Androgens in Health and Disease.pdf - E Library

Chapter 4/Dihydrotestosterone and 5α-Reductase 77
4 Dihydrotestosterone and 5α-Reductase
Normal Physiology and Inhibition
Paul R. Sutton, MD, PhD, John K. Amory, MD,
and Richard V. Clark, MD, PhD
CONTENTS
DIHYDROTESTOSTERONE IN EMBRYOGENESIS AND NORMAL ADULT
PHYSIOLOGY
INHIBITION OF 5α-REDUCTASE
SUMMARY
REFERENCES
DIHYDROTESTOSTERONE IN EMBRYOGENESIS
AND NORMAL ADULT PHYSIOLOGY
In man, 4–8% of testosterone (T) undergoes 5α-reduction, resulting in the formation
of the potent androgen dihydrotestosterone (DHT). DHT plays a crucial role in the
formation of the external male genitalia and prostate during fetal life. In the adult,
however, DHT is associated with a variety of chronic conditions, including benign
prostatic hyperplasia, androgenic alopecia, acne vulgaris, and, perhaps, carcinoma of the
prostate—making inhibition of DHT production an attractive target for pharmacotherapy.
This chapter will review the role of DHT in normal development during fetal
life as well as its functions in the adult. We will also discuss pharmaceutical means of
reducing DHT synthesis in the treatment of DHT-dependent diseases, with particular
emphasis on the emergence of the new class of 5α-reductase inhibitors.
DHT Metabolism
DHT is produced by 5α-reduction from the 4–8 mg of testosterone produced daily by
the adult male testes (1). Four to eight percent of this T is 5α-reduced to DHT—mostly
in androgen-responsive organs. Approximately 50 µg of DHT is produced from 5αreduction
within the testes, whereas production in other tissues is approx 300 µg daily.
Circulating serum DHT levels are 30–86 ng/dL (1.0–2.9 nmol/L) in normal men (2,3).
Tissue DHT levels within androgen-dependent organs are many times higher than
DHT concentrations in circulating plasma. In the prostate, for example, tissue DHT
concentrations are 10 times higher than plasma concentrations (4–6). Intraprostatic T
From: Contemporary Endocrinology: Androgens in Health and Disease
Edited by: C. Bagatell and W. J. Bremner © Humana Press Inc., Totowa, NJ
77