Clomiphene citrate adjunctives & alternatives

2. CC
50%: ovulate using the 50-mg/d
Another 25%: ovulate if the dosage increased to 100 mg/d
(Hughes et al., 2000).
Most CC-induced pregnancies occur within the first 3 cycles.
There is no benefit to increase dosage once ovulation has occurred or to continuing beyond 6 ms
Derman et al., 1995).
Aboubakr Elnashar

3. CC should be discontinued if the patient is anovulatory after the dose has been increased in 3 consecutive cycles up to 100 mg (Balen, ,1999).
•150 mg or more confer no benefit (Kousta et al., 1997) & only worsen the side effects: thickened cervical mucus antiestrogenic effect on the endometrium (Sereepapong et al., 2000).
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4. CC Resistant PCOS
Incidence:
20%
Define
No ovulation (Absence of follicular development on TVS with concomitant failure of E2 levels to rise) after treatment with CC, {100 mg, for 5 days in 3 cycles} (Coelingh Bennink, 1998).
Causes:
hyperandrogenic
Obese
Severe insulin resistance (Murakawa et al., 1999; Speroff et al., 1999).
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5. CC failure
Define:
No pregnancy despite of ovulation with CC
Causes:
cervical and endometrial changes
low fertilization rate,
variable implantation rate and
deficient corpus luteum function (Speroff et al., 1999)
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6. I
1. Life style changes:
Weight reduction,
Exercise,
stop smoking
2. CC + corticosteroids if DHEAS > 2ug/ml
II
Alternatives
1. Tamoxifen
2. Letrozole
3. Metformin
Adjuvants
1. Corticosteroid
2. NAC
3. Prett with COC
Bromocriptine
Extended CC.
Antiandrogens:
a. Ketoconazole
b. Aldactone
c. cyproterone acetate
Naltrexone
Prett with progesterone
Aboubakr Elnashar

7. Alternatives 1. Tamoxifen
•No evidence of a difference in effect between CC & tamoxifen (Cochrane library, 2005) The recent NICE report (NICE 2004) regarded both CC & tamoxifen as equally effective agents for ovulation induction.
•CC in combination with tamoxifen has no effect on PR when compared to CC alone (Cochrane library, 2005)
Aboubakr Elnashar

8. 2. Insulin sensitizers
Types:
1. Metformin
2. D-Chiro-inositol: induced ovulation sucessfully with no serious side effects, but limted studies
3. Rosiglitazone, Pioglitazone: limited studies
4. Troglitazone: Withdrawn by FDA because of liver toxicity & other side effects
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9. Metformin: oral biguanide
Mechanism of action:
A. Decrease blood glucose level by:
a.Mainly: decrease hepatic glucose production
b.To lesser extent: increases peripheral glucose uptake.
B.Increases insulin sensitivity at the post-receptor level
Unlike S. urea it does not cause hypoglycaemia because it does not increase insulin secretion.
C. Directly inhibits human ovarian steroidogenesis (Mansfield et al,2000)
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10. Side effects:
diarrhea, n,v, abd bloating, metallic taste, v. rare lactic acidosis
Contraindications:
1. Renal (creatinine >1.4mg/dl) or hepatic impairment
2. Cardiac or respiratory disease.
Dose:
500 mg/d for 1 w then 500 mg bid for 1 w then 500 mg tds then 850 mg bid
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11. Aboubakr Elnashar

12. Effects:
1. Increase SHBG,decrease insulin, A, FT, LH. These improvements occurred in absence of any change in body weight (Iurno & Nestler,2001)
2. Increase both spontaneous & CC induced ovulation rate (Nestler,1998)
3. Enhance the response to induction with FSH injection (Deleo et al, 1999)
Aboubakr Elnashar

