PCOS

Question 1

What is Polycystic Ovarian Syndrome?

Answer 1

• Most common endocrine disease in women of reproductive age
  
  • Prevalence estimated at 5-10%
• Often presents with insulin resistance
• Often, but not always, associated with diabetes
• Major risk factor for type 2 diabetes, gestational diabetes and cardiovascular disease

Question 2

PCOS Criteria

Answer 2

1991 NIH criteria- all of the following;

• Hyprandrogenism
• Chronic anovulation
• Exclusion of known disorders

2003 Rotterdam criteria- 2 of the following 3;

• Hyperandgrogenism
• Chronic annovulation
• Polycystic ovaries (enlarged ovaries containing at least 12 follicles each)

Question 3

Ovarian Hyperandrogenism

Answer 3

• Pulsatile GnRH release is essential for maintenance of gonadotropins secretion
• Frequency of GnRH pulses determine which gonadotropins hormone is preferentially synthesized
  
  • Rapid GnRH pulses favor LH
  • Slower GnRH pulses favor FSH

*overstimulate Theca cells and understimulate Granulosa cells

Increased pulsatility–> favors LH over FSH –>favors androgen production with less aromatization to estrogen by granulosa cells –> ovaries overproduce androgens relative to estrogens

Question 4

Consequences of Androgen Excess

Answer 4

• Hirstutism- dark, coarse, thick hair on face, chest, abdomen and back
• Acne- stimulated by androgens
• Androgenic alopecia- male pattern hair loss

Question 5

Polycystic Ovaries

Answer 5

• Ovarian cysts are small, fluid-filled sacs that develop in the ovary
• In an ultrasound, ovarian cysts appear black
• Ovary tends to be larger
• There are many different kinds of cysts- some are non-cancerous and some are cancerous
• Follicular cysts are noncancerous cysts that form when ovulation does not occur or when a mature follicle collapses on itself
• Women with PCOS have large numbers of small follicular cysts

Question 6

Chronic Anovulation

Answer 6

• Arrest of follicular development and anovulation can be caused by abnormal secretion of gonadotropins (LH>FSH), androgen excess, genetic factors
• Androgens promote early follicle growth
• Elevated androgen:estrogen ratio decreases quality of developing oocyte in follicle
• Low FSH is not sufficient to stimulate follicle development
• Corpus luteum doesn’t form so progesterone remains low
• Small follicular cysts and low ovulation –> low fertility

Question 7

Insulin Resistance with PCOS

Answer 7

• Skeletal muscle (and adipose) are principle sites of glucose disposal (uptake)
• Skeletal muscle glucose uptake is determined by insulin, exercise and genetic factors
• PCOS patients are insulin resistant resulting in elevated blood glucose
• Elevated blood glucose stimulates more insulin secretion from pancreatic b-cells in effort to stimulate glucose uptake
• PCOS patients exhibit elevated blood insulin

Question 8

Insulin Receptor Signaling

Answer 8

• GSK3- glycogen synthase kinase-2
• elF2B0 eukaryotic initiation factor 2B
• PTP1B- protein tyrosine phosphotase 1B
• PTEN- phosphotase and tension homolog deleted on chromosome 10

Metabolic pathways- energy storage (glucose uptake, glycogen synthesis, fatty acid synthesis)

Mitogenic pathways- growth and differentiation (translation and gene expression)

Question 9

Metabolic Actions of Insulin Receptor Signaling Pathways

Answer 9

• Tyrosine-phosphorylated insulin receptor (IR) phosphorylates intracellular substrates, such as IRS1-4 and Shc, initiating signal transduction pathways mediating the pleiotropic actions of insulin
• Major pathway for metabolic actions of insulin is mediated through activation of PI2K and Akt/PKB resulting in the translocation of GLUT4
• Insulin activation of PI3K and Akt/PKB also leads to serine phosphorylation of GSK3, resulting in inhibition of its kinase activity
• Inhibition of GSK3 results in dephosphorylation of glycogen synthase increasing glycogen synthesis

Question 10

Mitogenic Actions of Insulin Receptor Signaling Pathways

Answer 10

• Ras-ERK/MAPK pathway regulate gene expression
• Insulin modulate protein synthesis and degradation via mTOR, which is activated via PI3K and Akt/PKB
  
  • mTOR pathway is also important in nutrient sensing
• Insulin0stumulated inhibition of GSK3 via PI3K and Akt/PKA also results in dephosphorylation of eIF2B increasing protein synthesis

Question 11

Terminating Signal of Insulin Receptor Signaling Pathways

Answer 11

• Insulin signaling can be terminated by tyrosine phosphotases, such as dephosphorylation of IR by PTP1B or dephosphorylation of PI3K by PTEN
• Serine phosphorylation of insulin receptor and IRSs can also decrease insulin signaling
  
  • May be mediated by serine kinases in insulin signaling pathway providing feedback mechanism to terminate insulin action

