Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
Abstract Background Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult...
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| Format: | Article |
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BMC
2022-10-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02602-y |
| _version_ | 1828140569439764480 |
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| author | Malene Lundgaard Riis Gabriele Matilionyte John E. Nielsen Cecilie Melau David Greenald Kristine Juul Hare Lea Langhoff Thuesen Eva Dreisler Kasper Aaboe Pia Tutein Brenøe Anna-Maria Andersson Jakob Albrethsen Hanne Frederiksen Ewa Rajpert-De Meyts Anders Juul Rod T. Mitchell Anne Jørgensen |
| author_facet | Malene Lundgaard Riis Gabriele Matilionyte John E. Nielsen Cecilie Melau David Greenald Kristine Juul Hare Lea Langhoff Thuesen Eva Dreisler Kasper Aaboe Pia Tutein Brenøe Anna-Maria Andersson Jakob Albrethsen Hanne Frederiksen Ewa Rajpert-De Meyts Anders Juul Rod T. Mitchell Anne Jørgensen |
| author_sort | Malene Lundgaard Riis |
| collection | DOAJ |
| description | Abstract Background Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats. Methods The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry. Results Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7–21, which were subsequently divided into four age groups: GW 7–10, 10–12, 12–16 and 16–21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7–10 and 10–12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7–10 age group. Flutamide treatment in specimens aged GW 7–12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed. Conclusions This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7–14 period—thereby indicating the presence of a window of androgen sensitivity in the human fetal testis. |
| first_indexed | 2024-04-11T19:11:47Z |
| format | Article |
| id | doaj.art-6faa0696ef594229b30882d592bea05d |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-04-11T19:11:47Z |
| publishDate | 2022-10-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-6faa0696ef594229b30882d592bea05d2022-12-22T04:07:36ZengBMCBMC Medicine1741-70152022-10-0120111810.1186/s12916-022-02602-yIdentification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivoMalene Lundgaard Riis0Gabriele Matilionyte1John E. Nielsen2Cecilie Melau3David Greenald4Kristine Juul Hare5Lea Langhoff Thuesen6Eva Dreisler7Kasper Aaboe8Pia Tutein Brenøe9Anna-Maria Andersson10Jakob Albrethsen11Hanne Frederiksen12Ewa Rajpert-De Meyts13Anders Juul14Rod T. Mitchell15Anne Jørgensen16Department of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletMRC Centre for Reproductive Health, The Queen’s Medical Research Institute, University of EdinburghDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletMRC Centre for Reproductive Health, The Queen’s Medical Research Institute, University of EdinburghDepartment of Obstetrics and Gynaecology, Copenhagen University Hospital - Hvidovre and Amager HospitalDepartment of Obstetrics and Gynaecology, Copenhagen University Hospital - Hvidovre and Amager HospitalDepartment of Gynaecology, Copenhagen University Hospital – RigshospitaletDepartment of Gynaecology, Copenhagen University Hospital – RigshospitaletDepartment of Obstetrics and Gynaecology, Copenhagen University Hospital - Herlev and Gentofte HospitalDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletMRC Centre for Reproductive Health, The Queen’s Medical Research Institute, University of EdinburghDepartment of Growth and Reproduction, Copenhagen University Hospital - RigshospitaletAbstract Background Reduced androgen action during early fetal development has been suggested as the origin of reproductive disorders comprised within the testicular dysgenesis syndrome (TDS). This hypothesis has been supported by studies in rats demonstrating that normal male development and adult reproductive function depend on sufficient androgen exposure during a sensitive fetal period, called the masculinization programming window (MPW). The main aim of this study was therefore to examine the effects of manipulating androgen production during different timepoints during early human fetal testis development to identify the existence and timing of a possible window of androgen sensitivity resembling the MPW in rats. Methods The effects of experimentally reduced androgen exposure during different periods of human fetal testis development and function were examined using an established and validated human ex vivo tissue culture model. The androgen production was reduced by treatment with ketoconazole and validated by treatment with flutamide which blocks the androgen receptor. Testicular hormone production ex vivo was measured by liquid chromatography-tandem mass spectrometry or ELISA assays, and selected protein markers were assessed by immunohistochemistry. Results Ketoconazole reduced androgen production in testes from gestational weeks (GW) 7–21, which were subsequently divided into four age groups: GW 7–10, 10–12, 12–16 and 16–21. Additionally, reduced secretion of testicular hormones INSL3, AMH and Inhibin B was observed, but only in the age groups GW 7–10 and 10–12, while a decrease in the total density of germ cells and OCT4+ gonocytes was found in the GW 7–10 age group. Flutamide treatment in specimens aged GW 7–12 did not alter androgen production, but the secretion of INSL3, AMH and Inhibin B was reduced, and a reduced number of pre-spermatogonia was observed. Conclusions This study showed that reduced androgen action during early development affects the function and density of several cell types in the human fetal testis, with similar effects observed after ketoconazole and flutamide treatment. The effects were only observed within the GW 7–14 period—thereby indicating the presence of a window of androgen sensitivity in the human fetal testis.https://doi.org/10.1186/s12916-022-02602-yHuman fetal testisEx vivo cultureReduced androgen exposureAndrogen sensitivityMasculinization programming window |
| spellingShingle | Malene Lundgaard Riis Gabriele Matilionyte John E. Nielsen Cecilie Melau David Greenald Kristine Juul Hare Lea Langhoff Thuesen Eva Dreisler Kasper Aaboe Pia Tutein Brenøe Anna-Maria Andersson Jakob Albrethsen Hanne Frederiksen Ewa Rajpert-De Meyts Anders Juul Rod T. Mitchell Anne Jørgensen Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo BMC Medicine Human fetal testis Ex vivo culture Reduced androgen exposure Androgen sensitivity Masculinization programming window |
| title | Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| title_full | Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| title_fullStr | Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| title_full_unstemmed | Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| title_short | Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| title_sort | identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
| topic | Human fetal testis Ex vivo culture Reduced androgen exposure Androgen sensitivity Masculinization programming window |
| url | https://doi.org/10.1186/s12916-022-02602-y |
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