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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 3 807-813
Copyright © 1998 by The Endocrine Society

Original Studies

Bone Marker and Bone Density Responses to Dopamine Agonist Therapy in Hyperprolactinemic Males

Carolina Di Somma, Annamaria Colao, Antonella Di Sarno, Michele Klain, Maria Luisa Landi, Giuseppina Facciolli, Rosario Pivonello, Nicola Panza, Marco Salvatore and Gaetano Lombardi

Departments of Molecular and Clinical Endocrinology and Oncology (C.D.S., A.C., A.D.S., M.L.L., G.F., R.P., G.L.) and Nuclear Medicine (M.K., M.S.), Federico II University; and the Division of Oncology, A. Cardarelli Hospital (N.P.), Naples 80131, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Departments of Molecular and Clinical Endocrinology and Oncology, Federico II University, Via S. Pansini 5, 80131 Naples, Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of this prospective study was to evaluate the bone mineral density (BMD) at lumbar spine and femoral neck levels and biochemical parameters of bone turnover in 20 consecutive hyperprolactinemic males before and after an 18-month treatment with different dopamine agonists. Six patients received bromocriptine at a dose of 2.5–10 mg/day; 7 patients received quinagolide at a dose of 0.075–0.3 mg/day; 7 patients received cabergoline at a dose of 0.5–1.5 mg/week. BMD, serum PRL, testosterone, dihydrotestosterone, and osteocalcin (OC), and urinary cross-linked N-telopeptides of type I collagen (Ntx) levels were measured before and every 6 months during treatment.

At study entry, BMD values were lower in patients than controls at both lumbar spine (0.82 ± 0.03 vs. 1.18 ± 0.01 g/cm2; P < 0.001) and femoral neck (0.85 ± 0.02 vs. 0.92 ± 0.02 g/cm2; P < 0.05) levels. Osteopenia or osteoporosis was diagnosed in 16 patients at the lumbar spine and in 6 of them at the femoral neck level. A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (P < 0.01). In the 20 patients, serum OC levels were significantly lower (2.1 ± 0.1 vs. 9.3 ± 2.4 µg/L; P < 0.01), whereas Ntx levels were significantly higher (157.8 ± 1.1 vs. 96.4 ± 7.4 nmol bone collagen equivalent/mmol creatinine; P < 0.001) than control values. A significant inverse correlation was found between serum PRL and OC (P < 0.01), but not Ntx, levels. After 18 months of treatment, serum PRL levels were suppressed, and gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 ± 0.2 to 5.0 ± 0.2 µg/L) and dihydrotestosterone (0.3 ± 0.02 vs. 0.5 ± 0.01 nmol/L) levels, without any significant difference among groups. A progressive significant increase in serum OC levels together with a significant decrease in Ntx levels were observed after 6, 12, and 18 months of treatment in the 3 groups of patients. A slight, although significant, increase in BMD values was recorded in all patients after 18 months of bromocriptine, quinagolide, and cabergoline treatment, serum OC levels were normalized after treatment, whereas neither urinary Ntx levels nor BMD values were normalized by 18 months of treatment with dopaminergic agents.

