Polycystic Ovary Syndrome Obstetrics & Gynecology Vol 103, No 1, Jau 2004 부산백병원 산부인과 R4 강영미

Introduction Chronic anovulation and androgen excess not attributable to another cause Chronic anovulation and androgen excess not attributable to another cause Occurs in approximately 4% of women Occurs in approximately 4% of women Fundamental pathophysiologic defect Fundamental pathophysiologic defect Unknown Unknown Important characteristics ; insulin resistance, hyperandrogenism, and altered gonadotropin dynamics Important characteristics ; insulin resistance, hyperandrogenism, and altered gonadotropin dynamics Inadequate FSH ; hypothesized to be a proximate cause of anovulation Inadequate FSH ; hypothesized to be a proximate cause of anovulation Obesity complicates PCOS but is not a defining characteristic Obesity complicates PCOS but is not a defining characteristic

Introduction Diagnostic approach ; should based on history and physical exam Diagnostic approach ; should based on history and physical exam Irregular bleeding, hirsutism and/or infertility Irregular bleeding, hirsutism and/or infertility Treated with OCs, OCs with spironolactone and ovulation induction Treated with OCs, OCs with spironolactone and ovulation induction Higher prevalence of diabetes and increased risk factors for cardiovascular ds. Higher prevalence of diabetes and increased risk factors for cardiovascular ds. should also be screened should also be screened for obese women with PCOS, for obese women with PCOS, behavioral weight management ; central behavioral weight management ; central component of the overall treatment strategy component of the overall treatment strategy

Definition Since its first description in 1935, a variety of histologic, biochemical, sonographic and clinical characteristics ; associated with PCOS Since its first description in 1935, a variety of histologic, biochemical, sonographic and clinical characteristics ; associated with PCOS Practical and useful clinical definition of PCOS in the United States Practical and useful clinical definition of PCOS in the United States If have chronic anovulation and evidence of androgen excess for which there is no other cause If have chronic anovulation and evidence of androgen excess for which there is no other cause Referred to as the "NIH Conference" definition, despite wide variety of views regarding the clinical, endocrinologic features (Table 1) Referred to as the "NIH Conference" definition, despite wide variety of views regarding the clinical, endocrinologic features (Table 1)

Prevalence Best prevalence study, reported in 1998, with unselected sample of white and African-American women between the ages of 18 and 45 years Best prevalence study, reported in 1998, with unselected sample of white and African-American women between the ages of 18 and 45 years 277 women who consented to a history, physical exam, and hormonal evaluation, overall prevalence of PCOS 277 women who consented to a history, physical exam, and hormonal evaluation, overall prevalence of PCOS 4-4.7% for white women 4-4.7% for white women 3.4% for African American women 3.4% for African American women

Clinical Importance In clinical gynecologic practice, In clinical gynecologic practice, Primarily for menstrual irregularity, hirsutism, and infertility Primarily for menstrual irregularity, hirsutism, and infertility Treatment is directed at the immediate presenting complaint Treatment is directed at the immediate presenting complaint Long-term goals Long-term goals Prevent diabetes, coronary heart ds. Prevent diabetes, coronary heart ds. Screen cancer Screen cancer Unopposed estrogen exposure -> increased risk of endometrial ca. Unopposed estrogen exposure -> increased risk of endometrial ca.

Pathophysiology Fundamental pathophysiologic defect in PCOS Fundamental pathophysiologic defect in PCOS Unknown Unknown Several interrelated characteristics ; insulin resistance, hyperandrogenism, and altered gonadotropin dynamics Several interrelated characteristics ; insulin resistance, hyperandrogenism, and altered gonadotropin dynamics Hypothesis that inadequate FSH stimulation ; proximate cause of anovulation in PCOS Hypothesis that inadequate FSH stimulation ; proximate cause of anovulation in PCOS

Pathophysiology Insulin resistance Insulin resistance Defined as a subnormal biological response to insulin Defined as a subnormal biological response to insulin Associated with obesity Associated with obesity Extent of insulin resistance - cannot be explained entirely by obesity Extent of insulin resistance - cannot be explained entirely by obesity

Pathophysiology Hyperandrogenism Hyperandrogenism strong correlation between insulin resistance and hyperandrogenism strong correlation between insulin resistance and hyperandrogenism HAIR-AN syndrome HAIR-AN syndrome Acanthosis nigricans Acanthosis nigricans Strongly suggests insulin resistance Strongly suggests insulin resistance Dermatologic disorder characterized by velvety hyperpigmented skin, usually over the nape of the neck, in the axillae, or beneath the breasts) Dermatologic disorder characterized by velvety hyperpigmented skin, usually over the nape of the neck, in the axillae, or beneath the breasts)

