Clomiphene Citrate Resistant Polycystic Ovary Syndrome DR Seyed Mehdi Ahmadi OB amp Gynecologist Isfahan Fertility amp Infertility Center Indications I Ovulation induction in the following cases ID: 635376
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Slide1Slide2
Management of Women with
Clomiphene
CitrateResistant Polycystic Ovary Syndrome
DR
Seyed
Mehdi Ahmadi
OB & Gynecologist
Isfahan Fertility & Infertility CenterSlide3
Indications
I. Ovulation induction: in the following cases:
a) C.C resistant PCO: Defined as failure to ovulate on a dose of 100 mg, for 5 days (recently in 3 cycles, in contrast to 6 cycles in the past ) orfailure to ovulate on incremental doses of CC(50-150mg).
b)
C.C failure PCO
:
Defined when pregnancy does not occur despite of regular ovulation on C.C for 6-9 cycles.
c)
C.C pregnancy failure:
Defined as failure to maintain pregnancy conceived with C.C.Slide4Slide5Slide6
Various treatment modalities
Tre PharmacologicalCC
Gonadotropin
Hyperinsulinemia
? hMG Insulin sensitizer uFSH GnRH-analogs HP-FSH rec-FSHSlide7
A. Medical Treatment
Infertility is treated by increasing the rate of ovulation, in part by reducing insulin drive through exercise and weight loss .
Ovarian stimulation is used for those patients who do not ovulate, despite loosing weight by different drugs and different protocols.Slide8
Medical Treatment (cont.)
Treat
Hyperprolactinaemia with Bromocriptine.Glucocorticoids for adrenal hyperplasia . ( 0.25mg Dexamethasone at night )
COC pills or POP for dysfunctional uterine bleeding and to reduce the risk of endometrial
carcinoma
. Slide9
B. Surgical treatment modalities
Surgical Treatment
Cauterization Wedge resection ( laser, electric ) Slide10
Methods of Ovarian Surgery For Ovulation Induction In PCOS
Laparoscopic Techniques of Ovarian Surgery (LOS)
Laparoscopic Ovarian Drilling (LOD) : Diathermy / LASER. Transvaginal Techniques of Ovarian Surgery (TVOS)
1)
Transvaginal
mini-laparoscopy (Fertiloscopy)
2)
Transvaginal
ultrasound (TVS)-guided ovarian drilling. Slide11
LASER versus
electrocautery
for LOS:Electrocautery IS superior why?
1) Less coast &easy application.
2) Achieve higher ovulation and pregnancy rate.
3) Less surface injury than CO2 LASER → Surface adhesion.
4) Effect of diathermy may last longer than the effect of LASER . Slide12
1)
lifestyle modifications :Weight lossC
affeine intake
A
lcohol consumption
Smoking
D
ietary modification
ExercisePsychosocial stressorsSlide13
Role of weight loss in PCOS treatment:
R
educe insulin resistance by about 50%
R
estore ovulation
R
egulate menstrual cycles
R
educe pregnancy complications
I
mprove fertility
I
mprove health during pregnancy
I
mprove the health of a child during pregnancy
I
mprove emotional health (self-esteem, anxiety, depression)
R
educe risk factors for diabetes and heart diseaseSlide14
PROTOCOLS OF MANAGEMENT IN ADOLESCENTS
Counselling
for weight reduction and life style modification.Carbohydrate and fat restricted diet.Diet restriction and exercise is the sheet anchor of treatment for overweight.Low glycemic index diet upto 85% will improve menstrual cycle regularity and ovulation in about six monthsSlide15
Even 7% weight reduction may lead to spontaneous resumption of menses
.
Moderate physical activity, 30-60 minutes per day should be goal of all patient with adolescent PCOS.M.O.A:-lowers circulating free androgen and insulin levels.Increases SHBG, thereby decreases level of free testosterone.Slide16
FSH Ovulation Induction Protocol
Increase dose slowly - can be very sensitive
25-50iu/day
Increase dose
by 50%
Increase dose
by 50%
Starting
dose
Scan
d14
Scan
d7
Scan
d21
hCG 5000u
Follicle
=16mmSlide17Slide18
2) Gonadotrophins :
Ovulation
induction with gonadotrophins has been used as a second line treatment for CC-resistant PCOS women.Disadvantage : expensive/ requires extensive monitoring /risk for OHSS & multiple pregnancy .The high sensitivity of the
PCOS to
gonadotrophic stimulation
is: they
contain twice
the number
of
FSH -sensitive antral follicles than the normal ovary.A lowdose,step-up gonadotrophin therapy should be preferred.Slide19
R
ecommended
approach is : begin with a low dose of gonadotrophin, (typically 37.5– 75 IU/day) increasing after 7 days or more if no follicle >10 mm has yet emerged, in small increments, at intervals, until evidence of progressive follicular development is observed.The maximum required daily dose of FSH/hMG seldom exceeds 225
IU/day.
