|Year : 2022 | Volume
| Issue : 2 | Page : 89-94
Polycystic ovary syndrome: Current perspectives and recent advances
AY Nirupama1, Jennifer Britto John2, D Vinoth Gnana Chellaiyan3
1 Department of Public Health Research, Indian Institute of Public Health, Hyderabad, Telangana, India
2 Department of Obstetrics and Gynecology, Chettinad Hospital and Research Institute, Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India
3 Department of Community Medicine, Chettinad Academy of Research and Education, Chennai, Tamil Nadu, India
|Date of Submission||06-Jan-2022|
|Date of Decision||17-Feb-2022|
|Date of Acceptance||31-Mar-2022|
|Date of Web Publication||07-May-2022|
Dr. D Vinoth Gnana Chellaiyan
Department of Community Medicine, Chettinad Academy of Research and Education, Kelambakkam, Chennai - 603 103, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Excess ovarian activity, chronic anovulation, and androgen excess are the common traits of polycystic ovary syndrome (PCOS). Several advances have been made in understanding the pathophysiology in the process of finding quicker and more effective management measures. Androgen excess in PCOS was found to correlate with markedly elevated luteinizing hormone pulsatility. Impaired insulin response is also attributed to PCOS. Regimen with 3 mg drospirenone + 20 μg ethinyl estradiol combination is beneficial for hormonal imbalance and lipid profile while having a substantial safety profile. Clinical evidence has demonstrated that a 40:1 combination of Myo-inositol and D-chiro-inositol restores ovulation in PCOS women. For women with clomiphene citrate-resistant PCOS, laparoscopic ovarian drilling has proved to be a safe and effective surgical alternative. PCOS is also an indication of bariatric surgery. To conclude, constitutional management by a multidisciplinary team may be helpful for women with PCOS. Lifestyle interventions are best advised and, in so doing, decrease body adiposity and recuperate their metabolic and reproductive health.
Keywords: Bariatric surgery, polycystic ovary syndrome, recent advances, Stein–Leventhal
|How to cite this article:|
Nirupama A Y, John JB, Chellaiyan D V. Polycystic ovary syndrome: Current perspectives and recent advances. Curr Med Issues 2022;20:89-94
| Introduction|| |
Stein–Leventhal syndrome, popularly known as polycystic ovary syndrome (PCOS), is one of the foremost causes of female infertility. The “Rotterdam Consensus” in 2003, held conjointly by the North American and European Associations of Reproductive Medicine, stated that the occurrence of any two out of the following features will be considered as diagnostic criteria for PCOS: hyperandrogenism (clinical or laboratory), ovulatory dysfunction (characterized by irregularities in menstrual cycles), or polycystic ovarian morphology by ultrasound. The prevalence of PCOS among women of reproductive age group ranges from 4% to 20% globally and 3.7% to 22.5% nationally in India, depending on the population studied and the criteria used for diagnosis.,
As expressed, PCOS is a multidimensional disorder depicted by an amalgamation of signs and symptoms of ovarian dysfunction and androgen excess without another identifiable diagnosis. Unlike erstwhile causes of anovulation involving ovarian inactivity or primary insufficiency, PCOS presents with chronic anovulation in the presence of hyperactivity of the ovaries. In addition to synchronicity of insulin resistance (IR) and obesity, the effect of androgen excess is considered the driving force behind the inflammatory and metabolic instabilities associated with PCOS. High circulating testosterone levels have been demonstrated in PCOS, produced either from the ovary (where androgen production is controlled by luteinizing hormone [LH] levels) or adrenal or both.
The past decade has witnessed several advances in understanding the underlying pathophysiological mechanisms of PCOS, leading to further advancement in the scope for independent diagnosis and effective multidisciplinary management of PCOS.
| Pathophysiology|| |
In a contemporary genome-wide meta-analysis incorporating over 10,000 cases of PCOS, 14 independent loci (including three novel loci) linked with increased risk for PCOS were identified. No difference whatsoever was observed in the association between various clinical phenotypes and a major portion of the PCOS-susceptibility loci, implying similar underlying genetic traits for the various phenotypes.
