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Testicular Function After Cytotoxic Chemotherapy: Evidence of Leydig Cell Insufficiency

From the Departments of Endocrinology, Medical Oncology, and Statistics, Christie Hospital National Health Service Trust, Withington, Manchester, United Kingdom.

Address reprint requests to S.M. Shalet, MD, Department of Endocrinology, Christie Hospital National Health Service Trust, Withington, Manchester, M20 4BX United Kingdom; email mmassey{at}picr.man.ac.uk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate testicular function in men after treatment with cytotoxic chemotherapy.

PATIENTS AND METHODS: We measured testosterone, sex hormone–binding globulin (SHBG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) levels in 209 men after treatment with mechlorethamine, vinblastine, procarbazine, and prednisone, hybrid chemotherapy, or high-dose chemotherapy and in 54 healthy age-matched controls.

RESULTS: The mean age of the patients was 38 years (range, 19 to 68 years), and all patients had received chemotherapy between 1 and 22 years previously. Patients had significantly higher mean LH (7.9 v 4.1 IU/L; P < .0001) and FSH levels (18.8 v 3.1 IU/L; P < .0001) than controls. There was no significant difference in mean total testosterone level between the patients and controls, but there was a trend toward a lower mean testosterone/SHBG ratio in the patients (0.63 v 0.7; P = .08). Analysis of the hormonal parameters using a model that allowed for the effects of increasing age on testicular function showed evidence of significant recovery of gonadal function in the first 10 years after treatment. Fifty-two percent of patients had LH levels at or above the upper limit of normal, and 32% of patients had increased LH with testosterone levels in the lower half of the normal range, suggesting a degree of Leydig cell impairment.

CONCLUSION: In a significant proportion of men, there is good evidence of Leydig cell dysfunction after cytotoxic chemotherapy. The clinical significance of this Leydig cell dysfunction is not clear, but some of these men may benefit from testosterone replacement. Further studies are warranted.

	INTRODUCTION

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WITH THE USE OF cytotoxic chemotherapy, long-term cure rates for several hematologic malignancies have greatly improved during the last two decades. As a result of better survival figures, the long-term side effects of treatment are becoming more important. Gonadal dysfunction is one of the most common side effects of cytotoxic chemotherapy. Azoospermia after chemotherapy with nitrogen mustard was first described by Spitz¹ in 1948, and since then, most research has focused on the effect of cytotoxic agents on germinal cell function. Oligospermia and azoospermia have been demonstrated after chemotherapy with a number of drugs, particularly alkylating agents and procarbazine. Standard combination chemotherapy for Hodgkin's disease with mustine, vinblastine, procarbazine, and prednisolone (MVPP),^2,3 cyclophosphamide, vincristine, procarbazine, and prednisolone (COPP),⁴ and mechlorethamine, vincristine, procarbazine, and prednisone⁵ has been associated with azoospermia in 90% to 100% of men. High-dose chemotherapy used as conditioning for bone marrow transplantation has also been shown to result in a similar incidence of germinal cell dysfunction.⁶

Although the Leydig cells of the testes are more resistant to cytotoxic damage than the germinal epithelium, a number of studies have reported increased luteinizing hormone (LH) levels in men after chemotherapy.^2-4,6 This likely represents a compensatory mechanism resulting from reduced negative feedback by testosterone at the hypothalamopituitary level, thereby reflecting a degree of impairment of testosterone production by the Leydig cells. However, the numbers of patients studied in these previous reports have been fairly small (no study has reported on more than 75 patients), and there are few data on the longitudinal effect of chemotherapy on Leydig cell function or comparisons of the effects of different chemotherapy regimens. Therefore, we measured gonadotrophin, testosterone, and sex hormone–binding globulin (SHBG) levels in a large number of men at varying times after three different chemotherapeutic regimens for a variety of hematologic malignancies.

