CMS250 - Wk 1, PCOS

Polycystic Ovary Syndrome (PCOS) and Menstrual Irregularities

• PCOS affects reproductive-age women and its variable clinical presentation involves gynecologic, dermatologic, and metabolic manifestations.
• PCOS association with metabolic syndrome, insulin resistance, obesity, type 2 diabetes mellitus, cardiovascular disease, and endometrial hyperplasia needs to be appraised.
• Diagnostic analysis includes the Rotterdam criteria, ultrasonography, laboratory tests, and imaging studies.
• It is necessary to evaluate clinical and biochemical evidence of hyperandrogenism, and measure serum FSH, estradiol, prolactin, TSH, lipid profiles, and glucose.
• Differential diagnosis of PCOS requires differentiating other potential causes of anovulation in reproductive years and excluding other disorders with mimic its clinical features.
• It is useful to synthesize how to perform a targeted history and physical examination for patients with suspected or known PCOS
• Patients should also screened for comorbidities like depression and obstructive sleep apnea.
• The history of PCOS, its various names, and the diagnostic criteria proposed by different organizations and guidelines should be assessed for context
• Managing PCOS requires collaboration and communication among the interprofessional healthcare team
• The impact of PCOS on self-image, quality of life, and reproductive health should be evaluated

What is PCOS?

• PCOS is the most common endocrine disorder in reproductive-age people with a uterus and ovaries.
• PCOS is characterized by irregular menstrual periods, high androgen levels, and polycystic ovaries.

Condition: Epidemiology

• The prevalence of PCOS is 5-15%, with a greater than 20% incidence and prevalence in overweight and obese populations.
• PCOS symptoms of androgen excess and metabolic dysfunction vary among race/ethnicities, therefore PCOS incidence varies across ethnicities.
• PCOS risk factors are 70% hereditary, with the environment being a fundamental component in the expression of genes, and the development and progression of the disease.

History of PCOS

• In 1935, PCOS was originally described as a phenomenon by Stein and Leventhal.
• In 1990, the National Institute of Health (NIH) proposed the first criteria for diagnosis.
• In 2003 the Rotterdam Criteria for diagnosis was established by the European Society for Human Reproduction and Embryology and the American Society of Reproductive Medicine.

Clinical Presentation and Health Risks

• Appraising the association between PCOS and metabolic syndrome, insulin resistance, obesity requires understanding the long-term health risks
  • Type 2 diabetes mellitus, cardiovascular disease, endometrial hyperplasia, cancer, and perinatal complications.
  • Evaluating blood pressure, lipid levels, and glucose tolerance in patients with PCOS

Clinical Presentation

• Clinical Presentation includes:
  • Menstrual Dysfunction
  • Hyperandrogenism
  • Insulin resistance
  • Dyslipidemia
  • Obesity
  • Obstructive Sleep Apnea
  • Metabolic syndrome and cardiovascular disease
  • Endometrial Neoplasia
  • Infertility
  • Complications in pregnancy
  • Psychological health

Health Risks associated with PCOS

• Short term health risks from PCOS include:
  • Obesity
  • Infertility
  • Obstructive sleep apnea
  • Irregular menses
  • Endometrial Hyperplasia
  • Depression/anxiety
  • Abnormal lipid levels
  • Non-alcoholic fatty liver disease
  • Hirsutism/acne/androgenic alopecia
  • Insulin resistance/acanthosis nigricans
  • Pregnancy-related complications
• Long term health risks from PCOS include:
  • Endometrial cancer
  • Type 2 Diabetes Mellitus
  • Cardiovascular disease

Menstrual Dysfunction

• Menstrual dysfunction often includes:
  • Oligomenorrhea
  • Anovulation
  • Heavy menstrual bleeding
• Lack of ovulation → lack of progesterone production by corpus luteum results in constant estrogen exposure that constantly stimulates of the endometrium.
• Instability of the thickened endometrium leads to unpredictable bleeding.
• Heavy menstrual bleeding often leads to iron deficiency anemia.
• Menstrual dysfunction is common and normal at menarche.
• Regular ovulatory cycles are usually established by mid-adolescence
• In adolescents with PCOS menstrual irregularity continues
• Menstrual intervals <20 days or <45 days for girls >2 years after menarche OR a menstrual interval >90 days anytime after menarche merit evaluation

