Update: Polycystic Ovarian SyndromeDr. Douglas Austin

Fertility Center of Oregon

(541) 683-1559

daustin@womenscare.com

Lecture Goals• Describe the evaluation to determine the diagnosis.

• Understand the pathophysiology of PCOS.

• Define treatment goals based on the stage of life.

• Outline treatments.

• Understand the natural consequences of untreated and treated PCOS.

Prevalence• 6-10% of women

• Representation in ethnic/geographic populations

• Methodologically complex

• The classic PCOS phenotype indicates that the disorder seems to have originated before Homo Sapiens separated in to racial groups

“From an evolutionary perspective, the increasing prevalence of complex metabolic disorders such as obesity, diabetes, and PCOS in developed and developing countries brings attention to the idea that genetic triggers leading to pathogenic mechanisms underlying these syndromes might be candidate factors for survival advantage of the human being”

Evolutionary determinants of polycystic ovary syndrome: part 1Ünlütürk, Uğur et al.Fertility and Sterility, Volume 106, Issue 1, 33 - 41

Rotterdam Criteria (May 2003)Two of three of the following:

• Signs of chemical or biochemical hyperandrogenism

• Chronic ovulatory dysfunction (OD)

• Polycystic ovarian morphology (PCOM) excluding secondary causes

NIH (1990)Two of two criteria:

• Hyperandrogenism

• Ovulatory dysfunction

PCOS PhenotypesNIH 2012 extension of ESHRE/ARSM 2003

A hyperandrogenism, ovariandysfunction, polycystic ovarian morphology

• Increased menstrual dysfunction• Increased IR• Increased risk of metabolic syndrome• Increased BMI• More severe atherogenic dyslipidemia• Increased hepatic steatosis• Increased AMH

B hyperandrogenism, ovariandysfunction

C hyperandrogenism, polycystic ovarian morphology

• Increased SES• Unclear whether obesity is the deciding

factor

D ovarian dysfunction, polycystic ovarian morphology

• endocrine/metabolic• Lower LH:FSH• Lower total and free testosterone• Increased SHBG• Increased incidence of regular and irregular

cycles

PCOS Associated Morbidity• Reproductive difficulties

• Insulin resistance

• Increased risk of type II diabetes mellitus

• Coronary artery disease

• Atherogenic dyslipidemia Lower HDL, elevated triglycerides and LDL cholesterol

• Obstructive sleep apnea

• Cerebrovascular morbidity

• Anxiety/depression

• Endometrial hyperplasia/cancer

PCOS Pregnancy-Related Difficulties• Increased gestational diabetes mellitus

• Pre-eclampsia

• Fetal macrosomia

• SGA infant

• Increased perinatal mortality

“…when PCOS is not clearly evident by adult standards, in adolescents the disorder could be considered on the basis of the presence of increased serum androgens levels and/or progressive hirsutism, in association with persistent oligo/amenorrhea for at least 2 years after menarche and/or primary amenorrhea by age 16 years, and/or an ovarian volume >10 cm3, after exclusion of secondary causes.”

Criteria, prevalence, and phenotypes of polycystic ovary syndromeLizneva, Daria et al.Fertility and Sterility, Volume 106, Issue 1, 6 - 15

Adolescents• Phenotype will develop fully by age

18

• Ferriman-Gallwey sore Not associated with age

Two years after menarche

• Follicle count is higher in adolescents

Peri and Postmenopausal Women• Perimenopause ameliorates with increased menstrual

cycles, decreased androgens and decreased ovarian volume

• Make a diagnosis based on history of menstrual dysfunction and hyperandrogenism during reproductive life

Diagnosis of Exclusion• Non classical congenital adrenal hyperplasia

17-OH progesterone level < 200 mg/dL on AM follicular

• Pregnancy

• Hyperprolactinemia

• Hypothyroidism

• Ovarian failure

• Hypogonadotropic hypogonadism

• Adrenal secretory tumors

• Cushing’s syndrome

• Acromegaly

Pathophysiology• Inherent abnormalities of ovarian steroidogenesis and follicular

development Persistent and rapid GnRH pulses

Excess LH and insufficient FSH secretion

• Insulin Resistance Increased insulin enhances ovarian and adrenal androgen production

Leads to decrease in SHBG levels which increases androgen bioavailability

30-35% with insulin resistance

8-10% with type II diabetes mellitus

Evolution of Genetic Hypothesis• Initially autosomal dominant trait

Prevalence in 1st order relatives

• Polygenic or X-linked disorder Twin studies

• Candidate Gene Approach Gonadotropin receptors Beta subunit of FSH Insulin receptors (INSR)

Linked to the fibrillin-3 gene

Differentially expressed in normal and neoplastic DENN domain containing protein 1A (DENND1A)

Thyroid adenoma associated protein (THADA)

• Genomic Wide Associating Studies 2p16.3 LHCGR 2p21 THADA 9q33.3 DENND1A

Treatment Plans

Early in Life• Ovulatory/menstrual

abnormalities

• Cosmetic

• Metabolic

Late in Life• Metabolic

• Neoplastic

Middle of Life• Ovulatory/menstrual

abnormalities

• Fertility

Therapeutic Options• Weight loss

• Mechanical hair removal

• Combined OCP’s (low androgenic OCP’s)

• Spironolactone 50 mg BID to 100 mg BID

• Metformin 500 mg TID with meals

20-25% reduction in androgen production

Increased pregnancy but not an increased live birth rate

Possible cardiovascular improvement but lacks confirmatory data

• Progestin intermittent or continuous

• Levonorgestrel-releasing IUD

Therapeutic Options• Selenium

200 micrograms/day

Decreases serum insulin and triglycerides

• ZnSO4

220 milligrams/day

Decreases fasting glucose and insulin

• Vitamin D3

20,000-50,000 iu/week

Decreases fasting glucose, C-peptide and triglyceride levels

Improves menstrual cycles

Decreases acne and hirsutism

Therapeutic Options• Inositols

Myo-inositol

Promotes glucose uptake in liver

Increases glucose uptake and FSH signaling in PCOS ovary

D-chiro inositol

Increases glycogen synthesis

Decreased insulin-mediated androgen synthesis

2-4 grams/day

40:1 ratio of myo-inositol to d-chiro inositol is recommended for improved ovulation and embryo quality due to decreased hyperandrogenism and dyslipidemia

• Omega 3 fatty acids

1200 ng/day

Decreases fasting glucose and insulin

Ovulation Options• Weight loss

• Ovulation medications Metformin

7.2% success rate

Clomid

22.5% success rate

Femara (letrozole)

27.5% success rate

• Gonadotropins

• IVF

Ongoing Assessment• Measure of BMI

• Waist-hip circumference

• Blood pressure

• Fasting lipid levels

Every two years

• Screening for impaired glucose tolerance and type II diabetes mellitus

2 hour GTT q 1-5 years

Measure of hgbA1C (>6.5%)

Lecture Goals• Describe the evaluation to determine the diagnosis.

• Understand the pathophysiology of PCOS.

• Define treatment goals based on the stage of life.

• Outline treatments.

• Understand the natural consequences of untreated and treated PCOS.