The role of thyroid hormone function and prokineticin-1 in pregnancy and offspring outcome in women with polycystic ovary syndrome

Thyroid disorders are common in women with polycystic ovary syndrome (PCOS) and both conditions are associated with adverse pregnancy outcomes, such as intrauterine growth restriction, preterm delivery, and gestational diabetes (GDM). Furthermore, increased serum levels of prokineticin-1 (PROK1) are associated with similar complications. However, data is scarce on how pregnancy and neonatal outcomes are associated with maternal thyroid function and PROK1 in PCOS. Two similar randomized controlled studies, in which pregnant women with PCOS were treated with metformin or placebo and followed longitudinally during pregnancy, provided the data for papers I-IV. In this thesis, we aimed to study the role of thyroid hormone function and PROK1 for pregnancy and offspring outcomes in PCOS, as well as the effect of metformin.

In paper I, we studied thyroid status longitudinally in association with pregnancy complications, and in relation to metformin treatment in pregnant women with PCOS. Metformin treatment resulted in less decrease in free thyroxine (fT4) compared to placebo without affecting thyroid stimulating hormone (TSH). Moreover, a smaller decrease in fT4 correlated to less maternal weight gain and tended to be associated with a lower risk of GDM.

In paper II, we analyzed the contribution of PROK1 in the development of pregnancy complications, and in relation to metformin treatment and the PCOS phenotypes. Maternal serum-PROK1 in the second trimester was not predictive of pregnancy complications. Women using metformin at conception and/or during pregnancy had lower PROK1 levels, as well as women with hyperandrogenic PCOS phenotypes.

In paper III, we aimed to study associations between maternal thyroid function and offspring’s anthropometry. Higher maternal fT4 in early pregnancy and a greater decrease in fT4 during pregnancy was associated with lower offspring birthweight and shorter birth length. Higher TSH by mid-gestation and smaller increase in TSH during pregnancy were associated with less risk of large for gestational age (LGA) neonates.

In paper IV, we examined associations of maternal thyroid function during pregnancy with measures of insulin resistance. We found that lower maternal fT4 levels and smaller TSH increase during pregnancy were associated with higher subsequent insulin/homeostatic model assessment for insulin resistance (HOMA-IR) and glucose levels, respectively.

In summary, metformin treatment during pregnancy in women with PCOS induces less decrease in fT4 compared to placebo, without affecting TSH. This change in fT4 tends to be associated with a lower risk of GDM. PROK1 in the second trimester does not predict complications. Even subclinical variations in maternal thyroid function might play a role for birth anthropometrics of PCOS offspring and predict metabolic profile later in pregnancy.

List of scientific papers

I. Thyroid Status During Pregnancy in Women with Polycystic Ovary Syndrome and the Effect of Metformin. Trouva A, Alvarsson M, Calissendorff J, Åsvold BO, Vanky E*, Hirschberg AL*. Front Endocrinol (Lausanne). 2022 Feb 21;13:772801. *Shared last authorship.
https://doi.org/10.3389/fendo.2022.772801

II. Maternal serum levels of prokineticin-1 related to pregnancy complications and metformin use in women with polycystic ovary syndrome: a post hoc analysis of two prospective, randomised, placebo-controlled trials. Ujvari D, Trouva A, Hirschberg AL*, Vanky E*. BMJ Open. 2023 Nov 21;13(11):e073619. *Shared last authorship.
https://doi.org/10.1136/bmjopen-2023-073619

III. Maternal thyroid function and offspring birth anthropometrics in women with polycystic ovary syndrome. Trouva A, Alvarsson M, Calissendorff J, Åsvold BO, Ujvari D, Hirschberg AL* and Vanky E*. *Shared last authorship. [Submitted]

IV. Maternal thyroid function as predictor of markers of insulin resistance in pregnant women with PCOS. Trouva A, Vanky E, Alvarsson M, Calissendorff J, Åsvold BO, Ujvari D* and Hirschberg AL*. *Shared last authorship. [Manuscript]