Delayed Puberty Including Constitutional Delay: Differential and Outcome.

Constitutional delay of growth and puberty (CDGP) is the most common cause of delayed puberty in both male and female individuals. This article reviews the causes of delayed puberty focusing on CDGP, including new advances in the understanding of the genetics underpinning CDGP, a clinical approach to discriminating CDGP from other causes of delayed puberty, outcomes, as well as current and potential emerging management options.

Assessing hypothalamic pituitary gonadal function in reproductive disorders.

Reproductive conditions secondary to disorders of the hypothalamic-pituitary-gonadal (HPG) axis are common and are associated with important health implications and considerable psychosocial impact. Basal and dynamic tests enable interrogation of individual components of the HPG axis, facilitating diagnosis and understanding of the pathophysiology of reproductive disorders. Onset of puberty is controlled by hypothalamic gonadotrophin-releasing hormone (GnRH) neuronal function. To date, a dynamic test of hypothalamic function is not yet available. Therefore, accurate differentiation of pubertal disorders such as constitutional delay of growth and puberty (CDGP) and congenital hypogonadotrophic hypogonadism (CHH) as causes of delayed puberty is challenging due to similar clinical presentations and hormonal profiles. Likewise, although the two commonest reproductive disorders in women, polycystic ovary syndrome (PCOS) and functional hypothalamic amenorrhoea (FHA) have disparate hypothalamic function, oligo/amenorrhoea frequently poses a diagnostic conundrum owing to the overlap in the criteria used to define both conditions. This review aims to describe pubertal and reproductive disorders secondary to pathologies affecting the HPG axis. Challenges encountered in clinical practice in differentiating pubertal and reproductive conditions are reviewed in conjunction with the utility of baseline and dynamic endocrine tests to interrogate specific components of the HPG axis. We also highlight putative hypothalamic, pituitary, and gonadal markers in development that could improve the diagnosis of patients presenting with disorders of puberty or reproduction.

Insulin-like peptide 3 (INSL3) in congenital hypogonadotrophic hypogonadism (CHH) in boys with delayed puberty and adult men.

Background: Delayed puberty in males is almost invariably associated with constitutional delay of growth and puberty (CDGP) or congenital hypogonadotrophic hypogonadism (CHH). Establishing the cause at presentation is challenging, with "red flag" features of CHH commonly overlooked. Thus, several markers have been evaluated in both the basal state or after stimulation e.g. with gonadotrophin releasing hormone agonist (GnRHa).Insulin-like peptide 3 (INSL3) is a constitutive secretory product of Leydig cells and thus a possible candidate marker, but there have been limited data examining its role in distinguishing CDGP from CHH. In this manuscript, we assess INSL3 and inhibin B (INB) in two cohorts: 1. Adolescent boys with delayed puberty due to CDGP or CHH and 2. Adult men, both eugonadal and having CHH. Materials and methods: Retrospective cohort studies of 60 boys with CDGP or CHH, as well as 44 adult men who were either eugonadal or had CHH, in whom INSL3, INB, testosterone and gonadotrophins were measured. Cohort 1: Boys with delayed puberty aged 13-17 years (51 with CDGP and 9 with CHH) who had GnRHa stimulation (subcutaneous triptorelin 100mcg), previously reported with respect to INB. Cohort 2: Adult cohort of 44 men (22 eugonadal men and 22 men with CHH), previously reported with respect to gonadotrophin responses to kisspeptin-54. Results: Median INSL3 was higher in boys with CDGP than CHH (0.35 vs 0.15 ng/ml; p=0.0002). Similarly, in adult men, median INSL3 was higher in eugonadal men than CHH (1.08 vs 0.05 ng/ml; p<0.0001). However, INSL3 more accurately differentiated CHH in adult men than in boys with delayed puberty (auROC with 95% CI in adult men: 100%, 100-100%; boys with delayed puberty: 86.7%, 77.7-95.7%).Median INB was higher in boys with CDGP than CHH (182 vs 59 pg/ml; p<0.0001). Likewise, in adult men, median INB was higher in eugonadal men than CHH (170 vs 36.5 pg/ml; p<0.0001). INB performed better than INSL3 in differentiating CHH in boys with delayed puberty (auROC 98.5%, 95.9-100%), than in adult men (auROC 93.9%, 87.2-100%). Conclusion: INSL3 better identifies CHH in adult men, whereas INB better identifies CHH in boys with delayed puberty.

