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Estrogen Replacement in Women of Fertile Years with Hypopituitarism

Division of Clinical Sciences (North) (P.M.M., J.W., R.J.M.R.), University of Sheffield, Sheffield S5 7AU, United Kingdom; KIGS/KIMS/Acrostudy Medical Outcomes (Pfizer Endocrine Care) (P.J., M.K.-H.), Stockholm, Sweden; Riks Hospitalet (U.F.-R.), Copenhagen, DK-2100 Denmark; and Department of Pharmacy (M.K.-H.), Uppsala University, Uppsala, Sweden

Address all correspondence and requests for reprints to: Prof. R. J. M. Ross, Clinical Sciences Center, Northern General Hospital, Sheffield, United Kingdom S5 7AU. E-mail: r.j.ross{at}sheffield.ac.uk.

	Abstract

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Background: What form of estrogen to prescribe a young hypopituitary woman with gonadal failure remains an open question despite evidence that oral estrogen therapy induces GH resistance and an increase in fat mass.

Methods: Using an international surveillance study of hypopituitary patients, we examined two questions: 1) What estrogen is prescribed to young women of fertile years with hypopituitarism? 2) Is there a difference in body composition or IGF-I levels dependent on the type of estrogen prescribed?

Results: Six hundred twenty-eight GH-deficient women, aged 18–50 yr, were identified. Three hundred thirteen had normal gonadal function, and 315 were receiving estrogen therapy; of these 14% were using transdermal estradiol, and 86% were taking an oral estrogen preparation (38% oral estradiol, 18% conjugated estrogens, and 30% ethinyl estradiol in the oral contraceptive). There was no difference in weight, waist/hip ratio, or body composition between the women taking different estrogen therapies. However, if the oral estrogen groups were combined, they showed less change in waist and hip measurement and had a greater waist/hip ratio after 1 yr of GH treatment compared with patients with normal gonadal function (0.85 vs. 0.83; P = 0.022). Patients taking ethinyl estradiol had lower age-adjusted IGF-I SD scores and required almost twice the GH dose to achieve an IGF-I SD score that remained lower than patients with normal gonadal function and patients receiving transdermal estradiol.

Conclusions: 1) The majority of women of fertile years with hypo-pituitarism take oral estrogen replacement therapy. 2) Waist/hip ratio was greater in women taking oral estrogens, and there is indirect evidence that oral estrogens reduce the action of GH on fat mass. 3) Patients using the oral contraceptive had lower IGF-I levels and required twice the GH dose compared with patients receiving transdermal estradiol.

	Introduction

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IN WOMEN, ESTROGEN is essential for normal growth, puberty, fusion of epiphyses, breast development, menstruation, achievement of peak bone mass, and maintenance of normal adult female body composition. Estrogen deficiency may be congenital, as in Turner’s syndrome, or acquired, as in ovarian and pituitary disease. Young women with estrogen deficiency require replacement therapy at least until the age of expected menopause. At present there are no data on what estrogens are prescribed for women of fertile years with hypopituitarism, nor is there evidence to guide the physician as to which estrogen therapy to recommend during fertile years.

In postmenopausal women the indications for estrogen replacement therapy (HRT) are being reassessed after the publication of studies demonstrating that HRT may increase the risk of thromboembolic and cardiovascular disease (1, 2, 3, 4). The picture has become more confusing, with recent evidence suggesting that oral contraceptive use may be protective for later life events (5), although these data have been heavily criticized (Women’s Health Initiative web site, http://www.whi.org/news/press_oral_contraceptives.php). In healthy postmenopausal women, oral estrogens increase fat mass and reduce lipid oxidation compared with transdermal therapy (6); oral estrogens result in an accumulation of 1 kg fat mass over a 6-month period. This effect is in part mediated through an interaction with the GH-IGF-I axis (6, 7, 8, 9). Based on these and other studies, it appears that the route and dose of estrogen have an important impact on IGF-I levels in both healthy postmenopausal women and patients with hypopituitarism requiring GH replacement (8, 10, 11, 12, 13). This effect is thought to be related to a first-pass hepatic action (14). IGF-I levels are increasingly seen as a marker for predicting health later in life. High IGF-I levels are associated with increased risk of some cancers (15, 16, 17, 18, 19), and there is evidence that chronic exposure to low IGF-I levels may play a role in the pathogenesis of both type 2 diabetes and myocardial infarction (20, 21).

