Associations between DE and PE and hypo- [10] and hyperthyroidism [2, 6, 10], respectively, have been extensively documented, even in animal models [7, 8]. L-Thyroxin-induced hyperthyroidism in rats leads to enhanced seminal vesicle contraction frequency and BS muscle contractile activity, suggesting that hyperthyroidism affects both the emission and expulsion phases of the ejaculation process. In that study, after a 28-day washout period (to determine spontaneous recovery from hyperthyroidism) all the previously described alterations were reversed [8]. Similar results have been obtained by several clinical studies (Fig. 12.1). In a consecutive series of 755 men presenting with SD, a two-fold greater prevalence of hyperthyroidism was evident among the men with PE [2]. Carani et al. [10] in a small multicenter, prospective study demonstrated that 50 % of hyperthyroid patients have PE, a prevalence that was substantially reduced (15 %) by treating the underlying disease, with a consequent doubling of ejaculatory latency. Cihan and coworkers [6] studied the prevalence and characteristics of premature ejaculation (PE) in a single-center prospective study in a small Turkish population of hyperthyroid subjects (n = 43; 40 % with Graves-Basedow disease, the rest of the sample with toxic nodules). PE was defined according to the Diagnostic and Statistical Manual of Mental Disorders, (4th Edn. Revision) criteria along with patient-reported outcome and stopwatch measurement of intravaginal ejaculation latency time (IELT; PE: IELT of <1 min). PE was observed in 31 (72 %) hyperthyroid subjects. There was a positive correlation between thyroid-stimulating hormone (TSH) and IELT. After 2 months of high-dose medical therapy, subjects were enrolled in continuing medical therapy (n = 10) or had definitive treatment with surgery (n = 7) or radioactive iodine (n = 7). Achieving euthyroidism at follow-up (24 patients), regardless of therapeutic intervention, increased mean IELT by a factor of two in the total population or by a factor of three in the PE population. Beck anxiety scores and international index of erectile function also significantly improved in the euthyroid state. The authors concluded that hyperthyroidism should be considered a novel and reversible etiological risk factor for PE. However, it should be recognized that Waldinger et al. [89] did not find any association between TSH levels and IELT in a cohort of Dutch subjects with lifelong PE, without erectile dysfunction. Since thyroid diseases represent a risk factor for ED [10], it cannot be excluded that our population was abundant in thyroid diseases, explaining, at least partially, this difference. Overall, the majority of studies suggest a direct role for thyroid hormones in decreasing ejaculation latency that is independent from hyperthyroidism-induced anxiety. Furthermore, Carani et al. [10] showed that medical treatment of the opposite state, hypothyroidism, resulted in a two-fold decrease in ejaculatory latency and a reduction in delayed ejaculation. Hence, the view that thyroid hormones regulate not only the ankle reflex but also the ejaculatory reflex is consistently emerging. Accordingly, in a recent study [9], after excluding subjects with low TSH due to pituitary diseases, we found that TSH levels were positively related to reported ejaculatory latencies. Because TSH levels are tightly related, by a negative feedback, to thyroid function, it can be assumed that thyroid hormones negatively affect ejaculatory latency (Fig. 12.1). Since hyperthyroidism, even in its subclinical form, is associated with 41 % increase in all-cause mortality, especially in men [90], and hyperthyroidism-associated PE is a treatable condition, clinical screening with eventual laboratory confirmation for thyroid diseases in men with ejaculatory dysfunction is strongly advised.

Human prolactin (PRL) is a non-glycosylated protein, which contains a simple polypeptide chain of 198 aminoacids. Circulating forms of prolactin include, besides the usually predominant monomer, high-molecular forms, such as macroprolactin (>100 kDa), a biologically inactive complex of PRL and IgG [91, 92]. In women, the main biological function of PRL is to control breast development and lactation, while the role of PRL in men is unclear. Gene deletion of PRL, or of its receptor (PRLR), does not alter male reproductive fitness [93–95], although PRLRs are expressed in the male brain, testis, and accessory glands [93] and even in the penis [96]. Hence, up to now, the physiological effect of PRL on male reproductive fitness is unknown. Conversely, the association between PRL pathological elevation and derangements in both reproductive and sexual behavior is well defined [97–99]. A wealth of data demonstrate a marked inhibitory effect of hyperprolactinemia on sexual desire [97, 99–101], most probably acting on hypothalamic GnRH (and therefore on T production) and/or dopamine production and turnover. Several studies have shown that PRL increases following male orgasm ([26, 102, 103], see for review [104]), hypothesizing a negative feedback control of this PRL surge on sexual motivation, contributing, therefore, to the post-orgasmic refractory period. However, it is noteworthy that the post-orgasmic rise in PRL is relatively modest and similar in men and women, which are less prone to post-orgasmic refractoriness and satiety. In addition, PRL increases during other emotionally stressful or disturbing conditions (including venipuncture) or following stimulation of the nipple or areola [105]. The prevalence of mild hyperprolactinemia (PRL > 420 mU/l or 20 ng/ml) in male subjects with sexual dysfunction is quite variable, ranging from more than 13 % [106] to less than 2 % [97]. In these subjects, severe hyperprolactinemia (SHPRL, PRL > 735 mU/l or 35 ng/ml) is a relatively rare event (less than 1 %; [97, 99]). Milder forms of hyperprolactinemia do not play a significant role in the pathogenesis of male sexual dysfunction [97, 99], while severe hyperprolactinemia has a negative impact on sexual function, impairing sexual desire as well as erectile function, and testosterone production [97–101].

