Abstract
PURPOSE
Direct assessment of Leydig cell function in childhood cancer survivors has been limited. The objectives of this study were to describe the prevalence of and risk factors for Leydig cell failure (LCF), Leydig cell dysfunction (LCD), and associated adverse health outcomes.
PATIENTS AND METHODS
In this retrospective study with cross-sectional health outcomes analysis, we evaluated 1,516 participants (median age, 30.8 years) at a median of 22.0 years after cancer diagnosis. LCF was defined as serum total testosterone less than 250 ng/dL (or 8.67 nmol/L) and luteinizing hormone greater than 9.85 IU/L, and LCD by testosterone as 250 ng/dL or greater and luteinizing hormone greater than 9.85 IU/L. Polytomous logistic regression evaluated associations with demographic and treatment-related risk factors. Log-binomial regression evaluated associations with adverse physical and psychosocial outcomes. Piecewise exponential models assessed the association with all-cause mortality.
RESULTS
The prevalence of LCF and LCD was 6.9% and 14.7%, respectively. Independent risk factors for LCF included an age of 26 years or older at assessment, testicular radiotherapy at any dose, and alkylating agents at cyclophosphamide equivalent doses of 4,000 mg/m2 or greater. The risk increased with older age, higher doses of testicular radiotherapy, and cyclophosphamide equivalent doses. LCF was significantly associated with abdominal obesity, diabetes mellitus, erectile dysfunction, muscle weakness, and all-cause mortality. LCD was associated with unilateral orchiectomy and the same risk factors as LCF; no significant associations were found with adverse physical or psychosocial outcomes.
CONCLUSION
Older age, testicular radiotherapy, and exposure to alkylating agents were associated with LCF, which was associated with adverse physical and psychosexual outcomes. LCD, although having similar risk factors, was not associated with adverse health outcomes. Additional studies are needed to investigate the role of sex hormone replacement in mitigating the burden from adverse outcomes in survivors.
INTRODUCTION
Improved treatments have resulted in increased life expectancy for childhood cancer survivors (CCS).1,2 Cancer and treatment-related complications have nevertheless resulted in higher-than-expected rates of chronic health conditions,3 frail health,4 and all-cause mortality,5 increasing efforts to identify potentially modifiable risk factors.6 Gonadal impairment, a common complication of cancer therapy,7,8 may result in decreased fertility and insufficient sex hormone production.9 In males, Leydig cells, which are responsible for testosterone secretion, are less vulnerable than the reproductive germ cells.9 Leydig cell failure (LCF) has been reported after testicular radiotherapy and alkylating agent chemotherapy,10-16 albeit less frequently than oligospermia and azo-ospermia.8 The majority of affected individuals experience subclinical Leydig cell dysfunction (LCD), with normal serum testosterone and elevated luteinizing hormone (LH).9,15,17
Long-term follow-up data on LCF are scarce because the diagnosis requires clinical and laboratory evaluations.14 Furthermore, assessment of the impact of LCF in adults requires the inclusion of erectile dysfunction (ED), which is challenging to capture.18 Possible associations between elevated LH and decreased physical fitness with aging,19,20 as well as concerns regarding frailty,4 raise questions regarding the impact of LCF and LCD on long-term health. We undertook this study to evaluate the prevalence of and risk factors for LCF and LCD, as well as associated long-term adverse health outcomes in clinically evaluated CCS with extended follow-up.
PATIENTS AND METHODS
St Jude Lifetime Cohort Study
Individuals were enrolled in the institutional review board–approved St Jude Lifetime Cohort Study (SJLIFE), a retrospective cohort study with prospective follow-up and ongoing data accrual.8,21-23 Eligibility criteria included male sex, age of 18 years or older, and at least 5 years of follow-up since cancer diagnosis. Eligible participants were invited to complete questionnaires assessing demographic, medical, and behavioral health and to participate in on-campus evaluations that included physical examination, cardiopulmonary and neuromuscular performance testing, and laboratory and psychological tests. Follow-up was offered to all participants. During subsequent visits, confirmatory endocrine assessments and additional clinical data were obtained. An age- and sex-matched community control group was recruited among friends and non–first-degree relatives of current and former patients (Table 1).
