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Neglected and Overlooked Causes of Infertility: A Comprehensive Evidence-Based Review 2026

Explore overlooked medical conditions affecting fertility, including infections, immune factors, anatomical issues, and environmental exposures, to improve diagnosis and treatment beyond standard infertility evaluations.

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Neglected Causes of Infertility A Comprehensive Evidence-Based Review (2026) Infertility Dr Muhammad M Al Hennawy Senior Consultant of Obestetrics , gynecology, and Infertility https://mmhennawy.github.io https://www.youtube.com/c/mmhennawy https://www.slideshare.net/muhammadelhennawy5
Neglected Causes of Infertility • A Comprehensive Evidence-Based Review (2026) Infertility is traditionally attributed to ovulatory disorders, tubal disease, male factor infertility, endometriosis, and diminished ovarian reserve. • However, 10–30% of couples have overlooked or under-recognized factors that contribute to delayed conception. • Identifying these neglected causes • By a more comprehensive, individualized evaluation improve pregnancy rates while avoiding unnecessary assisted reproductive technologies.
While common fertility discussions focus • on age, blocked fallopian tubes, and sperm counts, • several neglected and overlooked medical conditions significantly impair reproductive health. • These hidden causes often fall outside routine screening panels, delaying accurate diagnosis and treatment.
Simple flow for the lecture INFERTILITY ↓ Standard evaluation ( ovulation, tubes , semen analysis , uterine anatomy when indicated ) ↓ Cause identified? YES → KNOWN INFERTILITY → Specific treatment NO Lifestyle modification Are there clues to a missed cause? → Look again and investigate selectively YES → NEGLECTED / OVERLOOKED INFERTILITY Targeted re-investigation Specific treatment → → NO → IDIOPATHIC / UNEXPLAINED INFERTILITY Expectant management / → IUI ± stimulation / IVF according to patient factors
Classification of Infertility Type Definition Examples Main approach Known / Identified Infertility A specific cause has been identified after appropriate evaluation Ovulatory dysfunction, tubal occlusion, hydrosalpinx, severe male factor, endometriosis, uterine cavity lesions Treat the identified cause Neglected / Overlooked Infertility A potentially relevant cause exists but was missed, overlooked, or not adequately investigated Chronic endometritis, adenomyosis, subtle endometriosis, intrauterine adhesions, small cavity lesions, sexual dysfunction, selected genital infections Re-evaluate targeted → investigation specific → treatment Idiopathic / Unexplained Infertility No cause is identified after an appropriate standard infertility evaluation Normal ovulation, adequate ovarian reserve for age, patent tubes, normal uterine assessment, and no significant male factor Expectant management / IUI ± stimulation / IVF according to age, duration and prognosis
The key difference Known infertility Cause found → Treat the cause Neglected infertility Cause may be present → It was missed → Look again and investigate selectively Idiopathic / Unexplained infertility Appropriate evaluation completed → No cause found Very important distinction Neglected ≠ Idiopathic A patient should not be labeled "unexplained infertility" simply because the basic work-up is normal if there are clinical clues suggesting an overlooked condition.
Schistosomiasis (Bilharzia) •This neglected tropical disease causes structural damage. •Eggs deposited •by the parasite induce chronic inflammation, granulomas, and fibrosis •, leading to physical blockages • in both male and female reproductive tracts. • It also disrupts the hypothalamic-pituitary-gonadal (HPG) axis by releasing estrogen-like metabolites
Genital Tuberculosis (TB) • Often asymptomatic in its early stages, • pelvic and endometrial tuberculosis causes severe tubal damage, pelvic adhesions, and • endometrial scarring (Asherman’s syndrome), destroying the lining where an embryo would implant.
Unrecognized Asherman Syndrome • Occurs after: Curettage ,Postpartum infection , Postpartum hemorrhage • Diagnosis: Hysteroscopy • Treatment: Hysteroscopic adhesiolysis
Chronic Pelvic Inflammatory Disease Without Tubal Occlusion • Tubes may remain patent despite chronic inflammation affecting fertility.
