The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 2 344-347
Copyright © 1998 by The Endocrine Society
Evidence of High Circulating Testosterone in Women with Prior Preeclampsia1
Hannele Laivuori,
Risto Kaaja,
Eeva-Marja Rutanen,
Lasse Viinikka and
Olavi Ylikorkala
Department of Obstetrics and Gynecology, and Clinical Chemistry,
Helsinki University Central Hospital, Finland
Address all correspondence and requests for reprints to: Hannele Laivuori, Department of Obstetrics and Gynecology, University Central Hospital of Helsinki, Haartmaninkatu 2, FIN-00290 Helsinki, Finland. E-mail: hannele.laivuori{at}pp.fimnet.fi
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Abstract
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Women with prior preeclampsia are characterized by hyperinsulinemia and
a 2- to 3-fold excess risk of hypertension and ischemic heart disease
in later life. We therefore studied whether these women present changes
in pituitary, ovarian, and endothelial factors that could also affect
the risk of vascular disorders. Twenty-two women with prior
preeclampsia and 22 control women matched by age and body mass index
were studied an average of 17 yr after delivery. Women with prior
preeclampsia had elevated serum free testosterone levels (20.6 ±
2.2 vs. 15.0 ± 1.3 pmol/L, mean ±
SE, P = 0.03), an elevated free
androgen index (3.2 ± 0.5 vs. 1.9 ± 0.2,
P = 0.04), and an elevated free testosterone
estradiol ratio (0.089 ± 0.017 vs. 0.046 ±
0.006, P = 0.02). The levels of insulin-like growth
factor binding protein-1 decreased as expected during a 3-h oral
glucose tolerance test without differences between the groups. Levels
of FSH, LH, androstenedione, dehydroepiandrosterone sulfate, and
endothelin-1, as well as urinary output of prostacyclin and thromboxane
A2 metabolites, showed no difference between study groups.
A history of preeclampsia an average of 17 yr earlier thus appears to
be associated with elevated levels of testosterone, which may
contribute to the increased risk of vascular morbidity in such women.
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Introduction
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WOMEN with a prior preeclamptic
pregnancy have an increased risk of cardiovascular disease in their
subsequent life (1, 2, 3, 4, 5, 6, 7). This may imply that some harmful endocrine or
metabolic changes thought to be specific for preeclamptic pregnancy may
persist after pregnancy and perhaps predispose these women to increased
risk of vascular disorders. These changes may involve endothelial
function deficient in preeclampsia, as seen from reduced prostacyclin
and/or elevated endothelin-1 or thromboxane A2 production
(8). However, no long-term data exist on prostacyclin, thromboxane
A2, and endothelin-1 after preeclamptic pregnancy. Another
explanation may involve metabolism that presents changes similar to
those in metabolic syndrome in preeclampsia (9, 10). We have reported
that women with a preeclamptic first pregnancy show hyperinsulinemia 17
yr later (11). Because, on the other hand, hyperinsulinemia and
possibly changes in the insulin-like growth factor (IGF) system and
hyperandrogenism are key features in polycystic ovarian disease (PCO)
(12), and because women with PCO also show excess risk of preeclampsia
(13, 14) and subsequent cardiovascular morbidity (15), it seemed
pertinent to study endothelial function and endocrine changes in women
with a prior preeclamptic pregnancy.
