Human Reproduction, Vol. 14, No. 1, 18-20,
January 1999
© 1999 European Society of Human Reproduction and Embryology
Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion
Department of Obstetrics and Gynaecology, The University of Wuerzburg, Josef-Schneider-Str. 4, D-97080 Wuerzburg, Germany
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Abstract |
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The frequency of endocrine abnormalities during the follicular phase in non-pregnant women with a history of recurrent abortion was investigated in a case-control study. A total of 42 consecutive women with recurrent spontaneous abortion (three or more consecutive abortions, mean ± SD: 3.9 ± 1.1 range 3–8) with no parental chromosome rearrangement or uterine abnormality were studied during the early follicular phase under standardized conditions. Serum concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, androstenedione, testosterone, dehydroepiandrostenedione, 17-OH-progesterone, oestradiol, progesterone and thyroid stimulating hormone (TSH) were measured by commercially available radioimmunoassays. Controls were 42 nulligravid females with tubal or male factor infertility without miscarriage. Mean (SD) concentrations of prolactin and androstenedione were 14.2 ± 6.7 ng/ml versus 10.5 ± 3.5 ng/ml (95% CI 0.8–6.1) and 2.3 ± 0.9 ng/ml versus 1.7 ± 0.6 ng/ml (95% CI 0.2–0.9) in the study and control groups respectively. The other endocrine parameters were comparable in both groups. Obesity [BMI weight (kg)/height (m2)
25] was more prevalent (23 versus 5 women, P = 0.0001) in the study than the control group. Recurrent spontaneous abortion is associated with abnormalities in prolactin and androgen secretion during the follicular phase, suggesting an endocrine aetiology in this disorder. Reduction of body weight and correction of hyperprolactinaemia and of hyperandrogenism may reduce the rate of miscarriage in a subsequent pregnancy in these women.
Key words: endocrine factors/hyperprolactinaemia/obesity/recurrent spontaneous abortion
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Introduction |
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Recurrent spontaneous abortion is a multifactorial disorder. Endocrine abnormalities may be responsible in a substantial proportion of these abortions. Most previous studies have focused on the association between recurrent spontaneous abortion and luteal phase defects, based on retarded endometrium (McNeely and Soules, 1989
; Searle et al., 1994), or decreased progesterone concentrations (Ginsburg, 1992) or short duration of the second phase of the cycle (Coulam and Stern, 1994; Bulletti et al., 1996). Recently, amenorrhoea (Quensby and Farquharson, 1993), immuno-endocrinological disorders (Lim et al., 1996), hyperandrogenism (Tulppala et al., 1993), obesity (Franks and Hamilton-Fairley, 1994) and polycystic ovaries (Clifford et al., 1994) have been identified in a substantial proportion of women with recurrent spontaneous abortion.
Little information is available on the role of endocrine abnormalities during the follicular phase as possible risk factors for recurrent spontaneous abortion. Both phases of the menstrual cycle have to be considered together, as luteal defects are frequently associated with inadequate follicular growth, premature luteinization or basal hormone imbalances during the follicular phase (Soules et al., 1989).
Therefore, we investigated the frequency of abnormalities of basal hormone concentrations in women with recurrent spontaneous abortion in whom no other underlying cause for the repeated loss was apparent. We aimed to identify endocrine risk factors during follicular phase associated with recurrent spontaneous abortion.
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Materials and methods |
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Study and control subjects
A total of 42 non-pregnant women (mean ± SD: 33.2 ± 4.2 years, range 27–42 years) with a history of three or more (mean ± SD: 3.9 ± 1.1, range 3–8) previous spontaneous abortions attending our recurrent miscarriage clinic were investigated for endocrine disturbances. The patients underwent routine workup to exclude parental chromosome abnormality by blood testing and uterine malformations by vaginal ultrasound and hysteroscopy. Women were screened for chlamydia infection, bacterial vaginosis, antiphospholipid antibodies and anti-cardiolipin. Vaginal sonography of ovarian morphology was performed in all patients to search for ultrasonographic signs of polycystic ovaries. Applying the criteria published by Ardeans et al. (1991), two patients were diagnosed to have polycystic ovaries. Cycle irregularities were noted in three women.
Control subjects (n = 42) were nulligravid women of similar age (mean ± SD: 33.3 ± 4.7 years, range 24–41) with no previously recognized miscarriage, and no clinical evidence of endocrine abnormality. They were attending our assisted reproduction clinic for tubal or male factor infertility. Twenty-four women had regular ovulatory cycles and four suffered from oligomenorrhoea. In one of these patients, polycystic ovaries could be demonstrated by vaginal ultrasound.
None of the patients or controls was pregnant at the time of the study or in the 6 months beforehand, and none was taking any medication likely to affect results (e.g. oestrogens, progestagens, dopamine antagonists and glucocorticoids).
The body mass index (BMI) of each study and control subject was calculated using the formula weight (kg)/height (m2) (study group mean ± SD: 26.1 ± 6.4 kg/m2, range 19.9–35.6 kg/m2; control group mean ± SD: 22.6 ± 3.0 kg/m2, range 17.1–33.4 kg/m2). Women with a BMI 
25 kg/m2 were regarded as obese.
All subjects gave informed consent.
