Sustained Maternal Hyperandrogenism During PCOS Pregnancy Reduced by Metformin in Non-obese Women Carrying a Male Fetus

Frida Andræ, David Abbott, Solhild Stridsklev, Anne Vibeke Schmedes, Ingrid Hov Odsæter, Eszter Vanky, Øyvind Salvesen, Frida Andræ, David Abbott, Solhild Stridsklev, Anne Vibeke Schmedes, Ingrid Hov Odsæter, Eszter Vanky, Øyvind Salvesen

Abstract

Context: Large, longitudinal studies on androgen levels in pregnant women with polycystic ovary syndrome (PCOS) are lacking. While metformin has a mild androgen-lowering effect in non-pregnant women with PCOS, its effects on maternal androgen levels in pregnancy are less well understood.

Objective: To describe androgen patterns in pregnant women with PCOS and in healthy control women, and to explore the potential effects of metformin on maternal androgen levels in PCOS.

Design and setting: A post hoc analysis from a randomized, placebo-controlled, multicenter study carried out at 11 secondary care centers and a longitudinal single-center study on healthy pregnant women in Norway.

Participants: A total of 262 women with PCOS and 119 controls.

Intervention: The participants with PCOS were randomly assigned to metformin (2 g daily) or placebo, from first trimester to delivery.

Main outcome measures: Androstenedione (A4), testosterone (T), sex-hormone binding globulin (SHBG), and free testosterone index (FTI) at 4 time points in pregnancy.

Results: Women with PCOS versus healthy controls had higher A4, T, and FTI, and lower SHBG at all measured time points in pregnancy. In the overall cohort of women with PCOS, metformin had no effect on A4, T, SHBG, and FTI. In subgroup analyses, metformin reduced A4 (P = 0.019) in nonobese women. Metformin also reduced A4 (P = 0.036), T (P = 0.023), and SHBG (P = 0.010) levels through pregnancy in mothers with a male fetus.

Conclusion: Metformin had no effect on maternal androgens in PCOS pregnancies. In subgroup analyses, a modest androgen-lowering effect was observed in nonobese women with PCOS. In PCOS women carrying a male fetus, metformin exhibited an androgen-lowering effect.

Trial registration: ClinicalTrials.gov NCT00159536.

Keywords: PCOS; androgens; androstenedione; gender; metformin; obesity; pregnancy; testosterone.

© Endocrine Society 2020.

Figures

Figure 1.
Figure 1.
Flow chart on enrollment and randomization of pregnant women with polycystic ovary syndrome (PCOS).
Figure 2.
Figure 2.
Androstenedione (a), testosterone (b), free testosterone index (FTI) (c), and sex-hormone binding globulin (SHBG) (d) in women with polycystic ovary syndrome (PCOS), treated with metformin versus placebo in pregnancy and healthy pregnant controls.
Figure 3.
Figure 3.
Androstenedione (a), testosterone (b), free testosteroneindex (FTI) (c), and sex-hormone binding globulin (SHBG) (d) in women with polycystic ovary syndrome (PCOS), treated with metformin versus placebo in pregnancy according to body mass index (BMI) category.
Figure 4.
Figure 4.
Androstenedione (a), testosterone (b), and free testosterone index (FTI) (c), and sex-hormone binding globulin (SHBG) (d) in women with polycystic ovary syndrome (PCOS), treated with metformin versus placebo in pregnancy, according to fetal sex.

