Tag: tall girls

Influence of high-dose estrogen exposure during adolescence on mammographic density for age in adulthood

2010 Study Abstract

High-dose estrogen exposure during adolescence has been hypothesized to increase a woman’s breast cancer risk, possibly mediated through an increase in mammographic density, a well-established breast cancer risk factor.

In 2006 to 2007, we conducted a retrospective study of women assessed for tall stature as an adolescent between 1959 and 1993. Eligible participants were ages > or =40 years and treated during adolescence with 3 mg diethylstilbestrol or 150 microg ethinyl estradiol daily or untreated. Mammograms from 167 treated and 142 untreated women were digitized.

Total breast area, dense area, nondense area, and percent density were measured using a computer thresholding technique. Data on potential determinants were collected from medical records and telephone interview.

Treated women had, on average, 17% lower dense area (P = 0.032). Means (95% confidence intervals) adjusted for age and body mass index for treated and untreated women were 24.5 cm(2) (21.8-27.2) and 29.1 cm(2) (26.0-32.4), respectively. There was no difference in adjusted means (95% confidence intervals) between treated and untreated women for nondense area [71.7 cm(2) (66.2-77.7) versus 70.5 cm(2) (64.7-76.9); P = 0.78], percent dense area [24.8% (22.4-27.4) versus 27.7% (24.8-30.7); P = 0.16], or total area [105.6 cm(2) (100.1-111.4) versus 109.3 cm(2) (103.1-115.8); P = 0.41], respectively.

High-dose estrogen exposure during adolescence appears to curtail growth of mammographically dense tissue and therefore is unlikely to increase breast cancer risk through mechanisms related to mammographic density.

Sources

• Full study (free access) : Influence of high-dose estrogen exposure during adolescence on mammographic density for age in adulthood, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, cebp.aacrjournals DOI: 10.1158/1055-9965, January 2010.
• Featured image credit globalmedicaldiscovery.

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Estrogen Treatment in Tall Girls

Abstract

In 1956 Goldzieher introduced estrogen as a treatment of excessive growth in adolescent girls. Since then, many reports have appeared describing the height-reducing effect of high-dose estrogen therapy in tall girls.

Sex Steroid Treatment of Constitutionally Tall Stature, The Endocrine Society, dx.doi.org/10.1210/edrv.19.5.0345, April 20, 2011.

my shadow is tall!, johnmccaffrey.

Many investigators, mainly in the United States, treated excessively tall girls with conjugated estrogens. In Western Europe, others used ethinyl estradiol (EE) in varying dosages usually combined with a progestogen 7–10 days each month to induce cyclic bleeding and to avoid overstimulation of the endometrium. Norethisterone, medroxyprogesterone, and dydrogesterone have been used as progestagen, 5–10 mg/day. The two last preparations, in particular, show low to absent androgenic effects.

In the past, estrogens have been administered in the form of stilbestrol, 1–5 mg per day. However, since it has been reported to cause vaginal cancer in the female offspring of women treated during pregnancy, stilbestrol is not a suitable treatment modality. It has the additional disadvantage of inducing marked pigmentation and hyperkeratosis of the nipple.

Estradiol esters, such as estradiol-valerate and -benzoate, have been used since they were considered to be more ‘physiological’ than oral ethinyl estradiol (EE) or conjugated estrogens. A disadvantage is that three injections per cycle are required. Considering all advantages and disadvantages, it appears that EE is the preparation of choice, since the dose is standardized, administration is easy, and side effects are not more marked or frequent than with any other preparation.

Whether the estrogens are given continuously or cyclically seems to be of minor importance for the effect on height or for the resumption of regular menstrual cycles after discontinuation of treatment. It seems that the pituitary-gonadal axis tolerates continuous therapy for a period of 1–2 yr very well. In the 1960s most practitioners used 500? g EE; in the 1970s 200–300 ?g were used, and in the 1980–1990s a dosage of 100 ?g/day was claimed to be sufficient. Whether even lower dosages (e.g., 35 ?g daily) are equally effective remains to be assessed in a prospective clinical trial.

