Celebrating 75 years of oestradiol

Abstract

Oestrogens exert important effects on the reproductive as well as many other organ systems in both men and women. The history of the discovery of oestrogens, the mechanisms of their synthesis, and their therapeutic applications are very important components of the fabric of endocrinology. These aspects provide the rationale for highlighting several key components of this story. Two investigators, Edward Doisy and Alfred Butenandt, purified and crystalized oestrone nearly simultaneously in 1929, and Doisy later discovered oestriol and oestradiol. Butenandt won the Nobel Prize for this work and Doisy's had to await his purification of vitamin K. Early investigators quickly recognized that oestrogens must be synthesized from androgens and later investigators called this process aromatization. The aromatase enzyme was then characterized, its mechanism determined, and its structure identified after successful crystallization. With the development of knock-out methodology, the precise effects of oestrogen in males and females were defined and clinical syndromes of deficiency and excess described. Their discovery ultimately led to the development of oral contraceptives, treatment of menopausal symptoms, therapies for breast cancer, and induction of fertility, among others. The history of the use of oestrogens for postmenopausal women to relieve symptoms has been characterized by cyclic periods of enthusiasm and concern. The individuals involved in these studies, the innovative thinking required, and the detailed understanding made possible by evolving biologic and molecular techniques provide many lessons for current endocrinologists. Discovery of oestrogenThe concept that substances secreted by one organ could then be transported internally to another via the blood stream is the underpinning of the field of endocrinology. The 'father of physiology', Claude Bernard, articulated the concept of internal secretion by describing how the liver produces glucose, which then travels to and is utilized by other tissues in the body. This concept underlies studies on the ovaries, which became a focus of investigation later in the century. In 1896, Emil Knauer, a 29-year-old Austrian, excised the ovaries of adult rabbits and then re-implanted pieces into different locations in the same animals (Watkins 2007 Doisy then enlisted a nurse in the obstetrics clinic to supply each pregnant patient with a 1 gal jug and ask for her urine. This provided the needed material but was fraught with difficulties. Suspected to be a bootlegger because of the large jugs of yellow material in his car, one of Doisy's drivers was nearly arrested until he suggested using the sniff test with the response 'My god, it is urine'. Doisy, then being recruited to St Louis University, continued his efforts to purify the active substance. Each extract was tested with a bioassay and its effect on uterine stimulation. Urine, the material of choice for study, was initially extracted with a very large countercurrent apparatus (Fig. 1). Costing the exorbitan...

On gonads and gadflies: the estrus angle

“…In the event, estrone and estriol proved to be weak metabolites of 17β-estradiol (estradiol), which is the major estrogen secreted by the ovary (Simpson & Santen 2015). Estradiol itself was purified (from porcine ovarian follicular fluid) five years later (MacCorquodale et al 1936).…”

1062 Increasing estrus expression in lactating dairy cows

“…Edgar Allen extracted fluids from sow's ovaries and injected it into immature rats and mice and observed the effect the fluid had on the uterus (Simpson and Santen, 2015). Doisy developed a multi-step purification process for refining estrone.…”

“…Alfred Butenandt, who purified estrone at the same time as Doisy, is credited with the purification of estrone. Doisy and colleagues later isolated a compound they called dihydrotheelin, which was later termed estradiol in 1940 (Simpson and Santen, 2015). In 1943, Edgar Allen and Edward Doisy postulated that the ovaries secrete a hormone (Simpson and Santen, 2015).…”

Precision medicine in cancer: beyond wishful thinking?

“…In solid tumors, tamoxifen therapy can be considered as the first real example of personalized therapy [3]. Tamoxifen is given to patients with a positive estrogen receptor.…”