- Email: [email protected]
Elevated serum estradiol associated with increased androstenedione-testosterone ratio in adolescent males with varicocele and gynecomastia*
FERTILITY AND STERILITY
Vol. 56, No.3, September 1991
Copyright e 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Elevated serum estradiol associated with increased androstenedione-testosterone ratio in adolescent males with varicocele and gynecomastia*
Mariano Castro-Magana, M.D.t Moris Angulo, M.D. John Uy, M.D. Department of Pediatrics, Winthrop-University Hospital, Mineola, and State University of New York, Health Science Center at Stony Brook, Stony Brook, New York
Objective: To investigate the testicular function in adolescents with pubertal gynecomastia associated with varicocele before and after varicocelectomy. Design and Patients: We have studied six male adolescents 15 to 19 years of age with bilateral gynecomastia. They were selected among other adolescents with gynecomastia because of the presence of visible varicoceles. All of them had normal physical examination and secondary sexual characteristics. This was a prospective study of 3 months' duration. All the patients that were included finished the study. Setting: All the patients were evaluated in the Endocrine Clinic of Winthrop-University Hospital, a tertiary care unit. Interventions: Serum testosterone (T), androstenedione (A), and estradiol (E2 ) responses to the administration of human chorionic gonadotropin (hCG) 2,000 IU for 3 consecutive days before and 3 months after varicocelectomy were determined. Results: Varicocelectomy did not cause any significant changes in the basal (pre-hCG) levels of the steroid. However, the increase in T levels achieved with hCG was significantly (P < 0.005) higher after varicocelectomy (before T, 925 ± 212 ng%; after T, 1,649 ± 406 ng%). Simultaneously, the stimulated levels of E 2 and A were significantly lower (P < 0.005) after varicocelectomy (E2 , 62 ± 12 pg/mL; A, 326 ng% ± 80 ng%) than before (E 2 , 106 ± 13 pg/mL; A, 580 ng% ± 95 ng%). Conclusion: The reciprocal effect on the levels ofT and its immediate precursor, A, suggests an impairment of the 17-ketoreductase enzyme activity. The increased levels of E 2 after hCG and its normalization after varicocelectomy suggests that varicoceles may play a pathogenetic role in the development of gynecomastia. Fertil Steril 56:515, 1991
The incidence of varicoceles in adolescent males has been reported to range from 6% at 10 years of age to 19% at age 14 years, with a mean of 16% for the whole group of boys 10 to 19 years of age. 1 We have found, however, the incidence of visible variReceived January 2, 1991; revised and accepted April 25, 1991.
* Presented at the 46th Annual Meeting of The American Fertility Society, Washington, D.C., October 15 to 18, 1990. t Reprint requests: Mariano Castro-Magana, M.D., Pediatric Endocrinology and Metabolism, Winthrop-University Hospital, 222 Station Plaza North Suite 611, Mineola, New York 11501.
Vol. 56, No. 3, September 1991
cocele in adolescent males with pubertal gynecomastia as high as 26%. There is evidence that at least some men with varicoceles have a lower serum testosterone (T) levels than normal men. 2 We have demonstrated that adolescent males with visible varicoceles have a greater than normal rise in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in response to gonadotropinreleasing hormone (GnRH) and that surgical correction of the variococele may result in normalization of the gonadotropin response and an improvement of the testicular capacity ofT secretion.3 The
Castro-Magana et al.
Varicocele and gynecomastia
515
Table 1
Response ofT, A, and E 2 to HCG Before and After Varicocelectomya After
Before Basal T (ng/dL) A (ng/dL) E 2 (pg/mL) A/T ratio EdT ratio a
575 210 43 0.42 O.D7
± ± ± ± ±
159 40 19 0.14 0.03
Peak 925 580 106 0.71 0.16
± ± ± ± ±
Basal
212 95 13 0.48 0.06
762 129 37 0.19 0.05
± ± ± ± ±
201 34 7 0.08 0.02
Peak 1,649 346 62 0.23 0.04
± ± ± ± ±
406 80 12 0.09 0.01
Values are means± SD.
