ESPE Abstracts

Background: Congenital hypogonadotropic hypogonadism (CHH) is defined by a partial or complete failure of pubertal development due to inadequate secretion of gonadotropins, which is triggered by deficient GnRH activity. Diagnosis is confirmed by low sex hormone levels and low or inappropriately normal levels of LH and FSH, in the absence of anatomical abnormalities in the hypothalamic-pituitary axis, and without other pituitary hormone deficiencies.

Case Report: We present a 14-year-old female without thelarche (M1), with axillary (A3) and pubic hair (P3), and preserved olfactory function. She was born from non-consanguineous parents, with uneventful pregnancy and full-term eutocic delivery. As a pathological history, she has an already corrected cleft lip and palate, and attention-deficit/hyperactivity disorder treated with methylphenidate. Her karyotype was 46, XX, and the endocrine profiling revealed markedly reduced FSH, LH, oestradiol, and progesterone levels. Thyroid and adrenal function levels were unremarkable. Her height was on the 60^th percentile, IGF1 was normal and bone age was according to her chronological age, suggesting regular skeletal development. Magnetic resonance imaging (MRI) of the hypothalamic-pituitary axis excluded structural anomalies. Pelvic MRI revealed a severely small hypoplastic uterus, lacking any evidence of hormonal impregnation. The right ovary was diminutive yet exhibiting follicular activity, while the left ovary was extremely underdeveloped and devoid of follicular structures. Genetic studies revealed a compound heterozygous missense mutation (c.[401T>G];[415C>T]) (p.[Val134Gly];[Arg139Cys]) in the gonadotropin-releasing hormone receptor (GnRHR) gene. Oestradiol patch was started at 25μg/day and titrated to 50μg/day four months later. Progressive breast and ultrasound uterine enlargement was noticed. Menarche occurred in seven months, and treatment was then switched to combined oral ethinylestradiol(30mcg)/dienogest(2 mg). Serum oestradiol and progesterone have progressively increased and are currently within appropriate ranges.

Discussion: CHH can present with anosmia (Kallmann syndrome) or without olfactory deficits, known as normosmic CHH (nCHH). The GnRHR gene was among the first to be associated with nCHH. It accounts for approximately 3.5-16% of sporadic nCHH cases and up to 40% of familial ones. Inheritance is autosomal recessive, involving homozygous or compound heterozygous mutations. This case highlights the importance of a comprehensive diagnostic approach in young females presenting with primary amenorrhoea and absent pubertal development. Early diagnosis of CHH allows for timely intervention with hormone replacement therapy to induce secondary sexual characteristics and potentially address fertility concerns. Multidisciplinary management, involving endocrinologists, gynecologists, and geneticists, is crucial for optimizing patient outcomes and addressing the psychosocial aspects of delayed puberty.