Reproductive system disease

Reproductive system disease refers to disorders of the male or female reproductive organs and their endocrine regulation, including reproductive tract infections, congenital anomalies, benign and malignant tumours, ovulation and hormonal disorders, endometriosis, pregnancy-related disease and sexual and fertility problems. The common feature is involvement of reproductive organs with direct effects on fertility, sexual health, hormonal balance and psychosocial function. The World Health Organization estimated in 2023 that about 17.5% of adults experience infertility in their lifetime, cervical cancer causes about 660000 new cases and 350000 deaths each year, and reproductive tract infections account for hundreds of millions of new cases annually.

Terminology and classification

• Reproductive system disease is an umbrella term, and clinical classification crosses sex, anatomy and cause, dividing female disease into vulvar, vaginal, cervical, uterine, tubal and ovarian groups and male disease into penile, testicular, epididymal, prostatic and seminal vesicle groups.
• Reproductive tract infection (RTI) is classified as endogenous, iatrogenic or sexually transmitted, with endogenous infection arising from vaginal flora imbalance, iatrogenic infection from procedures or devices and sexually transmitted infection from sexual contact.
• Sexually transmitted infection and sexually transmitted disease are often used interchangeably, but infection emphasises the carrier state and may be asymptomatic while disease emphasises clinical manifestation, and epidemiological reporting should use infection.
• ICD-10 places reproductive disease at N00 to N99, covering female pelvic inflammation, endometriosis, reproductive tumours, menstrual disorders and male genital disease, while pregnancy complications sit separately at O00 to O99.
• ICD-11 places reproductive organ disease in chapter 16 on genitourinary disease and subdivides by sex and anatomy, so cross-version conversion needs official mapping rather than name matching.
• MeSH organises the field under female and male urogenital disease, and retrieval must combine organ and cause terms or obstetric and sexual health entries will be mixed in.
• MONDO and Orphanet hold only specific rare entities such as androgen insensitivity syndrome and Kallmann syndrome, not an umbrella term, so a review entry must use component disease codes.
• Reproductive health is a public health concept describing the state of reproductive processes across the lifespan, whereas reproductive system disease is a pathological concept, and policy documents must distinguish them.
• Gynaecological disease is limited to female reproductive organs, while urogenital disease also includes the urinary tract, and the anatomical boundary should be stated in multidisciplinary care.
• Infertility definitions vary, and the 2023 World Health Organization guideline defines it as no pregnancy after 12 months of regular unprotected intercourse, with assessment after 6 months for women older than 35.
• Recurrent pregnancy loss usually means three or more consecutive losses, but thresholds and counting methods differ between societies, so the consensus version should be stated.
• Polycystic ovary syndrome is diagnosed by the Rotterdam criteria or the international evidence-based guideline after excluding thyroid disease, hyperprolactinaemia and non-classical adrenal hyperplasia.
• Endometriosis is classified as peritoneal, ovarian or deep infiltrating, and FIGO stage does not fully correspond to clinical phenotype because pain correlates weakly with lesion extent.
• Cervical intraepithelial lesions use a two-tier low-grade and high-grade system, while three-tier terminology persists in some laboratories, so reports should name the system.
• Erectile dysfunction and premature ejaculation are functional disorders, whereas testicular torsion and epididymitis are acute organic disease, and their emergency and chronic pathways differ completely.

