Sexual function in chronic illness and cancer perspectives of the patient, partner, and healthcare provider; innovations; and updates: recommendations from the Fifth International Consultation on Sexual Medicine (ICSM 2024).

RECOMMENDATIONS

SECTION A

The complications of DM represent a major health problem, macroangiopathy, microangiopathy, and neuropathy all leading to sexual dysfunction in both men and women. Strong.

Risk factors, physical inactivity, obesity, metabolic syndrome, diabetes, and cardiovascular disease lead to low sexual desire and sexual dysfunction. Strong.

Sexual problems may be a warning sign of underlying disease or a consequence of chronic diseases. Strong.

Erectile dysfunction is a hallmark of CVD. Strong.

Men with priapism are at increased risk for cardiovascular and cerebrovascular events in the years following a priapism. Weak

Postmenopausal women, particularly those in the middle-age range, should be assessed for CV risk factors and FSD, sexual dysfunction is a harbinger of cardiovascular disease in postmenopausal women. Strong.

Low sexual desire and sexual dysfunction are often associated with low testosterone levels and higher fat mass. Therefore, the prevalence of sexual problems in healthy middle-aged individuals may be associated with the presence of a portfolio of these risk factors. Strong.

DM has a negative impact on male fertility, particularly the quality of sperm, semen constituents, sperm motility, and sperm DNA damage. Strong

Ejaculatory dysfunction encompasses several disorders related to DM and its complications, such as premature ejaculation, anejaculation (AE), delayed ejaculation, retrograde ejaculation (RE), ejaculatory pain, anesthetic ejaculation, decreased ejaculate volume, and decreased force of ejaculation. The problems linked to ejaculatory dysfunction may lead to mediocre quality of life as both AE and RE are alleged to alter the fertility potential. Strong.

The initial management for PE is controlling the patient’s blood glucose, in some cases this may allow recovery of the normal ejaculatory function. Amelioration of glycemic variability will improve PE in type 1 diabetes patients. In cases of concomitant ED and PE, ED should receive phosphodiesterase type 5 inhibitors before, or at least at the same time as other treatments. Strong.

SD is commonly encountered in older T2DM patients and diabetic kidney disease (DKD) affects almost 50%. The eGFR has been significantly associated with SD, ED, and FSD, while SD and ED were proven to be significant determinants for the eGFR levels. Strong.

Female sexual dysfunction is more common among women with type 1 diabetes than among women without type 1 diabetes. Patients with type 1 diabetes should be questioned in terms of sexual health. Health professionals should give more attention to and provide guidance regarding sexual function in both men and women with type 1 diabetes. Strong.

S-Klotho plasma levels have been associated with sexual desire and sexual function in men and, also, with dyadic sexual desire and sexual function in women. S-Klotho plasma levels may represent a potential new biomarker for sexual desire and sexual function. Weak

Testosterone therapy enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids, and suppressing inflammation. Leading to, improved glycaemia, endothelial function, and lipid profile, together with improvement in the symptoms of hypogonadism, and potentially reducing cardiovascular risk. Strong.

Testosterone therapy prevents progression from prediabetes to diabetes and improves HbA1c. Strong.

Obesity is associated with hypogonadism, sexual dysfunction, and impaired fertility in men. Strong.

Exercise protects against erectile dysfunction in men and sexual dysfunction in women and in addition improves sexual desire and sexual function in women. Strong.

Bariatric surgery improves male and female sexual health. It is associated with significant increase in IIEF score and serum testosterone levels. Similar benefits in sexual function and self-esteem are seen in women. Strong.

The role of different anti-diabetes therapies in the potential remission of ED and FSD, need to be explored, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting. Strong.

The Mediterranean diet is effective for the protection of sexual function. Furthermore, anti-hyperglycemic drugs seem to show an overall protective role on sexual function. Strong.

Despite being used for ED, PDE5is have favorable effects on the cardiovascular system. Strong.

SECTION B

Evaluating sexual functioning in CP condition is strongly suggested within the diagnostic or routine care since data report a high prevalence of sexual impairment in both women and men. Strong.

In the evaluation, a multifactorial cause involving the CP condition per se, associated symptoms, treatments used, and relational and social experience of the condition should be considered. Strong.

It is suggested to incorporate questionnaires considering sexual health in the CP assessment. Strong recommendation.

Opioid-based therapy side effects, although not related to sexuality, can exacerbate sexual difficulties in CP patients. Strong.

Using medications to address sexual dysfunction among opioid users, although commonly reported, should be evaluated case by case. Weak recommendation.

It remains challenging to determine the extent to which antidepressant therapies directly impact sexuality versus inherent features of CP. Weak recommendation.

Using the ReConnect model in both individual and group sessions may aid HCPs in supporting their patients’ sexual activity goals. Weak.

Effective communication and the exploration of alternative forms of intimacy may facilitate personal empowerment, enabling individuals and couples to adapt and discover new strategies to sustain their sexual lives despite experiencing pain.

Emphasis should be on mitigating symptoms associated with CP and promoting sexual satisfaction rather than solely concentrating on functioning. Weak.

SECTION C

Vaginal moisturizers and lubricants should be considered frontline for the treatment of GSM in BCP (Strong)

Other non-hormonal interventions (pharmacological/psychological): should be incorporated the treatment paradigm (Strong)

Minimally absorbed local vaginal estradiol products maybe be used for refractory cases to OTC vaginal moisturizers and lubricants (Strong)

Ospemifene and intravaginal DHEA can be considered for use in the BCP with GSM (Strong)

CO2 Laser and Radiofrequency both show excellent promise for the treatment of GSM in BCP. However long term, sham controlled RCT is lacking, and the HCP should proceed with caution. (Strong)

The HCP should be cautious of cash-based center’s or medi-spas which strongly advocate device-based interventions for breast cancer patients. (Strong)
There is insufficient safety and efficacy data at the current time to recommend Testosterone use in breast cancer patients (Strong)

Shared decision making should take place for the treatment of GSM in BC, P, and involve the patient, survivorship specialist and the oncological team (Strong).

SECTION D

Pelvic floor function interventions, including pelvic floor training along with the use of dilators and other strategies, are well-tested (Strong).

Vaginal dilators alone are promising but have a smaller evidence base (Strong).

DHEA lacks rigorous testing in women with gynecologic cancer (Weak)

Bupropion for improving sexual desire lacks substantial rigorous testing in women with gynecologic cancer (Weak).

Ospemifene, an estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator (SERM), has some promising evidence but lacks testing in large randomized controlled trials (Weak).

Microablative fractional CO2 laser lack data is available in gynecologic cancer patients (Weak).

Psychoeducational and behavioral interventions show benefit for women with gynecologic cancer in improving sexual function and these interventions have the benefit of few risks or negative side effects (Strong).

Limited data exist showing that exercise interventions improve sexual function in endometrial cancer survivors, but they do not have side effects and can have other health benefits (Strong).

SECTION E

Sexual function sparing approaches to definitive cancer treatment, such as those that involve functional anatomy sparing or tumor down staging, should be considered, when medically appropriate (Weak).

When available, advanced imaging guidance should be utilized to minimize adverse effects of definitive local cancer treatments on sexual functioning (Weak).

Shared-decision making can guide treatment choice when sexual function may be impacted (Weak).

Equitable approaches to preventing sexual dysfunction due to oncologic treatments in female and sexual/gender minority persons are needed (Strong).

