Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline

ESE · 2022 · Europe

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Authors: A Nordenström, S F Ahmed, E van den Akker et al.
Title: Pubertal induction and transition to adult sex hormone replacement in patients with congenital pituitary or gonadal reproductive hormone deficiency: an Endo-ERN clinical practice guideline
Journal: European Journal of Endocrinology, 2022
DOI: 10.1530/EJE-22-0073
Licence: CC BY 4.0
Changes: Verbatim excerpts; formatting adapted

Full text retrieved 2026-10-27 from Europe PMC · PMC9066594

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Androgen insensitivity syndrome (PAIS and CAIS)

Reduced AR residual activity results in PAIS with variable virilisation of the external genitalia during fetal life. Individuals generally present with ambiguous genitalia at birth. Earlier studies described a grading scheme (grade 1–5) for the description of virilisation (249). The residual activity of the AR also leads to a variable degree of virilisation of the external genitalia and the presence of gynaecomastia at the onset of puberty. Unfortunately, the phenotype–genotype correlation is poor (257). However, it has been shown that the degree of virilisation at birth estimated by the external masculinisation score (EMS) is a good predictor of the degree of virilisation at puberty (175, 258, 259). In only 22% of the cases with a clinical diagnosis of PAIS, a pathogenic variant in the AR is found, making it a more complex and a highly variable clinical and diagnostic challenge (258, 260).

Abstract

An Endo-European Reference Network guideline initiative was launched including 16 clinicians experienced in endocrinology, pediatric and adult and 2 patient representatives. The guideline was endorsed by the European Society for Pediatric Endocrinology, the European Society for Endocrinology and the European Academy of Andrology. The aim was to create practice guidelines for clinical assessment and puberty induction in individuals with congenital pituitary or gonadal hormone deficiency. A systematic literature search was conducted, and the evidence was graded according to the Grading of Recommendations, Assessment, Development and Evaluation system. If the evidence was insufficient or lacking, then the conclusions were based on expert opinion. The guideline includes recommendations for puberty induction with oestrogen or testosterone. Publications on the induction of puberty with follicle-stimulation hormone and human chorionic gonadotrophin in hypogonadotropic hypogonadism are reviewed. Specific issues in individuals with Klinefelter syndrome or androgen insensitivity syndrome are considered. The expert panel recommends that pubertal induction or sex hormone replacement to sustain puberty should be cared for by a multidisciplinary team. Children with a known condition should be followed from the age of 8 years for girls and 9 years for boys. Puberty induction should be individualised but considered at 11 years in girls and 12 years in boys. Psychological aspects of puberty and fertility issues are especially important to address in individuals with sex development disorders or congenital pituitary deficiencies. The transition of these young adults highlights the importance of a multidisciplinary approach, to discuss both medical issues and social and psychological issues that arise in the context of these chronic conditions.

Contents of the original publication

The section headings of the original.

Introduction
Puberty normal physiology
Mini-puberty
Deficiencies of sexual development; DSD and gonadotropin deficiency
The role of hormonal replacement therapy during puberty
Aromatase inhibitors in puberty
Biochemical hormonal testing
Puberty induction general issues to consider
Methods
Guideline working group
Target group and aims
Summary of methods used for guideline development
Clinical questions, eligibility criteria and endpoint definition
Description of search and selection of literature
Summary and interpretation of the evidence from the systematic literature review
Clinical question I What is the optimal treatment to induce or sustain puberty in boys with partial gonadal dysgenesis?
Clinical question II What is the optimal treatment to induce or sustain puberty in boys with hypogonadotropic hypogonadism?
Clinical question III What is the optimal treatment to induce or sustain puberty in female patients with partial gonadal dysgenesis?
Clinical question IV What is the optimal treatment to induce or sustain puberty in female patients with hypogonadotropic hypogonadism?
Clinical question V What is the optimal treatment to induce or sustain puberty in women with complete androgen insensitivity syndrome?
Clinical question VI What is the optimal treatment to induce or sustain puberty in patients with partial androgen insensitivity syndrome?
Recommendations and rationales
General
Puberty induction in girls
Puberty induction in boys
Introduction
Pubertal induction in patients with hypogonadotropic hypogonadism
Puberty induction in Klinefelter
Androgen insensitivity syndrome (PAIS and CAIS)
Pubertal induction in CAIS
Pubertal induction in PAIS
Future perspectives
Conclusion

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