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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Reproductive performance of women with müllerian anomalies

uterinecongenitalanomalies
Classification of the anomalies of Müllerian duct developed by American Fertility Society (1988) and reproduced by Troiano and McCarthy.

Abstract

Reproductive performance of women with müllerian anomalies, Current opinion in obstetrics & gynecology, NCBI PubMed PMID: 17495638, 2007 Jun.

PURPOSE OF REVIEW
This review discusses current diagnostic techniques for müllerian anomalies, reproductive outcome data, and management options in reproductive-age women.

RECENT FINDINGS
Multiple retrospective studies have investigated reproductive outcomes with müllerian anomalies, but few current prospective studies exist. Uterine anomalies are associated with normal and adverse reproductive outcomes such as recurrent pregnancy loss and preterm delivery, but not infertility. Furthermore, unicornuate, didelphic, bicornuate, septate, arcuate, and diethylstilbestrol-exposed uteri have their own reproductive implications and associated abnormalities. Common presentations of müllerian anomalies and current diagnostic techniques are reviewed. Surgical intervention for müllerian anomalies is indicated in women with pelvic pain, endometriosis, obstructive anomalies, recurrent pregnancy loss, and preterm delivery. Although surgery for most uterine anomalies is a major intervention, the uterine septum is preferentially managed with a hysteroscopic procedure. Several recent studies and review articles discuss management of the septate uterus in asymptomatic women, infertile women, and women with a history of poor reproductive outcomes. Current assessment of reproductive outcomes with uterine anomalies and management techniques is warranted.

SUMMARY
Müllerian anomalies, especially uterine anomalies, are associated with both normal and adverse reproductive outcomes, and management in infertile women remains controversial.

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DES Grand Daughters Menstrual and Reproductive Characteristics

image of menstrual-cup
This 2006 data provide evidence of menstrual irregularity, delayed menstrual regularization, and increased infertility in DES Grand Daughters. Although this data provide limited evidence of an increased frequency of adverse pregnancy outcomes in third-generation women, most have not married or attempted to start families, and further follow-up will assess their reproductive experience.. Menstrual cup.

Abstract

Menstrual and reproductive characteristics of women whose mothers were exposed in utero to diethylstilbestrol (DES), International journal of epidemiology, NCBI PubMed PMID: 16723367, 2006 Aug.

Full text: Oxford Journals, Medicine & Health, International Journal of Epidemiology, Volume 35, Issue 4Pp. 862-868, doi: 10.1093/ije/dyl106, August 2006.

Background
In women, prenatal exposure to diethylstilbestrol (DES) is associated with adult reproductive dysfunction. The mouse model, which replicates many DES outcomes, suggests DES causes epigenetic alterations, which are transmissable to daughters of prenatally exposed animals. We report menstrual and reproductive characteristics in a unique cohort comprising daughters of women exposed prenatally to DES.

Methods
Menstrual and reproductive outcomes and baseline characteristics were assessed by mailed questionnaire in 793 women whose mothers had documented information regarding in utero DES exposure.

Results
Mean age at menarche was 12.6 years in both groups,

  • but daughters of the exposed women attained menstrual regularization later (mean age of 16.2 years vs. 15.8 years; P = 0.05),
  • and were more likely to report irregular menstrual periods, odds ratio (OR) = 1.54 [95% confidence interval (95% CI 1.02–2.32)].

A possible association between mothers’ DES exposure and daughters’ infertility was compatible with chance, age, and cohort adjusted OR = 2.19 (95% CI 0.95–5.07). We found limited evidence that daughters of the exposed had more adverse reproductive outcomes, but daughters of exposed women had fewer live births (1.6) than the unexposed (1.9) (P = 0.005).

Conclusions
The high risk of reproductive dysfunction seen in women exposed to DES in utero was not observed in their daughters, but most women in our cohort have not yet attempted to start their families, and further follow-up is needed to assess their reproductive health. Our findings of menstrual irregularity and possible infertility in third-generation women are preliminary but compatible with speculation regarding transgenerational transmission of DES-related epigenetic alterations in humans.

