Sex hormone-binding globulin genetic variation: associations with type 2 diabetes mellitus and polycystic ovary syndrome.

Sex hormone-binding globulin (SHBG) is the primary plasma transport protein for sex steroid hormones and regulates the bioavailability of these hormones to target tissues. The gene encoding SHBG is complex and any of several polymorphisms in SHBG have been associated with alterations in circulating SHBG levels. Epidemiological studies have revealed that low plasma SHBG levels are an early indicator of insulin resistance and predict the development of type 2 diabetes mellitus (T2DM) in both men and women. Although associations between low SHBG levels and risk of diabetes could be explained by the observation that elevations in insulin suppress hepatic SHBG production, recent studies documenting that the transmission of SHBG-altering polymorphisms are associated with risk of T2DM suggest that SHBG may have a more direct physiologic role in glucose homeostasis. However, the exact mechanism(s) underlying this association is not known. Non-diabetic women with the polycystic ovary syndrome (PCOS), a common endocrine disorder that is associated with insulin resistance, similarly demonstrate lower levels of SHBG. In light of studies investigating polymorphisms in SHBG and T2DM, our group and others have hypothesized that SHBG may represent a candidate gene for PCOS. In this manuscript, we review studies investigating the association between SHBG polymorphisms and PCOS. In summary, multiple studies in women with PCOS confirm that certain genetic polymorphisms are associated with circulating SHBG levels, but they are not consistently associated with PCOS per se.

Effect of weight loss by a low-fat diet and a low-carbohydrate diet on peptide YY levels.

OBJECTIVE: To compare the effects of weight loss by an energy-restricted low-fat diet vs low-carbohydrate diet on serum peptide YY (PYY) levels. DESIGN: 8-Week prospective study of 30 obese adults (mean age: 42.8+/-2.0 years, mean body mass index 35.5+/-0.6 kg m(-2)). RESULTS: After 8 weeks, subjects on the low-carbohydrate diet lost substantially more weight than those on the low-fat diet (5.8 vs 0.99 kg, P<0.001). Weight loss by either diet resulted in a 9% reduction in both mean fasting serum PYY levels (baseline: 103.5+/-8.8 pg ml(-1), after weight loss: 94.1+/-6.5 pg ml(-1), P<0.01) and postprandial area under the curve (AUC) PYY (baseline: (20.5+/-1.5) x 10(3) pg h(-1) ml(-1), after weight loss: mean AUC PYY (18.8+/-1.4) x 10(3) pg h(-1) ml(-1), P<0.001). There was a trend towards lower levels of PYY with greater degrees of weight loss. CONCLUSIONS: Reduced PYY levels after weight loss by an energy-restricted low-fat or low-carbohydrate diet likely represents a compensatory response to maintain energy homeostasis and contributes to difficulty in weight loss during energy-restricted diets.

Comorbidities in polycystic ovary syndrome: their relationship to insulin resistance.

The polycystic ovary syndrome (PCOS) affects 5-10% of women of child-bearing age, and the diagnosis carries with it associated metabolic and cardiovascular risk factors that are likely linked to insulin resistance. Consequently, women affected by PCOS are at significant risk for developing type 2 diabetes mellitus, cardiovascular disease, and obstructive sleep apnea. Aggressive screening for glucose intolerance and cardiovascular risk factors should be performed in all PCOS patients, and, when indicated by symptomatology, affected women should be screened for sleep apnea. Long-term goals of therapy should focus on prevention of these comorbidities.

Differences in dyslipidemia between American and Italian women with polycystic ovary syndrome.

BACKGROUND: Dyslipidemia is a common metabolic complication in polycystic ovary syndrome (PCOS). The aim of this study was to determine if differences exist in dyslipidemia in women with PCOS from different ethnic and geographical backgrounds. METHODS: This retrospective study evaluated the serum fasting lipid profiles of 106 women with PCOS from the United States and 108 women with PCOS from Italy evaluated at endocrinology clinics. RESULTS: American women had higher mean body mass index than Italian women (36.1+/-8.6 vs 28.1+/-5.8 kg/m2, p<0.01). Low HDL-cholesterol was the most prevalent lipid abnormality in both populations. U.S. women had higher mean levels of serum total cholesterol, LDL-cholesterol, and triglycerides, and lower mean serum HDL-cholesterol. Most of these differences were due to differences in weight. After controlling for differences in weight and age, fasting serum triglycerides remained higher in U.S. women compared with Italian women [131.1 mg/dl, SE=7.8, 95% confidence interval =(115.7, 146.5) vs 99.3, SE=8.4, 95% confidence interval =(82.9, 115.8)]. CONCLUSIONS: Variations in body weight alone do not fully explain differences in dyslipidemia in women of diverse ethnic and geographical backgrounds. Genetic and environmental factors, such as diet and activity level, likely contribute to these differences.

