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.     

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.     

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.     

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 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.     

Treatment of premenstrual syndrome with gonadotropin-releasing hormone agonist in a low dose regimen

BACKGROUND: GnRH agonists constitute a well-documented treatment for premenstrual syndrome (PMS). However, the hypo-estrogenic state induced by the treatment renders it less suitable for long-term clinical use. The aim of the current study was to investigate the efficacy of a low dose GnRH agonist with respect to its ability to relieve premenstrual symptoms and maintain regular ovulatory cycles. METHODS: The effect of a low dose GnRH agonist (buserelin) on luteal phase symptomatology was evaluated in 27 women with severe premenstrual syndrome. The design was doubleblind, placebo-controlled and cross-over. Patients were randomized to either GnRH-agonist intranasally in a dosage of 100 microg once daily for two months or placebo for two months before the cross-over was made. The primary outcome measure consisted of daily symptom ratings for mood and physical symptoms made by the patients throughout the study. Adverse events and hormone concentrations were assessed at visits every second week. RESULTS: Premenstrual irritability and depression were significantly relieved by low dose GnRH agonist. Positive symptoms such as friendliness and cheerfulness were also improved during the premenstrual week. Likewise physical symptoms of swelling and headache displayed a significant improvement during buserelin treatment, whereas breast tenderness scores were unaffected by the treatment. The low dose GnRH agonist treatment regimen induced anovulation in as much as 56% of patients, but these subjects were significantly older than those women who maintained ovulatory cycles throughout the study. CONCLUSION: GnRH treatment significantly reduced premenstrual depression and irritability. However, low dose GnRH therapy is prone to induce anovulation, particularly with increasing age.     

Endocrine effects of ovarian electrocautery in patients with polycystic ovarian disease

The mechanism by which ovarian electrocautery induces regular ovulatory cycles was studied in 16 women with polycystic ovarian disease (PCO) and compared with 25 normal fertile women who were undergoing sterilization by tubal electrocautery. Gonadotrophins (LH and FSH), prolactin, androgens, oestrogens, 17-hydroxyprogesterone and progesterone were determined immediately before operation and 24 h later. Following the sampling of blood for these tests, 100 micrograms of gonadotrophin releasing hormone (GnRH) was given intravenously and the LH and FSH responses were measured at 30 min. In the PCO-group, these tests were repeated after the first induced ovulatory cycle. After operation, LH increased only in the patients with PCO and this increase was associated with an enhanced response to GnRH, FSH showed a similar response to GnRH, also confined to the PCO-group. These pituitary responses are best explained by a change in ovarian feedback induced by the direct electrocautery of the glands in the PCO-group. There was little change in serum oestrogen. Prolactin showed an increment in all cases and serum androgens were reduced in all groups, most pronounced in the PCO patients, possibly as a result of the stress of operation. An ovarian factor--released or reduced by the electrocautery--seems to be responsible for the changes.     

Endocrinology of gonadotropin-releasing hormone induced cycles in hypothalamic amenorrhea: the role of the pulse dose.

OBJECTIVE: To find the treatment regimen giving a maximum chance of ovulation and a minimal chance of multiple follicular development in pulsatile gonadotropin-releasing hormone (GnRH) therapy in patients with hypothalamic amenorrhea. DESIGN: We propectively studied the endocrinology of cycles induced with 5, 10, and 20 micrograms GnRH pulse doses, randomly assigned per patient, comparing this with the endocrinology of spontaneous menstrual cycles. SETTING: All patients were treated at the Academic Hospital of the Vrije Universiteit, Division of Reproductive Endocrinology and Fertility. PATIENTS: Fifteen patients with hypothalamic amenorrhea were treated for one to three cycles; 14 normally cycling volunteers were studied for one cycle. MAIN OUTCOME MEASURE: Number of ovulations per pulse dose; luteinizing hormone, follicle-stimulating hormone, total urinary estrogens (Es), and pregnanediol were measured per cycle day and per stimulation day. RESULTS: The endocrinology of all ovulatory cycles remained within the normal range. First treatment cycles showed significantly higher ovulation rates compared with subsequent cycles. Significantly more anovulation was observed in cycles with 5-micrograms pulse doses. Luteal Es were significantly higher in induction cycles compared with controls. CONCLUSIONS: The optimum treatment regimen should be to start induction with 5 micrograms/pulse in the first cycle and to raise the dose to 10 micrograms/pulse in subsequent cycles, regardless of the outcome of the first cycle. After ovulation, the pulse interval should be changed to 240 minutes.     

