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Delayed puberty

Delayed puberty is a medical condition defined as the absence of secondary sexual characteristics by specific age thresholds, including no breast development by age 13 years or no menarche by age 16 years in girls, and no testicular enlargement (to a volume of at least 4 mL or length of 2.5 cm) by age 14 years in boys.^[1]^[2] This delay disrupts the normal maturation of the hypothalamic-pituitary-gonadal axis, which regulates puberty, and affects approximately 2% of adolescents, occurring more frequently in boys than girls.^[1]^[2] The most common cause of delayed puberty is constitutional delay of growth and puberty (CDPG), a benign variant accounting for about 53-60% of cases in boys and 30% in girls, often with a familial pattern where parents experienced late puberty.^[1]^[2] Other etiologies include functional hypogonadotropic hypogonadism due to chronic illnesses (e.g., malnutrition, eating disorders, or excessive exercise), permanent hypogonadotropic conditions (e.g., Kallmann syndrome), and hypergonadotropic hypogonadism from primary gonadal failure (e.g., Turner syndrome in girls or Klinefelter syndrome in boys).^[1]^[2] Less frequently, it may stem from central nervous system tumors, genetic disorders, or iatrogenic factors like chemotherapy.^[1] Diagnosis involves a thorough history assessing family pubertal timing, nutritional status, and chronic conditions, combined with physical examination using Tanner staging to evaluate sexual maturity and growth charts to identify short stature.^[2] Laboratory tests typically include measurements of luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (in boys), estradiol (in girls), and bone age assessment via hand X-ray; further imaging or karyotyping may be indicated for suspected underlying pathologies.^[1]^[2] Management depends on the underlying cause: CDPG often requires only reassurance and monitoring, as most individuals experience spontaneous puberty by age 18, though short-term sex steroid therapy (e.g., low-dose testosterone for boys or estrogen for girls) may be used to alleviate psychosocial distress in those over age 13-14.^[1]^[2] For pathological cases, treatment addresses the root issue, such as hormone replacement therapy for hypogonadism, with long-term monitoring to support fertility and bone health.^[1] Early intervention by a pediatric endocrinologist is crucial to distinguish benign delays from treatable disorders and optimize outcomes.^[2]

Definitions and Epidemiology

Definitions and Timing

Delayed puberty is clinically defined as the absence of secondary sexual characteristics by age 13 years in girls (specifically, the onset of breast development) or by age 14 years in boys (specifically, testicular enlargement to a volume greater than 4 mL), or the lack of progression of pubertal development for more than 3 to 4 years after initial signs appear.^[3]^[4]^[5] These thresholds correspond to more than 2 to 2.5 standard deviations above the mean age of pubertal onset in the general population, reflecting a significant deviation from normal timelines.^[6]^[7] The Tanner staging system, developed to quantify pubertal maturation, provides a standardized framework for assessing development across five stages (I to V) for both sexes, focusing on secondary sexual characteristics and associated changes.^[8] In girls, breast development progresses from stage I (prepubertal, no glandular tissue) to stage V (mature adult breast with full areola integration), while pubic hair advances from sparse growth at stage II to coarse, adult-type distribution covering the mons pubis by stage V; the growth spurt typically peaks during stages II to III.^[8] In boys, genital development follows a similar progression, with stage I indicating prepubertal testes (less than 4 mL), stage II marking initial enlargement to 4-12 mL with scrotal thinning, and stage V representing adult genitalia; pubic hair staging mirrors that of girls, and the growth spurt occurs later, often peaking in stage III.^[8] Delayed puberty is thus characterized by prolonged residence in stage I or stalled progression beyond early stages.^[8] Bone age assessment, a critical tool for evaluating pubertal timing, is typically determined using the Greulich-Pyle method, which compares a left hand and wrist radiograph to an atlas of reference images from healthy children to estimate skeletal maturation in years.^[9] In delayed puberty, bone age is often delayed by more than 2 standard deviations below chronological age, indicating slower skeletal advancement relative to peers and helping to predict final height potential.^[10] This method remains widely used due to its simplicity and correlation with pubertal events, though it requires trained interpretation for accuracy.^[9] Delayed puberty must be distinguished from isolated short stature, where height is below the third percentile but pubertal timing and progression occur within normal age ranges, and from variants of precocious puberty, which involve accelerated rather than retarded development of secondary sexual characteristics.^[11] In isolated short stature, such as familial or idiopathic forms, bone age may be normal or slightly delayed without pubertal delay, whereas precocious puberty features Tanner stage advancement before age 8 in girls or 9 in boys.^[11]^[12] The foundational definitions of delayed puberty trace back to the 1960s studies by James M. Tanner and William A. Marshall, who longitudinally observed pubertal changes in British children and established the Tanner staging system based on empirical data from over 200 participants, quantifying the sequence and variability of maturation events.^[13]^[14] These works, published in 1969 for girls and 1970 for boys, provided the first detailed norms for pubertal timing, influencing subsequent diagnostic criteria.^[13]^[14] Modern guidelines, such as those from the Pediatric Endocrine Society (aligned with the Endocrine Society), refine these thresholds using updated population data to account for secular trends in earlier puberty onset, with the most recent consensus emphasizing age- and sex-specific cutoffs as of 2020, though ongoing reviews incorporate 2023 epidemiological insights.^[3]^[4]^[15]

