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Original Articles: Hormones and Reproductive Health |
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey Medical Center (P.A.L.), Hershey, Pennsylvania 17033; Department of Epidemiology, University of Pittsburgh Graduate School of Public Health (M.T.C.), Pittsburgh, Pennsylvania 15213; and Department of Pediatric Surgery, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh (M.F.B.), Pittsburgh, Pennsylvania 15213
Address all correspondence and requests for reprints to: Dr. Peter A. Lee, Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, Pennsylvania 17033.
Abstract
Infertility may be a consequence of cryptorchidism. We previously reported, using a large study cohort, that 38% of formerly bilateral cryptorchid men, 10% of unilateral cryptorchid men, and 5% of the control group were infertile. Men from this cohort donated blood and semen samples for inhibin B, FSH, LH, testosterone, free testosterone, and semen analyses. Results are reported comparing the entire group; some comparisons are based on normal or low sperm density. Data are also presented for men who had fathered children or had unsuccessfully attempted paternity.
Mean (±SD) inhibin B levels were lower for the cryptorchid men (109 ± 59 pg/mL) than the control men (153 ± 60; P < 0.001), and FSH levels were higher (7.4 ± 6.2 and 4.0 ± 3.2; P < 0.0001). Inhibin B levels correlated with all other parameters for the cryptorchid group; however, correlations for the control group were only found with gonadotropins. Among the cryptorchid men, levels were significantly greater among men with normal sperm counts than men with low sperm counts (124 ± 47 vs. 75 ± 48 pg/mL; P < 0.0001). No difference was present for the control group (155 ± 61 vs. 149 ± 63 pg/mL). When the fertile group (based on paternity) vs. the infertile group (based on attempted paternity) were compared, significant differences were found for the cryptorchid group (117 ± 62 vs. 73 ± 52 pg/mL; P < 0.03), but not the control group (163 ± 62 vs. 146 ± 73 pg/mL).
These data reveal relationships not apparent among the control group of men, which includes infertile men. Inhibin B data suggest that a larger portion of formerly cryptorchid men have compromised testicular function than indicated by paternity data. Low levels of inhibin B among individuals are an indication of diminished seminiferous tubule function and thus compromised potential for fertility. Low inhibin B levels together with elevated FSH levels and decreased sperm density are indicative of a high risk of infertility.
INFERTILITY IS the most common consequence of cryptorchidism. Although infertility is primarily a result of compromised spermatogenesis, other factors may preclude the development and delivery of mature sperm. In our studies of a large cohort of formerly cryptorchid men, we found that about 10% of men who had unilateral cryptorchidism (1) and about 38% of men who had bilateral cryptorchidism (2) were infertile based on paternity data. Except for men with azoospermia or severe oligospermia, however, there are no clear criteria to determine which men are at significant risk for infertility. Although low sperm counts, elevated FSH levels, and decreased testicular volume may be suggestive of decreased fertility, men with each of these findings in our cohort have fathered children. We therefore evaluated inhibin B, basal and GnRH-stimulated FSH and LH, testosterone, and free testosterone levels to determine indexes of compromised fertility among the formerly cryptorchid men and a group of men who did not have cryptorchidism. This comparison group is not necessarily a normally fertile control group, because they may have other conditions resulting in infertility.
Although semen analyses and serum FSH levels have been well studied in relation to male fertility, the assay for inhibin B has become available relatively recently. Inhibin B, produced by the Sertoli cells of the seminiferous tubule, is the principal form of inhibin in men and regulates FSH secretion by a closed loop, negative feedback mechanism (3, 4, 5). FSH, in turn, is a stimulator of inhibin B production (4, 5). Although treatment of hypogonadotropic men with GnRH (4) and cross-sectional studies in boys (5) are consistent with factors other than FSH stimulating inhibin B production, the administration of recombinant FSH results in a significant increase in inhibin B levels (4, 6). Exogenous testosterone administration is followed by suppression of FSH and inhibin (7). The measurements of FSH and inhibin B thus provide information concerning the integrity of the seminiferous tubule. Although a negative correlation between inhibin B and FSH has not been consistently reported (8, 9), a reciprocal relationship is present among men with testicular dysfunction (5, 10).
