Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. Before we can discuss the impact of medical illness and disease on sexual functioning, it is important to define “disease” as a pathological process, deviation from a biological norm [1]. This definition, however, is very limited without functional or psychosocial context. As clinicians we strive to help bring our patient as close to “health” as possible and need to consider the wide range of consequences a disease might have on an individual and their ability to function in their personal, societal, work, and cultural context. The International Classification of Functioning (ICF) is a useful framework to use when addressing a patient’s disease state because it addresses all aspects of functioning and integrates the physical, mental, and social aspects of disease. The main broad components that are considered are body function, activities, and participation. The dynamic interplay between personal, environmental factors and health conditions are critical elements that drive the outcome.

The most benign disease course is a self-limited illness which has a restricted course or can be cured. Other times the illness may present as a single occurrence or result in significant life altering disability (e.g., spinal cord injury or cerebrovascular accident). Chronic illnesses may have a prolonged gradual decline (e.g., dementia), a trajectory with gradual decline, punctuated by episodes of acute deterioration and some recovery (e.g., multiple sclerosis); or a course with steadily progressive trajectory (e.g., amyotrophic lateral sclerosis).

There is generally a positive relationship between informed sexual education, empowerment and sexual activity [2]. Depending on the diagnosis and the trajectory of the illness, the accompanying sexual needs may also change over time. Health care professionals must remain vigilant to assess, monitor, and assist their patients in maintaining sexual health during the entire disease process.

Over the last century, Americans have experienced dramatic gains in life expectancy. As the diagnosis and management of diseases improve, there is a growing prevalence of chronic diseases. Not only does the illness often result in its own disability, but the treatment of the primary disease often results in secondary health conditions. For example, an individual treated for cancer may develop neuropathy, incontinence, and obesity as a product of the treatment. The resultant multi-morbidity has a cumulative impact on exercise capacity, quality of life, and survival as well as interest in and ability to have and enjoy sexual activity [3].

Chronic illness and its treatments usually have a negative impact on relationships and sexual satisfaction of both patients and partners, either directly as a result of the illness itself or indirectly due to secondary physical, functional, or psychological ramifications. Individuals with chronic illness may develop misconceptions about their ability and the safety of having sex. They may either feel that their illness precludes sexual activity or have experienced sexual “failure” (e.g., erectile dysfunction, anorgasmia) that then reinforces perception of their inability to engage in meaningful sexual activity.

The effects of chronic illness on sexuality can be classified into biopsychosocial categories [4]. Nonspecific systemic causes limiting sexual activity include reduced cardiovascular and pulmonary reserve, weakness, fatigue, or pain. Anemia and deconditioning are common to chronic illnesses and amplify these problems. Treatments such as surgery, radiation therapy, chemotherapy, and immunotherapy can result in exhaustion, nausea, loss of appetite, and dehydration. When treatment is time limited (e.g., radiation therapy for cancer) these symptoms are expected to improve. However, in many illnesses, the gradual disease progression is associated with increasing symptom burden.

The medical illness and its treatment often directly interfere with the ability to experience arousal and orgasm. Neurological and vascular effects such as neuropathy, accelerated atherosclerosis, and endothelial dysfunction negatively affect ability to appreciate sexual stimulation and stymie the physiological response of arousal. Bladder incontinence due to urinary stress incontinence or detrusor instability can cause shame and embarrassment and interferes with sexual motivation and expression. Similarly, bowel incontinence from neurological or surgical sequelae can have a devastating impact on sexual engagement.

Endocrine abnormalities such as alterations in gonadal hormones result in loss of sexual interest, erectile dysfunction, retrograde and premature ejaculation in men and loss of libido, hot flashes, vaginal tightness or dryness, and anorgasmia in women. Furthermore, medications used to treat the primary and associated conditions may impair sexual function.

The expression and practice of sexuality are affected by self-esteem, body image, and interpersonal relationships. Body image can be negatively affected by medical illness and loss or disfigurement of parts of the body. Surgical procedures and medical treatments may result in altered bodily appearance (e.g., scarring, amputation, tracheostomy, mastectomy, ostomy, hair loss). Bodily changes and the loss of a body part, such as a limb, the uterus, ovaries, or genitalia, can have a profound impact on self-esteem, defined as an individual’s self-perception of his/her abilities, skills, and overall qualities that guides cognitive processes and behaviors. Individuals with medical illness can experience depression, fatigue, pain, stress, and anxiety which may further contribute to sexual dysfunction. The psychological distress that often accompanies altered body image causes a person to feel devalued and incomplete. This situation can limit patients’ or their partners’ sexual satisfaction and their motivation to engage in intimacy and sexual activities.

Fear of sexual intercourse is comorbid with decreased desire, satisfaction, and sexual frequency among male and female patients. Patients and their partner may feel apprehensive about engaging in sex fearing that sexual activity may be medically contraindicated or may hurt the partner experiencing the medical illness. In individuals with heart disease, sexual partners may fear that the physical exertion of intercourse could place too great of a strain on the heart and result in sudden death during sex [5].

Chronic medical illness is consistently associated with an increased prevalence of anxiety, depressive symptoms and disorders [6]. Patients with chronic medical illnesses have been found to have two- to threefold higher rates of major depression compared with age- and gender-matched primary care patients. Depression can result from the either direct biologic effects of chronic medical illness (e.g., multiple sclerosis) or be a result of the functional changes and stressors resulting from their medical illness. Not only is depression a common consequence of chronic medical illness, but it is itself a risk factor for the development of chronic illnesses such as diabetes and coronary heart disease and adversely affects the course, complications, and management of chronic medical illness. Risk factors for depression include worsening condition, unrelieved pain, functional impairment, social isolation, and history of mood disorders [7].

Even though views on sexuality vary enormously between different cultures and religions, many societies are uncomfortable with the notion that medically compromised and individuals with disabilities have sexual needs and desires. Pervasive social and cultural norms, standards, and expectations create negative attitudes toward the disabled population and perpetuate a culture of undesirability and inability [8]. Current issues within the sexuality field and the disability movement include the misconceptions about sexual desires and potential expression of sexuality from individuals with disability. Such misconceptions rooted in culture and media, have resulted in the sexual concerns of individuals with disabilities being ignored [9]. Such cultural and societal norms further constrain the initiation and sexual engagement of individuals with complex medial disease and disability.

Education is vital to interrupting the cycle of stigmatization which needs to start with health care providers. However, sexuality is often overlooked by medical personnel who often do not feel comfortable addressing sexual concerns and lack knowledge regarding the impact medical illness has on sexual functioning. Furthermore, many professionals wrongly regard decline of sexual function as an inevitable consequence of ageing and disability.