Prevalence and Risk Factors

Delayed puberty affects approximately 2% to 3% of adolescents globally, with estimates varying slightly across studies based on diagnostic criteria and population sampling.^[16]^[17] Constitutional delay of growth and puberty (CDGP) represents the most common etiology, accounting for 53% of cases among adolescents aged 18 years or younger evaluated for delayed puberty.^[1] Sex differences are notable, with delayed puberty occurring approximately twice as frequently in boys as in girls, partly due to greater clinical concern and referral rates among males.^[18]^[19] CDGP accounts for 63% of delayed puberty cases in boys and 30% in girls, reflecting differences in pubertal timing thresholds and progression.^[1] Ethnic variations also influence prevalence; for instance, CDGP appears more common among Caucasians compared to African Americans, who tend to experience earlier pubertal onset overall.^[20]^[21] Key risk factors include a strong familial component, with 50% to 80% of individuals with CDGP reporting a family history of delayed puberty, underscoring its high heritability.^[22] Low birth weight is associated with delayed pubertal onset, particularly in boys, potentially due to intrauterine growth restriction affecting hypothalamic-pituitary-gonadal axis maturation.^[23] Adoption from low-resource settings increases risk, as early institutional deprivation often leads to growth delays and subsequent pubertal postponement in international adoptees.^[24]^[25] Intense athletic training and eating disorders further elevate susceptibility through energy deficits that disrupt gonadotropin-releasing hormone pulsatility.^[26]^[27] Recent epidemiological data reinforce these patterns; for example, a 2023 analysis confirmed CDGP in over half of pediatric cases under 18 years.^[1] Emerging trends suggest a potential rise in delayed puberty among certain subgroups amid increasing childhood obesity, which paradoxically delays onset in boys via altered sex steroid signaling, contrasting its advancing effect in girls.^[28]^[29]

Etiology

Constitutional Delay of Growth and Puberty

Constitutional delay of growth and puberty (CDGP) represents a benign, self-limited variant of normal pubertal timing, characterized by a delayed but spontaneous onset of puberty without any underlying pathological condition. This condition manifests as a transient state of hypogonadotropic hypogonadism, where the childhood phase of growth is prolonged, leading to a slower tempo of overall development. It is considered the extreme tail of the normal Gaussian distribution for pubertal onset, affecting the hypothalamic-pituitary-gonadal axis through subtle delays in maturation rather than complete dysfunction. Polygenic factors play a key role in this pathophysiology, influencing the frequency and amplitude of gonadotropin-releasing hormone (GnRH) pulses, which ultimately delay the activation of puberty but allow for eventual progression. A 2017 study in the Journal of Clinical Endocrinology & Metabolism identified contributions of function-altering variants in genes implicated in pubertal timing, such as TACR3 and MKRN3, to self-limited delayed puberty, explaining familial patterns.^[30] Clinically, CDGP is distinguished by a characteristic prepubertal growth trajectory, where children maintain a normal growth velocity for their age until a late adolescent growth spurt occurs, often aligning with peers by adulthood. Bone age, assessed via wrist X-ray, is typically delayed by 2-4 years compared to chronological age but corresponds closely to the child's height age, reflecting the synchronized but shifted developmental timeline. A family history of delayed growth or puberty is present in 50-75% of cases, underscoring its hereditary nature and supporting its diagnosis as a physiologic rather than acquired delay. The genetic basis of CDGP involves common variants in multiple genes that regulate pubertal timing, contributing to a polygenic risk profile that differs from monogenic disorders. These variants explain the familial clustering and self-resolving nature of CDGP, distinguishing it from permanent hypogonadism. Differentiation from pathologic forms of delayed puberty relies on the observation of spontaneous pubertal progression, which occurs by age 18 years in approximately 95% of untreated CDGP cases, serving as the gold standard for confirmation. This self-resolution contrasts with chronic conditions like IHH, where puberty fails to initiate without intervention. Historically, CDGP was first described in the 1940s as a "physiologic variant" of growth and development, based on early systematic observations of pubertal variability in pediatric populations. Longitudinal studies have since validated its benign course, showing that affected individuals achieve normal adult height and reproductive function without long-term deficits.

