Doi:10.1016/j.fertnstert.2005.07.1312

A randomized controlled trial of the efficacy of
rosiglitazone and clomiphene citrate versus metformin
and clomiphene citrate in women with clomiphene
citrate–resistant polycystic ovary syndrome
Abdulrahim A. Rouzi, FRCSC,a and Mohammed Salleh M. Ardawi, Ph.D., F.R.C.Path.b a Department of Obstetrics and Gynecology, and b Clinical Biochemistry, Faculty of Medicine, King Abdulaziz University,Jeddah, Saudi Arabia Objective: To compare the efficacy of rosiglitazone and clomiphene citrate (CC) with metformin and CC in
women with CC-resistant polycystic ovary syndrome (PCOS).
Design: Randomized controlled trial (RCT).
Setting: A university teaching hospital in Jeddah, Saudi Arabia.
Patient(s): Twenty-five women with CC-resistant PCOS.
Intervention(s): Twelve women were assigned to the rosiglitazone and CC group, and 13 women were assigned
to the metformin and CC group for three treatment cycles. The first cycle was started on the first day of the period
with either rosiglitazone (4 mg twice daily) or metformin (500 mg three times daily) and continued for three
cycles. Clomiphene citrate (100 mg) from the third day for 5 days was added to each cycle.
Main Outcome Measure(s): Ovulation rate, number of follicles and estradiol (E ) on day 12 of the cycle,
pregnancy rate, and changes in fasting glucose, serum insulin, HbA , total testosterone (T), free T, luteinizing hormone (LH), follicle-stimulating hormone (FSH), dehydroepiandrosterone sulfate (DHEAS), ␦4-androstenedione
(␦4-A), sex hormone-binding globulin (SHBG), insulin-like growth factor (IGF)-1, insulin-like growth factor
binding protein (IGFBP)-1, and IGFBP-3.
Result(s): No significant differences were found in the baseline characteristics of both groups. Ovulation rate was
significantly higher in the rosiglitazone and CC group (18 out of 28 cycles [[64.3%]]) than the metformin and CC
group (12 out of 33 cycles [[36.4%]]) (Pϭ.035). Similarly, statistically significant differences were found in the
number of follicles Ն14 mm in the rosiglitazone and CC group (2.2 Ϯ 1) compared with the metformin and CC
group (1.1 Ϯ 0.9) (Pϭ.02) and E on day 12 of the cycle in the rosiglitazone and CC group (1,991 Ϯ 1,389
pmol/L) compared with the metformin and CC group (548 Ϯ 327) (PϽ.001). The pregnancy rate was also higherin the rosiglitazone and CC group (6 out of 12 [[50%]] women) than the metformin and CC group (5 out of 13[[38.5%]] women), but did not reach statistical significance (Pϭ.58). Both groups showed no significant changesin fasting plasma glucose or HbA or IGFBP-3 values. However, in both groups, fasting serum insulin, total T, free T, LH, DHEA-S, ␦4A, and IGF-1 levels decreased significantly, and SHBG and IGFBP-1 exhibited
significant increases.
Conclusion(s): These findings suggest that short-term use of rosiglitazone and CC is more efficacious than
metformin and CC in ovulation induction in women with CC-resistant PCOS. (Fertil Steril௡ 2006;85:
428 –35. 2006 by American Society for Reproductive Medicine.)
Key Words: Rosiglitazone, metformin, PCOS
Polycystic ovary syndrome (PCOS) is a common complex weight loss usually leads to decrease in insulin and androgen and heterogeneous endocrine disorder affecting up to 10% of levels with a marked improved fertility outcome Clomi- women of reproductive age It is frequently associated phene citrate (CC) is currently the first-line therapeutic modal- with insulin resistance (IR) and compensatory hyperinsulin- ity for women with infertility and PCOS. Ovulation occurs in emia. The IR is enhanced by the interaction between obesity 70%– 85% of women, but 33%– 45% achieve pregnancy If and the syndrome The hyperinsulinemia reportedly CC does result in ovulation, the American College of Obste- contributes significantly to the development of ovarian hy- tricians and Gynecologists recommends the use of the insu- perandrogenism and chronic anovulation commonly encoun- lin sensitizer metformin and CC regardless of whether there tered in women with PCOS. In obese women with PCOS, is insulin resistance or not Other insulin sensitizers fromthe thiazolidenediones family, namely troglitazone, piogilt- Received January 8, 2005; revised and accepted July 5, 2005.
