Polycystic Ovary Syndrome: What Every Internist Needs to Know! By George Sarka MD,MPH,CPH,FACP,FACR,FACPM DrPH Candidate in Public Health,UCLA Associate. - презентация

1 Polycystic Ovary Syndrome: What Every Internist Needs to Know! By George Sarka MD,MPH,CPH,FACP,FACR,FACPM DrPH Candidate in Public Health,UCLA Associate Clinical Professor of Medicine, UCLA Medical Historian and Lecturer Member of the American Osler Society Vice President of the California Neurology Society ( ) California Neurology Society Director-South ( ) Immediate Past Governor of the ACP, Southern CA, Region II( ) Past President of the LA Neurological Society( ) Past President-Elect of LACMA-District 1( ) Staff Physician/Multispecialist at the Klotz SHC at CSUN Staff Rheumatologist at CSMC Diplomate in Rheumatology, Sports Medicine, Internal Medicine, Neurology, Headache Medicine, Geriatrics, Emergency Medicine, Occupational Medicine, Public Health/ General Preventive Medicine via ABPM, Public Health via NBPHE and Hypertension

2 Drug Company Affiliations I have no drug company affiliations germane to this lecture.

3 Objectives Describe the basic pathophysiology and the role for early intervention Choose evidence-based treatment options for patients seeking fertility and non-fertility care Avoid the metabolic and reproductive complications of PCOS Encourage parents and patients to discuss PCOS to ensure early diagnosis and treatment taking into consideration age, ethnicity and other culturally-related aspects

4 Case Presentation Patient FH is a 25 year old female with type II DM x 2 years here for transference of care. Patient was diagnosed with type II DM with elevated FBS over 200 and HgbA1C of Patient has been obese most of her life with BMIs around 35 to 39 in the last 5 years.

5 Case Presentation continued Patient was put on a diabetic diet, metformin and now glipizide with HgbA1Cs around 7.0. She has a yearly ophthalmology exam the latest of which as been normal. ROS is essentially non contributory. LMP 2 weeks ago Family Hx: Both parents have type II DM, hyperlipidemia and are obese.

6 Case Presentation continued Physical Exam was significant for the following: –BP of 145/85 –BMI of 39 –Pustular, papular and cystic acne on face and back –Some hair thinning –Hyperpigmented areas in the neck and axillae

7 Case Presentation continued Diagnoses?

8 Case Presentation continued Type II DM Obesity Elevated BPr/o Hypertension Menstrual Irregularities Acne Alopecia Acanthosis negricans

9 Case Presentation continued What do you order at this time? –CBC –FBS and 2 hour post prandial or HgbA1C –Chem panel –Lipid Panel –U/A –Spot urine for microalbuminuria –Gynecological exam –TSH, Prolactin, Free and Total Testosterone, DHEAs, 17- Hydroxyprogesterone –Some may get fasting insulin level –Consider an Ultrasound of the pelvis to look at the endometrium and ovaries

10 Final Diagnoses Type II DM Obesity Elevated BPr/o Hypertension Hyperlipidemia NASH PCOS –Menstrual Irregularities –Acne –Alopecia –Acanthosis negricans

11 PreLecture Quiz (The 64,000 Dollar Question) What is the most common endocrinopathy in a woman of reproductive age? A. Diabetes Type I B. Diabetes Type II C. Hyperthyroidism D. Polycystic Ovary Syndrome E. Hypothyroidism secondary to Hashimotos Thyroiditis F. Hypothalamic Amenorrhea

12 Answer Polycystic Ovary Syndrome (5% to 10% of the female population)

13 PCOS AKAs Polycystic Ovarian Syndrome, Functional Ovarian Hyperandrogenism, Chronic Hyperandrogenic Anovulation, Ovarian Hyperandrogenic Dysfunction, Hirsutism-Anovulation Syndrome, Stein Leventhal Syndrome, PCO, PCOD, Polycystic Ovaries, Sclerocystic ovary, Steins Syndrome.

14 Polycystic Ovary Syndrome Although PCOS is associated with hyperandrogenism and infertility early in life, it is a harbinger of a lifelong condition that can lead to serious sequelae such as diabetes mellitus, hyperlipidemia, endometrial hyperplasia/carcinoma, central obesity, sleep apnea, etc. I will review the pathophysiology,Dx and treatment of this condition.

15 PCOS-INTRODUCTION PCOS is not merely a reproductive disorder but an endocrinological disorder affecting women in their reproductive years. Although hyperandrogenism and infertility that PCOS causes are distressing to young women, its metabolic sequelae eventually plague the individual in terms of morbidity and mortality.

16 PCOS-INTRODUCTION It is crucial to diagnose PCOS early in its course. It is imperative not only to recognize it but also to delay or arrest its metabolic sequelae. Additionally, screening for the expected complications may allow for proper and timely management of these conditions.

17 Why Should Physicians Know about PCOS? The Dx of PCOS implies that a woman is at increased risk for the following: Infertility Dysfunctional Bleeding Endometrial Carcinoma Obesity Obstructive Sleep Apnea Type 2 Diabetes Dyslipidemia HTN Possibly Cardiovascular Disease Her Sisters, Daughters and other close Female Relatives may also be a risk She may require lifelong therapy and find that her access to healthcare coverage is limited.

