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

1 Introduction

Primary amenorrhea (PA) represents a clinically relevant condition in adolescent endocrinology and gynecology. It is traditionally defined as the absence of menarche by 15 years of age in girls with normal secondary sexual characteristics, by 13 years in those without pubertal development, or more than three years after thelarche (1).

Although relatively uncommon, PA may represent the first clinical manifestation of endocrine, genetic, chromosomal, or anatomical disorders affecting the hypothalamic–pituitary–gonadal (HPG) axis or the reproductive tract, with potential long- term consequences on future fertility, metabolic and bone health (2–4).

The clinical spectrum of PA is broad, ranging from adolescents with normal pubertal development and preserved ovarian function to patients presenting with delayed puberty, hypogonadism, ovarian insufficiency, or congenital abnormalities of the reproductive tract (5, 6).

The diagnostic evaluation of girls with PA requires the integrated interpretation of clinical and auxological findings, biochemical markers, pelvic imaging, and, when indicated, genetic testing.

This process is often complicated by the physiological variability of pubertal maturation and by the overlap between different pathological conditions. Hormonal assessment may be particularly challenging during adolescence because physiological pubertal maturation is characterized by substantial variability in gonadotropin and sex steroid secretion (7, 8).

A structured diagnostic evaluation is therefore essential to avoid delayed diagnosis, unnecessary investigations, and missed therapeutic interventions.

Previous works were centered on the description of the causes of PA according to etiological categories. However, clinicians often experienced the diagnostic challenge before the underlying etiology is known, requiring a stepwise approach (Figure 1) that localizes the site of dysfunction within the reproductive axis, especially in evaluation of young girls with PA (9–11).

Most clinicians do not begin the diagnostic process with a specific etiological diagnosis in mind and they often narrow the differential diagnosis through the integration of clinical findings, hormonal evaluation, imaging studies, and genetic investigations.

Unlike traditional etiology-based reviews, the present manuscript proposes a case- based diagnostic approach to help clinician in managing girls with PA. Through four representative clinical scenarios, we illustrate the major diagnostic pathways leading to structural, central, primary ovarian, and chromosomal causes of PA, highlighting key clinical clues, common diagnostic pitfalls, and the role of endocrine, imaging, and genetic investigations in contemporary clinical practice.

We believe that this approach more closely reflects real-world clinical reasoning and may facilitate translation of endocrine principles into daily practice.

2 Clinical case description

2.1 Case 1: PA with normal thelarche – a focus on Mayer–Rokitansky–Küster–Hauser syndrome

A 16-year-old girl was referred to our Pediatric Endocrinology outpatient clinic for PA. She reported normal breast development beginning at approximately 12 years of age and progressive pubertal changes consistent with her peers. She denied cyclic pelvic pain, galactorrhea, significant weight loss, excessive physical exercise. Her past medical history was unremarkable excepting for early onset hypoacusia. There was no family history of delayed puberty or reproductive disorders.

On physical examination, height (H) was 153 cm (−1.4 SDS) and weight (W) was 51 kg (−0.67 SDS), within normal percentiles for age and sex and appropriated for target height (TH, −1.35 SDS). Secondary sexual characteristics were fully developed (Tanner stage B5Ph5). External genitalia appeared normal. No signs of virilization, dysmorphic features, or thyroid abnormalities were observed.

Given the presence of normal secondary sexual characteristics, initial endocrine assessment focused on evaluating ovarian function and hypothalamic–pituitary axis activation. Basal FSH, LH and estradiol levels were within the normal range (FSH 5.8 mIU/mL, LH 4.09 mIU/mL, Estradiol 62 pg/mL) and the other hormonal tests (prolactin, TSH, FT4, ACTH, cortisol) yielded normal results. Coeliac disease was also ruled out. Karyotype analysis confirmed a 46, XX chromosomal pattern.

Pelvic ultrasound revealed normal appearing ovaries, with normal pubertal volumes (5 cm3) and presence of multiple follicles, but no evidence of uterine body was observed.

