Definition

Metabolic infertility describes impaired reproductive potential associated with disturbances in energy balance, insulin action, adipose-tissue signaling, lipid and glucose metabolism, vascular function, inflammation, and redox homeostasis. It is not a separate diagnostic entity, but a clinically useful framework linking cardiovascular–kidney–metabolic syndrome, obesity, insulin resistance, polyendocrine metabolic ovarian syndrome (PMOS; formerly polycystic ovary syndrome, PCOS), type 2 diabetes, thyroid dysfunction, and male hypogonadism with ovulatory dysfunction, reduced oocyte competence, impaired endometrial receptivity, abnormal semen parameters, sperm DNA damage, and adverse outcomes of assisted reproduction. Because many contributing factors are modifiable, metabolic assessment and optimization should be integrated into preconception and infertility care for both partners.

1. Introduction

Cardiovascular–kidney–metabolic (CKM) syndrome is a systemic disorder arising from the complex interplay among excess or dysfunctional adiposity, metabolic risk factors, chronic kidney disease, and cardiovascular disease. Unlike the conventional metabolic syndrome, CKM syndrome is not diagnosed by the presence of a fixed number of criteria. Instead, the American Heart Association classifies CKM health across five progressive stages: Stage 0 represents optimal CKM health without identifiable risk factors; Stage 1 includes excess or dysfunctional adiposity; Stage 2 comprises established metabolic risk factors or chronic kidney disease; Stage 3 includes subclinical cardiovascular disease (CVD) or a high predicted cardiovascular risk; and Stage 4 denotes clinically manifest cardiovascular disease, such as coronary heart disease, heart failure, stroke, peripheral artery disease, or atrial fibrillation [3,4]^[1][2][3][4]. This staging system emphasizes early detection, longitudinal risk assessment, and integrated management of cardiovascular, kidney, and metabolic abnormalities.

The relationship between CKM health and fertility is bidirectional and extends beyond body mass index (BMI). Adipose-tissue distribution, insulin resistance, dysglycemia, dyslipidemia, hypertension, impaired kidney function, sleep disorders, physical inactivity, diet quality, exposure to endocrine-disrupting chemicals, and socioeconomic determinants may collectively influence reproductive function. Conversely, PCOS and obesity-related functional hypogonadism identify women and men who may have an increased long-term CKM risk. Metabolic and reproductive abnormalities should therefore be assessed as interconnected manifestations of systemic dysfunction. A couple-centered, multidisciplinary approach that integrates reproductive, metabolic, cardiovascular, and kidney health is preferable to an exclusively female-centered infertility evaluation.

2. Shared Pathophysiological Pathways

2.1. Insulin Resistance and Compensatory Hyperinsulinemia

Insulin resistance is a central mechanism connecting CKM-related metabolic dysfunction with reproductive dysfunction. In women, hyperinsulinemia stimulates ovarian theca-cell androgen production and enhances luteinizing hormone (LH)-mediated steroidogenesis. It also suppresses hepatic synthesis of sex hormone-binding globulin (SHBG), increasing biologically active free testosterone. These changes promote follicular arrest, oligo-anovulation, and the clinical manifestations of hyperandrogenism, particularly in PCOS [5–7]^[5][6][7]. Insulin resistance may additionally affect granulosa-cell metabolism, meiotic competence, mitochondrial function, and endometrial signaling.

In men, insulin resistance is associated with reduced SHBG, altered gonadotropin signaling, impaired Leydig- and Sertoli-cell function, and a higher likelihood of functional hypogonadism. Hyperglycemia and advanced glycation products may impair sperm motility, acrosomal function, chromatin integrity, and mitochondrial energy production. Diabetes can further compromise fertility through erectile or ejaculatory dysfunction and autonomic neuropathy.