Health Risk: Endometrial Hyperplasia and Cancer

• Endometrial hyperplasia (EH) is a precancerous condition, irregular thickening of the endometrium (uterine lining)
• Anovulation causes prolonged exposure of the endometrium to estrogen, without regular exposure to progesterone.
• Anovulation leads to an increase in the risk of endometrial hyperplasia.
• Obesity and T2DM are independent risk factors for endometrial cancer.
• Women with PCOS have a 3.5-fold increased risk of endometrial cancer.
• It is essential to medically induce withdrawal bleeds in women with PCOS at least every 3-4 months.
• Oral contraceptive pills and long-acting progestin-only methods (IUD, etc) reduce the risk of endometrial cancer.
• Transvaginal US can be used to measure endometrial thickness in women without withdrawal bleeds, but routine screening is not recommended (Endocrine Society).
• Endometrial assessment is done in any woman older than 45 years with abnormal uterine bleeding, or younger than 45 with a history of unopposed estrogen.

Clinical Manifestation: Hyperandrogenism

• Clinical manifestation includes:
  • Acne
  • Hirsutism
  • Androgenic alopecia
• Hyperandrogenism does not present with signs typical of virilization: deepening voice, increased muscle mass, clitoromegaly.
• The presence of signs of virilization should results in investigation for an androgen-producing tumour.

Hirsutism

• Hirsutism is coarse, dark, terminal hair distributed in a male pattern.
• Typically begins in late adolescence or early 20s.
• PCOS is the cause of 70-80% of all hirsutism cases.
• Hirsutism is most commonly on the upper lip, chin, sideburns, chest, and linea alba.
• Racial and ethnic hair distribution differences: Mediterranean women have a higher concentration of androgen-sensitive hair follicles than Asian women.

Acne

• Acne is common in adolescence.
• Persistent, severe, or late-onset acne should raise suspicion for PCOS or other conditions of androgen excess.
• Androgen excess overstimulation with androgens elevates sebum production, leading to inflammation and comedone production in women.

Androgenic Alopecia

• Female pattern androgenic alopecia is less common in PCOS
• The hair slowly thins at the crown, but the frontal hairline remains intact;
• Alopecia can also be caused by other illnesses and alopecia should be evaluated for thyroid dysfunction, iron-deficiency anemia

Clinical manifestation: Insulin Resistance

• People with PCOS display greater degrees of insulin resistance and compensatory hyperinsulinemia.
• Insulin resistance is associated with metabolic and reproductive abnormalities (menstrual dysfunction).
• Insulin resistance contributes greatly to hyperandrogenism.
• Clinical manifestation of insulin resistance is subtle.

Health Risk: Insulin Resistance

• Insulin resistance impacts both obese and lean women with PCOS to a greater degree than in age-matched controls.
• Insulin resistance associates with type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease.
• Insulin resistance is the fundamental underlying mechanism of long-term health risks of PCOS.

Dyslipidemia

• The Prevalence of dyslipidemia is near 70% in women with PCOS, and most commonly:
  • Increased low-density lipoprotein (LDL) and triglycerides
  • Elevated total cholesterol to high density lipoprotein (HDL) ratios
  • Low HDL levels
• Dyslipidemia may raise cardiovascular disease risk in women with PCOS

Obesity

• Women with PCOS are more likely to be obese, and especially centrally obese.
• Central obesity is an independent risk factor for cardiovascular disease and predicts insulin resistance.

Obstructive Sleep Apnea (OSA)

• In the general population OSA is related to central obesity.
• In one meta-analysis, 35% of women with PCOS had OSA, especially obese women with PCOS.
• Metabolic factors contribute so women with PCOS who are weight-matched have a higher risk of OSA compared to controls.

Metabolic Syndrome

• Metabolic syndrome is characterized by insulin resistance, obesity, dyslipidemia, and hypertension.
• Women with PCOS have an increased risk of metabolic syndrome compared to age-matched controls.
• The Prevalence of metabolic syndrome is 45% compared to 4% in age-adjusted controls.
• Metabolic syndrome begins earlier in women with PCOS.

Cardiovascular Disease

• Small studies suggest a higher relative risk of myocardial infarction and cardiovascular disease with PCOS.
• People with PCOS have a 7-fold increased risk of myocardial infarction compared to age-matched controls.
• Risk is greatest in post-menopause.

