ACLEAR-CUT GENDER difference exists in the clinical

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1 X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(2): Printed in U.S.A. Copyright 2004 by The Endocrine Society doi: /jc Six Months of Treatment with Cabergoline Restores Sexual Potency in Hyperprolactinemic Males: An Open Longitudinal Study Monitoring Nocturnal Penile Tumescence MICHELE DE ROSA, STEFANO ZARRILLI, GIOVANNI VITALE, CAROLINA DI SOMMA, FRANCESCO ORIO, LIBUSE TAUCHMANOVA, GAETANO LOMBARDI, AND ANNAMARIA COLAO Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Naples, Italy This open longitudinal study investigated the prevalence of depressed sexual potency by monitoring erectile dysfunction using nocturnal penile tumescence (NPT) in 51 consecutive men with hyperprolactinemia (41 macroprolactinomas and 10 microprolactinomas) and evaluated potential reversibility of sexual failure after 6 months of treatment with cabergoline. Fifty-one healthy men served as controls. Compared with controls, the patients with either micro- or macroprolactinoma had low levels with severe alterations of erectile function. Testosterone deficiency was present in 73.2% of macro- and 50% of microprolactinomas; reduced libido and sexual potency were referred by 53.6% of macroprolactinomas, 50% of microprolactinomas, and none of controls. Fewer than three erectile events per night by NPT were found in 96.7% of patients and 13.7% of controls (P < ACLEAR-CUT GENDER difference exists in the clinical presentation of hyperprolactinemia; it is more frequent in women than in men and more frequently due to a microadenoma than to a macroadenoma in women and more frequently due to a macroadenoma than to a microadenoma in men, with gonadal disturbances as a presenting symptom more frequent in women than in men (1 7). Because of the scant number of men with hyperprolactinemia, the effects of medical therapy with dopamine agonists, especially with cabergoline, a D 2 -selective receptor agonist, are well documented, prevalently in women (8 16). Presently, male sexual function can be easily studied by measuring nocturnal penile tumescence (NPT), which evaluates the presence or absence of involuntary unconscious erections, normally occurring during the rapid eye movement (REM) stage of sleep (17). A change in penile circumference of 16 mm or 80% of a full erection reflects a sufficient degree of penile rigidity for vaginal intromission (18). Two previous studies have reported slight hyperprolactinemia in a small group of men with erectile dysfunction. Of 445 patients with erectile dysfunction, Delavierre et al. (19) reported that nine patients (2%) had prolactin (PRL) levels greater Abbreviations: NPT, Nocturnal penile tumescence; PRL, prolactin; RAU, rigidity activity unit; TAU, tumescense activity unit. JCEM is published monthly by The Endocrine Society ( endo-society.org), the foremost professional society serving the endocrine community ). After 6 months of cabergoline treatment, prolactin levels normalized in 74.5% of patients: 73.2% of macroprolactinomas and 80% of microprolactinomas. Testosterone levels normalized in 68.6% of patients, whereas NPT normalized in 60.6% of patients who had normalized prolactin levels and in 7.7% of patients who did not. In conclusion, at study entry, 50% of the patients complained of sexual disturbances, 96.7% of whom had an impairment of erectile events per night compared with 13.7% of controls. Six months of treatment with cabergoline normalized levels in most cases, thus restoring and maintaining during treatment the capability of normal sexual activity in hyperprolactinemic males. (J Clin Endocrinol Metab 89: , 2004) than 25 g/liter, and four (0.9%) of them had levels higher than 35 g/liter. From a review of the literature among men with erectile dysfunction, 2.7% had PRL levels just above the normal range, 1.3% had PRL levels of approximately ng/ml, and 0.6% had a pituitary tumor (19); of 1022 men with erectile dysfunction, Buvat and Lemaire (20) found PRL levels above 20 g/liter in only three men and prolactinoma in only one. In contrast, erectile dysfunction has been rarely investigated in men with hyperprolactinemia. In a previous study including 17 men with macroprolactinoma, seven treated with cabergoline at a dose of mg/wk and 10 treated with bromocriptine at a dose of 5 15 mg/d, we used the Rigiscan equipment to measure NPT (21). After 6 months of either treatment, we showed an increase in the number of erections that normalized in all patients treated with cabergoline and in all but one of those treated with bromocriptine (21). However, the series was too small to draw definitive conclusions. To give additional insights into sexual impairment in hyperprolactinemia, one of the earliest symptoms of the disease and very frequently underestimated, we designed this open longitudinal study aimed 1) at investigating the prevalence of depressed sexual potency in a large series of consecutive men with hyperprolactinemia and 2) at evaluating the potential reversibility of sexual failure after 6 months of treatment with cabergoline. The 6-month time point was chosen because sexual potency could be evaluated before deficiency was replaced in some cases. 621