Excerpts and Discussion

The mean birth weight of offspring appeared lower in daughters of the exposed than in the unexposed (3374.2 g vs. 3540.5 g) (P = 0.08).

Our data indicate that DES Grand Daughters attain menstrual regularity at a slightly later age than daughters of the unexposed and are more likely to experience menstrual irregularity.

Our study suggests that infertility may also be more frequent in the DES Grand Daughters, and that DES exposure may exacerbate age-related infertility, a possibility compatible with findings in men who were exposed to DES in utero. The proportion of third-generation women affected by infertility (5%) in this study was far lower than that observed in the (second) generation of women exposed in utero to DES (30%).

In the prenatally exposed women, infertility is primarily due to anatomic anomalies of the uterus or fallopian tubes; other diagnoses, including hormonal/ovulatory problems, play a less striking role. Anatomic and tissue anomalies were not observed in a study of 28 third-generation women, but the number of participants was too small to rule out a low prevalence, and some irregularities (e.g. uterine, tubal) might not be evident on physical examination.

Further follow-up is needed to confirm the possible infertility in the third-generation women, and to evaluate specific diagnoses, which may provide insight into DES-related mechanisms.

It is well-known that women exposed to DES in utero have increased pregnancy complications and adverse birth outcomes, including ectopic pregnancy, pregnancy loss, and preterm delivery. Our data are not conclusive regarding adverse pregnancy outcomes in third-generation women, although daughters of the exposed had somewhat fewer live born children and babies of slightly lower average birth weight. Further follow-up will be essential to assess reproductive outcomes as more of the third-generation women enter their reproductive years.

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Reducing the Adult Height of Tall Girls with DES: Effects on Fertility

image of tall-girls
Estrogens have been used to reduce the height of unusually tall girls since the 1950s based upon the concept that, during normal puberty, increased estrogen levels lead to epiphyseal fusion in the long bones. DES treatment in adolescence seems to reduce female fertility in later life by 40%.

Abstract

Oestrogen treatment to reduce the adult height of tall girls: long-term effects on fertility, Lancet (London, England), NCBI PubMed PMID 15500896, 2004 Oct.

BACKGROUND
Treatment with oestrogen to reduce the adult height of tall girls has been available since the 1950s. We undertook a retrospective cohort study to assess the long-term effects of this treatment on fertility.

METHODS
Eligible participants were identified from the records of Australian paediatric endocrinologists who assessed tall girls from 1959 to 1993, and from self-referrals. Individuals included girls who had received oestrogen treatment (diethylstilboestrol or ethinyl oestradiol) (treated group) and those who were assessed but not treated (untreated group). Information about reproductive history was sought by telephone interview.

FINDINGS
1432 eligible individuals were identified, of whom 1243 (87%) could be traced. Of these, 780 (63%) completed interviews: 651 were identified from endocrinologists’ records, 129 were self-referred. Treated (n=371) and untreated (n=409) women were similar in socioeconomic and other characteristics. After adjustment for age, treated women

  • were more likely to have ever tried for 12 months or more to become pregnant without success (relative risk [RR] 1.80, 95% CI 1.40-2.30);
  • more likely to have seen a doctor because they were having difficulty becoming pregnant (RR 1.80, 1.39-2.32);
  • and more likely to have ever taken fertility drugs (RR 2.05, 1.39-3.04).

Time to first pregnancy analysis showed that the treated group was 40% less likely to conceive in any given menstrual cycle of unprotected intercourse (age-adjusted fecundability ratio 0.59, 95% CI 0.46-0.76). These associations persisted when self-referred women were excluded.

INTERPRETATION
High-dose oestrogen treatment in adolescence seems to reduce female fertility in later life. This finding has implications for current treatment practices and for our understanding of reproductive biology.

