Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome.

Hyperinsulinemia secondary to a poorly characterized disorder of insulin action is a feature of the polycystic ovary syndrome (PCO). However, controversy exists as to whether insulin resistance results from PCO or the obesity that is frequently associated with it. Thus, we determined in vivo insulin action on peripheral glucose utilization (M) and hepatic glucose production (HGP) with the euglycemic glucose-clamp technique in obese (n = 19) and nonobese (n = 10) PCO women and age- and body-composition-matched normal ovulatory women (n = 11 obese and n = 8 nonobese women). None had fasting hyperglycemia. Two obese PCO women had diabetes mellitus, established with an oral glucose tolerance test; no other women had impairment of glucose tolerance. However, the obese PCO women had significantly increased fasting and 2-h glucose levels after an oral glucose load and increased basal HGP compared with their body-composition-matched control group. There were statistically significant interactions between obesity and PCO in fasting glucose levels and basal HGP (P less than .05). Steady-state insulin levels of approximately 100 microU/ml were achieved during the clamp. Insulin-stimulated glucose utilization was significantly decreased in both PCO groups whether expressed per kilogram total weight (P less than .001) or per kilogram fat free mass (P less than .001) or when divided by the steady-state plasma insulin (l) level (M/l, P less than .001). There was residual HGP in 4 of 15 obese PCO, 0 of 11 obese normal, 2 of 10 nonobese PCO, and 0 of 8 nonobese normal women. The metabolic clearance rate of insulin did not differ in the four groups. We conclude that 1) PCO women have significant insulin resistance that is independent of obesity, changes in body composition, and impairment of glucose tolerance, 2) PCO and obesity have a synergistic deleterious effect on glucose tolerance, 3) hyperinsulinemia in PCO is not the result of decreased insulin clearance, and 4) PCO is associated with a unique disorder of insulin action.

Histopathological effects of exogenously administered testosterone in 19 female to male transsexuals.

The effects of exogenously administered testosterone were evaluated in a group of 19 female to male transsexuals who underwent bilateral salpingo-oophorectomy after a variable period of androgen therapy. The findings were compared to those in an age-matched group of 12 patients who underwent pelvic surgery for nonendocrine reasons. The most significant findings in the 19 androgen-treated female transsexuals was the finding of enlarged or borderline enlarged ovaries in 5 subjects. In addition, we found multiple cystic follicles in 17 patients (89.5%), diffuse ovarian stromal hyperplasia in 16 patients (84.2%), collagenization of the outer cortex in 13 patients, and 4) luteinization of stromal cells in 5 patients (26.3%). Findings consistent with polycystic ovaries were thus present in 13 of the 19 patients based on the presence of 3 of the above 4 findings. The data suggest that increased blood levels and presumably increased ovarian concentrations of testosterone may produce the morphological features of polycystic ovarian disease.

Normal plasma gonadotropin response to gonadotropin-releasing hormone after diethylstilbestrol priming in transsexual women.

Plasma LH and FSH responses to GnRH (100 micrograms, iv) were measured in four female transsexuals with normal ovulatory menstrual cycles before and after the administration of 2.0 mg diethylstilbestrol (DES) daily for 7 days. One normal ovulatory woman was also studied in the early follicular phase of the menstrual cycle. No difference was found in the augmented response of the four female transsexuals to GnRH after DES priming from that of the normal adult female. The augmented response to GnRH found in the female transsexuals after DES treatment provides evidence that hypothalamic-pituitary feedback control is normal in the female transsexuals studied.

Suppression of hyperandrogenism does not improve peripheral or hepatic insulin resistance in the polycystic ovary syndrome.

Women with the polycystic ovary syndrome (PCO) have significant insulin resistance and are at risk to develop noninsulin-dependent diabetes mellitus. It remains controversial, however, whether hyperandrogenism directly decreases insulin action. Hence, we performed 2-h euglycemic glucose (approximately 772 pmol/L steady state insulin levels) clamps in nine PCO women with insulin resistance basally and after the 12th week of therapy with a superagonist GnRH analog (40 micrograms every 8 h, sc). Diet, activity, and weight were kept constant. Despite significant decreases in plasma testosterone and androstenedione levels (both P less than 0.05), there was no significant change in insulin-mediated glucose disposal, plasma insulin levels, or hepatic glucose production. The sample size was adequate to detect a clinically significant change in insulin-stimulated glucose disposal (i.e. approximately 3.3 mumol/kg.min; P less than or equal to 0.05). We conclude that suppressing androgen levels into the normal range did not result in significant changes in insulin resistance in PCO. Thus, controlling hyperandrogenemia is not a clinically effective modality to improve insulin action and thereby decrease the risk of noninsulin-dependent diabetes in PCO.

