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Anovulation in reproductive years [keywords]
- Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: evidence from 1345 women with the syndrome. [Journal Article]
- Eur J Endocrinol 2014 Sep; 171(3):301-9.
Polycystic ovary syndrome (PCOS) represents a moving spectrum of hormonal to metabolic abnormalities, as women with the syndrome are aging. Hormonal abnormalities, anovulation, and hyperandrogenic signs were predominant during the early years of PCOS and fade away with the years. Metabolic abnormalities and insulin resistance (IR) remain throughout the PCOS life cycle; however, it is unclear as to how they change, as women with the syndrome are aging.To evaluate the changes in IR and its associations with clinical, biochemical, hormonal, and ultrasound findings in a large cohort of women with PCOS and controls, as they are aging.A cross-sectional study was carried out to evaluate the diverse impacts of aging on IR.An outpatient clinic was chosen for the study.A total of 1345 women with PCOS (Rotterdam criteria) and 302 controls of Caucasian origin and Greek ethnicity comprised the study group.The impact of age on IR, as calculated using homeostasis model assessment of IR (HOMA-IR) index, and several PCOS characteristics were evaluated.In PCOS, age (-0.045±0.008) was negatively, and BMI positively (0.18±0.007) associated with HOMA-IR (R(2)=0.36). When data were stratified with regard to the BMI status, a negative association of age with HOMA-IR was found in lean, normal, and overweight patients (r: -0.266, -0.233, -0.192, P<0.001), which was neutralized in obese patients (r: -0.009, P: NS). Free androgen index and BMI were positively associated with HOMA-IR in all age quartiles. When mean HOMA-IR values were plotted according to BMI subgroups at different age quartiles, a significant gradual decrease in HOMA-IR was observed in normal (P<0.001) and overweight (P: 0.004), but not obese, women (P: 0.202) across age quartiles.Aging increases IR in obese but not in lean and overweight women with PCOS. As BMI and androgens are positively associated with HOMA-IR and androgens decline through time, it appears that if women with PCOS do not become obese they may exhibit a better metabolic profile during their reproductive years.
- Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. [Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural]
- N Engl J Med 2014 Jul 10; 371(2):119-29.
Clomiphene is the current first-line infertility treatment in women with the polycystic ovary syndrome, but aromatase inhibitors, including letrozole, might result in better pregnancy outcomes.In this double-blind, multicenter trial, we randomly assigned 750 women, in a 1:1 ratio, to receive letrozole or clomiphene for up to five treatment cycles, with visits to determine ovulation and pregnancy, followed by tracking of pregnancies. The polycystic ovary syndrome was defined according to modified Rotterdam criteria (anovulation with either hyperandrogenism or polycystic ovaries). Participants were 18 to 40 years of age, had at least one patent fallopian tube and a normal uterine cavity, and had a male partner with a sperm concentration of at least 14 million per milliliter; the women and their partners agreed to have regular intercourse with the intent of conception during the study. The primary outcome was live birth during the treatment period.Women who received letrozole had more cumulative live births than those who received clomiphene (103 of 374 [27.5%] vs. 72 of 376 [19.1%], P=0.007; rate ratio for live birth, 1.44; 95% confidence interval, 1.10 to 1.87) without significant differences in overall congenital anomalies, though there were four major congenital anomalies in the letrozole group versus one in the clomiphene group (P=0.65). The cumulative ovulation rate was higher with letrozole than with clomiphene (834 of 1352 treatment cycles [61.7%] vs. 688 of 1425 treatment cycles [48.3%], P<0.001). There were no significant between-group differences in pregnancy loss (49 of 154 pregnancies in the letrozole group [31.8%] and 30 of 103 pregnancies in the clomiphene group [29.1%]) or twin pregnancy (3.4% and 7.4%, respectively). Clomiphene was associated with a higher incidence of hot flushes, and letrozole was associated with higher incidences of fatigue and dizziness. Rates of other adverse events were similar in the two treatment groups.As compared with clomiphene, letrozole was associated with higher live-birth and ovulation rates among infertile women with the polycystic ovary syndrome. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT00719186.).
- Hemostatic and Fibrinolytic Abnormalities in Polycystic Ovary Syndrome. [JOURNAL ARTICLE]
- Semin Thromb Hemost 2014 Jul 7.
