Although the modern history of polycystic ovary syndrome (PCOS) started with the pivotal paper by Stein and Leventhal in 1935,[Reference Stein and Leventhal1] there are suggestions that the “syndrome” was referred to as early as in the time of Hippocrates (ca. 460–377 BC). Medical notes at the time referred to women “whose menstruation is less than three days or is meager, are robust, with a healthy complexion and a masculine appearance; yet they are not concerned about bearing children nor do they become pregnant” and suggest that they may have been describing women with PCOS.[Reference Azziz, Dumesic and Goodarzi2]

It has also been recorded that Soranus of Ephesus (ca. AD 98–138) described some women “who did not menstruate at all, whose bodies are of a masculine type … we observe that the majority of those not menstruating are rather robust, like mannish and sterile women.” More recent accounts of women who probably had PCOS are given by Maimonides (1135–1204): “there are women whose skin is dry and hard, and whose nature resembles the nature of a man. However, if any woman’s nature tends to be transformed to the nature of a man, this does not arise from medications, but is caused by heavy menstrual activity”; and by the sixteenth-century obstetrician and surgeon Ambroise Paré (1510–1590), who observed: “Many women, when their flowers or tearmes be stopped, degenerate after a manner into a certaine manly nature, whence they are called Viragines, that is to say stout, or manly women; therefore their voice is loud and bigger, like unto a mans, and they become bearded.”

All these observations fit the symptomatology of PCOS – menstrual irregularity, subfertility, masculine features and obesity. However, it was the 1934 presentation and subsequent publication by Irving Stein and Michael Leventhal that identified this condition as a reproductive disorder and proposed an effective treatment – bilateral ovarian wedge resection (BOWR) – for the associated subfertility.[Reference Stein and Leventhal1]

Irving Stein was born in Chicago on September 19, 1887, the seventh of ten children, to Adolf Stein and Emma Freiler. Stein initially completed a science degree at the University of Michigan and subsequently obtained a medical degree from Rush Medical College in Chicago in 1912. After a two-year internship at Michael Reese Hospital in Chicago, he joined the hospital’s obstetrics and gynecology department as an assistant in surgery, focusing on women’s reproductive health and obstetrics and reaching “attending physician” status by 1915. He married Lucile Oberfelder in 1921, and they had two children, a son, Irving F. Stein Junior, and a daughter, Eleanor H. Rusnak. Stein was also a professor at Northwestern University and established a private practice at Highland Park Hospital, Illinois.[Reference Darby3]

Stein was known as a warm and caring doctor as well as a dignified and respected teacher, often found with a large group of fellow doctors and nurses following him while he did his rounds. One of his colleagues, Melvin Cohen, stated that “Stein was meticulous in everything he did, including patient care, surgery, and even his appearance, as Stein often wore a boutonniere to the hospital.”

Michael Leventhal joined Stein at the Michael Reese Hospital in 1926, where they collaborated on research into “sterility in women.” Michael Leo Leventhal was also born in Chicago and graduated from Rush Medical College, but 12 years after Stein (1924). Apart from military service as a medical officer in the US Army, he spent his entire career working at the Michael Reese Hospital.

Before Leventhal, Stein was working with Robert Arens studying ovarian abnormalities and developed a method for imaging the reproductive organs by injecting carbon dioxide into the pelvis and iodized oil into the fallopian tubes, combined with X-ray examination. This enabled measuring the dimensions of the ovaries and the patency of the tubes. It was through using this technology that Stein was able to observe a group of women with abnormally large ovaries – two to four times the normal size – who became the subject of Stein and Leventhal’s seminal 1935 paper.

In an article commemorating the 80th anniversary of Stein and Leventhal’s original publication, Ricardo Azziz and Eli Adashi wrote that the research, “although not flawless, was both seminal and transformative.”[Reference Azziz and Adashi4] They pointed out that not only was the Stein and Leventhal paper the first report of a case series but it also described a possible therapy, BOWR. Azziz and Adashi concluded that “we have much to celebrate, as we commemorate the 80th anniversary of the publication of the report by Stein and Leventhal in 1935, for a new disorder was described, one that we know today affects, in its various forms, 1 in every 7–17 women worldwide.” We will therefore look at the 1935 paper in detail. The title and details of this paper are shown in Figure 1.1.

