Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2022; 68(6): 3-11

Endocrine and behavioral effects in male rats after birth with their pregnant mother taking ibuprofen

A.G. Reznikov, O.V. Sachynska, A.A. Lymareva, O.A. Faliush, I.G. Perchyk

    SI V.P. Komisarenko Institute of Endocrinology and Metabolism, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine


Ibuprofen, a non-selective inhibitor of cyclooxygenase, is one of the most used non-steroidal anti- inflammatory drugs (NSAID) and pain relievers. Its effect on developing fetal neuroendocrine system when taken by a pregnant mother does not well established. The aim of this study was to evaluate the long-term consequences of the administration of ibuprofen to pregnant rats with regard to hormonal profile and sexual differentiation of the brain in male offspring. Pregnant rats were given ibuprofen per os in a dose of 30 mg/kg bw twice a day during days 15-21 of gestation. On the 2 and 10 postnatal days (PND), anogenital distance (AGD) was measured in male pups. In adulthood, sexual behavior, hormone levels, and hypothalamic-pituitary-adrenal axis (HPAA) response to acute immobilization stress were studied. Prenatal ibuprofen increased AGD on PND 2 and caused incomplete masculinization of copulative behavior in adult offspring. Significant increases in the latent periods of the first mount, the first intromission, and a decrease in the number of intromissions were observed. Basal blood plasma levels of testosterone, estradiol, and corticosterone, as well as HPAA response to immobilization stress, did not change. Orchidectomized and primed with estradiol and progesterone males did not exhibit lordosis response to the presence of a sexually experienced male. Conclusion: Administration of ibuprofen to female Wistar rats during the last week of gestation disrupts partially neuroendocrine programming of male-type copulative behavior in male offspring with no changes in female-type sexual behavior and HPAA function. It is hypothesized that incomplete masculinization of the developing fetal brain with ibuprofen is due to two co-operative mechanisms: inhibition of synthesis of testosterone in the fetal gonads and prostaglandin E2 in the preoptic area of the hypothalamus.

Keywords: ibuprofen; prenatal effect; sexual behavior; testosterone; estradiol; corticosterone; stress response; male rats.


