Endometrial biopsies during treatment with subcutaneous pulsatile gonadotropin-releasing hormone and luteal-phase human chorionic gonadotropin

A high incidence of luteal phase defect (LPD) has been reported using subcutaneous pulsatile gonadotropin-releasing hormone for induction of ovulation. We reviewed all patients treated with the combination of subcutaneous pulsatile gonadotropin-releasing hormone during the follicular phase and human chorionic gonadotropin during the luteal phase (GnRH-hCG) who underwent endometrial biopsy during a treatment cycle. All of these patients had biopsy-proven LPD which persisted despite traditional therapy with progesterone vaginal suppositories and/or clomiphene citrate. The mean number of biopsies out of phase per patient prior to GnRH-hCG treatment was 2.8 +/- 0.2 (+/- SEM). When treated with GnRH-hCG, 15/16 patients (94%) showed a normal endometrial biopsy. The probability of this result occurring by chance alone allowing for a 50% treatment independent correction rate is less than .001. These results show that the combination of subcutaneous pulsatile gonadotropin-releasing hormone and luteal-phase human chorionic gonadotropin can result in normal endometrial maturation in a high percentage of cycles when administered as described. It appears to be an effective alternative to traditional treatment modalities for luteal phase defect should one be needed.     

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 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.     

Luteal dysfunction in ovulation induction: the role of repetitive human chorionic gonadotropin supplementation during the luteal phase

Several studies have indicated that ovulation induction with human menopausal gonadotropin (hMG)/human chorionic gonadotropin (hCG) or clomiphene citrate (CC) is associated with luteal phase defect. To assess the efficiency of luteal support by hCG to an infertile population undergoing ovulation induction, with CC/hCG or hMG/hCG, we have randomly administered 2500 IU hCG intramuscularly on days 3, 6, and 9 after ovulation induction by 10,000 IU of hCG to 74 patients on 265 treatment cycles. As controls served 357 ovulation induction cycles in the same 74 patients. The treatment cycles were randomly alternated with control cycles so that each patient served as her own control. However, the mean +/- standard deviation (SD) midluteal P was 38.1 +/- 10.8 ng/ml in the study group versus 15.7 +/- 10.5 ng/ml in the control group (P less than 0.001). Luteal phase length was 15.4 +/- 1.5 days in the treatment group versus 12.1 +/- 1.7 in the control group (P less than 0.01). In the treatment group, 64.8% of the patients achieved pregnancy (27% pregnancies/treatment cycle) versus 47.3% in the control group (11.5% pregnancies/control cycle) (P less than 0.01). The pregnancy wastage rates (including abortions and "chemical" pregnancies) were 30.6% in the treatment group versus 56% in the control group (P less than 0.01). We conclude that repetitive hCG administration may be an efficient luteal support in infertile patients undergoing ovulation induction.     

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.     

The treatment of luteal phase defects with pulsatile infusion of gonadotropin-releasing hormone

Because pulsatile administration of gonadotropin-releasing hormone (GnRH) can initiate normal follicular maturation and corpus luteum function in women with hypothalamic amenorrhea, the authors attempted to treat five women with inadequate and one with short luteal phase with GnRH therapy. Pulsatile administration of GnRH (5 micrograms intravenously every 90 minutes) was begun on days 1 to 4 and continued throughout the cycle. Blood levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), estrogen, and progesterone were monitored daily throughout the control and treatment cycles. There were 12 GnRH treatment cycles, all of them ovulatory. The length of the induced luteal phases varied from 11 to 17 days in all patients. Mean progesterone levels during GnRH treatment were significantly increased over those of the matched control cycles (control cycle 3.5 +/- 0.5 ng/ml; treatment cycle 8.2 +/- 1.45 ng/ml [mean +/- standard error]). Endometrial biopsies obtained during the luteal phase (days 25 to 27) in five women were in phase during the GnRH treatment cycle, in contrast to the control cycle in which they were two or more days out of phase. One patient achieved pregnancy during the treatment cycle, but aborted spontaneously at 8 1/2 weeks. The data demonstrate that pulsatile GnRH infusion, when initiated in the early follicular phase, can restore normal corpus luteum function in women with luteal phase defects.     

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.     

Ovulation induction with pulsatile human menopausal gonadotropin (HMG) administration

A computerized pump for continuous pulsatile HMG administration was used with 5 patients having prolonged anovulatory infertility, for 14 consecutive cycles. All of these women had previously failed to respond to various treatment regimens, or repeatedly developed ovarian overstimulation syndrome. In 12 out of 14 cycles, ovulation was detected by hormonal and ultrasonic evaluation, and pregnancy was achieved in 2 out of 5 cases. A mild form of overstimulation was observed in only 3 out of 14 cycles. A summary of the results of the present and similar previously published series demonstrated overall ovulation and pregnancy rates of 75% and 23.5% respectively. We concluded that inducing ovulation by administering pulsatile HMG is an appropriate alternative method of treatment when ovulation and conception fail with conventional regimens.     

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.     

Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin

OBJECTIVE: To investigate the effect of triggering oocyte maturation with GnRH agonist on corpus luteum function by measuring luteal phase levels of inhibin A and pro-alphaC. DESIGN: Prospective randomized trial. SETTING: In vitro fertilization (IVF) program at a university hospital. PATIENT(S): Infertile women undergoing IVF-ET treatment. INTERVENTION(S): Controlled ovarian hyperstimulation with FSH and GnRH antagonist, triggering of final oocyte maturation with either hCG (n = 8) or GnRH agonist (n = 8), IVF-ET, and collection of blood samples every 2-3 days during the luteal phase. MEASUREMENTS AND MAIN RESULTS: Luteal phase serum levels of inhibin A and pro-alphaC, P, and E(2). RESULT(S): Levels of inhibin A, pro-alphaC, estrogen, and P were significantly lower from day 4 to day 14 after triggering final oocyte maturation by GnRH agonist compared with hCG. Maximal luteal serum inhibin A and pro-alphaC levels were 91.5 +/- 23.6 and 184.1 +/- 23.5 pg/mL in the GnRH agonist-treated women compared with 464.7 +/- 209.1 and 7,351.6 +/- 934.3 pg/mL in women treated with hCG. CONCLUSION(S): Triggering final oocyte maturation with GnRH agonist instead of hCG in IVF cycles dramatically decreases luteal levels of inhibins, reflecting significant inhibition of the corpus luteum function. This effect may explain, at least in part, the mechanism of ovarian hyperstimulation syndrome prevention by the use of GnRH agonist.     

The luteal phase during gonadotropin therapy: effects of two human chorionic gonadotropin regimens

OBJECTIVE: Luteal phase abnormalities are known to complicate ovulation induction with gonadotropins. This study was performed to test the effect of a modified human chorionic gonadotropin (hCG) regimen on the luteal phase during gonadotropin treatment. DESIGN: Fifteen women from a private practice setting volunteered to be studied during each of two nonconception, gonadotropin-stimulated cycles. After ovarian stimulation with human menopausal gonadotropins (hMG), hCG was administered either as a single dose of 10,000 IU (single dose) or in two divided doses of 5,000 IU given 1 week apart (split dose). MAIN OUTCOME MEASURES: Early, midluteal, and late luteal estradiol (E2) and progesterone (P) levels and luteal phase lengths were measured, and their median values and intraquartile ranges (IQR) compared using nonparametric analysis. RESULTS: Early and midluteal E2 and P levels were similar regardless of which hCG regimen was administered. The median late luteal E2 level was 1,146.0 pg/mL (the IQR ranged from 633 to 1,650, IQR = 1,017) with the split-dose regimen and 240.0 pg/mL (the IQR ranged from 150 to 460, IQR = 310) with the single-dose regimen. The median late luteal P level was 108.0 ng/mL (the IQR ranged from 58.5 to 129, IQR = 70.5) with the split-dose regimen and 4.2 ng/mL (the IQR ranged from 1.9 to 11.7, IQR = 9.8) with the single-dose regimen. Median luteal phase lengths were 16 days (the IQR ranged from 15 to 17, IQR = 2) for the split-dose regimen and 11 days (the IQR ranged from 10 to 12, IQR = 2) for the single-dose regimen. CONCLUSION: In hMG-stimulated cycles, a second dose of hCG given during the midluteal phase significantly increases late luteal E2 and P levels and consistently lengthens the luteal phase.     

Prevention of gonadotropin-releasing hormone antagonist induced luteal regression by concurrent exogenous pulsatile gonadotropin administration in monkeys

We studied the effects of a gonadotropin-releasing hormone (GnRH) antagonist given in midluteal phase. Monkeys received the antagonist (n = 6), [N-Ac-D-p-Cl-Phe1,2,D-Trp3,D-Arg6,D-Ala10]-GnRH: hydrochloride or vehicle (n = 5). Absent luteinizing hormone (LH) pulsatility, diminished progesterone (P) secretion (P less than 0.01), luteal phase truncation and premature menstruation were observed in all receiving the antagonist. To investigate the site of action, four females received pulsatile exogenous human menopausal gonadotropins (hMG) concurrently, whereby P secretion was sustained and premature menstruation was averted. Equivalent treatment using "pure" FSH, failed to sustain P levels and timely menstruation occurred, confirming the continuing dependence of the corpus luteum on LH. The antagonist acts by central suppression and in turn, diminishes P biosynthesis. LH is luteotropic, since pulsatile LH (hMG), not "pure" FSH, prevented luteolysis.     

Pregnancy rate and ovarian hyperstimulation after luteal human chorionic gonadotropin in in vitro fertilization stimulated with gonadotropin-releasing hormone analog and menotropins

The value of luteal phase supplementation with human chorionic gonadotropin (hCG) was assessed after a combined protocol of ovarian stimulation, using a long acting gonadotropin releasing hormone analog (GnRH-a) and human menopausal gonadotropins (hMG), in a randomized prospective study of 36 consecutive cycles in an in vitro fertilization (IVF) program. The patients were allocated on the transfer day to either luteal phase supplementation with hCG (Group A, n = 18) or none (Group B, n = 18). Nine patients of Group A conceived as compared with 3 in Group B. Five patients, all in Group A, developed ovarian hyperstimulation syndrome (OHSS) (3 moderate and 2 severe forms). Analysis of the hormonal profiles disclosed similar progesterone (P), estradiol (E2), and E2/P ratio up to the 6th post ovum pick-up day. Then, E2 and mainly P levels decreased only in Group B resulting in a rising E2/P ratio. These findings stress the importance of luteal support in IVF cycles treated with GnRH-a. In light of the increased risk of OHSS among hCG treated patients, further studies are needed to assess the optimal preparation needed.