Primary or secondary amenorrhea—defined as the absence of menstruation by age 15 without secondary sexual characteristics, or by age 13 with no menses and no signs of puberty, or the cessation of regular periods for three consecutive cycles (or six months in women with established cycles)—requires systematic evaluation to identify underlying causes. Clinicians begin with a detailed history, including onset timing, associated symptoms (e.g., galactorrhea, hirsutism, headaches, vision changes), lifestyle factors (such as intense exercise, rapid weight loss, or eating disorders), medication use (including hormonal contraceptives, antipsychotics, or antidepressants), and family history of reproductive or endocrine disorders.

Physical examination focuses on assessing growth parameters, body mass index, signs of androgen excess (acne, hirsutism, alopecia), thyroid abnormalities, galactorrhea, and pelvic anatomy—including evidence of outflow obstruction or Müllerian anomalies. Initial laboratory testing typically includes serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, thyroid-stimulating hormone (TSH), and estradiol. Elevated FSH suggests primary ovarian insufficiency; low FSH and LH point to hypothalamic or pituitary dysfunction; hyperprolactinemia may indicate a prolactinoma or medication effect; and abnormal TSH signals thyroid disease as a potential contributor.

Further diagnostic steps depend on initial findings. For example, elevated testosterone or androstenedione warrants evaluation for polycystic ovary syndrome (PCOS) or nonclassical congenital adrenal hyperplasia. Imaging—such as pelvic ultrasound—helps detect structural abnormalities like uterine agenesis, intrauterine adhesions (Asherman syndrome), or ovarian morphology consistent with PCOS. Brain MRI is indicated when prolactin is markedly elevated or when neurological symptoms suggest a pituitary or hypothalamic lesion. Karyotyping or chromosomal microarray analysis may be considered in cases of primary amenorrhea with elevated gonadotropins and absent or incomplete puberty, to rule out disorders of sex development such as Turner syndrome or gonadal dysgenesis.

Importantly, pregnancy must always be excluded first—even in patients perceived to be at low risk—using a sensitive serum or urine β-hCG assay. A multidisciplinary approach involving gynecologists, endocrinologists, geneticists, and mental health professionals ensures comprehensive care, particularly when psychosocial contributors (e.g., chronic stress, disordered eating) or complex endocrine conditions are involved.