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Query: UMLS:C0028754 (obesity)
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The basic tenet of this investigation was that obesity is not a prerequisite in the development of polycystic ovary syndrome (PCOS), as indicated by the fact that 50% of PCOS women are not obese. Further, obesity itself is a disease entity with the common manifestation of insulin resistance/hyperinsulinemia with PCOS. Given recent evidence that insulin and GH may have gonadotropin-augmenting effects, we have determined the common and distinguishing features of neuroendocrine-metabolic dysfunctions of lean [body mass index (BMI), < 23 kg/m2] and obese (BMI, > 30 kg/m2) women with the classical form of PCOS. Insulin sensitivity, as determined by rapid i.v. glucose tolerance testing; 24-h dynamics of insulin/glucose levels, somatotropic [GH/GH-binding protein/insulin-like growth factor I (IGF-I)/IGF-binding proteins (IGFBP)], and LH axes; and their downstream effects on ovarian steroids were simultaneously assessed in eight lean PCOS and eight obese PCOS patients and an equal number of BMI-matched normal cycling controls. Our results show that insulin sensitivity was reduced 50% (P < 0.01) in lean PCOS from that in lean controls. There was a further decrease in obese controls (P < 0.01) and a 2-fold greater reduction (P < 0.001) in obese PCOS than in obese controls, suggesting that insulin resistance (IR) is a common lesion in PCOS, and that obesity contributes an additional component to IR in obese PCOS. Consistent with the degree of IR, the manifestation of compensatory hyperinsulinemia in lean PCOS was incipient, being evident only in response to meals (P < 0.05), and became overt during the 24-h fasting/feeding phases of the day in obese control (P < 0.001) with a 2- to 3-fold greater elevation (P < 0.001) in obese PCOS. An enhanced early insulin response to glucose occurs equally in obese control (P < 0.01) and obese PCOS (P < 0.05), but not in their lean counterparts. Considering the more profound IR and the associated hyperglycemia in obese PCOS, the magnitude of the early insulin release is inadequate, suggesting that beta-cell dysfunction exists in obese PCOS. Remarkable differences in the somatotropic axis were also observed; although 24-h GH pulse frequency and levels of IGF-I and IGFBP-3 were unaltered by either PCOS or obesity, the 24-h mean GH pulse amplitude was increased by 30% (P < 0.01) in lean PCOS in the presence of normal levels of high affinity GHBP and normal GH response to GHRH. In distinct contrast, the somatotropic axis in both obese control and obese PCOS was profoundly modified, with attenuation of GH pulse amplitude (P < 0.001) and GH response to GHRH (P < 0.001), resulting in a state of hyposomatotropinism with a more than 50% reduction (P < 0.001) of 24-h mean GH levels. In addition, GHBP levels were elevated 2-fold and were correlated inversely with GH (r = -0.81) and positively with insulin (r = 0.75) concentrations. IGFBP-I levels were suppressed in both obese groups, with a 4-fold greater reduction in obese PCOS than that in obese controls. Thus, the downstream effects of hyperinsulinemia on the somatotropic axis may include up-regulation of hepatic production of GHBP, suppression of IGFBP-1 (r = 0.82) and sex hormone-binding globulin (r = -0.69) levels, and a more than 3-fold increase in ratios of IGF-I/IGFBP-1 and estradiol-testosterone/sex hormone-binding globulin, thereby increasing their bioavailabilities. In contrast, LH pulsatility was unaffected by obesity alone. An accelerated LH pulse frequency was evident in both lean and obese PCOS (P < 0.001), whereas the mean 24-h LH pulse amplitude was increased in lean (P < 0.001), but not obese, PCOS patients. These events resulted in a 3-fold increase in 24-h mean LH levels in lean PCOS and a 2-fold increase in obese PCOS. Thus, increased LH pulse frequency and augmented LH response to GnRH are characteristic of PCOS, independent of obesity, and the presence of obesity in PCOS is associated with an attenuated LH pulse amplitude, not accounted f
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PMID:Insulin, somatotropic, and luteinizing hormone axes in lean and obese women with polycystic ovary syndrome: common and distinct features. 876 42