In conclusion, treatment with bromocriptine, quinagolide, and cabergoline for 18 months, although successfull in suppressing serum PRL levels and restoring gonadal function, was unable to restore lumbar spine and femoral neck BMD and normalize Ntx levels. However, BMD was slightly increased during treatment, suggesting that additional bone loss was prevented after treatment of hyperprolactinemia.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN WOMEN with hyperprolactinemia, a decrease in bone mineral density (BMD), probably caused by the low circulating estrogen levels, has been demonstrated (1, 2). A more prominent loss of trabecular than cortical bone was found in these patients (3, 4, 5), with an increased risk for further bone loss (6). In addition, osteocalcin (OC), an index of osteoblastic activity, was significantly reduced in hyperprolactinemic patients (7). Treatment with dopamine agonists, particularly bromocriptine (BRC), restores gonadal function and increases vertebral BMD in most hyperprolactinemic women (8, 9). The mechanism(s) of bone loss in hyperprolactinemia has not been clearly delineated, although the duration of the disease seems to be strictly correlated with the entity of bone loss (10). Despite the wide body of evidence for osteopenia and its consequences in hyperprolactinemic women (1, 2, 3, 4, 5, 6, 8, 9, 11), only a few data have been reported to date in hyperprolactinemic males (10, 12, 13). Similar to that in women, hypogonadism seems to be the most relevant factor in causing osteopenia in men (10, 12, 13, 14). The effects of long term treatment with BRC in restoring gonadal function in hyperprolactinemic males are controversial (15, 16). In a previous study, we reported that a period of at least 24 months of treatment with quinagolide (CV) was necessary to normalize serum testosterone (T) levels and seminal fluid characteristics in hyperprolactinemic males (17).

The aim of this prospective study was to evaluate the prevalence of osteopenia/osteoporosis in hyperprolactinemic males and the effect of chronic treatment with different dopamine agonists. BMD, measured at the lumbar spine and femoral neck levels, together with biochemical parameters of bone turnover were assessed before and after 6, 12, and 18 months of treatment with BRC, CV, and cabergoline (CAB) in 20 consecutive hyperprolactinemic males.


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

Twenty hyperprolactinemic males (aged 28–45 yr) and 20 age- and BMI- matched healthy subjects, who served as a control group for baseline evaluation, consecutively admitted to our department for hyperprolactinemia entered this open prospective and uncontrolled study after their informed consent had been obtained. The diagnosis of hyperprolactinemia was established on the basis of physical examination and the evidence of high PRL levels assayed during a diurnal profile with 30-min samples (0800–1400 h). All patients showed complete pubertal development (according to Tanner stage) and heights appropriate for age and genetic target. The presumed disease duration was calculated from the time of appearance of symptoms probably related to the adenoma or hyperprolactinemia, such as headache, galactorrhea, visual field defects, impairment of libido, and potency. Eleven patients had macroadenoma, and 9 had microadenoma documented at computed tomography and/or magnetic resonance imaging. Five of 11 patients with macroadenoma had been previously unsuccessfully operated, but none of the patients received radiotherapy. No patients had any other hormonal deficiency or received replacement therapy, including T. Visual impairment was present in 5 of 11 patients with macroprolactinoma. Libido impairment was present in all patients for at least 6 months; 14 of them had infertility, 19 had reduced sexual potency, and in 6 bilateral induced galactorrhea was noted. Clinical and hormonal characteristics of patients and controls are summarized in Table 1Go.


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  		Table 1. Clinical and hormonal data in hyperprolactinemic patients and healthy subjects

 
Treatment protocol

On the basis of different drug availabilities during the study period (1992–1997), the patients were treated for 18 months with BRC (Parlodel, Sandoz, Milan, Italy), CV (Sandoz, Italy), or CAB (Dostinex, Pharmacia and Upjohn, Italy) as follows: group 1, six patients received BRC at a dose of 2.5–10 mg two or three times a day; group 2, seven patients received CV at a dose of 0.075–0.3 mg once or twice a day; and group 3, seven patients received CAB at a dose of 0.5–1.5 mg once or twice a week.

In all patients the dose of different drugs was increased to obtain serum PRL suppression.

Study protocol

At study entry, serum FSH, LH, T, dihydrotestosterone (DHT), calcium, phosphorus, and creatinine, circulating alkaline phosphatase; intact PTH, and osteocalcin (OC) were assayed twice in a single sample, whereas serum PRL was calculated as the mean of a 6-h blood sampling (0800–1400 h, with every 30 min sampling). Urinary cross-linked N-telopeptides of type I collagen (Ntx), calcium, phosphorus, and creatinine were assayed in the 24-h urinary collection the day before the study. During treatment, the final PRL level was calculated as the average value from at least three blood samples collected at 15-min intervals, whereas the other biochemical parameters were assayed in a single sample. BMD values measured at lumbar spine and femoral neck levels were evaluated at study entry and after 6, 12, and 18 months of BRC, CV, and CAB treatments.

