Prevalence of polycystic ovarian changes and polycystic ovary syndrome in premenopausal women with treated type 2 diabetes mellitus

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1 Prevalence of polycystic ovarian changes and polycystic ovary syndrome in premenopausal women with treated type 2 diabetes mellitus Fahrettin Kelestimur, M.D., a Kürşad Unluhizarci, M.D., a Hür Baybuga, M.D., a Hulusi Atmaca, M.D., b Fahri Bayram, M.D., a and Yılmaz Şahin, M.D. c a Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey; b Department of Endocrinology, Karaelmas University, Zonguldak, Turkey; and c Department of Obstetrics and Gynecology, Erciyes University Medical School, Kayseri, Turkey Objectıve: To investigate the prevalence of polycystic ovary syndrome (PCOS) and polycystic ovary (PCO) among premenopausal women with type 2 diabetes mellitus (DM). Desıgn: Case-control study of women with type 2 DM. Settıng: Tertiary referral university hospital. Patıent(s): Ninety-two premenopausal women with DM, 30 years of age, and 20 age- and body mass index matched healthy premenapousal eumenorrheic women were recruited into the study. Interventıon(s): An oral glucose tolerance test was performed according to the American Diabetes Association criteria for each healthy woman. After an overnight fasting, blood samples were obtained for the determination of fasting blood glucose, LH, FSH, free T, androstenedione (A 4 ), 17-hydroxyprogesterone (17-OHP), DHEAS, PRL, free T 4, TSH, E 2, and sex hormone binding globulin (SHBG) levels. A GnRH analog (buserelin) test was carried out in 36 patients with DM and PCO (including PCOS subjects), 20 patients with DM without PCO or PCOS, and 20 healthy subjects. Maın Outcome Measure(s): The prevalence of PCO and PCOS in women with type 2 DM. Result(s): Fifty-seven (62%) of diabetic patients had normal ovaries, 31 (33.7%) had PCO, and 4 (4.3%) had PCOS. The women with DM (n 92) and healthy women (n 20) had similar basal A 4, FSH, E 2, 17-OHP, free T, and DHEAS levels. The LH and SHBG levels were lower and the hirsutism score higher in diabetic patients than in healthy women (P.05). Peak and area under the curve LH and FSH levels after buserelin testing were significantly higher in healthy women than in the patients (P.05). Peak A 4 levels after buserelin were significantly higher in the patients than in the healthy women (P.05). Ovarian volume was significantly greater in the patients with PCO ( ml) than in the healthy women ( ml) (P.05). Conclusion(s): We conclude that PCO but not PCOS is a common finding in premenopausal women with type 2 DM. Suppression of gonadotropins, particularly LH secretion, may play a role in the absence of increased PCOS prevalence among type 2 diabetic patients. (Fertil Steril 2006;86: by American Society for Reproductive Medicine.) Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder which is characterized by menstrual abnormalities, hirsutism, and hyperandrogenemia. It is the most common endocrine disorder of women, affecting 5% 10% of women of reproductive age (1). Although the mechanisms underlying PCOS are not well understood, insulin resistance and hyperinsulinemia have been recognized in a large number of PCOS subjects (2, 3). It has been suggested that insulin resistance and hyperinsulinemia play an important role in the pathogenesis of this syndrome (3). Type 2 diabetes mellitus (DM) is the most common form of hyperglycemic state and is characterized by insulin resistance and compensatory hyperinsulinemia, particularly in obese subjects. Although obesity is an important contributing factor, insulin resistance and hyperinsulinemia are not Received October 22, 2005; revised and accepted January 13, Reprint requests: Fahrettin Kelestimur, M.D., Department of Endocrinology, Erciyes University Medical School, Kayseri, Turkey (FAX: ; fktimur@erciyes.edu.tr). solely related to obesity, and women with PCOS are candidates for type 2 DM (4 6). Because insulin resistance is common to both type 2 DM and PCOS, it would be expected that women with type 2 DM are at increased risk for PCOS. Although a number of studies have been performed regarding the prevalence of DM in women with PCOS, there are not enough data about the prevalence of PCOS and polycystic ovary (PCO) in women with type 2 DM. In this study, our aim was to investigate the prevalence of PCOS and PCO among women with premenopausal type 2 DM. MATERIALS AND METHODS The study was approved by the Ethics Committee of Erciyes University Medical School, and Institutional Review Board approval was obtained. Each woman gave informed consent. Ninety-two premenopausal women with DM, between 30 and 50 years of age, were recruited into the study from the outpatient clinic. Sixteen of the patients had newly diag /06/$32.00 Fertility and Sterility Vol. 86, No. 2, August 2006 doi: /j.fertnstert Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. 405

