Adrenal Disorders and Pubertal Development in Children: Hormonal Pathways, Timing Disruptions and Clinical Outcome

 Corresponding author: Ashraf T. Soliman. Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. Adrenal Disorders and Pubertal Development in Children: Hormonal Pathways, Timing Disruptions and Clinical Outcome Ashraf T. Soliman 1, *, Ashraf Adel 2, Fawzia Alyafei 1, Nada M. Alaaraj 1, Noor Hamed 1, Shayma M. Ahmed 1 and Ahmed ElAwwa 3 1 Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar. 2 Department of Pediatrics, Sidra Medicine, Doha, Qatar. 3 Department of Pediatrics, Division of Endocrinology, Alexandria University Children’s Hospital, Alexandria, Egypt. GSC Advanced Research and Reviews, 2025, 25(02), 363-376 Publication history: Received 16 October 2025; revised on 22 November 2025; accepted on 24 November 2025 Article DOI: https://doi.org/10.30574/gscarr.2025.25.2.0361 Abstract Background: Pubertal development is tightly regulated by the hypothalamic–pituitary–gonadal axis and modulated by adrenal glucocorticoids and androgens. Disruption of adrenal function—through hyposecretion or hypersecretion— can alter the timing, tempo, and outcome of puberty, but data are scattered across heterogeneous pediatric conditions. This review integrates current evidence on how adrenal disorders shape pubertal development and growth outcomes, and to what extent these abnormalities are reversible with treatment. Methods: A structured narrative review was conducted using PubMed/MEDLINE, Scopus, and Google Scholar (January 2000–June 2025). Search terms combined adrenal disorders (e.g., adrenal insufficiency, congenital adrenal hyperplasia, Cushing syndrome, premature adrenarche, adrenal hypoplasia congenita, Triple A syndrome, McCune–Albright syndrome) with pubertal terms (delayed puberty, precocious puberty, pubertal progression, adrenarche, pubarche). Human studies in patients <20 years reporting adrenal diagnosis plus at least one pubertal or growth outcome were included. Case reports (<5 patients), adult-only series, purely biochemical reports, and non–full-text abstracts were excluded. Study quality was assessed using a modified Newcastle–Ottawa Scale and synthesized qualitatively in four domains: adrenal hyposecretion, hypersecretion, syndromic disorders, and reversibility. Results: Adrenal hyposecretion (primary and central adrenal insufficiency, adrenal hypoplasia, familial glucocorticoid deficiency, autoimmune polyglandular syndromes) was consistently associated with delayed adrenarche, delayed or sparse pubarche, slow pubertal progression, and reduced growth velocity. Syndromic forms (e.g., DAX-1–related adrenal hypoplasia, Triple A, IMAGe, APS-1) frequently combined adrenal failure with hypogonadotropic hypogonadism or primary gonadal failure, leading to profound pubertal delay or absent puberty. In contrast, adrenal hypersecretion states showed a spectrum from mild to severe precocious development. Classic 21-hydroxylase–deficient congenital adrenal hyperplasia, nonclassic CAH, premature adrenarche, and androgen-secreting adrenal tumors were linked to premature pubarche, virilization, advanced bone age, and, in many cases, central precocious puberty with compromised adult height. Cushing syndrome (ACTH-dependent and independent) uniquely caused growth failure and pubertal delay due to cortisol-mediated suppression of GnRH, gonadotropins, and growth hormone action. Across disorders, early and optimized treatment improved pubertal trajectories: strict androgen control in CAH limited progression and preserved height; surgical cure of Cushing syndrome allowed recovery of pubertal progression; metabolic management in premature adrenarche mitigated progression to early menarche and PCOS. However, in genetic syndromic adrenal insufficiency, pubertal abnormalities were rarely reversible without exogenous sex-steroid or gonadotropin replacement. Overall study quality was moderate to high, supporting the robustness of these patterns. GSC Advanced Research and Reviews, 2025, 25(02), 363-376 364 Conclusions: Adrenal hypofunction predominantly delays puberty, whereas adrenal androgen excess accelerates or distorts pubertal onset, and cortisol excess suppresses pubertal maturation and growth. Many pubertal disturbances are partially