The International Society for Sexual Medicine's Process of Care for the Assessment and Management of Testosterone Deficiency in Adult Men.

INTRODUCTION: In 2014, the International Society for Sexual Medicine (ISSM) convened a panel of experts to develop an evidence-based process of care for the diagnosis and management of testosterone deficiency (TD) in adult men. The panel considered the definition, epidemiology, etiology, physiologic effects, diagnosis, assessment and treatment of TD. It also considered the treatment of TD in special populations and commented on contemporary controversies about testosterone replacement therapy, cardiovascular risk and prostate cancer. AIM: The aim was to develop clearly worded, practical, evidenced-based recommendations for the diagnosis and treatment of diagnosis and management of TD for clinicians without expertise in endocrinology, such as physicians in family medicine and general urology practice. METHOD: A comprehensive literature review was performed, followed by a structured, 3-day panel meeting and 6-month panel consultation process using electronic communication. The final guideline was compiled from reports by individual panel members on areas reflecting their special expertise, and then agreed by all through an iterative process. RESULTS: This article contains the report of the ISSM TD Process of Care Committee. It offers a definition of TD and recommendations for assessment and treatment in different populations. Finally, best practice treatment recommendations are presented to guide clinicians, both familiar and unfamiliar with TD. CONCLUSION: Development of a process of care is an evolutionary process that continually reviews data and incorporates the best new research. We expect that ongoing research will lead to new insights into the pathophysiology of TD, as well as new, efficacious and safe treatments. We recommend that this process of care be reevaluated and updated by the ISSM in 4 years.

Testosterone therapy and cardiovascular risk: advances and controversies.

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

5α-Reductase inhibitors alter steroid metabolism and may contribute to insulin resistance, diabetes, metabolic syndrome and vascular disease: a medical hypothesis.

5α-reductases, a unique family of enzymes with a wide host of substrates and tissue distributions, play a key role in the metabolism of androgens, progestins, mineralocorticoids and glucocorticoids. These enzymes are the rate-limiting step in the synthesis of a host of neurosteroids, which are critical for central nervous system function. Androgens and glucocorticoids modulate mitochondrial function, carbohydrate, protein and lipid metabolism and energy balance. Thus, the inhibition of these regulatory enzymes results in an imbalance in steroid metabolism and clearance rates, which leads to altered physiological processes. In this report, we advance the hypothesis that inhibition of 5α-reductases by finasteride and dutasteride alters not only steroid metabolism but also interferes with the downstream actions and signaling of these hormones. We suggest that finasteride and dutasteride inhibit 5α-reductase activities and reduce the clearance of glucocorticoids and mineralocorticoids, potentiating insulin resistance, diabetes and vascular disease.

Clinical Use of Aromatase Inhibitors in Adult Males.

INTRODUCTION: There is a growing interest in the treatment of late-onset hypogonadism, another name for the study of testosterone deficiency in an older age group. Initial attempts at testosterone replacement have also brought attention to the possible adverse effects on the patients' cardiovascular risk factors and their prostate health. The "female" hormone estradiol is no longer considered as the feminizing hormone, as it has been identified to have an effect on the sexual and general well-being of adult males. Urologists and endocrinologists alike have started to pay attention to the serum T/E2 (testosterone : estradiol) ratio that appears to be more important than the respective individual hormonal levels. Therein lies the possible role of aromatase inhibitors (AIs) in restoring the normal balance of serum testosterone and estradiol levels for the adequate treatment of late-onset hypogonadism, while limiting the potential adverse effects. Currently, other established clinical indications of AIs include the treatment of breast cancer in female patients and developmental growth problems in pediatric patients. AIM: This review evaluates the role of AIs as a treatment option for late-onset hypogonadism and the evidence for its other clinical uses in men, including its possible adverse effects. METHODS: A literature review was performed with regards to the use of aromatase inhibitors in adult males, the role of estrogens in adult males, as well as adverse effect of AIs on bone health in adult males. MAIN OUTCOME MEASURES: To evaluate the evidence for the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, and male subfertility. To evaluate the evidence for the possible adverse effects on the bone health of adult males with the use of AIs. RESULTS: Currently there is no literature to recommend the use of AIs in adult males to treat late-onset hypogonadism, obesity-related hypogonadotropic hypogonadism, gynecomastia, or male subfertility, although some positive effects have been reported. The adverse effects on bone health seen in females treated with AIs are not seen in males. CONCLUSIONS: With the better understanding of the T/E2 ratio in adult males, the lack of scientific data to show that bone health is adversely affected by AI usage in adult males, the positive effects of AIs on the treatment of conditions like late-onset hypogonadism and male subfertility encourages conducting large-scale, multicenter, randomized controlled trials for the clinical use of AIs in adult males. Tan RBW, Guay AT, and Hellstrom WJG. Clinical use of aromatase inhibitors in adult males. Sex Med Rev 2014;2:79-90.

