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Menstrual Dysfunction in PCOS
Abstract
Menstrual irregularities due to anovulation or severe oligoovulation are a key feature of polycystic ovary syndrome for many women. First-line intervention should entail dietary and lifestyle modifications for overweight or obese polycystic ovary syndrome women. For women not seeking fertility, combination low-dose hormonal contraception are the most effective and first-line choice for regulating menstrual cycles. This option, as well as progestin-only options, have the important added benefit of reducing risks of endometrial hyperplasia and cancer. Metformin is an appropriate medical option to improve ovulation rates for women who cannot take combined hormone contraception or whom are attempting conception.
... 36,37 Menstrual function Irregular menstruation or amenorrhoea are classic symptoms of PCOS, associated with insulin resistance, hyperandrogenism and anovulation. 38,39 Indeed, many women with PCOS never achieve normal cyclicity. 38,39 Cochrane meta-analyses have shown that metformin increases menstrual frequency versus placebo, while metformin was inferior compared with combined oral contraceptives. ...
... 38,39 Indeed, many women with PCOS never achieve normal cyclicity. 38,39 Cochrane meta-analyses have shown that metformin increases menstrual frequency versus placebo, while metformin was inferior compared with combined oral contraceptives. [40][41][42][43] These hormonal treatments may, however, adversely affect some cardiovascular disease risk factors and have been associated with increased risk of insulin resistance. ...
Influential guidelines have supported the role of metformin in the management of polycystic ovary syndrome (PCOS) for a number of years. However, regulatory approvals for this therapeutic indication are still exceptional and exist only in a few countries, including for the originator, Glucophage®. PCOS is an insulin-resistant state, which drives hyperandrogenism and anovulatory infertility. The metabolic action of metformin involves amelioration of insulin resistance, which helps to resolve hormonal and metabolic disturbances and increases ovulation, pregnancy, and live birth rates relative to placebo. A combination of metformin with clomifene citrate (another widely used treatment for PCOS) is more effective than either alone and is a useful option in women with clomifene-resistant PCOS. Combining metformin with letrozole (1st-line agent for ovulation induction in women with PCOS and no other infertility risk factors) is not more effective than letrozole alone. Continuing metformin to the end of the 1st trimester at an effective dose (e.g. 1000–2000 mg/day) may help to reduce the rate of miscarriages. Metformin also has an adjunctive role in women with PCOS receiving assisted reproduction technology (ART) using the long gonadotrophin-releasing hormone agonist protocol, where it appears to increase the pregnancy rate and to reduce the risk of ovarian hyperstimulation syndrome. There is no role for metformin in women receiving short ART protocols. Where a successful pregnancy is achieved, metformin is generally safe for the mother and neonate. Further research is needed to define with greater precision the optimal dosage and times to initiate and discontinue metformin in women with PCOS who achieve pregnancy.
... [5] There are different clinical significances like infertility, irregular periods, hirsutism, alopecia. [6,7] Several treatments were used to address the symptoms of polycystic ovarian syndrome and to trigger ovulation. [8,9] Yet, some treatments have had significant serious side effects [10] Hence, emphasis is increasingly being placed on medications derived from natural sources that exhibit fewer or no negative effects, Lifestyle adjustment is vastly considered to be the cornerstone of PCOS treatment. ...
... [27] The amino acid molecules arginine and aspartic acid are abundant in roots. [17] Nitric oxide, one of the key components, is produced when arginine, a component of asparagus root, is transformed in key proceedings of reproduction inclusive gamete activation, early cell divisions (ovarian cells), fertilization, and implantation [28] while Aspartic acid promotes the release of hormones that release gonadotropins that involved in reproduction and development of the oocyte in function, promotes growth and differentiation of the theca cells and granulosa cells, where the Granulosa cells are significant cells in the ovary that undergo changes physiologically and morphologically during the processes of follicular proliferation, ovulation, differentiation, lutenization and atresia, [29,30] besides elements including calcium, magnesium, zinc, and phosphorus are abundant in asparagus roots [5,6] that control follicle growth and steroidogenesis,and different levels of vitamins A, B1, B2,C and E, and folic acid additionally impact ovarian function and fertility. [31,32] while in results [ Figure 3] all the process of folliculogenesis disturbed in PCOS, inclusion that could be an substantial ovarian abnormality in PCOS. ...
Background
Polycystic ovary syndrome (PCOS) which a series reproductive, metabolic and psychological condition that is characterized by abnormal gonadotropin secretion or hyperandrogenism and associated with insulin resistance and most commonly found in the reproductive age female.
Objectives
This research paper were conducted to examine the effects of Asparagus officinalis L. roots extract on letrozole induced PCOS where the effect of 400 mg/kg A. officinalis L. root extract on the PCOS was studied for 28 days in female rats.
