What is this?
How is it sometimes described?
Can be described as a "ring of pearls": multiple small peripheral follicles with a very dense stroma/theca cells in the interior.
PCOS is associated with what 4 findings?
-Chronic anovulation (irregular menses, dysfunctional uterine bleeding, amenorrhea)
-Androgen excess (may be male pattern facial hair)
-Physical characteristics of obesity and androgen excess
-Physical features of insulin resistance (acanthosis nigricans)
(all these are found to variable degrees)
Describe the physical manifestations of PCOS related to androgen excess.
-Hirsutism: male hair patterns: face, chest, abdomen, lower back)
-Male pattern hair loss
PCOS: what is the typical body habitus?
75% are obese
But there is a "lean" form of PCOS also
Why do PCOS patients have high levels of androgens?
Increased release of LH from the pituitary --> overstimulation of the ovarian theca cells --> high levels of androgens.
Review: what is the sequence of events in the uterus that yields endometrial shedding in the normal ovulatory cycle?
1. Estrogen primes the endometrium - it builds up
2. Progesterone then stabilizes/compacts it
3. Withdrawal of Progesterone and Estrogen
4. Universal endometrial shedding
In adolescents who are not ovulating regularly, how do they have menstrual bleeding?
Normal adolescent oligo-ovulatory cycles:
Menstrual bleeding ("estrogen withdrawal bleed") occurs during the spontaneously operative negative feedback system between estrogen and FSH.
However, for ovulation to occur, estrogen levels must peak for a SUSTAINED period of 2 days at the end of the follicular phase for (+) feedback to occur (for LH surge). In btwn the start of menstruation and regular ovulation, the estrogen isn't high enough for long enough to cause the LH surge that is necessary to induce ovulation.
A patient with PCOS will have higher or lower average levels of LH than a normal patient?
LH: PCOS patient will be higher than normal
FSH: PCOS patient will be slightly lower and will not have the FSH bump at day -14.
(PCOS = yellow and red lines)
In PCOS, the increased LH is due to what?
increased pulsatile GnRH (both amount and frequency)
PCOS: what causes the polycystic ovaries?
A number of causes:
-slightly decreased FSH is enough to recruit follicles, but the lack of FSH blip prevents the recruitment of a dominant follicle from the cohort
-increased ovarian androgens -> follicular atrophy
- elevated LH -> a dominant follicle is discouraged
-insulin resistance -> increases androgen production at the ovary
What is the direct result of not having an FSH 'blip' at day -14?
The FSH blip normally stimulates one follicle to emerge from the cohort and become dominant.
Without the blip, you are unlikely to get a dominant follicle.
Even if a follicle were to try to emerge as dominant, what (besides the lack of FSH blip) is discouraging this?
High ovarian androgen concentration (in the micro-environment of the ovary) prevents one follicle from emerging from the cohort.
Insulin resistant also plays a role: unknown mechanism.
LH stimulates the theca cells to produce what?
in PCOS you have increased LH --> increased androgens
What is the fundamental problem causing PCOS?
nonfunctional feedback in the HPO axis.
prevents spontaneous negative and positive feedback to endogenous hormones.
Patients don't often ovulate, have long stretches of unopposed estrogen, thus endometrial proliferation.
Given that PCOS patients have unopposed estrogen, what is their bleeding pattern like?
Why is this?
Endometrium grows unabated until it is really unstable. It's not compacted due to lack of progesterone. Eventually it will become excessively unstable and will spontaneously shed - might bleed for 1-3 weeks and very heavy bleeding.
What treatment may work for PCOS patients?
Pharmacologic levels of exogenous hormones -- ie birth control pills.
These suppress gonadotropins and thus ovarian androgen production.
If this is the pattern of normal negative feedback for FSH and estrogen, what does the pattern look like for a PCOS patient?
(Yellow dots: endometrial growth.
Red arrows = menses)
PCOS: lacks pulsation, no feedback. If estrogen rises, FSH/LH do not lower.
FSH is tonically elevated; stimulates multiple follicles (but rarely enough FSH for one follicle to break out of the pack and become dominant)
(Yellow dots: endometrial growth.
Red arrows = menses)
In this depiction of PCOS uterine activity, what is happening at each stage?
left: long term unopposed estrogen influence on endometrium. leads to thickened, unstable endometrium.
center: erratic shedding of unstable endometrium - prolonged heavy menses.
right: after prolonged menses, incomplete shedding to basal layer.
PCOS: the big picture.
walk through the steps related to high LH levels.
Top: desuppressed arcuate nucleus via increased GnRH pulsatility. Widens the difference between LH and FSH levels -> higher LH, lower FSH.
High LH stimulates increased ovarian androgens. Androgens knock off follicles as they are developing (follicular atresia). Leads to anovulation and unopposed estrogen.
