Maternal prolactin is associated with glucose status and PCOS in pregnancy: Odense Child Cohort

in European Journal of Endocrinology
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  • 1 Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark
  • 2 Department of Clinical Research, University of Southern Denmark, Odense, Denmark
  • 3 Department of Endocrinology, Odense University Hospital, Odense, Denmark
  • 4 Odense Child Cohort, Hans Christian Andersen Hospital for Children and Adolescents, Odense University Hospital, Odense, Denmark
  • 5 Department of Environmental Medicine, Odense University Hospital, Odense, Denmark
  • 6 Odense Patient data Explorative Network (OPEN), University of Southern Denmark, Odense, Denmark

Correspondence should be addressed to M Overgaard; Email: Martin.Overgaard@rsyd.dk

*(M Overgaard and D Glintborg contributed equally to this work)

Objective:

Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS).

Design:

Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included.

Methods:

Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L.

Results:

The median (IQR) prolactin increased from 633 (451–829) mIU/L in first–second trimester to 5223 (4151–6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = −0.19, P < 0.001) and third trimester (r = −0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051).

Conclusions:

Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.

Abstract

Objective:

Low circulating prolactin is a potential marker of metabolic risk during pregnancy. We aimed to investigate associations between prolactin and glucose status in pregnant women with and without gestational diabetes mellitus (GDM) or polycystic ovary syndrome (PCOS).

Design:

Prospective observational cohort study. From the Odense Child Cohort, 1497 pregnant women were included.

Methods:

Blood samples were assessed during first, second (prolactin, hemoglobin A1c (HbA1c)) and third trimester (fasting prolactin, testosterone, HbA1c, insulin, glucose). Oral glucose tolerance test (OGTT) was performed around gestation week 28 in 350 women with risk factors for GDM and in 272 randomly included women. GDM was defined by 2-h plasma glucose ≥9.0 mmol/L.

Results:

The median (IQR) prolactin increased from 633 (451–829) mIU/L in first–second trimester to 5223 (4151–6127) mIU/L at third trimester. Prolactin was inversely associated with HbA1c in first (r = −0.19, P < 0.001) and third trimester (r = −0.07, P = 0.014). In third trimester, women with GDM (n = 37; 6.0%) had lower prolactin compared to women without GDM (4269 vs 5072 mIU/L, P = 0.004). Third trimester prolactin multiple of the median (MoM) was inversely associated with risk of GDM in multivariate regression analysis (OR 0.30, P = 0.034). PCOS was diagnosed in 10.0% (n = 146). Early pregnancy prolactin MoM was positively associated to PCOS diagnosis (OR 1.38, P = 0.051).

Conclusions:

Low prolactin levels during pregnancy were associated with higher HbA1c and risk of GDM. A diagnosis of PCOS was associated with higher early pregnancy prolactin levels.

Introduction

Maternal serum prolactin levels rise during pregnancy and the concentration of prolactin at term is about ten times the concentration observed in the non-pregnant state (1). The best known physiological effect of prolactin in premenopausal women is the initiation and maintenance of lactation, but prolactin is also important for normal beta-cell function (2, 3, 4). In non-pregnant study populations, low prolactin levels predicted progression to type 2 diabetes (T2D) (5, 6, 7, 8, 9). In animal studies, prolactin receptor knockout was associated with reduced beta-cell mass and glucose intolerance during pregnancy (10). Limited data are available regarding prolactin and beta-cell function in human pregnancy (11).

During the first trimester of pregnancy, insulin sensitivity is high and fasting plasma glucose is reduced by approximately 10% (12). Insulin secretion increases throughout gestation in normal pregnancy, and peripheral insulin sensitivity is reduced during second–third trimester. Elevated amounts of insulin antagonistic hormones secreted by the placenta may play a role in this adaptation (3, 12). The development of insulin resistance during mid-late gestation is considered a physiologic stress test for pancreatic beta-cells. Gestational diabetes mellitus (GDM) is the best predictor of future T2D in women. Late pregnancy could therefore be a window of opportunity to investigate putative hormonal predictors of GDM and T2D (3, 13).

Recently, an association between low prolactin levels and risk of postpartum pre-diabetes or diabetes was reported in 367 healthy women, during third trimester (13). However, these findings could not be confirmed by another study (14). Previous clinical studies also showed conflicting data regarding serum prolactin levels in women with GDM, assessed during pregnancy and at term (15, 16, 17). Most likely, these differences could be ascribed to lack of statistical power due to small sample size.

Polycystic ovary syndrome (PCOS) is defined by androgen excess, irregular cycles and polycystic ovaries (18). More than 50% of women with PCOS are insulin resistant, but the risk of GDM and development of T2D in PCOS is closely associated with obesity (19). In lean women with PCOS, the risk of GDM was comparable in pregnant women with PCOS and controls (20). We previously reported significantly lower prolactin levels in non-pregnant women with PCOS compared to controls (21) and prolactin levels were inversely associated with metabolic risk factors (21). In pregnancy, high prolactin levels and increase in breast size were associated with lower third trimester fasting glucose levels and more favorable long-term metabolic health in women with PCOS (22). We are not aware of studies regarding prolactin levels and risk of GDM in pregnant women with PCOS.

The aim of the present study was to investigate possible associations between maternal prolactin levels and hemoglobin A1c (HbA1c), GDM and PCOS status in pregnancy. We hypothesized that low prolactin levels could be associated with higher metabolic risk in pregnancy and that this metabolic risk could be even higher in pregnant women with PCOS.