Men with abnormal sperm counts have lower levels of inhibin B and higher levels of FSH than men with normal semen analysis (4, 10). Serum inhibin levels among subfertile men have been found to be negatively correlated with FSH and positively correlated with total sperm count (10). The strong correlations among the subfertile men suggest that inhibin B may be the best marker of compromised spermatogenesis. The goals of this study were to assess whether there is evidence of compromised spermatogenesis among a cohort of formerly cryptorchid men compared with a control group who did not have cryptorchidism, but may have other problems of infertility.
As both groups include men who have been successful and unsuccessful at attempted paternity, we hypothesize that men in both the cyprotochid and comparison cohorts can be classified as fertile, infertile, or at risk of infertility based upon inhibin B and FSH levels and sperm parameters. Inhibin B and FSH levels and semen analyses will not only identify men who can be expected to be fertile and infertile, but also men at risk for infertility, including those with compromised spermatogenesis who have fathered children. Our evaluation includes assessment of inhibin B, FSH, and sperm parameters to identify men who can be expected to be fertile, infertile, or at risk for infertility.
Materials and Methods
Study subjects are from a cohort of formerly cryptorchid and control men treated at the Children’s Hospital of Pittsburgh (CHP) (1, 2). The cryptorchid men all had orchiopexies at CHP between 1955 and 1975. The control group, of similar age, had minor surgery (e.g. tonsillectomy) at CHP during the same years. This control group was chosen as a comparison group for the cryptorchid, not as a group of fertile men, because men in both groups may have causes of infertility other than cryptorchidism. Both groups were located after review of medical records during the years indicated above. Both groups had surgery during the same years, at the same age. Blood and semen samples have been obtained from a portion of this cohort who still live in the Pittsburgh area. Although a small portion of the men provided more than one blood and semen sample, results only for the initial samples were used for statistical analyses and are reported in this study. Semen was analyzed according to the WHO guidelines on samples obtained by masturbation after 48–72 h of abstinence. Blood samples were analyzed for inhibin B, FSH, LH, testosterone, and free testosterone. The first 103 men studied had GnRH stimulation testing (100 µg Factrel; Wyeth-Ayerst Pharmaceuticals, Philadelphia, PA) with LH and FSH measured at 0, 20, 40, 60, and 90 min.
Inhibin B levels were assayed using the commercially available, double antibody enzyme-linked immunosorbent assay from Serotec (Oxford, UK) performed by the Reproductive Endocrine Laboratory at the Massachusetts General Hospital. The lower limit of detection for this assay was 15.6 pg/mL; values below this limit were assigned a value of 15.6 for statistical analyses. LH and FSH levels were assayed by the Delfia fluoroimmunoassay method. The lower limits of detection were 0.15 U/L for LH and 0.50 U/L for FSH. Testosterone and free testosterone were determined using, respectively, the ImmunoChem double antibody testosterone 125I RIA kit from ICN Biomedicals, Inc. (Costa Mesa, CA), and the solid phase 125I RIA from Diagnostic Products (Los Angeles, CA). Although all samples could not be measured in the same assay because of the total number and the duration of time required to collect the samples, samples were batched for assays with samples from the cryptorchid group and the comparison control group included in each assay.
The interassay variation for inhibin B for 92 consecutive assays, including those for samples reported herein, for 3 quality control samples was 16.3% for a sample with a mean of 122.0 pg/mL, 13.1% with a sample mean of 249.7 pg/mL, and 14.5% with a mean of 740.6 pg/mL. Intraassay variation for this assay, as previously reported, varied from 4–6% (11). Inter- and intraassay coefficients of variation were 4.0% and 1.6% for LH, 2.2% and 1.4% for FSH, 5.6% and 4.1% for testosterone, and 4.2% and 3.5% for free testosterone. The ranges for normal adult males for these assays are 2.3–13.6 U/L for FSH, 2.0–12.6 U/L for LH, 285–980 ng/dL for testosterone, 12–40 pg/mL for free testosterone, and 110–365 pg/mL for inhibin B.