Cerebrovascular diseases are the third leading cause of death and one of the major causes of long-term disability in western countries. Strokes can result in a myriad of physical, autonomic and cognitive impairments that can interfere with sexual satisfaction. Twenty to 75% of patients with stroke suffer some form of sexual dysfunction [10]. The most common sexual problems after stroke are decline in sexual desire and intercourse frequency for both genders, decline in vaginal lubrication and orgasm in females, and decline in erection and ejaculatory function in males.

Post-stroke sexual dysfunction is thought to result from multiple factors, both psychosocial (i.e., depression, anxiety, fear of stroke recurrence, loss of self-esteem, role changes) and/or organic (i.e., stroke lesion, comorbidity, and medications). Additionally, patients who have had a stroke often have comorbidities such as hypertension, diabetes mellitus, atherosclerosis that not only put them at risk for the stroke itself but also cause reduction in blood flow to end organs including genitalia.

Physical limitations were cited by a majority of patients with stroke as having a negative impact on sexual functioning. The extent of sexual dysfunction often parallels the extent of motor disability and the level of independence in activities of daily living can be used as a predictor of sexual activity after stroke [11]. Physical barriers to sexual function after stroke include spasticity, weakness, sensory loss and pain which can restrict mobility, compromise comfort, and interfere with positioning. Flexor spasms can be disruptive and cause pain. Drooling and bladder and bowel incontinence are associated with social stigma and heavily impact social acceptance, and ability to engage intimately with partners. Sensory and perceptual impairments diminish an individual’s ability to perceive pleasure with tactile stimulation. Post-stroke fatigue, manifesting as both physical and mental lack of energy, is another common symptom which can impact libido and motivation. Fatigue is likely the culmination of multiple factors, including organic brain lesion, psychosocial stress, altered sleep–wake cycles, and contributions from sedating medications. Nevertheless, nearly half of patients following stroke with no or mild physical disability also experience a decrease in libido, coital frequency, sexual arousal, orgasm, and sexual satisfaction [12].

While most individuals describe decreased sexual activity after a stroke, hypersexuality was reported in 10% of 192 stroke patients in one study [13]. This condition appears to occur in younger individuals and is most commonly associated with temporal lobe lesions but can also occur in subthalamic or bilateral thalamic infarctions [14].

Even though the sidedness of the stroke (right versus left) has not been shown to influence the extent of sexual impairments, it is clear that stroke location determines the physical and cognitive deficits that, in turn, affect sexual functioning. Patients with right sided cerebral strokes are likely to experience hemispatial neglect resulting in an inability to attend to and perceive stimuli from the contralateral side of the body or environment. Neglect can result in an individual’s inability to groom and care for one’s self as well as extinction of sexual and sensual stimuli emanating from the neglected hemi-body. Left sided lesions located in the middle cerebral artery territory can result in receptive and expressive aphasia which can have detrimental effects on ability to communicate with partners. Loss of effective communication can lead to difficulty with forming and maintaining social and sexual relationships and inability in expressing one’s sexual needs and desires.

Persons who had a stroke commonly take medications that have a dampening effect on libido and sexual performance. Many antihypertensive medications, notably beta blockers, calcium channel blockers as well as diuretics reduce libido and result in erectile dysfunction. Antidepressants that are commonly used after stroke for depression and recovery are also associated with sexual side effects.

Even though most strokes do not usually cause significant hormonal changes that influence sexual functioning, aneurysmal subarachnoid hemorrhage is associated with a high risk for hypothalamic–pituitary dysfunction, given the proximity of the pituitary gland to the arterial circle of Willis. The most common neuroendocrine changes resulting from subarachnoid hemorrhage are deficiencies in growth hormone and hypogonadism. Thus, screening of pituitary function is recommended in this patient population.

The prevalence of major depression after stroke is reported to range from 12% to 60% with an estimated pooled frequency of 33% [15, 16]. Post-stroke depression is more commonly associated with left sided lesions and can result in severe apathy and social withdrawal as well as decrease in motor disability and sexual activity.

The effects of stroke on psychological and social functioning may be equally, if not more important in the decline of sexual activity in stroke survivors. Various psychosocial factors such as changes in body image, loss of self-esteem, role changes, and spousal relationships, partner availability, and fear of suffering another stroke may become barriers to healthy sexual functioning [17]. Furthermore patients may lack privacy due to their living arrangements (such as living with a caregiver or residing in a long-term care facility) and encounter negative attitudes towards sexuality.

Sexual dysfunction is highly prevalent in individuals with chronic kidney disease (CKD), especially those receiving dialysis. The etiology of sexual dysfunction in chronic kidney disease is multifactorial: abnormalities in gonadal–pituitary system, autonomic nervous system dysfunction, endothelial dysfunction, anemia and erythropoietin deficiency, secondary hyperparathyroidism, drugs, and psychological problems have been implicated [18]. Sexual dysfunction is inversely associated with glomerular filtration rate [19] and some studies have reported improvements following renal transplantation [20] suggesting that chronic kidney disease may directly contribute to sexual dysfunction.

CKD leads to dysfunction of the hypothalamic–pituitary–gonadal axis in both sexes resulting in loss of the pulsatile release of gonadotropin-releasing hormone (GnRH), low testosterone, and elevated luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. CKD is also associated with autonomous production and reduced clearance of prolactin resulting in hyperprolactinemia which reduces gonadal responses to gonadotrophins and has been implicated in impotence, hypogonadism, and reduced desire. The severity of endocrine dysfunction is proportional to the degree of renal impairment and worsens with progression of renal disease. Decreased libido, difficulty with arousal and orgasm, erectile and ejaculatory dysfunction, lack of vaginal lubrication, menstrual irregularities, and amenorrhea are common problems in patients with CKD [21, 22]. Men with CKD experience impaired spermatogenesis, testicular atrophy, hypospermatogenesis, and infertility. Testosterone deficiency occurs in 26–66% of individuals [23]. Approximately 70–80% of men with chronic renal failure endorse ED, due to the effects of renal disease as well as comorbid vascular disease, diabetes, or uremic toxicity to the autonomic nervous system [21].

Women with CKD experience decreased libido and difficulties with arousal and orgasm. Up to 65% of women on hemodialysis report problems with sexual function, and up to 40% no longer engage in sexual intercourse [24]. Reduced ovarian function and hyperprolactinemia result in diminished estrogen production causing pubic hair loss, atrophic vaginitis, dyspareunia, and premature menopause. Menstrual irregularities with anovulation and infertility are common [25].

Treatment includes dialysis, optimization of nutritional intake, discontinuation of offending medications and correcting anemia of chronic renal disease. Vitamin D supplementation helps reduce incidence of secondary hyperparathyroidism, which promotes prolactin production. In some studies, zinc deficiency has been implicated in gonadal failure, and supplementation led to improved libido, sperm counts, and testosterone levels [26].

