Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome.

CONTEXT: Adults with polycystic ovary syndrome (PCOS) may be at increased risk for metabolic syndrome (MBS) and related cardiovascular disease. It is not clear whether PCOS diagnosed in adolescence increases the risk of MBS in this age group. OBJECTIVE: The aim was to compare the prevalence and related characteristics of MBS in obese adolescents with and without PCOS. DESIGN: We conducted a cross-sectional study of overweight and obese PCOS adolescents and BMI matched controls. PATIENTS AND PARTICIPANTS: A total of 74 subjects, 43 with PCOS and 31 controls, participated in the study. INTERVENTIONS: Each subject underwent a physical examination and laboratory evaluation for a diagnosis of MBS. Regional fat distribution was determined by computerized tomography scan in the PCOS adolescents. MAIN OUTCOME MEASURES: We measured the prevalence of MBS and its components in adolescent subjects and controls. RESULTS: The PCOS group had larger ovarian volume and higher measures of total testosterone and free androgen index than controls, but there were no differences in waist circumference, fasting glucose, blood pressure, or lipids. PCOS adolescents demonstrated more glucose abnormalities and higher plasminogen activator inhibitor-1. By pediatric criteria, 53% of the PCOS and 55% of the control adolescents had MBS. By adult criteria, 26% of PCOS and 29% of controls met diagnostic criteria for MBS. CONCLUSIONS: Obese adolescent women have a high prevalence of MBS, and PCOS does not add additional risk for MBS. There appears to be an association between MBS and visceral adiposity. PCOS is associated with increased incidence of glucose intolerance and increased plasminogen activator inhibitor-1. Our results reinforce the importance of obesity counseling in adolescents to recognize the possible risk of future cardiovascular disease in these young women.

The impact of metformin, oral contraceptives, and lifestyle modification on polycystic ovary syndrome in obese adolescent women in two randomized, placebo-controlled clinical trials.

CONTEXT: Polycystic ovary syndrome (PCOS) presents in adolescence, and obesity is a common finding. The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear. OBJECTIVE: We investigated the effects of metformin, oral contraceptives (OCs), and/or lifestyle modification in obese adolescent women with PCOS. DESIGN: Two small, randomized, placebo-controlled clinical trials were performed. PATIENTS AND PARTICIPANTS: A total of 79 obese adolescent women with PCOS participated. INTERVENTIONS: In the single treatment trial, subjects were randomized to metformin, placebo, a lifestyle modification program, or OC. In the combined treatment trial, all subjects received lifestyle modification and OC and were randomized to metformin or placebo. MAIN OUTCOME MEASURES: Serum concentrations of androgens and lipids were measured. RESULTS: Lifestyle modification alone resulted in a 59% reduction in free androgen index with a 122% increase in SHBG. OC resulted in a significant decrease in total testosterone (44%) and free androgen index (86%) but also resulted in an increase in C-reactive protein (39.7%) and cholesterol (14%). The combination of lifestyle modification, OC, and metformin resulted in a 55% decrease in total testosterone, as compared to 33% with combined treatment and placebo, a 4% reduction in waist circumference, and a significant increase in HDL (46%). CONCLUSIONS: In these preliminary trials, both lifestyle modification and OCs significantly reduce androgens and increase SHBG in obese adolescents with PCOS. Metformin, in combination with lifestyle modification and OC, reduces central adiposity, reduces total testosterone, and increases HDL, but does not enhance overall weight reduction.

Ovulation induction management of PCOS.

Ovulation induction is the principal infertility treatment for women with polycystic ovarian syndrome (PCOS). Among PCOS patients who are overweight or obese, weight loss is the most physiologic method of inducing ovulation. For women in whom weight loss is not possible, or for lean women with PCOS, clomiphene citrate is an effective first-line method of ovulation induction. In clomiphene-resistant women, alternative treatments include adjunctive metformin or dexamethasone, aromatase inhibitors, or ovarian drilling. If there is no pregnancy despite several cycles of successful ovulation induction, gonadotropin treatment should be considered, in which case in vitro fertilization is recommended as the safest and most effective strategy.

Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial.

OBJECTIVE: To assess the effect of low-dose mifepristone on quality of life, pain, bleeding, and uterine size among women with symptomatic leiomyomata. METHODS: Forty-two women with symptomatic uterine leiomyomata and uterine volume of 160 mL or more were randomized to mifepristone, 5 mg daily, or placebo for 26 weeks. Quality of life (Uterine Fibroid Symptoms Quality of Life Questionnaire and Medical Outcomes Study 36-Item Short Form survey) and uterine and leiomyoma size (ultrasonography) were assessed at baseline, and at 1 month, 3 months, and 6 months of treatment. Bleeding (daily logs and pictorial charts) and pain (McGill Pain Questionnaire) were assessed monthly. Endometrial pathology was assessed at baseline and 6 months. RESULTS: Forty-two women were randomized; 37 women completed all 6 months. Women randomized to mifepristone showed an improvement in leiomyoma-specific quality of life. Forty-one percent became amenorrheic, rates of anemia improved, and adjusted uterine size was reduced by 47%. Compared with the placebo group, improvements in these outcomes in the treatment group were significantly greater (P<.05 to .001). There were no significant differences in adverse effects between the groups. No endometrial hyperplasia was noted in any participant. CONCLUSION: Low-dose mifepristone improves leiomyoma-specific quality of life and reduces leiomyoma size among women with symptomatic leiomyomata. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov www.clinicaltrials.gov NCT00133705 LEVEL OF EVIDENCE: I.

Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial.

OBJECTIVE: To compare the efficacy of gabapentin, estrogen, and placebo in the treatment of hot flushes. METHODS: We performed a randomized, double-blind, placebo-controlled trial of 60 postmenopausal women to assess the efficacy of estrogen and gabapentin in the treatment of moderate-to-severe hot flushes. Participants were randomly assigned to receive either 0.625 mg/d of conjugated estrogens (n = 20), placebo (n = 20), or gabapentin titrated to 2,400 mg/d (n = 20) for 12 weeks. Participants recorded frequency and severity of baseline hot flushes on a hot flush diary for 2 weeks before randomization and for 12 weeks after randomization. The primary outcome measure was the weekly hot flush composite score, which takes into account both severity and frequency of hot flushes. Secondary outcome measures were differences in pre- and posttreatment scores pertaining to depression (Zung Depression Scale) and other climacteric symptoms (Greene Climacteric Scale). RESULTS: Intention-to-treat analysis showed that the reduction in the hot flush composite score for both estrogen (72%, P = .016) and gabapentin (71%, P = .004) was greater than the reduction associated with placebo (54%) at the conclusion of the 12th week. The extent of reduction in hot flush composite score, however, was not significantly different between estrogen and gabapentin (P = .63). No differences were seen between groups in the Zung Depression Scale, or in any of the Greene Climacteric subscales except for the Somatic Symptom cluster, which was significantly greater in the gabapentin arm than in the placebo arm. Despite a lack of group differences in adverse events, the Headache, Dizziness, and Disorientation cluster appeared with greater frequency in the gabapentin group. Estimation of the number needed to harm in this cluster suggests that these symptoms may occur with every fourth patient treated with gabapentin. CONCLUSION: Despite the small scale of this study, gabapentin appears to be as effective as estrogen in the treatment of postmenopausal hot flushes. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT 00276081. LEVEL OF EVIDENCE: I.

Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas.