18 Historical Aspects of PCOS Vallisneri gave the first histological description of the polycystic ovary, 1721 Sclerocystic changes in the ovary described by Chereau, 1844 Class description of a bearded women with DM, Achard/Thiers 1921

19 Historical Aspects of PCOS 1935-Stein and Leventhal described the features of 7 hirsute, amenorrheic women based on the characteristic ovarian morphology from histological specimens taken at wedge resection of the ovaries Paper on 75 women who underwent bilateral wedge resections, nearly 90% of whom began to have spontaneous menstrual cycles and 65% of those seeking fertility conceived(Stein,Cohen and Elson 1948)

20 Historical Aspects of PCOS Laparotomy and wedge biopsy became the mainstay of both diagnosis and treatment (Goldzieher and Green l962) The next diagnostic milestone occurred in the late l960s and early l970s with derangements in the hypothalamic- pituitary axis. Endocrinological criteria were used for the diagnosis such as elevated LH/FSH ratios

21 Historical Aspects of PCOS Pelvic Ultrasound in the l970s and l980s(first abdominal sonography and, later, vaginal sonography) complicated the diagnosis PCO/PCOS 1990 NIH criteria established for PCOS 2003 ESHRE/ASRM(Rotterdam,Netherlands) consensus definition of PCOS which now included the possibility of using polycystic ovaries as part of the Dx 2006 Task Force Appointed by the Androgen Excess Society Todays Picture

22 Summary of the Historical Aspects In 1935, Stein and Leventhal described 7 women with bilateral enlarged PCO, amenorrhea or irregular menses, infertility and masculinizing features. This seminal paper introduced clinicians to the concept of reproductive endocrinopathies. Nearly 70 years later, as with most syndromic illness, the parameters for defining PCOS remain vague or subjective.

23 Definition of PCOS There is no universally accepted definition for PCOS!

24 Definition of PCOS 1990 US NIH Consensus Conference: 2 minimal criteria 1. Menstrual Irregularity due to oligo- or anovulation 2. Clinical or biochemical hyperandrogenism a.Hirsutism,Acne,Male Pattern Baldness b.Elevated Serum Androgen Levels 3. Above not attributable to other causes

25 Definition of PCOS No laboratory evidence required for Dx No radiologic evidence required for Dx( in the North America) Ovarian appearance not pathognomic Insulin resistance not included in diagnostic criteria Excludes women with other known causes of hyperandrogenism; Diagnosis of exclusion Clinical heterogeneity

26 2003 ESHRE/ASRM(Rotterdam,Netherlands) Consensus on the Dx of PCOS Requires the presence of two out of the following three criteria: 1.Oligo- and/or Anovulation 2.Hyperandrogenism (clinical and/or biochemical) 3.Polycystic Ovaries, with the exclusion of other etiologies

27 Task Force Appointed by the Androgen Excess Society 2006 Reviewed all available data and recommended a new evidence-based definition.(J Clin Endocrinol Metab.2006 Aug 29) The Task Force identified 4 key clinical features of PCOS: 1.Ovulatory and Menstrual Dysfunction 2.Hyperandrogenism 3.Hirsutism, Acne and Androgenic Alopecia 4.Polycystic Ovaries Plus the exclusion of other disorders of androgen

28 PCOS-Epidemiology PCOS affects 5% to 10% of women of reproductive age which approximately 4 million individuals Its prevalence among infertile women is 15% to 20%. It is the most common endocrine disorder of women in this age group. It is often seen in the student health population and general medical practice but most often diagnosed when a women presents with infertility

29 PCOS- Economic Cost to Health Care We estimated the mean annual cost of the initial evaluation to be $93 million (2.1% of total costs), that of hormonally treating menstrual dysfunction/abnormal uterine bleeding to be $1.35 billion (31.0% of total), that of providing infertility care to be $533 million (12.2% of total), that of PCOS-associated diabetes to be $1.77 billion (40.5% of total), and that of treating hirsutism to be $622 million (14.2% of total). *Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August 2005, 90(8):4650–4658.

30 PCOS- Economic Cost to Health Care Conclusions: The total cost of evaluating and providing care to reproductive-aged PCOS women in the United States is $4.36 billion. Because the cost of the diagnostic evaluation accounted for a relatively minor part of the total costs (approximately 2%), more widespread and liberal screening for the disorder appears be a cost-effective strategy, leading to earlier diagnosis and intervention and possibly the amelioration and prevention of serious sequelae. *Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August 2005, 90(8):4650–4658.

31 PCOS-Epidemiology PCOS accounts for 95% of cases of hyperandrogenism PCOS is responsible for over 20% of all cases of amenorrhea PCOS is responsible for up to 75% of all cases of anovulatory infertility.

32 Question: Are There Advantages in Having PCOS? With a syndrome affecting 5% to 10% of women, what would selective advantage of having such a gene? With time, a syndrome deleterious to ones health would be deleted from the gene pool.

33 Advantages of Having PCOS Enhanced Survival of the species via the following 1. retaining calories and storing adipose tissue, especially important in times of famine, wintertime 2. pregnancy issue 3. less likely to develop osteopenia, osteoporosisless fractures

34 Genetics of PCOS Complex Genetic Trait Disorder. While the precise mode of inheritance is still uncertain, a familial basis for the syndrome is well established and it is not uncommon to find a mother or sister with l or more symptoms of PCOS.