The administration of recombinant human erythropoietin to raise the hematocrit to 33–36% may enhance physical and sexual function as well as health-related quality of life [27].

There is some evidence that human erythropoietin administration normalizes the pituitary gonadal axis, lowering FSH, LH, and prolactin levels and raising serum testosterone [28].

A trial of hormone replacement therapy can be considered in a patient with CKD and hypogonadism. Unfortunately, testosterone supplementation in uremic men generally fails to restore libido or potency, despite normalized serum testosterone and reduced LH and FSH. Women with low estradiol levels may benefit from estradiol replacement which can be helpful in treating vaginal atrophy and dyspareunia. Women with CKD who suffer from chronic anovulation and lack of progesterone secretion can be treated with progesterone to restore menstrual cycles. Correction of hyperprolactinemia with dopaminergic agonists such as bromocriptine and cabergolide can yield improved sexual function but treatment is often limited by side effects.

Phosphodiesterase inhibitors result in improvements in sexual satisfaction and erectile dysfunction in men with CKD [26]. No single phosphodiesterase inhibitor (PDEi) has been identified as being superior in this population. Sildenafil, the most widely used agent, is mainly metabolized in the liver and excreted in the feces; therefore, its pharmacokinetics do not appear to be affected by mild to moderate renal impairment, but clearance is reduced in patients with creatinine clearance <30 mL/min [29]. Therefore, a lower starting dose is recommended for patients with creatinine clearance <30 mL/min or on hemodialysis. The occurrence of side effects is similar to that in other patients. Hypotension can be severe in a patient on hemodialysis but these effects can be limited by administering PDEi on nondialysis days [30].

Even though renal transplantation is associated with normalization of hormonal and metabolic profiles, its therapeutic effect on libido, erectile function, and sexual satisfaction remains debated [31]. Several studies suggest that rates of erectile dysfunction remain very high even after kidney transplant [32]. Sexual function after renal transplantation may be affected by graft malfunction, duration of dialysis prior to transplant, comorbid conditions, and side effects of immunosuppressive or hypertension therapy. Erectile dysfunction is caused by many other factors and thus, can be highly prevalent in patients with renal insufficiency even after kidney transplantation.

Sexual dysfunction is usually thought to be a consequence of cardiovascular disease, though ED and vaginal dryness may actually be presenting signs of heart disease [33]. As the ability to achieve erectile dysfunction is dependent on a robust vascular supply to the genitals, risk factors that compromise genital blood flow are similar to those that cause cardiovascular disease. Consequently, ED occurs commonly in individuals with occult cardiovascular and peripheral vascular disease and the degree of ED appears to correlate with the severity of cardiovascular disease [34–36]. ED and vaginal dryness may be presenting signs of heart disease and may appear 1–3 years before the onset of cardiovascular symptoms. A number of studies have estimated the interval between the onset of ED symptoms and the occurrence of coronary artery disease (CAD) symptoms as 2–3 years and a cardiovascular event as 3–5 years [37–39].

The coexistence and link between ED and CAD should prompt health care providers to inquire about the presence of one if the other has declared itself. Routine assessment of sexual problems should be a component of rehabilitation and management of patients with cardiovascular disease [33].

Patients who have experienced a cardiac event often experience physiological and psychological barriers to sexual activity including general anxiety, and fear of having angina or another myocardial infarction (MI). Fewer than 1% of myocardial infarctions occur during sexual intercourse, and only about 0.6% of sudden cardiac deaths may be related to sexual activity [40]. Even if associated with a very low absolute risk, sexual MI in patients with known cardiac disease [41].

Regular physical activity and cardiovascular risk factor modification might further reduce the risk [42, 43].

Sexual dysfunction after a myocardial infarction is estimated to occur in 50–75% of patients. Both men and women have less sexual activity and less satisfaction with sexual activity after an MI and there appear to be no gender differences in the quantity and quality of sexual activity after MI [44, 45]. Similarly, most patients with heart failure (HF) experience decreased libido, decreased sexual performance and frequency as well as a general dissatisfaction with their sexual function. ED occurs in 69.3% in patients with HF and is exceptionally high in patients with ischemic HF, with a prevalence of 81.1% [46]. A significant relation exists between a patient’s sexual function and their New York Heart Association (NYHA) functional class [47]. A patient’s exercise tolerance should be evaluated when counseling patients, as the increased exertion associated with sexual activity may increase the risk of another cardiovascular event.

The standard clinical measure of exertion is the metabolic equivalent of oxygen consumption (MET), where 1 MET is equivalent to the resting state. Sexual activity is often equated with an exercise workload of 2–3 METs in the pre-orgasmic stage and 3–4 METs during the orgasmic stage. The metabolic cost of sex in middle-aged married men is no more than 5 METS. If a person with coronary artery disease can achieve an energy expenditure of ≥3–5 METs without demonstrating ischemia during exercise testing, then the risk of an event associated with sexual activity is very low. Patients able to climb two flights of stairs without limiting symptoms and those who can complete stage II of a standard Bruce treadmill test (equivalent to 6–7 METs) are generally free of cardiovascular symptoms during sexual activity. Therefore, exercise testing is often used to assess both exercise tolerance and ability to safely return to sexual activity. The incidence of exertional angina and MI during sexual activities is believed to be reduced by revascularization and optimized medical treatment using aspirin, β-blockers, and lipid-lowering strategies [48–50].

A risk stratification algorithm was developed by the Third Princeton Consensus Panel to evaluate the degree of cardiovascular risk associated with sexual activity for men with varying degrees of cardiovascular disease. The risk stratification is also the basis for treatment recommendations of sexual dysfunction in men and women with known cardiovascular disease. Patients are assigned to three categories based on cardiovascular risk factors and exercise capacity: low, indeterminate (including those requiring further evaluation), and high risk. Those at low risk can resume sexual activity and be treated for sexual dysfunction. Most patients with cardiovascular disease are categorized as low risk and can safely resume sexual activities and receiver phosphodiesterase inhibitors for erectile dysfunction. Patients with uncertain cardiac conditions are at indeterminate risk. It is recommended that these individuals undergo further evaluation and be re-stratified into low or high risk groups before resuming sexual activity. This is often achieved by stress testing, particularly in patients with a sedentary lifestyle. Patients in the high-risk group are deemed to have a potentially significant risk associated with sexual activity, and should undergo cardiac assessment and be appropriately treated before resuming sexual activity and considered for PDE inhibitors. Patients need to be educated about the interaction of phosphodiesterase inhibitors and nitrates.

