Constitutional Delay Of Growth And Puberty Research Articles

Bone structure assessed with pQCT in prepubertal males with delayed puberty or congenital hypogonadotropic hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is associated with impaired bone mineral density in adulthood, whereas the estimates on bone structure in adolescents with CHH has not been previously evaluated. This study describes bone structure in CHH patients and compares it to that in boys with constitutional delay of growth and puberty (CDGP). A cross-sectional study. Peripheral quantitative computed tomography (pQCT) of non-dominant arm and left leg were performed. Volumetric bone mineral density (BMD), bone mineral content, and area in trabecular and cortical bone compartments were evaluated, and bone age-adjusted Z-scores for the bone parameters were determined. The participants with CHH had more advanced bone age and were older, taller and heavier than the CDGP boys, yet they had lower trabecular BMD in distal radius (147.7mg/mm3 [95% CI, 128-168mg/mm3 ] vs. 181.2mg/mm3 [172-192mg/mm3 ], p=.002) and distal tibia (167.6mg/mm3 [145-190mg/mm3 ] vs. 207.2mg/mm3 [187-227mg/mm3 ], p=.012), respectively. CHH males had lower cortical thickness at diaphyseal tibia than the participants with CDGP (p=.001). These between-group differences remained significant in corresponding Z-scores adjusted for bone age and height (p=.001). In CDGP group, serum testosterone correlated positively with trabecular BMD (r=0.51, p=.013) at distal radius, and estradiol levels correlated positively with trabecular BMD at the distal site of tibia (r=0.58, p=.004). Five treatment-naïve male patients with CHH exhibited poorer trabecular BMD than untreated males with CDGP. We speculate that timely low-dose sex steroid replacement in CHH males may benefit skeletal health in adulthood.

Circulating miR-30b levels increase during male puberty.

The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

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.

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

PurposeThe 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.MethodsPubMed, 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.ResultsSeven 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.ConclusionINHB exhibits excellent diagnostic efficiency in distinguishing CHH from CDGP, especially in boys with severe puberty deficiency (TV ≤ 3 ml).

Качество жизни мальчиков-подростков с конституциональной задержкой роста и пубертата до и после различных вариантов лечения

Objective. To compare the quality of life of adolescents with constitutional delay of growth and puberty (CDGP) before and after hormonal therapy. Patients and methods. This prospective single-center study had two stages. At the first stage, we evaluated the quality of life of 67 boys diagnosed with CDGP (experimental group) and 30 healthy boys of the same age (control group) using the Pediatric Quality of Life Inventory – PedsQL™ 4.0. At the second stage, we performed repeated assessment of the quality of life of CDGP boys after medical stimulation of puberty. Results. We found that delayed sexual development and progressive stunting in boys with CDGP was associated with a significant decrease in the quality of life by all functional scales compared to their healthy peers. We observed significant differences between the subgroups upon the repeated assessment 6 months after treatment completion. Conclusion. Timely initiation of pharmacotherapy to start puberty improves the quality of life. Short courses of androgens were found to be the most effective treatment in adolescents with CDGP according to their dynamics of sexual development and quality of life. Keywords: androgens, quality of life, constitutional delay of growth and puberty (CDGP)

Delayed puberty.

The onset of puberty may be late - in the latter part of the predicted normal range or truly delayed - beyond this range. The latest age to start is usually regarded as 13 years in girls and 14 years in boys. There may also be a delayed completion of puberty, 16 years in girls and 17 years in boys. The initial approach requires a detailed history and clinical examination to exclude other medical or psychological problems. The presence or absence or pubertal signs should be documented. Investigations should be targeted at ruling out any medical causes and determining whether the delay is due to central gonadotropin deficiency (hypogonadotropic hypogonadism) or a gonadal disorder (hypergonadotropic hypogonadism). Physiological or constitutional delay of growth and puberty (CDGP) is more common in boys but is a diagnosis of exclusion. Current research suggests that CDGP and congenital hypogonadotropic hypogonadism have distinct genetic profiles which may aid in the differential diagnosis. Treatment may be given using low doses of sex steroids, testosterone or estradiol initially in a short course of 3-6 months but continuing in escalating doses mimicking the normal course of puberty, watching regularly for the spontaneous resumption of progress and gonadotropin secretion. In gonadotropin deficiency, sex hormone treatment needs to be continued until completion of pubertal development and growth. Counselling, reassurance and support are key elements in the management of adolescents with delayed puberty.

