Polycystic Ovary Syndrome: Challenging Issues in the Modern Era of Individualized Medicine

Women’s healthcare regarding polycystic ovarian syndrome remains challenging. Patients often go from one specialist to another trying to fully understand and management the disorder. Women often go years before a diagnosis, seeing three or more doctors before a confirmed diagnosis. Polycystic Ovarian Syndrome: Challenging Issues in the Modern Era of Individualized Medicine brings together multiple medical disciplines to improve the care of women with PCOS. Such a multidisciplinary clinical and scientific approach integrates obstetrics and gynecology, pediatric and medical endocrinology, internal medicine, genetics, psychology and laboratory medicine into relevant translational clinical and scientific discussions that update both the scientific understanding of PCOS and the diagnosis and management of all aspects of the syndrome. The impact of PCO on the onset of puberty is subdivided in sub sections to get a better understanding of this condition and the management at different stages in a woman’s life.

• Represents an unparalleled compilation of chapters from experts in the field relevant to contemporary polycystic ovarian syndrome
• Covers aspects such as obesity, metabolic changes, and emotional changes associated with PCOS
• Highlights contemporary management and the current understanding of this unique syndrome with a comprehensive and fresh approach

• Language: English
• Publisher: Elsevier Science
• Release date: Nov 25, 2021
• ISBN: 9780128230466

Book preview

Part I

Polycystic ovary syndrome: Challenges and controversies

Chapter 1: Defining PCOS: A syndrome with an intrinsic heterogeneous nature

Héctor F. Escobar-Morreale    Department of Endocrinology and Nutrition, Universidad de Alcalá & Hospital Universitario Ramón y Cajal & Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) & Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, Spain

Abstract

Heterogeneous by nature, polycystic ovary syndrome (PCOS) consists of a combination of signs and symptoms of androgen excess and ovarian dysfunction in the absence of other specific diagnoses. In addition, PCOS is frequently associated with abdominal adiposity, insulin resistance, obesity, metabolic disorders, and cardiovascular risk factors. Mounting evidence suggests that PCOS is a complex multigenic disorder with strong epigenetic and environmental influences, including diet and lifestyle factors that vary widely among individual patients. This chapter will address the challenge imposed historically by the intrinsic heterogeneity of PCOS on the criteria used for its definition, proposing strategies directed to overcome the limitations derived from such variability on our understanding of the disorder.

Keywords

Abdominal adiposity; Androgen excess; Heterogeneity; Insulin resistance; Polycystic ovary syndrome

Acknowledgments

This work was supported by Grants PI1501686, PIE1600050, and PI1801122 from Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness, and co-financed by the European Development Regional Fund A way to achieve Europe (EDRF). CIBERDEM and IRYCIS are also initiatives of from Instituto de Salud Carlos III.

Competing interests statement

The author declares no competing interests.

Introduction

Polycystic ovary syndrome (PCOS) is nothing more, but also nothing less, than a very common female phenotype consisting of a combination of signs and symptoms of androgen excess (hirsutism and/or hyperandrogenemia) and ovarian dysfunction [oligo-ovulation and/or polycystic ovarian morphology (PCOM)], provided that other specific diagnoses such as hyperprolactinemia and nonclassic congenital adrenal hyperplasia have been excluded [1]. The prevalence of PCOS in premenopausal women ranges from ~ 6% (using the older more restrictive criteria) to ~ 20% (when applying current more inclusive definitions) [2–5], possibly making this syndrome the most common endocrine and metabolic disorder in women of reproductive age [6, 7].

Even though PCOS is quite homogeneous in a few characteristics such as its peripubertal onset and similar worldwide prevalence [8], the PCOS phenotype may result from different combinations of pathophysiological mechanisms making heterogeneity intrinsic to the syndrome [9]. I will here provide hypotheses to explain how the pathophysiological heterogeneity of PCOS is translated into most aspects of the disorder, from clinical presentation to management, but very particularly to its definition.

Etiology and pathophysiology of PCOS

Familial aggregation

Familial aggregation of PCOS and its related traits suggests a genetic basis [10–21]. However, only the association of a few genetic variants and mutations have been replicated in different populations of patients with PCOS, accounting only for around 10% of the heritability of PCOS [22]. PCOS is now considered a complex multigenic disorder with predisposing and protective genetic variants interacting with strong environmental influences to result in the different PCOS phenotypes [9]. We hypothesized that transmission over generations of these variants may be the result of the survival advantage provided by them. Accordingly, causes of survival advantage in women with PCOS and their progeny include a rapid maturation of the reproductive axis; assertive behavior secondary to increased androgen secretion; subfertility resulting in larger interval between pregnancies, decreasing the birth rate and favoring maternal and infant survival; and oligo-ovulation leading to pregnancies occurring at older ages—when women are more fit than very young women to care for their babies—favoring their survival [23–25].

