Clifford A. Walters

A randomized study of dexamethasone in ovulation induction with clomiphene citrate

Improved understanding of follicular dynamics has led to a reevaluation of suppression of adrenal androgens in ovulation induction. To test whether adrenal suppression during clomiphene citrate (CC) therapy would improve ovulation/pregnancy rates, 64 anovulatory patients who had not previously received CC were randomly assigned to receive either 50 mg CC on days 5 to 9 alone or with 0.5 mg dexamethasone (CC + DEX). Patients were then screened for dehydroepiandrosterone sulfate (DHEA-S) (normal range, 80 to 320 micrograms/dl), prolactin, testosterone, and semen analysis of the partner. Nine patients discontinued participation prior to completing the first treatment cycle, and ten patients were found to have either elevated prolactin (4), severe male factors (3), or tubal disease (3) and were discontinued. CC was increased 50 mg/day per cycle through 150 mg/day until ovulation occurred. Once the patient was ovulatory on therapy, a properly timed postcoital test and endometrial biopsy for luteal phase defect were performed. If anovulatory at 150 mg/day of CC or demonstrating abnormal postcoital test or endometrial biopsy at 150 mg/day of CC, patients were crossed to the other arm of the treatment protocol. The results revealed a significantly higher rate of ovulation (P less than 0.01) and conception (P less than 0.05) in the CC + DEX-treated group. When correlated with DHEA-S levels, this improvement occurred in patients with DHEA-S greater than 200 micrograms/dl (P less than 0.05).

Endometrial biopsy during treatment of luteal phase defects is predictive of therapeutic outcome

Luteal phase deficiency (LPD), as diagnosed by endometrial biopsy, is not a single disorder but rather a spectrum of dysfunction that reflects both endometrial cycle and ovarian cycle abnormalities. Forty-three patients were diagnosed as having LPD by two consecutive abnormal cycles. Seven patients (16%) with hyperprolactinemia received bromocriptine, and one hypothyroid patient received thyroid replacement. The remaining patients were treated sequentially with progesterone suppositories, clomiphene, the combination, and follicle-stimulating hormone and luteinizing hormone. If no conception occurred in 6 months on a given type of therapy, treatment was advanced. Patients were rebiopsied on each medication. In all, 33 of 41 (81%) compliant patients conceived. No viable pregnancies occurred without normal endometrial maturation, regardless of the treatment modality employed. When compared with time-life table projections, pregnancies occurred at rates comparable to those of a normal population once normal endometrial maturation was obtained with therapy. The endometrial biopsy accurately reflects the functional state of both the ovarian cycle and the endometrial cycle and can be used to determine adequacy of therapy, thereby improving conception rates in patients with LPD and eliminating the need for therapeutic trials.

Hysteroscopic metroplasty: surgical technique and obstetric outcome

Congenital Müllerian abnormalities, particularly the septate uterus, may result in recurrent abortion or premature labor. Twenty-five patients found to have a septate uterus during evaluation for infertility or recurrent abortion were treated by hysteroscopic metroplasty with laparoscopic visualization. Surgical outcome was excellent, intraoperative and postoperative morbidity was negligible, and the postoperative course was similar to that following laparoscopy alone. Preoperative fetal wastage in 17 previously fertile patients was 90%. Of 11 patients, 6 or more months postoperatively, 10 had conceived: 5 delivered vaginally at term, 2 delivered by cesarean section, and 2 pregnancies are in progress. One pregnancy miscarried at 21 weeks secondary to an incompetent cervix. With hysteroscopic metroplasty, septa can be incised successfully with lower morbidity and as good a surgical outcome as with abdominal procedures. If further studies confirm the pregnancy outcome reported, then hysteroscopic metroplasty should become the treatment of choice for the septate uterus.

Human myometrium: A new potential source of prolactin

Human myometrium is shown for the first time to produce prolactin in vitro. This prolactin is similar to pituitary prolactin by criteria of immunologic identity, gel chromatography and bioassay. The de novo synthesis of myometrical prolactin is supported by no detectable prolactin in initial tissue homogenate, nondetectable prolactin production during the first 24 hours of culture, cycloheximide inhibition of prolactin production with recovery of production in control medium, and tritiated leucine incorporation into prolactin. Although human myometrium is capable of producing prolactin without the addition of exogenous hormones, the addition of estrogen and progesterone, respectively, enhances and suppresses prolactin production in contrast to decidualized human endometrium where opposite effects on prolactin production are found.