35 What is the Male Homologue to PCOS in Women? In families with PCOS, males with balding before the age of 30.

36 Pathogenesis Remains unclear Complex Genetic Disorder Ovarian Genetic Trait that interacts with other congenital or cellular environment factors Dysregulation of Steroidogenesis ?Centrality of Insulin Resistance

37 The Etiology of PCOS A genetic disorder of ovarian androgen secretion Etiology of PCOS is hotly debated Most agree that the ovary, rather than the adrenal is the principal source of excess androgen production.

38 PCOS-MAJOR CRITERIA 1.CHRONIC ANOVULATION-Oligo-and/or Anovulation 2.CLINICAL and/or BIOCHEMICAL SIGNS OF ANGROGEN EXCESS: Hirsutism Acne Alopecia Menstrual Disturbance Infertility Virilization 3.EXCLUSION OF OTHER CAUSES OF ANDROGEN EXCESS

39 PCOS-MINOR CRITERIA INSULIN RESISTANCE ONSET AT PUBERTY ELEVATED LH:FSH RATIO (>2.5-3) ULTRASONOGRAPHIC EVIDENCE OF POLYCYSTIC OVARIES

40 Source of Image:

41 A classic reference indicating the prevalence of various presenting clinical symptoms and complaints among a large cohort of women with PCOS ( N = 1089) culled from 187 previously published papers (46). The frequency is still relevant to todays population of women with PCOS. Source of Image:

42 What Defines Irregular Menses?

43 Menses Irregular Menses are defined as being less than 21 days or greater than 35 days. Women with PCOS typically have prolonged(>35 days) cycles. Both decreased menstrual cycle regularity and dysfunctional uterine bleeding are clinical consequences of chronic anovulation.

44 Menstrual Dysfunction in PCOS Erratic menstruation secondary to anovulation Increased risk of endometrial hyperplasia/carcinoma Prolonged amenorrhea associated with endometrial atrophy Menstrual disturbances in PCOS classically have a peripubertal onset PCOS patients generally do no have premenstrual or pain during ovulation

45 Ovulatory and Menstrual Dysfunction per the Task Force of the AES % of patients have clinically evident menstrual dysfunction, and 20% have a history of apparent eumenorrhea. In women with hirsutism and eumenorrhea, anovulation can be confirmed by measuring serum progesterone during days 20 through 24 of the cycle.

46 Clinical Hyperandrogenism Hirsutism Acne Seborrhea Male-pattern Balding Increased Muscle Mass Deepening Voice Clitoromegaly

47 Hirsutism Definition How does it differ from hypertrichosis? Ferriman-Gallwey Model Scoring System for the severity of hirsutism Hirsutism is from Latin hirsutus = shaggy, hairy

48 Hirsutism Defined as excess terminal (thick pigmented) body hair in a male distribution and is commonly noted on the upper lip, around the breast nipples and along the linea alba of the lower abdomen. Ferriman-Gallwey Model Scoring System for severity of hirsutism

49 Hirsutism and PCOS Most women with hirsutism of gradual onset, with or without menstrual cycle irregularity, have polycystic ovaries. More serious pathology is usually obvious on clinical history and examination alone and tends to be associated with a gross elevation of circulating testosterone.

50 Hypertrichosis Increased in total body hair Rare condition that usually reflects an adverse effect of a drug such as: 1.phenytoin 2.penicillamine 3.diazoxide 4.minoxidil 5.cyclosporine 6.streptomycin 7.hexachlorbenzene

51 Hypertrichosis Also occurs in patients with systemic illnesses such as the following: 1.hypothyroidism 2.anorexia nervosa 3.malnutrition 4.porphyria 5.dermatomyositis Sometimes occurs idiopathically

52 Ferriman-Gallway Scoring System for Hirsutism 1.Upper Lip 2.Chin 3.Chest 4.Upper Back 5.Lower Back 6.Upper Abdomen 7.Upper Arm 8.Forearm 9.Thigh /Leg

53 Differential Dx of Hirsutism PCOS Idiopathic Hyperthecosis Late Onset CAH Cushings Syndrome Androgen-secreting tumors of adrenal Acromegaly Iatrogenic-Testosterone,Danazol, Anabolic Steroids

54 Lab Evaluations to Consider for Hirsutism Investigations to consider for hirsutism in women Free and TotalTestosterone - The only investigation needed in most cases; Gonadotrophins - Luteinising hormone concentration is greater than follicle stimulating hormone in polycystic ovary syndrome not consistant Prolactin - Raised in patients with prolactinomas and taking certain medications 17-hydroxyprogesterone - Raised in congenital adrenal hyperplasia Dehydroepiandrostenedione acetate - Raised in adrenal tumours Thyroid function tests

55 Dermatological Manifestations of PCOS Hirsutism Acne Androgenic Alopecia Seborrhea Acanthosis Nigricans

56 Acne Acne is seen in approximately one-third or more of PCOS patients(Task Force of the AES in % to 25%) A majority of women with severe or resistant acne have PCOS Androgen excess has also been associated with more severe acne

57 Acne Primarily affects the face, less often, the back and chest. Lesions are grouped into non-inflammatory-open/closed comedones inflammatory (papules,pustules,nodules,cysts) Rx-to be discussed

58 Androgenic Alopecia Progressive, non-scarring,patterned loss of scalp terminal hairs. Requires hereditary predisposition/ sufficient androgens. Commonly underdiagnosed. Incidence is 8%, an underestimation

59 Androgenic Alopecia Clinical features 1.diffuse hair loss over the crown, with preservation of the frontal hair line; 2.widening of the hair parting is an early sign of androgenic alopecia.

