Hypogonadotropic hypogonadism in subjects with DAX1 mutations

Abstract

DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; also known as NROB1, nuclear receptor subfamily 0, group B, member 1) encodes a nuclear receptor that is expressed in embryonic stem (ES) cells, steroidogenic tissues (gonads, adrenals), the ventromedial hypothalamus (VMH), and pituitary gonadotropes. Humans with DAX1 mutations develop an X-linked syndrome referred to as adrenal hypoplasia congenita (AHC). These boys typically present in infancy with adrenal failure but later fail to undergo puberty because of hypogonadotropic hypogonadism (HHG). The adrenal failure reflects a developmental abnormality in the transition of the fetal to adult zone, resulting in glucocorticoid and mineralocorticoid deficiency. The etiology of HHG involves a combined and variable deficiency of hypothalamic GnRH secretion and/or pituitary responsiveness to GnRH resulting in low LH, FSH and testosterone. Treatment with exogenous gonadotropins generally does not induce spermatogenesis. Animal models indicate that DAX1 also plays a critical role in testis development and function. As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as steroidogenic factor 1 (SF1). In addition to reproductive tissues, DAX1 is also expressed at high levels in ES cells and plays a role in the maintenance of pluripotentiality. Here we review the clinical manifestations associated with DAX1 mutations as well as the evolving information about its function based on animal models and in vitro studies.

GENETICS IN ENDOCRINOLOGY: Genetic counseling for congenital hypogonadotropic hypogonadism and Kallmann syndrome: new challenges in the era of oligogenism and next-generation sequencing

“…DAX1 mutations are associated with a syndromic form in which CHH is associated with primary adrenal failure due to congenital adrenal hypoplasia (CAH) (OMIM: 300200). DAX1, also called NR0B1 according to recent nomenclature, codes for an orphan receptor composed of 470 amino acids and expressed in the adrenal cortex, the gonads, the ventro-median nucleus of the hypothalamus, and the pituitary gland (79,80). NR0B1 has a key role in the development of the gonads and adrenal cortex.…”

“…DAX1/NROB1 is located on the short arm of chromosome X, in region Xp21.2 (77,78). Logically, CAH associated with CHH linked to DAX1/NROB1 mutations affects only males (hemizygotes), whereas heterozygous female carriers are free of CHH and CAH (79,80). A single exception has been reported, in a family in which women with biallelic mutations were affected (81).…”

Human 3β-hydroxysteroid dehydrogenase deficiency seems to affect fertility but may not harbor a tumor risk: lesson from an experiment of nature

“…In addition, patients with X-linked CAH due to NR0B1/DAX1 mutations may present in the testis a Sertoli-cell-only pattern with rare spermatogonia and no apparent spermatogenesis, but also pronounced Leydig cell hyperplasia (38,39,42). Contrary to 21-hydroxylase deficiency, they also have a hypogonadotrophic hypogonadism (43). Malignancy risk in these patients is probably also low (39).…”

Orally applied doxazosin disturbed testosterone homeostasis and changed the transcriptional profile of steroidogenic machinery, cAMP/cGMP signalling and adrenergic receptors in Leydig cells of adult rats

“…As a nuclear receptor, DAX1 has been shown to function as a transcriptional repressor, particularly of pathways regulated by other nuclear receptors, such as SF1. The exact mechanism of DAX1 action during adulthood and critical stages of development are not fully understood (Jadhav et al, 2011). It is well known that regulation of steroidogenic genes transcription is quite complicated, multifactorial, tissue-specific, constitutive, cAMP-dependent/independent and it includes a broad range of different transcription factors.…”