A role for the androgen receptor in follicular atresia of estrogen receptor beta knockout mouse ovary.
Estrogen receptor beta (ERbeta) is highly expressed, but ERalpha is not detectable in granulosa cells in the mouse ovary. In ERbeta 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 ERbeta 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.
Cheng
Guojun
G
Department of Medical Nutrition, Karolinska Institute, NOVUM, S-14186 Huddinge, Sweden.
Weihua
Zhang
Z
Mäkinen
Sirpa
S
Mäkelä
Sari
S
Saji
Shigehira
S
Warner
Margaret
M
Gustafsson
Jan-Ake
JA
Hovatta
Outi
O
D000726:Androgen Antagonists / Q000494:pharmacology; D000818:Animals; D001391:Azo Compounds; D047629:Estrogen Receptor beta; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D005496:Follicular Atresia / Q000502:physiology*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D051379:Mice; D018345:Mice, Knockout; D006080:Ovarian Follicle / Q000502:physiology; D010053:Ovary / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D011944:Receptors, Androgen / Q000502:physiology*; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology*
D000726:Androgen Antagonists; D001391:Azo Compounds; D047629:Estrogen Receptor beta; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D007334:Insulin-Like Growth Factor I; D005485:Flutamide; C011049:oil red O