Polycystic ovary syndrome (PCOS) is the most common form of anovulatory infertility, affecting up to 10% of women of reproductive age. This syndrome was first described in 1935 when American gynecologists Stein and Leventhal associated the presence of ovarian cysts with anovulation, obesity, and hirsutism. For many years, the effects of PCOS on coagulation and fibrinolysis have remained largely unexplored. This review summarizes current knowledge of the effects of PCOS on coagulation and fibrinolysis, and the putative mechanisms by which PCOS may contribute to the development of coagulation and fibrinolytic disorders. To date, there is relatively strong evidence suggesting that PCOS is associated with increased platelet aggregation and decreased plasma fibrinolytic activity. However, whether these hemostatic disorders are linked to the abnormal hormonal system in PCOS remains to be elucidated. Moreover, it should be emphasized that PCOS is a heterogeneous endocrine condition, and that the number of published studies is limited, the sample size of most of these studies is relatively small, and the selection of control subjects has not been always appropriate. Furthermore, well-designed studies on larger cohorts of carefully characterized PCOS patients are needed to provide more comprehensive information on this issue.
- Prevalence of metabolic syndrome in the family members of women with polycystic ovary syndrome from North India. [Journal Article]
- Indian J Endocrinol Metab 2014 May; 18(3):364-9.
Polycystic ovary syndrome (PCOS) is the most complex and common endocrine disorder of women in reproductive years. In addition to irregular menstrual cycles, chronic anovulation and hyperandrogenism, it has many metabolic manifestations such as obesity, hyperlipidemia, hyperinsulinemia, insulin resistance, dysglycemia, increased risk of cardiovascular disease or possibly endometrial cancer. Familial clustering of PCOS in consistence with the genetic susceptibility has been described.The present study assessed the clinical, biochemical and hormonal parameters including prevalence of metabolic syndrome by two different criteria in the first- degree relatives of patients with PCOS.The average age of 37 index patients was 23 ± 3.6 years, with the mean age of menarche as 13.3 ± 1.2 years. The mean age and age of menarche in mothers (n = 22) was 48.8 ± 5.1 and 13 ± 1.3 years, respectively, whereas as it was 23.5 ± 4.7 and 13.3 ± 1.2 years in sisters (n = 22), respectively. Metabolic syndrome (MS) defined by International Diabetes Federation (IDF) criteria was present in 10 index patients, 1 brother, 4 sisters, 17 mothers and 15 fathers while as by Adult Treatment Panel III (ATP III) it was in 8 index patients, 5 sisters, 16 mothers and 11 fathers.The presence of MS or related metabolic derangements is high in the family members of women with PCOS.
- Biological variability in serum anti-Müllerian hormone throughout the menstrual cycle in ovulatory and sporadic anovulatory cycles in eumenorrheic women. [Journal Article]
- Hum Reprod 2014 Aug; 29(8):1764-72.
Does serum anti-Müllerian hormone (AMH) vary significantly throughout both ovulatory and sporadic anovulatory menstrual cycles in healthy premenopausal women?Serum AMH levels vary statistically significantly across the menstrual cycle in both ovulatory and sporadic anovulatory cycles of healthy eumenorrheic women.Studies to date evaluating serum AMH levels throughout the menstrual cycle have conflicting results regarding intra-woman cyclicity. No previous studies have evaluated an association between AMH and sporadic anovulation.We conducted a prospective cohort study of 259 regularly menstruating women recruited between 2005 and 2007.Women aged 18-44 years were followed for one (n = 9) or two (n = 250) menstrual cycles. Anovulatory cycles were defined as any cycle with peak progesterone concentration ≤5 ng/ml and no serum LH peak on the mid or late luteal visits. Serum AMH was measured at up to eight-time points throughout each cycle.Geometric mean AMH levels were observed to vary across the menstrual cycle (P < 0.01) with the highest levels observed during the mid-follicular phase at 2.06 ng/ml, decreasing around the time of ovulation to 1.79 ng/ml and increasing thereafter to 1.93 (mid-follicular versus ovulation, P < 0.01; ovulation versus late luteal, P = 0.01; mid-follicular versus late luteal, P = 0.05). Patterns were similar across all age groups and during ovulatory and anovulatory cycles, with higher levels of AMH observed among women with one or more anovulatory cycles (P = 0.03).Ovulatory status was not verified by direct visualization. AMH was analyzed using the original Generation II enzymatically amplified two-site immunoassay, which has been shown to be susceptible to assay interference. Thus, absolute levels should be interpreted with caution, however, patterns and associations remain consistent and any potential bias would be non-differential.This study demonstrates a significant variation in serum AMH levels across the menstrual cycle regardless of ovulatory status. This variability, although statistically significant, is not large enough to warrant a change in current clinical practice to time AMH measurements to cycle day/phase.This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, MD (Contracts # HHSN275200403394C, HHSN275201100002I Task 1 HHSN27500001). The authors have no conflicts of interest to declare.
