Obstetrics & Gynecology:
Determinants of Maternal Sex Steroids During the First Half of Pregnancy
Toriola, Adetunji T. MD, PhD; Vääräsmäki, Marja MD; Lehtinen, Matti MD, PhD; Zeleniuch-Jacquotte, Anne PhD; Lundin, Eva MD, PhD; Rodgers, Kenneth-Gary; Lakso, Hans-Ake PhD; Chen, Tianhui PhD; Schock, Helena MSc; Hallmans, Goran MD, PhD; Pukkala, Eero PhD; Toniolo, Paolo MD, MSPH; Grankvist, Kjell MD, PhD; Surcel, Helja-Marja PhD; Lukanova, Annekatrin MD, PhD
From the Division of Preventive Oncology, National Center for Tumor Diseases and German Cancer Research Center, Heidelberg, Germany; National Institute for Health and Welfare, Oulu, Finland; University of Tampere, Tampere, Finland; Department of Environmental Medicine, New York University School of Medicine, New York; New York University Cancer Institute, New York, New York; Department of Medical Biosciences, University of Umeå, Umeå, Sweden; Public Health and Clinical Medicine, Nutritional Research, University of Umeå, Umeå, Sweden; School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland; Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York; Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland,
Supported by U.S. National Cancer Institute grant (R01 CA120061). The funding source had no role in the study design, interpretation of data, or publication of the results.
The authors thank Professor Mika Gissler for assisting in the retrieval of data from the Finnish Birth Registry and for providing advice about its quality and completeness.
Corresponding author: Annekatrin Lukanova, MD, PhD, Division of Cancer Epidemiology, German Cancer Research Center, In Neuenheimer Feld 581, Heidelberg 69120, Germany; e-mail: firstname.lastname@example.org.
Financial Disclosure Matti Lehtinen has received grants for HPV vaccination studies through his employer, University of Tampere, Finland, from Merck & Co, and from GSK Biologicals. The other authors did not report any potential conflicts of interest.
OBJECTIVE: To examine the associations of maternal and child characteristics with early pregnancy maternal concentrations of testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2).
METHODS: We analyzed these hormones among 1,343 women with singleton pregnancies who donated serum samples to the Finnish Maternity Cohort from 1986 to 2006 during the first half of pregnancy (median 11 weeks). The associations of maternal and child characteristics with hormone concentrations were investigated by correlation and multivariable regression.
RESULTS: Women older than age 30 years had lower androgen and E2 but higher progesterone concentrations than women younger than that age. Multiparous women had 14% lower testosterone, 11% lower androstenedione and 17-hydroxyprogesterone, 9% lower progesterone, and 16% lower E2 concentrations compared with nulliparous women (all P<.05). Smoking mothers had 11%, 18%, and 8% higher testosterone, androstenedione, and 17-hydroxyprogesterone levels, respectively, but 10% lower progesterone compared with nonsmoking women (all P<.05). E2 concentrations were 9% higher (P<.05) among women with a female fetus compared with those with a male fetus.
CONCLUSION: Parity, smoking, and, to a lesser extent, maternal age and child sex are associated with sex steroid levels during the first half of a singleton pregnancy. The effects of smoking on the maternal hormonal environment and the possible long-term deleterious consequences on the fetus deserve further evaluation.
LEVEL OF EVIDENCE: II
The surge in sex steroids during pregnancy has been increasingly implicated in the development of disease in later life in both the mother and the child. In the mother, sex steroids are believed to underlie the association of pregnancy with risk of breast1 and ovarian2 cancers. In the child, an increasing body of evidence suggests that maternal sex steroids may influence the in utero environment, which may result in increased risk of atopy,3 autism spectrum and attention deficit hyperactivity disorders,4 polycystic ovary syndrome,5 testicular cancer,6 and probably breast cancer.7 High maternal testosterone concentrations also have been associated with low birth weight in the offspring,8 with attendant negative cardiovascular and metabolic sequelae.9
Because the hormonal environment during pregnancy is likely to be a predictor of health outcomes for both mother and child, it is important to have an understanding of the factors that can affect it. Furthermore, the identification of characteristics that could serve as surrogate measures of hormonal exposure will be useful in future epidemiological research to circumvent some of the huge logistic difficulties in the conduct of studies directly relating hormone concentrations during pregnancy to risk of chronic disease years after.
Because most studies have investigated the correlates of maternal hormones during mid or late pregnancy, comparatively little is known about their determinants during the first half of pregnancy.10 Early pregnancy is especially important to the fetus because this is the period when organogenesis takes place.