Acanthosis Nigricans, insulin action, and hyperandrogenism: clinical, histological, and biochemical findings.

Acanthosis nigricans (AN) is a frequent clinical finding in hyperandrogenic women. Its presence has been used to subgroup such women. We performed this study in order to determine the actual histological prevalence of AN and its relationship to sex hormone levels and insulin action. Insulin-mediated glucose disposal was determined by the euglycemic clamp technique, and neck or axillary skin biopsies were graded blind for the presence and severity of AN in lean and obese women with the polycystic ovary syndrome (PCO) and in age- and weight-matched normal ovulatory controls. AN was present on clinical examination in 11 of 13 obese PCO, 3 of 6 lean PCO, 4 of 14 obese normal, and 0 of 4 lean normal women. AN was present on histological examination in 13 of 13 obese PCO, 5 of 6 lean PCO, 13 of 14 obese normal, and 1 of 4 lean normal women. The severity of histological AN was most highly correlated with insulin-mediated glucose disposal (r = -0.61; P less than 0.001) rather than fasting (r = 0.46; P less than 0.05) or glucose-stimulated insulin levels (r = 0.48; P less than 0.01). The only sex steroid correlated with histological AN was dehydroepiandrosterone sulfate (r = 0.46; P less than 0.01). We conclude that 1) clinical skin examination was very insensitive for detecting AN; 2) the best biochemical correlate of histological AN was decreased insulin action, rather than insulin or androgen levels per se; and 3) AN is a very common epiphenomenon of insulin resistance, and its clinical presence should not be used as a criterion for stratifying hyperandrogenic women.

Development of a health-related quality-of-life questionnaire (PCOSQ) for women with polycystic ovary syndrome (PCOS).

OBJECTIVE: To develop a self-administered questionnaire for measuring health-related quality of life (HRQL) in women with polycystic ovary syndrome (PCOS). METHODS: We identified a pool of 182 items potentially relevant to women with PCOS through semistructured interviews with PCOS patients, a survey of health professionals who worked closely with PCOS women, and a literature review. One hundred women with PCOS completed a questionnaire in which they told us whether the 182 items were relevant to them and, if so, how important the issue was in their daily lives. We included items endorsed by at least 50% of women in the analysis plus additional items considered crucial by clinicians and an important subgroup of patients in a factor analysis. We chose items for the final questionnaire taking into account both item impact (the frequency and importance of the items) and the results of the factor analysis. RESULTS: Over 50% of the women with PCOS labelled 47 items as important to them. Clinicians chose 5 additional items from the infertility domain, 4 of which were identified as important by women who were younger, less educated, married, and African-American. The Cattell's Scree plot from a factor analysis of these 51 items suggested 5 factors that made intuitive sense: emotions, body hair, weight, infertility, and menstrual problems. We chose the highest impact items from these 5 domains to construct a final questionnaire, the Polycystic Ovary Syndrome Questionnaire (PCOSQ), which includes a total of 26 items and takes 10-15 minutes to complete. CONCLUSIONS: We have used established principles to construct a questionnaire that promises to be useful in measuring health-related quality of life. The questionnaire should be tested prior to, or concurrent with, its use in randomized trials of new treatment approaches.

Evidence for association of polycystic ovary syndrome in caucasian women with a marker at the insulin receptor gene locus.

The polycystic ovary syndrome (PCOS) is one of the commonest female endocrinopathies affecting 5-10% of women of reproductive age. The disorder, characterized by chronic anovulation and signs of hyperandrogenism, results from a complex interaction between genetic predisposing factors and environmental triggers. We have studied 85 Caucasian PCOS patients and 87 age-matched Caucasian control women for associations with four candidate genes: follistatin, CYP19 (aromatase), CYP17a, and the insulin receptor (INSR). These genes were analyzed using microsatellite markers located near or inside the genes. We found that only the insulin receptor gene marker D19S884 was significantly associated with PCOS (p=0.006 and even after a conservative correction p=0.042). The INSR gene region was then fine mapped with an additional panel of 9 markers but only marker D19S884, located 1 cM telomeric to the INSR gene, was again associated with PCOS. In conclusion, our results suggested that a susceptibility gene for PCOS was located on chromosome 19p13.3 in the insulin receptor gene region. It remains to be determined if this susceptibility gene is the insulin receptor gene itself or a closely located gene. Since insulin stimulates androgen secretion by the ovarian stroma it is likely that INSR function in the ovary is involved in the genetic susceptibility ot PCOS.

