DES-treated tall girls fertility, a dose-response relationship

Fertility of tall girls treated with high-dose estrogen.

Abstract

Fertility of tall girls treated with high-dose estrogen, a dose-response relationship, National Institutes of Health, NCBI PubMed PMID 22723330, 2012 Sep.

Full text: The Endocrine Society, dx.doi.org/10.1210/jc.2012-1078, June 20, 2012.

CONTEXT
High-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life.

OBJECTIVE
The aim was to study the effect of estrogen dose on fertility outcome of these women.

DESIGN/SETTING
We conducted a retrospective cohort study of university hospital patients.

PATIENTS
We studied 125 tall women aged 20-42 yr, of whom 52 women had been treated with 100 ?g and 43 with 200 ?g of ethinyl estradiol (EE) in adolescence.

MAIN OUTCOMES
Time to first pregnancy, treatment for infertility, and live birth rate were measured.

RESULTS
The time to first pregnancy was increased in treated women. Of untreated women, 80% conceived within 1 yr vs. 69% of women treated with 100 ?g EE and 59% of women treated with 200 ?g EE. This trend of increased time to pregnancy with increasing estrogen dose was significant (log rank trend test, P = 0.01). Compared with untreated women, fecundability was reduced in women treated with both 100 ?g EE [hazard ratio = 0.42; 95% confidence interval (CI), 0.19-0.95] and 200 ?g EE (hazard ratio = 0.30; 95% CI, 0.13-0.72). We also observed a significant trend in the incidence of treatment for infertility with increased estrogen dose (P = 0.04). Fecundity was affected in women treated with 200 ?g EE who had reduced odds of achieving at least one live birth (odds ratio = 0.13; 95% CI, 0.02-0.81), but not in women treated with 100 ?g EE.

CONCLUSIONS
We report a dose-response relationship between fertility in later life and estrogen dose used for the treatment of tall stature in adolescent girls; a higher estrogen dose is associated with increased infertility.

Discussion

It has been shown that high-dose estrogen treatment to reduce final height of tall girls increases their risk for infertility in later life (3, 4). Here, we studied the effect of estrogen dose on fertility outcome of these women. We compared women who received no treatment to women who received either 100 ?g EE or 200 ?g EE. Our study confirms that tall women treated with high-dose estrogen have an increased time to pregnancy and experience more fertility problems compared with untreated women. We demonstrate for the first time that the association between estrogen treatment and the observed infertility is dose-dependent.

Although human studies on the effects of treatment with estrogens have mostly focused on OCP users, animal studies have focused on environmental exposure to EE as an endocrine-disruptor and on the effects of diethylstilbestrol (DES). In rodents, both in utero and postnatal exposure to EE or DES produces permanent adverse effects on the developing female reproductive system. Animal studies on in utero exposure to DES have shown disruption at the follicle level. In DES-exposed mice, reduced numbers of primordial follicles and of oocytes after ovulation induction have been found. Neonatal exposure to DES in lambs reduces the primordial follicle pool by stimulating their initial recruitment, resulting in increased numbers of atretic follicles. Finally, DES induces transient changes in gene expression during gestation; these changes could be involved in follicle development, rate of atresia, or patterns of secretion or metabolism of steroid hormones. These animal studies suggest that pharmacological doses of estrogens may influence fertility in many ways and at various time points. This knowledge, although difficult to extrapolate, may help in better understanding the mechanism behind the observed infertility in tall women treated with high-dose estrogen.

Previously, it has been shown that a considerable number of tall women treated with high-dose estrogen in adolescence suffer from primary ovarian insufficiency with concomitant early follicle pool depletion diagnosed by increased serum FSH levels, decreased serum anti-Müllerian hormone levels, and low antral follicle counts. Although the mechanism behind this accelerated follicle loss observed in these women remains unknown, based on our results we conclude that estrogen may play a key dose-dependent role. This is supported by a study on in utero exposure of women to DES, who reported an earlier age at menopause with cumulating doses of DES.

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