high incidence of visible varicoceles in patients with pubertal gynecomastia and the early Leydig cell dysfunction seen in some of these patients suggest a pathogenetic role of the varicocele in the development of gynecomastia. The aim of the present study is to investigate the testicular function in a group of adolescents with pubertal gynecomastia associated with variococele before and after varicocelectomy. MATERIALS AND METHODS Patients
Our patients were six male adolescents 15 to 19 years of age who were seen in the pediatric endocrine clinic for evaluation of gynecomastia. They were selected among other adolescents with gynecomastia because of the presence of visible varicoceles and their possible deleterious effect in testicular function. All these patients had bilateral gynecomastia corresponding to Tanner stage III to IV of breast development and visible left-sided varicocele. Testicular diameters (L, length; W, width) were measured with a caliper and the volume was calculated from the formula 11/6 X LX W 2 •4 All the patients had achieved pubic hair stage IV and V5 and had testicular volumes between 20 and 30 mL, which correspond to the volume between the mean and 90th percentile for healthy male adolescents. 6 Testicular consistency was evaluated subjectively by palpation and considered to be normal in all the patients. Medical history and physical examination was otherwise unremarkable in all participants. Varicocelectomy was performed in all the patients by ligation of the internal spermatic vein at the level of the inguinal canal, and testicular biopsy specimens were obtained. The testicular tissue specimens were fixed in Bouin's solution and processed by standard histologic methods. Histologic sections
516
Castro-Magana et al.
Varicocele and gynecomastia
were stained with periodic acid-Schiff reagent, hematoxylin and eosin stain, and the Masson trichrome method. Chromosome analysis from peripheral blood lymphocytes, to exclude Klinefelter syndrome, was performed in each patient. Informed consents were obtained from all participants. Protocols and Hormone Assays
Serum concentrations of T 7, androstenedione (A), 8 and estradiol (E 2) 9 were measured by previously described radioimmunoassays (RIAs) before and 24 hours after the intramuscular administration of human chorionic gonadotropin 2,000 IU for 3 consecutive days before variococelectomy and 3 months after varicocelectomy. The interassay coefficients of variation were <13% and the intra-assay CVs were <8% for all determinations. Serum LH and FSH were measured by RIA, as previously described10 before and 3 months after varicocelectomy. Statistical analysis was performed with the Student's paired t-test. Data are presented as means ± SD. Statistical significance was assumed at P < 0.05. RESULTS
Histologic studies of all the biopsy specimens showed normal spermatogenesis. No thickening of the tubular walls or degenerative changes of the Leydig cells were observed. Chromosome analysis in all patients showed normal 46,XY male chromosomal complement. Table 1 shows serum steroid levels response to the administration of hCG. Varicocelectomy did not cause any significant changes in the basal (pre-hCG) levels ofT, A, and E 2 • However, the increase in T levels achieved with hCG was significantly higher (P < 0.005) than that before varicocelectomy. Simultaneously, the stimulated levels of E 2 and A were significantly lower (P < 0.005) after varicocelectomy than before. The basal (pre-
Fertility and Sterility
hCG) as well as stimulated (after hCG) A/T ratios were significantly higher (P < 0.001) before than after varicocelectomy. Estradiol/T ratio increased significantly (P < 0.001) with hCG only before varicocelectomy. The basal levels ofboth gonadotropins in the puberty range (LH, 9.1 ± 1.7 miU/ml; FSH, 8. 7 ± 2.3 miU /ml) did not significantly differ before and after varicocelectomy (P > 0.20).
