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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 4 1250-1254
Copyright © 1999 by The Endocrine Society

Original Studies

Spironolactone, But Not Flutamide, Administration Prevents Bone Loss in Hyperandrogenic Women Treated with Gonadotropin-Releasing Hormone Agonist1

P. Moghetti, R. Castello, N. Zamberlan, M. Rossini, D. Gatti, C. Negri, F. Tosi, M. Muggeo and S. Adami

Division of Endocrinology and Metabolic Diseases, University of Verona and Azienda Ospedaliera di Verona (P.M., R.C., C.N., F.T., M.M.), and Department of Rheumatology, University of Verona (N.Z., M.R., D.G., S.A.), Verona, Italy

Address all correspondence and requests for reprints to: Dr. Silvano Adami, Ospedale Universitario, 37067 Valeggio, Verona. E-mail: adami{at}borgoroma.univr.it


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
GnRH agonists (GnRHa) have recently been proposed for the treatment of hirsutism in women with the polycystic ovary syndrome (PCOS). As most of these subjects have increased androgen secretion from both ovaries and adrenal glands, the association of GnRHa with antiandrogen drugs might enhance the clinical response to treatment. On the other hand, this association might also potentiate the adverse effects of GnRHa on bone metabolism, generating a potentially harmful situation at the skeletal level. In this study we investigated in 41 PCOS patients the skeletal effects of a 6-month course of GnRHa (tryptorelin, 3.75 mg, im, monthly), either alone (n = 12) or associated with the antiandrogen drugs spironolactone (100 mg, orally, once daily; n = 14) or flutamide (250 mg, once daily; n = 15). In all subjects bone mineral density was measured before and after treatment by dual energy x-ray absorptiometry at the lumbar spine (L2–L4) and at the femoral neck and Ward’s triangle. In addition, at baseline and after 6 months of therapy, bone metabolism markers (serum and urinary calcium, serum phosphorus and alkaline phosphatase, plasma osteocalcin, and urinary hydroxyproline) and endocrine parameters (serum gonadotropins, estradiol, and free testosterone) were assayed. Women given either GnRHa alone or associated with spironolactone or flutamide were similar for age and body mass index. At baseline, the 3 groups of PCOS women were also similar for endocrine and bone parameters. After 6 months, all treatments determined similar striking suppressions of serum gonadotropins and sex steroids. Concurrently, bone mineral density was significantly reduced at all examined sites in subjects receiving either GnRHa alone or GnRHa plus flutamide. Conversely, women given GnRHa plus spironolactone did not show any change in skeletal mass from baseline values (P < 0.05–0.01 among groups). Biochemical parameters of bone metabolism were consistent with densitometric assessments. In conclusion, after a 6-month course of therapy, bone mineral density is reduced in PCOS women given either GnRHa alone or GnRHa plus flutamide, but not in those receiving GnRHa plus spironolactone. The mechanisms of the bone-sparing effect of spironolactone remain to be determined. Nevertheless, this drug could represent a useful tool to prevent skeletal loss in women given GnRHa as well as in other hypoestrogenic conditions, in particular when estrogens are not recommended.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GnRH AGONIST (GnRHa) treatment induces a reduction in the circulating serum gonadotropin concentration and inhibition of ovarian function. This treatment is associated with the adverse effects of secondary hypogonadism, including enhanced bone turnover and accelerated bone loss (1, 2, 3, 4, 5, 6). GnRHa has been shown to be an effective treatment for endometriosis or uterine leiomyomatomas, but it is potentially applicable also for the treatment of hirsute subjects with polycystic ovary syndrome (PCOS) (7, 8, 9, 10, 11). In these patients the therapeutic activity of GnRHa associated with the suppression of gonadal androgens could be enhanced by antiandrogen compounds such as spironolactone (SPL) (12, 13) or flutamide (FLU) (14, 15). Combined therapy with GnRHa plus antiandrogens is currently used in male subjects with metastatic prostate cancer (16) to obtain complete androgen deprivation.