Epilepsy is a central nervous system disorder characterized by a predisposition to generate epileptic seizures which is frequently associated with cognitive, psychological, and social consequences. A significant number of individuals have some degree of sexual dysfunction, including problems with libido, arousal, and orgasm [51]. Epileptiform discharges may cause disruption of pathways in the limbic system which plays an essential role in human sexual behavior. Sexual dysfunction can be caused by recurrent seizures as well as neurological, endocrine, psychiatric, and psychosocial factors [52, 53]. The most common sexual dysfunction is hyposexuality, defined as a global reduction in sexual interest, awareness, and activity due to altered neuroendocrine regulation, and effects of antiepileptic medications [54]. Right sided temporal lobe epilepsy has also been associated with other sexual behaviors such as sexual auras, ictal orgasms, and sexual automatisms.

Endocrine abnormalities are more common in people with epilepsy due to hypothalamic dysfunction. Hypogonadotropic hypogonadism is one of the more common endocrine abnormalities described in patients with epilepsy, commonly presenting as sexual dysfunction and lower fertility rates. Seizures of temporal lobe origin are particularly associated with reproductive and endocrine abnormalities as well as sexual dysfunction, with right sided temporal lobe seizures having greater impact than left sided ones. Sexual dysfunction occurs more frequently in persons with temporal lobe epilepsy than other seizure types [55].

Males with epilepsy have been found to have an increased risk of ED of up to 57% compared to 3–9% in the general population [56] and report dissatisfaction with their sexual life [57]. Diminished libido, arousal, and orgasm have also been reported in women with epilepsy. Hirsutism, menstrual cycle irregularities, anovulatory cycles, polycystic ovarian syndrome, and premature menopause are more common than in the general population [58].

Another common complaint in females is decreased sexual interest as well as painful intercourse because of vaginal dryness and vaginismus. In fact, genital blood flow was significantly decreased in women with epilepsy compared with controls during erotic visual stimulation [59].

The contribution of the social and psychological stresses of living with epilepsy may be an important factor in the higher rates of sexual dysfunction. Poor self-esteem, fear of rejection, and fear of having seizures during intercourse may interfere with the development of normal sexual interactions and lead to avoidance of sexual activity. This can make sexual partners feel rejected resulting in relationship problems in existing relationships.

Since antiepileptic agents are known to lower serum testosterone levels and have a significant impact on sexual function, the American Academy of Neurology (AAN) issued a practice parameter advocating single-drug therapy at the lowest possible dose that effectively controls seizures.

Parkinson’s disease (PD) is a neurodegenerative disorder whose cardinal features are tremor, bradykinesia, and rigidity. Pathologically, it is characterized by a loss of nigrostriatal dopaminergic neurons and widespread accumulation of Lewy bodies. The cause of PD is probably multifactorial, with contributions from hereditary predisposition, environmental toxins, and aging. In contrast to Parkinson’s disease, Parkinson’s Plus syndrome constitutes a group of neurodegenerative disorders that have overlapping clinical symptoms of Parkinson’s disease and do not respond to dopamine. The most common Parkinson’s plus syndromes are multiple system atrophy (MSA), progressive supranuclear palsy (PSP), cortico-basal ganglionic degeneration (CBGD), and Lewy body dementia.

Parkinson’s disease is progressive causing mounting physical disability over time. Most people with PD lose independent function between 3 and 7 years after the onset of symptoms. Motor symptoms include bradykinesia, resting tremor, rigidity and akinesia, impairment of postural reflexes, and loss of fine motor skills. Non-motor symptoms include neuropsychiatric disorders such as anxiety, depression, hallucinations, impaired impulse control, cognitive impairment, and depression as well as autonomic dysfunction, which may present as gastrointestinal, urinary, and sexual disturbances. The combination of motor and non-motor symptoms in PD can result in a host of problems in sexual functioning.

Sexual dysfunction is common in patients with PD and results in depression and disruption in relationships. Males experience decreased libido, erectile dysfunction, premature or no ejaculation, and inability to achieve an orgasm. Erectile dysfunction has been reported in 54–79% of men with PD [60, 61].

Similarly, most women with PD report decreased libido and difficulties reaching orgasm [61]. Women are more likely to report vaginal tightness, loss of lubrication, involuntary urination, anxiety, and inhibition than in matched controls [62].

Loss of normal dopamine levels in the brain may be a primary cause of decreased libido in some persons with PD. Dysfunction of dopamine transmission in the reward circuit in PD is associated with anhedonia, apathy, and dysphoria which results in diminished sexual motivation and difficulty experiencing sexual pleasure and orgasm. PD can result in apathy and lack of sexual drive even in the absence of erectile dysfunction. Profound fatigue, cognitive and psychiatric factors, and hypogonadism have a profoundly negative impact on sexual drive and function. A pilot study reported that nearly 50% of the men with Parkinson’s disease studied were testosterone deficient which correlated with apathy [63]. Testosterone deficiency can cause depression, fatigue, decreased libido, and erectile dysfunction which responds to treatment with testosterone replacement therapy [64].

Depression and anxiety are common causes of sexual dysfunction and decreased motivation that can respond to antidepressants and anxiolytics.

Common autonomic manifestations of PD can affect sexual function and sense of self-worth. Sialorrhea is caused by a combination of dysphagia and head posture. It can respond to speech therapy, anticholinergic medications and botulinum toxin injections to the salivary glands. The most common cardiovascular features of PD are hypotension and orthostatic hypotension caused by loss of sympathetic innervation to end-organs. Hypotension and orthostatic hypotension can be associated with fatigue, dizziness, lightheadedness, and generalized weakness which can impact sexual motivation and energy. Sympathomimetic agents such as ephedrine and midodrine increase peripheral vascular resistance and are useful in the treatment of symptomatic hypotension. In PD, degeneration of the substantia nigra, which normally has an inhibitory effect on the micturition reflex [65, 66], leads to hyperreflexia of the detrusor muscle, with involuntary or uninhibited contractions and urinary urgency. Urinary urgency, frequency, and incontinence become more common as the disease progresses.

The treatment of PD can result in improvement in sexual dysfunction. The use of dopaminergic drugs sometimes results in improvement of sexual desire or function [67] and deep brain stimulation of the subthalamic nucleus (STN) has been found to have a small, albeit positive influence on sexual well-being [68]. Compulsive hypersexual behavior with or without mania has been described with the use of dopamine agonists as well as with therapeutic deep brain stimulation [69].

