Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes

Area of Science:

• Endocrinology
• Reproductive Biology
• Genetics

Background:

• Steroid 5 alpha-reductases (SRD5A1 and SRD5A2) are critical enzymes in androgen metabolism.
• Dihydrotestosterone (DHT), a metabolite of testosterone (T), is known to play a role in male sexual development.

Purpose of the Study:

• To investigate the specific roles of steroid 5 alpha-reductase 1 and 2 in male mouse reproductive tract differentiation and function.
• To determine whether T or DHT is the primary androgen responsible for male urogenital development.

Main Methods:

• Gene targeting and breeding to create mice deficient in SRD5A1 and/or SRD5A2.
• Administration of T, DHT, and a 5 alpha-reductase inhibitor (GI 208335X).
• Analysis of reproductive tissue weights, androgen levels, and androgen-dependent gene expression.

Main Results:

• Male mice lacking SRD5A2 or both SRD5A1/SRD5A2 had normal genitalia but smaller prostates and seminal vesicles.
• DHT administration partially restored reproductive tissue weights in mutant mice.
• Inhibitor studies and castration confirmed the role of 5 alpha-reductases in maintaining tissue size.
• Androgen-dependent gene expression was impaired in mutants but restored by T or DHT administration.

Conclusions:

• Testosterone (T) is the essential androgen for male urogenital tract differentiation in mice.
• DHT synthesis primarily functions as a signal amplification mechanism rather than a critical differentiation signal.
• SRD5A1 and SRD5A2 play significant roles in maintaining the size and function of male reproductive tissues post-differentiation.