Our objective was to investigate the associations of maternal sex steroids with maternal and fetal characteristics. Using data from control participants in a case-control study nested within the Finnish Maternity Cohort, we examined the associations of maternal age, parity, smoking, child sex, birth weight, height, and Ponderal index with maternal sex steroids, including testosterone, androstenedione, progesterone, 17-hydroxyprogesterone, and estradiol (E2) measured during the early part (mostly first trimester) of a singleton pregnancy.
MATERIALS AND METHODS
The Finnish Maternity Cohort, the world's largest biorepository of serum specimens from pregnant women, was established in 1983. After informed consent, first trimester and early second trimester blood samples are taken from pregnant women to screen for intrauterine infections.11 After testing, the leftover sera are stored at −25°C in a central repository and can be used for scientific research with the aim of maintaining population health and preventing diseases. Currently, the Finnish Maternity Cohort has more than 1.5 million samples from more than 850,000 women.
Study participants were selected among the controls included in an ongoing nested case-control study on pregnancy hormones and ovarian cancer within the Finnish Maternity Cohort. Eligibility criteria for the original study included blood donation between 6 and 20 weeks of gestation in a singleton pregnancy with duration 301 days or less and no history of invasive cancer (except nonmelanoma skin cancer). Data on gestational age at blood donation in the Finnish Maternity Cohort have been collected since 1986, and only controls who donated a blood sample after 1986 were considered eligible for the current analyses. Sixty-nine women with incomplete information on maternal or child characteristics were also excluded, leaving 1,343 women for the study.
Data on index pregnancy were obtained by performing a linkage with the high-quality Finnish Medical Birth Registry, which has information on more than 98% of all births in the country since 1987.12 Data collection is through a standardized form that must be sent to the Finnish Medical Birth Registry within 7 days of each birth by the hospital where the delivery took place.12 Information was available on maternal characteristics during the index pregnancy, such as age, parity, pregnancy length, smoking, and child characteristics (sex, birth weight, and length). Information on breast cancer diagnosed among parents and siblings of the study participants was obtained through separate linkages with the Population and Cancer Registries. The study was approved by the ethical committees of the National Institute for Health and Welfare, Finland, and the German Cancer Research Center, Germany.
The assays of sex steroids were performed in the Laboratory of Clinical Chemistry at the Umeå University Hospital, Umeå, Sweden. In addition to the routine laboratory quality controls, a pool of serum from the cohort was created at the beginning of the study and two aliquots, undistinguishable from the test samples, were inserted in each laboratory run. Sex steroids were quantified by liquid chromatography tandem mass spectrometry, on an Applied Biosystems API4000 triple-stage quadrupole mass spectrometer. Laboratory quality controls at 0.10/5.0 ng/mL for testosterone, 0.25/5.0 ng/mL for androstenedione, 0.25/5.0 ng/mL for 17-hydroxyprogesterone, 2.0/75.0 ng/mL for progesterone, and 0.1/5.0 ng/mL for E2 showed inter-run coefficients of variation of 10.3%/5.2%, 7.0%/5.0%, 8.8%/6.1%, 9.0%/5.2%, and 12.2%/5.4%, respectively. The mean steroid concentrations of the blinded pool controls were 0.9 ng/mL for testosterone, 1.8 ng/mL for androstenedione, 2.4 ng/mL for 17-hydroxyprogesterone, 25.2 ng/mL for progesterone, and 2.6 ng/mL for E2. Inter-run and intra-run coefficients of variation based on the blinded pool of quality controls were 3.6% and 7.6% for testosterone, 3.8% and 8.1% for androstenedione, 5.2% and 8.0% for 17-hydroxyprogesterone, 3.5% and 6.8% for progesterone, and 5.2% and 6.3% for E2.
