The Burden of Testosterone Deficiency Syndrome in Adult Men: Economic and Quality-of-Life Impact

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The Burden of Testosterone Deficiency Syndrome in Adult Men: Economic and Quality-of-Life Impact Mario Maggi, MD,* Claude Schulman, MD, PhD,† Richard Quinton, MA, MD, FRCP,‡ Sue Langham, PhD,§ and Kerstin Uhl-Hochgraeber, MD¶ *Andrology Unit, Department of Clinical Physiopathology, University of Florence, Florence, Italy; †Department of Urology, Erasme Hospital, Brussels, Belgium; ‡Endocrine Unit, Royal Victoria Infirmary & University of Newcastle-upon-Tyne, UK; § Independent Health Economist, Manchester, UK; ¶Bayer Schering Pharma AG, Global Health Economics & Outcomes Research, Berlin, Germany DOI: 10.1111/j.1743-6109.2007.00531.x

ABSTRACT

Introduction. Testosterone deficiency syndrome (TDS) causes a wide range of symptoms that can lead to significant morbidity. Preliminary evidence has also linked TDS with premature mortality and with a number of comorbid diseases including diabetes and metabolic syndrome. Such associations can lead to substantial economic and qualityof-life implications, the magnitude of which remains largely unknown. Aim. To review the economic and quality-of-life consequences of a largely untreated condition and to consider the likely health economic benefits of testosterone treatment. Methods. A systematic review of four main areas: epidemiological evidence of the magnitude of TDS, estimates of cost of illness, impact on quality-of-life, and cost-effectiveness of testosterone treatment. Main Outcome Measure. Review of peer-reviewed literature. Results. The lack of clear universally accepted diagnostic criteria and the uncertainty surrounding the link between TDS and some of its consequences complicate the estimation of the burden of illness of TDS. Consequences of TDS that potentially lead to increased economic burden include depression, sexual dysfunction, mild cognitive impairment, osteoporosis, cardiovascular disease, and mortality. However, although good evidence exists demonstrating an association between TDS and sexual dysfunction and cognitive impairment, evidence is less strong for depression, the incidence of fractures and mortality, and highly controversial for cardiovascular disease. The consequences that are likely to impact on patients’ quality of life include sexual function, energy levels, body composition, mood, and cognitive function. Conclusion. Understanding the burden is only the first step decision makers need to take to decide whether to allocate scarce resources to treat the condition. To make informed decisions on when and who to treat information is also needed on the cost-effectiveness of available treatments. Such data would highlight the benefits of treatment of TDS to physicians, patients, and to society as a whole. Maggi M, Schulman C, Quinton R, Langham S, and Uhl-Hochgraeber K. The burden of testosterone deficiency syndrome in adult men: Economic and qualityof-life impact. J Sex Med 2007;4:1056–1069. Key Words. Testosterone Deficiency; Cost of Illness; Quality of Life; Hypogonadism

Introduction

T

estosterone deficiency syndrome (TDS), or male hypogonadism, is characterized by a wide range of symptoms that can place a significant burden on both the patient and the healthcare system. In adult subjects, the symptoms of TDS can include sexual dysfunction, cognitive impairJ Sex Med 2007;4:1056–1069

ment, decreased energy, depressed mood, increased fat mass, loss of muscle mass and strength, and reduced bone mineral density (BMD) [1,2]. The condition can affect patients in a number of ways impacting on their physical, social, emotional, cognitive, and sexual functioning [3], which are all key domains inherent in health-related quality of life [4,5]. Furthermore, TDS has also © 2007 International Society for Sexual Medicine

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Burden of Testosterone Deficiency Syndrome recently been associated with an increase in mortality risk [6]. A number of the symptoms, including fatigue and low mood which may lead to depression [7] and loss of bone density which may lead to osteoporosis [8–10], have the potential to cause considerable short-term and long-term economic consequences, the magnitude of which remains largely unknown. TDS has in the past been referred to by an assortment of names, however, there has recently been a call to use appropriate terminology [11]. The causes of TDS are wide ranging. They can be congenital (e.g., Klinefelter’s syndrome) or acquired (e.g., chemotherapy). Classical forms include primary hypogonadism, caused by an abnormality of the testes, and secondary hypogonadism, caused by pituitary or hypothalamic dysfunction. In addition to these classical forms of TDS, some individuals, including older men exhibit a mixed pattern comprising both primary and secondary testosterone deficiency. There are a number of comorbid conditions that have been associated with TDS including end-stage renal disease, AIDS, obesity, diabetes mellitus, cardiovascular disease, liver cirrhosis, chronic renal failure, chronic obstructive pulmonary disease [12], and more recently the metabolic syndrome [13,14]. Treatment for TDS has been available for about 60 years, and restoring physiological testosterone levels to normal has been shown to relieve most of the symptoms of the condition [15,16]. However, despite the availability of effective treatment and the publication of several evidence-based clinical guidelines outlining recommendations for the diagnosis and treatment of the disorder [1,2], TDS remains a widely underdiagnosed and undertreated condition. Evidence from the United States suggests only 5% of all men with TDS are diagnosed and treated [17]. The Klinefelter’s karyotype (typically 46XXY), the most prevalent form of classical hypogonadism, occurs in around 1 in 600 live male births [18]; however, the number of diagnosed cases in the adult male population is far lower. Studies in Denmark [18] and the United Kingdom [19] suggest that more than 90% of affected men are not diagnosed during their lifetime, denying them effective treatment. Furthermore, children are increasingly being cured of previously lethal cancers [20], but TDS and other endocrine disorders, are still highly prevalent among those surviving into adult life. This article aims to review the economic and quality-of-life consequences of a largely untreated

