To investigate the possibility of direct effects of metformin on ovarian steroidogenesis.
Design
Cultured ovarian cells.
Setting
Academic research environment.
PATIENT(S): Women undergoing bilateral salpingoophorectomy for benign gynecological disease.
MAIN OUTCOME MEASURE(S): Estradiol and P were measured in granulosa cell (GC) conditioned medium and androstenedione (A) and P in theca conditioned medium.
RESULT(S): The effect of addition of metformin alone to GCs was variable, but significant inhibition of both P and E2 was seen (range 0%-30%). Metformin dose-dependently inhibited gonadotrophin and insulin-stimulated P and E2 production (range 25%-50%). In theca, metformin inhibited A production (0%-40%) with no effect on P. In the presence of insulin, A was inhibited dose-dependently and P increased by a similar magnitude.
CONCLUSION(S): These results demonstrate a direct effect of metformin on ovarian steroidogenesis. The inhibitory effects on androgen production in particular would be beneficial in polycystic ovary syndrome (PCOS).
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PMID 12749437 12749437 DOI 10.1016/s0015-0282(02)04925-7 10.1016/s0015-0282(02)04925-7
Cite this article
Mansfield, R., Galea, R., Brincat, M., Hole, D., & Mason, H. (2003). Metformin has direct effects on human ovarian steroidogenesis. Fertility and sterility, 79(4), 956-962. https://doi.org/10.1016/s0015-0282(02)04925-7
Mansfield R, Galea R, Brincat M, Hole D, Mason H. Metformin has direct effects on human ovarian steroidogenesis. Fertil Steril. 2003;79(4):956-962. doi:10.1016/s0015-0282(02)04925-7
Mansfield, Rebecca, et al. "Metformin has direct effects on human ovarian steroidogenesis." Fertility and sterility, vol. 79, no. 4, 2003, pp. 956-962.
To review the effectiveness of metformin in restoring regular menstrual cycles and ovulation and achieving pregnancy in women with polycystic ovary syndrome (PCOS). Systematic review of pertinent studies identified using the bibliographic databases MEDLINE and EMBASE. References of selected articles identified were hand-searched for additional relevant citations. PATIENT(S): Women with PCOS undergoing treatment with metformin alone, metformin combined with other methods of ovulation induction such as clomiphene citrate (CC) or gonadotropin injections, or metformin combined with in vitro fertilization (IVF). RESULT(S): Thirty published studies were included in the overall review. Studies consisted of 12 randomized controlled trials, two cohort studies, and 16 uncontrolled descriptive studies. Due to a strong variability in the use of metformin according to study population, exposure, and outcome of interest, it was not possible to combine the data of the 12 randomized controlled trials to perform a meta-analysis. Limited data on predominately obese PCOS patients demonstrate that metformin alone improves both restoration of regular menses and spontaneous ovulation, but there are no data supporting an improvement in pregnancy rate. The addition of metformin to CC results in an improved ovulation and pregnancy rate in both unselected and CC-resistant PCOS women. There are insufficient data to make any conclusions on the effect of metformin on FSH ovulation induction or IVF. CONCLUSION(S): The effectiveness and role of metformin in the treatment of PCOS anovulatory infertility in clinical practice is difficult to assess from currently available research. Further well-designed prospective, perhaps multicenter, randomized controlled trials with the primary end point of pregnancy or live-birth rate are required.
PCOSMetforminInsulin Resistance and HyperandrogenismAromatase Activity
To investigate the effects of reduction of insulin resistance and hyperinsulinemia associated with the polycystic ovary syndrome (PCOS) on FSH-stimulated ovarian aromatase activity. Prospective study. Academic health center, Siena, Italy. PATIENT(S): Twenty women 18 to 26 years of age in whom PCOS was diagnosed on the basis of oligomenorrhea or amenorrhea and hyperandrogenemia. INTERVENTION(S): Recombinant FSH was administered. The next day, therapy with metformin (500 mg t.i.d.) was begun. After 35 to 40 days of treatment, the pretreatment protocol was repeated. MAIN OUTCOME MEASURE(S): Plasma levels of estradiol (E(2)), androstenedione (A), and testosterone (T). The ratios of basal levels and areas under the curve (AUCs) of products and substrates were compared before and after metformin administration to detect differences in aromatase activity. RESULT(S): Metformin treatment was associated with significant reduction in basal free testosterone plasma levels, insulin plasma levels, and insulin response to oral glucose tolerance testing. Administration of FSH was followed by a significantly lesser E(2) response after metformin therapy than before this therapy. The ratios of AUC(E2) to AUC(A) and to AUC(T), indicative of aromatase activity in response to FSH, were significantly lower after metformin therapy than before. CONCLUSION(S): Metformin therapy in women with PCOS is associated with a reduction in aromatase activity in response to FSH. Insulin affects production of both androgen and estrogen. Insulin therefore plays a central role in regulating the activity of thecal and granulosa cells.
Practice Committee of the American Society for Reproductive Medicine, 2026·Fertility and Sterility
Current strategies for the assessment and treatment of recurrent pregnancy loss are discussed. This replaces the previous document, titled, "Evaluation and treatment a committee opinion," last published in 2012.
This narrative review examines the evidence for medical optimization of inflammatory conditions, vitamin deficiencies, endocrine disorders, immune dysregulation, oligo-ovulation, and luteal phase factors to improve fertility outcomes in women attempting to conceive through natural or timed intercourse. Overall, there is a paucity of data with respect to these categories among patients pursuing timed intercourse, precluding our ability to draw strong recommendations. However, there is strong evidence supporting treatment of endocrine disorders, specifically overt thyroid dysfunction and hyperprolactinemia, as well as oligo-ovulation. Conversely, treatment of subclinical hypothyroidism is not recommended. The current data are insufficient to support empiric use of antiinflammatory medications, corticosteroids, thyroid hormones, or vitamins or supplements to improve chances of pregnancy in a general infertility population.