reversible when adrenal disorders are recognized and treated early, but syndromic forms often require lifelong hormone replacement. Routine pubertal surveillance in children with adrenal disease and integrated hormonal, metabolic, and genetic evaluation are essential to optimize growth and reproductive outcomes. Keywords: Adrenal disorders; Puberty; Congenital adrenal hyperplasia; Cushing syndrome; Premature adrenarche 1. Introduction Pubertal development is a complex neuroendocrine transition driven by the activation of the hypothalamic–pituitary– gonadal (HPG) axis and influenced by adrenal steroid production. Adrenal glucocorticoids, mineralocorticoids, and adrenal androgens are important modulators of growth, skeletal maturation, metabolic signaling, and the hormonal milieu that shapes the timing and tempo of puberty (1). Disruptions of these adrenal pathways—through either hormone deficiency or excess—can produce marked deviations in pubertal onset and progression. In normal development, adrenarche begins around 6–8 years of age and reflects the maturation of the adrenal zona reticularis with rising secretion of DHEA and DHEAS. Pubarche, the appearance of pubic hair, occurs after adrenarche, typically 1–2 years later, and represents the clinical manifestation of increased adrenal androgen production (2). This sequence—adrenarche → pubarche → gonadarche—is critical for normal pubertal maturation. When adrenal hormone production is impaired, pubarche may be delayed or absent; when excessive, pubarche may occur prematurely and may progress independently of true central puberty. Adrenal hypofunction—including primary adrenal insufficiency, central adrenal failure, and adrenal hypoplasia—may blunt adrenarche and delay pubarche. Reduced adrenal androgen production contributes to sparse or late development of pubic and axillary hair, slower skeletal maturation, impaired growth velocity, and delayed gonadal activation. Chronic cortisol deficiency additionally alters metabolic cues and inflammatory pathways that influence HPG axis responsiveness (3). Conversely, adrenal hyperfunction—most commonly from congenital adrenal hyperplasia (CAH), but also adrenal tumors and ACTH-independent hypercortisolism—can markedly alter pubertal timing. Excess adrenal androgens drive premature adrenarche, early pubarche, accelerated bone maturation, and rapid progression of puberty. If untreated, these children may progress into central precocious puberty or experience compromised adult height due to premature epiphyseal fusion (4). Cushing syndrome represents the opposite phenotype, in which chronic hypercortisolism suppresses GnRH pulsatility, reduces gonadotropin release, and induces severe growth hormone resistance. Affected children often develop delayed puberty, hypogonadotropic hypogonadism, reduced growth velocity, and significant loss of height potential. These effects are frequently compounded by cortisol-mediated metabolic changes, including increased adiposity and insulin resistance, further influencing pubertal timing (5). A number of multisystem syndromes illustrate the tight integration between adrenal and pubertal physiology. Disorders such as adrenal hypoplasia congenita (DAX-1 mutations), triple A syndrome, and McCune–Albright syndrome may combine adrenal insufficiency or adrenal hypersecretion with delayed, absent, or peripheral precocious puberty. Although individual adrenal disorders have been well described, there remains no unified summary examining how adrenal hypoand hypersecretion shape pubertal timing, progression, and final outcomes across the pediatric age range. Updated synthesis is necessary to improve early recognition, guide monitoring strategies, and emphasize the potential reversibility of pubertal abnormalities when adrenal disorders are properly diagnosed and treated (6). Objectives • To synthesize current evidence on how adrenal hyposecretion and hypersecretion affect pubertal timing, progression, and final outcomes in children and adolescents. • To systematically classify acute and chronic pubertal abnormalities associated with adrenal disorders, including syndromes that involve both adrenal and gonadal axes. • To elucidate the underlying pathophysiological mechanisms linking adrenal dysfunction to pubertal disturbances