Subsequent pelvic magnetic resonance imaging (MRI) revealed uterine agenesis with a rudimentary vaginal canal and the presence of bilateral and normal structured ovaries.

The combination of normal secondary sexual characteristics, normal gonadotropin and estradiol levels, evidence of functional ovaries and absence of fully developed uterine structure was consistent with Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome, a congenital condition characterized by agenesis or hypoplasia of the uterus and upper two-thirds of the vagina in individuals with a 46, XX karyotype and normal ovarian function.

Given the history of hearing loss, type 2 MRKH syndrome was considered (12); however, the renal ultrasound was normal and no further associated urological, cardiac and/or skeletal abnormalities were found.

2.2 Case 2: delayed puberty and PA: when to suspect hypogonadotropic hypogonadism (HH)

A 17-year-old girl was referred for evaluation of PA and absent progression of puberty. She reported minimal breast development since age 13 and no menarche. She denied excessive physical activity, eating disorders, chronic illness, or significant weight loss. Family history was negative for pubertal and gynecological disorders.

Physical examination showed Tanner stage B2 PH2, with normal body proportions and no dysmorphic features. H was 157.7 cm (−0.69 SDS), appropriate for TH (−0.72 SDS) and BMI was normal (19.9 kg/m2, −0,42 SDS).

Laboratory tests showed very low levels of FSH (1.4 mIU/mL), LH (0.1 mIU/mL) and estradiol (<5 pg/mL). Thyroid dysfunction and hyperprolactinemia were ruled out due to the normal results of hormonal assays. Pelvic ultrasound revealed the presence of normal structured uterus and ovaries, with prepubertal features. Bone age (BA) examination revealed a significant delay in skeletal maturation (BA 13 years). Serum inhibin B was reduced, supporting impaired gonadal stimulation.

A GnRH stimulation test demonstrated a blunted gonadotropin response (peak LH 2.9 mIU/mL), confirming HH.

Particular attention was paid to olfactory function. Although the patient did not spontaneously report smell impairment, formal olfactory testing revealed hyposmia. Subsequent brain MRI demonstrated hypoplasia of the olfactory bulbs, further supporting the suspicion of Kallmann syndrome (13).

Given the clinical, biochemical, and neuroradiological findings, genetic testing was performed and identified a heterozygous pathogenic missense variant in FGFR1 (c.142G > A; p.Gly48Ser), confirming a diagnosis within the spectrum of congenital HH associated with Kallmann syndrome.

2.3 Case 3 – PA due to premature ovarian insufficiency associated with distal X chromosome deletion

A 16-years-old girl was referred to the outpatient pediatric endocrinology clinic for a history of PA. She was born at term to non-consanguineous parents and childhood history was unremarkable. Pubertal onset occurred at 12 years, but since a year ago no significant pubertal progression was observed.

Family history was characterized by several endocrine disorders. Her mother had polycystic ovary syndrome, severe obesity, and dyslipidemia. Notably, both her mother and maternal grandmother experienced early menopause at the age of 40.

At presentation, H was 155.9 cm (−1.03 SDS), W (+2.7 SDS), and BMI 34.15 kg/m2 (+1.84 SDS), consistent with severe obesity. TH was −0.45 SDS. Pubertal development was Tanner stage B3 PH4. Physical examination revealed fair skin with freckles and a mild dorsal hump.

Biochemical evaluation disclosed hypergonadotropic hypogonadism, with markedly elevated FSH (84.7 mIU/mL), LH (55.1 mIU/mL) and reduced estradiol levels (< 5pg/mL), confirmed by two different hormonal assays. Inhibin B (3.10 pg/mL) and anti-Müllerian hormone (0.1 ng/mL) levels were markedly reduced. Thyroid function, serum levels of other pituitary hormones, including circadian ACTH and cortisol secretion, urinary cortisol assay, and celiac screening were normal. Lipid profile showed mildly elevated LDL cholesterol. Pelvic ultrasound showed uterine and ovarian dimensions at the lower limits of normal for age and pubertal stage.