TABLE 1.
Participant and Nonparticipant Demographic and Treatment Characteristics
Cancer Treatment Quantification
Radiation fields potentially affecting the testes included whole abdomen, inverted-Y, pelvis, prostate, bladder, testes, iliac, femoral, inguinal, total lymphoid, and total body. Testicular doses were based on prescribed doses for direct exposures. For indirect exposures, doses were estimated using treatment records and phantom measurements to reconstitute past therapy conditions.24 Cumulative treatment exposure for alkylating agents was quantified using the cyclophosphamide equivalent dose (CED).25 History of orchiectomy was abstracted from the medical record.
Diagnosis of LCF and LCD
Serum total testosterone and LH were collected before 10 am and measured using electrochemiluminescent immunometric assay (Roche Cobas 6000 Analyzer; Roche Diagnostics, Indianapolis, IN). For individuals not receiving sex hormone replacement therapy, LCF was defined as morning serum levels of total testosterone less than 250 ng/dL (or 8.67 nmol/L) and LH greater than 9.85 IU/L, and LCD was defined as testosterone levels of 250 ng/dL or greater and LH greater than 9.85 IU/L. Morning serum testosterone and LH levels measured in community controls who were not receiving sex hormone replacement (n = 160; ages 18.3 to 62.7 years) were used to validate cutoff values (Appendix Table A1, online only). The cutoff for testosterone, suggested by the assay manufacturer, was between the 5th to 10th percentiles in controls, in line with the accepted definition for hypogonadism.26 The LH value corresponding to the 97th percentile in controls was used as a cutoff in the absence of a standard definition for LCD.26 Testosterone replacement was not an exclusion criterion and was not interrupted during SJLIFE evaluations. The diagnosis of LCF was then based on data abstracted from the medical record. Participants with hormone levels indicative of LCF before replacement and those without pretreatment laboratory data but whose medical records specifically documented LCF as the reason for treatment were considered to have LCF. Participants whose Leydig cell function could not be assessed because of missing historical information, incomplete laboratory results, or gonadotropin (LH/follicle-stimulating hormone) deficiency (defined by testosterone < 250 ng/dL and LH ≤ 9.85 IU/L or documentation of treatment of this condition)27 were excluded (Fig 1).
FIG 1.
Flow diagram. FSH, follicle-stimulating hormone; LCD, Leydig cell dysfunction; LCF, Leydig cell failure; LH, luteinizing hormone.
Physical Health Outcomes
Height, weight, body mass index (BMI), and waist circumference were measured in all participants. Fasting serum glucose and lipids were measured using an enzymatic spectrophotometric assay (Roche Modular P Chemistry Analyzer). Bone mineral density was measured using quantitative computed tomography with VCT LightSpeed 64-detector (GE Healthcare, Waukesha, WI) and Mindways software (Austin, TX). Diagnostic criteria for impaired physical outcomes are listed in Table 2.28-33
TABLE 2.
Criteria Used to Define Adverse Physical Health Outcomes in the St Jude Lifetime Cohort
ED and Psychological Distress Parameters
A questionnaire was used to assess for ED (n = 892).21 Mild to severe ED was defined by scores of 25 or less using the validated six-item version of the International Index of Erectile Function in sexually active participants; responses to additional items querying problems getting or sustaining an erection were used for others (n = 115).18,34, Psychological distress was measured by the Brief Symptom Inventory-18 questionnaire.35
Statistical Analysis
The study design incorporated two separate analyses. The prevalence of LCF and LCD and their associations with demographic and cancer treatment factors were assessed using the status at the most recent SJLIFE evaluation. Unadjusted associations of the outcome expressed as three mutually exclusive categories (LCF, LCD, and neither) were assessed using polytomous logistic regression models including race/ethnicity, age at cancer diagnosis, age at first exposure to testicular radiotherapy or to alkylating agents, BMI, heavy drinking, cigarette smoking, illicit drug use, testicular radiotherapy dose, CED, and unilateral orchiectomy. Variable categorizations were based on clinical relevance and considered statistical power to ensure that adequate numbers were available in each group. Variables with P ≤ .10 from the unadjusted analysis entered the multivariable analysis. Association results are presented with estimated adjusted odds ratios (ORs) and corresponding 95% CIs. We also compared SJLIFE participants and community controls using a similar approach.