Question 12

Defects with PCOS of Insulin Receptor Signaling Pathways

Answer 12

• In PCOS there is post-binding defect in insulin signaling in skeletal muscle affecting metabolic but not mitogenic pathways (selective insulin resistance)
  
  • Signaling steps compromised in PCOS are circles with a dotted line in the figure
    
    • IR
    • IRS-1/2
  • Signaling steps downstream of these abnormalities may also be compromised

Glucose infusion rate (GIR) in

Question 13

Data of Insulin resistance with PCOS

Answer 13

• Glucose infusion rate (GIR) in the last 30 min of a 120 min hyperinsulinemic-euglycemic clamp
• Plasma glucose maintained at 5mmol/L
• Higher GIR indicates higher rater of peripheral glucose uptake
• PCOS causes more insulin resistance in both lean and overweight people

Question 14

Insulin resistance in Skeletal Muscle in PCOS

Answer 14

• Insulin stimulates glucose uptake under normal conditions
• Increased serine phosphorylation of IR and IRS-1 with PCOS

PCOS: ^insulin–> decrease PI3K –> decrease glucose uptake

Question 15

Consequences of insulin resistance in PCOS

Answer 15

Elevated blood insulin:

• Inhibits liver SHBG output which increases circulating free androgens
• Stimulates release of free fatty acids from liver which increases adipose tissue growth (excess glucose is stored as fat in adipose)
• Obesity results in further insulin resistance

Question 16

Insulin Activity in Theca Cells in PCOS

Answer 16

• PCOS patients have increased GnRH pulsatility which favors LH over FSH
• Increased LH:FSH ratio causes ovaries to overproduce androgens relative to estrogens
• While most tissues (skeletal muscle and adipose) become insulin resistant with PCOS, theca cells remain responsive or become hypersensitive to insulin

Question 17

Insulin Signaling Defects

Answer 17

PCOS Serine Kinase: decrease Metabolic ^ Mitogenic ^ P450c17

• Insulin signaling defects in PCOS are due to serine phosphorylation of IR and IRS-1/2 (in skeletal muscle) and P450c17 (in theca cells)
  
  • Increases androgens made in those tissues
• PCOS defects in skeletal muscle result in decreased insulin-mediated activation of PI3K and resistance to the metabolic actions of insulin

Question 18

Selective Insulin Resistance

Answer 18

In PCOS there is constitutive activation of kinases in the ERL/MAPK mitogenic pathway

• These kinases contribute to inhibitory serine phosphorylation of IR and IRS-1/2 in PCOS skeletal muscle

Serine phosphorylation increases the activity of P450c17 enzyme (17a-hydroxylase; encoded by gene CYP17) in theca cells

• It has been postulated that in PCOS the same kinase (i.e., serine phosphorylation) may inhibit insulin signaling (metabolic action) in skeletal muscle and increase androgen production (mitogenic action) in theca cells

Question 19

Excess androgen production in PCOS

Answer 19

• There are several proposed pathways for increased theca cell androgen production in PCOS
• Insulin;
  
  • Stimulates 17a-hydroxylase (P450c17) activity in theca cells
  • Acts synergistically with LH to stimulate ovarian overproduction of androgen

Question 20

Androgen Overproduction in Theca Cells in PCOS

Answer 20

PCOS: ^ LH –> ^cAMP –> ^ androgens

• Excess LH stimulates excess androgen production via increased camp and protein kinase A
• Insulin acts synergistically with LH to increase CYP17 expression (gene that encodes P450c17 [i.e., 17a-hydroxylase] enzyme)
  
  • Increase amount of enzyme and the activity of that enzyme

Question 21

Treatment of PCOS

Answer 21

• PCOS has major lifelong effects on reproductive, metabolic and cardiovascular health
• Treatment focuses on:
  
  • Hirsutism and acne
  • Anolvulation
  • Insulin Resistance

Question 22

Treatment of Hirsutism and Acne

Answer 22

• Oral contraceptive containing both estrogen and progestin
  
  • suppress LH and FSH
  • Suppress ovarian androgen production
  • Increase liver SHBG production
• Progestins with minimal androgenic properties are preferred
  
  • Norgestimate and desogestrel are virtually nonandrogenic
  • Drospirenone is anti-androgenic

Question 23

Treatment of Anovulation

Answer 23

• Oral contraceptives containing both estrogen and progestin to prevent endometrial hyperplasia
• Weight reduction
  
  • Caloric restriction
  • Dietary modification (restrict simple carbohydrates)
  • Exercise
• Clomiphene citrate (Clomid)
  
  • Estrogen anatagonist to increase FSH for ovulation induction
• Exogenous FSH administration

Question 24

Treatment of Insulin Resistance

Answer 24

• Weight reduction
  
  • Caloric restriction
  • Dietary modification (restrict simple carbohydrates; e.g., low glycemic index diet)
  • Exercise- increase muscle glucose uptake
• Metformin
  
  • Interferes with simple carbohydrates absorption in GI tract
  • Inhibit liver glucose output
  • Increase peripheral glucose uptake