Manubai Nagamani

Treatment of menopausal hot flashes with transdermal administration of clonidine

A randomized prospective double-blind study was performed to evaluate the efficacy of a transdermal therapeutic system delivering clonidine in the treatment of menopausal hot flashes. Frequency, severity and duration of the flushing attacks before and during the 8-week treatment period were evaluated. The reduction in the number of hot flashes was highly significant in patients receiving the clonidine transdermal therapeutic system. On subjective comparison of flushing attacks before and during treatment, of the 15 patients who received the clonidine transdermal therapeutic system, 80% reported fewer hot flashes; 73% a decrease in severity; and 67% a decrease in duration. Among the 14 patients who were treated with placebo only, 36% reported fewer hot flashes; 29% a decrease in severity; and 21%, shorter duration (frequency, p less than 0.04; severity, p less than 0.04; and duration, p less than 0.03). Reported side effects were minimal, and no significant effect was observed on blood pressure or pulse rate. Transdermal clonidine therapy had no effect on the pulsatile luteinizing hormone secretion.

Acanthosis Nigricans as a Risk Factor for Non-Insulin Dependent Diabetes Mellitus

The prevalences of obesity and of non-insulin dependent diabetes mellitus (NIDDM) have increased in the United States population over the past two decades, and thus diabetes preven tion has become a major concern of public health agencies such as the National Institutes of Health. Identification of individuals at risk for diabetes is an essential first step in designing and implementing intervention programs. Insulin resistance is the hallmark of the pathophysiology of NIDDM. Subjects with hyperinsulinemia, impaired glucose tolerance, or gestational diabetes are well accepted as being at high risk for diabetes. We propose that the easily identifiable skin lesion, acanthosis nigricans, is common in the major minority groups in the United States and that its presence is a surrogate for laboratory-determined hyperinsulinemia. Clin Pediatr. 1998;37:73-80

Hyperinsulinemia in hyperthecosis of the ovaries

Fasting insulin concentrations and the insulin response to an oral glucose tolerance test were measured in six virilized women with ovarian hyperthecosis and six weight-matched normal women. For comparison, six women with polycystic ovarian disease were also studied. The diagnosis of hyperthecosis was confirmed in all six virilized women by histologic examination of the ovaries. The fasting insulin concentrations were increased in all of the hyperthecosis patients (84 +/- 32 microU/ml). Insulin response to an oral glucose tolerance test was greatly increased (p less than 0.01) in comparison to normal women and women with polycystic ovarian disease. Significant positive correlations were found between peripheral insulin concentrations and ovarian vein testosterone (r = 0.879, p less than 0.02), dihydrotestosterone (r = 0.866, p less than 0.03), and androstenedione (r = 0.992, p less than 0.01) levels. Insulin resistance persisted after removal of the ovaries even though androgen levels returned to normal. These results suggest that a significant degree of insulin resistance exists in women with hyperthecosis and that insulin stimulates ovarian stromal androgen synthesis and thus may play a role in the pathogenesis of ovarian hyperthecosis.

Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture ☆ ☆☆ ★ ★★

OBJECTIVE Insulin is known to be mitogenic to a variety of cells in culture. The purpose of this study was to investigate the possible role of insulin in the growth and development of endometrial cancers. STUDY DESIGN Specific binding and growth effects of insulin were studied in 5 different human endometrial cancer cell lines derived from cancers with different degrees of differentiation: HEC-1-A and HEC-1-B (from a moderately well-differentiated adenocarcinoma), RL95-2 (from a moderately well-differentiated adenosquamous carcinoma), KLE (from poorly differentiated carcinoma), and AN3 CA (from a metastatic undifferentiated endometrial carcinoma). The receptors were further characterized by competitive binding and chemical cross-linking studies. RESULTS Binding studies with 125I-insulin revealed the presence of high-affinity binding sites for insulin on all the 5 cell lines. Binding of insulin was found to be highly specific. Competitive binding studies with 125I-insulin revealed that insulin was most effective in displacing the labeled hormone, whereas insulin-like growth factor-I and insulin-like growth factor-II competed for binding only at very high concentrations. Scatchard analysis of the binding data revealed that the association constant for the high-affinity binding sites ranged from 0.72 to 1.91 x 10(9) L/mol. Estrogen-receptor-negative cell lines HEC-1-A and HEC-1-B had the highest number of insulin receptors, whereas the estrogen-receptor-positive cell line RL95-2 had the least number of receptors. The effect of insulin on cell proliferation was studied by monitoring cell number and incorporating [3H]thymidine into deoxyribonucleic acid of the cells. Insulin stimulated cell growth of all the cell lines. CONCLUSIONS The results of this study indicate the potential role of hyperinsulinemia in the growth and development of endometrial cancer.

