Testosterone and Male Sexual Function (2023)
Logan B. Galansky, MD, Jason A. Levy, DO, MS, Arthur L. Burnett, MD, MBA
INTRODUCTION
Male sexual function involves a complex interplay between hormonal, anatomic, and neuropsychologic functions and mediators. At the basis of any discussion surrounding normal and abnormal male sexual function is the “male sexual hormone,” testosterone (T). Hypogonadism, defined broadly as testicular failure with androgen deficiency, can disrupt the male sexual response cycle as well as normal systemic physiology. The resulting signs and symptoms can include decreased libido, erectile dysfunction, ejaculatory dysfunction, infertility, fatigue, decreased bone density, decreased lean body mass, increased body fat, and sleep disturbances.1
The most widely accepted model of the human sexual response cycle was developed by Masters and Johnson in 1996. They described a four-stage linear process through the phases of arousal, plateau, orgasm, and resolution.1 Some frameworks, such as that proposed by Singer Kaplan, also include a desire phase which precedes the arousal phase.2
For men, the corresponding physiologic processes to the sexual response cycle are libido and sexual desire, arousal and erection, and ejaculation and orgasm. These physiologic functions are mediated by central and peripheral nervous system pathways, end-organ motor and sensory mechanisms, and molecular signaling pathways of the vascular system.
*Basics of Testosterone
*Role of Testosterone in Male Sexual Anatomy Development
MALE SEXUAL FUNCTION PHYSIOLOGY: ROLE OF TESTOSTERONE
Physiologic Mechanisms
Despite numerous studies investigating the physiology of the male sexual response cycle, the exact role of T in mediating the steps of the process remains incompletely known. However, the literature suggests that T is key in coordinating the processing of sexual libido, the mechanics of erections, and ejaculatory function.
The first stage of the sexual response cycle involves sexual desire and libido. Sexual desire is influenced by many factors, including psychosocial, cultural, and situational, whereas libido is a biologic response directly related to T levels. Mediation of libido by T occurs in the central nervous system. Studies have shown expression of the androgen receptor in key brain areas, including the amygdala, preoptic area, and paraventricular nucleus of the hypothalamus.10
It has also been demonstrated that T is involved in the physiology of erections, most likely through its influence on molecular mediators of erectile function, formation of penile architecture, and activity of smooth muscle pathways.8 T has been shown to influence enzymatic activity in the corpora cavernosa that is responsible for both erection and detumescence.8 In hypogonadal animal models, T regulates the formation of molecules involved with erection, namely nitric oxide (NO), RhoA-ROCK, and PDE5.8 Castration models have also demonstrated the downregulation of the NO/cyclic guanosine monophosphate(cGMP) pathway in conjunction with other T-dependent biologic effects, causing smooth muscle and endothelial apoptosis and lipofibrosis of the penile corpora cavernosa that results in corporal venoocclusive dysfunction.11
The neural networks involved in ejaculation include both peripheral pelvic and genital nerves as well as galaninergic neurons in the central spinal cord.12 It has been suggested that the formation of galaninergic neurons is at least partially androgen-mediated, as studies of female and male cadavers show a greater density of galaninergic neurons in the L3–L4 segments of male spinal cords.13 Lesions to these structures have been associated with ejaculatory failure despite penile stimulation.13 The ejaculatory reflex is coordinated by neuromuscular mediators in the hypothalamic nuclei, specifically serotoninergic and dopaminergic neurons, responsible for inhibition and promotion, respectively.14 In the peripheral nervous system, emission and expulsion are then controlled by sympathetic and parasympathetic pathways.15 In rat models and some human studies examining ejaculatory dysfunction, T deficiency has been associated with decreased dopaminergic response, leading to a delay in orgasmic function, as dopaminergic neurons facilitate the central ejaculatory reflex.13 It has been hypothesized that low T is associated with increased inhibitory tone in male genital smooth muscle cells, which subsequently contributes to delayed ejaculation.16
MALE SEXUAL DYSFUNCTION PATHOPHYSIOLOGY: ROLE OF TESTOSTERONE