2.2. Adipose-Tissue Dysfunction and Adipokines

Adipose tissue is an active endocrine organ. With adipocyte hypertrophy, hypoxia and immune-cell recruitment promote secretion of tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein-1, and other inflammatory mediators. Circulating leptin typically rises, whereas adiponectin declines. Hyperleptinemia may coexist with central leptin resistance, disrupting hypothalamic energy sensing and kisspeptin-GnRH signaling. At the gonadal level, excessive leptin exposure can interfere with ovarian steroidogenesis and testicular function.

In women, adipokine imbalance can influence folliculogenesis, oocyte maturation, corpus-luteum function, and endometrial receptivity. In men, excess adiposity increases aromatase activity and conversion of testosterone to estradiol. The resulting estrogenic feedback may suppress gonadotropin secretion and exacerbate low testosterone. Scrotal adiposity and increased testicular temperature may provide additional mechanisms linking obesity to altered spermatogenesis.

2.3. Chronic Inflammation, Oxidative Stress, and Mitochondrial Dysfunction

Low-grade inflammation and oxidative stress form a self-reinforcing network with insulin resistance. Physiological concentrations of reactive oxygen species participate in ovulation, sperm capacitation, hyperactivation, and the acrosome reaction. Excess production, however, overwhelms antioxidant defenses and causes lipid peroxidation, protein oxidation, mitochondrial injury, and DNA damage.

Oocytes are particularly vulnerable because their developmental competence depends on mitochondrial ATP production and accurate meiotic spindle function. Oxidative stress may contribute to aneuploidy, reduced fertilization, impaired embryo development, and placental dysfunction. Spermatozoa are also highly susceptible because their membranes contain abundant polyunsaturated fatty acids and their cytoplasmic antioxidant capacity is limited. Oxidative injury is associated with reduced motility, abnormal morphology, and increased sperm DNA fragmentation [8,9]^[8][9]. Nevertheless, oxidative-stress testing and empirical antioxidant supplementation should not be used indiscriminately; clinical benefit depends on the population, cause, dose, and combination used.

2.4. Epigenetic and Intergenerational Effects

Metabolic exposures may alter DNA methylation, histone modifications, chromatin packaging, and non-coding RNA profiles in gametes. Obesity-related changes in sperm DNA methylation and small RNA content have raised concern about possible intergenerational transmission of metabolic risk ^[10]. Human evidence is biologically plausible but remains heterogeneous, and causality should not be overstated. These observations nonetheless reinforce the importance of optimizing the health of both partners before conception.

3. Female Fertility

3.1. Obesity, Ovulatory Dysfunction, and Oocyte Competence

Obesity is associated with menstrual irregularity, anovulation, longer time to pregnancy, and higher obstetric risk. These associations are strongest when obesity coexists with insulin resistance or PMOS, but they are not uniform across all women. BMI is an imperfect proxy for metabolic health and should be interpreted alongside waist circumference, blood pressure, glucose regulation, and lipid profile. The American Society for Reproductive Medicine concludes that obesity can adversely affect ovulatory function, natural fecundity, responses to fertility treatment, procedural safety, and pregnancy outcomes ^[11].

The follicular microenvironment may be modified by hyperinsulinemia, dyslipidemia, lipotoxicity, altered adipokines, and inflammatory mediators. Experimental and clinical observations suggest that these changes can impair granulosa-cell function, oocyte mitochondrial activity, and embryo development [12,13]^[12][13]. At the endometrial level, insulin resistance and inflammation may alter decidualization and receptivity. However, age and ovarian reserve remain powerful determinants of reproductive prognosis; delaying indicated fertility treatment solely to achieve a specific BMI may reduce cumulative opportunity for pregnancy in some patients. Decisions should therefore be individualized and based on treatment safety, age, comorbidities, and patient preferences.

