A Role for the Androgen Receptor in Follicular Atresia of Estrogen Receptor Beta Knockout Mouse Ovary

• Published in: Biology of reproduction Vol. 66; no. 1; pp. 77 - 84
• Main Authors: Cheng, Guojun, Weihua, Zhang, Mäkinen, Sirpa, Mäkelä, Sari, Saji, Shigehira, Warner, Margaret, Gustafsson, Jan-Ake, Hovatta, Outi
• Format: Journal Article
• Language: English
• Published: Madison, WI Society for the Study of Reproduction 01-01-2002
• Subjects: Androgen Antagonists - pharmacology; Animals; Azo Compounds; Biological and medical sciences; Estrogen Receptor beta; Female; Flutamide - pharmacology; Follicular Atresia - physiology; Immunohistochemistry; Insulin-Like Growth Factor I - biosynthesis; Medicin och hälsovetenskap; Mice; Mice, Knockout; Ovarian Follicle - physiology; Ovary - anatomy & histology; Ovary - drug effects; Ovary - metabolism; Phenotype; Receptors, Androgen - physiology; Receptors, Estrogen - genetics; Receptors, Estrogen - physiology
• ISSN: 0006-3363; 1529-7268
• DOI: 10.1095/biolreprod66.1.77

Estrogen receptor beta (ERβ) is highly expressed, but ERα is not detectable in granulosa cells in the mouse ovary. In ERβ
knockout (BERKO) mice, there is abnormal follicular development and very reduced fertility. At 3 wk of age, no significant
morphologic differences were discernable between wild type (WT) and BERKO mouse ovaries, but by 5 mo of age, atretic follicles
were abundant in BERKO mice and there were very few healthy late antral follicles or corpora lutea. At 2 yr of age, unlike
the ovaries of their WT littermates, BERKO mouse ovaries were devoid of healthy follicles but had numerous large, foamy lipid-filled
stromal cells. The late antral and atretic follicles in BERKO mice were characterized by a high level of expression of the
androgen receptor (AR) and IGF-1 receptor. These proteins were abundantly expressed in granulosa cells of preantral and early
antral follicles in both genotypes, but their expression was extinguished in late antral follicles of WT mice. Healthy late
antral follicles and corpora lutea were restored in BERKO ovaries after 15 days of treatment of mice with the antiandrogen
flutamide. The results suggest that in the absence of ERβ there was a loss of regulation of AR. Because androgens enhance
recruitment of primordial follicles into the growth pool and cause atresia of late antral follicles, the inappropriately high
level of AR probably is related to the follicular atresia and to the early exhaustion of follicles in BERKO mice.