To further contribute to the etiological heterogeneity of PCOS, the environmental factors include diet and lifestyle issues that are heavily influenced by race and/or ethnicity [9]. Accordingly, the genes interfering with these environmental factors might differ depending on the population studied explaining, at least partly, the repeated difficulties in replicating the association of PCOS with genomic variants and loci in populations of diverse origin [9].

In addition, familial aggregation of PCOS might be related to certain environmental factors that are only present in the affected families and not in the families of unaffected women and might initiate epigenetic mechanisms—that is, stably heritable phenotypes resulting from changes in a chromosome without actual alterations in the DNA sequence [26]. Epigenetic initiators include mechanisms during fetal and childhood development, exposure to environmental chemicals such as endocrine disruptors and certain drugs, the aging process, and diet [26], most of which might contribute to PCOS [8].

Androgen excess and insulin resistance: Cause or consequence?

Albeit androgen excess is the main contributor to PCOS [1, 27], insulin resistance and compensatory hyperinsulinism contribute to androgen excess in these patients [28]. Animal and human studies indicate that insulin acts as a co-gonadotropin on the ovary [29, 30], facilitates androgen secretion from the adrenal glands [31, 32] and modulates luteinizing hormone pulsatility [28, 33]. Accordingly, the prevalence of PCOS is increased, compared with the general population, in patients with any disorder characterized by systemic hyperinsulinism, either endogenous—obesity [34], gestational diabetes [35] and type 2 diabetes mellitus [36, 37], syndromes of extreme insulin resistance caused by mutations in the gene that encodes the insulin receptor [38] or from autoantibodies against the insulin receptor [39], portosystemic shunts [40], or even in women with insulinomas [41, 42]—or exogenous such as in type 1 diabetes mellitus [43]. The fact that PCOS is not universal in women presenting with insulin resistance and hyperinsulinism and that insulin resistance is not universal in PCOS [44, 45] suggest that a primary defect that favors androgen excess [46] is essential for the development of the syndrome in response to insulin or other triggering factors [47].

Also, androgen excess is not only a major mechanism in the oligo-ovulation and cutaneous manifestations of the syndrome, but also facilitates insulin resistance and metabolic dysfunction in women with PCOS by favoring abdominal and visceral adiposity [47–49]. My colleagues and I hypothesized a decade ago that PCOS results from a vicious circle of androgen excess favoring abdominal adipose tissue deposition and visceral adiposity that, by inducing insulin resistance and compensatory hyperinsulinism, further facilitates androgen secretion by the ovaries and adrenal glands in women with PCOS (Fig. 1) [47].

Fig. 1

Fig. 1 Abdominal adiposity and polycystic ovary syndrome (PCOS). The interplay between PCOS and abdominal adiposity might be the result of a vicious circle (represented by the black arrows ) of androgen excess favoring abdominal visceral adiposity, which facilitates androgen excess of ovarian and/or adrenal origin by the direct effects (white arrow) of several autocrine, paracrine and endocrine mediators , or indirectly by the induction of insulin resistance and hyperinsulinism. IL , interleukin; TNF , tumor necrosis factor. Reproduced with permission from Escobar-Morreale HF, San Millan JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab 2007;18:266–272, Copyright Elsevier, 2007.

The PCOS phenotype covers a spectrum of etiological contributions of a primary defect in androgen secretion mixed with triggering factors