3.2. Polyendocrine Metabolic Ovarian Syndrom as a Reproductive-Metabolic Disorder

PMOS is the most common endocrine disorder associated with anovulatory infertility. It combines reproductive, dermatologic, metabolic, and psychological features and affects approximately 8-13% of reproductive-aged women, depending on the population and diagnostic criteria [5,6]^[5][6]. Insulin resistance may occur independently of BMI and is amplified by weight gain. Women with PMOS have increased risks of impaired glucose tolerance, type 2 diabetes, dyslipidemia, sleep apnea, and adverse pregnancy outcomes.

The 2023 International Evidence-based Guideline recommends diagnosis in adults using two of three features—clinical or biochemical hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology—after exclusion of alternative disorders. Anti-Müllerian hormone may be used as an alternative to ultrasound for defining polycystic ovarian morphology in adults within an appropriate diagnostic algorithm, but it should not be used as a stand-alone test [5]. Lifestyle management is a core component of care for all women with PMOS. When pharmacologic ovulation induction is required, letrozole is recommended as first-line treatment for anovulatory infertility in the absence of other infertility factors [5,14]^[5][14].

3.3. Other Endocrine and Metabolic Conditions

Thyroid disease and hyperprolactinemia can cause menstrual disturbance and anovulation and should be investigated when clinically indicated. Primary ovarian insufficiency should be considered in women younger than 40 years with amenorrhea or irregular cycles and elevated follicle-stimulating hormone. Ovarian reserve tests such as anti-Müllerian hormone and antral follicle count predict ovarian response to stimulation more reliably than natural fecundability and should not be interpreted as direct tests of the ability to conceive ^[15].

Pre-existing diabetes requires structured preconception care. Glycemic optimization reduces the risk of miscarriage, congenital anomalies, preeclampsia, macrosomia, and other maternal-fetal complications. Medication review is essential because some glucose-lowering, lipid-lowering, and antihypertensive drugs are unsuitable during pregnancy.

4. Male Fertility

4.1. Obesity-Related Functional Hypogonadism

Male obesity is commonly associated with lower total testosterone, partly because insulin resistance reduces SHBG. With greater severity, free testosterone may also decline and gonadotropins may be inappropriately normal or low, producing functional hypogonadotropic hypogonadism. Aromatization in adipose tissue, inflammatory signaling, leptin resistance, sleep apnea, and chronic illness contribute to this phenotype [16,17]^[16][17]. Low testosterone can reduce libido and sexual function, but exogenous testosterone must not be prescribed to men actively seeking fertility because it suppresses intratesticular testosterone and spermatogenesis ^[18].

4.2. Semen Quality and Sperm DNA Integrity

Meta-analytic evidence associates overweight and obesity with increased odds of oligozoospermia or azoospermia, although effect sizes vary and residual confounding is substantial [19,20]^[19][20]. Dyslipidemia, oxidative stress, scrotal heat, endocrine disruption, and comorbid diabetes may impair sperm concentration, motility, morphology, and DNA integrity. A standard semen analysis remains the initial laboratory test, and abnormal findings generally require confirmation because semen parameters vary over time [18,21]^[18][21]. Sperm DNA-fragmentation testing is not a universal first-line test; it may be considered in selected clinical scenarios according to specialist guidance.

Lifestyle improvement and clinically meaningful weight loss may increase testosterone and improve some semen parameters, but evidence that these changes consistently increase live-birth rates remains limited. Bariatric surgery can markedly improve metabolic health and testosterone, yet semen outcomes after surgery are variable and may be influenced by rapid weight loss and micronutrient deficiencies. Fertility goals should be discussed before surgery.

5. Endocrine-Disrupting Chemicals and the Metabolic-Reproductive Interface

Endocrine-disrupting chemicals include bisphenols, phthalates, persistent organic pollutants, pesticides, and other compounds capable of interfering with hormone synthesis, transport, receptor signaling, or metabolism. Human exposure has been associated with obesity, diabetes, thyroid dysfunction, altered ovarian reserve, endometriosis, semen abnormalities, and subfertility, although observational designs and complex mixtures make causal attribution difficult [22,23]^[22][23]. Practical exposure-reduction advice can include avoiding heating food in plastic, choosing glass or stainless-steel containers when feasible, reducing tobacco exposure, and following occupational safety recommendations. Such measures should complement—not replace—evidence-based infertility evaluation.