Readdressing Short Stature in India: The "Long and the Short" of it.

Readdressing Short Stature in India: The "Long and the Short" of it.

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.

Adolescent boys with constitutional delay of growth and puberty grow faster than patients with organic growth hormone deficiency.

Constitutional delay of growth and puberty (CDGP) is a tempo variant with a good prognosis. Healthy late-maturing adolescents grow slower than postulated by age-related references, and therefore, CDGP is frequently confused with growth hormone deficiency (GHD). For differential diagnosis, height velocity references for CDGP are needed. Here, we provide height velocity data for late-maturing boys based on mixed longitudinal and cross-sectional observations in a group of 38 German adolescents with proven CDGP and compare them with cross-sectional observations in a group of 164 adolescents with organic GHD from the National Cooperative Growth Study registry. In the critical age interval from 13.4 to 14.9years, the growth of prepubertal adolescents with CDGP was faster (mean/median height velocity, 5.2/5.4cm/years; quartiles, 4.4-6.2cm/years) than that of prepubertal adolescents with organic GHD (3.5/3.2cm/years; quartiles, 2.0-4.4cm/years) in the cross-sectional analysis (p<.0001). Based on our mixed longitudinal and cross-sectional analysis, the height velocity of adolescent boys with CDGP exceeded previous model calculations on average by 1.0cm. In conclusion, prepubertal adolescents with CDGP grow faster than patients with organic GHD. Previous model estimates underestimated height velocity of boys with CDGP.

Testosterone Use in Adolescent Males: Current Practice and Unmet Needs.

Testosterone replacement therapy (TRT) is routinely prescribed in adolescent males with constitutional delay of growth and puberty (CDGP) or hypogonadism. With many new testosterone (T) formulations entering the market targeted for adults, we review current evidence and TRT options for adolescents and identify areas of unmet needs. We searched PubMed for articles (in English) on testosterone therapy, androgens, adolescence, and puberty in humans. The results indicate that short-term use of T enanthate (TE) or oral T undecanoate is safe and effective in inducing puberty and increasing growth in males with CDGP. Reassuring evidence is emerging on the use of transdermal T to induce and maintain puberty. The long-term safety and efficacy of TRT for puberty completion and maintenance have not been established. Current TRT regimens are based on consensus and expert opinion, but evidence-based guidelines are lacking. Limited guidance exists on when and how T should be administered and optimal strategies for monitoring therapy once it is initiated. Only TE and T pellets are US Food and Drug Administration approved for use in adolescent males in the United States. Despite the introduction of a wide variety of new T formulations, they are designed for adults, and their metered doses are difficult to titrate in adolescents. In conclusion, TRT in adolescent males is hindered by lack of long-term safety and efficacy data and limited options approved for use in this population. Additional research is needed to identify the route, dose, duration, and optimal timing for TRT in adolescents requiring androgen therapy.

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-Mullerian 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 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.

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.

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. Retrospective study among three paediatric University Hospitals in Italy and UK. 184 children (72 females) aged 12.4±2.08years 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. 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). In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP.

GnRH stimulation testing and serum inhibin B in males: insufficient specificity for discriminating between congenital hypogonadotropic hypogonadism from constitutional delay of growth and puberty.

