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Department of Pediatrics, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York, New York 10021
Address all correspondence and requests for reprints to: Maria I. New, M.D., Department of Pediatrics, Division of Pediatric Endocrinology, New York Presbyterian Hospital-Weill Medical College, 525 East 68th Street, Room M-622, New York, New York 10021. E-mail: minew{at}med.cornell.edu
Abstract
The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17–43 yr. The mean adult height of these patients was 165.64 ± 8.4 cm (mean ± SD), with a mean SD score of -1.65 ± 1.2 cm. The difference between the mean final height SD score and mean target height SD score was -1.67 ± 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed.
Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone.
In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility.
IT IS WELL known that patients with classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD) commonly have impaired gonadal function and poor adult height predictions. However, the majority of long-term follow-up data published on height and fertility in CAH is reported in female patients only (1, 2, 3, 4). The sequelae of chronically elevated adrenal androgen concentrations in male patients with CAH have not been well described (5, 6, 7, 8, 9, 10, 11).
Elevated adrenal androgen secretion in male CAH patients may suppress the hypothalamic-gonadal axis with resultant small testes and decreased spermatogenesis (11, 12, 13, 14). In addition, male CAH patients frequently have ectopic testicular adrenal rests, which may become hypertrophic under chronic ACTH stimulation. The clinical manifestation of testicular adrenal rests includes increased testicular volume and the presence of multiple firm, tender nodules. It has been suggested that these nodules gradually expand and destroy the testicular parenchyma, resulting in low testosterone production and infertility (8, 15).
Herein we evaluate the final height and fertility of 30 adult genetic (46,XY) male patients with CAH followed at the New York Presbyterian Hospital-Weill Medical College of Cornell University.
Subjects and Methods
Patient population
The subjects were selected by reviewing the charts of all male patients with classical CAH due to 21-hydroxylase deficiency who were followed at our institution between 1970 and 1999 (n = 95). Of these, 48 subjects were age 18 yr or older. These charts were reviewed for growth and gonadal fertility data. If data for gonadal function or fertility were unavailable, the patients were contacted and asked to undergo an LHRH test, sperm analysis, and testicular sonogram. Several subjects were excluded for the following reasons: 1) history of other medical conditions that may affect gonadal function, such as hypopituitarism due to radiotherapy after resection of a pineal germinoma and orchitis; 2) failure to maintain regular follow-up beyond puberty or being lost to follow-up because of either change of residence or change of medical caregiver (with the exception of patient 5, who was referred in adulthood for follow-up medical care and eventually found to have gonadal dysfunction); 3) unavailable data on gonadal function or fertility; and 5) main indication for referral was decreased fertility potential.
This resulted in data collection for 30 adult males with classic CAH
(Table 1
). The study was approved by our
institution’s review board for human rights in research. Patients with
the classical form of CAH were phenotypically classified as
salt-wasting (SW) or simple virilizing (SV) based on history of
salt-wasting crisis, presence of electrolyte abnormalities
(i.e. hyperkalemia and hyponatremia), and serum levels of
aldosterone and PRA at the time of diagnosis and during follow-up
visits. Mineralocorticoid replacement therapy was added to the
treatment regimen of SW patients. The diagnosis of CAH was confirmed
based on the serum 17-hydroxyprogesterone (17-OHP) levels before and
after an ACTH stimulation test. Using DNA analysis, mutations were
identified in the gene for 21-hydroxylase (CYP21) in all
patients except patient 27, whose diagnosis was based upon human
leukocyte antigen genotyping.
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). The clinical care
and hormonal follow-up in most of these patients before the study was
sporadic. Many of the patients were noncompliant with their medical
treatment. Compliance was evaluated based on hormonal data. Hormonal
control was assessed by routinely monitoring the adrenal hormones and
PRA.
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Methods
Height was determined with a Harpenden stadiometer.
Reported parental heights were used in calculating the midparental or
target height according to the formula: father’s height + mother’s
height + 13 cm/2. Bone age was determined
according to the standards established by Greulich and Pyle
(16), and all were read by the same physician. Bone ages
and hormonal measurements were obtained until final height was
achieved. The degree of hormonal control before epiphyseal fusion was
assessed from levels of 24-h urinary 17-ketosteroids obtained before
1972, serum 
4-androstenedione after 1972, and
serum 17-OHP, 4-androstenedione, and PRA after
1977. Patients were classified as under good control if 50% or more of
the total daily urinary 17-ketosteroids or serum
4-androstenedione concentrations were within
normal limits for age (mean ± 2 SD) or if 50% or
more of the baseline serum 17-OHP concentrations were less than 30.3
nmol/L, and 4-androstenedione concentrations
and PRA were within normal limits for age. The preference for a target
range of 17-OHP less than 30.3 nmol/L (1000 ng/dL) was based upon
studies showing that above normal 17-OHP levels are observed even
during adequate adrenal androgen suppression (22, 23) and
that treatment with glucocorticoid doses to attain normal levels often
results in growth retardation (24, 25, 26).