To define the most appropriate preparation for HRT in the young woman would require a large prospective study, but there has been no move to support or fund such a study, nor is there a mechanism or patient group who could be readily approached to support such a study. We currently do not know the prescribing practice of clinicians with respect to estrogen replacement in young women. Despite their obvious limitations, observational postmarketing surveillance studies have the ability to answer important questions based on their access to large patient numbers; availability of longitudinal, long-term, observational data; and documentation of everyday clinical practice. We have used the KIMS database (Pfizer International Metabolic Database), an international postmarketing surveillance study of hypopituitary patients receiving GH therapy, to examine two fundamental questions. 1) What forms of estrogen replacement are being prescribed to young women with GH deficiency of fertile years? 2) Is there a difference in weight, waist/hip ratio, body mass index (BMI), body composition, or IGF-I levels dependent on type and route of estrogen prescribed?

	Subjects and Methods

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Database

The KIMS (Pfizer International Metabolic Database) database was established in 1994 as an ongoing record of adult patients with GH deficiency. The primary objective was to monitor the safety and outcomes of long-term GH replacement treatment in adult patients with GH deficiency treated in a conventional clinical setting. Data are collected at clinic visits on specially designed case record folders. The data collection process is monitored, and the quality of the data entered has been audited and confirmed. Patients gave informed consent, verbally or in writing, depending on the local legal requirements. Local ethics committees gave their approval.

Subjects

Female patients in the KIMS database were identified, and two groups were selected: 1) those stated to have normal gonadal function and not taking estrogens, and 2) women receiving estrogen therapy including those taking oral contraceptives. The patients included were less than 50 yr of age and had not received GH therapy for the 6 months before entering the database. Patients taking estrogens were included in the analysis if they had been taking estrogens for at least 1 month before entering the database. Patients excluded from the analysis were those who started or stopped estrogen within the first year of entry to the database and patients who had been diagnosed or had received treatment for craniopharyngioma, acromegaly, or Cushing’s disease, because these conditions may, independent from hyposomatotropism, affect body composition. Patients taking estrogens were divided into the following categories: transdermal estradiol or oral estrogen; then the oral categories were also broken down: oral estradiol valerate, conjugated estrogen, and ethinyl estradiol. Where the estrogen treatment did not fit into one of these categories, the patients were excluded from the analysis.

The following variables were analyzed for each patient group: age, weight, BMI, waist/hip ratio, body composition measured by bioimpedance, and IGF-I SD score (SDS), which is age adjusted. The change from baseline () in these variables after 1 yr of GH therapy were also analyzed, as was the GH dose at the end of that year. Values are expressed as either mean ± SD or the median (10th–90th percentiles in parentheses).

Statistics

Comparison between patients groups was performed by t test and Mann-Whitney U test in normally distributed and non-normally distributed variables, respectively. If there was a difference in age between the groups, a multiple linear regression analysis was performed to correct for age in those variables that showed significant differences in the univariate analysis.

	Results

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The analysis dataset used for this study contained data from 6065 patients, of whom 2964 (48.9%) were women. Six hundred twenty-eight women fulfilled the inclusion and exclusion criteria; 315 were receiving estrogen therapy, and 313 had a normal gonadal axis and were not taking estrogens.

Types of estrogen

For those patients receiving estrogen therapy, 44 (14%) were using transdermal estradiol, and 271 (86%) were taking oral estrogen preparations [121 (38%) were taking oral estradiol valerate, 55 (18%) were taking conjugated estrogen, and 95 (30%) were taking ethinyl estradiol].

Age distribution (Fig. 1)

Patients taking ethinyl estradiol were younger [median, 30.6 yr (10th–90th percentiles, 18.9–42.5)] compared with non-estrogen-treated patients [37.8 yr (21.0–47.3); P = 0.0001], patients using transdermal estradiol [43.6 yr (25.4–48.0); P = 0.0001], patients taking estradiol valerate [39.0 yr (23.5–47.9); P = 0.0001], and patients taking conjugated estrogen [39.2 yr (22.3–49.2); P = 0.0001]. Patients using transdermal estradiol were older than non-estrogen-treated patients (P = 0.0017) and patients taking estradiol valerate (P = 0.0111).

View larger version (23K): [in this window] [in a new window]   FIG. 1. Age distribution of patients not taking estrogen and those using various estrogen preparations.