Pathophysiology what is the directionality of the relationship between insulin resistance and hyperandrogenism? what is the directionality of the relationship between insulin resistance and hyperandrogenism? Direction of causation is from insulin to androgen and not reverse Direction of causation is from insulin to androgen and not reverse Administration of diazoxide -> results in reduction in circulating androgen concentrations Administration of diazoxide -> results in reduction in circulating androgen concentrations Weight loss and insulin sensitizers -> reduction in androgen Weight loss and insulin sensitizers -> reduction in androgen in vivo effect on ovarian androgens by insulin in vivo effect on ovarian androgens by insulin insulin synergizes with LH to promote androgen production by the thecal cells insulin synergizes with LH to promote androgen production by the thecal cells

Pathophysiology Altered gonadotropin-releasing hormone dynamics Altered gonadotropin-releasing hormone dynamics Another key pathophysiologic feature of PCOS Another key pathophysiologic feature of PCOS Increased LH pulse frequency and amplitude, leading to increased 24-hour mean concentrations in both lean and obese women with PCOS Increased LH pulse frequency and amplitude, leading to increased 24-hour mean concentrations in both lean and obese women with PCOS Elevated LH levels Elevated LH levels Responsible for the excess androgen production Responsible for the excess androgen production Androgen production by theca cell is LH dependent Androgen production by theca cell is LH dependent Suppression of LH by GnRH agonists or by OCs reduces circulating testosterone and androstenedione Suppression of LH by GnRH agonists or by OCs reduces circulating testosterone and androstenedione

Pathophysiology Inadequate concentrations of endogenous FSH Inadequate concentrations of endogenous FSH Absolute concentrations of FSH above a specified threshold Absolute concentrations of FSH above a specified threshold Essential for both the initiation of preovulatory follicle development as well as the selection of a single preovulatory follicle Essential for both the initiation of preovulatory follicle development as well as the selection of a single preovulatory follicle

Pathophysiology In PCOS, In PCOS, E2 production ; limited E2 production ; limited Follicles not mature fully Follicles not mature fully Granulosa cells number and in aromatase activity decreased Granulosa cells number and in aromatase activity decreased Therefore, E2 production is limited, in the range of pg/mL higher than early follicular E2 Therefore, E2 production is limited, in the range of pg/mL higher than early follicular E2 Suppressing FSH, but never reaching the levels needed to initiate an LH surge Suppressing FSH, but never reaching the levels needed to initiate an LH surge Concentration of FSH Concentration of FSH Not rise above levels seen in the mid-follicular range Not rise above levels seen in the mid-follicular range Insufficient to stimulate preovulatroy follicle development Insufficient to stimulate preovulatroy follicle development Constrained by negative feedback inhibition of E2 which never exceeds mid-follicular levels Constrained by negative feedback inhibition of E2 which never exceeds mid-follicular levels

Pathophysiology Currently lack a satisfactory integrative model of PCOS pathophysiology Currently lack a satisfactory integrative model of PCOS pathophysiology Genetic factors are at the root of the condition Genetic factors are at the root of the condition In view of characteristics such as insulin resistance and gonadotropin changes In view of characteristics such as insulin resistance and gonadotropin changes Likely that more than one genetic "hit" Likely that more than one genetic "hit" Influenced by environmental factors Influenced by environmental factors

Diagnostic Approach Relatively safe ground on combination of chronic anovulation and androgen excess Relatively safe ground on combination of chronic anovulation and androgen excess With respect to ovulatory history With respect to ovulatory history History of irregular menstrual cycles dating to menarche History of irregular menstrual cycles dating to menarche Report 6 or fewer episodes of spontaneous vaginal bleeding per year Report 6 or fewer episodes of spontaneous vaginal bleeding per year

Diagnostic Approach oily skin and acne oily skin and acne subtle signs of androgen excess subtle signs of androgen excess Hirsutism Hirsutism Most common manifestation of the androgen component of PCOS Most common manifestation of the androgen component of PCOS should inquire about and examine for should inquire about and examine for "male-pattern" hair(hair located on the upper lip, chin, chest, lower abdomen, and inner aspects of the thighs) "male-pattern" hair(hair located on the upper lip, chin, chest, lower abdomen, and inner aspects of the thighs)