The ongoing search for the likely driving forces behind increased androgen secretion in PCOS led to the findings of markedly elevated LH pulsatility in letrozole-treated mice, compared to that in PCOS women. This hyperactive LH pulse secretion may be attributed to the increased hypothalamic kisspeptin and neurokinin B levels. Disconcerted gonadotropin-releasing hormone (GnRH) pulsatility is reported as an alternative reason for increased LH pulsatility. Intracerebroventricular administration of anti-Müllerian hormone (AMH) was reported to increase GnRH-dependent LH pulsatility due to the expression of AMH receptors in GnRH neurons.
The constructive effects of exercise on metabolism can be attributed to “irisin,” a myokine induced by exercise. A recent systematic review meta-analysis (SRMA) stated that PCOS patients seem to have standard irisin levels after adjustment for body mass index (BMI). Nevertheless, the response of “irisin” to hyperinsulinemia may be weakened in women with PCOS.
| Risk Factors for Polycystic Ovary Syndrome|| |
Positive family history, obesity/weight gain, history of epilepsy, diabetes, etc., have been identified as risk factors for PCOS among women in the reproductive age group.,,,, Girls born to obese/overweight women, low birth weight, and congenital virilization were identified to increase the risk of PCOS in children. Irregular menstruation, premature pubarche, obesity syndromes, and acanthosis nigricans are a few of the risk factors evident later in childhood.,
IR has been demonstrated widely in women with PCOS. This has been shown to occur independent of obesity, and the effect of obesity was additive to the effect of PCOS on IR. A recent SRMA studied literature with BMI-matched controls and showed a higher prevalence of metabolic syndrome in women with PCOS compared to women without PCOS (odds ratio [OR] 2.20, 95% confidence interval [CI] 1.36–3.56).
| Polycystic Ovary Syndrome and COVID-19 Pandemic|| |
Ethnic predisposition, hyperinflammation, hyperandrogenism, and low Vitamin D levels are certain factors that have been strongly associated with PCOS as well as a risk of severe COVID-19. Along with these, women in the reproductive age group are highly prone to multiple cardiometabolic conditions, such as type 2 diabetes, hypertension, obesity, and alterations in the gut microbiome, which increase the risk for adverse COVID-19–related outcomes. This strong overlap of risk factors for PCOS and severe COVID-19 should be highlighted since women with PCOS tend to receive care from multiple health services.,,
In obese/overweight women, a minimum of 5% weight loss has been associated with increased fertility and improved pregnancy outcomes. This was a major challenge during the lockdown due to COVID-19 pandemic, which led to a drastic lowering of success in weight loss programs despite adaptations. This not only added to the already existing challenges of living with PCOS but also had a detrimental effect on their mental health. A high level of anxiety and stress was experienced by them due to uncertainty about their increased risk for COVID-19 and lack of support strategies due to limitations imposed on healthcare services.
| Diagnosis|| |
Updated diagnostic guidelines from the International PCOS Network endorsed the use of “Rotterdam criteria” in adults and the combined presence of hyperandrogenism and oligo-anovulation in adolescents. Hyperandrogenism is reported in about 60%–80% of PCOS cases established by the Rotterdam criteria. As long as “biochemical hyperandrogenism” persists as a diagnostic challenge deprived of an affordable, sensitive, reproducible, and validated testosterone assay, its assessment to diagnose PCOS should be subject to sex hormone-binding globulin, total serum testosterone, and free androgen index.
Existing evidence points toward a key role for adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) in the intra-ovary adiponectin, insulin, and follicle-stimulating hormone (FSH) signaling pathways. Recent studies on mouse model systems point toward the potential role of APPL in preventing IR, diabetes, and endothelial disorders. With APPL1 deficiency leading to metabolic and vascular disorders, APPL1 is now an innovative diagnostic and therapeutic option for ovarian dysfunctions and reproductive disorders, particularly PCOS.
| Management: Lifestyle and Behavioral Approaches|| |
“International evidence-based guideline (2018) for the assessment and management of PCOS” recommends lifestyle interventions such as diet, exercise, and behavioral approaches for all women with PCOS. An earlier study on a hyperandrogenic PCOS mouse model revealed that PCOS traits were augmented selectively by diet. Reproductive traits were shown to have a greater sensitivity to dietary macronutrient balance than metabolic traits, suggesting that the development of evidence-based dietary interventions would be a hopeful strategy for PCOS management, specifically for reproductive traits.