Weight and BMI (Fig. 2)

Patients not taking estrogens had a higher baseline weight than patients taking estradiol valerate, conjugated estrogen, and ethinyl estradiol (Fig. 2A). However, after 1 yr of GH therapy, there was no difference in weight between the patient groups, no difference in weight , and no difference when comparing the oral estrogen patients vs. patch and normal gonadal function patients. A similar pattern was seen for BMI (Fig. 2B), although after 1 yr of GH therapy, patients taking estradiol valerate had lower BMI compared with non-estrogen-treated patients and patients taking ethinyl estradiol.

View larger version (33K): [in this window] [in a new window]   FIG. 2. A, Patient weight at baseline and after 1 yr of GH therapy according to estrogen group. B, Patient BMIs at baseline and after 1 yr of GH therapy according to estrogen group.

Waist/hip ratio (Table 1)

There was no difference in waist circumference, hip circumference, or waist/hip ratio among the different estrogen-treated groups of patients at baseline and after 1 yr of GH therapy and no difference in the in these parameters at 1 yr. However, if the oral estrogen groups were combined, there was a significant difference in waist circumference (median, –2.0 vs. 0.0 cm; P = 0.007), hip circumference (median, –1.0 vs. 0.0 cm; P = 0.019), and absolute waist/hip ratio (0.83 vs. 0.85; P = 0.022) between the no-estrogen group and the oral estrogen group. There were no differences in waist and hip measurements between the patch group and those with normal gonadal function, and for both the normal gonadal function and patch groups there was a significant reduction in waist circumference after 1 yr of treatment, as assessed by (P < 0.01).

Body composition (Table 2)

There was no difference in body fat or lean body mass among the patient groups at baseline and after 1 yr of GH therapy after correction for age, and there was no difference in the in these parameters even when the oral estrogen groups were combined.

IGF-I SDS and response to GH therapy (Fig. 3)

Patients taking ethinyl estradiol had a lower IGF-I SDS [–4.44 (–5.84 to –2.12)] at baseline compared with patients with normal gonadal function not taking estrogens [–2.21 (–4.62 to –0.36); P = 0.0001], patients using transdermal estradiol [–2.37 (–4.17 to –0.51); P = 0.0001], patients taking estradiol valerate [–3.08 (–7.04 to –1.02); P = 0.0326], and patients taking conjugated estrogen [–2.76 (–6.51 to –0.53); P = 0.0159]. Patients taking estradiol valerate had a lower baseline IGF-I SDS compared with non-estrogen-treated patients (P = 0.0003) and patients using transdermal estradiol (P = 0.0385).

View larger version (26K): [in this window] [in a new window]   FIG. 3. A, Comparison of IGF-I SDS at baseline and after 1 yr of GH therapy, in parallel (B) with the GH dose after 1 yr, among patients receiving no-estrogen and those using various estrogen preparations.

The distribution of GH dose according to patient group is shown in Fig. 3B. Patients receiving ethinyl estradiol were taking significantly higher GH doses [2.0 (1.0–2.8) U/d] than patients not receiving estrogens [1.2 (0.8–2.0) U/d; P = 0.0001] and those taking transdermal estradiol [1.2 (0.5–2.0) U/d; P = 0.0015].

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this cohort of women of fertile years with hypopituitarism, we found that 86% of women using estrogens were receiving oral therapy; of these, 30% were using ethinyl estradiol. Thirty to 40% of young women in the United Kingdom general population use an oral contraceptive (22); therefore, it is not surprising that the physician and patient may choose the oral contraceptive. However, the high use of oral estrogens is surprising considering the recent evidence that transdermal estrogen provides more physiological hormone replacement therapy (14). Our data suggest that the physician should question the choice of ethinyl estradiol as replacement therapy in hypopituitary young woman of fertile years.

We observed that women with hypopituitarism with normal gonadal function were heavier and had a greater BMI than the patient groups receiving oral estrogen replacement before GH treatment. However, after 1 yr of GH treatment, there was no difference in weight, waist/hip ratio, or body composition between the patients using the different estrogen preparations. When all patients taking oral estrogens were compared with those with normal gonadal function, the subjects taking oral estrogens showed less reduction in waist and hip measurement and a greater waist/hip ratio at the end of 1 yr of GH treatment. In contrast, patients using patch therapy showed no difference in waist/hip ratio from patients with normal gonadal function. These results suggest that oral estrogens do reduce the effect of GH on the waist/hip ratio, providing indirect evidence that oral estrogens reduce the effect of GH on fat mass. Previous studies (6, 23) would predict that oral estrogen replacement would be associated with an increase in fat mass, although we did not observe this. There are a number of possible reasons for our study not finding an effect on fat mass. The period of time of estrogen use may be important in determining the degree of change in body composition, and although all women taking estrogens had been receiving treatment for a minimum of 1 month before the study and then for the 1 yr of the study, this may be insufficient to detect changes. Bioelectrical impedance analysis has an SE of estimate for fat mass up to 6.4% (24), so it is possible important changes in fat mass could have been missed. Our results are consistent with reports that oral contraceptive use does not lead to weight gain (25, 26), but it should be recognized that measurement of weight alone will miss changes in lean body and fat masses.