Increased ovarian androgens -> high peripheral aromatization (testosterone -> incr estrogen). Helps to widen the GnRH pulse frequency.
Increased ovarian androgens -> decrease levels of Sex Hormone Binding Globulin (SGBH) in liver. -> higher free androgen -> hirsutism, acne, etc.
PCOS: the big picture.
walk through the steps related to low FSH levels.
Low FSH means that multicle follicles mature, but there is not enough FSH to allow one to dominate.
Bottom line: no ovulation.
PCOS big picture again: if a PCOS patient is given birth control, which points of this cycle are affected?
Birth control will increase SHBG as well as suppress GnRH pulsatility and suppress androgen production.
What is the role of insulin resistance in PCOS?
At which points of the cycle does it have an effect?
Acts at multiple levels:
-Hypothalamus: increased GnRH pulsatility
Hypothalamus: Stimulates appetite
-Ovaries and adrenals: increased production of androgens
-Liver: decr SHBG levels
Review: what are the s/s of metabolic syndrome?
BP > what?
Waist circum > what?
Fasting glucose > what?
HDL < what?
Triglycerides > what?
(Relevance: some PCOS phenotypes will have metabolic syndrome)
BP > 130/85
Waist circum > 35 in
Fasting glucose > 100
HDL < 50
Triglycerides > 150
Systemically, what are PCOS patients at higher risk for than the rest of the population?
-Type 2 diabetes (50% lifetime risk)
-Cardiovasc disease (from metabolic syndrome and insulin resistance)
-dysphoria and depression
How do we diagnose PCOS?
-Hyperandrogenism - defined by elevated blood androgen levels, or physical signs (acne, hirsutism)
-Oligomenorrhea - cycles less frequent than 35d
-Ultrasound of ovaries - 12 or more follicles of small size in one or both ovaries
-Exclusion of anything else!
How do we treat PCOS to address the following:
-Abnl uterine bleeding, amenorrhea?
-high androgens & low SHBG?
-Abnl uterine bleeding, amenorrhea --> Progestins
-high androgens & low SHBG --> Combined hormonal contraceptives
-high androgens --> anti-androgens (spironolactone, flutamide)
-glucose intolerance --> insulin sensitizing agent
-hirsutism --> physical hair removal; Eflornithine hydrochloride (topical hair growth inhibitor)
For a woman with PCOS who is most concerned about her hirsutism, what is a good long-term treatment (drug) that will address the hair growth?
Combined hormonal contraceptives.
First task = suppression of ovarian androgens. Combined hormonal contraceptives = best way to begin this suppression.
It takes 4 – 6 months before hair growth slows. Once new hair is not appearing, can remove existing hair w laser or electrolysis. May add an anti-androgen (e.g spironolactone) to the hormone therapy.
For a woman with PCOS who is concerned about hirsutism, what lifestyle modification can help address the problem?
Weight loss helps at least 50% of these patients to reduce insulin resistance and break the vicious cycle that perpetuates the syndrome.
They may begin to cycle on their own but this takes time and is very difficult.
What are some ways we can induce ovulation in PCOS patients? (4 meds + 1 procedure)
1. Clomiphene Citrate (weak estrogen, acts like an anti-estrogen)
2. Letrozole (aromatase inhibitor)
3. Gonatodropin therapy (injectible FSH and LH)
4. Insulin-sensitizing agents ie Metformin (may help induce ovulation in patients with BMI > 37)
Procedure: ovarian wedge biopsy/ovarian drilling.
What are the risks of inducing ovulation in a woman with PCOS?
Ovarian hyperstimulation syndrome (he didn't explain what this is; I doubt it's important...)
A patient with PCOS has had heavy bleeding for 3 weeks (but didn't bleed for the prior 18 months).
What would we give her to stop her bleeding?
Why might we give her a little estrogen as well?
Give her progesterone.
She lacks the stabilizing and compaction effects of progesterone -- give this over 2 – 3 weeks.
When we stop the progesterone, a withdrawal subsequent menses will result. If they have been bleeding for a prolonged time, they may also need some estrogen to allow a bit of growth and “healing” effect along with the progesterone.
PCOS: what are the levels of LH, FSH, testosterone, estrogen and progesterone relative to normal patients?
high estrogen (from testosterone aromatization)
Rapid association: PCOS manifests clinically with what 4 main issues?
PCOS: why is there an increased risk of endometrial cancer?
Secondary to increased estrogen levels from the aromatization of testosterone in fat cells (?), without progesterone to oppose it.
-low dose OCPs or medroxyprogesterone (to reduce LH and androgenesis)
-spironolactone (for acne and hirsutism)
-clomiphene (to help get pregnant)
-metformin (for diabetes/met syndrome)
High levels of LH leads to anovulation --> NO progesterone.
Hyperandrogenism due to deranged steroid synthesis by theca cells.
Enlarged, bilateral cystic ovaries.