James R. Givens

Androgen parameters and their correlation with body weight in one hundred thirty-eight women thought to have hyperandrogenism

The first objective of this study was to determine which plasma androgen assay or combination of assays would be the most useful in documenting hyperandrogenism in women with hirsutism, acne, oligomenorrhea, or unexplained infertility. Plasma levels of androstenedione (A), total testosterone (T), and dehydroepiandrosterone sulfate (DHEAS) were measured and free T (FTc) was calculated from the measured total T and T-estradiol-binding globulin binding capacity (TeBG-BC) in 138 consecutive women referred to our clinic for hirsutism, acne, oligomenorrhea, and/or unexplained infertility. FTc was elevated in 82% and was most frequently elevated parameter. DHEAS was elevated in 59% of the women, and 93% were noted to have hyperandrogenemia on the basis of a combination of FTc and DHEAS levels. The second objective of this study was to determine whether there was significant correlation between the androgen parameters and any of the clinical features. Body weight was significantly negatively correlated with DHEAS and TeBG-BC in those women with a normal DHEAS level but not in those with an elevated level. A strong positive correlation (simple and partial) was noted between body weight and plasma T levels in the whole group of patients, as well as in those with a normal or an elevated DHEAS level. It is suggested that the relationship between T and body weight is multifaceted. Conceivably, T could influence body mass by effects on food intake or through alterations in intermediary metabolism.

Mumps Oophoritis: A Cause of Premature Menopause *

One cause of secondary oligomenorrhea is ovarian infection. A rare type of infection related to the disturbance of menstrual function is mumps oophoritis. Three patients with premature menopause presumably caused by this agent were described. In one patient the symptoms coincided with a subclinical infection during the perinatal period, with subsequent infertility. Another patient seemed to have had a clinically mild oophoritis during the pubertal period, and the third patient became symptomatic following parturition. It appears that this aberration in menstrual function and fertility may be related to the time during which the infection occurs as well as to the severity of the infection. In addition, it is apparent that mumps oophoritis may be a more frequent cause of premature menopause than has heen previously suspected.

The effectiveness of two oral contraceptives in suppressing plasma androstenedione, testosterone, LH, and FSH, and in stimulating plasma testosterone-binding capacity in hirsute women

The effectiveness of two oral contraceptives in suppressing plasma androstenedione (A), testosterone (T), LH, and FSH and in stimulating testosterone-estradiol-binding globulin (TeBG) was evaluated in 39 hirsute women. Twenty-seven hirsute women received norethindrone 2 mg.-mestranol 0.1 mg. (Group I) and 12 received norgestrel 0.5 mg.-ethinyl estradiol 0.05 mg. (Group II). Hormone assays were performed before treatment and at the end of 3 weeks of therapy. Ninety percent of the women in both groups had an elevated plasma A and/or T. During treatment, plasma A,T, LH, and FSH were significantly reduced in both groups (p less than 0.01). In Group I, 78% of the women had a normal plasma A and T during treatment. In Group II, 83% of the women had a normal A and T during treatment. There was a greater increase in TeBG in Group I (p less than 0.01). It is concluded that these two oral contraceptives effectively suppressed the hyperandrogenism of most of the hirsute women.

Familial Male Pseudohermaphroditism without Gynecomastia Due to Deficient Testicular 17-Ketosteroid Reductase Activity

Abstract To evaluate possible 17-ketosteroid reductase deficiency, we studied two sisters with primary amenorrhea, hirsutism, clitoral enlargement and a 46,XY karyotype, who lacked breast development. Plasma luteinizing hormone, follicle-stimulating hormone and urinary 17-ketosteroids were elevated in both subjects. Plasma Δ4-androstenedione was seven to nine times greater than normal, whereas plasma testosterone was low or in the low-normal male range. Spermatic venous plasma of Case 2 contained increased amounts of Δ4-androstenedione and estrone and subnormal amounts of testosterone and estradiol, findings consistent with testicular 17-ketosteroid reductase deficiency. In vitro incubation of testicular tissue of Case 2 confirmed a partial defect in testicular 17-ketosteroid reductase activity and documented increased 3β-hydroxysteroid dehydrogenase activity. Failure of breast development was probably due to lower estrogen levels than in previously reported cases. We conclude that testicular 17-ketostero...

Familial ovarian hyperthecosis: A study of two families☆☆☆

Abstract Two families containing 41 women with hirsutism and/or oligomenorrhea were studied. Ovarian histology of eight demonstrated hyperplasia of theca cells in atretic follicles, a paucity of primordial and developing follicles, and stromal hyperplasia. Elevated levels of androstenedione and/or testosterone and luteinizing hormone (LH) were found. Estradiol and follicle-stimulating hormone (FSH) were low. Following bilateral ovarian wedge resection, the LH and FSH levels of the proband of Family I were normal. Three men of Family I had low plasma testosterone and an abnormally high LH/FSH ratio similar to that of the women. Conclusions were: (1) Ovarian hyperthecosis can be inherited; (2) the inheritance is consistent with an autosomal dominant pattern, but X-linked inheritance cannot be ruled out if the males are excluded; (3) the abnormal LH/FSH ratio can serve as a biochemical marker; (4) ovarian wedge resection corrected the abnormal LH/FSH ratio in one case; and (5) ovarian hyperthecosis may be a type of gonadal dysgenesis.