Endocrine evaluations
Fasting blood samples were taken routinely between 8.00 and 10.00 a.m. after a resting period of 30 min during the early follicular phase. Hormonal analyses were performed using commercially available radioimmunoassays for follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, (Serono, Freiburg, Germany), testosterone, androstenedione, dehydroepiandrostenedione, oestradiol, progesterone and 17-OH-progesterone (Biermann, Bad Nauheim, Germany). Thyroid stimulating hormone (TSH) was measured using an automated fluorimetric enzyme immunoassay (Chemilumineszenz IXM; Abbott, Wiesbaden, Germany). The normal ranges were taken from the manufacturer's instructions. They are given in Table I. Both the variability within and that between assays were <10%.
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Statistics
The results of laboratory tests in the study and control groups were compared using Student's t-test, and the frequencies of abnormal results in both collectives using
2-analysis or Fisher's exact test. All reported values are given as mean ± SD and 95% confidence interval (95% CI). P < 0.05 was regarded as significant. |
Results |
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Prolactin and androstenedione concentrations were significantly higher in the study group than in controls, although serum concentrations of both hormones were within the normal range. Concentrations of gonadotrophins did not differ significantly in the study and control subjects. TSH serum concentrations were similar in both groups (Table I
).
Table II shows the frequency of abnormal endocrine test results in both groups. Abnormal FSH and LH concentrations were equally distributed in the study and control groups. The prevalences of hyperprolactinaemia and of raised androstenedione concentrations were higher in study women than in controls. Thirteen patients had elevated prolactin concentrations, another four patients had elevated androstenedione concentrations, whereas in two women in the study group, both prolactin and androstenedione concentrations were raised. Twenty-three study women and five control women were obese (P = 0.0001). In Table III, the amount of abnormal endocrine test results in obese compared to non-obese women, whether they belong to the study or the control group, is shown.
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Discussion |
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This study shows some women with a history of recurrent spontaneous miscarriage have raised serum concentrations of prolactin and androstenedione in the follicular phase. It can be assumed that these findings are causally related to the development of miscarriage, especially in women with recurrent spontaneous abortion in whom no other cause for their repeated pregnancy loss was apparent. Increased frequencies of hyperprolactinaemia (Ando et al., 1994
) and of hypersecretion of LH (Balen et al., 1993) have been reported in women with miscarriage. However, to our knowledge, this is the first report of full endocrine investigation of women with a history of recurrent spontaneous abortion during the follicular phase.
Our finding of increased serum concentrations of androstenedione is supported by the observation of an increased miscarriage rate in women with polycystic ovarian disease, a disorder which is characterized by amenorrhoea, hirsutism, and raised androgen concentrations. The prevalence of polycystic ovarian disease in women with recurrent spontaneous abortion has been reported to be between 44% (Tulppala et al., 1993) and 82% (Clifford et al., 1994). A similar frequency of polycystic ovaries was also observed in this study. It is surprising that we were unable to detect raised concentrations of serum testosterone in women with recurrent spontaneous abortion, as testosterone is the androgen with the highest sensitivity for the disorder (Goldzieher, 1981) and as high serum concentrations of testosterone, free testosterone and dehydroepiandrostenedione were associated with an increased miscarriage rate in one study (Tulppala et al., 1993). We did not observe increased concentrations of dehydroepiandrostenedione in our study. These divergent observations may be partly explained by the known variability of the clinical and endocrine features associated with polycystic ovarian disease.
Several studies have been reported that hypersecretion of basal LH with or without polycystic ovaries is a risk factor for miscarriage (Turner, 1991; Watson et al., 1993; Chandler, 1994; Clifford et al., 1994). It has been stated that high basal LH concentrations, leading to premature luteinization, may be found in up to 33% of women with recurrent spontaneous abortion (Clifford et al., 1994). In contrast, we observed a high basal LH in only one woman in the study group, which argues against its use as a diagnostic test for endocrine-mediated abortion.
Hyperprolactinaemia and hypoprolactinaemia have been causally related with luteal phase defects and with miscarriage (Gu, 1993; Ando et al., 1994), a finding which is supported by our observation of a significant excess of hyperprolactinaemia in women with recurrent spontaneous abortion. Medical suppression by dopamine antagonists proved effective in preventing miscarriage in one study (Ando et al., 1994). We are unable to comment on the effectiveness of prolactin antagonists in preventing pregnancy loss in our study.
Our observation of normal serum TSH concentrations in all but one study group women is supported by previous investigators who reported a relatively low prevalence of abnormal thyroid function (~2%) in women with recurrent spontaneous abortion (Harger et al., 1983; Stray-Pederson and Stray-Pederson, 1984). Despite this low frequency, we still think that TSH screening is generally warranted in all women with recurrent spontaneous abortion because both hypothyroidism and hyperthyroidism are easy to correct medically.
In conclusion, we observed an increased rate of prolactin and androgen abnormalities in women with recurrent spontaneous abortion. It is possible that these disturbances may be causally related to miscarriage. Identification of these women with presumably `endocrine-mediated' abortions may make them amenable to endocrine therapeutic strategies for the prevention of further miscarriage.
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Notes |
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1 To whom correspondence should be addressed
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References |
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Submitted on January 12, 1998; accepted on September 29, 1998.
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