Polycystic ovary syndrome is a heterogeneous endocrine-metabolic disorder characterized by ovulatory dysfunction, hyperandrogenism and polycystic ovarian morphology after exclusion of alternative causes. This review uses polyendocrine metabolic ovarian syndrome (PMOS) as a systems-based framing term while retaining PCOS when reporting established diagnostic criteria and indexed evidence. Weight management is central because excess adiposity can amplify insulin resistance androgen excess and subfertility. A contemporary review found that lifestyle, pharmacological and surgical weight-loss strategies differ in their metabolic and reproductive effects [1]. A preconception synthesis also identified developing but limited evidence that weight optimization improves pregnancy-related outcomes [2].

The condition affects reproductive function through disrupted follicular maturation, excess androgen exposure, altered gonadotropin signalling and impaired endometrial receptivity. Its metabolic component includes insulin resistance, central adiposity, dyslipidaemia and increased risk of impaired glucose tolerance. The 2023 international guideline recognizes metabolic risk, psychological morbidity, sleep apnoea and adverse pregnancy outcomes as core features rather than incidental comorbidities [3]. Contemporary clinical reviews likewise describe PCOS as a lifelong disorder whose manifestations change from adolescence through fertility treatment, pregnancy and later cardiometabolic life [4].

Metabolic and reproductive pathways interact but are not interchangeable. Obesity and insulin resistance can amplify ovarian androgen production and reduce sex hormone-binding globulin yet lean women may also have severe ovulatory dysfunction. Recent work has therefore reframed PCOS as a metabolic disease with clinically distinct reproductive phenotypes [5]. Pregnancy adds another stress test: a large updated synthesis found excess miscarriage, gestational diabetes, hypertensive disorders and cesarean delivery even after analyses restricted to age-matched, body mass index-matched or high-quality studies [6]. Data-driven subtyping further suggests that obesity-predominant, hyperandrogenic and high anti-Mullerian hormone phenotypes follow different fertility and metabolic trajectories [7].

The major research gap is translation of this heterogeneity into individualized preconception and fertility care. Lifestyle intervention is recommended universally although reproductive endpoints and maintenance are inconsistently measured [8]. Letrozole is effective for anovulatory infertility but access, monitoring and treatment escalation differ between health systems [9]. Metabolic therapies and bariatric procedures may restore ovulation yet pregnancy safety and optimal treatment-free intervals require care. Evidence from Pakistan remains fragmented and is dominated by cross-sectional or small intervention studies. This review evaluated metabolic dysfunction, infertility treatments, pregnancy complications and emerging precision strategies in PMOS/PCOS [10-13].

A systematic review was conducted according to PRISMA 2020 principles. The target population comprised reproductive-age women diagnosed with PCOS by accepted Rotterdam, National Institutes of Health or international guideline criteria. PMOS was used as an interpretive framework for the multisystem endocrine-metabolic phenotype and not as a separate diagnostic definition. The principal outcomes were weight-related change, ovulation, clinical pregnancy, live birth and adverse pregnancy outcomes. Secondary outcomes included insulin resistance, adiposity androgen status, menstrual recovery and treatment safety. MEDLINE/PubMed was searched from database inception to 30 April 2026. The strategy combined 'polycystic ovary syndrome', 'polyendocrine metabolic ovarian syndrome' or PMOS with metabolic dysfunction, insulin resistance, obesity, weight management, infertility, ovulation, assisted reproduction, pregnancy, live birth, miscarriage, gestational diabetes and hypertensive disorders. Citation tracking was used for key guidelines and recent systematic reviews. The reproducible electronic query identified 12,659 indexed records. This was a sensitive retrieval count rather than a claim that every record underwent full-text assessment. Guidelines, systematic reviews, randomized controlled trials, prospective cohorts and large retrospective cohorts were eligible. Human adult studies were prioritized. Reports limited to animal models, isolated molecular pathways, non-reproductive outcomes without metabolic relevance, unvalidated supplements or self-diagnosed PCOS were excluded from the outcome synthesis. For overlapping evidence the most recent or complete publication was used for each outcome. Alternative nomenclature was considered only when the underlying diagnostic criteria mapped to PCOS and was not treated as independent effectiveness evidence. A structured extraction form recorded study design, diagnostic criteria, setting, sample size, metabolic phenotype, intervention, comparator, duration, ovulation, pregnancy, live birth, obstetric outcomes, adverse events, effect measures and confidence intervals. Metabolic dysfunction was operationally defined as reported insulin resistance, impaired glucose regulation, dyslipidaemia, excess adiposity or metabolic syndrome. Infertility was accepted according to the source study. Values reported as n (%), mean ± SD, median (IQR), OR, rate ratio or RR were retained in their original form. Risk of bias was evaluated by study design. Randomized trials were considered for allocation, deviations from intervention, missing outcomes and selective reporting. Cohorts were considered for diagnostic accuracy, confounding, treatment selection and follow-up. Systematic reviews were evaluated for database coverage, duplicate assessment, heterogeneity and certainty appraisal. Meta-analysis was not repeated because several reviews overlapped and interventions were not clinically exchangeable. Results were organized as a structured narrative synthesis with three evidence tables. Ethical approval was unnecessary because only published aggregate data were used. Confidentiality was not applicable. Statistical significance was accepted at p<0.05 when used by the original study [14]