Figure 1.1 The Stein and Leventhal paper of 1935

In their paper, they commence by commenting that bilateral polycystic ovaries are usually described in association with uterine bleeding and endometrial hyperplasia, but no mention is made of bilateral polycystic ovaries and amenorrhea. They then describe a series of patients with ovaries enlarged up to four times the normal size, associated with absent menses. They described the cortex as hypertrophied and the tunica as tough fibrotic and thickened. The cysts were follicular, contained clear fluid and were confined to the surface of the cortex, numbering from 20 to 100 in each ovary. On section, the ovary was “oyster grey” with corpora lutea rarely found, and if present they were small and deeply placed. They described the uteri as either normal sized or smaller and firmer than normal. They also reported masculinizing changes in some patients, with rhomboid escutcheon and hirsutism on the arms, legs and face. The external genitalia were reported as normal in most, but some showed hypertrophied labia minora and clitoris.

They then described seven women with PCOS, all amenorrheic, who underwent bilateral wedge resection of the ovaries, all of whom reported a regular 28-day cycle postoperatively, with one woman (their first patient) conceiving two children. Stein and Leventhal recommended that diagnosis should include pneumo-roentgenography as pelvic examination of ovarian size was not reliable. Their reference for normal size of the ovary was “about one fourth the size of the uterine corpus.” They also discussed the etiology of this condition and disputed the previous hypothesis that it was the result of an inflammatory process, as there was never any evidence of adhesions that one would expect if it was due to infection. They postulated an endocrine causal relationship.

In summary, they concluded that the treatment of PCOS by estrogenic hormone was unsatisfactory, whereas surgical wedge resection was successful in restoring physiologic function – menstruation – with pregnancies in two out of seven patients. A recurrence of polycystic change in the ovary was not found in the follow-up of any of these women. With respect to the pathophysiology of PCOS, they believed that mechanical overcrowding of the cortex by cysts interferes with the progress of normal Graafian follicle to the surface of the ovary.

By 1964, Stein had expanded his experience and reported on a successful series of 108 women treated by “wedge resection.”[Reference Stein5] Consequently, BOWR became the standard treatment for anovulation associated with PCOS. An example of the efficacy and widespread acceptance of BOWR as a treatment for PCOS-associated anovulation came from Sweden, where Lunde and colleagues reported on 149 women with polycystic ovarian syndrome (PCOS), who were treated at a university teaching hospital 15–25 years after ovarian wedge resection (BOWR) and studied three times by means of a questionnaire.[Reference Lunde, Djoseland and Grottum6] Life-table analysis showed a cumulative rate of spontaneous pregnancies of 76%, increasing to 88% when induced pregnancies were included, with a cumulated live birth rate of 78% and with a regular menstrual pattern restored up to 25 years after BOWR.

When less invasive alternatives for the treatment of anovulation using oral clomiphene citrate and injectable follicle-stimulating hormone (FSH) preparations became available in the 1960s, the popularity of BOWR waned.[Reference Greenblatt, Barfield and Jungck7, Reference Gemzell, Diczfalusy and Tillinger8] Furthermore, evidence emerged that BWRO could be followed by periovarian/peritubal scarring, which had its own negative effect on fertility. Toaff and colleagues reported in 1976 that all seven patients who underwent laparoscopy subsequent to BOWR had extensive periovarian and peritubal adhesions.[Reference Toaff, Toaff and Peyser9] They concluded that “our observations support the plea to relegate the surgical approach to a minor position in patients with Stein-Leventhal syndrome.” The current status of surgical management of PCOS is discussed in detail in Chapter 12.

