PCOS/Hirsutism/Obesity

Question 1

Contributors to obesity

Answer 1

• Down-regulation of adiponectin (which increases insulin sensitivity)
• Defect in leptin receptor

Question 2

4 Adipokines that change after meal

Answer 2

Somatostatin, ghrelin, leptin, NPY

Question 3

Somatostatin change after meal

Answer 3

Increases after meal

Question 4

Somatostatin source cells

Answer 4

Release from gastric D-cells

Question 5

Somatostatin regulation

Answer 5

Regulated by ANS with catecholamines inhibiting and cholinergic mediators stimulating peptide release

Question 6

Somatostatin function and MOA

Answer 6

Inhibitory function; decreases blood flow, GI motility, gallbladder contraction and inhibition of GI hormones

Question 7

Ghrelin change after meal

Answer 7

Decreases after meal

Question 8

Ghrelin production location

Answer 8

Upper stomach

Question 9

Ghrelin action

Answer 9

Stimulates secretion of GH, increases food intake and produces weight gain

Question 10

Ghrelin relation to fasting, eating, and hyperglycemia

Answer 10

• Secreted under fasting conditions
• Low levels after eating and with hyperglycemia

Question 11

Leptin after meal

Answer 11

Increases after meal

Question 12

Leptin function

Answer 12

• Decreases appetite and food consumption
• Increases heat production and activity
• Stimulates CRH expression

Question 13

NPY after meal

Answer 13

Decreases after meal

Question 14

Adipokine levels after gastric bypass surgery

Answer 14

 Ghrelin – decreases
 Leptin – decreases (less body fat?)
 NPY – increases

Question 15

Mechanism of hyperandrogenemia in PCOS

Answer 15

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

Question 16

When is development of hair follicles complete

Answer 16

22 weeks gestation (no new follicles develop afterwards)

Question 17

Concentration of hair follicles where does not vary between sexes

Answer 17

Facial skin

Question 18

Major factor determining hair follicle concentration

Answer 18

Race/ethnicity

Question 19

MOA insulin and androgen synthesis

Answer 19

Insulin acts directly on the theca cells via insulin (tyrosine kinase) receptors - to stimulate androgen synthesis

Question 20

Other receptor/mediator insulin acts on besides those in theca cells

Answer 20

• Insulin also acts on the IGF-1 receptor at high concentrations
• Insulin acts via inositolphosphoglycan (PI-3K) mediators – different than that of LH

Question 21

Metformin drug class

Answer 21

Biguanide oral insulin-sensitizing agent

Question 22

Metformin MOA

Answer 22

• 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)

Question 23

Metformin clinical benefits

Answer 23

• Decreases weight and BMI (3-5%)
• Decreases BP and LDL

Question 24

Metformin guidelines for stopping pre-procedure for CT

Answer 24

• Canadian guidelines: eGFR < 60, stop taking metformin at the time of contrast administration
• European guidelines: eGFR < 45, stop metformin 48 hours before CT

Question 25

Metformin guidelines for stopping pre-procedure

Answer 25

* Canadian guidelines: eGFR \< 60, stop taking metformin at the time of contrast administration * European guidelines: eGFR \< 45, stop metformin 48 hours before CT

Question 26

Ovarian drilling subsequent physiologic changes

Answer 26

- Destroys theca cells -\> decreased androgen and LH levels - Androstenedione, LH, and LH/FSH ratio all decrease; no change in dopaminergic inputs

Question 27

Obesity and hormone levels: What's increased? Decreased?

Answer 27

Decreased: NPY, SHBG, GH Increased: E2, cortisol, testosterone, insulin, leptin Obesity -\> insulin level -\> inhibit expression of neuropeptide Y (mediated via leptin)

Question 28

Exercise-induced hormone changes

Answer 28

* 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**

Question 29

Risk of mood disorder in obese women?

Answer 29

25-50% more likely to experience mood disorder Depression can also lead to obesity from low serotonin levels, leading to overeating

Question 30

Dx of metabolic syndrome

Answer 30

* Need 3/5: 1. HTN (130/85 or higher) 2. TG level (\>150 mg/dL or higher) 3. HDL-cholesterol (\<50mg/dL) 4. Abdominal obesity (\>35 inch waist circumference) 5. Fasting glucose (100 mg/dL or higher)

Question 31

In PCOS, what regulatory systems are messed up?

Answer 31

1. Gonadotropin secretion 2. Insulin secretion & action 3. Weight & energy regulation 4. Androgen biosynthesis & action

Question 32

IGF-1: Where is it made? and in response to what? What are low levels associated w/?

Answer 32

Made in liver in response to GH Low levels associated w/ DM

Question 33

Insulin transduction pathways up & down-regulated in PCOS

Answer 33

* Phosphatidyl-inositol 3-kinase (PI-3K) pathway **(down-regulated in PCOS)** * Metabolic effects via Akt (signal transduction molecule) 1. 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)** 1. Proliferative actions

Question 34

Most common mechanism of insulin resistance?

Answer 34

Obesity

Question 35

Causes of hyperandrogenism in PCOS (2)

Answer 35

1. Insulin acts on insulin receptors within ovarian theca and stromal cells 1. Hyperinsulinemia → increased GnRH pulse frequency → LH over FSH dominance → increased ovarian androgen production → decreased follicular maturation 2. Decreases SHBG production from the liver

Question 36

Cutoffs for 75g 2hr OGTT (insulin & glucose)

Answer 36

1. Interpretation of insulin response (2h) 1. Normal \<100 U/mL 2. Insulin resistance likely 100-150 U/mL 3. Resistance 151-300 U/mL 4. Severe resistance \>300 U/mL Interpretation of glucose response 1. Fasting: \<110 mg/dL normal, 110-125 mg/dL borderline, \>125 mg/dL dx of DM 2. 2h: \<140 mg/dL normal, 140-200 mg/dL impaired glucose tolerance, \>200 dx of DM

Question 37

Effects of metformin on cholesterol levels

Answer 37

* Decreases total serum cholesterol * Decreases LDL * No change in HDL cholesterol * No change in triglycerides

Question 38

How is insulin receptor DEactivated?

Answer 38

* 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)

Question 39

Spironolactone effect on DHT? SHBG?

Answer 39

blocks DHT binding to skin androgen receptors Increases SHBG concentration

Question 40

Best test for insulin resistance…but no longer used

Answer 40

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

Question 41

Effect of OCPs on patients with PCOS

Answer 41

Mechanism of action 1. Increases SHBG (decreases free androgens) 2. Decreases LH (decreases androgen production by theca cells) 3. Inhibits 5α-reductase and androgen receptor binding

Question 42

most elevated serum androgen with hirsutism?

Answer 42

Free testosterone

Question 43

1st test in PCOS-appearing pt? when would you want to check 17-OHP?

Answer 43

1. Total testosterone Early onset hirsutism (pre- or perimenarcheal) Family history of CAH High-risk ethnic group (Hispanic, Mediterranean, Slavic, Ashkenazi Jewish)

Question 44

* Which of the following does NOT inhibit an androgen receptor? * Finasteride * Spironolactone * Flutamide * Danazol

Answer 44

Danazol - Binds androgen receptors (displaces testosterone, increases free testosterone levels)

Question 45

MOA of spironolactone

Answer 45

Selective aldosterone blocker (competes with aldosterone for receptor sites in distal renal tubules) Blocks DHT binding to skin androgen recpetors

Question 46

What enzyme does a pilosebaceous unit (i.e., hair follicle, sebaceous gland, and arrector pili muscle) display?

Answer 46

substantial aromatase activity - significant source of estrogen synthesis, both in men and women