Subjects and methods

Study population

This study was based on the population-based Odense Child Cohort (OCC) (23). OCC is a joint research project in which pregnant women within the Municipality of Odense, Denmark, were recruited between January 1 2010 and December 31 2012. Of 6707 pregnancies, 4017 women received information about the study and 2874 pregnant women gave informed consent and were included (Fig. 1). Participating women attended blood sampling during first–second trimester (gestation weeks: 7–16) and during third trimester (gestation weeks: 27–30). Participants with multiple pregnancies (n = 74), or blood sampling outside gestation weeks 7–16 or 27–30 (n = 14), were excluded. Blood samples (serum) were available for 1043 of 2800 women in first–second trimester and for 1489 of 2800 women in third trimester. A total of 1035 participants had available blood samples from both visits. Early pregnancy (first–second trimester) median (range) gestational age at blood sampling was 11.9 (10.2–14.6) weeks, whereas late pregnancy (third trimester) median gestational age at blood sampling was 29.0 (28.5–29.5) (Table 1).

Figure 1
Figure 1

Flowchart of the Odense Child Cohort study population, blood sampling and analyses.

Citation: European Journal of Endocrinology 183, 3; 10.1530/EJE-20-0144

Table 1

Baseline maternal and pregnancy characteristics in women in the Odense Child Cohort. Data from women with available prolactin measurement in early and late pregnancy. Women divided according to diagnosis of GDM in third trimester. Data are presented as median and interquartile range, n (%), multiple of the gestation week median (MoM) or ratio (third trimester/first–second trimester). Gestational age is presented in weeks.

CharacteristicAllGDM+NGTGDMNGTP-value
n148961737580
BMI kg/m223.5 (21.3–26.6)25.1 (22.0–29.0)29.8 (25.2–31.6)24.8 (21.9–28.7)<0.001
Age30 (27–33)30 (27–33)31 (27–36)30 (27–33)0.14
Nulliparous, n (%)852 (57.8)350 (56.7)22 (59.5)328 (56.6)0.92
Early pregnancy, n104350928481
 Gestational age at blood sampling11.9 (10.2–14.6)12 (10.2–14.5)12.8 (10.2–14.8)11.9 (10.2–14.5)0.85
 HbA1c (mmol/mol)32 (30–33)32 (30–33)33 (32–34)32 (30–33)0.016
 HbA1c (%)5.1 (4.9–5.2)5.1 (4.9–5.3)5.2 (5.1–5.3)5.1 (4.9–5.2)
 Prolactin (mIU/L)861 (585–1317)886 (589–1347)861 (591–1245)887 (589–1351)0.65
 Prolactin (MoM)1.00 (0.71–1.37)1.01 (0.72–1.38)0.91 (0.78–1.27)1.03 (0.72–1.39)0.41
Late pregnancy, n148961737580
 Gestational age at blood sampling29 (28.5–29.5)29 (28.6–29.5)28.9 (28.5–29.5)29 (28.6–29.0)0.77
 HbA1c (mmol/mol)30 (29–32)31 (29–33)33 (31–36)30 (29–32)< 0.001
 HbA1c (%)4.9 (4.8–5.1)4.9 (4.8–5.1)5.2 (5.0–5.4)4.9 (4.8–5.1)
 Glucose (mmol/L)5.0 (4.8–5.3)5.1 (4.8–5.4)5.7 (5.2–6.1)5.1 (4.8–5.4)< 0.001
 Insulin (pmol/L)68 (49–97)77 (52–113)102 (69–152)75 (51–111)< 0.001
 HOMA2-B112 (93–134)117 (94–142)116 (100–149)117 (93–141)0.54
 HOMA2-IR1.27 (0.91–1.81)1.45 (0.96–2.11)1.94 (1.34–2.89)1.41 (0.94–2.07)< 0.001
 Testosterone (nmol/L)1.99 (1.43–2.80)2.01 (1.39–2.84)2.09 (1.23–2.88)2.01 (1.39–2.84)0.94
 Prolactin (mIU/L)5000 (3797–6276)5020 (3873–6290)4269 (3178–5125)5072 (3940–6344)0.004



 Prolactin ratio5.71 (3.73–8.02)5.89 (3.74–7.81)5.05 (3.58–7.40)5.91 (3.78–7.86)0.42
 Prolactin (MoM)1.00 (0.76–1.25)

1.00 (0.78–1.27)0.86 (0.63–1.02)1.01 (0.79–1.27)0.004

P-values for differences between GDM and NGT were calculated using the Mann–Whitney U-test for continuous variables and the Pearson’s χ2 test for categorical variables. P < 0.05 in boldface.

BMI, BMI before pregnancy; HOMA2-B, homeostatic model assessment of β-cell function; HOMA2-IR, homeostatic model assessment of insulin resistance; NGT, normal glucose tolerance.

Glucose status and gestational diabetes mellitus

HbA1c was analyzed using ion exchange HPLC on a Tosoh G8 instrument (Tosoh Bioscience, Tokyo, Japan) set up for routine testing. Results were reported as International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) units in mmol/mol. Glucose levels were measured by the hexokinase method (Architect, Abbott), the intra-assay coefficient of variation (CV) was 5.2–5.4% and the inter-assay CV was 1.2–1.7%. Serum insulin was analyzed by an electro-chemiluminescence immunoassay (ECLIA, Cobas e411, Roche), the intra-assay CV was 0.8–3.7% and the inter-assay CV was 2.5–4.9%. Insulin resistance (HOMA2-IR) and β-cell function (HOMA2-B) were estimated using the HOMA2 Calculator (HOMA2 v2.2.3; Diabetes Trials Unit, University of Oxford) based on fasting plasma glucose and fasting serum insulin values.