The database query identified 12,659 records. Focused screening retained 35 publications that directly informed metabolic phenotype, weight management, infertility treatment, pregnancy risk or future research. Evidence comprised an international guideline, systematic reviews, randomized trials and observational cohorts. The flow of evidence is shown in Figure 1. PMOS was used as a systems-based framing term while all quantitative studies used established PCOS diagnostic terminology.

The largest pregnancy synthesis included 104 studies and 106,690 pregnancies. Compared with women without PCOS, women with PCOS had higher odds of miscarriage (44 studies; OR 1.49, 95% CI 1.20-1.85), gestational diabetes (55 studies; OR 2.41, 95% CI 1.95-2.99), gestational hypertension (39 studies; OR 2.20, 95% CI 1.82-2.67), pre-eclampsia (34 studies; OR 2.30, 95% CI 1.88-2.82) and cesarean section (37 studies; OR 1.23, 95% CI 1.06-1.43). Mean gestational weight gain was 0.96 kg higher (95% CI 0.01-1.90). Heterogeneity was 82.8% for miscarriage, 81.9% for gestational diabetes, 53.3% for gestational hypertension, 28.1% for pre-eclampsia and 63.5% for cesarean section.

Reproductive treatment evidence supported letrozole as first-line pharmacological ovulation induction. A review of 41 randomized trials involving 6,522 women found higher live birth with letrozole than selective estrogen receptor modulators (OR 1.72, 95% CI 1.40-2.11; 11 trials, 2,060 participants). Clinical pregnancy was also higher (OR 1.69, 95% CI 1.45-1.98; 23 trials, 3,321 participants). Ovarian hyperstimulation syndrome occurred in 0.5% in both groups. Miscarriage per pregnancy was 25% with selective estrogen receptor modulators and 24% with letrozole (OR 0.94, 95% CI 0.66-1.32).

A randomized stair-step trial enrolled 100 women. Ovulation occurred in 86.0% with letrozole and 72.0% with clomiphene (p=0.086). Pregnancy occurred in 22.0% and 18.0% (p=0.617). Time from menstruation to ovulation was shorter with letrozole (17.20 ± 1.32 days versus 24.08 ± 1.56 days, p<0.001). In a secondary analysis of 322 women, mean anti-Mullerian hormone was 11.7 ± 8.3 ng/mL. Each 1 ng/mL increase was associated with 10% lower odds of ovulation (OR 0.90, 95% CI 0.86-0.93) although anti-Mullerian hormone did not independently predict pregnancy or live birth.

Metabolic interventions showed reproductive signals but differed in maturity. In the BAMBINI randomized trial 80 women with PCOS and body mass index ≥35 kg/m² were assigned to sleeve gastrectomy or medical care. Median ovulations over 52 weeks were 6 (IQR 3.5-10.0) after surgery and 2 (IQR 0.0-4.0) with medical care. Surgery produced 2.5 times more spontaneous ovulations (95% CI 1.5-4.2, p<0.0007) but adverse events occurred in 24 (66.7%) and 12 (30.0%), respectively.