Libido Dysfunction (Symptomatic Hypogonadism)
Libido plays a critical role in initiating the male sexual response cycle. Low libido is characterized by a persistent deficient desire for sexual activity. This can be experienced in isolation, as with hypoactive sexual desire disorder, or as one symptom among a cluster of problems, as in symptomatic hypogonadism. Prevalence of low libido in men is variable with studies reporting between 5 and 17% of men endorsing problems with libido and other aspects of sexual desire, and further diminishing libido with increasing age.15
The American Urologic Association (AUA) defines T deficiency as < 300 ng/dL.17 In men with T deficiency, diminished libido is a common sexual symptom. Although the exact mechanism of T’s effect on libido remains unknown, studies have shown that in men undergoing androgen deprivation therapy (ADT), libido is severely impacted with only 5% of men maintaining a high level of sexual interest.18 Moreover, many human and animal castration studies have demonstrated the connection between hypogonadism and decreased libido.8 A study on T and hypogonadism found that as T drops below a threshold of 15 nmol/L (433 ng/dL), men can start experiencing loss of libido. Interestingly, libido seems to be one of the early signs of hypogonadism as other symptoms, such as changes in sleep, concentration and mood, obesity and diabetes, and erectile dysfunction, are not observed until T levels drop below 8–12 nmol/L (231– 346 ng/dL).19 Thus, T has been linked to sexual behaviors and connecting these behaviors when an appropriate stimulus is present. As such, in men diagnosed with hypogonadism, treatment with T supplementation has been shown to improve libido along with other sexual symptoms.17 Interestingly, in eugonadal men with low libido, over-supplementation with exogenous T was not shown to improve sexual drive, suggesting that there are multiple factors underlying male hypoactive sexual desire.17
Erectile Dysfunction
Erectile dysfunction (ED) is defined as, “an impairment in the arousal phase of [the male] sexual response” with “consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction, including satisfactory sexual performance.”20
The prevalence of ED has been widely reported by a variety of sources. Approximately 20 percent of adult men are reported to have ED.21
ED is typically classified as psychogenic or organic.22 The pathogenesis of ED is multifactorial and can involve multiple underlying disturbances, including vasculogenic, neurogenic, hormonal, and/or medication-induced.
Although most men with ED do not have hypogonadism, ED has been shown to be related to low T levels in some cases. It has been postulated that T may exert local effects to mediate erections based on studies demonstrating fluctuations in serum and corporal T levels during erection.23 Studies have shown that once T drops below a threshold of roughly 230 ng/dL, men can begin to experience ED.21 This is particularly relevant for men undergoing ADT, for whom ED is a well-established potential side effect. Further research is being undertaken to better understand the mechanisms by which hypogonadism affects erectile function.
Ejaculatory Dysfunction
Disorders of ejaculation arise when a man does not have control of ejaculation and if there is distress by the man or sexual partner related to ejaculation.24 Based on when and if ejaculation occurs it can be classified as retrograde ejaculation, premature ejaculation, delayed ejaculation, or failure of ejaculation/anejaculation.
The AUA and Sexual Medicine Society of North America (SMSNA) 2020 guideline on disorders of ejaculation primarily details premature and delayed ejaculation. It defines premature ejaculation (PE) as, “poor ejaculatory control, associated bother, and ejaculation within about 2 minutes of the initiation of penetrative sex that has been present since sexual debut.”24
The epidemiology of PE has been challenging to capture due to the confounding factors of perceived PE and normal ejaculation latency time. Thus, although 30% of men have self-reported PE, most men have ejaculation latency times greater than two minutes.25 In turn, the actual prevalence of PE for those having distress is likely around 5%, but this does not discount that man with PE experience substantial distress.25 The exact pathophysiology of PE is not known. However, similar to ED, the hypothesized risk factors can be psychologic, neurologic, hormonal, and medication-related.
