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Identifying the outcomes important to men with hypogonadism: A qualitative evidence synthesis

Abstract Objective Men with male hypogonadism (MH) experience sexual dysfunction, which improves with testosterone replacement therapy (TRT). However, randomised controlled trials provide little consensus on functional and behavioural symptoms in hypogonadal men; these are often better captured by qualitative information from individual patient experience. Methods We systematically searched major electronic databases to identify qualitative data from men with hypogonadism, with or without TRT. Two independent authors performed the selection, extraction, and thematic analysis of data. Quality of eligible studies was assessed using the Critical Appraisals Skills Programme and Grading of Recommendations Assessment, Development and Evaluation‐Confidence in the Evidence from Reviews of Qualitative research tools. Results We analysed data from five studies published in nine reports that assessed a total of 284 participants. Published data were only available within North America, with no ethnic minority or other underserved groups included. In addition to sexual dysfunction, men with MH experienced adverse changes in physical strength, perceptions of masculinity, cognitive function, and quality of life. The experience of MH appeared dependent on the source(s) of educational material. Discussion We propose a patient‐centred approach to clinician interactions rather than focusing on discreet MH symptoms. Current evidence about the experience of MH is limited to North America and predominantly white ethnicity, which may not be broadly applicable to other geographic regions. Broadening our understanding of the MH experience may improve the targeting of information to patients. In addition, a multidisciplinary approach may better address symptoms neither attributable to MH nor alleviated by TRT.


INTRODUCTION
Numerous clinical trials have investigated the ability of testosterone replacement therapy (TRT) to alleviate male hypogonadism (MH) symptoms. 1 There is consensus that MH causes several symptoms that TRT can improve. However, men investigated for MH often complain of a constellation of less specific symptoms, including physical limitations, tiredness, low mood, and reduced cognition. 2 There is little agreement among clinicians whether these functional and psychological (behavioural) symptoms are indicative of MH and thus likely to be ameliorated by TRT. [3][4][5][6] Coupled with prevailing concerns highlighted by the US Food and Drugs Administration (FDA) regarding the cardiovascular safety profile of TRT (and the lack of long-term safety data in men with prostate cancer), men with MH face an uncertain journey from the onset and evolution of symptoms to seeking and establishing a medical diagnosis to the initiation of TRT and subsequent monitoring of therapy (clinical response and adverse effects). 7,8 In addition to (and/or as a consequence of) the above-mentioned 'traditional' androgendependent endpoints, MH is likely to disrupt many important aspects of life for affected individuals, including relationships, self-image, activities of daily living, and health-related quality of life (HR-QOL).
Such changes are more challenging to assess and tend to receive less attention from clinicians and researchers. 9 Hence, there is a paucity of substantive research exploring the subjective experience of men with MH.
Unlike clinical research outcomes, patient-reported outcomes (PRO) provide direct evidence of how patients feel or function. 10 The importance of PRO data is reflected by their inclusion in recent FDA guidance for designing trials establishing the efficacy of drugs to treat MH. 11 The Testosterone Efficacy and Safety (TestES) Consortium was commissioned by the Health Technology Assessment Board, National Institute of Health Research, UK (Project reference HTA 17/68) to conduct a comprehensive evidence synthesis of all aspects of healthcare for MH. Herein, we report the qualitative evidence reporting how men experience MH and the impacts on their lives.