DISCUSSION
In spite of the high incidence of varicocele in pubertal males, there are very few studies concerning the effect of varicocele on the endocrine function of the testis at this age. We have previously shown3 that male adolescents with visible varicoceles have Leydig cell dysfunction even before there is any detectable impairment in sperm production. We have been unable to show any histologic abnormalities in adolescent males with varicoceles; however, similar studies in adult males have shown significant thickening of the tubular walls and degenerative changes of the Leydig cells.U They had an excessive rise in gonadotropins response to GnRH, similar to that of men with testicular insufficiency. 12 This study confirms our previous observation that varicocelectomy improves the testicular capacity of T production. 3 However, the most noteworthy observations reported here are the changes in serum concentration ofE 2 and A. Before varicocelectomy, hCG increased the concentration of both steroids as well as the serum T levels. After varicocelectomy, the increase in E 2 and A was much smaller, and the increase in Twas much larger than before varicocelectomy. The reciprocal effect on the levels ofT and its immediate precursor, A, suggests an impairment of the 17ketoreductase enzyme activity. The increase in the A/T ratio observed with the administration of hCG before and its normalization 3 months after varicocelectomy strongly support the concept of impaired 17-ketoreductase activity in adolescent males with varicocele and gynecomastia. Enzymatic deficiencies in T biosynthesis have also been reported by others. In 1983, Ando et al. 13 found an increased 17-hydroxyprogesterone/T ratio on hCG stimulation in middle-aged men with varicoceles and suggested that some enzymatic impairment should be present involving the last steps ofT biosynthesis. The increased E 2/T ratio has been previously described in patients with pubertal gynecomastia; 14•15 however, its normalization after varicocelectomy suggests a
Vol. 56, No.3, September 1991
causal-effect relationship between the varicocele and the increased E 2 levels. Because of the severity of their gynecomastia and its psychological consequences, surgical treatment was selected by the patients. Therefore, the effect of varicocelectomy in the clinical course of gynecomastia was not observed. The source of E 2 in our patients, as well as the physiological importance, is still unclear, but the increase in the testicular capacity for T production associated with the simultaneous decrease in E 2 levels after varicocelectomy might reflect a causal relationship. Estrogens could play an important role within the testis. It has been shown that testicular 17-ketoreductase in the Leydig cell is inhibited by E 2 ; 16 therefore, it may be possible that the increased E 2 in our patients would inhibit the 17-ketoreductase enzyme, decreasing the levels ofT with the concomitant increase in its precursor, A. Gynecomastia develops in 60% to 70% of normal boys during puberty. 17 Because it is a transient phenomenon, however, the projection has been made that virtually all boys have gynecomastia at some time during puberty. Adolescent gynecomastia can be explained as the consequence of the fact that plasma E 2 reaches the adult level in men before the adult level of plasma T is attained. 14•15 As a result, the plasma ratios ofT to E 2 do not achieve the adult level until late in puberty. The mechanisms that lead to an increased E 2 toT ratio early in male puberty are not understood; however, our findings suggest that varicoceles may play a pathogenetic role in some cases of pubertal gynecomastia. REFERENCES 1. Oster J: Varicocele in children and adolescents. Scand J Urol Nephrol 5:27, 1971 2. Raboch J, Starka L: Hormonal testicular activity in men with a varicocele. Fertil Steril 22:152, 1971 3. Castro-Magana M, Angulo M, Canas A, Uy J: Improvement of Leydig cell function in male adolescents after varicocelectomy. J Pediatr 115:809, 1989 4. Cantu JM, Scaglia HE, Medina M: Inherited congenital normofunctional testicular hyperplasia and mental deficiency. Hum Genet 33:23, 1976 5. Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970 6. Castro- Magana M, Angulo M, Canas A, Sharp A, Fuentes B: Hypothalamic pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism. J Pediatr 112:397, 1988 7. Coyotupa J, Parlow AF, Abraham GE: Simultaneous radioimmunoassay of plasma testosterone and dihydrotestosterone. Anal Lett 5:329, 1972 8. Abraham GE, Chakmakjian ZH: Serum steroid levels during the menstrual cycle in a bilaterally adrenalectomized woman. J Clin Endocrinol Metab 37:581, 1973
Castro-Magana et al.
