Sheila M. Pride

Relationship of gonadotropin-releasing hormone, danazol, and prostaglandin blockade to ovarian enlargement and ascites formation of the ovarian hyperstimulation syndrome in the rabbit

The effects of pharmacologic doses of gonadotropin-releasing hormone, danazol, and indomethacin on the clinical and endocrinologic features of the ovarian hyperstimulation syndrome were studied in the rabbit. The ovarian hyperstimulation syndrome was induced with Pergonal (75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) and a follicle-stimulating hormone-dominant gonadotropin preparation (85 IU of follicle-stimulating hormone and 53 IU of luteinizing hormone). None of the three agents tested were effective in suppressing the ovarian enlargement and ascites formation in these animals. Ascites developed despite quite significant variations in plasma and intraovarian sex steroid hormone and intraovarian prostaglandin F levels induced by danazol and indomethacin. Ascites develops in hyperstimulated women in association with both follicular and luteal hyperstimulation. In contrast, the ascites response in the hyperstimulated rabbit develops in the presence of follicular hyperstimulation alone without a significant degree of luteal hyperstimulation.

Clinical, endocrinologic, and intraovarian prostaglandin F responses to H-1 receptor blockade in the ovarian hyperstimulation syndrome: studies in the rabbit model.

The effects of chlorpheniramine maleate, an H-1 receptor blocker, on clinical and endocrinologic features and intraovarian prostaglandin F (PGF) content were assessed in the rabbit model of the ovarian hyperstimulation syndrome. H-1 receptor blockade prevented ascites, attenuated ovarian enlargement (2.68 +/- 0.37 gm versus 4.15 +/- 0.056 gm; p less than 0.05), and augmented intraovarian PGF content (8.4 +/- 0.84 versus 3.95 +/- 1.12 pg/mg protein; p less than 0.05). Steroidogenesis was unaffected. In the control group, in which weights remained stable, animals with minimal ascites (scores less than or equal to 2; n = 4) were compared to other control animals with a greater accumulation of fluid (scores greater than or equal to 3; n = 4). The former also exhibited lower ovarian weights (2.94 +/- 0.41 versus 5.35 +/- 0.59 gm; p less than 0.05) and higher PGF ovarian content (6.05 +/- 1.56 versus 1.8 +/- 0.75 pg/mg of protein; p less than 0.05). This triad of minimal ascites, lower ovarian weights, and elevated intraovarian PGF seen both in treated animals and in inherently more resistant control animals did not appear to depend on changes in body weight. The conclusion reached was that H-1 receptor blockade prevented ascites, reduced ovarian enlargement, and augmented PGF content but did not affect steroidogenesis. This protective effect of chlorpheniramine may be mediated at least in part by prostaglandins.

Successful induction of ovulation and conception with pulsatile intravenous administration of human menopausal gonadotropins in anovulatory infertile women resistant to clomiphene and pulsatile gonadotropin-releasing hormone therapy

Gonadotropins are released in a pulsatile fashion at a frequency of between 1 and 2 hours in the follicular phase of the menstrual cycle. Human menopausal gonadotropins are usually administered intramuscularly. We evaluated the gonadal response to intravenous human menopausal gonadotropins administered in a pulsatile fashion over nine treatment cycles in three anovulatory infertile women. Human menopausal gonadotropin pulses in doses up to 12 IU follicle-stimulating hormone at frequencies between 2 to 3 hours over 3 to 17 days resulted in ovulation in five cycles with one pregnancy being conceived. In the ovulatory cycles (5,000 to 10,000 IU of human chorionic gonadotropin was used to induce ovulation), the 17 beta-plasma estradiol level was 961 +/- 128 versus 326 +/- 95 pg/ml (mean +/- SEM) in the anovulatory cycles (p = 0.015). The dose of human menopausal gonadotropins (in ampules of Pergonal, 75 IU of follicle-stimulating hormone and 75 IU of luteinizing hormone) in the intravenous cycles needed to induce ovulation was 12.3 +/- 1.4 versus 20.4 +/- 0.9 for intramuscular cycles (n = 80 in 23 women, p = 0.008). Treatment was well tolerated and without complications. We are continuing to explore the use of this apparently more efficient mode of administering human menopausal gonadotropins to anovulatory patients resistant to other techniques of ovulation induction therapy.

Failure of ovulation induction with pulsatile gonadotropin-releasing hormone and human menopausal gonadotropins in isolated gonadotropin deficiency

A 30-year-old woman with primary amenorrhea, hypothalamic hypogonadism, decreased sense of smell, and primary infertility failed to respond to pulsatile exogenous gonadotropin-releasing hormone. In addition, failure to respond to stimulation with human menopausal gonadotropins was consistent with concomitant ovarian failure. Perturbation of normal cellular migration during embryogenesis in the regions of the olfactory placode, yolk sac, hindgut, and gonadal ridge may explain both the hypothalamic defect and ovarian failure experienced by this woman. She demonstrates that gonadal failure need not be accompanied by elevated gonadotropin levels; nor do low gonadotropin levels necessarily indicate potentially responsive ovaries. These findings are consistent with the coexistence of isolated gonadotropin deficiency and ovarian failure in the same individual.

The action of clomiphene in stress-induced amenorrhea

Seven women with stress-induced amenorrhea were challenged with metoclopramide, 10 mg intravenously, before and at the end of a course of clomiphene. Initial testing with luteinizing hormone releasing hormone demonstrated that all subjects had the capacity to release luteinizing hormone (LH), but in response to metoclopramide there was no increase in the levels of LH. This lack of response did not change after 5 days of clomiphene, although basal levels of LH and estradiol increased significantly. The pattern of response of prolactin to metoclopramide did not change after clomiphene. These results suggest that there is no significant dopamine-mediated inhibition of release of luteinizing hormone releasing hormone in women with stress-induced amenorrhea. The administration of clomiphene to these women does not appear primarily to alter hypothalamic dopaminergic activity.