and to highlight opportunities for reversibility with timely diagnosis and treatment GSC Advanced Research and Reviews, 2025, 25(02), 363-376 365 2. Methods This review was conducted as a structured narrative synthesis of the literature on adrenal disorders and pubertal development in children and adolescents. A comprehensive search of PubMed/MEDLINE, Scopus, and Google Scholar was performed for articles published between January 2000 and June 2025, using combinations of the following terms: “adrenal insufficiency,” “primary adrenal failure,” “congenital adrenal hyperplasia,” “Cushing syndrome,” “premature adrenarche,” “adrenal hypoplasia congenita,” “triple A syndrome,” “Allgrove syndrome,” “McCune–Albright,” “puberty,” “delayed puberty,” “precocious puberty,” “pubertal progression,” “pubarche,” and “adrenarche.” Boolean operators and MeSH terms were applied where available, and reference lists of key reviews and guideline statements were handsearched to identify additional relevant publications (1–6). Eligible studies included human research involving children and adolescents (<20 years) with adrenal hypofunction or hyperfunction in whom pubertal timing, pubertal staging, growth, bone age, or gonadal function were reported. Observational cohort studies, case–control studies, cross-sectional studies, interventional series, and well-documented case series (≥5 patients) were included. Studies were required to report a defined adrenal diagnosis (e.g., primary adrenal insufficiency, congenital adrenal hyperplasia, Cushing syndrome, adrenal hypoplasia congenita, triple A syndrome, McCune–Albright syndrome) and at least one pubertal or growth-related outcome (e.g., age at pubarche or gonadarche, Tanner staging, pubertal tempo, hypogonadism, precocious puberty, final height). Exclusion criteria were animal or in vitro studies, isolated adult cohorts, isolated biochemical reports without clinical pubertal data, conference abstracts without full text, and single case reports unless they described a clearly novel mechanism directly linking adrenal dysfunction and puberty. Titles and abstracts were screened for relevance, followed by full-text review of potentially eligible articles. Data extracted from each study included study design, sample size, age range, adrenal diagnosis and etiology, hormonal profile (cortisol, ACTH, adrenal androgens, mineralocorticoids), pubertal parameters (age at onset, Tanner stage progression, presence of delayed or precocious puberty), growth and bone age data, treatment modalities, and reported reversibility or progression of pubertal abnormalities after therapy. Particular attention was paid to syndromic conditions in which adrenal insufficiency coexists with hypogonadotropic hypogonadism or peripheral precocious puberty, such as adrenal hypoplasia congenita and triple A syndrome (6,7). Methodological quality of observational studies was assessed using a modified Newcastle–Ottawa Scale adapted for pediatric endocrine cohorts, evaluating selection of participants, ascertainment of adrenal diagnosis, comparability of groups (where applicable), and objectivity of pubertal and growth outcome assessment. Interventional series and case series were appraised for clarity of inclusion criteria, completeness of follow-up, and consistency of pubertal outcome reporting. Because of substantial heterogeneity in study design, diagnostic criteria, and outcome measures, a formal meta-analysis was not attempted. Instead, findings were synthesized qualitatively and organized into three main categories: adrenal hyposecretion with pubertal delay or impairment, adrenal hypersecretion with precocious or rapidly progressive puberty, and syndromes that involve both adrenal dysfunction and primary pubertal axis abnormalities. Within each category, representative studies were highlighted, and consistent patterns of pubertal disturbance, mechanism, and reversibility with treatment were summarized. GSC Advanced Research and Reviews, 2025, 25(02), 363-376 366 Figure 1 PRISMA Flow Diagram for Study Selection Figure 1 summarizes the study identification and selection process. A total of 492 records were initially screened. After full-text review, 47 studies met all eligibility criteria and were included in the final qualitative synthesis. 