GDM was diagnosed by a 75 g, 2-h oral glucose tolerance test (OGTT) using a plasma glucose threshold ≥9.0 mmol/L according to Danish guidelines for antenatal care (24). Women were subjected to a selective screening strategy using risk factors for GDM, that is, BMI ≥27 kg/m2, family history of diabetes mellitus, glucosuria during pregnancy, previous GDM, or previous delivery of a macrocosmic child (24). Pregnant women with two or more of these risk factors, or who have previously had GDM, were offered an early diagnostic OGTT between gestational week 14 and 20 and again in week 28–30, whereas women with one risk factor were scheduled for only the late OGTT. Women with diabetes mellitus before gestation week (GW) 20 were excluded from the present study.

Table 2

Pairwise Pearson correlation analysis in early and late pregnancy.

VariableProlactin (mIU/L) first–second trimester*Prolactin (mIU/L) third trimester
Pearson’s correlation (r)P-valuePearson’s correlation (r)P-value
HbA1c–0.193< 0.001−0.0700.014
HOMA2-B--0.0530.043
HOMA2-IR--0.0210.43
Testosterone0.103< 0.001

P < 0.05 in boldface.

*first–second trimester (n = 934); third trimester (n = 1245).

HOMA2-B, homeostatic model assessment of β-cell function; HOMA2-IR, homeostatic model assessment of insulin resistance.

According to the design of OCC (20), one random woman without GDM risk factors was offered a late OGTT (week 28–30) for each woman undergoing an OGTT by indication. Randomization of women without risk factors for GDM was conducted consecutively throughout the study period.

A total of 622 women had data on third trimester OGTT in the present study. Blood samples for analysis of first trimester prolactin were available from 513 out of 622 women with third trimester OGTT (Fig. 1).

Testosterone and PCOS

Data regarding maternal testosterone in third trimester were available for 1489 women. Testosterone was analysed by liquid chromatography tandem mass spectrometry (LC-MS/MS) (25).

PCOS was defined according to the Rotterdam criteria (26). Data on PCOS diagnosis before pregnancy were extracted from an electronic questionnaire during the second trimester (27). Women were classified with PCOS if they reported a PCOS diagnosis given by a medical doctor or if they reported both facial hair and oligomenorrhea (pre-pregnancy menstrual cycles ≥35 days). Data on PCOS status in questionnaire for non-responders were extracted from medical records. Cohort staff was unaware of maternal PCOS diagnosis, and PCOS diagnosis did not affect follow-up during pregnancy. The control population included women with regular menstrual cycle (<35 days) before conception and no signs of androgen excess (hirsutism and/or acne). A total of 1030 women in first–second trimester had available blood samples and information of PCOS/control diagnosis as described previously (25). In the third trimester outcome analysis, 1473 women were part of the PCOS and control groups (Table 3).

Table 3

Baseline maternal and pregnancy characteristics in first–third trimesters for PCOS and control. Data are presented as median and interquartile range, n (%), multiple of the gestation week median (MoM) or ratio (third trimester/first–second trimester). Gestational age is presented in weeks.

CharacteristicPCOSControlP–value
n1461327
BMI (kg/m2)23.3 (21.6–27.8)23.5 (21.3–26.5)0.70
Age30 (28–34)30 (27–33)0.27
Nulliparous, n (%)81 (55)771 (58)0.55
Early pregnancy (first–second trimester), n95935
 Gestational age at blood sampling12.1 (10.2–14.6)11.9 (10.2–14.7)0.89
 HbA1c (mmol/mol)31 (30–33)32 (30–33)0.18
 HbA1c (%)5.0 (4.9–5.2)5.1 (4.9–5.2)
 Prolactin (mIU/L)919 (661–1356)857 (573–1317)0.080
 Prolactin (MoM)1.15 (0.84–1.40)0.99 (0.70–1.37)0.015
Late pregnancy (third trimester), n1461327
 Gestational age at blood sampling29.2 (28.5–29.6)29.0 (28.5–29.5)0.27
 HbA1c (mmol/mol)30 (29–32)30 (29–32)0.99
 HbA1c (%)4.9 (4.8–5.1)4.9 (4.8–5.1)0.99
 Glucose (mmol/L)5.0 (4.8–5.4)5.0 (4.8–5.3)0.31
 Insulin (pmol/L)71 (50–108)68 (49–96)0.16
 HOMA2-B116 (94–141)112 (93–134)0.17
 HOMA2-IR1.33 (0.94–2.01)1.27 (0.91–1.79)0.16
 Testosterone (nmol/L)2.39 (1.67–3.31)1.95 (1.40–2.74)< 0.001
 Prolactin (mIU/L)5026 (3842–6401)4999 (3797–6270)0.51
 Prolactin ratio5.44 (3.04–7.09)5.80 (3.81–8.13)0.06
 Prolactin (MoM)1.00 (0.76–1.29)1.00 (0.76–1.26)0.52

Data are presented as median and interquartile range, n (%), multiple of the gestation week median (MoM) or ratio (third trimester/first–second trimester). Gestational age is presented in weeks. P-values for differences between GDM and NGT were calculated using the Mann–Whitney U-test for continuous variables and the Pearson’s χ2 test for categorical variables. P < 0.05 in boldface.

HOMA2-B, homeostatic model assessment of β-cell function; HOMA2-IR, homeostatic model assessment of insulin resistance; NGT, normal glucose tolerance.

Serum prolactin analysis

Stored biobank samples (−80°C) were thawed and analysed batch-wise for prolactin in sera using an electro‐chemiluminescence immunoassay (ECLIA) on a Cobas e411 analyzer (Roche Diagnostics). The Cobas prolactin II assay was calibrated against the WHO third international standard for prolactin (84/500). Inter-assay CV’s for prolactin batch analysis were determined using Seronorm Immunoassay Liq-1/2 (Sero) and was <4.4% (QC level 1; 210 mIU/L) and <3.3% (QC level 2; 903 mIU/L). Prolactin multiple of the median (MoM) was, for each women, calculated as the concentration of prolactin (mIU/L) divided by the median prolactin concentration for all women in the same GW. MoM values were used to relate an individual prolactin concentration to the median value of prolactin in women sampled at the same age of gestation. Prolactin ratio was calculated as a ratio between late and early gestation prolactin concentration.