Varicocele and gynecomastia
517
9. Abraham GE, Hooper K, Tulchinsky D, Swerdloff RS, Odell WD: Simultaneous measurement of plasma progesterone, 17hydroxyprogesterone and estradiol17-B by radioimmunoasay. Anal Lett 4:325, 1971 10. Albert AA, Rosenberg E, Ross GT, Paulsen CA, Ryan RJ: Report of the National Pituitary Agency collaborative study on the radioimmunoassay of FSH and LH. J Clin Endocrinol Metab 28:1214, 1968 11. Etriby A, Girgis S, Hefnawy H, Ibrahim AA: Testicular changes in subfertile males with varicocele. Fertil Steril 18: 666, 1967 12. Castro-Magana M, Angulo M, Collipp PJ, Derenoncourt A, Sherman J, Borofsky L: Paradoxial association of central precocious puberty and hypergonadotropic hypogonadism in three patients with Klinefelter, Down and Turner Syndrome. J Pediatr Endocrinol 1:61, 1985
518
Castro-Magana et al.
Varicocele and gynecomastia
13. Ando S, Giacchetto C, Colpi G, Panno ML, Beraldi E, Lombardi A, Sposato G: Plasma levels of 17-0H-Progesterone and testosterone in patients with varicocele. Acta Endocrinol (Copenh) 102:463, 1983 14. La Franchi SH, Parlow AF, Luppe BM, Coytupa J, Kaplan SA: Pubertal gynecomastia and transient elevation of serum estradiol levels. Am J Dis Child 129:927, 1975 15. Lee P A: The relationship of concentrations of serum hormones to pubertal gynecomastia. J Pediatr 86:212, 1975 16. Kaartinen E, Laukkanen M, Saure A: Metabolism of dehydroepiandrosterone by rat testicular homogenates: kinetic study at different temperatures of direct effect of 17B-Oestradiol. Acta Endocrinol (Copenh) 66:50, 1971 17. Nydick M, Bustos J, Dale JH, Ralosm RW: Gynecomastia in adolescent boys. JAMA 178:449, 1961
Fertility and Sterility
Vol. 56, No.3, September 1991
Copyright e 1991 The American Fertility Society
Printed on acid-free paper in U.S.A.
Elevated serum estradiol associated with increased androstenedione-testosterone ratio in adolescent males with varicocele and gynecomastia*
Mariano Castro-Magana, M.D.t Moris Angulo, M.D. John Uy, M.D. Department of Pediatrics, Winthrop-University Hospital, Mineola, and State University of New York, Health Science Center at Stony Brook, Stony Brook, New York
Objective: To investigate the testicular function in adolescents with pubertal gynecomastia associated with varicocele before and after varicocelectomy. Design and Patients: We have studied six male adolescents 15 to 19 years of age with bilateral gynecomastia. They were selected among other adolescents with gynecomastia because of the presence of visible varicoceles. All of them had normal physical examination and secondary sexual characteristics. This was a prospective study of 3 months' duration. All the patients that were included finished the study. Setting: All the patients were evaluated in the Endocrine Clinic of Winthrop-University Hospital, a tertiary care unit. Interventions: Serum testosterone (T), androstenedione (A), and estradiol (E2 ) responses to the administration of human chorionic gonadotropin (hCG) 2,000 IU for 3 consecutive days before and 3 months after varicocelectomy were determined. Results: Varicocelectomy did not cause any significant changes in the basal (pre-hCG) levels of the steroid. However, the increase in T levels achieved with hCG was significantly (P < 0.005) higher after varicocelectomy (before T, 925 ± 212 ng%; after T, 1,649 ± 406 ng%). Simultaneously, the stimulated levels of E 2 and A were significantly lower (P < 0.005) after varicocelectomy (E2 , 62 ± 12 pg/mL; A, 326 ng% ± 80 ng%) than before (E 2 , 106 ± 13 pg/mL; A, 580 ng% ± 95 ng%). Conclusion: The reciprocal effect on the levels ofT and its immediate precursor, A, suggests an impairment of the 17-ketoreductase enzyme activity. The increased levels of E 2 after hCG and its normalization after varicocelectomy suggests that varicoceles may play a pathogenetic role in the development of gynecomastia. Fertil Steril 56:515, 1991
The incidence of varicoceles in adolescent males has been reported to range from 6% at 10 years of age to 19% at age 14 years, with a mean of 16% for the whole group of boys 10 to 19 years of age. 1 We have found, however, the incidence of visible variReceived January 2, 1991; revised and accepted April 25, 1991.