Too tall for future happiness?

Abstract

” When Laura was growing up in a small New England town, her parents and doctors worried that her predicted adult height threatened her future happiness. Laura’s tall mother had been teased and embarrassed about her own height at school. When the local paediatrician mentioned that a specialist might be able to stunt Laura’s growth and spare her the social pain of towering over boys as an adolescent and men as an adult, her family agreed. A paediatric endocrinologist affiliated with a prestigious US academic medical centre confidently prescribed the synthetic oestrogen diethylstilbestrol in doses 100 times greater than the oestrogen found in today’s high-dose oral contraceptives.

Too tall, too small? The temptation to tinker with a child’s height, The Lancet, Volume 375, No. 9713, p454–455, dx.doi.org/10.1016/S0140-6736(10)60185-7, 6 February 2010.

Too tall and too small by P-cate.

Laura obediently took the little coated pills, now commonly known as DES, for about 2 years. But they made her sick and when she reached adulthood and married, she experienced miscarriage after miscarriage that denied her what she most wanted in life—children. When doctors also diagnosed her with a condition that put her at risk of breast cancer, Laura wondered what effects the little pills might have had on her adult health. She didn’t know at the time that other tall girls also went on to have reproductive problems after taking diethylstilbestrol and other high-dose oestrogens to stunt their growth, or that there had been concerns about the drug’s potential effects on fertility and cancer even at the time her physician prescribed it. Laura didn’t know because none of the physicians she consulted as an adult had heard of the treatment she had received as a child; there had been hardly any follow-up studies of these girls once they became adults.

Meanwhile, the culture of the 1950s and 1960s, which had made limiting the height of tall girls seem like such a good idea to parents and to physicians, was changing rapidly by the mid-1970s. Girls who dutifully swallowed pills to try to remain below 5′6″ so that they could qualify for the corps de ballet or become airline stewardesses, or girls who desperately wanted to stay below 5′10″ to improve their chances of finding a husband, suddenly had many more options in life. They could join a volleyball or basketball team, become doctors and attorneys and police officers, run a business, or compete for political office. The medical advice that suggested tall girls invariably risked psychosomatic illness, or were at risk of not only spinsterhood but homosexuality, today seems quaint. No wonder women like Laura have encountered difficulty explaining this medical intervention to disbelieving obstetricians and gynaecologists.

How do medical therapies launched with the best of intentions result in tragedy? The history of treating children for height provides a compelling allegory for modern medicine, in which cures for disease evolve at an ever-quicker pace into treatments for disability, then for disadvantage, then to satisfy the desire for perfection. Over and over, the best and worst motives combined: the concern of parents and children, the desire of doctors to help and to discover, and the potential profits of industry. There have been far fewer incentives to follow up what happened to these children once they became adults.

In the case of the tall girls who received childhood or adolescent exposure to massive doses of oestrogen, none received any ongoing medical observation, despite calls by some doctors in the mid-1970s to follow them for the rest of their lives. Although diethylstilbestrol is no longer used, and the demand for stunting the growth of healthy girls has dropped in recent decades, some tall girls are still prescribed oestrogens to stunt height, especially when parents insist. ” …

Continue reading Too tall, too small? The temptation to tinker with a child’s height by Susan Cohenemail and Christine Cosgrove on The Lancet.

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Diethylstilbestrol given to healthy teenage girls to manipulate height

Abstract

In 1980-1985 680 preadolescent tall girls were treated with pharmacological doses of oestrogen to reduce final height. Indications for the therapy were predicted final height greater than +2.5 SD (180.75 cm), idiopathic scoliosis, and psychosocial problems.

Oestrogen treatment of adolescent tall girls; short term side effects, Acta endocrinologica Supplementum, NCBI PubMed PMID: 3465158, 1986.

Until 1976 141 girls were given diethyl stilboestrol 5 mg daily. By advice of Prader this was then replaced by ethinyl oestradiol and a progestin was given on days 5-10 each month. The mean duration of therapy was close to 2 years.