Hyperprolactinemia is associated with varying degrees of higher molecular weight complexes of prolactin (and immunoglobulins) commonly referred to as macroprolactin (28). Serum prolactin levels increase significantly during pregnancy, however, with insignificant contribution of macroprolactin in a previous study (29). To determine if macroprolactinemia is abundant in the third trimester of pregnancy, we performed PEG precipitation of (n = 101) sera according to a procedure described previously (30). The mean recovery was 82% (range: 65–100%) (Supplementary Table 2, see section on supplementary materials given at the end of this article). No samples had a recovery below the 50% cut-off threshold for macroprolactinemia on the Cobas platform, confirming that total prolactin measurements during pregnancy were not significantly confounded by macroprolactinemia.

Ethical approval

The study was performed in accordance with the Helsinki Declaration II and approved by the Regional Ethical Review Committee (Project ID S-20090130) and the Danish Data Protection Agency (j.no. 18/15692) (23). All participants received written and oral information and provided their written consent for participation. Additional consent to attend for fasting blood samples were given by the participants around gestational week 25.

Statistical analysis

Data handling and statistical analysis were carried out using Microsoft Excel 2010 (Microsoft) and STATA version 15.0. Data were presented as median and interquartile range or n (%). For univariate statistical analysis, the Mann–Whitney U-test was used for continuous variables and the Pearson’s χ2 test for categorical variables. Binary associations were established by pairwise Pearson correlation analyses of continuous variables. Multivariate analyses on binary outcomes (glucose tolerance and PCOS status) were performed using logistic regression, reporting odds ratios. Analyses were performed as crude models and after correcting for maternal age and BMI. A significance level of P < 0.05 was applied for all statistical tests in this study.

Results

The median (IQR) prolactin concentration increased eight-fold from 633 (451–829) mIU/L at GW 7 to 5223 (4151–6127) mIU/L at GW 30 (Fig. 2A and Supplementary Table 1).

Figure 2
Figure 2

Maternal serum prolactin concentration (mean ± s.e.m.) in the Odense Child Cohort according to gestational age (weeks). (A) Mean prolactin in the Odense Child Cohort. Each participant contributed with blood samples in first–second trimester and/or third trimester (n = 2532). (B) Mean prolactin in GDM (n = 65) and NGT women (n = 1061; Table 1). (C) Mean prolactin in PCOS (n = 241) and control women (n = 2262; Table 3). *P < 0.05 for case-control comparisons (Mann–Whitney U-test). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0144.

Citation: European Journal of Endocrinology 183, 3; 10.1530/EJE-20-0144

We found a significant negative correlation between prolactin and HbA1c during first and second trimester (early pregnancy; r = −0.19, P < 0.001) and third trimester (late pregnancy; r = −0.07, P = 0.014). Prolactin was weakly correlated to HOMA2-B but not to HOMA2-IR (Table 2).

GDM was diagnosed in 28/509 (5.5%) women with available data from early pregnancy and 37/617 (6.0%) women with data from late pregnancy (Table 1). In early pregnancy, prolactin concentration and prolactin MoM did not differ between women who later developed GDM and women with normal glucose tolerance (NGT) (Fig. 2B, Fig. 3 and Table 1). In late pregnancy, women diagnosed with GDM had significantly lower prolactin concentrations and prolactin MoM compared to women with NGT: 4269 vs 5072 mIU/L, P = 0.004 and 0.86 vs 1.01 MoM, P = 0.004, respectively.

Multivariate regression analysis for late pregnancy prolactin MoM showed a negative association to GDM (OR 0.26, P = 0.012), which remained significant after adjustment for pre-pregnancy BMI and maternal age (OR 0.30, P = 0.034) (Table 4).

Table 4

Multivariate regression models of early and late pregnancy prolactin in relation to GDM/NGT and PCOS/Control subgroups.

CrudeAdjusted
nOR (95% CI)PnOR (95% CI)P
GDM
 Prolactin (MoM)
  First–second trimester*5090.625 (0.295; 1.323)0.225090.726 (0.31; 1.53)0.36
  Third trimester6170.259 (0.095; 0.706)0.0126170.302 (0.100; 0.913)0.034
PCOS
 Prolactin (MoM)
  First–second trimester*10301.340 (0.974; 1.845)0.07210301.380 (0.999; 1.905)0.051
  Third trimester14731.104 (0.711; 1.715)0.6614731.179 (0.757; 1.836)0.47

P < 0.05 in boldface.

*First–second trimester: GDM/NGT (n = 28; n = 481), PCOS/control (n = 95; n = 935); Third trimester: GDM/NGT (n = 37; n = 580), PCOS/control (n = 146; n = 1327). Adjusted for maternal age and BMI.

Compared to women with NGT, women with GDM were characterized by significantly higher pre-pregnancy BMI (29.8 vs 24.8 kg/m2, P < 0.001), higher HbA1c (33 (5.2%) vs 30 mmol/mol (4.9%), P < 0.001), fasting plasma glucose (5.7 vs 5.1 mmol/L, P < 0.001), fasting plasma insulin (102 vs 75 pmol/L, P < 0.001) and HOMA2-IR (1.94 vs 1.41, P < 0.001). Women who later developed GDM had significantly higher early pregnancy HbA1c (33 (5.2%) vs 32 mmol/mol (5.1%), P = 0.016) compared to women with NGT.