Materials and Methods
Thirty-five female Albino rats were randomly divided into five groups, including control negative group, positive control, PCOS, treatment and preventive group. During 28 days, the positive control group got an extract of the A. officinalis roots. Letrozole 1 mg/kg dissolve in 0.5% carboxymethyl cellulose solution was used to cause PCOS for 28 days. Following the induction of PCOS, the treatment group received extract A. officinalis roots for 28 days. The preventative group received an extract of asparagus roots during PCOS induction.
Results
Immunohistochemical results are shown Ovary slices from of the therapeutic and preventative groups next to the asparagus group were immunostained for Ki 67, which showed high positive statistically ( P < 0.05) immunological activity in the granulosa nuclei and less in the theca cells. When compared to the PCOS group, both the granulosa and theca layers had very weak positive immunostaining ( P < 0.05). According to the morphological findings, granulosa cells from the Control group and asparagus group proliferated much more than granulosa cells from the PCOS group statistically significant ( P < 0.05).
Conclusion
The findings show that theca and granulosa cells are quickly stimulated to proliferate by asparagus root extract. Moreover, it therefore speeds up oogenesis and early cell divisions.
... 'They are responsive to changes in the transitioning phases of the menstrual cycle. Such sensitivity has been observed in many studies' (7,8). Alongside the physiological fluctuations of hormones, the appetite controlling systems can be impacted by the use of hormonal contraceptives as well (9,10)Estrogen and progestin contraceptives change the woman's internal hormonal clock and may either enhance or dampen appetite reflexes. ...
... A large meta-analysis reports the prevalence of PCOS in adolescents to be 11.0% using the Rotterdam criteria, 3.4% using the NIH criteria, and 8.0% using the Androgen Excess and PCOS Society criteria (11).Another source suggests that the prevalence of PCOS among adolescents is between 10.7% to 22.5%(12), (13) ...
... Additionally, they can lead to undesirable side effects like lower abdominal pain, unexpected spotting, nausea, weight gain, back pain, and prolonged hypomenorrhea. Many women find that their menstrual cycles return to normal only while they'reon medication (11)(12); this highlights the importance of long-term and comprehensive management measures. ...
... Additionally, they can lead to undesirable side effects like lower abdominal pain, unexpected spotting, nausea, weight gain, back pain, and prolonged hypomenorrhea. Many women find that their menstrual cycles return to normal only while they'reon medication (11)(12); this highlights the importance of long-term and comprehensive management measures. ...
Introduction: Polycystic Ovarian Syndrome (PCOS) is a common endocrine disorder affecting 11–13% of
women globally during reproductive age. It is characterized by a complex interaction of genetic and environmental
factors, leading to a wide array of symptoms, including menstrual irregularities, insulin resistance, obesity, infertility,
and mental health challenges. Obesity, often exacerbated by lifestyle factors such as poor diet and inactivity, worsens
PCOS outcomes. While medications provide short-term relief, they often have side effects, highlighting the need for
non-pharmacological approaches. Yoga therapy, which combines physical, mental, and dietary practices, has emerged
as a potential adjuvant therapy for managing PCOS symptoms. Methods: This study evaluated the feasibility and
effectiveness of yoga as an adjuvant therapy for PCOS. Data were collected from 150 women diagnosed with PCOS
based on the Rotterdam criteria, with 34 participants completing the 12-week online and offline yoga program. A
structured questionnaire assessed patient satisfaction with the yoga intervention, focusing on symptom management,
mental well-being, sleep, and quality of life. The yoga program included postures, breathing exercises, meditation,
relaxation techniques, and dietary guidance. Statistical analysis was conducted to examine the relationship between
yoga practice duration and improvement in PCOS-related outcomes. Results: Out of 43 respondents, 55.8% found the
yoga program "very easy" to attend, and 30.2% reported significant improvement in PCOS symptoms. 55.8%
experienced moderate mental well-being improvements, and 72.1% rated their post-intervention quality of life as
"good" or "excellent." Yoga was found to be "very helpful" for managing PCOS by 48.8% of participants, and 62.8%
found it an "acceptable" complementary therapy. The data showed statistically significant improvements in PCOS
symptoms and quality of life, correlating with the duration of yoga practice. Discussion: The study demonstrated that
yoga is a feasible and effective adjuvant therapy for PCOS. Although participants initially faced challenges
incorporating yoga into their routines, they gradually adapted and reported positive outcomes in terms of physical,
mental, and emotional well-being. Yoga provided benefits beyond medication, offering a holistic approach without
adverse effects. These findings align with previous research, suggesting that yoga can help regulate menstrual cycles,
manage weight, and improve mental health in women with PCOS. Conclusion: Yoga is a viable non-pharmacological
approach for managing PCOS, with potential long-term benefits for physical and mental health. The integration of
yoga with dietary guidance shows promise in improving both quality of life and symptom management. Future
studies should explore objective clinical measurements to validate these results further and investigate the
physiological and biochemical mechanisms underlying the effectiveness of yoga in PCOS.