Health-related quality of life in boys with constitutional delay of growth and puberty.

Introduction: Constitutional delay of growth and puberty (CDGP) is the most common reason for delayed puberty in healthy male adolescents. The main indication for medical treatment for this condition is psychosocial burden. However, to the best of our knowledge, no previous study has addressed the impact of puberty-promoting treatment on health-related quality of life (HRQoL) among boys with CDGP. Methods: We investigated HRQoL in 22 boys with CDGP, who participated in a randomized controlled trial in four Finnish pediatric endocrinology outpatient clinics between 2013 and 2017. The boys were randomized to receive either aromatase inhibitor letrozole (2.5mg/day; n=11) or intramuscular testosterone (1mg/kg/every 4 weeks; n=11) for 6 months and followed up to 12 months. HRQoL was assessed with a generic self-assessment 16D© instrument developed and validated for adolescents aged 12 to 15 years. The 16D includes 16 dimensions (vitality, sight, breathing, distress, hearing, sleeping, eating, discomfort and symptoms, speech, physical appearance, school and hobbies, mobility, friends, mental function, excretion and depression). The results were compared with an age-matched reference population that included 163 boys from the Finnish capital-city area. The study protocol is registered to ClinicalTrials.gov (registration number: NCT01797718). Results: At baseline, the mean 16D score of the CDGP boys was similar to the age-matched reference population (0.95 vs 0.96, p=0.838). However, the physical appearance score (satisfaction with general appearance, height and weight) was significantly lower in the CDGP boys (0.75 vs 0.92, p=0.004) than their peers. Twelve months after treatment, Appearance had improved significantly (0.75 vs 0.87, p=0.004) and no HRQoL dimension was inferior compared to the age-matched reference population. Discussion: In terms of HRQoL, the main impact of delayed puberty was dissatisfaction with physical appearance. Puberty promoting therapy was associated with a positive change in perceived appearance, with no clear difference between low-dose testosterone and letrozole treatments.

Recovery of hypothalamic-pituitary-gonadal function with low dose testosterone treatment in a male with congenital hypogonadotropic hypogonadism.

Congenital hypogonadotropic hypogonadism (CHH) is a rare disease caused by deficiency or action of gonadotropin-releasing hormone. While generally considered a long-life condition, CHH can be reversible in about 5%-20% of cases, but mechanisms of reversibility are unknown. We report the case of a male with CHH who began treatment with low dose (20 mg/day) transdermal testosterone to induce pubertal development at age 17. Following the start of treatment, he experienced testicular growth and his serum testosterone concentrations increased beyond the expectations in relation to the dose. Treatment was withdrawn, but this led to the reappearance of symptoms of hypogonadism and a drop in testosterone levels. Testosterone was again prescribed at the same dose and, for the subsequent years, he completed full puberty, including attainment of 20 cc testicular volume, mature secondary sexual characteristics, normal levels of testosterone and only partially arrested germinal function, as demonstrated by inhibin B levels and spermogram. Testosterone treatment was withdrawn three more times, but hypogonadism resumed on each occasion. This case suggests that low-dose testosterone treatment can induce reversal of CHH through the activation, albeit non-permanent, of the hypothalamic-pituitary-gonadal axis, indicating that testosterone administration might be a reliable therapeutic option for reverting GnRH deficiency.

