Fifty years of "the pill": risk reduction and discovery of benefits beyond contraception, reflections, and forecast.

Widely regarded as a revolutionary drug in its early years, "the pill" may be considered the first designer or lifestyle drug. Approximately 85% of women in the United States will use an oral contraceptive (OC) for an average of 5 years. Since the introduction of OCs in the 1960s, both health benefits and safety concerns have been attributed to their use. Widespread use of OC formulations by women throughout their reproductive life cycle gave rise to concerns about the effects of OCs on risk factors for cardiovascular disorders and cancer. In most instances, the noncontraceptive benefits of OCs outweigh the potential risks. As with many first in class drugs, lessons can be learned from its development and use. Indeed, "the pill" played a significant role in reshaping the regulatory process for new drugs during the second half of the 20th century. The birth control pill celebrates its 50th birthday this year, as women and men celebrate five decades of this revolutionary method of family planning. Recent scientific and technological advances in genomics, proteomics, new materials, and new drug delivery systems, along with a new understanding of reproductive biology, offer the promise of new, safe, and effective forms of contraception. In addition to the history of OC therapeutic advances and unintended side effects, the noncontraceptive health benefits that women experience beyond pregnancy prevention are discussed. This article summarizes a symposium presented at the 50th Anniversary of the Society of Toxicology National Meeting, held from 6 to 10 March 2011 in Washington, DC.

Developmental and reproductive toxicology studies in IL-12p40 knockout mice.

BACKGROUND: Interleukin (IL)-12 is a cytokine that can exert regulatory effects on T and NK cells. This study was designed to identify potential developmental and reproductive hazards associated with IL-12p40 knockout in mice. METHODS: In the combined fertility and teratology study, female F0 C57/BL6 wild-type control mice and female F0 C57/BL6 IL-12p40 homozgyous knockout mice were assessed for estrous cyclicity, sperm, and mating parameters. Pregnant females were euthanized on gestation day (GD) 18 and their fetuses were assessed for external, visceral, and skeletal development. In the peri and postnatal development study, the F1 wild-type control and IL-12p40 knockout mice were assessed for developmental landmarks, sexual development, passive avoidance, motor activity, and morris water maze. RESULTS: The IL-12p40 knockout male mice exhibited decreased testis weights when compared to the wild-type control group; however, this finding was not considered adverse, as it had no apparent functional effects on mating, fertility, and pregnancy rates or sperm motility. The IL-12p40 knockout group exhibited effects on estrous cycle length, passive avoidance, morris water maze, and motor activity when compared to the wild-type control group. However, since these findings were small in magnitude, transient and/or had no apparent effects on subsequent growth and development, they were not considered adverse. CONCLUSIONS: These results demonstrate that although IL-12p40 homozygous knockout in mice exhibited effects on developmental and reproductive parameters, these effects were relatively minor and were not considered adverse.