The understanding of the effect of T on ejaculatory response is limited, but some studies have shown that higher T levels are correlated with premature ejaculation while lower levels are associated with delayed ejaculation in humans.26 A randomized controlled trial of testosterone replacement therapy (TRT) in hypogonadal men found improvements in ejaculatory function, although perceived bother remained unchanged.27 Additionally, there is evidence to suggest that T may act on peripheral and central pathways that impact ejaculatory response time by increasing arousal, regulating CNS effects, and changing seminal fluid volume.8
In contrast to PE, some men may experience delayed ejaculation (DE), defined as, “lifelong, consistent, bothersome inability to achieve ejaculation, or excessive latency of ejaculation, despite adequate sexual stimulation and desire to ejaculate.”25
The epidemiology of DE is similarly difficult to capture as DE often exists concurrently with low libido or ED and is therefore underreported. According to the Global Survey of Sexual Attitudes and Beliefs, approximately 14% of men aged 40–80 years old reported difficulty attaining orgasm.25
The pathophysiology of DE can be related to problems with sexual stimulation resulting in complications with emission and expulsion. Risk factors that contribute to DE are increasing age, medications, drugs, or neurologic suppression of the normal CNS arousal responses that produce sexual climax, ED, lower urinary tract symptoms, hypothyroidism, and low serum T. In one systematic review, low T levels were significantly associated with mild to moderate DE and a history of hypogonadism doubled a man’s relative risk for DE.
CLINICAL EVALUATION OF LOW TESTOSTERONE
Men presenting with issues related to sexual function should undergo a comprehensive evaluation, including medical, surgical, and social history, medication reconciliation, physical examination, and laboratory/adjunct studies as indicated.
-History
-Physical Examination
-Laboratory Tests
-Other Studies
TREATMENT OPTIONS FOR MALE SEXUAL DYSFUNCTION
Interest in TRT has increased dramatically over the past decade and has been a topic of much debate among the FDA, general practitioners, and the urologic community. In general, the AUA/SMSNA guidelines state that TRT can be safely used for adult-onset hypogonadism with careful monitoring of treatment efficacy and side effects.33
Low Libido
Meta-analyses investigating the effect of TRT on male sexual function have demonstrated variable improvements in libido. In these studies, TRT led to reported improvements specifically in hypogonadal men, with no change in libido for eugonadal men.32 Furthermore, the benefits of TRT were found to be greater in men with lower baseline levels of T (< 288 ng/dL).35 Although the literature suggests that TRT can improve libido in hypogonadal men, some studies have shown no significant difference in sexual satisfaction after TRT.36
Erectile Dysfunction
In hypogonadal men, TRT has been shown to improve responses to PDE5 inhibitors (PDE5i) for ED.37 Several randomized controlled trials and systematic reviews of hypogonadal men with ED have shown that PDE5i therapy in conjunction with TRT is more effective in improving ED than PDE5i therapy or TRT alone.24,28 Therefore, the AUA recommends that urologists inform hypogonadal men with ED that PDE5i therapy may be augmented by TRT.24
While TRT in hypogonadal men may optimize the efficacy of other ED treatments by restoring normal T levels, there is not adequate data to support combining TRT with other ED treatments.
Similarly, TRT is not recommended as a monotherapy for ED.30
Ejaculatory Disorders
Some studies have shown the benefits of TRT on ejaculatory function in hypogonadal men.38 AUA/SMSNA guidelines on ejaculatory disorders state that clinicians can offer TRT in men with DE and T deficiency.39
It is important to note that there is no evidence-based target T level for hypogonadal men with DE, but a T level at or above the 50th percentile (>500– 550 ng/dL) is recommended unless symptoms improve at lower T levels. If TRT is to help with DE symptoms, clinical improvements are typically observed within 90 days of achieving eugonadal T levels. TRT is not indicated in eugonadal men with DE per AUA/SMSNA guidelines.40
CONSIDERATIONS FOR SPECIAL POPULATIONS
While the clinical evaluation will be largely the same for any man presenting with sexual dysfunction, it is prudent to consider several specific circumstances that may alter the clinician’s approach to evaluating concerns of low T.