Chronic Endometritis • Unlike acute pelvic inflammatory disease (PID), • chronic endometritis is a subtle, localized infection of the uterine lining. • It is often asymptomatic but alters the uterine immune environment, causing repeated implantation failures. • One of the most overlooked yet treatable causes of infertility. • Clinical importance • Recurrent implantation failure (RIF) • Recurrent pregnancy loss (RPL) • Unexplained infertility • Diagnosis • Endometrial biopsy • CD138 immunohistochemistry (gold standard) • Hysteroscopy • PCR or endometrial culture in selected cases • Treatment • Doxycycline-based antibiotic therapy • Confirmation of eradication in persistent cases
Celiac Disease: • Sometimes presents solely as infertility. • Screening:Tissue transglutaminase IgA • Undiagnosed or untreated celiac disease can cause • systemic inflammation • and nutrient malabsorption (such as zinc, iron, and folate deficiency), • which directly impairs ovarian function and semen quality
Antisperm Antibodies (ASA) • The body’s immune system can mistakenly identify sperm as foreign invaders. • In men, a breach in the blood-testis barrier can cause them to produce antibodies that immobilize their own sperm. • In women, cervical secretions may contain antibodies that destroy sperm before they reach the egg
Antiphospholipid syndrome (APS) Not recommended routinely: •NK-cell testing •Cytokine profiling •Most immune-based infertility tests outside research setting
Thrombophilia • Inherited or acquired blood-clotting disorders (like Antiphospholipid Syndrome) • can cause micro-clots in the developing placenta, • preventing successful embryo implantation and • leading to early, unnoticed pregnancy loss.
Endometrial Receptivity Disorders • A morphologically normal endometrium may not be functionally receptive. • Potential mechanisms include: • Altered progesterone signaling • Defective decidualization • Abnormal inflammatory cytokines • Altered endometrial microbiome • Routine endometrial receptivity testing (ERA) is not recommended for all patients and should be reserved for selected cases of repeated implantation failure.
Adenomyosis • Increasingly recognized as an independent cause of infertility. • Mechanisms: • Chronic inflammation • Abnormal uterine peristalsis • Impaired implantation • Increased miscarriage • Diagnosis: • Expert transvaginal ultrasound • MRI
Minimal or Occult Endometriosis • Even Stage I disease may significantly impair fertility despite normal imaging. • Mechanisms include: • Oxidative stress • Inflammatory cytokines • Reduced oocyte competence • Altered implantation
Endometriosis Without Pain • Absence of dysmenorrhea or pelvic pain does not exclude endometriosis. • Infertility may be the only clinical presentati
Abnormal Uterine Peristalsis • Excessive or disorganized uterine contractions may impair: • Sperm transport • Embryo migration • Implantation • Often associated with adenomyosis and endometriosis.
Hidden Male Factor Infertility Normal semen analysis does not guarantee normal fertility. Important abnormalities include: •Sperm DNA fragmentation •Oxidative stress •Aneuploidy •Mitochondrial dysfunction Advanced sperm testing should be considered in selected couples with unexplained infertility, recurrent miscarriage, or repeated ART failure. 7
Mild Varicocele • Borderline semen parameters • may hide significant DNA damage and • impaired sperm function.
Sexual Dysfunction • Frequently missed during infertility evaluation. • Includes: • Infrequent intercourse • Erectile dysfunction • Premature ejaculation • Dyspareunia • Vaginismus
Thyroid Dysfunction • Both overt and subclinical hypothyroidism may impair fertility. • Recommended investigations: • TSH • Free T4 • TPO antibodies (selected patients)
Hyperprolactinemia • May present without galactorrhea. • Effects: • Ovulatory dysfunction • Luteal insufficiency
Luteal Phase Deficiency • Although controversial, • luteal dysfunction may occur in: • PCOS • Obesity • Thyroid disorders • Hyperprolactinemia • No single diagnostic test has sufficient accuracy
Vitamin D Deficiency • Associated with: • PCOS • Endometriosis • Poor implantation • Correction of deficiency is recommended for general health, • although fertility benefits remain uncertain.
Obesity-Associated Chronic Inflammation • Beyond BMI, metabolic inflammation contributes to: • Insulin resistance • Oxidative stress • Poor oocyte quality • Reduced IVF success
Lean PCOS • Normal BMI does not exclude: • Insulin resistance • Hyperandrogenism • Ovulatory dysfunction
Cesarean Scar Defect (Isthmocele) • An increasingly recognized cause of secondary infertility. • Mechanisms: • In secondary infertility, a poorly healed C-section scar can create a small pocket (isthmocele) that collects menstrual blood. This fluid alters the vaginal pH and creates a chronically inflamed uterine environment hostile to sperm and embryos • Diagnosis: • Saline infusion sonography • 3D ultrasound • Hysteroscopy
Small Hydrosalpinx • Even minimal hydrosalpinges • may reduce implantation through embryotoxic tubal fluid. • Salpingectomy or proximal tubal occlusion improves IVF outcomes.
