PCOS Progesterone by mikeholy

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									PHM 463 - OB/GYN                                                                          October 10, 2002

                       Polycystic Ovarian Syndrome (PCOS) –Lecture #6

PCOS
 Most common endocrinopathy – more than diabetes
 Affects 5 to 7% of women of reproductive age
 Was called Stein Leventhal Syndrome (1940s) – important when doing research back in time since
  you won’t find anything under PCOS
 Syndrome characterized by: hyperandrogenism, oligomenorrhea, hyperinsulinemia
 Don’t have to all of these characteristics to have PCOS


Pathophysiology
                                              Hypothalamus



                                                   GnRH (pulsitile)            INSULIN


                                                   Pituitary
                                                                      -ve feedback
                                                                                          E2 (estradiol)



                                   FSH                           LH

                  estradiol            follicles                  GF progesterone
                                                       theca
                                   ovary

                                                               TESTOSTERONE

   PCOS due to imbalance in release of FSH and LH
    o Get large amounts of LH and tiny bit of FSH ovary is affected, follicles not stimulated, so no
       estradiol produced
    o No graafian follicle no progesterone
    o Lots of testosterone (T) since lots of LH stimulating theca cells hyperandrogenism
             T converts to estradiol (E2), lots of E2 made since lots of T, which negatively feedbacks
                to pituitary to signal for no more FSH
             No FSH, no E2 from follicles  but source of  E2 from  T
             helps perpetuates large amount of LH being produced
    o E2 get proliferation of endometrium, no ovulation  no progesterone for secretatory changes
             Get oligomenorrhea (few, scanty, periods, spotting) due to continued proliferation
             Or get amenorrhea due to anovulation
   Get  insulin (don’t know why)  insulin resistance hyperinsulinemia
    o Insulin affects hypothalamus to release LH
    o Insulin can stimulate theca cells to make T
             2 ways to release T hypothalamus (GnRH  LH etc.) & ovary (theca cells)
Hyperandrogenism
 Virilization (deepening of voice, muscular etc.) – rare in PCOS, but can happen theoretically
 Increased libido
 Hirsutism
 Acne           skin manifestations
 Alopecia
 Obesity
   o In 50% of individuals  central/android obesity – “beer belly”
   o Obese pts have more problems with PCOS vs. non-obese because:
           Tendency for insulin resistance -  insulin, further  T
           SHBG (binds T) is decreased even more free T
   o Have many more signs and symptoms and risks with PCOS

Note: Increase of E2 made from T is not enough to make SHBG (in E2 not like when giving OC) and
unknown why SBHG is decreased in obese people

   Pts may have  T levels, but show no skin manifestations
   No info on epidemiology, ie. don’t know the % of people who suffer from skin manifestations,
    majority of people have skin manifestations (certain people may not and still have PCOS)

Hyperinsulinemia
 Increase risk for diabetes  3-fold increase in PCOS vs. non-PCOS
          o 1% for non-obese PCOS pts & 7% obese PCOS pts
 Increase risk of cardiovascular disease
          o  LDL,  TG, HDL
 Significant morbidity and mortality


Oligomenorrhea/amenorrhea
 Alteration in menstrual function due to no progesterone
 At risk of endometrial cancer  constant proliferation ( E2) without full secretatory changes
 At risk of ovarian cancer  unknown MOA


Classic Presentation of PCOS
 Patient with acne, hirsutism, maybe alopecia with irregular periods/scanty periods/amenorrhea
 May show on ultrasound cysts in ovaries, but they don’t have to be present for PCOS diagnosis
 If polycystic ovaries present, may not also have oligomenorrhea, amenorrhea, hyperandrogenism,
   or hyperinsulinemia…it’s a syndrome
 PCOS really a diagnosis of exclusion
 Increased risk for DM, endometrial cancer, CVD


Treatment for Symptoms of PCOS
 Estrogen to  SHBG to bind T
   o Oral Contraceptive – Estrogen + Progestin
           estrogen will make SHBG to bind T
           Progestin will regulate menstrual function
                   free T
                   risk of both endometrial and ovarian cancer
                  may improve acne
                  potentially  hirsutism
Which OC to use?

