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Cited by 413Estrogen and related hormone effectsHormonal and reproductive studiesSexual Differentiation and Disorders

Role of Endocytosis in Cellular Uptake of Sex Steroids

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Hammes, Annette, Andreassen, Thomas K., Spoelgen, Robert, Raila, Jens, Hubner, Norbert, Schulz, Herbert, Metzger, Jochen, Schweigert, Florian J. +3 more·2005·Cell
DOI 10.1016/j.cell.2005.06.032
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Abstract

Androgens and estrogens are transported bound to the sex hormone binding globulin (SHBG). SHBG is believed to keep sex steroids inactive and to control the amount of free hormones that enter cells by passive diffusion. Contrary to the free hormone hypothesis, we demonstrate that megalin, an endocytic receptor in reproductive tissues, acts as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG. In line with this function, lack of receptor expression in megalin knockout mice results in impaired descent of the testes into the scrotum in males and blockade of vagina opening in females. Both processes are critically dependent on sex-steroid signaling, and similar defects are seen in animals treated with androgen- or estrogen-receptor antagonists. Thus, our findings uncover the existence of endocytic pathways for protein bound androgens and estrogens and their crucial role in development of the reproductive organs.

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Crossref · 10.1016/j.cell.2005.06.032

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  • A megalin-knockout mouse model provided evidence for a megalin-mediated cellular uptake pathway for internalization of the T-SHBG complex, with megalin absence causing impaired testicular descent.

    “A megalin-knockout mouse model was used to provide evidence for the existence of a megalin-mediated cellular uptake pathway for the internalization of the T-SHBG complex. When megalin was absent, mice would exhibit an impaired testicular descent into the scrotum, delivering evidence that the uptake of the protein-bound fraction is also relevant for intracellular hormone action [34].”

    From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [34]

  • In a study of 1072 men comparing estimates with assay-determined bioavailable testosterone, total testosterone had high predictability (r2=0.68) and was better than other tested modalities for determining biochemical hypogonadism (AUC: total testosterone 0.93, FAI 0.72, Nanjee and Wheeler 0.91, Vermeulen 0.88).

    “Results demonstrated high predictability using TT (r2=0.68), with TT being better than other tested modalities for determining biochemical hypogonadism (area under receiver operative curve; TT=0.93, FAI=0.72, Nanjee and Wheeler calculation=0.91, Vermeulen calculation=0.88).”

    From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [106]

  • At lower total testosterone levels (216-346 ng/dl), free testosterone was superior to total testosterone alone.

    “At lower TT levels (216–346ng/dl [7.5–12 nmol/L]), fT was found to be superior to TT alone.”

    From Challenges in Testosterone Measurement, Data Interpretation, and Methodological Appraisal of Interventional Trials (2016) · cites this paper as [106]

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Authors
Hammes, A., Andreassen, T. K., Spoelgen, R., Raila, J., Hubner, N., Schulz, H., Metzger, J., Schweigert, F. J., Luppa, P. B., Nykjaer, A., & Willnow, T. E.
Affiliations
  • Max Delbrück Center (DE)
  • Aarhus University (DK)
  • University of Potsdam (DE)
  • TUM Klinikum (DE)
Corresponding author
Willnow, Thomas E.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2005-09
Volume
122
Issue
5
Pages
751-762
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2005.06.032
OpenAlex
W2092723228
Cited by
413
References
0
Citations by year
2026: 5 · 2025: 9 · 2024: 17 · 2023: 11 · 2022: 21 · 2021: 15 · 2020: 12 · 2019: 16 · 2018: 20 · 2017: 14 · 2016: 28 · 2015: 12 · 2014: 18 · 2013: 19 · 2012: 24
FWCI
14.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
  • publish.UP (University of Potsdam) (submittedVersion)
  • mediaTUM (Technical University of Munich) (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft
  • Bundesministerium für Bildung und Forschung
  • Sundhed og Sygdom, Det Frie Forskningsråd (2107-04-0003)
  • Novo Nordisk Fonden
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
Keywords
endocytosis, sex hormone-binding globulin, megalin, androgens, estrogen, free hormone hypothesis, testicular descent, vaginal opening, reproductive organ development, androgen receptor antagonists, antiestrogens
MeSH terms
Androgens, Animals, Carrier Proteins, Cell Line, Endocrine System, Endocytosis, Estrogens, Eukaryotic Cells, Female, Humans, Immunohistochemistry, Male, Pregnancy, Receptors, Androgen, Receptors, Estrogen, Sex Hormone-Binding Globulin, Gonadal Steroid Hormones, Time Factors, Urogenital Abnormalities, Urogenital System, Mice, Knockout, Gene Expression Profiling, Low Density Lipoprotein Receptor-Related Protein-2, Mice

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