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Department of Growth and Reproduction, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Anna-Maria Andersson, M.Sci., Ph.D., Department of Growth and Reproduction, Copenhagen University Hospital, Section GR 5064, Blegdamsvej 9, DK-2100 Copenhagen OE, Denmark. E-mail: anna{at}rh.dk.
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Abstract |
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A shift toward lower serum T levels, cFT, and T/LH ratio and higher serum LH, E2, and E2/T levels was observed in the group of infertile men. On average, the infertile men had 18, 26, and 34% lower serum T, cFT, and T/LH levels, respectively, and 19, 18, and 33% higher serum LH, E2, and E2/T levels, respectively, than the fertile men. Twelve percent of the infertile men had a serum T level that fell below the 2.5 percentile of the fertile levels, and 15% of the infertile men had a LH level that was above the 97.5 percentile of the fertile levels.
Thus, the group of infertile men showed significant signs of impaired Leydig cell function in parallel to their impaired spermatogenesis. The association of decreased spermatogenesis and impaired Leydig cell function might reflect a disturbed paracrine communication between the seminiferous epithelium and the Leydig cells, triggered by distorted function of the seminiferous epithelium. On the other hand, the parallel impairment of spermatogenesis and Leydig cells may reflect a congenital dysfunction of both compartments caused by a testicular dysgenesis during fetal/infant development.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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An association between impaired Leydig cell function and testicular cancer has been indicated by a finding of significantly increased LH levels and generally low testosterone (T) levels in men with carcinoma in situ (the precursor cells of testicular cancer) in the testis compared with men with no carcinoma in situ in the testis (2).
Regarding an association between impaired Leydig cell function and impaired spermatogenesis, some studies have shown decreased circulating T levels in infertile men (3, 4, 5, 6, 7, 8, 9, 10). However, several studies have not found this (11, 12, 13, 14, 15, 16, 17, 18, 19). The reason for the conflicting results may be that most published studies have been based on relatively small, heterogeneous groups and poorly defined controls. There seems to be a more general agreement that infertile men may sustain normal T levels on the background of slightly elevated LH, indicating a compensated dysfunction of Leydig cells in these men (11, 14, 16, 18, 19). In line with this, subnormal T responses to human chorionic gonadotropin stimulation have been observed in infertile men (20). Some studies have found increased serum estradiol (E2) levels in infertile men (10, 15, 21), whereas others have found normal levels (5, 13, 14, 16, 18) and yet others have observed decreased serum E2 level in infertile men (8, 22). Thus, the function of Leydig cells in infertility remains debated.
In this study, we addressed the issue of Leydig cell function in infertility by comparing hormonal serum markers of Leydig cell function in 357 well-characterized infertile men with hormone levels in 318 well-defined, proven fertile men. The hormonal serum markers measured included T, LH, E2, and SHBG, and the T/LH ratio, E2/T ratio, and free T index were also calculated (cFT).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Infertile males were consecutive patients referred to our andrology clinic during the period 1997–1999 as partners in couples with a history of at least 1 yr unexplained childlessness, in which an obvious problem in the female partner was excluded. Because our clinic is a university andrology clinic and not a primary referral center for infertility, a male infertility problem has often already been identified at referral. Patients in whom there was evidence or a suspicion of obstructive forms of azoospermia or secondary oligozoospermia due to orchitis or iatrogenic causes were excluded from this study. All subjects had a normal 46, XY karyotype; an androgen receptor gene with a normal CAG repeat number [an increased CAG repeat number is associated with decreased androgen receptor function (23)]; and no microdeletions on the Y-chromosome. In total, blood and semen samples were available from 357 patients. The characteristics of the infertile men are given in Table 1
. Information on body mass index (BMI) was available from 76% of the infertile men, and information on self-reported history of cryptorchidism was available from 83% of the infertile men. No information on time of blood sampling was available for this group. All hormone measurements were performed in the infertile men as part of their clinical workup.