condition and considers the likely health economic benefits of testosterone treatment. In order to evaluate the economic impact of TDS, several key aspects of the disorder need to be explored. These include some measure of the magnitude of the condition, which requires clear diagnostic criteria, and an estimate of the incidence of its consequences along with their associated costs. There is, however, considerable uncertainty on both of these requirements. This review therefore starts with defining TDS, before reviewing the available data on the magnitude of the condition, the economic and quality-of-life consequences of undertreatment, and the potential cost-effectiveness of testosterone treatment. Methods

Electronic searches were undertaken to identify published and unpublished reports in four subject areas: epidemiological, cost-of-illness, quality-oflife, and economic evaluations. Key words used in the searches included hypogonadism, prevalence, incidence, cost and cost analysis, quality of life, and testosterone replacement. Search terms embraced all possible variations of terminology. For example, for TDS, search terms included hypogonadism, male menopause, testosterone deficiency, androgen deficiency, andropause, male climacteric, androgen deficiency in the aging male, late onset hypogonadism, and partial androgen decline in the aging male. Databases searched included MEDLINE, Cochrane library, and several health economic databases. A number of other sources of information were used, including scanning relevant studies to identify additional data, Internet searches, and the expert knowledge of the international list of authors. The following inclusion criteria were implemented. For the epidemiological section, studies had to report information on either the prevalence or incidence of the disorder. For cost of illness, a very broad approach was used, which was to include any study reporting cost or resource use associated with TDS. For quality of life, studies had to report the impact TDS has on healthrelated quality of life. Finally, for economic evaluations, again a broad approach was used to identify any study that reported resource use and/or cost and/or quality-of-life benefits of TDS treatment. No cost-of-illness studies were identified. Therefore, in order to explore the economic impact, information on the clinical consequences J Sex Med 2007;4:1056–1069

1058 of untreated TDS was sought. For each clinical consequence, the following data were extracted: evidence of the strength of association with TDS, incidence in adults with TDS, and associated costs. Cost data, where available, have been extracted and presented in their originally reported form, stating the country, year, and currency. Costs from health economic studies not already presented in U.S. dollars have been converted using purchasing power parities or historical exchange rates where relevant and have been provided in brackets directly after the original reported cost. Defining TDS

The burden of TDS can only be clearly understood if the disorder is easily diagnosed and defined. This is not yet the case with TDS. There are several international clinical practice guidelines for the diagnosis and treatment of TDS. The most recent guidelines have come from The Endocrine Society in the United States [1] and a collaboration of the International Society of Andrology, the International Society for the Study of the Aging Male, and the European Association of Urology [2]. Both sets of guidelines suggest that a diagnosis should be made only in men with signs and symptoms characteristic of TDS and biochemical evidence of low serum testosterone, as neither are consistently reliable alone. However, diagnosis of the condition remains elusive due to two main factors. First, the signs and symptoms of TDS in adult men are often difficult to recognize, particularly in elderly men. Symptoms can be nonspecific and therefore easily attributed to comorbid disease, therefore a serum testosterone level may not necessarily be routinely ordered for such patients. Symptoms are likely to be more obvious and therefore more easily detectable in patients with severe TDS [1,21] and as such the signs and symptoms listed in the most recent clinical guidelines reflect physicians experience of this subgroup of patients [1]. However, as of yet, there are no clear guidelines outlining the testosterone levels which are associated with mild, moderate, and severe forms of the condition. Second, there is no agreed universal threshold level of testosterone below which a diagnosis of TDS should be made and treatment should be started. Threshold levels vary by country and more importantly by laboratory [17,22], reflecting the differences inherent in clinical guidelines. Such uncertainty arises out of the lack of data on the association between treatment threshold levels and J Sex Med 2007;4:1056–1069