There is
no evidence of a difference between recombinant FSH (
rFSH
) and
uFSH
for ovulation induction in CC- resistant PCOS women.Slide20
3)
Laparoscopic
Ovarian Drilling WHO BENEFITS FROMMechanism LEOS • ?Removalresistant, CC androgen-producing tissueProblems Slim, Anovulatory ,
•
Hazards of laparoscopic surgery & GA (although rare) raised S.LH
•
TemporaryEfficacy
•
<50% clomiphene-resistant women conceive (ovulation rate 80%+) • Hormone profile returns to normal • ?Fewer miscarriages compared to gonadotrophin injection treatmentSlide21
3)
Laparoscopic Ovarian
Drilling (LOD):
Being
as effective as
gonadotrophin treatment
and is not associated with an increased risk of multiple pregnancy or
OHSS.
When applied properly
, does not seem to compromise the ovarian reserve in PCOS women.n economic evaluation has shown that the cost of a live birth after LOD is approximately one-third lower than the equivalent cost of gonadotrophin treatment.Four punctures per ovary using a power setting of 30 W applied for 5s per puncture.Slide22
Unilateral LOD
being equally efficacious as bilateral drilling in inducing ovulation and
achieving pregnancy in CC resistant PCOS patients and may be regarded as a suitable option with the potential advantage of decreasing the chances of adhesion formation.Mechanism :LOD drains the ovarian follicles containing a high concentration of androgens and inhibin reduction of blood androgens and blood inhibin resulting in an increase of FSH and recovery of the ovulation
function .Slide23
poor responders to
LOD :
Women with marked obesity (BMI >35 kg/m2)Marked hyperandrogenism (serum testosterone concentration >4.5 nmol/lfree androgen index (FAI) >15long duration of infertility (>3 years
)
Predictor of higher probability
of
pregnancy :
LH levels >10 IU/l in LOD respondersSlide24
Technique of Laparoscopic Ovarian DrillingSlide25
4)
Insulin-sensitizing
drugs :Slide26
IMPROVEMENT OF HYPERINSULINEMIA BY INSULIN SENSITIZERS
Directly
sensitizing insulin receptors.Preventing neoglucogenesis.Reducing absorption of glucose from intestine.Increasing hepatic synthesis of SHBG level thereby reducing the level of bioactive free testosteroneSlide27Slide28
Metformin
Decreases
basal hepatic glucose output in patients and lowers fasting plasma glucose concentration.It increases the uptake and oxidation of glucose by adipose tissue as well as lipogenesis.S/E- diarrhoea, nausea, vomiting ,specially initially. To avoid them metformin should be taken with meals and the dose increased gradually. Or SR release formulations are used once a day 1000 mg SR or 500mg SR twice a daySlide29Slide30
OTHER DRUGS WHICH CAN BE USED
•
Rosiglitazone ,• Pioglitazone,• D chiro inositol,• Myoinositol• N acetyl cysteine.
•
Micronutrients Slide31
OTHER DRUGS WHICH CAN BE USED IN ADDITION TO O.C.P
In
cases of failure or where there is clinical or biochemical evidence of gross hyperandrogenicity or hyperinsulinemia, addition of metformin is recommended.Spironolactone- it has antiandrogenic effects in doses 100-200 mg daily.Finasteride - a competitive inhibitor of Type-2 5a reductase to treat hirsutism. Dose 1-5 mg/day. Slide32Slide33Slide34Slide35Slide36Slide37
5)
Third-generation aromatase
inhibitors :Anastrozole, L
etrozole
,
E
xemestaneSlide38Slide39
DURING PREGNANCY
RECURRENT
MISCARRIAGES 50%GESTATIONAL DIABETESPREGNANCY INDUCED HYPERTENSIONINTRAUTERINE GROWTH RETARDATIONSlide40
6)
Oral
contraceptives : Oral contraceptive administration
reduce serum LH, estradiol and androgen
levels
improving the
ovarian microenvironment
Inhance
ovarian response to CCSlide41
7) N-acetyl-cysteine :
N
-acetyl cysteine (NAC) is the acetylated variant of the amino acid L-cysteine.It is an excellent source of sulfhydryl groups and is converted in vivo into metabolites that stimulate glutathione production, promote detoxification, and act directly as free-radical scavengers.combination of CC and NAC increases ovulation and pregnancy rates in CC-resistant PCOS patients who also suffer from infertility.NAC has antiapoptotic
effects on the ovary and apoptosis is definitely responsible for the process of follicular atresia.Slide42
Biological activities of N-acetyl cysteine Slide43
8)
Dexamethasone
therapy : Dexamethasone (after 2 weeks of treatment )
Reduced DHEAS
R
educed
Testostrone
R
educed LH levels and the LH/FSH ratioInhance ovarian invironmentSlide44
9) Bromocriptine :
Bromocriptine administration provided
no benefit in CC-resistant PCOS patients with normal prolactin levels.Bromocriptine administration improve ovarian response in hyperprolactinemic patients.
Dopaminergic components have control
of LH release in PCOS patients
Slide45
10) IVF/ET or IVM :
If all else fails for the infertile PCOS patient then in-vitro fertilization is a last resort providing excellent results.Slide46
33-50% OF PATIENTS REFERRED FOR IVF HAVE PCOSSlide47Slide48
MANAGEMENT
life
style and exercisesdietinsulin sensitisersocp’sprogesterone for bleedstatins/diabetes /antihypertensives if neededomega 3 and micronutrients(inositol or
myoinositol
or n-
actyl
cysteine or alternative medicines Slide49
Algorithm for ovulation induction treatment in
anovulatory
infertile women with CC-resistant PCOS Slide50Slide51