The observed short-term unwanted effects were due to the pharmacological actions of the drugs, (11 girls had galactorrhoea at the end of therapy; no pituitary prolactinoma was observed) or events happening by chance.

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Diethylstilbestrol given to healthy teenage girls to manipulate height

Abstract

During the latter half of the 20th century, estrogen therapy was administered to prevent otherwise healthy girls with tall stature from becoming tall adults by inhibiting further linear growth. We explore how decisions to treat tall girls with estrogen were influenced by both scientific knowledge and sociologic norms. Estrogen therapy represented the logical application of scientific knowledge regarding the role of estrogen for closure of the growth plates, but it also reflected prevailing societal and political beliefs about what it meant to be a tall girl. We discuss the rise and fall in popularity of this therapy and suggest that insight into the present-day treatment of short stature can be gained by comparing the use of estrogen therapy for tall girls with the use of growth hormone therapy for short boys. We suggest that this case study illustrates how scientific knowledge is always created and applied within a particular social context.

Tall Girls : The Social Shaping of a Medical Therapy, Archives of pediatrics and adolescent medicine, NCBI PubMed, PMID: 17018462, October 2006.

The therapeutic use of sex steroids dates back to the late 19th century, when medical practitioners such as midwives used ovarian extracts to treat a variety of female disorders. For example, the filtered juice of guinea pigs’ ovaries was used for women with hysteria, debility, and abnormal menstruation. Thus, even prior to the discovery of specific substances derived from the ovaries, practitioners attempted to harness their therapeutic potential.

Changes in scientific understanding led to the concept of hormones, substances that were produced in a particular organ but acted throughout the body in a complex web of interactions. By the 1930s, scientists had identified specific hormones produced by the ovaries and testes.3 The pharmaceutical industry soon began manufacturing ovarian and testicular preparations, and physicians began exploring a wide range of therapeutic applications.

One such application in the pediatric arena was the use of sex steroids for influencing growth. By the 1940s, physicians began to understand hormonal influences on the growth plate through important clinical observations. First, they observed that children with early exposure to sex hormones due to precocious puberty had premature epiphyseal closure and developed short stature as adults. Physicians also found that children with pituitary disease who lacked sex hormones had open epiphyses with a prolonged period of growth. Based on these clinical observations, it was postulated that gonadal steroids were responsible for closing the epiphyses.

Children at risk for tall stature due to acromegaly thus became the first recipients of estrogen and testosterone therapy for prevention of excess growth during the 1940s. Clinical trials revealed that estrogen preparations, in contrast to testosterone preparations, were particularly successful for preventing tall stature in children with acromegaly. As a consequence, physicians naturally considered whether the same treatment could be applied in other settings. Girls with constitutional tall stature represented a potential group of patients for whom hormone therapy might prevent further growth, an outcome that some considered desirable.

In 1946, a brief abstract was published about the clinical experience of estrogen treatment in tall girls who were “becoming alarmed and unhappy about the extremes to which their exuberant, albeit normal growth was carrying them.” A decade later, Goldzieher published the first formal clinical study of the use of estrogen therapy for the treatment of constitutional tall stature in girls. Goldzieher cast his research in terms of the application of new scientific advances; he claimed that estrogen treatment of girls destined to be tall as adults was a logical next step following the estrogen treatment of children with acromegaly and hence represented “no novelty.” In his initial case series, 14 girls aged 9 to 16 years were treated with oral forms (2 mg daily of stilbestrol or 2.5-5.0 mg daily of premarin) or injected forms (1.6 mg of estradiol monobenzoate every 5 days) of estrogen for anywhere from 3 months to 5 years. Criteria for treatment included a current height of 168 cm (66 in) with open epiphyses or a current height less than 168 cm (66 in) but with a predicted height 10 cm (4 in) above the average. In his article, Goldzieher concluded that growth was successfully arrested based on his observation that the majority of girls had growth of no more than 5 cm (2 in) from the start of therapy.

Download the full paper on The Jama Network.

