In the beginning …

Irving Freiler Stein was born in 1887 in Chicago, the seventh of 10 children to Adolf Stein and Emma Freiler Stein. His father, born in Bohemia, Austria, and like his father-in-law, owned a brewery and a tavern. His mother had been born in New York, although of immigrant parents. Stein’s grandparents had all immigrated to the United States in the mid- to late 1800s from the Czech Republic, with the exception of his maternal grandmother, who was born in Darmstadt, Germany.

Stein attended the University of Michigan and then Rush Medical College, graduating in 1912 ( Figure 1 A). We should recall that this was a tumultuous and changing period of time for medical education in the United States. Chicago was awash with proprietary medical schools, some no more than diploma mills, such that the 1910 Abraham Flexner report on medical education in the United States labeled Chicago, in terms of the quality of its medical schools, “the plague spot of the country.”

Dr Irving F. Stein

Dr Irving F. Stein as he appeared in his medical school graduation photo of 1912 ( A ), with first wife c. 1920 ( B ), circa 1940 ( C ), circa 1955 ( D ), and in 1975, with George D. Wilbanks, MD, at the 40th anniversary celebration of the Stein and Leventhal report ( E ).

Figure 1 , A and D, reprinted with permission of the Rush University Medical Center Archives; Figure 1 B reprinted, with permission, from Gardner ; and Figure 1 C reprinted with permission from Gordon.

Azziz. Stein and Leventhal 80 years later. Am J Obstet Gynecol 2016 .

To its fortune, Rush Medical College had an affiliation with the University of Chicago, which had begun in 1898 and lasted until 1942, when the University of Chicago established its own medical school. Flexner himself noted that “… efficient and intelligent administration of the law would thus reduce in short order the medical schools of Chicago to three, Rush, Northwestern, and the College of Physicians and Surgeons. In the matter of entrance requirements, Rush alone is secure.”

Thereafter, Dr Stein served a 2 year internship at the Michael Reese Hospital after which he served 1 year as an Assistant in Surgery to Drs Carl Beck and D. K. Eisendrath, 2 well-known and well-published surgeons. In 1915 he was appointed associate in obstetrics on the staff of the Michael Reese Hospital, an affiliation that was to continue until his death. He also served as clinical staff at Highland Park Hospital and as faculty at the Northwestern University School of Medicine in the Department of Obstetrics and Gynecology, becoming an Emeritus Associate Professor in 1953.

Shortly after graduating medical school, Dr Stein married Lucile Oberfelder ( Figure 1 B), with whom he had 2 children, Eleanor Stein Rusnak and Irving F. Stein Jr, the latter a physician and long-term faculty member of the Department of Surgery at Northwestern University School of Medicine. Following Lucile’s death in 1940 at the young age of 51 years, Dr Stein did not rewed until 1954, when he married Rosalind Ruth Weinberger Steif, a widow herself, to whom he remained married until his death at age 89 years in 1976.

Professionally, Dr Stein was a well-recognized figure around Michael Reese Hospital ( Figure 1 , C-E) as he rounded on his patients with his retinue of students and junior staff, elegantly dressed, boutonniere in place. He was a warm and caring physician and an excellent teacher. Like most teaching physicians of his day, he also maintained an active private practice.

His younger collaborator, Michael Leo Leventhal (born in 1901) attended the University of Chicago and subsequently graduated from Rush Medical College in 1924 ( Figure 2 A). Dr Leventhal met Stein while completing his internship at Michael Reese Hospital, whose staff he joined the following year (in 1925). Drs Stein and Leventhal together began to perform clinical research mostly related to the topic of sterility, a focus on scientific inquiry that was an important basis for their subsequent studies on the ovaries of amenorrheic women.

Dr. Michael L. Leventhal

Dr Michael L. Leventhal as he appeared in his medical school graduation photo of 1924 ( A ) and circa 1960 ( B ).

