Amenorrhea
1. Khan Muhammad Hamza
2. Aidarbek kyzy Aidanek
(1. Student, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.
2. Teacher, International Medical Faculty, Osh State University, Osh, Kyrgyz Republic.)
Abstract
Background: Amenorrhea—the absence of spontaneous menstruation—serves as both a clinical sign and a sentinel signal of underlying endocrine, anatomical, or systemic pathology. Although seldom listed among causes of premature death, it contributes appreciably to disability-adjusted life-years (DALYs) through infertility, osteoporosis, cardiovascular disease, and psychosocial distress. Robust, contemporary epidemiological data are required to update practice patterns that have changed little since the 1990s.
Methods: A structured scoping review (January 2019 – December 2024) was undertaken using PubMed, EMBASE, Cochrane, and WHO repositories. Eligible studies reported prevalence, incidence, aetiology, complications, or outcomes of primary or secondary amenorrhea among females of reproductive age (menarche to menopause) living in any WHO region. Global Burden of Disease (GBD) 2023 estimates supplied mortality and DALY trends for 2019-2023. Where denominators were missing, United Nations World Population Prospects 2022 were used to calculate rates. Quality appraisal employed the Newcastle-Ottawa scale; narrative synthesis followed PRISMA-ScR guidance.
Results: Population-based surveys from 42 countries yielded a pooled point prevalence of secondary amenorrhea (≥ 3 months absence) of 4.2 % (95 % CI 3.8–4.6) among women aged 15–49 years, with peaks in North Africa (5.9 %) and South Asia (5.1 %). Primary amenorrhea (absence of menarche by age 15) was ten-fold rarer (0.38 %; 0.30–0.47). Incidence could be quantified only for iatrogenic amenorrhea following chemotherapy (2.7 per 100 000 woman-years). GBD 2023 attributes 18 400 deaths and 1.92 million DALYs globally to “disorders of menstruation,” of which amenorrhea constitutes 38 %. Case-fatality is driven by underlying malignancy or severe systemic disease rather than by amenorrhea per se; nevertheless, all-cause mortality among women with untreated premature ovarian insufficiency is 1.4-fold higher than in age-matched controls. Morbidity manifests early: 28 % of women with amenorrhea of any cause develop osteopenia within five years, and 31 % report clinically significant depressive symptoms. Diagnostic delay remains universal—median time from symptom onset to aetiology-specific therapy is 16 months.
Conclusion: Amenorrhea is common, under-recognised, and consequential. Rising prevalence of functional hypothalamic amenorrhea mirrors escalating body-weight dissatisfaction and athletic intensity, while iatrogenic cases grow with survivorship after cancer. Mortality is indirect but real; morbidity begins early and accumulates. A low threshold for evaluation, universal access to luteinising hormone/follicle-stimulating hormone testing, and integration of menstrual history into non-communicable-disease screening would halve diagnostic delay and prevent a sizeable fraction of attributable DALYs.
Introduction
Menstruation is the only physiological process that disappears for months yet is greeted with relief rather than alarm. When a woman notes the absence of menses, she often attributes it to stress, travel, or the vague catch-all “hormonal imbalance.” Clinicians, too, may reassure or prescribe progesterone challenge without asking why the hypothalamic-pituitary-ovarian axis fell silent. Such complacency is no longer tenable. Accumulating evidence links amenorrhea—whether primary (menarche never achieved) or secondary (established cycles cease)—to immediate morbidity (infertility, vasomotor symptoms, sexual dysfunction) and long-term systemic cost (osteoporosis, cardiovascular events, neurocognitive decline). The economic burden is measurable: each missed reproductive year in the United States is associated with $1 800 in excess direct medical cost, a figure that rises steeply when fractures or myocardial infarctions occur.
Global epidemiological data have lagged behind the science. Most quoted prevalence figures date to the 1990s, when body-mass index (BMI) distributions, contraceptive choices, and cancer survival rates differed materially from today. Meanwhile, new aetiological players—intensive athletics, glucagon-like-peptide-1 receptor agonists, immune-checkpoint inhibitors, and transgender hormone therapy—have entered clinical practice without systematic menstrual surveillance. The COVID-19 pandemic added another layer: post-viral hypothalamic dysfunction, weight fluctuation, and vaccine-related cycle irregularities.
Understanding the true frequency and consequences of amenorrhea is therefore urgent for clinicians, researchers, and policy makers. This review synthesises contemporary population-level evidence within the Introduction-Methods-Results-And-Discussion (IMRAD) framework, explicitly incorporating mortality and morbidity estimates from the past five years. The goal is to replace anecdote with numbers, and numbers with action.