Considerations when treating male pubertal delay pharmacologically.

INTRODUCTION: Delayed puberty , usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most of the patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness. AREAS COVERED: The etiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review. EXPERT OPINION: High-quality evidence addressing the best pharmacological therapy approach for each etiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experience. Male teenagers seeking attention for pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years . When hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years . Testosterone replacement has been used for decades and is fairly standardized. Aromatase inhibitors have arisen as an interesting alternative . Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its efficacy and timing still need to be established.

Efficacy of short-term induction therapy with low-dose testosterone as a diagnostic tool in the workup of delayed growth and puberty in boys.

PURPOSE: Constitutional delay of growth and puberty (CDGP) represents the most frequent cause of delayed puberty in males, sharing some clinical features with growth hormone deficiency (GHD) and isolated hypogonadotropic hypogonadism (IHH). Short-term induction therapy (SIT) has been approved for the induction of puberty in CDGP. We aim to investigate the efficacy of SIT with transcutaneous testosterone gel (TTG) or intramuscular testosterone therapy (IMTT) in a cohort of CDGP subjects, compared to clinical observation. Furthermore, we aim to evaluate the role of SIT as a diagnostic tool to differentiate CDGP from GHD and IHH subjects. METHODS: The retrospective study included 246 male subjects with delayed puberty. The study population was divided into three groups: TTG, IMTT, and control group (CNT). RESULTS: At 6 months observation, height velocity (HV) was significantly increased in both treated groups compared to CNT group, particularly higher in TTG than IMTT group. A significant testicular enlargement was revealed in both CNT and TTG group compared to IMTT group. Furthermore, LH value was significantly greater in TTG compared to IMTT group. IGF-1 values after SIT rose significantly in both treated groups compared to CNT group. Moreover, almost all GH provocative tests performed after SIT showed a normal GH response. CONCLUSION: SIT with TTG appears to be more effective to induce growth spurt, better tolerated and with a more physiological effect on pubertal induction compared to IMTT in CDGP population. Finally, TTG might be a useful tool in the diagnostic work up to discriminate CDGP from GHD or IHH.

Constitutional delay of growth and puberty in female mice is induced by circadian rhythm disruption in utero.

Constitutional delay of growth and puberty (CDGP) refers to the late onset of puberty. CDGP is associated with poor psychosocial outcomes and elevated risk of cardiovascular and osteoporotic diseases, especially in women. The environmental factors that contribute to CDGP are poorly understood. Here, we investigated the effects of chronic circadian disturbance (CCD) during the fetal stage on the pubertal development of female mice. Compared to non-stressed female (NS-F) mice that were not exposed to CCD in utero, adolescent CCD female (CCD-F) mice exhibited phenotypes that were consistent with CDGP, including lower body weight, reduced levels of circulating gonadal hormones, decreased expression of gonadal hormones and steroid synthesis-related enzymes in the ovary and hypothalamus, irregular estrus cycles, and tardive vaginal introitus initial opening (VO) days (equivalent to the menarche). Phenotypic differences in the above-noted parameters were not observed in CCD-F mice once they had reached adulthood. The expression of genes involved in fatty acid metabolism was perturbed in the ovary and hypothalamus of CCD-F mice. In addition, the ovaries of these animals exhibited altered diurnal expression profiles of circadian clock genes. Together, our findings not only suggest that CCD during fetal development may result in delayed puberty in female mice, they also offer insights on potential mechanisms that underlie CDGP.

Growth variations with opposite clinical outcomes and the emerging role of IGF-1.