Figure 2 A reprinted, with permission, from the Rush University Medical Center Archives, and Figure 2 B reprinted, with permission, from Gordon.

Azziz. Stein and Leventhal 80 years later. Am J Obstet Gynecol 2016 .

To this effect, Dr Leventhal records that between 1926 and 1935, this last the year they published their initial observations on the polycystic ovary, he served as assistant to Dr Stein. He also served as clinical assistant, then instructor, at the Northwestern University Medical School. Dr Leventhal, between July 1942 and June 1945, during World War II, served in the US Army in evacuation hospitals in Africa, Sicily, and Italy, achieving the rank of lieutenant colonel in the Medical Corps ( Figure 2 B).

We should note that the vast majority of the research performed by Drs Stein and Leventhal was based on clinical experience, careful observation, and case reports, rather than on prospective experiments, not unlike the vast majority of medical research being performed at the time. However, the fact that these practitioners were excellent clinicians and careful observers was to be critically important when they subsequently defined a disorder that is as yet had been undefined.

Whereas both physicians were active in clinical research, it was Stein who would become the principal driver and proponent of much of their work together. Not only was this the result of Dr Stein’s seniority and proven adeptness at medical writing but also was in part the result of Dr Leventhal serving in the US military during World War II, a significant interruption to his academic career.

The presentation

Considering the relative risk of surgical intervention of the time, particularly for diagnostic purposes, early in his career Dr Stein developed an interest in the use of roentgenology (radiology) for assessing pelvic anatomy, in particular the use of peumoperitoneum to assist in outlining the outer contour of the pelvic organs. This technique had been inspired by Dr Isidor C. Rubin’s experiments with gas insufflation of the fallopian tubes and was further developed by Dr Reuben Peterson. Dr Stein’s interest went so far as to establish a research fund for this purpose in memory of his father, who had passed away in 1919 (the Adolf Stein Memorial for Research in Roentgenology).

Dr Stein began using the technique in his practice around 1923 and rapidly acquired great expertise with it, serving as a strong proponent, both in practice and in his writings, for its use. His level of expertise with this technique can be grasped from a 1926 report detailing his experience with pneumography in some 150 cases, in which he notes that he only “failed to obtain diagnostic films in 2 cases because the gas was injected subperitoneally, wholly or partially,” adding by way of explanation that the failures were “… in badly behaved subjects.”

That same year he, in collaboration with the radiologist Dr Robert A. Arens, reported on combining pelvic pneumography with the injection of opaque mediums (eg, lipiodol) to delineate the inner contours of the uterine and tubal cavities. Dr Stein’s significant expertise and leadership in the use of the nascent technique of pelvic pneumography would become an important basis for his subsequent work on the enlarged ovaries of his patients.

By the early 1930s, Stein had been in practice for more than 15 years and was well recognized in the field, having already published a number of peer-reviewed articles and writing chapters for some of the more eminent obstetrics and gynecology texts of the time. During this time, Dr Stein began to evaluate women with menstrual disturbances, in particular with secondary amenorrhea, who also complained of sterility, excess hair growth, and/or pelvic pain using initially transabdominal peumoperitoneum alone and subsequently combined with the transcervical instillation of lipiodol.

In the course of these evaluations, Dr Stein began to observe that some of his patients demonstrated bilaterally enlarged cystic ovaries, often larger than the uterus itself. These enlarged ovaries suggested the need for exploration via laparotomy, at which time each ovary was wedged, removing between half and three fourths of the ovary and cortex. We should note that ovarian wedge resection (OWR) was likely carried out not only for diagnostic purposes but also as therapy.

