Contrary to sexual arousal not accompanied by orgasm, penile–vaginal intercourse-induced orgasm and, to a lesser extent, also masturbation-induced orgasm result in an increase in circulating prolactin levels.1–4 Irrespective of the gender,3,4 postorgasmic prolactin surges are strongly related to the quality of orgasm and subsequent sexual satisfaction, suggesting that changes in prolactin secretion are an objective index of the presence and quality of orgasm. It is possible that prolactin surges may play a role in a negative feedback loop, the aim of which is to reduce arousal.1,3,4
From a sexual point of view, chronic prolactin excess may be unfavorable because it seems to impair sexual functioning of both women and men. Elevated prolactin levels were accompanied by a decrease in the overall Female Sexual Function Index (FSFI) score and by disturbances of all aspects of female sexual functioning assessed in this test.5,6 In turn, comparing with matched controls, men with hyperprolactinemia secondary to prolactin-secreting tumors were characterized by a higher prevalence of hypoactive sexual desire.7 However, impaired libido was reported less frequently in men with elevated prolactin levels than in those with hypotestosteronemia.8
Dopamine agonists, the drugs commonly used in the pharmacotherapy of elevated prolactin levels,9 seem to affect sexual functioning, at least in men. Cabergoline and bromocriptine increase erectile response in men with hyperprolactinemia.10,11 Additionally, cabergoline treatment was found to enhance sexual drive and function and led to a positive perception of the refractory period.12 In the light of the present state of knowledge, cabergoline seems to be a better treatment for patients with hyperprolactinemia than bromocriptine. Compared with bromocriptine, cabergoline exerts a stronger effect on prolactin levels, is better tolerated, and may be administered once or twice a week.9,13 Moreover, as our research suggests,14 cabergoline is superior to bromocriptine when it comes to affecting atherogenic dyslipidemia, insulin sensitivity, and plasma levels of cardiovascular risk factors in women with hyperprolactinemia. Unfortunately, no study has investigated whether pharmacokinetic and physicochemical differences between various dopamine agonists determine the strength of their action on sexual functioning. This study was aimed at comparing the impact of cabergoline and bromocriptine on various aspects on female and male sexual functioning and at determining whether these effects are related to their action on serum prolactin and insulin resistance.
MATERIALS AND METHODS
The participants of the study were selected among young women (age, 20–40 years) and men (age, 20–50 years) who because of hyperprolactinemia secondary to prolactin-secreting tumors, traumatic brain injury, or primary empty sella syndrome were treated for at least 12 weeks with bromocriptine (5–10 mg daily). At the time of recruitment, they had to have serum prolactin levels in the range between 10 and 30 ng/mL in women and between 5 and 25 ng/mL in men found on 2 different occasions. About one-half of patients were required to experience adverse effects of bromocriptine treatment (nausea, vomiting, dizziness, postural hypotension, and headache). The subjects were excluded if they met at least one of the following criteria: any other acute or chronic disease, psychiatric problems, postpartum complications, developmental or acquired anomalies of the male and female reproductive system, a history of urological or gynecological operations that might affect sexual function, any treatment (with the exception of bromocriptine), and pregnancy, breastfeeding, and sexual inactivity.
The study protocol was approved by the institutional review board, and all included subjects gave written, informed consent to participate in the study. Based on bromocriptine tolerance, both men and women were allocated to 1 of 2 treatment groups. Women (n = 20) and men (n = 10) not experiencing adverse effects of bromocriptine continued this treatment in the same daily dose. In women (n = 19) and men (n = 8) poorly tolerating bromocriptine, this drug was replaced with cabergoline (0.5 mg once weekly). Compliance was assessed during each visit by pill counts.