Normal growth pattern variations [i.e., constitutional advancement and constitutional delay of growth and puberty (CAGP and CDGP)] are the mirror image of each other and are associated with early puberty (EP) and delayed puberty (DP), respectively. Differences between CAGP and CDGP relate not only to auxological characteristics (height, weight) but also to insulin-like growth factor-1 (IGF-1). IGF-1 levels in CAGP are above average whereas in CDGP they are below average, suggesting a role for IGF-1 in the induction of these growth patterns. Herein, we provide data suggesting that early activation of the growth hormone (GH)/IGF-1 axis induces the growth pattern of CAGP. Moreover, we suggest that IGF-1 is a decisive factor for the release of the gonadotropin-releasing hormone (GnRH) inhibition brake that occurs in prepuberty. It is therefore crucial for puberty onset.

Current clinical management of constitutional delay of growth and puberty.

BACKGROUND: Constitutional delay of growth and puberty (CDGP) is classified as the most frequent cause of delayed puberty (DP). Finding out the etiology of DP during first evaluation may be a challenge. In details, pediatricians often cannot differentiate CDGP from permanent hypogonadotropic hypogonadism (PHH), with definitive diagnosis of PHH awaiting lack of puberty by age 18 yr. Neverthless, the ability in providing a precise and tempestive diagnosis has important clinical consequences. MAIN TEXT: A growth failure in adolescents with CDGP may occur until the onset of puberty; after that the growth rate increases with rapidity. Bone age is typically delayed. CDGP is generally a diagnosis of exclusion. Nevertheless, other causes of DP must be evaluated. A family history including timing of puberty in the mother and in the father as well as physical examination may givee information on the cause of DP. Patients with transient delay in hypothalamic-pituitary-gonadal axis maturation due to associated conditions, such as celiac disease, inflammatory bowel diseases, kidney insufficiency and anorexia nervosa, may experience a functional hypogonadotropic hypogonadism. PHH revealing testosterone or estradiol low serum values and reduced FSH and LH levels may be connected to abnormalities in the central nervous system. So, magnetic resonance imaging is required in order to exclude either morphological alterations or neoplasia. If the adolescent with CDGP meets psychological difficulties, treatment is recommended. CONCLUSION: Even if CDGP is considered a variant of normal growth rather than a disease, short stature and retarded sexual development may led to psychological problems, sometimes associated to a poor academic performance. A prompt and precise diagnosis has an important clinical outcome. Aim of this mini-review is throwing light on management of patients with CDGP, emphasizing the adolescent diagnosis and trying to answer all questions from paediatricians.

An Approach to the Patient With Delayed Puberty.

Pediatric endocrinologists often evaluate and treat youth with delayed puberty. Stereotypically, these patients are 14-year-old young men who present due to lack of pubertal development. Concerns about stature are often present, arising from gradual shifts to lower height percentiles on the population-based, cross-sectional curves. Fathers and/or mothers may have also experienced later than average pubertal onset. In this review, we will discuss a practical clinical approach to the evaluation and management of youth with delayed puberty, including the differential diagnosis and key aspects of evaluation and management informed by recent review of the existing literature. We will also discuss scenarios that pose additional clinical challenges, including: (1) the young woman whose case poses questions regarding how presentation and approach differs for females vs males; (2) the 14-year-old female or 16-year-old young man who highlight the need to reconsider the most likely diagnoses, including whether idiopathic delayed puberty can still be considered constitutional delay of growth and puberty at such late ages; and finally (3) the 12- to 13-year-old whose presentation raises questions about whether age cutoffs for the diagnosis and treatment of delayed puberty should be adjusted downward to coincide with the earlier onset of puberty in the general population.

Etiological Profile of Short Stature in Children and Adolescents.