Introduction
The direct and indirect impact of chronic disease, breast and gynecological cancers, and oncologic interventions more generally and the impact of associated treatment interventions on sexual function and relationships is considerable. These have been reported in previous consultations.1–5 This review addresses updates and innovations since the last consultation reported in 2015 specifically of chronic cardiovascular disease (CVD) states, diabetes mellitus (DM) and obesity, chronic pain (CP) conditions, breast and gynecological cancers, and oncologic interventions.
The consensus of a diverse group of global experts chose pertinent and clinically relevant conditions to review as a committee following extensive discussion and under the guidance and support of the task force of the International Consultation on Sexual Medicine (ICSM).
It is recognized that several common chronic conditions have not been discussed in this chapter, but we acknowledge existing reviews in the literature covering these topics such as colitis6 and dermatological conditions7 as well as general disabilities from chronic illness and disease.8,9 Whilst prostate cancer and some other chronic conditions are considered in more detail elsewhere within the consultation including, for instance, some neurological conditions,10 the general impact of ageing11 and the genitourinary syndrome of menopause,12 there will be some common recommendations that relate to people and their partners who are impacted by most chronic disease conditions and cancer.
The review is presented in five sections starting with an overview of CVD, DM, and obesity on sexual function, followed by CP conditions. The review then deals with breast cancer (BC), gynecological cancer, and then oncological interventions more generally.

Methods
Under the auspices of the ICSM, a multidisciplinary panel of experts on disorders of sexual function in chronic illness and cancer, selected from geographically representative parts of the world, was tasked with providing evidence-based recommendations for management of sexual function from perspectives of the Patient, Partner, and Healthcare Provider. The panel met virtually by Zoom and in person at the ICSM meeting in Madrid, 2024.
The panel reviewed the global literature on sexual function in various chronic illnesses and cancers. Each individual member was tasked with researching discrete topics and performed their own review and data synthesis for their assignment. Draft recommendations were produced by each committee member and presented to the larger group for discussion and debate and agreement of the related recommendations from each section. All authors approved the final manuscript.
Following the ICSM guidance, all recommendations include assessment of the quality of evidence and assignment to recommendations as either strong or weak, based on the GRADE system.

Results
Chronic disease conditions such as CVD, obesity and diabetes, CP, and breast and gynecological cancer states exert both direct and indirect effects on the body, with consequences that are multifaceted and frequently interactional. These impacts create a complex insult affecting several major systems, including the cardiovascular, neurological, endocrinological, and soft tissue structures.
Management of chronic diseases often involves a variety of interventions, ranging from pharmacological and surgical approaches to external treatments such as radiation and laser therapy. These interventions, while essential for disease management, can also contribute to a complex environment that may result in sexual dysfunction (SD).
SDs resulting from chronic disease and its treatment has a significant impact not only on affected individuals but also on their partners. This underscores the importance of recognizing the broader psychosocial effects of chronic disease management.
Given the considerable impact of SD related to chronic disease, the role of physicians and clinical care providers becomes especially important. Healthcare professionals (HCPs) are responsible for addressing these concerns, providing appropriate guidance, and offering relevant support and interventions to help patients and their partners navigate these challenges.
We discuss these common chronic disease states and cancers in the following section. We reiterate that while some findings that are reported are disease specific, there will be some common recommendations that relate to people and their partners who are impacted by most chronic disease conditions and cancer.

Section A: Chronic CVD and obesity

Introduction
Sexual desire and sexual function are important components of quality of life, being intricately linked with overall health and relationship satisfaction. Numerous studies suggest that risk factors, physical inactivity, obesity, metabolic syndrome, diabetes, and CVD lead to low sexual desire and SD.
Sexual problems may be a warning sign of underlying disease or a consequence of chronic diseases. Low sexual desire and SD are often associated with low testosterone levels and higher fat mass. Therefore, the prevalence of sexual problems in healthy middle-aged individuals may be associated with the presence of a portfolio of these risk factors. This review looks at the key papers studying this link over the last 5 years.

Diabetes mellitus
A chronic metabolic disease characterized by elevated levels of blood glucose, is among the most common chronic diseases. The incidence and prevalence of DM has been increasing over the years. The complications of DM represent a major health problem, macroangiopathy, microangiopathy, and neuropathy all leading to SD in both men and women.14–20
Many studies have shown that DM has a negative impact on male fertility, particularly the quality of sperm, semen constituents, sperm motility, and sperm DNA damage. It is possible that this may not only result in subfertility or infertility but will also pass to the offspring and cause subfertility or infertility.21
Managing low testosterone in men who wish to remain fertile is problematic and a randomized control trial (RCT) of leflutrozole in obesity associated hypogonadotrophic hypogonadism demonstrated normalization of total testosterone (TT) in obese men. Follicle-stimulating hormone (FSH) & Luteinizing hormone (LH) and semen parameter changes support that leflutrozole may preserve/improve testicular function.22
Ejaculatory dysfunction encompasses several disorders related to DM and its complications, such as premature ejaculation (PE), anejaculation (AE), delayed ejaculation, RE, ejaculatory pain, anesthetic ejaculation, decreased ejaculate volume, and decreased force of ejaculation.23 The problems linked to ejaculatory dysfunction may lead to inferior quality of life as both AE and RE are alleged to alter their fertility potential. The initial management for PE is controlling the patient’s blood glucose that in some cases may allow recovery the normal ejaculatory function. Amelioration of glycemic variability would improve PE in type 1 diabetes patients. In cases of concomitant erectile disorder (ED) and PE, ED should receive phosphodiesterase type 5 inhibitors before, or at least at the same time as PE. The efficacy of the combined use of phosphodiesterase type 5 inhibitors and dapoxetine in males with comorbid PE and ED are supported by some studies. Several drugs are recognized for the possible use in DE/AE. Those agents include testosterone, amantadine, cyproheptadine, cabergoline, bupropion, yohimbine, buspirone, bethanechol, and others. Yet, no drug has been approved for this indication. Infertility is usually the main concern in RE patients as the combination of dry orgasm and infertility makes the condition upsetting to the patient and his partner. Therefore, many lines of therapeutic approaches are advocated, either medical or surgical, with limited success rates.
The processes of ejaculation and orgasm are complex and include neuronal and hormonal factors exacerbated by underlying diabetes, as well as psychological and interpersonal dynamics. Care of the patient presenting with a potential Disorders of Ejaculation and Orgasm centers on sensitive history taking and selective testing. Declines in semen volume may occur naturally with age and can be seen in the context of medical or surgical therapies. Pain with ejaculation/orgasm has a myriad of potential etiologies and may be part of a complex chronic pelvic pain syndrome; assessment for related diagnoses that may be contributory is warranted.24
SD is commonly encountered in older T2DM patients and diabetic kidney disease (DKD) affects almost half of them. The eGFR has been significantly associated with SD, ED, and FSD, while SD and ED were proven to be significant determinants for the eGFR levels.25 Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5i’s) exert protective effects in DN improving perivascular inflammation.26,27
Female sexual dysfunction (FSD) is more common among women with type 1 diabetes than among women without type 1 diabetes. Patients with type 1 diabetes should be questioned in terms of sexual health. Health professionals should give more attention to and provide guidance regarding sexual function in both men and women with type 1 diabetes.28–36

Predictors of SD in CVD, diabetes, and obesity
Growing evidence suggests that the a-Klotho gene has a crucial role in the control of multiple metabolic processes and the pathophysiology of common aging-related disorders. Higher glycoprotein S-Klotho plasma levels are associated with a lower risk of CVDs, type 2 diabetes incidence, and all-cause mortality. Free testosterone, lean body mass, and physical fitness are linked to S-Klotho plasma levels in middle-aged adults.
S-Klotho plasma levels have been associated with sexual desire and sexual function in men and, also, with dyadic sexual desire and sexual function in women. S-Klotho plasma levels may represent a potential new biomarker for sexual desire and sexual function. The link to lean body mass may be related to benefits in sexual desire and sexual function.37
Growing evidence suggests that the FGF-Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis, and chronic kidney disease. Therefore, targeting the FGF-Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF-Klotho-FGFR complexes is paving the way for the development of drugs that can regulate these axes and treat SDs.38–46

