PCOS Flashcards
What is Polycystic Ovarian Syndrome?
- 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
PCOS Criteria
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)
Ovarian Hyperandrogenism
- 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
Consequences of Androgen Excess
- Hirstutism- dark, coarse, thick hair on face, chest, abdomen and back
- Acne- stimulated by androgens
- Androgenic alopecia- male pattern hair loss
Polycystic Ovaries
- 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
Chronic Anovulation
- 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
Insulin Resistance with PCOS
- 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
Insulin Receptor Signaling
- 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)
Metabolic Actions of Insulin Receptor Signaling Pathways
- 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
Mitogenic Actions of Insulin Receptor Signaling Pathways
- 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
Terminating Signal of Insulin Receptor Signaling Pathways
- 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
Defects with PCOS of Insulin Receptor Signaling Pathways
- 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
- Signaling steps compromised in PCOS are circles with a dotted line in the figure
Glucose infusion rate (GIR) in
Data of Insulin resistance with PCOS
- 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
Insulin resistance in Skeletal Muscle in PCOS
- Insulin stimulates glucose uptake under normal conditions
- Increased serine phosphorylation of IR and IRS-1 with PCOS
PCOS: ^insulin–> decrease PI3K –> decrease glucose uptake
Consequences of insulin resistance in PCOS
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
