Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
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 reproduct...
Ausführliche Beschreibung
Autor*in: |
Lundgaard Riis, Malene [verfasserIn] |
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E-Artikel |
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Englisch |
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2022 |
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Anmerkung: |
© The Author(s) 2022 |
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Übergeordnetes Werk: |
Enthalten in: BMC medicine - London : BioMed Central, 2003, 20(2022), 1 vom: 20. Okt. |
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Übergeordnetes Werk: |
volume:20 ; year:2022 ; number:1 ; day:20 ; month:10 |
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DOI / URN: |
10.1186/s12916-022-02602-y |
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Katalog-ID: |
SPR051076829 |
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100 | 1 | |a Lundgaard Riis, Malene |e verfasserin |4 aut | |
245 | 1 | 0 | |a Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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520 | |a 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. | ||
650 | 4 | |a Human fetal testis |7 (dpeaa)DE-He213 | |
650 | 4 | |a Ex vivo culture |7 (dpeaa)DE-He213 | |
650 | 4 | |a Reduced androgen exposure |7 (dpeaa)DE-He213 | |
650 | 4 | |a Androgen sensitivity |7 (dpeaa)DE-He213 | |
650 | 4 | |a Masculinization programming window |7 (dpeaa)DE-He213 | |
700 | 1 | |a Matilionyte, Gabriele |4 aut | |
700 | 1 | |a Nielsen, John E. |4 aut | |
700 | 1 | |a Melau, Cecilie |4 aut | |
700 | 1 | |a Greenald, David |4 aut | |
700 | 1 | |a Juul Hare, Kristine |4 aut | |
700 | 1 | |a Langhoff Thuesen, Lea |4 aut | |
700 | 1 | |a Dreisler, Eva |4 aut | |
700 | 1 | |a Aaboe, Kasper |4 aut | |
700 | 1 | |a Brenøe, Pia Tutein |4 aut | |
700 | 1 | |a Andersson, Anna-Maria |4 aut | |
700 | 1 | |a Albrethsen, Jakob |4 aut | |
700 | 1 | |a Frederiksen, Hanne |4 aut | |
700 | 1 | |a Rajpert-De Meyts, Ewa |4 aut | |
700 | 1 | |a Juul, Anders |4 aut | |
700 | 1 | |a Mitchell, Rod T. |4 aut | |
700 | 1 | |a Jørgensen, Anne |4 aut | |
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10.1186/s12916-022-02602-y doi (DE-627)SPR051076829 (SPR)s12916-022-02602-y-e DE-627 ger DE-627 rakwb eng Lundgaard Riis, Malene verfasserin aut Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 Matilionyte, Gabriele aut Nielsen, John E. aut Melau, Cecilie aut Greenald, David aut Juul Hare, Kristine aut Langhoff Thuesen, Lea aut Dreisler, Eva aut Aaboe, Kasper aut Brenøe, Pia Tutein aut Andersson, Anna-Maria aut Albrethsen, Jakob aut Frederiksen, Hanne aut Rajpert-De Meyts, Ewa aut Juul, Anders aut Mitchell, Rod T. aut Jørgensen, Anne aut Enthalten in BMC medicine London : BioMed Central, 2003 20(2022), 1 vom: 20. Okt. (DE-627)377271225 (DE-600)2131669-7 1741-7015 nnns volume:20 year:2022 number:1 day:20 month:10 https://dx.doi.org/10.1186/s12916-022-02602-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 20 10 |
spelling |
10.1186/s12916-022-02602-y doi (DE-627)SPR051076829 (SPR)s12916-022-02602-y-e DE-627 ger DE-627 rakwb eng Lundgaard Riis, Malene verfasserin aut Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 Matilionyte, Gabriele aut Nielsen, John E. aut Melau, Cecilie aut Greenald, David aut Juul Hare, Kristine aut Langhoff Thuesen, Lea aut Dreisler, Eva aut Aaboe, Kasper aut Brenøe, Pia Tutein aut Andersson, Anna-Maria aut Albrethsen, Jakob aut Frederiksen, Hanne aut Rajpert-De Meyts, Ewa aut Juul, Anders aut Mitchell, Rod T. aut Jørgensen, Anne aut Enthalten in BMC medicine London : BioMed Central, 2003 20(2022), 1 vom: 20. Okt. (DE-627)377271225 (DE-600)2131669-7 1741-7015 nnns volume:20 year:2022 number:1 day:20 month:10 https://dx.doi.org/10.1186/s12916-022-02602-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 20 10 |
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10.1186/s12916-022-02602-y doi (DE-627)SPR051076829 (SPR)s12916-022-02602-y-e DE-627 ger DE-627 rakwb eng Lundgaard Riis, Malene verfasserin aut Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 Matilionyte, Gabriele aut Nielsen, John E. aut Melau, Cecilie aut Greenald, David aut Juul Hare, Kristine aut Langhoff Thuesen, Lea aut Dreisler, Eva aut Aaboe, Kasper aut Brenøe, Pia Tutein aut Andersson, Anna-Maria aut Albrethsen, Jakob aut Frederiksen, Hanne aut Rajpert-De Meyts, Ewa aut Juul, Anders aut Mitchell, Rod T. aut Jørgensen, Anne aut Enthalten in BMC medicine London : BioMed Central, 2003 20(2022), 1 vom: 20. Okt. (DE-627)377271225 (DE-600)2131669-7 1741-7015 nnns volume:20 year:2022 number:1 day:20 month:10 https://dx.doi.org/10.1186/s12916-022-02602-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 20 10 |