Are there variances of calculated free testosterone attributed to variations in albumin and sex hormone-binding globulin concentrations in men?

OBJECTIVE: Calculated free testosterone (cFT) is determined from total testosterone (TT), sex hormone binding globulin (SHBG), and albumin (Alb) levels using mathematical formulae. Variations in cFT due to changes in SHBG or Alb have not been investigated. We evaluated potential cFT variances determined with fixed Alb (4.3 g/dL) and measured Alb, and the point at which low SHBG and Alb combinations produced significant cFT variance. METHOD: We analyzed 11,176 data points from 5,797 men. cFT values with fixed versus actual Alb values were evaluated and compared. cFT levels were theoretically determined for all possible combinations of TT, SHBG, and Alb (8,343,552 combinations). Agreement between the 2 measures was assessed with Lin's concordance coefficient. RESULTS: Mean Alb was 4.06 ± 0.32 g/dL. Mean SHBG was 39.0 ± 23.6 nmol/L. A fixed Alb of 4.3 g/dL did not produce significant variance for most cFT evaluations. Accuracy decreased when Alb was ≤3.5 g/dL in combination with SHBG ≤30 nmol/L, and this occurred in 1.2% of all data points. CONCLUSION: A fixed Alb of 4.3 g/dL is acceptable for most clinical evaluations. If Alb is ≤3.5 g/dL and SHBG is ≤30 nmol/L, the variance increases, and a free testosterone (FT) measurement by equilibrium dialysis is warranted for better accuracy.

Diagnosis and treatment of erectile dysfunction for reduction of cardiovascular risk.

PURPOSE: We established erectile dysfunction as an often neglected but valuable marker of cardiovascular risk, particularly in younger men and men with diabetes. We also reviewed evidence that lifestyle change, combined with informed prescribing of pharmacotherapies used to mitigate cardiovascular risk, can improve overall vascular health and sexual functioning in men with erectile dysfunction. MATERIALS AND METHODS: We performed a PubMed® search for articles and guidelines pertinent to relationships between erectile dysfunction and cardiovascular disease, cardiovascular and all cause mortality, and pharmacotherapies for dyslipidemia and hypertension. The clinical guidance presented incorporates the current literature and the expertise of the multispecialty investigator group. RESULTS: Numerous cardiovascular risk assessment tools exist but risk stratification remains challenging, particularly in patients at low or intermediate short-term risk. Erectile dysfunction has a predictive value for cardiovascular events that is comparable to or better than that of traditional risk factors. Interventional studies support lifestyle changes as a means of improving overall vascular health as well as sexual functioning. Statins, diuretics, ß-blockers and renin-angiotensin system modifiers may positively or negatively affect erectile function. Furthermore, the phosphodiesterase type 5 inhibitors used to treat erectile dysfunction may have systemic vascular benefits. CONCLUSIONS: Erectile dysfunction treatment should be considered secondary to decreasing cardiovascular risk. However, informed prescribing may prevent worsening sexual function in men receiving pharmacotherapy for dyslipidemia and hypertension. As the first point of medical contact for men with erectile dysfunction symptoms, the primary care physician or urologist has a unique opportunity to identify those who require early intervention to prevent cardiovascular disease.

