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This study examines the androgen-stimulating properties of pro-opiomelanocortin-derived peptides, ACTH, beta-endorphin (beta-End) and joining peptide (JP). Ten different cell suspensions were prepared from ten human adrenal glands. ACTH and JP stimulated cortisol, androstenedione (delta 4) and dehydroepiandrosterone (DHEA) production (P < 0.05); beta-End stimulated only delta 4 and DHEA production. beta-End brought about significant increases in the delta 4 or DHEA to cortisol ratios. The addition of beta-End (10(-10) M) suppressed ACTH-stimulated cortisol production from 7573 +/- 2960 to 5994 +/- 2654 pmol/10(6) cells (means +/- S.E.M.; P < 0.05). The addition of beta-End did not affect ACTH-stimulated delta 4 production (210 +/- 88 and 236 +/- 105 pmol/10(6) cells). JP (10(-10) M) inhibited ACTH-stimulated cortisol production so that the mean values fell to 5186 +/- 2588 and also inhibited DHEA production, from 240 +/- 48 to 180 +/- 33 pmol/10(6) cells. These results suggest that the relative production of androgen to cortisol is greater in response to beta-End and JP than in response to ACTH. If blood levels of these peptides rise to herald adrenarche as reported for beta-End, suppression of cortisol production may result in an increase in ACTH to correct cortisol levels resulting in an increase in delta 4 and DHEA levels. This may explain the occurrence of increasing androgen levels at adrenarche.

The differential control of adrenal androgens and cortisol may be due to intra-adrenal factors, which may be age-or sex-related, or due to extra-adrenal factors, such as circulating hormones. The purpose of this study was to identify any intrinsic differences that may exist in steroidogenic production occurring within adrenals obtained from males and females, and any maturational differences that may evolve with age. Using human adrenals from 48 transplant donors (32 males, 16 females; ages 5-60 years), the influences of age and sex on basal production of and ACTH-stimulated cortisol, androstenedione and dehydroepiandrosterone (DHEA) were examined in freshly prepared adrenal cell suspensions. Basal and ACTH-stimulated cortisol, androstenedione and DHEA production were similar in adrenals from males and females and did not correlate significantly with age when the whole group was examined. When steroidogenesis in male and female adrenals was examined separately against age, a significant correlation was observed only for basal and ACTH-stimulated androstenedione in adrenals from males in the younger age group, 5-30 years (basal: r ¼ 0.84, P ¼ 0.0001; ACTH-stimulated: r ¼ 0.52, P ¼ 0.007). Examination of the relationships between the steroids disclosed that the basal and ACTH-stimulated cortisol/androgen ratios did not correlate significantly with age, but the androstenedione/DHEA ratio showed a significant direct relationship with age in males only (basal: r ¼ 0.53, P ¼ 0.006; ACTH-stimulated: r ¼ 0.5, P=0.01).These data suggest that the influences of sex and age are minor in the modulation of adrenal steroidogenesis and support the concept that extra-adrenal factors dominate in the differential modulation of adrenal androgens and cortisol. The relationship between the androstenedione/ DHEA ratio and increasing age in men is consistent with the recently reported stimulatory effect of testosterone on adrenal steroidogenesis by induction of the conversion of DHEA to androstenedione.

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