History

• The Kahun papyrus from about 1825 BCE recorded uterine prolapse, abnormal bleeding and contraception, one of the earliest gynaecological documents, mixing observation with magical explanation.
• The Hippocratic school proposed that a wandering uterus caused hysteria, an error that influenced Western medicine for nearly two thousand years until anatomical evidence displaced it.
• In 1543 Vesalius published De humani corporis fabrica and corrected the anatomy of the uterus and ovaries, providing the morphological basis for localised diagnosis.
• In 1847 Semmelweis introduced hand disinfection in a Vienna obstetric ward and reduced puerperal fever mortality, a milestone in infection control and an early lesson in iatrogenic disease.
• Neisser described the gonococcus in 1879, and Schaudinn and Hoffmann identified Treponema pallidum in 1905, establishing the pathogen basis of sexually transmitted infection.
• In 1928 Papanicolaou developed cervical cytology, and its adoption in the 1940s made cervical cancer screening possible and contributed to a large fall in mortality.
• Sulphonamides appeared in 1935 and penicillin was scaled up in the 1940s, moving gonorrhoea and syphilis treatment from heavy metals and local measures to effective antibiotics.
• In 1960 the United States approved the first oral contraceptive, shifting reproductive control from barrier and surgical methods to hormonal regulation.
• In 1978 Steptoe and Edwards reported the first birth after in vitro fertilisation, and intracytoplasmic sperm injection followed in 1992.
• In 1983 and 1984 zur Hausen and colleagues established the causal link between high-risk human papillomavirus and cervical cancer, providing the basis for vaccination and screening.
• In the 1990s laparoscopy spread, allowing diagnosis and treatment of endometriosis and pelvic adhesions in one procedure and replacing some open surgery.
• In 2006 the quadrivalent human papillomavirus vaccine was approved in the United States, the bivalent vaccine followed in 2007 and the nine-valent vaccine in 2014.
• In 2010 a trial of oral pre-exposure prophylaxis showed a substantial reduction in human immunodeficiency virus acquisition, and the United States approved it for high-risk groups in 2012.
• In 2020 the World Health Organization launched a global strategy to accelerate cervical cancer elimination, targeting 90% of girls vaccinated, 70% of women screened and 90% of lesions treated.
• In 2023 the World Health Organization updated its infertility guideline, prioritising treatable causes in resource-limited settings and calling for assisted reproduction within universal health coverage.

Epidemiology

• The 2023 World Health Organization analysis of data from 1990 to 2021 estimated that about 17.5% of adults experience infertility, with male and female factors each accounting for about half and the remainder combined or unexplained.
• In 2016 about 376 million new cases of gonorrhoea, chlamydia, syphilis and trichomoniasis occurred worldwide, including about 127 million chlamydia, 156 million trichomoniasis, 87 million gonorrhoea and 6.3 million syphilis cases.^[1]
• In 2022 cervical cancer caused about 660000 new cases and 350000 deaths, the fourth most common cancer in women, with about 90% of deaths in low-income and middle-income countries.^[2]
• Endometriosis affects about 10% of reproductive-aged women, some 190 million people globally, and the median delay from symptoms to diagnosis often exceeds seven years.
• Polycystic ovary syndrome affects about 8% to 13% of reproductive-aged women and is the most common cause of anovulatory infertility, with prevalence varying by diagnostic criteria.
• Uterine fibroids have a cumulative lifetime incidence above 70% and are the most common indication for hysterectomy outside pregnancy, with earlier and more severe disease in women of African ancestry.
• Male factors contribute to about half of infertility, and semen parameters have declined over recent decades, with environmental exposure, obesity and lifestyle proposed as causes.
• Untreated pelvic inflammatory disease leads to tubal infertility in about 10% to 15% of cases, and a single episode substantially raises the risk of ectopic pregnancy.
• In 2020 about 287000 maternal deaths occurred worldwide, mostly in low-income countries, with postpartum haemorrhage, infection and hypertensive disorders as leading causes.
• Reproductive tract infections are far more common in low-income countries, driven by sanitation, access to care and differences in sexual health education.
• Risk factors include at least multiple partners, unprotected intercourse, early sexual debut, high-risk human papillomavirus infection, smoking, obesity, diabetes, endocrine disruptor exposure and immunosuppression.
• Age is the strongest determinant of female fertility, with oocyte number and quality declining after 35 and natural conception rates falling sharply after 40, as does assisted reproduction success.
• Cervical cancer incidence is inversely related to screening coverage, falling by more than 70% in countries with organised programmes while rising where no programme exists.
• The burden of reproductive tumours varies geographically, with breast and prostate cancer higher in high-income countries and cervical and infection-related cancers higher in low-income countries.
• Costs include direct treatment, out-of-pocket assisted reproduction and lost productivity, and infertility care is excluded from public coverage in many countries, widening social inequality.
• Adolescent reproductive health is often underestimated, with unintended pregnancy, sexually transmitted infection and sexual violence concentrated in this group, and school education plus accessible services are effective responses.

