Recent advancement in the treatment of boys and adolescents with hypogonadism

Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the period of neonatal activation of the gonadal axis has waned, the diagnosis of hypogonadism is challenging because androgen deficiency is not apparent until the age of puberty. Then, the differential diagnosis between constitutional delay of puberty and central hypogonadism may be difficult. During infancy and childhood, treatment is usually sought because of micropenis and/or cryptorchidism, whereas lack of pubertal development and relative short stature are the main complaints in teenagers. Testosterone therapy has been the standard, although off-label, in the vast majority of cases. However, more recently alternative therapies have been tested: aromatase inhibitors to induce the hypothalamic-pituitary-testicular axis in boys with constitutional delay of puberty and replacement with GnRH or gonadotrophins in those with central hypogonadism. Furthermore, follicle-stimulating hormone (FSH) priming prior to hCG or luteinizing hormone (LH) treatment seems effective to induce an enhanced testicular enlargement. Although the rationale for gonadotrophin or GnRH treatment is based on mimicking normal physiology, long-term results are still needed to assess their impact on adult fertility.

DEVELOPMENT AND IMPLEMENTATION OF A PROGRAM OF PERSONALIZED APPROACH TO THE MANAGEMENT OF PATIENTS WITH CONSTITUTIONAL DELAY OF GROWTH AND PUBERTY

Objective of the study: development and implementation of a program of personalized approach to the tactics of managing patients with constitutional delay of growth and puberty (CDGP). Materials and methods of research: a prospective, single-center, randomized study. The article presents the results of a comprehensive examination of 100 adolescent boys, of which the main group (n=70) – boys with CDGP at the age of 14–14.5 years and the comparison group (n=30) – healthy boys of 14–15 years. Clinical (SDS growth, SDS body mass index, orchiometry), laboratory (insulin-like growth factor 1, testosterone, luteinizing hormone, follicle-stimulating hormone, inhibin B, anti-Müllerian hormone, kisspeptin, thyroid stimulating hormone, thyroxin, prolactin), instrumental indicators (bone age, bioimpedansometry), indicators of psychological status (assessment of the quality of life, anxiety level, aggression level, depression level). Statistical processing: Statistica (Version 7 – Index, Stat. Soft Inc., USA) and Microsoft Exel, 2010. The following criteria were used: Mann–Whitney tests, Fisher's exact test, correlation analysis – Spearman® coefficient. In order to develop the algorithm, factor analysis is applied. Results: it was shown that patients with CDGP had a marked lag behind healthy peers in terms of clinical, metabolic and neuroendocrine indicators of physical and sexual development. With the help of factor analysis of the data obtained, a program of a personalized approach to the tactics of managing patients with CDGP has been developed. Various clinical applications of the program are presented. The sensitivity of the proposed method was 74.63%, 95% CI [62.51; 84.47%]; specificity of the method – 93%, 95% CI [77.93; 99.18%]; the accuracy of the diagnostic method – 80.4%, 95% CI [71.11; 87.78%].

A study of clinical profile of children with short stature

Background: Short stature is one of the common concerns among the Indian children. However, community-based studies in Indian context are rare compared to studies performed in Western countries. Aim: Here, we aimed to study the clinical profile of children with short stature and the different causes of it. Methods: This study was a hospital-based prospective study that included 65 children ?18 years (female: 57%, male: 43%) who met the inclusion criteria. Detailed history, physical examination, anthropometry, laboratory tests, bone age, and chromosomal analysis were included for evaluation. Results: The most common age group affected was 11–15 years (40%) followed by 6–10 years (34%) and <5 years (21.5%). Growth hormone (GH) deficiency (21.4%), followed by malnutrition (18.5%), familial short stature (13.9%), hypothyroidism (10.8%), turner syndrome (10.8%), constitutional delay of growth and puberty (9.2%), systemic diseases (6.2%), and miscellaneous (6.1%) were identified as the common causes of short stature. Conclusion: Commonly observed etiology of short stature was identified in this study. Proportionate and disproportionate short statures were 90.7% and 9.3%, respectively. About 23% of the cases were of physiological short stature and 77% were of pathological short stature.

Timing of Pubertal Onset in Girls and Boys with Constitutional Delay

Context The decision whether to treat a child with delayed puberty with sex steroids is primarily based on patient, family, and provider preference. Knowing when children with constitutional delay eventually enter puberty would inform this decision. Objective, Design, Setting, Participants, and Outcome Measures To estimate and compare rates of pubertal entry, we conducted a retrospective cohort study by reviewing medical records of children evaluated for delayed puberty at a large academic medical center between 2000 and 2015, extracting data on pubertal status for all clinical visits, then conducting time-to-event analyses. Results Of 392 girls and 683 boys with delayed puberty, constitutional delay was the most common cause, found in 32% of girls and 70% of boys. In a subcohort of 97 girls and 243 boys who were prepubertal at one or more visits, we observed a broad age range for pubertal entry, up to &gt;16 years for girls and &gt;17 years for boys. The probability of entering puberty within the next year for 12- to 15.5-year-old girls and 13.5- to 16.5-year-old boys with delayed puberty ranged between 38% and 74%. No differences in the rates of pubertal entry were seen between girls and boys after data harmonization. Conclusion The broad range of ages at pubertal entry for children with constitutional delay challenges the concept that constitutional delay is merely an extreme of normal variation. Discussions with patients and families about management should consider the possibility that some children may need to wait years after presentation until puberty starts.

Circulating miR-30b levels increase during male puberty

OBJECTIVE: The role of microRNAs 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. DESIGN AND METHODS: 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 (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. RESULTS: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (SD) 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). CONCLUSIONS: 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

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).