The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease.

The Princeton Consensus (Expert Panel) Conference is a multispecialty collaborative tradition dedicated to optimizing sexual function and preserving cardiovascular health. The third Princeton Consensus met November 8 to 10, 2010, and had 2 primary objectives. The first objective focused on the evaluation and management of cardiovascular risk in men with erectile dysfunction (ED) and no known cardiovascular disease (CVD), with particular emphasis on identification of men with ED who may require additional cardiologic work-up. The second objective focused on reevaluation and modification of previous recommendations for evaluation of cardiac risk associated with sexual activity in men with known CVD. The Panel's recommendations build on those developed during the first and second Princeton Consensus Conferences, first emphasizing the use of exercise ability and stress testing to ensure that each man's cardiovascular health is consistent with the physical demands of sexual activity before prescribing treatment for ED, and second highlighting the link between ED and CVD, which may be asymptomatic and may benefit from cardiovascular risk reduction.

Dehydroepiandrosterone (DHEA)--a precursor steroid or an active hormone in human physiology.

INTRODUCTION: The circulation of large amounts of dehydroepiandrosterone (DHEA) and its sulfated derivative (DHEA-S) suggests a physiological role in human physiology. In the central nervous system, DHEA is considered a neurosteroid with a wide range of functions. AIM: The goal of this review is to discuss metabolism, biochemical, and physiological mechanism of DHEA action and the potential role of DHEA in aging and in ameliorating a host of pathological conditions, associated with aging. METHODS: We examined preclinical and clinical data reported in various studies from the available literature concerning the effects of DHEA in normal and pathological conditions. MAIN OUTCOME MEASURES: Data reported in the literature were analyzed, reviewed, and discussed. RESULTS: DHEA mediates its action via multiple signaling pathways involving specific membrane receptors and via transformation into androgen and estrogen derivatives (e.g., androgens, estrogens, 7α and 7ß DHEA, and 7α and 7ß epiandrosterone derivatives) acting through their specific receptors. These pathways include: nitric oxide synthase activation, modulation of γ-amino butyric acid receptors, N-methyl D-aspartate, receptors sigma receptors (Sigma-1), differential expression of inflammatory factors, adhesion molecules and reactive oxygen species, among others. Clinical and epidemiological studies suggested that low DHEA levels might be associated with ischemic heart disease, endothelial dysfunction, atherosclerosis, bone loss, inflammatory diseases, and sexual dysfunction. Most importantly, no significant adverse or negative side effects of DHEA were reported in clinical studies of men and women. CONCLUSIONS: DHEA modulates endothelial function, reduces inflammation, improves insulin sensitivity, blood flow, cellular immunity, body composition, bone metabolism, sexual function, and physical strength in frailty and provides neuroprotection, improves cognitive function, and memory enhancement. DHEA possesses pleiotropic effects and reduced levels of DHEA and DHEA-S may be associated with a host of pathologies; however, the clinical efficacy of DHEA supplementation in ameliorating patho-physiological symptoms remains to be evaluated.

Testosterone deficiency and risk factors in the metabolic syndrome: implications for erectile dysfunction.

The most common cause of erectile dysfunction (ED) is penile vascular insufficiency. This is usually part of a generalized endothelial dysfunction and is related to several conditions, including type 2 diabetes mellitus, hypertension, hyperlipidemia, and obesity. These conditions underlie the pathophysiology of metabolic syndrome (MetS). Hypogonadism, or testosterone deficiency (TD), is an integral component of the pathology underlying endothelial dysfunction and MetS, with insulin resistance (IR) at its core. Testosterone replacement therapy for TD has been shown to ameliorate some of the components of the MetS, improve IR, and may serve as treatment for decreasing cardiovascular and ED risk.

Adverse side effects of 5α-reductase inhibitors therapy: persistent diminished libido and erectile dysfunction and depression in a subset of patients.