MATERIALS AND METHODS
We developed comprehensive search strategies to identify published papers reporting qualitative data on the perception and experiences of men with hypogonadism and/or those using TRT. An information scientist searched Ovid Medline, Embase, PsycInfo, EBSCO CINAHL, and Proquest ASSIA for papers published from 1992 to February 2020. References of included studies were perused for further relevant papers (Table S1). One review author (MA-M) screened all titles and abstracts with a randomly selected 10% cross-checked by a second review author (KG). A third author (CNJ) was consulted when consensus regarding eligibility could not be reached. We focused on primary studies that explored any aspect of TRT for low testosterone from the perspective of men, their partners, or their clinicians. Mixed methods studies were included if qualitative methods and results were reported separately. The population of interest consisted of adult men (>18 years old) diagnosed with hypogonadism, confirmed either by low testosterone levels or by using TRT. Studies restricted to a singular aetiology of hypogonadism (e.g., Klinefelter's syndrome, congenital hypogonadism, prostate cancer, and so forth) were excluded because of the potential of introducing the experience of symptoms unrelated to hypogonadism per se.
Two reviewers (MA-M. and KG) independently extracted data from the included papers, shared notes, and discussed study findings and interpretations during a series of meetings. Papers were initially organised alphabetically and subsequently grouped under emerging issues and themes. A data extraction form was developed and piloted for this qualitative systematic review. From each included study, we recorded quotes from participants and/or interpretation of findings by study authors irrespective of whether participants' quotes supported it.
We conducted a three-phase thematic synthesis using both inductive and deductive approaches. First, we closely scrutinised the included studies to identify the main recurring themes and recorded line-by-line coding of the qualitative findings of primary studies; next, we organised these 'free codes' (i.e., single quotes) into related areas to construct 'descriptive' themes; finally, if sufficient data were available, we developed an 'analytical' theme.
Two men with hypogonadism were recruited to advise the research team on key issues including verifying the importance of study questions, refining study design, and interpretation of study findings.
Video conferences were held on 27 January 2021 to give clinician members of the study team the opportunity to gain feedback on the study findings from members of the patient panel. Patients were sent simplified versions of the drafted results beforehand and received summary presentations from CNJ. Comments of the patient panel were into the current report.

Assessment of quality
We appraised eligible studies for methodological rigour and theoretical relevance using the Critical Appraisals Skills Programme (CASP) tool. 12 Included studies were quality-appraised by one reviewer (MA-M), with a second review author (KG) checking the completed assessments. Any disagreement was resolved by discussion or referred to a third review author (CNJ).

Confidence in review findings
We used the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) approach to assess our confidence in the findings of the thematic synthesis (MAM and KG double coded). 13

Sample demographics
The flow diagram of selected studies is shown in Figure 1. Despite comprehensive searches, only five qualitative studies (published in 9 reports) investigating the experience of men with hypogonadism were identified in the literature and deemed suitable for inclusion. Thirty studies were excluded as they did not meet our pre-specified inclusion criteria. Reasons for exclusion were ineligible populations (six studies), focus on a single symptom of hypogonadism (e.g., erectile dysfunction) (13 studies), or no relevant qualitative data (11 studies). All five included studies were conducted in North America (four in the United States and one in Canada) in men with hypogonadism (284 in total) who were either administered or not administered TRT (see Table 1). [14][15][16][17][18] One study also reported the perspectives of healthcare providers treating men with hypogonadism. 18

Findings
Five broad analytical themes (with several linked descriptive subthemes) were identified from the included studies (Table 1; Table S2) and were ordered according to the decision points that a man with hypogonadism may experience: (1) Symptoms of low testosterone and their impact on daily life; (2) low levels of serum testosterone (consistent with MH); (3) access to treatment information; (4) perceived effects of TRT; (5) expectations, experience, and preference of the type of TRT. Thirteen descriptive interconnected subthemes were identified within these five analytical themes (Table 2).

Theme 1: Symptoms of low testosterone and their impact on daily life
As expected, altered sexual desire and/or activity was one of the most frequently cited sub-themes of low testosterone symptomatology. Some men felt unable to perform sexually in their relationship. 16 Lack of energy impacted men throughout the day, with some reporting waking up exhausted even after a full night's sleep, and others stating it was worst in the evening. In general, the lack of energy was reported to affect the ability to conduct 'normal' daily activities, and men used terms such as 'tired' , 'totally exhausted' , 'lethargic' , 'sluggish' , and 'physically drained' to describe their lack of energy. 15 Two of the included studies reported that men suffered from sleep disturbances, including falling asleep during the day, night waking, and difficulties going back to sleep. 14,16 Some men expressed concerns about weight gain and explained that one of the effects of low testosterone was a lack of physical strength, especially concerning those activities they could carry out beforehand. 14,16 One study interrogated perceptions of masculinity, with men explaining they felt a sense of 'loss of manliness' or 'less of a man' , which was implicitly associated with the changes in sexual activity/function. 16 Low testosterone was described by men to adversely affect their cognitive function, especially memory, concentration, and attention span. 16 In general, within the cognitive domain, men reported issues with motivation (n = 16; 44%), loss of interest (n = 11; 31%), memory/forgetfulness (n = 11; 31%), focus/concentration (n = 6; 17%), drive/ambition (n = 3; 8%), attention span (n = 3; 8%), and indecisiveness (n = 1; 3%). 14 Men also reported broader impacts on everyday life, general well-being, and lower mood.

