Management of Women with Clomiphene Citrate Resistant Polycystic Ovary Syndrome DR Seyed Mehdi Ahmadi OB & Gynecologist Isfahan Fertility & Infertility Center

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 ) or failure 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.

Increased Serine phosphorylation Decreased glucose transport Hyperinsulinemia P450c 17 &17,20 lyase activity Adrenals : Increased DHEAS Ovaries : Increased Androstenedione& testosterone

Various treatment modalities Tre Pharmacological CC ? Gonadotropin Hyperinsulinemia? hMG Insulin sensitizer uFSH GnRH-analogs HP-FSH rec-FSH

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.

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.

B. Surgical treatment modalities Surgical Treatment Cauterization Wedge resection ( laser, electric )

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.

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.

1) lifestyle modifications :  Weight loss  Caffeine intake  Alcohol consumption  Smoking  Dietary modification  Exercise  Psychosocial stressors

Role of weight loss in PCOS treatment: Reduce insulin resistance by about 50% Restore ovulation Regulate menstrual cycles Reduce pregnancy complications Improve fertility Improve health during pregnancy Improve the health of a child during pregnancy Improve emotional health (self-esteem, anxiety, depression) Reduce risk factors for diabetes and heart disease

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 months

 Even 7% weight reduction may lead to spontaneous resumption of menses.  Moderate physical activity, 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.

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 =16mm

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.

 Recommended 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.

3) 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 treatment

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.

 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.

 poor responders to LOD : - Women with marked obesity (BMI >35 kg/m2) - Marked hyperandrogenism (serum testosterone concentration >4.5 nmol/l - free androgen index (FAI) >15 - long duration of infertility (>3 years)  Predictor of higher probability of pregnancy : LH levels >10 IU/l in LOD responders

Technique of Laparoscopic Ovarian Drilling

4) Insulin-sensitizing drugs :

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 testosterone

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 day

OTHER DRUGS WHICH CAN BE USED Rosiglitazone, Pioglitazone, D chiro inositol, Myoinositol N acetyl cysteine. Micronutrients

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 mg daily.  Finasteride - a competitive inhibitor of Type-2 5a reductase to treat hirsutism. Dose 1-5 mg/day.

5) Third-generation aromatase inhibitors : Anastrozole, Letrozole, Exemestane

DURING PREGNANCY  RECURRENT MISCARRIAGES 50%  GESTATIONAL DIABETES  PREGNANCY INDUCED HYPERTENSION  INTRAUTERINE GROWTH RETARDATION

6) Oral contraceptives : Oral contraceptive administration reduce serum LH, estradiol and androgen levels improving the ovarian microenvironment Inhance ovarian response to CC

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.

Biological activities of N-acetyl cysteine

8) Dexamethasone therapy : Dexamethasone (after 2 weeks of treatment ) Reduced DHEAS Reduced Testostrone Reduced LH levels and the LH/FSH ratio Inhance ovarian invironment

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

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.

33-50% OF PATIENTS REFERRED FOR IVF HAVE PCOS

MANAGEMENT  life style and exercises  diet  insulin sensitisers  ocp’s  progesterone for bleed  statins/diabetes /antihypertensives if needed  omega 3 and micronutrients(inositol or myoinositol or n-actyl cysteine or alternative medicines

Algorithm for ovulation induction treatment in anovulatory infertile women with CC-resistant PCOS