Preconception folic acid use modulates estradiol and follicular responses to ovarian stimulation.
BACKGROUND
Folate is a methyl donor. Availability of folate affects DNA methylation profiles and thereby gene expression profiles. We investigated the effects of low-dose folic acid use (0.4 mg/d) on the ovarian response to mild and conventional ovarian stimulation in women.


METHODS
In a randomized trial among subfertile women, 24 and 26 subjects received conventional and mild ovarian stimulation, respectively. Blood samples were taken during the early follicular phase of the cycle prior to treatment and on the day of human chorionic gonadotropin administration for determination of serum total homocysteine, anti-Müllerian hormone (AMH), estradiol, and folate. Folic acid use was validated by questionnaire and serum folate levels. Preovulatory follicles were visualized, counted, and diameters recorded using transvaginal ultrasound. The relation between folic acid use and ovarian response was assessed using linear regression analysis.


RESULTS
Folic acid use modified the ovarian response to ovarian stimulation treatment. The estradiol response was higher in nonfolic acid users receiving conventional treatment [β(interaction) = 0.52 (0.07-0.97); P = 0.03], and this effect was independent of serum AMH levels and the preovulatory follicle count. In the conventional treatment, the mean follicle number was also greater in nonusers compared with the users group (14.1 vs. 8.9, P = 0.03).


CONCLUSIONS
Low-dose folic acid use attenuates follicular and endocrine responses to conventional stimulation, independent of AMH and follicle count. The nature of this observation suggests that the effect of folic acid is most prominent during early follicle development, affecting immature follicles. Deleterious effects of folate deficiency, like DNA hypomethylation and oxidative stress, can help to explain our observations.
Department of Obstetrics and Gynaecology, Erasmus Medical Center, Rotterdam, The Netherlands.
John M
JM
Twigt
Fatima
F
Hammiche
Kevin D
KD
Sinclair
Nicole G
NG
Beckers
Jenny A
JA
Visser
Jan
J
Lindemans
Frank H
FH
de Jong
Joop S E
JS
Laven
Régine P
RP
Steegers-Theunissen
D000328:Adult; D054304:Anti-Mullerian Hormone / Q000097:blood; D015415:Biomarkers; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D005260:Female; D005307:Fertilization in Vitro; D005492:Folic Acid / Q000097:blood / Q000494:pharmacology*; D006062:Gonadotropins / Q000494:pharmacology; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D007247:Infertility, Female / Q000378:metabolism; D008297:Male; D006080:Ovarian Follicle / Q000502:physiology*; D010062:Ovulation Induction; D020554:Sperm Injections, Intracytoplasmic; D016896:Treatment Outcome; D014815:Vitamins / Q000097:blood / Q000494:pharmacology*
D015415:Biomarkers; D006062:Gonadotropins; D014815:Vitamins; D006710:Homocysteine; D004958:Estradiol; D054304:Anti-Mullerian Hormone; D005492:Folic Acid