2 622 J Clin Endocrinol Metab, February 2004, 89(2): De Rosa et al. Cabergoline and Erectile Dysfunction in Men Subjects Subjects and Methods From 1996 to 2000, 73 consecutive newly diagnosed men were admitted to our department for hyperprolactinemia, and 51 of them agreed to be included in this study after their informed consent had been obtained. Inclusion criteria were, for macroprolactinomas, serum PRL levels 200 g/liter or more and a pituitary tumor 1 cm or more in diameter on pituitary magnetic resonance imaging, and for microprolactinomas, serum PRL levels 50 g/liter or more and a pituitary tumor less than 1 cm in diameter. Forty-one men had a macroprolactinoma, whereas 10 had a microprolactinoma (Table 1). Fifty-one men randomly recruited among clerks, students, and doctors age-matched with the study population, living in the same geographical area, and without any known disease served as control. Study protocol At study entry, serum PRL levels were calculated as the average value of a 6-h profile by blood sampling every 30 min ( h). After 6, 12, 18, and 24 months of treatment, PRL levels were assayed at 0800, 0815, and 0830 h, and the average value was taken for statistical analysis. In all subjects, a general clinical examination, serum FSH, LH, and assay, and the NPT test were performed at baseline; only in the patients were all measurements repeated 6 months after cabergoline treatment. At diagnosis, 10 macroprolactinomas had secondary hypothyroidism that was replaced with l-thyroxin ( g by mouth daily) and three had hypocorticism that was replaced with cortisone acetate ( mg/d); none of the patients was receiving replacement. Serum, IGF-I, and free thyroid hormones and serum and urinary Na and K measurements periodically assessed the adequacy of hormone replacement therapy. Treatment protocol For all patients, cabergoline was the first line of therapy. Consistent with previous studies (8 11), treatment was started orally at a dose of 0.5 mg once weekly for the first week, twice weekly during the second week, and then 0.5 mg twice weekly. Dose adjustment was carried out every 2 months on the basis of PRL suppression; the dose was increased when hormone levels were 15 g/liter. Assessment of erectile dysfunction We evaluated erectile capability by NPT, using the Rigiscan by Dacomed (Minneapolis, MN). This device evaluates duration, frequency, and degree of both rigidity and tumescence during sleep (nocturnal mode); it gives for every session, which includes three nights, the total number of qualified ( 20%) erectile events (N) and the average event rigidity (percentage) at the tip and at the base of the penis. The rigidity activity unit (RAU) is a time-intensity measurement that represents the area under the rigidity curve during a qualified event. It is calculated by summing the rigidity values for the duration of a qualified event and dividing by 2 multiplied by 100. The tumescence activity unit (TAU) represents the area under the tumescence curve above the baseline during qualified events, proportional to the percent increase of tumescence over baseline. It is calculated by summing the tumescence value minus the baseline tumescence and dividing by 4 multiplied by the baseline. RAU and TAU are not modified by age, and RAU particularly appears more constant among nights (22). According to the literature (23), one episode of rigidity over 70% for almost 10 min with a variation of tumescence of 30 mm at the base and of 20 mm at the tip of the penis was considered normal with a frequency of at least three episodes per night. Assays Serum FSH, LH, and PRL levels were assessed by RIA using commercial kits. Testosterone levels were assessed using Immulite solidphase chemiluminescent enzyme immunoassay commercial kits. Serum PRL levels were assessed by RIA commercial kits. The intra- and interassay coefficients of variation were 5, and 7% respectively. Normal ranges in our laboratory were 3 8 IU/liter for FSH and LH, 3 9 g/liter for, and 5 15 g/liter for PRL. Statistical analysis Data are reported as mean sd. The statistical analysis was performed by means of the SPSS Inc. (Cary, NC) package using ANOVA. Statistical significance was set at 5%. Correlations were performed by calculating the Spearman s coefficient. The 2 test was also used where appropriate. Results Nocturnal penile tumescence at study entry As shown in Table 1, compared with controls, the patients with either micro- or macroprolactinoma had low levels with severe alterations of erectile function. Testosterone