TY - JOUR

T1 - Germ cell neoplasia in situ and preserved fertility despite suppressed gonadotropins in a patient with testotoxicosis

AU - Mortensen, Li Juel

AU - Jensen, Martin Blomberg

AU - Christiansen, Peter

AU - Rønholt, Ann Margrethe

AU - Jørgensen, Anne

AU - Frederiksen, Hanne

AU - Nielsen, John E.

AU - Loya, Anand C.

AU - Grønkær Toft, Birgitte

AU - Skakkebæk, Niels E.

AU - Rajpert-De Meyts, Ewa

AU - Juul, Anders

PY - 2017

Y1 - 2017

N2 - Context: Testotoxicosis is an autosomal-dominant, male-limited disorder. Activating mutations in the luteinizing hormone receptor gene (LHCGR) cause high autonomous testosterone secretion, resulting in early-onset peripheral precocious puberty. Little is known about long-termconsequences of testotoxicosis. Case Description: We present a rare case of a patient followed for 25 years with two remarkable outcomes: preserved fertility and germ cell neoplasia in situ (GCNIS). He presented with precocious puberty at 10 months of age and was diagnosed with testotoxicosis due to a de novo heterozygous Asp578Tyr mutation in LHCGR. Testicular biopsy in childhood showed Leydig cell hyperplasia with altered cell maturation. From infancy throughout adulthood, elevated testosterone and estradiol, lowinhibin B and anti-Müllerian hormone, and completely suppressed follicle-stimulating hormone and luteinizing hormone were noted. Height acceleration and advanced bone age resulted in a reduced final height. Semen analysis revealed ongoing spermatogenesis, and the patient fathered a child by natural conception. Ketoconazole treatment decreased circulating testosterone in childhood, supported by experimental suppression of testosterone production in his adult testis tissue cultured ex vivo. At 25 years of age, ultrasound revealed a testicular tumor, identified as a Leydig cell adenoma, but unexpectedly with GCNIS present in adjacent seminiferous tubules. Conclusion: The case illustrates that absence of gonadotropins but high intratesticular testosterone concentration is sufficient for spermatogenesis and to allow fatherhood. Our study is also the first description, to our knowledge, of GCNIS in a patient with testotoxicosis. We recommend regular clinical examination and ultrasonic evaluation of the testes in these patients due to potential increased risk of malignancy.

AB - Context: Testotoxicosis is an autosomal-dominant, male-limited disorder. Activating mutations in the luteinizing hormone receptor gene (LHCGR) cause high autonomous testosterone secretion, resulting in early-onset peripheral precocious puberty. Little is known about long-termconsequences of testotoxicosis. Case Description: We present a rare case of a patient followed for 25 years with two remarkable outcomes: preserved fertility and germ cell neoplasia in situ (GCNIS). He presented with precocious puberty at 10 months of age and was diagnosed with testotoxicosis due to a de novo heterozygous Asp578Tyr mutation in LHCGR. Testicular biopsy in childhood showed Leydig cell hyperplasia with altered cell maturation. From infancy throughout adulthood, elevated testosterone and estradiol, lowinhibin B and anti-Müllerian hormone, and completely suppressed follicle-stimulating hormone and luteinizing hormone were noted. Height acceleration and advanced bone age resulted in a reduced final height. Semen analysis revealed ongoing spermatogenesis, and the patient fathered a child by natural conception. Ketoconazole treatment decreased circulating testosterone in childhood, supported by experimental suppression of testosterone production in his adult testis tissue cultured ex vivo. At 25 years of age, ultrasound revealed a testicular tumor, identified as a Leydig cell adenoma, but unexpectedly with GCNIS present in adjacent seminiferous tubules. Conclusion: The case illustrates that absence of gonadotropins but high intratesticular testosterone concentration is sufficient for spermatogenesis and to allow fatherhood. Our study is also the first description, to our knowledge, of GCNIS in a patient with testotoxicosis. We recommend regular clinical examination and ultrasonic evaluation of the testes in these patients due to potential increased risk of malignancy.

U2 - 10.1210/jc.2017-01761

DO - 10.1210/jc.2017-01761

M3 - Journal article

C2 - 29029242

AN - SCOPUS:85038232038

VL - 102

SP - 4411

EP - 4416

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 12

ER -