Sexual function of men with severe organic hypogonadism
Data accumulated in such men show that T is required for pubertal acquisition of gender characteristics as well as adult sexual behavior and functional capacity, including libido, ejaculation, and spontaneous erections. Administration of T during placebo-controlled studies demonstrated that sexual desire and arousal are T-dependent [13,29,30] and represent the main impact of T on sexual function of men. The frequency of sexual activity [13,30,31] and spontaneous erections (especially sleep related, i.e. morning and nocturnal) [13,29,32] are also clearly T-dependent. The psychic erections (i.e. in response to erotic stimuli) were initially thought to be androgen-independent , but are in fact partly T-dependent . Ejaculations  and orgasm  are also partly androgen-dependent.
Threshold levels for testosterone effects on sexual function
The effects of T upon male sexual function are dose-dependent up to a serum level close to the lower limit of the normal adult range, at which they are maximum. Below this threshold sexual function is impaired. This threshold level is consistent within an individual [10,36], but markedly variable between individuals [10,31,36], and may be specific to each parameter of sexual function . For example, in a study by Kelleher, the average T level from which hy-pogonadal males on testosterone pellet implants began to perceive androgen deficiency symptoms leading them to request a new implantation was 2.6 ng/mL (or 10nmol/L), but the individual levels varied from less than 1 to 4.5 ng/mL. In another series of hypogonadal males on injectable T esters, the individual threshold level varied from 1.1 to 3.6 ng/ mL [10,36]. Overall, levels below 2ng/mL are in most cases associated with impairment of sexual function [10,31,36], and levels below 1.4-2ng/mL with diminished nocturnal erections . Conversely, from a ceiling level of 4.5-6 ng/mL, according to the studies [10,31,36,37], the effect of T is maximum and is not enhanced with additional T supplementation. In eugonadal males, a significant increase in sexual interest and arousal [27,39,40], along with rigidity and duration of the erections , was obtained in some studies by increasing the serum T level within or above the normal range. But others could not replicate these findings , and in the former the effect upon sexuality was too small to be clinically significant. Between these two thresholds levels of about 2 and 4.5-6 ng/mL, the impact of T on sexual activity may or may not be optimum according to the sensitivity to androgens of the individual.
Role of testosterone in control of erections • Data from experiments in animals: Studies in rodents suggest that besides its well-known effects on the brain centers of sexual function, especially the hypo-thalamic preoptic area and arcuate nucleus, T plays a key role in the peripheral modulation of erectile function. It is well known that the nitric oxide (NO) pathway is critical for initiation and maintenance of erections. In animals, the expression of both the en-dothelial and neuronal NO synthases (NOS), and therefore the capacity for NO production, is regulated by androgens [43,44]. Androgen suppression via castration results in marked decrease in NOS activity and cyclic guanosine monophosphate (cGMP) formation, through both NOS-dependent and -independent mechanisms, as well as in profound structural changes in penile tissue (atrophy con comitant with alterations in dorsal nerve structure and endothelial morphology, reduction in trabecular smooth muscle content, increased deposition of extracellular matrix, and accumulation of adipocytes in the subtunical region of the corpus cavernosum) . Thus androgens exert a direct effect on penile tissue to maintain erectile function, and androgen deficiency produces metabolic and structural imbalance in the corpus cavernosum, which results in venoocclusive dysfunction and ED, reversed by T administration [45,46].
• Data from experiments in men: In human males the main sites of the action of T upon sexual function are considered to be located in the brain. Positron emission tomography (PET) studies have begun to map them [47,48]. Until now a critical impact on the peripheral mechanisms of erection had not been demonstrated in men. However there are androgen receptors in the human corpus cavernosum , and some recent studies suggest T may modulate the vascular mechanisms of erection also in men. Peak systolic velocity was measured at the level of the cavernosal arteries with penile color Doppler ultrasound (CDU), following intracavernosal injection of alprostadil in ED patients with severe hypogonadism (serum T < 2 ng/mL) and no vascular co-morbidity . It was significantly lower than in a control group of psychogenic ED patients, and increased up to the range of the later group following T-replacement for six months. In another study based on CDU of the cavernosal arteries, Aversa et al. found a highly significant correlation of the resistive index with the serum value of FT . In a third study of arteriogenic ED patients with low-normal T—non-responders to sildenafil—T supplementation significantly enhanced the accelerating effect of sildenafil on peak systolic velocity measured in the cavernosal arteries . However, more evidence is required before the hypothesis of a significant impact of T on the penile vascular mechanisms of men can be totally accepted.