- What do we know about metabolic syndrome in adolescents with PCOS? [REVIEW]
- J Turk Ger Gynecol Assoc 2014; 15(1):49-55.
Polycystic ovary syndrome (PCOS) is the most common endocrinopathy of reproductive-aged women that manifests itself with a variety of features. For this reason, three different diagnostic criteria have been introduced. For adults, the National Institutes of Health Conference (NIH) criteria, which consists of hyperandrogenism and oligo-anovulation, is the most widely used. Symptoms of PCOS usually start with puberty and may overlap with normal pubertal development. Hormonal fluctuations during this period make the diagnosis of PCOS more difficult. Until now, there is no validated diagnostic criteria for PCOS in adolescents. Although menstrual disorders and cosmetic problems are the most common complaints of adolescents with PCOS, patients should also be evaluated for the potential risk for insulin resistance, obesity, subclinical atherosclerosis, diabetes, metabolic syndrome and cardiovascular disease. Obesity is the most prominent predictor of metabolic syndrome. As the incidence of obesity is increasing both in childhood and adolescence, governments will be faced with a social and economic burden in the future. Adolescents with PCOS are more obese than normal adolescents and have an increased risk of metabolic syndrome. It is suggested that abdominal adiposity increases the risk of metabolic syndrome by inducing various cytokine secretions. Although there is no consensus on metabolic syndrome criteria in the adolescent period, International Diabetes Federation (IDF) criteria may be used for children older than 10 years. Various clinical and metabolic markers are investigated for the prediction of metabolic syndrome in the literature. Waist circumference, serum triglycerides and androgens are the suspected predictors of metabolic syndrome. The prevention of abdominal adiposity and the early diagnosis of PCOS in adolescence should be the main target for the prevention of metabolic syndrome. Clinicians should investigate adolescents with PCOS for metabolic and cardiovascular risks and take preventive action. A Mediterranean diet, low in fat and high in fruits and vegetables, along with moderate-intensity exercise and smoking cessation are the recommended interventions for especially obese adolescents with PCOS. Metformin may be the treatment of choice when lifestyle modifications are ineffective.
- Pharmacokinetics of two low-dose levonorgestrel-releasing intrauterine systems and effects on ovulation rate and cervical function: pooled analyses of phase II and III studies. [JOURNAL ARTICLE]
- Fertil Steril 2014 Apr 10.
To assess the pharmacokinetics and pharmacodynamics of levonorgestrel intrauterine system (LNG-IUS) 13.5 mg and LNG-IUS 19.5 mg (total content).Pooled pharmacokinetic and pharmacodynamic analyses of phase II and III studies.Randomized, open-label, multicenter studies.Nulliparous and parous women.Levonorgestrel intrauterine system 13.5 mg, LNG-IUS 19.5 mg, or LNG-IUS 20 μg/24 h (total content 52 mg).Pharmacokinetics of LNG, ovulation rate, cervical function, and endometrium effects.The in vivo LNG release rate of LNG-IUS 13.5 mg was approximately 14 μg/24 h after 24 days, declining progressively to 5 μg/24 h after 3 years. The average LNG serum concentration over 3 years of use was 74.3 ng/L, 114 ng/L, and 218 ng/L for LNG-IUS 13.5 mg, LNG-IUS 19.5 mg, and LNG-IUS 20 μg/24 h, respectively. All treatments showed very similar progestogenic effects on cervical mucus, with low and similar cervical scores throughout treatment. Ovulation was observed in the majority of women in all groups where assessment was possible, although there was a lower incidence of anovulation with LNG-IUS 13.5 mg and LNG-IUS 19.5 mg compared with LNG-IUS 20 μg/24 h. The progestogenic effect on the endometrium was marked in all three LNG-IUS groups.Levonorgestrel intrauterine system 13.5 mg and LNG-IUS 19.5 mg result in a lower systemic exposure to LNG, lower incidence of anovulation, and similar progestin impact on the endometrium and cervical function compared with LNG-IUS 20 μg/24 h.
- Influence of oral contraceptives on anthropomorphometric, endocrine, and metabolic profiles of anovulatory polycystic ovary syndrome patients. [JOURNAL ARTICLE]
- Fertil Steril 2014 Mar 25.