Lifestyle and behavioral approach (LBA) has always been considered the first line of treatment for PCOS, especially in overweight/obese women. Despite substantial evidence-based guidelines, the intensity, complexity, and behavioral components of lifestyle modifications are not clearly understood, and 45% of women with PCOS report that LBA was never suggested as a management alternative., Increased physical activity, dietary alterations, and weight loss have been suggested as some of the first-line lifestyle interventions for women with PCOS.,, LBA should also include changes in alcohol use, psychosocial stress, and tobacco consumption, for long-term management of PCOS. LBA has found maximum effect in PCOS women with obesity or hyperglycemia but no significant effect on ovulation complications and hyperandrogenicity in nonobese women. In the current situation of the COVID-19 pandemic, lockdowns, quarantine, and isolation, maintaining good physical activity and monitoring diet are proving to be the major challenges for women with PCOS.
PCOS and weight gain have always gone hand-in-hand. Weight loss, maintenance of weight loss, and prevention of weight gain are hence significant in women with PCOS. Evidence suggests that short-term weight loss is successful in decreasing IR and restoring fertility. However, most often, then, women are faced with the challenge of sustainable weight loss. Inclusion of social support, motivation, and psychological and behavioral strategies such as goal setting and self-monitoring can give better weight loss outcomes.
A recent SRMA of 14 trials involving 517 women reported that a significant decrease in waist circumference, fasting glucose, lipid levels, and systolic blood pressure was noted with exercise. However, they went on mention that the effect of exercise on reproductive function was unclear. Quantitatively, there were insufficient published data, but semi-quantitative analysis suggested improvement in menstrual regularity and pregnancy outcomes.
A total of 583 women in nine trials comparing those who received LBA with those who either received metformin or minimal intervention or no intervention were taken up in an SRMA. A lifestyle modification significantly reduces fasting glucose (weighted mean difference, −2.3 mg/dL; P = 0.04) and fasting insulin (weighted mean difference, −2.1 μU/mL; P < 0.001) when compared to minimal intervention. Surprisingly, the betterment in blood glucose or insulin levels noted with metformin was not significantly different from that due to LBA.
| Management: Pharmaceutical|| |
Oral contraceptives combined with antiandrogens continue to be the standard management regimen to bring down androgen levels and treat symptoms while simultaneously offering endometrial protection. They act by suppressing ovulation through negative feedback on the hypothalamus and, at the same time, decreasing ovarian androgen secretion. Recent evidence also suggests that treatment of PCOS patients with 3 mg drospirenone + 20 μg ethinyl estradiol combination is beneficial for hormonal imbalance and lipid profile while having a substantial safety profile.
Clomiphene citrate (CC) continues to be the management choice for ovulation induction in anovulatory PCOS women. An alternative of 2.5 mg/day letrozole (aromatase inhibitor) has been suggested to induce ovulation in CC therapy failure patients. Evidence from an open-label randomized clinical trial in 2017 proposes that letrozole is better than metformin–CC combination to induce ovulation and clinical pregnancy. A higher rate of ovulation of 82% was reported among the patients in the letrozole arm, as opposed to the 43.1% in metformin–CC arm (P < 0.001). The participants in the letrozole arm also reported higher clinical pregnancy rate (36% vs. 9.8%, P < 0.001), higher multiple pregnancy rate (P < 0.05), better endometrial thickness (P < 0.001), more dominant follicles (P < 0.05), lesser adverse effects (P < 0.05), and higher acceptability (P < 0.001) compared to patients in the CC and metformin arm. Clomiphene acts by blocking the hypothalamic–pituitary axis from circulating estrogen. Being structurally similar to estrogen, clomiphene blocks hypothalamic receptors and thus triggers FSH release from the anterior pituitary following alterations in GnRH pulsatility.
Insulin-sensitizing agents, Myo-inositol and D-chiro-inositol, act as second messengers in insulin signaling, which are likely substitutes to metformin in PCOS with IR (IR-PCOS) by significantly reducing the theca/granulosa cell layer thickness ratio and the time to pregnancy. Given the existing body of evidence, it can be said that inositol therapy can be an alternative for metabolic improvement in metformin-intolerant PCOS women. Clinical evidence has exhibited that an optimal 40:1 combination of Myo-inositol and D-chiro-inositol restores ovulation in PCOS women. Often, inositol-based PCOS regimens are randomly chosen doses and combined with useless or counter-productive molecules, thereby weakening the efficacy of Myo-inositol. A trial on teenagers with PCOS reported that after receiving Myo-inositol, significant reduction in weight, BMI, glucose, C-peptide, insulin, and LH was detected. At the same time, the Oral Contraceptive pill (OCP) arm reported slight increase in weight and BMI slightly increased, while the metabolic parameters remained unchanged.