The prevalence of PCOS was 95/1030 women (9.2%) in the early pregnancy group and 146/1473 women (10.0%) in the late pregnancy group. Women with PCOS had higher prolactin concentration and prolactin MoM during early pregnancy compared to controls, 919 vs 857 mIU/L, P = 0.080, and 1.15 vs 0.99, P = 0.015, respectively (Fig. 2C, Fig. 3 and Table 3). In late pregnancy, women with PCOS had lower prolactin ratio (third/first trimester prolactin) 5.44 vs 5.80 (P = 0.06) compared to controls and significantly higher total testosterone (2.39 vs 1.95 nmol/L, P < 0.001), whereas prolactin concentration and MoM were comparable (Fig. 2C, Fig. 3 and Table 3).

Multivariate regression analysis showed positive association between prolactin MoM in early pregnancy and PCOS (OR: 1.34, P = 0.072), which reached borderline significance after adjustment for BMI and maternal age (OR: 1.38, P = 0.051) (Table 4). Late pregnancy prolactin MoM was not associated with PCOS in crude or adjusted models. Finally, prolactin showed a significant positive correlation with total testosterone (r = 0.103, P < 0.001) in third trimester (Table 2).

Discussion

In the present study, we showed that low prolactin levels during pregnancy were associated with higher HbA1c and that low third trimester prolactin levels were associated with GDM. Furthermore, in women with PCOS, early pregnancy prolactin levels were significantly higher compared to controls.

Figure 3
Figure 3

Box plot of prolactin MoM in GDM/NGT and PCOS/control in early pregnancy (left panels) and late pregnancy (right panels). Boxes represent median and IQR. P-values for differences between groups (Mann–Whitney U-test) are indicated. Statistical significance (P < 0.05) is marked by an asterix.

Citation: European Journal of Endocrinology 183, 3; 10.1530/EJE-20-0144

Our finding of an inverse association between prolactin and HbA1c in early and late pregnancy, as well as no significant association between prolactin levels and measures of insulin resistance, was in line with the hypothesis that prolactin is important for beta-cell function and not associated with insulin resistance. To our knowledge, this is the first study to investigate associations between early and late pregnancy prolactin levels and glucose status and GDM in a large prospective cohort. While conflicting data were reported regarding serum prolactin levels in GDM during pregnancy and at term (15, 16, 17), our data on late pregnancy supported those published by Catalano and coworkers (17). Also, our results expand findings from non-pregnant clinical studies, where low prolactin levels predicted the development of impaired glucose tolerance and T2D (5, 6, 7, 8, 9). Accordingly, Retnakaran and co-workers showed that higher prolactin levels during second and third trimester pregnancy were associated with a lower risk of postpartum pre-diabetes and T2D (13). In line with the present study, prolactin levels were not linked to insulin resistance, whereas prolactin was an independent negative predictor of beta-cell function and area under the curve for glucose during OGTT (13).

In animal studies, prolactin receptor knockout was associated with reduced beta-cell mass and glucose intolerance during pregnancy (10). Prolactin-mediated beta-cell proliferation was further shown to be mediated through Akt, STAT5-PIM and ERK signaling pathways including apoptosis inhibitor surviving during pregnancy (31). Specifically, prolactin stimulated induction of survivin expression and was required for cell cycle progression to S and G2/M phase (31). Although the importance and molecular mechanisms for prolactin and prolactin signaling are expanding in animal models, there is still a gap to bridge this understanding to human pregnancy (32).

In women with PCOS, we found that prolactin levels were higher in early pregnancy compared to controls, whereas prolactin levels were comparable in third trimester pregnancy and the ratio between third/first trimester prolactin levels were lower in women with PCOS compared to controls. Our finding of significantly higher first trimester prolactin levels in PCOS seemed to be an unexpected study finding given the increased risk of T2D in non-pregnant women with PCOS compared to controls (19). However, the risk of GDM in women with PCOS is debated and could be highly dependent of PCOS phenotype including BMI (20). As recently reported, women with PCOS in the Odense Child Cohort did not have an increased risk of GDM (20). During normal pregnancy, placental estrogen production is associated with a 5–10 fold increase in sex hormone-binding globulin (SHBG) levels (33, 34), which results in higher circulating total testosterone levels (35). In women with PCOS, free testosterone levels increased even further during pregnancy compared to controls (25, 35). The positive association between sex hormones and prolactin is well established (36) and higher testosterone levels during pregnancy in women with PCOS compared to controls could be associated with higher prolactin levels. Our finding of a positive association between testosterone and prolactin levels could support that high levels of sex hormones is a protective mechanism against the adverse effect of low prolactin on beta-cell function in women with PCOS. This hypothesis remains to be tested in future studies.

Serum prolactin levels increase significantly during pregnancy (Fig. 2A and Supplementary Table 1). We performed PEG precipitation on a late pregnancy subset of samples to show that the occurrence of macroprolactinemia (high molecular weight (presumably inactive) protein complexes) was not increased in pregnancy (Supplementary Table 2). These findings were supported by Guclu and coworkers, who found the contribution of macroprolactin during pregnancy was insignificant (29). These results confirm that PEG precipitation is not necessary in future studies regarding prolactin levels in pregnant study populations.

Strengths and limitations apply to the present study. Strengths included our relatively large, population-based cohort, the repeat measurements of prolactin during early and late pregnancy and OGTTs in both at-risk and control women; furthermore HbA1c as well as glucose and insulin levels were assessed. A limitation to our study is that the diagnostic threshold for GDM is not uniform, internationally; therefore, our data on the association between prolactin levels and GDM may vary depending on the definition used for GDM (37, 38). In terms of biochemical measures, our study is unable to discriminate between the contribution of circulating prolactin secreted from pituitary and placental origin and we do not know to which extend our prolactin assay recognize pituitary derived N-terminal prolactin fragments termed vasoinhibins (39). We did not follow pregnant women with PCOS more closely than controls, that is, there was no surveillance bias according to PCOS diagnosis. Women were included in OCC after a positive pregnancy test, and as PCOS cannot be diagnosed during pregnancy, the diagnosis of PCOS was obtained by retrospective information. We found a prevalence of 10% for PCOS in OCC, which corresponded to the estimated prevalence in the background population (18).

