Adrenarche: Physiology, Biochemistry and Human Disease

Richard J. Auchus; William E. Rainey


Clin Endocrinol. 2004;60(3) 

In This Article

Abnormal Adrenarche and DHEA-S Deficiency

In some individuals, particularly African-American (Banerjee et al., 1998) girls and children with low birthweight, adrenarche may begin early ('premature adrenarche', < 6 years of age) or progress with higher DHEA-S production and more abundant axillary and pubic hair growth than is typical ('exaggerated adrenarche'). Along with elevated age-adjusted DHEA-S production, children with exaggerated adrenarche may have slightly advanced bone age and accelerated linear growth. The premature development of axillary and pubic hair, particularly in girls, must be evaluated to exclude other pathological conditions such as Cushing's disease, virilizing adrenal tumours and undiagnosed 21-hydroxylase deficiency. Premature adrenarche is distinguished from precocious puberty or pseudopuberty by the slow progression of bone maturation, lack of virilization, lack of gonadotrophin pulses, lack of progressive breast development (in girls) and lack of testicular enlargement (in boys). Premature adrenarche is essentially a diagnosis of exclusion, and often 6-12 months of follow-up must pass before other processes can be confidently excluded.

While the causes of premature and exaggerated adrenarche remain to be defined, several studies now document that children with low birthweight are more likely to manifest these disorders (Oppenheimer et al., 1995; Ibanez et al., 1996, 1999b; Francois et al., 1997; Vuguin et al., 1999; Ghirri et al., 2001; Denburg et al., 2002). The association of premature adrenarche with low birthweight suggests that disorders of adrenarche might be a component of a foetal or neonatal programming event. Girls with early or exaggerated variations in adrenarche have a high incidence of PCOS later in life (Ibanez et al., 1999b) and boys have insulin resistance (Denburg et al., 2002). This association is also consistent with the observed elevated production of DHEA-S from adrenal glands of women with PCOS (Lachelin et al., 1979; Moran & Azziz, 2001), such that both the adrenals and gonads contribute to elevated circulating testosterone concentrations in women with PCOS. Many times, 'exaggerated adrenarche' is a forme fruste of PCOS in teenage girls who progress rapidly from adrenarche to puberty to oligomenorrhoea and hyperandrogenism, and these patients tend to have marked insulin resistance and/or obesity (Dunaif, 1997; Ibanez et al., 1999a). PCOS is not only a cause of hirsutism and infertility, but women with PCOS bear elevated risk profiles for cardiovascular disease (Dahlgren et al., 1992; Yarali et al., 2001; Kelly et al., 2002; Loverro et al., 2002; Yildiz et al., 2002). Women with PCOS are also at increased risk of developing type II diabetes mellitus (Legro et al., 1999), and even adolescents with PCOS have a high frequency of impaired glucose tolerance (Palmert et al., 2001). Whether exaggerated adrenal DHEA-S secretion during and after adrenarche contributes to the elevated cardiovascular risk profile of PCOS women is not known, but these observations indicate that premature adrenarche can no longer be considered a benign condition but is potentially a forerunner of adult disease states (Ibanez et al., 2000).

If the rise in DHEA-S production during adrenarche is physiologically important, then states of DHEA-S deficiency should have clinical manifestations that are ameliorated with DHEA replacement. A clear example of DHEA-S deficiency is subjects with primary adrenal insufficiency, who maintain a reduced general health perception even with optimal mineralocorticoid and glucocorticoid therapy (Lovas et al., 2002). Recent studies have shown that oral DHEA improves sexual satisfaction, mood and energy in women with adrenal insufficiency who make no DHEA-S and little testosterone (Arlt et al., 1999).

More generally, DHEA-S production declines inexorably with ageing, such that circulating DHEA-S concentrations in octogenarians are not much higher than those in preadrenarchal children (Smith et al., 1975; Orentreich et al., 1984). This decline in DHEA-S production has been termed 'adrenopause', although cortisol and aldosterone production do not decline as casual interpretation of this term might suggest. The loss of DHEA-S and possibly other adrenal hormones or neurosteroids has been proposed to contribute to the physical and cognitive deterioration in ageing adults (Yen & Laughlin, 1998; Vallee et al., 2001). The concept that this declining DHEA-S production with ageing might have deleterious consequences has led to the practice of oral DHEA supplementation in older adults (Allolio & Arlt, 2002). Data supporting this practice in healthy elderly subjects are limited, with no improvements of objective parameters, but only an increase in subjective feelings of well-being (Morales et al., 1994; Arlt et al., 2001). In the United States, DHEA is available as a 'nutritional supplement' in health-food stores and pharmacies, but preparations labelled as 25-mg tablets (a typical daily dose) have been found to contain anywhere from 0 to 140 mg (Parasrampuria et al., 1998). DHEA is a prescription drug in Europe, but no preparations currently meet regulatory standards. Hence, DHEA supplementation is hampered by a lack of reliable preparations and remains a promising yet investigational process.


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