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Subjects and Methods
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Women who had suffered severe preeclampsia (n =
20) (blood pressure constantly >160/110 mmHg; proteinuria >0.3 g/24
h) or eclampsia (n = 2) during pregnancy (16) and 22 age- and body
mass index (BMI)-matched controls, each of whom had given birth at
approximately the same time (±3–4 months) after a normotensive
pregnancy, were studied 17 yr after the first pregnancy (Table 1
). All patients and controls had been
healthy before this index pregnancy. In the meantime, 15 women in the
patient group had given birth to 21 infants. Of the second pregnancies
(n = 15), five (33%) had been complicated by preeclampsia, and
four (27%) by hypertension without proteinuria. In their third
pregnancies (n = 4), two developed preeclampsia, and in their
fourth pregnancies (n = 2), one was hypertensive. In the control
group, 19 women women had given birth 27 times, and none had developed
preeclampsia or hypertension without proteinuria. Three women (one
patient and two controls) were excluded because of their use of hormone
replacement therapy or progestin-only contraception. Two women in the
patient group and one in the control group wearing
levonorgestrel-releasing intrauterine devices (Levonova, Leiras,
Finland) were not excluded, because such women ovulate and are thus
endocrinologically representative (17). The patients and controls
menstruated regularly except for nine, of whom four patients and two
controls were hysterectomized and three used Levonova. All women were
studied during the same phase of their menstrual cycle, as reported
earlier (11). No one presented clinical features of androgen excess
such as hirsutism, acne, or alopecia, but the patient group exhibited
hyperinsulinemia, one marker of insulin resistance (11). The women came
to the research center at 0800 h after an overnight fast. After
the physical examination (height, weight, and blood pressure
measurement), blood was drawn for measurement of uric acid, lipids,
baseline blood glucose, and serum insulin, and a urine sample was
collected. Thereafter, a 3-h oral glucose tolerance test was started.
The patients and controls were advised to refrain from using aspirin or
other nonsteroidal antiinflammatory drugs for 10 days before the
study.
Basal blood samples were assayed for sex steroids and relevant protein
hormones, and in addition, urine samples were assayed for prostacyclin
and thromboxane A2 metabolites with established methods
(Table 2). Free testosterone was
calculated by using the formula: serum total testosterone (in
pmol/L)/100 x [2.28–1.38 x logarithm serum sex-hormone binding
globulin (SHBG) in nmol/L/10] (19). The ratio between serum total
testosterone and SHBG that is commonly expressed as the free androgen
index was calculated from serum total testosterone concentration in
nmol/L x 100 divided by serum SHBG concentration in nmol/L (20).
The prostanoid data are expressed against creatinine to avoid possible
errors caused by differences in urine dilution. The data are given as
means ± standard error (SE). Comparisons between
groups were made by Student’s two-tailed unpaired t test
(Statview II Program, Abacus Concepts, Berkeley, CA). Linear regression
analyses served to assess the relationships between parameters.
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Results
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The study groups were comparable except for blood pressure, which
was higher in the patient group than that in the control group (Table 1
). Women with prior preeclampsia were characterized by elevated serum
free testosterone levels (P = 0.03), free androgen
index (P = 0.04), and free testosterone/estradiol ratio
(P = 0.02) (Table 3),
whereas androstenedione, dehydroepiandrosterone sulfate, estradiol, and
total testosterone were normal (Table 3). Free testosterone correlated
positively with basal insulin (reported previously, Ref.5) (r =
0.52, P = 0.016), systolic blood pressure (r =
0.69, P = 0.001), diastolic blood pressure (r =
0.62, P = 0.004), triglycerides (reported previously,
Ref.5) (r = 0.55, P = 0.009), and BMI (r =
0.51, P = 0.018) in women with prior preeclampsia, but
not in the controls. The study groups did not differ with respect to
SHBG, thyroxine, LH, or FSH concentrations or LH/FSH ratio (Table 3).
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Table 3. Concentrations of hormones, related compounds, and
PG metabolites in women with and without prior preeclampsia/eclampsia
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The oral glucose tolerance test caused a progressive fall in IGF
binding protein-1 (IGFBP-1 levels), but this response, as well as the
basal levels of IGFBP-1, did not differ between the study groups (Table 3 and Fig. 1). Basal serum IGFBP-1 and
insulin were in negative relation to each other (r = -0.49,
P = 0.001).
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Figure 1. IGFBP-1 levels in serum before and during
oral glucose tolerance test (75 mg) in women with and without prior
preeclampsia/eclampsia (mean ± SE). Differences
between groups were not statistically significant.
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Plasma endothelin-1 concentrations, as well as the urinary output of
prostacyclin and thromboxane A2 metabolites, were similar
in the two groups and showed no correlations with steroid hormones
(Table 3).
