Aiming to decrease the estimated final heights of girls via DES hormone treatment

image of tall-girl-walking

Height as an infliction

“I was a lot taller than all the others, I shot up like a bamboo plant pretty early, and I remember thinking I was unlucky to be so tall”.

“Afterwards I’ve had a few problems, some of which have nothing to do with the treatment, but I’ve started to wonder whether there could be a connection,”

“I gained a lot of weight and had a strong need of sweets. And when I say strong I mean very strong. It was like a kind of dependency, as with tobacco or alcohol or whatever. Fortunately I was an active swimmer at the time, or I would have become terribly fat,”

“My nipples changed colour and became nearly black. This wasn’t so fun for a girl who was often in the public showers of the swimming hall,”

“My personality changed and I started stealing and lying. These were things that I had no tendencies toward before – I had been dutiful and terribly afraid of doing anything wrong,”

said Kristin Espestøyl who, from age 11 to 14, took one pill a day, which contained about three times as much oestrogen as a common contraceptive pill.

Read Height as an infliction, sciencenordic, December 11, 2011.

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Suppression of growth in excessively tall girls

DES Hormone Treatment Given to Healthy Teenage Girls to Manipulate Height

Abstract

Until recently, there has been little or no documentation in medical literature of therapeutic attempts to check the excessive height of growing girls. In 1956, Goldziehr reported a definite inhibition of skeletal growth by prepuberal estrogen administration in a series of 14 girls.

Suppression of growth in excessively tall girls, The JAMA Network, American Medical Association, doi:10.1001/jama.1958.62990110001011, March 15, 1958.

Excessive height in girls is not nearly as embarrassing as it was a number of years ago, inasmuch as tall girls have achieved some prestige in the entertainment world, in modeling, and in beauty contests. Nevertheless, some tall young girls are self-conscious about their height because of the great difference between them and their classmates and friends. These girls will often slump or stoop in an attempt to appear less conspicuous. This report is concerned with two such girls whose skeletal growth was inhibited by use of estrogens. By bringing this procedure to the attention of physicians, it is hoped that girls whose height is embarrassing…

… continue reading on JAMA.

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Normal at Any Cost

Tall Girls, Short Boys, and the Medical Industry’s Quest to Manipulate Height

Normal at Any Cost” – published March 19, 2009 – is the story, told decade by decade, of medical attempts to tinker with one inherited characteristic: height.

The first chapter tells the story of Laura, a happy child whose doctors prescribed massive doses of DES, a synthetic estrogen, because her mother worried that Laura would never find a husband or happiness if she grew too tall.

Normal-at-Any-Cost book cover image
Normal at Any Cost: Tall Girls Short Boys, and the Medical Industry’s Quest to Manipulate Height

Susan Cohen‘s book reveals the way drug companies redefined normal in order to expand markets, and how the best motives and worst motives combined to result in widespread experimentation on children. We think the temptations to tamper with heredity are just beginning.

Normal at Any Cost” tells the horrible story of drug use to adjust the height of adolescent boys and girls who were threatening to be short, or tall, adults. DES was prescribed to prevent girls from growing “too tall.”

SOURCES AND BOOK REVIEWS

  • Author’s website.
  • At What Height, Happiness? A Medical Tale, NY Times.
  • Normal at Any Cost: Tall Girls, Short Boys, and the Medical Industry’s Quest to Manipulate Height, N Engl J Med 2009.
  • Read reviews on Amazon and GoodReads.
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Estrogen use to reduce the growth rate of tall girls

image of tall girl

Abstract

In the past 15 years 450 girls have been seen because of concern about tall stature: 168 of them have been treated with stilbestrol to control the growth rate. Of the latter group 87 have been followed after treatment for a sufficiently long time to be sure growth had ceased and to provide the data for this report.

At the onset of treatment the following data (mean values) were recorded: chronologic age, 13.0 years; skeletal age, 13.2 years; height, 172.9 cm; estimated mature height 180.2 cm; and growth potential, 7.3 cm. At the end of treatment data of interest (mean values) were: reduction in final height, 3.5 cm; duration of therapy, 2.1 years; amount of stilbestrol given, 2.3 gm; age of last visit, 17.6 years.

Tall girls: a survey of 15 years of management and treatment, The Journal of pediatrics, NCBI PubMed PMID: 165277, 1975 Apr.

Side effects were minimal, though two girls developed parovarian cysts that required surgery during treatment. Not included in the series of 87, one additional girl was seen with a serous cystadenoma of the ovary, and one girl developed superficial venous thrombosis of the calf. Long-term follow-up has revealed no late complications.

It is concluded that estrogen can reduce significantly the growth rate of almost all tall girls, but treatment must be carried out under very careful supervision, bearing in mind possible side effects.

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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.

Click to download the full study.

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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.

Click to download the full study.

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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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