INTRODUCTION: 5α-reductase inhibitors (5α-RIs), finasteride and dutasteride, have been approved for treatment of lower urinary tract symptoms, due to benign prostatic hyperplasia, with marked clinical efficacy. Finasteride is also approved for treatment of hair loss (androgenetic alopecia). Although the adverse side effects of these agents are thought to be minimal, the magnitude of adverse effects on sexual function, gynecomastia, depression, and quality of life remains ill-defined. AIM: The goal of this review is to discuss 5α-RIs therapy, the potential persistent side effects, and the possible mechanisms responsible for these undesirable effects. METHODS: We examined data reported in various clinical studies from the available literature concerning the side effects of finasteride and dutasteride. MAIN OUTCOME MEASURES: Data reported in the literature were reviewed and discussed. Results. Prolonged adverse effects on sexual function such as erectile dysfunction and diminished libido are reported by a subset of men, raising the possibility of a causal relationship. CONCLUSIONS: We suggest discussion with patients on the potential sexual side effects of 5α-RIs before commencing therapy. Alternative therapies may be considered in the discussion, especially when treating androgenetic alopecia.

Endocrine aspects of male sexual dysfunctions.

INTRODUCTION: Endocrine disorders may adversely affect men's sexual function. AIM: To provide recommendations based on best evidence for diagnosis and treatment of endocrine-related male sexual dysfunctions. METHODS: The Endocrine Aspects of Male Sexual Dysfunctions Committee, including 11 members from eight countries and four continents, collaborated with the Endocrine subcommittee of the Standards Committee of the International Society for Sexual Medicine. Medical literature was reviewed in detail, followed by extensive internal committee discussion over 2 years, then public presentation and discussion with the other experts before finalizing the report. MAIN OUTCOME MEASURE: Recommendations based on grading of evidence-base medical literature and interactive discussion. RESULTS: From animal studies, it is derived that testosterone modulates mechanisms involved in erectile machinery, including expression of enzymes that both initiate and terminate erection. In addition, testosterone is essential for sexual motivation. Whether these findings could be extrapolated to human erections is unclear. Testosterone plays a broad role in men's overall health. Recent studies have established strong associations between low testosterone and metabolic and cardiovascular imbalances. In some studies, low testosterone decreased longevity; however, longitudinal studies do not support the predictive value of low testosterone for further cardiovascular events. The article proposes a standardized process for diagnosis and treatment of endocrine-related male sexual dysfunctions, updating the knowledge on testosterone and prostate safety. There is no compelling evidence that testosterone treatment causes prostate cancer or its progression in men without severe testosterone deficiency (TD). The possible roles of prolactin and thyroid hormones are also examined. CONCLUSIONS: Men with erectile dysfunction, hypoactive sexual desire and retarded ejaculation, as well as those with visceral obesity and metabolic diseases, should be screened for TD and treated. Prospective interventional studies are required before screening for TD in more conditions, including cardiovascular diseases, and considering correction as preventive medicine as much data suggests.

Assessing symptoms of hypogonadism by self-administered questionnaire: qualitative findings in patients and controls.

BACKGROUND: Current screening instruments for hypogonadism lack adequate specificity and diagnostic accuracy. A new self-administered questionnaire of hypogonadism symptoms is being developed to address this need. The process for questionnaire development and results from the first (qualitative) phase are presented. METHODS: Qualitative interviews were conducted based on a new conceptual model of hypogonadism and according to standards for questionnaire development. An item pool was generated from focus groups and in-depth interviews with two groups of hypogonadal patients, treated (N = 26) and untreated (N = 26), and age-equivalent controls (N = 28). Standardized scoring of the qualitative interviews was used to confirm conceptual domains in the model and to generate questionnaire items for further validation. RESULTS: Key domains identified in both patients and controls included: (a) physical function; (b) bodily signs and symptoms; (c) sexual function and libido; (d) sleep function; (e) mood and affective function; (f) memory and cognitive function. The final domain is distress or bother associated with hypogonadism symptoms. This domain was only relevant to the patient groups. CONCLUSIONS: The first stage in the design of a new hypogonadism screener has been completed. Seven domains were identified and draft items were developed in each domain according to current standards of patient-reported outcomes.