* Presented at the 46th Annual Meeting of The American Fertility Society, Washington, D.C., October 15 to 18, 1990. t Reprint requests: Mariano Castro-Magana, M.D., Pediatric Endocrinology and Metabolism, Winthrop-University Hospital, 222 Station Plaza North Suite 611, Mineola, New York 11501.
Vol. 56, No. 3, September 1991
cocele in adolescent males with pubertal gynecomastia as high as 26%. There is evidence that at least some men with varicoceles have a lower serum testosterone (T) levels than normal men. 2 We have demonstrated that adolescent males with visible varicoceles have a greater than normal rise in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in response to gonadotropinreleasing hormone (GnRH) and that surgical correction of the variococele may result in normalization of the gonadotropin response and an improvement of the testicular capacity ofT secretion.3 The
Castro-Magana et al.
Varicocele and gynecomastia
515
Table 1
Response ofT, A, and E 2 to HCG Before and After Varicocelectomya After
Before Basal T (ng/dL) A (ng/dL) E 2 (pg/mL) A/T ratio EdT ratio a
575 210 43 0.42 O.D7
± ± ± ± ±
159 40 19 0.14 0.03
Peak 925 580 106 0.71 0.16
± ± ± ± ±
Basal
212 95 13 0.48 0.06
762 129 37 0.19 0.05
± ± ± ± ±
201 34 7 0.08 0.02
Peak 1,649 346 62 0.23 0.04
± ± ± ± ±
406 80 12 0.09 0.01
Values are means± SD.
high incidence of visible varicoceles in patients with pubertal gynecomastia and the early Leydig cell dysfunction seen in some of these patients suggest a pathogenetic role of the varicocele in the development of gynecomastia. The aim of the present study is to investigate the testicular function in a group of adolescents with pubertal gynecomastia associated with variococele before and after varicocelectomy. MATERIALS AND METHODS Patients
Our patients were six male adolescents 15 to 19 years of age who were seen in the pediatric endocrine clinic for evaluation of gynecomastia. They were selected among other adolescents with gynecomastia because of the presence of visible varicoceles and their possible deleterious effect in testicular function. All these patients had bilateral gynecomastia corresponding to Tanner stage III to IV of breast development and visible left-sided varicocele. Testicular diameters (L, length; W, width) were measured with a caliper and the volume was calculated from the formula 11/6 X LX W 2 •4 All the patients had achieved pubic hair stage IV and V5 and had testicular volumes between 20 and 30 mL, which correspond to the volume between the mean and 90th percentile for healthy male adolescents. 6 Testicular consistency was evaluated subjectively by palpation and considered to be normal in all the patients. Medical history and physical examination was otherwise unremarkable in all participants. Varicocelectomy was performed in all the patients by ligation of the internal spermatic vein at the level of the inguinal canal, and testicular biopsy specimens were obtained. The testicular tissue specimens were fixed in Bouin's solution and processed by standard histologic methods. Histologic sections
516
Castro-Magana et al.