The efficacy of every-other-day administration of gonadotropin-releasing hormone in women with hypothalamic amenorrhea: gonadotropin-releasing hormone treatment can induce clomiphene responsiveness

The efficacy of every-other-day gonadotropin-releasing hormone administration was investigated in clomiphene-human chorionic gonadotropin (hCG) resistant, anovulatory women with hypogonadotropism or normogonadotropism. One hundred micrograms of gonadotropin-releasing hormone was injected intramuscularly three times a week for four weeks (one course). Ten of 11 hypogonadotropic patients responded to clomiphene or clomiphene-hCG after one to three courses of gonadotropin-releasing hormone treatment. Once the patients were converted to clomiphene responsiveness, ovulatory response continued without additional treatment, and all four patients who desired pregnancy conceived. Among eight normogonadotropic women, four with amenorrhea of one year or less became clomiphene-hCG responders after one or two courses of gonadotropin-releasing hormone treatment. They were subsequently treated with gonadotropin-releasing hormone after every one or two ovulatory cycles. One of the four women who desired to be pregnant conceived. We conclude that intramuscular gonadotropin-releasing hormone treatment is effective in inducing responsiveness to clomiphene, especially in hypogonadotropic anovulatory women. In normogonadotropic women, gonadotropin-releasing hormone treatment may be useful in those who have been amenorrheic for less than a year.     

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.     

Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report

OBJECTIVE: Recent success in polychemotherapy (PCT) in adolescent female cancer patients has become a source of concern for specialists who also strive to preserve fertility. We studied whether gonadotropin-releasing hormone (GnRH) analogs could prevent the early onset of ovarian insufficiency postchemotherapy and protect fertility. METHODS: The patients were divided into three groups: Control group 1 (Group A), premenarchal patients aged 3 to 7.5 years (n = 5), were not given GnRH analogs administered prior to PCT. Postmenarchal patients (Group B), aged 14.7 to 20 years (n = 12) with normal menstrual rhythm and ovulatory cycles, received treatment with GnRH analogs prior to PCT. Control group 2 (Group C), postmenarchal patients aged 15.9 to 20 years (n = 4), received PCT but no GnRH analog protection. All groups received the PCT regimens CAVPE, CVPP, ABVD, TAMO, ARA-C, and MTT. In group B, leuprolide acetate inhibition was obtained with a depot injection administered each month before and during treatment with PCT. To accelerate the timing of ovarian regression, a subcutaneous injection (0.2 mg) was administered simultaneously. RESULTS: In Group A, patients had spontaneous menarche between the ages of 12 and 17.9 years, followed by normal menstruation and ovulatory cycles. Three patients became pregnant. After GnRH analog withdrawal, Group B patients continued with normal ovulatory cycles. Two patients became pregnant. Group C patients presented hypergonadotrophic hypoestrogenic amenorrhea. CONCLUSION: GnRH analog treatment before and during PCT enhances ovarian function and preserves adolescent fertility. The results must be confirmed in a larger study.     

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.     

Use of combined exogenous gonadotropins and pulsatile gonadotropin-releasing hormone in patients with polycystic ovarian disease

We previously tested a combined regimen based on the administration of gonadotropin in the early follicular phase followed by pulsatile gonadotropin-releasing hormone (GnRH) until complete follicular maturation in patients suffering from polycystic ovarian disease. Despite good clinical results, a high rate of premature luteinization was observed with this approach. We therefore evaluated in this study whether starting pulsatile GnRH therapy before gonadotropin administration might reduce premature luteinization. Eight women underwent induction of ovulation with both combined therapy and pure exogenous follicle-stimulating hormone alone using a crossover scheme. No premature luteinization and a single follicular growth were recorded with the modified combined regimen. Clinical results (8/8 versus 3/7 ovulatory cycles; 3/8 versus 1/7 pregnancies) favor the combined approach over gonadotropin alone.     

Ovulation induction with pulsatile luteinizing hormone-releasing hormone in women with clomiphene citrate-resistant polycystic ovary-like disease: endocrine results

The pituitary and gonadal response to pulsatile luteinizing hormone-releasing hormone (LH-RH) administration during the first and consecutive second treatment unit (TU) was studied in nine women with clomiphene citrate-resistant polycystic ovary-like disease (PCOD). The control group consisted of eight eumenorrheic women. Luteinizing hormone levels, LH amplitudes, and total urinary excretion/24 hours did not differ between ovulatory and anovulatory TUs, but were significantly higher compared with the control group. Follicle-stimulating hormone (FSH) in PCOD did not differ from normal cycles. Androgen values in the anovulatory TUs were significantly higher compared with the ovulatory TUs (P = 0.001). We conclude that LH-RH therapy may result in ovulation; however, it does not redress the intrinsic abnormality in PCOD and FSH, and androgen levels do not seem to be critical in ovulation induction.     