Metabolic actions of testosterone in relation to diabetes
Testosterone enhances insulin sensitivity in obese men with hypogonadism by decreasing fat mass, increasing lean mass, decreasing free fatty acids, and suppressing inflammation. At a cellular level, testosterone increases the expression of insulin receptor β subunit, insulin receptor substrate-1, protein kinase B and glucose transporter type 4 in adipose tissue and adenosine 5′-monophosphate-activated protein kinase expression and activity in skeletal muscle. Observational studies show that long-term therapy with testosterone prevents progression from prediabetes to diabetes and improves HbA1c.
Testosterone increases skeletal muscle satellite cell activator, fibroblast growth factor-2 and decreases expression of the muscle growth suppressors, myostatin, and myogenic regulatory factor. Testosterone increases hematocrit by suppressing hepcidin and increasing expression of ferroportin along with that of transferrin receptor and plasma transferrin concentrations. Testosterone also increases serum osteocalcin concentrations, which may account for its anabolic actions on bone. In conclusion, testosterone exerts a series of potent metabolic effects, which include insulin sensitization, maintenance, and growth of the skeletal muscle, suppression of adipose tissue growth and maintenance of erythropoiesis and haematocrit.47
Two years of testosterone therapy (TTh) resulted in normalized serum testosterone levels, improved glycemia, endothelial function, lipids, and insulin sensitivity, and improved the symptoms of hypogonadism, potentially reducing cardiovascular risk in obese men with FH and T2D. This is supported by multiple studies.48–51
What emerges from the current clinical literature is that, irrespective of the length of study durations, TTh provides significant health benefits and reduces the risk of CVD. More important is that data from many observational and registry studies demonstrated that longer durations of TTh were associated with greater health benefits and reduced cardiovascular risk. T therapy in men with T deficiency reduces the incidence of major adverse cardiovascular events attributed to improving overall metabolic function.52
In men with hypogonadism and preexisting or an elevated risk of CVD, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events.53,54

Obesity
Obesity is a growing public health concern worldwide, and results in increased risk of CVD, type 2 diabetes, metabolic syndrome, insulin resistance, dyslipidemia, hypertension, sexual problems, and reduced sex hormone production.55–61

Impact of weight loss
Obesity is associated with hypogonadism, SD, and impaired fertility in men. Bariatric surgery improves male and female sexual health. It is associated with significant increase in International Index of Erectile Function (IIEF) score and serum testosterone levels. Similar benefits in sexual function and self-esteem are seen in women.62–68
Several papers confirm that exercise induces a series of cardiovascular, metabolic, and psychological adaptations that protect against erectile dysfunction (ED) in men and SD in women and in addition improves sexual desire and sexual function in women.28,69–71
Both low and high physical activity levels were associated with more than 20% reduction in the risk of ED in men aged 40 years or older.72
In addition, research supports the utility of encouraging healthy lifestyle habits among young men to reduce the subsequent risk of prostatic enlargement and ED.73
A study illustrated the potential value of promoting Sexual Activity (SA) support for both patients who are post-acute coronary syndrome and their partners and reports that SA support provided at clinical review would be viewed as important, needed, and acceptable.74
The potential of the oxytocin system as a behavioral and molecular target for the prevention and treatment of CVD is of interest as it is associated with sexual activity. Focus is put on the affiliative and sexual significance and the different options and limitations associated with a pharmaceutical approach.75
Postmenopausal women, particularly those in the middle-age range, should be assessed for CV risk factors and FSD, SD is a harbinger of CVD in postmenopausal women. Identification is important so that both CVDs and sexual problems do not persist unnoticed.76
ED is a hallmark of CVD and includes a family history of cardiometabolic events, alcohol abuse, fatherhood, decreased partner’s sexual interest, severe impairment in erection during intercourse or during masturbation, impaired fasting glucose, increased triglycerides, obesity even without metabolic complications, decreased penile blood flows, or impaired response to an intracavernosal injection test. Recognizing these risk factors may help in identifying, among subjects with ED, those who merit stricter lifestyle or pharmacological interventions to minimize their CV risk. Effective correction of risk factors in ED men considered as elevated risk, besides reducing CV risk, is also able to improve erectile function.77
Men with priapism are at increased risk for cardiovascular and cerebrovascular events in the years following a priapism.78

The impact of the new anti-diabetes medications on sexual function
Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. The complications of DM represent a serious health problem. The long-term complications include macroangiopathy, microangiopathy, and neuropathy as well as SD in both men and women. ED has been considered the most important SD in men with DM. The prevalence of ED is approximately 3.5-fold higher in men with DM than in those without DM. Common risk factors for the development of DM and its complications include sedentary lifestyle, overweight/obesity, and increased caloric consumption. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. The role of different anti-diabetes therapies in the potential remission of ED needs to be explored, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting. Randomized clinical trials are needed to provide evidence supporting the use of Glucagon-Like Peptide-1 Receptor Agonists for treating ED in T2D.79
The Mediterranean diet was effective in most studies for the protection of erectile function. Furthermore, anti-hyperglycemic drugs seem to show an overall protective role on erectile function.80
SGLT2i should be considered for a trial course of therapy in patients with TDM with ED. The select group of patients who are contraindicated for PDE5i would also gain from this novel approach. The improvement in the microvascular circulation with enhanced vascularity could be the mechanistic reason for the observed clinical benefits.81,82 A better glyco-metabolic profile, as well as new antihyperglycemic drugs, seem to have a positive effect on ED.83
Liraglutide exerts protective effects on ED associated with the regulation of smooth muscle dysfunction, oxidative stress, and autophagy, independently of a glucose- lowering effect. It provides new insight into the extra pancreatic actions of liraglutide and preclinical evidence for potential treatment for DMED.84
Liraglutide produced a significant increase in serum levels of testosterone (TT), free testosterone (Tl), and possibly sex hormone-binding globulin (A); in addition to improving the sexual function and quality of life of women. Liraglutide could become a promising drug for the treatment of obesity, achieving positive effects on sexual function and quality of life in women.85
Giagulli et al.86 evaluated the effect of liraglutide in obese, hypogonadal patients with T2DM who received metformin and testosterone replacement. The group with liraglutide showed greater benefits on erectile function as well as increased testosterone levels.
Evidence from animal models suggests that DPP4i drugs could improve erectile function in patients with T2DM, promoting vascular repair and endothelial function87 and improving the effects of vasorelaxants mediated by vascular endothelial growth factor.88

Lifestyle modifications and glycemic control
In a systematic review and meta-analysis including 740 participants from four countries, lifestyle modifications aimed at decreasing cardiovascular risk demonstrated an improvement in sexual function.89 Several RCTs analyzing the effects of reduced caloric intake, better food quality with a Mediterranean diet, and increased physical activity reported improvements in metabolic parameters, anthropometric measurements, and sexual function.90,91
A weight loss of 5% from the initial weight has been the minimum recommended weight loss percentage for clinical benefit. Greater weight loss leads to even greater benefits in terms of reducing BP; improving low-density lipoprotein and high-density lipoprotein levels and insulin resistance and reducing the number of medications to control DM, hypertension, and dyslipidemia92,93 As previously reported, weight loss is strongly recommended to improve erectile function considering that it can increase testosterone levels mainly by improving testicular function and reducing conversion of testosterone to β-estradiol via aromatase activity in the adipose tissue, as well as increasing Sex Hormone Binding Globulin (SHBG) concentration as a consequence of reduced insulin levels.
Physical exercise is strongly recommended for both patients with T1DM and T2DM given its contribution to weight loss, improved blood glucose control, reduced cardiovascular risk, and improved well-being and sexual function. While physical exercise may improve serum testosterone levels, high-intensity exercise can also be counterproductive.92–99
Despite being used for ED, PDE5’s clearly have favorable effects on the cardiovascular system, primarily due to the restoration of the nitric oxide (NO) cyclic guanosine monophosphate (cGMP) protein kinase G (PKG) (NO-cGMP-PKG) signaling pathway and amelioration of the pro-inflammatory state that characterizes T2DM and the consequent endothelial dysfunction and increased cardiovascular risk. Although results from preclinical and human studies have been promising, additional studies are needed to determine the role of PDE5is in cardiovascular protection in T2DM.100