Infertility

• Infertility is more common in women with PCOS and is caused by anovulatory cycles.
• To screen for anovulation, Endocrine Society guidelines recommend screening, even in people with PCOS with eumenorrhea (who are trying to get pregnant).
  • This is measured with mid-luteal phase serum progesterone.

Complications in Pregnancy

• Women with PCOS have a Higher rate of early miscarriage (30-50%) compared to a baseline rate of 15%
• The miscarriage may be at baseline in obese women with PCOS
• Higher rate of gestational diabetes also occurs in normal-weight women with PCOS
  • BMI remains associated with gestational diabetes likelihood and severity. Rate higher
• For those using ovulation induction medications to conceive, higher rates of multifetal gestation result.

Pregnancy Related Health Risks

• Higher rate of early miscarriage is related to weight, and there is a higher prevalence of this in obese people with PCOS
• There is more risk of gestational diabetes (even for those in normal weight ranges, but even more if elevated BMI)
• There is additional risk of pregnancy-induced hypertension and preterm birth
• Those using ovulation-induction medications to conceive have higher risks of multifetal gestation

Psychological Health

• Anxiety, depression, eating disorders and negative body image are more prevalent in people with PCOS.
• Screening for depression and anxiety is recommended.

Diagnostic Criteria

• Analyze the diagnostic criteria for PCOS, including the Rotterdam criteria, and the significance of ultrasonography, laboratory tests, and imaging studies in diagnosing PCOS.

Diagnostic Criteria: Rotterdam

• Rotterdam criteria was established in 2003
• Diagnosis requires meeting two of these three criteria:
  • Chronic anovulation
  • Clinical or biochemical hyperandrogenism
  • Polycystic ovarian morphology
• AND the exclusion of related disorders:
  • Thyroid dysfunction
  • Nonclassic congenital adrenal hyperplasia (NCAH)
  • Hypogonadotropic hypogonadism (hypothalamic amenorrhea)
  • Premature ovarian insufficiency
  • Hyperprolactinemia

Other organizations

• The National Institutes of Health required clinical finding of both hyperandrogenism and oligomenorrhea for a diagnosis in 1990
• The Rotterdam Criteria require two out of the the clinical findings of hyperandrogenism, oligomenorrhea, and/or polycystic ovaries
• The Androgen Excess & PCOS Society, requires hyperandrogenism and at least one of the additional criterion: oligomenorrhea or polycystic ovaries

Menstrual Dysfunction: Irregularity Definition

• Irregular menstrual cycles are defined as:
  • Normal in the first year post menarche as part of the pubertal transition
  • Cycles > 1 to < 3 years post menarche that are too short (< 21 days) or too long (> 45 days)
  • Cycles > 3 years post menarche to perimenopause that are too short (< 21 days), or too long ( ≥ 35 days) or occur in < 8 cycles per year
  • Cycles > 1 + years post menarche lasting 90 days for any single event
  • Primary amenorrhea by age 15 + or ≥ 3 yrs past breast development (thelarche)
• A PCOS diagnosis should be considered and assessed whenever irregular menstrual cycles are present.

Assessing Clinical or Biochemical Hyperandrogenism

• Diagnosis can be made based on clinical or biochemical evidence.
  • Clinical manifestations are hirsutism, acne, and/or androgenic alopecia.
  • Muscle mass increase, voice deepening, and clitoromegaly reflect greater exposures to androgens
    • These are not signs that PCOS is present
    • May reflect an androgen producing tumour of the ovary or adrenal gland.

Clinical or Biochemical Hyperandrogenism: Hirsutism

• Coarse, terminal hair distributed in a male pattern is referred to as hirsutism
• Hirsutism most commonly begins in late adolescence or early 20s.
• The hair follicle transforms to a terminal hair follicle with testosterone exposure, typically in androgen-sensitive areas.
• Hirsutism is detected frequently on the upper lip, sideburns, chin, chest, linea alba, and lower abdomen.

Assessing Hirsutism: Ferriman-Gallwey Score

• The tool used to assess for hirsutism is the Ferriman-Gallwey Score.
• The Ferriman-Gallwey Score has a range of 1-4 for nine areas
  • It defines hirsutism above the threshold: ≥4-6
• Far-East Asians have a different threshold (lower density of hair follicles), and a value >3
• It is also important to ask about self-treatment

Clinical Hyperandrogenism: Acne

• The frequent clinical finding of mild to moderate acne vulgaris can occur in adolescents
• Moderate to severe, persistent, or late-onset acne should raise concern for androgen excess/PCOS.

