Long-term treatment with dehydroepiandrosterone may lead to follicular atresia through interaction with anti-Mullerian hormone.
BACKGROUND
Hyperandrogenism is the primary manifestation of polycystic ovary syndrome (PCOS), which appears to be caused by excess exposure to androgen. As such, androgenized animal models have been developed and investigated to study the etiology of PCOS. Anti-Mullerian hormone (AMH) is known to be associated with follicle growth, and its levels are two to three times higher in women with PCOS than in those with normal ovaries. We studied how duration of androgen administration affects folliculogenesis and AMH expression.


METHODS
We divided 30 immature (3-week-old) Sprague Dawley rats into six groups. Three groups were injected each evening with dehydroepiandrosterone (DHEA) (6 mg/100 g body weight/0.2 ml sesame oil) for 7, 15 or 30 days, respectively. The three control groups were injected with 0.2 ml of sesame oil for the corresponding lengths of time. Resected ovaries were sectioned and examined to determine follicle numbers at each developmental stage, and immunostained to assess AMH expression.


RESULTS
On day 7, follicle numbers and AMH expression levels at each developmental stage of follicle growth were similar in the respective control and DHEA groups. On day 15, the total follicle number (P = 0.041), the percentage of primordial follicles (P = 0.039) and AMH expression were significantly greater in the DHEA than the control group. On day 30, the percentages of primordial (P = 0.005), primary (P = 0.0002) and atretic (P = 0.03) follicles were significantly greater in the DHEA group, whereas the percentage of intermediary follicles (early pre-antral, late preantral, and early antral follicles) was significantly lower in the DHEA group (P = <0.0001). AMH expression in DHEA-treated rats on day 30 was seen exclusively in the primordial (P = 0.0413) and late antral follicles (p = 0.028).


CONCLUSIONS
Androgen administration increases AMH production in a process that regulates the growth of primordial follicles. That is, androgen-induced AMH expression provides local negative feedback to folliculogenesis augmented by androgen.
Department of Obstetrics and Gynecology, Steel Memorial Muroran Hospital, 1-45, Chiribethutown, Muroran, Hokkaido 050 0076, Japan.
Keiko
K
Ikeda
Department of Obstetrics and Gynecology, Sapporo Medical University, South 1 West 16, Sapporo, Hokkaido 060 8543, Japan.
Tsuyoshi
T
Baba
Department of Obstetrics and Gynecology, Sapporo Medical University, South 1 West 16, Sapporo, Hokkaido 060 8543, Japan.
Miyuki
M
Morishita
Kamiya Ladies Clinic Sapporo, North 3 West 2, Sapporo, Hokkaido 060 0003, Japan.
Hiroyuki
H
Honnma
Department of Obstetrics and Gynecology, Sapporo Medical University, South 1 West 16, Sapporo, Hokkaido 060 8543, Japan.
Toshiaki
T
Endo
Ena Ladies Clinic, 9-1-86 Hanakawa-minami, Ishikari, Hokkaido 061-3209, Japan.
Tamotsu
T
Kiya
Department of Obstetrics and Gynecology, Sapporo Medical University, South 1 West 16, Sapporo, Hokkaido 060 8543, Japan.
Tsuyoshi
T
Saito
D000818:Animals; D054304:Anti-Mullerian Hormone / Q000097:blood*; D003687:Dehydroepiandrosterone / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D005496:Follicular Atresia; D017588:Hyperandrogenism / Q000097:blood; D009866:Oogenesis; D010053:Ovary / Q000187:drug effects / Q000473:pathology; D011085:Polycystic Ovary Syndrome / Q000097:blood; D017207:Rats, Sprague-Dawley
D003687:Dehydroepiandrosterone; D054304:Anti-Mullerian Hormone
Androgen; Animal model; Anti-mullerian hormone; Folliculogenesis; Polycystic ovary