Section B: Chronic pain

Introduction
CP is recognized as a prevalent global health concern often associated with significant disability and a noteworthy psychological and social impact.101 According to the International Association for the Study of Pain (IASP), CP is characterized by persistent sensory and emotional discomfort linked to actual or potential tissue damage.102 Prevalence rates of CP vary from 11% to 40%, with a study by the US Centers for Disease Control and Prevention estimating it at 20.4%.103 CP conditions encompass physical injuries, arthritis, neuropathies, musculoskeletal issues, and other etiologies.
Recent research on CP and sexuality has particularly focused on conditions such as chronic migraine (CM), fibromyalgia (FM), and irritable bowel syndrome (IBS), which are more prevalent in women than men. Additionally, in the last years, there has been an increase in literature regarding sexuality in arthritis rheumatoid (AR), genitopelvic pain-related conditions (eg, vulvodynia, vaginismus, endometriosis), and multiple sclerosis. Critical discussions in this context will primarily draw from studies on CM, FM, IBS, and AR, but not limited to these conditions. Gynecological conditions and multiple sclerosis are out of the scope of the current review and will be addressed separately in specific guidelines.

Innovation in CP treatment and sexual function

SDs and associated CP symptoms
About rates of SD, a lot of recent literature shows data that is often not comparable in terms of methodology and measurement used. Most of the studies assess sexual functioning through self-report questionnaires such as FSFI and IIEF.104,105 This gives us a limited view without considering the classification criteria of SD. Studies showing a prevalence of SD in CP range from 35% to 97%,106–122 with women appearing to be more affected than men. The most affected areas seem to be desire and sexual pain for women and arousal for both women and men.
This high presence of sexual impairment may be due to a multifactorial cause involving the CP condition per se, associated symptoms, treatments used, and relational and social experience of the condition.
People with CP often experience a range of physical, emotional, and psychological symptoms such as anxiety, depression, fatigue, difficulty sleeping, irritability, difficulty concentrating, and loss of interest in daily activities. Several studies have found a negative association between sexual functioning and depression, low sleep quality, anxiety, fatigue, and pain-related interference in life (Level 2 of evidence).123 The magnitude and strength of each of these associations were quite similar across gender and CP type. In addition, depression was identified as the most consistent negative predictor of sexual function across studies, followed by anxiety (Level 3 of evidence).109,124

Controversies in opioid therapy
Despite the demonstrated efficacy of opioid therapy in alleviating symptoms of CP, numerous studies report a range of significant side effects, although the evidence is not unanimous. Patients undergoing opioid treatment exhibit a heightened likelihood of experiencing constipation, dizziness, drowsiness, fatigue, hot flashes, increased sweating, nausea, itching, vomiting, and urinary retention compared to those receiving a placebo in clinical trials (Level 1-3 of evidence).125–127 While not related to sexuality, these factors can exacerbate sexual experiences in individuals with CP.
Men commonly experience opioid-induced hypogonadism, reduced sperm production, and alterations in testicular interstitial fluid as notable sexual and reproductive consequences (Levels of 1 and 2 of evidence).128,129 Similarly, women may encounter heightened vaginal dryness, infertility, irregular menstruation, and intensified menopausal symptoms, both in short and long-term opioid usage scenarios (Level 2 of evidence).130 Overall, opioid users are more prone to sexual dissatisfaction and issues, particularly pertaining to diminished sexual desire, erectile difficulties, premature/delayed ejaculation, painful intercourse, and difficulty achieving orgasm (Level 2-3 of evidence).131,132 This trend is corroborated by the increased utilization of medications to address SD among opioid users (Level 1 of evidence).133

Controversies in antidepressant therapy
Antidepressants are frequently used in the management of CP, particularly in FM, diabetic neuropathy, or chronic back pain. Antidepressants can effectively enhance CP management by reducing pain perception, possessing anti-inflammatory properties, and influencing sleep and mood. However, selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors like duloxetine, desipramine, or fluoxetine have been associated with challenging outcomes concerning patients’ sexual health. Specifically, women with FM who use antidepressants have reported decreased levels of sexual desire, both in partnered and solitary contexts, compared to non-users (Level 4 of evidence).134 Additionally, SSRIs are commonly linked with various adverse side effects that may indirectly affect sexual experiences, including headache, dry mouth, nausea, fatigue, dizziness, sweating, nervousness, and difficulties with urination (Level 1 of evidence).135,136 Nonetheless, due to the limited amount of scientific evidence available, it remains challenging to determine the extent to which antidepressant therapies directly impact sexuality versus inherent features of CP.

HCPs and CP: advances in integrated approaches and residuality of sexual health
The literature presents a uniform scenario characterized, on one hand, by CP patients who refrain from discussing their sexuality with HCPs, despite acknowledging that it could enhance guidance and support in managing their sexual issues (Level 3 of evidence).137 Additionally, patients lament the lack of visibility and information regarding sexuality and treatment side effects (Level 3 of evidence).110 On the other hand, HCPs often avoid exploring patients’ sexual and relational concerns due to taboos, lacking specific training, or overlooking the significance of sexual well-being and pleasure (Level 3 of evidence).138,139 This situation creates an area of “unmet need” (Level 1-4 of evidence).115,140–143
It is increasingly imperative for HCPs to recognize the significance of erotic expression and the potential for pleasure among CP patients despite their pain (Level 4 of evidence).144 Understanding the interplay among these factors is vital for a more comprehensive assessment and management of CP (Level 4 of evidence).145 Patient care should adopt a multidisciplinary approach to address the various levels of complexity in patients’ health, encompassing their sexual expression (Level 4 of evidence).144,146
Similarly, providing HCPs with tools to sensitively address this aspect and acknowledge their sexual and reproductive rights is crucial (Level 4 of evidence).144 In addition to standard clinical measurement tools, it is advisable to incorporate questionnaires assessing sexual health (Level 2 of evidence).147 Moreover, initial evidence suggests that utilizing the ReConnect model in both individual and group sessions may aid HCPs in supporting their patients’ sexual activity goals (Level 3 of evidence).148

Relationship and sexual expression issues
Most contributions come from qualitative studies (interviews and focus groups), more able to capture specific nuances of the sexual and relational experience of people with CP. Although there is considerable variability in how CP affects sexual and relational well-being, a key point is the significant prevalence of dissatisfaction with sexual life, particularly among older patients (Level 2 of evidence).132,149
CP affects sexual identity, body image, and self-worth (Levels 2-4 of evidence).146,150,151 On the relational side, Ragab et al.152 (Level 3 of evidence) sexual relationships are impacted in 86% of migraine patients, with a rate of 26% of divorce. In this sense, problems are not limited to sexual life or to the patient but also involve their partners (Level 3 of evidence).153 Interference in sexual life may create tension, anxiety, and emotional stress inside the relationship (Level 4 of evidence)144 since sexuality is often seen as the “glue” holding the relationship together (Level 4 of evidence).142
The study by Ferrari et al.141 (Level 4 of evidence) highlights the four main domains affecting the sexual and relational experience of CP patients: difficulty in allowing sexual activity; suffering from loss of pleasure and sexual identity; need for mental and physical support from a partner to maintain a sexual activity; need for support from HCPs to preserve their sexual life. In this sense, for certain couples, the illness serves as an opportunity to reinforce their bond, prompting the partner to adopt a supportive, non-judgmental, and proactive approach. Effective communication and the exploration of alternative forms of intimacy may facilitate this empowerment, enabling couples to adapt and discover new strategies to sustain their sexual lives despite experiencing pain (Level 4 of evidence).143

Section C: Breast cancer

Introduction
BC remains one of the most common malignancies in women, and the interventions to possible contain or cure disease (radiation, chemotherapy, cytostatic medications with and without chemically induced menopause) have far reaching implications on the female sexual response cycle. With advances in diagnostic techniques and genetic assessment of those at risk, there is a lead time bias which contributes to earlier diagnosis of younger women, and more survival time in the post therapeutic time. The intersection between BC and sexual function is a dynamic field of study and has been the focus of much research in the past decade. Due to limited content capacity, the primary focus for this intensive review will highlight innovations and updates on Genito-urinary Syndrome of Menopause (GSM), position statements, and controversies. New medications and novel device interventions will also be featured. The importance of sexual orientation, gender identity and ethnic diversity when discussing BC sexuality cannot be underscored yet is beyond scope of this concise review.

