Effects of intravaginal dehydroepiandrosterone on vaginal histomorphology, sex steroid receptor expression and cell proliferation in the rat.
OBJECTIVE
Recent clinical studies have shown that postmenopausal hormone therapy with estrogen plus progestogen increases breast cancer risk. Moreover, intravaginal estrogen-containing pills, creams and rings lead to significant systemic exposure to estrogen, thus indicating the need for a completely novel approach to alleviate vaginal atrophy in postmenopausal women.


METHODS
We have studied the effect of intravaginal application of dehydroepiandrosterone at daily doses of 0.33 mg, 0.66 mg or 1mg in ovariectomized animals for 2 weeks, with the objective of inducing local beneficial effects in the vagina without significant systemic action.


RESULTS
After 2 weeks, serum dehydroepiandrosterone, androst-5-ene-3beta,17beta-diol and dehydroepiandrosterone-sulfate were increased over a 4h time period, but serum testosterone, estradiol, estrone and dihydrotestosterone remained below detectable levels. The suppository vehicle alone produced minimal epithelial thickening limited to the vaginal distal half. The morphological effects of dehydroepiandrosterone on vaginal mucosa were observed at the lowest dose and consisted mainly of a typical androgenic effect of epithelial mucification. No change in morphological features related to cell proliferation was observed at any dehydroepiandrosterone dose on uterus, mammary gland and skin. At the highest dose, body weight showed a significant decrease, thus indicating a systemic effect on lipid accumulation. Immunohistochemistry for androgen, estrogen alpha and progesterone receptors did not reveal any significant systemic effects in the uterus, mammary gland and skin except some suggestion of increased androgen receptor labeling in mammary gland and skin at the highest dehydroepiandrosterone dose.


CONCLUSIONS
The present data show that intravaginal dehydroepiandrosterone can exert beneficial effects limited to the vagina.
Berger
Louise
L
Oncology and Molecular Endocrinology Research Center, Laval University Medical Center CHUL and Laval University, Quebec G1V 4G2, Canada.
El-Alfy
Mohamed
M
Labrie
Fernand
F
D000282:Administration, Intravaginal; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D003687:Dehydroepiandrosterone / Q000008:administration & dosage* / Q000097:blood; D047628:Estrogen Receptor alpha / Q000378:metabolism; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000187:drug effects; D023421:Models, Animal; D011644:Puerperal Disorders / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011944:Receptors, Androgen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D012867:Skin / Q000187:drug effects; D014599:Uterus / Q000187:drug effects; D014621:Vagina / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D003687:Dehydroepiandrosterone