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Long-Term Follow-up of a Patient with Congenital Adrenal Hyperplasia and Failure of Testicular Development
Vol. 24, No.4, April 1973 Printed in U.S.A.
FERTILITY AND STERILITY
Copyright © 1973 by The Williams & Wilkins Co.
Communications and C01n1nentaries
.
LONG-TERM FOLLOW-UP OF A PATIENT WITH CONGENITAL ADRENAL HYPERPLASIA AND FAILURE OF TESTICULAR DEVELOPMENT JOHN T. MOLITOR, M.D., BRUCE S. CHERTOW, M.D.,
AND
BRUCE L. FARISS, M.D.
Endocrine Service, Department of Medicine, and Clinical Research Service, Madigan General Hospital, Tacoma, Washington 98431
Congenital adrenal hyperplasia (CAH), due to 21-hydroxylase deficiency, may result in inadequate synthesis of cortisol and androgen excess. Steroid replacement is required to prevent adrenal insufficiency and to allow appropriate sexual differentiation. The effect of long-term therapy on testicular growth and development in children has been reported infrequently. Our rElcent experience with a 22-year-old male with this syndrome associated with gonadal insufficiency emphasizes the problems of long-term care. MATERIALS AND METHODS
.
Twenty-four-hour urines were collected from 7 A.M.-7 A.M. with total volumes and creatinine concentrations measured to determine the adequacy of collections. The urinary 17 -hydroxycorticosteroids were measured by the Porter-Silber method. 1 The 17-ketosteroids were measured by Zimmermann chromogens developed by the methods of Epstein,2 prepared by a modification of the method of Drekter, et al. 3 The plasma cortisol level was performed by the method of Mattingly.4 The urinary pregnanediol and pregnanetriol levels were measured by the method of Klein and Chernaik. 5 The serum follicle-stimulating hormone (FSH) 6 and luteinizing hormone (LH) 7 levels were determined by radioimmunoassay. The serum LH is exReceived March 14, 1972.
pressed in milli-International Units of 2nd
IRP per milliliter, and the serum FSH in nanograms of LER-907 per milliliter. The urinary pituitary gonadotropins were determined by the mouse uterine assay. The testosterone determinations were performed by Bio-Science Laboratories utilizing a competitive protein binding technic (normal range for men 400-1200 ng./ 100 mI.). Twenty-four-hour urine collections were made prior to and on 4 consecutive days of 8-hr. infusions of 40 units of adrenocorticotropic hormone (ACTH). The results are shown in Table 1. The ACTH studies were performed while the patient was receiving dexamethasone, 0.5 mg. every 8 hr., and 9-a fluorohydrocortisone, 0.1 mg. every 12 hr. by mouth. CASE HISTORY
T. P., a 22-year-old white male, was admitted to the hospital with nausea and vomiting of 3 days, duration. It was learned on further questioning and review of his old records that adrenal hyperplasia of the salt-losing type had been diagnosed at birth. He had been treated with desoxycorticosterone trimethylacetate and glucocorticoid injections through age 11 and then placed on oral cortisone. At age 11 he was in the 90th percentile for height and had well-developed genitalia and "a great deal of pubic hair." Approximately 8 months prior to ad-
319
"I
320
Vol. 24
MOLITOR ET AL.
TABLE 1. Twenty-Four-Hour Urine Collections before Steroid Replacement and during 4 Days of ACTH Administration while on Dexamethasone and 9-a Fluorohydrocortisone* Creatinine
Basal Day 1 Day 2 Day 3 Day 4
17 -Ketosteroids
17-Hydroxycortico steroids
Pregnanediol
Serum
Pregnanetriol
cortisol
gm.
mg.
mg.
mg.
mg.
"g./lOO mi.