Endocrine effects of ovarian electrocautery in patients with polycystic ovarian disease

Summary. The mechanism by which ovarian electrocautery induces regular ovulatory cycles was studied in 16 women with polycystic ovarian disease (PCO) and compared with 25 normal fertile women who were undergoing sterilization by tubal electrocautery. Gonadotrophins (LH and FSH), prolactin, androgens, oestrogens, 17-hydroxy-progesterone and progesterone were determined immediately before operation and 24 h later. Following the sampling of blood for these tests, 100 μg of gonadotrophin releasing hormone (GnRH) was given intravenously and the LH and FSH responses were measured at 30 min. In the PCO-group, these tests were repeated after the first induced ovulatory cycle. After operation, LH increased only in the patients with PCO and this increase was associated with an enhanced response to GnRH, FSH showed a similar response to GnRH, also confined to the PCO-group. These pituitary responses are best explained by a change in ovarian feedback induced by the direct electrocautery of the glands in the PCO-group. There was little change in serum oestrogen. Prolactin showed an increment in all cases and serum androgens were reduced in all groups, most pronounced in the PCO patients, possibly as a result of the stress of operation. An ovarian factor—released or reduced by the electrocautery—seems to be responsible for the changes.     

Active ovulation management increases the monthly probability of pregnancy occurrence in ovulatory women who receive intrauterine insemination

The authors examined the hypothesis that active ovulation management would increase the monthly probability of pregnancy occurrence (MPO) in ovulatory women who require intrauterine insemination (IUI). All patients were initially treated during spontaneous ovulatory cycles with IUI performed after the detection of an endogenous lutenizing hormone (LH) surge (phase 1). For phase 2, those patients who had not conceived were offered treatment with fertility medication and IUIs were scheduled accordingly. Four of 76 (5.3%) patients conceived during 180 treatment cycles in phase 1; 9 of 44 (20.5%) patients conceived during 105 treatment cycles in phase 2. The average MPO was 0.022 in phase 1, and 0.085 in phase 2: the difference is significant (P less than 0.02). The authors conclude that fertility medication improves MPO in ovulatory women who undergo IUI for certain infertility situations.     

Treatment of endometriosis with a potent agonist of gonadotropin-releasing hormone (nafarelin)

Administration of superactive agonistic analogs of gonadotropin-releasing hormone (GnRH) has been shown to induce a paradoxic and reversible suppression of gonadotropins, resulting in suppressed gonadal steroid concentrations. Because there currently is no uniformly successful and acceptable medical therapy for endometriosis, we examined the effects of 6 months of nasal administration (500 micrograms every 12 hours) of the agonistic analog of GnRH, nafarelin, on clinical signs and symptoms and hormonal profiles in eight women with endometriosis. All patients had prompt and near-complete relief from their painful symptoms of endometriosis. Laparoscopy or laparotomy, performed both before and after treatment in seven of the women, revealed complete resolution of active endometriotic lesions in five patients and only a single, small cul-de-sac implant in a sixth woman. A large ovarian endometrioma decreased slightly in response to treatment in the seventh woman. Serum luteinizing hormone and follicle-stimulating hormone concentrations, after a transitory stimulation at the onset of treatment, declined and were suppressed (P less than 0.001) during the remainder of treatment. Serum estradiol concentrations fell to approximately menopausal levels (less than 30 pg/ml) after 1 to 4 weeks. Reversibility of drug effect was prompt, with ovulatory menses returning 47 +/- 8 days (+/- standard deviation) after treatment. Thus, nasal administration of agonistic analogs of GnRH may represent a new treatment modality for endometriosis.     

Screening for hypothyroidism in infertile women.

OBJECTIVE: To determine the frequency of an elevated thyroid-stimulating hormone (TSH) level in 704 patients seeking treatment for infertility. STUDY DESIGN: Sera from 704 women evaluated for infertility were assayed for TSH levels using radioimmunoassay (normal, 0.45-4.09 mIU/mL). All women had at least one year of infertility. Women with a known history of thyroid disease were excluded from the review. RESULTS: Sixteen of 704 patients (2.3%) had elevated TSH levels and were treated with levothyroxine to normalize TSH. None of these women had overt clinical signs or symptoms of hypothyroidism. Of these women, 11 of 16, or 69%, had ovulatory dysfunction, and 7 (64%) later became pregnant while on thyroid replacement. Five of 704 (0.7%) women with infertility who presented without a history of ovulatory dysfunction had elevated TSH levels, and none became pregnant with treatment. CONCLUSION: The prevalence of elevated TSH in 704 women with at least one year of infertility was 2.3%. The majority of women diagnosed with hypothyroidism (11 of 16, or 69%) had ovulatory dysfunction. With treatment for hypothyroidism, successful pregnancies resulted in 7 of 11 (64%) of patients. Women with infertility and ovulatory dysfunction should be screened for hypothyroidism. Screening for hypothyroidism as part of a routine infertility workup in women with normal ovulatory function will yield few abnormal tests.     

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.