YL is a 25-year-old woman who presented to policlinic for her annual physical exam.

Her main health concern was having a regular period

Menstrual irregularity,LMP 5 months prior

Ammenorrhea responded to treatment with methoxyprogersterone acetate She had been on oral contraceptives since the age of 19 She was not in need of contraception at this time and desired to become pregnant at some future date

Irregular since menarche at the age of 12 Getting longer over time Each menstrual period lasts for 1 week For the first 2 days her period is heavy(changed 4 pads a day)

Sexually active Trying to have kids but no progression She also complains of weight gain of 10kg for the past 6months Having acne problems since age 0f 15years old Having facial hair growth Denied having family history with same complain

Height 160cm Weight 70kg BMI 29.3(obese) BP 120/80mmg, rr 16x/m, pulse 80x/m Skin - hirsute, moderate to severe acne with comedos on the face, acanthosis migrans Abd obese, no striae, pain in lower abdomen segment(-)

Pelvix exam external genitalia within normal limit(no mass,swollen,or leceration) ,normal appearing cervix, no white discharge Bimanual examination- uterus and adnexae not palpated

USG- normal appearing ovaries, no sign of swollen endometrium or any tumor in the uterus

Fasting glucose 130 (normal <126) Thyroid stimulating hormone=1.0 (0.8-5.0) Cholesterol= 238 (<200) Triglycerides=323 (<200), HDL=49 (>50) LDL=69 (<160)

Androgen secreting tumor Exogenous androgens Cushings syndrome Nonclassical congenital adrenal hyperplasia Acromegaly Genetic defect in insulin metabolism Primary hypothalamic amenorrhea Primary ovarian failure Thyroid dz Prolactin dz

Polycystic ovarian syndrome

Reduce weight Metformin 500mg

YL exhibits many of the classical features of a woman with polycystic ovarian syndrome (PCOS) including her history of irregular menses and ammenorrhea responding to progesterone withdrawal Her physical exam is consistent with PCOS: including hirsutism and acne suggestive of increased androgen production, acanthosis nigricans associated with insulin resistance Increased BMI also related to insulin resistance, and which may also be a function of other neuroendocrine abnormalities including interactions with leptin (known to be associated with eating disorders) Laboratory values such as elevated triglycerides,fasting gluvose and also LDL are a common feature of PCOS. Her history suggests she is at higher risk of long term sequelae of PCOS: reproductive, and non-reproductive.

These sequlae include infertility, cardiovascular disease secondary to insulin resistance, and diabetes mellitus type II(adult onset) especially at the time of menopause Although oligomenorrheic or ammenorrheic , these women are not at risk for osteoporosis, rather the increased estrogen and decreased progesterone puts women at risk for endometrial hyperplasia and endometrial cancer Other potential sequelae are disorders of thyroid function. The aim of the diagnostic work-up is to identify risk factors, determine which patients will benefit from certain therapies, and monitor response to treatment Studies should include FBS, insulin/glucose ratio, thyroid function studies, lipid profile, and may include LH, testosterone, and pelvic ultrasound

Most common cause of fertility in women Classic syndrome originally described by Stein and Levantal -hyperandrogenism - menstrual irregularity - polycystic ovaries - central adiposity

Most common hormonal and reproductive problem affecting women of child-bearing age
Present in 5-10% of women

Commonly under-diagnosed due to use of birth control pills

UNKNOWN High insulin levels High androgen levels High LH

Low estro/prog

Abnormal Pituitary Function Altered Negative Feedback Loop Increased GnRH from hypothalamus Excessive LH secretion relative to FSH by pituitary gland LH stimulates ovarian thecal cells-androgenproduction Ineffective suppression of the LH pulsefrequency by estradiol and progesterone Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone Androgen excess increases LH by blocking the hypothalamic inhibitory feedback of progesterone

Genetics
Insulin-receptor substrate (IRS-1,IRS-2) Calpain-5 Calpain-10

Pre-puberty
Increased levels of adrenal androgen Increased insulin levels Ovarian hyperandrogenism

