Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat.
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.


CONCLUSIONS
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.
Department of Growth and Reproduction, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark.
David Møbjerg
DM
Kristensen
Ulla
U
Hass
Laurianne
L
Lesné
Grete
G
Lottrup
Pernille Rosenskjold
PR
Jacobsen
Christele
C
Desdoits-Lethimonier
Julie
J
Boberg
Jørgen Holm
JH
Petersen
Jorma
J
Toppari
Tina Kold
TK
Jensen
Søren
S
Brunak
Niels E
NE
Skakkebaek
Christine
C
Nellemann
Katharina M
KM
Main
Bernard
B
Jégou
Henrik
H
Leffers
D000082:Acetaminophen / Q000009:adverse effects / Q000633:toxicity; D000700:Analgesics / Q000009:adverse effects* / Q000633:toxicity; D000818:Animals; D001241:Aspirin / Q000009:adverse effects / Q000633:toxicity; D015331:Cohort Studies; D003456:Cryptorchidism / Q000139:chemically induced*; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000009:adverse effects / Q000633:toxicity; D007248:Infertility, Male / Q000139:chemically induced*; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012307:Risk Factors
D000700:Analgesics; D000082:Acetaminophen; D001241:Aspirin; D007052:Ibuprofen