Associations of LCF or LCD with diabetes mellitus, dyslipidemia, abdominal obesity, severe bone mineral density deficit, frailty, ED, and psychological distress were examined in a cross-sectional fashion using participant LCF/LCD status at the time of the baseline evaluation, when physical and psychosocial assessments were systematically and synchronously made. Demographic and treatment-related covariables, similar to those used in the risk factor analysis, with P ≤ 0.10 from the unadjusted analysis, were entered in multivariable models and were adjusted using the propensity score method with polytomous logistic models.36 Log-binomial regression was used to estimate the adjusted prevalence ratios (PRs) and 95% CIs. A time-to-event subanalysis was conducted to examine the association of LCF or LCD with subsequent all-cause mortality, starting the analysis from the baseline visit when Leydig cell function was first assessed and adjusting for the same set of covariables; a piecewise exponential model was used to estimate the adjusted rate ratios and 95% CIs.
RESULTS
Point Prevalence of LCF and LCD
Of 2,880 potentially eligible male survivors, 2,272 had been invited to participate in SJLIFE, of whom 1,701 (75%) completed a clinical assessment. (Fig 1). Compared with nonparticipants, participants were less likely to have a diagnosis of a CNS tumor and more likely to have been exposed to a higher CED (Table 1).
Laboratory data from the baseline evaluation were available on 1,516 study participants (median age, 30.8 years; range, 18.1 to 63.8 years) after a median of 22.0 years (range, 7.5 to 49.8 years) since cancer diagnosis. At the baseline evaluation, 102 participants had LCF (38 treated with testosterone), and 200 had LCD. Follow-up data from multiple visits were available on 683 participants (45.2%) prospectively evaluated over a median 4.8 years (range, 0.8 to 7.6 years). At subsequent SJLIFE evaluations, four participants developed LH/follicle-stimulating hormone deficiency, whereas 25 previously unaffected participants developed LCF (n = 2) or LCD (n = 23). None of those with LCF or LCD at baseline had testosterone and/or LH values that spontaneously normalized, nor did anyone with LCD at baseline progress to LCF. The point prevalence of LCF and LCD on the basis of the most recent SJLIFE evaluation was 6.9% (95% CI, 5.6% to 8.2%) and 14.7% (95% CI, 13.0% to 16.5%), respectively. Among a total of 104 individuals with LCF, 42 (40.4%) were receiving therapy with testosterone at the time of their most recent assessment, 30 had laboratory data supporting the diagnosis of LCF before initiation of testosterone replacement (22 initiated by St Jude–affiliated physicians), three had LH values greater than 9 IU/L while receiving testosterone and nine had LCF documented as a diagnosis in the medical chart with no additional supporting laboratory data. Of 168 male community controls, eight (4.8%; 95% CI, 1.5% to 8.0%) were receiving exogenous testosterone. Data documenting the indications for treatment in this group were not available. There were no controls with LCF on the basis of laboratory measures alone; four individuals (2.4%; 95% CI, 0.1% to 4.7%) had LCD (Table 1).
Risk Factors of LCF and LCD
Thirty-five participants (27 with testicular cancer) were treated with unilateral orchiectomy. The multivariable analysis showed that an age of 26 years or older, testicular radiotherapy at any dose, and CEDs of 4,000mg/m2 or greater were significant risk factors for LCF (Table 3); these associations remained significant after the exclusion of the nine survivors who were receiving treatment for LCF but lacked laboratory data supporting the diagnosis (Appendix Table A2, online only).
TABLE 3.