Altered kinetics and extent of urinary daidzein and Genistein excretion in women during chronic Soya exposure

Soybean consumption may be protective for breast cancer, possibly due in part to the presence of the isoflavones daidzein and genistein, which are weakly estrogenic. The metabolism and disposition of these phytoestrogens during chronic soya exposure were studied on a metabolic unit. Six healthy 22- to 29-year-old women consumed an unrestricted hospital diet for most of the study and ingested 12 oz of soymilk with each meal for one month. At two-week intervals, excretion of isoflavones in urine was studied, during which time the subjects consumed a constant basal diet for three to four days, ingested the full daily 36-oz portion of soymilk within 30 minutes each day for one to two days, and collected urine continuously. Urinary recovery of genistein [initially 23.9 +/- 17.3% (SD) of ingested genistin + genistein], daidzein (initially 66.2 +/- 23.5% of ingested daidzin + daidzein), and equol (initially 28% of the ingested precursors daidzin + daidzein in 1 subject and < 1% in 5 subjects) decreased progressively over four weeks of daily soya ingestion by 42% for genistein (p < 0.05) and 31% for daidzein (p < 0.01) but increased by 3- to 100-fold for equol (4 subjects, p < 0.05). Total amounts excreted and peak levels were similarly affected. The absorption half-lives (t 1/2) for genistein and daidzein were initially 2.7 +/- 0.8 and 1.6 +/- 0.5 hours, respectively, and during four weeks of soymilk ingestion decreased to 2.0 +/- 0.6 (p = 0.04) and 1.4 +/- 0.2 hours (p = 0.06), respectively, suggesting more rapid absorption. The appearance t 1/2 of equol can be estimated for only one subject initially (2.9 hrs), but during four weeks of soya ingestion it could be estimated for three more subjects (4.7 +/- 2.3 hrs). The excretion t 1/2 values for genistein and daidzein were initially 6.7 +/- 0.8 and 4.4 +/- 0.7 hours, respectively, and during four weeks of soymilk ingestion decreased to 4.2 +/- 1.2 (p = 0.005) and 3.2 +/- 1.1 hours (p = 0.005), respectively, suggesting more rapid excretion. For equol, the excretion t 1/2 was initially 9.1 hours (1 subject), and after two and four weeks of soymilk ingestion it was 13.4 +/- 9.7 and 5.5 +/- 1.6 hours (4 subjects, p = 0.046, 2 wks vs. 4 wks), respectively. These results indicate that metabolism and disposition of ingested isoflavones are altered during chronic soya ingestion in women, perhaps from increased metabolic degradation to formation of nonisoflavone metabolites. Increased production of the longer- and stronger-acting estrogenic equol in some women during chronic soymilk ingestion may alter the estrogenic potency of dietary soya isoflavones.

Insulin-like growth factor I and II binding in human myometrium and leiomyomas

OBJECTIVES The purpose of this study is to determine if the human myometrium has receptors for insulin-like growth factors I and II and whether the concentration of these receptors is increased in leiomyomas. STUDY DESIGN Specific binding of iodine 125-labeled insulin-like growth factor I and II was examined in the membrane preparations of myometrium and leiomyomas obtained from 10 women with uterine leiomyomas. RESULTS Binding studies indicate presence of specific binding sites for both insulin-like growth factors I and II in the myometrium and leiomyoma. The concentration of binding sites for insulin-like growth factor I, but not for insulin-like growth factor II, was significantly (p less than 0.01) higher in leiomyomas than in the myometrium. The dissociation constants for insulin-like growth factors I and II receptors in both myometrium and leiomyoma were similar. CONCLUSION insulin-like growth factor I, but not insulin-like growth factor II, receptors are increased in leiomyomas compared with those in myometrium, indicating that insulin-like growth factor I may play a role in the generation and/or growth of this tumor.

Adiponectin Levels in Women With Polycystic Ovary Syndrome and Severe Insulin Resistance