60 Acanthosis Nigricans Mucocutaneous eruption characterized by hyperkeratosis, papillomatosis and increased pigmentation. Occurs in up to 5% of women. Occurs in the axillae, nape of neck, under the breast and the flexures. The variety associated with PCOS is benign acanthosis nigricans.

61 Other Signs in PCOS Increased Muscle Mass Voice Changes (Deepening Voice) Clitoromegaly *Note, all above are rare in PCOS

62 The Metabolic Syndrome and PCOS The prevalence of metabolic syndrome in women with PCOS is approximately %.* *Third report of the National Cholesterol Education Program. Expert panel on the detection, evaluation and treatment of high blood cholesterol in adults. Final report. Circulation 106, (2002).

63 Insulin Resistance Insulin resistance is commonly, though not universally, found in PCOS, with prevalence being estimated in 50-70% of cases.(*) *Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado A, Cortes ME. Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome. Hum. Reprod. 22(11), (2007).

64 More about PCOS and Insulin Resistance PCOS is associated with peripheral insulin resistance and hyperinsulinemia, and obesity amplifies the degrees of both abnormalities.

65 Adiponectin and PCOS Insulin resistance in PCOS has been associated with adiponectin, a hormone secreted by adipocytes that regulates lipid metabolism and glucose levels. Both lean and obese women with PCOS have lower adiponectin levels than women without PCOS.

66 Obesity in PCOS Obesity, seen in approximately 60% of cases, amplifies the severity of PCOS presentation.* The prevalence of obesity varies according to geographic location: it is greater in the USA than in other places.** *Legro RS, Castracane VD, Kauffman RP. Detecting insulin resistance in polycystic ovary syndrome: purpose and pitfalls. Obstet. Gynecol. Survey 59, (2004). **Carmina E, Legro RS, Stamets K, Lowell J, Lobo RA. Difference in body weight between American and Italian women with polycystic ovary syndrome: influence of the diet. Hum. Reprod. 18(11), (2003).

67 Impaired Glucose Tolerance and Diabetes Mellitus Of obese women with PCOS, 10% have undiagnosed diabetes and 35% have impaired glucose tolerance.* *Dunaif A. Insulin resistance and polycystic ovary syndrome: mechanisms and implications for atherogenesis. Endocr. Rev. 18, (1997).

68 Lipid Profiles and PCOS Almost 70% of patients with PCOS have an abnormal lipid profile and high triglycerides and low high-density lipoprotein (HDL) cholesterol are often found. * *Legro RS, Kunselman AR, Dunaif A. Prevalence and predictors of dyslipidemia in women with polycystic ovary syndrome. Am. J. Med. 111, (2001).

69 Long Term Risks Associated with PCOS

70 Source of Image: Teede, Helena j. et al., Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline, Med J Aust 2011; 195 (6): S69.

71 Risk of Coronary Artery Disease in Mothers of Women with PCOS Kai I Cheang, John E Nestler and Walter Futterweit The Endocrine Society's 89th Annual Meeting Abstract presented in Toronto June 4th 2007 Among the 270 women with PCOS, 60 had mothers with probable PCOS while 210 mothers did not meet the PCOS criteria. Complete cardiovascular history was successfully obtained from 39 PCOS mothers and 75 normal mothers. The mean age of PCOS mothers at the time of survey did not differ from that of non-PCOS mothers ( vs , respectively). Including only those mothers whose cardiovascular histories were available, 13 of 39 (33.3%) PCOS mothers had CAD compared with 1 of 75 (1.3%) normal mothers (p<0.0001). Eight of 39 (20.5%) PCOS mothers had suffered an MI compared with 1 of 75 (1.3%) normal mothers (p<0.0001). Notably, all PCOS mothers who had an MI were 65 years old or younger at the time of their incident MI. Conclusion: PCOS mothers of women with PCOS are at a higher risk of CAD events compared with non-PCOS mothers, and MI appears to occur at an earlier than expected age in PCOS mothers.

