The review, led by a team of pediatric endocrinologists and gynecologists at the University of Messina in Italy, tackles primary amenorrhea, defined as the absence of menarche by age fifteen in girls with normal secondary sexual characteristics, by age thirteen in those without any pubertal development, or more than three years after breast development begins. Although relatively uncommon, the condition can be the first visible sign of endocrine, genetic, chromosomal, or anatomical disorders affecting the hypothalamic–pituitary–gonadal axis or the reproductive tract, with long-term consequences for fertility, metabolic health, and bone strength. Despite existing guidelines, the authors note, evaluation in daily practice frequently produces delayed diagnoses and unnecessary investigations.

The core insight of the paper is that clinicians rarely begin with a specific diagnosis in mind. Instead, they narrow the possibilities step by step, integrating physical findings, hormones, imaging, and genetics. Traditional reviews list causes by category; this one adopts the perspective of the evaluating physician confronting an undifferentiated patient. The four cases were selected as archetypes of the major diagnostic pathways: structural, central, ovarian, and chromosomal causes of amenorrhea.

The first case involves a sixteen-year-old girl with completely normal breast and pubertal development but no period. Her hormones were unremarkable: follicle-stimulating hormone, luteinizing hormone, and estradiol all within normal range, confirming that her ovaries were working and her brain-ovary axis intact. Yet pelvic ultrasound revealed normally developed ovaries with no uterine body, and magnetic resonance imaging confirmed uterine agenesis with a rudimentary vaginal canal. The diagnosis was Mayer–Rokitansky–Küster–Hauser syndrome, a congenital condition in which the uterus and upper two-thirds of the vagina fail to form in an otherwise chromosomally and hormonally typical 46,XX individual. Her history of congenital hearing loss raised the possibility of type 2 disease, in which genital anomalies accompany renal, skeletal, or auditory malformations, though her renal ultrasound was normal and no other associated defects were found.

The second case illustrates the opposite end of the hormonal spectrum. A seventeen-year-old girl had barely begun puberty, with minimal breast development and no period. Her FSH and LH were profoundly low and estradiol nearly undetectable, a pattern called hypogonadotropic hypogonadism: the ovaries are healthy but never received the hormonal signal to wake up. A GnRH stimulation test confirmed a blunted pituitary response. Crucially, formal olfactory testing revealed hyposmia that the patient herself had never noticed, and brain MRI showed hypoplasia of the olfactory bulbs. Genetic testing identified a pathogenic variant in the FGFR1 gene, confirming Kallmann syndrome, a form of congenital hypogonadotropic hypogonadism in which GnRH-producing neurons fail to migrate to the hypothalamus during embryonic development, taking the olfactory nerves down with them.

The third and fourth cases both present elevated gonadotropins, signaling that the ovaries themselves are failing. A sixteen-year-old with obesity and stalled puberty had FSH of 84.7 mIU/mL and severely reduced ovarian reserve markers, anti-Müllerian hormone and inhibin B. Karyotyping revealed a large deletion on the long arm of the X chromosome spanning a region harboring genes critical for ovarian function, and sequencing identified an additional variant of uncertain significance in NOBOX, a transcription factor essential for early follicle formation. A fourteen-year-old girl, meanwhile, presented with subtle features, only modest breast development and no striking physical abnormalities, yet her FSH was dramatically elevated. Her karyotype was 45,X0: Turner syndrome, diagnosed only through the hormonal work-up. The authors emphasize that this patient’s phenotype was so mild the diagnosis could easily have been missed, a common pitfall that delays care.

From these cases the review distills a physiology-based algorithm. Breast development is the single most informative initial clue, because it reflects endogenous estrogen and therefore indirectly assesses ovarian function. Normal breast development points toward structural causes such as Müllerian anomalies; absent or incomplete development demands evaluation of the hypothalamic–pituitary–gonadal axis. Gonadotropin measurement then localizes the defect: normal FSH and LH with an absent uterus indicate an anatomical problem; low or inappropriately normal gonadotropins indicate hypothalamic or pituitary dysfunction; elevated FSH indicates primary ovarian failure and triggers karyotyping. Stature refines the picture further, since short stature with absent breast development should raise immediate suspicion of Turner syndrome, while normal stature with normal breast development suggests either Müllerian agenesis or central hypogonadism.