This report includes hormone levels and semen analyses from 117 formerly cryptorchid men (109 unilateral and 8 bilateral) and 53 men from the control group. The subsample of the control group included men who still lived in the Pittsburgh area or who visited the area during the time of data collection who were willing to participate in this portion of the study. The mean age for all 3 groups was 39 yr. The unilateral group ranged from 26–56 yr, the bilateral men from 35–45 yr, and the control group from 26–55 yr. Paternity data were obtained using a detailed questionnaire. Only a portion had attempted paternity or fathered children. Fertile men were those who reported fathering 1 or more children while in a long-term (>1-yr) relationship with a woman. Men who achieved fatherhood using assisted reproduction techniques were not included. These relationships included but were not limited to those men who were married. Infertile men had attempted paternity, having had regular intercourse with a partner who was menstruating regularly without contraception for more than 12 consecutive months not resulting in conception or a live birth. A questionnaire was administered to a subset of the partners, which verified reasonable authenticity of the data (12).
Forty-eight men in the unilaterally cryptorchid group and three in the bilateral group had indicated on the questionnaire that they had fathered one or more children, whereas nine and two in these respective groups reported failure after more than 12 months of attempted paternity (subfertility). Differences in numbers for individual variables are due to missing data points.
The study protocol was approved by the human rights committee of Children’s Hospital of Pittsburgh. Written informed consent was obtained before blood and semen sampling. Comparisons were made between the formerly cryptorchid group and the control men and between the fertile and infertile formerly cryptorchid groups using t tests and regression analyses. All statistical comparisons were performed using the Statistical Program for the Social Sciences, version 9.0 (SPSS, Inc., Chicago, IL), on a personal computer.
Study subject breakdown is listed in Table 1
. Data are presented for the entire
group of cryptorchid men (no. 117) and control men (no. 53).
Furthermore, data are presented for the portion of men who report
paternity (fertile; 48 unilateral, 3 bilateral, and 24 control) or were
unable to achieve paternity after attempting for 12 months (infertile;
9 unilateral, 2 bilateral, and 10 control). The remaining men had not
attempted paternity, had not been in a long-term (>12-month)
relationship, or had used contraception consistently.
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Formerly cryptorchid compared with control men
The formerly cryptorchid group consisted of 109 men who had unilateral cryptorchidism and 8 who had bilateral cryptorchidism. Forty-eight from the unilateral group had fathered children, and 9 had been unsuccessful at paternity after attempting it for more than 12 months. Five of the 8 men in the bilateral group had attempted paternity, 3 of whom were successful. The remainder had not attempted paternity or had never been in a long-term relationship.
The mean (±SD) values for hormone levels and sperm
characteristics are listed in Table 2 for
all formerly cryptorchid men, the unilateral group, and control men.
Among the formerly cryptorchid men, inhibin B levels and sperm density
were significantly lower than among the control men. Basal and
GnRH-stimulated FSH levels were significantly greater among the
cryptorchid men. Sperm motility and morphology and serum levels of LH,
testosterone, and free testosterone were not different. As noted in
Table 3, the significant differences
were the same when the bilateral group was excluded.
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).
Significant negative correlations were found in the cryptorchid group
between inhibin B and the following: basal and GnRH-stimulated FSH, and
basal and GnRH-stimulated LH (P < 0.0001). Significant
positive correlations were present between inhibin B and each of the
following: sperm density (P > 0.0001), sperm motility
(P > 0.001), sperm morphology (P >
0.002), testosterone (P > 0.003), and free
testosterone (P > 0.001). When only the unilateral
patients were analyzed, the same correlations persisted with slightly
different P values (Table 3). In contrast to the multiple
correlations between these parameters of fertility among the
cryptorchid group, the only significant correlations for the control
group were between inhibin B and basal FSH (P >
0.0001), GnRH-stimulated FSH (P > 0.0001), and basal
LH (P = 0.043). To determine whether the correlation between inhibin B and LH is a consequence of the correlation between LH and FSH, partial correlations were made. When partial correlations controlling for FSH were made, there were no significant correlations between inhibin B and LH for the cryptorchid groups (correlation coefficient = 0.0522; P = 0.58), the control group (correlation coefficient = -0.0851; P = 0.55), or both groups combined (correlation coefficient = 0.0427; P = 0.58). However, when partial correlations controlling for FSH were applied only to the unilateral group, a weak positive correlation was present (correlation coefficient = 0.2139; P = 0.026). Conversely, when controlling for LH, the correlation persisted between inhibin B and FSH (for the cryptorchid group: correlation coefficient = -0.5365; P = 0.0001; for the control group: correlation coefficient = -0.4646; P = 0.001; for both groups combined: correlation coefficient = -0.5346; P = 0.0001). The relationship, however, became less significant for the control group.