From a pathophysiological perspective, the most important factors responsible for the heterogeneity of PCOS are perhaps obesity, abdominal adiposity, and insulin resistance. Our unifying hypothesis [8, 47] explains PCOS as originated from a primary defect in steroidogenesis leading to androgen excess, the severity of which is quite variable and might be triggered by several factors, among which the best known are those related to excess weight (Fig. 2). The relative contribution of androgen excess and triggering factors to the phenotype of individual patients with PCOS covers a wide spectrum. In one extreme of this spectrum, which may be represented by lean women without any evidence of visceral adiposity or insulin resistance, androgen excess alone is severe enough to cause PCOS without the contribution of any other factors. In the other extreme of the spectrum, PCOS only fully manifests when obesity, abdominal adiposity, insulin resistance, and/or hyperinsulinism trigger a very mild alteration in steroidogenesis. These patients might represent secondary [50] forms of PCOS—that will be reviewed in the next chapter—as the PCOS phenotype in these patients frequently resolves once the triggering factor is removed [41, 42, 51]. This spectrum explains the heterogeneity of PCOS symptoms in patients with differing contributions of androgen excess, obesity, and insulin resistance to their individual phenotype (Fig. 2). Obviously, the most severe PCOS phenotypes develop in women with marked obesity or another factor that aggravates a substantial preexisting steroidogenic abnormality. However, some women who exhibit extreme obesity and insulin resistance do not develop PCOS [51]; therefore, a prerequisite for developing PCOS would be an excess in androgen secretion [46].

Fig. 2

Fig. 2 Pathophysiological heterogeneity in patients with polycystic ovary syndrome (PCOS). PCOS is the result of the interaction of a primary abnormality in androgen synthesis, (manifesting as androgen excess) with other factors, such as abdominal adiposity ( red and white targets), obesity and insulin resistance. At one extreme (*), the disorder in some patients is severe enough to result in PCOS even in the absence of triggering factors. At the other extreme (†), a very mild defect in androgen secretion is amplified by the coexistence of abdominal adiposity, obesity and/or insulin resistance. Between the two extremes, there is a spectrum in the severity of the primary defect in androgen secretion, providing an explanation for the heterogeneity of patients with PCOS with regards to the presence of obesity and metabolic comorbidities. However, all patients share a primary defect in androgen secretion. Modified and reproduced with permission from Escobar-Morreale HF, San Millan JL. Abdominal adiposity and the polycystic ovary syndrome. Trends Endocrinol Metab 2007;18:266–272, copyright Elsevier, 2007 and Escobar-Morreale HF, Santacruz E, Luque-Ramirez M, Botella Carretero JI. Prevalence of obesity-associated gonadal dysfunction in severely obese men and women and its resolution after bariatric surgery: a systematic review and meta-analysis. Hum Reprod Update 2017;23:390–408, Copyright Oxford University Press, 2017.

Historical definitions of PCOS: Cause or consequence of heterogeneity?

The term PCOS was introduced after Stein and Leventhal [52] reported in 1935 the combination of hirsutism, amenorrhea, chronic anovulation and infertility, obesity, and enlarged cystic ovaries [52]. Even though they entitled their article as Amenorrhea and polycystic ovaries, [52] and version 10 of the World Health Organization International Classification of Diseases (ICD-10) [53] refers to PCOS as E28.2 Polycystic ovarian syndrome (with sclerocystic ovary syndrome and Stein-Leventhal syndrome as synonyms), PCOS can be anything but polycystic!

The polycystic appearance of the ovaries frequently found in patients with PCOS is caused by the accumulation of ovarian follicles in different stages of maturation and/or atresia [54] which, by definition, are not actual cysts. The use of this misnomer diverts attention from the actual pathophysiology of the syndrome [55], the name PCOS is perceived as confusing both by primary health care physicians and patients, and it is not unusual for patients and their families to even express unreasonable concerns about the potential for malignancy of such cysts [56]. Accordingly, the 2012 National Institutes of Health Office for Disease Prevention-Sponsored Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome [57] recommended that a new name was needed for PCOS. This proposal was supported by certain professional associations, women's health organizations, and PCOS patient support groups that supported this proposal to ensure that an alternative name enhances understanding and recognition of the syndrome and its complex features [55]. To date, none of the names proposed to such avail have been widely accepted [8].

Moreover, whether or not polycystic ovaries are essential for the definition of PCOS have always been at the core of the endless debate about which is the most proper definition of PCOS [58, 59]. Undoubtedly, the heterogeneous nature of PCOS contributed to such debate. As in the Buddhist and Hindi parable of the blind men and the elephant, the definition of PCOS has usually been biased towards giving more emphasis to the areas of interest of the experts involved: Gynecologists focused on ovarian morphology and dysfunction and infertility, Internists and Endocrinologists tended to highlight the hormonal and metabolic dysfunction characteristic of these patients, Dermatologists cared mostly for hirsutism, acne and alopecia, Pediatricians for premature pubarche, etc. These different points of view made it almost impossible to reach a prolonged consensus among the professionals involved in the study and management of a multifaceted disorder such as PCOS, but also hampered progress in our understanding of PCOS, simply because the patients with PCOS included in some studies were entirely different than those in others precluding confirmation of the results across different populations. In other words, the heterogeneity in the definitions of PCOS across studies ended contributing to the heterogeneity of the syndrome in terms of pathophysiology, clinical presentation and management, and association with other disorders.

