Effects of experimental hyperandrogenemia on the female rat reproductive axis: suppression of progesterone-receptor messenger RNA expression in the brain and blockade of luteinizing hormone surges.
BACKGROUND
Preovulatory gonadotropin-releasing hormone and luteinizing hormone (LH) surges depend on activation of estrogen-inducible progesterone receptors (PRs) in the hypothalamus. Although testosterone treatment can suppress LH secretion under some circumstances, how androgens affect the release of preovulatory hormone surges, and the cellular mechanisms by which androgens exert any such effects, remains unknown.


OBJECTIVE
This study examined the hypothesis that testosterone can block the release of estrogen-induced gonadotropin surges via attenuation of estrogen's ability to induce PRs in the preoptic area (POA)-hypothalamus.


METHODS
In experiment 1, proestrus rats were implanted with capsules filled with crystalline testosterone or empty control capsules. Four days later, animals were bled via atrial catheters at 30-minute intervals from noon to 9:00 pm. In experiment 2, proestrus rats received testosterone-filled or empty control capsules, and 3 days later were ovariectomized (OVX) and injected with estradiol benzoate (EB) 30 mug SC or sesame oil vehicle. The next day, blood samples were obtained from the rats. In experiment 3, proestrus rats similarly implanted with testosterone-filled or empty control capsules, OVX, and injected with EB or vehicle were sacrificed, and POA-hypothalamic tissue was collected for quantitative reverse transcription-polymerase chain reaction analysis of PR messenger RNA.


RESULTS
In experiment 1, radioimmunoassay of serum revealed that testosterone completely blocked release of LH surges that were fully evident in the control group. In experiment 2, LH radioimmunoassay revealed that high-physiologic testosterone exposure completely abolished the release of EB-induced LH surges. In experiment 3, although EB treatment was found to induce an increase in PR expression in control animals, no such induction of PR expression was observed in the testosterone-treated rats.


CONCLUSIONS
Our findings are consistent with the hypothesis that hyperandrogenic interference in the release of preovulatory LH surges is mediated by the suppressive effects of androgens on PR expression in POA-hypothalamic tissue. These findings may have important implications in the understanding of reproductive dysregulation in female hyperandrogenic syndromes, including polycystic ovary syndrome.
Foecking
Eileen M
EM
Department of Neurobiology and Physiology, Northwestern Universirty, Evanston, Illinois 60208, USA.
Levine
Jon E
JE
D000818:Animals; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005498:Follicular Phase / Q000097:blood; D017588:Hyperandrogenism / Q000097:blood*; D007986:Luteinizing Hormone / Q000097:blood*; D010903:Pituitary Gland, Anterior / Q000187:drug effects* / Q000378:metabolism; D011301:Preoptic Area / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D011980:Receptors, Progesterone; C074283:estradiol 3-benzoate; D004958:Estradiol; D007986:Luteinizing Hormone