Men with Medical Chronic Health Conditions
Adult-onset hypogonadism (AOH) occurs more frequently in men who have a history of chronic disease.41 In particular, metabolic syndrome, obesity, and renal failure are some of the most common conditions associated with AOH.3,41
Metabolic syndrome is a collection of risk factors for heart disease, stroke, and type 2 diabetes, defined as high blood pressure, increased fasting glucose, central obesity, and dyslipidemia.42 In the United States, the incidence of metabolic syndrome has steadily increased with over 34% of adults diagnosed with the disorder and a 38% incidence of obesity among American men.43 Metabolic syndrome can cause secondary hypogonadism for a variety of reasons. For obese men, in particular, aromatization of T in adipose cells leads to higher physiologic levels of estrogen and resultant low libido, ED, and ejaculatory dysfunction in these men.41
Renal failure has a similar effect on the hypothalamic–pituitary–gonadal axis. While hypogonadism in renal failure is again multifactorial, it has been demonstrated that renal failure causes decreased production of LH and decreased prolactin clearance, both of which hinder T production.44 Studies have shown that hypogonadism is associated with increased morbidity and mortality in men with renal failure, due to systemic effects of low T such as anemia, reduced bone density and muscle mass, and premature cardiovascular disease.35 Although the risk–benefit ratio is controversial, in appropriately selected patients with renal failure, TRT has been shown to help normalize hormonal parameters, decrease medical morbidity, and improve sexual dysfunction.45
Men After Radical Prostatectomy
Pelvic surgery, and specifically radical prostatectomy, can impact erectile function, ejaculatory function, and orgasmic function to varying degrees depending on the patient’s preoperative baseline as well as the surgical approach.
In treating men who present with low T after radical prostatectomy, it is important to understand the theoretical risk of TRT on prostate cancer recurrence. Presently, both the AUA and European Association of Urology (EAU) have posited that the current literature does not demonstrate clear evidence connecting T to the development of prostate cancer.17,40 That being said, current practice guidelines recommend considering TRT postprostatectomy only in those men with favorable pathology (ie. negative margins, negative seminal vesicle involvement, negative lymph nodes) who have undetectable postoperative PSA levels.15 This is based on a series of studies demonstrating that in patients started on TRT who had undergone radical prostatectomy with undetectable postoperative PSA levels, there was no rise in PSA or recurrence of prostate cancer.36,46,47 For men on active surveillance, the literature suggests that TRT is not associated with the progression of prostate cancer in men with low volume and low-to-moderate-grade cancer when used for a limited amount of time.48 TRT may be harmful in men with advanced diseases who are on active surveillance protocols.49
Overall, it is essential that the clinician engages in shared-decision making with the patient the risks and benefits of TRT when treating symptomatic hypogonadal men with a history of prostate cancer.
Transgender Patients
Transgender patients pose unique work-up and treatment considerations as the hormonal milieu has been medically and/or surgically altered depending on the patient’s stage of transition.
For transgender men (female-to-male transition), the goal of gender affirmation hormonal therapy is to increase serum T levels to a male appropriate range and suppress estrogen levels. This is accomplished with both medical TRT (target physiologic T level of 300–1000 ng/dL) and surgical estrogen suppression (ie. bilateral oophorectomy). TRT can be delivered parenterally or transdermally, using testosterone cypionate, testosterone undecanoate, or testosterone gel or patch, with regular laboratory monitoring.50
As with cisgender men undergoing TRT, transgender men experience phenotypic and neuropsychiatric changes. In regards to sexual function, TRT most notably can cause increased libido and irreversible clitoral hypertrophy (in patients who have not yet undergone masculinizing genital gender affirmation surgery). Erectile function is dependent on the creation of a neophallus and implantation of an implantable penile prosthesis.
For transgender women (male-to-female transition), hormonal therapy involves androgen deprivation and estrogen supplementation. Androgen deprivation is achieved medically with GnRH analogs, spironolactone, or cyproterone acetate and surgically with bilateral orchiectomy.43 Estrogen is typically administered transdermally to minimize the cardiovascular risks associated with oral estrogen therapy.