Moisturizers and lubricants
Vaginal moisturizers (maintain hydration and use is independent of intercourse) and lubricants (used during coitus to increase lubricity) are considered the frontline mainstay treatment for vaginal dryness and painful intercourse in women with BC and much focus over the last few years has been on the concepts of vaginal pH, osmolality, and the vaginal biome. Palacios et al.154 demonstrated that with reformulated ingredients to maintain the World Health Organization new lubricant standards with vaginal pH and osmolality (≤1200 mOsm/kg)155 water-based lubricants are effective and well tolerated to relief vaginal dryness. While there remains, limited information comparing water based versus anhydrous, silicone-based lubricant, Hickey et al.156 randomized double blind cross over trial in breast cancer patients (BCPs) demonstrated that water- and silicone-based lubricants did not differ statistically in efficacy based on total sexual discomfort, but silicone was preferred over water based, and total discomfort was lower with silicone use. Polycarbophil-based vaginal moisturizers, can create a film over the vaginal tissues which remain adherent to the epithelial cells thereby improving objective symptoms of dryness, dyspareunia, and sexual function/satisfaction,157,158 without impact endometrial thickness in BCP.159 Juliato et al.160 confirmed that polyacrylic acid can help improve sexual function in BCP on tamoxifen. Advani et al demonstrated that a moisturizer/lubricant coupled with counseling and dilator helped women maintain stable sexual function on aromatase inhibitors.161 Sexual accessories (toys) or vaginal dilators, which are made of silicone, should not be used with silicone-based moisturizers or lubricants.
Many new novel non-hormonal products are under varying stages of study and investigation. A novel oil-in-water emulsion vaginal cream demonstrated efficacy and safety for BCP undergoing treatment in a limited 4-week, non-randomized trial.162 There remains scant information on non-hormonal vaginal products and their specific implications on the vaginal biome of BCP.

Professional organizations guidelines/consensus or reviews
Many professional organizations, such as joint consensus report from The Menopause Society (NAMS) and the International Society for the Study of Women’s Sexual Health (ISSWSH)163; The American College of Obstetricians and Gynecologists,164 2021; American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care guideline 165,166; and the International Society for the Study of Vulvovaginal Disease167; have published statements concerning the management of GSM associated with BC. In addition, NAMS has their own 2020 position statement.168 See key recommendations. The NAMS/ISSWSH, ACOG and other guidelines, and detailed literature review articles169–178 discuss and advocate nonpharmacological interventions such as: education, counseling/sex therapy, moisturizers/lubricants, self-stimulators/vibrators, dilators, and physical therapy as key components for front line interventions. Many review articles169–178 also suggest minimally absorbed local vaginal estradiol for refractory cases where symptoms are unrelieved. Ospemifene and Intravaginal dehydroepiandrosterone (DHEA) may also be used but long-term safety data are lacking. In a recent large claims-based analysis, Agarwal et al.179 did not find an increased risk of BC recurrence in women with a personal history of BC who were using vaginal estrogen for GSM. Vaginal Prasterone (DHEA) was studied in a small open prospective pilot study (VIBRA pilot) and180 demonstrated that serum estradiol levels remained low after 6 months of follow up while sexuality and vaginal health improved significantly. The authors concluded that Prasterone seems a safe and effective treatment option for BCP on AI who have GSM. Recent emerging controversies regarding the use of minimally absorbed local vaginal estrogen,181 neither vaginal nor systemic vaginal hormone therapy was associated with an increase of recurrence or mortality. A subgroup analysis, however demonstrated an increased risk of recurrence but not mortality in patients on vaginal estradiol therapy with adjunctive AI use. While intravaginal DHEA and minimally absorbed local vaginal estradiol remain unapproved in this patient population, it is critical to note that most sexual medicine specialists unanimously believe that low dose vaginal estrogen, and Prasterone, appear perfectly appropriate, beneficial, and safe in this setting. Further, and despite some outlier papers, as mentioned above, suggesting that such treatment may not be safe, most of the best literature is extremely reassuring on this point. The decision to use these medications should be based upon shared decision making between the patient, her oncological team, and her sexual health specialist.
Despite extensive reviews and consensus guidelines on the treatment of GSM on BCP, HCP (OB GYN/Primary care/Oncologist have low comfort for managing GSM and prescribing BCP vaginal estrogen.

Device treatment and BCP
There has been a plethora of published systematic reviews and meta-analyses concerning the efficacy and safety of CO2 laser for the treatment of GSM in BCPs.182–191
Cucinella et al.182 provide a current review and is an excellent summary that illustrates that most data is derived from single arm studies which are prospective; the data from randomized sham-controlled trials are limited 192,193 and while efficacy and safety for both fractional and Erbium laser 194,195 the short term are promising, further studies with longer durations of follow-up are necessary.
The scarce scientific research on radiofrequency use in the BCP for the treatment of GSM, has demonstrated extremely limited efficacy if any and mostly short-term safety surveillance.196–198
It remains important to mention that most novel devices used in BCP have shown efficacy (in improving vaginal dryness, dyspareunia, and sexual function measures). Tolerability and safety profile remains positive with limited side effects commonly reported as transient burning, procedural pain, and/or probe insertion discomfort.199 However, these procedures remain cash based, uncovered by medical insurance within the USA but may vary elsewhere and unapproved by regulatory bodies. The data are inconsistent, and many clinical trials remain nonrandomized, without shams, and are observational, retrospective, and are of small numbers, with varying design/protocols and have varying degrees of follow up. Further in-depth study and rigorous research is suggested and warranted. Consumer and health care professionals should exercise vigilance and remain wary of cash-based medi-spas that strongly advocate for these interventions over other simpler approved medications and or therapeutic interventions.

Testosterone
Although it is not feasible to perform an extensive review of testosterone use (pellets/injections/intravaginal cream) in this short summary, it is worthy to note that there is emerging data to support subcutaneous testosterone use for reduction in incidence of BC200,201 and that testosterone may improve symptoms of lowered libido and dyspareunia.201–204 Caution should be exercised as there is limited safety and long-term use data.