Before analysis, hormone levels were log2-transformed to limit heteroscedasticity. The concentrations of all hormones with the exception of testosterone varied linearly with gestational age (Fig. 1); to account for these variations, all statistical analyses were adjusted for gestational age (a linear term). No outliers, defined as concentrations exceeding three-times the interquartile range, for any of the hormones were identified. Ponderal index of the newborns was calculated by dividing birth weight by birth length.3
Association between continuous variables was evaluated by Spearman partial correlations (adjusted for gestational day). Multivariable regression models (adjusted for gestational age, maternal age, parity, smoking, term birth, child sex, and Ponderal index, with the exception of models for birth weight and height) were used to assess the independent effect of maternal and child characteristics on hormone concentrations. For these analyses, maternal age was categorized to age younger than 30 years and 30 years or older. Because there was no indication that any of the associations with birth weight, length, or Ponderal index followed a nonlinear association (by visual inspection of plots and introducing quadratic terms in the regression models), the results are presented for an increase of 100 g, 5 cm, and 5 units of Ponderal index, respectively. Laboratory batch had no effect on regression estimates and was omitted from the fully adjusted model. Additionally, stratified analyses by gestational age period (6–8, 8–12, and 12–20 weeks, corresponding to corpus luteum, transitional, and placental phases) were conducted and interaction terms with gestational age period were included in the main regression models. All analyses were performed by using SAS 9 (SAS Institute, Cary, NC).
Maternal and newborn characteristics and hormone concentrations during early pregnancy are presented in Table 1. Median maternal age was 32 years (range 17–46 years) and 25% (n=331) of the women were primiparous. The median gestational age at blood donation was 11 weeks (range 6–20 weeks). Fourteen percent (14%) of the women smoked during the index pregnancy.
Hormone concentrations were in the range expected for the period of pregnancy when the samples were collected. Gestational age correlated strongly with E2 (r=0.71), moderately with progesterone (r=0.52), and inversely (weakly) with androstenedione (r=−0.12) and 17-hydroxyprogesterone (r=−0.31), but not with testosterone (Fig. 1). The two androgens were strongly correlated (r=0.87). The correlations of testosterone and androstenedione with the other hormones were 0.50 and 0.56 with 17-hydroxyprogesterone, 0.45 and 0.37 with E2, and 0.13 and 0.16 with progesterone. E2 was more strongly correlated with progesterone (r=0.41) than with 17-hydroxyprogesterone (r=0.23). The correlation between progesterone and 17-hydroxyprogesterone was 0.46 (data not shown).
Table 2 shows the percentage changes in serum sex steroid concentrations across maternal and newborn characteristics. Women who were older than age 30 years at index pregnancy had significantly lower testosterone (6%), androstenedione (11%), and E2 (6%, P=.053), but higher progesterone (6%) concentrations than women younger than that age. The interaction term between maternal age and gestational age period was significant for E2; the decrease in maternal estrogen was confined to women who donated a blood sample after 12 weeks of gestation. All studied hormones were significantly lower in multiparous than in primiparous women, ranging from 9% for progesterone to 16% for E2 (P<.05). Serum testosterone and androstenedione concentrations were higher (11% and 18%, respectively), but progesterone concentrations were lower (10%) in smokers compared with nonsmokers (all P≤.05). Women who delivered before 37 weeks of gestation had lower progesterone concentrations than women who delivered at term; however, possibly attributable to the small number of women with preterm birth, the difference was of marginal significance (P=.09).
E2 concentrations were 9% higher among women with a female fetus than women with a male fetus. The interaction term between child sex and gestational age period was significant for progesterone, with significantly lower progesterone concentrations (6%) in mothers of girls compared with mothers of boys after gestational week 12. Birth weight, length, and Ponderal index were not significantly associated with any of the investigated maternal hormone concentrations, although there was a nonsignificant tendency for decreased androgens with birth length. There was no significant difference in hormone concentrations by family history of breast cancer, although women with such history tended to have lower androgen but higher E2 concentrations.
We observed that maternal age, parity, smoking, and child sex are associated with circulating sex steroids concentrations during the first half of a singleton pregnancy. During the first weeks of pregnancy, estrogens, progesterone, and 17-hydroxyprogesterone are produced exclusively by the corpus luteum. Gradually, for estrogens and progesterone, the major site of synthesis shifts to the placental trophoblast13–15 and their concentrations continue to increase. However, the placenta lacks 17 α-hydroxylase activity necessary for the synthesis of 17-hydroxyprogesterone and its concentrations decrease after the 5 weeks of gestation.15 Maternal testosterone increases gradually throughout pregnancy, but androstenedione concentrations remain relatively stable.16,17
The observed decrease in androgen concentrations with maternal age is in line with previous findings during the three trimesters of pregnancy.10,18,19 It is unlikely that the reduction is pregnancy-specific because androgen concentrations also decrease with age in nonpregnant women.20 The reported association of maternal age with E2 throughout pregnancy has been less consistent,19,21–23 although two studies reported a decrease in first trimester E2 concentrations with maternal age.10,22 In our data, the decrease in E2 was evident after gestational week 12, suggesting diminished placental production. One possibility is that the concomitant decrease in androgen concentrations with age presents the growing placenta and its increasing capacity for aromatization of androgens with less substrate, which later in pregnancy may not be evident because of increased androgen availability from fetal origin. Interestingly, despite the decrease in estrogen concentrations, there appears to be a concomitant increase in the other major placental sex steroid, progesterone, with age.10 However, the mechanisms underlying such an increase remain to be determined.