Objective: Adiponectin is an adipokine that is decreased in obesity and type 2 diabetes. Women with polycystic ovarian syndrome (PCOS) are obese and are at risk for type 2 diabetes. The objective of the current study was to investigate the relationship of adiponectin to obesity and insulin resistance in women with PCOS and severe insulin resistance. Methods: Thirty women with PCOS and acanthosis nigricans indicating severe insulin resistance were included in the study. Eleven body mass index (BMI)-matched women with normal ovulatory cycles served as controls. Fasting glucose, insulin, and adiponectin levels were measured, and a standard oral glucose tolerance test (OGTT) with insulin levels was performed. To further investigate the role of insulin sensitivity on adiponectin levels, 10 women with PCOS were treated with 4 mg rosiglitazone daily for 6 months and adiponectin levels were measured before and after treatment. Results: Fasting insulin levels (33.5 ± 3.8 μU/mL; P <.001) and insulin area under the curve (AUC) during OGTT (536.2 ± 70.5 μU/mL; P <.01) were higher in women with PCOS, while glucose levels were similar to controls. Adiponectin levels were lower (P <. 01) in women with PCOS (5.6 ± 2.6 μg/mL) compared with controls (8.5 ± 3.9 μg/mL). There was a significant negative correlation between adiponectin levels and fasting insulin levels (r =-0. 40, P =. 02), insulin AUC during OGTT (r =-0.47, P = .008),fasting glucose levels (r =-0.45, P = .01), andglucoseAUC during OGTT (r =-0.51, P = .003). There was no correlation between BMI and serum adiponectin (r =-0.12, P = .508) in women with PCOS, while there was a negative correlation (r =-0.746, P = .013) in controls. There was a significant (P <.01) increase in adiponectin levels when treated with rosiglitazone, despite unchanged BMI. Conclusion: These results indicate that in women with PCOS and severe insulin resistance, insulin sensitivity appears to be the major determinant of adiponectin levels rather than adiposity. Low adiponectin levels may predict women with PCOS who are at high risk for developing type 2 diabetes.

Efficacy of second versus third generation oral contraceptives in the treatment of hirsutism.

OBJECTIVE To compare second versus third generation combination oral contraceptives (OCs) in the treatment of hirsutism. METHODS Women with hirsutism, as defined by a minimum Ferriman-Gallwey score of 10, were randomized in a double-blind fashion to receive an OC containing either ethinyl estradiol/desogestrel or ethinyl estradiol/levonorgestrel for 9 months of treatment. Ferriman-Gallwey scores, androgen levels and sex hormone-binding globulin were measured at baseline and every 3 months for the duration of the study. Hormones were measured in duplicate by radioimmunoassay. RESULTS Of the 47 women enrolled, 24 were randomized to ethinyl estradiol/desogestrel and 23 were randomized to ethinyl estradiol/levonorgestrel. Mean sex hormone-binding globulin increased significantly in subjects using the desogestrel-containing contraceptive compared with the levonorgestrel-containing contraceptive. Ten subjects completed the 9 months of treatment in the levonorgestrel group and 11 completed the study in the desogestrel group. Mean free testosterone and 3alpha-androstanediol glucuronide decreased significantly in the group receiving ethinyl estradiol/desogestrel but not in the ethinyl estradiol/levonorgestrel group. Mean Ferriman-Gallwey scores decreased significantly in both treatment groups. Improvement in mean Ferriman-Gallwey score was 35.7 +/- 38.1% (p < 0.001) for the ethinyl estradiol/desogestrel arm and 33.4 +/- 27.3% (p < 0.001) for the ethinyl estradiol/levonorgestrel arm. There were no statistically significant differences found in the improvement of Ferriman-Gallwey scores between the two treatment arms, although the power to detect a difference was limited by the small sample size. CONCLUSIONS Treatment of hirsute women with third generation OCs containing desogestrel results in a significant increase in sex hormone-binding globulin and decrease in free testosterone and 3alpha-androstanediol glucuronide. Both second and third generation OCs were clinically effective in treating hirsutism.

Estrogen Regulation of Lactoferrin Expression in Human Endometrium

PROBLEM: Lactoferrin is an iron‐binding glycoprotein that has been shown to be overexpressed in human endometrial carcinomas. The purpose of our present study is to investigate the possible role of estradiol in the expression of lactoferrin.

Specific binding sites for insulin and insulin-like growth factor I in human endometrial cancer

Insulin and insulin-like growth factor I are known to be mitogenic and therefore may play a role in the development of endometrial cancer. We undertook this study to investigate whether human endometrial cancer tissue has receptors for these substances. Endometrial cancer tissue samples were obtained at hysterectomy from 10 women with endometrial cancer, and control endometrial tissue was collected from normal cycling women undergoing hysterectomy for nonendocrine problems. Binding studies with iodine 125-insulin and [125I]insulin-like growth factor I revealed the presence of specific binding sites for insulin and insulin-like growth factor I in both normal endometrium and endometrial cancer tissue. The percent binding of [125I]insulin in the endometrial cancer tissue (mean +/- SE 2.4% +/- 0.5%/100 micrograms protein) was not significantly different from that in normal endometrium (3.5% +/- 1%/100 micrograms protein). On the contrary, the percent total binding of [125]insulin-like growth factor I in the endometrial cancer (5.3% +/- 1.5%/100 micrograms protein) was significantly (p less than 0.04) higher than that observed in normal endometrium (2.1% +/- 0.4%/100 micrograms protein). There was a significant positive correlation between the histologic grade of the tumor and the insulin-like growth factor I binding (r = 0.865, p less than 0.02). The affinity constants for the high-affinity receptors were similar in the normal and neoplastic endometrium. These results indicate that insulin and insulin-like growth factor I may play a role in the growth and development of endometrial cancer.