1.08 1.45 1.80 1.50 1.44
14.2 18.5 27.4 22.4 36.9
0.5 4.1 4.7 10.9 3.0
2.0 1.3 3.5 4.3 6.6
14.3 2.5 13.0 23.2 33.8
7.8 6.0 14.0 14.0
* The creatinine is reported as grams per 24 hr.; 17-ketosteroids, 17-hydroxycorticosteroids, pregnanediol, and pregnanetriol are reported as milligrams per 24 hr.
mission, the patient discontinued his medication because he felt well. In the recent past, episodes of nausea, vomiting, and abdominal pain had rarely occurred. A sister died shortly after birth with what was thought to be adrenal insufficiency. On admission his pulse was 84 and regular, and his blood pressure was 90/70 mm. Hg. He was in mild distress and complained of abdominal pain. His height was 68 inches and his weight was 136 lb. Skin turgor was normal but there was generalized increase in skin pigmentation. Pubic and axillary hair were normal in amount and distribution. The thyroid was slightly enlarged without nodularity. The heart sounds and size were normal and the lungs were clear to percussion and auscultation. The abdomen was soft with no hepatosplenomegaly. His penis was adult size; however, the testicles were small, measuring approximately 2 cm. in greatest diameter. The hematocrit was 42%. The white blood count was 5300 with 39 neutrophils, 41 lymphocytes, 14 monocytes, and 6 eosinophils. Urinalysis revealed a large amount of acetone but otherwise was normal. The serum sodium was 133, potassium 5.0, CI 98, and CO 2 combining power was 25 mEq./L. The urine sodium was 168 and the potassium was 64 mEq./L. The serum creatinine and BUN were normal.
Saline infusions were started and basal 24-hr. urines were collected for 17hydroxy corticosteroids, 17 -ketosteroids, pregnanediol, and pregnanetriol. After completion of the urine collections, he was started on dexamethasone and subsequently on 9-a fluorohydrocortisone. Additional studi0s obtained later showed a negative buccal smear, normal chest and skull roentgenograms, a normal protein-bound iodine, and a 24-hr. p 3 l thyroid uptake of 12.3%. Skeletal epiphyses were closed. Three semen analyses were obtained and all showed approximately 1-2 ml. of gray, moderately viscous semen without sperm. Two months after admission, while taking cortisone acetate, 25 mg. by mouth twice daily, basal serum testosterones were 249, 219, and 301 ng./l00 ml. The serum LH was 3.2 mLU./ml. (normal range 5-24) and serum FSH was 248 ng./ml. (normal range 190-420). * A 24-hr. urine for pituitary gonadotropins was less than 6 MUU. Intramuscular administration of human chorionic gonadotropin (HCG) 3000 L U. daily for 7 days was followed by a rise in serum testosterone to 543 ng./l00 ml. DISCUSSION
The data in this case are consistent with a C-21 hydroxylase deficiency and * Kindly performed by Alvin Paulsen, M.D., Division of Endocrinology, U.S. Public Health Service Hospital, Seattle, Wash. 98114.
.
April 1973
CONGENITAL ADRENAL HYPERPLASIA
congenital adrenal hyperplasia (CAH). Basal urinary 17 -hydroxy corticosteroids were low, and 17-ketosteroids, pregnanediol, and pregnanetriol were elevated. The ACTH stimulation test confirmed the diagnosis by demonstrating impaired 17-hydroxycorticosteroid production associated with a marked increase in 17-ketosteroids and pregnanetriol (Table 1). The presence of hypotension, a low serum sodium associated with a high excretion of urine sodium, and a high normal serum potassium suggest that he had the salt wasting variety of the syndrome. In addition, an isolated defect of pituitary gonadotropin secretion was considered, but thought to be unlikely. There have been few reports on testicular development after treatment of patients with CAH since Wilkins' classic article. 8 In 1954, Wilkins and Cara 9 described testicular findings in CAH before and after cortisone treatment. The ages of the boys ranged from 31J2-8% years. Biopsies on patients prior to treatment were reported as showing immature tubules and absence of Leydig cells, spermatids, and spermatozoa. The germ cells either had not differentiated beyond the stage of spermatogonia or showed only occasional mitoses with development of spermatocytes. After treatment with cortisone, rapid growth occurred with active spermatogenesis and the appearance of numerous Leydig cells. The testicular maturation, however, occurred only in those patients with bone ages between 11-15 years. No growth or maturation of the testicles occurred despite cortisone therapy in boys with osseous maturity less than 11 years. 9, 10 Gonadal failure in CAH is thought to be a result of chronic suppression of gonadotropin secretion by excess adrenal androgens. 9 Urine testosterone excretion 11 and plasma testosterone and androstenedione levels 12 are high, while urine gonadotropin excretion is low. 8 Cortisone