... Additionally, they can lead to undesirable side effects like lower abdominal pain, unexpected spotting, nausea, weight gain, back pain, and prolonged hypomenorrhea. Many women find that their menstrual cycles return to normal only while they'reon medication (11)(12); this highlights the importance of long-term and comprehensive management measures. ...
... 52 Furthermore, the hormonal and physiological alterations that take place due to marriage and intimate relationships may also have an impact on regulating PMS encounters. 53 Possible explanations for the variations in PMS among single and married Omani students may include alterations in menstrual cycle patterns, ovulation, and levels of reproductive hormones. 54 Moreover, the sociocultural environment in Oman, characterized by distinct customs and societal expectations on marriage, can influence how Omani women perceive and feel PMS, depending on their marital status. ...
Background: This study examines the relationship between premenstrual syndrome (PMS) and the attitude toward seeking professional psychological help among Omani college students.
Method: This study used a cross-sectional design with a convenience sampling approach. The date was issued between January and March 2024. A sample of 601 undergraduate female students completed the study questionnaires, including (1) a sociodemographic questionnaire, (2) the Premenstrual Syndrome Scale and (3) the attitude toward seeking professional psychological distress scale.
Results: The study included 601 eligible participants of age 18–29 years who were mostly single (83.7%) and living on campus (68.6%). PMS prevalence was high at 87.9%, with a mean score of 109.4, indicating low severity for most (62.1%). Participants generally had positive attitudes toward seeking psychological help (41.6% high willingness). A linear regression showed a positive link between PMS severity and help-seeking attitudes.
Conclusion: This study highlights a significant association between the experiences of PMS and attitudes toward seeking professional psychological help among Omani female undergraduate students. With a high prevalence of PMS reported, the findings suggest that cultural factors and support systems play crucial roles in shaping these attitudes. The positive inclination toward seeking help indicates a growing awareness of mental health issues within this demographic. Enhancing mental health services and fostering supportive environments in educational settings can further empower students to address PMS-related challenges.
... In PCOS, ovulatory dysfunction is a key diagnostic criterion, and abnormal bleeding patterns impact approximately 60-85% of people with PCOS [12,13]. Menstrual bleeding patterns vary significantly, ranging from monthly to absent entirely [14]. Despite the lack of menstrual regularity, a recent case report suggests that patients with PCOS experience similar premenstrual exacerbations of mood symptoms [15]. ...
Purpose of Review
We reviewed a wide body of emerging research highlighting the possibility for premenstrual exacerbations of mood symptoms in polycystic ovary syndrome (PCOS).
Recent Findings
Neuroendocrine dysregulation, sensitivity to ovarian hormone fluctuations as well as higher levels and types of adverse childhood experiences and demographic factors are emerging factors explaining high rates of psychiatric disorders in PCOS. Ovulatory dysfunction, common in PCOS, significantly interferes with one’s identity and quality of life. Results on pharmacologic and non-pharmacologic treatments for mood symptoms are mixed, though improvements in the physical sequalae of PCOS could also improve mood symptoms. However, significant improvements on the methodological quality are needed, particularly the evaluation of mood symptoms across the menstrual cycle.
Summary
Evidence is preliminary on whether there are premenstrual exacerbations of psychiatric symptoms in PCOS. Prospective, longitudinal studies with larger sample sizes are needed to comprehensively understand the psychiatric profile in PCOS.
... In women with PCOS, the altered LH:FSH ratio prevents adequate maturation of the follicles, leading to anovulatory cycles [23]. This hormonal dysregulation contributes to menstrual irregularity, a cardinal symptom of PCOS [24], and reproductive problems such as infertility or difficulties conceiving, which are common concerns among women with this condition [25]. ...
Polycystic ovary syndrome (PCOS) is an endocrine and metabolic disorder with high prevalence in women around the world. The identification of single-nucleotide polymorphisms (SNPs) through genome-wide association studies has classified it as a polygenic disease. Most studies have independently evaluated the contribution of each SNP to the risk of PCOS. Few studies have assessed the effect of epistasis among the identified SNPs. Therefore, this exploratory study aimed to evaluate the interaction of 27 SNPs identified as risk candidates and their contribution to the pathogenesis of PCOS. The study population included 49 control women and 49 women with PCOS with a normal BMI. Genotyping was carried out through the MassARRAY iPLEX single-nucleotide polymorphism typing platform. Using the multifactor dimensionality reduction (MDR) method, the interaction between SNPs was evaluated. The analysis showed that the best interaction model (p < 0.0001) was composed of three loci (rs11692782-FSHR, rs2268361-FSHR, and rs4784165-TOX3). Furthermore, a tendency towards synergy was evident between rs2268361 and the SNPs rs7371084–rs11692782–rs4784165, as well as a redundancy in rs7371084–rs11692782–rs4784165. This pilot study suggests that epistasis may influence PCOS pathophysiology. Large-scale analysis is needed to deepen our understanding of its impact on this complex syndrome affecting thousands of women.
