Exposure of explants of human fetal ovaries to ibuprofen for short periods is associated with a sharp decrease in the number of germ cells, according to a report published in Human Reproduction. If the results reflect what happens in utero, then women who take ibuprofen early in pregnancy could have daughters with an insufficient ovarian reserve and subfertility.
More than a quarter of pregnant women take ibuprofen, making the drug the second most commonly used over-the-counter pain reliever after acetaminophen. Pregnant women are advised to avoid the drug after 24 weeks because of associated renal and cardiopulmonary malformations, but recommendations are less clear for early pregnancy.
“In the human fetal ovary, our ex vivo data reveal that ibuprofen massively impacts the viability of the germ cell lineage,” Sabrina Leverrier-Penna, PhD, from the Institute of Research in Health, Environment and Work in Rennes, France, and colleagues write in the new report.
“We found fewer cells growing and dividing, more cells dying, and a dramatic loss of germ cell numbers, regardless of the gestational age of the fetus,” said senior author Séverine Mazaud-Guittot, PhD, in a news release. Cell death became apparent as early as 2 days after initial exposure, and appeared to have lasting effects. “Five days after withdrawing ibuprofen, these harmful effects of ibuprofen were not fully reversed,” she added.
The findings raise “concern about ibuprofen consumption by pregnant women during the fetal ovarian organogenesis period and a subsequent risk for the establishment of the follicular reserve,” the researchers write.
They add that exposure to ibuprofen seems to affect both proliferation and viability of ovarian cells. “Further experiments will be required to investigate the fine molecular mechanism of action of ibuprofen on the human fetal ovary,” they note.
Explant Exposures
During the first trimester, a complex interplay of germ cell mitosis, differentiation, and apoptosis (also known as programmed cell death) sculpts the follicles of the maturing ovary, peaking with 6 to 7 million oocytes present between gestational weeks 16 and 20, and then shrinking to 1 to 2 million oocytes by the time of birth. A diminished ovarian reserve at birth may set the stage for subfertility in adulthood.
Ibuprofen could interfere with the developmental dynamics of the ovary through prostaglandin metabolism. Specifically, the drug blocks cyclooxygenase 1, reducing prostaglandin E2 synthesis, and thus reducing expression of genes that promote oocyte survival. In other words, the painkiller might shift the balance so that apoptosis destroys too many oocytes. The same research group showed last year that ibuprofen also disrupts human fetal testis development.
For the current study, the investigators cultured 185 fetal ovaries from healthy pregnancies legally terminated at 7 to 12 developmental weeks and cut each organ into two or three 1 mm3 pieces.
Explants from fetuses younger than 10 weeks were divided; one piece was exposed to ibuprofen and the other to dimethyl sulfoxide (an inert control). Explants of older fetuses were divided into four pieces, with one serving as a control and the other three pieces being exposed to increasing doses of ibuprofen (10 and 100 μM) for 2, 4, or 7 days. The therapeutic plasma range of the drug is 10 to 200 μM. The authors confirmed that ibuprofen crosses the placenta and measured drug levels in umbilical cord blood.
Effects on the explants were dramatic: greatly reduced numbers of germ cells, fewer dividing cells, and increased apoptosis, for all gestational ages investigated. Even at the lowest concentration of ibuprofen, apoptosis spiked after just 2 days of exposure to the drug. Apoptosis did not increase in the control explants.
Prostaglandin E2 levels plummeted by 66.3% after 1 day of exposure to ibuprofen at 10 μM for explants cultured from fetuses at 7 to 12 weeks (P = .0062).
In the explants exposed to the inert control, germ cell number increased per ovary from 2.6 × 105 at 7 weeks to 1.3 × 106 at 12 weeks. In ovaries exposed to 10 μM ibuprofen for 7 days, the total ovarian cell count fell by about 50%. Meanwhile, at the same drug dose, the investigators noted “a marked accumulation of dead cells” increasing by 85% at 7 weeks and by 170% at 8 to 12 weeks, an effect that was intensified in the oldest explants. All tested ibuprofen doses depleted the germ cell population by at least 30%.
Quantitative polymerase chain reaction detected increased activity of genes promoting apoptosis and inhibiting cell division.
The investigators used flow cytometry and immunohistochemistry to count germ cells and classify them as mitotic or apoptotic. Enzyme-linked immunosorbent assay measured prostaglandins, and quantitative polymerase chain reaction tracked expression of genes that indicate cell death, differentiation, and division.
Limitations of the study include the ex vivo setting and the short duration of drug exposure. “Further research at the population level is required to determine whether ibuprofen exposure during pregnancy will affect the fertility or the reproductive functioning of the daughters,” Dr Mazaud-Guittot concluded.
The researchers have disclosed no relevant financial relationships.
Human Repro. Published online February 2, 2018.
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