Testicular steroidogenic response to human chorionic gonadotropin of fifteen male transsexuals on chronic estrogen treatment.

Fifteen transsexuals were prepared for surgery with estrogen treatment. The response to human chorionic gonadotropin (hCG) in the untreated state was similar to that of normal subjects when testosterone (T), estradiol-17 beta (E2), 17 alpha-hydroxyprogesterone (17 alpha-OHP), progesterone (P), 4-androstenedione (delta 4A), and dehydroepiandrosterone (DHA) were used as indices. Following estrogen therapy, plasma T, 17 alpha-OHP, and DHA levels were markedly reduced whereas delta 4A and P were not. In spite of the suppressive effects of estrogen, a good response to hCG was noted in such subjects in plasma levels of T, 17 alpha-OHP, and, to a lesser extent, delta 4A even after estrogen administration for 24 months. The high rates of 17 alpha-OHP to T induced by estrogen treatment is restored to normal by the administration of hCG.

Pituitary tumors and polycystic ovarian disease.

Three patients with polycystic ovarian disease and an associated pituitary tumor are described. Oligomenorrhea was present with galactorrhea in one patient, and amenorrhea was the presenting symptom in the other two. Diagnosis of the pituitary tumor was confirmed by computed tomography. Hyperprolactinemia (39.2 to 72.0 ng/ml) was present in two patients, both of whom responded promptly to the administration of bromocriptine. One nonhyperprolactinemic patient had an associated empty sella diagnosed with metrizamide cisternography. The literature of pituitary neoplasms in polycystic ovarian disease is reviewed and possible pathophysiology is discussed.

Pituitary tumors associated with hyperprolactinemia and polycystic ovarian disease.

Galactorrhea and hyperprolactinemia, or both, have been described in some patients with polycystic ovarian disease. Three patients who had had previous bilateral wedge resection of the ovaries and who manifested persistent amenorrhea were found to have elevated levels of serum prolactin (180 to 540 ng/ml) 5 to 10 years later. All three patients initially demonstrated moderate hirsutism and failed to experience withdrawal bleeding after administration of progesterone or clomiphene citrate. Polytomographic evidence suggestive of an intrasellar tumor was present when elevated serum prolactin levels were noted. (Routine sellar roentgenograms prior to wedge resection had been reported as normal.) Two of the three patients underwent transsphenoidal surgery with removal of an 8-mm diameter chromophobe adenoma in each instance. Although serum prolactin levels decreased to 32 and 102 ng/ml, respectively, amenorrhea has persisted with gradual cessation of galactorrhea over a 1- to 2-year follow-up period. Our experience with the reported three cases supports the conclusion that in some cases an association may exist between polycystic ovarian disease and prolactin-producing adenomas.

Chronic high-dosage androgen administration to ovulatory women does not alter adrenocortical steroidogenesis.

OBJECTIVE: To evaluate the role of chronic long-term exogenous androgen administration to normal ovulatory women on adrenal steroidogenesis. DESIGN: Prospective study of four consecutive female-to-male transsexuals before and during chronic testosterone (T) therapy. SETTING: Clinical Research Center of the Mount Sinai Medical Center. PATIENTS: Four female-to-male transsexuals were studied before and during 6 to 12 months of chronic T enanthate therapy for desired virilization. All four subjects were ovulatory before treatment. Adrenocorticotropic hormone (ACTH) testing was performed before, and 6 and 12 months of androgen therapy and various adrenal androgens as well as precursor:product pairs were evaluated as an index of specific adrenocortical biosynthetic defects. RESULTS: Baseline and 1 hour after 0.25 mg ACTH intravenously, adrenal androgen levels as well as adrenal precursor/product pairs demonstrated no difference before and during chronic T treatment. Studies included determinations of plasma 17-hydroxypregnenolone, 17-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, 11-deoxycortisol, and cortisol. CONCLUSION: It is concluded that chronic hypertestosteronemia does not alter adrenal steroidogenesis.