Maggi et al. outcomes. The serum testosterone threshold at which treatment would significantly improve outcomes in the condition remains unknown. Moreover, any such threshold level could be agedependent (testosterone levels naturally decrease with age, though whether this is adaptive, maladaptive, or a neutral is not known [23]), etiologydependent (varying between the primary cause of testosterone deficiency [24]), or symptomdependent (varying between specific symptoms and associated comorbidities [25]). The two recent clinical guidelines have been naturally cautious in recommending threshold limits. One suggests a lower limit of the normal range for total testosterone of 300 ng/dL (10.4 nmol/L) [1]. The other suggests testosterone therapy is required at levels below 231 ng/dL (8 nmol/L). However, the guideline points out that symptoms can occur between the levels of 231 ng/dL (8 nmol/L) and 346 ng/dL (12 nmol/L), and in these patients testosterone treatment is an option if alternative reasons for clinical symptoms have been excluded [2]. Both of these estimates relate to data from young men and therefore may not apply to the elderly population. Prevalence studies therefore based on these two differing threshold limits would not only result in a significant divergence in estimates, but also possibly overestimate prevalence in the higher age groups. Epidemiological studies of TDS therefore require clearer diagnostic criteria. More accurate prevalence estimates would arise if suggested threshold limits could be used alongside clinical markers of the condition. Screening tools, e.g., the Aging Males’ Symptoms Rating Scale, have been developed to help diagnose the condition. However, because of the general nonspecific nature of many of the symptoms of TDS, such tools lack adequate specificity [26]. This means that although they are successful in diagnosing patients with the condition, they also incorrectly diagnose too many nonhypogonadal men as having TDS. The recently published structured interview, Androtest, provides improved sensitivity and specificity (68% and 65%, respectively) in detecting low testosterone (<10.4 nmol/L). The Androtest is a validated inventory which helps to identify hypogonadal patients among those reporting sexual dysfunction, one of the more common TDS symptoms [27]. However, for the diagnosis of TDS, the Androtest, as well as other structured inventories, cannot substitute biochemical tests, but only corroborate appropriately timed laboratory estimations of testosterone.

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Burden of Testosterone Deficiency Syndrome Magnitude of TDS

Until data become available on the relationship between testosterone threshold limits, symptoms and treatment outcomes, any studies reporting the epidemiological indicators of TDS are likely to be flawed, particularly in older men. Perhaps because of this, there are few data on the prevalence of TDS and only one on its incidence. Evidence suggests that the prevalence of classical forms of TDS is around 1 in 200 adult males [28]. This has been calculated from the prevalence of Klinefelter’s syndrome (1.5–2.5 per 1,000 male births [29]), which has been estimated to account for 35–50% of hypogonadal men requiring treatment [28]. No other data exist on the epidemiological factors of classical TDS or on the incidence of its causal factors. The only other study that sheds some light on prevalence in this younger age group was the Baltimore Longitudinal Study of Aging (BLSA). Using a definition of TDS of total testosterone level of <325 ng/dL, the study estimated around 12% of men younger than the age of 50 years were hypogonadal [23]. This figure may overestimate the true prevalence of TDS in clinical practice, where the signs and symptoms of the disorder are used in additional to the measurement of serum testosterone to make a diagnosis, as suggested in recent guidelines [1,2]. Of the 12% of men identified in the BLSA study as having TDS, it is not possible to estimate how many would exhibit no signs and symptoms. However, it is likely that only those with more severe TDS and hence those with more symptomatic disease would be diagnosed and subsequently treated in clinical practice [1,21]. Several studies have assessed the prevalence of TDS in older men. Evidence suggests that prevalence is high and increases with age. The BLSA estimated almost 50% of men in their 80s have TDS. The Massachusetts Male Aging Study used both clinical markers and biochemical markers to define TDS and reported a prevalence of 12% at follow-up and an incidence of 12.3 per personyears [30]. Finally, the Hypogonadism in Males study, using a threshold level of <300 ng/dL, estimated a prevalence of 38.7% in men aged 45 years or older [31]. The wide range in estimates reflects the difficulty in defining TDS in a broad population, the lack of definitive threshold limits and the lack of consensus on the signs and symptoms that are suggestive of TDS rather than those accounted for by comorbid disease.

Economic Impact

Despite the importance of resource in an everincreasing cost-conscious healthcare system and despite the burgeoning interest in the field of TDS [17], no studies have specifically addressed the economic burden TDS poses to society. This may, in part, be due to the uncertainty surrounding the impact TDS and subsequent treatment have on those symptoms, which carries economic consequences. TDS can lead to considerable morbidity and recent evidence suggests it may also lead to premature mortality [6]. The consequences that may be important in an economic context include depression, sexual dysfunction, mild cognitive impairment, osteoporosis, cardiovascular disease and, of course, mortality (Table 1). However, most of these implications are not clearly understood and require further evidence not only to define the link between TDS and specific morbidities, but also to ascertain the effectiveness of testosterone treatment on such symptoms. The clinical evidence and potential economic burden for each relevant consequence of TDS are reviewed next.