Women participating in the Odense Child Cohort were more ethnically homogenous, leaner, more educated, and they were less likely to smoke compared to the background population (23). Therefore, our study findings should be reproduced in more obese study populations and in women of other ethnicities.

Conclusions

Low prolactin levels in early and late pregnancy were associated with higher levels of HbA1c and low prolactin levels late in pregnancy were associated with GDM. Higher early pregnancy prolactin levels in women with PCOS may be linked to higher sex hormone levels in PCOS.

Supplementary materials

This is linked to the online version of the paper at https://doi.org/10.1530/EJE-20-0144.

Declaration of interest

Marianne Skovsager Andersen is on the editorial board of European Journal of Endocrinology. Marianne Skovsager Andersen was not involved in the review or editorial process for this paper, on which she is listed as an author. The other authors have nothing to disclose.

Funding

Financial grants for the study were supported by Simon Fougner Hartmanns Familiefond, the Danish Foundation for Scientific Innovation and Technology (09-067180), Ronald McDonald Children Foundation, Odense University Hospital, the Region of Southern Denmark, the Municipality of Odense, the Mental Health Service of the Region of Southern Denmark, The Danish Council for Strategic Research, Program Commission on Health, Food and Welfare (2101-08- 0058), Odense Patient data Explorative Network (OPEN), Novo Nordisk Foundation (grant nr. NNF15OC00017734), the Danish Council for Independent Research, and The Foundation for research collaboration between Rigshospitalet and Odense University Hospital, and the Health Foundation (Helsefonden). Roche Diagnostics A/S Denmark supported the study with reagents for the Cobas e 411 prolactin II assay.

Author contribution statement

Odense Child Cohort was established by H C, T K J and M S A. This study was conceptualized by M O, D G and M S A. M O supervised laboratory analyses and performed statistical data analysis. M O, D G and M S A wrote the paper, H C and T K J reviewed and edited the paper. M O and D G contributed equally to the paper.

Acknowledgements

The families in the Odense Child Cohort are acknowledged for their participation and commitment to the study. The technicians at Hans Christian Andersen Hospital for Children and Adolescents are acknowledged for their careful examination of the children.

References

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    • Search Google Scholar
    • Export Citation
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    Grattan DR. 60 years of neuroendocrinology: the hypothalamo-prolactin axis. Journal of Endocrinology 2015 226 T101T122. (https://doi.org/10.1530/JOE-15-0213)

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    • Export Citation
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    Ramos-Roman MA. Prolactin and lactation as modifiers of diabetes risk in gestational diabetes. Hormone and Metabolic Research 2011 43 593600. (https://doi.org/10.1055/s-0031-1284353)

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    • Export Citation
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    Kapur A, McIntyre HD, Hod M. Type 2 diabetes in pregnancy. Endocrinology and Metabolism Clinics of North America 2019 48 511531. (https://doi.org/10.1016/j.ecl.2019.05.009)

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    • Export Citation
  • 13

    Retnakaran R, Ye C, Kramer CK, Connelly PW, Hanley AJ, Sermer M, Zinman B. Maternal serum prolactin and prediction of postpartum beta-cell function and risk of prediabetes/diabetes. Diabetes Care 2016 39 12501258. (https://doi.org/10.2337/dc16-0043)

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    • Export Citation
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    Ekinci EI, Torkamani N, Ramchand SK, Churilov L, Sikaris KA, Lu ZX, Houlihan CA. Higher maternal serum prolactin levels are associated with reduced glucose tolerance during pregnancy. Journal of Diabetes Investigation 2017 8 697700. (https://doi.org/10.1111/jdi.12634)

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    • Export Citation
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    Botta RM, Donatelli M, Zampardi A, Incandela T, Valenza P, Albano V, Bompiani G. Study on maternal, fetal and amniotic prolactin in gestational diabetic women, at term. Acta Diabetologica Latina 1982 19 275280. (https://doi.org/10.1007/BF02624687)

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    • Export Citation
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    Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. American Journal of Physiology: Endocrinology and Metabolism 2002 282 E522E533. (https://doi.org/10.1152/ajpendo.00124.2001)

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    Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of Type 2 diabetes in a nationwide population of women With polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2017 102 38483857. (https://doi.org/10.1210/jc.2017-01354)

    • Search Google Scholar
    • Export Citation
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    Palm CVB, Glintborg D, Kyhl HB, McIntyre HD, Jensen RC, Jensen TK, Jensen DM, Andersen M. Polycystic ovary syndrome and hyperglycaemia in pregnancy. A narrative review and results from a prospective Danish cohort study. Diabetes Research and Clinical Practice 2018 145 167177. (https://doi.org/10.1016/j.diabres.2018.04.030)

    • Search Google Scholar
    • Export Citation
  • 21

    Glintborg D, Altinok M, Mumm H, Buch K, Ravn P, Andersen M. Prolactin is associated with metabolic risk and cortisol in 1007 women with polycystic ovary syndrome. Human Reproduction 2014 29 17731779. (https://doi.org/10.1093/humrep/deu133)

    • Search Google Scholar
    • Export Citation
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    Underdal MO, Salvesen Ø, Schmedes A, Andersen MS, Vanky E. Prolactin and breast increase during pregnancy in PCOS: linked to long-term metabolic health? European Journal of Endocrinology 2019 180 373380. (https://doi.org/10.1530/EJE-19-0002)

