THE BIOCHEMICAL AND PHENOTYPIC CHARACTERIZATION OF FEMALES HOMOZYGOUSFOR 5-ALPHA-REDUCTASE-2 DEFICIENCY

The biochemical and physiologic manifestations of decreased 5 alpha di hydrotestosterone (DHT) in females are characterized. Three females fr om the large Dominican kindred with 5 alpha-reductase-2 deficiency wer e identified as homozygous for a point mutation (R246W, C-->T) on exon 5 of the 5 alpha-reductase-2 gene by single strand DNA conformational polymorphism analysis and DNA sequence analysis. Body hair was decrea sed; there was no history of acne. Despite delayed menarche, all were fertile, and two had twins. Urinary 5 beta/5a C-19 and C-21 steroid me tabolite ratios were elevated. Plasma testosterone was normal to eleva ted, with low DHT, resulting in an increased testosterone/DHT ratio. 3 alpha,5 alpha-Androstanediol glucuronide was low. Menstrual cycle pro filing performed in two subjects showed ovulatory gonadotropin peaks. Sebum production was normal. 5 alpha-Reductase-2-deficient homozygotic females demonstrate the importance of DHT in the physiology and patho physiology of body hair growth. Normal sebum implies regulation by the 5 alpha-reductase-1 isoenzyme. Delayed puberty suggests involvement o f 5 alpha-reductase-2 in menarche at the hypothalamic/pituitary and/or ovarian level. As two had nonidentical twins, DHT and/or the DHT/estr adiol ratio may regulate follicular development, with lower levels per mitting more than one dominant follicle per cycle and higher levels im pairing follicular development and ovulation. Thus, females with 5 alp ha-reductase-2 deficiency highlight a role for DHT in hirsutism and/or menstrual disorders.