Moreover, this happens at a time when psychosocial issues often affect adherence to medical therapy [2]. Therefore, treatment regimens should be reassessed during adolescence and adulthood. In a prospective, cross-sectional study, the pharmacokinetic parameters of total and free cortisol in subjects with classic SW CAH have been determined [11]. The clearance of total and free cortisol was significantly higher in the pubertal than the prepubertal and postpubertal CAH patients. The volume of distribution of total and free cortisol was significantly higher in the pubertal and postpubertal than in prepubertal patients. No difference in the half-life of total or free cortisol was observed between groups. This was thought to be due to the concomitant rise in cortisol clearance and volume of distribution, both important determinants of the elimination of a drug from the body and, hence, its half-life. Comparison of the pharmacokinetic parameters of free cortisol between males and females in each separate group of patients (prepubertal, pubertal, and postpubertal) revealed a significantly shorter half-life of free cortisol in pubertal females than in pubertal males. The net effect of these changes in cortisol pharmacokinetics, if the administration schedule of hydrocortisone remains unchanged, will be a loss of control of the hypothalamic-pituitary-adrenal axis, inadequate suppression of the adrenal cortex, and excessive production of adrenal androgens and steroid precursors [11].
In children, hydrocortisone is the GC of choice because longer-acting GCs are more likely to impair growth [1, 12, 13]. Most oral GC regimens are proposed with at least half or 2/3 of the global dose in the morning [6, 14].Cross-sectional studies from France, the UK, and the USA show the use of varied GC regimens in adults, with some adult CAH patients given hydrocortisone and some given long-acting GC preparations such as dexamethasone, prednisone, or prednisolone [15–17]. No randomized controlled trials have assessed these varied regimens. There is no established cutoff of 17-hydroxyprogesterone levels in adults, and probably the optimal dose of GCs is that which fails to fully suppress 17-hydroxyprogesterone and maintains androgens in the mid-normal range [18]. The dose of mineralocorticoid (MC) treatment required for adults is generally lower than that required for infants and children. The dose should be adjusted to avoid hypertension and to maintain plasma renin activity in the upper normal range, although there is no consensus on the exact therapeutic goal of this treatment in adult patients [18]. The use of fludrocortisone therapy in patients with the SV form of CAH should be recommended in some patients because it might allow management with lower doses of GC [2]. Ideally, the treatment should be monitored in order to avoid iatrogenic comorbidities and to enable a good quality of life (QoL) [19]. However, this goal has not been reached up to now, since increased comorbidities and mortality are reported in patients with CAH [20, 21]. A recent study has shown that, at the time of transition between pediatric and adult care, the health status of young people with CAH was less than ideal with significant numbers having poor biochemical control, reduced final height, increased CV risk with elevated body mass index and blood pressure (BP), and reduced reproductive health [22]. These results were comparable to the recent UK study of adults with CAH [15]. These current data suggest that poor health status is likely to begin in adolescence and persist into adulthood, highlighting the importance of this time period in a patient’s endocrine care.
Management of Classic CAH in Adolescents and Adults
Female-Specific Issues
Sexuality and fertility in women with classic CAH have been described for many years as impaired, especially for the patients with the SW form. This results from several issues such as biological (poor hormonal balance), mechanical (related to surgeries), and psychological factors [2, 23].
Menstrual irregularities and anovulation are frequent in CAH women, affecting from 30 to 70% of women [15, 17]. Menstrual cycle control represents therefore an important therapeutic target in these patients. Several factors (androgen and progesterone overproduction, prenatal exposure to sexual steroid) are suspected to disturb the reproductive axis in CAH females [24]. A recent study has described luteinizing hormone (LH) pulsatility in women with classic CAH [24] and showed 2 different profiles in CAH women: one group of patients had LH pulsatility patterns similar to the controls; the other one had lower LH pulse amplitude and frequency, and presented more frequently with menstrual cycle disturbances, higher 17-hydroxyprogesterone, testosterone, progesterone, and androstenedione levels, and lower follicle-stimulating hormone levels. This study thus demonstrated that hormonal control is a key factor of gonadic function of CAH women. Optimized GC and MC regimens should thus be an important concern in CAH adolescents and women in order to avoid hirsutism and to obtain regular menstrual cycles. Antiandrogen treatment, such as a combined oral contraceptive, cyproterone acetate, should be considered to improve symptoms and avoid overtreatment by GC if symptoms persist [25].
The consequences of the feminizing surgery are also an important concern during transition. Surgery can include clitoroplasty, vaginoplasty, and labioplasty [26]. Urinary incontinence, vaginal stenosis and inadequate introitus, poor cosmetics, anorgasmia, and painful intercourse have been reported in adults and currently remain relevant issues [18, 26]. It is well established that there is a relationship between sexual activity and vaginal function; thus, genital surgery may result in sexual dissatisfaction. Surgical techniques for genital feminization in female CAH patients have nonetheless evolved significantly over time. There are nowadays new surgical procedures which, for instance, preserve innervation and clitoral sensation in order to conserve erotic sensitivity and orgasmic capacity secondary to the clitoroplasty [27] and improved vaginoplasty techniques [28]. Moreover, to date, the choice of the timing of the surgery (early or late surgery) remains therefore a matter of debate [29]. Unfortunately, there are few data in the literature about the outcomes of this surgery in terms of sexual function, and the outcomes of the current techniques will take time to emerge. In a cohort study of 138 CAH patients, Arlt et al. [15] have shown that 92 women had undergone genital reconstruction, 43% of whom had more than 1 surgery, and 23%