  1. Reznikov AG. Hormone-neurotransmitter imprinting in the neuroendocrine control of reproduction. New York: Harwood Acad Publ; 1994.
  2. Reznikov AG. Perinatal programming of disorders of en- docrine functions and behavior. Kyiv: Naukova dumka; 2019. [Ukrainian].
  3. Reznikov AG. Developmental neuroendocrinology of re- production and adaptation: Lessons from animal research. Fiziol Zh. 2021;67(3):54-74. CrossRef
  4. Reznikov A, Sachynska O, Lymareva A, Faliush O. Developmental, behavioral and endocrine alterations in male rats at early and late postnatal life following in utero exposure to low dose di-n-butylphthalate. Toxicol Res. 2020;37(2):173-81. CrossRef PubMed PubMedCentral
  5. Kristensen DM, Mazaud-Guittot S, Gaudriault P, Lesné L, Serrano T, Main KM, Jégou B. Analgesic use - preva- lence, biomonitoring and endocrine and reproductive effects. Nat Rev Endocrinol. 2016;12(7):381-93. CrossRef PubMed
  6. Kristensen DM, Lesné L, Le Fol V, Desdoits-Lethimonier C, Dejucq-Rainsford N, Leffers H, Jégou B. Paracetamol (acetaminophen), aspirin (acetylsalicylic acid) and indo- methacin are anti-androgenic in the rat foetal testis. Int J Androl. 2012;35(3):377-84. CrossRef PubMed
  7. Ben Maamar M, Lesné L, Hennig K, Desdoits-Lethimonier C, Kilcoyne KR, Coiffec I, et al. Ibuprofen results in alterations of human fetal testis development. Sci Rep. 2017;7:44184. CrossRef PubMed PubMedCentral
  8. Nezvalová-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of pregnancy and pregnancy outcome: a prospec- tive cohort study. BJOG. 2013;120(8):948-59. CrossRef PubMed PubMedCentral
  9. Rifas-Shiman SL, Cardenas A, Hivert MF, Tiemeier H, Bertoldi AD, Oken E. Associations of prenatal or infant exposure to acetaminophen or ibuprofen with mid-child- hood executive function and behavior. Paediatr Perinat Epidemiol. 2020;34(3):287-98. CrossRef PubMed PubMedCentral
  10. Cook JC, Jacobson CF, Gao F, Tassinari MS, Hurtt ME, DeSesso JM. Analysis of the nonsteroidal anti-inflamma- tory drug literature for potential developmental toxicity in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2003;68(1):5-26. CrossRef PubMed
  11. Burdan F. Developmental toxicity evaluation of ibuprofen and tolmetin administered in triple daily doses to Wistar CRL:(WI)WUBR rats. Birth Defects Res B Dev Reprod Toxicol. 2004;71(5):321-30. CrossRef PubMed
  12. Burdan F, Szumilo J, Marzec B, Klepacz R, Dudka J. Skeletal developmental effects of selective and nonselective cyclooxygenase-2 inhibitors administered through organogenesis and fetogenesis in Wistar CRL:(WI) WUBR rats. Toxicology. 2005;216(2-3):204-23. CrossRef PubMed
  13. Burdan F, Starosławska E, Szumiło J, Dworzańska A, Dworzański W, Kubiatowski T, et al. Developmental toxicity of the over-the-counter analgetics and antypiret- ics. Pol Merkur Lekarski. 2012;32(192):410-3. [Polish].
  14. Burdan F, Starosławska E, Szumiło J. Prenatal toler- ability of acetaminophen and other over-the-counter non-selective cyclooxygenase inhibitors. Pharmacol Rep. 2012b;64(3):521-7. CrossRef PubMed
  15. Jensen MS, Rebordosa C, Thulstrup AM, Toft G, Sørensen HT, Bonde JP, Henriksen TB, Olsen J. Maternal use of acetaminophen, ibuprofen, and acetylsalicylic acid dur- ing pregnancy and risk of cryptorchidism. Epidemiology. 2010;21(6):779-85. CrossRef PubMed
  16. Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, et al. Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat. Hum Reprod. 2011;26(1):235-44. CrossRef PubMed
  17. Brandlistuen RE, Ystrom E, Nulman I, Koren G, Nordeng H. Prenatal paracetamol exposure and child neurodevel- opment: a sibling-controlled cohort study. Int J Epide- miol. 2013;42(6):1702-13. CrossRef PubMed PubMedCentral
  18. Kilcoyne KR, Mitchell RT. Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development. Arch Dis Child. 2017;102(12):1169-75. CrossRef PubMed
  19. Gurney J, Richiardi L, McGlynn KA, Signal V, Sarfati D. Analgesia use during pregnancy and risk of cryptor- chidism: a systematic review and meta-analysis. Hum Reprod. 2017;32(5):1118-29. CrossRef PubMed PubMedCentral
  20. Hurtado-Gonzalez P, Anderson RA, Macdonald J, van den Driesche S, Kilcoyne K, Jørgensen A, et al. Effects of exposure to acetaminophen and ibuprofen on fetal germ cell development in both sexes in rodent and human using multiple experimental systems. Environ Health Perspect. 2018;126(4):047006. CrossRef PubMed PubMedCentral
  21. Rossitto M, Marchive C, Pruvost A, Sellem E, Ghettas A, Badiou S, et al. Intergenerational effects on mouse sperm quality after in utero exposure to acetaminophen and ibuprofen. FASEB J. 2019;33(1):339-57. CrossRef PubMed
  22. Balin PDS, Jorge BC, Leite ARR, Borges CS, Oba E, Silva EJR, et al. Maternal exposure to ibuprofen can affect the programming of the hypothalamus of the male offspring. Regul Toxicol Pharmacol. 2020 Mar;111:104576. CrossRef PubMed
  23. VanRyzin JW, Yu SJ, Perez-Pouchoulen M, McCarthy MM. Temporary depletion of microglia during the early postnatal period induces lasting sex-dependent and sex-independent effects on behavior in rats. eNeuro. 2016;3(6): ENEURO.0297-16.2016. CrossRef PubMed PubMedCentral
  24. Lenz KM, Pickett LA, Wright CL, Davis KT, Joshi A, Mc- Carthy MM. Mast cells in the developing brain determine adult sexual behavior. J Neurosci. 2018;38(37):8044-59. CrossRef PubMed PubMedCentral
  25. Holson RR, Gough B, Sullivan P, Badger T, Sheehan DM. Prenatal dexamethasone or stress but not ACTH or corti- costerone alter sexual behavior in male rats. Neurotoxicol Teratol. 1995;17:393-401. CrossRef PubMed
  26. Hull EM, Dominguez JM. Sexual behavior in male ro- dents. Horm Behav. 2007;52:45-55. CrossRef PubMed PubMedCentral
  27. Balashov YuG. Fluorimetric micromethod for corticoste- roid assay: comparison with other methods. Fiziol Zh SSSR im Sechenova 1990;76:280-3. [Russian].
  28. Sanotsky IV, Fomenko VN, Salnikova LS, Chirkova EM, Pashkova GA, Strekalova EE, Katosova LD. Methods of experimental research to eliminate the thresholds of the action of industrial poisons on the generative function for the purpose of hygienic regulation. Methodical recommendations. Moscow, 1978. [Russian].
  29. Kropotov AV, Lisakovskaia OV, Khotimchenko IuS. Seasonal features of the effect of adaptogens on sex behavior of experimental animals. Eksp Klin Farmakol. 2001;64:60-2. [Russian].
  30. Kristensen DM, Desdoits-Lethimonier C, Mackey AL, Dalgaard MD, De Masi F, Munkbøl CH, et al. Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism. Proc Natl Acad Sci USA. 2018;115(4):E715-24. CrossRef PubMed PubMedCentral
  31. Amateau SK, McCarthy MM. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci. 2004;7(6):643-50. CrossRef PubMed

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.