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ORIGINAL RESEARCH |
From the Departments of Obstetrics and Gynecology, and Biochemical Endocrinology, Haukeland University Hospital, University of Bergen, Bergen, Norway.
Address reprint requests to: Johan Arnt Steier, MD, IVF Department, Maternity Clinic, Haukeland University Hospital, NO-5021 Bergen, Norway; E-mail: jste{at}haukeland.no.
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ABSTRACT |
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METHODS: The study consisted of 137 women with singleton pregnancies in the third trimester. Seventy-three pregnancies were uncomplicated; among those were 35 male and 38 female fetuses. Sixty-four pregnancies were complicated by preeclampsia; among those were 33 male and 31 female fetuses. Human chorionic gonadotropin and total testosterone were measured in maternal peripheral blood.
RESULTS: In male-bearing pregnancies, maternal hCG and testosterone serum levels were significantly higher in preeclamptic than normotensive mothers (P < .001). In female-bearing pregnancies, testosterone levels were significantly higher in preeclamptic than normotensive mothers (P < .001), whereas the hCG levels were not significantly different. Male-bearing preeclamptic women had significantly higher testosterone levels than female-bearing preeclamptic women (P < .02), whereas the hCG levels were not significantly different. In uncomplicated pregnancies the hCG levels were significantly higher in female-bearing than in male-bearing mothers (P < .005), whereas the testosterone levels were not significantly different.
CONCLUSION: In preeclamptic pregnancies with male fetuses, the maternal serum hCG levels were significantly higher than in uncomplicated pregnancies. Total testosterone levels were significantly higher in pregnancies with either gender and significantly higher in male-bearing than in female-bearing pregnancies. This may indicate an androgen influence on the pathophysiologic mechanism of preeclampsia.
Human chorionic gonadotropin (hCG) is produced in the placental syncytiotrophoblast. The bulk of the hormone is secreted into the maternal circulation. During normal pregnancy the hCG levels increase rapidly until a peak is reached at 60–80 days’ gestation. Thereafter, the levels decrease, reaching a nadir at 16–18 weeks’ gestation.1,2
During the first and second trimesters of normal pregnancy, there are no gender differences in maternal hCG levels. However, from the second to the third trimesters there is a marked shift in maternal hCG serum concentrations. The hCG levels in female-bearing pregnancies increase significantly, whereas they decrease in male-bearing pregnancies.3–5
During pregnancy the maternal serum levels of total testosterone increase progressively, whereas the concentration of free testosterone changes little until the third trimester, when it increases two-fold.6,7
Elevated hCG levels are found in maternal serum in pregnancies complicated by preeclampsia, and significantly higher testosterone levels are found in preeclamptic than in normotensive pregnancies.8,9 The aim of the present study was to evaluate the effects of fetal sex on hCG and testosterone in preeclampsia compared with uncomplicated pregnancies.
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MATERIAL AND METHODS |
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Pregnancies with maternal diabetes, fetal malformations, or chromosomal abnormalities were excluded. Gestational age was calculated from the first day of the last menstrual period, unless ultrasonography results found a discrepancy of 14 days or more.
By the visit when the pregnant women entered the study, they were examined physically. Blood pressure and urine specimens were collected, and detailed ultrasonographic structural examinations of the fetuses were performed. Simultaneously, blood samples were drawn from an antecubital maternal vein for examination of hCG and total testosterone. Hematocrit was analyzed in an ADVIA 120 autoanalyzer (Bayer System, Bayer-Leverkusen, Germany).
Consistent with the definition of the ACOG, preeclampsia was defined as new-onset hypertension after 20 weeks’ gestation, with a diastolic blood pressure of 90 mm Hg or higher with concurrent proteinuria of 300 mg/24 hours or greater. Semiquantitative dipstick tests were used for measurement of proteinuria (1+ and 2+ corresponded to 
300 mg/24 hours and 500mg/24 hours, respectively).10
Human chorionic gonadotropin was measured with a commercial immunometric assay kit (ImmuliteHCG; Diagnostic Products Corporation, Los Angeles, CA). The Third International Standard for hCG was used as a reference standard. The assay has a detection limit of 3 IU/L. The intraassay coefficient of variation was 3.3 and 7.0 for mean hCG levels at 21 and 1500 IU/L, respectively. The interassay coefficient of variation was 7.2 and 9.1 for hCG levels at 21 and 1500 IU/L, respectively.
Testosterone level was determined by a commercially available test from Orion Diagnostica (Espoo, Finland). The test is based on a radioimmunoassay technique. The expected serum testosterone levels ranged between 0.3 and 2.8 nmol/L. The sensitivity was 0.1 nmol/L. The intraassay coefficient of variation was 7.5 and 5.5 for testosterone levels at 1.6 and 26.5 nmol/L, respectively. The interassay coefficient of variation was 7.0 and 4.8 for testosterone levels at 1.2 and 23.3 nmol/L, respectively.