... Irregular cycle length, variable volume and duration of bleeding, and amenorrhea indicate disturbances to the endocrine system and the hypothalamic-pituitary-ovarian (HPO) axis (42,43). Endocrine conditions that can perturb the menstrual cycle include type 1 and 2 diabetes (44), polycystic ovarian syndrome (PCOS) (45,46), thyroid diseases (47), primary or premature ovarian insufficiency (48,49), and ovulatory disorders (12,50). Documenting menstrual cycle patterns can help assess, diagnose, and treat infertility, guiding clinical testing and fertility treatment timing (14). ...
Some medical professional organizations have advocated for including the menstrual cycle as a vital sign in adolescence, but not in adulthood. However, documenting menstrual cycle patterns is not routine clinical or research practice. Vital signs are used to predict health outcomes, indicate needed treatment, and monitor a clinical course. They can help identify pathologies, affirm wellness, and are responsive to exposures. Here we review the scientific evidence showing how the menstrual cycle meets these criteria and should therefore be treated as a vital sign. Using key words and controlled vocabulary terms, we carried out multiple literature searches, prioritizing the inclusion of systematic reviews, meta-analyses, and clinical practice guidelines. This review describes how the menstrual cycle is a health indicator, can cyclically impact health conditions, and its associations with long-term post-menopausal health outcomes. We review exposures influencing the menstrual cycle, evidence underlying its use to optimize wellness, and available tools for documenting cycles. Supplementary materials include patient handouts on menstrual cycle tracking, and an index of related clinical practice guidelines and reviews by subject. The menstrual cycle is a vital sign from menarche through menopause, an underutilized but powerful tool for understanding gynecological and general health.
... Lifestyle optimization including a balanced diet and regular exercise can ameliorate the metabolic abnormalities associated with PCOS and improve the menstrual irregularity and anovulation [63]. PCOS in individuals with a BMI >= 25 [67] may be treated with calorie-restricted diets [68,69] because even a small weight loss, 5-10%, can improve menstrual irregularities [68]. In cases of individuals with a BMI >= 35 kg/m 2 , bariatric surgery could offer an option for sustained weight loss, allowing for restoration of menstrual regularity [67]. ...
The modifiable and non-modifiable determinants and the currently available methods of assessment of menstrual blood flow will be discussed, with the goal of helping healthcare providers, researchers, and those interested in public health.
Several factors can impact menstruation. The determinants include modifiable factors such as smoking, nutrition, exercise, stress, weight fluctuation, and benign gynecologic diseases, and non-modifiable factors such as age, race, and the individual’s genes. The intertwined dynamic among these determinants needs more critical attention. Currently, the methods for the assessment of menstruation all have advantages and disadvantages, often with a tradeoff between practicality and accuracy.
Considered by many as the fifth vital, menstruation provides a window to an individual’s general health. The discussion of its determinants and assessment can be more appropriate for individual contexts, especially from a public health perspective as it can improve the reproductive health of the population.
... Women with PCOS have an 11-fold increase in the prevalence of metabolic syndrome than age-matched controls, and these complications can eventually lead to cardiovascular disorders such as myocardial ischemia or infarction and an acute coronary syndrome that can be deadly [5]. In addition to infertility, women with PCOS also have an increased risk of gynaecological problems, including abnormal uterine bleeding and oligomenorrhea, which can ultimately cause uterine/endometrial cancer [6]. ...
Polycystic ovary syndrome is a multifactorial condition associated with reproductive and endocrine organs and might cause infertility and metabolic abnormalities in childbearing age. PCOS seems to be a multifactorial disorder resulting from the combination of several genetic and environmental factors. Little research has been conducted to date on the impact of polymorphisms in infertility. We aim to review the appearance of polymorphisms in females of diverse ethnicities and their effect on infertility in the population with polycystic ovary syndrome. There have been numerous reports of the importance of the steroidogenesis pathway and genetic variants in PCOS pathogenesis. The most important genes that play a role in the aetiology of PCOS are CYP11A1, CYP17A1, and CYP19A1. We evaluated the occurrence of polymorphisms in various ethnicities in the CYP11A1, CYP17A1, and CYP19A1 genes and their efficacy on increasing PCOS risk with infertility. Our findings revealed that polymorphisms in various ethnicities are associated with the risk of PCOS with infertility. Although conflicting results regarding CYP11A1, CYP17A1, and CYP19A1 polymorphisms and their influence on PCOS with infertility have been reported in a small number of papers, the authors feel this may be attributable to the sample size and ethnic composition of the examined populations. In conclusion, our study strongly suggests that the CYP11A1, CYP17A1, and CYP19A1 genes might significantly enhance the probability of developing PCOS with infertility.