It is important to note that removal of the prostate and seminal vesicles is not a standard procedure in feminizing genital gender affirmation surgery. As a result, transgender women can still be at risk for prostate cancer. For urologists taking care of these patients, the World Professional Association for Transgender Health (WPATH) recommends using current prostate cancer screening guidelines for cisgender men regarding age and risk stratification when counseling transgender women.51 Importantly, WPATH recommends that the PSA upper threshold of normal in transgender women should be set at 1 ng/mL.46 This recommendation was established based on evidence that a biopsy positive for prostate cancer despite a low PSA value is more common in the setting of T deficiency, which is akin to the hormonal status of transgender women.46 Finally, WPATH advises transvaginal prostate palpation over DRE in patients who have undergone gender affirmation surgery given the altered anatomy.46
Logan B. Galansky, MD, Jason A. Levy, DO, MS, Arthur L. Burnett, MD, MBA
INTRODUCTION
Male sexual function involves a complex interplay between hormonal, anatomic, and neuropsychologic functions and mediators. At the basis of any discussion surrounding normal and abnormal male sexual function is the “male sexual hormone,” testosterone (T). Hypogonadism, defined broadly as testicular failure with androgen deficiency, can disrupt the male sexual response cycle as well as normal systemic physiology. The resulting signs and symptoms can include decreased libido, erectile dysfunction, ejaculatory dysfunction, infertility, fatigue, decreased bone density, decreased lean body mass, increased body fat, and sleep disturbances.1
The most widely accepted model of the human sexual response cycle was developed by Masters and Johnson in 1996. They described a four-stage linear process through the phases of arousal, plateau, orgasm, and resolution.1 Some frameworks, such as that proposed by Singer Kaplan, also include a desire phase which precedes the arousal phase.2
For men, the corresponding physiologic processes to the sexual response cycle are libido and sexual desire, arousal and erection, and ejaculation and orgasm. These physiologic functions are mediated by central and peripheral nervous system pathways, end-organ motor and sensory mechanisms, and molecular signaling pathways of the vascular system.
*Basics of Testosterone
*Role of Testosterone in Male Sexual Anatomy Development
MALE SEXUAL FUNCTION PHYSIOLOGY: ROLE OF TESTOSTERONE
Physiologic Mechanisms
Despite numerous studies investigating the physiology of the male sexual response cycle, the exact role of T in mediating the steps of the process remains incompletely known. However, the literature suggests that T is key in coordinating the processing of sexual libido, the mechanics of erections, and ejaculatory function.
The first stage of the sexual response cycle involves sexual desire and libido. Sexual desire is influenced by many factors, including psychosocial, cultural, and situational, whereas libido is a biologic response directly related to T levels. Mediation of libido by T occurs in the central nervous system. Studies have shown expression of the androgen receptor in key brain areas, including the amygdala, preoptic area, and paraventricular nucleus of the hypothalamus.10
It has also been demonstrated that T is involved in the physiology of erections, most likely through its influence on molecular mediators of erectile function, formation of penile architecture, and activity of smooth muscle pathways.8 T has been shown to influence enzymatic activity in the corpora cavernosa that is responsible for both erection and detumescence.8 In hypogonadal animal models, T regulates the formation of molecules involved with erection, namely nitric oxide (NO), RhoA-ROCK, and PDE5.8 Castration models have also demonstrated the downregulation of the NO/cyclic guanosine monophosphate(cGMP) pathway in conjunction with other T-dependent biologic effects, causing smooth muscle and endothelial apoptosis and lipofibrosis of the penile corpora cavernosa that results in corporal venoocclusive dysfunction.11
The neural networks involved in ejaculation include both peripheral pelvic and genital nerves as well as galaninergic neurons in the central spinal cord.12 It has been suggested that the formation of galaninergic neurons is at least partially androgen-mediated, as studies of female and male cadavers show a greater density of galaninergic neurons in the L3–L4 segments of male spinal cords.13 Lesions to these structures have been associated with ejaculatory failure despite penile stimulation.13 The ejaculatory reflex is coordinated by neuromuscular mediators in the hypothalamic nuclei, specifically serotoninergic and dopaminergic neurons, responsible for inhibition and promotion, respectively.14 In the peripheral nervous system, emission and expulsion are then controlled by sympathetic and parasympathetic pathways.15 In rat models and some human studies examining ejaculatory dysfunction, T deficiency has been associated with decreased dopaminergic response, leading to a delay in orgasmic function, as dopaminergic neurons facilitate the central ejaculatory reflex.13 It has been hypothesized that low T is associated with increased inhibitory tone in male genital smooth muscle cells, which subsequently contributes to delayed ejaculation.16