If no medical or psychological reason appears to be causing impotence, medications used for erectile dysfunction can be instituted. Phosphodiesterase inhibitors are effective treatment options for ED in patients with PD. Delayed gastrointestinal motility often seen in PD may result in delayed drug absorption of drugs and patients with MSA, in particular, may be predisposed to symptomatic hypotension as a side effect of this class of medications. Sublingual apomorphine is another therapeutic option for PD patients with ED. The action is through a dopaminergic effect in the hypothalamus and can cause nausea in some patients.

Cerebral palsy (CP) is the most common cause of physical disability in childhood with a prevalence of 1.5–3.3 per 1000 live births. It is a chronic, non-progressive disorder of movement and posture caused by abnormal brain development or damage to the immature newborn brain. Posture and movement disorders in CP are often accompanied by disturbances in perception, cognition, communication, and behavior, as well as epilepsy.

Cerebral palsy can affect the motor system, resulting in weakness and spasticity. This can result in limb contractures, hip dislocations and scoliosis. Oromotor weakness and incoordination can result in dysarthria, dysphagia, sialorrhea, and aspiration and may necessitate a feeding tube placement. Motor and expressive language impairments can result in significant social and communication difficulties. Behavioral disorders including attention deficit hyperactivity disorder, frustration, aggression, and mood disturbances are more prevalent in children with CP. All of these impairments can have a negative impact on self-perception and self-esteem and interfere with social integration, peer interactions, and formation of romantic and sexual relationships.

The development of secondary sexual characteristics in children with cerebral palsy starts earlier and ends later compared with children in the general population. In girls, menarche occurs an average of 1.3 years later than for the general population [70].

Adolescents and young adults with CP exhibit normal psychosexual development with similar sexual interests as able bodied peers. Despite their interest, they are less likely to attain sexual milestones and attain these milestones at a later age than their peers. At the age of 16–20 years, adolescents with CP are less focused on sexuality and have significantly less sexual experience compared with their age matched peers [71].

Young adults with CP not only have to deal with the difficulties of finding their sexual identity and maturing as sexual and social beings, but they have to overcome the additional hurdle of learning to overcome physical and emotional barriers. It is unclear what effect motor functioning has on the likelihood of forming intimate sexual relationships though ambulatory individuals are more likely to engage in intercourse and are more likely to experience sexual satisfaction than their non-ambulatory counterparts [72, 73].

Children and adolescent with CP have difficulty with achieving social milestones as they mature and transition into adulthood. They have fewer friendships, exhibit fewer social behaviors, and are more isolated and victimized by their peers than classmates without disability [74, 75]. Furthermore, dependence on parents and caregivers can make it difficult for children with cerebral palsy to transition into adulthood and assume the adult roles that are important for building relationships. When engaging in intimate relationships, adults with physical disabilities worry about receiving personal care from potential partners. Their dependence may make them feel different from their peers and more vulnerable to physical, emotional and financial abuse. Psychological adjustment, self-efficacy, and sexual self-esteem are important factors in the development of social and sexual relationships. In fact, high sexual self-esteem can facilitate meeting and engaging with people, flirting and dating, resulting in a higher likelihood of engaging in romantic and sexual relationships.

It is important for family members, care providers, and other contacts to facilitate discussions about sexual questions and interests and provide acceptance of a child’s maturing sexual identity.

Spinal cord injury (SCI) is a traumatic, life-altering event that is usually associated with loss of motor and sensory function, disruption in autonomic innervation resulting in sexual impairment. The normal sexual response depends on a very intricate interaction between the peripheral somatic and autonomic nervous system, spinal reflexes, and the brain. The location and extent of a spinal cord injury as well as remaining neurological function are major determinants of sexual functioning and can be used to predict sexual responses.

For men, the ability to experience erections is preserved more frequently than the ability to experience ejaculation [76]. A study examining outcomes in 193 men at least 10 years after their spinal cord injury reported that 75% reported achieving an erection, 44% reported being able to achieve ejaculation [77]. There are two areas in the spinal cord that play a central role in controlling sexual function. The sacral cord (S2–4) mediates reflex erections which are erections elicited by penile stimulation. These erections occur reflexively and may or may not be associated with arousal. Genital stimulation triggers reflexogenic erections and the erections last as long as the stimulus is delivered. The erections in spinal cord injured males are usually less rigid and may not allow penetration. Men are generally able to achieve reflex erection if their spinal cord injury spares the sacral spinal cord segments. Largely, injuries higher in the spinal cord predict better likelihood for achieving reflex erections while injuries to the sacral cord segments and the cauda equine impair reflex activity and abolish reflex erection [78].

On the other hand, psychogenic erections are mediated by the brain and depend on cerebral and spinal cord integrity extending to the hypogastric plexus (T10 to L2 spinal cord levels). Lesions above T10 substantially impair the capacity for psychogenic erections. Psychogenic arousal can be predicted by the ability to perceive sensation to pinprick and light touch in the T11–L2 dermatomes.

The majority of men with SCI are unable to ejaculate, with the exception of men with incomplete paraplegia of whom 75% could ejaculate. Despite this, about half of men with SCI are able to experience orgasm. However; the quality of their orgasm may be different [79, 80].

Orgasm is more common among individuals with incomplete injuries (versus complete) and among individuals with upper motor lesions (versus lower motor lesions). The use of oral midodrine to encourage ejaculation may improve likelihood of orgasm but is associated with a significant increase in blood pressure, and can cause autonomic dysreflexia [81].

The location of spinal cord injuries has similar effects on the female sexual responses. The counterpart to an erection in males is vaginal and clitoral vasocongestion and lubrication. Reflexive vaginal lubrication is likely to occur when sacral segments S2–S5 are spared. Women with sacral preservation can utilize manual and vibratory self-stimulation to augment this response.

Women with complete SCIs above T10 are unable to experience psychogenically based genital vasocongestion, even if subjective sexual arousal is present. The ability to recognize light touch and pinprick sensation in the T11–L2 dermatomes predicts a women’s ability to experience psychogenically induced genital arousal. Similar to men, women can experience orgasm after spinal cord injury, even if their spinal cord injury is complete (i.e., an injury resulting in a loss of ability to send sensory and motor nerve impulses beyond the level of injury). Approximately one-half of women with spinal cord injury experience orgasm by self-report in the laboratory setting. Women with complete injuries to the S2–S5 spinal segments are less likely to achieve orgasm than women with other levels of spinal cord injury. The latency to orgasm is increased, but the qualitative description of orgasm is indistinguishable from non-injured controls [82].

Audiovisual stimulation leads to similar subjective and autonomic responses found in women without injury, and can be utilized in conjunction with other methods to facilitate arousal.

In both men and women sexual frequency decreases after SCI and sexual expression often changes. Individuals become more open and likely to engage in sexual fantasies. The frequency of hugging, kissing, manual stimulation, and use of oral–genital stimulation is not statistically different than in couples without spinal cord injury. Relationship factors such as partner satisfaction and relationship quality as well as mood and independence appear to be more important predictors of sexual satisfaction than genital functioning in both men and women [83, 84].

