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Effects of Estrogen Replacement Therapy on Pituitary Size, Prolactin and Thyroid-Stimulating Hormone Concentrations in Menopausal Women

Posted on: Tuesday, 3 January 2006, 03:02 CST

By Abech, Denise D; Moratelli, Hlio B; Leite, Srgio C B F S; Oliveira, Miriam C

Abstract

There are few studies in the literature investigating pituitary size at an age consistent with the menopause and the influence of estrogen replacement therapy on pituitary height. We therefore evaluated the effect of estrogen on pituitary size, prolactin and thyroid-stimulating hormone (TSH) levels in menopausal women. Sixty- nine women were evaluated, 47 using estrogen and 22 controls. The measure of pituitary height was obtained from magnetic resonance imaging. Hormone evaluation did not show a statistically significant difference in mean ( standard deviation) prolactin level between the group using estrogen (7.6 6.4 ng/ml) and controls (5.1 3.4 ng/ml; p = 0.15), yet mean TSH level was significantly higher in the treated group (1.9 1.5 vs. 1.2 0.9 U/ml; p = 0.03). Mean pituitary height in the estrogen-treated group (5.2 1.4 mm) was greater than in the controls (4.4 1.4 mm; p = 0.04). However, when such potential confounders as age, prolactin and TSH levels, treatment and duration of estrogen exposure were considered, the magnitude of difference did not attain significance. In conclusion, estrogen may play a role in pituitary size, since a mean difference in pituitary height, estimated as 0.78 mm, was detected between the groups in favor of the estrogen-treated group. This suggestion can be investigated in further studies.

Keywords: Pituitary, pituitary size, estrogen, prolactin, thyroid- stimulating hormone

Introduction

Estrogens exert an important regulatory action on cell proliferation in several organs and tissues [1], and are implicated in the pathogenesis of several types of benign and malignant tumor [2]. Experimental studies have shown that estrogens stimulate lactotroph proliferation and, in rodents, promote the development of prolactinomas [3,4]. In humans, physiological hyperestrogenic states such as puberty, pregnancy and the postnatal period are associated with increased pituitary volume [5,6]. Furthermore, prolactinomas are three times more frequent in females, especially during reproductive life [7]. There are few studies in the literature investigating pituitary size at an age consistent with the menopause [8-10] and, to the best of our knowledge, there are no published studies on the influence of estrogen replacement therapy on pituitary height. The present study evaluated pituitary size through the measure of pituitary height obtained by magnetic resonance imaging (MRI) in menopausal women submitted or not to estrogen.

Subjects and methods

A total of 74 females aged 48 to 70 years, with established menopause for at least 1 year, and submitted or not to estrogen for at least 1 year, were included in the study. After being informed about the aims of the study and signing an informed consent form, the patients were submitted to MRI examination of the pituitary gland and had their levels of prolactin and thyroid-stimulating hormone (TSH) determined. Exclusion criteria were the presence of hypothalamic-pituitary lesion, use of medications known to influence prolactin level, and hyperprolactinemia or hypothyroidism. Five patients were excluded from the sample, three with an empty sella turcica and two with hypothyroidism, resulting in a total of 69 patients. The patients answered a questionnaire focusing on information about hormone use. Two groups of patients were formed: group 1, composed of 47 patients exposed to estrogen (cases), and group 2, composed of 22 patients unexposed to estrogen (controls). All of the patients in group 1 were receiving estrogen at the minimum dose of 0.625mg, cyclically or continuously associated with a progestational agent.

Determination of serum prolactin and TSH was performed by chemiluminescence using commercial kits (Bayer Corporation, Tarrytown, NY, USA). The respective normality ranges were 1.8-20.3 ng/ml and 0.35-5.5 U/ml. MRI examination of the pituitary gland was performed with a 1.0 T magnetic resonance scanner (NT 10; Philips, Holland). A spin-echo pulse sequence was used with 3 mm thick slices, 20 cm field of view and in a 256 256 matrix. Precise midsagittal T!-weighted spin-echo images planed from an axial image were used for analysis. The height of the pituitary gland was determined by measuring the greatest distance between the base and the top of the gland using a cursor. All MRI tests were evaluated by the same neuroradiologist, who did not have any information about the patient. The measure of height of the pituitary at its median portion, obtained through the sagittal sections performed, was chosen as the parameter for evaluating the size of the pituitary gland. Besides this target variable, the usual interpretation of the findings of the region was performed. The study was approved by the Committee of Ethics and Research of the University Hospital.