13. 4. As adjunctive during COH: Improvement in oocyte quality, fertilization rate, embryo development (Geusa et al,2002), implantation & clinical pregnancy rates (Kahraman et al,2002)
5. Reduces FSH stimulated aromatase activity in PCOS (De Leo et al,2002)
6. Improves the features of syndrome X e.g hypertension & obesity.
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14. Uses: 1. In PCOS:
a.Induction of ovulation in: Insulin resistant PCOS: Both obese & lean with hyperinsluinaemia respond to metformin (Speroff,1999) CCR PCOS (ASRM, 2002) PCOS: as a first line drug (Sharma, 2005) b. To prevent OHSS in PCOS induced by gonadotrophin (Visnova et al,2002) c. To reduce the doses of gonadotrophin in PCOS patients undergoing ovarian stimulation (Atassi et al,2002) d. In adolescent PCOS: Use for 1 year to prevent full picture (Hassan & Yousef, 2002)
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15. 2. IN PCOS during pregnancy
a. Prevent early pregnancy loss (Jakubowicz et al,2000, Gluek et al,2001): by decreasing platelet activator inhibitor
b. Prevent Gestational D.M (Glueck et al,2002). 2.55 g/d, 10 fold decrease in GDM
c. Treatment of DM after the first trimester (Coetze et al,1979; Hellmuth et al,2000). It is not teratogenic (category B,FDA)
d. Prevent fetal virilization with increased androgen (Sarlis et al, 1999)
Aboubakr Elnashar

16. The Cochrane Database of Systematic Reviews 2005 Issue 4, Lord et al
•Metformin has a significant effect in reducing fasting insulin & LDL. There was no evidence of effect on BMI or WHR.
•Metformin was associated with a significantly higher incidence of GIT disturbance
•Metformin is an effective treatment for anovulation in women with PCOS.
Aboubakr Elnashar

17. Its choice as a first line agent seems justified.
•Ovulation rates are higher when combined with CC (76% Vs 46% when used alone)
•It should be used as an adjuvant to general lifestyle improvements, and not as a replacement for increased exercise and improved diet.
Aboubakr Elnashar

18. Systematic review of metformin Vs CC in PCOS (Kashyap, 2004).
•Metformin plus CC are 3-4-fold superior to CC alone for ovulation induction and pregnancy.
•No RCTs directly compare metformin to CC but the need for such a trial exists.
Aboubakr Elnashar

19. 3. Aromatase inhibitors
Mechanism
1. Release the pituitary/hypothalamic axis from the estrogenic negative feedback, increase Gnt secretion, stimulate ovarian follicle development (Mitwally & Casper, 2001).
2. locally in the ovary: increase the follicular sensitivity to FSH (Vendola et al,1998).
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20. Advantages
1. No adverse antiestrogenic effect on the endometrium or cervical mucus
a. absence of estrogen receptor depletion.
b. Rapid elimination from the body (half-life of 45 hours)
2. Limited number of mature follicles (decrease OHSS & multiple pregnancy).
Aboubakr Elnashar

21. Dose
• Letrozole: 2.5 -5 mg/ day on day 3 to 7 or Single dose of 20 mg on day 3 (Mitwally & Casper,2001).
•Anstrazole: 1-2 mg/day The comparison between two AIs (letrozole and anastrozole) did not find any evidence of a difference in effect on pregnancy rate (Cochrane library, 2005)
Aboubakr Elnashar

22. b.The largest study (44 patients) done by Elnashar et al (MEFS J; 2004): Induction of ovulation with Letrozole in CC R PCOS is associated with ovulation rate (54.6%) and pregnancy rate (25%) No significant difference between letrozole responders & non-responders as regards the age, period of infertility, BMI, W.C., LH, FSH or LH/FSH (Elnashar et al, Fertil Steril; Feb, 2006).
Aboubakr Elnashar