Clinical Hyperandrogenism: Female Alopecia

• Female androgenic alopecia: hair slowly diffuses at the crown but the frontal hairline is preserved.
• This is a less common clinical finding than hirsutism and acne

Biochemical Hyperandrogenism

• Elevated free testosterone is found in 70-80% of women with PCOS.
• Elevated DHEA-S is found in 25-65% of women with PCOS.
• In all patients, measure total and free testosterone.
• Biochemical androgens do not need to be assessed if clinical evidence exists.
• Biochemical Androgen testing is not reliably assessed when people are taking combined oral contraceptive pills (COCP) or for 3 months after stopping COCP.

Polycystic Ovarian Morphology

• Most accurately detected by transvaginal ultrasound (TVUS)
• Rotterdam criteria (2004) suggest PCOM cutoff is at least 12 follicles ("cysts") measuring 2-9mm in the whole ovary or ovarian size > 10ml
  • If not, 25 follicles (2-9mm) in the whole ovary according to AE and PCOS society
• There are improvements in US technology that have led to updated guidelines
• Anti-Mullerian hormone (AMH) for determining diagnosis of PCOS when US is not available.
  • AMH serves as a measure of ovarian reserve (follicle count).

Polycystic Ovarian Morphology

• Follicle number per ovary declines over the reproductive lifespan
• US assessments of ovaries are not recommended as there is no definitive criteria for PCOM in adolescents

Ruling out Related Disorders

• Related disorders to look into include:
  • Thyroid Dysfunction
  • Nonclassic Congenital Adrenal Hyperplasia (NCAH)
  • Hypogonadotropic Hypogonadism
  • Premature Ovarian Insufficiency
  • Hyperprolactinemia

Thyroid Dysfunction

• Routine screening for thyroid dysfunction is considered the norm (TSH test), thyroid exclusion may be of limited value in hyperandrogenism symptoms
• Even if thyroid dysfunction is relatively common, routine screening should be performed on reproductive aged women.

Nonclassic Congenital Adrenal Hyperplasia (NCAH)

• NCAH is a genetic disorder (autosomal recessive) that causes a deficiency of 21-hydroxylase enzyme function
• This causes an excessive amount of androgens, similar to PCOS
• Use a basal morning 17-OH-progesterone to detect

Hypogonadotropic hypogonadism

• Hypogonadotropic hypogonadism (HH) or functional hypothalamic amenorrhea suppresses GnRH secretion, FSH and LH
  • Ultimately there is a suppression of estrogen from the ovaries
• The test used is checking for both low levels of estradiol (E2), follicle stimulating hormone (FSH)

Premature Ovarian Insufficiency (Failure)

• Premature ovarian insufficiency (POI) is characterized by early loss of ovarian reserve and ovarian function (before the age of 40).
• Diagnose POI by testing for low levels of estradiol (E2) and high levels of follicle stimulating hormone (FSH).

Hyperprolactinemia

• High prolactin levels cause oligo-ovulation which needs to be ruled out as a cause of menstrual dysfunction
• Potential causes of hyperprolactinemia some physiologic like pregnancy, lactation, nipple stimulation, stress OR
• Some pathologic: pituitary adenoma (prolactin-secreting), acromegaly.
• The diagnostic Caveat is hyperandrogenism → prolactin levels in upper normal limit or slightly above normal, check Prolactin level

Other Disorders

• If Suspected, check for:
  • Cushing's Syndrome
  • Androgen secreting neoplasia
  • or High dose exogenous androgens

Learning Outcomes

• It important to differentiate other potential causes of anovulation in reproductive years in order to develop the correct differential for PCOS

Differential Diagnosis: Anovulation

• To diagnose Secondary Amenorrhea, Check in reproductive-aged women for:
  • Out Pregnancy (most common cause)
  • Ovarian diseases (40%)
  • PCOS (30%)
  • Premature ovarian failure (10%)
  • Hypothalamic dysfunction (35%)
  • Stress (10-21%)
  • Weight loss/disordered eating (15-54%) • Other Diagnoses: Pituitary disease (19%)
  • Prolactin secreting tumour (17%)
  • Empty sella syndrome (1%)
  • Sheehan's syndrome (1%)
  • Adrenocorticotropic hormone secreting tumor (<1%) Growth hormone secreting tumor (<1%)
• Other Diagnoses: Uterine (7%)
  • Asherman's Syndrome Other diagnoses 1%:
• NCAH
  • Acromegaly
  • Drug Induced
  • Post pill Amenorrhea

Considerations for Differential Diagnosis: PCOS

• In addition to testing, rule out hyper- or hypothyroidism, non-classic congenital adrenal hyperplasia (as per Rotterdam guidelines).