Systemic Disorders and Malnutrition

Systemic disorders and malnutrition represent a significant category of acquired causes for delayed puberty, primarily through the induction of secondary hypogonadotropic hypogonadism by disrupting the hypothalamic-pituitary-gonadal (HPG) axis.^[31] In chronic inflammatory conditions, elevated systemic cytokines, such as interleukin-6 and tumor necrosis factor-alpha, suppress gonadotropin-releasing hormone (GnRH) pulsatility at the hypothalamic level, thereby inhibiting downstream luteinizing hormone and follicle-stimulating hormone secretion.^[32] Concurrently, malnutrition from these disorders contributes by creating an energy deficit that halts HPG axis activation, as seen in states where body weight falls below 80% of ideal for age, leading to reduced kisspeptin signaling and GnRH neuron activity.^[33] For instance, in anorexia nervosa, critically low body fat levels—often below 20%—exacerbate this suppression, mimicking the effects of severe caloric restriction.^[34] Specific chronic illnesses frequently associated with delayed puberty include celiac disease, inflammatory bowel disease (IBD), cystic fibrosis, chronic renal failure, and even asthma when poorly controlled. Celiac disease, an autoimmune enteropathy triggered by gluten, leads to delayed puberty through malabsorption-induced nutritional deficits, with delayed puberty observed in up to 20% of untreated pediatric patients.^[35] In IBD, such as Crohn's disease, active inflammation and gastrointestinal losses lead to protein-calorie deficits and micronutrient deficiencies, delaying pubertal onset in a substantial proportion of adolescents.^[36] Cystic fibrosis impairs nutrient absorption due to pancreatic insufficiency, historically causing delayed puberty in over 50% of affected youth, though improved therapies have reduced this prevalence toward general population levels.^[37] Chronic renal failure disrupts puberty via uremic toxins and anemia, while severe asthma may contribute through chronic corticosteroid use and associated growth suppression.^[33] Additionally, extreme physical activity in athletes, particularly female ballet dancers engaging in high-intensity training with energy restriction, induces functional hypothalamic amenorrhea and pubertal delay due to low energy availability.^[38] Nutritional deficiencies alone can precipitate delayed puberty, independent of overt systemic disease, by impairing gonadal maturation and growth hormone signaling. Protein-calorie malnutrition, common in resource-limited settings, compromises the pubertal growth spurt and HPG activation through reduced insulin-like growth factor-1 production and altered leptin levels.^[39] Micronutrient shortages, including vitamin D and zinc, further hinder development; zinc deficiency disrupts GnRH secretion, while vitamin D insufficiency affects gonadal steroidogenesis, both reversible with supplementation.^[39] According to 2024 reviews, systemic disorders and malnutrition account for 20-30% of delayed puberty cases overall, with higher incidence in low socioeconomic status populations due to increased prevalence of undernutrition and untreated chronic conditions.^[33] Treatment of the underlying disorder often leads to reversal of pubertal delay, with resumption typically occurring 6-12 months post-intervention and accompanied by catch-up growth. In celiac disease, adherence to a gluten-free diet restores intestinal absorption, prompting pubertal progression within 6-8 months in most cases, as evidenced by normalized gonadotropin levels and secondary sexual characteristics.^[40] Refeeding in malnutrition syndromes similarly reactivates the HPG axis, yielding catch-up growth velocities exceeding 8 cm/year once energy balance is achieved.^[39] For chronic illnesses like IBD or cystic fibrosis, optimized medical management, including nutritional support, facilitates timely puberty without the need for hormonal induction in reversible scenarios.^[36]

Hypergonadotropic Hypogonadism

Hypergonadotropic hypogonadism represents a form of primary gonadal failure in delayed puberty, characterized by deficient production of sex steroids (estrogen in females and testosterone in males) due to impaired gonadal function, resulting in compensatory elevation of gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—typically more than two standard deviations above age-matched norms.^[1] This condition arises from either gonadal resistance to gonadotropin stimulation or direct destruction of gonadal tissue, disrupting the normal feedback loop of the hypothalamic-pituitary-gonadal axis and preventing spontaneous pubertal progression.^[41] In affected individuals, low sex steroid levels lead to absent or incomplete secondary sexual characteristics, such as lack of breast development in girls or testicular enlargement in boys, often accompanied by elevated gonadotropins detectable on laboratory evaluation.^[42] Congenital causes predominate in this etiology, with genetic disorders accounting for many cases of primary gonadal insufficiency. Turner syndrome, resulting from a 45,X karyotype, affects approximately 1 in 2,500 live female births and manifests as ovarian dysgenesis with streak gonads, leading to hypergonadotropic hypogonadism and delayed or absent puberty in the majority of cases (spontaneous puberty in ~30-40%, menarche in ~10-20%).^[43] In males, Klinefelter syndrome (47,XXY karyotype), occurring in about 1 in 650 to 1,000 newborn boys, causes progressive testicular failure with small, firm testes and elevated FSH/LH levels, often resulting in incomplete pubertal development despite initial onset within normal age limits.^[44] Anorchia, or congenital bilateral absence of testes, is another key cause in phenotypic males, leading to undetectable testosterone and markedly elevated gonadotropins from birth, typically requiring early diagnosis via imaging or surgical exploration.^[45] Additionally, Y-chromosome microdeletions, particularly in the azoospermia factor (AZF) regions, contribute to severe spermatogenic impairment and hypogonadism in some boys, though they more commonly present with infertility later in life rather than profound pubertal delay.^[46] Acquired causes of hypergonadotropic hypogonadism often stem from iatrogenic or infectious insults to the gonads. Chemotherapy and radiation therapy for childhood cancers pose a significant risk, with alkylating agents and pelvic irradiation associated with gonadal failure in 30-50% of survivors, depending on cumulative dose and regimen, leading to elevated gonadotropins and infertility.^[47] Autoimmune oophoritis in females and orchitis in males, frequently part of autoimmune polyglandular syndromes, result in lymphocytic infiltration and destruction of gonadal tissue, causing primary hypogonadism with high FSH/LH and delayed puberty.^[48] Viral infections like mumps orchitis, affecting up to 30% of post-pubertal males with mumps, can induce unilateral or bilateral testicular atrophy, contributing to long-term hypergonadotropic hypogonadism in a subset of cases.^[49] Recent advances in genetic testing have enhanced identification of underlying molecular defects in non-syndromic hypergonadotropic hypogonadism. Mutations in NR5A1 (also known as SF1), a key regulator of gonadal development, have been identified in cases without classic syndromic features, often presenting as 46,XY or 46,XX disorders of sex development with primary gonadal insufficiency and elevated gonadotropins.^[50] These findings underscore the role of next-generation sequencing in pinpointing monogenic causes previously classified as idiopathic.