23. Adjuvants 1. N-acetyl cysteine Effects of NAC on PCOS NAC: 1.8 g/d for 5-6 W (Fulghesu et al, 2002) 1. In hyperinsulinemic subjects:
•Significant increase in insulin sensitivity Significant reduction in insulin levels
•Significant reduction in T & FAI 2. In normoinsulinemie & placebo-treated subjects: No significant changes
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24. Effects
A. Metabolic:
1. Antioxidant:
in non-insulin dependent DM (De Mattia, et al., 1998).preserve vascular integrity (Sekhon et al. 2003) & protect against focal ischemia.
2. Insulin sensitizer:
Increase peripheral insulin sensitivity (Moghetti et al., 2000).
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25. B. Biological effects:
Antiapoptotic (Odetti et al., 2003).
Anticytokines (inhibit proinflammatory cytokine release) (Lappas et al. 2003)
Inhibition of phosopholipid metabolism& Protease activity.
NAC may exert the same effects at the ovarian level which may be important in inducing ovulation
Mucolytic.
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26. Dose:
1.2 gm/day with CC 100mg/day for 5 days
Advantages:
safe, well tolerated, inexpensive.
NAC alone is not an effective drug in inducing ovulation in CC resistant PCOS
(Elnashar et al, 2005)
Aboubakr Elnashar

27. Results:
1. CCPCOS:
The combination of CC and NAC significantly increased both ovulation and pregnancy rate (49.3&21.3% respectively)
(Rizk et al,2004)
2. PCOS:
NAC is effective , adjuvant to the CC for ovulation induction in PCOS even in the absence of insulin resistance
(Badawy, Elnashar, Totongy, 2005)
Aboubakr Elnashar

28. 2. Corticosteroids Regimen:
1.Small dose long course: Dexamethazone: 0.5 mg at night daily Prednisone: 5 mg/d 2. High dose short course: Dexamethazone 2 mg from D3-12 & CC from D 3 to 7 (100 mg /day)
Aboubakr Elnashar

29. Mechanism of action
1.Inhibits adrenal androgens (DHEAS, T) Act as a prehormone for T (Ray et al., 1984) and the reduction in this prehormone leads to a decrease in T level
2.Reduces circulating LH, and LH/FSH ratio (Baldwin, 1974; Karpas, 1984;Speroff, 1990). 3. Acts directly a. on the pituitary to suppress the action of E2, which my be involved in the process of induction of ovulation (Terkawa, 1985). b. influence follicular development (Smith et aL, 2000).
Aboubakr Elnashar

30. 4. Acts indirectly
a. by increasing serum GH (Casaneuva et aL, 1990), serum IGF-1 (Miell et aL, 1993) & consequently follicular fluid IGF-1 concentrations.
b. Enhances the FSH-stimulated follicular steroid production (Roy et al, 2003).
Aboubakr Elnashar

31. •DEX high dose, short course therapy combined with CC in the follicular phase can improve folliculogenesis, ovulation, & PR (Parsanenzhad, et al., 2003; Elnashar et al, 2005).
•CC plus Dex treatment resulted in a significant improvement in PR when compared to CC alone (Cochrane library, 2005)
Aboubakr Elnashar

32. Side effects:
There is no evidence that glucocorticoid treatment has any important side effects or risks when used in the doses & durations indicated
(Sperof & Fritz, 2005)
Aboubakr Elnashar

33. 3. Pretreatment with COC
Suppression of the HPO axis for 2 months with COC followed by CC results in:
excellent rates of ovulation and pregnancy in women who had previously failed to ovulate on CC alone (Genazzani et al, 1997; Branigan and Estes, 1999).
Aboubakr Elnashar

34. Effects:
1. lower the LH/FSH level
2. improve the androgen environment of the ovaries, by increasing Levels of SHBG while decreasing androgen secretion induced by the increased LH
(Branigan and Estes, 1999).
So, it reduces the free testosterone
(Sheu et al, 1994).
3. suppress androgen production, thus ameliorating skin androgenic symptoms and improving menstrual dysfunction.
Aboubakr Elnashar

35. Disadvantages:
•Exacerbates insulin resistance and since many patients are overweight & obesity is a relative contraindication, this treatment may be unsuitable (Sheu et al, 1994). # 1. The negative influence on insulin sensitivity is not expressed in non-obese patients (Vrbíková and Cibula, 2005) . 2.Impairment of glucose tolerance is reversible. 3. Lipid levels usually remain within the reference limits. 4. COC with weight reduction or insulin sensitizers suppress androgen levels and improve metabolic parameters.
Aboubakr Elnashar

