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Despite the high incidence of fetal loss following gonadotropin therapy, the etiologic factors that contribute to this loss remain unknown. In 203 women who conceived following gonadotropin therapy, the abortion rate was 28.5%. However, in 84 women who conceived a second time, also with gonadotropin treatment, the abortion rate was 11.9%. Second- and third-degree hyperstimulation of the ovary are accompanied by a 50% abortion rate, and the occurrence of abortion is more frequent in the first pregnancy. The contribution of multiple pregnancy, maternal age, and number of gonadotropin treatment cycles are also evaluated and discussed.

Monitoring of human menopausal gonadotropin (hMG) treatment for induction of ovulation according to either preovulatory estrogen levels or the presence of a dominant ovarian follicle was found insufficient to prevent ovarian hyperstimulation syndrome (OHS). In 65 infertile patients treated with hMG and human chorionic gonadotropin (hCG), a possible correlation between the number and size of all ovarian follicles on the day of assumed ovulation and the occurrence of OHS was evaluated in order to assess the value of ultrasonography in predicting OHS. It was found that patients with OHS had significantly more follicles at the time of hCG than patients without OHS. Mild OHS was characterized by the presence of eight to nine follicles, 68.7% of which were of intermediate size (9 to 15mm). In moderate to severe OHS 95% of the preovulatory follicles were<16mm, most of them (54.7%)<9mm in diameter. It can be concluded that a specific preovulatory follicular configuration characterizes mild and severe hyperstimulation. This is important information before hCG administration and emphasizes the value of ovarian ultrasonography in predicting OHS.

A prospective study of six unselected couples diagnosed as having unexplained infertility was done. In three of six patients, subtle abnormalities in follicular development were detected. In the first case poor follicular growth was observed. There was a premature small rise of luteinizing hormone (LH) with subsequent low levels of estradiol (E2) in the late follicular phase and unusual wide LH peak. This was followed by low progesterone levels in the luteal phase. In the second case follicular growth was abrupted by premature LH surge. This surge was triggered by early rise of E2level while the follicle was still small in size. In the third case luteinized unruptured follicle syndrome was diagnosed, on ultrasound examination. All of the abnormalities were repetitive.

Two hundred fifty-six children were born in 195 births from 176 women that conceived after human menopausal gonadotropin/human chorionic gonadotropin (hMG/hCG)-induced ovulation. The secondary sex ratio was 50% male to 50% female births, which is not statistically different from the Israeli or Occidental population. The same trend was observed for single births and for twins. Thus, the data presented do not support the reports of increased numbers of female infants in those conceived after induction of ovulation. Factors that are expected to have been shown to affect sex ratio: maternal age at delivery, total number of ampules of hMG/hCG administered in the conceptional cycle, urinary estrogen levels on the day of hCG injection, degree of ovarian hyperstimulation syndrome, and time of insemination in relation to the basal body temperature rise were found to be insignificant. Thus, the hypothesis that a local hormonal environment (gonadotropin or estrogen levels) during hMG/hCG treatment possibly affects sex selection was not confirmed.

Patients beginning an in vitro fertilization (IVF) treatment cycle were prospectively randomized in double-blind fashion to receive either follicle-stimulating hormone (FSH) (Metrodin, Serono Laboratories, Inc., Randolph, MA) (n=50) or human menopausal gonadotropin (hMG) (Pergonal, Serono) (n=48) in combination with clomephene citrate (CC) (Serophene, Serono). There were no statistically significant differences in the percentage of dropped cycles, follicular response as measured by serum estradiol or ultrasound imaging, cycle day for hCG administration, number of oocytes recovered, fertilization and cleavage rates of the recovered oocytes, or the rate of clinical pregnancy establishment. In conclusion, there were no clinically important differences between FSH and hMG when combined with CC for enhanced follicular recruitment for IVF. Therefore, there is no apparent justification for the use of FSH in CC combination regimens, considering FSH’s increased cost as compared with hMG.

Induction of ovulation is difficult to achieve in patients with PCOD when they are resistant to therapy with clomiphene citrate; moreover, treatment with human menopausal gonadotropins subjects the PCOD patient to the risk of mul- tifollicular ovulation and hyperstimulation. This article summarizes the hormonal picture and the initial therapeutic approach to the patient with PCOD. The proper administration, usage, and monitoring of conventional ovulation- inducing agents for these patients are discussed. Some of the newer approved agents that can be used in special patients who have not responded to conventional ovulation induction are also described.

The aim of the current study was to assess whether clomiphene citrate (CC) and/or active metabolites are present at presumed time of ovulation, nidation, or steroid-sensitive organogenesis, in serum of patients receiving CC for induction of ovulation. A radioreceptor assay, based on competitive replacement of 3H-estradiol on the rat uterus estrogen receptor, by ligands present in serum of patients after CC administration, was developed. Ligands reached maximal concentration 4 to 5 hours after a single dose of CC was administered, and declined with a half-life of 4.5 to 10 hours. In patients receiving CC on day 5 to day 9 in the cycle, ligands are still present on day 14 in the cycle and in some patients on day 22 of the cycle, but no ligands were detected 60 days after CC treatment.