Fertility potential was determined based on the results of semen analysis. Data on successful/unsuccessful impregnation were also collected. Paternity was not confirmed in the patients who had children. During clinic visits, the testes of patients were evaluated for size using an orchidometer, consistency, and the presence of nodules. Testicular sonogram was proposed to all 30 patients and was performed in 18 patients with normal and abnormal clinical examinations of the testes. The classification of fertile was only given to patients who had a history of impregnation.
Blood samples used for hormonal analysis were obtained between
0800–1000 h and approximately 2 h after morning medications.
Serum 17-OHP, 4-androstenedione, and
testosterone concentrations were assayed according to previously
reported methods (17, 18). Control of adrenal hormone
secretion was considered optimal when 17-OHP concentrations were within
the range of 6–30 nmol/L and
4-androstenedione concentrations were in the
normal range for adult males at 3.6 ± 1.7 nmol/L (mean ±
SD) (19, 20). In our laboratory, the normal
serum testosterone concentration for adult males is 20 ± 6.6
nmol/L (mean ± SD).
Serum LH and FSH concentrations were measured using the microparticle enzyme immunoassay (Abbott Laboratories, Chicago, IL). The GnRH stimulation test was performed by administering 100 µg GnRH as an iv bolus in the morning. Serum FSH and LH levels were measured at 0, 15, 30, 45, 60, 90, and 120 min after the GnRH dose. Testosterone and 17-OHP levels were also assayed at 0 and 120 min.
Semen analysis was carried out after 3–4 days of sexual abstinence. Normal seminal fluid analysis was based on the following parameters: sperm count greater than 20 x 106/ml, total sperm count greater than 40 x 106/ejaculate volume, greater than 2.0 mL ejaculate volume, more than 30% normal morphology, and more than 50% normal motility (21).
Statistical analysis
Statistical analysis of final height was performed on all 30
patients. LH and FSH concentrations at baseline and after GnRH
administration in 18 patients (groups 1 and 2) were compared using
Student’s t test. Hormonal data obtained during inadequate
adrenal suppression (>30.3 nmol/L) were excluded from the statistical
analysis and are presented separately (Table 4).
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Serum testosterone concentrations during optimal suppression of adrenal steroid secretion of the two groups were compared using the Mann-Whitney test. Significant differences between groups were accepted at P < 0.05.
Results
Age and height
The ages of the 30 patients at the time of the study ranged from
17–43 yr (mean ± SD, 26.9 ± 7.0). The mean
final adult height of these patients was 165.64 ± 8.4 cm
(mean ± SD; Fig. 3). The mean target height was
176.9 ± 4.9 cm. Of the 30 patients, 19 were salt-wasters, and 11
were simple virilizers. Simple virilizers reached a final height of
169.4 ± 8.5 cm (mean ± SD), whereas salt
wasters reached a final height of 163.5 ± 7.7 cm (mean ±
SD). This difference was not statistically significant.
Figure 2 shows height SD
scores for both SW and SV patients. The mean SD scores for
SW (-1.98 ± 1.1) and SV (-1.09 ± 1.3) were not
statistically significant. The mean SD score for target
height for all patients was 0.02 ± 0.8. The mean of the
difference between final height SD score and target height
SD score was -1.67 ± 1.07 cm (Table 2). The degree of bone age advancement at
the outset and the degree of hormonal control did not correlate with
the final height (P = NS; data not shown).
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Testicular sonograms were performed in 18 patients. Group 1
comprised 9 patients with findings of adrenal rests. Group 2 comprised
7 patients with either varicoceles or hydroceles that were of no
clinical significance and 2 patients with entirely normal findings
(Tables 1
and 3). In group 1, 8 of the 9
subjects were salt-wasters. In group 2, 4 were salt-wasters, and 5 were
simple virilizers. In group 1, 7 of 9 patients had semen analysis, all
of which showed azoospermia. In group 2, 6 of 9 patients had semen
analysis; 1 had azoospermia, and 5 were normal. Patients 3 and 7,
before developing nodular testes, were fertile and had children;
however, they are classified as infertile in Table 1 due to current
abnormal semen analysis and failure of recent pregnancy attempts.
Suppression of the excessive adrenal androgen secretion with
dexamethasone resulted in reversal of infertility in two patients
(patients 4 and 5), normospermia in 1 patient (patient 6), reduction in
size of testicular nodules in 2 patients (patients 3 and 8), and no
effect in 3 patients (patients 1, 11, and 12).
|
). In
group 2, patients 11 and 12 continued to have poor gonadotropin
response to GnRH stimulation despite suppression of adrenal hormones
with dexamethasone. In five patients whose adrenal control was poor, LH
and FSH levels were suppressed. These data were not included in the
statistical analysis of LH and FSH responses to GnRH, but are presented
separately in Table 4.