    • Search Google Scholar
    • Export Citation
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    Kyhl HB, Jensen TK, Barington T, Buhl S, Norberg LA, Jorgensen JS, Jensen DF, Christesen HT, Lamont RF, Husby S. The Odense Child Cohort: aims, design, and cohort profile. Paediatric and Perinatal Epidemiology 2015 29 250258. (https://doi.org/10.1111/ppe.12183)

    • Search Google Scholar
    • Export Citation
  • 24

    Jensen DM, Molsted-Pedersen L, Beck-Nielsen H, Westergaard JG, Ovesen P, Damm P. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study. American Journal of Obstetrics and Gynecology 2003 189 13831388. (https://doi.org/10.1067/s0002-9378(03)00601-x)

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  • View in gallery

    Flowchart of the Odense Child Cohort study population, blood sampling and analyses.

  • View in gallery

    Maternal serum prolactin concentration (mean ± s.e.m.) in the Odense Child Cohort according to gestational age (weeks). (A) Mean prolactin in the Odense Child Cohort. Each participant contributed with blood samples in first–second trimester and/or third trimester (n = 2532). (B) Mean prolactin in GDM (n = 65) and NGT women (n = 1061; Table 1). (C) Mean prolactin in PCOS (n = 241) and control women (n = 2262; Table 3). *P < 0.05 for case-control comparisons (Mann–Whitney U-test). A full color version of this figure is available at https://doi.org/10.1530/EJE-20-0144.

  • View in gallery

    Box plot of prolactin MoM in GDM/NGT and PCOS/control in early pregnancy (left panels) and late pregnancy (right panels). Boxes represent median and IQR. P-values for differences between groups (Mann–Whitney U-test) are indicated. Statistical significance (P < 0.05) is marked by an asterix.

  • 1

    Yen SSC & Jaffe RB. Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 3rd ed., 1016 p. Philadelphia: Saunders, 1991.

    • Search Google Scholar
    • Export Citation
  • 2

    Grattan DR. 60 years of neuroendocrinology: the hypothalamo-prolactin axis. Journal of Endocrinology 2015 226 T101T122. (https://doi.org/10.1530/JOE-15-0213)

    • Search Google Scholar
    • Export Citation
  • 3

    Moyce BL, Dolinsky VW. Maternal beta-cell adaptations in pregnancy and placental signalling: implications for gestational diabetes. International Journal of Molecular Sciences 2018 19 3467. (https://doi.org/10.3390/ijms19113467)

    • Search Google Scholar
    • Export Citation
  • 4

    Andersen M, Glintborg D. Metabolic syndrome in hyperprolactinemia. Frontiers of Hormone Research 2018 49 2947. (https://doi.org/10.1159/000486000)

    • Search Google Scholar
    • Export Citation
  • 5

    Balbach L, Wallaschofski H, Volzke H, Nauck M, Dorr M, Haring R. Serum prolactin concentrations as risk factor of metabolic syndrome or type 2 diabetes? BMC Endocrine Disorders 2013 13 12. (https://doi.org/10.1186/1472-6823-13-12)

    • Search Google Scholar
    • Export Citation
  • 6

    Chirico V, Cannavo S, Lacquaniti A, Salpietro V, Mandolfino M, Romeo PD, Cotta O, Munafo C, Giorgianni G & Salpietro C Prolactin in obese children: a bridge between inflammation and metabolic-endocrine dysfunction. Clinical Endocrinology 2013 79 537544. (https://doi.org/10.1111/cen.12183)

    • Search Google Scholar
    • Export Citation
  • 7

    Wang T, Lu J, Xu Y, Li M, Sun J, Zhang J, Xu B, Xu M, Chen Y & Bi Y Circulating prolactin associates with diabetes and impaired glucose regulation: a population-based study. Diabetes Care 2013 36 19741980. (https://doi.org/10.2337/dc12-1893)

    • Search Google Scholar
    • Export Citation
  • 8

    Corona G, Wu FC, Rastrelli G, Lee DM, Forti G, O'Connor DB, O'Neill TW, Pendleton N, Bartfai G & Boonen S Low prolactin is associated with sexual dysfunction and psychological or metabolic disturbances in middle-aged and elderly men: the European Male Aging Study (EMAS). Journal of Sexual Medicine 2014 11 240253. (https://doi.org/10.1111/jsm.12327)

    • Search Google Scholar
    • Export Citation
  • 9

    Wagner R, Heni M, Linder K, Ketterer C, Peter A, Bohm A, Hatziagelaki E, Stefan N, Staiger H & Haring HU Age-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans. Acta Diabetologica 2014 51 7178. (https://doi.org/10.1007/s00592-013-0493-7)

    • Search Google Scholar
    • Export Citation
  • 10

    Huang C, Snider F, Cross JC. Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology 2009 150 16181626. (https://doi.org/10.1210/en.2008-1003)

    • Search Google Scholar
    • Export Citation
  • 11

    Ramos-Roman MA. Prolactin and lactation as modifiers of diabetes risk in gestational diabetes. Hormone and Metabolic Research 2011 43 593600. (https://doi.org/10.1055/s-0031-1284353)

    • Search Google Scholar
    • Export Citation
  • 12

    Kapur A, McIntyre HD, Hod M. Type 2 diabetes in pregnancy. Endocrinology and Metabolism Clinics of North America 2019 48 511531. (https://doi.org/10.1016/j.ecl.2019.05.009)

    • Search Google Scholar
    • Export Citation
  • 13

    Retnakaran R, Ye C, Kramer CK, Connelly PW, Hanley AJ, Sermer M, Zinman B. Maternal serum prolactin and prediction of postpartum beta-cell function and risk of prediabetes/diabetes. Diabetes Care 2016 39 12501258. (https://doi.org/10.2337/dc16-0043)

    • Search Google Scholar
    • Export Citation
  • 14

    Ekinci EI, Torkamani N, Ramchand SK, Churilov L, Sikaris KA, Lu ZX, Houlihan CA. Higher maternal serum prolactin levels are associated with reduced glucose tolerance during pregnancy. Journal of Diabetes Investigation 2017 8 697700. (https://doi.org/10.1111/jdi.12634)

    • Search Google Scholar
    • Export Citation
  • 15

    Skouby SO, Kuhl C, Hornnes PJ, Andersen AN. Prolactin and glucose tolerance in normal and gestational diabetic pregnancy. Obstetrics and Gynecology 1986 67 1720.