The administration of GnRHa together with antiandrogen drugs in PCOS patients rises several queries regarding the deleterious effects on bone metabolism. Most studies with GnRHa have been carried out in women close to menopause, and this might have amplified the osteopenic effect of estrogen deficiency (17). In the PCOS patients the treatment is prescribed at a younger age, and the osteopenic effect could be blunted by the prevailing hyperandrogenism. We and others have recently shown that in the PCOS patients, bone mineral density (BMD) is well preserved despite the frequent presence of amenorrhea (18, 19), and this might be related at least in part to the protective effect of androgen overproduction on skeletal tissue or to obesity. On the other hand, the association of GnRHa and antiandrogen compounds might generate a particularly harmful situation.

In this study we investigated the skeletal consequences of 6-month therapy with GnRHa either alone or associated with SPL or FLU, two antiandrogen drugs, in 41 young patients with PCOS.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Forty-one Caucasian women with polycystic ovary syndrome (PCOS) were enrolled in the study. Diagnostic criteria included oligoamenorrhea with anovulatory cycles and clinical and/or biochemical features of hyperandrogenism, with the exclusion of specific disorders, such as adrenal 21-hydroxylase deficiency, thyroid dysfunction, hyperprolactinemia, Cushing’s syndrome, or androgen-secreting tumors according to recommendations of the NICHHD conference on PCOS (10). Tables 1Go and 2Go show the main clinical and endocrine characteristics of the subjects under examination. No patient suffered from any other disease or was taking any medications. In addition, none of them had been treated with oral contraceptives or antiandrogen drugs in the last 10 months. Women with a history of hyperthyroidism, hyperparathyroidism, hyperprolactinemia, Cushing’s syndrome, or previous treatment with glucocorticoids or T4 and those with altered serum calcium, phosphorus, or alkaline phosphatase levels were excluded.


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  		Table 1. Basal characteristics of patients under study

 

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  		Table 2. Endocrine parameters during the study

 
All women were informed of the potential risks of treatment and were instructed to use nonhormonal methods of contraception throughout the study. Written consent was obtained from each patient before starting the protocol, which was conducted in accordance with the Declaration of Helsinki and approved by the institutional ethical committee.

Protocol

After the initial evaluation, women were given the GnRHa tryptorelin (Decapeptyl, Ipsen, Milan, Italy), 3.75 mg, im, every 4 weeks for 6 months. In addition to GnRHa therapy, 29 patients were randomly assigned to 1 of 2 antiandrogen treatments: 1) SPL (Aldactone, Lepetit, Frosinone, Italy), 100 mg, orally, once daily (GnRHa + SPL group; n = 14); or 2) FLU (Eulexin, Schering-Plough Corp., Milan, Italy), 250 mg, orally, once daily (GnRHa + FLU group; n = 15). The remaining PCOS women received tryptorelin alone (GnRHa group; n = 12).

BMD was evaluated in all subjects at baseline and after 6 months of therapy. These measurements were performed using dual energy x-ray absorptiometry (Sophos LXRA, Paris, France) at the lumbar spine (L2–L4) and at the left femoral neck and Ward’s triangle. The coefficients of variation for bone density were 1% and 1.2–2% at the lumbar spine and femoral neck, respectively. All measurements for an individual patient were performed on the same instrument. Furthermore, all scans were reviewed by the same physician, who was blind to the woman’s treatment assignment. Follow-up scans were matched to baseline scans to ensure measurements of identical bone regions.

Blood and urinary samples were collected at baseline and at 2, 4, and 6 months of the study. Biochemical evaluations comprised safety parameters (hemoglobin, red blood cells, white blood cells, platelets, leukocyte differential count, plasma glucose, liver and renal function, serum uric acid, and electrolytes), which were determined at all of the above indicated time points, and bone metabolism markers (serum and urinary calcium and serum phosphorus, plasma osteocalcin, serum alkaline phosphatase, and urinary hydroxyproline), which were assayed at baseline and at 6 months. To be considered clinically significant, changes in safety parameters had to either exceed the normal limits or double the baseline values.

At baseline and after 6 months of therapy, serum gonadotropins, estradiol, and free testosterone were also assayed.

