Polycystic Ovarian Syndrome Flashcards
1
Q
Percent of women who are infertile due to PCOS
A
- 10%
2
Q
Stein-Leventhal PCOS characteristics
A
- Amenorrhea
- Hirsutism
- Obesity
- B/L enlarged ovaries
3
Q
PCOS genetic disease characteristics
A
- Heterogenous/ Variable phenotypic/ polygenic; women will have varying displays of the disease
- Manifests in reproductive problems; anovulation
- Cardiovascular features with a risk and propensity for DM II
4
Q
Physiologic GnRH Release
A
- GnRH neurons release GnRH in coordinate pulses
- too fast = desensitization/downregulation of FSH/LH
- too slow = insufficient FSH/LH to drive ovaries
- Frequency of pulses varies during the menstrual cycle
- 1st half of cycle = ~1 per min
- 2nd half of cycle = ~3 per min
- Possible surge of GnRH release at midcycle- contributes to triggering of LH/FSH surge
5
Q
Two cell-Two Gonadotropin Theory
A
- In thecal cells, LH under cAMP drives the conversion of LDL cholesterol using side-chain cleavage enzyme into androgens (androstenedione and testosterone)
- Androgens are then shifted over to the granulosa cells where cAMP under the influence of FSH drives their conversion into estrogen
6
Q
PCOS Definition
A
Endocrine Society Clinical Guidelines
2/3 of these = diagnosis of PCOS
- Ovulatory disturbance
- Androgen excess (clinical OR biochemical)
- Adolescent: androgen excess (clinical AND biochemical)
- Sonographic evidence
- Absence of other endocrine disorders
*nonclassical adrenal hyperplasia
*androgen-secreting tumors
*hyperprolactemia
*thyroid dysfunction
7
Q
PCOS Health Effects
A
Prevalence of
- Impaired glucose metabolism
- Dyslipidemia
- Obesity
- Sleep apnea
- Fatty liver (non-alcoholic hepatic steatosis)
8
Q
Overweight women w/ PCOS have increased incidence of?
A
- Obstructive sleep apnea
9
Q
PCOS Overall Health Implications
A
- Normal reproductive organs (just not getting the right signaling from the pituitary)
- May not regularly ovulate a mature egg on their own
- Ovulatory disturbance: means threshold levels of estradiol not sustained for pre-ovulatory LH surge
10
Q
PCOS Ovary
A
- Surface area is doubled
- Ovaries usually contain 10 or more small cysts
- cysts are generally <8mm
- cysts remain small and generally do not grow
- surgical removal is not necessary
- Same # of primoridal follicles present, however, the # of growing and atretic follicles is doubled
- so-called high antral follicle count
- Increased stroma is due to hyperplasia of thecal cells and increased formation subsequent to excess follicle maturation and atresia
11
Q
PCOS Hormonal Changes
A
- Increased LH
- too much LH = too much androgen or testosterone production; reason birth control works so well in polycystic pts, b/c it inhibits LH synthesis and release
- Constant estradiol exposure
- Minimal progesterone secretion
- Increased testosterone
- Decreased SHBG
- sex hormone binding globulin; made by liver, binds free testosterone, estrogen, etc.
- Increased free testosterone
- Increased insulin
12
Q
PCOS Symptoms
A
- Menstrual irregularities
*oligomenorrhea or amenorrhea
+eustrogenic exposure w/ little progesterone stimulation
+bleeding can be spotty and sometimes very heavy - Hair and skin
*hirsutism and acne (androgen excess) - Obesity
*estimates are 50% of women w/ PCOS obese
*enhances abnormal estrogen and androgen productions
13
Q
PCOS Patient History
A
- Abnormal menses
- amenorrhea or oligomenorrhea
- Reproductive abnormalities
- Endocrine disturbances
- Mothers or sister w/ PCOS
- Family history: premature cardiac disease
- cardiac disease based on diabetes
14
Q
PCOS Clinical Signs
A
Clinical
- Acne
- Androgenic alopecia
- Virilization
- “hirsutism on steroids”- more likely due to androgen secreting tumor
- rapid, high lvls of androgen production
- suspicious for androgen secreting tumor if serum testosterone >200
- Hirsutism
15
Q
PCOS Biochemical Signs
A
- Serum elevation of androgen(s)
- Not all PCOS pts demonstrate biochem hyperandrogenism
- inaccurate assays, inter-assay variations
- inconsistent timing of blood draw (ideal is fasting and early follicular portion of the menstrual cycle)
- wide variability in normal pop.