Primiparous women were characterized by higher concentrations of E2 in comparison with multiparous women, and these findings are in line with those of previous reports throughout pregnancy.10,23–25 The lower E2 levels in parous women could be attributable to increased metabolism of the hormone as a result of a pregnancy-induced persistent increase in liver CYP3A7 activity.26 For progesterone, most previous studies have found no significant differences between the first and subsequent pregnancies.10,24,25 However, our study was substantially larger, and thus more likely to detect an existing, albeit weaker, association. The decrease in progesterone and 17-hydroxyprogesterone in multiparous compared with primiparous women could be related to the decrease in the hormones that control its synthesis by the corpus luteum (eg, human chorionic gonadotropin23) in pregnancies after the first birth. We also observed lower maternal androgens in multiparous women, as reported previously by Troisi et al10,19 during the first trimester of pregnancy and possibly at term.
Smoking may increase circulating androgens by having an inhibitory effect on the adrenal cortex enzymes 21 and 11β-hydroxylase29 or by inducing ACTH production.30 Increased androstenedione27 and testosterone28 have been reported among smoking nonpregnant women. Our data add further evidence that smoking also could be associated with elevations in androgen concentrations during pregnancy.
We observed that smoking pregnant women had lower progesterone concentrations compared with nonsmoking pregnant women, which is similar to what has been reported previously during the first trimester10 and in nonpregnant women.27 Because high progesterone levels are needed to keep the pregnancy viable, the deleterious effects of smoking on maternal progesterone concentrations could be one of the mechanisms through which smoking may result in early pregnancy loss.
Experimental studies suggest that smoking has an antiestrogenic effect by preferentially increasing the synthesis of 2-hydroxyestrogens, which have low estrogenic potency and are rapidly cleared from the circulation.33,34 However, similar to other studies among pregnant10,19,31 and nonpregnant women,32 we found no association between smoking and E2 levels.
In contrast to the fetal ovary, the testis has the capacity to synthesis testosterone de novo. Testosterone-producing Leydig cells are first detected at approximately day 60 of gestation and then proliferate rapidly between the gestational weeks 12 and 18.14 It was proposed that because of the existing fetal–maternal gradient, testosterone from the male fetus could cross the placenta into maternal circulation.38 However, the high aromatase capacity of the placenta would tend to diminish fetal contribution to maternal androgens. We did not find differences in maternal androgens by child sex, as also observed by others,35–37 although higher testosterone concentrations in mothers of boys also have been reported.
Results from previous studies on pregnancy progesterone by child sex have shown either similar concentrations39,40 or lower concentrations in mothers of girls.25 Our findings are equally inconclusive, because although we observed no overall association, progesterone concentrations were lower in mothers of girls after gestational week 12. Most previous studies observed no differences in maternal estrogens by child sex;19,25,39 however, in some studies mothers of girls had somewhat higher estrogen levels.19,39 In our data, mothers of girls had significantly higher estrogens than mothers of boys. Because the fetal ovary is believed to be predominantly steroidogenically quiescent throughout most of pregnancy,14 this finding awaits confirmation in other studies.
We found no relationship between circulating sex steroids and birth weight, height, and Ponderal index. Most of the growth of the child occurs during the third trimester,41 and it is not surprising that an association has been observed with hormone concentrations measured after gestational week 27, but not with concentrations during the first half of pregnancy.42,43
Strengths of our study are its large size, the measurements of several sex steroids, and the availability of high-quality information from national registries. A limitation of the study is that serum samples were stored at a relatively high temperature, −25°C, but an earlier study within the Finnish Maternity Cohort observed no deleterious effects of long-term storage on sex steroids concentrations,44 and the observed hormonal variations with gestational age were in line with expectations.
In conclusion, our study showed that parity and smoking and, to a lesser extent, maternal age and sex of the child are associated with sex steroids concentrations during the first half of pregnancy. The effect of smoking on maternal hormone levels, especially testosterone and progesterone, deserves further evaluation because high maternal testosterone levels may be associated with low birth weight, with attendant negative metabolic sequelae, and a state of low progesterone level may not be conducive for fetal viability.
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