azone, and rosiglitazone, have been used effectively in Supported by King Abdulaziz University (Grant no. 012/422), Jeddah, Reprint requests: Abdulrahim A. Rouzi, FRCSC, P.O. Box 80215, Jeddah Recently, the American Society for Reproductive Medi- 21589, Saudi Arabia (FAX: 9662-6408316; E-mail: aarouzi@hotmail.
com).
cine concluded that “based on the clinical evidence to date, Fertility and Sterilityா Vol. 85, No. 2, February 2006 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc.
the use of novel insulin sensitizers such as biguanides and recommended, and none of the women studied engaged in thiazolidenediones promise new treatment options for PCOS intensive aerobic activity during the study. All women ex- for both fertility and long-term disease prevention” The amined agreed to participate in the present study, and a largest published experience with insulin sensitizers in written informed consent was obtained from each woman.
PCOS women has been with metformin. It is a second- No financial support was provided for this study by either of generation biguanide used clinically in many different parts the drug companies that manufacture the insulin-sensitizing of the world to treat type 2 diabetes mellitus. The most drug, or by any other drug company. The institutional review common complaint with metformin is gastrointestinal symp- toms including diarrhea, nausea, vomiting, and abdominalbloating. Lactic acidosis is a rare risk among patients taking Experimental Protocol
this medication. This most commonly occurs in poorly con-trolled diabetes and impaired renal function All women were examined clinically, and weight, height,body mass index (BMI), waist-to-hip ratio (WHR), and Troligatazone has been removed from the market due to blood pressure readings were recorded. They were evaluated hepatotoxicity. The newer thiazolidenediones rosiglitazone on the first day of spontaneous cycle or withdrawal bleeding and pioglitazone appear to be safer in terms of hepatotoxic- after a 5-day course of medroxyprogestoerone acetate (MPA) ity. Rosiglitazone is a more potent member of thiazoli- (Pharmacia and Upjohn, Peapack, NJ), at 10 mg/day. Ve- denediones family, with 100-fold greater binding affinity for nous blood was collected between 8:00 AM and 11:00 AM peroxisome-proliferator-activated receptor gamma, which after an overnight fast. The following hormones were mea- decreases peripheral insulin resistance, than that of troglita- sured: follicle-stimulating hormone (FSH), luteinizing hor- zone Currently, no published studies are available to mone (LH), prolactin, thyroid-stimulating hormone (TSH), determine which insulin sensitizer is better in women with free thyroxin (FT4), total testosterone (T), free T, dehydro- PCOS. The objective of this study was to compare the epiandrosterone sulfate (DHEA-S), 17-OH-progesterone efficacy of rosiglitazone and CC with metformin and CC in (17-OH-P), and ␦4-androstenedione (␦4-A). Serum levels of sex hormone-binding globulin (SHBG) and insulin (insulin-like growth factor [IGF]-1, insulin-like growth factor bind-ing protein [IGFBP]-1, and IGFBP-3), together with plasma MATERIALS AND METHODS
glucose, were also measured. Each woman underwent an oral glucose tolerance test (OGTT) by ingesting a 75-g The women were recruited from the Infertility Clinic at King dextrose solution orally and collecting blood samples for the Abdulaziz University Hospital (KAUH), Jeddah, Saudi Ara- determination of plasma glucose and insulin at intervals for bia, from April 2002 to April 2004. The inclusion criteria for 2 hours according to World Health Organization (WHO) the study included women who were 20 – 40 years of age criteria The plasma glucose and serum insulin re- with primary infertility and PCOS, wanted to become preg- sponses to OGTT were analyzed by calculating the areas nant, had documented patent tubes by hysterosalpingogra- under the curves (AUC) by the trapezoidal rule using abso- phy, had no other infertility factor, and failed to ovulate with a dose of CC of 150 mg/day for 5 days from day 3 of theperiod.