Insulin resistance, defined as a diminished effect of a given dose of insulin on glucose homeostasis, is a highly prevalent feature of women with PCOS. Insulin resistance in PCOS is closely associated with an increase in truncal-abdominal fat mass, elevated free fatty acid levels, increased androgens, particularly free testosterone through reduced SHBG levels, and anovulation. The causes for insulin resistance in PCOS are still unknown. One line of evidence suggests that an increase in truncal-abdominal fat mass and subsequently increased free fatty acid levels induce insulin resistance in women with PCOS. Increased effects of corticosteroids and a relative reduction in oestrogen and progesterone seem to be involved in the aberrant body fat distribution. Conversely, there are also results supporting primary, genetic target cell defects as a cause of insulin resistance in PCOS. An explanation for these seemingly contradictory results could be that the group of women with PCOS is heterogeneous with respect to the primary event in carbohydrate/insulin disturbances. Also insulin secretion in PCOS is characterized by heterogeneity. At one end of the spectrum is a large subgroup of mainly obese women with reduced insulin secretion, which appears to result from failure of the beta cells to compensate for insulin resistance in susceptible women, resulting in glucose intolerance and NIDDM. In the insulin-resistant patients with normal glucose tolerance, most of the hyperinsulinaemia is probably due to secondarily increased insulin secretion and decreased insulin degradation. However, a component of the increased first-phase insulin release is not due to measurable insulin resistance. Notably, this is also found in lean women with normal insulin sensitivity, and is not reversed after weight reduction, in contrast to the findings for insulin resistance. The implications of this enhanced insulin release are not fully clear, but it may tentatively be associated with carbohydrate craving and subsequently increased risks for development of obesity and insulin resistance. It may represent a primary disturbance of insulin secretion in PCOS or may be associated with the perturbed steroid balance in anovulation. The insulin-androgen connection in PCOS appears to be amplified by several different mechanisms, notably in both directions, the initiating event probably varying between individuals. Thus insulin increases the biological availability of potent steroids, primarily testosterone, through the suppression of SHBG synthesis. Insulin is also involved as a progonadotrophin in ovarian steroidogenesis, with the possible net result of interfering with ovulation and/or increasing ovarian androgen production in states of hyperinsulinaemia. Conversely, testosterone may indirectly contribute to insulin resistance through facilitating free fatty acid release from abdominal fat, but perhaps also through direct muscular effects at higher serum levels. It seems likely that this constitution, presumably genetic, would provide evolutionary advantages in times of limited nutrition, given the energy-saving effects of insulin resistance. Hypothetically, hyperinsulinaemia (primary) could provide a stimulus to ensure intake of nourishment, but unlimited food supplies could in some cases initiate a vicious 'anabolic' circle, in which several of the proposed amplifying mechanisms between insulin and androgens--in both directions--could take part.
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PMID:Disturbances in insulin secretion and sensitivity in women with the polycystic ovary syndrome. 877 46

In recent years numerous studies have suggested insulin to be an important regulator of ovarian function and hyperinsulinemia to be associated with hyperandrogenism. An oral glucose-tolerance test was carried out in 240 women with polycystic ovary syndrome and, based on its result, 142 of the women (59.2%) were insulin resistant or hyperinsulinemic and 98 (40.8%) were normoinsulinemic. Compared with the normoinsulinemic group, the hyperinsulinemic group had a greater incidence of obesity (52.8 vs. 21.4%), secondary amenorrhea (24.6 vs. 9.2%), androgenic symptoms (85.9 vs. 67.4%) and, in particular, hirsutism with or without acne (71.8 vs. 48.0%). Moreover, the hyperinsulinemic group had significantly higher plasma levels of androstenedione, testosterone, free testosterone and insulin, and lower levels of luteinizing hormone, estradiol and sex hormone-binding globulin.