• Effects of T therapy in the hypogonadal ED patients: Testosterone therapy consistently restores erectile function in young patients with organic hypogo-nadism . A recent meta-analysis by Isidori et al. integrated 17 randomized controlled trials (RCTs) that had studied the effects of T on male sexual function in men of any age . A significant improve ment of all aspects of sexual function was found in men with low (<7nmol/L, 2ng/mL) and low-normal T (7-12nmol/L, 2-3.46ng/mL) receiving standard replacement doses of T, with respect to placebo. Concerning erectile function, the magnitude of the effect was inversely related to the baseline T concentration and was detectable only in studies with mean baseline T level < 12 nmol/L (3.46 ng/mL). No statistically significant effect on libido (though close to significance) or erections was found in studies with mean baseline T level above this. The type of T preparation used, the length of follow-up assessment, as well as the presence of ED and other co-morbidities (diabetes mellitus, hypertension, dyslipidemia), all influenced response to treatment. The effect of age was not studied in this meta-analysis. Although this data suggests a significant effect of T therapy on erectile function in cases of marked or moderate hypogonadism, the effects reported in the literature regarding this treatment have been mostly disappointing when it was used alone in middle-aged patients consulting for ED who are subsequently found to be hypogonadal. This situation may be quite different from that of men with organic hypogonadism, diagnosed earlier in life, who constitute the majority of the populations studied in RCTs. No controlled trial has been specifically devoted to such patients, but the compilation of eight observational studies totalling 259 cases (T < 3 ng/mL or 11.5 nmol/L) leads to the conclusion that only 36% were definitely improved regarding their erectile function [18,20,54-59]. Perhaps TT is a poor index of androgenicity, and only its bioavailable fractions should be taken into account. This speculation was not confirmed by the results of T therapy in ED patients with low levels of FT or BT, since the success rate was even poorer in this category, including cases that had low FT or BT and normal TT levels [23,60]. Probably the low T level of some ED patients is not the real, or at least the sole cause of their ED. The lability of serum T has to be considered, and every low result should be confirmed by a second determination. In addition, ED is often multifactorial, and the meta-analysis by Isidori et al. found that comorbidities influence the effect of T therapy . Significant vascular factors, such as obstruction of the penile arteries or venoocclusive dysfunction were found in as many as 42% of ED patients with low T levels . More subtle alterations such as en-dothelial dysfunction, probably exist due to many other medical co-factors, and this may also hamper the effects of T therapy. It is even probable that in certain cases low T is more a consequence than the cause of ED. In two studies the low serum T increased following successful non-hormonal ED therapies (such as intracavernosal or phosphodiesterase type 5 inhibitor (PDE5i) therapies) [25,26]. In such cases the reduction in T secretion was likely caused by reduced sexual activity (that has been shown to stimulate T secretion) , and by the stress and depression that often result from ED, through the well-known inhibitory impact of the two latter factors on the hypothalamic gonadotropic centers [62,63]. Carosa et al. observed a reduction in the bioavailability of LH in ED patients that could result from a spacing out of the LHRH pulses via a psychosomatic mechanism, since it was also reversible with successful non-hormonal ED therapies . • Possible requirement of a minimum serum T level for a complete effect of PDE5i in ED patients: cGMP, the key intracavernosal signal for the relaxation of the cav-ernosal smooth muscle and thus erection, is inactivated by the enzyme PDE5, present in the cavernous bodies. This limits the effects of NO release on erection. By inhibiting PDE5, intracavernosal cGMP accumulation occurs, and that often improves the quality of erection. In rodents androgens modulate not only the expression of NOS but also that of PDE5 [65,66], as well as the response to electrostimulation of the corpora cavernosa . In animal models, it was demonstrated that normal androgen levels are a prerequisite for proper functioning of PDE5i [67,68]. The critical importance of a normal T level for intra-penile mechanisms of erection has not been proved until now in humans, but the expression of PDE5 is T-dependent in humans too . In addition in a group of ED patients without any other apparent cause of ED than severe hypogonadism, the PDE5i sildenafil failed to improve the blunted erectile response to visual sexual stimulation, as it did in eug-onadal psychogenic ED patients. This response was subsequently restored following T substitution for six months . Lastly in another study sildenafil improved sleep-related erections even in hypogonadal men, but the effect of sildenafil and T was greater than the sum of the two compounds alone .