Individuals who undergo amputations often have diseases that not only result in the amputation itself, but also put them at risk for erectile dysfunction (e.g., diabetes mellitus, vascular disease). Amputations performed for oncological reasons may be associated with decreased libido, and erectile dysfunction due to simultaneous treatment with chemotherapy and/or radiation therapy. Therefore changes in sexual behavior are often difficult to attribute to the amputation alone [85].

The site and level of amputation can result in limitations to physical activities affecting movement, positioning, stability, balance, hand control, and dexterity [86]. Sexual positions may need adaptation to accommodate these changes; after a major limb amputation side lying or bottom position may be preferable. Transfemoral amputees tend to experience a greater decline in sexual function and frequency than transtibial amputees [86, 87].

Ensuing pain is another factor that negatively impacts sexual function after amputation. While nearly all patients experience some degree of phantom limb sensation after an amputation, 55–85% experience phantom limb pain [88]. Amputees who suffered from amputation related pain or discomfort related to their prosthetic device experience more significant sexual dysfunction compared with those who did not have phantom phenomena [87, 89]. Amputation related pain may negatively impact sexual desire and thereby reduce sexual activity.

Other factors that negatively affected sexual functioning include single marital status, older age, and male gender [90].

Apart from these physical factors, psychological consequences of an amputation such as depression, performance anxiety, and an altered body image have been shown to influence sexual adjustment after amputation.

The diagnosis of human immunodeficiency virus infection (HIV) is often associated with considerable distress with changes in body image, social stigma, and fear of rejection from friends, family, and society.

In addition, individuals may experience feelings of anxiety or guilt as well as fear of infecting others after HIV diagnosis. Furthermore, the need for adherence to safe sex practices may have an added negative impact on sexual functioning [91]. The use of condoms reduces penile sensitivity and contributes to erectile dysfunction in males [92]. Generally, individuals are more likely to experience sexual dysfunction as disease severity worsens with rates of sexual dysfunction being higher in patients with AIDS than in patients who are HIV infected but do not have AIDS. The most prevalent sexual problems in females are low sexual desire, orgasmic dysfunction, and dyspareunia [93, 94].

Sexual dysfunction in men includes reduced libido, erectile dysfunction (ED), ejaculation disorders, lower orgasmic function, and depressed sexual satisfaction. The likelihood of developing sexual problems is not only increased by the chronic illness but by the comorbidities that are frequently associated with HIV including excessive consumption of alcohol, recreational drug use, and smoking. Metabolic disorders and cardiovascular disease are other risk factors that are more common in HIV infected individuals. Since the prevalence of ED increases with age, its occurrence among HIV-infected persons will likely rise with increasing life expectancy and the increasing prevalence of HIV among those older than 50 years.

Hypothalamic–pituitary function can also be affected resulting in higher rates of hypogonadism in HIV-infected men than in age-matched controls. The premature decline of serum testosterone levels is associated with inappropriately low or normal levels of luteinizing hormone and increased visceral adiposity [95]. The prevalence of hypogonadism has been lowered with the introduction of Highly Active Antiretroviral Therapy (HAART), but it still remains the most common endocrine disorder of HIV-infected men [96]. Estimated rates of hypogonadism in HIV-infected men are as high as 20–25% and 25–62% of HIV-infected men report ED in the post-HAART era [97, 98]. Hypogonadism can be effectively treated with testosterone replacement therapy which not only restores sexual drive and performance, but also enhances PDE-5 inhibitor effectiveness. Testosterone replacement provides multiple benefits beyond improved sexual function, including heightened erythropoiesis, weight gain, and prevention of bone loss, increased energy, and improved mood. However, since most men with ED have normal serum testosterone levels, erectile dysfunction is likely related to other factors.

Other contributing causes for sexual dysfunction in HIV infected individuals are neurological sequalae of the infection and treatment. In many patients with HIV infection or AIDS, sexual desire decreases because of fatigue, generalized wasting, muscle aches, pains, paresthesias, and depression. Body-image concerns also worsen with symptomatic disease. Reports of the prevalence of depression over the course of HIV infection vary widely however; one meta-analysis found that the diagnosis of major depressive disorder is nearly twice as likely in HIV-infected persons as compared to those without HIV [99].

The role of HAART in the pathogenesis of ED is still controversial. Although both protease inhibitors and nonnucleoside reverse transcriptase inhibitors are associated with sexual dysfunction, most studies are retrospective and a direct causal relationship has not been established. HAART treatment is known to contribute to metabolic and hormonal changes as well as alterations in body composition which together might have an adverse effect on erectile function. Specifically, HAART treatment results in lipodystrophy, a syndrome characterized by peripheral fat loss and central fat accumulation which is frequently, but not invariably, associated with alterations of lipid metabolism and derangement of insulin sensitivity and diabetes mellitus. These metabolic changes promote endothelial dysfunction which results in vascular compromise and cause changes in body habitus that can negatively impact self-esteem. Augmented peripheral conversion of androgens to estrogens in lipodystrophic fat tissue is thought to cause elevated estradiol levels in HIV infected men, though its impact on sexual function is not clear. Furthermore, peripheral neuropathy is another complication of both HAART and HIV infection which is associated with both erectile dysfunction and delayed ejaculation.

Current treatment approaches include management of underlying medical and psychological conditions, and testosterone replacement therapy for men with documented hypogonadism. PDE-5 inhibitors are the mainstay of pharmacologic treatment of ED when serum testosterone is normal. When used simultaneously with protease inhibitors which decrease cytochrome P450 efficiency it is important to reduce the dose and increase the interval between PDE-5 inhibitor administrations.

Chronic respiratory illness or chronic obstructive pulmonary disease (COPD) is a group of illnesses that cause breathing problems, such as emphysema and chronic bronchitis. The overall incidence of ED is 1.88-fold greater in the COPD cohort than in the non-COPD cohort and individuals with more severe disease have higher rates of ED [100].

Individuals with poor COPD control who require more emergency room visits and admissions are more likely to have ED. Sexual dysfunction tends to be worse in individuals with more severe pulmonary function impairments as assessed by pulmonary function tests, blood gases, and exercise tests [101].