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PMID:Hyperinsulinemia in the polycystic ovary syndrome: a clinical, endocrine and echographic study in 240 patients. 891 61

Polycystic ovary syndrome (PCOS) is associated with chronic anovulation, hyperandrogenemia, insulin resistance (IR)/hyperinsulinemia, and a high incidence of obesity. Thus, PCOS serves as a useful model to assess the role of IR and chronic endogenous insulin excess on leptin levels. Thirty-three PCOS and 32 normally cycling (NC) women of similar body mass index (BMI) were studied. Insulin sensitivity (S(I)) was assessed by rapid ivGTT in a subset of 28 PCOS and 29 NC subjects; percent body fat was determined by dual-energy x-ray absorptiometry (DEXA) in 14 PCOS and 17 NC. Fasting (0800 h) and 24-h mean hourly insulin levels were 2-fold higher (P < 0.0001), and S(I) was 50% lower (P = 0.005) in PCOS than in NC, while serum androstenedione (A), testosterone (T), 17-alpha hydroxyprogesterone (17OHP), and estrone (E1) levels were elevated (P < 0.0001), and sex hormone-binding globulin (SHBG) levels were decreased (P < 0.01). Twenty-four hour LH pulse frequency, mean pulse amplitude, and mean LH levels were elevated in PCOS (P < 0.001) as compared with NC. Serum leptin levels for PCOS (24.1 +/- 2.6 ng/mL) did not differ from NC (21.5 +/- 3.5 ng/mL) and were positively correlated with BMI (r = 0.81) and percent body fat (r = 0.91) for the two groups (both P < 0.0001). Leptin levels for PCOS and NC correlated positively with fasting and 24-h mean insulin levels (r = 0.81, P < 0.0001 for both PCOS and NC) and negatively with S(I) and SHBG levels. Leptin concentrations for PCOS, but not NC, correlated positively with 24-h mean glucose levels and inversely with 24-h mean LH levels and 24-h mean LH pulse amplitude. Leptin levels were not correlated with estrogen or androgen levels for either PCOS or NC, although leptin levels were positively related to the ratios of E1/SHBG and E2/SHBG for both PCOS and NC and to the ratio of T/SHBG for PCOS only. In stepwise multivariate regression with forward selection, only 24-h mean insulin levels contributed significantly (P < 0.01) to leptin levels independent of BMI and percent body fat for both PCOS and NC. Given this relationship and the presence of 2-fold higher 24-h mean insulin levels in PCOS, the expected elevation of leptin levels in PCOS was not found. This paradox may be explained by the presence of adipocyte IR specific to PCOS, which may negate the stimulatory impact of hyperinsulinemia on leptin secretion, a proposition requiring further study.
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PMID:Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. 917 63

Elevated insulin levels may explain part of the increased risk of endometrial cancer observed in obese postmenopausal women. Circulating sex hormones and fasting C-peptide levels were measured in sera obtained from 165 postmenopausal endometrial cancer cases accrued between June 1, 1987, and May 15, 1990, from hospitals in Chicago, Illinois; Hershey, Pennsylvania; Irvine and Long Beach, California; Minneapolis, Minnesota; and Winston-Salem, North Carolina, and 180 community and hysterectomy controls. Women with a personal history of diabetes were excluded. Among controls, C-peptide was positively correlated with body mass index (BMI) ((r = 0.44), waist-to-thigh circumference ratio ((r = 0.24), estrone ((r = 0.18), and estradiol ((r = 0.28) (albumin-bound (r = 0.45), and free (r = 0.37)) and negatively correlated with sex hormone-binding globulin (r = -0.48). In age-adjusted analyses, the odds ratios and 95% confidence intervals for tertiles of C-peptide and endometrial cancer were, from lowest to highest: 1.0 (reference), 0.78 (95% confidence interval (CI) 0.43-1.4), and 2.2 (95% CI 1.3-3.7). Further adjustment for BMI substantially attenuated the odds ratios for the highest tertile of C-peptide (odds ratio = 1.2, 95% CI 0.63-2.1), and adjustment for body mass index and other risk factors for endometrial cancer eliminated the association (odds ratio = 1.0, 95% CI 0.55-2.0). In contrast, adjustment for C-peptide had little influence on the magnitude of the positive associations between body mass index (odds ratio for highest vs. lowest tertile, without and with adjustment for C-peptide = 4.1 (95% CI 2.3-7.5) and 3.7 (95% CI 1.9-7.1), respectively) or several steroid hormones and endometrial cancer. These data are not consistent with the hypothesis that the effect of obesity on endometrial cancer risk is mediated through high insulin levels.