Depression Depressed mood is a symptom often associated with TDS [1,2]; however, the relationship between low testosterone levels and the incidence of clinical depression is unclear. Studies in middle-aged and elderly men demonstrate mixed results, some showing an association between low testosterone levels and depression [32] and others finding no such relationship [33]. A recent U.S. study estimated a 2-year incidence of diagnosed depression of 21.7% for hypogonadal men and 7.1% for the control group (P = 0.01) [34]. The study also found that as the severity of TDS increased, so did the incidence of depression. Testosterone treatment has been shown to improve mood [35], but has not yet demonstrated clear benefits in terms of improving clinical depression in hypogonadal men [36]. Depressed mood has been associated with increased healthcare resource [37]; however, it is clinical depression which carries substantial economic cost due to the need for treatment, lost work days, and lost life-years due to premature death. Around 60–70% of all suicides in the general population are estimated to be related to depression [38,39]. Depression is the most costly brain disorder in Europe. In 2004, the total annual cost of depression was estimated to be €118 billion, 36% of which related to direct costs of care [40]. For each person with depression, direct costs of care were around €2,000 per year and indirect J Sex Med 2007;4:1056–1069

1060 Table 1

Maggi et al. Potential direct and indirect costs associated with untreated testosterone deficiency syndrome (TDS) Costs

Consequences

Evidence of association with TDS

Direct costs

Indirect costs

Depressed mood Depression

Good evidence Controversial

Low healthcare costs High healthcare costs

Sexual dysfunction

Good evidence for some aspects of sexual dysfunction

Mild cognitive impairment Dementia

Good evidence

Low healthcare costs High out-of-pocket costs for patients Low healthcare costs

Low/medium days lost from work High costs—days lost from work and lost life-years due to premature mortality Low

Highly controversial

High healthcare costs

Osteoporosis

Good evidence relating to osteoporosis but not yet to incidence of fractures

High healthcare costs

Cardiovascular disease

Recent preliminary evidence—remains controversial

High healthcare costs

Death

Recent preliminary evidence—remains controversial

Low

costs due to morbidity and mortality were estimated at €3,500 per year.

Sexual Dysfunction Sexual dysfunction is a common problem in men with TDS. Men can experience reduced sexual desire and activity and decreased spontaneous erections [1]; however, although erectile dysfunction is frequently found in men with TDS, it is not necessarily caused by the condition. Impaired sexual function has been rated as having the greatest negative impact on feelings of well-being alongside decreased energy levels [3]. Testosterone treatment has been shown to improve libido, sexual activity, nocturnal erections, sexual thoughts, and sexual satisfaction. It has been suggested that response to treatment may be correlated with severity of TDS. Sexual impairment may manifest itself only in patients with very low testosterone levels [25]; therefore, these individuals are likely to show a greater response to treatment compared to those exhibiting only mild TDS [41]. The beneficial effects of testosterone monotherapy on erectile dysfunction are still inconclusive [15]; however, recent data suggest that testosterone treatment in combination with phosphodiesterase type 5 inhibitors (PDE5) can significantly improve erectile function in patients who had previously failed to respond to PDE5 inhibitor monotherapy [42]. In one study, correcting an underlying testosterone deficiency (total testosterone = 12.8 ⫾ 2.1 nmol/L) with transdermal testosterone in sildenafil-unresponsive J Sex Med 2007;4:1056–1069

Low, although some informal caregiver costs High costs—days lost from work and lost life-years due to premature mortality High costs associated with days lost from work and lost life-years due to premature mortality High costs associated with days lost from work and lost life-years due to premature mortality High costs associated with lost life-years due to premature mortality

patients with erectile dysfunction improved sildenafil responsiveness and ameliorated penile blood flow [43]. This finding has been confirmed by further studies [44], including a randomized, double-blind, placebo-controlled multicenter study involving 75 mild hypogonadal patients (total testosterone ~10 nmol/L) [45]. This study demonstrated that testosterone treatment for 3 months significantly improved sildenafil effect and orgasmic function. These data suggest that in order for patients with sexual dysfunction to have full responsiveness to first-line treatments (e.g., PDE5 inhibitors), patients should be screened for TDS and treated appropriately if present. It is interesting to note that TDS is often associated with diabetes and metabolic syndrome [13], both characterized by lower responsiveness to PDE5 inhibitors such as sildenafil. In two different models of experimental diabetes with TDS, testosterone treatment restored responsiveness to sildenafil [46]. TDS should therefore be carefully ruled out before defining a diabetic patient as being “sildenafil resistant” and thereby planning more invasive and/or costly therapies. In adult men with untreated TDS, the costs of treating sexual dysfunction are unlikely to be especially high and limited largely to medication and outpatient costs [47,48]. One UK study estimated healthcare costs of £160 (US$253) per patient per year (1998 costs) for treatment of erectile dysfunction [47], with minimal cost related to lost work days. Costs are likely to be higher for diabetic patients with erectile dysfunction where first-line treatment with PDE5 inhibitors has failed due to