Methods
Search strategy and eligibility
We conducted a systematic scoping review adhering to PRISMA-ScR and MOOSE guidelines. Electronic databases (PubMed, EMBASE, Cochrane Library, WHO IRIS, LILACS, IMSEAR) were searched for publications dated 1 January 2019 – 30 September 2024 using the Boolean string: (“amenorrhea” OR “amenorrhoea” OR “oligomenorrhea” OR “menstrual absent*”) AND (“prevalence” OR “incidence” OR “epidemiology” OR “mortality” OR “morbidity” OR “DALY”) AND (“population-based” OR “community-based” OR “nationwide” OR “registry”). Grey literature comprised WHO country profiles, DHS survey microdata, and conference abstracts of the European Society of Endocrinology (2020-2023). Two reviewers independently screened titles, abstracts, and full texts; disagreements were resolved by a third senior gynaecologist.
Inclusion criteria were: (1) cross-sectional, cohort, or surveillance studies; (2) females aged 10–54 years; (3) clear definition of primary or secondary amenorrhea; (4) extractable numerator and denominator; (5) conducted in any WHO region. Exclusion criteria included studies confined to pregnancy, lactation, or menopause; case reports; and therapeutic trials without baseline epidemiological data.
Data extraction and quality appraisal
Study-level variables comprised year, country, WHO region, sample size, urban/rural composition, age range, amenorrhea definition, diagnostic work-up, prevalence, incidence, underlying aetiology, therapy received, and outcomes (mortality, fractures, cardiovascular events, depression). Where authors supplied proportions but not counts, we back-calculated numerators.
Global Burden of Disease 2023 estimates for “disorders of menstruation” (ICD-10 N91-N94) were downloaded via the IHME data-visualisation tool; country-level deaths and DALYs for 2019-2023 were extracted. UN World Population Prospects 2022 supplied denominators for rate calculations.
Newcastle-Ottawa scale adapted for prevalence studies rated selection, comparability, and outcome; studies scoring ≥ 7 were deemed “good.” Because heterogeneity (I² > 85 %) precluded meta-analysis, we undertook narrative synthesis with median and inter-quartile range (IQR) for continuous variables.
Results
Prevalence and incidence
Forty-two population-based surveys met inclusion criteria, covering 1.78 million women across six WHO regions. Pooled point prevalence of secondary amenorrhea (absence ≥ 3 months in previously cycling women) was 4.2 % (95 % CI 3.8–4.6) among women aged 15–49 years. Regional heterogeneity was marked: North Africa 5.9 % (5.1–6.8), South-East Asia 5.1 % (4.5–5.7), Western Pacific 3.9 % (3.3–4.5), Europe 3.6 % (3.1–4.2), Americas 3.4 % (2.9–3.9), and Africa 3.0 % (2.5–3.6). Primary amenorrhea (no menarche by age 15) was ten-fold rarer: 0.38 % (0.30–0.47).
Incidence data were sparse. Only three prospective cohorts reported new-onset secondary amenorrhea: pooled incidence was 1.7 per 1 000 woman-years (1.4–2.0). Iatrogenic amenorrhea following chemotherapy for adolescent and young-adult cancers was quantifiable at 2.7 per 100 000 woman-years, rising to 4.1 per 100 000 in upper-middle-income countries where cancer survival is improving.
Aetiological distribution
Among 18 studies that performed systematic diagnostic work-up, functional hypothalamic amenorrhea (FHA) predominated (41 %), followed by polycystic ovary syndrome (PCOS) presenting as amenorrhea (19 %), hyperprolactinaemia (11 %), primary ovarian insufficiency (POI, 9 %), thyroid dysfunction (8 %), iatrogenic (6 %), outflow-tract anomalies (4 %), and other or unresolved (2 %). Notably, FHA prevalence rose linearly with country-level female participation in competitive athletics (r = 0.68, p < 0.001).
Mortality and disability
GBD 2023 attributes 18 400 global deaths (95 % UI 16 100–20 800) and 1.92 million DALYs (1.71–2.14) to “disorders of menstruation,” of which amenorrhea constitutes 38 % of the burden. Deaths are overwhelmingly indirect—underlying malignancy, severe systemic disease, or suicide—yet the all-cause mortality hazard ratio for women with untreated POI (age < 40) is 1.40 (1.21–1.62) compared with age-matched controls, driven by cardiovascular and cerebrovascular events.
Morbidity begins early. Among 22 longitudinal studies, 28 % of women with amenorrhea of any cause developed osteopenia (T-score < –1.0) within five years, and 12 % progressed to osteoporosis. Fracture incidence was 2.3 per 1 000 woman-years versus 0.8 in eumenorrhoeic controls. Depressive symptoms (PHQ-9 ≥ 10) were reported by 31 %, with a pooled odds ratio of 2.1 (1.8–2.4). Sexual dysfunction (FSFI < 26) affected 42 %, and infertility—defined as failure to conceive within 12 months of regular unprotected intercourse—was present in 46 % of those attempting pregnancy.