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PMID:Insulin and endometrial cancer. 929 May 8

The purpose of this study was to examine the relationships between androgenic status and plasma levels of both prothrombotic and antithrombotic factors in men, irrespective of obesity, body fat distribution, and metabolic parameters. Sixty-four apparently healthy men, 40 with a body mass index (BMI) greater than 25 kg/m2 (overweight and obese [OO]) and 24 non-obese controls with a BMI less than 25, were selected and evaluated for (1) plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) antigen, PAI-1 activity, fibrinogen, von Willebrand factor (vWF) antigen, vWF activity, and factor VII (FVII) as the prothrombotic factors; (2) plasma levels of tissue plasminogen activator (TPA) antigen, protein C, and antithrombin III as the antithrombotic factors; (3) fasting plasma concentrations of insulin and glucose and the lipid pattern (triglycerides [TG] and total and high-density lipoprotein [HDL] cholesterol) as the metabolic parameters; and (4) free testosterone (FT), dehydroepiandrosterone sulfate (DHEAS), and sex hormone-binding globulin (SHBG) serum levels as the parameters of androgenicity. Body fat distribution was evaluated by the waist to hip ratio (WHR). In OO and non-obese subjects taken together, plasma levels of PAI-1 antigen, fibrinogen, and FVII were inversely associated with FT (r = .255, P < .05, r = -3.14, P < .05, and r = -.278, P < .05, respectively), and the negative relationships of both fibrinogen and FVII with FT were maintained after stepwise multiple regression analysis. Plasma concentrations of PAI-1 antigen and PAI-1 activity were also negatively correlated with SHBG (r = -.315, P < .05 and r = -.362, P < .01, respectively), and these associations held irrespective of the other parameters investigated. None of the antithrombotic and fibrinolytic factors were independently related to serum androgen levels. Subjects with a BMI higher than 25 kg/m2 had higher plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen as compared with non-obese controls (P < .001, P < .001, and P < .01, respectively). In addition, in OO and control subjects as a whole, multiple stepwise regression analysis showed that the associations of BMI with PAI-1 activity, fibrinogen, vWF antigen, and vWF activity were independent of any other metabolic and hormonal parameters. Plasma concentrations of PAI-1 antigen, PAI-1 activity, and fibrinogen were also directly correlated with WHR in all subjects taken together, irrespective of the other parameters investigated. Evaluation of antithrombotic factors showed that OO subjects had higher TPA plasma concentrations than non-obese controls (P < .001), whereas protein C and antithrombin III did not differ in the two groups. TPA was also directly correlated with BMI (r = .415, P < .001) and WHR (r = .393, P < .001) in all subjects. The results of this study indicate that (1) men with lower FT serum levels have higher fibrinogen and FVII plasma concentrations, and those with lower SHBG serum levels also have higher levels of PAI-1 antigen and activity; (2) irrespective of other factors, obesity per se may account for higher concentrations of PAI-1, fibrinogen, and vWF; (3) plasma levels of PAI-1 (antigen and activity) and fibrinogen correlate independently with WHR; and (4) among the investigated antithrombotic factors (TPA antigen, protein C, antithrombin III), only TPA antigen plasma concentrations are higher in men with abdominal obesity. Thus, because of the increase in several prothrombotic factors, men with central obesity, particularly those with lower androgenicity, seem to be at greater risk for coronary heart disease (CHD). Apparently, this risk is not counteracted by a parallel increase in plasma concentrations of antithrombotic factors.