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. In addition to hormone values and semen parameters, information on BMI and time of blood sampling was also available for this group. Information on self-reported history of cryptorchidism was available from 84% of the fertile men. The study of reproductive health in partners of pregnant women was approved by the local ethical committee. Hormone analysis
Blood samples were drawn from an antecubital vein and centrifuged after clotting. Serum was stored at –20 C until analysis. Storage time before hormone analysis ranged from 0–5 yr. T was measured by a time-resolved fluoroimmunoassay (DELFIA, Wallac, Turku, Finland) with a detection limit of 0.23 nmol/liter and intra- and interassay coefficients of variation (CV) less than 6%. Samples from the fertile and infertile men were all analyzed for T from December 2002 to January 2003 within the same assay runs. LH, FSH, and SHBG were measured by time-resolved immunofluorometric assays (IFMA) (DELFIA). The detection limits were 0.05 IU/liter, 0.06 IU/liter, and 0.23 nmol/liter, respectively. In all three IFMA, the intra- and interassay CV were less than 8% in the full range. E2 was as measured in a RIA (Pantex, Santa Monica, CA) with a detection limit of 18 pmol/liter, an intraassay CV less than 8%, and an interassay CV less than 13% in the normal range. Inhibin B was determined using a specific two-sided enzyme immunometric assay from Oxford Bio-Innovation Ltd. (Oxford, UK). The sensitivity of the inhibin B assay was 18 pg/ml, and the intra- and interassay CV were less than 12% and less than 17%, respectively.
Samples from the fertile men were analyzed for LH, FSH, inhibin B, SHBG, and E2 during January to May 1998, and samples from infertile patients were analyzed for LH, FSH, inhibin B, SHBG, and E2 consecutively during 1997–1999. The detection limit was defined as the concentration corresponding to the value that is 2 SD above or below the mean of the zero standard measurement in the immunometric (IFMA) and competitive immunoassays (fluoroimmunoassay and RIA), respectively.
Calculations and statistics
For each subject, the T/LH ratio was calculated as T (nanomoles per liter)/LH (international units per liter), and the E2/T ratio was calculated as E2 (picomoles per liter)/T (nanomoles per liter). A cFT was calculated from total T and SHBG concentrations using the method of Vermeulen et al. (25) and a fixed albumin concentration of 43 g/liter. Because changes in the concentration of albumin only have minute effects on the ratio of total/free T, it is justifiable to use a fixed mean albumin concentration when individual albumin measurements are not available, provided that there is no reason to suspect significantly abnormal albumin levels (25). Descriptive statistics are given as median values and 2.5 and 97.5 percentiles.
Differences in hormone levels between the groups of fertile and infertile men were tested by Mann-Whitney U test or in a general linear model, which allowed adjustment for differences in age and BMI. In this model, transformed hormone levels or ratios (hormone levels were transformed using the natural logarithm to obtain homoscedasticity and an approximate normal distribution) were entered as the dependent variable, "group" was entered as a categorical variable (1, fertile men; 2, infertile men), and the confounders’ age and BMI were entered as continuous variables. For each analysis, the fit of the statistical model was evaluated by testing the residuals for normality and by inspection of the residual plots. To test the relationship between age and BMI and the different hormones, a similar model in which the variable "group" was excluded was used. The relationship between age and BMI and hormones were tested for each group separately as well as for both groups combined.
Spearman’s correlation coefficients were used to evaluate the correlation between hormones, calculated factors, and sperm concentration in infertile and fertile men separately. The Statistical Package for the Social Sciences (SPSS) for Windows, version 10.0.7 (SPSS, Inc., Chicago, IL) was used for all calculations and statistical analyses.
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Results |
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As a group, the infertile men had significantly lower serum T levels and significantly higher LH and E2 levels than the fertile men (Table 2). Consequently, infertile men also had significantly lower T/LH and higher E2/T ratios (Table 2). There was no difference in SHBG serum levels between the infertile and fertile men. However, due to the lower level of total serum T in infertile men, the cFT was also significantly lower in the infertile men (Table 2).
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The distribution of serum T, LH, E2, cFT, T/LH ratio, and E2/T ratio levels among all the infertile and fertile men is shown in Fig. 1, A–F. Although the infertile men as a group had lower levels of T, cFT, and T/LH ratio and higher levels of LH, E2, and E2/T ratio than the fertile men, there was an extensive overlap between infertile and fertile hormone levels. However, 12 and 15%, respectively, of the infertile men had a serum T level and a cFT level that was below the 2.5 percentile of the fertile levels (Fig. 1, A and D). Fifteen percent of the infertile men had a serum LH that was above the 97.5 percentile of the fertile levels, and 8% had a serum E2 level above the 97.5 percentile of the fertile levels (Fig. 1, B and E). With regard to the T/LH ratio and the E2/T ratio, the distributions in infertile and fertile men were even more distinct (Fig. 1, C and F): 16% of the infertile men had a T/LH ratio below the 2.5 percentile of the fertile levels, and 20% had an E2/T ratio above the 97.5 percentile of the fertile levels.