After the OGTT the women were randomized by a re- search nurse into two groups: rosiglitazone (Avandia; Smith- The diagnosis of PCOS was based on the presence of Kline Beecham Pharmaceuticals, Philadelphia, PA) (4 mg oligomenorrhea (i.e., interval between periods was Ն35 twice daily) and CC (Clomid; Hoechst Marion Roussel, days) or amenorrhea (i.e., absence of vaginal bleeding for 6 Paris, France) (100 mg daily from the third day of the period months), hirsutism, enlarged ovaries with multiple follicles for five days), or metformin (Glucophage, Lipha Sante, (Ն10 measuring 2– 8mm in diameter) arranged peripherally Lyon, France) (500 mg three times daily) and CC (100 mg and scattered throughout the dense core of stroma on trans- daily) from the third day of the period for five days. The vaginal ultrasonography (which was performed by the same randomization was completed by opening sealed enve- two ultrasonographers), and/or elevated serum testosterone.
lopes containing numbers from a computer-generated ran- In addition, the diagnosis of PCOS was also based on the exclusion of other PCOS-like syndromes, including adrenaldysfunction, Cushing’s syndrome, congenital adrenal hyper- Women of both groups had transvaginal ultrasonography plasia, androgen-producing tumors, hyperprolactinemia, and on cycle day 12. Ovulation was determined by measuring P levels on cycle days 21, 24, and 28. Whenovulation was evident (a serum progesterone level Ͼ5.0 Women were excluded from the study if they were dia- ng/mL [15.9 nmol/L]) and a blood pregnancy test was pos- betic, were taking any medication that could influence car- itive, the woman was asked to discontinue rosiglitazone or bohydrate metabolism, had hypertension, had used gonado- metformin, and a pelvic ultrasound was arranged to docu- tropins, had undergone ovarian drilling, had IVF, or had ment the pregnancy. Women without evidence of ovulation abnormal renal or liver function tests. No restrictive diet was and with negative pregnancy test were asked to continue rosiglitazone or metformin, and were given another course of Matthews et al. High HOMA scores denoted IR. The MPA to initiate another treatment cycle. Similarly, women glucose (mmol/L)-to-insulin (pmol/L) ratio (GIR), proposed who ovulated but did not get pregnant continued rosiglita- as an index of peripheral insulin sensitivity was also zone or metformin. Starting on day 3 of the period or with- calculated. In the present study, both GIR and HOMA values drawal bleeding, CC (100 mg/day for 5 days) was added. The were used in part of the analysis to stratify women according same process was repeated for the third treatment cycle. No to IR. In the present study, IR was defined as an abnormal other co-interventions, such as hCG or IUI, were performed.
result in fasting serum insulin, GIR, or HOMA values asdetermined by threshold values of Ͼ95th percentile of the Safety measures included clinical assessment for adverse healthy normo-ovulatory lean control women group. These events and monitoring of complete blood count and renal values were fasting serum insulin Ͼ64.4 pmol/L; GIR and liver function tests at the end of each treatment cycle.
Ͻ9.53, and HOMA Ͼ3.82; respectively.