References

    1. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod. 2016;31(12):2841–2855.
    1. Tehrani FR, Simbar M, Tohidi M, Hosseinpanah F, Azizi F. The prevalence of polycystic ovary syndrome in a community sample of Iranian population: Iranian PCOS prevalence study. Reprod Biol Endocrinol. 2011;9:39.
    1. March WA, Moore VM, Willson KJ, Phillips DI, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25(2):544–551.
    1. Alvarez-Blasco F, Botella-Carretero JI, San Millán JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med. 2006;166(19):2081–2086.
    1. Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in women with polycystic ovary syndrome. Semin Reprod Med. 2008;26(1):72–84.
    1. Yu HF, Chen HS, Rao DP, Gong J. Association between polycystic ovary syndrome and the risk of pregnancy complications: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2016;95(51):e4863.
    1. Qin JZ, Pang LH, Li MJ, Fan XJ, Huang RD, Chen HY. Obstetric complications in women with polycystic ovary syndrome: a systematic review and meta-analysis. Reprod Biol Endocrinol. 2013;11:56.
    1. Kjerulff LE, Sanchez-Ramos L, Duffy D. Pregnancy outcomes in women with polycystic ovary syndrome: a metaanalysis. Am J Obstet Gynecol. 2011;204(6):558.e1–558.e6.
    1. Dewailly D, Cortet-Rudelli C. Insulin resistance and polycystic ovarian syndrome. Horm Res. 1992;38(1-2):41–45.
    1. Fleming R, Hopkinson ZE, Wallace AM, Greer IA, Sattar N. Ovarian function and metabolic factors in women with oligomenorrhea treated with metformin in a randomized double blind placebo-controlled trial. J Clin Endocrinol Metab. 2002;87(2):569–574.
    1. Palomba S, Falbo A, Zullo F, Orio F Jr. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;30(1):1–50.
    1. Glueck CJ, Goldenberg N, Wang P, Loftspring M, Sherman A. Metformin during pregnancy reduces insulin, insulin resistance, insulin secretion, weight, testosterone and development of gestational diabetes: prospective longitudinal assessment of women with polycystic ovary syndrome from preconception throughout pregnancy. Hum Reprod. 2004;19(3): 510–521.
    1. Maliqueo M, Lara HE, Sánchez F, Echiburú B, Crisosto N, Sir-Petermann T. Placental steroidogenesis in pregnant women with polycystic ovary syndrome. Eur J Obstet Gynecol Reprod Biol. 2013;166(2):151–155.
    1. Palomba S, Falbo A, Russo T, Tolino A, Orio F, Zullo F. Pregnancy in women with polycystic ovary syndrome: the effect of different phenotypes and features on obstetric and neonatal outcomes. Fertil Steril. 2010;94(5):1805–1811.
    1. Palomba S, Russo T, Falbo A, et al. Macroscopic and microscopic findings of the placenta in women with polycystic ovary syndrome. Hum Reprod. 2013;28(10):2838–2847.
    1. Maliqueo M, Sundström Poromaa I, Vanky E, et al. Placental STAT3 signaling is activated in women with polycystic ovary syndrome. Hum Reprod. 2015;30(3):692–700.
    1. Beckett EM, Astapova O, Steckler TL, Veiga-Lopez A, Padmanabhan V. Developmental programing: impact of testosterone on placental differentiation. Reproduction. 2014;148(2):199–209.
    1. Padmanabhan V, Veiga-Lopez A. Animal models of the polycystic ovary syndrome phenotype. Steroids. 2013;78(8):734–740.
    1. Homburg R, Gudi A, Shah A, M Layton A. A novel method to demonstrate that pregnant women with polycystic ovary syndrome hyper-expose their fetus to androgens as a possible stepping stone for the developmental theory of PCOS. A pilot study. Reprod Biol Endocrinol. 2017;15(1):61.
    1. Abbott DH, Kraynak M, Dumesic DA, Levine JE. In utero androgen excess: a developmental commonality preceding polycystic ovary syndrome? Front Horm Res. 2019;53:1–17.
    1. Barrett ES, Hoeger KM, Sathyanarayana S, et al. Anogenital distance in newborn daughters of women with polycystic ovary syndrome indicates fetal testosterone exposure. J Dev Orig Health Dis. 2018;9(3):307–314.
    1. Palomba S, Marotta R, Di Cello A, et al. Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Clin Endocrinol (Oxf). 2012;77(6):898–904.
    1. Risal S, Pei Y, Lu H, et al. Prenatal androgen exposure and transgenerational susceptibility to polycystic ovary syndrome. Nat Med. 2019;25(12):1894–1904.
    1. Vanky E, Stridsklev S, Heimstad R, et al. Metformin versus placebo from first trimester to delivery in polycystic ovary syndrome: a randomized, controlled multicenter study. J Clin Endocrinol Metab. 2010;95(12):E448–E455.
    1. Consensus. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). HumReprod. 2004;19(1):41–47.
    1. Stridsklev S, Salvesen Ø, Salvesen KÅ, Carlsen SM, Husøy MA, Vanky E. Uterine artery Doppler measurements during first and second trimesters of normal pregnancy. Acta Obstet Gynecol Scand. 2017;96(3):366–371.
    1. Sir-Petermann T, Maliqueo M, Angel B, Lara HE, Pérez-Bravo F, Recabarren SE. Maternal serum androgens in pregnant women with polycystic ovarian syndrome: possible implications in prenatal androgenization. Hum Reprod. 2002;17(10):2573–2579.
    1. Caanen MR, Kuijper EA, Hompes PG, et al. Mass spectrometry methods measured androgen and estrogen concentrations during pregnancy and in newborns of mothers with polycystic ovary syndrome. Eur J Endocrinol. 2016;174(1):25–32.
    1. Glintborg D, Jensen RC, Bentsen K, et al. Testosterone levels in third trimester in polycystic ovary syndrome: odense child cohort. J Clin Endocrinol Metab. 2018;103(10): 3819–3827.
    1. Piltonen TT, Giacobini P, Edvinsson A, et al. Circulating antimullerian hormone and steroid hormone levels remain high in pregnant women with polycystic ovary syndrome at term. Fertil Steril. 2019;111(3):588-596.
    1. Sarlis NJ, Weil SJ, Nelson LM. Administration of metformin to a diabetic woman with extreme hyperandrogenemia of nontumoral origin: management of infertility and prevention of inadvertent masculinization of a female fetus. J Clin Endocrinol Metab. 1999;84(5):1510–1512.
    1. Vanky E, Salvesen KA, Heimstad R, Fougner KJ, Romundstad P, Carlsen SM. Metformin reduces pregnancy complications without affecting androgen levels in pregnant polycystic ovary syndrome women: results of a randomized study. Hum Reprod. 2004;19(8):1734–1740.
    1. International evidence based guideline for the assessment and management of polycystic ovary syndrome Vol 2018. ProMED-mail website. . Accessed April 01, 2020.
    1. Hirsch A, Hahn D, Kempná P, et al. Metformin inhibits human androgen production by regulating steroidogenic enzymes HSD3B2 and CYP17A1 and complex I activity of the respiratory chain. Endocrinology. 2012;153(9):4354–4366.
    1. Morley LC, Tang T, Yasmin E, Norman RJ, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility [published online ahead of print November 29, 2017]. Cochrane Database Syst Rev. 2017;11(11). doi:10.1002/14651858.CD003053.pub6
    1. Ghidini A, Salafia CM. Histologic placental lesions in women with recurrent preterm delivery. Acta Obstet Gynecol Scand. 2005;84(6):547–550.
    1. Rosenfeld CS. Sex-specific placental responses in fetal development. Endocrinology. 2015;156(10):3422–3434.
    1. Gabory A, Roseboom TJ, Moore T, Moore LG, Junien C. Placental contribution to the origins of sexual dimorphism in health and diseases: sex chromosomes and epigenetics. Biol Sex Differ. 2013;4(1):5.

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