Laboratory assays were performed at the beginning and 16 weeks later. Venous blood samples were taken 12 hours after the last meal from the antecubital vein in a temperature-controlled room (24°C–25°C). In women, samples were collected in the early follicular phase (between days 2 and 5, counting from the first day of the last menstrual period). Before blood collection, the participants had been resting in a quiet room for at least 30 minutes in the seated position. Plasma glucose levels, as well as serum insulin and prolactin levels, were measured with standard methods using commercial kits purchased from Roche Diagnostics (Basel, Switzerland). The homeostasis model assessment 1 of insulin resistance (HOMA1-IR) was calculated by dividing the product of insulin (milli international units per litre) and glucose (in milligrams/deciliter) by 405.
Immediately after blood collection, all participants were asked to fill in a questionnaire assessing their demographic characteristics, smoking, physical activity, education, occupation, stress exposure, general health, the number and duration of marriages, the number of sexual partners, deliveries and abortions (in women), and a questionnaire evaluating their sexual function: FSFI in women or International Index of Erectile Function (IIEF)-15 in men.
FSFI is a 19-item instrument addressing all phases of the female sexual cycle, sexual satisfaction, and dyspareunia in the previous 4 weeks, with a specific focus on 6 domains: desire (question 1 and 2), arousal (questions 3–6), lubrication (questions 7–10), orgasm (questions 11–13), satisfaction (questions 14–16), and pain (questions 17–19).15,16 Each answer was rated from 0 to 5 or 1 to 5 (0 means no sexual activity in the past 4 weeks). The scores in each domain multiplied by the domain factor (0.6 for desire, 0.3 for arousal and lubrication, and 0.4 for orgasm, satisfaction, and pain) were then added to yield the total score, which can range from 2 to 36 with lower values indicating higher symptom burden. Women with the total score less than 26.55 were classified as having sexual dysfunction.15,16
IIEF-15 is a 15-item, self-administered questionnaire evaluating 5 collective domains of male sexual functioning: erectile function (6 questions), orgasmic function (2 questions), sexual desire (2 questions), intercourse satisfaction (3 questions), and overall satisfaction (2 questions) in the past 4 weeks.17,18 Each answer was rated on a scale ranging from 0 to 5 (intercourse satisfaction and orgasmic function), 1 to 5 (erectile function), or from 2 to 5 (sexual desire and overall satisfaction), with a higher score corresponding to better sexual function. Erectile function was evaluated based on 6 questions (questions 1 to 5 and 15), yielding a maximum score of 30 points. Men with the overall score less than 26 were classified as presenting mild (22–25), mild to moderate (17–21), moderate (11–16), and severe (10 or less) erectile dysfunction. Intercourse satisfaction was evaluated using 3 questions (questions 6–8), whereas the remaining domains using 2 questions (orgasmic function: questions 9 and 10, sexual desire: questions 11 and 12, overall satisfaction: questions 13 and 14). Maximum scores were 15 for intercourse satisfaction and 10 for orgasmic function, sexual desire and overall satisfaction, whereas minimum scores were 0 for intercourse satisfaction and orgasmic function, 1 for erectile function, and 2 for sexual desire and overall satisfaction.17,18
To achieve approximately normal distribution, skewed variables were natural log transformed. Comparisons between the groups were performed using the t test for independent samples after consideration of age, smoking, body mass index, blood pressure, and a season during which samples were collected as potential confounders. The differences between the means of variables within the same treatment group were analyzed with Student paired t test. The χ2 test was used to compare associations between categorical variables. Correlations were calculated using Pearson r tests. Statistical significance was defined as P < 0.05.
At the beginning of the study, both groups of women were comparable with respect to age, body mass index, waist circumference, smoking (number of cigarettes and duration of smoking), education, occupational and physical activity, type of work performed, the number of sexual partners, the number and duration of marriages, the number of deliveries and abortions, stress exposure, systolic and diastolic blood pressure, and prolactin and glucose levels and HOMA1-IR (Table 1). There were no significant differences between the study groups of men in age, smoking, education, occupational and physical activity, a type of work, the number of sexual partners, the number and duration of marriages, stress exposure, blood pressure, prolactin and glucose levels and HOMA1-IR (Table 2).
