In 1951 he joined Searle as a senior research chemist. In 1952 Colton synthesized the progestin noretynodrel (anisomerofnorethisterone), which combined with the estrogenmestranol as Enovid was approved by the U.S. Food and Drug Administration (FDA) in 1956 for menstrual disorders and in 1960 as the first oral contraceptive. In 1953 he synthesized norethandrolone, which as Nilevar was approved in 1956 as the first oral anabolic steroid. In 1954 Colton and Paul D. Klimstra synthesized the progestin etynodiol diacetate, which combined with the estrogen mestranol as Ovulen was approved in 1965 as Searle's second oral contraceptive, and combined with the estrogen ethinylestradiol was approved in 1970 as Demulen. Colton retired from Searle in 1986 as research adviser. In 1988 he was inducted into the National Inventors Hall of Fame.