PCOS/Hirsutism/Obesity Flashcards
Contributors to obesity
- Down-regulation of adiponectin (which increases insulin sensitivity)
- Defect in leptin receptor
4 Adipokines that change after meal
Somatostatin, ghrelin, leptin, NPY
Somatostatin change after meal
Increases after meal
Somatostatin source cells
Release from gastric D-cells
Somatostatin regulation
Regulated by ANS with catecholamines inhibiting and cholinergic mediators stimulating peptide release
Somatostatin function and MOA
Inhibitory function; decreases blood flow, GI motility, gallbladder contraction and inhibition of GI hormones
Ghrelin change after meal
Decreases after meal
Ghrelin production location
Upper stomach
Ghrelin action
Stimulates secretion of GH, increases food intake and produces weight gain
Ghrelin relation to fasting, eating, and hyperglycemia
- Secreted under fasting conditions
- Low levels after eating and with hyperglycemia
Leptin after meal
Increases after meal
Leptin function
- Decreases appetite and food consumption
- Increases heat production and activity
- Stimulates CRH expression
NPY after meal
Decreases after meal
Adipokine levels after gastric bypass surgery
Ghrelin – decreases
Leptin – decreases (less body fat?)
NPY – increases
Mechanism of hyperandrogenemia in PCOS
o Insulin stimulation of theca via insulin receptor (inositolphosphoglycan mediates androgen production)
o Decreased hepatic SHBG production (+androgens, which also decrease hepatic SHBG production)
o Insulin potentiated action of LH – increase LH pulse frequency (~1 pulse/hour) and (lesser extent) amplitude
When is development of hair follicles complete
22 weeks gestation (no new follicles develop afterwards)
Concentration of hair follicles where does not vary between sexes
Facial skin
Major factor determining hair follicle concentration
Race/ethnicity
MOA insulin and androgen synthesis
Insulin acts directly on the theca cells via insulin (tyrosine kinase) receptors - to stimulate androgen synthesis
Other receptor/mediator insulin acts on besides those in theca cells
- Insulin also acts on the IGF-1 receptor at high concentrations
- Insulin acts via inositolphosphoglycan (PI-3K) mediators – different than that of LH
Metformin drug class
Biguanide oral insulin-sensitizing agent
Metformin MOA
- Decreases hepatic glucose production
- Decreases intestinal glucose uptake
- Increases peripheral insulin sensitivity (up to 20%)
- Inhibits lipolysis (decreases circulating free fatty acids, reduces hepatic gluconeogenesis)
Metformin clinical benefits
- Decreases weight and BMI (3-5%)
- Decreases BP and LDL
Metformin guidelines for stopping pre-procedure for CT
- Canadian guidelines: eGFR < 60, stop taking metformin at the time of contrast administration
- European guidelines: eGFR < 45, stop metformin 48 hours before CT
Metformin guidelines for stopping pre-procedure
- Canadian guidelines: eGFR < 60, stop taking metformin at the time of contrast administration
- European guidelines: eGFR < 45, stop metformin 48 hours before CT
Ovarian drilling subsequent physiologic changes
- Destroys theca cells -> decreased androgen and LH levels
- Androstenedione, LH, and LH/FSH ratio all decrease; no change in dopaminergic inputs
Obesity and hormone levels:
What’s increased? Decreased?
Decreased: NPY, SHBG, GH
Increased: E2, cortisol, testosterone, insulin, leptin
Obesity -> insulin level -> inhibit expression of neuropeptide Y (mediated via leptin)
Exercise-induced hormone changes
- Increased endogenous opioids (inhibit GnRH)
- Increased cortisol (reflection of increased CRH activity which also inhibits GnRH)
- Decreased leptin (recombinant leptin can restore menstrual function in amenorrheic women who exercise excessively) (suppresses the HPO, thyroid, and adrenal axis)
- Decreased LH pulse frequency and amplitude
- Decreased estradiol
Risk of mood disorder in obese women?