   Diane-35
    o  SHBG due to estrogen
    o Block T at receptor site
           Block FSH and LH at pituitary
           estrogen will make SHBG to bind T
           Should work to acne, hirsutism, regulates periods, endometrial & ovarian cancer
             protection

   3rd Generation Progestin – norgestimate, desogestrol (Marvelon, Orthocept, Cyclen, Tricyclen)
    o Not as much cardiovascular risk vs. 2nd generation (norethindrone)
    o Good since PCOS pts have increased of CVD
    o Low androgen

   Treatment used for symptomatic control (irregular menses, skin manifestations) does not really
    have affect on insulin

   Spironolactone (anti-androgen) - ~100mg/day
    o Spironolactone added with OC (2nd generation or other OC, except Diane-35)
            Blocks T effect on hair follicles on body (for hirsutism)
            Reverses alopecia which is due to  T

Infertility
 PCOS suffer from infertility because not enough FSH to stimulate follicles to get Graafian follicle
    for ovulation to occur
 Infertility not 100%  pts may spontaneously ovulate during cycle, and can try to get pregnant if
    they catch this cycle
 May have long bouts of amenorrhea, oligomenorrha, anovulation where eggs not produced


Treatment for Infertility

   FSH analog
    o Give lots of FSH and not affect LH,
    o Now giving proportionately greater FSH than LH  will get stimulation of ovary
    o Problem: get so much FSH that you can get a chance of multiple pregnancies, get 2 or 3 follicles
       stimulated at one time  at risk for ovarian hyperstimulation (life-threatening) (re: next class)

   Issue: want to block to estrogen at the pituitary, so hypothalamus reacts to make more estrogen by
    releasing FSH

   Clomiphene – 1st line for infertility
    o Blocks E2 at pituitary sends down more FSH
    o Very first SERM – selective estrogen receptor modulator, like tamoxifen & raloxifene
    o woman can produce an egg
    o Risk of multiple births b/c clomiphene directly affects FSH
Insulin
 Want to  insulin uptake &  insulin resistance
    o Metformin – 1500 to 2000mg/day – 2nd line for infertility
           insulin resistance which  free E2 ,  free testosterone
          Pt can ovulate
          Helps improve lipid profile
          Usually continued until ovulation and once pregnant it’s discontinued
          No risk of multiple pregnancy with metformin

   Clomiphene + Metformin – 3rd line for infertility

   Pts with PCOS have 50% miscarriage rate – double than in normal population
    o Getting pregnant a challenge: have to get pts to ovulate, have intercourse and egg gets fertilized
        and hope in 50% that doesn’t miscarriage
    o Small studies show that if you continue metformin until 1st month of pregnancy, it may affect
        miscarriage rate
    o in community may see metformin used until pregnancy & then D/C (this is ok)
    o Or may see metformin continued on in 1st months of pregnancy (MD read studies)
    o But shouldn’t call MD to suggest that metformin be kept on because not sure if really works

   Glitazones – pioglitazone, rosiglitzaone
    o Troglitazone only one with evidence for PCOS and infertility, not sure if pio and rosi work
    o Troglitazone removed from market because of liver disease
            Troglitazone was pregnancy category C
            A-safe in pregnancy; B-probably safe; C-shouldn’t use; D-don’t use
            Affected fetal maturation
            Blocked progesterone release from corpus luteum to cause miscarriage
            wouldn’t use it even if it was available & probably wouldn’t use other glitazones

   Metformin is pregnancy risk B – see preferential use instead of glitazone

   What’s the difference between giving clomiphene and FSH analog?
    o Body helps/regulates itself better than us giving it stuff
            Using clomiphene allows the body to release a more appropriate amount FSH
            Amount of FSH (analog) given is not as appropriate and can lead to hyperstimulation
                     Can use GnRH analog to wipe out system and then add back what is needed to
                       control the cycle (talk about in next class)

   PCOS pathology is not known, no one knows what the problem is…just know what happens:
    increase proportion of LH to FSHstimulates to make T  converts to E2 hyperinsulinemia etc.
   Other SERMs not used since it may not affect the pituitary, has selective effects on other tissue
   Clomiphene doesn’t work in everyone, but when it does it allows FSH and LH to be released in
    proportional amount (ie. doesn’t revert back to little FSH and lots of LH)

								
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