Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat
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Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. / Kristensen, David Møbjerg; Hass, Ulla; Lesné, Laurianne; Lottrup, Grete; Jacobsen, Pernille Rosenskjold; Desdoits-Lethimonier, Christele; Boberg, Julie; Petersen, Jørgen Holm; Toppari, Jorma; Jensen, Tina Kold; Brunak, Søren; Skakkebaek, Niels E; Nellemann, Christine; Main, Katharina M; Jégou, Bernard; Leffers, Henrik.
In: Human Reproduction, Vol. 26, No. 1, 2011, p. 235-44.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat
AU - Kristensen, David Møbjerg
AU - Hass, Ulla
AU - Lesné, Laurianne
AU - Lottrup, Grete
AU - Jacobsen, Pernille Rosenskjold
AU - Desdoits-Lethimonier, Christele
AU - Boberg, Julie
AU - Petersen, Jørgen Holm
AU - Toppari, Jorma
AU - Jensen, Tina Kold
AU - Brunak, Søren
AU - Skakkebaek, Niels E
AU - Nellemann, Christine
AU - Main, Katharina M
AU - Jégou, Bernard
AU - Leffers, Henrik
PY - 2011
Y1 - 2011
N2 - BACKGROUND More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. METHODS In a prospective birth cohort study, 2297 Danish and Finnish pregnant women completed a questionnaire and 491 of the Danish mothers participated in a telephone interview, reporting on their use of mild analgesics during pregnancy. The testicular position of newborns was assessed by trained paediatricians. In rats, the impact of mild analgesics on anogenital distance (AGD) after intrauterine exposure was examined together with the effect on ex vivo gestational day 14.5 testes. RESULTS In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort. Intrauterine exposure of rats to paracetamol led to a reduction in the AGD and mild analgesics accordingly reduced testosterone production in ex vivo fetal rat testes. CONCLUSION There was an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings were supported by anti-androgenic effects in rat models leading to impaired masculinization. Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders.
AB - BACKGROUND More than half of pregnant women in the Western world report intake of mild analgesics, and some of these drugs have been associated with anti-androgenic effects in animal experiments. Intrauterine exposure to anti-androgens is suspected to contribute to the recent increase in male reproductive problems, and many of the anti-androgenic compounds are like the mild analgesics potent inhibitors of prostaglandin synthesis. Therefore, it appears imperative to further investigate the potential endocrine disrupting properties of mild analgesics. METHODS In a prospective birth cohort study, 2297 Danish and Finnish pregnant women completed a questionnaire and 491 of the Danish mothers participated in a telephone interview, reporting on their use of mild analgesics during pregnancy. The testicular position of newborns was assessed by trained paediatricians. In rats, the impact of mild analgesics on anogenital distance (AGD) after intrauterine exposure was examined together with the effect on ex vivo gestational day 14.5 testes. RESULTS In the Danish birth cohort, the use of mild analgesics was dose-dependently associated with congenital cryptorchidism. In particular, use during the second trimester increased the risk. This risk was further increased after the simultaneous use of different analgesics. The association was not found in the Finnish birth cohort. Intrauterine exposure of rats to paracetamol led to a reduction in the AGD and mild analgesics accordingly reduced testosterone production in ex vivo fetal rat testes. CONCLUSION There was an association between the timing and the duration of mild analgesic use during pregnancy and the risk of cryptorchidism. These findings were supported by anti-androgenic effects in rat models leading to impaired masculinization. Our results suggest that intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders.
KW - Acetaminophen
KW - Analgesics
KW - Animals
KW - Aspirin
KW - Cohort Studies
KW - Cryptorchidism
KW - Female
KW - Humans
KW - Ibuprofen
KW - Infertility, Male
KW - Male
KW - Pregnancy
KW - Prenatal Exposure Delayed Effects
KW - Rats
KW - Risk Factors
U2 - 10.1093/humrep/deq323
DO - 10.1093/humrep/deq323
M3 - Journal article
C2 - 21059752
VL - 26
SP - 235
EP - 244
JO - Human Reproduction
JF - Human Reproduction
SN - 0268-1161
IS - 1
ER -
ID: 34138445