- age/BMI not factored into normative data
16
Q
PCOS Potential Genetic Defect
A
- Familial clustering is common
- 50% of sisters of PCOS women are hyperandrogenic
- 25% classic PCOS phenotype
- Increased prevalence of insulin resistance in first-degree males
- A single factor that causes
- serine phosphorylation of the insulin receptor
- serine phosphorylation of P450c17
- deficiency of the D-chiro-inositol phosphoglycan mediator
- Increased expression of certain mRNAs in theca and granulosa cells derived from PCOS women
17
Q
PCOS Treatment
A
- If BMI elevated, loss of at least 5% body weight
- weight reduction is critical
- Medications: clomiphene, letrazole or gonadotropins
- Metformin for metabolic abnormalities
- insulin sensitizer that helps lower LH lvls
- Ovarian surgery: none needed
- Adolescent treatment is extrapolated from adults
- Lifestyle changes
- Oral contraceptives (one of the best treatments)
- lowers LH, lowers androgens, increases SHBG
18
Q
PCOS: Weight
A
Obesity is assoc. w/ 3 alterations that interfere w/ normal ovulation
- Increased peripheral aromitization of androgens to estrogens
- Decreased lvls of SHBG
- Increased insulin lvls
Weight loss improves all three
50% of women w/ PCOS are obese
Obesity enhances abnormal estrogen and androgen production
19
Q
PCOS: Insulin
A
- Insulin resistance in other tissues but not in the ovary, overworks in the ovary to the extent that it drives the increased production of androgens
- Hyperinsulinemia may drive hyperandrogenemia
20
Q
How does hyperinsulinemia produce hyperandrogenism?
A
- Insulin binds to both the insulin receptor and the IGF-I receptors
- If insulin receptors are blocked or deficient in #, then insulin binds to IGF-I receptor
- IGF receptor on thecal cells which drives the conversion of cholesterol into androgens
- Insulin inhibits synthesis of SHBG and production of IGFBP-1
21
Q
Overall goals of PCOS treatment
A
- Reduce androgens
- Protect the endometrium against the effects of unopposed estrogen (endometrial hyperplasia)
- Support lifestyle changes to lower body weight
- Lower risk of cardiovascular disease
- Lower insulin lvls
- lowers risk for CV disease risk and diabetes
- Induction of ovulation…pregnancy
22
Q
Test for glucose tolerance and insulin resistance
A
- Euglycemic clamp
*best test for insulin resistance but not done frequently b/c its tedious - Glucose tolerance test
*insulin lvls (fasting, 1 and 2hrs)
*2 hr glucose lvl after 75g glucose load
Normal: <140 mg/dL
impaired: 140-199 mg/dL
NIDDM: >200 mg/dL
23
Q
How do we lower hyperinsulinemia?
A
Insulin sensitizing agents
- Metformin
- used to treat NIDDM
- category B drug for pregnant women; pregnant women are kept on it and has shown to reduce gestation diabetes
24
Q
Effects of Insulin Sensitizer for PCOS
A
- Indirectly reduces circulating insulin lvl
- Reduces cytochrome P450c17 activity
- Reduces ovarian androgen and estrogen production
- Increases IGFBP-I
- Decreases IGF-1
- Increases SHBG
- Increase circulating glycodelin
25
Metformin Effects
Lower blood glucose
- Increase intestinal use of glucose
- Enhancing peripheral glucose uptake
- Stimulates insulin mediated glucose disposal
26
PCOS Metformin Dosing
- 500mg P.O. 3x a day
| * titrate up to the full dose (1500 to 2000mg daily); to minimize GI side effects
27
Metformin Side Effects
- Decreased B-12 absorption
- Homocysteine elevation
- Rare cases, lactic acidosis
* do not give if serum creatinine > 1.4 mg/dL b/c of increased risk of lactic acidosis
28
Liraglutide
- "Victoza"
- Glucagon like peptide-1 receptor agonist
- DM2 treatment
- Lowers triglycerides
- Suppresses appetite
- Prevents "overshoot"-meaning secretes insulin only when blood sugar is elevated, so no hypoglycemia
- CAUTION: linked to medullary thyroid cancer and pancreatitis
29
Oral contraceptives treat
- Oligomenorrhea
- Hirsutism
- Acne
- Androgenic alopecia
30
Anti-androgens treat
- Hirsutism
| - Androgenic alopecia
31
Oral contraceptives benefits
- Increase SHBG and decrease free testosterone
- Improves androgen excess (so improves potentially hirsutism and acne)
- Decreases risk of endometrial carcinoma
- Menstrual cycle regulation
32
Spironolactone
- Anti-androgen
* blocks androgen receptor
- Treats hypertension but used off-label for androgen excess in treating hair growth
33
Insulin Sensitizer Alternatives
- Non-medical treatment is the first line of therapy, especially in younger pts
- Supplements w/ insulin sensitizing properties
* cinnamon
* Vit D
* D-chiro inositol and myo-inositol (Vit. B8)
34
PCOS Infertility Treatment
- First line therapy: oral agents
* Clomiphene (FDA approved, estrogen receptor blocker)
* Letrazole (aromatase inhibitor)
- Second line therapy
* injectable gonadotropins