Internet-based interventions
There is growing interest in internet-based survivorship care planning (SU) cognitive behavioral therapy (CBT) for interventions that improve sexual function in BCP. Hummel et al demonstrated that internet-based CBT has beneficial effects on sexual function, body image, and menopausal symptomatology in BCP.205 Gorman et al. demonstrated that virtual mindfulness-based intervention is acceptable for BCP.206

Section D: Gynecological cancer

Introduction
Gynecologic cancers, which include endometrial, cervical, ovarian, vaginal, and vulvar cancers, are among the most common cancer in women.207 Collectively, data from recent systematic reviews suggest that gynecologic cancers can lead to significant sexual sequelae,208–211 with gynecologic cancer patients reporting worse sexual function than women in the general population 1-5 years after cancer diagnosis.212 Sexual problems related to treatment for gynecologic cancers are common, multi-faceted,208 and considerable, with two-thirds to three-quarters of women treated for gynecologic cancer reporting decreased sexual activity213,214 and over half reporting decreased sexual satisfaction.213

Overview of sexual problems for gynecologic cancer survivors
The nature and severity of sexual sequelae in gynecologic cancer survivors depend on the cancer site and type and extent of treatment offered, including the extent of surgery and whether the surgery is nerve-sparing,212,215,216 if systemic therapy or pelvic radiation therapy are given,214 which combination of treatments are given,217 as well as other factors, such as partnered status218 and disease stage212; women with advanced disease have worse sexual function than those diagnosed with gynecologic cancer at an earlier stage.212,217 Ovarian insufficiency, which can result from pelvic surgery, radiation, or chemotherapy, can lead to significant sexual problems related to early or abrupt menopausal symptoms.219 A recent meta-analysis of studies examining SD in patients with cervical cancer reported an overall incidence of SD of 80%,210 and similar rates have been reported for women with ovarian cancer.220 When using the more stringent DSM-5 diagnostic criteria for FSD,221 a recent study found a prevalence of 44% in women with gynecologic cancer.213 Risk-reducing surgery for ovarian cancer and, to a lesser extent, hysterectomy, can significantly affect women’s sexual function, whereas use of hormone replacement therapy can mitigate some of these effects and make sex more comfortable.222,223

Sexual problems in diverse subgroups of gynecologic cancer survivors
Although much of the literature examining sexual function in patients with gynecologic cancer has historically suffered from the limitation of largely white and well-educated patient samples,224 a recent trend in research in this area suggests efforts are underway to change this. For instance, in the past few years, several review articles have focused on the unique concerns of female cancer survivors who identify as women of color225 or in older cancer populations, including those with gynecologic cancer.226 Findings from these studies have suggested increased effects of treatment on body image and femininity in Latina women, the unique role of spirituality in coping in African American women,225 and the need to address taboo associated with discussing sexual issues in Muslim women with gynecologic cancer.227 A 2015 study examining sexual problems in 243 medically underserved patients with gynecologic cancer found that lack of a partner was among the most commonly cited reasons for lack of sexual activity, which was high in this sample and comparable to those reported more broadly.224 Taken together, these studies find similar sexual complaints in patients from various races/ethnicities, ages, and religious backgrounds, while also pinpointing concerns unique to these populations.

Pelvic floor dysfunctions
Pelvic floor dysfunctions (also referred to as pelvic floor disorders [PFDs]) include symptoms related to urinary and bladder symptoms (eg, incontinence, urinary tract infections), SDs (eg, dyspareunia, obstructed intercourse), bowel symptoms (eg, incontinence, constipation), pelvic organ prolapse, and pelvic pain.228 Recent systematic reviews of PFD in patients with gynecologic cancers found that these symptoms are highly prevalent,229,230 with SDs, vaginal dryness, stenosis, and pain among the most common sexual side effects.230,231 In cervical cancer, recent data provide evidence for distinct changes in the vagina and vaginal epithelium after radiation therapy, including reduced vaginal epithelial volume and atrophy232; changes such as these, in turn, are related to reduced vaginal lubrication, loss of vaginal elasticity, and reduced vaginal length and swelling in the genitals occurring during sexual arousal.232

Clinical communication about sexual health in care of gynecologic cancer patients
Although the majority of women with gynecologic cancer believe that sexual function is important to their overall health and believe their providers should ask about these issues,233 most report never having had a discussion with their providers about sexual issues.234 Only around 20% of gynecologic cancer providers have received training in discussing sexual function,235 suggesting inadequate clinician knowledge and training in how to discuss these issues appropriately and effectively is a major barrier to communication about this issue. Additional communication barriers include clinician discomfort, lack of time, and certain beliefs, including that patients will raise the topic if needed.235,236 Discussions of sexual issues with gynecologic cancer patients should include open, honest communication, reputable information, and resources provided to patients, and the timing of information with patients’ preferences.237
While efforts to address cancer clinicians’ knowledge and training in discussing sexual health are critical, patient-focused approaches to prompt patients to raise sexual concerns according to their needs and preferences are growing.238–243 One recent example is a patient-focused multimedia intervention that was recently found feasible and acceptable and showed promising effects improving gynecologic cancer patients’ self-efficacy and communication with respect to sexual health.244 If shown to be effective in a larger trial that is currently underway, this intervention could be disseminated widely to facilitate integration of sexual health into cancer care in this population.

Interventions addressing sexual problems in gynecologic cancer

Overview
A recent systematic review of interventions to manage SDs in women with cancer included 36 studies, of which only four were conducted in gynecologic cancer samples; three of these were in mixed breast or gynecologic cancer samples, and one was conducted in an ovarian cancer sample.245 Unfortunately, of the 14 randomized controlled trials of interventions included in the review, only three included gynecologic cancer patients whereas most were in BC, suggesting a significant need for randomized controlled trials of interventions in gynecologic cancer relative to BC.
Pelvic Floor Rehabilitation Interventions. A systematic review and meta-analysis from 2020 on evidence for non-medical muscle interventions on PFDs in patients with gynecologic cancer found five RCTs and 2 retrospective cohort studies examining these interventions.246 Results showed support for pelvic floor muscle training alongside counseling and yoga or core exercises in improving patients’ sexual function in cervical cancer survivors,246 and studies conducted since that review was published in 2020 find further evidence supporting the use of pelvic floor physical therapy on sexual function.247 Regarding vaginal dilators alone, a randomized controlled trial conducted in 88 gynecologic cancer patients undergoing gynecologic brachytherapy found no significant differences in vaginal length, width, or area in patients who used vaginal dilators for 3 months as compared to a care-as-usual control group248; when stratified by adhesion, however, the control group saw a significant decrease in the vaginal area, and greater reduction in vaginal dryness and other pelvic floor symptoms in the dilator group only.248 Adding a psychoeducational booklet increased vaginal dilator use in women receiving pelvic radiation therapy for gynecologic or anorectal cancer, but did not have effects on women’s sexual function.249 Encouragingly, recent data find positive rates of patient engagement with pelvic floor therapy interventions,250 and the ability to train nurses to deliver sexual rehabilitation interventions including vaginal dilation,251 which may help increase the uptake of these interventions. Taken together, findings indicate that pelvic floor rehabilitation and vaginal dilators alone are recommended (Grades A and B, respectively).

Topical interventions
Relative to BC, there have been comparatively few high-quality trials evaluating topical interventions in the treatment of vaginal symptoms affecting sexual function in patients with gynecologic cancer. One of the largest such trials was a three-arm RCT led by Barton252 that compared two dosages of vaginal DHEA against plain vaginal moisturizer for alleviating vaginal symptoms in 464 women with either a breast or gynecologic cancer history reporting at least moderate vaginal symptoms. Findings revealed that all arms reported improvement in severity of dryness and dyspareunia, but the higher dose of DHEA led to greater improvements in sexual function as compared to the lower dose and moisturizer. Only 3% of the sample had gynecologic cancer, however, making it difficult to draw conclusions on the efficacy of this intervention, specifically in this population. Further rigorous studies with larger gynecologic cancer samples are needed to bolster recommendation strength (Grade D recommendation).

Pharmacological interventions
As with the topical agents, the research for pharmacological treatments in women with gynecologic cancer is also scarcer relative to BC. A 2022 trial by Barton253 evaluated two dosages of bupropion, a dopaminergic agent, in a randomized, placebo-controlled trial in 230 women with a history of non-metastatic breast or gynecologic cancer reporting low sexual desire and found that bupropion was no more effective than placebo in improving sexual desire (Grade D recommendation). Ospemifene, an estrogen receptor agonist/antagonist, also known as a selective estrogen receptor modulator selective estrogen receptor modulator, had previously demonstrated benefit in improving vulvo-vaginal atrophy in postmenopausal women without a cancer history,254,255 and was more recently assessed in a sample of 52 women with a diagnosis of early-stage cervical cancer.256 Results of the single arm trial suggested that vaginal health and sexual function outcomes improves significantly.256 However, to date, no large randomized controlled trials of ospemifene in gynecologic cancer patients have been conducted, leading to limited ability to draw conclusions about the efficacy of this medication in this population (Grade D recommendation).