A randomized open-label trial allocated 100 overweight or obese women to metformin or semaglutide plus metformin. Eighty participants completed treatment. Mean weight loss at 16 weeks was 6.09 ± 3.34 kg with combination therapy and 2.25 ± 4.27 kg with metformin. Natural pregnancy from weeks 16-40 was 35% and 15% (P<0.05). These findings require confirmation and do not establish use during pregnancy. A separate pregnancy trial randomized 464 women to myo-inositol or placebo. The composite of gestational diabetes, pre-eclampsia or preterm birth occurred in 56 (25.0%) and 61 (26.8%) (RR 0.93, 95% CI 0.68-1.28; P=.67).

Phenotype data reinforced heterogeneity. A study of 11,908 women identified four reproducible subtypes across five international cohorts. The obesity-predominant subtype had the most severe metabolic complications and lowest live birth rate. The hyperandrogenic subtype had the highest second-trimester loss and dyslipidaemia incidence. The high sex hormone-binding globulin subtype had favourable reproductive outcomes and the lowest diabetes and hypertension incidence. The high luteinizing hormone-anti-Mullerian hormone subtype had the greatest ovarian hyperstimulation risk. Tables 1-3 summarize baseline evidence, primary outcomes and clinically relevant modifiers.

Figure 1. Study selection and evidence-synthesis flow

Table 1. Principal evidence and population characteristics

Table 2. Main reproductive and pregnancy outcomes

Table 3. Factors modifying fertility or pregnancy care

This review found that a systems-based PMOS framing is clinically useful because reproductive dysfunction is inseparable from metabolic and obstetric risk. It is not a replacement diagnostic system and current quantitative evidence remains anchored to PCOS definitions. The increased risks of gestational diabetes and other adverse pregnancy outcomes demonstrate why metabolic assessment and weight management must be integrated with fertility care [15]. The excess pregnancy risk is clinically important. Miscarriage, gestational diabetes, hypertensive disorders and cesarean delivery remained increased across sensitivity analyses in the updated international synthesis [16]. These outcomes are compatible with insulin resistance, endothelial dysfunction, chronic inflammation androgen excess and obesity but the associations cannot be attributed to one pathway. Pakistani services should record a pre-existing PCOS diagnosis at booking and assess glucose, blood pressure and weight trajectory early rather than treating pregnancy as low risk after conception. Ovulation induction evidence was strongest for letrozole. Its higher live-birth and clinical-pregnancy effects were supported by high-certainty randomized evidence and did not increase ovarian hyperstimulation relative to selective estrogen receptor modulators [17]. The smaller stair-step trial also showed a shorter time to ovulation despite non-significant differences in ovulation and pregnancy proportions [18]. Clinically this supports letrozole as first-line therapy after preconception assessment and exclusion of other infertility factors. Monitoring intensity should reflect access, multiple-pregnancy risk and prior response. Metabolic optimization should precede treatment escalation. Metformin has established roles for metabolic features and may support cycle regulation although it is less effective than dedicated ovulation induction for live birth [19]. A Pakistan-linked meta-analysis of eight studies and 1,088 participants found no significant difference between metformin and myo-inositol for body mass index, fasting insulin, fasting glucose, HOMA index or luteinizing hormone/follicle-stimulating hormone ratio [20]. This local contribution is useful but does not justify unregulated supplementation or replacement of proven fertility therapy. Weight management improves more than laboratory values. Randomized evidence synthesis shows that structured interventions reduce weight and some androgen and glucose measures although live-birth evidence remains limited [21]. Liraglutide trials demonstrate weight and metabolic effects in women with obesity and PCOS [22]. GLP-1 receptor agonists may improve reproductive function indirectly through weight loss and insulin sensitivity [23]. They should be stopped before conception according to product and clinical guidance because pregnancy safety is insufficient. Bariatric surgery produced a clear ovulation benefit in women with severe obesity but generated more adverse events and requires delayed conception during rapid weight loss [24]. Surgery is therefore not an infertility procedure alone. It is a metabolic intervention for appropriately selected women who understand nutritional surveillance, contraception and future pregnancy planning. The observed increase from 2 to 6 median ovulations over 52 weeks is meaningful but it does not by itself prove a higher live-birth rate. The negative myo-inositol pregnancy trial is equally informative. A composite event occurred in one quarter of both treatment groups and the RR crossed unity [25]. This contradicts assumptions derived from small metabolic studies and demonstrates why pregnancy prevention claims require adequately powered trials. Nutritional supplements should not displace glucose