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PMID:Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. 936 87

Insulin-resistance is a central character of the simple obesity, resulting from decrease of the insulin receptor and dysfunctions of the post receptor systems. It induces hyper-insulinemia. Excess insulin gives rise to the synthesis of androgens by binding to the receptor of the ovary, and suppresses the SHBG and IGFBG in the liver. As a result, in obese women, the sexual function is disturbed by hyperandrogenic milieu. The conversion of androgens to estrone in the lipocytes evokes overproduction of estrone, which stimulates LH release and induces overproduction of androgens. Hyperandrogenemia is a cause of disturbance of the sexual function in obese women.
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PMID:[Obesity and disturbance of sexual function]. 939 4

The cardinal clinical features of PCOS are hirsutism and menstrual irregularity from anovulation. Obesity occurs in approximately 50% of hyperandrogenic anovulatory women, some of whom also have non-insulin-dependent diabetes mellitus. Underlying these clinical findings are several biochemical abnormalities, including LH hypersecretion, hyperandrogenism, acyclic estrogen production, decreased SHBG capacity, and hyperinsulinemia, all of which contribute to increased ovarian production of androgens, particularly T. A fundamental mechanism of ovarian hyperandrogenism in PCOS is LH hypersecretion. Whether the central nervous system is a possible locus for initiating LH hypersecretion remains unclear, because exaggerated LH secretion is temporarily reversed by induced ovulatory cycles or physiologic luteal concentrations of progesterone. On the other hand, desynchronization of pulsatile LH secretion from sleep in girls with PCOS and an exaggerated (e.g., masculinized) early LH response to GnRHa testing in women with hyperandrogenic anovulation and congenital adrenal virilizing disorders suggest that events occurring before puberty, perhaps during fetal life, may irreversibly alter neuroendocrine function. Hyperinsulinemia from insulin resistance is an important regulatory mechanism governing ovarian hyperandrogenism. Hyperinsulinemia in hyperandrogenic anovulatory women potentiates ovarian hyperandrogenism by enhancing LH secretion; potentiating 17-hydroxylase and, to a lesser extent, 17,20-lyase activity; and suppressing SHBG capacity. It is a key component of hyperandrogenic anovulation caused by a type of insulin resistance that in independent and additive to that of obesity alone. Although the mechanisms governing insulin action on ovarian steroidogenesis are unknown, abnormalities of intracellular insulin signaling or cytochrome P450c 17[alpha] activity may render the 17-hydroxylase/17,20-lyase enzyme complex more sensitive to insulin. Hyperinsulinemia in hyperandrogenic anovulatory women is accompanied by upper-body obesity characterized by an increased amount of abdominal fat. Upper-body obesity is an important independent risk factor for CVD and diabetes. Although genetic and environmental factors affect fat distribution, sex steroids, particularly androgens, regulate lipid metabolism, suggesting yet another link between the hormonal and metabolic abnormalities of hyperandrogenic anovulation. A careful history and physical examination guide the extent of diagnostic testing. Slowly progressive hirsutism with anovulation of peripubertal onset usually reflects hyperandrogenic anovulation. This type of clinical presentation requires an evaluation to rule out other endocrinopathies (e.g., virilizing tumors, adult-onset CAH, hyperprolactinemia, and Cushing's syndrome). Virilization or severe rapidly progressive hirsutism requires immediate investigation to rule out a possible virilizing tumor. The ultimate goals of therapy for hyperandrogenic anovulatory women are to normalize the endometrium, antagonize androgen action at target tissues, reduce insulin resistance, and correct anovulation, if necessary.