Are GnRH tests and serum inhibin B levels sufficiently discriminating to distinguish transient constitutional delay of growth and puberty (CDGP) from congenital hypogonadotropic hypogonadism (CHH) that affects reproductive health for life? Both parameters lack the specificity to discriminate CDGP from CHH. GnRH tests and inhibin B levels have been proposed to differentiate CDGP from CHH. However, their diagnostic accuracies have been hampered by the small numbers of CHH included and enrichment of CHH patients with more severe forms. The aim of this study was to assess the diagnostic performance of GnRH tests and inhibin B measurements in a large cohort of CHH male patients with the whole reproductive spectrum. From 2008 to 2018, 232 males were assessed: 127 with CHH, 74 with CDGP and 31 healthy controls. The participants were enrolled in two French academic referral centres. The following measurements were taken: testicular volume (TV), serum testosterone, inhibin B, LH and FSH, both at baseline and following the GnRH test. Among CHH patients, the LH response to the GnRH test was very variable and correlated with TV. Among CDGP patients, the LH peak was also variable and 47% of CHH patients had peak LH levels overlapping with the CDGP group. However, no patients with CDGP had an LH peak below 4.0 IU/l, while 53% CHH patients had LH peak below this threshold. Among CHH patients, inhibin B levels were also variable and correlated with TV and peak LH. Inhibin B was significantly lower in CHH patients than in CDGP patients but 50% of CHH values overlapped with CDGP values. Interestingly, all patients with CDGP had inhibin B levels above 35 pg/ml but 50% of CHH patients also had levels above this threshold. As CHH is very rare, an international study would be necessary to recruit a larger CHH cohort and consolidate the conclusion reached here. Peak LH and basal inhibin B levels are variable in both CHH and CDGP with significant overlap. Both parameters lack specificity and sensitivity to efficiently discriminate CHH from CDGP. This reflects the varying degree of gonadotropin deficiency inherent to CHH. These two diagnostic procedures may misdiagnose partial forms of isolated (non-syndromic) CHH, allowing them to be erroneously considered as CDGP. This study was funded by Agence Française de Lutte contre le Dopage: Grant Hypoproteo AFLD-10 (to J.Y.); Agence Nationale de la Recherche (ANR): Grant ANR-09-GENO-017-01 (to J.Y.); European Cooperation in Science and Technology, COST Action BM1105; Programme Hospitalier de Recherche Clinique (PHRC), French Ministry of Health: PHRC-2009 HYPO-PROTEO (to J.Y.); and Programme Hospitalier de Recherche Clinique (PHRC) "Variété", French Ministry of Health, N° P081216/IDRCB 2009-A00892-55 (to P.C.). There are no competing interests. N/A.

Longitudinal Increases in Serum Insulin-like Factor 3 and Testosterone Determined by LC-MS/MS in Pubertal Danish Boys.

Serum concentrations of the peptide hormone insulin-like factor 3 (INSL3) is a candidate marker for improved distinction between constitutional delay of growth and puberty (CDGP) and permanent hypogonadotropic hypogonadism (HH) in boys. To assess the possible diagnostic role of LC-MS/MS-based INSL3 measurements as a marker of imminent puberty by comparison with testosterone (T) and luteinizing hormone (LH) levels in serum longitudinally collected from 18 healthy boys throughout puberty. The first increase in serum LH was detected on average 4 months earlier, as compared with the first observed increases in INSL3 and T. When comparing the 2 testicular hormones only, we found that in 22% (4 of 18) of the boys the first increase in serum INSL3 was observed prior to the first observed increase in T, whereas in 44% (8 of 18) the first increase in T was observed before the first observed increase in INSL3. In the remaining 6 boys, the 2 testicular hormones showed the first increase at the same examination. In some boys with delayed puberty, the first indication of testicular maturation may be detectable by observing serum INSL3. Further studies of LC-MS/MS determination of serum INSL3 in patients with CDGP and HH are warranted.