3. Results The review identified consistent patterns across adrenal hyposecretion, adrenal hypersecretion, and syndromic conditions, demonstrating distinct and predictable effects on pubertal timing, progression, and growth outcomes in children and adolescents. GSC Advanced Research and Reviews, 2025, 25(02), 363-376 367 Table 1 Pubertal Abnormalities Associated with Adrenal Hyposecretion in Children and Adolescents Adrenal Disorder (Hyposecretion) Pubertal Abnormality Mechanism / Pathophysiology Clinical Notes Ref Primary Adrenal Insufficiency (Addison disease) Delayed pubarche; slow pubertal tempo Low DHEA/DHEAS → impaired adrenarche; cortisol deficiency alters HPG signaling Often presents with fatigue, hyperpigmentation, salt craving (7) Central (Secondary) Adrenal Insufficiency Delayed puberty; poor progression ACTH deficiency → low adrenal androgens; pituitary involvement may also suppress LH/FSH May mimic functional hypothalamic hypogonadism (8) Adrenal Hypoplasia Congenita (NR0B1 / DAX-1 mutations) Absent or incomplete puberty; hypogonadotropic hypogonadism Combined adrenal failure + defective GnRH/gonadotropin secretion Requires sex-steroid induction for normal secondary sexual development (9) Triple A (Allgrove) Syndrome Delayed or stalled puberty ACTH resistance + autonomic neuropathy disrupts endocrine regulation May show partial pubertal progression but delayed completion (10) Familial Glucocorticoid Deficiency Delayed adrenarche and pubarche Profound ACTH elevation with deficient adrenal androgen output Often associated with hyperpigmentation and growth faltering (11) Chronic Untreated Adrenal Insufficiency (any etiology) Slow puberty, reduced growth velocity Chronic cortisol deficiency → inflammation, GH resistance, impaired HPG maturation Many features improve after adequate steroid replacement (12) Nonclassic CAH with Low Androgen Output (rare variants) Blunted adrenarche; mild pubertal delay Partial enzymatic defects result in insufficient DHEA/DHEAS rise Phenotype mild; normal puberty possible after treatment (13,14) Table 1 demonstrates that adrenal hyposecretion leads primarily to delayed adrenarche and pubarche, reflecting the essential role of adrenal androgens in initiating sexual hair development. Conditions such as Addison disease, familial glucocorticoid deficiency, and Allgrove syndrome typically present with slow pubertal progression, while adrenal hypoplasia congenita adds central hypogonadism, producing more severe pubertal impairment. Chronic cortisol deficiency further disrupts metabolic and inflammatory pathways critical for HPG activation. Importantly, many of these abnormalities are reversible with timely glucocorticoid/mineralocorticoid replacement and appropriate induction of puberty. Table 2 Pubertal Abnormalities Associated with Adrenal Hypersecretion in Children and Adolescents Adrenal Disorder (Hypersecretion) Mechanism Pubertal Abnormality Representative Validated Studies Classic CAH due to 21hydroxylase deficiency (androgen excess) Cortisol deficiency → ↑ ACTH → adrenal androgen overproduction (androstenedione, testosterone) Premature adrenarche and pubarche, rapid virilization, accelerated growth and bone age, central precocious puberty, reduced adult height if undertreated (17) Eugster EA et al.; (18) Bonfig W et al. Nonclassic CAH with androgen excess Partial 21-hydroxylase defect → mild cortisol impairment, excess Premature pubarche, advanced bone age, earlier thelarche/menarche, adolescent (19) Moran C et al.; (20) GSC Advanced Research and Reviews, 2025, 25(02), 363-376 368 androgens mainly postnatally hyperandrogenism and PCOSlike phenotype in girls Finkielstain GP et al. Idiopathic / Obesity-related Premature Adrenarche Early zona reticularis maturation, ↑ DHEA/DHEAS; often associated with excess adiposity and insulin resistance Early pubarche (before 8 years in girls, 9 in boys), modest acceleration of growth and bone age, increased risk of earlier menarche and adolescent PCOS (21) Ibáñez L et al.; (22) Rosenfield RL et al. Androgen-secreting adrenal tumors (adenoma/carcinoma) Autonomous adrenal androgen production independent of ACTH Rapid onset virilization, very early pubarche, clitoromegaly or penile growth, advanced bone age, peripheral precocious puberty; possible progression to central