An experimental study on female SpragueDawley rats showed that MitoQ10 (mitochondria-targeted antioxidant) may have a positive therapeutic effect on animals with IR-PCOS. The fortification of mitochondrial functions and the adaptation of programmed cell death-related proteins have been suggested as the most likely reasons behind this effect.
| Management: Surgical|| |
Since 1984, laparoscopic ovarian drilling (LOD) has advanced into a highly effective and safe surgical treatment for PCOS women, impassive to CC therapy. It mirrors the effects of gonadotropins using pregnancy and live births excluding risks of ovarian hyperstimulation or multiple pregnancies, along with a marked improvement in ovarian responsiveness to succeeding therapy with ovulation induction agents.
Irrespective of the presence or absence of other causes of infertility, women with PCOS often have a receptivity defect in the endometrium which subsequently affects their fertility status. LOD also produces a substantial increase in the endometrial mRNA expressions (HOXA-10 and HOXA-11) and improvement in endometrial receptivity in CC-resistant PCOS. In terms of ovarian drilling, bilateral LOD technique was shown to be more effective than the unilateral in terms of menstrual cycle regularity, ovulation induction, and snowballing pregnancy rates in women with CC-resistant PCOS.
Endometrial hyperplasia and PCOS (both of which are related to an amplified risk for developing endometrial carcinoma) have been identified as hypothetically novel indications for bariatric surgery. Bariatric surgeries have been shown to improve most of the crucial diagnostic features seen in PCOS and women with ovarian volume., Some of the foremost bariatric procedures in the present era are laparoscopic adjustable gastric banding, laparoscopic sleeve gastrectomy, and Roux-en-Y gastric bypass. The likelihood of a metabolic benefit from the surgical procedure could be achieved by the assessment of free testosterone levels.,
| Management: Other Practices of Medicine|| |
PCOS has always been a well-explored field with many complementary medical practices coming up with possible remedies from their diverse knowledge spectrum. Irrespective of whether it is the administration of the Chinese traditional herbal medicine, Cangfu Daotan decoction, role of gut microbiota, or the use of Yoga and Ayurvedic herbal mixtures, or the effect of homeopathic formulations such as Calcarea carbonica in improving menstrual regularity, there are a vast variety of probable remedies being suggested for PCOS.,,,,,
| Complications|| |
A 2017 meta-analysis presented a greater prevalence of nonalcoholic fatty liver disease (NAFLD) among women with hyperandrogenic PCOS compared to other PCOS phenotypes (OR [95% CI] = 2.54 [2.19–2.95]). The odds remained significantly high even after adjusting for confounding variables. Subsequently, elevated serum androgen levels were noted in PCOS women presenting with NAFLD compared to those without (mean difference [95% CI] = 0.40 [0.29–0.50] nmol/L).
Irrespective of age, the risk and severity of stroke can be regulated by gonadal hormones. A growing body of evidence shows that continued gonadal hormone dysfunction in PCOS results in hyperandrogenism and metabolic comorbidities, which in turn is accompanied by an increased risk of stroke.
| Conclusions|| |
Updated acumens into the interrelation between brain, fat, muscle, and ovarian tissue aid the concept of PCOS being a systemic syndrome. The metabolic and inflammatory instabilities associated with PCOS can be partly explained by the co-existence of obesity and IR but are reinforced by hyperandrogenicity. The management plan should hence be custom-made, taking into consideration the patient phenotype, complaints, and planning for the family. Medical treatments have seen only insignificant advances in recent years. The increased effectiveness of aromatase inhibitor letrozole over CC to treat infertility due to PCOS may be considered noteworthy. Evidence for the positive effect of bariatric surgery in relieving PCOS symptoms can be taken as a positive step toward the future of interdisciplinary approaches in PCOS management. To conclude, constitutional management by a multidisciplinary team may be helpful for women with PCOS. Lifestyle interventions are best advised and, in so doing, decrease body adiposity and recuperate their metabolic and reproductive health.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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