Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss.

BACKGROUND: Recurrent fetal loss has been well described in women with antiphospholipid antibodies. Such women also often have other autoantibodies commonly found in patients with systemic lupus erythematosus. Treating them with prednisone and aspirin may reduce the risk of fetal loss. METHODS: We screened 773 nonpregnant women who had the unexplained loss of at least two fetuses for antinuclear, anti-DNA, antilymphocyte, and anticardiolipin antibodies and for the lupus anticoagulant. Of 385 women with at least one autoantibody, 202 who later became pregnant were randomly assigned in equal numbers to receive either prednisone (0.5 to 0.8 mg per kilogram of body weight per day) and aspirin (100 mg per day) or placebo for the duration of the pregnancy. The women were stratified according to age (18 to 34 years or 35 to 39 years) and the week of gestation at which the previous fetal losses had occurred (< or = 12 or > 12 weeks). The primary outcome measure was a successful pregnancy. RESULTS: Live infants were born to 66 women in the treatment group (65 percent) and 57 women in the placebo group (56 percent, P=0.19). More infants were born prematurely in the treatment group than in the placebo group (62 percent vs. 12 percent, P<0.001). The major side effects of therapy in the mothers were hypertension (treatment group, 13 percent; placebo group, 5 percent; P=0.05) and diabetes mellitus (15 percent and 5 percent, P=0.02). CONCLUSIONS: Treating women who have autoantibodies and recurrent fetal loss with prednisone and aspirin is not effective in promoting live birth, and it increases the risk of prematurity.

Biological effects of various doses of vaginally administered conjugated equine estrogens in postmenopausal women.

To determine whether vaginal administration of conjugated equine estrogens (VCE) could provide physiological replacement while avoiding effects on hepatic function, as occurs with oral administration, a study was conducted in which 20 postmenopausal women were evaluated before and after the vaginal administration of CE. The dosages studied were 0.3, 0.625, 1.25, and 2.5 mg/day for 4 weeks. Twenty premenopausal women were also studied, and their values were presumed to reflect normal physiological function. The findings in the postmenopausal women were compared with previously reported results obtained in a similar group of subjects given oral CE (OCE). Vaginal cytology returned to premenopausal values with 0.3 mg VCE. This response was similar to that exerted with 1.25 mg OCE. Stepwise increases in circulating estrone and estradiol occurred with increasing dosages. The 2.5-mg dosage of VCE raised estrone levels to values similar to those in premenopausal women in the late follicular phase, and estradiol concentrations were similar to early follicular phase concentrations. Limited or no responses of the systemic markers of estrogen action occurred with all doses of VCE. Small decreases in LH and FSH levels occurred, but no dosage significantly reduced the level of either gonadotropin. Although the urinary calcium to creatinine ratio was significantly reduced by the two largest dosages of VCE, the effect of the 2.5-mg dosage was less than that observed with 0.625 mg OCE, the lowest dosage that protects against osteoporosis. Hepatic protein synthesis was significantly increased only by the higher dosages tested. No dosage had a significant effect on circulating levels of triglycerides or total or fractionated cholesterol levels. These data suggest that the vaginal administration of CE exerts mainly a local effect, with limited or no measurable changes in systemic markers of the action of estrogen.

HLA genotyping in family members and patients with familial polycystic ovarian disease.

To determine whether the familial occurrence of polycystic ovarian disease (PCO) is related to the major histocompatibility complex (HLA), four families in whom at least two siblings had clinical evidence of disease were examined. The diagnosis of PCO was confirmed by increased serum testosterone, androstenedione, and LH levels compared to those in normal women. Elevated concentrations of dehydroepiandrosterone sulfate indicated excess adrenal androgen secretion. The result of HLA genotyping in the families studied demonstrate that PCO does not exhibit linkage to the HLA system.

Biologic effects of various doses of ethinyl estradiol in postmenopausal women.

To determine which dosage of estrogen might provide physiologic replacement while minimizing adverse effects, 20 postmenopausal women were studied before and after oral administration of ethinyl estradiol. Twenty premenopausal women studied in the early and late follicular phases of the menstrual cycle were presumed to reflect normal physiologic function. Variable responses of the different biochemical and biologic markers to the actions of ethinyl estradiol were observed. Liver protein synthesis was the most sensitive measure of the action of ethinyl estradiol. In comparing the relative potencies of ethinyl estradiol with previously reported results observed with the usage of conjugated equine estrogens, the actions of 10 micrograms ethinyl estradiol were approximately equivalent to the biologic effects of 1.25 mg conjugated estrogens. The results suggest that ethinyl estradiol is far more potent than previously believed and that the daily administration of 10 micrograms, a dose lower than currently available commercial preparations, may be adequate for relief of symptoms of vaginal atrophy and may provide protection from the occurrence of osteoporotic fractures.