Tests performed at the baseline were repeated again on thefirst day of menses in women who did not become pregnantafter three cycles of rosiglitazone and CC or metformin and Statistical Analysis
CC. The primary outcome of the present study was ovulation Results are presented as means Ϯ SD, and data were rate, and the secondary outcomes included the number of analyzed using the SPSS Statistical Package, version 11.0 follicles and E on day 12 of the cycle, pregnancy rate, and for Windows (SPSS Inc., Chicago, IL). The Fisher’s exact changes in the fasting levels of plasma glucose and other test was used to analyze the differences in the rates of endocrine indices, including serum insulin, total T, free T, ovulation and pregnancy. Before treatment, variables be- LH, FSH, DHEAS, ␦4A, SHBG, IGF-1, IGFBP-1, IGFBP-3, tween the two groups were compared by using the Stu- dent’s t-test or the Mann-Whitney rank-sum test as ap-propriate. Comparisons for the changes in the valuesbefore and after treatment in both groups were made by using the Student two-tailed, unpaired t-test or the Mann- All hormones were measured by methods based on electro- Whitney rank-sum test. The differences were considered chemiluminescence immunoassay (ECLIA) using Elecsys 2010 Autoanalyzer System (Boehringer Mannheim, Mann-heim, Germany) with dedicated reagents obtained fromBoehringer Mannheim. The intra- and interassay coefficients of variation (CVs) for the hormones measured were as fol- During the study period, 360 women were evaluated for lows: FSH (1.6% and 4.5%); LH (1.1% and 2.9%); PROL infertility. Twenty-six women were eligible, but 25 entered (2.7% and 4.0%); TSH (4.3% and 5.1%); FT4 (2.1% and and completed the study. One woman refused to participate 4.3%); T (2.2% and 3.5%); free T (2.7% and 4.1%); E2 in the study before randomization. Three women were ex- (2.2% and 3.5%); insulin (3.0% and 4.5%); and DHEA-S cluded because of diabetes mellitus. Twelve women were (4.2% and 5.1%), respectively. ␦4-A (intra- and interassay assigned to the rosiglitazone and CC group, and 13 were CVs: 6.5% and 7.1%, respectively) was measured by EIA assigned to the metformin and CC group. All women Kits (Diagnostic Systems Laboratories, Inc., Webster, received and continued the assigned treatments, were Texas). 17-OH-P was measured with an ImmuChem Dou- available to follow up, and were included in the analysis.
ble Antibody [I125] RIA Kit (intra- and interassay CVs: The results were analyzed according to intention-to-treat 5.1% and 7.6%, respectively); (ICN Pharmaceuticals, Inc., principle. No significant differences were found in the base- Costa Mesa, CA); and SHBG with an immunoradiometric line characteristics of both groups The women assay (IRMA) kit (intra- and interassay CVs: 4.5% and studied were young (28.58 Ϯ 3.73, 23–36 years [mean 5.6%, respectively); (Orion Diagnostica, Espoo, Finland).
Ϯ SD, range] in the rosiglitazone and CC group and 27.38 Ϯ 4.29, 23–35 years in the metformin and CC group) but The IGF-1, IGFBP-1, and IGFBP-3 serum levels were obese, and all had abdominal obesity with a WHR greater measured by ELISA kits (intra- and interassay CV%: 3.8% than 0.8. Before treatment, 18 women were oligomenorrheic and 3.7% for IGF-1; 4.7% and 3.7% for IGFBP-1; and 5.5% (8 in rosiglitazone group vs. 10 in metformin group) and 7 and 4.8% for IGFBP-3, respectively) (Diagnostic Systems were amenorrheic. All studied women were insulin-resistant Laboratories, Inc.,). Glucose levels and renal (creatinine, urea) as indicated by their fasting insulin levels, GIR, and HOMA and liver (aspartate and alanine aminotransferases, bilirubin, values, whcih were Ͼ95th percentile of healthy, normo- albumin, alkaline phosphatase, and gama-glytamyltransferase) function tests were measured by methods using an Autoana-lyzer (Hitachi 912; Boehringer Mannheim) with dedicated In the rosiglitazone and CC group, 11 of 12 (91.7%) reagents obtained form Boehringer Mannheim. Insulin resis- women ovulated (18 out of 28 cycles [64.3%]) compared tance in the fasting state was assessed with homeostasis with 10 of 13 (76.9%) women (12 out of 33 cycles [36.4%]) model assessment (HOMA) and calculated with the follow- in the metformin and CC group. This was a statistically ing formula: fasting plasma glucose (mmol/L) ϫ fasting significant difference (Pϭ.035). Similarly, statistically sig- serum insulin (uU/mL) divided by 22.5 as described by nificant differences were found in the number of follicles Ն14 Rosiglitazone or metformin in PCOS
Baseline characteristics of women with PCOS before treatment.