25-50% more likely to experience mood disorder
Depression can also lead to obesity from low serotonin levels, leading to overeating
Dx of metabolic syndrome
- Need 3/5:
- HTN (130/85 or higher)
- TG level (>150 mg/dL or higher)
- HDL-cholesterol (<50mg/dL)
- Abdominal obesity (>35 inch waist circumference)
- Fasting glucose (100 mg/dL or higher)
In PCOS, what regulatory systems are messed up?
- Gonadotropin secretion
- Insulin secretion & action
- Weight & energy regulation
- Androgen biosynthesis & action
IGF-1: Where is it made? and in response to what?
What are low levels associated w/?
Made in liver in response to GH
Low levels associated w/ DM
Insulin transduction pathways up & down-regulated in PCOS
- Phosphatidyl-inositol 3-kinase (PI-3K) pathway (down-regulated in PCOS)
- Metabolic effects via Akt (signal transduction molecule)
- Akt activation moves glucose transporter 4 (GLUT4) from intracellular compartments to the plasma membrane – thus increasing glucose uptake
- Mitogen-activated protein kinase (MAPK) pathway (up-regulated in PCOS)
- Proliferative actions
- Metabolic effects via Akt (signal transduction molecule)
Most common mechanism of insulin resistance?
Obesity
Causes of hyperandrogenism in PCOS (2)
- Insulin acts on insulin receptors within ovarian theca and stromal cells
- Hyperinsulinemia → increased GnRH pulse frequency → LH over FSH dominance → increased ovarian androgen production → decreased follicular maturation
- Decreases SHBG production from the liver
Cutoffs for 75g 2hr OGTT (insulin & glucose)
- Interpretation of insulin response (2h)
- Normal <100 U/mL
- Insulin resistance likely 100-150 U/mL
- Resistance 151-300 U/mL
- Severe resistance >300 U/mL
Interpretation of glucose response
- Fasting: <110 mg/dL normal, 110-125 mg/dL borderline, >125 mg/dL dx of DM
- 2h: <140 mg/dL normal, 140-200 mg/dL impaired glucose tolerance, >200 dx of DM
Effects of metformin on cholesterol levels
- Decreases total serum cholesterol
- Decreases LDL
- No change in HDL cholesterol
- No change in triglycerides
How is insulin receptor DEactivated?
- Tyrosine dephosphorylation via tyrosine phosphatase**
- Degradation by cathepsin D
- Acidification of the internalized insulin receptors (within endosomes)
- Sequestering of activated insulin receptor from signal transduction elements
In insulin resistance, more serine phosphorylation instead of tyrosine phosphorylation (see other card)
Spironolactone effect on DHT? SHBG?
blocks DHT binding to skin androgen receptors
Increases SHBG concentration
Best test for insulin resistance…but no longer used
Euglycemic clamp technique
Insulin-induced glucose uptake is measured while blood glucose concentration is maintained at a steady concentration (via exogenous dextrose infusion) to avoid the confounding effects of counter-regulatory hormones such as epinephrine and glucagon.
Ratio of fasting glucose: insulin (ratio <4.5 = insulin resistance)
varies w/ ethnicity, takes time & IV sticks
Effect of OCPs on patients with PCOS
Mechanism of action
- Increases SHBG (decreases free androgens)
- Decreases LH (decreases androgen production by theca cells)
- Inhibits 5α-reductase and androgen receptor binding
most elevated serum androgen with hirsutism?
Free testosterone
1st test in PCOS-appearing pt? when would you want to check 17-OHP?
- Total testosterone
Early onset hirsutism (pre- or perimenarcheal)
Family history of CAH
High-risk ethnic group (Hispanic, Mediterranean, Slavic, Ashkenazi Jewish)
- Which of the following does NOT inhibit an androgen receptor?
- Finasteride
- Spironolactone
- Flutamide
- Danazol
Danazol - Binds androgen receptors (displaces testosterone, increases free testosterone levels)
MOA of spironolactone
Selective aldosterone blocker (competes with aldosterone for receptor sites in distal renal tubules)
Blocks DHT binding to skin androgen recpetors
What enzyme does a pilosebaceous unit (i.e., hair follicle, sebaceous gland, and arrector pili muscle) display?
substantial aromatase activity - significant source of estrogen synthesis, both in men and women