Leads to precocious puberty

Adolescence and Adulthood

Anovulation Hyperandrogenism Polycystic ovaries Obesity-50% of women

Leads to reproductive disorders

Late Adulthood
Diabetes Hypertension Dyslipidemia Cardiovascular disease

Leads to metabolic effects

Endometrial Cancer Breast Cancer

Acne

Hirsutism

Acanthosis nigricans

Skin tags

Male-pattern alopecia

Central obesity

DIFFERENTIAL DIAGNOSIS 1.Hyperprolactinemia Prominent menstrual dysfunction Little hyperandrogenism 2. Congenital Adrenal Hyperplasia morning serum 17-hydroxyprogesterone concentration greater than 200 ng/dL in the early follicular phase strongly suggests the diagnosis confirmed by a high dose (250 mcg) ACTH stimulation test: post-ACTH serum 17-hydroxyprogesterone value less than 1000 ng/dL

3. Ovarian and adrenal tumors serum testosterone concentrations are always higher than 150 ng/dL adrenal tumors: serum DHEA-S concentrations higher than 800 mcg/dL LOW serum LH concentrations 4. Cushings syndrome 5. Drugs: danazol; OCPs with highandrogenicity

TESTING

Serum HCG
Serum prolactin Thyroid panel FSH: r/o ovarian failure Serum luteinizing hormone (LH)-elevated Serum estradiol -normal Serum estrone -elevated Fasting glucose: elevated Fasting insulin: elevated Free testosterone: elevated DHEA-S: normal 17-hydroxyprogesterone: normal Pelvic US Lipids

1990 NIH criteria (all 3 must be met)

Hyperandrogenism, either clinical or

biochemical Menstrual irregularity (oligo- or anovulation) Exclusion of other causes

Prolactinoma Thyroid disease Virilizing tumors of adrenal or ovarian tumors Congenital adrenal hyperplasia Cushing's syndrome

2003 Rotterdam Criteria

Presence of at least two of the following: Oligo/anovulation Hyperandrogenism Polycystic ovaries on ultrasound And the exclusion of other causes

 Laboratory tests Elevated androgen (i.e., testosterone) levels Elevated LH with normal to mildly elevated FSH level Insulin resistance with hyperinsulinemia Glucose intolerance Hyperlipidemia Ultrasound findings Multiple (nine or more) subcortical follicular cysts Increased ovarian stromal density and/or volume

Urine HCG Prolactin level TSH Testosterone LH/FSH (3:1) Fasting insulin Fasting glucose, 2 hr GTT Fasting lipids

Pelvic US* DHEAS* 17-OHP* Dexamethasone suppression test* Endometrial biopsy*

*--Suggested only in selected patients.

Decrease hyperinsulinism Decrease hyperandrogenism Induce ovulation Prevent endometrial hyperplasia Prevent metabolic complications Weight loss

Weight reduction
Diet and exercise

Decreases serum androgen, insulin and LH levels and improves lipid abnormalities

Drug
*Clomiphene (Clomid)

Dose
50-100 mg/d

Preg
X

Mechanism
ovulation induction

Use
infertility

Eflornithine (Vaniqa)
Metformin (Glucophage)

13.9% cream applied BID

1500 to 2,250 mg/d

C
B

inhibits hair growth

insulin sensitizing

hirsutism
hirsutism infertility insulin resistance menstrual irreg hirsutism menstrual irreg endometrial hyperplasia

OCPs Provera

Varies 5-10 mg/d x 10-14d

Increases sex hormone binding glob, decr ovarian androgen secretion

Pioglitazone (Actos) Rosiglitazone (Avandia)

Spironolactone (Aldactone)

30 mg/d
2-8 mg/d 50-200 mg/d

insulin sensitizing

hirsutism infertility insulin resistance menstrual irreg

hirsutism menstrual irreg

antiandrogenic antimineralocorticoid

Drug
Acarbose (Precose)
Finasteride (Propecia) Flutamide Letrozole (Femara)

Dose
150 mg/d
5 mg/d 250 mg/d 2.5 mg/d

Preg
B
X D C

Mechanism
Insulin-sensitizing
5-alpha-reductase inhibitor Nonsteroidal antiandrogen Nonsteroidal competitive inhibitor of aromatase Centrally acting appetite suppressant

Use
hirsutism menstrual irreg
hirsutism hirsutism infertility

Sibutramine 10 mg/d (Meridia)

obesity hirsutism