Statistical analysis

Data are presented as mean standard deviation. Student's t test was used for comparisons between means and the χ^sup 2^ test for qualitative variables, with a multiple linear regression model to identify potential confounders. The Mann-Whitney test was used for prolactin and TSH values and Pearson's test was used for correlation. The level of significance used was 5% (p < 0.05). The data were processed using the Statistical Package for the Social Sciences, version 11.0 (SPSS Inc., Chicago, IL, USA).

Results

After the exclusion of the three patients with an empty sella turcica and the two with elevated TSH and later confirmed hypothyroidism, the mean age of all patients was 59.1 5.9 years, ranging from 48 to 70 years. In group 1 (cases) the mean age of patients was 57.9 5.5 years, while in group 2 (controls) it was 61.5 6.2 years, being significantly higher in the latter (Table I).

Table I. Pituitary height, clinical and hormone characteristics of menopausal women.

The mean value of prolactin in all patients was 6.8 5.7ng/ml. The difference found between prolactin level in groups 1 and 2 was not significant (p = 0.15). The mean value of TSH in all patients was 1.7 1.4 U/ml. The TSH level in group 1 (1.9 1.5 U/ml) was significantly higher than that in group 2 (1.2 0.9 U/ml; p = 0.03).

The mean height of the pituitary obtained in all patients was 4.9 1.4mm. In group 1 the mean pituitary height was 5.2 1.4mm, and in group 2 it was 4.4 1.4mm, being significantly greater in estrogen- treated patients (p = 0.04) (Table I). There was no statistical difference in pituitary height between the 50-59 years and 60-69 years age brackets, either in group 1 (means 5.4 and 5.01 mm, respectively) or in group 2 (4.87 and 4.25 mm, respectively).

The correlation between patient age and pituitary height (r = - 0.20) did not attain statistical significance (p = 0.09). Nor did the correlations between pituitary height, prolactin (r=0.17, p = 0.16) and TSH (r= 0.061, p = 0.62) levels.

Among the patients of the estrogen-exposed group, 17 were receiving estrogen only and 30 a combination of estrogen and progesterone. There was no difference in pituitary height between the group that used estrogen alone (4.78 1.4mm) and the group using estrogen in association with progesterone (5.48 1.37mm). The duration of estrogen exposure ranged from 1 to 20 years, with a mean of 4.6 + 5.0 years. No significant correlation was found (r = - 0.138, p = 0.35) between the time of estrogen exposure and pituitary height. The bivariate analysis comparing the estrogen-exposed group with the untreated group with regard to pituitary height revealed a difference of 0.78 mm in favor of the former (p = 0.04). However, when we considered the effect of potential confounders such as age, treatment and duration of estrogen exposure, and prolactin and TSH levels through multiple linear regression, the magnitude of the difference failed to attain statistical significance.

Discussion

Published data on the values of prolactin in the menopause are controversial. Some studies have reported a decline in prolactin level [11,12] or a reduction in its pulsatile secretion [13], while an elevation of its level has also been reported [14]. In a study that followed hyperprolactinemic patients, normalization of prolactin level was observed in 45% of women after menopause [15]. In the present study the mean level of prolactin was lower in patients unexposed to estrogen, although with no significant statistical difference. Balint-Peric and Prelevic, who also observed a reduction in prolactin level with aging in women without estrogen, justified the finding as a consequence of the aging process of the lactotrophs and of an indirect effect of factors involved in the regulation of prolactin secretion such as dopamine and opioid levels [12].