Several uncontrolled studies recently reported an increased prevalence of low or low-normal T levels in ED patients who were non-responders to PDE5i, with a frequent improvement of their response following T substitution [70-72]. The speculation that hypogonadism was responsible for the PDE5i failure is supported by two controlled studies. Aversa et al. studied 20 patients (mean age 55) with arteriogenic ED and both TT and FT in the lower quartile of normal range . These had been non-responders to six trials with 100 mg sildenafil and were randomized to T or placebo patches combined with sildenafil on demand. With respect to placebo, T-treatment significantly increased the arterial inflow to cavernous bodies (peak systolic velocity measured with CDU following sildenafil administration), as well as increased scores of the "erectile function," "intercourse satisfaction," and "overall satisfaction" domains of the international index of erectile function (IIEF). The Shabsigh et al. study (Fig. 18.2) involved more ED patients (75) with low or low-normal TT (< 4ng/mL)—non-responders to sildenafil 100mg . They were randomized to T or placebo gels combined with sildenafil on demand during this time, for 12 weeks. After four weeks the scores of the "erectile function," "orgasmic function," and "overall satisfaction" domains of the IIEF, as well as the number of patients reporting that their gel improved their response to sildenafil, were significantly higher in the T group. However the statistical differences between the T and placebo groups waned or disappeared at eight and 12 weeks, probably in part because of the small size of the patient sample and the rather high drop-out rate. However the speculation that a certain threshold level of T is required for a complete effect of PDE5i has still to be confirmed in larger studies.
What are the practical consequences of diagnosing hypogonadism in an ED patient? Hypogonadism is present in 5-15% of ED patients according to age. Although low T may not be the main cause of ED in many patients, due to the frequent multifactorial-ity of ED, and the preponderance of vascular factors, there are clearly benefits to screening for T deficiency:
• Achieving physiologic levels of T is one of the rare opportunities to restore spontaneous erections and save patients from having to plan sexual activity, as is the case with most other therapies of ED.
• Providing T therapy is the only possibility of restoring sexual desire [13,74], which is often low in such patients, especially since low sexual desire is a frequent cause of drop-out from PDE5i therapy.
• Replacing T may also improve other symptoms associated with hypogonadism, including lack of energy and mood disturbances [71,72].
• A threshold serum T level could be required to achieve full efficacy with PDE5i. Therefore if an ED patient does not satisfactorily respond to PDE5i, it is indicated to determine serum T if not already done. In case the level is low or low-normal (<4ng/mL, 14nmol/L), combining T therapy with PDE5i for at least two months is recommended.
Week 4 Week 8 Week 12 Endpoint
■ Placebo + Sildenafil □ Testogel + Sildenafil
Fig. 18.2 Testosterone therapy (5g testosterone gel/d/12 wk) converts sildenafil 100mg non-responders to responders in men with hypogonadism (T <4ng/mL) and erectile dysfunction. The figure represents the mean change in "erectile function" domain score. The difference was no longer significant from week eight. Source: Shabsigh R, et al. J Urol 2004;172:658-663 .
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