6. Clinical Assessment: A Couple-Centered Metabolic Approach

Evaluation should begin after 12 months of regular unprotected intercourse when the female partner is younger than 35 years and after 6 months when she is 35 years or older. Immediate or earlier evaluation is indicated with amenorrhea, marked cycle irregularity, known tubal or uterine disease, endometriosis, previous gonadotoxic therapy, sexual dysfunction, known male-factor risk, or other conditions associated with reduced fertility ^[15]. Both partners should be assessed in parallel.

History should cover reproductive duration, menstrual and sexual history, previous pregnancies, medications and supplements, weight trajectory, dietary and physical-activity patterns, smoking, alcohol, sleep, psychological stress, occupational exposures, and family history. Examination may include BMI, waist circumference, blood pressure, signs of hyperandrogenism or insulin resistance, thyroid findings, and male genital examination when appropriate.

Metabolic testing should be targeted rather than indiscriminate. Fasting glucose or glycated hemoglobin and a lipid profile are reasonable when obesity, PMOS, diabetes risk, hypertension, or other metabolic abnormalities are present. The PMOS guideline favors a 75-g oral glucose-tolerance test as the most accurate assessment of glycemic status in PMOS, particularly when pregnancy is planned or fertility treatment is sought ^[5]. Routine measurement of fasting insulin or HOMA-IR is not standardized for clinical diagnosis and is not required in every infertility assessment. Thyroid-stimulating hormone, prolactin, and androgen evaluation should be guided by menstrual pattern and clinical findings. Vitamin D testing should follow general clinical indications rather than being presented as a universal infertility test.

7. Therapeutic Strategies

7.1. Lifestyle and Weight Management

Lifestyle intervention is the foundation of metabolic optimization. A Mediterranean-style dietary pattern emphasizing vegetables, fruit, legumes, whole grains, nuts, fish, and unsaturated fats is appropriate for cardiometabolic health. The optimal fertility-specific diet has not been established, and rigid or highly restrictive diets should be avoided. Adults should generally aim for at least 150 minutes of moderate-intensity aerobic activity weekly plus muscle-strengthening activity, adapted to clinical capacity. Sleep disorders, particularly obstructive sleep apnea, should be identified and treated.

In people with excess adiposity, a realistic 5-10% weight reduction can improve insulin sensitivity, blood pressure, liver fat, and ovulatory function. However, weight loss should not be presented as a guarantee of pregnancy or live birth. In women of advanced reproductive age or diminished ovarian reserve, the benefits of delaying fertility treatment must be balanced against age-related decline. Weight-neutral health gains—improved fitness, sleep, diet quality, and glycemic control—remain valuable even when substantial weight loss is not achieved [5,11]^[5][11].

Smoking cessation is essential for both partners. Alcohol intake should be minimized when attempting conception, and illicit anabolic steroids must be stopped under medical supervision. Psychological support is important because infertility and weight stigma can impair wellbeing and treatment engagement.

7.2. Insulin-Sensitizing and Ovulation-Induction Therapy

Metformin is appropriate for selected women with PMOS, especially those with impaired glucose tolerance, type 2 diabetes, or high metabolic risk. It can improve metabolic measures and may improve ovulation, but it is less effective than letrozole as first-line pharmacologic ovulation induction [5,14]. Treatment should be individualized, with gradual titration and attention to gastrointestinal adverse effects and vitamin B12 status during long-term use.

Inositol preparations are widely marketed for PMOS, but product composition and study quality vary. The 2023 guideline notes limited clinical benefit and insufficient evidence to recommend a specific type, dose, or combination for fertility outcomes ^[5]. Likewise, vitamin D, omega-3 fatty acids, coenzyme Q10, and other antioxidants should correct documented deficiency or address a defined indication rather than be routinely prescribed as universal infertility therapy.

