The first American attempt to treat menopausal symptoms is attributed to E. L. Severinghaus and J. Evans, who administer a derivative from the amniotic fluid of cattle (1).

Bernhard Zondek in Germany discovers that the urine of horses contains water-soluble estrogens. Guy Marrian in London finds a water-soluble estrogen in pregnancy urine, which is different from estrone. He finds that by letting the urine decompose, its estrogenic activity increases. This compound is later identified as estriol glucuronide, the activity of which increases after hydrolysis to form estradiol.

estradiol

James B. Collip of McGill University obtains Emmenin® from the urine of pregnant women. Emmenin, consisting of water-soluble estrogens, is the first replacement product to contain conjugated estrogens (7) and is marketed in the U.S. in 1933. Emmenin, containing estriol glucuronide, exhibits one-third of the estrogenic activity of the subcutaneous route when given orally.

1934
Guy Marrian and Desmond Beale at the University of Toronto publish a method for the large-scale production of estrone from pregnant mares' urine (PMU) (8).

1937
Establishing the physiologic basis for hormone contraception, Makepeace, Wienstein and Friedman, at the University of Pennsylvania, prevent ovulation in a rabbit with progesterone (9). The search begins for an orally active progestin with a long duration of action and high potency. Progesterone, inactive at this time when taken orally, provides the basic structure for modification to create highly potent oral progestins.

1939
Because of difficulties in production, Emmenin cannot be made quickly enough to keep up with consumer demand. A more practical source for potent estrogens is needed. Ayerst discovers that PMU contains large quantities of orally active, water-soluble estrogen conjugates.