Multivariable Logistic Regression Model Fits for LCF and LCD
The risk of LCD was significantly higher in individuals ages 26 years or older and was lower in overweight (BMI, 25 to 29.9 kg/m2) or obese individuals (BMI, ≥ 30 kg/m2). Treatment-related risk factors for LCD included testicular radiotherapy at doses of 12 Gy or greater, CEDs of 4,000 mg/m2 or greater, and unilateral orchiectomy (Table 3). Among the 683 prospectively followed participants, progression from normal function to LCD or LCF (n = 25) was significantly associated with higher CEDs (P = .025).
After adjusting for age at SJLIFE, race, and BMI, survivors were more likely than community controls to have LCD. There were no differences in risk of LCF between survivors and controls when controls receiving testosterone (n = 8) were presumed to have LCF; the difference was, however, infinite when treated controls were excluded because no controls had LCF on the basis of laboratory results alone (Appendix Table A3, online only).
Associations Between LCF/LCD, and Physical, Psychosocial, and Psychosexual Impairment
The multivariable cross-sectional analysis showed significant associations between LCF and increased waist circumference, diabetes mellitus, ED, and muscle weakness after adjustment for other potential risk factors (Table 4). Subsequent all-cause mortality was also independently associated with the baseline status of LCF (PR, 4.9; 95% CI, 2.2 to 10.8; P < .001) after adjusting for potential confounders. Significant associations were unchanged after the exclusion of the nine survivors who were receiving treatment for LCF but lacked laboratory data supporting the diagnosis (Appendix Table A4, online only). Untreated LCF maintained the same independent associations as those described for LCF except for muscle weakness (Table 5). Treated LCF was associated with increased waist circumference, ED, muscle weakness, and depression but not with all-cause mortality (Table 5). However, associations with frailty (PR, 4.3; 95% CI, 1.2 to 15.8) and all-cause mortality (rate ratio, 8.0; 95% CI, 1.7 to 37.8) became significant after the exclusion of the nine survivors whose diagnosis could not be confirmed by laboratory measures (Appendix Table A5, online only). Individuals with increased waist circumference were less likely to have LCD; no associations were found between LCD and other adverse outcomes (Table 4).
TABLE 4.
Multivariable Regression Model Fits for LCF, LCD, and Physical and Sexual Health Parameters
TABLE 5.
Multivariable Regression Model Fits for Treated, Untreated LCF, LCD, and Physical, Psychological, and Sexual Health Parameters
DISCUSSION
LCF or dysfunction affects a substantial proportion of survivors at a relatively young age. In this large cohort of clinically assessed survivors, we identified significant long-term adverse physical and psychosexual health outcomes that were associated with LCF. Many of these associations persisted among individuals who reported taking hormonal replacement therapy. Our findings also extend previous knowledge regarding associations between LCF and treatment-related risk factors, such as testicular radiotherapy and alkylating agents.14
Reports on LCF are scarce and have limitations, including short follow-up,37 single cross-sectional evaluations,14,38 and absence of clear distinctions between LCF, germ cell failure, and/or central hypogonadism.12,39-41 These distinctions are, however, essential,42 given the differential vulnerability of Leydig cells and germ cells to cancer therapies and the need to counsel and screen individuals based on treatment exposures.8,9 The prevalence of LCF in SJLIFE was within the 5.8% to 10.8% range previously reported by others14,37,38 and was substantially lower than that of oligospermia or azo-ospermia, reported in 25% and 28% of tested individuals, respectively.43 The prevalence of LCD in SJLIFE (14.8%) was lower than limited data (23.8%) inferred from previous work.14 Comparisons between survivor and community controls support a higher risk of LCD in survivors than in the general population. The unexpected lack of difference in the risk of LCF between survivors and controls is most likely the result of the treatment of a subset of controls for reasons other than LCF because data documenting the indication for treatment in this group were not available. The prevalence of LCF and LCD reported in aging men (2% and 9.5%, respectively) was lower than that reported in SJLIFE despite the substantially older age of participants compared with our study (mean, 59.7 ± 11 years v 31.9 ± 8.9 years).19