The authors also catalogue the traps. Physiological variability of puberty means borderline hormone values in early adolescence may need longitudinal reassessment rather than immediate labeling. The differential between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty remains one of the hardest calls in adolescent endocrinology, because basal hormone levels overlap substantially; slow pubertal progression, smell impairment, and persistently low gonadotropins favor the congenital form, while family history of delayed puberty and spontaneous progression favor the benign variant. Functional hypothalamic amenorrhea from restrictive eating or excessive exercise can biochemically mimic congenital hypogonadism. Preserved breast development does not exclude complete androgen insensitivity syndrome, a 46,XY condition accounting for roughly five percent of primary amenorrhea cases, recognizable by testosterone in the male range and absent pubic hair. Pregnancy testing, thyroid function, prolactin, and celiac screening round out the basic work-up for every patient.

Imaging and genetics each have defined roles in the sequence. Pelvic ultrasound is the first-line tool, non-invasive and widely available, confirming the presence or absence of the uterus and gauging ovarian volume and follicular activity, though its findings must always be read against the hormonal context. Pelvic MRI is reserved for characterizing Müllerian anomalies in detail, and brain MRI is indicated in hypogonadotropic hypogonadism to exclude structural lesions and support syndromic diagnoses such as Kallmann syndrome. Genetic testing should follow endocrine localization, not precede it: karyotyping is first-line whenever FSH is persistently elevated, pubertal progression is incomplete, or dysmorphic features are present, since chromosomal abnormalities are reported in anywhere from about sixteen to sixty-three percent of primary amenorrhea series, with Turner syndrome the leading chromosomal cause. Congenital hypogonadotropic hypogonadism, by contrast, involves more than thirty known genes and frequent incomplete penetrance, so its genetic results demand cautious interpretation.

The review closes by widening the lens beyond diagnosis. Hypoestrogenism in central and gonadal forms threatens peak bone mass during adolescence, arguing for early estrogen replacement, adequate vitamin D and calcium, and weight-bearing exercise. Most etiologies, except simple constitutional delay, carry fertility implications that deserve age-appropriate counseling about assisted reproduction, oocyte donation, and where legally permitted, gestational surrogacy. Given the psychological weight of these diagnoses, particularly disorders of sex development and sex chromosome abnormalities, the authors call for multidisciplinary, patient-centered care. Their central message is counterintuitive and liberating: accurate diagnosis relies less on exhaustive testing than on the strategic interpretation of a few key findings, chiefly gonadotropin measurement and pelvic imaging, applied within a coherent physiological framework.

Subject of Research: Diagnostic evaluation of primary amenorrhea in adolescent girls using a case-based, physiology-based framework

Article Title: Primary amenorrhea in adolescents: a case-based narrative review to diagnostic evaluation

Article References: Morabito, L. A., Lugarà, C., Fazio, C., Corica, D., Inì, E., Romeo, P., Ieno, L., Li Pomi, A., Luppino, G., Aversa, T., & Wasniewska, M. (2026). Primary amenorrhea in adolescents: a case-based narrative review to diagnostic evaluation. Frontiers in Adolescent Medicine, 4, Article 1870452. https://doi.org/10.3389/fradm.2026.1870452

Image Credits: AI Generated

DOI: 10.3389/fradm.2026.1870452

Keywords: primary amenorrhea, adolescent medicine, puberty, hypogonadism, Kallmann syndrome, Turner syndrome, MRKH syndrome, premature ovarian insufficiency, gonadotropins, pelvic ultrasound, genetic testing, hypothalamic-pituitary-gonadal axis