The combination of incomplete pubertal progression, markedly elevated gonadotropins, low estradiol concentrations, and severely reduced ovarian reserve markers (AMH and inhibin B) strongly suggested primary ovarian insufficiency (POI).

Karyotype analysis revealed a deletion of the long arm of chromosome X (Xq25), a region known to harbor genes critical for ovarian function. Chromosomal microarray analysis (CMA) further characterized this abnormality, identifying a ∼38.2 Mb deletion spanning Xq24–Xq28.

FMR1 premutation was excluded. In addition, next-generation sequencing (NGS) targeting genes associated with POI identified a heterozygous variant of uncertain significance in NOBOX gene (c.1441G > A; p. Asp481Asn), a transcription factor essential for early folliculogenesis and previously implicated in autosomal dominant type 5 POI (OMIM:169 611548).

Hormone replacement therapy with estradiol and micronized progesterone was initiated, together with a structured nutritional program for obesity management.

2.4 Case 4- PA with hypergonadotropic hypogonadism: Turner syndrome diagnosed during evaluation

A 14.3- year- old girl was to the Pediatric Endocrinology outpatient clinic for evaluation of PA. Family history was negative for constitutional delay of growth and puberty (CDGP).

She was born at 40 weeks of gestation after an uncomplicated pregnancy, with no perinatal complications. Growth had been regular, and psychomotor development was normal. Her past medical history was unremarkable. Thelarche had appeared at approximately 10.5 years of age, followed by slow progression of breast volume.

At first evaluation, her H was −1.2 SDS and BMI was +0.2 SDS. Pubertal development was Tanner stage B2 Ph2. Physical examination revealed no abnormalities across organ systems. Blood pressure was within normal limits.

An endocrine work-up for PA was started. Routine laboratory investigations, including liver, renal, and nutritional parameters, screening for celiac disease, thyroid function, and autoimmunity were all within normal ranges. Gonadotropin levels were consistent with hypergonadotropic hypogonadism (FSH 79.2 mIU/mL; LH 16 mIU/mL) and serum estradiol levels were undetectable. Pelvic ultrasound demonstrated a uterus with a longitudinal diameter of 42 mm and a body-to-cervix ratio >1, without structural abnormalities and in the absence of an endometrial stripe. The right ovary showed reduced volume (<2 cm3), while the left ovary was not detected.

Based on the clinical and laboratory findings, karyotype analysis and array-CGH were performed to investigate for X chromosome abnormalities associated with hypergonadotropic hypogonadism. Cytogenetic analysis revealed a 45, X0 karyotype, allowing the diagnosis of Turner syndrome (TS) as the cause of PA.

A subsequent targeted clinical evaluation identified phenotypic features consistent with the diagnosis: a trident hairline, an increased number of melanocytic nevi, and nail dysplasia.

Following diagnostic confirmation, pubertal induction was initiated with transdermal estradiol at a starting dose of 12.5 μg every 3.5 days.

3 Discussion

PA is not a diagnosis, but a clinical manifestation of a biologically heterogeneous group of conditions affecting the hypothalamic-pituitary-gonadal axis, gonadal function, sexual development, or the anatomy of the reproductive system.

The prevalence of the various etiologies of PA varies significantly depending on the level of the degree of spontaneous pubertal development at presentation (14).

As illustrated by our cases, the diagnostic evaluation of PA may be particularly challenging in adolescents when physiological pubertal maturation and pathological conditions often share overlapping clinical and hormonal features (9).

Unlike traditional reviews that classify PA according to its causes, the present manuscript adopts the perspective of the evaluating clinician. By sequentially localizing the site of dysfunction within the reproductive axis, it provides a practical framework for approaching an undifferentiated patient before the underlying etiology is known. This stepwise strategy allows a more rational interpretation of clinical findings and helps avoid unnecessary investigations.

The four illustrative cases were intentionally selected as archetypes of distinct diagnostic pathways in PA, namely structural, central, ovarian, and chromosomal causes. This case-based approach aims to illustrate how a limited number of key clinical, biochemical, imaging, and genetic findings can guide the localization of the underlying defect and facilitate a rational diagnostic work-up.