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There were slight but significant differences in age and BMI between the group of fertile men and the group of infertile men (Table 1). We therefore also tested whether the differences in hormone levels between the two groups remained significant after adjusting for age and BMI in a general linear model as described in Patients and Methods. In Table 3, the estimated average differences in hormone levels between the fertile and infertile men after adjusting for age and BMI are presented. The group of infertile men had on average 18, 28, and 34% lower serum T, cFT, and T/LH ratio, respectively, and 19, 18, 12, and 33% higher serum LH, E2, SHBG, and E2/T ratio, respectively, than the group of fertile men.
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Self-reported information on history of cryptorchidism was available from 226 of the 318 fertile men and from 297 of the 357 infertile men. In both fertile and infertile men, a history of cryptorchidism was associated with significantly reduced sperm concentration and serum inhibin B (Table 1). In addition, among the infertile men, history of cryptorchidism was also associated with significantly higher LH level and lower T/LH ratio and E2 (Table 2).
However, if the infertile men with a history of cryptorchidism were excluded, the remaining idiopathic infertile men with no history of cryptorchidism still had significantly lower T, T/LH ratio, and cFT levels and higher LH, E2, and E2/T ratio levels than the fertile men (respectively 17, 29, and 27% lower and 14, 22, and 35% higher).
Correlation of hormone markers of Leydig cell function with semen concentration and with the serum markers of spermatogenesis, FSH, and inhibin B
T levels did not correlate with sperm concentration (neither in infertile nor fertile men), but in the infertile men, T was positively correlated with inhibin B (r = 0.183; P = 0.001). LH was negatively correlated with sperm concentration and inhibin B and positively correlated with FSH in both the group of infertile men (r = –0.368, P < 0.001; r = –0.513, P < 0.001; and r = 0.610, P < 0.001, respectively) and in the group of fertile men (r = –0.189, P = 0.001; r = –0.222, P < 0.001; and r = 0.424, P < 0.001, respectively). The T/LH ratio was positively correlated with sperm concentration and inhibin B and negatively correlated with FSH in both the group of infertile men (r = 0.337, P < 0.001; r = 0.549, P < 0.001; and r = –0.553, P < 0.001, respectively) and in the group of fertile men (r = 0.131, P = 0.02; r = 0.252, P < 0.001; and r = –301, P < 0.001, respectively). Neither E2 nor the E2/T ratio correlated with sperm concentration, inhibin B, or FSH.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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These findings seem to be in line with a previous observation that impaired spermatogenesis was associated with the occurrence of Leydig cell micronodules and decreased T/LH ratio (26) and also support previous studies showing evidence of Leydig cell dysfunction in infertile men (3, 7, 9, 14, 18, 19). The strong correlations of LH and T/LH to sperm concentration and to the serum markers of spermatogenesis, FSH and inhibin B, also suggest an association between impaired Leydig cell function and impaired spermatogenesis. In contrast to our observations, some studies have found infertile men to have T levels comparable to healthy men (6, 11, 12, 13, 14, 15, 17). However, these studies are generally based on study groups of 30–50 subjects or fewer, groups that may be too small to reach valid conclusions. Nevertheless, several of these studies do find increased LH levels in infertile men in accordance with a compensated Leydig cell dysfunction (11, 14, 15, 16, 17, 18, 19).
In accordance with some studies (10, 15, 21) but in conflict with others (8, 18, 22), we also found significantly increased serum E2 levels and E2/T ratio in the infertile men compared with fertile men. E2 levels in spermatic venous blood have been found to be higher in patients with spermatogenic failure compared with men with normal testicular histology (21). In human testis, aromatase expression is mainly confined to Leydig cells (27), and the majority of circulating E2 in men is produced in the testes by the Leydig cells (28, 29). In rats, Leydig cell aromatase activity has been shown to be stimulated by human chorionic gonadotropin or LH in vivo (30) and in vitro (30, 31, 32). Animal and in vitro studies have furthermore shown that 17-
hydroxylase and 17,20-desmolase activities can be inhibited by E2, leading to accumulation of 17-OH-progesterone and decreased T production (33, 34, 35, 36). Thus, the increased E2 and E2/T ratio we observed in the infertile men may reflect a steroidogenic dysfunction in the Leydig cells involving increased aromatase activity due to hyperstimulation by increased LH levels. Our observation of a combination of lower T and T/LH ratio and higher LH, E2, and E2/T ratio in the idiopathic infertile men compared with fertile men strongly suggests a higher incidence of primary Leydig cell dysfunction in the infertile men.