testing, blood-pressure surveillance or evidence-based management of pre-eclampsia risk. Precision care is a major future direction. The four-subtype analysis suggests that women grouped under one diagnosis can have opposing metabolic and reproductive trajectories [26]. Oxidative stress and energy-metabolism research provides plausible mechanisms [27] and endometrial studies identify altered receptivity pathways [28]. These discoveries are not ready for routine panels. Useful clinical stratification can already begin with body mass index, waist measures, glucose status, blood pressure androgen burden, cycle pattern, anti-Mullerian hormone and pregnancy history. International guideline implementation should be adapted to ethnicity and health-system capacity. Metabolic phenotype varies across populations [29] and adiposity has a causal relationship with PCOS risk [30]. Ethnic differences influence diabetes susceptibility and thresholds for central obesity [31]. South Asian women may develop dysglycaemia at lower body mass index. Pakistani clinics therefore need affordable oral glucose testing, standardized infertility pathways and coordinated endocrinology-obstetric care rather than reliance on ovarian ultrasound alone. Comorbid endocrine and behavioural conditions also affect fertility care. Thyroid disorders can mimic or accompany cycle disturbance [32]. Sleep problems and psychological distress can reduce treatment adherence and quality of life [33]. The emerging WHO infertility guidance supports people-centred pathways that move from diagnosis and lifestyle support to effective treatment without unnecessary delay [34]. PMOS terminology may help multidisciplinary communication only if it does not create confusion, stigma or duplicated diagnoses. Future research should prospectively test whether phenotype-guided treatment improves live birth and maternal outcomes. Studies should report diagnostic criteria, ethnicity, adiposity, insulin resistance, medication exposure before conception, mode of conception and obstetric follow-up. Mechanistic evidence on impaired endometrial receptivity is expanding [35] but clinical utility requires validated thresholds and interventions. National registries would allow Pakistan to compare spontaneous conception, ovulation induction and assisted reproduction while measuring pregnancy safety. A practical preconception pathway begins with confirmation that ovulatory dysfunction is attributable to PCOS rather than pregnancy, thyroid disease, hyperprolactinaemia, non-classic congenital adrenal hyperplasia or hypothalamic causes. Semen analysis and tubal assessment should be timed according to history rather than postponed through repeated empirical cycles. Blood pressure, body mass index, glucose status, medication exposure, folate intake, smoking and sleep should be reviewed before treatment. This approach prevents metabolic optimization from becoming an indefinite barrier to fertility care. Assisted reproduction requires attention to both high ovarian response and lower live-birth probability in selected phenotypes. A high anti-Mullerian hormone level can predict reduced ovulation with oral induction yet PCOS ovaries may produce many follicles during gonadotropin treatment. Individualized starting doses, ultrasound monitoring and agonist-trigger or freeze-all strategies can reduce ovarian hyperstimulation. Treatment success should be reported as cumulative live birth rather than oocyte yield alone because a larger oocyte number does not guarantee implantation or safe pregnancy. Menstrual recovery is a useful intermediate endpoint but not a substitute for ovulation confirmation. Weight loss, metformin or incretin-based treatment can regularize bleeding without establishing consistently ovulatory cycles. Conversely occasional ovulation can occur despite persistent irregularity. Studies should use progesterone, ultrasound or clearly defined cycle outcomes. For women not immediately seeking pregnancy, cycle protection and contraception remain necessary because metabolic treatment may restore fertility unexpectedly. The metabolic component continues after reproductive treatment. A woman who conceives after ovulation induction still carries baseline risk related to insulin resistance, adiposity and blood pressure. Postpartum follow-up is also important after gestational diabetes or hypertensive pregnancy because these events identify future cardiometabolic vulnerability. PMOS framing may improve continuity if fertility clinics communicate metabolic findings to primary care and obstetric teams rather than ending management after a positive pregnancy test. Terminology choices require governance. Diagnostic codes, trial registries, electronic records and patient information currently use PCOS. Immediate replacement could fragment literature searches or cause women to believe that they have a different disease. Dual labelling such as PMOS/PCOS should therefore be accompanied by a clear explanation that the systems-based framing broadens clinical emphasis but does not alter validated diagnostic criteria. Patient preference should be measured because some may find 'metabolic' more accurate and others may experience added stigma. Core outcome sets would improve comparability. Trials should report menstrual