PRL secretion from the pituitary is influenced negatively by hypothalamic dopaminergic neurons and positively by central serotonergic pathways. A low PRL response to a serotonergic challenge, which could be considered a mirror of a blunted central serotonergic function [107, 108], is associated with carotid artery thickening, suggesting that individual differences in central serotonergic responsivity are inversely related to preclinical vascular disease [109]. We previously demonstrated that even basal PRL determination could be used as a marker of blunted central serotonergic function [5]. In the brain, serotonin modulates neuronal activity and is actively involved in mediating many cognitive functions and behaviors, including eating and locomotion. Different abnormalities in serotonin function have been detected in patients with anxious symptoms and disorders [110], and the serotonin system is a primary target for drugs used in the treatment of these conditions [10]. The classical view that anxiety is secondary to excessive serotonin activity has been challenged by more sophisticated models, which place less emphasis on global levels, but consider different serotonergic neural circuitry and receptors, mediating different aspects of anxiety [111]. In particular, the discovery of genetic variation in a crucial regulatory molecule within the serotonin system, the serotonin transporter, and its influence on emotional traits [112] provided a new foundation for understanding the neurobiological and genetic basis of emotional regulation and anxiety disorders [113].

We originally reported that hypoprolactinemia (i.e., prolactin levels in the lowest quartile) is associated to men with sexual dysfunction with peculiar psychobiological features, including a higher prevalence of MetS and arteriogenic ED, as well as anxiety symptoms and PE. According to the Waldinger’ s neurobiological hypothesis, a disturbance in the central serotonin pathway (serotonin-2C receptor hyposensitivity and/or serotonin-1A receptor hypersensitivity; [114]) has been advocated—but never demonstrated in humans—as a possible cause of lifelong PE. In experimental animal models, the serotonergic system acts, at the hypothalamic level, as a suppressor of the ejaculatory reflex [114]. Accordingly, both selective serotonin reuptake inhibitors (SSRIs) and serotonin agonists determine the extension of ejaculatory latency [114]. Our data provide the first clinical finding apparently in keeping with the Waldinger’s hypothesis. In our cohort of patients, the relatively low prolactin levels were in fact associated with a higher risk of PE, even after adjustment for confounders. However, no differences were observed when lifelong or acquired PE were considered. Hence, it could be speculated that even secondary causes of PE would act mainly influencing the brain serotonergic system [2–6]. On the other hand, this may be true also for lifelong PE: it can, in fact, be speculated that the serotonergic central changes, mirrored by low prolactin levels both in lifelong and acquired PE, are a consequence, and not a cause, of the absence of ejaculatory control. In fact, many psychological disturbances (such as stress and frustration for chronic or acquired inability to enjoy sex) are capable of provoking a neuroendocrine imbalance. Furthermore, the effectiveness of serotonergic antidepressants has been demonstrated in both lifelong and acquired PE. The ejaculation-delaying effects of some long-acting or specifically designed short-acting SSRIs are currently used therapeutically to treat PE [11–14]. Our results cannot clarify the cause-effect relationship between serotonergic imbalance and PE, but they demonstrate that lower levels of PRL characterize patients with PE with respect to others with different sexual dysfunctions. We recently found that PRL levels are positively correlated to the reported ejaculatory latency (starting with severe PE ante portas and ending with anejaculation), after excluding from the analysis subjects with pathological hyperprolactinemia (PRL > 735 mU/l or 35 ng/ml) and adjusting for SSRI use ([9], see also Fig. 12.1). Interestingly, in this study, the MHQ-A score, which is an index of symptoms of free-floating anxiety, decreased across PRL quartiles. These data suggest that low PRL levels should be considered in the evaluation of subjects with sexual dysfunction, since it can give insights into ejaculatory behavior and might reflect central serotoninergic tone.