321
replacement suppresses the excessive production of androgens. In our case, excessive androgen production was reflected in elevated basal levels of 17-ketosteroids, pregnanediol, and pregnanetriol. Although serum testosterone was below the range found in normal adult males, the level was higher than that expected in a patient with preadolescent testicles. It is also possible that cortisone replacement may have already decreased the serum testosterone by suppressing adrenal androgen secretion. Our patient's failure to develop normal testicular size and function suggests inadequate doses of cortisone were taken through puberty and adolescence. As a result, excessive adrenal androgen secretion was not suppressed and inhibited the normal release of FSH and LH that occurs at puberty. In turn, testicular development did not occur normally. The finding of low levels of LH and relatively low levels of FSH are consistent with chronic suppression by excessive androgens. Moreover, the serum testosterone rose significantly from low basal levels following HCG administration, a finding similar to that in normal prepuberal boys IS and consistent with functional prepuberal testes. The changes in gonadotropin seen in our case were interpreted in the perspective of current concepts relating to the regulation of the pituitary-gonadal axis. It is thought that in man, FSH secretion is regulated by some unidentified substance produced by the germinal epithelium of the testicle or by testicular production of estrogen. The patient presented was azoospermic with small testicles, and therefore, FSH levels would be expected to be high. Contrary to expectations, the FSH level was low normal, suggesting that either androgens or perhaps estrogens converted from androgens suppressed FSH secretion. The low FSH levels would indicate that FSH secretion is suppressed
322
Vol. 24
MOLITOR ET AL.
either by androgens or estrogens rather than by an unidentified testicular substance from the germinal epithelium, although it does not exclude the latter possibility. LH secretion is inhibited by testosterone. In our patient, a low LH level suggests that testosterone or other, androgens may inhibit LH secretion. Our findings, in a natural setting, are consistent with those of Stewart-Bentley, Odell, and Horton,14 who showed that pharmacologic amounts of estradiol and of testosterone suppressed serum FSH and LH in normal individuals. Our patient demonstrates one of several possible outcomes in the natural history of CAH. Inadequate replacement, as in our patient, may result in persistent elevation of adrenal androgens sufficient to inhibit normal growth and maturation of the testicles. Also, failure to suppress ACTH secretion with steroids may result in the development of testicular tumors. 15 On the other hand, with adequate treatment, as measured by the return to normal of urinary 17-ketosteroids and pregnanetriol, there is inhibition of virilization, restoration of normal physical and skeletal growth, and normal testicular growth and function. 8 , 9 SUMMARY
A 22-year-old man with congenital adrenal hyperplasia (CAH) and associated salt-losing syndrome is presented with associated failure of gonadal development. Study of his testicular function showed azoospermia and low basal serum testosterone which increased significantly after HCG administration. Serum FSH and LH levels were low, suggesting chronic suppression of LH by adrenal androgens and of FSH by either adrenal androgens or their subsequent conversion to estrogens. Chronic suppression by adrenal androgens probably prevented normal tes-