The major risk factor for LCF in SJLIFE was testicular radiotherapy as previously reported.10-12,16,44 Nearly 95% of participants treated with doses of 20 Gy or greater had either LCD or LCF. Testicular doses of 20 Gy or greater have been shown to pose the greatest risk for LCF over the short-term, whereas individuals treated with lower doses were reported to enter and progress through puberty spontaneously.11,44 Our findings demonstrate that, with longer follow-up, doses less than 20 Gy represent a significant risk factor for LCF and LCD.45,46 Data pertaining to the protective effect of gonadal shielding remain limited.47 The evidence supporting an association between alkylating agents and LCF has historically been less convincing than data on radiotherapy.13,15,48,49 SJLIFE data demonstrate, with a greater level of confidence, that CEDs of 4,000 mg/m2 or greater represent an independent risk factor for both LCF and LCD. Furthermore, higher CEDs were associated with deterioration of Leydig cell function over time. Exposed individuals should be screened and counseled regarding their risk for both impaired testosterone production and infertility.50 Unilateral orchiectomy was associated with a significant risk of LCD. Longitudinal data from testicular cancer survivors indicate that LCD after unilateral orchiectomy with or without chemotherapy may be predictive of age-adjusted decline in testosterone levels with extended follow-up.51 Despite the known increase in the prevalence of LCF with aging in the noncancer population,19,26 it is important to note the relatively young age of SJLIFE participants (median, 32.7 years) and that the risk of LCF increased during the third decade of life. LCD was less common in overweight or obese participants, possibly because of the known association between obesity and lower LH levels.26 The unexpected finding of a nonstatistically significant trend of a positive association between LCF and increased BMI warrants confirmation in other cohorts.
Few studies have assessed associations between LCF and health outcomes in CCS.14,52 Low testosterone was associated with increased body fat, impaired glucose tolerance, insulin resistance, and decreased quality of life in a cross-sectional study of 176 survivors and 213 controls.14 In another study, CEDs of 10,000 mg/m2 or less with or without testicular radiotherapy were associated with lower quality of life, impaired emotional well-being, and decreased energy.52 Our findings support an independent association between LCF and impaired physical and psychosexual health, similar to hypogonadism in the noncancer population.26 Because survivors are more likely to develop associated comorbidities, the adverse consequences of LCF may be even greater in this population.8 The analysis does not allow us, however, to speculate on causality, in particular, for the association between LCF and all-cause mortality, because older age and burden from chronic disease are known to be associated with elevated LH and low testosterone levels in the general population.20,26,53 Interestingly, LCD was not independently associated with any adverse health outcome.
The amenability of LCF to treatment with sex hormone replacement should provide impetus for the screening of at-risk individuals and the treatment of those affected. However, only a minority (40.4%) of affected SJLIFE participants were treated, which may indicate challenges with accessing treatment.8 The contrast with community controls, none of whom had untreated LCF, suggests that medical providers may be more reluctant to treat survivors. We further speculate that physically fit survivors may have easier access to this treatment in the community setting, but this is not verifiable in the absence of data pertaining to the circumstances surrounding testosterone initiation in some participants. The cross-sectional nature of the analysis and the small numbers of participants do not allow definitive conclusions regarding the benefits or effects of this treatment. Endocrine Society practice guidelines recommend treatment with testosterone in males with documented hypogonadism to maintain secondary sex characteristics and ameliorate androgen deficiency symptoms.26
This study has several limitations. Prevalence estimates have to be interpreted with caution, given the substantial number of nonparticipants and individuals pending invitations for campus visits. The assay used for measuring testosterone does not meet the standards recommended by the Endocrine Society.26 Our use of total testosterone may have resulted in overdiagnosing hypogonadism in obese individuals.26 Serial clinical and laboratory evaluations were available on only 45% of participants, whereas confirmatory data supporting the diagnosis of LCF on two separate occasions are recommended.26 The statistical analysis cannot establish causality in the context of the potentially bidirectional associations between LCF and various health outcomes. Other limitations include the assumption that diagnoses of LCF before SJLIFE were accurate and persistent, the lack of data other than historical medical records to support the diagnosis of LCF in a subset of survivors and of data pertaining to treatment indications in controls, the cross-sectional nature of the analysis of association with chronic health outcomes, the lack of standard diagnostic tools for ED in the nonsexually active, and the need to retrospectively estimate testicular radiotherapy doses. Changes in treatment protocols and improvements in the delivery of radiotherapy may reduce the risk of LCF in some survivors treated more recently and in the future.
