Of Leaves and Butterflies

Abstract

A little more than half a century ago, young women were frequently dying of reproductive sequelae such as ectopic pregnancies and gestational trophoblastic disease. Mortality from these conditions was as high as 90% in the case of metastatic choriocarcinoma. If lives could be saved, it was in the operating theater and often at the expense of future reproductive potential. By the 1940s, however, targeted chemotherapy was starting to be explored, and the development of methotrexate for the treatment of childhood leukemia in 1949 eventually resulted in an unexpected, but nevertheless long and happy association with the field of gynecology. Here we trace the origins of methotrexate and how it came to be an effective medical treatment for two life-threatening gynecologic conditions. It illustrates how the contributions of many clinicians and scientists from many disciplines, over the greater part of a century, come together to improve the care of a single patient today.

The Evolution of Methotrexate as a Treatment for Ectopic Pregnancy and Gestational Trophoblastic Neoplasia: A Review

“…Methotrexate induced remission of ALL in children but did not cure the disease [6]. Its application to the treatment of a woman with terminal choriocarcinoma in 1956 produced the first cure of a solid tumour by chemotherapy [6], and its use in the treatment of GTN and ectopic pregnancy expanded from there [8]. …”

“…It has been found to have an immunomodulatory effect in autoimmune conditions such as rheumatoid arthritis, although its mechanism of action here remains unknown, and psoriasis, where it is thought to impede the rapid turnover of skin cells characteristic of the condition [1, 11], and is used occasionally in Crohn's disease, multiple sclerosis, and psoriatic arthritis [11]. It is also used in the treatment of ectopic pregnancies by extension of its use in GTN [8, 11]. …”

“…By its mechanism of action methotrexate preferentially targets rapidly dividing cells; therefore, the hematological, gastrointestinal, and dermatological systems which feature a high turnover of cells are the most likely to display signs and symptoms of toxicity such as neutropenia and generalized myelosuppression, nausea, vomiting, diarrhoea, and gastrointestinal inflammation as well as generalized erythema, rash, photosensitivity, and alopecia [11]. These side effects have been greatly ameliorated in the field of gynaecology by the development of a low, single-dose protocol in the treatment of ectopic pregnancies [12], and to some extent with the use of folinic acid (a form of tetrahydrofolate) rescue in GTN chemotherapy protocols [8, 11, 13]. …”

“…Extirpative surgery remained the only effective medical intervention for ectopic pregnancy until medical management was (re-)introduced in the 1980s [8]. Methotrexate was first used in diagnosed ectopic pregnancies in the 1960s to aide safe surgical removal of the placenta from its abdominal implantation sites in second- and third-trimester cases [50].…”

“…At this time, however, the gold standard of diagnosis of ectopic pregnancy was by direct visualization at surgery, as ultrasound was still too crude an instrument to rely upon in this potentially life-threatening situation [52]. Surgery as part of the diagnostic logarithm of ectopic pregnancy heavily negated the benefits of then proceeding to medical management, both in terms of cost effectiveness and acceptability to patients [8, 46]. …”