3.1 Clinical evaluation and assessment of pubertal development in girls with PA

The presence or absence of secondary sexual characteristics, particularly breast development, represents the most informative initial clinical observation in adolescents presenting with PA. Breast development reflects endogenous estrogen exposure (7) and therefore provides an indirect assessment of ovarian function.

The absence of breast development by the age of 13 (two standard deviations above the 10-year average) or a lack of progression in breast development combined with the absence of menses within five years of the onset of thelarche (if this occurs before the age of 10) are important indicators in patients with PA and require further diagnostic investigation (14).

Our first case illustrates how normal pubertal progression and complete breast development strongly suggest preserved ovarian steroidogenesis. In such circumstances, structural abnormalities of the reproductive tract, including Müllerian anomalies, should be considered early in the diagnostic process, as seen in Figure 1.

Conversely, absent, or incomplete breast development, as observed in Cases 2, 3 and 4, indicates insufficient estrogen production and should prompt evaluation of the hypothalamic–pituitary–gonadal axis.

Previous studies have shown that auxological assessment, particularly H and growth pattern, may provide important clues regarding the underlying etiology of PA. Additional clinical findings, including TH, dysmorphic features, nutritional status, excessive physical activity, chronic disease, and family history of delayed puberty, may further refine the differential diagnosis.

Patients with normal stature and normal breast development are more likely to present with Müllerian agenesis or HH, with the differential diagnosis further refined by evaluation of vaginal patency. Conversely, short stature associated with absent or incomplete breast development should raise suspicion for TS (9). Notably, our patient with TS presented only subtle phenotypic features, highlighting how the diagnosis may easily be overlooked in clinical practice.

Examination of the external genitalia and, when appropriate, internal genital anatomy can complement the clinical assessment and may reveal relevant abnormalities in a significant proportion of patients with PA (15).

Careful clinical assessment therefore remains the cornerstone of the diagnostic work-up and frequently narrows the differential diagnosis before laboratory investigations are performed.

3.2 Second diagnostic step: localization of the defect through gonadotropin evaluation

Measurement of FSH, LH and estradiol levels represents an essential element in the diagnostic assessment in girls with PA. Gonadotropin levels are primarily useful for identifying where the defect lies within the reproductive axis (Table 1).

Table 1. Hormonal patterns and diagnostic implications in PA.

FSH, folliculostimulating hormone; LH, luteinizing hormone; HPG, hypothalamus-pituitary- gonads axis; MKRH, Mayer–Rokitansky–Kuster–Hauser syndrome; POI, premature ovarian insufficiency.

However, the interpretation of hormonal findings must be carefully made and take pubertal stage into account: borderline values in early adolescence may require longitudinal reassessment, whereas persistently elevated FSH in mid-to-late adolescence is consistently pathological and warrant further evaluation. Estradiol levels are usually fluctuating and may also remain low in the early pubertal stages despite the presence of pubertal gonadotropin secretion and/or secondary sexual characteristics (7, 15).

Cases 3 and 4 exemplify how elevated gonadotropin concentrations indicate hypergonadotropic hypogonadism resulting from primary ovarian dysfunction or gonadal dysgenesis: in both patients, markedly elevated FSH concentrations were indicative of the presence of POI and justified subsequent genetic investigations.

In addition to chromosomal and monogenic causes, POI may occur as part of autoimmune disorders, particularly autoimmune polyglandular syndromes (APS). Therefore, screening for thyroid autoimmunity, adrenal autoimmunity, and other associated endocrine disorders should be considered in selected patients (16).

In contrast, low or inappropriately normal gonadotropin concentrations, as shown in case 2, are suggestive of HH. However, differential diagnosis between congenital HH and CDGP remains one of the most challenging aspects of adolescent endocrinology. Basal gonadotropin and estradiol concentrations frequently overlap between these conditions, particularly during early adolescence (8). However, several features increase the likelihood of congenital HH, such as a slow course of pubertal progression, anosmya or hyposmia, cryptorchidism or micropenis in males, presence of midline defects, and persistently low gonadotropin concentrations during follow-up.