CONTEXT: The delayed growth of a child is a major cause of concern for the parents. There is a multitude of etiological factors which must be considered in relation to this common aspect of healthcare. AIM: The study was done to evaluate the etiological profile of short stature in children and adolescents. SETTINGS AND DESIGN: The cross-sectional study was conducted for 12 months including 111 cases of short stature (out of the 1,058 cases screened), at the endocrinology outpatient department (OPD) of a tertiary care institute in Haryana. SUBJECTS AND METHODS: As per the inclusion criteria, cases with age <18 years were enrolled. The examination and anthropometric measurements were performed in the presence of parents/guardians. RESULTS: Out of the 1,058 cases screened; 111 cases of short stature were recruited as per the inclusion and exclusion criteria. The prevalence was about 10.49% of the total population. The mean age of the sample was 12.34 ± 3.19 years. The endocrine causes were the most common followed by normal variants of growth and delay, chronic systemic illness, and nutritional and skeletal causes. Among the endocrine causes, hypothyroidism was the most common followed by growth hormone deficiency and type 1 diabetes mellitus (T1DM). CONCLUSIONS: The mean chronological age of 12.34 ± 3.19 years suggests the delayed detection of short stature in the population. This highlights the importance of educating parents so that timely therapeutic intervention can be done to achieve the potential height.

Serum inhibin B for differentiating between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty: a systematic review and meta-analysis.

PURPOSE: The distinction between congenital hypogonadotropic hypogonadism (CHH) and constitutional delay of growth and puberty (CDGP) in patients with delayed puberty is difficult to distinguish, but important for timely treatment. The aim of this study is to perform a systematic review and meta-analysis to determine the diagnostic performance of serum inhibin B (INHB) levels for differentiating CHH and CDGP. METHODS: PubMed, EMBASE, and Cochrane Library databases were systematically searched from the date of database inception to November 10, 2019 for studies examining the use of serum INHB to discriminate between CHH and CDGP. Pooled odds ratios (OR), sensitivity, specificity, and 95% confidence intervals (CI) were calculated. The Quality Assessment of Diagnostic Studies-2 (QUADAS-2) was used to assess the quality of the included studies. Sub-analyses were performed including that based on testicular volume (TV) and study design. RESULTS: Seven studies, comprising of 349 patients (96 CHH and 253 CDGP), were included in the meta-analysis. For differentiating between CHH and CDGP, INHB level exhibited good diagnostic accuracy with a pooled sensitivity of 92% (95% confidence interval [CI]: 0.86-0.96, I2 = 0.4%, p = 0.4343), specificity of 92% (95% CI: 0.88-0.94, I2 = 68.1%, p = 0.0009), and pooled area under the receiver operating characteristic curve (AUC) of 0.9619. The cut-off values of INHB for boys were 56, 66, 80, 96, 94.7, 111, and 113 pg/ml (assay method standardized to Gen II ELISA). Sub-analyses showed that testicular volume and study design could be a source of statistically significant heterogeneity in specificity. In boys with a testicular volume of ≤3 ml, INHB performed well with a sensitivity of 92%, specificity of 98%, and AUC of 0.9956. CONCLUSION: INHB exhibits excellent diagnostic efficiency in distinguishing CHH from CDGP, especially in boys with severe puberty deficiency (TV ≤ 3 ml).

ENDO-ERN expert opinion on the differential diagnosis of pubertal delay.

The differential diagnoses of pubertal delay include hypergonadotropic hypogonadism and congenital hypogonadotropic hypogonadism (CHH), as well as constitutional delay of growth and puberty (CDGP). Distinguishing between CDGP and CHH may be challenging, and the scientific community has been struggling to develop diagnostic tests that allow an accurate differential diagnosis. Indeed, an adequate and timely management is critical in order to enable optimal clinical and psychosocial outcomes of the different forms of pubertal delays. In this review, we provide an updated insight on the differential diagnoses of pubertal delay, including the available tests, their meanings and accuracy, as well as some clues to effectively orientate towards either constitutional pubertal delay or pathologic CHH and hypergonadotropic hypogonadism.

ESR1 gene polymorphism (rs827421) as a potential genetic marker for constitutional delay of growth and puberty in Egyptian adolescents.