2 nosed DM, 17 had diet-controlled DM, 44 were receiving an oral antidiabetic agent, and 15 were receiving insulin treatment. Twenty healthy premenopausal eumenorrheic women without personal or family history of hirsutism, endocrine disorder, or DM and having normal ovarian appearance on ultrasonography served as the control group. All women had normal liver and renal function tests and none were taking any medication affecting ovarian function or carbohydrate metabolism. A complete clinical and laboratory evaluation was performed to exclude patients with androgen-secreting tumors of ovarian or adrenal origin, Cushing s syndrome, thyroid dysfunctions, 21-hydroxylase deficiency, or hyperprolactinemia. Hirsutism was defined according to the modified Ferriman-Gallwey scoring system (7) by one of the investigators in a blinded fashion, and a woman with a score of 8 points was considered clinically hirsute. An oral glucose tolerance test was conducted according to the American Diabetes Association criteria for each healthy woman between 7:30 and 10:00 in the morning. After a basal blood sample was obtained, a 75-g glucose load was administered orally and blood samples were obtained at 30 minute intervals for 2 hours for the measurement of blood glucose level. After an overnight fast, blood samples were obtained for the determination of fasting blood glucose, LH, FSH, free T, androstenedione (A 4 ), 17-hydroxyprogesterone (17-OHP), DHEAS, PRL, free T 4, TSH, E 2, and sex hormone binding globulin (SHBG) levels. Buserelin testing was performed as described previously (8). Briefly, at 8:00 a.m., after an overnight fast, blood samples were obtained for basal values and 1 mg buserelin (Suprefact, Hoechst, Germany) given SC, and blood samples were obtained at 6-hour intervals during 24 hours for determination of LH, FSH, 17-OHP, and A 4. Because the buserelin test requires a day of hospitalization, not all the patients accepted the test. Therefore, the test was carried out in 36 patients with DM and PCO (including 4 PCOS subjects), 20 patients with DM without PCO or PCOS, and 20 healthy subjects. The diagnosis of PCOS was made according to National Institutes of Health/National Institute of Child Health and Human Development (NIH/NICHHD) criteria (9). Pelvic ultrasound examinations were performed by the same investigator using a 3.5-MHz abdominal transducer and 6.5-MHz vaginal endoprobe (SDU-350 A; Shimadzu, Kyoto, Japan). The ultrasound diagnosis of PCO was made by the presence of 10 or more cysts, 2 10 mm in diameter, arranged around a dense stroma or scattered throughout an increased amount of stroma (10). We also reanalyzed the data according to the Rotterdam European Society for Human Reproduction & Embryology/American Society for Reproductive Medicine sponsored PCOS Consensus Workshop Group (11) and presented the results separately. The patients and healthy women were studied in the follicular phase (day 2 9) of their cycles with either regular cycles or oligomenorrhea or in the event that the patient was amenorrheic when serum P level was 8.0 nmol/l. The ovarian volume was obtained using a formula for the volume of an ellipsoid ( /6 length height width), and the volume of both ovaries gave the total ovarian volume (12). Assays Serum A 4 (DPC; Diagnostic Products Corporation, Los Angeles, CA), free T (DSL, Diagnostic Systems Laboraties, Inc., Webster, TX), 17-OHP, and DHEAS (ICN; ICN Biomedicals, Inc., Costa Mesa, CA) were measured by radioimmunoassay, FSH (ACS 180; Bayer, New York, NY) and LH (ACS 180; Bayer) were measured by chemiluminescence assay, and SHBG levels were measured by Immunoradiometric assay (Orion Diagnostica, Espoo, Finland) using commercial kits. Intra- and interassay coefficients of variation were, respectively, 3.6% and 7.5% for FSH, 6.8% and 7.3% for LH, 3.7% and 7.9% for free T, 9% and 9.5% for DHEAS, 7.8% and 9.8% for 17-OHP, and 4.6% and 5.1% for SHBG. All samples from the same patients were assayed in the same assay. Data are presented as mean SEM. Statistical significance was considered to be P.05. Comparisons between the patients and the control group were made with the use of independent samples t test. RESULTS The patients with DM and healthy subjects were comparable with respect to age and body mass index.the women with DM and healthy women had similar basal A 4, FSH, E 2, 17-OHP, free T, and DHEAS levels. Although within normal limits and having no clinical significance, hirsutism score was significantly higher in the diabetic patients than in the healthy women (P.05). The LH and SHBG levels were lower in the diabetic patients than in the healthy women (P.05). The data are shown in Table 1. Fifty-seven (62%) of diabetic patients had normal ovaries, 31 (33.7%) had PCO, and 4 (4.3%) had PCOS. Buserelin testing was carried out in 56 patients with DM. Peak and area under the curve (AUC) FSH and LH levels after buserelin testing were significantly lower (P.05), and peak and AUC A 4 levels after buserelin were significantly higher (P.05) in patients than in healthy women (Table 2). After excluding the PCOS subjects, peak FSH, LH, AUC FSH, and AUC LH levels were significantly lower (P.05) and peak and AUC A 4 levels higher in the patients with DM than in the healthy subjects (Table 3). When we compared the patients with DM and normal ovaries with the patients with DM and PCO; ovarian volume was significantly greater (P.005) in the patients with PCO 406 Kelestimur et al. PCOS and type 2 diabetes mellitus Vol. 86, No. 2, August 2006