Cabergoline reduced prolactin levels by 47% (P < 0.05) and HOMA1-IR by 25% (P < 0.05) in women, and decreased prolactin levels by 50% (P < 0.05) and HOMA1-IR by 34% (P < 0.05) in men. No effect was observed in patients who continued bromocriptine treatment. At the end of the study, prolactin levels and HOMA1-IR were lower in cabergoline-treated patients than in bromocriptine-treated patients (P < 0.05). Plasma glucose in both treatment arms did not differ at the beginning and at the end of the study (data not shown).
Baseline sexual functioning did not differ between patients well and poorly tolerating bromocriptine treatment (Figures 1–4). Sexual dysfunction was found in 6 women (32%) poorly and 6 women (30%) well tolerating bromocriptine treatment. Erectile dysfunction was observed in 2 men (25%) poorly and 2 men (20%) well tolerating bromocriptine treatment. All reported cases of impaired sexual functioning in men fulfilled the criteria of mild erectile dysfunction. Neither in men nor in women, continuation of bromocriptine treatment affected sexual functioning. Replacing bromocriptine with cabergoline improved sexual desire and sexual arousal in women (Figure 1) and sexual desire, erectile, and orgasmic function in men (Figures 3 and 4). Moreover, cabergoline tended to increase the total FSFI score (P = 0.065) (Figure 1), tended to decrease the percentage of women with sexual dysfunction (from 32% to 21%, P = 0.095), and insignificantly decreased the percentage of men with erectile dysfunction (from 25% to 13%; P = 0.097). At the end of the study, there were significant differences between cabergoline-treated and bromocriptine-treated women in desire and arousal (Figure 2), as well as between cabergoline-treated and bromocriptine-treated men in sexual desire, erectile, and organism function in men (Figures 3 and 4). The overall FSFI score was insignificantly higher (P = 0.068) (Figure 1), whereas the percentage of patients with sexual dysfunction was insignificantly lower (21 vs. 32%) (P = 0.086) in the group of women receiving cabergoline than bromocriptine.
In both genders, the effect of cabergoline on serum prolactin levels correlated with the effect of this drug on HOMA1-IR (women: r = 0.47; P < 0.001; men: r = 0.41; P < 0.001). The effect of cabergoline on serum prolactin levels correlated with its impact on the total FSFI score (r = 0.31; P < 0.05), sexual desire (r = 0.43; P < 0.001), and sexual arousal (r = 0.29; P < 0.05) in women and with the impact of this drug on male sexual desire (r = 0.41; P < 0.001), erectile function (r = 0.28; P < 0.05), and organism function (r = 0.26; P < 0.05). There were correlations between cabergoline-induced changes in HOMA1-IR and the effect of this drug on the total FSFI score (r = 0.25; P < 0.05), sexual desire (r = 0.35; P < 0.01), and sexual arousal (r = 0.24; P < 0.05) in women, and with the impact of this drug on sexual desire (r = 0.34; P < 0.01), erectile function (r = 0.24; P < 0.05), and organism function (r = 0.29; P < 0.05) in men. No other correlations were found.