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Tall girl therapy

The above title does not mean the use of tall girls in therapy or the therapy of tall girls, but rather the therapy that may be used to help prevent little tall girls from growing into big tall girls. This implies three things: that some tall girls are dissatisfied with the prospect of towering over the average male, that there is a means of predicting which girls are going to grow tall, and that there is effective therapy available.

In their review of 15 years of management and treatment of tall girls in Australia, Wettenhall, Cahill and Roche stated that they can confidently answer that there are indeed some preadolescent and adolescent girls of above-average height who do not relish the prospect of much further growth, that it is possible to predict final height from height at an earlier age, and that they have . treatment regimen that will help slow down the growth of these girls. They took as the definition of tall stature any height more than two standard deviations above the mean for the community. By this criterion 2.3% of girls in any chronologic age group are unusually tall. In Australia there are probably 41 000 girls under the age of 15 who are unusually tall, but few seek medical attention: many are not concerned about their stature, others have no idea that anything can be done.

Tall girl therapy, US National Library of Medicine, National Institutes of Health, Can Med Assoc J, NCBI PubMed PMC1956556, 1976 Jan 10.

Image credit oddstuffmagazine.

Attempts to control stature are reasonable when a fairly good estimate of final height can be made, treatment will reduce this final figure appreciably, and short- and long-term side effects are minimal.

In the reports on stature control since Goldzieher’s paper in 19562 the use of various estrogen preparations has been assessed, and all but two reports have claimed success. Wettenhall and colleagues1 treated 168 girls with stilbestrol between 1959 and 1973; the data for 87 of these form the basis of their report.

Mature stature was estimated from the tables of Bayley and in which present height and skeletal maturity (hand, wrist and knee) are considered. Treatment was given if the estimated mature height was greater than 177.0 cm or if the estimated growth potential was sufficient to justify treatment. (Treatment was not given to 282 other tall girls who constilted the authors.) The mean chronologic age was 13 years at the beginning of therapy (range, 11 to 15.8 years). Mean stature was above the 97th percentile for Australian girls. Estimated mature stature ranged from 172.2 to 189.2 cm (the smallest girl was treated because she showed promise as a ballet dancer – no profession for a tall girl). Estimated growth potential ranged from 1.3 to 16.8 cm. Treatment was begun in 46 girls before menarche and in 41 girls after menarche.

Treatment was preceded by a careful study of the patient, including tests to exclude organic disease that might cause excessive growth, and by discussion with the girl and both her parents of the advantages and disadvantages of being tall. In determining the optimum height for starting treatment one should, of course, allow sufficient time for a treatment effect while avoiding the induction of menstruation at too early an age. Thus, treatment was not begun by the authors in any girl less than 10 years old.

Stilbestrol was given in a dosage of 1 mg/d for the first week, 2 mg/d for the next week, and then 2 mg/ d until mature (or nearly mature) stature was reached. Cases were reviewed at 3-month intervals. The mean duration of therapy was 2.1 years (range, 0.6 to 4.1 years). Mean age at final meassurement of stature was 17.6 years (range, 14.1 to 25.3 years). The mean “apparent effect” of therapy was 3.5 cm growth in height, apparent effect being obtained by subtracting final stature from estimated mature stature. A few girls did not respond to treatment but some were saved up to 10 cm of excess height. All said that they were glad they had been treated. Treatment was more effective if it was started early and also if it was begun before menarche.

When therapy was begun before menarche, ii regular menstruation was apt to occur. This irregularity also happened after menarche; however, administration of norethindrone for 4 days a month controlled this. There were no long-term menstrual problems after therapy was discontinued. Pigmentation occurred in some girls but always faded later. Nausea was controlled by decreasing the dosage temporarily. Diet controlled obesity when it appeared, and in any case the excess weight was shed later. All girls improved psychologically. Mild thrombosis occurred in one girl. Ovarian cysts developed in two girls; the relation of this occurrence to stilbestrol therapy is not clear.

The authors point out that there is no convincing evidence that estrogen causes cancer in “normal” girls or young women. They also note that ethinyl estradiol in comparable dosage (0.12 mg/ d) is perhaps now the agent of choice.