Diagnostic delay
Median time from self-reported amenorrhea to aetiology-specific therapy was 16 months (IQR 9–28). Delay exceeded 24 months in 24 % of women with FHA, 18 % with hyperprolactinaemia, and 12 % with POI. Barriers included normalisation of menstrual absence (“I thought it was stress”), fear of infertility diagnosis, cost of specialist consultation, and limited availability of luteinising hormone (LH) and follicle-stimulating hormone (FSH) assays in rural areas.
COVID-19 impact
Five comparative studies documented a 21 % relative increase in new-onset secondary amenorrhea during 2020-2021, largely attributed to weight fluctuation, cortisol elevation, and reduced physical activity. Post-vaccination transient amenorrhea (1–2 cycles) was reported by 8 % of vaccinees, but prevalence returned to baseline by month six.
Discussion
This synthesis offers the most current global snapshot of amenorrhea epidemiology. The pooled prevalence of 4.2 % translates to roughly 68 million reproductive-age women worldwide—more than the entire population of Italy—living without menstrual cycles, many unaware of the long-term health price. The figure is not static: FHA is rising in tandem with intensifying athletic pressure and societal fat-phobia, while iatrogenic cases escalate as more girls survive leukaemia, lymphoma, and autoimmune disease.
Regional heterogeneity is instructive. North Africa’s 5.9 % prevalence coincides with high consanguinity and outflow-tract anomalies, whereas South Asia’s 5.1 % reflects both PCOS phenotypes and nutritional stress. The Western Pacific figure (3.9 %) may under-represent functional cases because many surveys exclude women using hormonal contraception—common in that region—thereby masking pill-withdrawal amenorrhoea.
Mortality is indirect but measurable. The 40 % excess mortality among untreated POI patients rivals that of established hypertension, yet unlike blood pressure, menstrual history is seldom captured in non-communicable-disease registries. Cardiovascular risk accrues through oestrogen-deprived endothelial dysfunction and adverse lipid patterns; fracture risk accumulates silently until a hip breaks at age 55.
The disability burden is front-loaded. One in three women with amenorrhea experiences clinically significant depression, a prevalence approaching that seen after myocardial infarction. Sexual dysfunction affects four in ten, straining intimate relationships and compounding psychosocial isolation. Infertility, while not universal, is feared disproportionately; in many cultures the social penalty for childlessness exceeds that for serious medical illness.
Diagnostic delay of 16 months is indefensible in an era when LH, FSH, prolactin, and thyroid-stimulating hormone can be assayed for less than the price of a restaurant meal. The bottleneck is not technology but perception: amenorrhea is still framed as a lifestyle inconvenience rather than a systemic red flag. Community-level menstrual literacy campaigns and integration of cycle history into existing hypertension-diabetes screening platforms could shorten delay by half, as demonstrated in Sri Lanka’s Healthy Life pilot.
Strengths of this review include triangulation of community surveys with GBD modelling, strict diagnostic definitions, and region-specific stratification. Limitations are the absence of incidence data outside cancer cohorts, heavy reliance on self-reported menstrual history, and under-representation of francophone Africa and the Caribbean.
Policy implications are concrete. A one-time LH/FSH and prolactin reflex panel for any woman who reports ≥ 3 months amenorrhea would cost less than US $8 and identify 90 % of organic cases. Adding a single menstrual question to existing adult-vaccination or cervical-cancer screening visits would capture millions who never present for gynaecological care. Finally, subsidising bone-density screening for women with POI or FHA would pay for itself by preventing one hip fracture for every 200 scans.
Conclusion
Amenorrhea is common, consequential, and chronically neglected. Four in every hundred reproductive-age women have lost their menstrual cycle; millions more will join them as athletic intensity, cancer survivorship, and body-weight pressures escalate. Mortality is indirect but quantifiable—18 000 deaths and nearly two million DALYs annually—while morbidity begins early: osteopenia in one quarter, depression in one third, infertility in nearly one half. Diagnostic delay of 16 months is a modifiable scandal.
The remedy is not high-tech but high-attention: universal menstrual history capture, reflex LH/FSH testing, and affordable access to bone-density screening. Implementing these measures would halve delay, prevent a sizeable fraction of attributable disability, and send a powerful cultural signal that menstrual health is not a niche concern but a vital sign. When a woman loses her period, she loses more than blood—she loses years of healthy life. Recognising amenorrhea as a sentinel event rather than a silent one is a task overdue for health systems everywhere.
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