Among the patients initially enrolled in this study, two presented increased TSH levels with a confirmed diagnosis of hypothyroidism, thus being excluded from the investigation. These patients showed pituitary heights of 8.1mm and 7.5 mm, values above the mean obtained in the studied population (4.98 1.48mm), which is in agreement with literature data on the chronic stimulation of lactotrophs and thyrotrophs leading to pituitary hyperplasia in the presence of hypothyroidism [16]. The estrogenexposed patients in the present series exhibited mean TSH levels significantly greater than t\hose of unexposed patients. This finding cannot be explained by increased prevalence of autoimmune thyroiditis associated with aging in this group, since the untreated control group presented higher mean age than the treated group. In fact, the result is consistent with the observation that women with hypothyroidism under treatment with thyroxine often need higher doses when they are pregnant. Increased TSH during estrogen treatment was also described in women with hypothyroidism treated with thyroxine, suggesting that estrogen therapy may increase the need for thyroxine [17].

MRI has proved to be the most sensitive method for the evaluation of pituitary size and lesions [9,18]. Using the measure of pituitary volume, Lurie and colleagues confirmed previous findings that the height of the pituitary gland is negatively correlated with age [9]. The same authors demonstrated that the alterations in pituitary size determined by aging occur primarily in the height of the gland, supporting that an isolated measure of pituitary height, obtained in sagittal sections in Tl, is a good means of estimating its size. In the present investigation pituitary height measured in the whole population of menopausal women was 4.98 1.48mm, which is close to values observed by other authors in women aged 50-59 years and 60- 69 years of 4.6 and 4.9mm, respectively [8] and 5.4 and 4.8mm, respectively [10]. The mean value of 4.98mm is smaller than that observed in younger women (aged between 30 and 39 years) of 5.68mm [10].

The effect of exogenous estrogen on the size of the human pituitary has seldom been investigated. Asscheman and associates evaluated prolactin level and pituitary size in male transsexuals who were heavy users of estrogens and observed increased prolactin level in all examined individuals, as well as increased pituitary size, evaluated through computerized tomography, in five of the 15 patients [19]. Scheithauer and co-workers, studying pituitary glands obtained from autopsies of 67 males who had prostate carcinoma and were treated with estrogen, observed hyperplasia of lactotrophs and a higher prevalence of prolactin-secreting adenomas, yet without statistical significance [20]. The possible influence of chronic estrogen administration in the progression of a previously established prolactinoma was questioned too [21]. In relation to the pituitary effects of progestin, norethisterone reduces the wellknown stimulatory effect of estradiol on the pituitary of ovariectomized animals [22].

The present study detected an increase in pituitary height in menopausal women using estrogen, although the multiple linear regression analysis indicated possible confounders leading to bias. When we assessed the possibility of there being a connection between length of exposure to estrogen and the increase in pituitary height, similarly as observed by Asscheman and colleagues [19], we did not find any statistically significant correlation.

In a study on the relationship between the measure of pituitary height, age and sex, Tsunoda and coinvestigators observed an increase in pituitary height at the climacterium (50-59 years) and postulated that this increase could be related to hormone alterations in the pituitary during this time [1O]. The design of the present study allowed the inclusion of patients who experienced the menopause recently (1 year), and it could be suggested that the recent stimulation of gonadotrophs, secondary to the elevation of gonadotropins, may have interfered with the results. However, the inclusion of patients in the 50-59 years age bracket was similar in both groups evaluated, thus excluding a possible bias in the comparison between the groups.

In conclusion, our findings point to a possible stimulatory effect of estrogens on pituitary size in menopausal women. Studies with larger samples and using a longer time postmenopausal as cut- off point for inclusion in the protocol may confirm this challenging finding.

References

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DENISE D. ABECH1, HLIO B. MORATELLI1, SRGIO C. B. F. S. LEITE1, & MIRIAM C. OLIVEIRA2

1 Discipline of Internal Medicine, Faculdade de Medicina, Universida de de Cuiab, Brazil, and 2 Neuroendomnology Center, Santa Casa de Porto AlegrelFundao Faculdade Federal de Cincias Mdicas de Porto Alegre, Brazil

Correspondence: M. da Costa Oliveira, Rua Dona Mimi Moro 40, 90480-050 Porto Alegre, RS, Brazil. Tel/Fax: 55 51 33286761. E- mail: mcoraiportoweb.com.br

Copyright CRC Press Oct 2005

Source: Gynecological Endocrinology

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