The Historical Development of Diagnostic Criteria for PCOS

From Ovarian Pathology of Stein-Leventhal Syndrome to a Multisystem Endocrine Disease

Stein-Leventhal syndrome was a recognized disorder for more than five decades until the focus shifted to it being a “metabolic multisystem syndrome.” In 1990, an expert conference was sponsored by the National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH). The expert group concluded that diagnostic criteria should include (in order of importance):

The subsequent discovery that many women with PCOS are insulin-resistant with compensatory hyperinsulinemia designated this condition as a reproductive-metabolic disorder, with broader implications than those defined by the NIH in 1990.

To arrive at an international agreement on the diagnostic criteria, and to define the clinical implications of PCOS, a consensus conference chaired by Basil Tarlatzis (Greece) and Bart Fauser (Netherlands) was held on May 1–3, 2003, in Rotterdam, the Netherlands.[14] A scientific committee consisting of Jeff Chang (USA), Ricardo Azziz (USA), Rick Legro (USA), Didier Dewailly (France), Steve Franks (UK), Basil Tarlatzis (Greece) and Bart Fauser (Netherlands) was established. Also invited were a number of international experts as discussants: Adam Balen (UK), Phillipe Bouchard (France), Eva Dahlgren (Sweden), Luigi Devoto (Chile), Evita Diamanti (Greece), Andrea Dunaif (USA), Marco Filicori (Italy), Roy Homburg (Israel), Lourdes Ibanez (Spain), Joop Laven (Netherlands), Dennis Magoffin (USA), John Nestler (USA), Rob Norman (Australia), Renato Pasquali (Italy), Michel Pugeat (France), Jerome Strauss (USA), Seang Lin Tan (Canada), Anne Taylor (USA), Robert Wild (USA) and Sarah Wild (UK). This symposium was financially sponsored by an unconditional grant from NV Organon and by the European Society of Human Reproduction (ESHRE) and the American Society for Reproductive Medicine (ASRM). They concluded that PCOS is a syndrome of ovarian dysfunction along with the cardinal features of hyperandrogenism and PCO morphology. A finding of at least 12 follicles in one ovary, or an ovarian volume of 10 cc, was considered the ultrasonic diagnostic criterion for PCO. They agreed that clinical manifestations may include menstrual irregularities, signs of androgen excess and obesity. They noted that insulin resistance and elevated serum LH levels were also common features in PCOS, and PCOS was associated with an increased risk of type 2 diabetes and cardiovascular events.[14]

Although the Rotterdam Conference concentrated on a definition for diagnosis, there was a need for consensus on which treatments should be offered. To define appropriate therapeutic guidelines another consensus conference was organized on March 2–3, 2007, in Thessaloniki, Greece. The experts invited included Basil Tarlatzis (Greece), Bart Fauser (Netherlands), Rick Legro (USA), Rob Norman (Australia), Kathleen Hoeger (USA), Renato Pasquali (Italy), Steve Franks (UK), Ioannis Messinis (Greece), Robert Casper (Canada), Roy Homburg (Israel), Rick Lobo (USA), Robert Rebar (USA), Richard Fleming (UK), B. R. Carr (USA), Phillipe Bouchard (France), J. Chang (USA), J. N. Hugues (France), R. Azziz (USA), Efstratios Kolibianakis (Greece), George Griesinger (Germany), Klaus Diedrich (Germany), Adam Balen (UK), Cindy Farquhar (New Zealand), Paul Devroey (Belgium), Pak  Chung Ho (Hong Kong), John Collins (Canada), Dimitrios Goulis (Greece), René Eijkemans (Netherlands), Piergiorgio Crosignani (Italy), Alan DeCherney (USA) and Andre van Steirteghem (Belgium). This symposium was also supported by an unconditional grant from NV Organon and by ESHRE and ASRM.