    • Search Google Scholar
    • Export Citation
  • 16

    Botta RM, Donatelli M, Zampardi A, Incandela T, Valenza P, Albano V, Bompiani G. Study on maternal, fetal and amniotic prolactin in gestational diabetic women, at term. Acta Diabetologica Latina 1982 19 275280. (https://doi.org/10.1007/BF02624687)

    • Search Google Scholar
    • Export Citation
  • 17

    Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE. Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. American Journal of Physiology: Endocrinology and Metabolism 2002 282 E522E533. (https://doi.org/10.1152/ajpendo.00124.2001)

    • Search Google Scholar
    • Export Citation
  • 18

    Conway G, Dewailly D, Diamanti-Kandarakis E, Escobar-Morreale HF, Franks S, Gambineri A, Kelestimur F, Macut D, Micic D & Pasquali R The polycystic ovary syndrome: a position statement from the European Society of Endocrinology. European Journal of Endocrinology 2014 171 P129. (https://doi.org/10.1530/EJE-14-0253)

    • Search Google Scholar
    • Export Citation
  • 19

    Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of Type 2 diabetes in a nationwide population of women With polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 2017 102 38483857. (https://doi.org/10.1210/jc.2017-01354)

    • Search Google Scholar
    • Export Citation
  • 20

    Palm CVB, Glintborg D, Kyhl HB, McIntyre HD, Jensen RC, Jensen TK, Jensen DM, Andersen M. Polycystic ovary syndrome and hyperglycaemia in pregnancy. A narrative review and results from a prospective Danish cohort study. Diabetes Research and Clinical Practice 2018 145 167177. (https://doi.org/10.1016/j.diabres.2018.04.030)

    • Search Google Scholar
    • Export Citation
  • 21

    Glintborg D, Altinok M, Mumm H, Buch K, Ravn P, Andersen M. Prolactin is associated with metabolic risk and cortisol in 1007 women with polycystic ovary syndrome. Human Reproduction 2014 29 17731779. (https://doi.org/10.1093/humrep/deu133)

    • Search Google Scholar
    • Export Citation
  • 22

    Underdal MO, Salvesen Ø, Schmedes A, Andersen MS, Vanky E. Prolactin and breast increase during pregnancy in PCOS: linked to long-term metabolic health? European Journal of Endocrinology 2019 180 373380. (https://doi.org/10.1530/EJE-19-0002)

    • Search Google Scholar
    • Export Citation
  • 23

    Kyhl HB, Jensen TK, Barington T, Buhl S, Norberg LA, Jorgensen JS, Jensen DF, Christesen HT, Lamont RF, Husby S. The Odense Child Cohort: aims, design, and cohort profile. Paediatric and Perinatal Epidemiology 2015 29 250258. (https://doi.org/10.1111/ppe.12183)

    • Search Google Scholar
    • Export Citation
  • 24

    Jensen DM, Molsted-Pedersen L, Beck-Nielsen H, Westergaard JG, Ovesen P, Damm P. Screening for gestational diabetes mellitus by a model based on risk indicators: a prospective study. American Journal of Obstetrics and Gynecology 2003 189 13831388. (https://doi.org/10.1067/s0002-9378(03)00601-x)

    • Search Google Scholar
    • Export Citation
  • 25

    Glintborg D, Jensen RC, Bentsen K, Schmedes AV, Brandslund I, Kyhl HB, Bilenberg N, Andersen MS. Testosterone levels in third trimester in polycystic ovary syndrome: Odense child cohort. Journal of Clinical Endocrinology and Metabolism 2018 103 38193827. (https://doi.org/10.1210/jc.2018-00889)

    • Search Google Scholar
    • Export Citation
  • 26

    Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Human Reproduction 2004 19 4147. (https://doi.org/10.1093/humrep/deh098)

    • Search Google Scholar
    • Export Citation
  • 27

    Finnbogadottir SK, Glintborg D, Jensen TK, Kyhl HB, Nohr EA, Andersen M. Insulin resistance in pregnant women with and without polycystic ovary syndrome, and measures of body composition in offspring at birth and three years of age. Acta Obstetricia and Gynecologica Scandinavica 2017 96 13071314. (https://doi.org/10.1111/aogs.13200)

    • Search Google Scholar
    • Export Citation
  • 28

    Vilar L, Vilar CF, Lyra R, Freitas MDC. Pitfalls in the diagnostic evaluation of hyperprolactinemia. Neuroendocrinology 2019 109 719. (https://doi.org/10.1159/000499694)

    • Search Google Scholar
    • Export Citation
  • 29

    Guclu M, Cander S, Kiyici S, Vatansever E, Hacihasanoglu AB, Kisakol G. Serum macroprolactin levels in pregnancy and association with thyroid autoimmunity. BMC Endocrine Disorders 2015 15 31. (https://doi.org/10.1186/s12902-015-0025-2)

    • Search Google Scholar
    • Export Citation
  • 30

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