Evidence suggests that fat-soluble vitamins are involved in reproduction, but their association with the menstrual cycle, the proxy of female fecundity, remains largely unexplored in women of childbearing age. Serum fat-soluble vitamin levels were measured by HPLC-MS/MS and menstrual cycle data were acquired from 3123 women of reproductive age in Nanjing, China, using standard questionnaires. Irregular and long menstrual cycles occurred in 725 (23.2%) and 604 (19.3%) participants, respectively. Participants with higher levels of vitamins A and K had increased odds of irregular menstrual cycles (vitamin A: OR = 1.39 (95% CI: 1.12, 1.74); vitamin K: OR = 1.41 (95% CI: 1.13, 1.76)) and long menstrual cycles (vitamin A: OR = 1.34 (95% CI: 1.06, 1.69); vitamin K: OR = 1.27 (95% CI: 1.00, 1.61)), and the relationship showed a linear dose-response pattern (P-overall < 0.05, P-nonlinearity > 0.05). Vitamin A was positively associated with the average menstrual cycle length (β: 1.83, 95% CI: 0.28, 3.39). Vitamins A and K were interacted in their associations with irregular menstrual cycles and long cycles. In sensitivity analysis with further exclusion of participants with abnormal thyroid function or a history of polycystic ovary syndrome (PCOS), the association of vitamins A and K with the menstrual cycle remained robust. This study indicates that higher serum vitamin A and K levels in women of childbearing age are significantly associated with higher odds of irregular and long menstrual cycles with a linear dose-response curve. Further investigations are warranted to determine the appropriate fat-soluble vitamin levels for women of childbearing age.
The polycystic ovary (PCO) is defined by the increased number of subcapsular hyperandrogenic follicles and a tendency towards anovulation. This chapter details current knowledge regarding the morphological and functional defects present in these ovaries. Genome-wide association studies (GWAS) of women with polycystic ovary syndrome (PCOS) have revealed linkage to sites close to genes encoding proteins involved in ovarian function, but the majority have not provided definitive mechanistic explanations. Primordial follicle numbers appear normal but increase upon commencement of growth with enhanced survival creating a stockpiling effect. Much has been learned from prenatally androgenised primate models of PCOS, surplus human ovarian tissue from cryopreserved sections, in vitro cell culture models and the ability to perform microarray on small samples. Impaired folliculogenesis and failure of dominant follicle selection underlie the ovulatory dysfunction of PCOS, but ovulatory status appears to fluctuate. Members of the TGFβ family are strongly implicated both pre- and postnatally in disordered preantral and antral follicular development. Overproduction of androgens by the ovarian theca cells of PCO is intrinsic, and GWAS consistently show linkage to DENND1A, a splice variant of which increases steroidogenesis and is overexpressed in PCOS theca. Insulin resistance is common in PCOS with systemic and local ovarian effects, resulting in alteration of cell metabolism that affects both follicle growth and oocyte health.
Objective:
Long-term efficacy of metformin in polycystic ovarian syndrome (PCOS) apart from in those with impaired glucose tolerance or diabetes remains unproven. We aimed to evaluate the impact of metformin in overweight-obese patients with PCOS and normal baseline glycemic homeostasis.
Methods:
10 year longitudinal follow up of retrospective cohort comprising of 159 patients with PCOS defined by Rotterdam criteria, BMI≥ 25kg/m2 and normal initial glucose homeostasis (age 28.4±6.4 years, BMI 34.9±6.6 kg/m2) that had been receiving metformin 1000 mg BID. Collection data contained 6085time-points including anthropometric, hormonal and metabolic parameters.
Results:
After the 1st year body mass(BM) decreased for 3,9±6.8kg (p<0.001) and remained stable during the following 3 years. Menstrual frequency (MF) increased for3.0±3.9 bleeds/year (p<0.001) after 1st year to over 11 bleeds/year in the following years. The total testosterone and androstenedione decreased for 15.4±47.9% and 11.3±46.4% within 1st year, with further decrease in total testosterone and androstenedione for 37.8±61.8 and 24.8±40.5% at the 5th year of the follow up. The total conversion rate to prediabetes and diabetes was extremely low throughout observation period. Less than 25% of patients continued with metformin for more than five years with further dropout to only 6% on metformin therapy at the 10th year of follow up.
Conclusions:
Long-term metformin treatment of overweight-obese women with PCOS and normal baseline glycemic homeostasis resulted in reduction and stabilization of BM, improvements of MF and androgen profile and low conversion rate to diabetes.
Objective:
To characterize the impact of bariatric surgery on reproductive and metabolic features common to polycystic ovary syndrome (PCOS) and to assess the relevance of preoperative evaluations in predicting likelihood of benefit from surgery.
Methods:
A retrospective chart review of records from 930 women who had undergone bariatric surgery at the Cleveland Clinic Foundation from 2009 to 2014 was completed. Cases of PCOS were identified from ICD coding and healthy women with pelvic ultrasound evaluations were identified using Healthcare Common Procedure Coding System coding. Pre- and postoperative anthropometric evaluations, menstrual cyclicity, ovarian volume (OV) as well as markers of hyperandrogenism, dyslipidemia, and dysglycemia were evaluated.