ticular development from occurring under the influence of FSH and LH. The case represents a 22-year followup of a patient with treated CAH and emphasizes the necessity of adequate doses of steroids to allow normal testicular development and fertility. REFERENCES 1. SILBER, R H., AND PORTER, C. C. The determination of 17, 21-dihydroxy, 20-ketosteroids in urine and plasma. J Bioi Chem 210:923, 1954. 2. EpSTEIN, E. An aqueous Zimmermann reagent for the determination of 17-ketosteroids. Clin Chim Acta 7:735, 1962. 3. DREKTER, I. J., HEISLER, A., SCISM, G. R, STERN, S., PEARSON, S., AND MCGAUACK, T. H. The determination of urinary steroids. I. The preparation of pigment-free extract and a simplified procedure for the estimation of total 17-ketosteroids. J Clin Endocr 12:55, 1952. 4. MATTINGLY, D. A simple fluorimetric method for the estimation of free ll-hydroxycorticoids in human plasma. J Clin Path 15:374, 1962. 5. KLEIN, D., AND CHERNAIK, J. M. Urinary pregnanediol and pregnanetriol: Spectrophotometric determination following aluminum oxide column chromatography. Clin Chem 10:170, 1964. 6. MIDGLEY, A. R, JR. Radioimmunoassay for human follicle-stimulating hormone. J Clin Endocr 27:295, 1967. 7. PAULSEN, C. A., GORDON, D. L., CARPENTER, R W., GONDY, H. M., AND PRUCKER, W. D. Klinefelter's syndrome and its variants: A hormonal and chromosomal study. Recent Progr Hormone Res 24:321, 1968. 8. WILKINS, L., CRIGLER, J. F., JR., SILVERMAN, S. H., GARDNER, C. I., AND MIGEON, C. J. Further studies on the treatment of congenital adrenal hyperplasia with cortisone: II. The effects of cortisone on sexual and somatic development with a hypothesis concerning the mechanism of feminization. J Clin Endocr 12:277, 1952. 9. WILKINS, L., AND CARA, J. Further studies on the treatment of congenital adrenal hyperplasia with cortisone. V. Effects of cortisone therapy on testicular development. J Clin Endocr 14:287, 1954. 10. BLIZZARD, R M., AND WILKINS, L. Present concepts of steroid therapy in virilizing adrenal hyperplasia. Arch Intern Med (Chicago) 100:729, 1957. 11. CAMACHO, A. M., AND MIGEON, C. J. Testosterone excretion and production rate in normal
April 1973
CONGENITAL ADRENAL HYPERPLASIA
adults and in patients with congenital adrenal hyperplasia. J Clin Endocr 26:893, 1966. 12. RIVAROLA, M. A., SAEZ, J. M., AND MIGEON, C. J. Studies of androgens in patients with congenital adrenal hyperplasia. J Clin Endocr 27: 624,1967. 13. BARDIN, C. W., Ross, G. T., RiFKIND, A. B., CARGILLE, C. M., AND LIPSETI', M. B. Studies of the pituitary-Leydig cell axis in young men with hypogonadotrophic hypogonadism and hyposmia: Comparison with normal men, pre-
..
323
puberal boys and hypopituitary patients. J Clin Invest 48:2046, 1969. 14. STEWART-BENTLEY, M., ODELL, W., AND HORTON, R. "FSH-LH Feedback in Normal and Hypergonadotropic Man." In The 53rd Meeting of the Endocrine Society. San Francisco, 1971. 15. SCHOEN, E. J., DIRAIMONDO, V., AND DOMINQUEZ, O. V. Bilateral testicular tumors complicating congenital adrenocortical hyperplasia. J C.lin Endocr 21:518, 1961.
FERTILITY AND STERILITY
Copyright © 1973 by The Williams & Wilkins Co.
Communications and C01n1nentaries
.
LONG-TERM FOLLOW-UP OF A PATIENT WITH CONGENITAL ADRENAL HYPERPLASIA AND FAILURE OF TESTICULAR DEVELOPMENT JOHN T. MOLITOR, M.D., BRUCE S. CHERTOW, M.D.,
AND
BRUCE L. FARISS, M.D.
Endocrine Service, Department of Medicine, and Clinical Research Service, Madigan General Hospital, Tacoma, Washington 98431
Congenital adrenal hyperplasia (CAH), due to 21-hydroxylase deficiency, may result in inadequate synthesis of cortisol and androgen excess. Steroid replacement is required to prevent adrenal insufficiency and to allow appropriate sexual differentiation. The effect of long-term therapy on testicular growth and development in children has been reported infrequently. Our rElcent experience with a 22-year-old male with this syndrome associated with gonadal insufficiency emphasizes the problems of long-term care. MATERIALS AND METHODS
.
Twenty-four-hour urines were collected from 7 A.M.-7 A.M. with total volumes and creatinine concentrations measured to determine the adequacy of collections. The urinary 17 -hydroxycorticosteroids were measured by the Porter-Silber method. 1 The 17-ketosteroids were measured by Zimmermann chromogens developed by the methods of Epstein,2 prepared by a modification of the method of Drekter, et al. 3 The plasma cortisol level was performed by the method of Mattingly.4 The urinary pregnanediol and pregnanetriol levels were measured by the method of Klein and Chernaik. 5 The serum follicle-stimulating hormone (FSH) 6 and luteinizing hormone (LH) 7 levels were determined by radioimmunoassay. The serum LH is exReceived March 14, 1972.