Prolactin production from proliferative phase leiomyoma

In vivo and in vitro endometrial stromal synthesis of prolactin occurs after progesterone-induced decidualization. Synthesis of prolactin by myometrium in vitro suggests that cells whose embryologic origin is the loose mesenchyme surrounding the paramesonephric ducts may retain the capacity to synthesize prolactin. Since physiologic myometrial synthesis of prolactin has not been demonstrated in vivo, prolactin genome expression in pathologic conditions was considered. Follicular phase leiomyomas were diced to 8 mm3 and cultured in Dulbeccos modified Eagles medium (DMEM) with either no hormones, estradiol 200 pg/ml, progesterone 20 ng/ml, or estradiol and progesterone. Media were sampled and changed every other day for 8 days, followed by culture in tritium-labeled leucine DMEM for 2 days. Portions of leiomyomas were homogenized for initial prolactin content, and all samples were assayed for prolactin by radioimmunoassay. Follicular phase leiomyomas contained prolactin (47 +/- 15 ng/gm) in excess of normal serum values. Synthesis was demonstrated during all time periods from leiomyomas not exposed to progesterone. Progesterone variably suppressed the synthesis of prolactin until after 144 hours of culture. Determination of molecular weight on a 60 by 1.5 cm Sephadex G-100 column revealed identical estimates for pituitary, decidual, and leiomyoma prolactin. Tritium-labeled leucine incorporation into prolactin was confirmed by immunoprecipitation of Sephadex G-100 column fractions. Similar antigenicity was confirmed by parallel dilution curves for pituitary, decidual, and leiomyoma prolactin. Preliminary bioactivity in lymphoma proliferation assays confirmed prolactin activity. The conclusion reached was that proliferative phase leiomyomas contained elevated prolactin presumably secondary to in vivo synthesis. This synthesis was confirmed in vitro.

Ultrasonographic assessment of luteinized unruptured follicle syndrome in unexplained infertility

Ultrasound can be used to monitor the growth and rupture of the dominant follicle. Thirty-three patients with unexplained infertility underwent serial sonography (mean, 3.2 scans/cycle) for luteinized unruptured follicle syndrome (LUFS). The incidence of LUFS was 9% (three patients) in the initial scan cycle. Three patients (9%) demonstrated rupture of a follicle significantly smaller than the mean (22.1 mm) (z less than 0.01) in the initial scan cycle. At standard radiology fees (

Prolactin production by explants of normal, luteal phase defective, and corrected luteal phase defective late secretory endometrium

7000 +/ diagnosed LUFS) the cost/benefit ratio of this method of diagnosis will be controversial. It is suggested that scanning at reduced fees in the gynecologists office, particularly in conjunction with postcoital tests, would decrease cost and increase the potential benefit.

The Neglected Laboratory Test The Semen Analysis

The production of prolactin by explants of late secretory endometrium has been correlated with the extent of decidual differentiation. This correlation is strengthened by the observation that luteal phase defective endometrium produces less prolactin than normal control endometrium in a 24-hour in vitro culture system. In the present study the prolactin production by explants of normal, luteal phase defective, progesterone-corrected luteal phase defective, and clomiphene- or follicle-stimulating hormone/luteinizing hormone-corrected luteal phase defective late secretory endometrium was measured over 96 hours at 24-hour intervals. Progesterone in physiologic concentrations was added to the culture medium to maintain tissue integrity and prolactin synthesis. The prolactin production of normal late secretory endometrium rose over 96 hours under progesterone stimulation. The luteal phase defective endometrium produced significantly less prolactin under the same conditions. Histologically proven corrected luteal phase defective endometrium, regardless of treatment method, produced prolactin not different from the normal controls of the same dates. From these results it is concluded that histologic correction of luteal phase defective endometrium is associated with a corresponding biochemical correction with use of prolactin as a metabolic marker. The findings also strongly support timed endometrial biopsy as the method of diagnosis and evaluation of treatment of luteal phase defect.