Hypogonadotropic Hypogonadism

Hypogonadotropic hypogonadism (HH) arises from central defects in the hypothalamic-pituitary-gonadal (HPG) axis, characterized by impaired secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus or inadequate gonadotropin response from the pituitary gland. This disruption prevents the pulsatile release of GnRH, which is essential for stimulating the production of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the anterior pituitary. Consequently, serum levels of LH and FSH are typically low, often below 1 IU/L, leading to deficient sex steroid production by the gonads and resulting in delayed or absent puberty.^[51]^[52] Genetic causes predominate in congenital forms of HH, with isolated hypogonadotropic hypogonadism (IHH) often linked to monogenic or oligogenic mutations disrupting GnRH neuron migration, development, or function. Kallmann syndrome, a subtype of IHH, combines HH with anosmia or hyposmia due to defective olfactory bulb formation and is associated with mutations in genes such as ANOS1 (formerly KAL1) and FGFR1, which impair neural migration during embryogenesis. Over 50 genes have been implicated in IHH and related disorders, including PROK2, which affects GnRH neuron survival, and CHD7, a chromatin-remodeling protein linked to both normosmic IHH and Kallmann syndrome phenotypes. Recent polygenic analyses highlight contributions from common variants in these pathways, underscoring the genetic complexity beyond rare mutations.^[53]^[54]^[55] Acquired causes of HH stem from insults to the hypothalamic-pituitary region, including tumors such as craniopharyngiomas, a notable cause of pediatric HH cases by compressing GnRH neurons or pituitary tissue. Other etiologies encompass head trauma disrupting the HPG axis, infiltrative diseases like sarcoidosis causing granulomatous inflammation in the hypothalamus, and severe eating disorders that induce functional suppression through chronic energy deficits. These acquired forms contrast with congenital ones by often presenting later in life and potentially involving multiple pituitary hormone deficiencies.^[56]^[33]^[57] IHH represents about 40% of all HH cases, manifesting as isolated GnRH deficiency without other pituitary involvement, while combined forms may include deficiencies in additional hormones like growth hormone or thyroid-stimulating hormone. In females, functional hypothalamic amenorrhea—a reversible acquired HH variant driven by stress, excessive exercise, or undernutrition—affects 20-30% of cases, leading to low gonadotropins and amenorrhea through suppressed GnRH pulsatility. Recent 2025 research emphasizes epigenetic regulators, such as variants in KISS1R (encoding the kisspeptin receptor critical for GnRH activation), which modulate pubertal timing via DNA methylation and histone modifications, offering insights into both congenital and acquired HH mechanisms.^[58]^[59]^[60]

Clinical Presentation

History

The history in evaluating delayed puberty focuses on gathering a detailed timeline and contextual information from the patient and family to guide the differential diagnosis, particularly distinguishing constitutional delay of growth and puberty (CDGP) from underlying pathologic conditions. Essential inquiries include the onset and progression of any pubertal signs, such as breast development in girls, testicular enlargement in boys, pubic hair growth, or acne, as the absence of these by age 13 in girls or 14 in boys prompts further evaluation.^[1] Family history of pubertal timing is crucial, with questions about delayed puberty or late menarche in parents or siblings, as CDGP has a strong familial component in over 75% of cases.^[2] A thorough review of growth patterns is vital, including plotting height, weight, and body mass index on standardized growth charts to assess velocity; for instance, a normal but delayed growth spurt (typically 2-4 cm/year prepubertally, accelerating later in CDGP) helps differentiate benign delay from pathologic growth failure associated with systemic disorders or hypogonadism.^[1] Chronic symptoms should be explored, such as gastrointestinal issues suggestive of celiac disease, recurrent infections indicating immunodeficiency, or excessive exercise and nutritional deficits that may contribute to functional hypogonadotropic hypogonadism.^[29] Psychosocial aspects warrant attention, including experiences of bullying, body image concerns, academic performance, or mood changes, which can exacerbate distress in adolescents with delayed development; in girls, menstrual history following thelarche (if present) is also elicited to evaluate cycle regularity.^[2] Red flags in the history signal potential serious etiologies and necessitate urgent evaluation, such as headaches or vision changes raising concern for pituitary tumors, anosmia pointing to Kallmann syndrome, or dysmorphic features like webbed neck suggesting Turner syndrome.^[1] A comprehensive systemic review covers fatigue, unexplained weight loss, or polyuria/polydipsia that might indicate chronic illnesses like inflammatory bowel disease or diabetes mellitus.^[29] Overall, this history-taking approach aids in categorizing potential etiologies, from transient functional delays to permanent gonadal or hypothalamic-pituitary axis disorders.^[2]