Overlooked Anatomical and Structural Factors •Silent Endometriosis / Adenomyosis: •Many individuals experience "silent" endometriosis, • which lacks the classic symptom of debilitating pelvic pain. •Instead, localized inflammatory cytokines and • altered pelvic anatomy quietly impair egg quality and fertilization
Endocrine Disrupting Chemicals (EDCs) • Low-level, daily exposure to everyday toxins—such as phthalates, bisphenols (BPA), and parabens found in plastics and cosmetics—can alter hormone receptor sensitivity and silently degrade egg and sperm quality over tim
Environmental Exposure • Potential contributors include: • BPA • Phthalates • Heavy metals • Pesticides • Air pollution • Through endocrine disruption and oxidative stress.
Microbiome Disruptions •Vaginal and Uterine Dysbiosis: • A healthy reproductive tract relies heavily on Lactobacillus-dominated microbiomes. • A shift toward pathogenic bacteria (dysbiosis) •triggers a localized immune response that prevents successful embryo implantation, • even without presenting as a full-blown infection.
Genetic Factors • Female: • Balanced translocations • FMR1 premutation • Mosaic Turner syndrome • Male: • Y chromosome microdeletions • CFTR mutations • Chromosomal abnormalitie
Sleep Disorders • Circadian disruption may adversely affect: • Ovulation • Hormonal regulation • Fecundity • Especially among night-shift workers.
Suggested Diagnostic Approach • A modern infertility evaluation should include: • Comprehensive female assessment • High-quality semen evaluation • Consideration of advanced sperm function tests when indicated • High-resolution transvaginal ultrasound • Evaluation for chronic endometritis when suspected • Thyroid and prolactin assessment • Lifestyle and metabolic evaluation • Genetic testing in selected couples • Careful assessment before labeling infertility as "unexplained"
Key Clinical Messages (2026) • Chronic endometritis remains one of the most underdiagnosed yet highly treatable causes of infertility. • Mild adenomyosis, occult endometriosis, and cesarean scar defects are increasingly recognized contributors to implantation failure. • Normal semen analysis does not exclude clinically significant male infertility. • Immune testing, microbiome testing, and routine endometrial receptivity assays should not be performed routinely and should be reserved for carefully selected patients according to current ASRM, ESHRE, and NICE recommendations.
Difference Between Routine Infertility Investigation and Neglected Infertility Investigation Aspect Routine Infertility Investigation Neglected / Overlooked Infertility Investigation Main aim Identify common causes of infertility Detect less obvious or missed causes Ovulation Menstrual history ± ovulation assessment Reassess subtle ovulatory/endocrine disorders when suspected Ovarian reserve AMH + AFC ± FSH/E2 Interpretation in relation to age, previous surgery, endometriosis and treatment history Male factor Semen analysis Repeat semen analysis + targeted hormonal/genetic evaluation when abnormal Uterus TVUS Expert TVUS ± SIS ± hysteroscopy for subtle cavity lesions Fallopian tubes HSG / HyCoSy Look specifically for hydrosalpinx, distal tubal disease and peritubal adhesions Endometrial cavity TVUS ± HSG SIS / hysteroscopy for polyps, adhesions and subtle submucous fibroids Chronic Endometritis Usually not routinely investigated Endometrial biopsy ± CD138 when clinically indicated Endometriosis May be suspected from symptoms/US Detailed assessment ± expert TVUS/MRI; laparoscopy in selected cases Adenomyosis May be detected on routine US Expert TVUS ± MRI when suspected Pelvic adhesions Usually not directly assessed Consider laparoscopy when clinical suspicion is significant Genital TB Not routine Targeted investigation in women with relevant epidemiological/clinical risk Sexual dysfunction May be overlooked Detailed sexual history and examination Recurrent implantation failure Not applicable initially Review uterine cavity, endometrium, embryo-related and other relevant factors systematically Unexplained infertility Diagnosis after standard work-up is normal Re-review the diagnosis and look for previously missed causes Advanced investigations Used selectively More likely to be considered, but only when clinically indicated
The practical difference Routine infertility work-up: Ovulation → Ovarian reserve → Semen analysis → Uterus → Tubal patency ⬇️ If normal but infertility persists: Neglected/Overlooked causes → Endometriosis → Adenomyosis → Chronic Endometritis → Polyps → Adhesions → Hydrosalpinx → Subtle tubal disease → Sexual dysfunction → Selected endocrine/infectious causes Important message for your lecture Neglected infertility does NOT mean ordering more tests for everyone. It means revisiting the diagnosis and performing targeted investigations when the clinical history or previous treatment suggests a missed cause. This distinction is important because indiscriminate testing can lead to false-positive results and unnecessary treatment.