Absorption of testosterone gel 1% (Testim) from three different application sites.

INTRODUCTION: A popular treatment choice for male hypogonadism is topical testosterone gel. Two proprietary formulations, Testim Gel 1% (Auxilium Pharmaceuticals, Malvern, PA, USA) and AndroGel 1% (Solvay Pharmaceuticals, Marietta, GA, USA), are available. The recommended Testim application site is limited to the arms/shoulders, whereas AndroGel may be applied to the abdomen, shoulders, and upper arms. AIM: To compare absorption variability when applying Testim to various body sites. MAIN OUTCOME MEASURES: Total testosterone (TT) and calculated free testosterone (CT(free)). METHODS: Hypogonadal men (TT < 300 ng/mL) applied Testim to three distinct anatomical sites for 1 month per site: arms/shoulders (A), chest/abdomen (C), and calves/legs (L). Pretreatment TT and CT(free) were compared with end-of-month measurements. Safety was assessed with prostate-specific antigen (PSA) and hemoglobin (Hb) measurements. RESULTS: Twenty-one hypogonadal men (age 56.9 +/- 9.0) naïve to prior testosterone therapy and otherwise in good health participated. Three groups of seven applied Testim in the sequence ACL, CLA, and LAC. Overall TT and CT(free) increased significantly over pretreatment levels (P < 0.0001) into the normal range. Application sites differed with regard to TT levels achieved, A > C >or= L (P = 0.011). No significant sequence effects were observed, however, the ACL group achieved the highest levels. CT(free) correlated well with TT in all men (R(2) = 0.87) and by application site (R(2) = 0.91, 0.85, and 0.86 for A, C, L, respectively). Pre- and post-treatment PSAs were similar; mean pretreatment Hb increased from 14.7 +/- 1.47 to 15.5 +/- 1.3 g/dL at month 3. Hemoglobin corrected to normal in four subjects with anemia at enrollment (Hb < 13.5 g/dL). CONCLUSIONS: Testim Gel 1% applied to various anatomical sites increases TT and CT(free) into the normal range; the best levels are achieved with arms/shoulder application. Flexibility in the application site of Testim is possible if TT or CT(free) is monitored to ensure adequate therapeutic levels. Anemia, possibly associated with testosterone deficiency, was an incidental finding in several men and was corrected with topical testosterone replacement.

Testosterone therapy in women with gynecological and sexual disorders: a triumph of clinical endocrinology from 1938 to 2008.

INTRODUCTION: Although the term "medicalization" has been used by some to describe contemporary testosterone use in women with sexual disorders and testosterone deficiency syndrome, testosterone therapy for women with various gynecological and sexual disorders has been practiced since the late 1930s. AIM: The study aimed to perform a historical review of testosterone use in women with sexual and gynecological disorders. This review is necessary to bridge important knowledge gaps in the clinical use of testosterone in women with sexual health concerns and to provoke new thoughts and understanding of the multidisciplinary role of testosterone in women's overall health. METHODS: Review of medical literature on androgen therapy in women was carried out from 1938 through 2008. RESULTS: Approximately 70 years ago, clinicians from various disciplines relied on personal experience and clinical observations for outcome assessment of testosterone therapy in women. These early reports on testosterone use in women with sexual medical problems served as a foundation for the development of contemporary approaches and subsequent testosterone treatment regimens. Testosterone use was reported for sexual dysfunction, abnormal uterine bleeding, dysmenorrhea, menopausal symptoms, chronic mastitis and lactation, and benign and malignant tumors of the breast, uterus, and ovaries. CONCLUSIONS: Health-care professionals engaged in the management of women's health issues have observed the benefits of androgen therapy throughout much of the 20th century. Despite this clinical use of testosterone in women for more than seven decades, contemporary testosterone therapy in women is hotly debated, misunderstood, and often misrepresented in the medical community.

The emerging link between hypogonadism and metabolic syndrome.

