Induction of ovulation with clomiphene citrate. A double-blind study.
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Each of 14 anovulatory patients received a single injection of 150 micrograms of synthetic luteinizing hormone-releasing hormone (LH-RH) in one induced menstrual cycle. In two subsequent cycles, patients were pretreated with clomiphene before LH-RH injection. Four patients received LH-RH after pretreatment with human menopausal gonadotropin (HMG) in another cycle. In each cycle, gonadotropin release and ovulation were recorded. All patients had previously failed to ovulate when treated with large doses of clomiphene. No patient ovulated following injection of LH-RH alone, although five patients exhibited a good pituitary response. Nine patients ovulated when they received LH-RH after pretreatment with clomiphene, and one patient ovulated when pretreated with HMG. The diagnostic value of a single injection of LH-RH is not clear. In the present study, gonadotropin response to LH-RH was not an entirely accurate predictor of a patient's ovulatory response in any of the four cycles. On the other hand, when clomiphene-LH-RH was administered, a good response was associated with ovulation in that cycle. The exact role of LH-RH in inducing ovulation is unclear, but the results of using LH-RH in conjunction with clomiphene are encouraging enough to warrant continued use and further study.
Ten infertile patients with polycystic ovarian disease were treated with 18 cycles of "pure" human pituitary follicle-stimulating hormone (HP-FSH) and 10 cycles of human menopausal gonadotropin (HMG) consisting of FSH and luteinizing hormone (LH) in a 1:1 ratio. Human chorionic gonadotropin was used to trigger ovulation when optimal follicular development was achieved as judged by urinary estrogen determinations. Of the 18 cycles utilizing HP-FSH, 14 were presumptively ovulatory, 2 were conceptual, and in 5 cycles ovarian enlargement was noted. Of the 10 HMG cycles, none was ovulatory, no conceptions resulted, and 6 instances of hyperstimulation were noted. Pretreatment serum LH levels were significantly higher than normal follicular phase values. These observations suggest that endogenous LH levels in patients with polycystic ovaries are quite adequate for follicular development so that the administration of exogenous LH is unwarranted. Furthermore, the data suggest that HP-FSH or low-LH-containing HMG may prove to be an additional safe and effective nonsurgical treatment modality for patients who are anovulatory because of polycystic ovaries.
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Twenty-two infertile and clomiphene-nonresponding patients received a course of clomiphene, 100 mg/day for 5 days, followed 7 days later by an intramuscular injection of 1 mg of estradiol benzoate. The diagnosis of idiopathic chronic anovulation had been established. None of these patients had galactorrhea, hirsutism, or ovarian enlargement. Thirteen of the twenty-two women had surges of both luteinizing hormone and follicle-stimulating hormone after the estradiol injection; the peak gonadotropin levels occurred within 72 hours of the injection. These 13 patients ovulated and pregnancy ensued in 10 of them. The estradiol benzoate injection also elicited a significant increase in serum prolactin levels- This enhanced prolactin release had no apparent effect on the gonadotropin surge. These results suggest that the association of clomiphene and estradiol benzoate potentiates the action of clomiphene and may prove useful in clomiphene nonresponders.
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Clomiphene citrate (Clomid), when given alone, is generally considered ineffective in inducing ovulation in women with hyperprolactinemia. This study reports the treatment of 29 infertile women with hyperprolactinemic amenorrhea. Twenty-one patients (eighteen of whom had previously had no ovulation response to Clomid alone) were treated with a combined regimen of Clomid (100 to 200 mg/day for 5 days) and two injections of 5000 IU of human chorionic gonadotropin (HCG), the first 8 to 10 days after Clomid withdrawal and a second injection 1 week later. Basal body temperature charts, conception, and/or plasma progesterone measurements showed that 19 patients ovulated (90%). There were 17 pregnancies in 12 of 21 patients (57% pregnancy rate) with 15 single live births and two abortions. When bromocriptine (Parlodel) became available, a total of 22 patients (including 14 patients previously treated with Clomid/HCG, six of them successfully) with amenorrhea associated with hyperprolactinemia were treated with this drug with dosages varying from 2.5 mg to 15 mg/day. Ovulation was confirmed in 20 patients (90%). There were 17 pregnancies in 15 patients (68% pregnancy rate) with 15 single live births and two first-trimester abortions. In all, 21 of 29 patients (73%) achieved one or more pregnancies resulting in live births with one or both of the above treatments. It is concluded that a combined Clomid/HCG regimen can often be used as an effective alternative to bromocriptine therapy in the treatment of infertility associated with hyperprolactinemic amenorrhea.