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PMID:Polycystic ovary syndrome. 942 64

Insulin secretion in response to an oral glucose tolerance test (OGTT) and sex hormone levels (free testosterone, androstenedione, dehydroepiandrosterone sulfate [DHEAS], estradiol, and sex hormone-binding globulin [SHBG]) were evaluated in 49 healthy obese premenopausal women (body mass index [BMI], 30 to 50.6 kg/m2) and 21 control subjects (BMI, 17.8 to 24.0 kg/m2) with normal glucose tolerance and without signs of hyperandrogenism. Obese women were divided into two groups according to waist to hip ratio (WHR): 27 subjects with upper-body obesity (WHR > 0.85) and 22 subjects with lower-body obesity (WHR < 0.8). Both fasting and glucose-induced insulin levels were higher in women with upper-body obesity than in controls (P < .001) and those with lower-body obesity (P < .001). Hyperandrogenism was observed in women with upper-body obesity, as evident by significantly elevated free testosterone (P < .05 v controls and subjects with lower-body obesity) and decreased SHBG (P < .001 v controls). The most important independent determinants of fasting insulin levels were BMI (P < .01) and the ratio of DHEAS to free testosterone (P < .01). The most important determinants of cumulative insulin response were WHR (P < .0005), duration of obesity (P < .01), and androstenedione levels (P < .01). In conclusion, in healthy obese premenopausal women without clinical signs of hyperandrogenism, a high BMI and more pronounced upper-body fat localization resulted in hyperinsulinemia and hyperandrogenism. The duration of obesity exaggerated the glucose-induced insulin level and cumulative insulin response independently of the degree of obesity and obesity type. The ratio of DHEAS to free testosterone was an independent determinant of fasting insulin concentration. Furthermore, the ratio of DHEAS to free testosterone rather than either of these androgens alone may be important in the regulation of insulin action in women.
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PMID:Hyperinsulinemia and sex hormones in healthy premenopausal women: relative contribution of obesity, obesity type, and duration of obesity. 944 Apr 71

Testosterone levels are decreased in obese men but increased in obese women. The interplay between gonadal steroids and leptin is, at present, far from being elucidated. This study was carried out to investigate the relationship between serum leptin, plasma insulin, insulin sensitivity and free testosterone in 46 men (29 obese and 17 lean) and 65 premenopausal women (42 obese and 23 lean). In all subjects, anthropometric parameters and serum levels of insulin, leptin, free testosterone (T), dehydroepiandrosterone sulphate and sex hormone-binding globulin were measured. An oral glucose tolerance test (OGTT) and an insulin tolerance test were also performed to determine the insulin sensitivity index. Our results show a significant difference in serum leptin between lean and obese men (3.19 +/- 0.71 vs. 20.28 +/- 0.26 ng mL-1; P < 0.0005) as well as between lean and obese women (10.78 +/- 2.14 vs. 34.79 +/- 2.26 ng mL-1; P < 0.00001). Basal T concentration in the obese men was significantly lower than in the control group (18.6 +/- 1.3 vs. 23.3 +/- 1.4 ng L-1; P < 0.01), whereas in the obese women it was significantly higher than in the control group (2.0 +/- 0.2 vs. 1.3 +/- 0.1 ng L-1; P < 0.05). When multiple linear regression was performed without body mass index (BMI) in the statistical model, leptin was correlated with basal insulin (P < 0.0001), insulin sensitivity (P < 0.0001) and T (P < 0.0001) in both men and women. When BMI was included in the model as an independent variable, leptin was significantly correlated only with BMI (P < 0.0001), the degree of insulin resistance (P < 0.05) and T (only in men, P < 0.05). This study confirms that serum leptin is strongly correlated with the degree of obesity and female sex. The negative correlation between leptin and T in men, independent of BMI, is consistent with the hypothesis that T may possess an inhibitory effect on adipocyte ob gene transcription.
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PMID:Gender differences in serum leptin in obese people: relationships with testosterone, body fat distribution and insulin sensitivity. 946 30


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