Among the entire group of formerly cryptorchid men who had hormone measurements, 58 of 102 (56.9%) had abnormal inhibin B levels. Nine of these (8.8%) also had elevated FSH levels. Twenty-eight of the 58 (48.3%) men who had low inhibin B levels also had sperm density less than 20 million/cc.
Hormone and seminal fluid analysis of cryptorchid men and controls
Inhibin B and FSH levels are depicted in Fig. 1 for cryptorchid and control groups of
men with normal and low sperm density. Hormone levels for the men who
had normal or low sperm density are listed in Table 4 for the formerly cryptorchid and
control men. Of the 103 men in the cryptorchid group who had sperm
counts, 64 had sperm density greater than 20 million, and 39 had lower
levels. Among the 48 in the control group, there were 34 who had normal
sperm counts and 14 with low counts.
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2 analyses of normal and low inhibin B
vs. sperm counts was significant at P <
0.0001, indicating that low sperm counts occur with low inhibin B
levels and vice versa. A similar relationship was present
between low sperm counts and elevated FSH levels (P <
0.0001). Among the control men, no significant differences were found
between the men when grouped according to normal or subnormal sperm
concentrations. Eight men had azoospermia; five of these had undetectable inhibin B levels (<15.6 pg/mL), and four had abnormally elevated FSH levels. In this group were three men with bilateral cryptorchidism, all with elevated FSH and undetectable inhibin B levels.
Fertile and infertile formerly cryptorchid and control men
Among the formerly cryptorchid men for whom paternity information
was available, when the fertile (n = 51) and infertile (n =
11) men were compared significant differences were found for mean
inhibin B, FSH, LH, and GnRH-stimulated FSH and LH levels, whereas mean
testosterone levels and sperm density did not differ (Table 5). Figure 2 depicts inhibin B and FSH levels for
men with known fertility or infertility from the cryptorchid and
control groups. However, when the 5 men who had had bilateral
cryptorchidism were excluded, the unilateral group comparisons of 48
fertile and 9 infertile men failed to indicate significant differences
between the groups for inhibin B and FSH levels. GnRH-stimulated FSH
(P = 0.031) and LH (P = 0.009) levels
were still significantly different.
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2, P = 0.026). Two (4%) of
the fertile men and 3 (27%) of the infertile men had FSH levels above
the normal range (>15 U/L; P = 0.010). Twenty-seven
(67.5%) of 40 in the fertile group had normal sperm density (20
million/cc or more), whereas 3 of 10 (30%) in the infertile group had
normal sperm density (P = 0.030).
No differences were present between mean levels of the fertile and
infertile men in the noncryptorchid control group (Table 5).
Discussion
The significant correlation of inhibin B with FSH, LH, testosterone, free testosterone, sperm density, and sperm motility among the formerly cryptorchid men reveals interrelationships not apparent in the noncryptorchid control group and not typically found among groups of normal men. It is recognized that correlations may be indirect; hence, partial correlations were calculated. As inhibin B and FSH correlated, and LH and FSH correlated, the correlation between inhibin B and LH did not persist when partial correlations were made controlling for FSH, except for the unilateral group, in which a weak positive correlation was found. The significance of this weak correlation is not known. Although early studies were performed to ascertain whether Leydig cells might secrete inhibin, we have been unable to locate reports suggesting that there is a relationship between Leydig cells and inhibin B secretion. The noncryptorchid control group in this report contains a greater number of men than expected for a control population with low sperm counts and infertility based upon paternity. Although the paternity questionnaire is a representative sampling of this population, it is clear that the group volunteering for blood and semen analyses is not. A disproportionate number of men with concerns about their fertility participated in this part of the study. This is not a detriment, because these data are not presented as a representative group, and having a greater number with abnormalities of hormone levels and sperm counts allows better comparisons.
It is of interest that although sperm density varied considerably, the percentage of sperm with normal motility and morphology did not. This would suggest that although sperm precursors may be diminished in the testes of formerly cryptorchid men, the sperm that are produced are of similar quality as those in men with normal sperm counts. These results are similar to those previously reported (13).