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Discussion
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A 2- to 3-fold excess risk of hypertension and ischemic heart
disease in women with prior preeclampsia (1, 2, 3, 4, 5, 6, 7) implies that women with
preeclampsia may have inherent endocrine or metabolic abnormalities
expressed during preeclampsia; such abnormalities may persist,
predisposing these women to vascular disease. We have previously shown
that women with preeclampsia show changes similar to those in metabolic
syndrome (9), and that hyperinsulinemia persists up to 17 yr after
preeclamptic first pregnancy (11). We now show that these women are
characterized by mild hyperandrogenism, as seen from increased free
testosterone, free androgen index, and free testosterone/estradiol
ratio. These changes could result from increased ovarian testosterone
production or decreased circulating SHBG levels, or both, but our data
do not allow us to deduce the initial cause of these changes.
Regardless of the cause of testosterone changes and of the presence of
normal androstenedione levels, we feel that our patients had slight
ovarian hyperandrogenism. To the best of our knowledge, this is the
first evidence to suggest an association between a history of
preeclampsia and ovarian hyperandrogenism.
At the moment we do not know which of the two major abnormalities,
hyperinsulinemia or high levels of testosterone, is the primary change.
Insulin stimulates the production of testosterone by ovarian tissue
in vitro (24), which suggests that hyperinsulinemia could be
the primary change that triggered the increased release of
testosterone. However, hyperinsulinemia should also stimulate the
production of adrenal androgens (25), but this was not seen in our
patients. On the other hand, androgens are known to decrease both
hepatic removal of insulin and peripheral sensitivity to insulin (26),
which suggests that hyperandrogenism could lead to hyperinsulinemia.
Similar coexistence of hyperinsulinemia and hyperandrogenism is present
in PCO (12), and these patients appear to be at increased risk of
preeclampsia (13, 14). This suggests that hyperinsulinemia and
hyperandrogenism could precede the onset of preeclampsia. Although our
patients had significantly elevated levels of free testosterone and
free androgen index, they had no clinical signs of hyperandrogenism,
menstruated normally, and had normal BMI, IGFBP-1, SHBG and LH/FSH
ratio. Thus it is unlikely that our patients suffered from classic PCO,
although their blood pressure was higher than that in the controls, a
feature typical of PCO patients (27). It was unfortunate that our study
design did not include the use of ultrasound to assess presence or
absence of multiple ovarian follicular cysts that could have been of
help in the diagnosis of PCO (28).
Prostacyclin and thromboxane A2 are important in pregnancy
physiology and in preeclampsia (29), in which endothelin-1
production can also be disturbed (30, 31, 32). We present the first
long-term follow-up data on prostacyclin, thromboxane A2,
and endothelin-1 in women who have had a preeclamptic first pregnancy.
These data show that the prostacyclin deficiency and/or thromboxane
A2 or endothelin-1 dominance characterizing preeclamptic
pregnancy (29, 30, 31, 32) had vanished within 17 yr after pregnancy. That
these endothelial factors contributed to increased vascular morbidity
in these subjects is thus very unlikely (1, 2, 3, 4, 5, 6, 7).
Combining our present data with the previous data (11), we can state
that women with a prior preeclamptic pregnancy are characterized by
hyperinsulinemia and mild hyperandrogenism for up to 17 yr after
delivery. Epidemiological observational studies have linked
hyperinsulinemia to increased risk of occlusive vascular disorders in
men (33, 34). There is also abundant evidence that women with androgen
excess are at increased risk of cardiovascular disease, although we do
not have any clear-cut threshold values for definitively vasotoxic
levels of androgens in women (35, 36). Nevertheless, our present data
on hyperandrogenism in women with prior preeclamptic pregnancy can
provide one explanation as to why these women have a 2- to 3-fold
excess of cardiovascular morbidity (1, 2, 3, 4, 5, 6, 7).
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Footnotes
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1 This work was supported by grants from the Finnish Academy of
Science, the Obstetric and Gynecology Research Foundation, and the
Clinical Research Institute of the Helsinki University Central
Hospital. 
Received July 23, 1997.
Revised October 8, 1997.
Accepted October 15, 1997.
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Top
Abstract
Introduction