BMD assessment

In all patients and controls, BMD was assessed by dual x-ray absorptiometry. The measurement of the integral bone density in lumbar spine (L1–L4) and in femoral neck was made by Hologic QDR 1000 analyzer (Hologic, Waltham, MA). Data were expressed as grams per cm2. In line with the previous reports, patients were considered osteopenic when the t score was between -1 and -2.5 and were considered osteoporotic when the t score was lower than -2.5. All scans were analyzed by the same operator (M.K.), who was blind in respect to patient treatment.

Assays

PRL, FSH, LH, T, and DHT levels were assessed by RIA using available commercial kits. The normal ranges were: PRL, 5–15 µg/L; FSH and LH, 5–18 U/L; T, 3.5–9.0 µg/L; and DHT, 0.4–1.6 nmol/L. PTH was assayed by immunoradiometric assay, using a kit provided by Radim (Pomezia, Italy); the normal range was 9–55 pg/mL. Serum OC levels were measured by RIA, using a kit provided by Nichols Institute (San Juan Capistrano, CA); the normal range was 3.0–13.0 µg/L. Urinary Ntx levels were measured by enzyme-linked immunosorbent assay, using a kit provided by Nichols Institute; the normal range was 23–110 nmol bone collagen equivalent/mmol. Urinary and serum calcium, phosphorus, creatinine, and alkaline phosphatase were assayed using standard methods in our laboratory.

Statistical analysis

Statistical analysis was carried out using ANOVA followed by the Newman-Keuls test for intergroup comparison and Student’s t test for paired data for intragroup comparison. Linear correlation analysis was performed by calculating the Pearson’s coefficient, and multiple regression analysis was performed by calculating the coefficient for the variables related to BMD at linear correlation. Data are reported as the mean ± SEM. The significance was set at 5%.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Assessment of BMD and bone turnover parameters at study entry

All patients had low serum T and DHT levels without any difference among the 3 groups (Table 2Go). BMD values were lower in hyperprolactinemic patients than in controls at both lumbar spine and femoral neck (Table 1Go). No difference in BMD values was found among the 3 groups of patients at both bone sites examined (Table 2Go). Sixteen of 20 patients had osteoporosis and/or osteopenia in 1 or both skeletal sites, whereas 4 patients had normal BMD (no. 5, 6, 13, and 20; Table 2Go). In particular, at the lumbar spine level, 8 patients were osteoporotic (no. 1, 2, 3, 8, 9, 14, 15, and 19; Table 2Go), and 8 patients were osteopenic (no. 4, 7, 10, 11, 12, 16, 17, and 18; Table 2Go). At the femoral neck level, 2 patients were osteoporotic (no. 9 and 14; Table 2Go), and 4 were osteopenic (no. 2, 3, 8, and 15; Table 2Go). A significant inverse correlation was found between lumbar spine and femoral neck BMD values and both PRL levels and disease duration (Fig. 1Go and Table 3Go). Conversely, no significant correlation was found between BMD values and serum T and DHT levels (Table 3Go). Urinary and serum calcium, phosphorus, and creatinine and serum ALP and PTH levels were in the normal range in all patients, without any difference among the 3 groups (data not shown). Lastly, serum OC levels were significantly lower, and urinary Ntx levels were significantly higher in patients than in controls (Table 1Go), and in all patients, serum OC levels were lower and urinary Ntx levels were higher than the normal ranges. A significant inverse correlation was found between serum PRL and OC, but not urinary Ntx levels (Table 3Go).