Diagnostic Approach Differing opinions on what laboratory studies should be ordered in evaluating a woman with PCOS Differing opinions on what laboratory studies should be ordered in evaluating a woman with PCOS Primarily a clinical diagnosis - few laboratory studies are needed Primarily a clinical diagnosis - few laboratory studies are needed Only condition that needs to be excluded to secure the diagnosis of PCOS - nonclassical CAH Only condition that needs to be excluded to secure the diagnosis of PCOS - nonclassical CAH Diagnostic pathway in Figure 3 Diagnostic pathway in Figure 3

Diagnostic Approach Figure 3 Figure 3

Diagnostic Approach Ratio of LH to FSH greater than 2;1 - consistent with PCOS Ratio of LH to FSH greater than 2;1 - consistent with PCOS LH ; FSH ratio often in the "normal range" LH ; FSH ratio often in the "normal range" ∵ pulsatile nature of gonadotropins, resulting in broad range of LH ; FSH ratios in PCOS when a single blood sample is drawn ∵ pulsatile nature of gonadotropins, resulting in broad range of LH ; FSH ratios in PCOS when a single blood sample is drawn In author's practice, evaluating a women with chronic anovulation since menarche and hirsutism In author's practice, evaluating a women with chronic anovulation since menarche and hirsutism Only blood sample - 17-hydroxyprogesterone concentration to rule out 21-hydroxylase-deficient nonclassical adrenal hyperplasia Only blood sample - 17-hydroxyprogesterone concentration to rule out 21-hydroxylase-deficient nonclassical adrenal hyperplasia

Diagnostic Approach Testosterone Testosterone Not necessary for diagnosis when clear hirsutism is present Not necessary for diagnosis when clear hirsutism is present Sometimes helpful in evaluating a women with chronic anovulation but who does not have clinical evidence of hirsutism or other signs of androgen excess Sometimes helpful in evaluating a women with chronic anovulation but who does not have clinical evidence of hirsutism or other signs of androgen excess Total testosterone concentration greater than 60 ng/dL ; consistent with PCOS Total testosterone concentration greater than 60 ng/dL ; consistent with PCOS

Diagnostic Approach Ovarian anatomy Ovarian anatomy Show multiple, small, subcapsular cysts, reflecting repeated episodes of incomplete follicular growth Show multiple, small, subcapsular cysts, reflecting repeated episodes of incomplete follicular growth Dense, hyperplastic stroma, reflecting an active thecal component that is over-secreting androgens Dense, hyperplastic stroma, reflecting an active thecal component that is over-secreting androgens Ultrasound picture Ultrasound picture Numerous, small subcapsular cysts that produces a "string of pearls" sign(Figure 4) Numerous, small subcapsular cysts that produces a "string of pearls" sign(Figure 4) Small subcapsular cysts and hyperechogenic stroma Small subcapsular cysts and hyperechogenic stroma

Diagnostic Approach Figure 4 Figure 4

Diagnostic Approach In summary, In summary, Best diagnosed clinically with a minimum of laboratory tests Best diagnosed clinically with a minimum of laboratory tests History of chronic anovulation dating since menarche History of chronic anovulation dating since menarche Evidence of androgen excess, principally hirsutism Evidence of androgen excess, principally hirsutism Blood sample for serum 17- hydroxyprogesterone concentration to rule-out 21- hydroxylase-deficient nonclassical adrenal hyperplasia Blood sample for serum 17- hydroxyprogesterone concentration to rule-out 21- hydroxylase-deficient nonclassical adrenal hyperplasia Obesity in conjunction with anovulation and androgen excess Obesity in conjunction with anovulation and androgen excess Increase further one's suspicion of PCOS Increase further one's suspicion of PCOS

Diagnostic Approach In cases in which the clinical diagnosis is not clear In cases in which the clinical diagnosis is not clear Chronic anovulation without hirsutism Chronic anovulation without hirsutism Hirsutism with a history of cyclic menses Hirsutism with a history of cyclic menses Obesity ; increases the clinical suspicion of PCOS Obesity ; increases the clinical suspicion of PCOS Serum testosterone greater than 60 ng/dL ; suggests diagnosis of PCOS Serum testosterone greater than 60 ng/dL ; suggests diagnosis of PCOS

Long-term risk of PCOS Increased risk of endometrial cancer Increased risk of endometrial cancer ∵ Unopposed estrogen that results from chronic anovulation ∵ Unopposed estrogen that results from chronic anovulation In recent years, diabetes and cardiovascular ds. In recent years, diabetes and cardiovascular ds.