Varicocele and gynecomastia
were stained with periodic acid-Schiff reagent, hematoxylin and eosin stain, and the Masson trichrome method. Chromosome analysis from peripheral blood lymphocytes, to exclude Klinefelter syndrome, was performed in each patient. Informed consents were obtained from all participants. Protocols and Hormone Assays
Serum concentrations of T 7, androstenedione (A), 8 and estradiol (E 2) 9 were measured by previously described radioimmunoassays (RIAs) before and 24 hours after the intramuscular administration of human chorionic gonadotropin 2,000 IU for 3 consecutive days before variococelectomy and 3 months after varicocelectomy. The interassay coefficients of variation were <13% and the intra-assay CVs were <8% for all determinations. Serum LH and FSH were measured by RIA, as previously described10 before and 3 months after varicocelectomy. Statistical analysis was performed with the Student's paired t-test. Data are presented as means ± SD. Statistical significance was assumed at P < 0.05. RESULTS
Histologic studies of all the biopsy specimens showed normal spermatogenesis. No thickening of the tubular walls or degenerative changes of the Leydig cells were observed. Chromosome analysis in all patients showed normal 46,XY male chromosomal complement. Table 1 shows serum steroid levels response to the administration of hCG. Varicocelectomy did not cause any significant changes in the basal (pre-hCG) levels ofT, A, and E 2 • However, the increase in T levels achieved with hCG was significantly higher (P < 0.005) than that before varicocelectomy. Simultaneously, the stimulated levels of E 2 and A were significantly lower (P < 0.005) after varicocelectomy than before. The basal (pre-
Fertility and Sterility
hCG) as well as stimulated (after hCG) A/T ratios were significantly higher (P < 0.001) before than after varicocelectomy. Estradiol/T ratio increased significantly (P < 0.001) with hCG only before varicocelectomy. The basal levels ofboth gonadotropins in the puberty range (LH, 9.1 ± 1.7 miU/ml; FSH, 8. 7 ± 2.3 miU /ml) did not significantly differ before and after varicocelectomy (P > 0.20).
DISCUSSION
In spite of the high incidence of varicocele in pubertal males, there are very few studies concerning the effect of varicocele on the endocrine function of the testis at this age. We have previously shown3 that male adolescents with visible varicoceles have Leydig cell dysfunction even before there is any detectable impairment in sperm production. We have been unable to show any histologic abnormalities in adolescent males with varicoceles; however, similar studies in adult males have shown significant thickening of the tubular walls and degenerative changes of the Leydig cells.U They had an excessive rise in gonadotropins response to GnRH, similar to that of men with testicular insufficiency. 12 This study confirms our previous observation that varicocelectomy improves the testicular capacity of T production. 3 However, the most noteworthy observations reported here are the changes in serum concentration ofE 2 and A. Before varicocelectomy, hCG increased the concentration of both steroids as well as the serum T levels. After varicocelectomy, the increase in E 2 and A was much smaller, and the increase in Twas much larger than before varicocelectomy. The reciprocal effect on the levels ofT and its immediate precursor, A, suggests an impairment of the 17ketoreductase enzyme activity. The increase in the A/T ratio observed with the administration of hCG before and its normalization 3 months after varicocelectomy strongly support the concept of impaired 17-ketoreductase activity in adolescent males with varicocele and gynecomastia. Enzymatic deficiencies in T biosynthesis have also been reported by others. In 1983, Ando et al. 13 found an increased 17-hydroxyprogesterone/T ratio on hCG stimulation in middle-aged men with varicoceles and suggested that some enzymatic impairment should be present involving the last steps ofT biosynthesis. The increased E 2/T ratio has been previously described in patients with pubertal gynecomastia; 14•15 however, its normalization after varicocelectomy suggests a
Vol. 56, No.3, September 1991
