Phylogenetic Comparisons Implicate Sex Hormone-Binding Globulin in “Masculinization” of the Female Spotted Hyena (Crocuta crocuta)

Abstract

Exposures to sex steroids during fetal development are thought to contribute to the unique urogenital anatomy and social dominance of the female spotted hyena: overt phenotypes not shared by other hyenids (i.e. striped hyena, brown hyena, and aardwolf). Because both androgens and estrogens influence development of genitalia and behavior, and because plasma SHBG regulates their access to tissues, we compared the Shbg gene sequences, structures, and steroid-binding properties in the four extant hyenids. We found the hyenid Shbg genes (>95% identical) and mature protein sequences (98% identical) are highly conserved. As in other mammals, the hyenid SHBG all bind 5α-dihydrotestosterone with high affinity (Kd = 0.62–1.47 nm), but they also bind estrone and dehydroepiandrosterone with similarly high affinity, and this unusual property was attributed to specific amino acids within their SHBG steroid-binding sites. Phylogenetic comparisons also indicated that the spotted hyena SHBG precursor uniquely lacks two leucine residues and has a L15W substitution within its secretion signal polypeptide, the reduced size and hydrophobicity of which markedly decreases the production of SHBG and may therefore explain why serum SHBG concentrations in male and female spotted hyenas are approximately five times lower than in other hyenids. This is important because low plasma SHBG concentrations in spotted hyenas will increase exposure to biologically active androgens and estrogen as well as to their precursors (dehydroepiandrosterone and estrone), which may contribute to the masculinized external genitalia of female spotted hyenas and to female social dominance over males.