For the analyses performed, only a single sample result for the blood and semen parameters has been used. Although repeated sampling may increase the reliability of the use of these indexes as evidence of compromised fertility, we have chosen to analyze using a single data point, because this is a far more reasonable approach for both research and clinical assessment. Further, there is indirect evidence that a single semen sample is related to fertility (14, 15). A classic study demonstrated that repeated semen sampling in the same population had within-person variation with the range of most hormone measurements currently used regularly for research and clinical purposes (16).
The significant correlations suggest that there is a spectrum of testicular function among the cryptorchid men ranging from normal to somewhat compromised function to severe dysfunction, with the more severely affected being infertile. An inverse correlation is expected between inhibin B and FSH among the men due to the feedback relationship between these two hormones. Among the noncryptorchid control group of men, this inverse relationship was the only correlation to inhibin B for the parameters tested even though this control group of men probably includes men at risk of infertility from causes other than cryptorchidism. Inhibin B levels were significantly lower among the formerly cryptorchid men, both the entire group and the unilateral only group, than among the control men. Although the latter group excludes cryptorchidism, other causes of male infertility have not been excluded, and a portion of this population had subnormal inhibin levels. Conversely, among the men in the formerly cryptorchid group, many men had inhibin B levels within the normal range.
The hormonal and seminal fluid analyses indicate compromised seminiferous tubule action among the formerly unilateral cryptorchid group as well as the bilateral group. The interrelationships demonstrable among these men are similar to those found among a group of men with different medical histories who presented for evaluation of infertility (8). Both this previous report and the current study suggest that low inhibin B levels correlate with diminished spermatogenesis and may provide an indication for risk of infertility. In the current study some men with low inhibin B levels were able to father children. It is well known that men with low sperm counts may be successful at paternity (14, 15, 17), and it should not be surprising that men with low inhibin B levels may also be successful. Furthermore, not all men in the cryptorchid group who had low inhibin levels were infertile, nor did all men with subnormal sperm counts have low inhibin B levels. This suggests a spectrum from normal to decreased seminiferous tubule function after corrected cryptorchidism, with no single indicator being indicative of infertility. The lack of difference between the two groups for LH, testosterone, and free testosterone suggests that although a correlation exists between the different indexes of testicular function, Leydig cell function is not compromised below the normal range among the cryptorchid men.
Published reports of inhibin B levels among groups that include infertile or subfertile men show a negative correlation between FSH and inhibin B (3, 4), with a positive correlation between inhibin B levels and sperm parameters (4, 10). A study of two groups of normal men with different mean sperm counts showed the expected correlation between sperm counts and inhibin B and FSH levels (8). A recent study of 218 consecutive men referred for fertility problems by Pierik et al. (10), which included 17 cryptorchid men (8%), also found correlation of inhibin B to LH and testosterone. Overall, our analyses for correlation between inhibin B and LH failed to show a correlation when controlled for FSH.
Although inhibin B measurements are useful in the assessment of the potential for fertility among formerly cryptorchid men, not all men with low inhibin levels were infertile, nor did all of the infertile men have low inhibin levels. This is probably related to the fact that all infertility among this group is not due to seminiferous tubule dysfunction. Thus, these data must be interpreted realizing that there may be multiple causes for infertility after corrected cryptorchidism. Infertility may be related to the cause of testicular maldescent, the duration of uncorrected cryptorchidism, or consequences of treatment of cryptorchidism. If there are anatomical abnormalities precluding normal delivery of active sperm, hormone levels regulating seminiferous tubule function may be normal while semen samples have decreased sperm density. In this study questions were asked about fertility disturbances in the partner. These were not different between groups. Although levels of inhibin B and FSH reflect the integrity of seminiferous tubule function, because of other factors, this may or may not be reflected in normal sperm density and paternity.
When hormone levels were compared between the men who had sperm density above or below 20 million/cc, there was a significant difference not only for inhibin B and basal and GnRH-stimulated FSH, but also in basal and GnRH-stimulated LH and testosterone. Such differences were not found when the hormone levels among the noncryptorchid group were compared based upon normal or subnormal sperm density. These data are further evidence that testicular dysfunction after cryptorchidism involves the entire testis, not just the seminiferous tubule.