MALE SEXUAL DYSFUNCTION PATHOPHYSIOLOGY: ROLE OF TESTOSTERONE
Libido Dysfunction (Symptomatic Hypogonadism)
Libido plays a critical role in initiating the male sexual response cycle. Low libido is characterized by a persistent deficient desire for sexual activity. This can be experienced in isolation, as with hypoactive sexual desire disorder, or as one symptom among a cluster of problems, as in symptomatic hypogonadism. Prevalence of low libido in men is variable with studies reporting between 5 and 17% of men endorsing problems with libido and other aspects of sexual desire, and further diminishing libido with increasing age.15
The American Urologic Association (AUA) defines T deficiency as < 300 ng/dL.17 In men with T deficiency, diminished libido is a common sexual symptom. Although the exact mechanism of T’s effect on libido remains unknown, studies have shown that in men undergoing androgen deprivation therapy (ADT), libido is severely impacted with only 5% of men maintaining a high level of sexual interest.18 Moreover, many human and animal castration studies have demonstrated the connection between hypogonadism and decreased libido.8 A study on T and hypogonadism found that as T drops below a threshold of 15 nmol/L (433 ng/dL), men can start experiencing loss of libido. Interestingly, libido seems to be one of the early signs of hypogonadism as other symptoms, such as changes in sleep, concentration and mood, obesity and diabetes, and erectile dysfunction, are not observed until T levels drop below 8–12 nmol/L (231– 346 ng/dL).19 Thus, T has been linked to sexual behaviors and connecting these behaviors when an appropriate stimulus is present. As such, in men diagnosed with hypogonadism, treatment with T supplementation has been shown to improve libido along with other sexual symptoms.17 Interestingly, in eugonadal men with low libido, over-supplementation with exogenous T was not shown to improve sexual drive, suggesting that there are multiple factors underlying male hypoactive sexual desire.17
Erectile Dysfunction
Erectile dysfunction (ED) is defined as, “an impairment in the arousal phase of [the male] sexual response” with “consistent or recurrent inability to attain and/or maintain penile erection sufficient for sexual satisfaction, including satisfactory sexual performance.”20
The prevalence of ED has been widely reported by a variety of sources. Approximately 20 percent of adult men are reported to have ED.21
ED is typically classified as psychogenic or organic.22 The pathogenesis of ED is multifactorial and can involve multiple underlying disturbances, including vasculogenic, neurogenic, hormonal, and/or medication-induced.
Although most men with ED do not have hypogonadism, ED has been shown to be related to low T levels in some cases. It has been postulated that T may exert local effects to mediate erections based on studies demonstrating fluctuations in serum and corporal T levels during erection.23 Studies have shown that once T drops below a threshold of roughly 230 ng/dL, men can begin to experience ED.21 This is particularly relevant for men undergoing ADT, for whom ED is a well-established potential side effect. Further research is being undertaken to better understand the mechanisms by which hypogonadism affects erectile function.
Ejaculatory Dysfunction
Disorders of ejaculation arise when a man does not have control of ejaculation and if there is distress by the man or sexual partner related to ejaculation.24 Based on when and if ejaculation occurs it can be classified as retrograde ejaculation, premature ejaculation, delayed ejaculation, or failure of ejaculation/anejaculation.
The AUA and Sexual Medicine Society of North America (SMSNA) 2020 guideline on disorders of ejaculation primarily details premature and delayed ejaculation. It defines premature ejaculation (PE) as, “poor ejaculatory control, associated bother, and ejaculation within about 2 minutes of the initiation of penetrative sex that has been present since sexual debut.”24
The epidemiology of PE has been challenging to capture due to the confounding factors of perceived PE and normal ejaculation latency time. Thus, although 30% of men have self-reported PE, most men have ejaculation latency times greater than two minutes.25 In turn, the actual prevalence of PE for those having distress is likely around 5%, but this does not discount that man with PE experience substantial distress.25 The exact pathophysiology of PE is not known. However, similar to ED, the hypothesized risk factors can be psychologic, neurologic, hormonal, and medication-related.
