Maternal PCOS status and metformin in pregnancy: Steroid hormones in 5–10 years old children from the PregMet randomized controlled study

Abstract

Objective Polycystic ovary syndrome (PCOS) is a common endocrine disorder, with potential effects on offspring both genetically and through altered intrauterine environment. Metformin, which ameliorate hormonal disturbances in non-pregnant women with PCOS is increasingly used in pregnancy. It passes the placenta, and the evidence on potential consequences for offspring endocrine development is scarce. We explore the potential effects of maternal PCOS status and intrauterine metformin exposure on offspring steroid hormone levels. Design This is a follow-up study of 5–10 years old children from the PregMet-study–a randomized controlled trial comparing metformin (2000 mg/day) to placebo during PCOS pregnancies. Of the 255 children invited, 117 (46%) were included. Methods There was no intervention in this follow-up study. Outcomes were serum levels of androstenedione, testosterone, SHBG, cortisol, 17-hydroxyprogesterone, 11-deoxycortisol and calculated free testosterone converted to gender-and age adjusted z-scores from a Norwegian reference population. These were compared in i) placebo-exposed children versus children from the reference population (z-score zero) by the deviation in z-score by one-sample t-tests and ii) metformin versus placebo-exposed children by two-sample t-tests. Holm-Bonferroni adjustments were performed to account for multiple endpoints. Results Girls of mothers with PCOS (n = 30) had higher mean z-scores of androstenedione (0.73 (95% confidence interval (CI) 0.41 to 1.06), p<0.0001), testosterone (0.76 (0.51 to 1.00), p<0.0001), and free testosterone (0.99 (0.67 to 1.32), p<0.0001) than the reference population. Metformin-exposed boys (n = 31) tended to have higher 11-deoxycortisol z-score than placebo-exposed boys (n = 24) (mean difference 0.65 (95% CI 0.14–1.17), p = 0.014). Conclusion Maternal PCOS status was associated with elevated androgens in 5- to 10-year-old daughters, which might indicate earlier maturation and increased risk of developing PCOS. An impact of metformin in pregnancy on steroidogenesis in children born to mothers with PCOS cannot be excluded. Our findings need confirmation in studies that include participants that have entered puberty.

Effects of metformin on pregnancy outcome, metabolic profile, and sex hormone levels in women with polycystic ovary syndrome and their offspring: a systematic review and meta-analysis

“…A total of 3,149 records were included in the initial search, and 2,837 remained after duplicates were removed. After excluding articles that did not meet the inclusion criteria, 48 studies were full-text screened, and finally 18 articles were determined to be eligible and included in this analysis (Figure 1) (1,(9)(10)(11)(12)(14)(15)(16)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28).…”

“…Besides, whether metformin is associated with metabolic profile and sex hormone levels also remain a subject of debate. Recent published studies showed controversial results of fasting glucose and SHGB hormone levels (9,(14)(15)(16). The small sample size of the studies might contribute to the various and inconsistent results, thus it is necessary to develop a meta-analysis to assess the efficacy of metformin.…”

Reference Curves for Pediatric Endocrinology: Leveraging Biomarker Z-Scores for Clinical Classifications

“…While nonparametric hormone references represent clinical cutoff values and primarily provide a qualitative indication as to whether the patient is within or outside the reference interval, LMS models enable quantitative benchmarking and longitudinal tracking of patients’ biomarker levels in terms of z-scores. This feature was recently leveraged to quantify endocrine abnormalities in a pediatric cohort that were exposed to metformin in utero due to treatment of maternal polycystic ovary syndrome ( 22 ). Applying reference curves to monitor individual patients over time may also be useful for evaluating pediatric endocrinopathies, differences of sex development, and general follow-up.…”

“…Furthermore, we hypothesized that pediatric overweight may be associated with an altered endocrine profile that, in particular, may be characterized by increased levels of estrogens due to increased adipose tissue aromatase activity. The current reference curves have not been published previously but were recently used to benchmark biomarker z-scores in an unrelated cohort of children exposed to metformin in utero due to maternal polycystic ovary syndrome ( 22 ).…”

Clinical management of pregnancy in women with polycystic ovary syndrome: An expert opinion

“…70,71 Interestingly, in the same study subanalysis when disaggregated by foetal sex, Metformin showed a modest decrease in maternal androgen levels during pregnancy for women with female foetuses, although no effect was observed in the androgen levels of the girls subsequently at age 5-10 years. 72 A recent meta-analysis of children born to women with GDM or PCOS found that Metformin intake in pregnancy was associated with higher long-term weight in children. 73 Given the positive effects of Metformin in systemic level, 74 it seems rational to use Metformin as a pre-pregnancy treatment for weight management although the role of Metformin on improving pregnancy rate or live birth rate is still debatable 75,76 and the benefit seems to be linked to ovulation induction rather than IVF/ICSI.…”