Biochemical assays

Serum and urinary calcium and creatinine, and serum phosphorus and alkaline phosphatase were assayed by multichannel autoanalyzer (Hitachi, Tokyo, Japan). Urinary hydroxyproline was measured by spectrophotometry after high performance liquid chromatographic separation (20). Plasma osteocalcin was assayed by an immunometric method (Henning, Berlin, Germany). Endocrine parameters were assessed as previously reported (21). All urine analyses were performed on spots of fasting urines. For each subject, all metabolic and hormonal measurements were performed in the same assay in duplicate.

Statistical analyses and calculations

Results were analyzed by Student’s test for paired and unpaired data and two-way ANOVA. All tests of significance were two-tailed, and P < 0.05 or less was considered to indicate significance. Data were expressed as the mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Side-effects

During tryptorelin administration, the large majority of women experienced hot flashes, but in no patient was the discomfort so severe that it was necessary to discontinue the medication. Three patients reported mild transient headache, and three additional patients had breast tenderness. No women complained of decreased libido. No subjects had clinically relevant changes in safety parameters.

Endocrine features

At baseline, serum gonadotropin and steroid levels were similar in the three groups of patients (Table 2Go). As expected, tryptorelin administration suppressed serum LH and, to a lesser degree, FSH, with parallel decreases in estradiol and testosterone levels. The gonadotropin suppressions were similar among the three groups. Further details on endocrine features of these subjects are reported elsewhere (Moghetti et al., in preparation).

BMD

At baseline, BMD at all sites considered did not show significant differences among groups (Table 1Go). Figure 1Go shows the percent changes in densitometric values from baseline after the treatment. In the patients given GnRHa alone, after 6 months of therapy BMD was significantly decreased (P < 0.05) at all examined sites (-4.2 ± 4.9, -3.3 ± 3.1, and -4.6 ± 4.4 at the lumbar spine, femoral neck, and Ward’s triangle, respectively). Patients receiving GnRHa plus FLU also showed significant reductions (P < 0.05) in bone mineral content at each site examined (-5.6 ± 4.0, -4.1 ± 3.9, and -5.4 ± 3.7 at lumbar spine, femoral neck, and Ward’s triangle, respectively). The BMD changes in the two groups were comparable.



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  		Figure 1. Changes in densitometric parameters: percent changes (±SEM) in lumbar spine, femoral neck, and Ward’s triangle BMD in the three groups: black bar, patients treated with GnRHa + SPL; white bar, patients treated with GnRHa + FLU; and gray bar, patients treated with GnRHa alone. *, P < 0.05 vs. baseline {circ}, P < 0,05 vs. GnRHa + SPL.

 
In contrast, no significant change in comparison with baseline values was found at any site in patients receiving GnRH-A + SPL (0.0 ± 2.2, -1 ± 2.4, and -1.0 ± 3.9, respectively), and these changes were significantly different from those observed in the other two groups (P < 0.05–0.01, by ANOVA among groups). When a multiple logistic regression was performed, including treatment group, body mass index, serum testosterone, and estradiol as independent variables and changes in BMD as the dependent variable, treatment group was the only predictive variable at all examined sites (standardized partial regression coefficients ß = 0.43–0.60).

Biochemical markers of bone metabolism

Table 3Go shows serum and urinary markers of bone turnover examined in the study at baseline and after treatment. At baseline, biochemical markers of bone metabolism did not show significant differences among groups. After 6 months of tryptorelin administration, serum calcium was similarly increased in all groups of patients. Urinary calcium excretion rose also in all groups, but the change was statistically significant only in women given either GnRHa + FLU or GnRHa alone. Urinary hydroxyproline as well as plasma osteocalcin rose in women receiving either GnRHa alone or GnRHa + FLU. In contrast, changes in these parameters were negligible and did not reach statistical significance in the GnRHa + SPL group. Serum alkaline phosphatase significantly increased only in the GnRHa + FLU group, although a similar trend was seen also in the other two groups.