Results:
Forty-four women with PCOS and 65 controls were evaluated. Both PCOS and non-PCOS had significant reductions in body mass index (BMI) and markers of dyslipidemia postoperatively (p < 0.05). PCOS had significant reductions in androgen levels (p < 0.05) and percent meeting criteria for hyperandrogenism and irregular menses (p < 0.05). OV did not significantly decline in either group postoperatively. Among PCOS, independent of preoperative BMI and age, preoperative OV associated with change in hemoglobin A1c (β 95% (confidence interval) 0.202 (0.011-0.393), p = 0.04) and change in triglycerides (6.681 (1.028-12.334), p = 0.03), and preoperative free testosterone associated with change in total cholesterol (3.744 (0.906-6.583), p = 0.02) and change in non-HDL-C (3.125 (0.453-5.796), p = 0.03).
Conclusions:
Bariatric surgery improves key diagnostic features seen in women with PCOS and ovarian volume, and free testosterone may have utility in predicting likelihood of metabolic benefit from surgery.
Background:
Polycystic ovary syndrome (PCOS) is characterised by infrequent or absent ovulation, and high levels of androgens and insulin (hyperinsulinaemia). Hyperinsulinaemia occurs secondary to insulin resistance and is associated with increased risk of cardiovascular disease and diabetes mellitus. Insulin-sensitising agents such as metformin may be effective in treating PCOS-related anovulation.
Objectives:
To evaluate the effectiveness and safety of insulin-sensitising drugs in improving reproductive and metabolic outcomes for women with PCOS undergoing ovulation induction.
Search methods:
We searched the following databases from inception to January 2017: Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. We searched registers of ongoing trials and reference lists from relevant studies.
Selection criteria:
We included randomised controlled trials of insulin-sensitising drugs compared with placebo, no treatment, or an ovulation-induction agent for women with oligo and anovulatory PCOS.
Data collection and analysis:
Two review authors independently assessed studies for eligibility and bias. Primary outcomes were live birth rate and gastrointestinal adverse effects. Secondary outcomes included other pregnancy outcomes, menstrual frequency and metabolic effects. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We assessed statistical heterogeneity using the I2 statistic and reported quality of the evidence for primary outcomes using GRADE methodology.
Main results:
We assessed the interventions metformin, clomiphene citrate, metformin plus clomiphene citrate, D-chiro-inositol, rosiglitazone and pioglitazone. We compared these with each other, placebo or no treatment. We included 48 studies (4451 women), 42 of which investigated metformin (4024 women). Evidence quality ranged from very low to moderate. Limitations were risk of bias (poor reporting of methodology and incomplete outcome data), imprecision and inconsistency. Metformin versus placebo or no treatmentThe evidence suggests that metformin may improve live birth rates compared with placebo (OR 1.59, 95% CI 1.00 to 2.51, 4 studies, 435 women, I2 = 0%, low-quality evidence). The metformin group experienced more gastrointestinal side effects (OR 4.76, 95% CI 3.06 to 7.41, 7 studies, 670 women, I2 = 61%, moderate-quality evidence) but had higher rates of clinical pregnancy (OR 1.93, 95% CI 1.42 to 2.64, 9 studies, 1027 women, I2 = 43%, moderate-quality evidence), ovulation (OR 2.55, 95% CI 1.81 to 3.59, 14 studies, 701 women, I2 = 58%, moderate-quality evidence) and menstrual frequency (OR 1.72, 95% CI 1.14 to 2.61, 7 studies, 427 women, I2 = 54%, low-quality evidence). There was no clear evidence of a difference in miscarriage rates (OR 1.08, 95% CI 0.50 to 2.35, 4 studies, 748 women, I2 = 0%, low-quality evidence). Metformin plus clomiphene citrate versus clomiphene citrate alone There was no conclusive evidence of a difference between the groups in live birth rates (OR 1.21, 95% CI 0.92 to 1.59, 9 studies, 1079 women, I2 = 20%, low-quality evidence), but gastrointestinal side effects were more common with combined therapy (OR 3.97, 95% CI 2.59 to 6.08, 3 studies, 591 women, I2 = 47%, moderate-quality evidence). However, the combined therapy group had higher rates of clinical pregnancy (OR 1.59, 95% CI 1.27 to 1.99, 16 studies, 1529 women, I2 = 33%, moderate-quality evidence) and ovulation (OR 1.57, 95% CI 1.28 to 1.92, 21 studies, 1624 women, I2 = 64%, moderate-quality evidence). There was a statistically significant difference in miscarriage rate per woman, with higher rates in the combined therapy group (OR 1.59, 95% CI 1.03 to 2.46, 9 studies, 1096 women, I2 = 0%, low-quality evidence) but this is of uncertain clinical significance due to low-quality evidence, and no clear difference