Theme 2: Diagnosis of low testosterone
The authors of two of the included studies reported the participants' experience of getting a diagnosis of hypogonadism. 17 Patients with any major medical or psychiatric disorder were excluded.
Participants were recruited from different sources, including physician providers, community-based services, health forums and media advertisements. Diagnosed hypogonadal patients (treated and untreated) were recruited from the practices of three physicians who are knowledgeable in the diagnosis and management of hypogonadism.
They generated an item pool from focus groups (90-120 min) and in-depth interviews (45-90 min). Standardised scoring of the qualitative interviews was used to confirm conceptual domains to generate a questionnaire.
Data collection was through three focus groups (for each of the study groups), including 4-6 patients. Once the recruitment quota for each focus group was met, patients were invited for in-depth semi-structured individual interviews. Inductive and deductive approaches and saturation approaches were used.
Focus groups and interviews were led by a trained moderator (sex nor reported). Grounded theory was used. Broad topic areas identification. Analysis conducted by two researchers. (Continues)

Condition of focus
Participants' characteristics

Qualitative methods
First author: Szeinbach 17 Year: 2012 Country: USA To create a final conceptual model and the Preference for the testosterone Replacement Therapy (P-TRT) instrument Participants agreed to participate in research studies about TRT for conditions associated with a deficiency or absence of endogenous TT. All participants were recruited from a TRT manufacturer's mailing list since they were, or had been, taking TRT for conditions associated with a deficiency or absence of endogenous testosterone. The diagnosis of hypogonadism was not confirmed.
In exchange for their participation, participants had the option to accept coupons toward their next purchase of a testosterone replacement therapy product. were conducted using the standard set of questions from the discussion guide. Afterwards, a group of experts (one physician, three researchers with extensive experience in psychometrics, and a nurse practitioner with clinical experience with TRT) tested data and once consensus was reached that all possible items and themes, the final stage included the development of an instrument and conducted in-depth interviews.
One-on-one participant interviews end expert's analysis to create an instrument to conduct in-depth interviews as part of the cognitive debriefing process. Researchers elicited and recorded responses from participants during interview sessions.
Grounded theory was used. Broad topic areas identification. The transcription process included the identification of recurring definitions and themes throughout the text, which produced detailed descriptions and theoretical explanations of the concepts under investigation.
First author: Mascarenhas 18 Year

Broader impacts
on everyday life and general well-being "Many of the men reported having less confidence or lower self-esteem (n = 10; 28%). " 14 "Few men also reported symptoms such as feeling mellow, introversion, feeling alone, fear of rejection, anxiety, and being moody, emotional, or sensitive. " 14 (Continues)

TA B L E 2 (Continued)
Theme

Key concepts identified
Sub-theme (if applicable)

Example quotes
The diagnosis of low testosterone and access to treatment information Two studies reported patients' perspective regarding getting a diagnosis of HG and the role and relevance of health professionals in this process. However, this information was reported by the authors from the paper rather than from quotes of participants. Szeinbach et al. and Mascarenhas et al. reported that some participants understood the importance of testosterone monitoring and stated it would be easy to get this information from their physicians.
Both patients and providers participants mentioned that they know of primary care physicians or specialists who prescribe TRT without testing for low testosterone levels and based on informal discussions or e-mail communication" 18 "While only two participants were able to recall their testosterone levels, the other three participants understood the importance of testosterone monitoring and stated it would be easy to obtain this information from their physicians. Perceived effects of ART Most of the studies reported participants' perceptions of the effects of TRT on different symptoms, which mostly was positive perception towards the improvement of outcomes. However, some participants also reported no effect at all. Across studies, dosages, frequency, and duration of TRT among participants were poorly or not described. Overall, participants preferred a product that was accessible to use, effortless and comfortable to apply, easy to handle, with accessible application location, and dried quickly.
Ease of administration "The first theme, ease of use, encompassed all topical characteristics associated with testosterone gel products. Participants preferred a product that was convenient to use, easy to apply, easy to handle, with accessible application location, and dried quickly" (Authors interpretations -Szeinbach et al.) 17 Mode of administration "I used another product where I had to do the injection into the muscle, and the gel is easier because there is no sticking and blood, and so forth.