Nowadays there are three valid PCOS definitions in use, with only minor differences between them that derive from the ways of combining three individual criteria: hyperandrogenism, ovulatory dysfunction, and PCOM [1, 60, 61]. The 2012 NIH-sponsored workshop [57] favored the more ample definition proposed in 2003 by the European Society of Human Reproduction & Embryology and the American Society of Reproductive Medicine [61]—PCOS is diagnosed when two of the three criteria abovementioned are present after specific etiologies have been excluded—but highlighted the need of providing a precise description of the combination of signs and symptoms that led to such a diagnosis (Table 1) in each case, as a way of minimizing the impact of the heterogeneity in the phenotypes covered by the PCOS definition for research studies [57].

Table 1

Strategies to overcome the limitations imposed by the heterogeneity of PCOS

Changing the name of the syndrome?

As happens with the debate of diagnostic criteria, the different names proposed to substitute PCOS reflect largely the interpretations and beliefs of the proponents causing conflict with those of others. Experts who defend the role of hyperandrogenism proposed names such as functional ovarian hyperandrogenism [62], hyperandrogenic-chronic anovulation [63] or female functional hyperandrogenism [9, 64]. Others who consider insulin resistance and metabolic dysfunction as the most important etiopathogenic mechanisms proposed names such as metabolic-reproductive syndrome [65], syndrome XX [66], or even prevalent cardiometabolic ovary syndrome, which would also take the abbreviation of PCOS. Furthermore, names such as polyfollicular ovarian syndrome rely only on an assessment of altered ovarian morphology, which is a criterion that is neither necessary nor sufficient to diagnose the syndrome.

Of note, there are also experts [67] and patient's associations reluctant about renaming PCOS, mostly because this name has been finally included by the WHO as a disease and is increasingly recognized by the general public as an important health problem. Any change in this terminology might draw all previous efforts in the dissemination of knowledge back to square one [8]. I tend to agree with the latter, but giving Stein and Leventhal due credit for their original observations [52] and continue to name PCOS after them may be an elegant alternative [68]. The term Stein-Leventhal syndrome has already been used to name PCOS for decades [56], and it is well-known to health authorities, patients, and other organizations. Using the names of the persons providing the first description of a disease to term it is not uncommon in modern medicine; i.e., using Graves Basedow disease to term autoimmune hyperthyroidism has not caused any problem for close to two centuries [69, 70].

Changing the definition of PCOS?

Fortunately, after the Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome mentioned earlier [57], most experts in the field consider the debate closed. If any, in my humble opinion, the ESHRE/ASMR criteria are too ample. Yet this amplitude, which on the one hand may contribute to heterogeneity, on the other hand, has the advantage of covering all phenotypes possibly associated with the term PCOS, including phenotypes lacking any evidence of androgen excess. The current definition reflects perfectly the intrinsic heterogeneity of PCOS but, at the same time, every effort must be made to avoid the frequent belief that a diagnosis of PCOS has the same implications for the present and future health of all patients!

Each individual criteria used to define PCOS has its own clinical consequences. Androgen excess may result in cutaneous manifestations such as hirsutism, acne, and alopecia [1]; ovulatory dysfunction and chronic oligomenorrhea might result in infertility and endometrial hyperplasia and/or carcinoma [1]; and isolated PCOM is only associated with a risk of ovarian hyperstimulation syndrome during ovulation induction [71]. As a rule of thumb, the more criteria met by the individual patient with PCOS, the more severe her particular phenotype [8].

The most severe clinical manifestation is the classic PCOS phenotype that combines hyperandrogenism with oligo-ovulation, regardless of the presence of PCOM. The next phenotype in severity is ovulatory PCOS (presents with hyperandrogenism and PCOM), and the nonhyperandrogenic phenotype, which consists of oligo-ovulation and PCOM, is the milder phenotype (Fig. 3A) [72].