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  		Table 2. Patient’s profile at study entry

 


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  		Figure 1. Linear correlation analysis between BMD (grams per cm2) measured at the lumbar spine level and baseline serum PRL (top left), serum osteocalcin (top right), urinary Ntx (bottom right), and disease duration (bottom left).

 

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  		Table 3. Linear correlation between BMD and biochemical parameters in 20 hyperprolactinemic males

 
Furthermore, a positive correlation between OC and lumbar BMD and a negative correlation between Ntx and lumbar BMD were found (Fig. 1Go and Table 3Go). In addition, among different variables related to lumbar BMD, such as OC, PRL, and Ntx levels and disease duration, a significant multiple linear regression coefficient was found only between BMD and disease duration (coefficient = -0.05; P = 0.001).

Effect of 18-month BRC, CV, and CAB treatments on BMD and bone turnover parameters

After 6 months of treatment, serum PRL levels were suppressed in all CAB-treated patients, in 4 of 6 BRC-treated patients, and in 6 of 7 CV-treated patients. These remaining 3 patients achieved serum PRL suppression after 12–18 months of treatment (Fig. 2Go). After 18 months of treatment, gonadal function was restored in all 20 patients, as shown by the normalization of serum T (from 2.2 ± 0.2 to 5.0 ± 0.2 µg/L) and DHT levels (0.3 ± 0.02 vs. 0.5 ± 0.01 nmol/L), without any significant difference among groups. In particular, serum T and DHT levels normalized as early as after 3–6 months of treatment with dopamine agonist in 17 of 20 patients; the remaining 3 patients (no. 2, 4, and 9; Table 3Go) achieved androgen normalization during the following treatment period (Fig. 2Go). A significant increase in serum OC levels together with a significant decrease in urinary Ntx levels was progressively observed after 6, 12, and 18 months of BRC, CV, and CAB treatments in the three groups of patients (Fig. 3Go). At the same time points, a slight, but significant, increase in BMD values was recorded in the 3 groups of patients (Fig. 4Go). In fact, after 18 months of treatment, the percent increment in BMD was 3.6 ± 1.5% at the lumbar spine level and 2.3 ± 0.5% at the femoral neck level in the entire group of 20 patients. Indeed, urinary and serum calcium, phosphorus, and creatinine and serum ALP and PTH levels did not change during the study period in any of the patients (data not shown).



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  		Figure 2. Serum PRL (left) and testosterone (right) levels measured before and after 6, 12, and 18 months of treatment with BRC (top), CV (middle), and CAB (bottom) in the 20 hyperprolactinemic patients.

 


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  		Figure 3. Serum osteocalcin (top) and urinary Ntx (bottom) at study entry and after 6, 12, and 18 months of treatment with BRC ({blacksquare}), CV ({square}), and CAB (). *, P < 0.01 vs. baseline values.

 