72 Polycystic Ovary Syndrome and Cardiovascular Disease: Premature Association? Richard S. Legro Endocrine Reviews June 1, 2003; 24 (3): Women with polycystic ovary syndrome (PCOS) are often assumed, a priori, to be at increased risk for cardiovascular disease (CVD), given the high prevalence of the metabolic syndrome X among them. There is, however, no single definition of PCOS, and for that reason a comparison of studies that have analyzed its association with CVD is compromised from the start. Long-term studies of well characterized women with PCOS are lacking, and the link to primary cardiovascular events such as stroke or myocardial infarction remains more speculative than substantive. Epidemiological studies that have focused on isolated signs and stigmata of PCOS, such as polycystic ovaries, hyperandrogenism, or chronic anovulation, have found mixed results. There are studies that suggest a slight increase in cardiovascular events in women with polycystic ovaries, with perhaps stronger evidence between an increased risk of cardiovascular events in women with menstrual irregularity. However, there is little evidence for an association between hyperandrogenism per se and cardiovascular events. Furthermore, there are less data to substantiate an increased risk of events in women with PCOS identified on the basis of a combination of signs and symptoms, such as hyperandrogenic chronic anovulation. The existing data suggest that PCOS may adversely affect or accelerate the development of an adverse cardiovascular risk profile, and even of subclinical signs of atherosclerosis, but it does not appear to lower the age of clinical presentation to a premenopausal age group. Future studies to identify the risk of cardiovascular events in women with PCOS will benefit from clear and extensive phenotyping of PCOS abnormalities at baseline, from a prospective design, from larger sample sizes, and from longer follow-up.

73 Cardiovascular Risk in PCOS Several studies using intima media thickness as a surrogate for cardiovascular risk evaluation have shown potential increased cardiovascular risk in women with PCOS. * * Talbot EO, Guzick DS, Sutton-Tyrrell K et al. Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women. Arterioscler. Thromb. Vasc. Biol. 20, (2000). * Vryonidou A, Papatheodorou A, Tauridou A et al. Association of hyperandrogenism and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, (2005). * Luque-Ramirez M, Mendieta-Azcona C, Alvarez-Blasco F, Escobar-Morreale HF. Androgen excess is associated with increased carotid intima-media thickness observed in young women with polycystic ovary syndrome. Hum. Reprod. 22, (2007).

74 Coronary Artery Calcification and PCOS A similar study using coronary artery calcification as risk stratification has shown increased risk in patients with PCOS. * * Christian R, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzparick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 88, (2003).

75 Sleep Apnea and Other Sleep Disorders Multiple groups have documented an increased risk for sleep apnea and other sleep disorders including increased daytime somnolence, such as sleep disordered breathing in women with PCOS. This is surprising as sleep apnea is relatively uncommon in women, especially premenopausal women.

76 Body Image and Quality of Life in PCOS Patients There is little study of the psychopathology of women defined as having PCOS in literature PCOS disease-specific questionnaire known as the PCOSQ has been developed to study the above questions. Obesity and infertility cause the greatest degree of stress

77 Body Image and Quality of Life in PCOS Patients Both anorexia nervosa and bulimia have been linked with PCOS(etiological link?) Many conditions co-exist with PCOS such as pelvic pain, depression and altered mood but it is unclear where there is a casual or causal association.

78 Pregnancy in PCOS Increased risk of Pregnancy-related Hypertension Increased risk of Pregnancy-related Diabetes Increased risk for Miscarriages

79 Morphology of the Polycystic Ovary Ovary with 12 or more follicles* measuring 2-9 mm in diameter and/or Increased ovarian volume(>10 cubic centimeters) *Note that the follicles are usually peripheral in location.

80 Imaging Ultrasound is the imaging modality of choice Polycystic ovaries are enlarged and rounder than normal with increased stromal echogenicity There are numerous small cysts, less than 5mm, that line up on the periphery, in a string-of- pearls appearance Ultrasonographic criteria for establishing the diagnosis of PCOS are 10 or more cysts that are 2-8 mm in diameter and are peripherally arranged around an echodense stroma

81 Ovarian Morphology on Pelvic Ultrasound Ovarian pattern is both insufficient and unnecessary to make the diagnosis of PCOS per NIH Conference on PCOS criteria of l990 However, it has been considered necessary to redefine PCOS and include with it an appropriate definition of the polycystic ovary per 2003 ESHRE/ASRM criteria

82 Polycystic Ovaries per the Task Force by AES % of patients have polycystic ovaries detected by transvaginal ultrasonography, although the false-positive rate is high (approximately 25% of women in the general population have the same ovarian morphology). The Dx of polycystic ovaries should not be based merely on a polycystic or multicystic appearance. At least 1 ovary should have a volume of >10cm3 (mL), or there should be >= 12 follicles measuring 2 to 9 mm in diameter.

83 Additional Use for Pelvic Ultrasound To check the endometrium for hyperplasia and carcinoma

84 The Pathophysiology of PCOS The pathophysiology of PCOS, although still not entirely clear, is mainly due to the hormone imbalance caused by both hyperandrogenism and hyperinsulinemia, which are also effects of PCOS.

85 Source of Image:

86 Figure 1 Pathophysiological role of hyperandrogenism and the insulin resistance- hyperinsulinemic state in determining the PCOS phenotype. Pasquali R, Gambineri A Eur J Endocrinol 2006;154: © 2006 Society of the European Journal of Endocrinology

87 PCOS and Infertility Menstrual Irregularity Ovaries Contain Small Cysts Cysts Produce Hormone Imbalance Good chance of Pregnancy with IVF

88 Laboratory Testing for PCOS is to Exclude Other Causes Total or Free Testosteroner/o androgen- secreting tumor DHEAsr/o androgen-secreting tumor of the adrenal gland Morning 17-hydroxyprogesteroner/o late- onset CAH 24-Hr urine for cortisol and creatininer/o Cushings Syndrome Prolactinr/o hyperprolactinemia TSH,(T4/T3 if indicated)r/o hyper-or hypothryoidism

89 PCOS-Laboratory Evaluation Hyperandrogenemia: 60% to 80% of patients have increased circulating androgen levels, primarily free testosterone. This cannot be the sole diagnostic criterion, because 20% to 40% of patients with PCOS have normal androgen levels and assays are NORTORIOUSLY INACCURATE.