3 TABLE 1 Comparison of patients with diabetes mellitus and healthy women. Characteristic Diabetes mellitus (n 92) Control (n 20) P value Ovarian volume (ml) NS Age (y) NS Hirsutism score Body mass index (kg/m 2 ) NS FSH (miu/ml) NS LH (miu/ml) E 2 (pg/ml) NS 17-OHP (ng/ml) NS A 4 (ng/ml) NS Free T (pg/ml) NS SHBG (nmol/l) DHEAS (ng/ml) NS LH/FSH NS Note: Values presented as mean SEM. NS not significant. Other abbreviations as in text. Kelestimur. PCOS and type 2 diabetes mellitus. Fertil Steril ( ml) than in the patients with normal ovaries ( ml). After the exclusion of the patients and control subjects over 40 years of age, we had 53 patients with type 2 DM and 12 controls. All the patients with DM and PCOS were 40 years of age. In that case, the prevalance of PCOS becomes 7.5% (4 of 53 patients). When we excluded the data of the patients using insulin therapy, we had 77 patients with DM. Among the patients with DM and PCOS there was only one using insulin therapy. That patient s basal hormonal values were not different (in terms of statistical significance) from the whole original group. When we reanalyzed our data applying the definition of the new PCOS criteria we found that four additional patients had PCOS. In accordance with that criteria, the prevalence of PCOS was 8.7%. However, unless otherwise indicated the prevalance of PCOS is given according to NIH/NICHHD criteria. DISCUSSION Polycystic ovary syndrome is one of the most common endocrinologic disorders of women during reproductive age. It has been recognized that many patients with PCOS exhibit metabolic alterations, and PCOS patients need to be followed for developing type 2 DM. TABLE 2 Peak FSH, LH, E 2,A 4, and 17-OHP responses to buserelin stimulation test in patients with diabetes mellitus and healthy control subjects. Characteristic Diabetes mellitus (n 56) Control (n 20) P value FSH (miu/ml) LH (miu/ml) E 2 (pg/ml) NS A 4 (ng/ml) OHP (ng/ml) NS AUC FSH (miu/ml 24 h) AUC LH (miu/ml 24 h) AUC E 2 (pg/ml 24 h) NS AUC A 4 (ng/ml 24 h) AUC 17-OHP (ng/ml 24 h) NS Note: Values are mean SEM. NS not significant. Other abbreviations as in text. Kelestimur. PCOS and type 2 diabetes mellitus. Fertil Steril Fertility and Sterility 407

4 TABLE 3 Peak and AUC FSH, LH, E 2,A 4, and 17-OHP responses to buserelin stimulation test in patients with diabetes mellitus (excluding PCOS) and healthy control subjects. Characteristic Diabetes mellitus (n 52) Control (n 20) P value FSH (miu/ml) LH (miu/ml) E 2 (pg/ml) NS A 4 (ng/ml) OHP (ngl/ml) NS AUC FSH (miu/ml 24 h) AUC LH (miu/ml 24 h) AUC E 2 (pg/ml 24 h) NS AUC A 4 (ng/ml 24 h) AUC 17-OHP (nmol/l 24 h) NS Note: Data presented as mean SEM. NS not significant. Other abbreviations as in text. Kelestimur. PCOS and type 2 diabetes mellitus. Fertil Steril Type 2 DM is a heterogeneous metabolic disorder characterized by combination of resistance to insulin action and compensatory hyperinsulinemia, at least during the evolution of the disease. Because insulin resistance has a key role in the pathogenesis of PCOS, it would be expected that PCOS is more common in women with type 2 DM. But there are not enough data about the prevalence of PCOS in women with type 2 DM. We have found a 4.3% prevalence of PCOS among women with type 2 DM, which is not higher than the 5% 10% prevalence of PCOS reported in studies of unselected reproductive-age women. Excluding the patients 40 years and a patient using insulin therapy did not result in a higher prevalance of PCOS than that in the general population. Peppard et al. (13) reported that the prevalence of PCOS in women with type 2 DM was 26.7%, which is significantly higher than what we found. The former study, however, was a review of medical records of only 30 women. Eight women who had a menstrual history of oligomenorrhea were invited to undergo further evaluation, but only five of them could be evaluated. The other diabetic women were not investigated hormonally, and no control women were included in the study. Zargar et al. (14) investigated the prevalance of PCO and PCOS in 105 women with diet- and/or oral hypoglycemic treated type 2 DM and 60 nondiabetic control women. They found that 61% of women with type 2 DM had PCO and 37% had