The understanding of the effect of T on ejaculatory response is limited, but some studies have shown that higher T levels are correlated with premature ejaculation while lower levels are associated with delayed ejaculation in humans.26 A randomized controlled trial of testosterone replacement therapy (TRT) in hypogonadal men found improvements in ejaculatory function, although perceived bother remained unchanged.27 Additionally, there is evidence to suggest that T may act on peripheral and central pathways that impact ejaculatory response time by increasing arousal, regulating CNS effects, and changing seminal fluid volume.8
In contrast to PE, some men may experience delayed ejaculation (DE), defined as, “lifelong, consistent, bothersome inability to achieve ejaculation, or excessive latency of ejaculation, despite adequate sexual stimulation and desire to ejaculate.”25
The epidemiology of DE is similarly difficult to capture as DE often exists concurrently with low libido or ED and is therefore underreported. According to the Global Survey of Sexual Attitudes and Beliefs, approximately 14% of men aged 40–80 years old reported difficulty attaining orgasm.25
The pathophysiology of DE can be related to problems with sexual stimulation resulting in complications with emission and expulsion. Risk factors that contribute to DE are increasing age, medications, drugs, or neurologic suppression of the normal CNS arousal responses that produce sexual climax, ED, lower urinary tract symptoms, hypothyroidism, and low serum T. In one systematic review, low T levels were significantly associated with mild to moderate DE and a history of hypogonadism doubled a man’s relative risk for DE.
CLINICAL EVALUATION OF LOW TESTOSTERONE
Men presenting with issues related to sexual function should undergo a comprehensive evaluation, including medical, surgical, and social history, medication reconciliation, physical examination, and laboratory/adjunct studies as indicated.
-History
-Physical Examination
-Laboratory Tests
-Other Studies
TREATMENT OPTIONS FOR MALE SEXUAL DYSFUNCTION
Interest in TRT has increased dramatically over the past decade and has been a topic of much debate among the FDA, general practitioners, and the urologic community. In general, the AUA/SMSNA guidelines state that TRT can be safely used for adult-onset hypogonadism with careful monitoring of treatment efficacy and side effects.33
Low Libido
Meta-analyses investigating the effect of TRT on male sexual function have demonstrated variable improvements in libido. In these studies, TRT led to reported improvements specifically in hypogonadal men, with no change in libido for eugonadal men.32 Furthermore, the benefits of TRT were found to be greater in men with lower baseline levels of T (< 288 ng/dL).35 Although the literature suggests that TRT can improve libido in hypogonadal men, some studies have shown no significant difference in sexual satisfaction after TRT.36
Erectile Dysfunction
In hypogonadal men, TRT has been shown to improve responses to PDE5 inhibitors (PDE5i) for ED.37 Several randomized controlled trials and systematic reviews of hypogonadal men with ED have shown that PDE5i therapy in conjunction with TRT is more effective in improving ED than PDE5i therapy or TRT alone.24,28 Therefore, the AUA recommends that urologists inform hypogonadal men with ED that PDE5i therapy may be augmented by TRT.24
While TRT in hypogonadal men may optimize the efficacy of other ED treatments by restoring normal T levels, there is not adequate data to support combining TRT with other ED treatments.
Similarly, TRT is not recommended as a monotherapy for ED.30
Ejaculatory Disorders
Some studies have shown the benefits of TRT on ejaculatory function in hypogonadal men.38 AUA/SMSNA guidelines on ejaculatory disorders state that clinicians can offer TRT in men with DE and T deficiency.39
It is important to note that there is no evidence-based target T level for hypogonadal men with DE, but a T level at or above the 50th percentile (>500– 550 ng/dL) is recommended unless symptoms improve at lower T levels. If TRT is to help with DE symptoms, clinical improvements are typically observed within 90 days of achieving eugonadal T levels. TRT is not indicated in eugonadal men with DE per AUA/SMSNA guidelines.40
CONSIDERATIONS FOR SPECIAL POPULATIONS
While the clinical evaluation will be largely the same for any man presenting with sexual dysfunction, it is prudent to consider several specific circumstances that may alter the clinician’s approach to evaluating concerns of low T.