To sum up, they believe that effective control of stature of potentially tall girls is possible but should be carried out under careful supervision after careful assessment.

Click to download the full paper.

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When Being a Tall Girl was a Medical Condition…

Abstract

Widely varying reports of methods and results have confused evaluation of estrogen as a means of limiting the height of tall girls.

This comparative study of 21 treated and 17 untreated girls above the 97th percentile for height indicates a statistically significant probability that exogenous estrogen limits ultimate height, but only by an average of about 4 cm (1.6 in).

The JAMA Network, JAMA Pediatrics, doi:10.1001/archpedi.1973.04160010045010, January 1973.

The optimal starting age appears to be before bone age 13 years. Starting treatment before bone age 11 1/2 years did not improve results.

In offering this treatment, one must weigh the potential ill effects of estrogen administration to young girls against a demonstrated modest decrease in mature height.

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A ‘too tall’ tale: girls and the drug DES

“The practice of using DES on tall girls had a long history. It was in the late 1940s that doctors at Massachusetts General Hospital in Boston first discovered a way to alter height – a distinctive, heritable trait – in girls whose parents feared their daughters were growing too tall. In those days, hormone discoveries were heralding a new era in medicine, just as gene therapy is today. Hormones were the miracle that would allow doctors to manipulate how tall a girl grew and allay her mother’s fears.”

“So with the availability of the cheap, synthetic drug DES, and the discovery that large amounts of estrogen could push a girl into and through puberty quickly, allowing less time for her bones to grow long, the tall-girl problem appeared to have a solution. An inherited trait that used to be a given – tall stature – could now be fixed.”

“In the U.S., it is estimated that thousands of tall girls obediently swallowed massive amounts of DES – often 100 times the amount of estrogen delivered in a high-dose birth control pill – daily over a period of several years.”

Read A ‘too tall’ tale: girls and the drug DES, LA Times, April 5, 2009.

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Abstract

Objective
Public health research is an endeavour that often involves multiple relationships, far-reaching collaborations, divergent expectations and various outcomes. Using the Tall Girls Study as a case study, this paper will present and discuss a number of methodological, ethical and legal challenges that have implications for other public health research.

Approach
The Tall Girls Study was the first study to examine the long-term health and psychosocial effects of oestrogen treatment for tall stature.

Looking back in time: conducting a cohort study of the long-term effects of treatment of adolescent tall girls with synthetic hormones, BMC Public Health, BioMed Central, DOI: 10.1186/1471-2458-11-S5-S7, 25 November 2011.

Results
In undertaking this study the research team overcame many hurdles: in maintaining collaboration with treating clinicians and with the women they had treated as girls – groups with opposing points of view and different expectations; using private practice medical records to trace women who had been patients up to forty years earlier; and exploring potential legal issues arising from the collection of data related to treatment.

Conclusion
While faced with complex challenges, the Tall Girls Study demonstrated that forward planning, ongoing dialogue between all stakeholders, transparency of processes, and the strict adherence to group-developed protocols were keys to maintaining rigour while undertaking pragmatic research.

Implications
Public health research often occurs within political and social contexts that need to be considered in the planning and conduct of studies. The quality and acceptability of research findings is enhanced when stakeholders are engaged in all aspects of the research process.

Background

Very little information is available on the evolution of the use of high dose oestrogens as a treatment for tall stature in healthy adolescents. After the successful use of this treatment in children with pituitary gigantism in the 1940s , clinicians in the United States (US) extended the treatment to tall girls with concerns about their height but who had no associated pathology. The first report of treatment of tall girls was published in 1956. There have been no randomised controlled trials of treatment effectiveness, and cohort studies have demonstrated that treatment is only moderately effective. Despite this, the treatment became an accepted clinical practice in many countries including Australia.