Differential diagnosis between constitutional delay of growth and puberty, idiopathic growth hormone deficiency and congenital hypogonadotropic hypogonadism: a clinical challenge for the pediatric endocrinologist

Differential diagnosis between constitutional delay of growth and puberty (CDGP), partial growth hormone deficiency (pGHD) and congenital hypogonadotropic hypogonadism (cHH) may be difficult. All these conditions usually present with poor growth in pre- or peri-pubertal age and they may recur within one familial setting, constituting a highly variable, but somehow common, spectrum of pubertal delay. Narrative review of the most relevant English papers published between 1981 and march 2020 using the following search terms "constitutional delay of growth and puberty," "central hypogonadism," "priming," "growth hormone deficiency," "pituitary," "pituitary magnetic resonance imaging," with a special regard to the latest scientific acquisitions. CDGP is by far the most prevalent entity in boys and recurs within families. pGHD is a rare, often idiopathic and transient condition, where hypostaturism presents more severely. Specificity of pGHD diagnosis is increased by priming children before growth hormone stimulation test (GHST); pituitary MRI and genetic analysis are recommended to personalize future follow-up. Diagnosing cHH may be obvious when anosmia and eunuchoid proportions concomitate. However, cHH can either overlap with pGHD in forms of multiple pituitary hormone deficiencies (MPHD) or syndromic conditions either with CDGP in family pedigrees, so endocrine workup and genetic investigations are necessary. The use of growth charts, bone age, predictors of adult height, primed GHST and low dose sex steroids (LDSS) treatment are recommended. Only a step-by-step diagnostic process based on appropriate endocrine and genetic markers together with LDSS treatment can help achieving the correct diagnosis and optimizing outcomes.

Pubertal delay: the challenge of a timely differential diagnosis between congenital hypogonadotropic hypogonadism and constitutional delay of growth and puberty.

Distinguishing between constitutional delay of growth and puberty (CDGP) and congenital hypogonadotropic hypogonadism (CHH) may be challenging. CDGP and CHH appear to belong to the same clinical spectrum (with low sex hormones and low LH and FSH), although one is classically transient and known as a self-limited form of delayed puberty (CDGP) while the other is permanent (CHH). Thus, the clinical history and the outcomes of these two conditions require different approaches, and an adequate and timely management for the patients is mandatory. Since the initial presentation of CDGP and CHH is almost identical and given the similarities of CDGP and partial forms of CHH (i.e. patients with partial and early interrupted pubertal development) the scientific community has been struggling to find some diagnostic tests able to allow an accurate differential diagnosis between these two conditions in delayed puberty. In this review we provide an up to date insight on the tests available, their meanings and accuracy, as well as some clues to effectively differentiate between constitutional pubertal delay and pathologic CHH.

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

STUDY QUESTIONDoes 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 ANSWERAnti-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 ALREADYBoys 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, DURATIONSera 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, METHODSThe 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 CHANCEAMH 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 CAUTIONThe original trial was not blinded for practical reasons and included a limited number of participants.WIDER IMPLICATIONS OF THE FINDINGSIn 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 NUMBERNCT01797718

Clinical and Genetic Characterization of a Constitutional Delay of Growth and Puberty Cohort

Introduction: Constitutional delay of growth and puberty (CDGP) is the most prevalent cause of delayed puberty in both sexes. Family history of delayed puberty (2 or more affected members in a family) has been evidenced in 50–75% of patients with CDGP and the inheritance is often consistent with autosomal dominant pattern, with or without complete penetrance. However, the molecular basis of CDGP is not completely understood. Objective: To characterize the clinical and genetic features of a CDGP cohort. Methods: Fifty-nine patients with CDGP (48 boys and 11 girls) underwent careful and long-term clinical evaluation. Genetic analysis was performed using a custom DNA target enrichment panel designed to capture 36 known and candidate genes implicated with pubertal development. Results: All patients had spontaneous or induced pubertal development (transient hormonal therapy) prior to 18 years of age. The mean clinical follow-up time was 46 ± 28 months. Male predominance (81%), short stature (91%), and family history of delayed puberty (59%) were the main clinical features of this CDGP ­cohort. Genetic analyses revealed 15 rare heterozygous missense variants in 15 patients with CDGP (25%) in seven different genes (IGSF10, GHSR, CHD7, SPRY4, WDR11, SEMA3A,and IL17RD). IGSF10 and GHSR were the most prevalent affected genes in this group. Conclusions: Several rare dominant variants in genes implicated with GnRH migration and metabolism were identified in a quarter of the patients with familial or sporadic CDGP, suggesting genetic heterogeneity in this frequent pediatric condition.