Sexual dysfunction and erectile impotence occur in patients with COPD in the absence of other known causes of sexual problems [101]. The mechanism by which COPD results in higher rates of ED is likely multifactorial. Increased arterial stiffness in COPD is related to the severity of airflow obstruction and may be a factor in the excess risk for erectile dysfunction [102]. Hypoxemia itself is likely a cause for ED both by reducing functional capacity as well as its effects on endothelial function. Hypoxia increases sympathetic activation causing vasoconstriction and a significant reduction in nitric oxide synthase activity, the rate-limiting factor for nitric oxide production in the penile corpus cavernosum necessary for erectile function [103]. Tissue hypoxia also contributes to systemic inflammation in COPD which is related to the presence and severity of ED [104]. Long-term treatment with oxygen therapy has been shown to result in modest improvement in arterial pO2, serum testosterone, and erectile function [105].

Dyspnea is prevalent in patients with COPD and the high energy demands of sexual activity can result in increased dyspnea, generalized weakness, and compromised stamina for sexual activity [106]. The fear and anticipation of dyspnea and reduced exercise tolerance may further limit sexual activity [107]. Cough, muscular weakness, and the associated reduction of physical activity are important causes of reduced sexual activity in COPD patients [107]. Fatigue, a perception of mental or physical exhaustion due to exertion, is another frequent and distressing symptom. Furthermore, cardiovascular disease, diabetes mellitus, metabolic syndrome, and hypertension are common conditions coexisting with COPD which are themselves associated with high rates of sexual dysfunction [108].

Individuals with COPD often have progressive weight loss, and loss of lean body mass which has been linked to skeletal muscle dysfunction and debility. Hypogonadism with lower testosterone levels in males with COPD may further exacerbate lean body weight loss and contribute to decreased libido, ED, and reduced ejaculation [109]. Androgen deficiency can also induce depression, anxiety, anger, fatigue, and sleep disorders which negatively impact sexual functioning.

With improvements in cancer diagnosis and treatment, life expectancy after cancer is increasing with more cancer survivors living with the effects of cancer.

Sexual dysfunction represents a long-term complication among cancer survivors with a wide range of manifestations and a huge impact on quality of life [110]. Most sexual problems are not caused by the cancer itself, but by toxicities of cancer treatment [111]. Cancer and its treatment result in a host of problems including physical disfigurement, pain, and neurovascular and organ injury which often lead to significant and long-term disruption in sexual function and intimacy, regardless of cancer type [112].

Problems after cancer can be categorized as disorders of sexual response (e.g., arousal, erectile dysfunction, ejaculatory dysfunction, reduced lubrication in females, chronic dyspareunia, orgasmic dysfunction), and disorders of sexual desire and motivation (e.g., hypoactive sexual desire, reduced sexual motivation, body image disturbances, loss of sexual self-esteem) [113].

Pelvic surgeries are among the most common causes of organic sexual dysfunction in men and women. Radical prostatectomies and cystectomies and low anterior or abdominoperineal resections for rectal cancer are associated with considerable rates of erectile dysfunction [114]. If nerve sparing technique is used to perform radical prostatectomies, recovery from erectile dysfunction may occur within the first year following the procedure. External beam radiation therapy induces ED in 30–40% of the patients, between 1 and 2 years of treatment [115]. Even though the reported incidence of erectile dysfunction varies widely, the rate of ED is quite high. Brachytherapy was originally introduced to limit the detrimental effects of external beam radiation therapy on bowel and bladder function and sexual function In contrast to radical prostatectomy, the onset of erectile dysfunction following brachytherapy is gradual and can occur over years with stabilization occurring after approximately 3 years [116, 117].

Penile rehabilitation attempts to address loss of erections by improving oxygen delivery to preserve erectile tissue. Treatment options include PDE inhibitors, intraurethral alprostadil, intracavernosal injections, and vacuum erection devices though no consensus has been reached on an optimal treatment protocol.

Similarly, radical cystectomies, and hysterectomy for cancers of the cervix and endometrium are associated with sexual dysfunction in women. Gynecological surgeries frequently result in vaginal dryness, a shortened and fibrosed vaginal vault and loss of libido. These complications are further aggravated when accompanied by bilateral oophorectomy which causes premature menopause symptoms or treatment with endocrine therapy. Commonly used endocrine therapies that cause estrogen deprivation often have extensive sexual side effects that affect quality of life [118]. The risk of developing more severe sexual problems increases when radiation or chemotherapy is used in addition to surgery. As in men, pelvic radiation therapy contributes to the risk of sexual dysfunction, from a combination of ovarian failure and direct tissue damage to genital areas in the radiation field [119].

Loss of libido is often the result of fatigue and general malaise. In addition, it can be due to “de-prioritization” of sexual activity. Chemotherapy is associated with a loss of desire and decreased frequency of intercourse. Common side effects of chemotherapy such as nausea, vomiting, diarrhea, constipation, mucositis, weight loss or gain, and alopecia can affect self-image. Psychosocial ramifications of the cancer itself and cancer treatments affect mood, self-esteem, sexual drive, and sexual identity posing another layer of challenges [111, 120].

Problems with sexual function, unlike other side effects of cancer therapy, often do not resolve with time [121, 122]. The most common reasons cited for sexual dysfunction in cancer patients have been poorly controlled pain, chronic nausea, anxiety, fatigue, and treatment-related effects such as the cytotoxic effects of certain types of chemotherapy. Chronic opioid use, as an independent factor, can lead to sexual dysfunction, decreased libido, increased fatigue, and generally poor function. Studies have shown that sexual health concerns impose a considerable negative effect on patients’ health-related quality of life (HRQoL).

Libido in both sexes depends on an interplay between hormonal levels, balance of neurotransmitter actions, and social cues. Both men and women depend on the androgen dehydroepiandrosterone (DHEA), a precursor to testosterone and estrogen, for arousal. Decreased libido can be observed with decreased androgen levels (testosterone and DHEA), increased estrogen or an increased estrogen: testosterone ratio.

Dopamine and serotonin are important neurotransmitters that help regulate libido and sexual function. Dopamine is a vital neurotransmitter in the limbic area associated with pleasure and reward and is implicated in heightening sexual motivation. Stimulation of dopaminergic receptors in the hypothalamus is important in obtaining erections. Dopamine in the tuberoinfundibular dopaminergic system of the hypothalamus also has a strong inhibiting influence on hypothalamic prolactin synthesis and secretion. In contrast, serotonin and thyrotrophin releasing hormone increase prolactin release which has an inverse effect on libido, and erectile function. Although the mechanism by which selective serotonin reuptake inhibitors (SSRIs) impair sexual functioning is not fully understood, it is generally agreed that serotonin exerts an inhibitory effect on sexual function, including sexual motivation, orgasm, and ejaculation. In addition, serotonin inhibits nitric oxide production, which has an important role in relaxing the vasculature in erectile tissue.