To evaluate the influence of oral contraceptive pills (OCPs) on anthromorphometric, endocrine, and metabolic parameters in women with polycystic ovary syndrome (PCOS).Retrospective cross-sectional cohort study for the period 1993-2011.Tertiary university hospital.PCOS patients, who never, ever, or at time of screening were using OCPs were included. A total of 1,297 patients, of whom 827 were white, were included. All PCOS patients diagnosed according to the Rotterdam 2003 consensus criteria were divided into three groups: current users, (n = 76; 6% of total), ever users (n = 1,018; 78%), and never users (n = 203; 16%). Ever users were subdivided based on the OCP-free interval.None.Anthromorphometric (blood pressure, cycle duration) and ultrasound (follicle count, mean ovarian volume) parameters, endocrine (SHBG, testosterone, free androgen index, antimüllerian hormone [AMH]) and lipid profiles.Current users and ever users were compared with never users. In current users, SHBG was increased and androgen levels decreased. Patients with an OCP-free interval of <1 year had a higher mean follicle count, higher AMH level, and increased serum androgen level compared with never users. SHBG levels remained increased until 5-10 years after cessation of OCP use.OCP use causes a milder phenotypic presentation of PCOS regarding hyperandrogenism. However, it does not alter parameters associated with increased health risks.
- Liver diseases in pregnancy: liver transplantation in pregnancy. [Journal Article, Review]
- World J Gastroenterol 2013 Nov 21; 19(43):7647-51.
Pregnancy in patients with advanced liver disease is uncommon as most women with decompensated cirrhosis are infertile and have high rate of anovulation. However, if gestation ensued; it is very challenging and carries high risks for both the mother and the baby such as higher rates of spontaneous abortion, prematurity, pulmonary hypertension, splenic artery aneurysm rupture, postpartum hemorrhage, and a potential for life-threatening variceal hemorrhage and hepatic decompensation. In contrary, with orthotopic liver transplantation, menstruation resumes and most women of childbearing age are able to conceive, give birth and lead a better quality of life. Women with orthotopic liver transplantation seeking pregnancy should be managed carefully by a team consultation with transplant hepatologist, maternal-fetal medicine specialist and other specialists. Pregnant liver transplant recipients need to stay on immunosuppression medication to prevent allograft rejection. Furthermore, these medications need to be monitored carefully and continued throughout pregnancy to avoid potential adverse effects to mother and baby. Thus delaying pregnancy 1 to 2 years after transplantation minimizes fetal exposure to high doses of immunosuppressants. Pregnant female liver transplant patients have a high rate of cesarean delivery likely due to the high rate of prematurity in this population. Recent reports suggest that with close monitoring and multidisciplinary team approach, most female liver transplant recipient of childbearing age will lead a successful pregnancy.
- Negative spinal bone mineral density changes and subclinical ovulatory disturbances--prospective data in healthy premenopausal women with regular menstrual cycles. [Journal Article]
- Epidemiol Rev 2014; 36(1):137-47.
Subclinical ovulatory disturbances (anovulation or short luteal phases within normal-length menstrual cycles) indicate lower progesterone-to-estrogen levels. Given that progesterone plays a bone formation role, subclinical ovulatory disturbances may be associated with bone loss or less than expected bone gain. Our purpose was to perform a meta-analysis of prospective studies in healthy premenopausal women to determine the overall relationship of subclinical ovulatory disturbances to change in bone mineral density. Two reviewers independently identified from serial literature searches 6 studies meeting inclusion criteria: a 2-year study in 114 young adult women, 2006-2009, Vancouver, Canada; a 2-year study in 189 premenopausal women, 2000-2005, Toronto, Canada; a single-cycle study in 14 young women, 1996-1997, Melbourne, Australia; an 18-month study in 53 women, 1990-1995, Santa Clara, California; a 4-year study in 27 women, 1988-1995, Vancouver, Canada; and a 1-year study in 66 women, 1985-1988, Vancouver, Canada. This meta-analysis included a combined sample size of 473 observations in 436 premenopausal women studied over 1-4 years and aged 14-47 years. The percentage of women with ovulatory disturbances varied significantly from 13% to 82%. Women with more frequent ovulatory disturbances had more negative percentage changes in spine bone mineral density (weighted mean difference = -0.86; P = 0.040) for random-effects analysis. There was significant heterogeneity among these 6 studies (I(2) = 80%). In summary, these data show that regularly menstruating women with more frequent ovulatory disturbances experience more negative changes in bone (approximately -0.9% per year). These cycles with silent estrogen/progesterone imbalance may be clinically important.