When hormone and sperm density data were compared for the fertile and infertile formerly cryptorchid men based upon paternity and attempted paternity information, all hormones and sperm density were again significantly different, whereas no differences were found among the control group when paternity and unsuccessful attempted paternity groups were compared. Although no previous reports compare formerly cryptorchid men successful or unsuccessful at paternity, the data presented herein for fertile and infertile formerly cryptorchid men are consistent with published reports of groups of infertile men (3, 10). Inhibin B, testosterone levels, and sperm density are lower among these infertile men than among men who report lack of success at attempted paternity. However, among the fertile men, there were men who had abnormal values. Two of 51 men had elevated FSH levels, whereas 69% (35 of 51) had low inhibin levels. If one accepts the premise that some men with compromised seminiferous tubule function are still able to father children, these data suggest that inhibin B levels are a sensitive indicator of testicular compromise.
Thirteen of 40 fertile men (32.5%) had subnormal sperm density. Given the nature of the male contribution to fertility, it is not surprising that some men with abnormal indices but some sperm production were successful at paternity. Among both the fertile and infertile men, a larger percentage had subnormal sperm counts than either hormone abnormality. The significant differences of hormone B levels between the fertile and infertile group suggest that the profile of these hormones can provide a sensitive index of compromised seminiferous tubule function.
Indicators of risk of infertility include inhibin B, FSH levels, and sperm density. Among formerly unilateral cryptorchid men, 55–60% have been reported to have normal sperm counts, whereas the remainder have subnormal levels (18, 19, 20, 21, 22, 23, 24), verifying that some men with subnormal sperm counts can father children. Low sperm counts are evidence of risk of infertility. Likewise, elevated FSH levels are suggestive of risk of infertility. We have previously reported data indicating that elevated FSH and low sperm counts may be considered risks for infertility among formerly cryptorchid men (25). Among cryptorchid men, baseline FSH (13, 26, 27) and GnRH-stimulated FSH release are greater than control values (27). Inverse relationships have been found between FSH and sperm density (27, 28, 29). Our study demonstrated not only higher basal and GnRH-stimulated FSH among cryptorchid men compared with control men, but also higher levels among infertile than fertile, formerly cryptorchid men.
Although a recent study found inhibin B to be a better predictor of impaired spermatogenesis than FSH among subfertile men (10), our data suggest that combined data are more useful. Low inhibin B levels are the best indicator of compromised testicular function, but some men with low inhibin B levels are still fertile. Thus, this hormone identifies the men at potential risk. We suggest that sperm density in combination with inhibin B and FSH levels will provide a better index of risk.
Sperm parameters, FSH, and inhibin B levels can be used together to assess the potential for fertility. Abnormalities among two or three of the parameters suggest a greater likelihood of infertility. Eight men in the infertile group had azoospermia, five of these with undetectable inhibin B and four with abnormally elevated FSH levels. These findings clearly indicate infertility. Conversely, two men among the fertile group had low inhibin B levels, elevated FSH, and oligospermia, whereas three others had low inhibin B and oligospermia, but nonelevated FSH levels.
In summary, although azoospermia is the only certain predictor of infertility, decreased sperm counts, low inhibin B, and elevated FSH levels are associated with increased risk of infertility. Inhibin B is the most sensitive index of the integrity of the seminiferous tubule unit, but FSH and sperm density data are also valuable predictors. The hormone levels and sperm density data in both the fertile and infertile men indicate that both groups have compromised testicular function extending beyond the seminiferous tubule.
Based on the significant correlations among formerly cryptorchid men, but not in the noncryptorchid group, we conclude that compromised testicular function is present among formerly cryptorchid men. The pathology within this group unmasks relationships in hormone levels not apparent among men with normal testicular function. When levels were compared for the subset of this group that had attempted paternity, significant differences between fertile and infertile cryptorchid men were found for all hormones evaluated. These data indicate not only that inhibin B and FSH levels as well as sperm density are markers for compromised fertility among formerly cryptorchid men, but also that a greater portion of these men have compromised testicular function than paternity data would indicate.
Received February 17, 2000.
Revised August 30, 2000.
Revised November 27, 2000.
Accepted January 22, 2001.
References
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