Menstrual patterns can indicate overall health and reflect changes in endocrine, metabolic, or other systemic functions. Primary amenorrhea, defined as the lifelong absence of menses, warrants evaluation by age 15 years or 3 years postthelarche. Secondary amenorrhea is defined as the cessation of previously regular menses for 3 months or irregular menses for 6 months. Evaluation begins with a focused medical history, including prior menstrual patterns; eating and exercise habits; psychosocial stressors; medication use; chronic illness; and neurologic, vasomotor, or hyperandrogenic symptoms. Physical examination should assess anthropometric trends and pubertal development. Routine laboratory testing includes pregnancy testing and serum estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone (thyrotropin) levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, is individualized. Functional hypothalamic amenorrhea may indicate treatment for underlying disordered eating or low bone density. Patients with premature ovarian insufficiency benefit from hormone therapy until the average age of natural menopause. Addressing lifetime metabolic disease and endometrial cancer risk is necessary for patients with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome).

Primary amenorrhoea is defined as the absence of menarche by the expected age, with or without delayed pubertal development in adolescents. It may result from anatomical, genetic, endocrine, and functional causes. Among the latter, we propose the term primary functional hypothalamic amenorrhoea (P-FHA) to describe primary amenorrhoea characterised by hypothalamic-pituitary-ovarian axis suppression in the absence of organic disease. P-FHA is frequently associated with low energy availability (LEA), particularly in individuals with feeding and eating disorders (FEDs) or excessive exercise, often within the spectrum of Relative Energy Deficiency in Sport (REDs). Despite its clinical relevance, P-FHA remains under-recognised, with limited dedicated research. This review aims to synthesise clinical studies addressing P-FHA in the context of FEDs or excessive exercise. A systematic literature search was conducted using PubMed, Web of Science, and Scopus. Studies focusing on P-FHA and its association with FEDs, excessive exercise, and REDs were included. Case reports and aggregated studies combining P-FHA and S-FHA were excluded to ensure specificity. Twenty-four studies addressing patients with P-FHA were identified. Available evidence suggests that the reported frequency of functional hypothalamic causes of primary amenorrhoea may have increased over time, although estimates varied substantially across populations and study designs. In patients with FEDs, the prevalence of PA ranged from 2.4% to 14.8%, while athlete cohorts reported frequencies ranging from 7.3% to 53.8%. FEDs and excessive exercise, including REDs-related conditions, emerged as major clinical settings. Data specifically addressing hormonal profiles or body composition in this context remain limited. P-FHA may represent an early clinical manifestation of chronic LEA occurring during a critical developmental window. Early recognition and multidisciplinary management are essential to minimise potential consequences on growth, skeletal health, reproductive function, body composition, and psychological well-being. Further prospective studies are needed to better define its epidemiology, neuroendocrine mechanisms, and optimal management strategies.

Primary amenorrhea is a common referral indication in pediatric and adolescent endocrinology and can occur due to hypothalamic-pituitary disorders, uterovaginal anatomical anomalies, or gonadal dysfunction. We describe 3 adolescents presenting with primary amenorrhea and otherwise appropriate pubertal development, due to Mayer-Rokitansky-Kuster-Hauser syndrome, each illustrating a distinct diagnostic challenge. The patient in case 1, who also had concerns of short stature, had elevated gonadotropin levels, suggesting a possibility of primary ovarian insufficiency. However, a normal estradiol level and repeat gonadotropin testing clarified the underlying hormonal physiology. The patient in case 2 presented with bilateral inguinal swellings and primary amenorrhea mimicking androgen insensitivity, but imaging demonstrated ectopic ovaries with absent Müllerian structures. The patient in case 3 had primary amenorrhea and a large lumbosacral mass with neurological symptoms, due to a lipomeningomyelocele associated with Müllerian agenesis. A structured evaluation incorporating repeat hormonal assessment and detailed imaging clarified the diagnosis in all cases. This report highlights the common diagnostic pitfalls during evaluation for primary amenorrhea and emphasizes the importance of reviewing the biochemical data in the context of clinical and imaging findings. In addition, a retrospective review of our cohort of adolescent girls with similar presentations is elaborated to highlight the range of associated findings.

Long COVID affects multiple organ systems and disproportionately affects women, raising concerns about reproductive health. This updated narrative review summarizes evidence from PubMed, Scopus, and Web of Science through March 2026 and extends previous reviews by distinguishing Long COVID-specific findings from acute and early post-infection observations and integrating newer evidence on ovarian reserve, follicular-fluid biology, assisted reproduction, and endometrial function. Reported menstrual changes include irregular cycles, heavy or prolonged bleeding, intermenstrual bleeding, and amenorrhea. Evidence regarding ovarian reserve remains inconsistent: some studies reported lower anti-Müllerian hormone (AMH) levels and/or antral follicle count (AFC), whereas others found no significant changes. Case reports describe premature ovarian insufficiency (POI) and possible autoimmune oophoritis but do not establish causality. Proposed mechanisms include immune dysregulation, inflammation, oxidative stress, endothelial dysfunction, and hypothalamic-pituitary-ovarian axis disturbance. Available evidence does not indicate adverse effects of COVID-19 vaccination on ovarian reserve or fertility outcomes. Most studies suggest transient changes. Direct Long COVID-specific evidence for persistent ovarian or endometrial injury remains limited. However, short follow-up precludes conclusions regarding ovarian aging, menopausal timing, lifetime fertility, or long-term endometrial receptivity. Symptom-guided assessment may include menstrual tracking, AMH, early-follicular-phase follicle-stimulating and luteinizing hormones, and pelvic ultrasonography when clinically indicated.

We describe a family, with the same biological mother and father, in which complete androgen insensitivity syndrome (CAIS) was identified across 4 phenotypic female sisters spanning a 14-year diagnostic interval from the eldest sister's diagnosis in adolescence to the proband's self-presentation as an adult. The proband, a 27-year-old, presented with primary amenorrhea, Tanner 5 breast development, absent axillary and pubic hair, and bilateral inguinal gonads on imaging. Pre-operative hormonal evaluation revealed elevated luteinizing hormone (28.1 mIU/mL), total testosterone within the adult male reference range (8.2 ng/mL; 820 ng/dL; 28.5 nmol/L), and estradiol within the lower female range (42 pg/mL; 154 pmol/L). Sequencing of the AR gene in the proband, a 22-year-old affected dizygotic twin sister, and a 14-year-old youngest sister consistently identified the same hemizygous missense variant, NM_000044.6:c.2225G>T, p.(Trp742Leu), in exon 6 within the ligand-binding domain. The variant was absent from gnomAD and classified as pathogenic per American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria, with co-segregation across three affected siblings. Laparoscopic bilateral gonadectomy was performed in the proband; histopathology showed immature testicular tissue without germ cell neoplasia in situ. Two features of this family deserve attention: first, AR Trp742 is well known as a recurrent gain-of-function hot-spot residue in castration-resistant prostate cancer, and its identification as a hemizygous germline variant associated with a complete loss-of-function phenotype underlines the context-dependent interpretation of AR variants; second, the 14-year delay between the eldest sister's diagnosis at age 16 years and the recognition of the family cluster reflects a tractable failure to initiate cascade evaluation rather than a biological challenge. The case argues for embedding pediatric-initiated structured genetic counseling and protocol-driven sibling assessment into the standard care plan for any 46,XY difference of sex development (DSD) diagnosis.