The metabolic syndrome in polycystic ovary syndrome.

Much overlap is present between the polycystic ovary syndrome (PCOS) and the metabolic syndrome. This article reviews the existing data regarding the prevalence, characteristics, and treatment of the metabolic syndrome in women with PCOS. The prevalence of the metabolic syndrome in PCOS is approximately 43-47%, a rate 2-fold higher than that for women in the general population. High body mass index and low serum HDL cholesterol are the most frequently occurring components of the metabolic syndrome in PCOS. The pathogenic link between the metabolic syndrome and PCOS is most likely insulin resistance. Therefore, the presence of the metabolic syndrome in PCOS suggests a greater degree of insulin resistance compared to PCOS without the metabolic syndrome. Obesity, atherogenic dyslipidemia, hypertension, impaired fasting glucose/impaired glucose tolerance, and vascular abnormalities are all common metabolic abnormalities present in PCOS. Lifestyle modification has proven benefit and pharmacological therapy with insulin-sensitizing agents has potential benefit in the treatment of the metabolic syndrome in women with PCOS.

Hypoglycemic potential of nateglinide versus glyburide in patients with type 2 diabetes mellitus.

Antidiabetic agents that augment insulin secretion can cause hypoglycemia. With the current trend toward early and aggressive treatment of patients with type 2 diabetes, the hypoglycemic potential of insulinotropic agents is of concern. This study aimed to compare the propensity of the "glinide," nateglinide, and the sulfonylurea (SU), glyburide, to elicit hypoglycemia in type 2 diabetic patients with moderately elevated fasting plasma glucose (FPG). Hyperglycemic clamps (target plasma glucose = 11.1 mmol/L) were initiated, and 30 minutes later patients received a single oral dose of nateglinide (120 mg, n = 15) or glyburide (10 mg, n = 12) in a double-blind fashion. At the end of the 2-hour clamp when the glucose infusion was terminated, plasma glucose and insulin levels were measured for 4 additional hours. The minimum plasma glucose level achieved after terminating the glucose infusion (glucose nadir) was used as an index of hypoglycemic potential. The mean (+/-SEM) glucose nadir was significantly lower in patients given glyburide (3.3 +/- 0.2 mmol/L) versus nateglinide (4.4 +/- 0.3 mmol/L, P = .025). Confirmed hypoglycemia (plasma glucose < or = 2.8 mmol/L) occurred in 2 of 12 patients given glyburide and in none of those given nateglinide. Plasma insulin levels were significantly higher from 100 to 240 minutes after clamp termination in patients given glyburide versus nateglinide. Nateglinide has less hypoglycemic potential than glyburide, suggesting that nateglinide may be a more appropriate insulinotropic agent for patients with moderate fasting hyperglycemia, such as elderly patients and those with comorbid cardiac ischemia.

Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes.

OBJECTIVE: Women with polycystic ovary syndrome (PCOS) have an increased risk for developing type 2 diabetes. Few studies have assessed women with type 2 diabetes to determine the frequency of PCOS in this population. RESEARCH DESIGN AND METHODS: To determine the prevalence of PCOS among premenopausal women with type 2 diabetes, we conducted a retrospective cross-sectional prevalence study. We reviewed the medical records of all women seen in the Diabetes Clinic of the Medical College of Virginia Hospitals between January 1995 through February 2000. A diagnosis of PCOS was based on 1) oligomenorrhea, 2) hyperandrogenism (biochemical or clinical), and 3) exclusion of other related disorders. RESULTS: We reviewed the medical records of 618 women with diabetes and identified 47 women eligible for study. Of the 47 women, 30 consented to an evaluation. Of the 30 women evaluated, 8 were identified as having PCOS (6 women reported a previous PCOS diagnosis and 2 women were newly diagnosed), resulting in a prevalence of 26.7%. CONCLUSIONS: We concluded that PCOS occurs frequently among premenopausal women with type 2 diabetes.