Ten infertile menstruating women were treated with daily injections of gonadotropin-releasing hormone agonist (GnRH-a). The GnRH-a (Buserelin; Hoe 766, Hoechst-AG, Frankfurt/Main, West Germany) was administered subcutaneously (SC) from day 9 of the cycle for 6 days, and intranasally (1.2 mg) for 15 days. Before treatment, all ten women had a normal response to Buserelin challenge test and the GnRH test, and seven of the ten responded to estradiol (E2) benzoate test (2 mg intramuscularly). The SC administration ofBuserelin (1.5 mg) for 6 days resulted in suppression of pituitary activity. Continuous treatment with Buserelin (1.2 mg for 3 weeks) was effective as demonstrated by decreasing serum E2levels to below 20 pg/ml, and in the absence of ovarian follicles in ultrasonographic scanning. Three days after cessation of Buserelin treatment, the pituitary again responded to the GnRH test. Thus, the authors concluded that the administration of Buserelin in very high doses can induce medical hypophysectomy within 6 days, but over 3 weeks of suppression therapy are required to abolish ovarian findings. Desensitization of the pituitary was reversible within 3 days of cessation of the treatment.

The authors’ program for matched, anonymous oocyte donation has resulted in two successful pregnancies among the first eight oocyte recipients. All oocyte recipients to date have had ovarian failure or absence with premature ovarian failure the most common cause. All recipients were cycled on a program of incremental oral micronized estradiol and intramuscular progesterone-in-oil. Thirteen candidates for oocyte donation were screened to obtain 8 donors. One donor candidate was excluded because of her medical history. The psychological screening of 2 of the other donor candidates (who subsequently did not complete the donation cycle) revealed a primary motive of financial gain. In general, the psychological profiles of donor candidates revealed a high incidence of troubled families and either reproductive loss or loss of a parent. Ovarian stimulation of the donors followed our standard in vitro fertilization protocol. The recipients’ exogenous steroid replacement continued until days 97 and 101, respectively, of the two gestations. Both pregnancies resulted in the delivery of normal singleton males—the first at 40 weeks, the second at 35 weeks.

The anti-estrogenic effect of clomiphene citrate (CC) and tamoxifen (TMX) on cervical mucus was evaluated in a prospective crossover study. Ten women underwent randomized alternate cyclical treatment with either 100 mg CC, 40 mg TMX daily, or with placebo. The effect of CC, TMX and placebo on serum estradiol (E2), cervical mucus secretion and on the development of ovarian follicles was evaluated. Compared with placebo, treatment with CC and TMX significantly increased the number of mature ovarian follicles on the day of assumed ovulation (p <0.05), elevated E, secretion (p <0.05) and decreased cervical score (p <0.05). It can be concluded that anti-estrogenic agents reduced the secretion of cervical mucus. However, in most cases, the excessive E, production due to multiple follicular growth overcomes the anti-estrogenic effect.

One hundred fifty-six women with cycle disorders presenting as absence or infrequency of ovulation and with luteal phase deficiency (group II, according to the World Health Organization classification) received clomiphene citrate (CC) for ovulation induction. The administered dosage ranged from 50 to 250 mg/d. The follicular development in terms of numbers of small (<8 mm), intermediate (9 to 15 mm), and large (>15 mm) follicles and their distribution in either one or both ovaries on the day of assumed ovulation was related to the dosage of CC. A statistically significant increase was found in the total number of follicles in relation to the dosage of CC (P< 0.003). In view of the development of the mature follicles, the gradual increase in CC daily dosage was thought to be associated with additional mature follicles before ovulation. However, this increased follicular recruitment was not regarded as statistically significant. Treatment with low doses of CC resulted in follicular development in only one ovary, whereas increased follicular recruitment after high CC dosage was found in association with follicular development in both ovaries.

Twenty-six daughters born to amenorrheic women after gonadotropininduced ovulation were studied at 10 to 16 years of age. The aim of the study was to assess whether the mothers' condition, namely, amenorrhea and infertility followed by the pharmacologic induction of ovulation, had any effect on their female offspring in terms of endocrine disorders at puberty. The daughters were found to have normal onset of puberty as well as normal physical and mental development. The mean age at menarche, body weight, and height were similar to those of the general female population in Israel. A functioning hypothalamic-pituitary-ovarian axis was evidenced by the appearance of menarche followed by regular cycles. These data form a reassuring sample for the clinicians, the treated mothers, and their offspring.(JAMA 1983;250:3202-3204)