Differential Diagnosis: PCOS

• Hypothalamic amenorrhea: Usually accompanied by low body weight (fat mass), eating disorder or excessive exercise.
  • Test by checking if FSH, LH, and Estradiol are all low.
• Premature ovarian insufficiency: Usually accompanied by vasomotor symptoms (hot flashes) and urogenital symptoms (vaginal dryness).
  • Test by checking if FSH is high and Estradiol is low.

Differential Diagnosis: PCOS

• Androgen Secreting Tumor diagnosis needs total testosterone and levels of DHEAS (both elevated); there may be associated rapid change in voice and clitoromegaly.
• Cushing Syndrome diagnosis requires buffalo hump, hypertension, purple striae along with elevated Urinary cortisol for diagnoses

Differential Diagnosis: PCOS

• An Acromegaly Diagnosis requires change in hat/glove size, protruding jaw with impaired in vision
  • The test is by diagnosing growth factor (elevated).

Functional Ovarian Hyperandrogenism (FOH)

• FOH is a dysregulation of ovarian androgen secretion, causing an over-secretion of androgen hormones by the ovary.
• Nearly all causes of PCOS are due to FOH.
• FOH results by dysregulating androgen secretion in the ovary
  • It Also causes an over-response of 17-OH progesterone to gonadotropin stimulation from the pituitary Clinical features include; Hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology
  • It is caused FOH is influenced by both genetic & Environmental influences

Getting History for suspected PCOS cases

• Often a Diagnosis can be established with careful history, physical exam, and basic laboratory testing (ideally without the need for ultrasound).
  • 2 of the 3 diagnostic criteria hinge on exam and patient History; it can help rule out other clinical presentations Check for menstrual disturbance, a patients weight and PCOS Symptoms (Terminal hair, acne, etc...)
• Assess for clinical findings and Co-morbidities

Obtaining the History and Symptoms of a patient with PCOS

• Here are some important information to acquire from the history of a patient:
  • Period cycle (when it started, the last time it started, regularity and length, pregnancy risk Always let the patient tell their story unobstructed
• Assess weight history from the patient
• Inquire about clinical findings and Co-morbidities
  • Important red flags include Unprotected sex, headaches/loss of Peripheral Vision

History on Physical Examinations(know PCOS)

• History and physicals should take should account Co-morbidities and general well-being to track well-being such as
• Blood Pressure
• Symptoms for the possibility of Obstructive Sleep Apnea with a proper Diagnosis through formal sleep study.
• Women with PCOS should be also asked on their perception towards; PCOS through a quality-of-screen
• Depression/Screening Tooling to screen

Patient Screening

• Screen and assess for comorbidities and patient well being, for instances:
• Comorbidities like menstrual cycle (induce bleeds if longer than 3 to 4 months;
• Fasting or oral glucose load
• The need to asses weight and circumference often

Screening for Comorbidities

• Screenings Include:
  • BMI & WAIST Measurements
  • B/P Measurements
  • OGTT Cardiovascular Disease
  • Assess to assess cigarette smoking, dyslipidemia( levels for cholesterol).
    • Family history of stroke or vascular disease.

Collaboration on PCOS Patient Wellbeing

• Assess the Importance, impact, Communication, Collaboration along with the team
• Help improve: -Patient wellbeing
  • Disease Satisfaction

Interprofessional Collaboration

• Patients that report PCOS report delays with diagnosis and dissatisfactions with care.
• A care team requires a multidisciplinary to share in patient centered principles

Professional Expertise

• Members include:
  • A Family Doctor / a Nurse
  • A Physician
  • A Specialist
    • Dietician to help patient adhere to a meal plan.
  • Pharmacist

Impacts On Patients

• Patients Often Face Issues, but the impacts of PCOS on life of quality have:
  • Psychological/ Psychosexual Issues
• A Dislike In Overall Quality And self Esteem