In summary, LCF and LCD are not uncommon in CCS and can present years after cancer therapy. LCF is associated with adverse physical and psychosexual outcomes, as well as mortality. LCD does not seem to be independently associated with adverse outcomes. The benefits and risks of replacement with testosterone require additional study.
Appendix
TABLE A1.
Age-Adjusted LH and Testosterone Levels in Community Controls
TABLE A2.
Multivariable Logistic Regression Model Fits for LCF and LCD: Survivors With Laboratory Studies Supporting the Diagnosis of LCF
TABLE A3.
Comparison of the Risk of LCF and LCD Between SJLIFE Participants and Community Controls
TABLE A4.
Multivariable Regression Model Fits for LCF, LCD, and Physical and Sexual Health Parameters: Survivors With Laboratory Studies Supporting the Diagnosis of LCF
TABLE A5.
Multivariable Regression Model Fits for Treated, Untreated LCF and LCD, and Physical and Sexual Health Parameters: Survivors With Laboratory Studies Supporting the Diagnosis of LCF
Footnotes
Supported by the National Cancer Institute (U01 CA195547). Additional support was provided by the National Cancer Institute Cancer Center Support (CORE) grant for St Jude Children’s Research Hospital (P30 CA021765) and the American Lebanese Syrian Associated Charities.
AUTHOR CONTRIBUTIONS
Conception and design: Wassim Chemaitilly, Kirsten K. Ness, Tara M. Brinkman, James L. Klosky, Monika L. Metzger, Gregory T. Armstrong, Hanneke M. van Santen, Deo Kumar Srivastava, Melissa M. Hudson, Leslie L. Robison
Financial support: Melissa M. Hudson, Leslie L. Robison
Administrative support: Melissa M. Hudson, Leslie L. Robison
Provision of study materials or patients: Ching-Hon Pui, Melissa M. Hudson, Leslie L. Robison
Collection and assembly of data: Wassim Chemaitilly, Zhenghong Li, James L. Klosky, Nicole Barnes, Karen L. Clark, Susan A. Smith, Matthew J. Krasin, Ching-Hon Pui, Melissa M. Hudson, Leslie L. Robison
Data analysis and interpretation: Wassim Chemaitilly, Qi Liu, Laura van Iersel, Kirsten K. Ness, Zhenghong Li, Carmen L. Wilson, James L. Klosky, Rebecca M. Howell, Susan A. Smith, Matthew J. Krasin, Michael W. Bishop, Hanneke M. van Santen, Deo Kumar Srivastava, Yutaka Yasui, Melissa M. Hudson, Daniel M. Green, Charles A. Sklar
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Leydig Cell Function in Male Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
James L. Klosky
Employment: InTown Physical Therapy (I)
Research Funding: Merck Sharp & Dohme
Susan A. Smith
Honoraria: Memorial Sloan Kettering Cancer Center
Travel, Accommodations, Expenses: Memorial Sloan Kettering Cancer Center
Monika L. Metzger
Research Funding: Seattle Genetics
Michael W. Bishop
Research Funding: Pfizer
Hanneke M. van Santen
Consulting or Advisory Role: Ferring BV
Ching-Hon Pui
Consulting or Advisory Role: Adaptive Biotechnologies
Melissa M. Hudson
Consulting or Advisory Role: Oncology Research Information Exchange Network, Princess Máxima Center, SurvivorLink
Charles A. Sklar
Patents, Royalties, Other Intellectual Property: UpToDate
No other potential conflicts of interest were reported.
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