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  		Table 3. Biochemical markers of bone metabolism during the study

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
GnRHa treatment has been shown to be associated with hypogonadism and rapid bone losses (1, 5, 6). In most studies the patients had either uterine leiomyomas or endometriosis and were very close to menopause or had endocrine imbalances (17), which could have facilitated the osteopenic effect of GnRHa. The patients included in this study were all young and had PCOS, a condition in which the androgen overproduction is expected to exert a positive effect on bone mass (18, 19). In this study, we have been able to confirm our earlier report (22) that bone loss during GnRHa therapy occurs also in young subjects with androgen excess.

In PCOS women, the therapeutic activity on hirsutism of GnRHa may be enhanced by the administration of antiandrogen compounds, which also counteract the adrenal androgens. The effects of these drugs on bone metabolism in women have never been thoroughly investigated, but are potentially adverse. Accordingly, the addition of FLU to GnRHa was associated with a tendency to more severe reduction of BMD than that observed in the women given GnRHa alone. These effects were consistently associated with increases in bone markers that were also somewhat more accentuated in the FLU-treated patients. Although most of these differences were not statistically significant, this might be due to the limited number of observations. Thus, in our opinion, FLU therapy should be seen with some caution regarding its capacity to enhance the osteopenic effect of GnRHa. In these two groups, GnRHa administration was associated with important increases in the biochemical indexes of bone turnover, and this is expected to be associated with expansion of the so-called remodeling space (23), which explains at least in part the observed BMD changes. In these women the bone losses are more likely linked to the suppression of estrogen production, even if in the PCOS patients GnRH therapy is also associated with suppression of the ovarian androgen excess, which may contribute to the maintenance of the normal high bone mass typical of these patients (24).

The most intriguing finding of our study was the demonstration that the administration of 100 mg SPL largely prevents the osteopenic effect of GnRHa administration in young women with PCOS. This effect was consistent in all skeletal sites investigated and was also associated with an almost full prevention of the increases in bone turnover markers observed in the other GnRHa-treated patients. The characteristics of this study do not allow a conclusive identification of the mechanism of action of SPL on bone metabolism. SPL is a mineralocorticoid antagonist that is also an antagonist of androgen receptors. It is extensively used in the treatment of hirsutism (13), particularly in the United States, where other antiandrogens are not available (25). Interestingly, SPL is often associated with erratic bleeding, which might reflect some effect on estrogen and/or progestogen receptors in a manner resembling that of so-called selective estrogen receptor modulators (26). This hypothetical effect of SPL may provide an explanation for its ability to almost fully prevent the increases in bone turnover associated with GnRHa therapy.

An additional explanation of the bone protective effect of SPL may be linked to its renal effect as an antagonist of mineralocorticoid hormones. The lack of mineralocorticoid activity is associated with enhanced tubular reabsorption of calcium, increases in serum calcium, and suppression of PTH secretion (27). Therefore, SPL might exerts an effect on the renal handling of calcium similar to that of thiazide diuretics, which have been shown to suppress bone turnover and prevent postmenopausal bone loss (28). The significant increases in serum calcium associated with only marginal changes in calcium excretion observed in the patients given SPL lend support to the hypothesis of a thiazide-like effect on calcium and bone metabolism.

Whatever the mechanism of action, the results of this study indicate that SPL is as effective as bisphosphonates (22) or estrogen-progestin therapy (29, 30) in preventing the GnRHa-induced bone loss. Additional studies are necessary to assess this bone protective effect in other hypoestrogenic conditions and to evaluate its potential in preventing other forms of osteoporosis.

In conclusion, after a 6-month course of therapy, BMD is significantly reduced in PCOS women given either GnRHa alone or GnRHa plus FLU, but not in those receiving GnRHa plus SPL. SPL could represent a useful tool to prevent skeletal loss in women given GnRHa, in particular when estrogens are not recommended.


   Footnotes
 
1 This work was supported by grants from the Italian Ministry of Higher Education and Scientific Research and the Regione del Veneto (DRGV 964). Back

Received August 20, 1998.

Revised November 2, 1998.

Accepted November 17, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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