STUDY OBJECTIVES: The primary aim was to assess long-term effects of low-dose mifepristone on myoma regression, symptoms, and endometrial pathology. The secondary aim was to assess regrowth of myomas after cessation of mifepristone. DESIGN: Prospective, open-label, randomized, controlled trial of 5 mg versus 10 mg mifepristone daily for 1 year, in women with large, symptomatic myomas, with variable follow-up among a subset of subjects (Canadian Task Force classification II-2). SETTING: University research group set in a community hospital. PATIENTS: Forty premenopausal women with large, symptomatic myomas. INTERVENTION: Oral mifepristone 5 or 10 mg daily for 1 year. MEASUREMENTS AND MAIN RESULTS: Mean uterine volumes decreased in both groups by 48% after 6 months of mifepristone and by 52% to 53 % in both groups after 12 months. Amenorrhea occurred in 61% to 65% at 6 months, and 40% to 70 % at 12 months. Eighty endometrial biopsies were performed. Simple hyperplasia was seen in 5 (13.9 %) of 36 subjects at 6 months and 1 (4.8 %) of 21 at 12 months. All cases of hyperplasia occurred in the 10 mg group. No endometrial sample showed cytologic atypia. Nine women were followed posttreatment for an average of 5.7 months. Uterine volumes increased among most of these subjects, although they remained on average 42% less than baseline. CONCLUSIONS: Long-term administration of low-dose mifepristone results in myoma shrinkage and amelioration of symptoms; modest rates of low-grade endometrial hyperplasia, but no evidence of premalignant potential, also occur. Regrowth occurs slowly following cessation of the drug.

Histological dating of timed endometrial biopsy tissue is not related to fertility status.

OBJECTIVE: To assess the ability of histological dating to discriminate between women of fertile and infertile couples. The utility of histological dating of endometrium in the evaluation of infertile couples is uncertain. DESIGN: Prospective multicenter study, with subjects randomly assigned to biopsy timing. Criterion standard for infertility was 12 months of unprotected, regular intercourse without conception and for fertility at least one live birth within 2 years. SETTING: University-based infertility practices. PATIENT(S): Volunteer subjects (847) recruited at 12 clinical sites participating in the National Institutes of Health-funded Reproductive Medicine Network. Inclusion criteria included ages 20-39 years, regular menstrual cycles, and no hormonal treatment or contraceptive use for 1 month before the study. Fertile controls were excluded if they had a history of infertility, recurrent pregnancy loss, or recent breastfeeding. INTERVENTION(S): Subjects underwent daily urinary LH testing. After detection of the LH surge, subjects were randomized to biopsy in the mid (days 21-22) or the late (days 26-27) luteal phase. Pathologists at each site estimated the cycle day based on standard criteria. For the primary analysis, an out-of-phase biopsy was defined as a greater than 2-day delay in the histological maturation of the endometrium. MAIN OUTCOME MEASURE(S): The proportion of out-of-phase biopsies in fertile and infertile women was compared using logistic regression models with age at randomization as a covariate. Comparisons were also made between fertile vs. infertile at the midluteal or late luteal phase time points. RESULT(S): Biopsies were evaluated (301 mid and 318 late; N = 619). Out-of-phase biopsy results poorly discriminated between women from fertile and infertile couples in either the midluteal (fertile: 49.4%, infertile: 43.2%) or late luteal phase (fertile: 35.3%, infertile 23.0%). Results did not substantially differ using alternative definitions of "out-of-phase" or standardized cycle day. CONCLUSION(S): Histological dating of the endometrium does not discriminate between women of fertile and infertile couples and should not be used in the routine evaluation of infertility.

A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study.