Physical Examination

The physical examination in delayed puberty begins with anthropometric measurements, including height, weight, and body mass index (BMI), plotted on age- and sex-specific growth charts to assess growth patterns and velocity. Short stature, defined as height below the 3rd percentile, is present in approximately 70-80% of cases, often reflecting underlying etiologies such as constitutional delay or chronic conditions.^[61] Dysmorphic features may also be noted, such as a webbed neck in Turner syndrome, which warrants further evaluation for chromosomal abnormalities.^[43] Calculation of midparental target height during this assessment helps predict expected adult stature, particularly in cases suggestive of constitutional delay of growth and puberty (CDGP), where the child's height is typically within 2 standard deviations of this target.^[62] A comprehensive genital examination follows, tailored by sex. In boys, testicular volume is measured using a Prader orchidometer, with volumes less than 4 mL indicating prepubertal status and confirming delayed puberty.^[1] In girls, inspection for rare findings such as clitoromegaly (suggesting androgen excess, e.g., in congenital adrenal hyperplasia) or labial fusion (more common in prepubertal states but not causative of delay) is performed, though these are infrequent in isolated delayed puberty.^[2] Tanner staging is essential to objectively document the absence of secondary sexual characteristics, including breast development (stage 1 in girls) and testicular enlargement (stage 1 in boys), alongside evaluation of pubic and axillary hair distribution.^[2] This staging aligns with normal pubertal timelines but highlights the delay when no progression is evident by expected ages. Additional systemic signs are screened during the examination. A simple bedside test for anosmia, such as identifying the scent of coffee grounds, is conducted to detect Kallmann syndrome, where olfactory deficits accompany hypogonadotropic hypogonadism.^[1] Visual field confrontation testing checks for bitemporal hemianopia, indicative of pituitary lesions compressing the optic chiasm.^[63] Neck palpation assesses for thyroid enlargement or goiter, which may signal hypothyroidism contributing to pubertal delay.

Diagnostic Approach

Laboratory Evaluation

Laboratory evaluation begins with baseline hormone measurements to assess gonadal function and distinguish between types of hypogonadism, guided by clinical suspicion from history and physical examination.^[64] Morning serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex steroids—testosterone in males and estradiol in females—are obtained using pediatric-specific assays, as levels are typically low in both hypergonadotropic and hypogonadotropic hypogonadism but help differentiate the etiology.^[64] In hypergonadotropic hypogonadism, LH and FSH are elevated (e.g., FSH often >20 mIU/mL indicating gonadal dysfunction), reflecting primary gonadal failure, whereas low or inappropriately normal LH and FSH with low sex steroids suggest hypogonadotropic hypogonadism or constitutional delay.^[64] Anti-Müllerian hormone (AMH) may be measured as a marker of gonadal reserve, with low levels in primary hypogonadism and variable patterns in central causes reflecting FSH stimulation status.^[64] If baseline gonadotropins are low, a gonadotropin-releasing hormone (GnRH) stimulation test is performed to confirm hypogonadotropic hypogonadism by evaluating pituitary responsiveness.^[1] The protocol involves administering 100 mcg of GnRH intravenously as a bolus, with blood samples collected at baseline (0 minutes) and at 20, 30, and 60 minutes post-injection to measure LH and FSH peaks.^[65] A peak LH response less than 5 IU/L indicates a prepubertal or hypogonadotropic state, distinguishing it from early pubertal activation where peaks exceed this threshold.^[65] Additional laboratory tests screen for systemic causes of delayed puberty. A complete blood count (CBC), serum electrolytes, thyroid function tests (TSH and free T4), insulin-like growth factor-1 (IGF-1) for growth hormone assessment, and celiac disease screening via tissue transglutaminase IgA (tTG-IgA) antibodies are routinely evaluated to identify malnutrition, chronic illness, or endocrine disorders.^[1] In cases of suspected chromosomal abnormalities, such as Turner syndrome in females or Klinefelter syndrome in males, karyotype analysis is indicated.^[1] Bone turnover markers, such as alkaline phosphatase, provide insight into skeletal activity and growth potential, often elevated in active but delayed pubertal states.^[1]