frequency, biochemically confirmed ovulation, clinical pregnancy, ongoing pregnancy, live birth, multiple pregnancy, miscarriage and adverse events using consistent denominators. Metabolic outcomes should include waist measure, glucose method, insulin-resistance metric, lipids and blood pressure. Pregnancy trials should stratify spontaneous and assisted conception. These standards would reduce the selective emphasis on favourable surrogate outcomes. Implementation in Pakistan can begin without advanced molecular testing. A shared clinic proforma can document phenotype, metabolic screening, infertility duration, prior treatment and pregnancy risk. Letrozole protocols can be standardized and referral thresholds defined for gonadotropins or in-vitro fertilization. Women with severe obesity or diabetes need coordinated care but should not face stigmatizing refusal without individualized risk discussion. Prospective multicentre audit could generate the national evidence that is presently missing. Medication sequencing should follow the woman's primary goal. Combined hormonal contraception or antiandrogen treatment for hirsutism is unsuitable when conception is intended and antiandrogens require reliable contraception because of fetal risk. Metformin can address metabolic features and menstrual irregularity but should not delay letrozole when anovulatory infertility is established. Newer obesity medicines require a planned washout. Clear sequencing reduces contradictory prescriptions from separate clinics. Male and tubal factors remain relevant even when PCOS appears to explain irregular cycles. Repeated ovulation induction without basic couple assessment wastes time and can expose women to unnecessary monitoring. Age and infertility duration should guide the pace of investigation. Early referral is appropriate for diminished ovarian reserve, previous pelvic infection, severe semen abnormality or failed oral induction. A PMOS framework should broaden clinical vision rather than make every infertility outcome attributable to metabolism. Patient-centred outcomes deserve equal weight. Women frequently experience stigma related to weight, infertility, acne and excess hair. Counseling should use neutral language and shared decisions. Lifestyle care should offer achievable dietary and activity support rather than a demand for a fixed weight before treatment. Psychological screening is justified when distress affects adherence or wellbeing. A diagnosis that emphasizes multiple endocrine systems must still preserve the patient's immediate reproductive priorities. Prevention of pregnancy complications should be tested rather than inferred from metabolic improvement. A lower fasting insulin or body weight before conception may be beneficial but it does not prove reduction in pre-eclampsia or miscarriage. Trials need sufficient follow-up through delivery and should prespecify maternal and neonatal outcomes. The neutral myo-inositol trial illustrates the difference between plausible mechanism and demonstrated obstetric benefit. Clinical education should explain that polycystic ovarian morphology alone does not establish the syndrome. Overdiagnosis can expose healthy women to anxiety and unnecessary treatment while underdiagnosis misses metabolic risk. Adult diagnostic algorithms should apply validated combinations of ovulatory dysfunction, hyperandrogenism and ovarian morphology or anti-Mullerian hormone after exclusion of mimics. The PMOS framing used in this review does not change this requirement. Follow-up should be longitudinal. Reproductive priorities change and a woman treated for irregular cycles in adolescence may later seek fertility care or develop dysglycaemia. A portable record of diagnosis, metabolic tests and treatment response can reduce repeated investigation. Continuity is particularly valuable where women move between primary care, private fertility clinics and public maternity services. This review had limitations. PMOS was used as a systems-based framing term and not as an independent diagnostic entity. Most included quantitative reports used PCOS and varied in diagnostic criteria, phenotype, treatment exposure and outcome definition. Several intervention studies were small or open label. Pregnancy meta-analyses had substantial heterogeneity and residual confounding. Long-term live-birth and offspring data after newer metabolic drugs were limited. The focused MEDLINE/PubMed strategy may have missed non-indexed regional studies and no new pooled analysis was performed.

Giant. PMOS usefully emphasizes that ovarian dysfunction, infertility and pregnancy risk occur within a systemic endocrine-metabolic disorder although PCOS remains the validated diagnostic term. Current evidence supports metabolic screening, individualized weight management, letrozole-based ovulation induction and enhanced surveillance for miscarriage, gestational diabetes and hypertensive disorders. Bariatric surgery and newer metabolic drugs may restore ovulation in selected women but require preconception planning and stronger live-birth safety evidence. Future studies should validate phenotype-guided care in South Asian populations.

Declarations

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

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