The autonomic nervous system regulates the peripheral aspects of sexual function with the parasympathetic nervous system causing vasodilation and engorgement of sexual organs while the sympathetic nervous system is active during orgasm. Orgasm and male ejaculation is controlled by the sympathetic autonomic division and utilizes the neurotransmitter acetylcholine. Many antidepressants have some efficacy at cholinergic and alpha1-adrenergic receptors, thereby inhibiting the autonomic nervous system and consequently inhibiting normal sexual function.

Medications that affect libido and sexual functioning mediate their side effects by altering levels of hormones and neurotransmitters in the brain and/or peripheral targets.

Many antidepressants have been linked to sexual dysfunction. Selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs) increase serotonin levels and cause sexual dysfunction. Erectile dysfunction and delayed ejaculation or anejaculation are observed in men and reduced sexual desire and difficulty reaching orgasm in women. Monoamine oxidase inhibitors can also depress libido. Tricyclic antidepressants have adverse sexual effects due to their anticholinergic effects and can cause decreased ability to achieve orgasm in both sexes, erectile dysfunction in men and breast enlargement in women.

Fortunately, some antidepressants do not affect libido and sexual function to the same extent as most SSRIs and SNRIs. Medications that promote dopamine activity have a beneficial effect on libido. A much lower incidence of sexual dysfunction is reported for the newer 5-HT2 blockers. These types of antidepressants, which include nefazodone and mirtazapine encourage dopamine activity. Bupropion, unlike the majority of antidepressants, has less serotonergic effects and is a mild dopamine agonist. Therefore, bupropion can actually have a positive influence on sexual desire and can be prescribed to counter the sexual side effects seen with SSRIs and SNRIs.

When starting a patient on an antidepressant, sexual concerns and history should be elicited with goal of choosing an antidepressant that has the best individualized side effect profile. If an individual is on a medication which has sexual side effects, there are several options one can explore short of discontinuing the medication altogether. Since sexual dysfunction associated with serotonergic activity is dose-dependent decreasing the dosage of the antidepressant may improve libido while maintaining adequate treatment of depression. The only evidence about drug holidays comes from a small, open study in which findings suggest that 1- to 2-day holidays from the shorter half-life SSRIs (i.e., sertraline, paroxetine) may be helpful. This effect did not apply to fluoxetine. All antidepressants require adequate trials of at least 6 weeks before a change in dose or medication is considered.

Antipsychotics and lithium also contribute to depressed libido and sexual function, with a reported prevalence of 45–80% in males and 30–80% in females [123]. Antipsychotics have multiple mechanisms by which they disrupt sexual functioning: their anti-dopaminergic effects can cause hyperprolactinemia resulting in galactorrhea, erection disorders, and reduced libido. Most antipsychotics block noradrenergic receptors, which can cause erectile and ejaculatory problems and decreased lubrication in women [124]. Finally, they have generalized sedating properties which reduce energy and sexual motivation. First-generation classical antipsychotics are associated with a very high incidence of sexual dysfunction [125].

Olanzapine, paliperidone, risperidone, and ziprasidone are atypical antipsychotics that increase prolactin to a much lesser extent than typical antipsychotics. Atypical antipsychotics such as aripiprazole, clozapine, and quetiapine do not elevate prolactin levels and therefore have a more benign side effect profile in regards to libido and sexual function [126].

Anticonvulsants have been associated with sexual dysfunction due to increased prolactin levels and reduced sex hormones. In particular, enzyme-inducing antiepileptic drugs (AEDs) such as phenobarbital, phenytoin, and carbamazepine influence the metabolism of sex hormones and their binding. This results in abnormalities in sex hormone profiles (increased sex hormone-binding globulin, low estradiol, low testosterone, low dehydroepiandrosterone), resulting in sexual dysfunction. Newer antiepileptic agents that are not enzyme inducing such as oxcarbazepine, levetiracetam, and lamotrigene appear to have a better side effect profile [127, 128].

The use of long-term opioid therapy has been associated with androgen deficiency referred to as opioid associated androgen deficiency which persists even after cessation of treatment and can last months to years. Opioid associated androgen deficiency is thought to result from the inhibitory action of morphine on hypothalamic gonadotropin-releasing hormone secretion. The syndrome is characterized by the presence of inappropriately low levels of gonadotropins (follicle stimulating hormone and luteinizing hormone) leading to inadequate production of sex hormones, particularly testosterone. Symptoms include reduced libido, erectile dysfunction, fatigue, hot flashes, and depression [129]. There should be a high index of suspicion for the development of opioid associated androgen deficiency when treatment duration is longer than a few weeks [130]. Doses exceeding approximately 100 mg of oral morphine equivalents daily may be more likely to cause androgen deficiency than lower opioid doses [131].

Antihypertensive drugs represent one of the most implicated classes of drugs in causing sexual dysfunction. Even though antihypertensive agents are used in patients who likely have coexisting small vessel disease that would affect erectile ability, the observation that sexual problems occur more frequently in patients receiving antihypertensive medication than in those with untreated hypertension underscores the separate effect antihypertensive medications have on erectile potential [132]. Diuretics, methyldopa, clonidine, and β blockers (especially nonselective ones), are well known to cause sexual problems or exacerbate existing problems. One of the proposed mechanisms by which β-blockers may cause sexual dysfunction is inhibition of the sympathetic nervous system, which is involved during sexual arousal and in the regulation of luteinizing hormone and testosterone secretion [133]. Of the beta blockers on the market, metoprolol and especially nebivolol appear to have a very low risk of sexual side effects compared with other agents in its class.

Spironolactone, a diuretic commonly used in congestive heart failure also has a detrimental side effect profile causing gynecomastia, impotence, and decreased libido [134]. Spironolactone is structurally similar to sex hormones and acts as an androgen receptor blocker which results in these side effects.

Thiazide diuretics are associated with an exceptional high risk for erectile dysfunction, likely due to their link to vascular and metabolic abnormalities, including endothelial dysfunction, insulin resistance, and diabetes mellitus. Thiazide diuretics including hydrochlorothiazide and chlorthalidone cause decreased libido, erectile dysfunction, and anejaculation with an incidence that varies from 3% to 32%, and may be associated with decreased vaginal lubrication [135]. Loop diuretics might have a more favorable side effect on sexual functioning than thiazides [136].

On the other hand, calcium channel blockers, alpha-blockers, ACE inhibitors and angiotensin II receptor antagonists (ARBs) generally have relatively neutral effects on erectile function in hypertensive patients [137, 138].

Statins and lipid-lowering medications also appear to improve erectile function in patients who have no cardiovascular risks other than erectile dysfunction. It is thought that statins may provide sexual benefit due to antioxidant effects. However, in patients with cardiovascular risk factors such as smoking or diabetes, erectile dysfunction was more likely to occur after statin initiation [138].