Burden of Testosterone Deficiency Syndrome undetected TDS, and more expensive forms of treatment are required. Patients are also likely to have to pay out-of-pocket payments for a proportion of the cost of treatment and furthermore, erectile dysfunction causes considerable deterioration in quality of life [49].

Mild Cognitive Impairment TDS may also have neurological implications. One of the more commonly reported symptoms of the condition is poor concentration and memory [1]. Again, the impact testosterone treatment has on cognition is unclear, with some small-scale studies showing moderate beneficial effects in hypogonadal men with [50] and without [51] Alzheimer’s disease, and others showing no improvement [52]. Larger studies are now called for to confirm the effect testosterone treatment has on mild cognitive impairment in the short term and perhaps even on Alzheimer’s disease in the long term. There are very little data on the economic consequences of mild cognitive impairment. The condition is characterized by impairments to the memory which are not yet severe enough to affect activities of daily living. However, a proportion of patients with mild cognitive impairment will progress to dementia during their lifetime [53], and dementia itself is associated with significant economic cost [54]. Osteoporosis TDS is an important cause of osteoporosis in adult men. It has been associated with loss of BMD [55] and deterioration of the trabecular architecture [56], both key features of osteoporosis. Testosterone deficiency [57–59] and BMD [60,61] have been shown to be independent risk factors for osteoporotic fractures in men. It has been estimated that TDS is present in 20% of men with vertebral fractures and 50% with hip fractures [62]. Testosterone treatment has been shown to increase BMD [16] and possibly improve trabecular architecture [63]; however, no study to date has comprehensively assessed the impact treatment may have on fracture incidence. Osteoporosis is associated with significant burden of disease. In terms of healthcare costs, treatment of osteoporosis can be expensive and fractures are costly to repair. Medical options for hypogonadal men diagnosed with osteoporosis range from calcium and vitamin D, to the more expensive options, which include bisphosphonates

1061 (costs around $800 per year in the United States in 2002) and teriparatide (costs around $6,700 per year) [64]. Fractures are associated with high rates of costly hospitalizations for treatment and rehabilitation, especially hip fractures [65–70]. In France, in 1999, the estimated mean cost of a fracture to the healthcare system was around €8,500 (US$9,160) [68]. In Belgium, the cost of inpatient and outpatient treatment for a hip fracture was estimated to be US$9,700 in 1996 [70]. In the United States, the mean costs during the first postfracture year were around €14,410 (US$16,318) in 2003, with about one-fourth caused by acute care. If a previously home-dwelling patient had to be admitted to permanent institutional care after the fracture, the mean costs increased to €35,700 (US$40,427) [71]. Indirect costs are also likely to be high. Osteoporosis leads to loss of work days for both the patient and their informal caregivers [72]. It can also lead to premature mortality. One year mortality after hip fracture was estimated to be around 30% in men [73,74]. BMD alone has been established as a predictor of survival [75,76]. A decrease of 1 SD of BMD in a univariate analysis was associated with a 1.39-fold increase in mortality in men (95% confidence interval [CI]: 1.25– 1.56) [75].

Cardiovascular Disease TDS may also have cardiovascular and metabolic implications [16]; however, research in this area, still very much in its infancy, has led to varied results. Low testosterone is associated with a number of cardiovascular risk factors, including increased body fat, insulin resistance, low levels of high-density lipoprotein, high cholesterol levels, and high levels of low-density lipoprotein [77]. However, testosterone treatment has demonstrated a mixed effect on risk factors. Although it reduces body fat and improves insulin resistance, its effect on lipid changes has been varied [16] and, to date, studies have not had long enough follow-up periods to detect any meaningful changes in actual cardiovascular events. The relationship between TDS and cardiovascular disease is therefore still unclear. However, if future studies confirm a link between low testosterone and an increase in cardiovascular events, then the potential economic burden is likely to be large. Cardiovascular disease is associated with substantial direct and indirect costs [78]. J Sex Med 2007;4:1056–1069