causal-effect relationship between the varicocele and the increased E 2 levels. Because of the severity of their gynecomastia and its psychological consequences, surgical treatment was selected by the patients. Therefore, the effect of varicocelectomy in the clinical course of gynecomastia was not observed. The source of E 2 in our patients, as well as the physiological importance, is still unclear, but the increase in the testicular capacity for T production associated with the simultaneous decrease in E 2 levels after varicocelectomy might reflect a causal relationship. Estrogens could play an important role within the testis. It has been shown that testicular 17-ketoreductase in the Leydig cell is inhibited by E 2 ; 16 therefore, it may be possible that the increased E 2 in our patients would inhibit the 17-ketoreductase enzyme, decreasing the levels ofT with the concomitant increase in its precursor, A. Gynecomastia develops in 60% to 70% of normal boys during puberty. 17 Because it is a transient phenomenon, however, the projection has been made that virtually all boys have gynecomastia at some time during puberty. Adolescent gynecomastia can be explained as the consequence of the fact that plasma E 2 reaches the adult level in men before the adult level of plasma T is attained. 14•15 As a result, the plasma ratios ofT to E 2 do not achieve the adult level until late in puberty. The mechanisms that lead to an increased E 2 toT ratio early in male puberty are not understood; however, our findings suggest that varicoceles may play a pathogenetic role in some cases of pubertal gynecomastia. REFERENCES 1. Oster J: Varicocele in children and adolescents. Scand J Urol Nephrol 5:27, 1971 2. Raboch J, Starka L: Hormonal testicular activity in men with a varicocele. Fertil Steril 22:152, 1971 3. Castro-Magana M, Angulo M, Canas A, Uy J: Improvement of Leydig cell function in male adolescents after varicocelectomy. J Pediatr 115:809, 1989 4. Cantu JM, Scaglia HE, Medina M: Inherited congenital normofunctional testicular hyperplasia and mental deficiency. Hum Genet 33:23, 1976 5. Marshall WA, Tanner JM: Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13, 1970 6. Castro- Magana M, Angulo M, Canas A, Sharp A, Fuentes B: Hypothalamic pituitary gonadal axis in boys with primary hypothyroidism and macroorchidism. J Pediatr 112:397, 1988 7. Coyotupa J, Parlow AF, Abraham GE: Simultaneous radioimmunoassay of plasma testosterone and dihydrotestosterone. Anal Lett 5:329, 1972 8. Abraham GE, Chakmakjian ZH: Serum steroid levels during the menstrual cycle in a bilaterally adrenalectomized woman. J Clin Endocrinol Metab 37:581, 1973
Castro-Magana et al.
Varicocele and gynecomastia
517
9. Abraham GE, Hooper K, Tulchinsky D, Swerdloff RS, Odell WD: Simultaneous measurement of plasma progesterone, 17hydroxyprogesterone and estradiol17-B by radioimmunoasay. Anal Lett 4:325, 1971 10. Albert AA, Rosenberg E, Ross GT, Paulsen CA, Ryan RJ: Report of the National Pituitary Agency collaborative study on the radioimmunoassay of FSH and LH. J Clin Endocrinol Metab 28:1214, 1968 11. Etriby A, Girgis S, Hefnawy H, Ibrahim AA: Testicular changes in subfertile males with varicocele. Fertil Steril 18: 666, 1967 12. Castro-Magana M, Angulo M, Collipp PJ, Derenoncourt A, Sherman J, Borofsky L: Paradoxial association of central precocious puberty and hypergonadotropic hypogonadism in three patients with Klinefelter, Down and Turner Syndrome. J Pediatr Endocrinol 1:61, 1985
518
Castro-Magana et al.
Varicocele and gynecomastia
13. Ando S, Giacchetto C, Colpi G, Panno ML, Beraldi E, Lombardi A, Sposato G: Plasma levels of 17-0H-Progesterone and testosterone in patients with varicocele. Acta Endocrinol (Copenh) 102:463, 1983 14. La Franchi SH, Parlow AF, Luppe BM, Coytupa J, Kaplan SA: Pubertal gynecomastia and transient elevation of serum estradiol levels. Am J Dis Child 129:927, 1975 15. Lee P A: The relationship of concentrations of serum hormones to pubertal gynecomastia. J Pediatr 86:212, 1975 16. Kaartinen E, Laukkanen M, Saure A: Metabolism of dehydroepiandrosterone by rat testicular homogenates: kinetic study at different temperatures of direct effect of 17B-Oestradiol. Acta Endocrinol (Copenh) 66:50, 1971 17. Nydick M, Bustos J, Dale JH, Ralosm RW: Gynecomastia in adolescent boys. JAMA 178:449, 1961
Fertility and Sterility