Insulin-lowering drugs in polycystic ovary syndrome.

The discovery that insulin resistance has a key role in the pathophysiology of PCOS has led to a novel and promising form of therapy in the form of the insulin-sensitizing drugs. Although no extremely large trials using these drugs for this indication have been performed, more than 18 trials have specifically examined the effects of these drugs on ovulation, hyperandrogenemia, and dysmetabolic features in PCOS. Table 1 summarizes the results of previous trials using each of the insulin-sensitizing drugs discussed herein. Among the various agents (i.e., thiazolidinediones, [table: see text] metformin, and D-chiro-inositol), metformin is the most widely tested. Metformin may have the added benefit of improving at least some features of syndrome X, such as hypertension and obesity. All of the evidence to date suggests that metformin is a safe drug to administer to women who may become pregnant. In contrast, the two thiazolidinediones currently available, rosiglitazone and pioglitazone, are category C drugs that have been demonstrated to retard fetal development in animal studies. Overall, insulin-sensitizing therapy presents a promising and unique therapeutic intervention for the treatment of PCOS, offering metabolic and gynecologic benefits for women who sustain this syndrome.

Insulin reduction with metformin increases luteal phase serum glycodelin and insulin-like growth factor-binding protein 1 concentrations and enhances uterine vascularity and blood flow in the polycystic ovary syndrome.

We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment. Serum glycodelin, a putative biomarker of endometrial function, is decreased in women with early pregnancy loss. Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface. We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin (n = 26) or placebo (n = 22) 3 times daily. Oral glucose tolerance tests were performed, and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses. In the metformin group, the mean (+/-SE) area under the serum insulin curve after glucose administration decreased from 62 +/- 6 to 19 +/- 2 nmol/L.min (P < 0.001). Follicular phase serum glycodelin concentrations increased 20-fold from 150 +/- 46 to 2813 +/- 1192 pmol/L (P < 0.001), and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 +/- 152 to 2396 +/- 300 pmol/L (P < 0.001). Similarly, luteal phase serum glycodelin concentrations increased 3-fold from 3434 +/- 1299 to 10624 +/- 1803 pmol/L (P < 0.001), and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 +/- 136 to 4916 +/- 596 pmol/L (P < 0.001). Uterine vascular penetration also increased in the metformin group, as did blood flow of spiral arteries, as demonstrated by a 20% decrease in the resistance index from 0.71 +/- 0.02 to 0.57 +/- 0.03 (P < 0.001). These variables did not change in the placebo group. We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome. These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy.

Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone.

OBJECTIVE: To determine whether metformin treatment increases the ovulation and pregnancy rates in response to clomiphene citrate (CC) in women who are resistant to CC alone. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Multicenter environment. PATIENT(S): Anovulatory women with the polycystic ovary syndrome (PCOS) who were resistant to CC. INTERVENTION(S): Participants received placebo or metformin, 500 mg three times daily, for 7 weeks. Information on reproductive steroids, gonadotropins, and oral glucose tolerance testing was obtained at baseline and after treatment. Metformin or placebo was continued and CC treatment was begun at 50 mg daily for 5 days. Serum P level > or =4 ng/mL was considered to indicate ovulation. With ovulation, the daily CC dose was not changed, but with anovulation it was increased by 50 mg for the next cycle. Patients completed the study when they had had six ovulatory cycles, became pregnant, or experienced anovulation while receiving 150 mg of CC. MAIN OUTCOME MEASURE(S): Ovulation and pregnancy rates. RESULT(S): In the metformin and placebo groups, 9 of 12 participants (75%) and 4 of 15 participants (27%) ovulated, and 6 of 11 participants (55%) and 1 of 14 participants (7%) conceived, respectively. Comparisons between the groups were significant. CONCLUSION(S): In anovulatory women with PCOS who are resistant to CC, metformin use significantly increased the ovulation rate and pregnancy rate from CC treatment.

Role of inositolphosphoglycan mediators of insulin action in the polycystic ovary syndrome.