Rosiglitazone group
Metformin group
Variable
P value
Note: Data are presented as mean Ϯ SD. NS ϭ not significant (PϾ.05); PCOS ϭ polycystic ovary syndrome; BMI ϭ body mass index; WHR ϭ waist-to-hip ratio; FSH ϭ follicle-stimulating hormone; LH ϭ luteinizing hormone; TSH ϭthyroid-stimulating hormone; FT4 ϭ free thyroxin; T ϭ testosterone; 17-OH-P ϭ 17-OH-progesterone; ⌬4-A ϭ ⌬4-androstenedione; DHEAS ϭ dehydroepiandrosterone sulfate; SHBG ϭ sex hormone-binding globulin; AUC ϭ areaunder the curve.
Rouzi. Rosiglitazone or metformin in PCOS. Fertil Steril 2006. mm in the rosiglitazone and CC group (2.2 Ϯ 1) (mean Ϯ SD) Both the rosiglitazone and CC and metformin and CC compared with the metformin and CC group (1.1 Ϯ 0.9) groups showed no significant changes in either fasting plasma (Pϭ.02) and E on day 12 of the cycle in the rosiglitazone and CC group (1,991 Ϯ 1,389 pmol/L) compared with the levels decreased significantly in both groups: by 50.4% in the metformin and CC group (548 Ϯ 327) (PϽ.001). In contrast, rosiglitazone and CC group (Pϭ.004) and by 49.9% in the no statistically significant difference was found in the preg- metformin and CC group (PϽ.001). The latter was accompa- nancy rate. Six of 12 (50%) women in the rosiglitazone and nied by a significant increase in the GIR values in both groups CC group became pregnant, whereas 5 of 13 (38.5%) women (93.4% vs. 123.1%, respectively) and a significant decrease in became pregnant in the metformin and CC (Pϭ0.58). These the HOMA values in both groups (50.9% vs. 50.6%), respec- findings have a power of 0.17 for ovulation, 0.79 for the tively, which confirm improvements in insulin sensitivity.
number of the follicles, 0.94 for E level, and 0.08 for pregnancy with an ␣ of 0.05 and two-tailed tests. The preg- The serum levels of IGF-1 before treatment were similar nancy rate per cycle was 21.4% for rosiglitazone and CC and in women of both groups, but a significant decrease was 15.2% for metformin and CC. The cumulative conception observed after treatment (by 27.8% in the rosiglitazone and curve for both groups is depicted in One twin CC group vs. 25.3% in the metformin and CC group), pregnancy occurred in the rosiglitazone and CC group. One although values remained within the reference ranges of first trimester abortion occurred in each group, and the rest of healthy age-matched non-PCOS women. Both groups exhib- the pregnant women completed their pregnancies with suc- ited significant increases in the serum levels of IGFBP-1 (by 86.9% in the rosiglitazone and CC group vs. 73.9% in the The cumulative conception curve. Straight line represents rosiglitazone and CC and broken line representsmetformin and CC.