between groups when we analysed miscarriage per pregnancy (OR 1.30, 95% CI 0.80 to 2.12, 8 studies; 400 pregnancies, I2 = 0%, low-quality evidence). Metformin versus clomiphene citrateWhen all studies were combined, findings for live birth were inconclusive and inconsistent (OR 0.71, 95% CI 0.49 to 1.01, 5 studies, 741 women, I2 = 86%, very low-quality evidence). In subgroup analysis by obesity status, obese women had a lower birth rate in the metformin group (OR 0.30, 95% CI 0.17 to 0.52, 2 studies, 500 women, I2 = 0%, very low-quality evidence), while data from the non-obese group showed a possible benefit from metformin, with high heterogeneity (OR 1.71, 95% CI 1.00 to 2.94, 3 studies, 241 women, I2 = 78%, very low-quality evidence). Similarly, among obese women taking metformin there were lower rates of clinical pregnancy (OR 0.34, 95% CI 0.21 to 0.55, 2 studies, 500 women, I2 = 0%, very low-quality evidence) and ovulation (OR 0.29, 95% CI 0.20 to 0.43 2 studies, 500 women, I2 = 0%, low-quality evidence) while among non-obese women, the metformin group had more pregnancies (OR 1.56, 95% CI 1.05 to 2.33, 5 studies, 490 women, I2 = 41%, very low-quality evidence) and no clear difference in ovulation rates (OR 0.81, 95% CI 0.51 to 1.28, 4 studies, 312 women, low-quality evidence, I2=0%). There was no clear evidence of a difference in miscarriage rates (overall: OR 0.92, 95% CI 0.50 to 1.67, 5 studies, 741 women, I2 = 52%, very low-quality evidence). D-chiro-inositol (2 studies), rosiglitazone (1 study) or pioglitazone (1 study) versus placebo or no treatmentWe were unable to draw conclusions regarding other insulin-sensitising drugs as no studies reported primary outcomes.
Authors' conclusions:
Our updated review suggests that metformin alone may be beneficial over placebo for live birth, although the evidence quality was low. When metformin was compared with clomiphene citrate, data for live birth were inconclusive, and our findings were limited by lack of evidence. Results differed by body mass index (BMI), emphasising the importance of stratifying results by BMI. An improvement in clinical pregnancy and ovulation suggests that clomiphene citrate remains preferable to metformin for ovulation induction in obese women with PCOS.An improved clinical pregnancy and ovulation rate with metformin and clomiphene citrate versus clomiphene citrate alone suggests that combined therapy may be useful although we do not know whether this translates into increased live births. Women taking metformin alone or with combined therapy should be advised that there is no evidence of increased miscarriages, but gastrointestinal side effects are more likely.
Background:
Oral contraceptives (OCs) have been used as a first-line option for medical treatment in women with polycystic ovary syndrome (PCOS). Despite theoretical superiority of products containing antiandrogenic progestins compared to OCs containing levonorgestrel (LNG), the clinical advantage of these compounds remains unclear.
Objective:
The aim of this study was to compare the effects of OCs containing LNG with products containing antiandrogenic progestins including cyproterone acetate, drospirenone, and desogestrel on clinical, hormonal, and metabolic parameters and quality of life in women with PCOS.
Methods:
We conducted a 6-arm crossover randomized controlled trial with each arm including OCs containing LNG and one of those 3 OCs containing antiandrogenic progestins. The anthropometric and clinical manifestations and hormonal and biochemical parameters of participants were assessed at 6 time points including baseline, after washout period, and 3 and 6 months after intervention.
Results:
The study is ongoing and follow-up of recruited women will continue until 2018.
Conclusions:
This study will provide scientific evidence on comparability of OCs with the various progesterones that will assist in decision making taking into account cost effectiveness.
Trial registration:
Iranian Registry of Clinical Trials IRCT201702071281N2; http://www.irct.ir/searchresult.php? keyword=&id=1281&number=2&prt=12869&total=10&m=1 (Archived by WebCite at http://www.webcitation.org/6tSP8FNWo).
Objective:
The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome (PCOS).
Participants:
An Endocrine Society-appointed Task Force of experts, a methodologist, and a medical writer developed the guideline.
Evidence:
This evidence-based guideline was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence.
Consensus process:
One group meeting, several conference calls, and e-mail communications enabled consensus. Committees and members of The Endocrine Society and the European Society of Endocrinology reviewed and commented on preliminary drafts of these guidelines. Two systematic reviews were conducted to summarize supporting evidence.