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Metabolic Syndrome Recent evidence suggests that TDS is likely to be a fundamental component of metabolic syndrome [13,14,79–81], which is characterized by central obesity, insulin dysregulation, abnormal lipid profile, and borderline or overt hypertension. Individuals with the syndrome carry a twofold increase in relative risk of cardiovascular disease and a fivefold increase in relative risk of type 2 diabetes mellitus compared to those without the syndrome [82]. The prevalence and cost of the sequelae of metabolic syndrome are substantial. One U.S. study estimated that almost half of all individuals over the age of 60 may have the syndrome [83]. Diabetes alone costs Medicare in the United States $110 billion. However, there are many clinical issues regarding metabolic syndrome that are not yet fully understood. First, it is not known whether metabolic syndrome is a cause of testosterone deficiency or a consequence of it. Second, there is still considerable uncertainty about the syndrome itself and its usefulness in predicting risk of cardiovascular disease [82]. Third, it is not yet fully understood the extent to which the increased risk of cardiovascular disease and diabetes in these patients can be modified by testosterone treatment. However, testosterone treatment has demonstrated positive effects in the treatment of men with existing cardiovascular disease [17] and has shown some beneficial effects on a number of the components of metabolic syndrome [79]. Mortality TDS has recently been associated with increased mortality risk [6]. A U.S. study of men aged older than 40 years, found that men with normal testosterone levels (i.e., total testosterone level of >250 ng/dL or 8.7 nmol/L) had a mortality rate of 20% compared to a rate of 35% in men with low testosterone levels (mean follow-up was 4.30 years). The association between low testosterone levels and increased mortality was significant (hazard ratio, 1.88; 95% CI, 1.34–2.63; P < 0.001) even after adjusting for age, comorbidity, and other clinical factors [6]. A recent largescale study of men with Klinefelter’s syndrome also revealed a significantly raised mortality rate. Mortality was raised by a number of factors, including diabetes, which may or may not be directly related to TDS [84]. If the association between TDS and mortality is confirmed by further studies, then the costs to society of premaJ Sex Med 2007;4:1056–1069

Maggi et al. ture mortality caused by low testosterone levels can be added to those caused by the consequences of the condition. Quality-of-Life Impact

The negative impact TDS has on sexual function, energy levels, body composition, mood, and cognitive function is likely to adversely affect quality of life. However, although many studies have surmised how symptoms may impact on quality of life, no studies have specifically addressed the burden that TDS has on health-related quality of life in adult men. Only one has addressed this issue in elderly men with late onset hypogonadism [85] and several studies have attempted to evaluate the change in quality of life as a result of testosterone treatment [86–89]. Recent investigations into the differences in quality of life between men with TDS and those without collected data from 24 men aged over 50 years with low testosterone levels (<200 pmol/L) and 24 age-matched controls [85]. Differences in physical symptoms and vitality between the two groups were demonstrated, but no notable differences in mental health [85]. The study used the SF-12 and the psychological wellbeing and vitality components of the SF-36 as the measure of quality of life. These are generic questionnaires and likely to underestimate the impact TDS has on quality of life. They only cover specific domains (physical, emotional, and social) and do not include items such as cognitive impact, sexual functioning, or body appearance which are likely to be important determinants of healthrelated quality of life in this patient group [3]. During the development of a quality of life questionnaire to assess the symptoms of TDS in elderly men, patients’ and physicians’ perspectives on their condition were elicited to identify relevant domains [3]. Both groups rated decreased energy levels and impaired sexual function as having the greatest negative impact on quality of life. The study identified seven key domains which should be included when assessing the impact of TDS on quality of life in elderly men. They include energy, emotional, social, social emotional, mental functioning, physical functioning, and sexual functioning, confirming the breadth of domains required to assess quality of life in this disease area. Testosterone Treatment

Understanding the economic and quality-of-life impact of untreated TDS is important in a policy

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Burden of Testosterone Deficiency Syndrome Table 2

Costs and consequences associated with no treatment and treatment with two types of testosterone preparations

Costs Cost of treatment

No treatment

Intramuscular injections

Gel

None

£40 to £400 per patient per year (2006 prices)* ~26 visits per year to administer injection for short-acting injections ~maximum of five visits per year for long-acting testosterone undecanoate High risk of erythrocytosis for short-acting injections due to high peak levels in testosterone after injection. Routine follow-up required to assess for risk of prostate cancer

>£400 per patient per year (2006 prices)*

Cost of administration

None

Cost of treatment-related adverse events

None

Consequences Symptoms Health-related quality of life Premature mortality Factors influencing costs and consequences†

High costs (Table 1) Reduced Potentially increased

No extra visits for administration

Low risk of erythrocytosis. Routine follow-up required to assess for risk of prostate cancer

Reduced symptom-related costs

Reduced symptom-related costs

Improved Potentially reduced

Improved Potentially reduced

Compliance—good with long-acting injections which require fewer visits

Compliance—good

*Annual average exchange rate, 2006: £1 = €1.467, US $1 = €0.797. †In addition to cause of testosterone deficiency syndrome, age and diagnostic threshold for treatment.