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  		Figure 4. BMD (grams per cm2) measured at the lumbar spine level (top) and at the femoral neck level (bottom) at study entry and after 6, 12, and 18 months of treatment with BRC ({blacksquare}), CV ({square}), and CAB (). *, P < 0.01 vs. baseline values.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
It is widely known that hyperprolactinemia is associated with bone loss; this has been mainly attributed to the concomitant hypogonadism rather than to hyperprolactinemia per se (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 18). In fact, a positive relationship was reported between the duration of hypogonadism and the magnitude of bone loss (19). Some studies demonstrated that BMD values increase in hyperprolactinemic patients cured by surgery or medical treatment (8, 9, 10, 13, 19), whereas in other patients it may simply not worsen (6, 20). However, despite the number of reports on osteopenia and its consequences in hyperprolactinemic women, scant data have been provided on osteopenia in hyperprolactinemic males (10, 12, 13). The recovery of hypogonadism, more than the suppression of PRL levels, was associated with an improvement in bone mass (10, 13). This finding suggested that gonadal steroids are crucial in maintaining skeletal integrity in men (10, 13). On the other hand, the recovery of gonadal function in hyperprolactinemic males with large prolactinomas and long standing impairment of T secretion remains questionable (21). In a previous study, we reported the recovery of gonadal function, on the basis of the normalization of T and DHT levels and sperm parameters, in 13 hyperprolactinemic patients treated with CV for 12–24 months (17). These data suggest that a long period of serum PRL suppression is necessary to completely restore gonadal function in hyperprolactinemic male patients in the presence of gonadotroph function integrity. Most of the patients included in the present study (80%) showed a reduction of BMD at the lumbar spine, whereas only a minority of them (30%) showed a low BMD at the femoral neck. This finding suggests that trabecular bone is damaged earlier than cortical bone. Similar observation was reported in hyperprolactinemic women (3, 4, 5, 6). The results of the current study demonstrated that lumbar and femoral BMD values were significantly correlated with serum PRL levels and disease duration, but not with T and DHT levels. Interestingly, 6 of 20 patients (no. 2, 3, 8, 9, 14, and 15), who presented with the lowest BMD values at both sites, presumably had hyperprolactinemia onset at the age of 16–22 yr. The peak bone mass is considered to be achieved at the age of 22 yr for the femoral neck and at the age of 30 yr for the lumbar spine. As the peak bone mass is considered the best protection against age-related bone loss, the occurrence of any pathological event that impairs the achievement of peak bone mass severely affects future bone integrity. In fact, small differences (of 5–10%) in bone mass and BMD at maturity could contribute to substantial differences in the incidence of osteoporotic fractures (22). It should be mentioned that BMD values were found in the normal range in 4 of 20 hyperprolactinemic males, but serum OC levels were lower and Ntx levels higher than the normal range in all patients. Therefore, alterations in bone turnover do occur in hyperprolactinemic patients even in the presence of normal BMD values. The evaluation of the parameters of bone metabolism can be considered useful in diagnosing an early bone turnover alteration before a change in BMD becomes apparent. On the other hand, previous studies on biochemical parameters of bone turnover (such as bone-specific phosphatase alkaline and OC) reported controversial data in hypogonadal men (23, 24, 25, 26). However, most studies were carried out in severe hypogonadal patients (i.e. after castration or D-Trp6-GnRH treatment), whereas hyperprolactinemia generally induces a mild hypogonadism. Moreover, a correlation between bone density and bone marker with serum PRL, but not with androgen, levels was found in the present study. In fact, a progressive and significant increase in OC levels and a decrease in Ntx levels, indicating an improvement of bone formation together with a decrease in bone resorption, was clearly recorded after 6–18 months of treatment with BRC, CV, and CAB in the 20 patients. Conversely, BMD values were only slightly increased at both bone sites, and neither urinary Ntx levels nor BMD values were normalized by a 6- to 18-month treatment with dopaminergic agents despite the suppression of serum PRL levels and the normalization of serum T levels. Only serum OC levels were normalized after treatment. On the other hand, the partial success of the treatment with dopamine agonists can be explained by taking into account that a period of at least 24 months of PRL suppression was necessary to completely restore seminal fluid characteristics in hyperprolactinemic males (17).

In conclusion, osteopenia or osteoporosis at the lumbar spine was found in the great majority of hyperprolactinemic males, whereas at the femoral neck level it was found in only a minority of them. As hyperprolactinemia in males is often diagnosed late, the patients may be exposed to a high risk of vertebral fractures. It should be considered that the reduction of 1 SD in BMD from the age-specific mean population value confers a 2- to 3-fold increase in fracture risk (27, 28, 29). This event might occur especially in patients with a long duration and early beginning of the disease due to the impairment in achieving peak bone mass. Treatment with dopamine agonists for 18 months though normalizing gonadal function is unable to completely restore BMD values and biochemical parameters of bone turnover.


   Acknowledgments
 
We are indebted to Novartis Italy for kindly providing CV 205–502.

Received September 10, 1997.

Revised November 21, 1997.

Accepted December 8, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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