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10.1186/s12916-022-02602-y doi (DE-627)SPR051076829 (SPR)s12916-022-02602-y-e DE-627 ger DE-627 rakwb eng Lundgaard Riis, Malene verfasserin aut Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 Matilionyte, Gabriele aut Nielsen, John E. aut Melau, Cecilie aut Greenald, David aut Juul Hare, Kristine aut Langhoff Thuesen, Lea aut Dreisler, Eva aut Aaboe, Kasper aut Brenøe, Pia Tutein aut Andersson, Anna-Maria aut Albrethsen, Jakob aut Frederiksen, Hanne aut Rajpert-De Meyts, Ewa aut Juul, Anders aut Mitchell, Rod T. aut Jørgensen, Anne aut Enthalten in BMC medicine London : BioMed Central, 2003 20(2022), 1 vom: 20. Okt. (DE-627)377271225 (DE-600)2131669-7 1741-7015 nnns volume:20 year:2022 number:1 day:20 month:10 https://dx.doi.org/10.1186/s12916-022-02602-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 20 10 |
allfieldsSound |
10.1186/s12916-022-02602-y doi (DE-627)SPR051076829 (SPR)s12916-022-02602-y-e DE-627 ger DE-627 rakwb eng Lundgaard Riis, Malene verfasserin aut Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2022 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. Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 Matilionyte, Gabriele aut Nielsen, John E. aut Melau, Cecilie aut Greenald, David aut Juul Hare, Kristine aut Langhoff Thuesen, Lea aut Dreisler, Eva aut Aaboe, Kasper aut Brenøe, Pia Tutein aut Andersson, Anna-Maria aut Albrethsen, Jakob aut Frederiksen, Hanne aut Rajpert-De Meyts, Ewa aut Juul, Anders aut Mitchell, Rod T. aut Jørgensen, Anne aut Enthalten in BMC medicine London : BioMed Central, 2003 20(2022), 1 vom: 20. Okt. (DE-627)377271225 (DE-600)2131669-7 1741-7015 nnns volume:20 year:2022 number:1 day:20 month:10 https://dx.doi.org/10.1186/s12916-022-02602-y kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2031 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2061 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2190 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 20 2022 1 20 10 |
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Enthalten in BMC medicine 20(2022), 1 vom: 20. Okt. volume:20 year:2022 number:1 day:20 month:10 |
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Enthalten in BMC medicine 20(2022), 1 vom: 20. Okt. volume:20 year:2022 number:1 day:20 month:10 |
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Human fetal testis Ex vivo culture Reduced androgen exposure Androgen sensitivity Masculinization programming window |
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Lundgaard Riis, Malene @@aut@@ Matilionyte, Gabriele @@aut@@ Nielsen, John E. @@aut@@ Melau, Cecilie @@aut@@ Greenald, David @@aut@@ Juul Hare, Kristine @@aut@@ Langhoff Thuesen, Lea @@aut@@ Dreisler, Eva @@aut@@ Aaboe, Kasper @@aut@@ Brenøe, Pia Tutein @@aut@@ Andersson, Anna-Maria @@aut@@ Albrethsen, Jakob @@aut@@ Frederiksen, Hanne @@aut@@ Rajpert-De Meyts, Ewa @@aut@@ Juul, Anders @@aut@@ Mitchell, Rod T. @@aut@@ Jørgensen, Anne @@aut@@ |
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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. 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Lundgaard Riis, Malene |
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Lundgaard Riis, Malene misc Human fetal testis misc Ex vivo culture misc Reduced androgen exposure misc Androgen sensitivity misc Masculinization programming window Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo Human fetal testis (dpeaa)DE-He213 Ex vivo culture (dpeaa)DE-He213 Reduced androgen exposure (dpeaa)DE-He213 Androgen sensitivity (dpeaa)DE-He213 Masculinization programming window (dpeaa)DE-He213 |
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Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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Lundgaard Riis, Malene Matilionyte, Gabriele Nielsen, John E. Melau, Cecilie Greenald, David Juul Hare, Kristine Langhoff Thuesen, Lea Dreisler, Eva Aaboe, Kasper Brenøe, Pia Tutein Andersson, Anna-Maria Albrethsen, Jakob Frederiksen, Hanne Rajpert-De Meyts, Ewa Juul, Anders Mitchell, Rod T. Jørgensen, Anne |
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identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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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 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. © The Author(s) 2022 |
abstractGer |
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. © The Author(s) 2022 |
abstract_unstemmed |
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. © The Author(s) 2022 |
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Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo |
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Matilionyte, Gabriele Nielsen, John E. Melau, Cecilie Greenald, David Juul Hare, Kristine Langhoff Thuesen, Lea Dreisler, Eva Aaboe, Kasper Brenøe, Pia Tutein Andersson, Anna-Maria Albrethsen, Jakob Frederiksen, Hanne Rajpert-De Meyts, Ewa Juul, Anders Mitchell, Rod T. Jørgensen, Anne |
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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. 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score |
7.3998165 |