The metabolic syndrome (MS) is comprised of various medical conditions that confer increased risk of diabetes and cardiovascular disease. The pathophysiologic components of MS include glucose abnormality, obesity or increased waist circumference, increased blood pressure, and hyperlipidemia. There is an increased risk of hypogonadism in men with MS and its individual components, including insulin resistance, considered by some to be at the core of MS. Hypogonadism may even predict MS. These factors are interwoven and impact overall health, including sexual dysfunction. One interesting and important question is whether treating hypogonadism with testosterone replacement will ameliorate the pathological components of MS.

The brain, the penis and steroid hormones: clinical correlates with endothelial dysfunction.

Erectile function is a complex neurovascular process that depends on the health of the central and peripheral nervous systems and the vasculature. Thus, signaling from the central nervous system (brain) to the peripheral nervous system (penis) is critical and is modulated by a set of complex interactions that depend on cerebral and vascular circulation. The cerebral and peripheral vasculatures are target tissues for sex steroid hormones. Gonadal, adrenal and neurosteroids regulate the function and physiology of the endothelium and modulate vascular and cerebral circulation by genomic and non-genomic dependent mechanisms. Recent advances in cell and molecular biology have defined a critical role of endothelium in vascular function. A host of biochemical and clinical markers of endothelium function and dysfunction have been identified to assess vascular pathology. Emerging evidence suggests that sex steroid hormones play an important role in maintaining endothelial health and sex steroid deficiency is associated with endothelial dysfunction, vascular disease and erectile dysfunction. Such information has important clinical implications in patient management with sex steroid hormone insufficiency, diabetes, metabolic syndrome, vascular disease and erectile dysfunction. In this review, we discuss the role of sex steroid hormones in modulation of the biochemical and clinical markers associated with endothelial dysfunction. Specifically the regulation of endothelial nitric oxide synthase, asymmetric dimethylarginine, reactive oxygen species, endothelin-1, inflammatory cytokines, tumor necrosis factor-alpha, markers of cell adhesion, dysregulation of fibrinolytic factors and the inability to regenerate from endothelial progenitor cells concomitant with increased endothelial apoptosis, increased cellular permeability and increased vascular tone.

Are the Endocrine Society's Clinical Practice Guidelines on Androgen Therapy in Women misguided? A commentary.

The Endocrine Society Clinical Guidelines on Androgen Therapy in Women (henceforth referred to as the Guidelines) do not necessarily represent the opinion held by the many health-care professionals and clinicians who are specialized in the evaluation, diagnosis, and treatment of women's health in androgen insufficiency states. The recommendations provided in the published Guidelines are neither accurate nor complete. We disagree with the therapeutic nihilism promoted by these Guidelines. The members of the Guidelines Panel (henceforth referred to as the Panel), in their own disclaimer, stated that the Guidelines do not establish a standard of care. Based on data available in the contemporary literature, on the role of androgens in women's health, we provide in this commentary a point-by-point discussion of the arguments made by the Panel in arriving at their recommendations. It is our view that the Guidelines are not based on the preponderance of scientific evidence. Health-care professionals, physicians, and scientists often disagree when determining how best to address and manage new and emerging clinical issues. This is where we stand now as we endeavor to understand the role of androgens in a woman's health and welfare. Indeed, some basic facts are not in contention. All agree that dehydroepiandrosterone sulfate (DHEA-S) production from the adrenal gland begins during the preteen years, peaks in the mid 20s, then declines progressively over time. In contrast, ovarian androgen (i.e., testosterone) secretion commences at puberty, is sustained during a woman's peak reproductive years and declines as a woman ages, with a more rapid and steep decrease after surgical menopause. However, there are ample data to suggest that adrenal androgens play a role in the development of axillary and pubic hair, and that testosterone is critical for women's libido and sexual function. We take this opportunity to invite members of the Panel on Androgen Therapy in Women to discuss, clarify, comment, or rebut any of the points made in this Commentary. It is our goal to elevate this debate in order to provide women who are afflicted with androgen insufficiency and sexual disorders with the highest quality health care and to relieve their distress and suffering, as well as to improve their quality of life.