Constitutional delay of growth and puberty (CDGP) is a variant of normal pubertal timing and progress. It is the most common form of delayed puberty in both genders. The genetic director of CDGP is ill-understood despite the positive family history result noted in those patients. The current study aimed at assessing the role of estrogen receptor 1 (ESR1) gene variant (rs827421) in Egyptian adolescents with CDGP. A cross-sectional study with follow-up part was carried out on 6760 children aged 4 to15 years. The study focused generally on children aged 13-15 years in order to evaluate the prevalence of delayed puberty in relation to all ages in general and to their peers in specific. Assessment of serum TSH, FSH, and LH was conducted on all participants, along with the measurement of serum-free testosterone for males and estradiol for females. Genotyping of ESR1 (rs827421) was done to all subjects through the use of TaqMan discrimination assay by real-time PCR. ESR1 (rs827421) GG genotype and G allele were significantly dominant among CDGP adolescents in comparison with controls (OR = 25.67 and 6.90). As regards follow-up of testicular size, AA genotype was significantly associated with increased size in the right and left testis compared to other genotypes (P = 0.021 and 0.006, respectively). Moreover, AA genotype showed significantly higher Tanner stage in both males and females in comparison with other genotypes. Serum estradiol level was significantly higher in AA genotype group than other genotypes groups. ESR1 gene polymorphism can be considered a potential genetic marker for CDGP in both sexes in a sample of Egyptian adolescents.

Clinical benefits of sex steroids given as a priming prior to GH provocative test or as a growth-promoting therapy in peripubertal growth delays: Results of a retrospective study among ENDO-ERN centres.

OBJECTIVES: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP. DESIGN: Retrospective study among three paediatric University Hospitals in Italy and UK. METHODS: 184 children (72 females) aged 12.4 ± 2.08 years underwent primed (/P+ ) or unprimed (/P- ) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P- ) or received LDSS (CDGP+ ). The cohort included 34 CDG P- /P+ , 12 CDGP+ /P+ , 51 GHD/P+ , 29 CDG P- /P- , 2 CDGP+ /P- and 56 GHD/P- . FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (-1 ≤ Δ SDS FH-SDS TH ≤ +1) were outcomes of interest. RESULTS: GHD/P+ had better FH-SDS (-0.87 vs -1.49; P = .023) and ΔSDS FH-TH (-0.35 vs -0.77; P = .002) than CDGP- /P+ . Overall, GHD/P+ showed the highest degree of success (90%, P = .006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P = .0009). GHD/P+ showed a trend towards a higher proportion of permanent GHD compared to GHD/P- (30.43% vs 15.09%; P = .067). CONCLUSION: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP.

Anti-Müllerian hormone and letrozole levels in boys with constitutional delay of growth and puberty treated with letrozole or testosterone.