Dissociation of serum prolactin response to sequential thyrotropin-releasing hormone and chlorpromazine stimulation in patients with primary empty sella syndrome.

The presence of galactorrhea and/or hyperprolactinemia in patients with the primary empty sella syndrome (PESS) has been proposed to be of hypothalamic etiology. To further elucidate this possible mechanism, sequential testing of 19 subjects with PESS with 500 micrograms thyrotropin-releasing hormone (TRH), followed by the injection of 0.7 mg/kg chlorpromazine (CPZ) 150 minutes later, was compared with results obtained in 6 patients with idiopathic galactorrhea (IG) and 3 normal adult women in the early follicular phase of the menstrual cycle. The thyroid-stimulating hormone and prolactin (PRL) response to TRH was similar in all three groups. The mean maximal increase of serum PRL following CPZ, however, was 16.1 +/- 18.5 ng/ml (standard deviation) in the PESS group, whereas the mean maximal PRL response was 68.6 +/- 40.9 ng/ml in subjects with IG and 67.7 +/- 48.1 ng/ml in the seven normal women. The impaired responsiveness of CPZ in the PESS group was significant (P less than 0.05) when compared with the normal CPZ response in the other two groups. The results of this study suggest that patients with PESS may have hypothalamic dysfunction, and that sequential testing of subjects with TRH and CPZ may be of value in differentiating patients with PESS from those with IG.

Adrenocorticotropic hormone testing in idiopathic hirsutism and polycystic ovarian disease: a test of limited usefulness.

The plasma 17 alpha-hydroxyprogesterone (17-OHP) concentration was determined in the basal state and 60 minutes after cosyntropin, 0.25 mg, in 139 patients with idiopathic hirsutism (IH) and polycystic ovarian disease (PCOD). Although there was an increased response of 17-OHP in subjects with PCOD when compared with IH subjects, in no instance was stimulated 17-OHP abnormal in the presence of normal basal 17-OHP. Two subjects with 21-hydroxylase (21-OH) deficiency were discovered; both demonstrated elevated basal levels of 17-OHP. We therefore conclude that routine adrenocorticotropic hormone testing is not a useful tool in detecting 21-OH deficiency in hyperandrogenic women.

Oral contraceptive history as a risk indicator in patients with pituitary tumors with hyperprolactinemia: a case comparison study of twenty patients.

This report presents a retrospective case comparison study of 20 hyperprolactinemic patients with pituitary adenomas treated at the Mount Sinai Hospital (1976-1079). An association between oral contraceptive (OC) use and 20 subjects with pituitary tumors was substantiated using discordant paired analysis. The comparison group consisted of appendectomy patients admitted during the same time period and matched for sex and age. The estimated relative risk was 4.0 (P less than 0.025). This study suggests that there is a significant association between OC use and pituitary tumors associated with hyperprolactinemia.

PIP: A retrospective case-comparison study of 20 hyperprolactinemic patients with pituitary adenomas is presented. Cases were from the period 1976-1979. Using discordant paired analysis, an association between oral contraceptive use and 20 subjects with pituitary tumors was substantiated. For comparison, a group of appendectomy patients admitted during the same time period and matched for sex and age was studied. An estimated relative risk of 4 (P .025) was found based on this comparison, and it is concluded that a significant association between use of oral contraceptives and pituitary tumors associated with hyperprolactinemia is suggested.

Ultrasonographic study of ovaries of 19 women with weight loss-related hypothalamic oligo-amenorrhea.

A study of 19 nonhirsute women with weight loss-related hypothalamic oligo-amenorrhea revealed evidence of multifollicular ovaries in 17. Enlarged ovaries greater than 10 cm3 were found in 8 of these subjects (42.1%). High-resolution real-time ultrasonography of the pelvis of 19 weight loss-related oligo-amenorrheic subjects revealed a mean +/- SD maximum ovarian volume (MOV) of 11.8 +/- 7.0 cm3, which was significantly different from those of control subjects whose mean +/- SD MOV was 5.2 +/- 1.9 cm3 (P = less than 0.001). The data do not allow a specific ultrasonographic distinction between hyperandrogenic women with polycystic ovarian disease and women with weight loss-related hypothalamic amenorrhea.

