Puberty and Fertility in Congenital Adrenal Hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. The symptoms and signs of CAH depend on the degree of enzyme deficiency; severe salt-wasting (SW) form, less severe simple virilizing (SV) form and mild nonclassic (NC) form. In this paper, puberty and fertility in CAH are discussed. The time of onset of puberty and progress of pubertal development is quite normal, except in NC patients (earlier). Also the age of menarche in CAH girls is normal, but it can depend on the level of therapeutic control. In prepuberty, bone age is advanced. In puberty, peak height velocity is normal but occurs at a younger age and can therefore be considered to be low (compared to healthy early maturers). In puberty there seems to be an increased sensitivity for glucocorticoids leading to growth inhibition. All three above factors can play a role in reducing adult height. Subfertility is frequently found in both female and male CAH patients. In females, the pregnancy rate depends on the severity of 21-hydroxylase deficiency (SW<SV<NC). Adrenal progestagens and androgens are the main cause of disturbed ovarian activity. In addition psychosexual problems (e.g. as a result of genital surgery) are an important factor. In males, the main cause of subfertiltiy is the presence of testicular adrenal rest tumors, which are thought to originate from aberrant adrenal tissue and respond to treatment with glucocorticoids. Although in general fertility is not a paediatric item, in CAH most fertility problems have their origins in childhood years. Therefore prevention of subfertility has to be implemented as a treatment goal in paediatric endocrinology from the start of puberty.

Abundance of DLK1, differential expression of CYP11B1, CYP21A2 and MC2R, and lack of INSL3 distinguish testicular adrenal rest tumours from Leydig cell tumours

“…The high expression of DLK1 in TART may suggest that these nodules develop from an immature or even fetal cell type. The similar expression profiles of TART and fetal (this study) and adult (21) adrenal cortical cells lend support to the hypothesis that TART derives from an adrenal-like cell type, possibly misplaced in the gonad during early embryonic development (6,7,8). Moreover, the absence of INSL3 expression in TARTs is at odds with the development of TART from a cell population within one of the LC lineages.…”

“…TART is not an invasive tumour, but may eventually cause a testicular degeneration by obstruction of the rete testis and destruction of the surrounding testicular tissue (5). The current consensus among researchers is that TARTs are derived from ectopic adrenal cells that have migrated to the gonad in early fetal life (6,7,8). This hypothesis is in agreement with the findings of the expression in TART of mRNAs that are normally expressed in the adrenal cortex, and that TART cells are able to produce steroid hormones characteristic of the adrenal cortex and Leydig cells (LCs) in the testis (9,10).…”

Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency

“…Due to an intact feedback system with activation of the CRH-ACTH axis, the production of androgens and steroid precursors prior to the enzyme defect is increased [1,2]. Adequate substitution therapy with glucocorticoids and mineralocorticoids is a prerequisite in order to avoid short-term and/or long-term complications such as electrolyte imbalances, addisonian crisis, accelerated bone maturation, short stature, hirsutism and virilization, decreased fertility, obesity, and hypertension [3,4,5]. …”

21-Hydroxylase Deficiency Associated with Male Infertility: Report of 2 Cases with Gene Analyses

“…Although controversial (14,15), male infertility has been described in patients with 21-hydroxylase deficiency. Regarding the underlying mechanism of male infertility in 21-hydroxylase deficient patients, suppression of gonadotropin secretion by increased adrenal steroids due to the untreated deficiency is considered to be the cause of spermatogenesis failure (16), while it has also been suggested that the main cause of infertility in such patients is the presence of testicular adrenal rest tumors, thought to originate from aberrant adrenal tissue (17), which compress the seminiferous tubules, causing obstructive azoospermia (18). In the present two cases, though low serum concentrations of LH and FSH were observed, neither steno-sis nor compression of seminiferous tubules by a testicular tumor was identified, which supports the speculation that the suppression of gonadotropin by increased adrenal androgens due to untreated 21-hydroxylase deficiency may result in sperm dysfunction (19).…”