Circulating levels of plasma adrenocorticotropin in polycystic ovary disease.

Excessive adrenal androgen production contributes to hyperandrogenism in polycystic ovarian disease (PCO). This study was performed to determine the concentration of basal plasma ACTH in PCO patients and normal women and correlate its level with that of circulating adrenal androgen. In PCO patients, significant increases in serum testosterone, androstenedione, and dehydroepiandrosterone sulfate were noted compared to levels in normal women. The mean circulating plasma ACTH in PCO patients (22 +/- 2 pg/ml) was not different from that in normal controls (20 +/- 2 pg/ml). The mean ratio of dehydroepiandrosterone sulfate to ACTH in individual PCO patients was significantly greater than that in normal subjects, whereas the cortisol to ACTH ratio was similar in both groups. These results suggest that increased adrenal androgen production in PCO patients is not due to abnormal ACTH secretion but arises from either altered adrenal responsiveness to ACTH or abnormal adrenal stimulation by a factor(s) other than ACTH.

Enhanced disparity of gonadotropin secretion by estrone in women with polycystic ovarian disease.

The disassociation between serum LH and FSH levels in polycystic ovarian disease (PCO) has been attributed to chronic acyclic estrogen production characterized by a predominance of circulating estrone (E1). This study was designed to determine whether the administration of estrone benzoate (E1B) modulates gonadotropin release in PCO. In five normal women studied during the early follicular phase of a control and subsequent treatment cycle, daily LH and FSH levels were unaltered by E1B administered from days 2 to 6. Gonadotropin responses to LRF given on day 7 were similar during control and treatment cycles. In seven patients with PCO, the mean LH concentration (25.7 +/- 0.7 mIU/ml) and the daily pattern of release were unchanged by E1B administered for 14 days. In contrast, a progressive decline in FSH occurred in each subject. Mean FSH levels decreased significantly from a pretreatment value of 11.3 +/- 0.2 to 9.3 +/- 0.9 mIU/ml by day 2 (P less than 0.05) and 7.2 +/- 1.2 mIU/ml by day 14 (P less than 0.005) of E1B administration. The LH response to LRF in PCO was significantly greater than that observed in the normal subjects, whereas responses before, during, and after E1B administration were similar. The FSH responses to LRF in PCO subjects were comparable to those of the normal subjects. These data indicate that the administration of E1B to PCO subjects reduces FSH levels without altering LH release, thereby enhancing the disparity of gonadotropin secretion encountered in this syndrome. This finding is consistent with the hypothesis that impairment of FSH release by chronic acyclic estrogen production derived from nonglandular aromatization of circulating androgen could in large part be responsible for anovulation in PCO.

Steroid secretion by masculinizing and "feminizing" Hilus cell tumors.

The clinical course, histology, and steroid secretion observed in two patients with hilus cell tumors are presented. One patient had signs of virilism and the other had estrogenic signs only. Steroid secretion was examined by measuring peripheral and ovarian venous gradients and pre- and postoperative levels of hormones to explain the profound differences in the biological effects exerted by the neoplasms. In the patient with virilism, the tumor's major secretory product was testosterone (T), and the dominant biosynthetic pathway was pregnenolone (Pe) leads to 17-hydroxypregnenolone leads to 17-hydroxyprogesterone leads to androstenedione (delta) leads to T. In the patient with estrogenic signs, the major secretory product was delta, derived from a similar pathway of pregnenolone leads to 17-hydroxypregnenolone leads to 17-hydroxyprogesterone leads to delta. Circulating estrone and estradiol levels were elevated, but the tumor showed limited aromatase activity, as reflected by 60- to 1500-fold larger peripheral-ovarian venous gradients of delta and T than estrone and estradiol. The high circulating estrogen levels mainly arose from the peripheral aromatization of the increased secretion of delta by the tumor. It was concluded that a similar steroidogenic pathway was employed by both tumors. The predominant secretion by the neoplasm of either T of delta was determined by the presence and the oxidation reduction equilibrium of the 17 beta-dehydrogenase enzyme. The action of this enzyme resulted in profound differences in the biological effects exerted by these tumors.