Pathophysiology

• Ascending spread is the main mechanism of pelvic inflammatory disease, as pathogens pass the cervical barrier into the endometrium and tubes, causing mucosal inflammation, ciliary damage and adhesions that lead to infertility or ectopic pregnancy.
• Bacterial vaginosis follows replacement of lactobacilli by anaerobic flora, raising vaginal pH and creating conditions for other pathogens, and it is associated with preterm birth, postoperative infection and increased sexually transmitted infection risk.
• The E6 and E7 proteins of high-risk human papillomavirus degrade p53 and retinoblastoma protein respectively, allowing cells to bypass apoptosis and cycle arrest, and persistent infection over years to decades can progress to invasive cancer.^[3]
• Cervical carcinogenesis is a continuum from infection to low-grade intraepithelial lesion, high-grade lesion and invasive cancer, and most infections clear within two years so only persistence carries malignant risk.
• Endometriosis involves retrograde menstruation, defective immune surveillance, local oestrogen synthesis and neurogenesis, creating an inflammatory pelvic microenvironment that causes pain and adhesions.
• Polycystic ovary syndrome centres on mutually amplifying hyperandrogenism and insulin resistance, in which granulosa cells overproduce androgens under insulin-like growth factor signalling and follicular maturation fails.
• Hypothalamic amenorrhoea follows low energy availability, excessive exercise and psychological stress, reducing gonadotropin-releasing hormone pulse frequency and distorting luteinising and follicle-stimulating hormone secretion.
• Uterine fibroids are oestrogen and progesterone-dependent benign tumours in which smooth muscle and fibroblasts form nodules under hormonal, growth factor and extracellular matrix remodelling.
• Ovarian cancer is heterogeneous in origin, with high-grade serous carcinoma often arising from tubal epithelium while endometrioid and clear cell tumours relate to endometriosis, which has changed prevention and staging.
• Spermatogenic failure can result from chromosomal abnormality, cryptorchidism, varicocele, infection, chemotherapy or radiotherapy and endocrine disease, while obstructive azoospermia reflects ductal blockage.
• Reproductive ageing reflects follicle pool depletion and oocyte quality decline, with rising aneuploidy, mitochondrial dysfunction and oxidative damage.
• Ectopic pregnancy and placenta accreta relate to tubal damage or endometrial trauma, with inflammation and scarring as the pathological basis.
• The reproductive microbiota influences infection susceptibility, reproductive outcome and assisted reproduction success, and lactobacillus dominance is considered healthy although normal profiles vary between populations.
• Endocrine disruptors mimic or antagonise sex hormones at the hypothalamic-pituitary-gonadal axis and are associated with declining sperm quality, earlier puberty and endometriosis, although causal evidence remains limited.

Clinical features

• Abnormal vaginal bleeding is the most common reason for consultation and may present as heavy menses, intermenstrual bleeding, postcoital bleeding or postmenopausal bleeding, and the last requires exclusion of endometrial cancer.
• Abnormal discharge suggests infection or flora imbalance, with grey malodorous discharge in bacterial vaginosis, yellow-green frothy discharge in trichomoniasis and curd-like discharge in candidiasis.
• Pelvic pain is acute or chronic, and acute pain with fever and cervical motion tenderness suggests pelvic inflammatory disease while chronic pain raises endometriosis, adhesions, pelvic congestion and neuropathic pain.
• Dysmenorrhoea is primary or secondary, and progressive secondary dysmenorrhoea with dyspareunia or infertility should raise suspicion of endometriosis or adenomyosis.
• A pelvic mass may be asymptomatic and found on examination or imaging, or may cause pressure, bloating, urinary frequency or constipation, and its nature depends on age, tumour markers and imaging.
• Infertility is a shared outcome of many reproductive diseases, and assessment must cover ovulation, tubal patency, uterine cavity and male factors because unilateral evaluation misses diagnoses.
• Men may present with urethral discharge, dysuria, testicular pain and swelling, reduced libido, erectile dysfunction or ejaculatory disorder, and acute scrotal pain requires exclusion of torsion.
• Complications include at least pelvic inflammatory disease, tubal infertility, ectopic pregnancy, chronic pelvic pain, metastatic reproductive cancer, maternal death and neonatal infection.
• Ruptured ectopic pregnancy is a leading cause of early pregnancy death, presenting with abdominal pain and bleeding after amenorrhoea and progressing to haemorrhagic shock that requires emergency surgery.
• Early cervical cancer may be asymptomatic, while advanced disease causes contact bleeding, malodorous discharge, pelvic pain and leg oedema and can invade bladder and rectum to form fistulae.
• Ovarian cancer is often delayed because early symptoms are non-specific, and persistent bloating, early satiety and urinary frequency should prompt pelvic imaging.
• Presentations differ by group, with menstrual disorders, dysmenorrhoea and unintended pregnancy in adolescents, infection and obstetric complications in pregnancy and bleeding and cancer after menopause.
• Psychosocial consequences include stigma, shame, partner strain, depression and anxiety, and a sexually transmitted infection diagnosis often raises concerns about disclosure and partner notification.
• Severe disease and death result mainly from metastatic cancer, pelvic sepsis, ruptured ectopic pregnancy and obstetric complications, and delayed presentation is a shared modifiable factor.