In contrast, a positive family history of delayed puberty and spontaneous pubertal progression over time favor CDGP. Therefore, longitudinal clinical assessment remains essential whenever diagnostic uncertainty persists.

Functional hypothalamic amenorrhea (FHA), particularly in the setting of restrictive eating disorders, low energy availability, or excessive physical exercise, may closely mimic the biochemical profile of congenital HH (17).

Although basal gonadotropin measurement is usually indicated, dynamic testing may occasionally be considered in selected clinical scenarios. GnRH stimulation testing, performed in case 2, may provide supportive information regarding pituitary responsiveness, but current evidence indicates that no single stimulation test can reliably distinguish self-limited delayed puberty from congenital HH. Consequently, test results should always be interpreted within the broader clinical context, integrating auxological data, pubertal progression, family history, imaging findings, and, when appropriate, genetic investigations (7, 8, 15).

Ovarian reserve markers, including anti-Müllerian hormone (AMH) and inhibin B, may provide complementary information in selected patients, particularly in the evaluation of POI or suspected gonadal dysfunction, as illustrated by Cases 2 and 3. However, their diagnostic utility should always be interpreted in the context of pubertal stage.

Normal gonadotropin and estradiol concentrations, as observed in Case 1, indicate preserved hypothalamic–pituitary–ovarian function and should prompt evaluation for anatomical causes of amenorrhea, such as Mullerian abnormalities including MKRH syndrome.

MKRH syndrome is traditionally classified into type 1 (isolated uterovaginal aplasia) and type 2, in which genital anomalies are associated with renal, skeletal, auditory, or other extragenital malformations (12). In our first case, we hypothesize a type 2 MKRH syndrome due to the presence of congenital hypoacusia.

However, a normal result from basal gonadotropin assays should not rule out the possibility of other causes of PA.

Cases with discordant clinical and hormonal findings should raise suspicion of a disorder of sex development (DSD). In these conditions, cytogenetic analysis (karyotype) provides essential diagnostic information.

In some cases, resembling Müllerian agenesis, an underlying complete androgen insensitivity syndrome (CAIS) is found, as in both conditions the vagina may be absent or short. CAIS is a very rare condition and accounts for approximately 5% of cases of PA. A 46, XY chromosomal pattern and elevated testosterone levels, falling within the normal male range, are highly suggestive of CAIS. A positive family history, relatively tall stature, absence of pubic hair and the occasional presence of inguinal masses are other clinical features suggestive of CAIS, the diagnosis of which must be confirmed by cytogenetic and molecular analyses (18, 19).

Among 46, XY DSDs presenting with PA, defects of the luteinizing hormone/choriogonadotropin receptor (LHCGR) represent a rare but important differential diagnosis (20).

In adolescents with a 46, XX karyotype, normal gonadotropin concentrations associated with clinical or biochemical hyperandrogenism non-classical form of congenital adrenal hyperplasia (CAH) should be suspected. Measurement of basal 17-hydroxyprogesterone represents the recommended first-line biochemical investigation, while androstenedione and dehydroepiandrosterone sulfate (DHEAS) may provide additional information. When basal 17-hydroxyprogesterone levels are elevated or borderline, an ACTH stimulation test is required to confirm the diagnosis (21).

Several diagnostic pitfalls deserve consideration. First, physiological immaturity during early adolescence may lead to under recognition of congenital HH. Second, preserved breast development should not exclude 46, XY DSD, particularly CAIS. Third, subtle phenotypic manifestations of TS may delay diagnosis despite the presence of hypergonadotropic hypogonadism (8, 18). Awareness of these pitfalls may reduce diagnostic delays and unnecessary investigations (Table 2).

Table 2. Comparative summary of diagnostic pathways in primary amenorrhea across illustrative cases.