precocious puberty (23) Michalkiewicz E et al.; (24) Teinturier C et al. Adrenocorticotropic hormone (ACTH)- independent Cushing syndrome (adrenal adenoma, carcinoma, PBMAH) Autonomous cortisol excess → suppression of CRH, ACTH, GH, and gonadotropin secretion Marked growth failure, delayed or arrested puberty, hypogonadotropic hypogonadism, obesity, insulin resistance (25) Newell-Price J et al.; (26) Stratakis CA et al. ACTH-dependent Cushing disease (pituitary corticotroph adenoma) Chronic ACTH and cortisol excess → GH resistance and gonadotropin suppression Severe deceleration of growth velocity, pubertal delay, sometimes regression of secondary sexual characteristics (27) Batista DL et al. McCune–Albright syndrome with adrenal hyperfunction Somatic GNAS mutations → constitutive Gsα activation and adrenal hypercortisolism or androgen excess Peripheral precocious puberty, asymmetric or rapidly progressive puberty, advanced bone age, compromised adult height (28) Dumitrescu CE et al. Table 2 shows that adrenal hypersecretion states are predominantly associated with precocious or rapidly progressive puberty, driven by androgen excess and, in some syndromic forms, by mixed cortisol and sex-steroid overproduction. Classic 21-hydroxylase–deficient CAH, nonclassic CAH, and premature adrenarche illustrate a spectrum from mild early pubarche to severe virilization and central precocious puberty when adrenal androgens are markedly elevated. Androgen-secreting adrenal tumors cause abrupt, rapidly progressive virilization with advanced bone age and peripheral precocious puberty. Conversely, Cushing syndrome (ACTH-dependent or independent) demonstrates that excess cortisol primarily leads to growth failure and delayed puberty through GH resistance and gonadotropin suppression. McCune–Albright syndrome exemplifies syndromic adrenal hyperfunction, in which adrenal overproduction of cortisol or androgens contributes to complex patterns of peripheral precocious puberty and compromised adult height. Table 3 Genetic Syndromes Affecting Both Adrenal Function and Pubertal Development Syndrome Genetic / Pathophysiologic Basis Adrenal Phenotype Pubertal Phenotype Representative Studies X-linked adrenal hypoplasia congenita (AHC) Mutations in NR0B1 (DAX-1) → defective nuclear receptors involved in adrenal and gonadotropic development Primary adrenal insufficiency presenting in infancy/childhood with salt wasting, hyperpigmentation, low cortisol Hypogonadotropic hypogonadism; absent or severely delayed puberty; failure of testicular enlargement, low testosterone; occasional atypical precocious puberty reported (10,29) GSC Advanced Research and Reviews, 2025, 25(02), 363-376 369 Triple A (Allgrove) syndrome Autosomal recessive mutations in AAAS → ALADIN protein defect; autonomic and neuroendocrine dysfunction ACTH-resistant primary adrenal insufficiency, often presenting in childhood with hypoglycemia, hypotension Delayed or arrested puberty; hypogonadotropic hypogonadism described in many adolescents; possible fertility impairment (11) IMAGe syndrome Gain-of-function mutations in CDKN1C (PCNA-binding domain) → growth restriction, adrenal hypoplasia, skeletal dysplasia Adrenal hypoplasia congenita with primary adrenal insufficiency in early infancy Genital anomalies (especially males), delayed or disordered pubertal development; risk of hypogonadism in survivors (16,30) Autoimmune polyglandular syndrome type 1 (APS-1) AIRE mutations → autoimmune destruction of multiple endocrine organs Autoimmune primary adrenal insufficiency (often with hypoparathyroidism and mucocutaneous candidiasis) Primary ovarian failure in girls and testicular failure in some boys → delayed puberty, primary amenorrhea, or secondary amenorrhea (13) McCune– Albright syndrome (with adrenal involvement) Somatic activating mutations in GNAS → constitutive Gsα signaling; mosaic distribution Adrenal hypercortisolism and/or androgen excess in a subset (Cushing syndrome or virilization) Peripheral precocious puberty (often ovarian/testicular or adrenal origin), asymmetric or rapidly progressive puberty, advanced bone age, reduced final height (28) Table 3 illustrates how shared genetic defects can simultaneously disrupt adrenal and pubertal axes. In X-linked adrenal hypoplasia congenita, NR0B1/DAX-1 