Long-term risk of PCOS Dramatically increased risk of impaired glucose tolerance and non-insulin-dependent diabetes mellitus Dramatically increased risk of impaired glucose tolerance and non-insulin-dependent diabetes mellitus Fasting glucose concentrations - poor predictors of non-insulin-dependent diabetes mellitus Fasting glucose concentrations - poor predictors of non-insulin-dependent diabetes mellitus ∵ As shown in Figure 5, women with PCOS ∵ As shown in Figure 5, women with PCOS - Normal fasting glucose concentration - Normal fasting glucose concentration - IGT and DM based on 2-hour oral glucose - IGT and DM based on 2-hour oral glucose tolerance test value tolerance test value 30% for IGT, 8-10% DM(Figure 6) 30% for IGT, 8-10% DM(Figure 6)

Long-term risk of PCOS

Do the diabetes, adverse lipid profile and preclinical atherosclerotic changes seen in women with PCOS translate into an increase in actual cardiovascular events? Do the diabetes, adverse lipid profile and preclinical atherosclerotic changes seen in women with PCOS translate into an increase in actual cardiovascular events? Limited and inconsistent Limited and inconsistent Clear need for a prospective study Clear need for a prospective study

Treatment Figure 8 Figure 8

Treatment Patient's height and weight to calculate her body mass index Patient's height and weight to calculate her body mass index BP at the first visit BP at the first visit Fasting lipid panel to evaluate cardiovascular risk Fasting lipid panel to evaluate cardiovascular risk Fasting glucose concentration to evlauate the possibility of IGT or non-insulin-dependent diabetes mellitus Fasting glucose concentration to evlauate the possibility of IGT or non-insulin-dependent diabetes mellitus 2-hour oral glucose tolerance test is preferable 2-hour oral glucose tolerance test is preferable

Treatment In overweight patient(body mass index 26 or higher), In overweight patient(body mass index 26 or higher), major component of any treatment should be directed at weight reduction major component of any treatment should be directed at weight reduction Best weight loss strategy - integrated behavioral program Best weight loss strategy - integrated behavioral program Include exercise, moderate calorie restriction Include exercise, moderate calorie restriction Result in significant favorable impact on insulin, androgens, and ovulation Result in significant favorable impact on insulin, androgens, and ovulation No data on long-term outcomes of such lifestyle modification programs No data on long-term outcomes of such lifestyle modification programs

Treatment Initial therapeutic strategy in the management of PCOS Initial therapeutic strategy in the management of PCOS Behavioral weight management in obese patients follows directly from the patient's chief complaint Behavioral weight management in obese patients follows directly from the patient's chief complaint Metformin - not sliver bullet for all aspects of PCOS treatment Metformin - not sliver bullet for all aspects of PCOS treatment

Treatment Irregular menstruation Irregular menstruation Without the additional concerns of hirsutism or infertility Without the additional concerns of hirsutism or infertility OCs remain an excellent choice OCs remain an excellent choice Present hirsutism Present hirsutism OCs plus spironolactone, at a dose of 200 mg/d is standard choice OCs plus spironolactone, at a dose of 200 mg/d is standard choice

Treatment Several clear benefits in the treatment of irregular menstrual cycles in women with PCOS Several clear benefits in the treatment of irregular menstrual cycles in women with PCOS 1.Regular withdrawal bleeding 1.Regular withdrawal bleeding 2. Reduction in the risk of endometrial hyperplasia or cancer because of progestin opposition of estrogen 2. Reduction in the risk of endometrial hyperplasia or cancer because of progestin opposition of estrogen 3. Reduction in LH secretion and consequent reduction of ovarian androgens 3. Reduction in LH secretion and consequent reduction of ovarian androgens 4. Increased sex hormone binding globulin production and consequent reduction in free testosterone 4. Increased sex hormone binding globulin production and consequent reduction in free testosterone 5. Improvement in hirsutism and acne 5. Improvement in hirsutism and acne Measruable decline in hirsutism after 6 months of treatment, while no effect on hirsutism was seen with metformin Measruable decline in hirsutism after 6 months of treatment, while no effect on hirsutism was seen with metformin

Treatment Common reason for a physician consultation ; infertility Common reason for a physician consultation ; infertility Assuming a normal semen analysis, ovulation induction Assuming a normal semen analysis, ovulation induction Recommended approach in Figure 9 Recommended approach in Figure 9 Hysterosalpingography to confirm a normal genital tract if history of PID, endometriosis, or previous abdominal surgery Hysterosalpingography to confirm a normal genital tract if history of PID, endometriosis, or previous abdominal surgery

