An 18-yr-old woman with primary amenorrhea, anosmia, and total lack of secondary sexual development was treated for 230 days using sc pulsatile GnRH. GnRH testing with 100 micrograms, sc, initially revealed a peak FSH to LH ratio greater than 1. After 28 days of treatment, this ratio had reversed. A dosage of 20 micrograms/2 h for 200 days resulted in a LH to FSH ratio greater than 2. Widening the interval to 20 micrograms/3 h significantly lowered LH, but not FSH, levels. Increasing the frequency to 20 micrograms/90 min again increased the LH to FSH ratio. Twenty-four-hour testing revealed a sleep-entrained PRL rise both during and after GnRH therapy, but no sleep-entrained rise in LH. Ultrasound monitoring revealed cyclic changes in ovarian diameter at 30- to 60-day intervals that coincided with cyclic increases in LH and estradiol. The uterine fundus doubled in length between days 50 and 110 of treatment. The patient progressed from Tanner pubic hair and breast stage I to stage II during treatment, which was terminated due to an allergic reaction to GnRH. This study provides the first report of hormonal and ultrasound events surrounding puberty induction with GnRH in the female. We conclude widening the interval of GnRH administration can reduce LH levels while maintaining FSH levels, cyclic changes in ovarian diameter, LH, and estradiol occur before menarche, and although pulsatile GnRH provides a fascinating model for the study of puberty in the female, the chronicity of therapy needed and its potential for allergic reaction make this method of inducing puberty suboptimal.
INTRODUCTION: To evaluate the clinical efficacy of next-generation sequencing for carrier screening for professional society-recommended disorders across a range of ethnicities. It is often difficult to ascertain a patient's true race or ethnicity to determine the appropriate tests to offer. Consequently, a growing number of physicians offer screening for the same disorders to all patients, regardless of ethnicity. Traditional screening assays have reasonable detection rates in high-risk populations but are suboptimal for patients of low-risk or mixed ethnicities, resulting in a large number of low-risk patients receiving screening with low detection rates. In contrast, next-generation sequencing more accurately determines carrier status because it is not limited to a small mutation set. METHODS: Using next-generation sequencing, carrier status was evaluated by Good Start Genetics for up to 14 disorders, as ordered by physicians, for patients seen at several fertility centers across the country. RESULTS: A total of 4,894 patients from six in vitro fertilization centers were screened, representing a multitude of unique ethnicity combinations. A total of 196 disease-causing mutations were identified. Twelve percent of these mutations would not have been detected by traditional genotyping assays. Moreover, 43% of pathogenic mutations were found in patients who did not identify as the corresponding high-risk ethnicity. CONCLUSION: Carrier screening is often ordered outside of the ethnicity-based guidelines. In this cohort, next-generation sequencing found 84 carriers that did not identify as the “high-risk” ethnicity. Traditional genotyping assays are not sufficient in centers routinely testing individuals of all ethnicities. Next-generation sequencing provides a more comprehensive determination of carrier status regardless of patient ethnicity.
Recent work has suggested that a central deficiency or defect of dopamine may contribute significantly to the inappropriate gonadotropin secretion commonly associated with polycystic ovary disease. To evaluate this hypothesis, 2.5 to 5 mg of the dopamine agonist bromocriptine was administered daily to patients with polycystic ovary disease. Prolactin (PRL) levels were normal in all cases and there was no evidence of galactorrhea. All patients had failed to conceive while on clomiphene citrate. Seven patients were treated for a total of nine cycles. Ovulation occurred in four cycles, and two of these patients conceived. In five cycles, no ovulation occurred. Among ovulatory cycles, PRL levels declined, but not to undetectable levels. There was also a periovulatory drop in dehydroepiandrosterone sulfate. Levels of luteinizing hormones rose initially and then dropped to below baseline postovulation. Among anovulatory cycles, PRL fell to undetectable levels and dehydroepiandrosterone sulfate was unaffected. Luteinizing hormone levels rose initially and then dropped slightly. In both ovulatory and anovulatory cycles, follicle-stimulating hormone (FSH) levels remained low. These preliminary data suggest: 1) bromocriptine appears capable of altering gonadotropin secretion in polycystic ovary disease, and 2) variable results on ovulation in polycystic ovary disease may reflect the diverse etiology of the pathophysiology of polycystic ovary disease and/or choosing inappropriate dosages of bromocriptine.
This chapter will review the current approach to ovulation induction. Clomiphene citrate (CC) was first introduced in 1961 and is the most commonly prescribed medication for the infertile woman. Prolonged administration of CC through its anti-estrogenic action can diminish cervical mucus production and thin the endometrial lining, which could lower the chance of pregnancy. Many practitioners begin CC in anovulatory women following confirmation of a negative pregnancy test without inducing menses. Theoretically, it seems that CC would improve fecundity by increasing the number of eggs that are released at the time of ovulation and CC may correct subtle ovulatory dysfunction. Many women with polycystic ovary syndrome (PCOS) respond poorly to CC and have to be treated with injectable gonadotropins to induce ovulation, which is associated with a higher multiple pregnancy rate and greater chance of Ovarian hyperstimulation syndrome (OHSS).