A number of interventions were reviewed and recommendations were made including lifestyle modifications (diet and exercise), administration of pharmaceutical agents such as clomiphene citrate (CC), insulin-sensitizing agents, gonadotropins and gonadotropin-releasing hormone (GnRH) analogues, the use of laparoscopic ovarian drilling and the application of assisted reproductive techniques (ART).[19]

A third consensus conference was held in 2011 in Amsterdam to summarize the then current knowledge and to identify knowledge gaps regarding various women’s health aspects of PCOS.[20] Topics addressed included PCOS in adolescence, the symptoms of hirsutism and acne, contraceptive options, menstrual cycle abnormalities, quality of life, ethnicity, pregnancy complications, long-term metabolic and cardiovascular health and, finally, cancer risk. Participants included Bart Fauser (Netherlands), Basil Tarlatzis (Greece), Robert Rebar (USA), Rick Legro (USA), Adam Balen (UK), Rick Lobo (USA), E. Carmina (Sicily), Jeff Chang (USA), Bulent Yildiz (Turkey), Joop Laven (Netherlands), J. Boivin (UK), F. Petraglia (Italy), C. N. Wijeyeratne (Sri Lanka), Rob Norman (Australia), Andrea Dunaif (USA), Steve Franks (UK), Robert Wild (USA), Daniel Dumesic (USA) and Kurt Barnhart (USA). For each aspect, the consensus committee published concluding statements (where there was agreement), a summary of areas of disagreement (if any) and knowledge gaps with recommended directions for future research.

Simultaneously, in Australia, the Australian government’s Department of Health and Ageing funded a Guideline Development Group, chaired by Helena Teede. The Department of Health recognized that PCOS has potential for major metabolic consequences, including obesity and type 2 diabetes mellitus (DM2) as well as cardiovascular disease (CVD), all of which were national health priority areas. The recommendations of the group were published as a supplement to the Medical Journal of Australia in 2011.[Reference Teede, Misso and Deeks21]

A European approach to define the criteria required for the diagnosis of PCO emphasized the phenotypic heterogeneity of the syndrome.[Reference Conway, Dewailly and Diamanti-Kandarakis22] The group focused on the impact of metabolic issues, specifically insulin resistance and obesity, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes. They concentrated on an endocrine and European perspective in the debate on the definition of PCOS listed as etiological factors, such as early life events, potentially involved in the development of the disorder. They placed an emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. They considered the role of obesity, sleep disorders and neuropsychological aspects of PCOS as well as the relevant pathogenetic aspects of cardiovascular risk factors. They also discussed how to target treatment choices according to the phenotype and individual patient’s needs.

In November 2015, the American Association of Clinical Endocrinologists (AACE), the American College of Endocrinology (ACE), and the Androgen Excess and PCOS Society (AE-PCOS) released new guidelines in the evaluation and treatment of PCOS. They recommended that diagnosis be based on the presence of at least two of the following three criteria: chronic anovulation, hyperandrogenism (clinical or biological) and PCO. They stated that free T levels are more sensitive than the measurement of total T and that the value of measuring levels of androgens other than T in patients with PCOS is relatively low. With respect to imaging, new ultrasound machines allow a threshold for diagnosis of PCOM in patients having at least 25 small follicles (2–9 mm) in the whole ovary, and ovarian size greater than 10 mL should be considered increased ovarian size. They felt that AMH was useful for diagnosis of PCOS.

They recommended that management of women with PCOS should include reproductive function, as well as the care of hirsutism, alopecia and acne. They also recognized the increased prevalence of endometrial hyperplasia and endometrial cancer. They highlighted that, in PCOS, hirsutism develops gradually and intensifies with weight gain and that girls with severe acne may have a 40% likelihood of developing PCOS. It was also pointed out that oral contraceptives can effectively lower androgens. They further warned against diagnosis in the first few years after menarche, as many features of PCOS, including acne, menstrual irregularities and hyperinsulinemia, are common in normal puberty.[Reference Goodman, Cobin and Futterweit23]

The Australian group was important, as it was the catalyst for the formation of the International PCOS Network driven by Helena Teede and Rob Norman, who then undertook the development of international evidence-based guidelines on the assessment and management of polycystic ovary syndrome. Funding for the group came principally from the Australian National Health and Medical Research Council (NHMRC) through the funded Centre for Research Excellence in Polycystic Ovary Syndrome (CREPCOS) as well as from ESHRE and ASRM.