Statistical analyses were carried out by Mann-Whitney test for group differences. A P value less than .05 was considered statistically significant. For correlations, Pearson and Spearman rank correlation tests were used. The study was approved by the Regional Committee for Biomedical Research in West Norway. All participants gave written consent.
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RESULTS |
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In the group of preeclamptic women, the diastolic blood pressure ranged from 90 to 110 mm Hg, and no differences were seen between male- and female-bearing pregnancies. Proteinuria was measured to 1+ and 2+, and no difference was found between pregnancies with male and female fetuses.
In the preeclamptic pregnancies the hematocrit values were within the normal range (0.35–0.44). No difference was seen between male- and female-bearing pregnancies. None of the fetuses were growth restricted, and no weight differences between the sexes were found after delivery. Relevant clinical data are shown in Table 1
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The maternal serum levels of total testosterone were significantly higher in preeclamptic than in normotensive pregnancies with male as well as with female fetuses (P < .001). Male-bearing preeclamptic pregnancies had significantly higher maternal serum testosterone levels than female-bearing pregnancies complicated by preeclampsia (P < .02).
No statistical correlations were found between hCG and total testosterone in maternal blood either in male-or female-bearing pregnancies. Data for the hCG and testosterone values are given in Tables 2 and 3, respectively.
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DISCUSSION |
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The placenta seems to play a fundamental role in preeclampsia, as the condition improves rapidly after its removal. Examinations of the placenta in pregnancies complicated by preeclampsia have revealed focal cellular necrosis with increased mitotic activity in the syncytiotrophoblast and cellular proliferation in the cytotrophoblast. A transformation of the cytotrophoblast into the syncytiotrophoblast also has been reported.15,16 These changes might explain the elevated maternal serum hCG levels in male-bearing preeclamptic pregnancies, but there is still no explanation for no increase in maternal serum hCG levels in female-bearing pregnancies with preeclampsia.
The serum levels of total testosterone increase throughout normal pregnancy and are primarily a result of progressive estrogen-induced increase in the concentration in sex hormone-binding globulin concentrations.6,7 In preeclamptic pregnancies, however, studies have found lower maternal serum levels of estrogen than in normal pregnancies, so it is likely that other mechanisms mediate the maternal serum testosterone levels.17
The sources for the increased testosterone levels in maternal serum are not known but could be the ovarian theca-interstitial cells and the maternal adrenal cortex, which might be stimulated by hCG throughout pregnancy. The fetal serum levels of testosterone are much lower than the maternal levels. Because of the stimulating effect of hCG on the fetal testis, the testosterone levels in male fetuses are significantly higher than in female fetuses. The fetal ovaries are regarded as hormonally inactive in the first part of pregnancy, but later they might have steroidogenic capacity.18–21
In the present study no correlations were found between maternal serum levels of hCG and total testosterone. In uncomplicated pregnancies no significant gender differences were found. The significantly increased maternal serum testosterone levels in preeclamptic pregnancies with male fetuses as well as with female fetuses, and the significantly higher total testosterone maternal serum levels in male- than in female-bearing preeclamptic pregnancies, were not related to maternal hCG levels only.
It has been postulated that preeclampsia could result from a mutation in a paternally imprinted, maternally active gene. It is also known that only the paternal allele is expressed in human placenta.22,23 A paternal immunogenetic factor has been suggested, because significantly more preeclampsia is found in pregnancies with changed paternity.24
Preeclampsia is a complex disease of unknown origin. A placental involvement in the pathophysiologic mechanism of the disease is likely, and our observations could indicate an androgenic-mediated effect on preeclampsia.
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Footnotes |
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Received December 7, 2001. Received in revised form April 2, 2002. Accepted April 18, 2002.
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REFERENCES |
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2. Braunstein GD, Rasor J, Adler R, Danzer H, Wade ME. Serum human chorionic gonadotropin levels throughout normal pregnancy. Am J Obstet Gynecol 1976;126: 678–81.[Medline]
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6. Bammann BL, Coulam CB, Yang NS. Total and free testosterone during pregnancy. Am J Obstet Gynecol 1980;137:293–8.[Medline]
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19. Jaffe RB, Serón-Ferré M, Huhtaniemi I, Korenbrot C. Regulation of the primate fetal adrenal gland and testis in vitro and in vivo. J Steroid Biochem 1977;8:479–90.[Medline]
20. Jaffe RB. Neuroendocrine-metabolic regulation of pregnancy. In: Reproductive endocrinology. Physiology, pathophysiology, and clinical management. In: Yen SSC, Jaffe RB, Barbieri RL, eds. Philadelphia: WB Saunders Company, 1999:751–811.
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