Polycystic Ovarian Disease, Maturation Arrest of Spermiogenesis, and Klinefelter’s Syndrome in Siblings of a Family with Familial Hirsutism *

A family with hirsutism in five generations in which polycystic or bilaterally enlarged ovaries were documented in three different sibships of two generations is described. Two brothers of one of the women with polycystic ovaries had a low or low-normal plasma follicle-stimulating hormone level and one of these had oligospermia due to maturation arrest of spermiogenesis. A third brother had Klinefelters syndrome. Other abnormal features in the family included precocious adrenarche, beardless males, eunuchoidism, and prepubertal grand mal seizures.

Sensitivity of Pyruvate Dehydrogenase to Insulin in Activated T Lymphocytes: Lack of Responsiveness to Insulin in Patients With Polycystic Ovarian Disease and Diabetes

Using phytohemagglutinin-activated T lymphocytes, we studied possible mechanisms responsible for insulin resistance in patients with polycystic ovarian disease (PCO) and acanthosis nigricans (AN) by examining insulin binding to erythrocytes and activated T lymphocytes and T-lymphocyte pyruvate dehydrogenase (PDH) responsiveness to insulin in three groups. These groups of subjects consisted of six PCO-AN patients with normal glucose tolerance, six PCO-AN patients with mild non-insulin-dependent diabetes mellitus (NIDDM), and six weight-matched control subjects. We found that insulin binding to both erythrocytes and activated T lymphocytes was significantly lower in PCO and PCO-NIDDM patients than control subjects but did not differ between the PCO groups. Insulin binding to erythrocytes and T lymphocytes varied inversely with basal insulin. In activated T lymphocytes of PCO-NIDDM patients, PDH responsiveness to both submaximal and maximal insulin concentrations was impaired, the extent of which varied in proportion to their degree of carbohydrate intolerance. In contrast, PDH responsiveness to maximal amounts of insulin in T lymphocytes of PCO patients without NIDDM was similar to the weight-matched control subjects. These data may suggest that lesions at the level of the receptor are primarily responsible for insulin resistance in patients with PCO but that both receptor and postreceptor defects (i.e., PDH responsiveness to insulin) contribute to the insulin-resistant state of PCO patients with NIDDM.

Response of the binding capacity of plasma testosterone-estradiol-binding globulin to norethindrone, 2 mg., and mestranol, 0.1 mg., in polycystic ovarian disease☆

The binding capacity of plasma testosterone-estradiol-binding globulin (TeBG) and testosterone (T) levels were measured in four women with proved polycystic ovaries and three women with a clinical diagnosis of polycystic ovarian disease before, during, and after administration of norethindrone, 2 mg., and mestranol, 0.1 mg. (N + M)...

Enhanced post-receptor insulin effects in women following dehydroepiandrosterone infusion.

OBJECTIVE: We hypothesized that intravenous dehydroepiandrosterone (DHEA) would de crease insulin resistance in normal and insulin-resistant women. METHODS: Five insulin-resistant women diagnosed as having polycystic ovaries (PCO) with elevated testosterone and normal dehydroepiandrosterone sulfate (DHEAS) with amenorrhea were recruited. Obese controls (OC) with normal menses and normal testosterone and DHEAS were recruited and matched to each PCO woman for age and weight. The PCO women had a mean testosterone of 3.2 ± 0.4 nmol/L, fasting serum insulin level of 330 ± 55 pmol/L, and DHEAS level of 3.4 ± 1.3 μmol/L. An oral glucose tolerance test (OGTT) was performed at 8 AM after an overnightfast. A DHEA infusion (1 mg/hour for 17 hours) was begun at 6 PM and continued until the completion of the second OGTT performed the following morning at 8 AM. T-lympho cytes were drawn at 8 AM each morning. RESULTS: The DHEA infusion had no significant effect on any of the in vivo indices of insulin sensitivity, ie, basal and OGTT insulin, C-peptide, and ratios of insulin/glucose. In vitro, DHEA significantly increased insulin binding to T-lymphocytes of PCO women but caused no significant change in OC women. There was, however, marked enhancement of T-lymphocyte pyruvate dehydrogenase (PDH) activities in both groups of study subjects following DHEA. CONCLUSION: We conclude that a 17-hour infusion of DHEA enhanced T-lymphocyte insulin binding and PDH activity while producing no detectable improvements in in vivo indices of insulin sensitivity. (J Soc Gynecol Invest 1994;1:74-8)

In vitro studies on an hcg responsive, testosterone secreting adrenal cortical adenomal

Abstract Clinical and biochemical investigation of a virilized woman has shown an adrenal cortical adenoma to be the source of elevated plasma testosterone levels and to be responsive to gonadotropin administration in vivo (Givens et al.) (2). In the present study, the gonadotropin responsiveness and biosynthetic potential of the adenoma were evaluated in vitro . Incubation of minced adrenal tumor with hCG resulted in increased 14 C-acetate incorporation into pregnenolone, progesterone, dehydroepiandrosterone (DHA), androstenedione, and testosterone. Androstenedione and testosterone were the major products, accounting for 27% and 20% respectively of the total radio-activity added, when 3 H-pregnenolone was incubated with homogenized tissue. Estrogen synthesis was not observed in the tumor. The adenoma contained 9.0 μg/g testosterone and 1.9 μg/g androstenedione as determined by radio immunoassay. 17β-hydroxysteroid oxido-reductase was active in the adenoma. Androstenedione was reduced to testosterone at a rate of 0.6 μg/100mg/hr. Under the same conditions, reduction of estrone to estradiol was undetectable. The reductase activity was present in both the mitochondrial and microsomal fractions. NADPH was the required cofactor. When NADH was substituted, the rate was less than 10% of that with NADPH in both particulate fractions. The experimental results indicate the presence of steroid path-way(s) necessary to synthesize testosterone, and represent the first in vitro demonstration of gonadotropin sensitive steroidogenesis in an adrenal cortical adenoma.