Diagnosis

• Diagnosis starts with a detailed history of menstruation, sexual behaviour, contraception, pregnancy, previous infection and family cancer history, and sensitive information requires privacy and non-judgemental communication.
• Pelvic examination is fundamental, with bimanual palpation assessing uterine size, mobility and adnexal tenderness, and cervical motion tenderness is highly suggestive of pelvic inflammatory disease.
• Cervical screening uses human papillomavirus testing as the preferred method, and the 2021 World Health Organization guideline recommends testing every five to ten years for women aged 30 to 65 with same-visit treatment where feasible.^[4]
• Colposcopy evaluates abnormal cytology or viral testing, and acetic acid application with biopsy localises high-grade lesions, while conisation is both diagnostic and therapeutic.
• Transvaginal ultrasound is first-line imaging for the uterus, ovaries and adnexa and identifies fibroids, cysts, endometrial thickness and ectopic pregnancy, with colour Doppler assessing vascularity.
• Magnetic resonance imaging is superior for endometrial cancer staging, deep infiltrating endometriosis and uterine anomalies and is important for surgical planning.
• Nucleic acid amplification is the preferred test for Chlamydia trachomatis and Neisseria gonorrhoeae, with higher sensitivity than culture, and urine or self-collected samples enable asymptomatic screening.
• Syphilis diagnosis relies on serology, with non-treponemal tests for screening and treatment monitoring and treponemal tests for confirmation, interpreted together with history.
• Hormonal assessment includes follicle-stimulating hormone, luteinising hormone, oestradiol, progesterone, prolactin, thyroid function and anti-Müllerian hormone, with timing adjusted to the menstrual cycle.
• Semen analysis follows the sixth edition of the World Health Organization manual and assesses volume, concentration, total count, motility and morphology, with abnormal results repeated after an interval.
• Laparoscopy is the reference standard for endometriosis and pelvic adhesions and allows excision and adhesiolysis at the same time, although it is invasive.
• Pathology confirms reproductive tumours, with cervical cancer staged by FIGO 2018 and endometrial and ovarian cancers staged by FIGO surgical-pathological systems.^[5]
• Differential diagnosis includes at least ectopic pregnancy, pelvic inflammatory disease, ovarian cyst torsion, degenerating fibroid, endometrial cancer, urinary tract infection, irritable bowel syndrome and primary dysmenorrhoea.
• Infertility assessment begins after 12 months without conception, or 6 months for women older than 35, and covers ovulation, tubal patency, uterine cavity and semen analysis.
• Screening for cervical cancer, sexually transmitted infection, infection in pregnancy and genetic carriers is among the most cost-effective interventions, and coverage plus follow-up completion determines real benefit.