mutations cause both primary adrenal failure and hypogonadotropic hypogonadism, leading to severe pubertal delay despite adequate steroid replacement (10,29). Triple A syndrome combines ACTH-resistant adrenal insufficiency with autonomic and neurological features, and many adolescents develop delayed puberty or hypogonadotropic hypogonadism (11). IMAGe syndrome, due to gain-of-function CDKN1C mutations, features intrauterine growth restriction, adrenal hypoplasia, and genital anomalies, with a high risk of later pubertal impairment (16,30). In APS-1, autoimmune adrenalitis is frequently accompanied by primary gonadal failure, resulting in delayed or absent puberty (13). McCune–Albright syndrome represents the converse scenario, where adrenal hyperfunction and gonadal activation can drive peripheral precocious puberty, often with advanced bone age and compromised adult height (28). Together, these disorders emphasize the importance of considering syndromic diagnoses when adrenal dysfunction and pubertal abnormalities coexist. Table 4 Reversibility of Pubertal Abnormalities After Treatment of Adrenal Disorders in Children and Adolescents Adrenal Disorder Main Treatment Approach Reversibility of Pubertal Abnormalities Representative Validated Studies Classic CAH (21hydroxylase deficiency, androgen excess) Physiologic glucocorticoid ± mineralocorticoid replacement; dose adjustment to suppress excess androgens; GnRH analogs if central precocious puberty present Partial reversibility: virilization progression can be slowed; pubertal tempo can be normalized with good control; compromised adult height is often only partially reversible if treatment is delayed, but early diagnosis and strict control improve final height and reduce early puberty Early therapy & height outcome: (31) Bizzarri C et al., 2018; central puberty management: (32) Nebesio TD et al., 2007 GSC Advanced Research and Reviews, 2025, 25(02), 363-376 370 Nonclassic CAH with premature pubarche and advanced bone age Low-dose glucocorticoids in symptomatic cases; lifestyle & metabolic management in milder forms Generally good reversibility: premature pubarche may stabilize; bone age advancement can slow, and menstrual regularity and hyperandrogenic symptoms improve in many treated adolescents (33) Turcu AF et al., 2017; (34) Bidet M et al., 2009 Cushing syndrome (ACTH-dependent or independent) Surgical removal of pituitary or adrenal tumor; bilateral adrenalectomy in selected cases; medical adrenal blockade as bridge Pubertal delay is often reversible: recovery of gonadotropin secretion and resumption of puberty typically occur within 1–2 years after cure. Catch-up growth is variable— younger age at cure and shorter disease duration predicts better height recovery (35) Lodish MB et al., 2010; (36) Devoe DJ et al., 2015 Premature adrenarche (idiopathic / obesity-related) Weight optimization, insulin-sensitizing strategies; in selected highrisk girls, low-dose antiandrogens or metformin Pubertal course is usually benign; early pubarche does not always require pharmacologic treatment. However, risk of earlier menarche and adolescent PCOS can be attenuated by improving metabolic status; reversal of pubertal timing is limited, but progression can be moderated (37) Ibáñez L et al., 2004; (38) Utriainen P et al., 2015 Adrenal hypoplasia congenita / Triple A / IMAGe / APS-1 (syndromic adrenal insufficiency) Lifelong glucocorticoid ± mineralocorticoid replacement; in many cases, sex steroid replacement and sometimes gonadotropin therapy Adrenal failure is permanent; pubertal failure due to hypogonadotropic hypogonadism or primary gonadal failure generally requires hormone replacement. Spontaneous normalization of puberty is rare; reversibility is mainly functional via appropriate sex steroid or gonadotropin therapy Summarized in (29), (30) and additional series—overall evidence indicates limited spontaneous recovery of pubertal axis Table 4 addresses the reversibility of pubertal abnormalities in adrenal disease is highly dependent on the underlying mechanism, age at onset, and timing of treatment. In classic and nonclassic CAH, good hormonal control can slow or normalize pubertal tempo, improve menstrual function, and protect adult height, but full catch-up is rarely achieved when