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Marked Attenuation of Ultradian and Circadian Rhythms of Dehydroepiandrosterone in Postmenopausal Women: Evidence for a Reduced 17,20-Desmolase Enzymatic Activity^*

C. H. LIU, G. A. LAUGHLIN, U. G. FISCHER and S. S. C. YEN

Department of Reproductive Medicine, School of Medicine (T-002), and the General Clinical Research Center, University of California-San Diego La Jolla, California 92093

Address all correspondence and requests for reprints to: Dr. Samuel S. C. Yen, Department of Reproductive Medicine, University of California-San Diego School of Medicine, La Jolla, California 92093.

Circulating levels of adrenal ⁵-androgens [dehydroepiandrosterone (DHEA), and its sulfate (DS)] selectively decrease with age in both sexes, while cortisol secretion remains unchanged. The mechanism(s) to account for this dissociation is unclear. We tested the hypothesis that a reduced enzymatic activity for ⁵-androgen biosynthesis may be responsible for this phenomenon by examining the ultradian and circadian rhythmicity (15-min sampling frequency for 24 h) of DHEA and cortisol and the responsiveness of DHEA, DS, and cortisol to human CRF stimulation and by the analysis of relative enzymatic activities in the biosynthesis of adrenal steroids in older postmenopausal women (PMW) and younger cycling women (NCW).

Our data show that the timing of the circadian rhythm of DHEA secretion was not altered, but the acrophase amplitude was decreased (P < 0.01) in aged PMW compared to NCW. While the pulse frequency of DHEA remained unchanged, the pulse amplitude was markedly attenuated in PMW compared with NCW (3.5 ± 0.6 us. 8.1 ± 1.1 nmol/L; P < 0.01). Correspondingly, the 24-h mean of DHEA was markedly reduced (P < 0.001) in PMW (5.5 ± 0.8 nmol/L) from that in NCW (12.1 ±1.4 nmol/L). For cortisol, all parameters were similar between the two groups. Thus, compared to NCW, the decline of circulating DHEA level in PMW was expressed by attenuations of pulse amplitude and circadian amplitude, without changes in the timing of the circadian rhythm or pulse frequency. Further, DHEA and DS, but not cortisol, responses to 8-h hCRF infusion were significantly (P < 0.01) diminished in PMW. These findings together with decreased product/precursor ratios for DHEA/17-hydroxypregnenolone (P < 0.01) and androstenedione/17-hydroxyprogesterone (P < 0.05) suggest a reduction of 17,20-desmolase enzymatic activity in PMW compared to that in NCW. Steroid ratios for 3β-hydroxysteroid dehydrogenase and 17-hydroxylase were unaltered. We conclude from these preliminary data that the disparity of DHEA and cortisol secretion in aged PMW is probably related to an intraadrenal event, resulting from a decrease in 17,20-desmolase expression, which governs the biosynthesis of ⁵-adrenal androgen.

^* This work was supported by NIH Grant HD-12303-12 and GCRC Grant RR-00827, and it was conducted in part by Clayton Foundation for Research, California Division.

Fellow in Reproductive Endocrinology. Current address: Department of Obstetrics and Gynecology, National Cheng Kung University, Sheng-Li Road, Tainan, Taiwan 70101, Repubic of China.

Clayton Foundation Investigator.

Received March 20, 1990.

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