Polycystic ovary syndrome: clinical perspectives and management.

The polycystic ovary syndrome (PCOS) is a common hyperandrogenic disorder and is characterized by a constellation of signs and symptoms often in association with a family history of hyperandrogenism and/or PCOS. It is often associated with hyperinsulinism and insulin resistance, which puts patients at risk for possible potential complications including type 2 diabetes mellitus and cardiovascular disease. Clinical signs may be subtle, and biochemical markers most often include an elevation of free testosterone (T) and possibly dehydroepiandrosterone sulfate (DHEAS). The diagnosis should be sought in any woman with hyperandrogenic features so that appropriate treatment may be used. There is often a good therapeutic response of the hirsutism, acne, or oligomenorrhea associated with PCOS. The new modalities that increase insulin sensitivity as well as weight reduction in the obese woman with PCOS may potentially be useful in modifying the potential later complications of this common endocrinopathy of young adult women.

Cerebellar tumor causing hypertensive crisis and simulating pheochromocytoma and Cushing's syndrome.

We describe a case of posterior fossa medulloblastoma in which the initial symptom was severe hypertension that evolved into a hypertensive crisis. Initial diagnostic evaluation was suggestive of both pheochromocytoma and Cushing's syndrome: elevated plasma norepinephrine and urine VMA, normal ACTH level with elevated plasma and urine cortisol, and lack of suppressibility with dexamethasone. CAT scan and cerebral angiogram subsequently revealed the presence of an intracranial mass. After surgical removal of the tumor, blood pressure pattern and endocrine abnormalities reverted to normal.

Hyperthyroidism in patients treated with lithium: report of nine cases.

Nine cases of hyperthyroidism which developed in patients on lithium therapy are presented and analyzed and the literature is briefly reviewed. The findings strongly suggest that lithium therapy does not cause hyperthyroidism.

Use of insulin-sensitizing agents in patients with polycystic ovary syndrome.

OBJECTIVE: To review the subject of polycystic ovary syndrome and the therapeutic use of insulin-sensitizing agents in patients with this endocrinopathy. METHODS: We present background information on this disorder and summarize the pertinent published literature. RESULTS: Polycystic ovary syndrome affects approximately 7.5% of reproductive-age women in the United States. Although specific diagnostic criteria for this condition have not been established, the presence of three major factors-chronic anovulation, hyperandrogenemia, and clinical signs of hyperandrogenism-has been proposed as essential for consideration of the diagnosis. A high ratio of serum luteinizing hormone to follicle-stimulating hormone is found in 60 to 75% of women with this syndrome. Treatment with metformin may yield heterogeneous responses in differing populations with polycystic ovary syndrome, but most studies have shown evidence of restoration of ovulatory cycling. In addition, weight loss and decreases in free and total testosterone levels have been reported. Troglitazone therapy proved somewhat less efficacious than metformin for restoring menstrual cycles and similar to metformin in producing hormonal responses. Because troglitazone is no longer available for clinical use, studies will need to be extended to other thiazolidinediones. Patients treated with another insulin sensitizer, D-chiro-inositol, have demonstrated improved insulin sensitivity, ovulatory rates, and biochemical findings. CONCLUSION: Current evidence suggests that the use of insulin-sensitizing agents in patients with polycystic ovary syndrome not only improves their sensitivity to the effects of insulin on glucose and lipid metabolism but also ameliorates clinical and biochemical manifestations of hyperandrogenism and increases rates of ovulation. Multicenter studies with larger numbers of patients are needed.

Refractory biventricular heart failure in secondary hemochromatosis.

Cardiac hemochromatosis usually presents with clinical congestive heart failure and an enlarged heart. A woman with secondary hemochromatosis and features of both restrictive and congestive cardiomyopathy with a normal sized heart is described. Despite all interventions she had progressive cardiac impairment and expired eight days following presentation. The clinical and laboratory findings of 49 cases of cardiac hemochromatosis during the last 50 years are reviewed. While the disease usually progresses slowly, a significant minority die within fourteen days of recognition. Not infrequently pericardial tamponade is entertained as a cause for this rapid deterioration; however, both a restrictive and congestive cardiomyopathy appear to be responsible for this catastrophic presentation.