	PATIENTS AND METHODS

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We studied 209 men aged 19 to 68 years who had been treated with MVPP, hybrid chemotherapy (chlorambucil, vinblastine, procarbazine, prednisolone, etoposide, vincristine, and doxorubicin), or high-dose chemotherapy (either cyclophosphamide, carmustine and etoposide; busulfan and cyclophosphamide; or carmustine, etoposide, cytarabine, and melphalan). The pathologic diagnosis was Hodgkin's disease in 160 patients, non-Hodgkin's lymphoma in 17 patients, acute myeloid leukemia in 14 patients, acute lymphoblastic leukemia in six patients, and multiple myeloma in 12 patients. Of those patients with Hodgkin's disease, 59 had received a median of eight cycles (range, five to 10 cycles) of MVPP only and 76 had received a median of seven cycles (range, six to eight cycles) of hybrid chemotherapy only. Six patients had been treated with hybrid chemotherapy in addition to vincristine, adriamycin, prednisolone, etoposide, cyclophosphamide, and bleomycin (n = 4), mechlorethamine, vincristine, procarbazine, and prednisone (n = 1), or MVPP (n = 1), and another 19 patients had received high-dose chemotherapy after relapse after treatment with MVPP, hybrid chemotherapy, or both. All of the non-Hodgkin's lymphoma patients had received high-dose chemotherapy after relapse after treatment with either vincristine, adriamycin, prednisolone, etoposide, cyclophosphamide, and bleomycin (n = 14) or cyclophosphamide, doxorubicin, vincristine, and prednisone (n = 3), and all of the leukemia and myeloma patients had received high-dose chemotherapy.

All patients were in remission at the time of analysis and had completed chemotherapy at least 12 months previously. No patient had any past history of testicular disease or had received radiotherapy to the testes. All patients had blood taken for the measurement of serum testosterone, SHBG, follicle-stimulating hormone (FSH), and LH levels.

Testosterone was measured with a competitive radioimmunoassay using rabbit antitestosterone antibodies and separation using polyethylene glycol–accelerated second antibody (Diasorin Ltd, Wokingham, United Kingdom; interassay coefficient of variance [CV] < 10%). LH and FSH were measured using two-site chemiluminometric immunoassays (Chiron Diagnostic, Essex, United Kingdom) with interassay CVs of 4.4% and 5.3%, respectively. SHBG was measured with a solid-phase, time-resolved, two-site fluoroimmunometric assay with an interassay CV of 6.3%. The results were compared with the results from a group of 54 age-matched healthy controls. The study was approved by the South Manchester Medical Research Ethics Committee.

Statistics
The Mann-Whitney U test was used to compare hormone values between the patients and the controls and between different treatment groups. Pearson's two-tailed test was used to determine whether there were any significant correlations between any of the variables. To attempt to jointly consider the effects of age, treatment group, and years since treatment on the assessed response variables, an additive model was used.⁷ The reason for this was to be flexible in modeling the effects of the two continuous variables, age and time since treatment, because the expectation was that any recovery or continued decline in testicular function with time after cytotoxic insult was likely to be nonlinear. The covariates used were age (age at assessment for controls and age at treatment for patients), treatment group (control, MVPP, hybrid chemotherapy, and high-dose chemotherapy), and years since completion of chemotherapy.

	RESULTS

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The mean age and the testosterone, SHBG, LH, and FSH levels of the 209 patients and 54 controls are listed in Table 1. There was no significant difference in mean age or mean total testosterone level between the patients and the controls, but the patients had significantly higher mean LH (7.9 v 4.1 IU/L; P < .0001) and FSH levels (18.8 v 3.1 IU/L; P < .0001). The assay for testosterone measures the total hormone level, which consists of protein-bound testosterone and physiologically active free hormone. The measurement of SHBG, the main testosterone-binding protein, therefore allows a better estimation of physiologically active testosterone levels. A higher SHBG is associated with a lower free testosterone level for any given total testosterone level, and calculation of the testosterone/SHBG ratio provides a good estimation of the free testosterone level. There was a nonsignificant trend toward a higher mean SHBG level in the patients (33.3 v 29.2 nmol/L; P = .06) compared with the controls, with a lower mean testosterone/SHBG ratio (0.63 v 0.7; P = .08).

Table 1 also lists the mean hormone levels for the patients by treatment group. All of the patients treated with high-dose chemotherapy were included in the high-dose group irrespective of whether they had also received MVPP or hybrid chemotherapy, and the six other patients who had been treated with more than one chemotherapy regimen were excluded from this analysis. There were no significant differences in testosterone or LH levels among the three groups, although there was a trend toward higher testosterone and lower LH levels in the hybrid group. There was no significant correlation between the number of cycles of chemotherapy and LH or testosterone levels.

There was a significant inverse correlation between age and testosterone level (r = -.34; P < .001) and a positive correlation between age and LH (r = .21; P = .002) in the patient group as a whole, suggesting decreasing gonadal function with increasing age. There was no significant correlation between testosterone and LH levels, although there was an inverse correlation between testosterone/SHBG ratio and LH level (r = -.25; P < .001). The effect of time since completion of chemotherapy on hormonal parameters was difficult to define clearly because of the confounding variables of the age of the patients and the time since treatment.