Rouzi. Rosiglitazone or metformin in PCOS. Fertil Steril 2006. metformin and CC group, respectively). In addition, both 26 women were given PCOS treatment with metformin for 8 groups induced a significant decrease in the IGF-1:IGFBP-3 weeks and showed improved insulin sensitivity, lowered ratio (the mean percentage decrease was 28.4% in the ros- serum testosterone concentration (by 50%), and increased iglitazone and CC group vs. 26.3% in the metformin and CC SHBG. Furthermore, three pregnancies occurred. Subse- group). No significant changes were observed in the serum quently, several studies were published on the effects of metformin in women with PCOS. In a meta-analysis of Although both the rosiglitazone and CC and metformin randomized clinical trials between metformin vs. placebo or and CC groups exhibited a significant decline in the levels of no treatment, significantly increased ovulation rates (odds LH (by 22.6% vs. 25.6%), no significant differences were ratio 3.8 [95% CI 2.25 to 6.69]) and significant reduction in observed in the FSH values. However, there were significant fasting insulin (odds ratio Ϫ5.37 [95% CI Ϫ8.11 to Ϫ2.63]) decreases in the levels of total T (50.5% vs. 39.9%), free T were observed In contrast, some studies did not report (62.8% vs. 54.9%), ␦4A (26.3% vs. 19.8%) and DHEAS benefits from metformin therapy. Morbidly obese women (23.9% vs. 22.2%) in the rosiglitazone and CC and met- (BMI as high as 50 in one study and Ͼ37 in another study) formin and CC groups, respectively. Both groups showed with PCOS did not respond to metformin in the usual doses significant increases in the levels of SHBG in response to With respect to metformin and CC in women with CC-resistant PCOS, Nestler et al., showed that 19 out of 21 The BMI remained unchanged, and no significant changes (90%) obese women with CC-resistant PCOS ovulated in were observed in the liver or renal function tests or the response to metformin and CC therapy via decreasing insulin complete blood counts after treatment. One woman devel- secretion compared with 2 out of 25 (8%) women in the oped bilateral lower limb edema in early pregnancy after the corresponding placebo and CC control group Vander- use of rosiglitazone and CC. Her investigations were normal.
molen et al., in a multi-center RCT of 25 women with She was managed conservatively, and the edema subsided CC-resistant PCOS reported that metformin and CC treat- within 1 week. Four (31%) women in the metformin and CC ment increased ovulation rates as compared with the placebo complained of diarrhea, nausea, and abdominal bloating.
and CC (75% vs. 27%) and pregnancy rates (55% vs. 7%), These were mild, tolerated, and did not cause discontinua- respectively Moreover, Kocak et al., in a larger study involving 56 CC-resistant women with PCOS, demonstratedsignificantly higher ovulation rates in women treated with DISCUSSION
metformin and CC as compared with the placebo and CC In 1994, Velazquez et al. published the first report on the use group (77.7% vs. 14.2%) as well as greater pregnancy rates of metformin in women with PCOS In this case series, Rosiglitazone or metformin in PCOS
Endocrine and metabolic parameters of women with PCOS before and after treatment with
rosiglitazone or metformin.
Rosiglitazone group (n ؍ 6)
Metformin group (n ؍ 8)
Variable
P value
P value
Note: Data are presented as mean Ϯ SD. NS ϭ not significant (PϾ.05); FSH ϭ follicle-stimulating hormone; LH ϭ luteinizing hormone; T ϭ testosterone; ⌬4-A ϭ ⌬4-androstenedione; DHEAS ϭ dehydroepiandrosterone sulfate; SHBG ϭ sexhormone-binding globulin; GIR ϭ glucose-to-insulin ratio; HOMA ϭ homeostasis model assessment; IGF ϭ insulin-likegrowth factor; IGFBP ϭ insulin-like growth factor binding protein.
Rouzi. Rosiglitazone or metformin in PCOS. Fertil Steril 2006. Rosiglitazone and CC were also used to treat women with gested that pretreatment with metformin for 5 weeks should CC-resistant PCOS. Ghazeeri et al. treated 25 such women be given before starting CC This remains an area of with rosiglitazone and CC (13 women) or rosiglitazone and placebo (12 women) for 2 months only The primaryoutcome was ovulation rate; changes in insulin sensitivity In the present study, insulin-sensitizing therapy with ros- and androgens were some secondary outcomes. The ovula- iglitazone and CC or metformin and CC resulted in increased tion rate in women treated with rosiglitazone and CC was rates of ovulation (64.3% vs. 36.4%) and pregnancy (58.3% 77% compared with 33% in women treated with rosiglita- vs. 38.5%), respectively, in CC-resistant women with PCOS.