Men with Medical Chronic Health Conditions
Adult-onset hypogonadism (AOH) occurs more frequently in men who have a history of chronic disease.41 In particular, metabolic syndrome, obesity, and renal failure are some of the most common conditions associated with AOH.3,41
Metabolic syndrome is a collection of risk factors for heart disease, stroke, and type 2 diabetes, defined as high blood pressure, increased fasting glucose, central obesity, and dyslipidemia.42 In the United States, the incidence of metabolic syndrome has steadily increased with over 34% of adults diagnosed with the disorder and a 38% incidence of obesity among American men.43 Metabolic syndrome can cause secondary hypogonadism for a variety of reasons. For obese men, in particular, aromatization of T in adipose cells leads to higher physiologic levels of estrogen and resultant low libido, ED, and ejaculatory dysfunction in these men.41
Renal failure has a similar effect on the hypothalamic–pituitary–gonadal axis. While hypogonadism in renal failure is again multifactorial, it has been demonstrated that renal failure causes decreased production of LH and decreased prolactin clearance, both of which hinder T production.44 Studies have shown that hypogonadism is associated with increased morbidity and mortality in men with renal failure, due to systemic effects of low T such as anemia, reduced bone density and muscle mass, and premature cardiovascular disease.35 Although the risk–benefit ratio is controversial, in appropriately selected patients with renal failure, TRT has been shown to help normalize hormonal parameters, decrease medical morbidity, and improve sexual dysfunction.45
Men After Radical Prostatectomy
Pelvic surgery, and specifically radical prostatectomy, can impact erectile function, ejaculatory function, and orgasmic function to varying degrees depending on the patient’s preoperative baseline as well as the surgical approach.
In treating men who present with low T after radical prostatectomy, it is important to understand the theoretical risk of TRT on prostate cancer recurrence. Presently, both the AUA and European Association of Urology (EAU) have posited that the current literature does not demonstrate clear evidence connecting T to the development of prostate cancer.17,40 That being said, current practice guidelines recommend considering TRT postprostatectomy only in those men with favorable pathology (ie. negative margins, negative seminal vesicle involvement, negative lymph nodes) who have undetectable postoperative PSA levels.15 This is based on a series of studies demonstrating that in patients started on TRT who had undergone radical prostatectomy with undetectable postoperative PSA levels, there was no rise in PSA or recurrence of prostate cancer.36,46,47 For men on active surveillance, the literature suggests that TRT is not associated with the progression of prostate cancer in men with low volume and low-to-moderate-grade cancer when used for a limited amount of time.48 TRT may be harmful in men with advanced diseases who are on active surveillance protocols.49
Overall, it is essential that the clinician engages in shared-decision making with the patient the risks and benefits of TRT when treating symptomatic hypogonadal men with a history of prostate cancer.
Transgender Patients
Transgender patients pose unique work-up and treatment considerations as the hormonal milieu has been medically and/or surgically altered depending on the patient’s stage of transition.
For transgender men (female-to-male transition), the goal of gender affirmation hormonal therapy is to increase serum T levels to a male appropriate range and suppress estrogen levels. This is accomplished with both medical TRT (target physiologic T level of 300–1000 ng/dL) and surgical estrogen suppression (ie. bilateral oophorectomy). TRT can be delivered parenterally or transdermally, using testosterone cypionate, testosterone undecanoate, or testosterone gel or patch, with regular laboratory monitoring.50
As with cisgender men undergoing TRT, transgender men experience phenotypic and neuropsychiatric changes. In regards to sexual function, TRT most notably can cause increased libido and irreversible clitoral hypertrophy (in patients who have not yet undergone masculinizing genital gender affirmation surgery). Erectile function is dependent on the creation of a neophallus and implantation of an implantable penile prosthesis.
For transgender women (male-to-female transition), hormonal therapy involves androgen deprivation and estrogen supplementation. Androgen deprivation is achieved medically with GnRH analogs, spironolactone, or cyproterone acetate and surgically with bilateral orchiectomy.43 Estrogen is typically administered transdermally to minimize the cardiovascular risks associated with oral estrogen therapy.
It is important to note that removal of the prostate and seminal vesicles is not a standard procedure in feminizing genital gender affirmation surgery. As a result, transgender women can still be at risk for prostate cancer. For urologists taking care of these patients, the World Professional Association for Transgender Health (WPATH) recommends using current prostate cancer screening guidelines for cisgender men regarding age and risk stratification when counseling transgender women.51 Importantly, WPATH recommends that the PSA upper threshold of normal in transgender women should be set at 1 ng/mL.46 This recommendation was established based on evidence that a biopsy positive for prostate cancer despite a low PSA value is more common in the setting of T deficiency, which is akin to the hormonal status of transgender women.46 Finally, WPATH advises transvaginal prostate palpation over DRE in patients who have undergone gender affirmation surgery given the altered anatomy.46