OBJECTIVE: To obtain data from a pilot randomized trial on the effect of metformin therapy and lifestyle modification on ovulation and androgen concentrations in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective, randomized, placebo-controlled pilot trial. SETTING: Academic medical center. PATIENT(S): Thirty-eight overweight or obese women with PCOS. INTERVENTION(S): All subjects were randomized to one of four 48-week interventions: metformin 850 mg two times per day, lifestyle modification plus metformin 850 mg two times per day, lifestyle modification plus placebo, or placebo alone. MAIN OUTCOME MEASURE(S): Recruitment, dropout, and compliance with a long-term lifestyle intervention in PCOS; preliminary estimates of treatment effect on ovulation, as measured by weekly urinary pregnanediol glucuronide, and on total T and free androgen index. RESULT(S): It was necessary to screen seven women to have one subject randomized. The dropout rate was 39%, with the majority of dropouts occurring within the first 24 weeks. Mean body mass index was >39 mg/kg(2). Modest weight reduction was found in all treatment groups, with the most significant reduction occurring with the combination of metformin and lifestyle intervention. Significant androgen reduction occurred in the combination group only. Ovulation rates did not differ significantly between groups. However, when data were analyzed by presence or absence of weight reduction in subjects, independent of treatment group, the estimated odds ratio for weight loss was 9.0 (95% confidence interval 1.2-64.7) with respect to regular ovulation. If weight loss occurred during metformin therapy, the odds ratio for regular ovulation was 16.2 (95% confidence interval 4.4-60.2). CONCLUSION(S): Key methodologic issues for a large-scale, randomized trial of lifestyle intervention in PCOS include minimizing early dropout from the lifestyle intervention and including a range of body mass index that is not skewed toward severe obesity. Weight reduction might play the most significant role in restoration of ovulation in obese women with PCOS.

Polycystic ovary syndrome.

Women with polycystic ovarian syndrome have chronic anovulation and androgen excess not attributable to another cause. This condition occurs in approximately 4% of women. The fundamental pathophysiologic defect is unknown, but important characteristics include insulin resistance, hyperandrogenism, and altered gonadotropin dynamics. Inadequate follicle-stimulating hormone is hypothesized to be a proximate cause of anovulation. Obesity frequently complicates polycystic ovarian syndrome but is not a defining characteristic. The diagnostic approach should be based largely on history and physical examination, thus avoiding numerous laboratory tests that don't contribute to clinical management. Women with polycystic ovarian syndrome typically present because of irregular bleeding, hirsutism, and/or infertility. These conditions can be treated directly with oral contraceptives, oral contraceptives plus spironolactone, and ovulation induction, respectively. However, women with polycystic ovarian syndrome also have a substantially higher prevalence of diabetes and increased risk factors for cardiovascular disease. They should also be screened, therefore, for these conditions and followed closely if any risk factors are uncovered. For obese women with polycystic ovarian syndrome, behavioral weight management is a central component of the overall treatment strategy.

Low-dose mifepristone for uterine leiomyomata.

OBJECTIVE: To compare the effect of 5 and 10 mg of mifepristone on uterine leiomyoma size and symptoms, and to measure side effects. METHODS: Forty premenopausal women with large, symptomatic leiomyomata were randomized to receive either 5 or 10 mg of mifepristone daily for 6 months in an open-label study. Uterine volume was measured at bimonthly intervals by sonography. Serum concentrations of hemoglobin levels, follicle-stimulating hormone, and liver enzymes were obtained, and endometrial samples, symptoms, and menstrual bleeding were also assessed. RESULTS: Nineteen of 20 subjects taking 5 mg and all 20 subjects taking 10 mg completed all 6 months of the study. Mean uterine volume shrank by 48% (P <.001) in the 5-mg group and 49% (P <.001) in the 10-mg group, a nonsignificant difference. Leiomyoma-related symptoms were comparably reduced in both groups. Amenorrhea occurred in 60-65% of both groups. Hemoglobin levels increased by 2.5 g/dL in anemic subjects. The incidence of hot flashes increased significantly over baseline in the 10-mg group but not in the 5-mg group. Simple endometrial hyperplasia occurred in 28% of all subjects, with no difference between groups. No atypical hyperplasia was noted. CONCLUSION: Mifepristone in doses of 5 mg or 10 mg results in comparable leiomyoma regression, improvement in symptoms, and few side effects. Further study is needed to assess the long-term safety and efficacy of low-dose mifepristone.