90 Testosterone Total Testosterone levels below 150 ng/dl usually exclude ovarian and adrenal tumors and ovarian hyperthecosis Serum free testosterone concentrations are disproportionately higher than the total concentration in PCOS

91 DHEA-S DHEA-S are normal to slightly increased in most female patients with androgen excess DHEA-S levels about 700 to 800ug/dl in young females may suggest the presence of adrenal tumor DHEA-S secretion begins to fall after the age of 30; Measurements must be interpreted to age-specific normal ranges

92 DHEA-S Low DHEA-S does not r/o tumors with 100% sensitivity Low levels have been reported in a few women with adrenal CA due to the lack of sulfating activity within the tumor

93 PCOS-Laboratory Evaluation Although not essential to the diagnosis, insulin resistance is common and may affect treatment decisions. Therefore, a fasting blood glucose, 2-hr oral tolerance test, glycated Hgb and fasting insulin levels can be measured for hyperinsulinemia. Additionally, a fasting lipid panel should also be done to r/o hyperlipidemia.

94 Lab in PCOS One may see the following: –Increased free testosterone/N testosterone, increased androstenedione –Increased DHEA-S, DHEA –Increased LH, normal FH; Inc. LH/FSH –Increased estradiol, estrone –Increased fasting insulin –Increased insulin resistance –Decreased SHBG –Mildly elevated prolactin –Increased AST,ALT in pts with NASH

95 Summary for Dx of PCOS 1.Hx and Physical 2.Pelvic Ultrasound(Transvaginal is best); Endometrial thickness should always be assessed to exclude significant endometrial pathology. 3.Hormone Assays(to exclude other mimickers of PCOS) 4.Glucose Testing; 2 Hour Post Prandial 5.Lipid Status (to check Total Cholesterol, HDL and Triglyceride Levels) 6.Other investigations 7.Exclusion of other conditions that may mimic PCOS

96 Differential Dx in PCOS Congenital Adrenal Hyperplasia Androgen-Secreting Ovarian or Adrenal Tumors Idiopathic Hyperandrogenism Idiopathic Hirsutism Syndromes of Severe Insulin Resistance Hyperprolactinomia Thyroid Abnormalities Cushings Syndrome Androgenic Anabolic Steroid Usage Other Medications Usage :Danazol, Phenothiazines, Corticotropin or ACTH analogues, ?Valproate

97 Late Onset Congenital Adrenal Hyperplasia 21-Hyrpoxylase deficiency 11B-Hydroxylase deficiency 3B-Hydroxysteroid dehydrogenase deficiency

98 PCOS-Treatment 1930s Ovarian Wedge Resection Traditional Treatmentaimed at the clinical features and dependent on the ones most bothersome to the patient. Response to therapy is slow, 6-9 months Rx of acne,hirsutism and menstrual irregulaties when fertility is not an issue requires a concentrated effort on many fronts.

99 PCOS Treatment-Key Points Nonpharmacologic measures are universally recommended. –These measures include the following(Lifestyle Measures): A) Diet including seeing a dietician who is knowledgeable in PCOS B) Exercise C) Weight Reduction if the patient is obese or insulin- resistant.

100 Lifestyle Modification and Weight Loss in PCOS Risk modification and symptom relief (e.g., restoration of ovulatory cycles) has clearly been achieved with lifestyle modification and weight loss. * All strategies for weight loss, including surgery, need to be explored in PCOS patients. *Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang XJ. Improving reproductive performance in overweight/obese women with effective weight management. Hum. Reprod. Update 10, (2004).

101 Lifestyle Modification and Weight Loss in PCOS For example, the combination of weight- reducing medications and group lifestyle modification was shown to be more effective than either alone, in a group of obese adults. * * Wadden TA, Berkowitz R, Womble LG et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N. Engl. J. Med. 353, (2005).

102 Lifestyle Modification and Weight Loss in PCOS Bariatric surgery as treatment for obesity is highly relevant to the PCOS population, and has been shown to reverse much of the metabolic, as well as the reproductive, problems in these patients, including hirsutism.* *Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome association with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, (2005). *Eid GM, Cottam DR, Velcu et al. Effective treatment of polycystic ovarian syndrome with Roux- en-Y gastric bypass. Surg. Obes. Relat. Dis. 1(2), (2005).

103 Lifestyle Modification and Weight Loss in PCOS In a study of morbidly obese PCOS women, weight loss was paralleled by a decrease in hirsutism score, testosterone and dehydroepiandrosterone sulfate; amelioration of insulin resistance occurred and ovulatory cycles were also restored. * * Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome association with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, (2005).

104 Lifestyle Modification and Weight Loss in PCOS In addition to these benefits, bariatric surgery for severe obesity has been associated with a decreased overall mortality. * * Sjostrom L, Narbro K, Sjostrom CD et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, (2007).