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IVF: effect of in-utero DES exposure on human egg quality and fertilization

Factors such as aneuploidy, embryonic genome expression and ultrastructure have not been assessed in this 1999 study.

Abstract

Effect of in-utero diethylstilboestrol exposure on human oocyte quality and fertilization in a programme of in-vitro fertilization, Human reproduction (Oxford,  England), NCBI PubMed PMID 10357979, 1999 Jun.
Full study: Oxford Journals, Medicine & Health Human Reproduction Volume 14, Issue 6 Pp. 1578-1581 doi: 10.1093/humrep/14.6.1578, February 15, 1999.

Genital tract abnormalities and adverse pregnancy outcome are well known in women exposed in utero to diethylstilboestrol (DES).

Data about adverse reproductive performance in women exposed to DES have been published, including controversial reports of menstrual dysfunction, poor responses after ovarian stimulation, oocyte maturation and fertilization abnormalities.

We compared oocyte quality, in-vitro fertilization results and embryo quality for women exposed in utero to DES with a control group. Between 1989 and 1996, 56 DES-exposed women who had 125 in-vitro fertilization (IVF) attempts were retrospectively compared to a control group of 45 women with tubal disease, who underwent 73 IVF attempts. Couples suffering from male infertility were excluded. The parameters compared were oocyte quality (maturation abnormalities, immature oocyte, mature oocyte), fertilization and cleavage rate (per treated and metaphase II oocytes), and embryo quality (number and grade).

We found no significant difference in oocyte maturational status, fertilization rates, cleavage rates, embryo quality and development between DES-exposed subjects and control subjects. These results suggest that in-utero exposure to DES has no significant influence on oocyte quality and fertilization ability as judged during IVF attempts.

Discussion

In the group of in-utero DES-exposed women analysed here, the prevalence of ovulatory dysfunction and endometriosis was very high, but the number and quality of oocytes retrieved after stimulation were similar to those from women not exposed to DES.

The clinical pregnancy rate (number of cycles with fetal sacs on ultrasound) per embryo transfer was not significantly different between the two groups although lower in the IVF cycles performed in DES-exposed patients. Thus, lower delivery rate could be related to other important variables such as uterine defects and endometrial morphology and thickness as previously reported.

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The history of DES points out prescriptions of a therapeutic without proofs of its efficiency

distilbene drugs image
With DES, the silence of pharmaceutical laboratories created major difficulties for physicians in affording useful information. Many questions are not still resolved.

Abstract

Drug surveillance and reproduction: the bad example of distilbene, Contraception, fertilité, sexualité, NCBI PubMed PMID 8261014, 1993 Sep.

In the 1940’s, diethylstilboestrol (DES) is one of the first hormonal therapeutics which was prescribed to many pregnant women by a lot of gynecologists. Until 1970, the indications of this therapy was enlarged, before carcinologic and reproductive consequences leaded to forbid obstetrical indications of DES (in France, in 1977 only).

In France, 80,000 girls and 80,000 boys are suspected to have been exposed. As far as girls are concerned, the studies estimate between 23% and 36% the rate of infertility. These studies show also an increased incidence of ectopic pregnancy, spontaneous abortions, and premature delivery. The association between various factors of infertility, and typical uterine abnormalities leads to specific therapeutical indications, mostly in assisted procreations.

The history of DES points out prescriptions of a therapeutic without proofs of its efficiency, the silence of pharmaceutical laboratories which did not take into consideration Dieckman’s evaluation, and the difficulties for physicians in affording information.

Nevertheless, the last patients exposed will be 40 years old in 2016 in France. The other hormonal therapeutics which were discovered gave in turn rise hope for enhancing the fertility and providing from miscarriage. Over the examples such as DES are not still resolved questions that patients and physicians ask concerning the lack of adverse effects of a therapy on the foetus, when its clinical efficiency on the pregnancy is supposed to be proved.