The International Advisory Panel (representatives from six continents) was chaired by Bart Fauser (Netherlands), the deputy chair Rob Norman (Australia) and included JuhaTapanainen (Finland), Zephne van der Spuy (South Africa), Duru Shah (Inida), Rick Legro (USA), Frank Broekmans (Germany), Anuja Dokras (USA), Marie Misso (Austalia), Chir Ruey Tzeng (Taiwan), Jie Qiao (China) and Poli Mara Spritzer (Brazil).

The International PCOS Network was able to collaborate and engage with 37 organizations (including consumers) across 71 countries and organized 23 face-to-face international meetings over 15 months. The various groups involved more than 3000 health professionals and consumers internationally.[Reference Teede, Misso and Costello17] These international evidence-based guidelines included the assessment and management of PCOS and were designed to provide clear information to assist clinical decision-making and support optimal patient care. Addressing psychological, metabolic and reproductive features of PCOS, there were 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews, generating 166 recommendations and practice points. This is discussed in detail in Chapter 5.

How Has PCOS Survived Natural Selection?

The inheritance of PCO/PCOS is still poorly understood and is discussed in detail in Chapter 2. However, there is consensus that there is some genetic hereditary factor. One may then ask, how did these series of symptoms, which have a reproductive handicap (subfertility, cardiac disease, diabetes), survive natural selection?

If we go back to the hunter-gatherer existence, while the phenotype of PCOS had a reproductive disadvantage, being a female with the greatest capacity for the energy storage necessary to endure prolonged episodes of starvation, the so-called thrifty genotype, was an advantage, as women with PCOS were able to survive during periods of food deprivation. Furthermore, insulin resistance that diminishes energy expenditure in times of famine was an additional evolutionary advantage. Also, despite a community belief that women with PCOS are sterile, they are certainly not but they do have lower fertility. Consequently, in the absence of contraception, they will have lower fecundity and therefore have longer spacing between pregnancies, which would have resulted in better maternal health. Birth-associated mortality was also high, so that having fewer pregnancies and births was also an advantage. For women who were nomadic hunters, having fewer children made it easier for them to be transported and, additionally, there were fewer mouths to feed. With delayed fecundity and aging parturition, PCOS women may have attained significant nurturing skills, given their wisdom and strength in surviving a physically demanding environment. They also created an environment suitable for child-rearing as it was not focused on or threatened by pregnancy.

At the individual level, the greater lean muscle mass and bone mineral density of women with PCOS would have been advantageous to their own survival and that of their progeny. It could therefore be argued that PCOS favored the survival of those family units containing women with PCOS.

With a change to human settlement in communities that underwent a shift to agricultural farming and animal husbandry, with sufficient food becoming available, there was a need to have several children in order to provide a rural workforce, therefore PCOS should have become a teleological disadvantage. However, for PCOS women, even in sedentary agricultural societies, they could still conceive, albeit at a rate lower than normal, and they may have had lower maternal mortality and would have been sturdier than average. Even for agricultural societies during the eighteenth and nineteenth centuries, significant periodic famines remained a fact of life for which women with PCOS were better suited to survive.

Considering the male genetically related relatives of PCOS women, they may have symptoms and signs of androgen excess and insulin resistance but neither their ability to attract partners nor their fertility has been shown to be impaired, and, as discussed, they also carry the metabolic advantage of being able to survive famine. All these factors seem to have potentially counterbalanced any disadvantages arising from the overall lower number of children conceived by PCOS women and explain why the condition has not been teleologically genetically eliminated.

We still have a lot to learn about PCO(M)/PCOS, especially about its etiology and pathogenesis. Long-term studies, or “big data” analysis, may answer some of these questions. Certainly, this introductory chapter on the history of PCOS will need to be updated for the fourth edition of Polycystic Ovary Syndrome.