STUDY QUESTION: Does treatment of constitutional delay of growth and puberty (CDGP) in boys with aromatase inhibitor letrozole (Lz) or conventional low-dose testosterone (T) have differing effects on developing seminiferous epithelium? SUMMARY ANSWER: Anti-Müllerian hormone (AMH) declined similarly in both treatment groups, and the two Sertoli cell-derived markers (AMH and inhibin B (iB)) exhibited differing responses to changes in gonadotrophin milieu. WHAT IS KNOWN ALREADY: Boys with CDGP may benefit from puberty-inducing medication. Peroral Lz activates gonadotrophin secretion, whereas intramuscular low-dose T may transiently suppress gonadotrophins and iB. STUDY DESIGN, SIZE, DURATION: Sera of 28 boys with CDGP who participated in a randomised, controlled, open-label trial at four paediatric centres in Finland between August 2013 and January 2017 were analysed. The patients were randomly assigned to receive either Lz (2.5 mg/day) (n = 15) or T (1 mg/kg/month) (n = 13) for 6 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 28 patients were at least 14 years of age, showed first signs of puberty, wanted medical attention for CDGP and were evaluated at 0, 3, 6 and 12 months of visits. AMH levels were measured with an electrochemiluminescence immunoassay and Lz levels with liquid chromatography coupled with tandem mass spectrometry. MAIN RESULTS AND THE ROLE OF CHANCE: AMH levels decreased in both treatment groups during the 12-month follow-up (P < 0.0001). Between 0 and 3 months, the changes in gonadotrophin levels (increase in the Lz group, decrease in the T group) correlated strongly with the changes in levels of iB (FSH vs iB, r = 0.55, P = 0.002; LH vs iB, r = 0.72, P < 0.0001), but not with the changes in AMH (P = NS). At 12 months, AMH levels did not differ between the groups (P = NS). Serum Lz levels (range, 124-1262 nmol/L) were largely explained by the Lz dose per weight (at 3 months r = 0.62, P = 0.01; at 6 months r = 0.52, P = 0.05). Lz levels did not associate with changes in indices of hypothalamic-pituitary-gonadal axis activity or Sertoli cell markers (in all, P = NS). LIMITATIONS, REASONS FOR CAUTION: The original trial was not blinded for practical reasons and included a limited number of participants. WIDER IMPLICATIONS OF THE FINDINGS: In early puberty, treatment-induced gonadotrophin stimulus was unable to counteract the androgen-mediated decrease in AMH, while changes in iB levels were associated with changes in gonadotrophin levels. AMH decreased similarly in both groups during the treatment, reassuring safety of developing seminiferous epithelium in both treatment approaches. Since a fixed dose of Lz induced variable serum Lz levels with a desired puberty-promoting effect in all boys, more research is needed to aim at a minimal efficient dose per weight. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Academy of Finland, the Foundation for Pediatric Research, the Emil Aaltonen Foundation, Sigrid Juselius Foundation and Helsinki University Hospital Research Funds. The authors have nothing to disclose. TRIAL REGISTRATION NUMBER: NCT01797718.

The Genetic Basis of Delayed Puberty.

Delayed pubertal onset has many etiologies, but on average two-thirds of patients presenting with late puberty have self-limited (or constitutional) delayed puberty. Self-limited delayed puberty often has a strong familial basis. Segregation analyses from previous studies show complex models of inheritance, most commonly autosomal dominant, but also including autosomal recessive, bilineal, and X-linked. Sporadic cases are also observed. Despite this, the neuroendocrine mechanisms and genetic regulation remain unclear in the majority of patients with self-limited delayed puberty. Only rarely have mutations in genes known to cause aberrations of the hypothalamic-pituitary-gonadal axis been identified in cases of delayed puberty, and the majority of these are in relatives of patients with congenital hypogonadotropic hypogonadism (CHH), for example in the FGFR1 and GNRHR genes. Using next generation sequencing in a large family with isolated self-limited delayed puberty, a pathogenic mutation in the CHH gene HS6ST1 was found as the likely cause for this phenotype. Additionally, a study comparing the frequency of mutations in genes that cause GnRH deficiency between probands with CHH and probands with isolated self-limited delayed puberty identified that a significantly higher proportion of mutations with a greater degree of oligogenicity were seen in the CHH group. Mutations in the gene IGSF10 have been implicated in the pathogenesis of familial late puberty in a large Finnish cohort. IGSF10 disruption represents a fetal origin of delayed puberty, with dysregulation of GnRH neuronal migration during embryonic development presenting for the first time in adolescence as late puberty. Some patients with self-limited delayed puberty have distinct constitutional features of growth and puberty. Deleterious variants in FTO have been found in families with delayed puberty with extremely low BMI and maturational delay in growth in early childhood. Recent exciting evidence highlights the importance of epigenetic up-regulation of GnRH transcription by a network of miRNAs and transcription factors, including EAP1, during puberty. Whilst a fascinating heterogeneity of genetic defects have been shown to result in delayed and disordered puberty, and many are yet to be discovered, genetic testing may become a realistic diagnostic tool for the differentiation of conditions of delayed puberty.