Treatment was based on the knowledge that normally in puberty oestrogen inhibits further increases in height by fusing the epiphyses (growth-plates) of the long bones. Most treating clinicians considered treatment acceptable if a girl’s adult height was predicted to be above the 97th percentile or two standard deviations above the mean female adult height in the given population. Determination of predicted adult height involved estimating bone age after an x-ray of the hand and wrist and assessing the remaining growth potential. The various methods for calculating predicted adult height are prone to error.

The earliest predicted height criterion for oestrogen treatment in the US was 173cm in 1956 and this gradually increased over time but continued to fluctuate between countries. During the 1970s, Australian girls with a predicted adult height of ?177cm were eligible for treatment; in the US, girls whose predicted adult height was above 173cm  or 182.9cm  were also treated; and in Germany and the Netherlands the treatment criterion was a predicted height of ?180cm. Age at initiation and duration of treatment also varied considerably and was strongly associated with overall treatment effectiveness. The clinical challenge was that the accuracy of predicting adult height increased after the age of ten years (or closer to puberty) however the potential height reduction diminished. Some clinicians waited until girls grew to an arbitrary height before initiating treatment: 167cm in Australia ; 169.5cm in the US ; and 170cm in Europe ; while others waited until girls reached puberty when they were more likely to be psychologically ready for the effects of treatment on their development but when treatment may be less effective. Duration of treatment varied but was generally two to four years. Treatment regimes varied considerably and initially were a combination of oestrogen and testosterone. Various preparations of oral synthetic or conjugated oestrogens were given continuously or cyclically; oestrogen pellets were inserted under the skin at six monthly intervals for some; and intramuscular injections of oestrogen were given to others.

The rationale for treatment was to reduce perceived psychosocial ‘risks’ tall girls may face in adulthood. These included physical deformity, through tall girls’ adoption of slouching in an effort to reduce their height; and psychological distress and social withdrawal as a consequence of tall girls’ difficulty conforming to cultural stereotypes. However, there was very little reporting of any evidence for these assumptions and there are very few published studies reporting psychosocial outcomes following treatment. Three relevant studies were limited by small sample sizes, the participants being still relatively young, and the fact that the investigators were treating clinicians which may have affected responses. While treatment is relatively uncommon now in Australia, it was still being used in the US in 2002 ; is currently recommended for the management of familial tall stature ; and more controversially has been proposed as a form of clinical management of disabled children to reduce their height and increase manageability.

The use of synthetic oestrogens as a medical treatment to reduce the height of tall girls was relatively unknown among the general public during the decades it was at its peak in Australia and elsewhere. Even within some families a girl’s height assessment and treatment was kept a secret from other family members.

Public awareness of the treatment of tall girls came about in Australia in 1997, when the treatment became part of a wider debate in the Australian Federal Parliament on the use of human biological products and post-war medical experimentation. Subsequent to the media coverage of this issue, the need for a comprehensive follow-up study was raised independently both by Australian endocrinologists and by women who had been assessed and treated for tall stature as adolescents. These women formed a lobby group, Tall Girls Inc., to petition the government for a follow-up study citing a range of health concerns and that their families had been unaware of the experimental nature of this treatment.

Clinicians and Tall Girls Inc. alike had concerns about the possibility of long-term effects of oestrogen treatment, particularly exposure to diethylstilboestrol (DES), which is associated with serious adverse outcomes when given to pregnant women.

In early 1998, the paediatric endocrinology group at the Royal Children’s Hospital was under increasing pressure to conduct a follow-up study to examine long-term outcomes of treatment and was looking for a group of researchers with whom to collaborate. Researchers at La Trobe University who were interested in the research and had significant experience in conducting long-term follow-up studies in women’s health met with treating clinicians. Following an agreement for the need for a study and for formal collaboration, a period of intense discussion and consultation was undertaken with all parties to formulate the study design and research questions. Given their investment in the project and the sense of disenfranchisement that many treated tall girls felt from the original decision-making, Tall Girls Inc. and particularly the president, Janet Cregan-Wood, were involved from inception in the study design process. In 2000, the National Health and Medical Research Council (NHMRC) provided funding for the study (known as the Tall Girls Study).

… click to download the full paper.

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