To examine the changes in hormonal parameters with time after chemotherapy, a statistical model was developed that incorporated the change in testicular function with increasing age. This allowed an estimation of the hormone levels at the time of chemotherapy and an analysis of the trend of these levels thereafter. The model assumed normal premorbid testicular function followed by an acute insult to the testes from the disease and chemotherapy, then a phase during which testicular function may gradually recover, remain stable, or gradually decline. Figure 1 (graphs 1a, 2a, and 3a) shows the estimated mean hormone levels before chemotherapy plotted against the age of the patients at treatment. Because the model assumes that patients had normal premorbid hormone levels, data from the control population can also be used in producing these curves. Curves obtained using only data from the control group (not shown) were broadly similar to those shown, in keeping with the model's assumption of normal premorbid hormone levels. Figure 1 also shows the estimated acute change in mean hormone levels at the time of treatment (graphs 1b, 2b, and 3b) and the change in mean hormone levels with time after chemotherapy (graphs 1c, 2c, and 3c). If there was no recovery or continued decline of testicular function after the initial chemotherapy insult, then the slopes in Fig 1, graphs 1a to 3a and 1c to 3c, should be similar, indicating that the change in hormone levels with time after chemotherapy was the same as before.

View larger version (28K): [in this window] [in a new window]   Fig 1. (1a–3a) Changes in estimated mean hormone levels before chemotherapy with increasing age. (1b–3b) Estimated acute changes after chemotherapy. (1c–3c) Estimated changes in hormone levels with time after chemotherapy. Solid lines represent means, and broken lines represent 95% pointwise error bands. Abbreviations: T, Testosterone; HDCT, high-dose chemotherapy; CT, chemotherapy.

Using this model, there was a highly significant acute increase in estimated LH levels at the time of chemotherapy (P < .0001, all patients compared with controls; Fig 1, graph 1b) followed by recovery of Leydig cell function, with a gradual decline in LH levels in the first 10 years, after which the trend reverted to that expected with increasing age (Fig 1, graph 1c). There was no significant acute change in testosterone levels (not shown), but when a correction was made for bound testosterone by using the testosterone/SHBG ratio (an indication of the free testosterone level), a significant acute reduction was seen (P < .01, all patients compared with controls; Fig 1, graph 2b). No formally significant difference was apparent at the time of evaluation, suggesting a degree of recovery of testosterone production, which was also suggested by the initial flattening of the slope in Fig 1, graph 2c compared with graph 2a. There was a significant acute increase in estimated FSH levels (P < .0001, all patients compared with controls; Fig 1, graph 3b), after which the change with time was similar to that expected with increasing age (Fig 1, graph 3c).

The normal range for LH calculated from the control subjects was less than 1 to 8 IU/L, and that for testosterone was 8 to 30 nmol/L. A large proportion of the patients had LH levels at or above the upper limit of normal, and these are listed in Table 2. Because the normal range for testosterone in adults is fairly wide, small but significant reductions in hormone levels will often result in values that remain within the normal range. Thus, increased LH in the presence of a testosterone level in the lower part of the normal range may still indicate a reduction in testosterone production that may be clinically significant. Table 2 lists the number of patients with this combination of LH level of 8 IU/L and testosterone level less than 20 nmol/L, which we have defined arbitrarily as an indication of Leydig cell insufficiency. Overall, almost one third of patients satisfied these criteria for Leydig cell dysfunction. There was no significant difference in underlying diagnosis or treatment received between the patients who satisfied the biochemical criteria and the patients who did not, although the patients with Leydig cell insufficiency were significantly older (mean age, 42.2 v 36.3 years; P = .001).

Normal FSH levels (<8 IU/L) were found in only 16 patients (8%), all of whom also had normal LH levels. Mean FSH levels were significantly higher in patients with evidence of Leydig cell dysfunction than in patients with either LH levels less than 8 IU/L or testosterone levels more than 20 nmol/L (24.3 v 16.4 IU/L; P < .0001).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We have confirmed the finding of previous smaller studies that more than 90% of men have biochemical evidence of germinal epithelial failure, indicated by increased FSH levels, after treatment with MVPP, hybrid chemotherapy, or high-dose chemotherapy. However, in addition, we have also demonstrated that one third of these men have evidence of Leydig cell dysfunction, with increased LH levels in the presence of low or normal testosterone. We have also shown that chemotherapy-induced Leydig cell dysfunction is more common with increasing age. This is not surprising given the well documented decline in gonadal function with advancing age in the normal population. We could find no significant difference in the degree of Leydig cell impairment between the three different chemotherapy regimens, although there was a trend toward reduced gonadotoxicity after hybrid chemotherapy. In addition, we have demonstrated that Leydig cell dysfunction tends to occur in those patients with more marked germinal epithelial damage and is not found in men with intact germinal epithelium as indicated by normal FSH levels.

