Germ cell neoplasia in situ and preserved fertility despite suppressed gonadotropins in a patient with testotoxicosis
Open accessAbstract
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-term consequences 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, low inhibin 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.
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Confirmatory evidence in humans from rare cases of men with an activating mutation of the chorionic gonadotropin/LH receptor shows that high testosterone without gonadotropin stimulation induced sperm production and allowed natural paternity.
“Nevertheless, confirmatory evidence in humans is available from rare cases of men with an activating mutation of the chorionic gonadotropin/LH receptor (73, 74).”
From Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance (2018) · cites this paper as [73]
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Skakkebæk, N. E., Berthelsen, J., Giwercman, A., & Müller, J. (1987) · International Journal of Andrology · doi:10.1111/j.1365-2605.1987.tb00161.x · Cited by 741 · see citing works
Self-citationPakarainen, T., Zhang, F., Mäkelä, S., POUTANEN, M. H., & Huhtaniemi, I. T. (2004) · Endocrinology · doi:10.1210/en.2004-0913 · Cited by 126 · see citing works
Testicular Leydig Cell Hyperplasia as a Cause of Familial Sexual Precocity*
Schedewie, H., Reiter, E. O., Beitins, I. Z., SEYED, S., WOOTEN, V. D., Jimenez, J. F., Aiman, E. J., DeVane, G. W., Redman, J. F., & Elders, M. J. (1981) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-52-2-271 · Cited by 126 · see citing works
Jørgensen, A., Young, J., Nielsen, J. E., Joensen, U. N., Toft, B. G., Meyts, E. R., & Loveland, K. L. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.160 · Cited by 94 · see citing works
Self-citationLottrup, G., Nielsen, J. E., Maroun, L. L., Møller, L. M. A., Yassin, M., Leffers, H. C. B., Skakkebæk, N. E., & Meyts, E. R. (2014) · Human Reproduction · doi:10.1093/humrep/deu124 · Cited by 87 · see citing works
Self-citationSøeborg, T., Frederiksen, H., Johannsen, T. H., Andersson, A.-M., & Juul, A. (2017) · Clinica Chimica Acta · doi:10.1016/j.cca.2017.03.002 · Cited by 83 · see citing works
Self-citationBoot, A. M., Lumbroso, S., Verhoef‐Post, M., Richter-Unruh, A., Looijenga, L. H. J., Funaro, A., Beishuizen, A., van Marle, A., Drop, S. L. S., & Themmen, A. P. N. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2010-3031 · Cited by 60 · see citing works
Martin, M. S., Sm, W., Martin, A., Rennert, O., & Chan, W. (1998) · European Journal of Endocrinology · doi:10.1530/eje.0.1390101 · Cited by 58 · see citing works
Dysregulation of the mitosis–meiosis switch in testicular carcinoma in situ
Jørgensen, A., Nielsen, J. E., Almstrup, K., Toft, B. G., Petersen, B. L., & Meyts, E. R. (2013) · The Journal of Pathology · doi:10.1002/path.4154 · Cited by 56 · see citing works
Self-citationMüller, J., Gondos, B., Kosugi, S., Mori, T., & Shenker, A. (1998) · Journal of Medical Genetics · doi:10.1136/jmg.35.4.340 · Cited by 51 · see citing works
Lottrup, G., Nielsen, J. E., Skakkebæk, N. E., Juul, A., & Meyts, E. R. (2015) · European Journal of Endocrinology · doi:10.1530/eje-14-0810 · Cited by 44 · see citing works
Self-citationGondos, B., Ca, E., Sm, R., & Mm, G. (1985) · PubMed · Cited by 42 · see citing works
Gondos, B., EGLI, C. A., Rosenthal, S. M., & Grumbach, M. M. (1986) · The Journal of Urology · doi:10.1016/s0022-5347(17)45800-9 · Cited by 22 · see citing works
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Circulating Testosterone as the Hormonal Basis of Sex Differences in Athletic Performance
Handelsman, D. J., Hirschberg, A. L., & Bermon, S. (2018) · Endocrine Reviews · doi:10.1210/er.2018-00020 · Cited by 594 · see citing works
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Gurnurkar, S., DiLillo, E., & Carakushansky, M. (2020) · Journal of Clinical Research in Pediatric Endocrinology · doi:10.4274/jcrpe.galenos.2020.2020.0067 · Cited by 10 · see citing works
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Kooij, C. D., Mavinkurve‐Groothuis, A. M. C., Hovinga, I. C. L. K., Looijenga, L. H. J., Rinne, T., Giltay, J. C., de Kort, L. M. O., Klijn, A. J., de Krijger, R. R., & Stuart, A. A. V. (2022) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgac516 · Cited by 9 · see citing works
Lorenzen, M., Nielsen, J. E., Andreassen, C. H., Juul, A., Toft, B. G., Meyts, E. R., Daugaard, G., & Jensen, M. B. (2020) · Cancers · doi:10.3390/cancers12061358 · Cited by 7 · see citing works
Self-citationSpontaneous fertility in a male patient with testotoxicosis despite suppression of FSH levels
Cunha-Silva, M., Brito, V. N., Macedo, D. B., Bessa, D. S., Ramos, C. O., Lima, L. G., Barroso, P. S., Arnhold, I. J. P., Segaloff, D. L., Mendonca, B. B., et al. (2018) · Human Reproduction · doi:10.1093/humrep/dey049 · Cited by 6 · see citing works
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Drop, S. L. S., & der Grinten, H. L. C. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.11101-8
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Shahid, A., & Ibrahim, M. N. (2023) · Journal of the Pakistan Medical Association · doi:10.47391/jpma.7455
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Cannarella, R., & Calogero, A. E. (2025) · L Endocrinologo · doi:10.1007/s40619-025-01590-4
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- Authors
- Juel Mortensen, L., Blomberg Jensen, M., Christiansen, P., Rønholt, A.-M., Jørgensen, A., Frederiksen, H., Nielsen, J. E., Loya, A. C., Grønkær Toft, B., Skakkebæk, N. E., Rajpert-De Meyts, E., & Juul, A.
- Affiliations
- Department of Growth and Reproduction, Rigshospitalet, University of Copenhagen, Denmark
- University of Copenhagen (DK)
- Regionshospitalet Viborg (DK)
- Department of Pathology, Rigshospitalet, University of Copenhagen, Denmark
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2017-10-05
- Volume
- 102
- Issue
- 12
- Pages
- 4411-4416
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2764135170
- Cited by
- 12
- References
- 13
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 1 · 2020: 2 · 2018: 4
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Rigshospitalet
- Novo Nordisk Fonden (NNF17OC0026096)
- Topics
- Health Sciences › Medicine › Surgery › Testicular diseases and treatments
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- testotoxicosis, germ cell neoplasia in situ, luteinizing hormone receptor, precocious puberty, Leydig cell hyperplasia, Leydig cell adenoma, spermatogenesis, gonadotropin suppression, testosterone, fertility preservation, ketoconazole, testicular ultrasound, long-term outcomes
- MeSH terms
- Adult, Body Composition, Body Height, Bone and Bones, Fertility, Gonadotropins, Hormone Antagonists, Humans, Ketoconazole, Leydig Cell Tumor, Male, Neoplasms, Germ Cell and Embryonal, Puberty, Precocious, Receptors, LH, Spermatogenesis, Testis
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