The results of the present study indicate that cabergoline is superior to bromocriptine in affecting sexual functioning in both genders. Replacing long-term bromocriptine treatment with cabergoline resulted in an improvement in sexual desire, erectile function, and orgasmic function in men and improved desire and sexual arousal in women. On the basis of the obtained results, it seems that cabergoline should be considered a dopamine agonist of choice in the treatment of hyperprolactinemic patients with disturbed sexual functioning, irrespectively of their gender. The more favorable effect of cabergoline on sexual functioning may be partially explained by a stronger impact of the former drug on plasma prolactin and/or on insulin sensitivity. On the last day of the study, prolactin levels and HOMA1-IR differed between both treatment arms. Only in cabergoline-treated patients, prolactin levels and HOMA1-IR were significantly lower at the end than at the beginning of the study. Finally, the effect of cabergoline on various aspect of sexual functioning correlated with treatment-induced changes in prolactin levels and insulin sensitivity. A stronger effect on sexual functioning may be attributed to the fact that cabergoline more potently and for a longer period stimulates D2 receptors (half-life period of 65 hours), although its affinity for D1 receptors is less pronounced than that of bromocriptine.9
Cabergoline increased the need to engage in sexual activities in both genders and its impact on desire was more pronounced than on other aspects of sexual functioning assessed using FSFI and IIEF-15. Interestingly, previously, we observed that sexual dysfunction caused by small quantities of monomeric prolactin released during the breakdown of complexes of prolactin with IgG (macroprolactinemia) in women was accompanied by selective loss of sexual desire.6 Moreover, unlike other domains of female sexual functioning, young women with vitamin D insufficiency complained of reduced libido.19 All these findings taken together suggest that changes in desire are more susceptible to hormonal imbalance secondary to various endocrine disorders than the remaining domains of sexual functioning and may appear at earlier stages of these disorders than other sexual disturbances.
Because the beneficial effect of cabergoline on sexual functioning only moderately correlated with treatment-induced changes in serum prolactin and HOMA1-IR, it seems that other mechanisms not assessed in our study may in part explain the obtained results. Cabergoline more potently than bromocriptine reduced plasma levels of cardiovascular risk factors (C-reactive protein, homocysteine, fibrinogen, free fatty acids, uric acid, and 25-hydroxyvitamin D),14 elevated concentrations of which are associated with an increased risk of the development of atherosclerosis and its complications.20–25 This suggests a stronger vasoprotective effect of the former drug, which may be associated with better blood flow through genital organs during sexual activity.
Our findings may also be attributed to cabergoline-induced changes in the production (or metabolism) of other hormones, playing a role in the regulation of the human sexual response.26,27 Elevated prolactin levels inhibit hypothalamic–pituitary–gonadal axis activity, and this effect is reversed after normalizing prolactin levels.28,29 Therefore, differences in prolactin levels may be responsible for differences in testosterone and estrogen levels between both treatment arms (lower in hyperprolactinemic patients). In turn, the role of dehydroepiandrosterone is much less likely because elevated prolactin levels are accompanied by higher, not lower, levels of dehydroepiandrosterone sulphate.30 Finally, our results may be in part a consequence of a more beneficial effect of cabergoline on the innervation of genital organs. Hyperprolactinemia is often accompanied by glucose metabolism abnormalities, the presence of which increases the risk of peripheral neuropathy, predominantly affecting small fibers mediating sensory function, and of autonomic neuropathy.31 If these changes are reversible, the beneficial effect on glucose homeostasis, taking place more frequently after cabergoline than after bromocriptine, may improve the function of peripheral and autonomic nerves innervating genital organs.
Our study has some limitations which have to be pointed out. Owing to a small number of participants (particularly of men), our study should be regarded as a pilot study and its results need to be confirmed in larger clinical trials. Although FSFI and IIEF-15 questionnaires are well validated, their utility is limited by subjectivity. Because the study was nonrandomized, it cannot be totally ruled out that the obtained results would be different in patients randomly allocated to both treatment arms. Finally, it is possible that the effect of cabergoline would be stronger in women and men not receiving previously any dopaminergic agents, not investigated in the present study.
Summing up, cabergoline improved various aspects of sexual functioning in patients poorly tolerating bromocriptine treatment. This effect was observed in both genders and correlated with the impact of cabergoline on serum prolactin and insulin resistance. The obtained results suggest that cabergoline stronger than bromocriptine affects sexual functioning and should be preferred in hyperprolactinemic men and women with sexual dysfunction.
The study was not supported by any specific grant. The experiments comply with the current law of Poland.
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Keywords:Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
bromocriptine; cabergoline; hyperprolactinemia; sexual functioning