Several smaller reports have documented increased LH levels in a proportion of men after cytotoxic chemotherapy. Increased basal and gonadotropin–releasing hormone-stimulated levels of LH have been described in patients treated for Hodgkin's disease during childhood with vincristine, procarbazine, prednisolone, and adriamycin alternating with COPP^8,9 and chlorambucil, vincristine, procarbazine, and prednisolone.⁹ Similar results have also been observed in adults after treatment with MVPP,^2,3 COPP,⁴and high-dose chemotherapy.⁶ Testosterone levels are usually within the normal range in the majority of these patients after chemotherapy, although a few reports have noted a reduction in testosterone levels compared with those in healthy controls² or with pretreatment levels.⁶

None of the previous studies has been able to compare different chemotherapy regimens, and there are few longitudinal data regarding Leydig cell function. Although our data are cross-sectional, the large number of patients has enabled us to perform some analysis of the change in Leydig cell function with time after cytotoxic insult. This analysis was performed using a model based on the likely effect of chemotherapy on testicular function. Using this model, there was evidence of recovery of Leydig cell function in the first 10 years after chemotherapy, with a decrease in LH levels and a relative increase in testosterone/SHBG ratio.

The mechanism of Leydig cell impairment after chemotherapy is not known. There is no histologic evidence of Leydig cell abnormalities on testicular biopsy after cytotoxic therapy. Chemotherapy may have a direct toxic effect on the Leydig cell, but there is also some evidence that germinal epithelial damage may indirectly affect Leydig cell function. Azoospermia after germinal cell damage causes a reduction in testicular volume and testicular blood flow.¹⁰ The testosterone output of the testes is a product of the venoarterial concentration difference of testosterone and the venous outflow from the testes, and thus it is reduced by any reduction in testicular blood flow. Although a modest reduction in blood flow may be corrected by an increase in intratesticular testosterone concentration, there is evidence from an animal model that more marked reductions in blood flow cannot be overcome.¹¹ In addition, as arterial flow into the testes is reduced, the stimulatory effect of LH may be diminished. Damage to the germinal epithelium and a reduction in testicular volume may also affect Leydig cell function by causing structural changes within the testes or alterations in the paracrine control of Leydig cell function.^12,13

The association between Leydig cell function and germinal epithelial function was clearly illustrated in our cohort, with those patients with evidence of Leydig cell insufficiency having significantly higher FSH levels than those patients with normal testosterone and LH levels. In addition, none of the 13 patients with a normal FSH level, suggesting normal germinal epithelial function, had an increased LH level. Although this is not surprising given the relative susceptibilities of the Leydig cells and the germinal epithelium to damage, it leaves open the possibility that germinal cell dysfunction plays a role in Leydig cell insufficiency.

In addition, we found evidence of recovery of Leydig cell function during the first 10 years after chemotherapy. Although we could not demonstrate a significant reduction in FSH levels with time in our cohort, a gradual recovery of germinal cell function, with a return of spermatogenesis in a proportion of patients, has been well documented after cytotoxic chemotherapy.^14-16 Therefore, the finding of a similar pattern of Leydig cell function in our patients may indicate that germinal epithelial dysfunction may be etiologically important in the occurrence of Leydig cell insufficiency.

The clinical effect of mild Leydig cell insufficiency is not clear. Overt testosterone deficiency in adult men is associated with reductions in energy levels, altered body composition, reduced sexual function, increased incidence of anxiety and depression, and reduction in bone mineral density (BMD). All of these abnormalities occur more commonly in men after treatment with cytotoxic chemotherapy,^3,17 and Holmes et al¹⁷ found a reduction in BMD after chemotherapy for Hodgkin's disease, with a significant positive correlation between serum testosterone and BMD at the lumbar spine and femoral neck. Thus, although there are a number of alternative explanations for these abnormalities after chemotherapy, there is some evidence that mild testosterone deficiency may be implicated. This raises the possibility that treatment with testosterone replacement may be beneficial in patients with mild Leydig cell insufficiency; this requires further evaluation.