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DES Daughters and Reproduction: 1986 update

DES daughters are about 35% less likely than a non-DES-exposed woman of equivalent age and health to have a noneventful pregnancy. Image © Michael Orange.

Abstract

An update on DES in the field of reproduction,, International journal of fertility, NCBI PubMed PMID 2875034, 1986 May.

The general consensus is that a DES daughter is about 35% less likely than a non-DES-exposed woman of equivalent age and health to have a noneventful pregnancy.

It is important to state that fertility rates refer to couples. The male partner is responsible for 40% to 50% of infertility problems. Age is also an important factor, and female fertility is known to decrease with age from the early 20s. These two factors receive little consideration in most articles.

However, it can be said that if there are no marked congenital anomalies present in the cervix and the uterus, then the probability that a DES-exposed daughter will have a normal child is quite good.

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Intractable primary infertility in DES-exposed women

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

Abstract

Intractable primary infertility in women exposed to diethylstilbestrol in utero, The Journal of reproductive medicine, NCBI PubMed PMID 3712361, 1986 April.

Fertility factors were examined in 50 women with primary infertility and presumed in utero diethylstilbestrol (DES) exposure and in 50 age-matched controls.

Uterine deformities and endometriosis were more frequent in the DES-exposed women than the controls.

When managed from one to four years, only 4% of DES-exposed women with primary infertility conceived (with no conceptions resulting in a viable fetus) as compared to 44% of controls.

Primary infertility of one to two years’ duration with uterine deformities characteristic of DES exposure seems to signal a poor prognosis for pregnancy despite treatment of identifiable fertility factors.

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Primary infertility in DES-exposed women

In this 1986 study, more than 50% of the DES-exposed females showed primary infertility. Quiet in the Park.

Abstract

Primary infertility in women exposed to diethylstilboestrol in utero, British journal of obstetrics and gynaecology, NCBI PubMed PMID 3707881, 1986 May.

In a selected group of 40 women who had been exposed to diethylstilboestrol in utero, 18 conceived without difficulty and 22 had primary infertility.

Among those with primary infertility there was a significantly higher rate of anatomical structural defects and a greater tendency for menstrual disorders than in those without infertility.

Thirteen (59%) of the women with primary infertility conceived, most after treatment with ovulation stimulating drugs.

Spontaneous abortion and tubal pregnancy were frequent (47% and 10% respectively) and similar in both fertility groups.

Of 13 infertile women examined, 4 (31%) had mild hyperprolactinemia–a hithero unreported finding for such women.

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Infertility and upper genital tract changes in DES-exposed women

infertility-woman
In this 1986 study, more than 70% of the DES-exposed females showed abnormal hysterosalpingograms.

Abstract

Upper genital tract changes and infertility in diethylstilbestrol-exposed women, American journal of obstetrics and gynecology, NCBI PubMed PMID 3717241, 1986 Jun.

A possible relationship of upper genital tract abnormalities in the diethylstilbestrol-exposed woman and infertility was studied.

Six hundred thirty-two women had roentgenography performed. Three hundred sixty-seven of these women were not using contraception and were actively trying to become pregnant.

  • One hundred thirty-four (36%) of these women reported difficulties conceiving for a period of 1 or more years.
  • Seventy-three percent of these women had abnormal hysterosalpingograms.
  • The frequency of abnormal x-ray films in the women who did conceive within 1 year was essentially the same (74%). Furthermore, a similar number of women with normal x-ray films (37%) had difficulty conceiving as did women with abnormal x-ray films (36%).
  • When specific hysterosalpingographic abnormalities were related to the presence or absence of infertility, it was observed that the presence of a constriction of the upper uterine cavity resulted in a 2.26-times greater likelihood that a woman would not be able to conceive.
  • If a T-shaped uterus was found in association with constriction of the upper uterine cavity, the odds ratio for inability to conceive was found to be 2.63.
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