Bromocriptine is known to be effective in the treatment of women with hyperprolactinemic anovulation or amenorrhea-galactorrhea. A new schedule of combined treatment with bromocriptine and clomiphene citrate was applied to 23 patients with normoprolactinemic amenorrhea who failed to respond to clomiphene alone. Ovulation was restored by treatment in 14 of these patients (60.9%), resulting in pregnancy in 3 women. Treatment resulted in immediate suppression of serum prolactin levels and a gradual increase in serum luteinizing hormone levels and estradiol levels followed by a luteinizing hormone surge. The present results indicate that bromocriptine/clomiphene combination therapy is effective in the treatment of amenorrheic patients with normoprolactinemia who do not respond to clomiphene alone, and suggest that bromocriptine restores the responsiveness of the hypothalamic-pituitary-ovarian system to clomiphene.
Females with pituitary dwarfism of the multiple pituitary hormone deficiency form have ovarian failure due to hypogonadotropism which would be expected to respond favorably to human gonadotropin treatment. This is a description of a pituitary dwarf in whom pregnancy was achieved with gonadotropin therapy; its progress was followed regularly by hormone assays.
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Forty-six women remaining infertile with clomiphene citrate (CC) with or without human chorionic gonadotropin (hCG) were treated by either human menopausal gonadotropin (hMG, 44 cycles) or CC + hMG (33 cycles) and monitored by serum estradiol (E2) and ultrasonography. Ovarian hyperstimulation syndrome (OHS) and pregnancy outcome were compared in both regimens. In the presence of dominant follicles (greater than or equal to 18 mm) alone or with a single secondary follicle (14 to 16 mm) at hCG administration, OHS did not develop. A significant increase in OHS was noted when three or more secondary follicles were observed. Overall pregnancy rates were similar in both regimens but significantly higher when hCG was injected before rather than after the E2 peak. The results suggest secondary follicles rather than dominant follicles are a valuable sign of possible OHS development; and CC + hMG should be considered in CC-failure patients.
Patients failing to ovulate and conceive on clomiphene citrate (CC) or CC plus human chorionic gonadotropin (hCG) or patients with pituitary gonadotropin deficiency are candidates for human menopausal gonadotropin (hMG) plus hCG therapy. The duration and number of ampules needed to stimulate ovarian response leading to ovulation and/or pregnancy vary individually. Seventy-one patients who had complete follow-up evaluation and accurately documented body weights at the time of therapy were considered for the study. Of these 71 patients, 41 (57.3%) conceived in 293 cycles. The average number of ampules of hMG used by patients with 10% to 20% below ideal body weight (IBW) was 13.9 +/- 6.3 (mean +/- standard deviation [SD]). The average number of ampules used by patients with normal +/- 10% IBW was 14.2 +/- 3.5. Patients who were overweight by 10% to 25% used 15.3 +/- 5.4 ampules, and patients overweight by greater than or equal to 25% used 20.9 +/- 5.6 ampules of hMG. Eleven patients with severe hypothalamic chronic anovulation needed an average of 20.6 +/- 6.2 ampules. The data reveal a direct relationship between IBW and the amount of hMG needed to induce ovulation and/or pregnancy; however, in the presence of chronic hypoestrogenic conditions, it is expected that these patients will need higher amounts of hMG, regardless of body weight.
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Cerebral infarction due to menotropin therapy without evidence of ovarian hyperstimulation is presented. The patient was successfully treated with aspirin and anticonvulsive agents and was discharged without residual neurologic symptoms.
This study evaluated the activity of central opiate receptors modulating luteinizing hormone (LH) secretion before and during treatment with human menopausal gonadotropin (n = 8) or purified human urinary follicle-stimulating hormone (n = 6) in 14 patients with hypogonadotropic hypogonadism (n = 6) or secondary amenorrhea (n = 8). LH response to saline infusion and naloxone administration (4 mg intravenously) was assessed. As control, 6 normal ovulating women were studied. Before therapy, all amenorrheic patients showed no LH increase after naloxone injection. Gonadotropin treatment restored the naloxone-induced LH response at preovulatory and midluteal phases in ovulating patients with secondary amenorrhea. The same response was present in spontaneously ovulating women but was absent in the hypogonadotropic hypogonad patients, despite the gonadotropin therapy's efficiency. In conclusion, when the alteration of gonadotropin-releasing hormone synthesis and/or release is reversible, the opioid system actively participates in the regulation of the hypothalamus-pituitary-gonadal axis.