infants weighing 1500 gm or less at birth and 23 others whose birthweights ranged from 1501 to 2500 gm made up the study population. Serum tobramycin levels were measured by an enzymatic immunoassay (EMIT) at one, four to six, and 12 hours after injection. Peak serum levels increased from day 1 (means, 5.2 +/- 2.2 mcg/ml) to day 3 (means, 6.1 +/- 2.6 mg/ml) and then remained unchanged at day 5 (means, 6.1 +/- 2.4 mg/ml). Approximately 40% of the study population presented trough levels above 2 mcg/ml on day 1 and over 70% on days 3 and 5. No evidence of renal toxicity or auditory dysfunction was observed. In light of the high trough levels observed during the first week of life in premature infants, it may be judicious to monitor serum tobramycin concentration and to decrease the dosage or to prolong the dose interval in order to maintain trough concentrations below 2 mcg/ml.