Diagnosis of Idiopathic GHD in Children Based on Response to rhGH Treatment: The Importance of GH Provocative Tests and IGF-1.

Purpose: Serum IGF-1 (Insulin like growth factor 1) and Growth Hormone (GH) provocative tests are reasonable tools for screening and diagnosis of idiopathic GH Deficiency (IGHD). However, the average cut-off points applied on these tests have a lower level of evidence and produce large amounts of false results. The aim of this study is to evaluate the sensitivity, specificity, and accuracy of IGF-1 and GH stimulation tests as diagnostic tools for IGHD, using clinical response to recombinant human GH (rhGH) treatment as diagnostic standard [increase of at least 0.3 in height standard deviation (H-SD) in 1 year].Methods: We performed a prospective study with 115 children and adolescents presenting short stature (SS), without secondary SS etiologies such as organic lesions, genetic syndromes, thyroid disorders. They were separated into Group 1 [patients with familial SS or constitutional delay of growth and puberty (CDGP), not treated with rhGH], Group 2 (patients with suspicion of IGHD with clinical response to rhGH treatment), and Group 3 (patients with suspicion of IGHD without growth response to rhGH treatment). Then, they were assessed for diagnostic performance of IGF-1, Insulin Tolerance Test (ITT) and clonidine test (CT) alone and combined at different cut-off points.Results: Based on the ROC curve, the best cut-off points found for IGF-1, ITT, and CT when they were used isolated were −0.492 SDS (sensitivity: 50%; specificity: 53.8%; accuracy: 46.5%), 4.515 μg/L (sensitivity: 75.5%; specificity: 45.5%; accuracy: 52.7%), and 4.095 μg/L (sensitivity: 54.5%; specificity: 52.6%; accuracy: 56.9%), respectively. When we had combined IGF-1 with−2SD as cut-off alongside ITT or CT, we found 7 μg/L as the best cut-off point. In this situation, ITT had sensitivity, specificity and accuracy of 93.9, 81.8, and 90.1%, while CT had 93.2, 68.4, and 85.7%, respectively.Conclusion: Our data suggest that diagnosis of IGHD should be established based on a combination of clinical expertise, auxologic, radiologic, and laboratorial data, using IGF-1 at the −2SD threshold combined, with ITT or CT at the cut-off point of 7 μg/L. Additional studies, similar to ours, are imperative to establish cut-off points based on therapeutic response to rhGH in IGHD, which would be directly related to a better treatment outcome.

Characteristic dynamics of height and weight in preschool boys with constitutional delay of growth and puberty or hypogonadotropic hypogonadism.

Constitutional delay of growth and puberty (CDGP) is a frequent variant of the normal leading to short stature and/or pubertal delay. To distinguish CDGP from hypogonadotropic hypogonadism (HH), we evaluated height, growth and weight pattern of CDGP and HH in the first 5years of life. We studied retrospectively height and weight in the first 5years (y) of life in 54 boys with CDGP and 8 boys with HH. In boys with CDGP, height-SDS decreased (change -0.94 (interquartile range [IQR] -1.69 to -0.05); P<0.001) between birth and 2years. BMI-SDS decreased (change -0.38 (IQR -1.21-0.16); P<0.001) in the same time period. There were no significant changes in height-SDS or BMI-SDS between 2years and 5years, while height-SDS (change+1.49 (IQR 1.02-1.95); P<0.001) and BMI-SDS (change+0.91 (IQR 0.12-1.69); P<0.001) increased between pubertal and adult age. In boys with HH, height-SDS and BMI-SDS did not change significantly in the first 5years of life. Height-SDS decreased (change -1.39 (IQR -1.96 to -0.67); P=0.018) significantly between 5years of life and puberty, while there were no significant changes in BMI-SDS in this time period. At pubertal age, BMI-SDS was significantly (P=0.001) higher in boys with HH compared with boys with CDGP. Height deflection and weight deflection in CDGP occur already during the first two years of life in contrast to HH. This different pattern of growth and weight might be helpful to distinguish CDGP from HH.