deficiency was present in 30 of the macroprolactinomas (73.2%) and five of the microprolactinomas (50%; P 0.3). Symptoms of reduced libido and sexual potency had been referred by 22 macroprolactinomas (53.6%), five microprolactinomas (50%), and none of controls. However, NPT was significantly reduced in the patients compared with controls, and less than three erectile events per night were found in 49 patients (96.7%) and seven controls (13.7%; P ); abnormal NPT values were found in all macroprolactinomas and in eight of 10 microprolactinomas. All seven controls were older than 50 yr (57 70 yr). In the patients, the number of qualified erectile events per night during NPT was correlated with PRL levels (r 0.5; P ) but not with age (r ; P 0.98) or with levels (r 0.23; P 0.09), whereas in controls, it was correlated with age (r 0.77; P ), PRL levels (r 0.3; P 0.02), and levels (r 0.3; P 0.02). In addition, as expected, PRL levels were correlated with levels in TABLE 1. Demographic, endocrine, and seminal fluid parameters in patients and controls at study entry Macro prolactinoma Micro prolactinoma Controls No. of patients Age (yr) Serum PRL ( g/liter) Serum FSH (IU/liter) Serum LH (IU/liter) Serum ( g/liter) Events/night RAU TAU Data are shown as mean SD. P

3 De Rosa et al. Cabergoline and Erectile Dysfunction in Men J Clin Endocrinol Metab, February 2004, 89(2): the patients (r 0.43; P ) and, weakly, also in controls (r 0.29; P 0.04). Nocturnal penile tumescence after cabergoline treatment After 6 months of cabergoline treatment, PRL levels were normalized in 38 patients (74.5%), 30 of 41 macroprolactinomas (73.2%) and eight of 10 microprolactinomas (80%; P 0.9). No changes were noted in FSH levels (to IU/liter in macroprolactinomas and to IU/liter in microprolactinomas), whereas LH levels slightly but significantly increased (to IU/liter in macroprolactinomas and to IU/liter in microprolactinomas; P 0.05). Testosterone levels normalized in 35 patients, 27 macroprolactinomas and all microprolactinomas, who achieved PRL normalization, but in none of the 13 patients not achieving PRL normalization. Table 2 shows the results of NPT according to PRL and response. There was a clear improvement of NPT results in patients who had PRL normalization, even when levels were not normalized. Conversely, in the 13 patients who did not have PRL normalization, only a modest improvement was observed (Table 2). According to the currently accepted criteria of three erectile events per night as the normal value, NPT normalized in 23 of 38 patients (60.6%) who normalized PRL levels and in one of 13 patients (7.7%) who did not. However, when the results of our control were stratified according to age, because secretion physiologically declines with aging (24), both levels and NPT were in the normal range according to our controls in patients older than 50 yr but not in younger ones, despite achieving normal PRL levels (Fig. 1). We note that our 11 controls older than 50 yr had a median level of 4 g/liter and a median NPT of two events per night. In contrast, as expected, patients not achieving PRL normalization still had very low and NPT values compared with age-matched healthy men. Discussion The most important finding of this open longitudinal study aimed at evaluating prevalence and reversibility of erectile dysfunction in men with hyperprolactinemia is that there is a relevant difference between the subjective perception of sexual failure and its objective demonstration by measuring nocturnal penile tumescence. Approximately 50% of the patients coming to our observation for hyperprolactinemia complained of sexual disturbances, whereas 96.7% of them had an impairment of erectile events per night compared with 13.7% of controls. Importantly, there was an age-dependent decline of levels, as expected (24, 25), and also of NPT events that should be considered when facing sexual failure; our patients older than 50 yr indeed achieved levels and NPT events in a similar range as observed in our healthy controls, whose number of median events per night was only two. In fact, age is a relevant variable for sexual dysfunction. In elderly men, coordination between neural signals directing intermittent LH secretion and those governing sleep-associated penile tumescence are lost (26). Moreover, age and erectile dysfunction duration are the most important variables affecting the results after an intracavernous injection test, evaluated by NPT, probably for a venous insufficiency (27). It is also worth noting that patients younger than 50 yr and achieving normalization of PRL levels did not completely normalize secretion and NPT according to their age-matched controls. The full normalization of levels is crucial to achieve restoration of sexual function as demonstrated by several reports investigating nocturnal erections. In fact, it has been demonstrated that androgen