Fractional CO2 lasers
Microablative fractional CO2 lasers, which are believed to promote tissue regeneration within the vaginal wall, have been evaluated as an additional approach to managing vulvo-vaginal atrophy in patients with cancer. A systematic review of fractional CO2 lasers conducted in 2022 surveyed nine studies of this treatment for female cancer survivors, the vast majority of which were conducted in BCP samples.257 However, only one study included gynecologic cancer patients and that was a retrospective study which included both patients with breast and gynecologic cancers (18% gynecologic cancer). Although significant improvements were seen over time in vaginal dryness, dyspareunia, and other vaginal symptoms, because most of the sample had BC, there is limited data supporting this treatment for gynecologic cancer patients (Grade D evidence).258

Psychoeducation and behavioral interventions
A 2022 systematic review of RCTs of six psychoeducation interventions in gynecologic cancer patients and survivors found that these interventions overall improved sexual function in patients, with more substantial effects seen when the partner was involved.259 However, effects varied, with some of the studies finding less substantial effects on patients’ sexual outcomes.260 Different approaches have also shown promise in uncontrolled studies, including a 12-week psychoeducational program featuring mindfulness meditation training for gynecologic and colorectal cancer survivors, which found significant increases over time in sexual function and distress,261 a single half-day mixed educational and behavioral sexual rehabilitation intervention for ovarian cancer survivors that found significant effects on patient sexual outcomes to 6-month follow-up,262 and an online self-help intervention for patients with breast or gynecologic cancer, which saw improvement in sexual outcomes but low uptake.263 There is thus mounting evidence for benefits of psychoeducational and behavioral interventions in this population, and because these interventions generally do not incur side effects or other negative risks, they are highly recommended (Grade A recommendation). Exercise interventions were reviewed for gynecologic cancer survivors in 2016, and at that time, there was insufficient data available to assess effects on sexual function.264 In a more recent review, one single-arm physical activity trial demonstrated improvements in sexual function for endometrial cancer survivors at 6-month follow-up265 (Grade D recommendation).

Section E: Oncologic interventions

Introduction
In 2040, the expected global number of cancer cases is expected to reach 28 million.266 Oncologic outcomes continue to improve, with an increasing number of cancer patients surviving 5 years or more. Thus, it remains imperative to improve the therapeutic index of curative therapies about health-related quality of life (QOL) by reducing treatment-related toxicities. Sexual functioning is an essential component of human health across the lifespan, therefore maintaining sexual function after cancer treatments is an important priority. Herein, we review advancements integrating primary prevention of SD due to cancer treatment, by describing innovations and updates in oncologic interventions that preserve sexual function in cancer survivorship.

Innovations in oncologic interventions and sexual function

Surgical interventions

Bladder
Cystectomy is a preferred treatment for muscle-invasive bladder cancer, with well-established minimally invasive and open techniques that also involve urinary diversion. While minimally invasive techniques, including intracorporeal diversion expectedly improve peri-operative outcomes, outcomes from either approach share similar QOL outcomes.267–270 Continent diversion may improve sexual function.271–273 Neurovascular bundle,271 prostate,274 prostate capsule,275 and seminal vesicle sparing approaches have promising early data for males.276 Female pelvic organ sparing techniques are also evolving, with early data demonstrating functional improvement.277 As with any organ sparing technique, careful patient selection and mature data are needed to ensure oncologic equivalence.

Breast
In BC surgery, image-guidance with ultrasound as compared to palpation in breast-conservation improves cosmetic and sexual outcomes,278 via the reducing in resection margin and positive margin status. Similarly, robotic nipple sparing mastectomy improves both surgical complications and QOL, including sexual well-being compared with open surgery,279 and nipple-sparing mastectomy is generally associated with higher scores for sexual well-being as compared to skin sparing.280

Gynecologic
Minimally invasive laparoscopic or robotic approaches are the most common surgical approaches to hysterectomy. Nerve-sparing surgeries remain under investigation with early data mixed.281 Few developments have emerged in the previous 10 years. Notably, in ovarian cancer patients, lymphadenectomy did not have impacts on sexual function other than for orgasm, showing deterioration from baseline to 12 months as compared to no lympadenectomy282 prompting exploration into plexus-sparing to improve functional outcomes.

Prostate
Radical prostatectomy minimally invasive surgical techniques incorporating nerve-sparing when feasible continue to evolve to maximize tumor control while minimizing postoperative side effects.283 Randomized data demonstrate that robotic assistance and nerve-sparing techniques offer improved peri-operative outcomes,284–289 do not offer a clear benefit to preservation of sexual function over standard approaches,289–293 although meta-analysis suggest some improvements.294 Careful consideration for well-studied techniques,294 and surgical experience295 are critical, given the risk for positive surgical margins292,296 and longer follow-up is necessary.284 Extended PLND, when indicated, does not appear to impact sexual function.297

Rectum
Surgical approaches to rectal cancer have continued to evolve with several new developments related to sexual function preservation when such options can be oncologically considered. Open and laparoscopic techniques show similar results for sexual functioning, though open techniques may have fewer sexual complications in the short term (eg, 3 months298); robotic techniques appear to either improve SD compared to laparoscopy299–301 or have similar outcomes.300,302 In males, several studies have investigated nerve-sparing approaches, including preservation of Denonvillier’s fascia in Total Mesorectal Excision (TME)303,304 resulting in lower rates of erectile and ejaculation dysfunction.
Trans anal mesorectal excision appears to improve sexual function compared to conventional laparoscopic low anterior resection,305 as well as vascular ligation techniques to spare the inferior mesenteric artery and pelvic autonomic nerves.306,307 Finally, incorporating trans-abdominal levator transection into APR improves sexual problems, particularly in males.308

Radiation interventions

Anal/rectal
Late sexual function outcomes from anal cancer Intensity-modulated radiation therapy (IMRT) trials demonstrated that sexual function was largely rare or underreported309,310 with one study showing a clinically significant worsening of dyspareunia at 5 years.310
As neoadjuvant rectal treatment paradigms evolve, understanding the differences in sexual outcomes with short versus long course radiotherapy will continue to be important. When comparing short to long course chemoradiation, while few female patients completed questionnaires, men experienced a decline in function, enjoyment, and sexual problems after surgery that did not return to baseline.311
Functional organ sparing radiotherapy techniques are emerging in anal and rectal cancer, including for females.312–314

Gynecologic
The EMBRACE group published robust data in gynecologic cancer for vaginal dose and toxicity after chemoradiotherapy and image-guided brachytherapy. Dose–effect relationships were established for Grade 2 or higher vaginal stenosis and the Posterior-Inferior Border of Symphysis points and recto-vaginal reference (RV-RP) point doses.315 The recommendation of keeping the external beam dose to 45 Gy and the RV-RP to <65 Gy provides actionable planning objectives to limit vaginal toxicity.316 Long-term data from the PORTEC-2 trial compared sexual outcomes in stage I high-intermediate-risk EC randomized to External Beam Radiation Therapy (EBRT) or vaginal brachytherapy (VBT).317 Sexual function largely did not differ in sexual activity or interest, vaginal dryness/shortening/pain; however, sex was less likely to be enjoyable in patients receiving VBT.