105 PCOS Treatment-Key Points Pharmacologic treatments include the following: oral contraceptives antiandrogen drugs (usually spironolactone) insulin sensitizers ?statins.

106 OCPs and PCOS One of the most commonly used medications in PCOS patients are OCPs. In addition to their androgen-lowering effects, it is likely that they protect the endometrium against hyperplasia and cancer (as they do in the general population) and may also reduce the incidence of functional follicular ovarian cysts, as shown in the general population.

107 PCOS Treatment-Key Points When using BCPS to regulate the menstrual cycle, it is best to work with the gynecologist. Avoid Norgestrel and Levonorgestrel because of their risk of increased hirsutism.

108 PCOS Treatment-Key Points Spironolactone : For Hirsutism Oral aldosterone antagonist with antiandrogenic properties Dosage 50mg to 200mg/day in divided dosages Potential Side Effects: menstrual irregularities, breast tenderness, GI disturbances, HA, dizziness and hyperkalemia. Should be given with BCPs because of the above and the risk of teratogenicity

109 Metformin and PCOS While the long-term benefits have not been extensively documented, use of insulin-lowering and -sensitizing medications, such as metformin, would be advisable, although they are unapproved for such use in the USA.

110 Metformin and PCOS A recent, uncontrolled, retrospective, observational study, showing that long- term treatment with metformin delays or prevents the development of impaired glucose tolerance and diabetes in women with PCOS, is certainly in keeping with this concept.* * Sharma ST,Wickham III EP, Nestler JE. Changes in glucose tolerance with metformin treatment in polycystic ovary syndrome: a retrospective analysis. Endo. Prac. 13(4), (2007).

111 Metformin and PCOS Another study showed decreased weight and systolic blood pressure as well as increased HDL in metformin-treated women with PCOS. * In this study, metformin was also shown to increase insulin sensitivity and lower testosterone in obese but not nonobese PCOS women. * Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled, cross-over trial. Hum. Reprod. 22(11), (2007).

112 When Fertility is Desired BCPs and antiandrogens cannot be used –Sometimes weight loss helps –Insulin sensitizers, especially metformin. –Thiazolidinediones(not studied, ?risks) –Fertility Drugs-clomiphene citrate, aromatase inhibitors, glucocorticoids, gonadotropin therapy –Laparoscopic Ovarian diathermy –In vitro fertilization/embryo transfer

113 Nonsystemic Hair Removal Mechanical Means: bleaching,plucking, waxing, shaving, depilatory creams, electrolysis and laser therapy. Laser therapy requires long-term Rx; most successful in women of light skin,dark hair Eflornithine(Vaniqa), a topical agent, interferes with an enzyme in the hair follicle and slows hair growth. Takes 6-8 wks to work but the hair will reappear after stopping treatment.

114 PCOS and Menopause Very few studies have focused on this age group Fewer studies have longitudinally tracked the natural history over the vital transition time between 45 to 55 year of age. Serum testosterone is maintained in the menopausal years, while DHEAS declines, reflecting diminished adrenal androgen production.

115 PCOS and Menopause Hirsutism after menopause probably increases since the polycystic theca spontaneously hypersecretes androgen. In clinical terms, hirsute women with PCOS may experience post-menopausal hirsutism more often than average and may need continuing anti-androgen cover into the sixth decade of life.

116 PCOS, Menopause and Osteoporosis Studies are lacking but is felt that patient with PCOS are less likely to have osteopenia/osteoporosis. Obesity, hyperandrogenemia, hyperinsulinemia, and possibly hyperestrogenemiathe critical dimensions through which PCOS may positively influence bone massare not observed in every PCOS subject.

117 PCOS, Menopause and Osteoporosis Future regarding this issue: Comparisons of bone density and fracture rates among normal postmenopausal women and postmenopausal women with PCOS will ultimately determine the relative protective influence of androgen excess on the later-life risk of osteoporosis and its deleterious health outcomes.

118 Types of Physicians/Ancillary Professionals Involved with PCOS Internist Family Practitioner General Practitioner Pediatrician Obstetrician/Gynecologist Fertility/Reproductive Specialist Dermatologist Dietician Endocrinologist Gastroenterologist/Hepatologist Neurologist/Pulmonologist Cardiologist Oncologist Surgeon(Bariatric Surgery) Radiologist Psychiatrist

119 Who Should Manage PCOS? PCOS has evolved out of the purview of the reproductive specialist and gynecologist. PCOS is probably best managed by an internist, family practitioner or endocrinologist with the assistance of subspecialists including gynecologists, fertility specialist, dermatologists and in the long run, cardiologists and oncologists as indicated.

120 PCOS-Key Points PCOS is the most common cause of anovulatory infertility. PCOS is one of the commonest endocrinopathies to affect women(5-10%). PCOS probably represents a spectrum of disease with variable presentations. Is important to diagnose PCOS because of the potential long-term consequences. Early diagnosis may delay or possible prevent some of sequelae associated with PCOS. Further research is necessary in this syndrome.

121 Why is PCOS unfamiliar to most Clinicians? 1. Poorly taught if it all, in medical school 2. PCOS probably represents a spectrum of disease and variable presentations which may be elusive to the generalist or specialist. 3. There is no definitive lab test or noninvasive procedure to make the diagnosis.