pressed in milli-International Units of 2nd
IRP per milliliter, and the serum FSH in nanograms of LER-907 per milliliter. The urinary pituitary gonadotropins were determined by the mouse uterine assay. The testosterone determinations were performed by Bio-Science Laboratories utilizing a competitive protein binding technic (normal range for men 400-1200 ng./ 100 mI.). Twenty-four-hour urine collections were made prior to and on 4 consecutive days of 8-hr. infusions of 40 units of adrenocorticotropic hormone (ACTH). The results are shown in Table 1. The ACTH studies were performed while the patient was receiving dexamethasone, 0.5 mg. every 8 hr., and 9-a fluorohydrocortisone, 0.1 mg. every 12 hr. by mouth. CASE HISTORY
T. P., a 22-year-old white male, was admitted to the hospital with nausea and vomiting of 3 days, duration. It was learned on further questioning and review of his old records that adrenal hyperplasia of the salt-losing type had been diagnosed at birth. He had been treated with desoxycorticosterone trimethylacetate and glucocorticoid injections through age 11 and then placed on oral cortisone. At age 11 he was in the 90th percentile for height and had well-developed genitalia and "a great deal of pubic hair." Approximately 8 months prior to ad-
319
"I
320
Vol. 24
MOLITOR ET AL.
TABLE 1. Twenty-Four-Hour Urine Collections before Steroid Replacement and during 4 Days of ACTH Administration while on Dexamethasone and 9-a Fluorohydrocortisone* Creatinine
Basal Day 1 Day 2 Day 3 Day 4
17 -Ketosteroids
17-Hydroxycortico steroids
Pregnanediol
Serum
Pregnanetriol
cortisol
gm.
mg.
mg.
mg.
mg.
"g./lOO mi.
1.08 1.45 1.80 1.50 1.44
14.2 18.5 27.4 22.4 36.9
0.5 4.1 4.7 10.9 3.0
2.0 1.3 3.5 4.3 6.6
14.3 2.5 13.0 23.2 33.8
7.8 6.0 14.0 14.0
* The creatinine is reported as grams per 24 hr.; 17-ketosteroids, 17-hydroxycorticosteroids, pregnanediol, and pregnanetriol are reported as milligrams per 24 hr.
mission, the patient discontinued his medication because he felt well. In the recent past, episodes of nausea, vomiting, and abdominal pain had rarely occurred. A sister died shortly after birth with what was thought to be adrenal insufficiency. On admission his pulse was 84 and regular, and his blood pressure was 90/70 mm. Hg. He was in mild distress and complained of abdominal pain. His height was 68 inches and his weight was 136 lb. Skin turgor was normal but there was generalized increase in skin pigmentation. Pubic and axillary hair were normal in amount and distribution. The thyroid was slightly enlarged without nodularity. The heart sounds and size were normal and the lungs were clear to percussion and auscultation. The abdomen was soft with no hepatosplenomegaly. His penis was adult size; however, the testicles were small, measuring approximately 2 cm. in greatest diameter. The hematocrit was 42%. The white blood count was 5300 with 39 neutrophils, 41 lymphocytes, 14 monocytes, and 6 eosinophils. Urinalysis revealed a large amount of acetone but otherwise was normal. The serum sodium was 133, potassium 5.0, CI 98, and CO 2 combining power was 25 mEq./L. The urine sodium was 168 and the potassium was 64 mEq./L. The serum creatinine and BUN were normal.
Saline infusions were started and basal 24-hr. urines were collected for 17hydroxy corticosteroids, 17 -ketosteroids, pregnanediol, and pregnanetriol. After completion of the urine collections, he was started on dexamethasone and subsequently on 9-a fluorohydrocortisone. Additional studi0s obtained later showed a negative buccal smear, normal chest and skull roentgenograms, a normal protein-bound iodine, and a 24-hr. p 3 l thyroid uptake of 12.3%. Skeletal epiphyses were closed. Three semen analyses were obtained and all showed approximately 1-2 ml. of gray, moderately viscous semen without sperm. Two months after admission, while taking cortisone acetate, 25 mg. by mouth twice daily, basal serum testosterones were 249, 219, and 301 ng./l00 ml. The serum LH was 3.2 mLU./ml. (normal range 5-24) and serum FSH was 248 ng./ml. (normal range 190-420). * A 24-hr. urine for pituitary gonadotropins was less than 6 MUU. Intramuscular administration of human chorionic gonadotropin (HCG) 3000 L U. daily for 7 days was followed by a rise in serum testosterone to 543 ng./l00 ml. DISCUSSION
The data in this case are consistent with a C-21 hydroxylase deficiency and * Kindly performed by Alvin Paulsen, M.D., Division of Endocrinology, U.S. Public Health Service Hospital, Seattle, Wash. 98114.