FSH, folliculostimulating hormone; LH, luteinizing hormone; HPG, hypothalamus-pituitary- gonads axis; MKRH, Mayer–Rokitansky–Kuster–Hauser syndrome; POI, premature ovarian insufficiency; CDGP, constitutional delay of growth and puberty; MRI, magnetic resonance imaging.

Additionally, other useful hormonal assays should be considered in girls with PA to establish the etiology. Estimation of TSH is useful to rule out subclinical hypothyroidism, even in the absence of thyroid-related symptoms. If the serum prolactin is persistently elevated, and there is no history of medication or drug use that may elevate prolactin, MRI is preferred to identify a pituitary tumor. Pregnancy tests should be performed in all patients with PA a with secondary sexual characteristics to exclude pregnancy (22).

Also celiac disease should be rule out in the diagnostic assessment of PA (23).

3.3 Third diagnostic step: the role of imaging studies

Pelvic imaging represents a key component of the diagnostic work-up of PA. Pelvic ultrasonography (PUS) is generally considered the first-line imaging modality because it is non-invasive, widely available, and provides valuable information regarding uterine morphology, endometrial thickness, ovarian size, and follicular development.

The diagnostic value of pelvic imaging largely depends on the clinical context and becomes particularly useful if a genital examination is not feasible to confirm the presence or absence of the uterus (5).

In adolescents with normal breast development and normal gonadotropin concentrations, PUS allows us to identify structural abnormalities of the reproductive tract. Case 1 illustrates this scenario, in which the combination of normal secondary sexual characteristics and an absent uterus on imaging rapidly directed the diagnostic pathway toward Müllerian agenesis.

In contrast, in adolescents with absent or incomplete pubertal development, PUS provides indirect evidence of estrogen exposure. Reduced uterine dimensions, delayed uterine maturation, and small ovarian volume may support a diagnosis of hypogonadism but are not specific for the underlying etiology. Similar findings may be observed in congenital HH, CDGP and POI.

Therefore, imaging findings should always be interpreted carefully and in conjunction with hormonal and clinical data.

Pelvic MRI should be considered in selected cases and may be useful when ultrasound findings are inconclusive or when detailed characterization of Müllerian anomalies is required. Brain MRI is indicated in patients with HH to exclude structural hypothalamic–pituitary abnormalities and may provide supportive findings in syndromic forms, including Kallmann syndrome (13).

Therefore, imaging should not be considered an isolated diagnostic tool but rather an essential component of a physiology-based approach aimed at localizing the site of dysfunction within the reproductive axis.

3.4 Fourth diagnostic step: when to perform genetic investigations

The increasing availability of genetic technologies has substantially expanded the diagnostic possibilities in PA. Nevertheless, they should not be performed indiscriminately and their execution should follow endocrine localization rather than precede it.

The choice of genetic investigations should be guided by the clinical phenotype, hormonal profile, and imaging findings, while also considering local availability of genetic technologies and access to specialized molecular diagnostics.

Karyotyping remains the first-line investigation in patients with hypergonadotropic hypogonadism or suspected DSD, whereas chromosomal microarray analysis and targeted or next-generation sequencing are reserved for selected cases according to the suspected underlying etiology.

Previous published studies reported that frequency of chromosomal abnormalities in PA varies greatly from 15.9% to 63.3% (24, 25).

Karyotype analysis is strongly indicated in cases of PA when: Cases 3 and 4 exemplify this principle, as chromosomal abnormalities were identified following the demonstration of POI. Despite advances in molecular diagnostics, conventional cytogenetic analysis remains essential for detecting sex chromosome abnormalities, including TS and structural X chromosome defects. It is also reported that TS is the leading chromosomal abnormality causing PA, either in the form of a pure 45, X karyotype or in it mosaic form (45, XO/46,XX) or (45 XO/46Xi(Xq) (26).

• FSH is persistently elevated,
• Pubertal progression is incomplete,
• Ovarian morphology is abnormal,
• Dysmorphic features are present, even subtly.