In summary, we have demonstrated mild Leydig cell impairment in more than 30% of men after treatment for various malignancies with MVPP, hybrid chemotherapy, or high-dose chemotherapy. There was some evidence of partial recovery of Leydig cell function in the first decade after chemotherapy, and there was no significant difference in the gonadotoxicity of the three different regimens. Further research into the clinical effect of this mild Leydig cell dysfunction and the possible benefits of testosterone replacement in these men is warranted.

	ACKNOWLEDGMENTS

 
Supported by Eli Lilly, Basingstoke, Hampshire, United Kingdom.

We thank Sue Lee for data management and Professor J.H. Scarffe and Dr G.R. Morgenstern for their help in identifying patients for this study.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Spitz S: The histological effects of nitrogen mustard on human tumours and tissues. Cancer 1:383-398, 1948[Medline]

2. Whitehead E, Shalet SM, Blackledge G, et al: The effects of Hodgkin's disease and combination chemotherapy on gonadal function in the adult male. Cancer 49:418-422, 1982[Medline]

3. Chapman RM, Sutcliffe SB, Rees LH, et al: Cyclical combination chemotherapy and gonadal function: Retrospective study in males. Lancet 1:285-289, 1979[Medline]

4. Charak BS, Gupta R, Mandrekar P, et al: Testicular dysfunction after cyclophosphamide-vincristine-procarbazine-prednisolone chemotherapy for advanced Hodgkin's disease: A long-term follow-up study. Cancer 65:1903-1906, 1990[Medline]

5. Viviani S, Ragni G, Santoro A, et al: Testicular dysfunction in Hodgkin's disease before and after treatment. Eur J Cancer 27:1389-1392, 1991

6. Chatterjee R, Mills W, Katz M, et al: Germ cell failure and Leydig cell insufficiency in post-pubertal males after autologous bone marrow transplantation with BEAM for lymphoma. Bone Marrow Transplant 13:519-522, 1994[Medline]

7. Hastie TJ, Tibshirani RJ: Generalised additive models. London, United Kingdom, Chapman and Hall, 1990

8. Bramswig JH, Heimes U, Heiermann E, et al: The effects of different cumulative doses of chemotherapy on testicular function: Results in 75 patients treated for Hodgkin's disease during childhood or adolescence. Cancer 65:1298-1302, 1990[Medline]

9. Mackie EJ, Radford M, Shalet SM: Gonadal function following chemotherapy for childhood Hodgkin's disease. Med Pediatr Oncol 27:74-78, 1996[Medline]

10. Wang J, Galil KA, Setchell BP: Changes in testicular blood flow and testosterone production during aspermatogenesis after irradiation. J Endocrinol 98:35-46, 1983[Abstract/Free Full Text]

11. Setchell BP, Galil KA: Limitations imposed by testicular blood flow on the function of Leydig cells in rats in vivo. Aust J Biol Sci 36:285-293, 1983[Medline]

12. Carreau S: Paracrine control of human Leydig cell and Sertoli cell functions. Folia Histochem Cytobiol 34:111-119, 1996[Medline]

13. Huhtaniemi I, Toppari J: Endocrine, paracrine and autocrine regulation of testicular steroidogenesis. Adv Exp Med Biol 377:33-54, 1995[Medline]

14. Viviani S, Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin's disease: Comparative results of MOPP vs ABVD. Eur J Cancer Clin Oncol 21:601-605, 1985[Medline]

15. Lampe H, Horwich A, Norman A, et al: Fertility after chemotherapy for testicular germ cell cancers. J Clin Oncol 15:239-245, 1997[Abstract/Free Full Text]

16. Shamberger RC, Sherins RJ, Rosenberg SA: The effects of postoperative adjuvant chemotherapy and radiotherapy on testicular function in men undergoing treatment for soft tissue sarcoma. Cancer 47:2368-2374, 1981[Medline]

17. Holmes SJ, Whitehouse RW, Clark ST, et al: Reduced bone mineral density in men following chemotherapy for Hodgkin's disease. Br J Cancer 70:371-375, 1994[Medline]

Submitted August 24, 1998; accepted January 21, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Howell, S. J. Articles by Shalet, S. M. Search for Related Content PubMed PubMed Citation Articles by Howell, S. J. Articles by Shalet, S. M.