Conclusions:
We suggest using the Rotterdam criteria for diagnosing PCOS (presence of two of the following criteria: androgen excess, ovulatory dysfunction, or polycystic ovaries). Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women. Hyperandrogenism is central to the presentation in adolescents, whereas there is no consistent phenotype in postmenopausal women. Evaluation of women with PCOS should exclude alternate androgen-excess disorders and risk factors for endometrial cancer, mood disorders, obstructive sleep apnea, diabetes, and cardiovascular disease. Hormonal contraceptives are the first-line management for menstrual abnormalities and hirsutism/acne in PCOS. Clomiphene is currently the first-line therapy for infertility; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities, but it has limited or no benefit in treating hirsutism, acne, or infertility. Hormonal contraceptives and metformin are the treatment options in adolescents with PCOS. The role of weight loss in improving PCOS status per se is uncertain, but lifestyle intervention is beneficial in overweight/obese patients for other health benefits. Thiazolidinediones have an unfavorable risk-benefit ratio overall, and statins require further study.
Background
Polycystic ovary syndrome (PCOS) has a prevalence of 8‐13%. Given the prevalence, diverse health impacts and variation in care, rigorous evidence‐based guidelines are needed in PCOS management. This systematic review with meta‐analyses aims to investigate the effect of the combined oral contraceptive pill (COCP) and/or metformin in the management of hormonal and clinical features of PCOS, to inform international guidelines.
Methods
Electronic databases were searched systematically from inception until 11 January 2017 to inform the guideline process. Eligible studies were randomized controlled trials (RCTs) which investigated the effect of COCPs and/or metformin alone or combined on hormonal and clinical features in women with PCOS. Outcomes were prioritised as critical for informing a decision about an intervention or important or not important, according to GRADE. Articles were assessed by one author against selection criteria, in consultation with a second author. Data were double extracted independently by four authors, and data quality appraisal completed. Meta‐analyses were conducted, where appropriate.
Results
Fifty‐six studies were eligible for inclusion. Outcomes prioritised by women and health professionals included: irregular cycles, insulin resistance, weight, BMI, thromboembolic events and gastrointestinal effects. In low quality evidence in adolescents, meta‐analyses demonstrated that metformin was better than COCP for BMI (mean difference (MD) −4.02 [−5.23, −2.81], p <0.001); and COCP was better than metformin for menstrual regulation (MD ‐0.19 [‐0.25, ‐0.13], p <0.00001). In low quality evidence in adults, meta‐analyses demonstrated that metformin was better than placebo for BMI (MD ‐0.48 [‐0.94, ‐0.02], p= 0.04); metformin was better than COCP for fasting insulin (MD 4.00 [2.59, 5.41], p= 0.00001), whereas COCP was better than metformin for irregular cycles (MD 12.49 [1.34, 116.62], p= 0.03). COCP alone was better than the combination with an anti‐androgen for BMI (MD ‐3.04 [‐5.45, ‐0.64], p= 0.01). Metformin was associated with generally mild gastrointestinal adverse events. Differences in statistical significance were observed when outcomes were sub‐grouped by BMI.
Conclusions
This review identified that COCP therapy has benefits for management of hyperandrogenism and menstrual regulation. Metformin combined with the COCP may be useful for management of metabolic features. There is minimal evidence of benefits of adding an anti‐androgen to COCP therapy.
Metformin alone has benefits for adult women for management of weight, hormonal, and metabolic outcomes, especially for women with BMI≥25 kg/m². There is inadequate evidence to suggest the optimal COCP formulation, or dosing regimen and formulation of metformin.
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The polycystic ovary syndrome is the most common endocrinological disorder of reproductive age women with a prevalence of 5 to 8 %. The most common diagnostic criteria used for polycystic ovary syndrome are oligo- or an-ovulation, clinical and/ or biochemical signs of hyperandrogenism and polycystic ovaries. Hyperandrogenism results in increased estrogen levels and lack of cyclic progesterone due to anovulation and persistent stimulation of the endometrium may lead to endometrial hyperplasia or adenocarcinoma development. In this mini review, we aimed to evaluate the possible relationship between polycystic ovary syndrome and endometrial cancer.
To summarize current evidence on lifestyle management (dietary, exercise, or behavioral interventions) of obesity in women with polycystic ovary syndrome (PCOS), to indicate gaps in knowledge, and to review the medical and surgical alternatives for weight management.
Expert panel appointed by the Androgen Excess and PCOS Society (AEPCOS Society) to review the literature and draft the initial report after a consensus process via electronic communication. The initial report was reviewed and critiqued by all expert panel members and the AEPCOS Society Board of Directors and modified based on their comments.
Lifestyle management should be used as the primary therapy in overweight and obese women with PCOS for the treatment of metabolic complications. For reproductive abnormalities, lifestyle modification may improve ovulatory function and pregnancy. Data are preliminary for improvement in pregnancy and live-birth rates, and further research is needed. There is currently no evidence that modifying dietary macronutrient composition offers additional benefits over conventional dietary approaches for weight loss, and further research is needed. Emerging evidence suggests that exercise offers additional benefits to dietary energy restriction for reproductive features of PCOS.
ACOG Practice Bulletin No. 194: Polycystic ovary syndrome