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.

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.

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.

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.

Endocrine therapy of transsexualism and potential complications of long-term treatment.

Physiological principles of the interrelationship of sex hormones and their regulation are the foundation of understanding appropriate treatment of the transsexual patient. While both genetic males and females have estrogens and androgens, the quantitative sex hormone production is genetically predetermined by sex hormone production both in the gonads and via peripheral conversion of hormone precursors to sex steroids. Sex hormones exert a negative feedback on the hypothalamus and pituitary gland whereby gonadotropin-releasing hormone (GnRH), pituitary luteinizing hormone (LH), and follicle-stimulating hormone (FSH) are regulated or suppressed by the endogenous levels of these hormones. Sex hormonal therapy induces attenuated GnRH stimulation of LH and FSH causing a reduction of serum sex hormone levels. It is clear that estrogen as well as androgen therapy have a dual role: (i) induction of feminization or virilization and (ii) suppression of the hypothalamic-pituitary-gonadal axis leading to a reduction of endogenous estradiol or testosterone secretion. Cross-sex hormonal treatment may have substantial medical side effects. The smallest dosage of hormonal therapy compatible with the above clinical aims should be used.

Micronodulation: ultrasonographic sign of Hashimoto thyroiditis.

The purpose of this work is to assess the validity of an ultrasonographic sign, micronodulation, in the diagnosis of Hashimoto thyroiditis. Among 101 patients found to have ultrasonographic features of micronodulation, 57 patients had autoantibody test results available. Fifty-four patients were positive and three were negative for the autoantibodies. Therefore, the positive predictive value for micronodulation in diagnosing Hashimoto thyroitis is 94.7%. The micronodules were 0.1 to 0.65 cm in size, hypoechoic, and surrounded by an echogenic rim. This corresponds to accentuated lobulation on the pathologic specimen. Although micronodulation is highly diagnostic of Hashimoto thyroiditis, the ultrasonographic features of eight biopsy-proved masses caused by Hashimoto thyroiditis varied and were not specific for the disease.

Müllerian remnants in complete androgen insensitivity syndrome.

Patients with complete androgen insensitivity syndrome rarely have Müllerian remnants. A patient with this syndrome found to have a microscopic fallopian tube at the time of gonadectomy is described and possible etiologies for the finding are discussed.

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.

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.

Gestational diabetes and neonatal macrosomia in the polycystic ovary syndrome.

Since patients with polycystic ovary syndrome (PCOS) commonly have insulin resistance, albeit with normal glucose tolerance, we evaluated glucose tolerance in PCOS patients exposed to the diabetogenic effect of pregnancy. The clinical material was obtained from two centers, in Springfield, Illinois (22 patients), and New York, New York (31 patients), and the results were compared with a control population with 2,306 consecutive general pregnancies. There were no differences between PCOS patients from the two centers in regard to age or ponderal index (P greater than .1). A review of the medical records showed that the incidence of gestational diabetes in the PCOS patients was 7.5%, similar (P greater than .1) to the 6.6% frequency of gestational diabetes in the controls. The overall incidence of neonatal macrosomia (birth weight greater than 4,000 g) was 7% (4 of 57) among infants born to PCOS women. That was similar to the 12.4% incidence of neonatal macrosomia among infants born to women with normal glucose tolerance and to the 14.5% incidence among infants born to women with gestational diabetes. Preexisting PCOS does not appear to increase the risk of developing gestational diabetes or neonatal macrosomia.

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.

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.

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.

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.

The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia.

Endocrine dysfunction was studied in 109 consecutive female patients with moderate to severe alopecia, mostly of a diffuse pattern. The study included an evaluation of associated hirsutism and/or menstrual dysfunction, plasma hormonal measurements, and ultrasonography of the ovaries. A control group of 24 ovulatory, nonhirsute, nonalopecia individuals was also studied. Of the 109 patients, 70 (64.2%) had no clinical evidence of hirsutism or menstrual dysfunction. Two of 44 patients tested with cosyntropin (Cortrosyn) had 21-hydroxylase deficiency, whereas two other patients had hyperprolactinemia caused by pituitary tumors. Hyperandrogenism was defined as an increase in any of the plasma androgens (testosterone, non-sex hormone-binding globulin bound testosterone, dehydroepiandrosterone sulfate, androstenedione, or dihydrotestosterone) and was noted in 42 of the 109 patients studied (38.5%). Of these 42 patients, 11 were ovulatory with no evidence of clinical hirsutism, 13 were ovulatory and hirsute, and 18 had oligomenorrhea or amenorrhea with or without hirsutism with confirmatory evidence of polycystic ovarian disease. Patients with diffuse alopecia may demonstrate hyperandrogenism, even in the absence of hirsutism, oligomenorrhea, or amenorrhea. The most common endocrine disorder in this series of patients with diffuse alopecia was polycystic ovarian disease.

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.

Lack of correlation of ultrasonographically determined ovarian size with age, ponderal index, and hormonal factors in 45 patients with polycystic ovarian disease.

An ultrasonographic study was performed on 45 patients with polycystic ovarian disease. These patients demonstrated hirsutism, menstrual disturbances, or infertility, as well as an increased LH/FSH ratio and/or evidence of hyperandrogenemia. Ovarian size was not correlated with age, Ponderal Index, serum testosterone, prolactin, androstenedione, dehydroepiandrosterone sulfate or LH/FSH ratio in the 45 subjects studied.