Fig. 3

Fig. 3 Polycystic ovary syndrome (PCOS) is a heterogeneous disorder in terms of phenotypes and clinical manifestations (A) and also in terms of metabolic consequences (B). The most severe classic phenotypes, consisting of hyperandrogenism (symptoms include hirsutism, acne, alopecia, and seborrhoea) and oligo-ovulation (symptoms include menstrual dysfunction, subfertility, and endometrial hyperplasia), are associated with the most severe insulin resistance and metabolic comorbidities. Ovulatory PCOS consists of hyperandrogenism and polycystic ovarian morphology (PCOM; clinical consequences include ovarian hyperstimulation syndrome), and it is associated with moderate insulin resistance and metabolic comorbidities. The nonhyperandrogenic phenotype consists of oligo-ovulation and PCOM and has a weak association with insulin resistance and metabolic comorbidities. The strength of the association ranges from weak (±) to strong (+++). Modified with permission from Escobar-Morreale HF. Reproductive endocrinology: menstrual dysfunction—a proxy for insulin resistance in PCOS? Nat Rev Endocrinol 2014;10:10–1 and Escobar-Morreale HF. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol 2018;14:270–284, Copyright Nature Publishing Group, 2013.

Similarly, PCOS is quite heterogeneous in terms of its association with insulin resistance and metabolic dysfunction (Fig. 3B). Such an association is much stronger in women with the classic PCOS phenotype than in those with ovulatory PCOS [45, 73–75] or in those with the nonhyperandrogenic phenotype who frequently do not show any evidence of insulin resistance [45] or metabolic dysfunction [76].

Paraphrasing Claude Bernard, there is no PCOS but patients with PCOS. An isolated diagnosis of PCOS is mostly meaningless, because of the broad spectrum of clinical manifestations and consequences of the syndrome according to its current definition. Happily, the large number of possible pathophysiological mechanisms, associations, and complications of PCOS as defined nowadays (reviewed in detail in the following chapters of this book) only cluster in a few patients. Much to the contrary, a diagnosis of PCOS may not even lead to any medical intervention in the not so rare patient presenting with mild symptoms, aside from providing healthy lifestyle recommendations.

As is, a diagnosis of PCOS makes it almost impossible to give homogeneous advice for prognosis and management given its very heterogeneous nature. But instead of changing the name or the definition of PCOS, providing an additional brief description of the specific criteria that they meet would help the patient and the healthcare professionals involved in her care to understand the particular health consequences, thereby facilitating her peace of mind and her correct long-term medical management.

In essence, this improvement in diagnostic information might be accomplished by identifying the individual's particular PCOS phenotype as recommended by the Evidence-Based Methodology Workshop on Polycystic Ovary Syndrome in 2012 [57] (Table 1). However, it is my usual practice to include even more detailed descriptions in the clinical reports of his patients, differentiating between clinical and biochemical androgen excess and giving information on the specific metabolic alterations experienced by each particular patient. This approach may help the individual patient to achieve realistic expectations about her disorder as well as guide their long-term management by other practitioners.

Standardizing the methods used to establish each of the individual criteria used to define PCOS!

Problems with the standardization of the methods used to assess the individual criteria—hyperandrogenism, oligo-ovulation, and PCOM—used in all current definitions of PCOS, and not the way in which these terms are combined, is possibly a major contributor to the existing confusion regarding this syndrome and the main culprit of the many uncertainties remaining about its etiology and pathophysiology [8].

Even if focusing on one of the possible phenotypes of PCOS, patients meeting these criteria may be entirely different depending on the methods used by their physicians to assess these criteria. For example, classic PCOS consisting of hyperandrogenism and oligo-ovulation may be diagnosed in one lean patient presenting with mild hirsutism, normal circulating androgen concentrations, and eight menses during the past year, and in other obese women presenting with severe hirsutism, hyperandrogenemia, and long-term amenorrhea. Albeit both share the same PCOS phenotype, it is not difficult to understand that the consequences of the syndrome for them are quite different.

The issue is further complicated if the hirsutism score is not standardized for the race, ethnicity, and country of origin of the patients [77], if inadequate assays are used to measure serum androgens or different androgens are used to define hyperandrogenemia [1], or if the criteria used for PCOM is not derived from evidence-based guidelines using state-of-the-art ultrasound examination [54].