Evidence suggests that some actions of insulin are mediated by putative inositolphosphoglycan (IPG) mediators, also known as second messengers. We review studies indicating that the IPG signaling system transduces insulin's stimulation of human thecal androgen biosynthesis, thus offering a mechanism by which insulin can stimulate ovarian androgen production even in women with PCOS whose tissues are resistant to insulin's stimulation of glucose metabolism. Furthermore, a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in women with PCOS. In support of this idea, administration of D-chiro-inositol has been demonstrated to improve glucose tolerance, decrease serum androgens and improve ovulation in PCOS. The hypothesis is advanced that PCOS may be characterized by a defect in the conversion of myo-inositol to D-chiro-inositol, and that such a defect would contribute to both insulin resistance and hyperandrogenism in the syndrome.

Obesity, insulin, sex steroids and ovulation.

Obesity is a major feature in women with polycystic ovary syndrome (PCOS), and evidence suggests that obesity contributes to the pathogenesis of PCOS by aggravating the intrinsic insulin resistance of these women. Hyperinsulinemia appears to increase circulating androgens in PCOS by stimulating ovarian androgen production and suppressing serum SHBG, and also appears to play a pathogenic role in the anovulation of the disorder. The use of insulin sensitizing drugs has been shown to decrease serum insulin in both obese and nonobese women with PCOS, and to simultaneously reduce circulating ovarian androgens and to improve ovulation.

The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine profiles, lipid parameters, and health-related quality of life.

Dehydroepiandrosterone (DHEA), an androgenic steroid hormone, exhibits an age-related decline. Perimenopausal women have only approximately 50% of peak DHEA levels. Despite limited scientific data, DHEA has gained recognition as a dietary supplement to reduce the symptoms of aging and improve well-being. This randomized, double-blind placebo-controlled trial examined the effects of 50 mg/day of oral DHEA supplementation, for 3 months, on 60 perimenopausal women with complaints of altered mood and well-being. Changes in the serum endocrine profile of women in the DHEA group were significantly greater than the placebo group, including a 242% [95% confidence interval (CI) +60.1, +423.9] increase in DHEAS, a 94.8% (95% CI +34.2, +155.4) increase in testosterone, and a 13.2% (95% CI -27.88, +0.5) decline in cortisol compared to baseline. Women receiving DHEA had a 10.1% (95% CI -15.0, -5.1) decline in high-density lipoprotein and an 18.1% (95% CI -32.2, -3.9) decline in Lp(a) from baseline, but these declines did not significantly differ from women who received placebo. Women receiving DHEA did not have any improvements significantly greater than placebo in the severity of perimenopausal symptoms, mood, dysphoria, libido, cognition, memory, or well-being. DHEA supplementation significantly effects the endocrine profile, may affect the lipid profile, but does not improve perimenopausal symptoms or well-being compared to placebo.

Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome.

BACKGROUND: Women with the polycystic ovary syndrome have insulin resistance and hyperinsulinemia, possibly because of a deficiency of a D-chiro-inositol-containing phosphoglycan that mediates the action of insulin. We hypothesized that the administration of D-chiro-inositol would replenish stores of the mediator and improve insulin sensitivity. METHODS: We measured steroids in serum and performed oral glucose-tolerance tests before and after the oral administration of 1200 mg of D-chiro-inositol or placebo once daily for six to eight weeks in 44 obese women with the polycystic ovary syndrome. The serum progesterone concentration was measured weekly to monitor for ovulation. RESULTS: In the 22 women given D-chiro-inositol, the mean (+/-SD) area under the plasma insulin curve after the oral administration of glucose decreased from 13,417+/-11,572 to 5158+/-6714 microU per milliliter per minute (81+/-69 to 31+/-40 nmol per liter per minute) (P=0.007; P=0.07 for the comparison of this change with the change in the placebo group); glucose tolerance did not change significantly. The serum free testosterone concentration in these 22 women decreased from 1.1+/-0.8 to 0.5+/-0.5 ng per deciliter (38+/-7 to 17+/-3 pmol per liter) (P=0.006 for the comparison with the change in the placebo group). The women's diastolic and systolic blood pressure decreased by 4 mm Hg (P<0.001 and P=0.05, respectively, for the comparisons with the changes in the placebo group), and their plasma triglyceride concentrations decreased from 184+/-88 to 110+/-61 mg per deciliter (2.1+/-0.2 to 1.2+/-0.1 mmol per liter) (P=0.002 for the comparison with the change in the placebo group). None of these variables changed appreciably in the placebo group. Nineteen of the 22 women who received D-chiro-inositol ovulated, as compared with 6 of the 22 women in the placebo group (P<0.001). CONCLUSIONS: D-Chiro-inositol increases the action of insulin in patients with the polycystic ovary syndrome, thereby improving ovulatory function and decreasing serum androgen concentrations, blood pressure, and plasma triglyceride concentrations.

Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system.

To determine whether insulin stimulates human ovarian testosterone production in the polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system, thecal cells from polycystic ovary syndrome women were isolated and cultured. Insulin and insulin-like growth factor I stimulated thecal testosterone biosynthesis. Antibody blockade of the insulin receptor abolished insulin's stimulatory action, whereas effective antibody blockade of the insulin-like growth factor I receptor did not alter insulin's stimulation of thecal testosterone biosynthesis. A chiro-inositol containing glycan (INS-2) increased thecal testosterone biosynthesis. Preincubation of cells with an antiinositolglycan antibody (A23939 or alpha IGP) abolished insulin's stimulatory effect, but not that of hCG. These findings suggest that inositolglycans serve as the signal transduction system for insulin's stimulation of human thecal testosterone biosynthesis.

Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome.

BACKGROUND: Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene. We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene. METHODS: We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome. Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo. Serum progesterone was measured on days 14, 28, 35, 44, and 53, and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter (26 nmol per liter) on any of these days. RESULTS: Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study. Among the 21 women given metformin plus clomiphene, the mean (+/-SE) area under the serum insulin curve after oral glucose administration decreased from 6745+/-2021 to 3479+/-455 microU per milliliter per minute (40.5+/-12.1 to 20.9+/-2.7 nmol per liter per minute, P=0.03), but it did not change significantly in the 25 women given placebo plus clomiphene. Nineteen of the 21 women (90 percent) who received metformin plus clomiphene ovulated (mean peak serum progesterone concentration, 23.8+/-3.4 ng per milliliter [7.6+/-10.9 nmol per liter]). Two of the 25 women (8 percent) who received placebo plus clomiphene ovulated (P<0.001). Overall, 31 of the 35 women (89 percent) treated with metformin ovulated spontaneously or in response to clomiphene, as compared with 3 of the 26 women (12 percent) treated with placebo. CONCLUSIONS: The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin.

Inositolphosphoglycans (IPGs) as mediators of insulin's steroidogenic actions.

PCOS is a unique model of insulin resistance in which one tissue (skeletal muscle) is resistant to insulin in terms of glucose metabolism whereas another tissue (ovarian thecal cells) maintains its responsiveness to insulin in terms of testosterone biosynthesis. During the past decade, a series of in vitro studies conducted in human placental cells /25/, swine granulosa cells /28/, and most recently, human thecal cells /17/, have provided compelling evidence that one factor involved in this apparent clinical paradox is the clear demonstration of the utilization of the IPG signal transduction system for insulin's effects on steroidogenesis. Nonetheless, many questions remain to be addressed. For example, it would be instructive to determine simultaneously the effects of insulin on glucose disposal and testosterone biosynthesis in isolated thecal cells. In other words, is the thecal cell itself resistant to insulin in terms of glucose disposal while remaining sensitive to insulin in terms of testosterone biosynthesis? Is the IPG content of human thecal cells from women with PCOS decreased compared with that in matched healthy women? There is substantial evidence to suggest that some IPGs may also be responsible in part for mediating insulin's stimulation of glucose disposal (see paper by Dr. Joseph Larner in this issue)--this raises the question as to whether specific forms of IPGs are responsible for glucose metabolism in vivo, whereas other IPGs are responsible for mediating insulin's effects on steroidogenesis. Is there a disparity in the ratio of different types of IPGs among various tissues (e.g., muscle, liver, ovary), and does that ratio determine the tissue's responsiveness to one or another action of insulin? These questions and others leave IPGs and insulin signal transduction a fruitful area for both clinical and laboratory investigations.