Imaging and Genetic Testing

Imaging modalities play a crucial role in evaluating structural abnormalities contributing to delayed puberty, particularly in cases of hypogonadotropic hypogonadism (HH). Brain magnetic resonance imaging (MRI) of the pituitary is recommended to identify tumors, malformations, or other lesions along the hypothalamic-pituitary-gonadal (HPG) axis, which have been reported in 10-35% of HH cases depending on the cohort.^[66] The standard protocol includes coronal T1-weighted sequences with gadolinium contrast to enhance visualization of the pituitary gland, stalk, and surrounding structures, helping to differentiate congenital anomalies from acquired pathologies.^[67] In patients with isolated HH or syndromic features like anosmia, MRI can reveal olfactory bulb hypoplasia or ectopic posterior pituitary, guiding further management.^[68] Pelvic ultrasound is a non-invasive initial imaging tool to assess gonadal development in suspected hypergonadotropic hypogonadism. In Turner syndrome, it typically reveals streak gonads characterized by small, hypoechoic structures without follicular activity, confirming ovarian dysgenesis.^[69] Similarly, in males with suspected anorchia or congenital bilateral absence of testes, ultrasound demonstrates absent or undescended gonads in the scrotum or pelvis, aiding diagnosis of 46,XY disorders of sex development.^[70] This modality is preferred due to its accessibility and lack of radiation, though it may require follow-up MRI for ambiguous findings. Bone age assessment via X-ray of the left hand and wrist is essential to quantify skeletal maturation delay, defined as a bone age more than 2 standard deviations or 2 years below chronological age in delayed puberty.^[71] The Greulich-Pyle atlas or Tanner-Whitehouse method is commonly used to interpret these radiographs, which reflect ossification centers influenced by sex steroids and growth factors.^[10] A significant delay supports diagnoses like constitutional delay of growth and puberty, while normal bone age may prompt evaluation for other etiologies. Genetic testing is integral for identifying syndromic or idiopathic causes of delayed puberty, beginning with karyotyping to detect chromosomal abnormalities such as 45,X in Turner syndrome or 47,XXY in Klinefelter syndrome.^[72] For idiopathic HH, next-generation sequencing (NGS) panels targeting over 50 genes involved in GnRH neuron migration, development, or function—such as KAL1, FGFR1, and PROKR2—yield a diagnostic rate of approximately 40% in unexplained cases.^[73] Emerging polygenic risk scores, derived from genome-wide association studies, assess the cumulative effect of common variants on puberty timing, with individuals in the top 1% of risk showing an 11-fold increased likelihood of delayed puberty.^[74] As of 2025, whole-exome sequencing (WES) is increasingly used for unsolved cases of delayed puberty, particularly in syndromic HH or self-limited variants, offering higher resolution for rare deleterious mutations with diagnostic yields of approximately 20-60% in cohorts with congenital hypogonadotropic hypogonadism.^[75] Updated guidelines emphasize its utility when initial karyotype and NGS are negative, integrating it into tiered diagnostic algorithms to improve etiological clarity and family counseling.^[1]

Management

Observation and Reassurance

Observation and reassurance form the cornerstone of management for constitutional delay of puberty and growth (CDPG), a common benign variant characterized by delayed onset of puberty without underlying pathology. This approach is appropriate when there is a positive family history of delayed puberty, a bone age delay typically exceeding 2 years but without extreme discrepancy, and absence of red flags such as systemic symptoms, abnormal growth velocity, or laboratory evidence of chronic illness or hypogonadism.^[1]^[29] In such cases, watchful waiting allows for natural progression of the hypothalamic-pituitary-gonadal axis, avoiding unnecessary interventions.^[33] Monitoring during observation involves regular follow-up every 6 months, including assessment of Tanner staging for secondary sexual characteristics, measurement of height and growth velocity, and repeat bone age evaluation if indicated.^[29]^[1] This schedule helps confirm ongoing progression toward spontaneous puberty while promptly identifying any deviation suggestive of pathologic causes. Patients and families should be educated on the normal variability in pubertal timing—typically breast development by age 13 in girls and testicular enlargement by age 14 in boys—and reassured that CDPG represents a self-limited condition without long-term health risks, thereby reducing anxiety and discouraging pursuit of unneeded diagnostic tests.^[29]^[33] Psychosocial support is integral, as delayed puberty can lead to diminished self-esteem, social isolation, or academic challenges due to peer discrepancies. Counseling focused on body image and emotional resilience, along with school accommodations such as extended timelines for physical education, can mitigate these effects.^[1] Data indicate that the vast majority of individuals with CDGP experience spontaneous pubertal onset by age 18, underscoring the favorable natural history.^[7] Observation is generally continued until age 16 in girls and 18 in boys, at which point lack of progression warrants further evaluation to distinguish CDPG from permanent hypogonadism. The use of low-dose "priming" sex steroid therapy remains controversial and is not routinely recommended in current guidelines, reserved instead for select cases with significant psychosocial burden.^[33] Outcomes for CDPG are excellent, with no adverse impact on fertility or adult height potential.^[1]^[29]