36. Advantages:
an effective, reasonable, inexpensive, and low- risk alternative before Gnt therapy
(Branigan and Estes, 1999).
COC are the most often used treatment modality for PCOS
(Vrbíková and Cibula, 2005) .
Pretreatment with COC followed by CC results in excellent rates of ovulation
(Cochrane library, 2005)
Aboubakr Elnashar

37. . Bromocriptin not recommended unless prolactin concentration are consistently elevated (Zacur , et al ., 1992). For CC plus bromocriptine Vs CC no evidence of a difference in effect on pregnancy rate was found (Cochrane library,2005) Two methods:
1.2.5mg bid until the patient is pregnant as judged by the BBT chart.
2.Follicular phase, and the drug is stopped when BBT rise indicates that ovulation has occurred (Ginsburg et al, 1992).
Aboubakr Elnashar

38. . Extended CC therapy
•Increase the duration to 10 days: previously unresponsive women ovulate in 65% of 48 cycles (Fluker et al., 1996).
•Extend the duration of CC until a follicle of 18 mm diameter (on ultrasound), then administer HCG (Speroff et al., 1999).
•The basic idea behind this therapy is to use more CC. It is not commonly used {little success & significant side effects} (Branigan & Estes, l999).
Aboubakr Elnashar

39. . Pretreatment with Progesterone
50 mg/day IM for 5 Days (Homburg et al ,1988).
FSH were reduced
LH were reduced LH (in 70%).
Following the withdrawal bleeding, these patients became responsive to CC as shown by ovulation.
Short-term progesterone treatment improves the efficiency & results of CC treatment in PCOS (Balen, 1999).
Aboubakr Elnashar

40. . Antiandrogens a. Ketoconazole is a CYP17a Inhibitor. It inhibits a different part of the cytochrome P450 complex to AIs. Mechanism of action:
1.Inhibition of the hydroxylase-lyase enzyme in the ovary, adrenal gland and liver. This inhibits steroidogenesis.
2.Inhibits aromatase activity in the gonads (Hassan 2001; Parsanezhad 2003). It therefore may have similar effects to AIs with added anti-androgenic effects.
Aboubakr Elnashar

41. CC (up to 150 mg) plus ketoconazole (400 mg) Vs CC (up to 150 mg) (Cochrane library,2005)
PR: no evidence of a difference between groups
Aboubakr Elnashar

42. b. Spironolactone
A. Alone
Dose:
50-200 mg daily for 6 cycles
Advantages:
(Kidson, 1998).
safety, availability, and low cost.
does not cause weight gain
Ovulation is commonly restored in 85%
slightly reduces insulin resistance
Aboubakr Elnashar

43. Effects: (Evron et al, 1981).
1.Significant decrease in LH, testosterone, prolactin, and 17-ketosteroid
2.Ovulation in 85%
3.Improvement of hirsutism in 70%
4.Restoration of regular cycles in 85%
Aboubakr Elnashar

44. Side effects
mild and did not lead to interruption of the treatment.
polymenorrhoea.
Antiandrogenic properties of spironolactone render it a suitable agent in the treatment of anovulatory, oligomenorrheic, and hyperandrogenic women.
Aboubakr Elnashar

45. Spironolactone (50 mg/d) Vs metformin (1000 mg/d) in adolescent and young women with PCOS for 6 months (Ganie et al, 2004).
Both groups showed improvement in glucose tolerance and insulin sensitivity, although the metformin effect was significant in the latter.
Serum LH/FSH and testosterone decreased in both groups.
Aboubakr Elnashar

46. Both drugs are effective in the management of PCOS.
Spironolactone appears better than metformin in the treatment of hirsutism, menstrual cycle frequency, and hormonal derangements and is associated with fewer adverse events.
Aboubakr Elnashar

47. B. Combined with CC
Three treatment groups CC plus dexamethasone or sprinolactone or cyproterone acetate
(Koloszar et al, 1996).
The highest ovulation & PR in the group treated with cyproterone acetate.
Adjuvant antiandrogen treatment with cyproterone acetate advisable in the cases of hyperandrongenic conditions.
Aboubakr Elnashar

48. Aboubakr Elnashar