Statins are treatments for cardiovascular-risk reduction, not established infertility treatments. Lipid-lowering therapy must be reviewed before conception and managed according to individual cardiovascular risk and current pregnancy guidance.

7.3. GLP-1 Receptor Agonists in PMOS and Preconception Care

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) produce clinically meaningful weight loss and improve glycemia in people with obesity or type 2 diabetes. In women with PMOS and excess weight, small randomized studies and meta-analyses report improvements in body weight, waist circumference, insulin resistance, androgen measures, and menstrual cyclicity; some analyses suggest a higher natural pregnancy rate, but the fertility evidence remains limited by small samples, heterogeneous comparators, and short follow-up [24-27]^{[24][25][26][27]}. GLP-1RAs are not established ovulation-induction drugs.

These agents should not be used during pregnancy. Effective contraception is required while treatment is ongoing when pregnancy is not intended. Before planned conception, the drug should be discontinued according to the product label and its pharmacokinetics; for semaglutide, current labeling advises discontinuation at least two months before a planned pregnancy ^[28]. Preconception use may be considered as a time-limited metabolic strategy in appropriately selected patients, coordinated among primary care, endocrinology, and reproductive-medicine clinicians. Counseling must include weight regain after discontinuation, gastrointestinal adverse effects, gallbladder disease, and the need for a clear transition plan.

7.4. Assisted Reproduction and Metabolic Risk

Metabolic optimization should complement rather than unnecessarily postpone indicated assisted reproductive technology. Obesity and metabolic syndrome can affect ovarian stimulation requirements, ultrasound visualization, anesthesia safety, oocyte retrieval, embryo development, and pregnancy complications. Clinics should use transparent, individualized safety assessments rather than arbitrary exclusion. In men with severe semen abnormalities, endocrine treatment, surgery, or assisted reproduction may be appropriate depending on etiology. Exogenous testosterone remains contraindicated when fertility is desired ^[18].

8. Precision Medicine and Emerging Technologies

Precision reproductive medicine aims to integrate clinical phenotype, metabolic biomarkers, imaging, genomics, and treatment-response data. Artificial-intelligence models are being investigated for embryo assessment, ovarian-response prediction, semen analysis, and individualized stimulation protocols. Their clinical value depends on external validation, representative datasets, transparency, calibration, and protection against algorithmic bias. Wearable devices can support activity, sleep, and cycle tracking, but consumer-generated data should not replace validated diagnostic methods.

In vitro gametogenesis seeks to recreate germ-cell development from pluripotent stem cells. Functional gametes have been produced through complex culture systems in animal models, while translation to humans remains experimental ^[29]. Major barriers include genomic and epigenomic integrity, meiotic accuracy, mitochondrial inheritance, long-term offspring safety, consent, parentage, and equitable governance. It should therefore be described as a future research frontier rather than a currently available infertility treatment.

9. Conclusions

Metabolic and reproductive health are closely connected through insulin resistance, adipose-tissue dysfunction, chronic inflammation, oxidative stress, mitochondrial impairment, and neuroendocrine disruption. In women, these pathways contribute to hyperandrogenism, anovulation, impaired oocyte competence, and altered endometrial function. In men, they are associated with functional hypogonadism, sexual dysfunction, abnormal semen parameters, and sperm DNA damage.

The clinical value of the metabolic-fertility framework lies in early identification of modifiable risk while avoiding deterministic conclusions based on body weight alone. Both partners require parallel assessment, targeted metabolic testing, evidence-based management of endocrine disease, and individualized reproductive planning. Lifestyle intervention is foundational; pharmacologic treatment should address defined indications, and GLP-1RAs may have a preconception role in selected patients but must be stopped before pregnancy. Multidisciplinary care linking primary care, endocrinology, nutrition, and reproductive medicine offers the most coherent path toward improved reproductive and long-term cardiometabolic outcomes.

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