Before chemists and medical researchers precisely determined the organic constitution of estrogen, it was known that placental extracts caused considerable hormonal activity in female organs. The placenta, therefore, became the suspected source of the large output of estrogens during pregnancies. As soon as estrogenic responses could be accurately recognized and measured, the hormones themselves were obtained from placental tissue and the umbilical cord.

Dr. B. P. Wiesner of the Department of Animal Breeding, Edinburgh University, was the first to demonstrate that two hormones exist in the adenohypophysis: one stimulates the follicles of the ovary to produce estrin; the other stimulates the secretion of the luteal hormone. On a visit to Montreal’s McGill University in September 1929, he interested Dr. J. Bertram Collip, a renowned scientist at that institution, and other of his colleagues in his research. At his suggestion, Collip and his team decided to take up further study of placental hormones.
 

J.C. Collip, co-discoverer of insulin in 1922, was a Ph.D. biochemist from the University of Toronto in 1916 and Chair of the Department of Endocrinology at McGill University in 1929 when he and his medical research team were approached by W.J. McKenna of Ayerst, McKenna & Harrison to carry out studies on placental hormones. Their research led to the production in 1930 of Emmenin, the first orally active estrogen. This discovery was but the first of a series of research steps that eventually lead to the discovery of the estrogenic complex, Premarin, that Ayerst laboratories began marketing worldwide in 1941. [Photo, courtesy The Royal Society of Canada]

After reviewing the previous experiments and carrying on further studies to overcome the difficulties of extraction and purification, Dr. Collip and his colleagues proved definitively the existence of three separate and distinct hormones in human placenta. One of these was a water-soluble substance that, although different in many ways, was somewhat like estrin. “Emmenin,” the name given to this hormone, became the first orally active estrogen. The year was 1930.

The Canadian Medical Journal in 1930 contained three separate papers by Dr. Collip in which he and his associates, step by step, describe the final isolation of Emmenin in its pure form from human placentae. The report by Dr. Collip was the stepping-stone of Ayerst’s interest in the field of estrogen replacement therapy (ERT). Working in collaboration with the McGill investigators, Ayerst deliberately entered into this new field. Prepared and biologically standardized, according to Dr. Collip’s technique, Emmenin, the first orally active, water-soluble female sex hormone, became available for clinical use. With the approval of the Department Of Biochemistry at McGill, Ayerst began to market Emmenin.

Ayerst’s source of estrogen used in the manufacture of Emmenin was the urine of Canadian women who were in the last trimester of pregnancy. Problems, including cost, threatened the long-term survival of the product.

By 1938, researchers Schachter and Marrian had reported in the Journal of Biological Chemistry (126:663) that the steroids present in the urine of pregnant mares occur in conjugated form, chiefly as water-soluble esters, and that researchers had been able to isolate a small amount of estrone sulfate. Drs. Cook and Grant of Ayerst decided to investigate further the merits of this estrogenic complex as a possible source for a new, orally active product.

Experiments with this unique estrogenic complex proved encouraging. Processing the substance at a low temperature produced a very active and stable concentrate of mare’s urine. Ayerst’s scientists enthusiastically set to work on the important development of a brand-new pharmaceutical product from this source.
 

Ayerst, McKenna & Harrison Limited began its operations in 1925 at 22-24 Craig Street in Montreal. Following a severe fire, the business in 1928 moved to larger quarters on William Street. After another move to McGill Street, Ayerst relocated its operations to St. Laurent, a fast-growing community northwest of Montreal. The Ayerst business, by 1975, as viewed here, had grown significantly and was serving five continents from its busy St. Laurent complex. [Photo, courtesy Wyeth-Ayerst Canada Inc.]

On January 17, 1939, under carefully controlled conditions the first gallon of this water-soluble estrogenic complex was processed at the Ayerst Laboratories. The chemical team then undertook stability and chemical fractionation studies while the bioassay team worked on potency determinations. Intensive investigations finally revealed that a stable, active preparation of the water-soluble estrogenic conjugates could indeed be made and that the material showed high oral activity.

After two years of work, Premarin was ready to be marketed worldwide. The company had made its first major impact on the pharmaceutical industry.

The product was introduced to the Canadian market in 1941, with U.S. sales initiated the following year. By the end of the 1940s, Premarin had been clinically established as a major new therapeutic agent enabling patients worldwide to combat crippling menopausal estrogen-deficiency diseases.

In 1966, American Home Products Corporation which, in 1943, had acquired both the Canadian and American branches of Ayerst, McKenna & Harrison, opened Ayerst Organics Ltd. in Brandon, Manitoba. Since that time, the facility has produced the active component for Premarin, a component that is exported to over 80 countries around the world.

Staff