Treatment Figure 9 Figure 9

Treatment Most physiologic approach to ovulation induction ; weight loss Most physiologic approach to ovulation induction ; weight loss Failing that -> clomiphene citrate Failing that -> clomiphene citrate Excellent initial pharmacologic strategy Excellent initial pharmacologic strategy Use the lowest clomiphene citrate dose that will initiate the smallest number of ovulatory follicles(hopefully, only one!) Use the lowest clomiphene citrate dose that will initiate the smallest number of ovulatory follicles(hopefully, only one!) Starting dose ; 50 mg/d for 5 days(usually days 5-9) Starting dose ; 50 mg/d for 5 days(usually days 5-9) approximately 50% ovulation on 50 mg approximately 50% ovulation on 50 mg

Treatment Ultrasound on day 13 to assess follicle development Ultrasound on day 13 to assess follicle development More than 2 preovulatory follicles on day 13 ; reduced to 25 mg/d in subsequent cycles More than 2 preovulatory follicles on day 13 ; reduced to 25 mg/d in subsequent cycles No follicle development ; dose and duration of treatment increased No follicle development ; dose and duration of treatment increased Never exceed 150 mg/d for 5 days Never exceed 150 mg/d for 5 days Once regimen that induces ovulation if there is no pregnancy Once regimen that induces ovulation if there is no pregnancy Should repeat that regimen and not increase the dose in subsequent cycles Should repeat that regimen and not increase the dose in subsequent cycles -> Goal is ovulation, not superovulation -> Goal is ovulation, not superovulation Overall, approximately 80% of women with PCOS - ovulate on clomiphene citrate Overall, approximately 80% of women with PCOS - ovulate on clomiphene citrate

Treatment How should ovulation be induced in the 20% of women who are refractory to clomiphene citrate? How should ovulation be induced in the 20% of women who are refractory to clomiphene citrate? Use of metformin hydrochloride Use of metformin hydrochloride Common and effective strategy Common and effective strategy Used extensively in the treatment of non-insulin-dependent diabetes mellitus Used extensively in the treatment of non-insulin-dependent diabetes mellitus Helps with glycemic control by reducing hepatic glucose output and by increasing peripheral uptake of glucose Helps with glycemic control by reducing hepatic glucose output and by increasing peripheral uptake of glucose Kidney or liver ds., alcoholism, heart failure treated with furosemide should not take metformin Kidney or liver ds., alcoholism, heart failure treated with furosemide should not take metformin ∵ lactic acidosis risk ↑ ∵ lactic acidosis risk ↑ Begun at a dose of 500 mg/d to minimize gastrointestinal side effects and increased gradually as tolerated Begun at a dose of 500 mg/d to minimize gastrointestinal side effects and increased gradually as tolerated

Treatment Small percentage of women with PCOS (about 5-10%) who are refractory to clomiphene citrate alone and to metformin plus clomiphene citrate or who cannot tolerate these medications Small percentage of women with PCOS (about 5-10%) who are refractory to clomiphene citrate alone and to metformin plus clomiphene citrate or who cannot tolerate these medications Laparoscopic ovarian drilling or injectable gonadotropin Laparoscopic ovarian drilling or injectable gonadotropin Gonadotropins Gonadotropins Hypersensitive to exogenous FSH Hypersensitive to exogenous FSH Risk of multiple pregnancy and hyperstimulation Risk of multiple pregnancy and hyperstimulation Should be used in conjunction with in vitro fertilization Should be used in conjunction with in vitro fertilization ; Number of embryos that are transferred to the uterine cavity controlled

Follow-Up Women with PCOS who are being seen for infertility Women with PCOS who are being seen for infertility Followed closely with regards to ovulation induction Followed closely with regards to ovulation induction If no pregnancy after 6 months of documented ovulation If no pregnancy after 6 months of documented ovulation Additional infertility evaluation Additional infertility evaluation If no pregnancy after 9-12 months of documented ovulation, and if no other infertility factors If no pregnancy after 9-12 months of documented ovulation, and if no other infertility factors Blend with unexplained infertility Blend with unexplained infertility Intrauterine insemination is added Intrauterine insemination is added If lack of pregnancy despite multiple cycles of ovulation induction and intrauterine insemination If lack of pregnancy despite multiple cycles of ovulation induction and intrauterine insemination Lead to consideration of the use of gonadotropins Lead to consideration of the use of gonadotropins

Follow-Up For women with PCOS who are not interested in pregnancy For women with PCOS who are not interested in pregnancy Follow-up at 6 month intervals Follow-up at 6 month intervals