Theme 3: Access to treatment information
Participants reported that access to information about TRT was an important factor determining their eventual use of TRT. For example, Szeinbach et al. observed that participants received TRT via different routes: During a consultation (e.g., with their general practitioner regarding a related condition), through posters at their pharmacy, through friends and co-workers, popular magazines, and Internet searching. 17 Mascarenhas et al. reported that some participants expressed the desire to receive more information on the advantages and risks of TRT from their physicians and explained that 'while most participants find it easy to access information on the positive effects of TRT and how to acquire it, they seem to have little knowledge about its side effects or risks'; they also pointed out that participants felt that the marketing and advertisements 'spoke to' their perceived needs. 18 Information on improved sexual function and energy levels was of greatest interest to participants, whereas information concerning the side effects of TRT was sought to a much lesser extent.

Theme 4: Perceived effects of TRT
In three studies, 14-17 participants described how TRT positively impacted their sexual desire/activity, while in one study, some participants did not experience any significant improvements. Participants from three of the included studies discussed their experience of improvements in strength/energy while receiving TRT. In one study, participants described an 'energy boost' after TRT. 17 Some participants observed positive changes in body shape and increased muscle bulk. Participants commented positively on the improved energy levels throughout the day. However, some participants did not achieve the expected impact of TRT on energy levels. One man experienced weight loss as a positive outcome of TRT. 14 Three studies reported positive impacts on general well-being. 14,16,17 Szeinbach et al. reported that some participants experienced general well-being changes, often described as 'I feel like myself again' . 17 One man described a positive change in self-esteem as a result of being more energetic and masculine. 16 Another man recognised that not all outcomes improved after TRT and acknowledged that some experienced benefits could be interrelated. Another man reported a broader range of symptoms and recognised the relatedness and interplay between them. 16 Some of these symptoms included psychological (e.g., anxiety), emotional (e.g., self-esteem), or well-being (e.g., masculinity perceptions) outcomes that were reported as improved after the therapy.

Theme 5: Expectations, experience, and preference of the type of TRT
Three studies reported participants' expectations, experience, and preference about TRT type. Five sub-themes were identified across the included studies, relating to ease of administration, mode of administration; beliefs about effectiveness; perceived adverse effects; and costs. One study was designed to create a conceptual model and tool to test participants' preference for ease of administration of TRT. 17 This study assessed the experiences and perceptions of participants for different types of TRTs (i.e., gel vs. injections vs. patches). Overall, participants expressed their preference for a product that was 'accessible to use' , 'effortless' , 'comfortable to apply' , and 'easy to handle' . In concerns about perceived adverse effects associated with the TRT. One study described specific problems such as rashes, itching, or pain after administration (referring to TRT injections). One study reported that the cost of treatment was among the factors considered by participants when expressing their preferences for TRT products. Some participants described how features of their insurance plans (e.g., co-pay help programmes to top up the cost of the preferred treatment) influenced their choice of treatment.

Quality assessment
The methodological quality of the five included studies was assessed using the CASP tool (  18 Documenting recruitment strategy and clinical setting are important to identify potential selection bias, these were explained in all studies except for Gelhorn et al. 14 Three studies provided information on the relationship between the researchers and the participants [15][16][17] ; for the remaining two studies, the researchers did not critically assess their role and potential influence during the study. 14,18 The study by Gelhorn et al. was considered at potential risk of bias as it was sponsored by a pharmaceutical company that remunerated some of the authors. 14 The funder's role in the analysis of data or presentation of conclusions was not reported. All the studies discussed the contribution of their findings to existing knowledge or understanding.

Confidence in the findings
GRADE-CERQual assessment was used to assess confidence in the themes/subthemes identified in this qualitative synthesis (Table 3).
Moderate confidence was expressed for 16 themes/subthemes and low confidence for four. None of the qualitative evidence received a high confidence judgement. Findings were downgraded for lack of reported researcher reflexivity (e.g., failing to acknowledge potential sponsor bias), adequacy of data, or poor reporting of participants' sociodemographic characteristics.