diagnosis and adequate control are delayed (31–34). In Cushing syndrome, removal of the cortisol source typically allows recovery of the HPG axis and resumption of puberty, although final height largely depends on duration of hypercortisolism and pre-existing growth plate damage (35,36). In premature adrenarche, the pubertal sequence is usually preserved, and while timing cannot be “reversed,” metabolic optimization can reduce the risk of exaggerated early puberty and later PCOS (37,38). In syndromic adrenal insufficiency, adrenal failure is permanent and pubertal impairment reflects intrinsic hypothalamic, pituitary, or gonadal defects; thus, reversibility is achieved mainly through exogenous sex steroid or gonadotropin replacement rather than spontaneous recovery. This table underscores the importance of early recognition and timely treatment of adrenal disorders to maximize the reversibility of pubertal disturbances. Table 5 Cochrane-Adapted Quality Assessment of the studies used. Study Category Representative Studies Study Type Overall Quality Key Strengths Main Limitations Adrenal Hyposecretion / Insufficiency Studies Charmandari 2014 (8), Bornstein 2016 (9), Achermann 1999 (10), Flokas 2019 (11), Meimaridou 2013 (12), Cohort / genetic / mechanistic clinical Moderate → High Clear adrenal diagnoses, strong mechanistic validity, appropriate Many are small sample sizes; some are older pre-2005 studies GSC Advanced Research and Reviews, 2025, 25(02), 363-376 371 Betterle 2015 (13), Merke 2005 (16) endocrine outcome measurement with limited follow-up Adrenal Hypersecretion (CAH, tumors, Cushing, MAS) Eugster 2001 (17), Bonfig 2007 (18), Moran 2000 (19), Finkielstain 2012 (20), Michalkiewicz 2004 (23), Newell-Price 2006 (25), Batista 2007 (27), Dumitrescu 2008 (28) Cohort / registry / retrospective clinical Moderate Large registry data for tumors, robust hormonal assessment, consistent definitions of virilization and puberty Retrospective designs, heterogeneity in treatment protocols and outcome timing Premature Adrenarche & Metabolic Puberty Interaction Ibáñez 2000 (21), Neville 2005 (22) Prospective & crosssectional Moderate Good endocrine and anthropometric measures, appropriate definitions of premature adrenarche Modest sample sizes; follow-up duration varies Reversibility Studies (Table 4) Bizzarri 2018 (31), Nebesio 2007 (32), Turcu 2017 (33), Bidet 2009 (34), Lodish 2010 (35), Devoe 2015 (36), Ibáñez 2004 (37), Utriainen 2015 (38) Prospective cohort / follow-up clinical outcome Moderate → High Long-term followup, clear preand post-treatment comparisons, validated pubertal metrics Selection bias (referral centers), heterogeneity in dosage and treatment adherence Syndromic Disorders (AHC, Triple A, IMAGe, APS-1) Seminara 1999 (29), Arboleda 2012 (30) Genetic / mechanistic case series Moderate Strong genetic confirmation, consistent phenotype description Table 5 reveals that collectively the studies included across all adrenal–puberty categories were of moderate to high quality, with clear adrenal diagnoses, validated hormonal assays, and well-defined pubertal outcomes. Evidence was particularly strong for CAH, Cushing syndrome, premature adrenarche, and adrenal insufficiency, where established diagnostic criteria and consistent phenotyping reduced selection and detection bias. Long-term follow-up studies, especially those evaluating treatment reversibility—showed good methodological rigor and reliable outcome reporting. The primary limitations involved small sample sizes in rare syndromic disorders and retrospective designs in adrenal hypersecretion studies, which introduced variability in follow-up duration and treatment exposures. Despite these constraints, the mechanistic coherence and consistency of findings across diverse study types provide a solid and credible evidence base for understanding how adrenal dysfunction alters pubertal timing, progression, and final outcomes. The collective evidence supporting the relationship between adrenal disorders and pubertal development is of overall moderate-to-high quality, with strong diagnostic accuracy and consistent endocrine outcome measures across studies, providing a reliable foundation for clinical interpretation despite inherent limitations in sample size for rare syndromic conditions.