Treatment of Underlying Causes

Treatment of underlying causes in delayed puberty focuses on addressing reversible etiologies such as malnutrition, chronic diseases, and endocrine deficiencies to restore the hypothalamic-pituitary-gonadal (HPG) axis and enable spontaneous pubertal progression.^[1] Nutritional rehabilitation is essential for cases linked to malnutrition, including anorexia nervosa, where severe caloric restriction suppresses gonadotropin-releasing hormone (GnRH) pulsatility. Refeeding protocols typically begin with 1,200–1,500 kcal/day, increasing gradually by 200–300 kcal every 2–3 days to prevent refeeding syndrome, characterized by electrolyte shifts like hypophosphatemia.^[76] Micronutrient supplementation, particularly iron, zinc, and vitamins, addresses deficiencies that further impair growth. With weight restoration to at least 90% of ideal body weight, puberty often resumes within 3–6 months, as improved energy availability reactivates the HPG axis.^[39] For chronic gastrointestinal disorders, targeted management promotes catch-up growth and pubertal onset. In celiac disease, a strict gluten-free diet (GFD) corrects malabsorption and inflammation, leading to growth velocity normalization in many affected children with delayed puberty.^[77] Similarly, optimized therapy for inflammatory bowel disease (IBD), such as infliximab in Crohn's disease, reduces systemic inflammation and improves linear growth and pubertal timing, with early initiation yielding superior height gains and Tanner stage progression.^[78] In end-stage renal disease (ESRD), renal transplantation restores renal function and endocrine balance, often facilitating puberty initiation within a few years post-transplant in pediatric cases, though catch-up may be incomplete if pre-transplant duration exceeds 5 years.^[79] Endocrine corrections target specific deficiencies contributing to hypogonadotropic hypogonadism. Levothyroxine replacement for hypothyroidism normalizes thyroid hormone levels, thereby alleviating suppression of GnRH secretion and allowing pubertal progression; untreated cases show delayed bone age reversal within 6–12 months of therapy.^[80] For growth hormone (GH) deficiency, recombinant GH therapy accelerates linear growth and advances the onset of puberty by 1–2 years, enhancing overall HPG axis maturation without adverse effects on final height.^[81] Post-treatment monitoring involves serial laboratory evaluations, including gonadotropins (LH, FSH), sex steroids, and bone age assessments every 3–6 months, to confirm HPG axis recovery and guide discontinuation of interventions if spontaneous puberty ensues.^[1] Integrated multidisciplinary care models, encompassing endocrinologists, nutritionists, and gastroenterologists, have demonstrated resolution of delayed puberty without hormone replacement in about 70% of reversible cases.^[33]

Hormone Replacement Therapy

Hormone replacement therapy (HRT) is the cornerstone of management for permanent hypogonadotropic hypogonadism causing delayed puberty, involving exogenous administration of sex steroids to induce and sustain secondary sexual characteristics, promote growth, and support bone health. This approach is indicated after exclusion of reversible causes and confirmation of gonadotropin deficiency, aiming to mimic the natural tempo of puberty while preserving fertility potential where possible.^[82] In boys, therapy typically begins with low-dose intramuscular testosterone enanthate or cypionate at 25-50 mg monthly, escalating gradually by 50 mg increments every 6-12 months to reach adult replacement doses of 100-200 mg every 2-4 weeks. The goal is to achieve a linear growth velocity of 2-3 cm per year during early induction and progressive advancement through Tanner stages, including testicular enlargement, penile growth, and pubic hair development, without accelerating skeletal maturation excessively.^[33]^[83] For girls, induction starts with low-dose estrogen, preferably transdermal 17β-estradiol at 0.05-0.12 μg/kg daily (or oral equivalent of 0.25-0.5 mg daily), with doses doubled every 6-12 months over 2-3 years to promote breast development (targeting Tanner stage 2-5) and uterine growth. Cyclic progesterone, such as micronized progesterone 100-200 mg daily for 10-12 days monthly, is added after 2-3 years or upon breakthrough bleeding to induce withdrawal menses and protect the endometrium.^[84]^[82] According to Endocrine Society clinical practice recommendations, pubertal induction should commence at age 11-12 years for girls and 12-13 years for boys to align with typical pubertal onset and mitigate psychosocial impacts.^[82] Advanced options for idiopathic hypogonadotropic hypogonadism include pulsatile GnRH pump therapy to mimic physiologic gonadotropin release, administered subcutaneously at 5-25 ng/kg per pulse every 90-120 minutes, titrated to achieve target testosterone or estradiol levels. Experimental kisspeptin administration, investigated in phase 1 trials as of 2024, shows promise in stimulating GnRH neurons but remains investigational.^[33] Monitoring involves serial evaluations of growth velocity, Tanner staging, and bone age via hand X-ray every 6-12 months; dual-energy X-ray absorptiometry (DEXA) for bone mineral density annually; lipid profiles and hormone levels (e.g., testosterone 350-700 ng/dL mid-cycle) every 3-6 months; and fertility counseling, particularly for those desiring future reproduction via gonadotropin therapy. Doses must be titrated carefully to avoid supraphysiologic levels that could prematurely close epiphyses and stunt final height.^[33]^[83]^[84]