Whereas surgeons in the later quarter of the 19th century had advocated oophorectomy as treatment for cystic degeneration of the ovary, particularly when associated with hysteria, epilepsy, or ovarian pain, later surgeons advocated conservatively wedging, rather than extirpating these ovaries. In this regard, it is not clear, however, whether Dr Stein was aware of or simply had opted to ignore the impassioned plea of Dr John A. McGlinn, who in his presentation to the Obstetrical Society of Philadelphia, Nov. 4, 1915, had noted that “following the era of destructive surgery, there came a period of conservative work in surgery. In the development of conservative work, however, we have gone to almost the same extremes as the older men did in their destructive work.”

Dr McGlinn went on to state that it was his belief that “the microcystic ovary should not be treated, in the majority of cases, by resection,” instead noting that he simply punctured “those cysts which are upon the surface with as little handling of the ovaries as possible.” Regardless, Dr Stein continued to wedge offending ovaries, although he did advocate for great caution and care when selecting patients for and undertaking such procedures.

Having collected their cases, Drs Stein and Leventhal arranged to have their observations presented orally at a meeting of the Central Association of Obstetricians and Gynecologists, Nov. 1-3, 1934, held at the Roosevelt Hotel in New Orleans, LA. Although commercial passenger air travel, with the introduction of the uncomfortable Ford Trimotor (also known as the Tin Goose) and the slightly less uncomfortable Boeing model 80, had recently become available, it is likely that Drs Stein and Leventhal traveled to New Orleans on trains operated by the Illinois Central Railroad Co. As this was the era before streamliners, the trip would take more than 24 hours because they passed through and changed trains in St Louis and Memphis. Unfortunately for them, service on the more comfortable Panama Limited, an all-Pullman sleeping cars-only passenger train, had been discontinued in May of 1932, a victim of the Great Depression, and would not resume service until after the meeting in December 1934.

At the meeting the investigators, likely Dr Leventhal because he was the more junior of the two, presented their 7 cases of amenorrhea associated with the presence of bilateral polycystic ovaries, although in fairness not all seven were amenorrheic because 2 of the women were described as having irregular menses. The record does not note how the presentation was received, although it certainly was positive enough to merit submission to and acceptance by the Journal, which at that time the official organ of the Central Association of Obstetricians and Gynecologists.

The presentation

Considering the relative risk of surgical intervention of the time, particularly for diagnostic purposes, early in his career Dr Stein developed an interest in the use of roentgenology (radiology) for assessing pelvic anatomy, in particular the use of peumoperitoneum to assist in outlining the outer contour of the pelvic organs. This technique had been inspired by Dr Isidor C. Rubin’s experiments with gas insufflation of the fallopian tubes and was further developed by Dr Reuben Peterson. Dr Stein’s interest went so far as to establish a research fund for this purpose in memory of his father, who had passed away in 1919 (the Adolf Stein Memorial for Research in Roentgenology).

Dr Stein began using the technique in his practice around 1923 and rapidly acquired great expertise with it, serving as a strong proponent, both in practice and in his writings, for its use. His level of expertise with this technique can be grasped from a 1926 report detailing his experience with pneumography in some 150 cases, in which he notes that he only “failed to obtain diagnostic films in 2 cases because the gas was injected subperitoneally, wholly or partially,” adding by way of explanation that the failures were “… in badly behaved subjects.”

That same year he, in collaboration with the radiologist Dr Robert A. Arens, reported on combining pelvic pneumography with the injection of opaque mediums (eg, lipiodol) to delineate the inner contours of the uterine and tubal cavities. Dr Stein’s significant expertise and leadership in the use of the nascent technique of pelvic pneumography would become an important basis for his subsequent work on the enlarged ovaries of his patients.

By the early 1930s, Stein had been in practice for more than 15 years and was well recognized in the field, having already published a number of peer-reviewed articles and writing chapters for some of the more eminent obstetrics and gynecology texts of the time. During this time, Dr Stein began to evaluate women with menstrual disturbances, in particular with secondary amenorrhea, who also complained of sterility, excess hair growth, and/or pelvic pain using initially transabdominal peumoperitoneum alone and subsequently combined with the transcervical instillation of lipiodol.

