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 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. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Lundgaard Riis, Malene [verfasserIn] 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

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2022

Schlagwörter:	Human fetal testis Ex vivo culture Reduced androgen exposure Androgen sensitivity Masculinization programming window

Anmerkung:	© The Author(s) 2022

Übergeordnetes Werk:	Enthalten in: BMC medicine - London : BioMed Central, 2003, 20(2022), 1 vom: 20. Okt.
Übergeordnetes Werk:	volume:20 ; year:2022 ; number:1 ; day:20 ; month:10

Links:	Volltext

DOI / URN:	10.1186/s12916-022-02602-y

Katalog-ID:	SPR051076829

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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.
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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
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700	1		\|a Brenøe, Pia Tutein \|4 aut
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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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allfields	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
allfields_unstemmed	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
allfieldsGer	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
language	English
source	Enthalten in BMC medicine 20(2022), 1 vom: 20. Okt. volume:20 year:2022 number:1 day:20 month:10
sourceStr	Enthalten in BMC medicine 20(2022), 1 vom: 20. Okt. volume:20 year:2022 number:1 day:20 month:10
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Human fetal testis Ex vivo culture Reduced androgen exposure Androgen sensitivity Masculinization programming window
isfreeaccess_bool	true
container_title	BMC medicine
authorswithroles_txt_mv	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@@
publishDateDaySort_date	2022-10-20T00:00:00Z
hierarchy_top_id	377271225
id	SPR051076829
language_de	englisch
fullrecord	<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR051076829</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230509114249.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">230508s2022 xx \|\|\|\|\|o 00\| \|\|eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1186/s12916-022-02602-y</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR051076829</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)s12916-022-02602-y-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Lundgaard Riis, Malene</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2022</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2022</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="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. 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author	Lundgaard Riis, Malene
spellingShingle	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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topic_title	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
topic	misc Human fetal testis misc Ex vivo culture misc Reduced androgen exposure misc Androgen sensitivity misc Masculinization programming window
topic_unstemmed	misc Human fetal testis misc Ex vivo culture misc Reduced androgen exposure misc Androgen sensitivity misc Masculinization programming window
topic_browse	misc Human fetal testis misc Ex vivo culture misc Reduced androgen exposure misc Androgen sensitivity misc Masculinization programming window
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title	Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
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title_full	Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
author_sort	Lundgaard Riis, Malene
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author_browse	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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author-letter	Lundgaard Riis, Malene
doi_str_mv	10.1186/s12916-022-02602-y
title_sort	identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
title_auth	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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title_short	Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo
url	https://dx.doi.org/10.1186/s12916-022-02602-y
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author2	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
author2Str	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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up_date	2024-07-03T19:37:52.398Z
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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. 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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Identification of a window of androgen sensitivity for somatic cell function in human fetal testis cultured ex vivo

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