Prognosis

Short-term Outcomes

In cases of constitutional delay of growth and puberty (CDGP), the most common form of delayed puberty, spontaneous progression to full pubertal development typically occurs within a median duration of 2.1 years following onset, with over 90% of instances resolving without intervention as the condition is self-limited.^[85]^[86] Hormone replacement therapy, such as short courses of low-dose testosterone in boys or estrogen in girls, accelerates the initiation of puberty, with treatment durations commonly lasting 3 to 6 months, after which endogenous hormone production drives further maturation, often completing key pubertal changes within 6 to 12 months post-onset.^[87]^[88] Growth outcomes in treated and untreated CDGP patients generally align with genetic potential, achieving final heights close to the midparental target (typically within ±8 cm), as therapy prevents excessive delays in the pubertal growth spurt without compromising predicted adult stature.^[89]^[90] In boys receiving testosterone, the first-year height velocity improves significantly, supporting catch-up growth while maintaining bone age advancement in balance with height gain.^[91] Following induction therapy, menarche in girls with delayed puberty usually occurs 2 to 3 years after the onset of breast development, mirroring physiological timelines once estrogen replacement initiates thelarche.^[92] Similarly, in boys, testicular maturation progresses post-testosterone therapy, with testicular volume increasing to 6 to 8 mL signaling the resumption of central gonadotropin drive, leading to full spermatogenesis and secondary sexual characteristics within 2 to 3 years of induction.^[93] Complication rates from hormone therapy are minimal when using proper low-dose regimens; for instance, gynecomastia in boys on testosterone occurs in less than one-third of cases and is typically transient, resolving without intervention in most instances.^[94] Post-treatment psychosocial adjustment shows high satisfaction, with puberty-promoting therapy linked to positive improvements in health-related quality of life and reduced dissatisfaction with physical appearance.^[95]

Long-term Complications

Untreated delayed puberty, particularly when associated with hypogonadism, significantly compromises bone health in adulthood, increasing the risk of osteoporosis due to impaired peak bone mass acquisition during critical developmental windows. Studies indicate that hypogonadism contributes to 16% to 30% of male osteoporosis cases, with affected individuals exhibiting lower bone mineral density (BMD) and an elevated fracture risk (odds ratio: 1.76; 95% CI, 1.37-2.26). In cohorts with untreated hypogonadism, approximately 30% demonstrate low BMD, often with Z-scores below -2 at key sites like the lumbar spine and hip, reflecting substantial deficits compared to age-matched norms. Hormone replacement therapy improves BMD accrual, though evidence on reducing fracture incidence remains inconclusive.^[96] Fertility outcomes are profoundly impacted by delayed puberty stemming from primary hypogonadism, where testicular failure leads to azoospermia and infertility in nearly all cases without intervention, as spermatogenesis requires adequate gonadotropin stimulation that is absent in these conditions. In contrast, isolated hypogonadotropic hypogonadism (IHH), a common cause of secondary delayed puberty, responds better to gonadotropin therapy, achieving spermatogenesis in 70-80% of men and enabling assisted reproduction success rates of around 40-44% for clinical pregnancies via techniques like intracytoplasmic sperm injection. These interventions are crucial, as untreated primary forms, such as in Klinefelter syndrome, result in persistent infertility for the majority, underscoring the need for early diagnosis to preserve reproductive potential. Metabolic complications arise from untreated delayed puberty, with emerging evidence linking pubertal delays to heightened cardiovascular disease (CVD) risk through disrupted hormonal milieu and adiposity patterns. Untreated hypogonadism exacerbates this by promoting visceral fat accumulation and insulin resistance, thereby elevating long-term CVD morbidity independent of obesity status. Psychosocial sequelae of delayed puberty persist into adulthood, manifesting as elevated rates of anxiety and depression, with affected individuals reporting symptoms at approximately twice the general population prevalence (20% versus 10%). Longitudinal data reveal that perceived late pubertal timing correlates with heightened depressive symptoms, particularly in high-stress environments, due to body image dissatisfaction and social isolation during adolescence. Early therapeutic intervention, such as hormone replacement, attenuates these risks by aligning physical development with peers, thereby reducing the chronic psychological burden and improving overall mental health trajectories. Individuals with delayed puberty due to underlying genetic conditions like Klinefelter syndrome face an amplified risk of gonadal tumors, including seminomas, necessitating vigilant cancer surveillance. Men with Klinefelter syndrome exhibit a 19-fold increased likelihood of germ cell tumors compared to the general population, with extragonadal forms comprising about 5% of cases and intratesticular seminomas also elevated due to dysgenetic gonadal tissue. Regular screening, including ultrasound and tumor markers like AFP and beta-hCG, is recommended starting in adolescence to detect malignancies early, as timely orchiectomy can prevent progression while preserving hormonal management options.

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