DISCUSSION
There exists high-quality evidence that MH is associated with an increased risk of sexual symptoms. 5 However, men often experience a multitude of functional symptoms and other impairments of wellbeing, which clinicians often dismiss because the evidence is less clear for their effective treatment by TRT. 2 Increased regulatory importance is being placed on establishing the efficacy of drugs for MH by measuring outcomes important to patients because they provide direct evidence of how patients feel or function. 11 Herein, we summarise the evidence for how men experience hypogonadism, TRT, and the impacts on their lives. Our analysis is based on limited data but suggests that hypogonadism may impact several physical and mental well-being aspects, many of which are not captured sufficiently by prior RCTs.
We also highlight that the extents to which cultural, ethnic, geographic and socioeconomic factors influence the experience of MH are largely unknown.
Functional symptoms such as tiredness and reduced cognition may arise for many reasons other than MH, particularly when combined with co-morbidities. 19 Our analysis, therefore, excluded studies that restricted the reporting of specific (sexual) symptoms. We also excluded studies restricted to subtypes of MH (e.g., androgen depri- As reported previously, some examples of men's and physicians' behaviour described in these studies may lead to unnecessary prescribing of TRT. 24,25 For instance, the described 'testosterone-seeking' attitude (wherein men sought new medical opinions until one eventually agreed to prescribe), along with the tendency of certain physicians to ascribe a broad generality of symptoms to 'low testosterone' and thus prescribe TRT with no prior meaningful diagnostics. This qualitative synthesis suggests that physician knowledge, experience, and preferences may impact the extent to which men might ascribe their symptoms to low testosterone level (or make alternative associations) and, hence, affect their expectations of what TRT might realistically achieve for them. Furthermore, data from the current study suggest that men with hypogonadism may require a more coherent, holistic narrative of their condition from their physicians that is not broken down into disconnected chunks labelled 'sexual function' , 'mental health' , or 'physical performance' .
Our analysis is limited by only having available published data from North American studies. There are likely to be important differences between US-based, privately funded clinics specialising in 'low testosterone' , and European-based endocrinology or andrology units in public hospitals. Therefore, the current analysis findings may not be broadly applicable outside North America. Most of the studies provided quotes directly from the participants to support the identification of specific themes/subthemes; however, some studies provided only the authors' interpretations. The quality of the five included studies according to the CASP tool showed that the results across studies were valid and relevant to the scope of this qualitative synthesis. However, the small number of identified studies that provided in-depth data directly from the participants is a limitation of this work. In two of the included studies, 17,18 the diagnostic criteria for MH were not specified, so it was assumed that only participants were given TRT following appropriate clinical and biochemical assessments.
Furthermore, information on the frequency of symptoms and characteristics of TRT (i.e., type, dose, route of administration, frequency of use) were poorly reported across included studies.
We excluded any study restricted to a single aetiology of hypogonadism, that is, reporting on specific named conditions or diseases associated with hypogonadism, such as men with Klinefelter's syndrome, congenital hypogonadal syndromes, or receiving androgendeprivation therapy for prostate cancer. The rationale for this was to avoid the confounding effect of symptoms arising directly from aspects of these conditions that are unconnected to hypogonadism. While this approach taken in our analysis led to a smaller number of included studies, loosening the inclusion criteria to encompass these may have paradoxically weakened our conclusions.
In summary, we acknowledge that the current study is based on limited evidence; nevertheless, it provides a framework of evidence that mirrors core aspects of the pragmatic experience of patients. Many facets of the MH experience are unaddressed and thought untreatable by clinicians. Symptoms such as tiredness, reduced cognition, and/or reduced muscle strength may not be thought consequential to MH in some patients; however, it is beyond doubt men with hypogonadism commonly experience them and therefore warrants treatment (endocrine or otherwise). Based on the current study, we make three recommendations. Firstly, some men with MH may benefit from a holistic, patient-centred approach to improving well-being and quality of life, rather than the traditional focus on discreet symptoms (often sexual) practised by most clinicians. Secondly, the experience of men with MH is likely to be profoundly influenced by cultural identity and background, but our study reveals that this hypothesis remains unexplored; studying the impact of MH on men within different populations could improve the targeting of information and treatment monitoring for under-served demographic groups. 26 Finally, further research is needed to determine what resources clinicians require to support men with less specific hypogonadal symptoms with regard to accessing unbiased, patient-focused educational resources. Such future approaches would have the potential to impact healthcare quality for men with hypogonadism positively.