In the course of these evaluations, Dr Stein began to observe that some of his patients demonstrated bilaterally enlarged cystic ovaries, often larger than the uterus itself. These enlarged ovaries suggested the need for exploration via laparotomy, at which time each ovary was wedged, removing between half and three fourths of the ovary and cortex. We should note that ovarian wedge resection (OWR) was likely carried out not only for diagnostic purposes but also as therapy.

Whereas surgeons in the later quarter of the 19th century had advocated oophorectomy as treatment for cystic degeneration of the ovary, particularly when associated with hysteria, epilepsy, or ovarian pain, later surgeons advocated conservatively wedging, rather than extirpating these ovaries. In this regard, it is not clear, however, whether Dr Stein was aware of or simply had opted to ignore the impassioned plea of Dr John A. McGlinn, who in his presentation to the Obstetrical Society of Philadelphia, Nov. 4, 1915, had noted that “following the era of destructive surgery, there came a period of conservative work in surgery. In the development of conservative work, however, we have gone to almost the same extremes as the older men did in their destructive work.”

Dr McGlinn went on to state that it was his belief that “the microcystic ovary should not be treated, in the majority of cases, by resection,” instead noting that he simply punctured “those cysts which are upon the surface with as little handling of the ovaries as possible.” Regardless, Dr Stein continued to wedge offending ovaries, although he did advocate for great caution and care when selecting patients for and undertaking such procedures.

Having collected their cases, Drs Stein and Leventhal arranged to have their observations presented orally at a meeting of the Central Association of Obstetricians and Gynecologists, Nov. 1-3, 1934, held at the Roosevelt Hotel in New Orleans, LA. Although commercial passenger air travel, with the introduction of the uncomfortable Ford Trimotor (also known as the Tin Goose) and the slightly less uncomfortable Boeing model 80, had recently become available, it is likely that Drs Stein and Leventhal traveled to New Orleans on trains operated by the Illinois Central Railroad Co. As this was the era before streamliners, the trip would take more than 24 hours because they passed through and changed trains in St Louis and Memphis. Unfortunately for them, service on the more comfortable Panama Limited, an all-Pullman sleeping cars-only passenger train, had been discontinued in May of 1932, a victim of the Great Depression, and would not resume service until after the meeting in December 1934.

At the meeting the investigators, likely Dr Leventhal because he was the more junior of the two, presented their 7 cases of amenorrhea associated with the presence of bilateral polycystic ovaries, although in fairness not all seven were amenorrheic because 2 of the women were described as having irregular menses. The record does not note how the presentation was received, although it certainly was positive enough to merit submission to and acceptance by the Journal, which at that time the official organ of the Central Association of Obstetricians and Gynecologists.

The publication

The study was published in the February 1935 issue of the Journal, a few short months after its oral presentation, as the face article in the issue, suggesting that even then the editors of the Journal recognized the important nature of the report. In the report Drs Stein and Leventhal detail the cases described at the meeting, which included 7 patients with enlarged ovaries detected by transabdominal pneumography in association with menstrual disturbances, notably amenorrhea, and with sterility, pain, or hyperandrogenism. Three of the women reported were obese, 5 were hirsute (1 obese), and 1 was thin, acneic, and with bilateral lower quadrant pain of 1 years’ duration. Of the women in the series, the first women to be treated (in 1930) delivered 2 children following OW,R and another patient was reported as being 3 months pregnant at the time of the report.

Dr Stein in a subsequent report noted that of these 7 original cases, 5 had been able to conceive following ovarian wedge resection; of the 2 remaining, 1 subject had been lost to follow-up after 11 months and 1 had concomitant male factor. Of the women followed up, they did not have recurrent amenorrhea or cystic ovaries (presumably large cystic ovaries assessed by palpation) after variable follow-up, ranging from 9 years to 11 months in follow-up.

So was this report truly seminal? Transformative? A landmark? The simple answer is … Yes