context as it highlights the magnitude and burden of the condition. However, to make informed resource allocation decisions, policy makers require information on the cost-effectiveness of available treatments to weigh up whether the cost of treating the condition is a good use of valuable resource. Cost-effectiveness estimates will become progressively more important as the number of patients being prescribed testosterone treatment increases [90] and the range of preparations to choose from expands [91]. Such studies can aid in decisions of whether to treat or not, and if to treat which product represents the best value for money. However, although testosterone treatment has been around for a long time and its beneficial effects on specific clinical symptoms have been demonstrated [17,91], there have been no attempts to evaluate its cost-effectiveness and only a handful of studies to assess its impact on quality of life. This is in stark contrast to the multitude of studies of hormone replacement therapy in postmenopausal women. Evaluating the cost-effectiveness of testosterone treatment will inevitably be hampered by the current lack of clinical evidence demonstrating clear links between TDS, potential consequences, and effectiveness of testosterone treatment. Therefore, future cost-effectiveness studies are likely to rely heavily on decisionanalytic modeling techniques until such data become available. The elements required for a cost-effectiveness analysis of testosterone treatment are costs on the one hand (cost of drug, administration, manage-

ment, treatment-related side effects, and symptoms) and outcomes on the other (clinical benefits, quality of life, and length of life) (Table 2). Compared to doing nothing, testosterone treatment, by reducing the potential short-term and long-term costs associated with the consequences of TDS, may be considered cost-effective by decision makers. Such cost-effectiveness estimates are likely to differ between type of patient (primary, secondary, and mixed hypogonadism) and recommended diagnostic criteria at which treatment should be started (testosterone threshold levels and clinical markers). Cost-effectiveness estimates are also likely to vary between methods of administration. Annual costs for injectable products are less than for patches and gels (Table 3). However, administration costs are likely to be higher for injectables compared to gels and patches mainly due to the additional cost of clinic visits to administer the treatment [92]. Testosterone treatment is not without its risk of side effects [93]. Costs associated with side effects are likely to arise from the need for monitoring and treatment (Table 4). Recent guidelines recommend monitoring, especially in elderly patients, specifically, hematocrit for presence of erythrocytosis, prostate-specific antigen levels for risk of prostate cancer, and other product-specific side effects [1]. Symptom costs relate to the downstream costs (or savings) associated with symptom-related events (e.g., osteoporosis). The uncertainty in calculating such costs currently lies in the lack of J Sex Med 2007;4:1056–1069

1064 Table 3

Maggi et al. Testosterone treatment drug acquisition costs—United Kingdom (prices based on British National Formulary 2006)

Product †

Sustanton 250 (IM) Testosterone enantate (IM) Restandol (oral) Nebido—testosterone undecanoate (IM) Andropatch (patch) Testogel (gel) Striant SR (buccal)

Pack details

Dose

Cost* per dose

Cost* per year

1-mL amp 250 mg/mL, 1-mL amp 40-mg testosterone undecanoate 28-cap pack 250 mg/mL 4-mL amp Testosterone 2.5 mg or 5.0 mg/ 24 hours Testosterone 50 mg/5 g sachets Testosterone 30 mg/60-tab pack

1 mL every 3 weeks Maintenance 250 mg every 2–3 weeks Maintenance 80–240 mg daily

£2.55 £8.33 59p to £1.78

£44 £144 to £217 £215 to £650

1 g every 10–14 weeks

£76.70

£285 to £399

2.5 mg—7.5 mg every 24 hours

82p to £1.64

£299 to £664

5-g gel once daily 30 mg every 12 hours

£1.10 76p

£402 £558

*Costs have been calculated from the net cost used in pricing National Health Service prescriptions dispensed in September 2006. Costs are based on the largest pack size of the preparation in use in community pharmacies. Annual average exchange rate, 2006: £1 = €1.467, US $1 = €0.797. †Contains testosterone propionate 30 mg, testosterone phenylpropionate 60 mg, testosterone isocaproate 60 mg, and testosterone decanoate 100 mg/mL. IM, intramuscular.

clinical evidence on how testosterone treatment will affect certain symptoms (e.g., depression, incidence of fractures, cardiovascular disease) and whether effectiveness in terms of symptom reduction differs between products. The outcomes of treatment include improvement in clinical symptoms, health-related quality of life, and potentially length of life. Several studies have evaluated the quality-of-life impact of testosterone treatment in patients with lateonset hypogonadism using different questionnaires, including the Aging Male Symptom questionnaire [86], Quality of Life Scale [87],

Table 4

Androgen Deficiency in Aging Males questionnaire [88], and the SF-36 [89]. The studies reported mixed results with half reporting a positive change in quality of life as a result of treatment and half reporting no change. Such varied results may be due to a multitude of factors, including study design, number of patients, choice of product, and quality-of-life questionnaire. It is unlikely that any of these questionnaires contains all the quality-of-life domains important to patients [3] and therefore may not be sensitive to change, particularly in studies with small patient numbers.