Serum testosterone concentrations during optimal suppression of adrenal
steroids were higher in patients with normal findings on testicular
sonogram (group 2: mean ± SD, 12.4 ± 8.6
nmol/L; range, 1.6–30 nmol/L) compared with those with abnormal
findings (group 1: mean ± SD, 10.4 ± 5.0
nmol/L; range, 4.9 ± 18.3 nmol/L). However, this did not reach
statistical significance (Fig. 4). The
serum androstenedione concentrations between groups 1 and 2 (mean
± SD, 1.3 ± 0.6 nmol/L; range, 0.4–2.6 nmol/L
vs. 1.9 ± 1.2 nmol/L; 0.4–4.7 nmol/L) were not
statistically significant. Overlap in serum testosterone concentrations
was seen among patients with documented infertility (azoospermia or
decreased fertility potential) and those with normal sperm analysis;
however, low serum testosterone concentrations (<5.2 nmol/L) were
found only in patients with azoospermia.
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The ideal management of patients with CAH requires a balance between the glucocorticoid treatment effects of adequate adrenal suppression and achievement of full height potential without excess virilization. Earlier studies have demonstrated that overtreatment with glucocorticoids during childhood and adolescence causes delayed skeletal maturation and growth retardation (24, 25). It was later proven that all classic CAH patients (SW or SV) displayed variable degrees of sodium depletion, which were not always clinically apparent. Sodium depletion can be subtle, as manifested only by an elevated PRA level. This hyperreninemia was correlated with hypersecretion of ACTH. It was therefore recommended that glucocorticoid and mineralocorticoid treatment be combined to achieve optimal hormonal control of CAH (27). The combination allowed reduction of the glucocorticoid doses needed to suppress adrenal hormones, resulting in improvement in linear growth.
Several studies show that despite close monitoring and good compliance, there is a failure to reach full adult height potential (3, 5, 28, 29, 30). It is thought that the poor outcome in adult height is multifactorial. Previous studies show that timing of the initiation of treatment affects outcome, in that early initiation of therapy resulted in increased final heights (1, 28). In keeping with previous experience at our institution, as reported by Di Martino (29) and New (30), our patients, as a whole and when classified as SW or SV, demonstrated final heights that were significantly below the average. The mean target height of the patients compared with that of the general population was not different (target height SD score, 0.02 ± 0.8). Overall, the patients had a 1.67 SD deficit from their target heights. The clinical form (SW vs. SV) did not have any significant influence on the final height. This study and other reports have not found any correlation between the degree of hormonal control and final height (29). Clearly, there are other factors involved in the determination of final height in CAH. A review of the clinical history showed that although patients had advanced bone ages at the start of treatment, optimal suppression of adrenal hormones slowed the bone age advancement. There was no estimation made of the effect of increased dosage of steroids during times of stress or intercurrent illness. Also, some of the patients included here were treated during childhood with prednisone or dexamethasone, which has been shown to slow the growth rate to a greater degree than hydrocortisone treatment (28).
The increased risk of gonadal abnormalities in adult males with classic 21-OHD in the form of testicular nodules, testicular atrophy, or suppression of gonadotropin secretion has been described previously (11, 12, 13, 14). There are, however, conflicting results about the frequency of these abnormalities and their impact on fertility (5, 6, 31, 32). Urban et al. (5), in a large study of 20 untreated adult males with CAH, found no testicular or hormonal abnormalities, whereas others report a frequency of testicular adrenal rests of 24–47% (33, 34, 35, 36), similar to our result of 30%. Most of these latter reports, however, involve a small number of patients and do not address the question of fertility.
The present study documents a high frequency of testicular abnormalities in adult males with classical 21-OHD. To avoid the problem of selection bias, we proposed testicular sonography to all of the patients, including those with normal testicular examination; however, self-selection bias remains a factor in this study. Of the 30 patients evaluated, testicular nodules were present in 30% of our patients by testicular examination alone, testicular atrophy was present in 6.7%, and infertility was documented in 30%. Of the 18 patients who had testicular sonograms, testicular adrenal rests were found in all 7 subjects who also had nodular testes on physical examination, in 1 of 3 patients with small testes, and in 1 of 8 patients with normal testicular examination. As 1 of the 8 patients with normal physical exams was found to have adrenal rests on ultrasound, it is certainly possible that subclinical adrenal rests may have been missed in one or more patients with normal physical exams who refused ultrasound. Because some of the patients did not have semen analysis and or/testicular sonograms, they were assumed to have normospermia and no testicular abnormalities. Thus, the reported incidences of abnormalities could even be greater, supporting the recommendation for testicular sonograms in all male CAH patients.