122 Why is PCOS unfamiliar to most Clinicians? 4. PCOS has traditionally fallen in the realm of the gynecologist when in reality, this syndrome should involve several different types of physicians. 5. There is no financial advantage for drug companies to promote this syndrome since most medications used to treat this syndrome are generic. 6. There is not prominent spokeswomen with PCOS for the media. 7. And thus, the purpose of my lecture!

123

124 September is PCOS Awareness Month

125 References Azziz, R. et al., Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span, J Clin Endocrinol Metab, August 2005, 90(8):4650–4658. Badaway, A., Elnashar, A,. Treatment options for polycystic ovary syndrome, International Journal of Womens Health 2011;3:25-35 Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in women with polycystic ovary syndrome, Semin Reprod Med 2008, 26 (1), 72–84. Eid GM, Cottam DR, Velcu et al. Effective treatment of polycystic ovarian syndrome with Roux-en-Y gastric bypass. Surg. Obes. Relat. Dis. 1(2), (2005). Escobar-Morreale HF, Botella-Carretero JI, Alvarez-Blasco F, Sancho J, San Millan JL. The polycystic ovary syndrome association with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, (2005). Goldenberg N, Glueck C. Medical therapy in women with polycystic ovarian syndrome before and during pregnancy and lactation, Minerva Ginecol 2008, 60 (1), 63–75.

126 References continued Norman RJ, Noakes M, Wu R, Davies MJ, Moran L, Wang XJ. Improving reproductive performance in overweight/obese women with effective weight management. Hum. Reprod. Update 10, (2004). Pasquali, R., Gambineri, A., Insulin-sensitizing agents in polycystic ovary syndrome, European Journal of Endocrinology June 1, 2006; 154: Sjostrom L, Narbro K, Sjostrom CD et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357, (2007). Teede, Helena j. et al., Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline, Med J Aust 2011; 195 (6): S65-S112. Trolle B, Flyvbjerg A, Kesmodel U, Lauszus FF. Efficacy of metformin in obese and non-obese women with polycystic ovary syndrome: a randomized, double-blinded, placebo-controlled, cross-over trial. Hum. Reprod. 22(11), (2007). Vigil P, Contreras P, Alvarado JL, Godoy A, Salgado A, Cortes ME. Evidence of subpopulations with different levels of insulin resistance in women with polycystic ovary syndrome. Hum. Reprod. 22(11), (2007). Vryonidou A, Papatheodorou A, Tauridou A et al. Association of hyperandrogenism and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, (2005).

127 Books on the PCOS Androgen Excess Disorders in Women:PCOS and Other Disorders, by Azziz,Nestler,Dewailly, Humana Press, 2006 PCOS, by Balen,Conway,Homburg,Lego, Taylor & Francis Publishers, 2005 PCOS, by Chang,Heindel, Dunaif, Marcel Dekker, Inc PCOS, by Roy Homburg, Martin Dunitz, 2001 PCOS, by Gabor T.Kovac, Cambridge University Press, 2000 PCOS the Hidden Epidemic,by S. Thatcher,Perspectives Press, 2000

128 Patient Support Groups PCOSA-Polycystic Ovarian Syndrome Association, Inc.(Patient Support Group) Telephone: PCOS Mail: P.O.Box 7007, Rosemont, Il Internet:

129 Androgen Excess and PCOS Society http:// The Androgen Excess and PCOS Society is an international organization dedicated to promoting knowledge, and original clinical and basic research, in every aspect of androgen excess disorders, including: Polycystic Ovary Syndrome Adrenal Hyperplasia: Congenital (CAH) | Adrenal Hyperplasia: Non-classic (late onset) Idiopathic Hirsutism Premature Adrenarche

130 Post Lecture Quiz Question #1 Criteria used in the diagnosis of PCOS include all of the following except? a.Menstrual Irregularities b.Hyperandrogenism c.Cystic Changes in the Kidney and Liver d.Exclusion of Other Diseases

131 Post Lecture Quiz Question #2 Which of the following is false concerning PCOS? a.Women with PCOS have an increased rate of infertility b.Women with PCOS have an increased rate of spontaneous abortion c.PCOS affects about 5-10% of premenopausal women d.The lack of hirsutism rules out PCOS

132 Post Lecture Quiz Question #3 Findings associated with PCOS include all except which of the following? a.Fatty Infiltration of the Liver b.Keratosis Pilaris c.Obesity d.Acanthosis Nigricans e.Acne

133 Post Lecture Quiz Question #4 Long-Term Sequelae associated with PCOS include all of the following except? a.Type I Diabetes Mellitus b.Type II Diabetes Mellitus c.Dyslipidemia d.Endometrial Carcinoma

134 Post Lecture Quiz Question #5 The Differential Dx of Hyperandrogenic Anovulation includes all except: a.Autoimmune/Connective Tissue Disease b.PCOS c.Cushings Syndrome d.Congenital Adrenal Hyperplasia e.Androgen-secreting Ovarian or Adrenal Tumors

135 Answer to Questions 1. C-Cystic changes in the kidney and liver 2. D-The lack of hirsutism rules out PCOS 3. B-Keratosis Pilaris 4. A-Type 1 Diabetes Mellitus 5. A-Autoimmune/Connective Tissue Disease