treatments to increase levels is accompanied by increased sexual interest and activity and spontaneous erections (28 30). Therefore, it is likely that 6 months of PRL normalization is a period not long enough to completely restore secretion and thus sexual function. According to some authors, severe erectile dysfunction might be considered as a precocious marker of hyperprolactinemia, even if only a few cases were studied (31). As already mentioned, healthy men have erectile activity during the rapid eye movement (REM) phase of sleep; the number and duration of those erectile episodes are correlated with patient age, and it is common to find four to five episodes per TABLE 2. NPT in the 51 patients according to PRL and levels Normal PRL and Normal PRL and low High PRL and normal High PRL and low No. of patients 35 (68.6%) 3 (5.9%) 3 (5.9%) 10 (19.6%) Age (yr) Basal PRL levels ( g/liter) a PRL levels after CAB ( g/liter) b b Basal levels ( g/liter) Testosterone levels after CAB ( g/liter) c Basal no. of events/night No. of events/night after CAB b b Basal RAU RAU after CAB d Basal TAU TAU after CAB a d d CAB, Cabergoline. P vs. all other groups. b P 0.01 vs. the two groups with high PRL levels. c P vs. the two groups with low levels. d P 0.01 vs. the 10 patients with high PRL and low. P

4 624 J Clin Endocrinol Metab, February 2004, 89(2): De Rosa et al. Cabergoline and Erectile Dysfunction in Men night. In 1970, Karacan (32) suggested that monitoring NPT could distinguish between organic and psychogenic erectile dysfunction. In fact, psychological factors that could inhibit a sexually induced erection are inactivated during sleeping, whereas clearly neurological and/or vascular factors are present during sleep, thus inhibiting nocturnal erections. On this basis, hyperprolactinemia can certainly be considered as an organic cause of reduced response to the NPT test. The NPT test can be an additional measure in the diagnosis of hyperprolactinemia in men because it fails in as high as 96.7% of cases. Besides the clear-cut PRL-inhibitory effect, cabergoline, in analogy with other dopamine agonists (33, 34), could improve erectile function also directly at a central level. This central effect has been better demonstrated by using apomorphine for the treatment of erectile dysfunction (34). The exact involvement of dopamine in the control of sexual motivation and genital arousal in men is still unknown, but experimental data in male rats suggest an implication of dopamine in sexual motivation as well as in copulatory performance (34). The anticipatory/motivational phase of copulatory behavior is regulated by dopamine released at the nucleus accumbens (innervated by the mesolimbic dopaminergic pathway) and the medial hypothalamic preoptic area (innervated by the dopaminergic incertohypothalamic pathway), but a permissive role of dopamine released at the median hypothalamic preoptic area has also been documented (34). In conclusion, 50% of the patients coming to our observation for hyperprolactinemia complained of sexual disturbances, whereas 96.7% of them had an impairment of erectile events per night compared with 13.7% of controls. Six months of treatment with cabergoline was successful not only in producing a rapid normalization of serum PRL levels but also in restoring and preserving gonadal function in hyperprolactinemic men. The treatment should be considered as a first choice in hyperprolactinemic hypogonadism, providing a normalizing of gonadotropin pulsatile secretion and consequently levels in most cases, thus restoring and maintaining during treatment the capability of normal sexual activity in male patients. Acknowledgments Received May 16, Accepted October 31, Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, via S. Pansini 5, Naples, Italy. colao@unina.it. This study was partially supported by a grant of the Italian Minister of Research and University in Rome (no ). FIG. 1. Testosterone levels (top) and erectile episodes per night by NPT (bottom) in patients after 6 months of treatment with cabergoline divided into those achieving (responsive) and those not achieving PRL normalization (resistant) compared with controls. Both patients and controls were divided on the basis of age (under 25 yr, yr, and older than 50 yr) to show the age-dependent decline in levels and qualified erectile episodes per night. *, P 0.01 vs. controls; **, P vs. responsive and controls. References 1. Colao A, Di Sarno A, Cappabianca P, Briganti F, Pivonello R, Di Somma C, Faggiano A, Biondi B, Lombardi G 2003 Gender differences in the prevalence, clinical features and response to cabergoline in hyperprolactinemia. Eur J Endocrinol 148: Delgrange E, Trouillas J, Maiter D, Donckier J, Tourniaire J 1997 Sex-related difference in the growth of prolactinomas: a clinical and proliferation marker study. 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