Testicular nodules caused by expanding adrenal rests have been recognized for many years in patients with classical 21-OHD (8, 9, 15, 37, 38). Although the nodules have histological features of Leydig cell tumors, these nodules are ACTH dependent, in that they develop during periods of sustained elevations of ACTH and decrease in size during the administration of glucocorticoids (7, 8, 9, 10, 39). The adrenal origin of these tumors has been documented by the presence of specific enzymes unique to adrenocortical cells, such as 11ß-hydroxylase (38, 40, 41, 42). Isolated cases of adrenal rests not responding to suppression with dexamethasone or associated with infertility have also been reported (41, 42).
Based on the testicular sonogram findings, the patients in this study were grouped according to the evidence of testicular adrenal rests. Fertility status, gonadotropin response, and serum testosterone levels of both groups were compared. Our data indicate a progressive loss of gonadal function in patients with abnormal findings on testicular sonogram. Two patients (patients 3 and 7) were able to impregnate their partners, but developed infertility after the development of testicular nodules. Dexamethasone treatment and suppression of adrenal steroids reversed infertility in three patients, but again this response was not universal. The time period from the initial detection of testicular abnormalities by examination until documented infertility in this study ranged from 0–10 yr. This wide variation may be attributed in part to the irregular follow-up of our patients, many seek medical care only when a problem arises.
Patients with abnormal findings on testicular sonogram had higher serum gonadotropin and lower serum testosterone concentrations during optimal adrenal suppression compared with patients with normal findings. These elevated serum gonadotropin concentrations reflect loss of Leydig cell secretion of testosterone. A considerable overlap of serum testosterone levels was seen between the groups with normal and abnormal testicular sonograms. Low serum testosterone concentrations (<5.2 nmol/L), however, were found only in patients with infertility. This study was limited by the wide variation in the number of measurements of serum testosterone concentrations due to sporadic follow-up and lack of semen analysis in some patients.
We have shown suppression of the hypothalamic-pituitary-gonadal axis during increased adrenal androgen secretion due to 21-OHD. It appears that adult males with CAH face a dual risk of developing infertility during inadequate adrenal suppression and development of testicular adrenal rests. Long-standing suppression of the pituitary-gonadal axis results in small testicular size and infertility (37), whereas adrenal rests can destroy the testicular tubules and lead to infertility (8, 15). Based on these findings, we advocate optimal control of adrenal steroid secretion to preserve fertility in adult males with CAH. However, we do not have sufficient long-term hormonal data to determine the role of treatment of CAH in the prevention of gonadal abnormalities.
SW had a much higher frequency of testicular abnormalities than SV in this review. By physical exam, 74% (14 of 19) of SW compared with 55% (6/11) of SV had abnormal testes. By testicular sonogram, 66% (8 of 12) of SW compared with 16% (1 of 6) of SV had abnormal testes. This suggests that the more severe degree of 21-hydroxylase deficiency in salt wasting patients may be related to the development of testicular nodules. In an effort to seek a correlation between the abnormality of the testes and specific mutations in the CYP21 gene, we found a greater number of gene deletions in SW patients with abnormal testes. All 5 SW patients with abnormal testicular sonogram findings had a deletion of the CYP21 gene, whereas 3 of 4 SW patients with normal testicular sonogram findings had intron 2 mutations. Similarly, 3 of 5 SV patients with normal testicular sonogram findings had intron 2 mutations. However, a larger sample should be studied to verify this correlation.
In conclusion, our experience demonstrates that male patients with classical CAH do not achieve target height if the adrenal androgens are well or poorly suppressed. The presence of testicular nodules or atrophy is associated with high infertility rates in adult males with CAH. Regular testicular examination, therefore, is very important in the care of these patients. We recommend periodic testicular ultrasonography because it permits early detection of small testicular lesions (33, 36, 43), the interval period from the detection of testicular abnormalities upon physical examination to infertility can be brief. The precise role of CAH treatment methods, the degree of adrenal suppression, and the genotype/phenotype in the development of gonadal abnormalities merits further evaluation.
Acknowledgments
We gratefully acknowledge Dr. Jean D. Wilson for his helpful insights and comments, Drs. Saroj Nimkarn and J. B. Quintos for their assistance in the follow-up of the patients. We also thank Andrea Putnam and Laurie Vandermolen for their editorial assistance, and Cristina Sison, Ph.D., for her expert advice and assistance with statistical analysis.
Footnotes
1 This work was supported by USPHS Grant HD-00072 and General
Research Center Grant RR-06020. 
Received October 18, 2000.
Revised January 24, 2001.
Revised March 28, 2001.
Accepted March 30, 2001.
References
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estradiol, and testosterone in the diagnosis and management of
congenital adrenal hyperplasia. J Pediatr. 85:782–787.[CrossRef][Medline]
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) and SV (•) patients (P
= NS).