zone only. Belli et al. demonstrated that treatment with In addition, hyperinsulinaemia and hyperandrogenism were rosiglitazone decreased LH levels, improved IR parameters, also decreased. These findings were in agreement with pre- and normalized the menstrual cycles in women with IR and vious studies. Higher ovulation rates, number of follicles and PCOS More recently, Sepilian and Nagamani studied E on day 12 of the cycle, and the pregnancy rates that were the effect of 6-month rosiglitazone therapy in 12 obese observed in the present study (in the rosiglitazone and CC women with PCOS but with severe IR. Eleven (91%) women group as compared with that of the metformin and CC reverted to regular ovulatory cycling during the treatment group) suggest that rosiglitazone and CC may be the favor- able therapeutic modality for obese women with PCOS whodesire fertility.
In contradistinction with the previous studies of met- formin and CC or rosiglitazone and CC vs. placebo and CC, Both therapy groups showed an improvement in IR, as the present study intended to compare metformin and CC to indicated by the changes in the calculated values of GIR and rosiglitazone and CC. Furthermore, rosiglitazone or met- HOMA, which were associated with a decrease in the levels formin were started in the same treatment cycle with CC.
of serum insulin. The latter is consistent with the mechanism Recent studies documented the effectiveness of this ap- of rosiglitazone therapy, which was not accompanied by proach Currently, no clear recommendations exist on changes in fasting plasma glucose levels The studied how long the insulin sensitizer need to be given before women were not diabetic, and the duration of the therapeutic starting CC to achieve maximal success. It has been sug- intervention was relatively short to demonstrate any signif- icant changes in the levels of HbA . The rosiglitazone and women with PCOS suggest that the metabolic and reproduc- CC group showed significant decreases in the serum levels tive abnormalities might be related to the hyperinsulinaemia of LH, total T, free T, DHEAS, and ␦4-A, which were per se and not to any specific mechanism of IR.
accompanied by increase in the levels of SHBG. Similar Unlike metformin, rosiglitazone decreases hepatic fat con- results were obtained in the metformin and CC group. Ehr- tent and increases insulin sensitivity in muscles. These ef- mann et al. reported significant decreases in androgen levels fects make the drug more useful in patients with insulin accompanied by improved glucose tolerance, together with resistance. Adverse effects were reported with rosiglitazone decreased plasminogen activator inhibitor-1 activity, in therapy, including peripheral edema and slight decreases in women with PCOS who were treated with troglitazone hemoglobin and hematocrit. The idiosyncratic liver toxicity Ghazeeri et al. demonstrated significant decreases in the with troglitazone does not appear to be a class effect serum levels of LH, total T, and DHEAS with increase in Alanine aminotransferase levels more than 10 times the SHBG in CC-resistant women with PCOS The changes upper limit of normal were observed in 0.68% of patients in LH levels were different from that described in previous taking troglitazone, compared with none in the patients tak- studies in women with PCOS treated with troglitazone, ing rosiglitazone or pioglitazone. In the present study, one which showed decreases in circulating androgen levels but woman developed lower limb edema, which resolved spon- without any changes in LH values This was attrib- taneously. In contrast, 31% of the women receiving met- uted to the fact that the obese women with PCOS and severe formin therapy complained of gastrointestinal symptoms IR did not exhibit increased LH levels at baseline commonly reported in the literature, which may influence the Furthermore, More et al. demonstrated low LH levels in degree of compliance with using the drug.
obese women with PCOS but with severe IR Othershave suggested two possible distinct phenotypes of women In conclusion, it appears that in women with CC-resistant with PCOS: a low-LH high insulin group and a high-LH low PCOS, treatment with insulin sensitizers rosiglitazone or insulin group It is not clear whether the decrease in metformin is promising, although preference is given to the DHEAS levels observed in the present study was related to use of rosiglitazone as indicated by better therapy outcomes.
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