PCOS. Although the prevalances were higher than that in the present study, PCO and PCOS were found in 36.7% and 25%, respectively, of the control subjects. The authors suggested that the prevalance of PCO was higher in type 2 DM. Escobar-Morreale et al. (15) evaluated the prevalence of PCOS and hirsutism in 85 women with type 1 DM. Only basal hormone levels were measured in that study. Thirtyeight percent of the patients had hyperandrogenism, and 18.8% had PCOS, which is considerably higher than the 6.5% prevalence of PCOS that they recently reported in a group of unselected nondiabetic caucasian women (16). In contrast, we investigated the women with type 2 DM and control subjects in detail. We not only measured basal hormone levels but also evaluated the pituitary-gonadal axis by a GnRH (buserelin) test. Buserelin test gives information about ovarian steroidogenesis. Basal LH level was lower in the women with type 2 DM than that found in the control subjects. Buserelin-stimulated LH levels also were significantly lower in the patients than in the control subjects. These findings clearly show that LH secretion, either in basal state or after GnRH stimulation, is suppressed in the patients with DM. South et al. (17) investigated the hypothalamic and/or pituitary abnormalities in women with poorly controlled insulin-dependent DM and found fewer LH secretory episodes per 24 h. In an another study, Corio et al. (18) suggested that a hypothalamopituitary disorder affects LH secretion with time after the onset of type 1 DM. Overall, we think that the diabetic millieu may result in hypothalamopituitary dysfunction in women with DM. Patients with DM had significantly lower SHBG levels compared with control subjects. Sex hormone binding globulin is an accepted marker of muscular insulin resistance, and its low level is associated with a higher risk for the development of type 2 DM (19). Lower SHBG levels have been reported in gestational DM (19, 20) and in patients with type 1 DM(21). Although drugs might alter serum SHBG levels, our results are an additonal clue for decreased SHBG levels in patients with DM. 408 Kelestimur et al. PCOS and type 2 diabetes mellitus Vol. 86, No. 2, August 2006

5 Although basal A 4 levels were within normal limits and were not different from healthy subjects, peak and AUC levels were higher in patients with type 2 DM. Higher androstenedione levels were reported in type 1 DM previously (15). There is no clear explanation for the increased buserelin-stimulated A 4 levels in our study; however, Stamataki et al. (22) suggested that the ovaries have a reduced ability to convert androgens to estrogen, probably owing to a reduction of ovarian aromatase activity. Although polycystic ovarian changes have been accepted as a diagnostic criteria, the significance of PCO in the diagnosis of PCOS has been debated extensively. It has been shown that 21% 23% of normally cycling women may have PCO (23, 24). It has been suggested that PCOS is a complex metabolic condition, rather than simply a morphologic problem of the ovaries, because polycystic ovarian changes may be associated with other conditions (25). Holte et al. (26) reported a higher prevalence of PCO detected by ultrasonography (41%) in a group of 34 women with a previous history of gestational DM. Those patients had similar plasma gonadotropin and androgen levels. Conn et al. (27) investigated the prevalence of PCO in premenopausal women with type 2 DM in a cross-sectional study. The study included only 38 women who represented at least seven different ethnic origins, which is an important factor in terms of the prevalence of PCOS. Some basal hormone levels were measured, but ovarian steroid responses to a GnRH analogue were not investigated. Eightytwo percent of the women had ultrasonographic evidence of PCO. Only A 4 was significantly different between PCO and non-pco women. The authors concluded that the prevalence of PCO was more common in women with type 2 DM than in the general population and that because all women with hyperinsulinemia due to type 2 DM did not develop PCO, hyperinsulinemia alone is not sufficient for the expression of this ovarian morphology. Most of the studies mentioned support the possibility that the risk for PCOS is significantly higher among premenoposal women with type 2 DM. Nonetheless, these studies were small and retrospective and/or used only a morphologic appearence of ovaries as an important marker of PCOS. By performing a larger and controlled study, we have found that PCOS is not higher than expected in women with type 2 DM. The 2003 revised consensus criteria (11) was not published yet when we were performing this study. Compared with the NNIH/NICHHD criteria, the most important factor is the consideration of polycystic ovarian changes as a diagnostic criteria. 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