HSD3B1

HSD3B1 Full Name

hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1

HSD3B1 Introduction

Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1 (HSD3B1), commonly referred to as 3β-hydroxysteroid dehydrogenase/Δ5-Δ4 isomerase type 1, is a bifunctional enzyme that catalyzes the oxidative conversion of Δ5-3β-hydroxysteroids to Δ4-3-ketosteroids, an essential step in the biosynthesis of all classes of steroid hormones. Encoded by the HSD3B1 gene on chromosome 1p12, this enzyme is predominantly expressed in the placenta, skin, breast, and prostate, in contrast to its paralog HSD3B2, which is expressed mainly in the adrenal cortex and gonads. HSD3B1 operates at the branch point of steroidogenesis, converting pregnenolone to progesterone, 17α-hydroxypregnenolone to 17α-hydroxyprogesterone, and dehydroepiandrosterone (DHEA) to androstenedione.

Figure 1. Strcuture of HSD3B1.

Peripheral Steroidogenesis and Intracrine Signaling
HSD3B1 is the primary HSD3B isoform responsible for peripheral (extragonadal/extradrenal) steroidogenesis, converting circulating dehydroepiandrosterone sulfate (DHEA-S) to active androgens and estrogens within target tissues. This intracrine mechanism is of particular importance in tissues such as the prostate and breast, where local androgen and estrogen production sustains hormone-dependent physiology and pathology. HSD3B1 is an integral membrane protein of the endoplasmic reticulum, with its dehydrogenase activity requiring NAD+ and its isomerase activity proceeding spontaneously following the dehydrogenase reaction. The enzyme is regulated transcriptionally by steroidogenic factor 1 (SF-1/NR5A1) and by inflammatory cytokines including IL-4 and IL-13, linking peripheral steroidogenesis to immune signaling pathways. A common germline missense variant in HSD3B1 (rs1047303, encoding Asn367Thr) results in a more stable protein resistant to ubiquitin-mediated degradation, leading to substantially increased peripheral androgen biosynthesis.

HSD3B1 in Prostate Cancer, Breast Cancer, and Congenital Adrenal Hyperplasia
The HSD3B1 Asn367Thr gain-of-function polymorphism has emerged as a major determinant of treatment outcomes in advanced prostate cancer. Men harboring the adrenal-permissive Thr367 allele exhibit accelerated conversion of adrenal DHEA to intratumoral androgens, leading to more rapid progression to castration-resistant prostate cancer (CRPC) and inferior responses to androgen deprivation therapy and abiraterone. HSD3B1 inhibitors are under clinical development as therapeutics to block this resistance mechanism. In breast cancer, HSD3B1-mediated local estrogen production in adipose and tumor tissue contributes to disease progression in postmenopausal women. Conversely, loss-of-function mutations in HSD3B2 (the related adrenal/gonadal isoform) cause congenital adrenal hyperplasia with salt-wasting and sexual ambiguity, while HSD3B1 deficiency has been reported only rarely due to its extra-adrenal expression pattern. The enzyme represents a compelling therapeutic target at the intersection of endocrinology and oncology.

Alternate Names for HSD3B1

HSD3B1; hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1; HSD3B, HSDB3; 3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1; SDR11E1; short chain dehydrogenase/reductase family 11E; member 1; 3 beta-hydroxysteroid dehydrogenase/Delta 5--> 4-isomerase type 1; 3-beta-HSD I; progesterone reductase