Management

• Treatment goals differ by disease, with infection aimed at pathogen clearance and transmission interruption, cancer at cure or survival, infertility at a safe live birth and functional disorders at quality of life.
• Bacterial vaginosis is treated with metronidazole or clindamycin, and sexually transmitted infections use ceftriaxone, doxycycline, azithromycin or penicillin according to pathogen, with partner treatment essential to prevent reinfection.^[6]
• Pelvic inflammatory disease requires broad coverage of anaerobes and sexually transmitted pathogens, with outpatient oral therapy for mild disease and inpatient intravenous therapy for severe disease or pregnancy, because delay increases infertility risk.
• Human papillomavirus vaccination is primary prevention of cervical cancer, with quadrivalent and bivalent vaccines approved in 2006 and 2007 and the nine-valent vaccine in 2014, and schedules vary by national immunisation programme.^[7]
• High-grade cervical lesions are treated by ablation or excision, commonly loop electrosurgical excision or cold knife conisation, and long-term follow-up is required because recurrence and progression risk persists.
• Cervical cancer treatment depends on stage, with surgery for early disease and fertility preservation where possible, concurrent chemoradiotherapy for locally advanced disease and bevacizumab or checkpoint inhibitors for recurrent or metastatic disease.
• Ovarian cancer is managed by cytoreductive surgery plus platinum chemotherapy, and BRCA-mutated patients benefit from poly ADP ribose polymerase inhibitor maintenance, with olaparib first approved in 2014.^[8]
• Endometriosis uses combined medical and surgical care, with non-steroidal anti-inflammatory drugs for pain, progestins, combined oral contraceptives and gonadotropin-releasing hormone agonists suppressing lesions, and conservative surgery for cysts and deep disease.
• Polycystic ovary syndrome starts with lifestyle change, metformin improves insulin resistance, combined oral contraceptives regulate cycles and reduce androgens, and letrozole is first-line for ovulation induction.^[9][10]
• Uterine fibroids are managed according to symptoms and fertility plans, with gonadotropin-releasing hormone agonists for preoperative shrinkage, uterine artery embolisation and focused ultrasound as minimally invasive options and hysterectomy for severe disease without fertility desire.
• Infertility follows a stepwise approach, correcting reversible causes first, then ovulation induction and intrauterine insemination and finally in vitro fertilisation, first achieved in 1978, with intracytoplasmic sperm injection introduced in 1992 for severe male factor.^[11]
• Erectile dysfunction may be treated with phosphodiesterase-5 inhibitors such as sildenafil, approved in 1998, after cardiovascular risk and drug interactions are assessed, while testosterone replacement is reserved for confirmed hypogonadism.^[12]
• Prevention includes safer sex and condom use, human papillomavirus vaccination, regular cervical screening, antenatal care, neonatal infection prevention and reproductive health education.
• Pre-exposure prophylaxis reduces human immunodeficiency virus acquisition in high-risk groups, with trial results published in 2010 and United States approval in 2012, and it requires adherence and renal monitoring.^[13]
• Prognosis depends on disease and stage, with five-year survival above 90% in early cervical cancer, below 30% in advanced ovarian cancer and live birth rates per in vitro fertilisation cycle falling from above 40% to about 10% with age.

Research and controversies

• Access to cervical cancer elimination is the central controversy, with vaccination and screening advancing rapidly in high-income countries while coverage remains low in low-income settings, and self-sampled human papillomavirus testing is seen as the key equaliser.
• Cost and equity in infertility care are prominent, as assisted reproduction is often self-funded and the World Health Organization calls for universal coverage, while fiscal sustainability and priority setting remain disputed.
• Endometriosis care combines diagnostic delay with overtreatment, as one side favours clinical diagnosis to reduce laparoscopy and the other insists on pathological confirmation and complete excision.
• The naming and diagnostic criteria of polycystic ovary syndrome remain contested, because the Rotterdam criteria are broad and may overdiagnose, and the international guideline has not eliminated practice variation.
• Ovarian cancer screening lacks an effective method, as combined CA125 and transvaginal ultrasound has not shown mortality benefit and false positives drive unnecessary surgery.
• Male contraceptive development lags far behind, with hormonal and non-hormonal candidates still in trials, and shared responsibility and acceptability are central to adoption.
• Social oocyte freezing has grown, with ethical debate over age limits, informed consent and resource allocation, while success rates are often exaggerated in commercial marketing.
• Artificial intelligence in embryo assessment, semen analysis and cervical cytology is expanding, but bias, unrepresentative data and missing regulatory standards limit clinical use.
• Reproductive microbiome research proposes probiotics or microbiota transfer to improve outcomes, but current evidence is mostly observational and causal direction is unclear.
• Guideline disagreement centres on cervical screening start age and interval, embryo transfer number in assisted reproduction and infertility assessment timing, and national recommendations differ.
• Politicisation of sex education affects adolescent infection and unintended pregnancy, and evidence supports comprehensive education although implementation is constrained by culture and religion.
• Unmet needs include affordable assisted reproduction, effective male contraception, targeted drugs for endometriosis, point-of-care cervical cancer testing and globally consistent reproductive health data.