In contrast, the genetic architecture of congenital HH is considerably more complex. More than 30 genes have been implicated, including ANOS1, FGFR1, FGF8, PROKR2, PROK2, and CHD7 (27). However, genetic findings must be interpreted cautiously because incomplete penetrance, variable expressivity, and oligogenic inheritance are common. Furthermore, the identification of a potentially pathogenic variant does not always establish causality.

For these reasons, genetic testing is most indicated in selected clinical scenarios, including persistent HH, syndromic presentations, severe pubertal delay, or familial cases. Importantly, genetic results should always be interpreted within the broader clinical context and should complement, rather than replace a careful phenotypic evaluation.

The four cases presented in this review highlight the complementary relationship between endocrine assessment and genetic investigations. In each scenario, genetic testing contributed to diagnostic confirmation only after the identification of the level of dysfunction within the reproductive axis through clinical, biochemical, and imaging evaluation.

3.5 Beyond diagnosis: endocrine, psychosocial and long-term implications

Diagnostic evaluation in PA has relevant prognostic implications beyond etiological classification. Central and gonadal forms are associated with hypoestrogenism, which may adversely affect bone mineral accrual during adolescence, leading to reduced peak bone mass and an increased risk of low bone density and fractures that may persist into adulthood.

These considerations support early recognition and timely intervention, together with evaluation of bone health when clinically indicated and optimization of sex steroid replacement, vitamin D and calcium intake, and weight-bearing physical activity (22, 28).

Beyond skeletal effects, most etiologies of PA—except CDGP—have important implications for fertility and long-term quality of life. Conditions associated with hypergonadotropic hypogonadism, including TS and POI, are associated with impaired reproductive potential, whereas Müllerian anomalies such as MRKH syndrome result in distinct reproductive limitations despite preserved ovarian function (29, 30).

In selected cases, assessment of ovarian reserve markers, including AMH and antral follicle count, may provide complementary information on residual gonadal function, although interpretation during adolescence should be undertaken with caution (31, 32). Early fertility counseling should therefore be considered as part of the diagnostic pathway, allowing timely discussion of available reproductive options, including assisted reproductive technologies, oocyte donation and, where legally permitted, gestational surrogacy.

The information about fertility should be provided in a clear and age-appropriate manner, focusing on available reproductive options and realistic expectations (32).

Given the psychological burden that may accompany several underlying conditions, particularly disorders of sex development and sex chromosome abnormalities, a multidisciplinary approach is recommended. Psychological support can be beneficial in addressing diagnostic uncertainty, concerns regarding identity, and anxiety related to future health and fertility outcomes, contributing to improved patient-centered care (32, 33).

This review has some limitations. The selected cases were designed to illustrate representative diagnostic pathways and do not encompass the full spectrum of causes of PA.

Rare conditions, overlapping phenotypes, and evolving genetic diagnoses may require individualized assessment beyond the framework presented here. Nevertheless, the proposed physiology-based approach may provide a practical starting point for the evaluation of most adolescents presenting with PA.

4 Conclusion

The evaluation of PA requires integration of clinical examination, biochemical markers, imaging, and genetic analysis within a physiologically coherent framework.

The four cases presented illustrate the biological heterogeneity of PA and highlight a central concept: accurate diagnosis relies less on extensive testing and more on the strategic interpretation of a limited number of key clinical and laboratory findings. Across diverse etiologies, a limited set of key investigations—particularly gonadotropin measurement and pelvic imaging—serve as decisive tools for axis localization. Early recognition and timely management by a multidisciplinary team are important to address the medical, reproductive, and psychosocial consequences associated with the underlying condition.

The application of structured and physiologically- based diagnostic approach, allow clinicians to navigate diagnostic complexity while avoiding unnecessary testing and ensuring timely, patient-centered management.

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Footnotes

Edited by: Rodolfo A. Rey, Centro de Investigaciones Endocrinológicas “Dr. César Bergadá” (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Argentina

Reviewed by: Leticia Silveira, Federal University of Minas Gerais, Brazil

Sarah Firdausa, Syiah Kuala University, Indonesia