Patients taking ethinyl estradiol had a lower IGF-I SDS than patients not treated with estrogen or patients taking transdermal estradiol and estradiol valerate both before and after GH replacement. This observation is consistent with oral estrogens partially antagonizing the actions of GH at the liver (27), and our data suggest that ethinyl estradiol has a greater inhibitory action on IGF-I production than other oral estrogen preparations. The observation that IGF-I levels are lower in patients taking ethinyl estradiol before GH treatment is consistent with these patients either still having a low background GH secretion antagonized by ethinyl estradiol or ethinyl estradiol having an effect on IGF-I levels independent of GH. Our data raise the possibility that use of the oral contraceptive may create a mild form of GH deficiency or resistance in healthy young women. Previous studies have shown that an increasing dose of oral estrogen has a greater suppressive effect on IGF-I levels, but that the type of estrogen was less important, although there was a trend to lower IGF-I levels after ethinyl estradiol therapy (7, 28). In our study, patients taking ethinyl estradiol received approximately twice the dose of GH as those not taking estrogens or those receiving transdermal therapy. Of significance, the patients receiving transdermal therapy were the only group to achieve a positive median IGF-I SDS. The results suggest that ethinyl estradiol, as prescribed in clinical practice, is a greater GH antagonist than other oral estrogens. The potency of different estrogen preparations may be important. By weight, ethinyl estradiol is the most potent, because it is not degraded by the liver, whereas conjugated estrogen, 17ß-estradiol, and estradiol valerate are metabolized by the liver. Based on published data using vaginal cytology and LH/FSH suppression, 20 µg ethinyl estradiol is similar to 1.25 mg conjugated estrogen and 100 µg transdermal 17ß-estradiol and is more potent than 2 mg estradiol valerate, which is equivalent to 2 mg 17ß-estradiol and 50 µg transdermal 17ß-estradiol (8, 14, 29, 30). Long-term exposure to IGF-I may be important for health, and recent data suggest that chronic low IGF-I levels may have an impact on risk for type II diabetes and heart disease (20, 21). Patients using ethinyl estradiol required twice the GH dose and still had lower IGF-I levels than patients using transdermal estrogens. This is consistent with a previous study, which found that women taking oral estrogen required twice the GH dose as women not taking estrogen or those using transdermal estrogen (31). The GH dose has cost implications, because GH therapy will cost twice as much for someone using ethinyl estradiol compared with the cost for a woman receiving transdermal replacement therapy. In the United Kingdom, this could equate to approximately £5000 for ethinyl estradiol vs. £2500 for transdermal therapy.

The retrospective nature of the data obtained from a postmarketing surveillance database makes it susceptible to physician and patient bias and nonpharmacological factors. However, our data provide the first detailed analysis of the prescribing habits of estrogens to hypopituitary patients, and we have been careful to limit our conclusions to those that can be derived from the database. Using a large cohort of hypopituitary patients at risk of hypogonadism, we have investigated the impact of the route and type of estrogen replacement on body composition and response to GH. Reassuringly, the route of estrogen replacement did not affect body weight, although the observation that the waist/hip ratio was greater in patients taking oral estrogens suggests an effect on fat mass. We identified that 30% of young women with GH deficiency who are receiving estrogen therapy are using ethinyl estradiol, and in these patients, there is evidence of GH resistance. Oral estrogens in healthy postmenopausal women antagonize the actions of GH, and our data provide evidence that ethinyl estradiol may affect the physiological actions of GH in healthy young women. It will be important to look prospectively at estrogen therapy in hypogonadal women of fertile years.

	Footnotes

 
First Published Online August 9, 2005

Abbreviations: BMI, Body mass index; , change at 1 yr from baseline;HRT, estrogen replacement therapy; SDS, SD score.

Received May 31, 2005.

Accepted August 2, 2005.

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