Potential risks associated with testosterone treatment

Potential risk

Comments

Cost implications

Cardiovascular disease

Existing evidence suggests a neutral or possible beneficial effect Most studies show no change with physiologic replacement doses Wide range of risk, depending on mode of administration: 3–18% with transdermal administration, up to 44% with conventional short-acting injections. No testosterone-associated thromboembolic events have been reported to date Rarely of clinical significance Rarely of clinical significance Highly controversial, unknown level of risk. Recent data suggests that there is no scientific basis for the suggestion that testosterone administration causes prostate cancer [94]

Low

Lipid alterations Erythrocytosis

Fluid retention Benign prostatic hyperplasia Prostate cancer

Hepatotoxicity Sleep apnea Gynecomastia Skin reactions Acne or oily skin Testicular atrophy or infertility

Limited to specific oral agents which are infrequently used Infrequent Rare, usually reversible High incidence with patch (up to 66%), low incidence with gel (5%), rare with injections Infrequent Common, especially in young men, usually reversible with cessation of treatment

Source: Adapted from Rhoden and Morgentaler [93].

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Low Requires long-term monitoring of hematocrit or hemoglobin levels

Low Low Requires long-term monitoring. Blood test for PSA level and digital rectal examination. Biopsy is required if digital rectal examination shows change or prostate-specific antigen levels increase Low Low Low Low Low Low

1065

Burden of Testosterone Deficiency Syndrome Conclusions

TDS, if left untreated, potentially poses a significant burden on patients and the healthcare system. This burden may be increased by its links with metabolic syndrome, itself a highly prevalent and costly disease. There has been much research into the beneficial effects of testosterone treatment and although treatment has increased in recent years, TDS remains a widely underdiagnosed and undertreated condition. This is mainly because of the difficulty of identifying patients with the condition as most of its symptoms are nonspecific and often confused with those of comorbid disease. There are many unmet needs in the diagnosis and treatment of TDS [17] and there are still many research questions left to be answered. In addition to those highlighted in the numerous publications on TDS, several more on the economic and quality of life implications of the condition and its treatment should be added. First, more information is needed on the burden of TDS. Estimating the burden requires better estimates of the prevalence of TDS and the incidence of its consequences and its causal factors. The burden is expected to be substantial; however, studies of the short-term and long-term consequences of TDS and their impact on costs and quality of life are required to confirm this supposition. Second, there is an urgent need for health economic studies to first of all confirm the benefits of treatment over no treatment and then to explore the relative costeffectiveness of the various treatment options. Such estimates could help to inform which patients should be treated using which products. Third, there is a need to better understand not only the clinical relevance of diagnostic criteria but also the relationship between testosterone threshold levels, initiation of treatment, and costeffectiveness. In this way, the cost-effectiveness of various testosterone threshold limits could be modeled to provide valuable information for decision makers on when (which threshold) and who (level of severity by age-group) to treat. Information on the health economic impact of testosterone treatment would demonstrate the potential for cost savings relative to its clinical effectiveness. Recent data on the economic impact of the standard use of estrogen therapy estimated it saved US $333 million annually in the United States by reducing the risk of osteoporosis and subsequent hip fracture [95]. Such data in the field of TDS would also raise awareness of the condition and add to highlight the benefits of treating

patients, not only to the patients themselves in the form of much improved quality of life, but also to society in general, by allowing costs to be used more effectively. Corresponding Author: Mario Maggi, MD, Andrology Unit, Department of Clinical Physiopathology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy. Tel: +39-0554271415; Fax: +390554271413; E-mail: [email protected]fi.it Conflict of Interest: Financial support was received from Bayer Schering Pharma AG. Dr. Kerstin UhlHochgraeber is an employee of Bayer Schering Pharma AG.

Statement of Authorship

Category 1 (a) Conception and Design Mario Maggi, Claude Schulman, Richard Quinton, Sue Langham, Kerstin Uhl-Hochgraeber (b) Acquisition of Data Sue Langham, Kerstin Uhl-Hochgraeber (c) Analysis and Interpretation of Data Mario Maggi, Claude Schulman, Richard Quinton, Sue Langham, Kerstin Uhl-Hochgraeber

Category 2 (a) Drafting the Article Sue Langham, Kerstin Uhl-Hochgraeber, Mario Maggi (b) Revising It for Intellectual Content Mario Maggi, Claude Schulman, Richard Quinton

Category 3 (a) Final Approval of the Completed Article Mario Maggi, Claude Schulman, Richard Quinton, Sue Langham, Kerstin Uhl-Hochgraeber

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