.
April 1973
CONGENITAL ADRENAL HYPERPLASIA
congenital adrenal hyperplasia (CAH). Basal urinary 17 -hydroxy corticosteroids were low, and 17-ketosteroids, pregnanediol, and pregnanetriol were elevated. The ACTH stimulation test confirmed the diagnosis by demonstrating impaired 17-hydroxycorticosteroid production associated with a marked increase in 17-ketosteroids and pregnanetriol (Table 1). The presence of hypotension, a low serum sodium associated with a high excretion of urine sodium, and a high normal serum potassium suggest that he had the salt wasting variety of the syndrome. In addition, an isolated defect of pituitary gonadotropin secretion was considered, but thought to be unlikely. There have been few reports on testicular development after treatment of patients with CAH since Wilkins' classic article. 8 In 1954, Wilkins and Cara 9 described testicular findings in CAH before and after cortisone treatment. The ages of the boys ranged from 31J2-8% years. Biopsies on patients prior to treatment were reported as showing immature tubules and absence of Leydig cells, spermatids, and spermatozoa. The germ cells either had not differentiated beyond the stage of spermatogonia or showed only occasional mitoses with development of spermatocytes. After treatment with cortisone, rapid growth occurred with active spermatogenesis and the appearance of numerous Leydig cells. The testicular maturation, however, occurred only in those patients with bone ages between 11-15 years. No growth or maturation of the testicles occurred despite cortisone therapy in boys with osseous maturity less than 11 years. 9, 10 Gonadal failure in CAH is thought to be a result of chronic suppression of gonadotropin secretion by excess adrenal androgens. 9 Urine testosterone excretion 11 and plasma testosterone and androstenedione levels 12 are high, while urine gonadotropin excretion is low. 8 Cortisone
321
replacement suppresses the excessive production of androgens. In our case, excessive androgen production was reflected in elevated basal levels of 17-ketosteroids, pregnanediol, and pregnanetriol. Although serum testosterone was below the range found in normal adult males, the level was higher than that expected in a patient with preadolescent testicles. It is also possible that cortisone replacement may have already decreased the serum testosterone by suppressing adrenal androgen secretion. Our patient's failure to develop normal testicular size and function suggests inadequate doses of cortisone were taken through puberty and adolescence. As a result, excessive adrenal androgen secretion was not suppressed and inhibited the normal release of FSH and LH that occurs at puberty. In turn, testicular development did not occur normally. The finding of low levels of LH and relatively low levels of FSH are consistent with chronic suppression by excessive androgens. Moreover, the serum testosterone rose significantly from low basal levels following HCG administration, a finding similar to that in normal prepuberal boys IS and consistent with functional prepuberal testes. The changes in gonadotropin seen in our case were interpreted in the perspective of current concepts relating to the regulation of the pituitary-gonadal axis. It is thought that in man, FSH secretion is regulated by some unidentified substance produced by the germinal epithelium of the testicle or by testicular production of estrogen. The patient presented was azoospermic with small testicles, and therefore, FSH levels would be expected to be high. Contrary to expectations, the FSH level was low normal, suggesting that either androgens or perhaps estrogens converted from androgens suppressed FSH secretion. The low FSH levels would indicate that FSH secretion is suppressed
322
Vol. 24
MOLITOR ET AL.
