Fertility and Ovarian Function in High-Dose DES-Treated Tall Women

image of tall-girls
Back in the day, school photographers put the tall guys at the back in the middle, the shorter guys on the end. If you were really short, they put you on the end of the middle’ row with the plain Janes — note the gender symmetry. Middle of the front row was always reserved for the prettiest girls. My future wife and I – 1969.

Abstract

Fertility and Ovarian Function in High-Dose Estrogen-Treated Tall Women, National Institutes of Health, NCBI PubMed PMID 21289262, 2011 Feb 2.
Full text: The Endocrine Society, dx.doi.org/10.1210/jc.2010-2244, February 02, 2011.

BACKGROUND/OBJECTIVE
High-dose estrogen treatment to reduce final height of tall girls has been shown to interfere with fertility. Ovarian function has not been studied. We therefore evaluated fertility and ovarian function in tall women who did or did not receive such treatment in adolescence.

METHODS
This was a retrospective cohort study of 413 tall women aged 23-48 yr, of whom 239 women had been treated. A separate group of 126 fertile, normoovulatory volunteers aged 22-47 yr served as controls.

RESULTS
Fertility was assessed in 285 tall women (157 treated, 128 untreated) who had attempted to conceive. After adjustment for age, treated women were at increased risk of experiencing subfertility [odds ratio (OR) 2.29, 95% confidence interval (CI) 1.38-3.81] and receiving infertility treatments (OR 3.44, 95% CI 1.76-6.73). Moreover, fecundity was notably affected because treated women had significantly reduced odds of achieving at least one live birth (OR 0.26, 95% CI 0.13-0.52). Remarkably, duration of treatment was correlated with time to pregnancy (r = 0.23, P = 0.008). Ovarian function was assessed in 174 tall women (119 treated, 55 untreated). Thirty-nine women (23%) exhibited a hypergonadotropic profile. After adjusting for age category, treated women had significantly higher odds of being diagnosed with imminent ovarian failure (OR 2.83, 95% CI 1.04-7.68). Serum FSH levels in these women were significantly increased, whereas antral follicle counts and serum anti-Müllerian hormone levels were decreased.

CONCLUSION
High-dose estrogen-treated tall women are at risk of subfertility in later life. Their fecundity is significantly reduced. Treated women exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility.

Discussion

We evaluated fertility and ovarian function in tall women who did or did not receive high-dose estrogen treatment in adolescence. Our results indicate that treated women experience more difficulties getting pregnant compared with untreated women and more often receive infertility treatments. We show for the first time that abnormal serum levels of hormones related to the hypothalamus-pituitary-gonadal axis, especially FSH, may be involved in the observed subfertility.

First we studied fertility of treated women, which was significantly reduced compared with untreated women. Fifty-six percent of treated women conceived their first pregnancy within 12 months of unprotected intercourse. As a consequence, 43% of treated women visited a doctor because of fertility problems and 28% required some form of infertility treatment. More importantly, we observed a significantly reduced chance of achieving a live birth. At the time of study almost one third of the treated women were suffering from involuntary childlessness for a median of 40 months. This is unexpected in light of earlier findings indicating only a slight reduction in the probability of eventually having a live birth. This may be explained by the fact that we studied fertility only in women who had attempted to conceive, which we believe better represents the women at risk of involuntary childlessness. Our time to pregnancy data are self-reported and may be confounded by recall bias. However, we believe that our conclusions are not affected by such bias because we also assessed fertility based on data such as having received infertility treatments, which is not prone to recall bias and showed similar results.

We also studied the effects of treatment within treated women only. We found that although age at initiation of treatment was not associated with outcome, duration of treatment was significantly correlated with time to pregnancy. Women with a TTP of more than 12 months had on average been treated for 3 months longer. Although the effect of oral contraceptives on subsequent fertility has not been extensively studied, one study has reported an effect of estrogen dose on conception delay. Recent studies did not find such an association, possibly because low-dosage estrogen pills were used. Because of no variation in dosage in our population, we were unable to study the effect of estrogen dose more specifically.

Next, we analyzed ovarian function to study possible causes of the reduced fertility. Ovarian function was categorized based on serum gonadotropin levels. We observed an increased frequency of women with a hypergonadotropic profile. Our principal finding is that treated women are at increased risk of being diagnosed with IOF compared with untreated women. To account for normal changes in ovarian function in the late reproductive stages, treated and untreated women were divided into two age categories for the analysis of ovarian function. Taking these age categories into account, the odds of IOF diagnosis in treated women was almost 3-fold higher than in untreated women. Although ovarian function was primarily categorized based on serum FSH levels, the diagnosis of IOF was also supported by other parameters. We observed significantly decreased antral follicle counts and serum AMH levels in women with IOF as compared with normogonadotropic tall women. Serum AMH is currently the best marker for primordial follicle pool size because in the ovary it is expressed in granulose cells of follicles that have undergone recruitment but have not yet been selected for dominance. In addition, AMH plays an important role in regulating folliculogenesis because it is involved in determining the individual FSH threshold of early antral follicles. In addition, we believe some other possible pathologies, such as PCOS, can now be excluded as a potential cause of the observed infertility because of prevalence levels similar to the estimated population frequency.

Finally, we compared our results to a cohort of healthy fertile controls. Parameters of ovarian function were comparable between normogonadotropic tall women and these controls. Comparison with hypergonadotropic women confirmed that parameters of ovarian function in these women are indicative of accelerated follicle pool depletion.

The results of our study do not only validate earlier epidemiological findings from an Australian study but may also provide physicians with clinically useful information aiding in the diagnosis and treatment of estrogen-treated tall women with fertility problems. To our best knowledge, this is the first report establishing ovarian dysfunction in these women. It seems that follicle dynamics have changed in that respect that a considerable number of these women seem to suffer from accelerated follicle loss being reflected by increased serum FSH levels along with decreased AMH levels as well as low antral follicle counts. Hence, it seems that tall women who have been treated with estrogens in the past are prone to lose their reproductive capacity earlier in life, and they should be counseled accordingly.

In conclusion, we evaluated fertility and ovarian function in later life of tall women who did or did not receive high-dose estrogen treatment in adolescence. We found that estrogen-treated women experienced more difficulties conceiving and more often received medical treatment for infertility compared with untreated women. Treated women had a decreased chance of achieving at least one live birth. We observed a possible dose-response relationship because duration of treatment was correlated with time to pregnancy. Finally, we showed that treated women were at increased risk of being diagnosed with IOF. They exhibit signs of accelerated ovarian aging with concomitant follicle pool depletion, which may be the basis of the observed subfertility. However, the mechanism behind this accelerated follicle loss by high-dose estrogen treatment remains unknown and requires future research.

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