Penile
Recent data help to establish brachytherapy as an organ-sparing treatment for early-stage penile cancer. Extensive experience from a French center suggests that brachytherapy can provide local control rate of 82%318 with successful surgical salvage options for local recurrence (77.4%). Another recently published series showed that total or partial penile preservation was maintained in 87.9% at 5 years319 with interstitial brachytherapy. Pulsed dose rate brachytherapy also maintained penile preservation with no salvage surgery required, though 30% had some tissue necrosis.320

Prostate
Robust recent literature in prostate cancer has demonstrated similar oncologic and sexual functioning outcomes with respect to hypofractionation,321–326 stereotactic body radiation (SBRT),327–332 and dose escalation/boost333–342 even with inclusion of pelvic lymph nodes,343 providing shorter treatment options to patients.
Sexual function-sparing approaches are now possible with advanced image-guided radiotherapy. A vessel-sparing phase 2 trial of localized prostate cancer reported 5-year results that showed significant improvements in erectile function at 2 years (78% CI 71%-85%) compared to conventional (42% CI 38%-45%) or nerve-sparing prostatectomy (24% CI 22%-27%), while maintaining tumor control. Similar prospective early data support MR image-guidance327 to improve sexual and other QOL outcomes.344
Rectal spacers may also improve sexual function with SBRT/IMRT.327,345 In a phase 3 trial, a hydrogel spacer decreased dose to the penile bulb, associated with improvements in erectile function compared to controls.345

Systemic therapy interventions

Nasopharyngeal
An emerging area of interest is the impact of head and neck cancer treatment on sexual function. Recent data from a phase 3 trial of induction chemotherapy for nasopharyngeal carcinoma346 showed improved oncologic outcomes, with concomitant improved QOL outcomes, including sexuality, in the induction group compared to no induction. As with other disease paradigms, downstaging likely contributes to optimizing definitive treatment such that there is less associated toxicity.

Rectum
With TNT as a preferred treatment paradigm in certain locally advanced rectal cancers based on recent practice changing trials,347,348 the impacts of oxaliplatin-based neoadjuvant chemotherapy Health-Related Quality of Life (HRQOL) and sexual function are of increasing importance. Unlike other HRQOL side effects experienced with NAC, the PRODIGE 23 trial found that that surgical intervention increased ED to a lesser degree in the NAC group (31%-51%) compared to the standard of care group (42%-79%) likely due to improved downstaging facilitating surgical resection. Sexual interest was generally low, especially among women, and men with a stoma postoperatively.349 In TNT with CAPEOX, the EXPERT-C trial demonstrated a similar pattern with worsening QOL due to NAC, but improved sexual functioning after surgery in the NAC group.350 This highlights the importance of downstaging for optimizing sexual functioning outcomes.

Uterine
Data from the PORTEC-3 trial comparing adjuvant chemoradiation to radiation alone for high-risk endometrial cancer351 demonstrated that there were no substantial differences in sexual activity after 3 and 5 years, with ~34% sexually active. Sexual activity scores were significantly lower than age-matched norms, with some reporting pain and vaginal dryness.

Treatment choice

Bladder
Bladder preservation with trimodality therapy remains an alternative option to cystectomy for select patients352 with very favorable late QOL, including sexual QOL outcomes, at 10 years in addition to favorable oncologic outcomes.

Penile
Penile preservation with brachytherapy is discussed above.

Prostate
Recent landmark trials for localized prostate cancer have transformed shared decision making. In the ProtecT trial, which demonstrated low prostate cancer specific mortality for active monitoring, surgery and radiotherapy, active monitoring maintained the best urinary and sexual function, though this declines with age. Surgery showed the greatest impacts on sexual function and urinary leakage, while radiotherapy also had decreased sexual and bowel function compared to active monitoring.353–356 Men can now make an informed decision regarding the reduced disease progression and metastases and each treatments side-effect profile. Active surveillance maintains the best erectile and SD profile in those with lower risk disease.357,358 For high and intermediate risk prostate cancer, the benefit of dose escalation with brachytherapy compared to external beam does not confer a greater decrease in sexual function.359
Unfortunately, these landmark trials do not include certain aspects of sexual functioning for sexual minority men, namely receptive anal intercourse, thus treatment choice remains less well informed.360
Several early phase trials evaluating new approaches to localized interventions (including laser ablation, microwave ablation, and cryoablation) have been completed in recent years, though local recurrence rates are sometimes higher so careful selection and target criteria continue to be developed.361–367

Rectum
Rectal cancer management has shifted in recent years towards total neoadjuvant therapy for many patients with locally advanced disease facilitating sphincter-sparing surgery.347 Emerging data support non-operative management in select patients with complete clinical response368 offering patients an option to avoid surgical toxicities, including the SDs described above. Overall, greater sexual toxicities are experienced in patients undergoing Low anterior resection (LAR) or non-TME surgical approaches. Response-guided use of chemoradiation after neoadjuvant chemo in select patients warrants consideration based on the PROSPECT data, offering patients an option to avoid radiation toxicities,369 though longer follow up is needed. Careful multidisciplinary discussion and shared-decision making may provide optimal treatment selection to spare or preserve pelvic organs and enable function-sparing surgery.

Conclusions
Section A: Sexual desire and sexual function are important components of QOL, being linked with overall health and relationship satisfaction. Numerous studies suggest that risk factors, physical inactivity, obesity, metabolic syndrome, diabetes, and CVD lead to low sexual desire and SD. Sexual problems may be a warning sign of underlying disease or a consequence of chronic diseases. Low sexual desire and SD are often associated with low testosterone levels and higher fat mass. Therefore, the prevalence of sexual problems in healthy middle-aged individuals may be associated with the presence of a portfolio of these risk factors and provide an opportunity to modify them as well as treating SD.
Section B: Regardless of the type of diagnosis under the CP umbrella, sexuality is an area that is strongly impacted in patients. Some diagnoses emphasize specificities with respect to the areas of sexual response most involved; however, the unanimous picture drawn is a wounded sexuality, with disruptive effects on romantic and social relationships, QOL, and which still too often remains unheeded by health care providers. In this sense, although early evidence is emerging of awareness and integration of sexological aspects in CP care, these interventions still too often remain limited and sporadic, far from being adopted in standard CP care practices.
Hence, it is crucial to highlight the importance of addressing two fundamental aspects: firstly, the need to assess the occurrence of sexual difficulties within the diagnostic or routine care framework of CP patients. Secondly, the emphasis should be on mitigating symptoms associated with CP and promoting sexual satisfaction rather than solely concentrating on functioning. This affects both research and care, facilitating a transition from a purely performance-oriented approach cantered on sexual function to one that prioritizes overall well-being and QOL.
Section C: The importance of managing GSM is essential for sexual recovery for the BCP and while moisturizers and lubricants have been the primary treatment, the use of alternative therapeutics including hormonal interventions are emerging and gathering significant and important data to support their use. Hormonal interventions for vaginal dryness and dyspareunia should be tailored to the patients’ specific needs and in consultation with her oncological team members. Novel, often costly device interventions and medical spas strongly advocate their use, should be viewed with cautious optimism and preference should be advocated to implement these device-based interventions in a clinical trial setting. Further data are necessary. The management of BC and GSM should include a multifaceted treatment paradigm. Precision medicine should tailor interventions, with patients’ symptoms, and her (and her oncological teams) assessment of the risk, benefit ratio in a shared decision process.
Section D: Sexual problems for women who have been diagnosed with and treated for gynecologic cancers are common, multi-faceted, and distressing, with pelvic floor dysfunctions and associated symptoms (eg, vaginal dryness, stenosis, and pain with vaginal penetration) among the most common sexual problems seen. Relative to BC, research on interventions addressing sexual problems in women with gynecologic cancer has been more limited. At present, there is a robust evidence base for the use of pelvic floor therapy and related management strategies (eg, dilator use) as well as psychosocial and behavioral interventions to treat sexual problems in women with gynecologic cancer. Well-designed controlled trials are needed to evaluate these management strategies and ensure that women experiencing SD after treatment for gynecologic cancer can obtain effective care and maintain their sexual health and well-being.
Section E: Cancer directed therapies continue to evolve to improve the therapeutic ratio and decrease toxicities such as those related to sexual function. Substantial research is dedicated to preserving sexual function are in males—a more equitable approach and distribution of resources is needed moving forward to serve female and sexual/gender minority patients.