Summary of the Main Issue • Neglected causes of infertility—ranging from hidden chronic infections and systemic autoimmune disorders to silent anatomical defects—frequently mimic "unexplained infertility" because they are omitted from standard diagnostic protocols. • Identifying these underlying issues requires looking beyond standard hormone and fluid checks to evaluate systemic immune, microbiome, and environmental health
Lifestyle Modification in Infertility Lifestyle factor Recommendation Weight Aim for a healthy BMI; both obesity and underweight can impair fertility Smoking Stop completely; applies to both partners Alcohol Avoid or minimize, particularly when trying to conceive Caffeine Moderate intake; avoid excessive caffeine Diet Balanced diet rich in vegetables, fruits, whole grains, legumes, fish and healthy fats Physical activity Regular moderate exercise; avoid excessive strenuous exercise if it causes menstrual dysfunction Sleep Adequate regular sleep Stress Stress reduction, counseling/CBT when needed; avoid blaming infertility on stress Environmental exposures Reduce exposure to tobacco smoke, recreational drugs and relevant occupational/environmental toxins Heat exposure in men Avoid prolonged excessive scrotal heat when possible Sexual timing Intercourse every 1–2 days during the fertile window is generally appropriate Medications Review medications that may affect fertility with a physician; do not stop essential medications without advice
Lifestyle modification In neglected/overlooked infertility •Lifestyle modification is particularly useful when there are modifiable risk factors, •but it will not correct conditions such as: •Hydrosalpinx •Endometrial polyp •Intrauterine adhesions •Significant endometriosis •Adenomyosis •Severe male-factor infertility •Tubal occlusion Key message for the lecture: Lifestyle modification should be offered to all couples trying to conceive, but treatment must be directed at the underlying cause when one is identified.
Empirical Treatment in Unexplained Infertility — 2026 Cause Evidence-based treatment when indicated Empirical treatment? Chronic Endometritis Appropriate antibiotics, commonly doxycycline; reassessment in selected cases May be considered when strongly suspected, but not routinely Adenomyosis GnRH agonist in selected cases; conservative surgery in selected patients; IVF according to individual factors Not routinely Endometriosis Surgery in selected cases; IVF according to age, duration of infertility and other factors No routine empirical treatment Sperm DNA Fragmentation Treat underlying causes; lifestyle modification; varicocele treatment when indicated Antioxidants may be considered selectively; evidence remains limited Varicocele Varicocele repair when clinical criteria are met No Luteal Phase Dysfunction Progesterone in selected clinical/ART settings Not routinely recommended Hypothyroidism Levothyroxine when hypothyroidism is diagnosed No — confirm diagnosis Hyperprolactinemia Cabergoline or bromocriptine after confirming the diagnosis and cause No Vitamin D Deficiency Vitamin D replacement when deficiency is documented No — not an empirical fertility treatment PCOS with Anovulation Letrozole is first-line ovulation induction; IUI may be added in selected cases Yes, but only when the clinical diagnosis is established Cesarean Scar Defect (Isthmocele) Hysteroscopic or laparoscopic repair in selected patients No Hydrosalpinx Salpingectomy or proximal tubal occlusion before IVF when indicated No Asherman Syndrome Hysteroscopic adhesiolysis No Genital Tuberculosis Anti-tuberculous therapy after appropriate diagnostic confirmation No Antiphospholipid Syndrome (APS) Low-dose aspirin + heparin according to established indications No — do not use routinely in unexplained infertility Abnormal Uterine Hyperperistalsis Treat the underlying cause; selected interventions have been studied during embryo transfer No established empirical regimen Isolated Uterine Spasm No established fertility-enhancing pharmacological treatment Not evidence-based
Empirical treatment ≠ treatment without thinking or without evaluation • better approach is: • Exclude major causes identify clinical clues select treatment → → according to the most likely mechanism reassess outcome. → • I would classify treatments into three groups: • 1. Evidence-based treatment Treatment of an identified disease. • 2. Selected empirical treatment Used when there is a strong clinical suspicion but definitive testing is unavailable, inappropriate, or unlikely to change management. • 3. Investigational treatment Promising mechanisms but insufficient evidence for routine clinical use. • Doxycycline can therefore be discussed under Selected Empirical Treatment when chronic endometritis is strongly suspected. • Low-dose aspirin, Librax, Drotaverine, or other antispasmodics should NOT be presented as standard empirical treatment for unexplained infertility.