either by androgens or estrogens rather than by an unidentified testicular substance from the germinal epithelium, although it does not exclude the latter possibility. LH secretion is inhibited by testosterone. In our patient, a low LH level suggests that testosterone or other, androgens may inhibit LH secretion. Our findings, in a natural setting, are consistent with those of Stewart-Bentley, Odell, and Horton,14 who showed that pharmacologic amounts of estradiol and of testosterone suppressed serum FSH and LH in normal individuals. Our patient demonstrates one of several possible outcomes in the natural history of CAH. Inadequate replacement, as in our patient, may result in persistent elevation of adrenal androgens sufficient to inhibit normal growth and maturation of the testicles. Also, failure to suppress ACTH secretion with steroids may result in the development of testicular tumors. 15 On the other hand, with adequate treatment, as measured by the return to normal of urinary 17-ketosteroids and pregnanetriol, there is inhibition of virilization, restoration of normal physical and skeletal growth, and normal testicular growth and function. 8 , 9 SUMMARY
A 22-year-old man with congenital adrenal hyperplasia (CAH) and associated salt-losing syndrome is presented with associated failure of gonadal development. Study of his testicular function showed azoospermia and low basal serum testosterone which increased significantly after HCG administration. Serum FSH and LH levels were low, suggesting chronic suppression of LH by adrenal androgens and of FSH by either adrenal androgens or their subsequent conversion to estrogens. Chronic suppression by adrenal androgens probably prevented normal tes-
ticular development from occurring under the influence of FSH and LH. The case represents a 22-year followup of a patient with treated CAH and emphasizes the necessity of adequate doses of steroids to allow normal testicular development and fertility. REFERENCES 1. SILBER, R H., AND PORTER, C. C. The determination of 17, 21-dihydroxy, 20-ketosteroids in urine and plasma. J Bioi Chem 210:923, 1954. 2. EpSTEIN, E. An aqueous Zimmermann reagent for the determination of 17-ketosteroids. Clin Chim Acta 7:735, 1962. 3. DREKTER, I. J., HEISLER, A., SCISM, G. R, STERN, S., PEARSON, S., AND MCGAUACK, T. H. The determination of urinary steroids. I. The preparation of pigment-free extract and a simplified procedure for the estimation of total 17-ketosteroids. J Clin Endocr 12:55, 1952. 4. MATTINGLY, D. A simple fluorimetric method for the estimation of free ll-hydroxycorticoids in human plasma. J Clin Path 15:374, 1962. 5. KLEIN, D., AND CHERNAIK, J. M. Urinary pregnanediol and pregnanetriol: Spectrophotometric determination following aluminum oxide column chromatography. Clin Chem 10:170, 1964. 6. MIDGLEY, A. R, JR. Radioimmunoassay for human follicle-stimulating hormone. J Clin Endocr 27:295, 1967. 7. PAULSEN, C. A., GORDON, D. L., CARPENTER, R W., GONDY, H. M., AND PRUCKER, W. D. Klinefelter's syndrome and its variants: A hormonal and chromosomal study. Recent Progr Hormone Res 24:321, 1968. 8. WILKINS, L., CRIGLER, J. F., JR., SILVERMAN, S. H., GARDNER, C. I., AND MIGEON, C. J. Further studies on the treatment of congenital adrenal hyperplasia with cortisone: II. The effects of cortisone on sexual and somatic development with a hypothesis concerning the mechanism of feminization. J Clin Endocr 12:277, 1952. 9. WILKINS, L., AND CARA, J. Further studies on the treatment of congenital adrenal hyperplasia with cortisone. V. Effects of cortisone therapy on testicular development. J Clin Endocr 14:287, 1954. 10. BLIZZARD, R M., AND WILKINS, L. Present concepts of steroid therapy in virilizing adrenal hyperplasia. Arch Intern Med (Chicago) 100:729, 1957. 11. CAMACHO, A. M., AND MIGEON, C. J. Testosterone excretion and production rate in normal
April 1973
CONGENITAL ADRENAL HYPERPLASIA
adults and in patients with congenital adrenal hyperplasia. J Clin Endocr 26:893, 1966. 12. RIVAROLA, M. A., SAEZ, J. M., AND MIGEON, C. J. Studies of androgens in patients with congenital adrenal hyperplasia. J Clin Endocr 27: 624,1967. 13. BARDIN, C. W., Ross, G. T., RiFKIND, A. B., CARGILLE, C. M., AND LIPSETI', M. B. Studies of the pituitary-Leydig cell axis in young men with hypogonadotrophic hypogonadism and hyposmia: Comparison with normal men, pre-
..
323
puberal boys and hypopituitary patients. J Clin Invest 48:2046, 1969. 14. STEWART-BENTLEY, M., ODELL, W., AND HORTON, R. "FSH-LH Feedback in Normal and Hypergonadotropic Man." In The 53rd Meeting of the Endocrine Society. San Francisco, 1971. 15. SCHOEN, E. J., DIRAIMONDO, V., AND DOMINQUEZ, O. V. Bilateral testicular tumors complicating congenital adrenocortical hyperplasia. J C.lin Endocr 21:518, 1961.