Age, BMI, and time of blood sampling during the day are all known to affect reproductive hormone levels. To exclude that a difference between the two groups with regard to these confounders might compromise the observed differences in Leydig cell function, the effect of these confounders was carefully considered. Information on age and BMI was available for both groups, and, therefore, these two confounders could be adjusted for. The differences between the two groups in hormonal markers of Leydig cell function all remained significant after adjusting for the small differences in age and BMI. Furthermore, the two groups had very similar serum SHBG, despite the fact that serum SHBG levels were highly correlated with BMI (r = –0.41; P < 0.001).
An average decrease in T of approximately 3.1% per hour during the daytime has been published previously (37). In the present study, blood samples from the fertile men were collected between 0800 and 1245 h. The precise time of sampling of blood from the infertile men was not recorded, but they all had their blood sample drawn within the opening hours of our andrology clinic, i.e. between 0830 and 1400 h. Thus, the difference in time of the day for blood sampling between the two groups was minor and potentially may only explain a minor part of the observed difference in T levels between the two groups. Furthermore, the observed differences in LH and E2 levels between the two groups could not be explained by differences in time of blood sampling because these two hormones do not change significantly during the daytime (unpublished data).
Another possible confounder considered was the effect of season. Blood sampling from the fertile men was spread over all seasons, with 29% sampled in spring (March through May), 26% sampled in summer (June through August), 31% sampled in autumn (September through November), and 14% sampled in winter (December through February). Because the infertile patients were recruited consecutively over a 3-yr period, blood sampling in this group was also spread over all seasons. Furthermore, in the group of fertile men (in which the date of blood sampling was available), no effect of season on T, T/LH ratio, E2, or E2/T ratio was observed. Thus, the observed differences in hormone markers of Leydig cell function between the groups of fertile and infertile men cannot be explained by seasonal variation, either. Hence, we are convinced that the observed differences in hormone levels between the idiopathic infertile and the fertile men reflect an increased occurrence of primary Leydig cell dysfunction in infertile men.
According to the theory of TDS, a range of male reproductive problems including impaired spermatogenesis, genital malformations (e.g. cryptorchidism), and testicular cancer can be viewed as symptoms of one underlying entity, and the more severely affected the individual is, the more of these symptoms will be manifested (1). Although the mechanisms behind the observed association between primary Leydig cell dysfunction and male infertility remains unknown, animal models indicate that hormonal disruption during fetal development may affect both testicular compartments (38). Thus, our observation is in line with the hypothesis that impaired Leydig cell function in adulthood may be yet another symptom of TDS. In this respect, is it interesting to note that the subgroup of infertile men who also had a history of cryptorchidism had lower sperm concentration and even poorer Leydig cell function reflected in significantly lower T/LH ratio than the infertile men with no history of cryptorchidism. On the other hand, it is possible that the Leydig cell dysfunction is secondary to the altered sperm production. Studies in men with normal sperm counts but with cancers requiring chemotherapy have been shown to develop Leydig cell dysfunction associated with chemotherapy-induced azoospermia (39). Furthermore, studies of adult rats showed that the induction of seminiferous tubule damage by surgically induced cryptorchidism resulted in Leydig cell dysfunction (40). Additionally, very focal damage to seminiferous tubules by implantation of capsules containing cyproterone acetate have been shown to result in focal Leydig cell hyperplasia adjacent to the damaged tubules, establishing the concept of a paracrine control of Leydig cell function (41).
In conclusion, in addition to impaired spermatogenesis, the infertile men showed significant signs of impaired Leydig cell function. In more than 10% of the infertile men, this Leydig cell dysfunction led to serum T levels below the fertile reference range. The association of decreased spermatogenesis and impaired Leydig cell function might reflect a disturbed paracrine communication between the seminiferous epithelium and the Leydig cells, triggered by distorted function of the seminiferous epithelium. On the other hand, the parallel impairment of spermatogenesis and Leydig cells may reflect a congenital dysfunction of both compartments caused by a testicular dysgenesis during fetal/infant development.
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Footnotes |
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Abbreviations: BMI, Body mass index; cFT, calculated free T index; CV, coefficient of variation; E2, estradiol; IFMA, immunofluorometric assays; TDS, testicular dysgenesis syndrome; T, testosterone.
Received October 29, 2003.
Accepted February 3, 2004.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-androstane-3 ß, 17 ß-diol: an important androgen metabolite of the human testicular-epididymal unit. J Steroid Biochem 16:567–571[CrossRef][Medline]
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