A consensus is definitely needed at present to re-define hirsutism and the ways of improving its diagnosis, particularly when previous depilation interferes with the visual assessment of the hirsutism score, the androgen or androgens that need to be increased to define hyperandrogenemia, the assays that are accurate enough to be used for such measurements and how to establish the cut-off concentrations, the ways of assessing oligo-ovulation—if the menstrual irregularity is enough for such diagnosis, and what is the minimum number of menses per year that excludes oligomenorrhea in such a case, or if ovulation must be monitored by more precise methods—and facilitate the accurate assessment of PCOM in routine clinical practice, possibly with the help of recent advances in ultrasound technology.

Reaching such an agreement would also permit dissecting with much more precision the main phenotypic components of PCOS and, focusing separately on each of these components for research, instead of addressing as a whole an elusive and very heterogeneous phenotype such as PCOS, will possibly facilitate our understanding of the pathophysiology of this extremely complex—yet fascinating—frequent female disorder.

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Chapter 2: Secondary PCOS: Well-defined causes, leading to the PCOS phenotype

Alessandra Gambineri; Carolina Cecchetti; Paola Altieri; Danilo Ribichini; Valentina Lo Preiato; Flaminia Fanelli; Uberto Pagotto    Unit of Endocrinology and Prevention and Care of Diabetes, Department of Medical and Surgical Sciences, S. Orsola Hospital, University of Bologna, Bologna, Italy

Abstract

Clinicians who deal with polycystic ovary syndrome (PCOS) should be alerted to the forms that are secondary to endocrinopathies. Some of these forms are frequent, such as those due to hyperprolactinemia, thyroid dysfunction, or a 21-hydroxylase deficiency (21-NCAH). Other forms are rare but possible, such as those due to Cushing's syndrome, acromegaly, or a severe insulin resistance state. These secondary forms of PCOS frequently benefit from tailored therapies, and therefore, they need to be recognized in the diagnostic approach to PCOS.

Specific phenotypic traits rarely help the clinician to recognize these forms as, more frequently, these forms have an unspecific PCOS-like phenotype. The laboratory is therefore fundamental to distinguish between secondary and primary PCOS.

Keywords

PCOS; Secondary forms

Acknowledgments

This chapter is dedicated to Prof. Renato Pasquali, for his constant commitment to the study of PCOS.

Introduction

PCOS has had a complex history punctuated by a constant improvement in its understanding and evolution of diagnostic criteria [1]. These include an awareness of forms of PCOS that are secondary to other endocrinopathies, and therefore the need for them to be recognized in the diagnostic approach to PCOS and, when possible, treated with tailored therapies [2, 3]. The management of secondary forms of PCOS is now possible and also thanks to the availability of increasingly precise, and extensive laboratory support [2, 3]. In this chapter, we describe the well-defined endocrinopathies that lead to secondary forms of PCOS, in particular, hyperprolactinemia, thyroid disorders, nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-NCAH), Cushing's syndrome, acromegaly, and severe insulin resistance states together with the recommended diagnostic approach to differentiate between these forms and PCOS.

PCOS—Secondary to hyperprolactinemia

Although there are no exhaustive studies investigating the association between PCOS and hyperprolactinemia, the literature available describes a high prevalence (50%–67%) of hyperprolactinemia in women with clinical, hormonal, or ultrasound features of PCOS. Prolactin exerts an important effect on the ovary, and physiologically, it stimulates follicular development synergistically with gonadotropins. In addition, it stimulates progesterone secretion, through the ovarian upregulation of LH (luteinizing hormone) receptor expression and repression of 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) [4, 5]. An excess of prolactin, however, blocks follicle development both directly and through the inhibition of GnRH (gonadotropin-releasing hormone) secretion and the LH pituitary response to GnRH stimulation, thus reducing LH pulse amplitude and frequency, finally leading to a PCOM (polycystic ovarian morphology) phenotype [6, 7]. In addition, with excess prolactin, the inhibitory effect of prolactin prevails over aromatase activity, thus leading to low ovarian estrogen production, and a consequent ovarian hyperandrogenism [4]. In addition, prolactin receptors have been documented in the adrenals, and it has also been suggested that hyperprolactinemia could augment adrenal androgen secretion [8].

Prolactin, therefore, needs to be measured in the diagnostic approach to PCOS, and the discovery of hyperprolactinemia should lead to etiological investigations to exclude all the causes of hyperprolactinemia such as prolactinoma, drugs, hypothyroidism, chronic renal failure, cirrhosis, chest wall lesions, or breast stimulation [9]. In all these cases, the treatment of hyperprolactinemia can lead to an improvement and eventually the remission of PCOS