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Clomiphene update in infertility Dr. Sharda Jain , Dr. Jyoti Agarwal Lifecarecentre

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Clomiphene update in infertility Dr. Sharda Jain , Dr. Jyoti Agarwal Lifecarecentre

  1. 1. Clomiphene Update : In Infertility Dr. Sharda Jain Dr Jyoti Agarwal
  2. 2. What is new in clomiphene The TRUTH about Infertility... IT HURTS!
  3. 3. Major Causes of female infertility Failure to ovulate ••Hormonal Hormonal problems problems ••Scarredovaries Scarred ovaries ••Premature Premature menopause menopause ••PCOS PCOS 20-40% Dysfunctional fallopian tubes ••Infection Infection ••Abdominal Abdominal diseases diseases ••Previoussurgeries Previous surgeries ••Ectopicsurgeries Ectopic surgeries Endometriosis ••Excessivegrowth of Excessive growth of the lining of the the lining of the uterus uterus
  4. 4. DRUGS USED FOR OVULATION INDUCTION • • • • CLOMIPHENE CITRATE GONADOTROPHINS TAMOXIPHENE AROMATASE INHIBITORS Most commonly used is CC
  5. 5. WHO Classification of Anovulation & Oligo-ovulation… • Grp I - hypothalamic pituitary failure or hypogonadotrophic hypogonadism, accounting for around 10% of ovulatory disorders; • Grp II - hypothalamic pituitary dysfunction or eugonadotrophic, 85% of ovulatory disorders; • Grp III - ovarian failure or hypergonadotropic hypogonadism, 4-5% of ovulatory disorders. Cochrane Reviews 2009, Issue 4. Art. No.: CD002249.
  6. 6. For Ovulation induction an anti-estrogen is required Anti-estrogens are the first line treatment strategy for WHO class 2 anovulatory infertility.
  7. 7. Clomiphene citrate Synthetic, nonsteroidal antiestrogen (SERM) First anti-estrogen, approved by the U.S. FDA in 1967 Widely used for past 45 years for induction ovulation Selective Estrogen Receptor Modulator
  8. 8. The uniqueness of SERMs The SERMs bind to estrogen receptors and have tissue-specific effects that allow them to function as estrogen agonists in some tissues and estrogen antagonists in other tissues
  9. 9. Clomiphene Citrate: Indications Practice Committee of the American Society for Reproductive Medicine. FERTILITY AND STERILITY.2003; 80(5): 1302-1308.
  10. 10. Clomiphene citrate….. Certainly an Old favorite in the world of ovulation induction.. But, it has negative effects… Fertil Steril 2009;92:860-3
  11. 11. Clomiphene citrate – A racemic mixture Cis- Zuclomiphene Cis- Zuclomiphene Trans- Enclomiphene Trans- Enclomiphene Isomer Ratio 38% Zuclomiphene & 62% Enclomiphene Pharmac. Ther. Vol. 15, pp. 467 to 519, 1982
  12. 12. CC: Mixed estrogen agonist-antagonist
  13. 13. Enclomiphene Anti-estrogenic centrally Property of ovulation induction Estrogenic peripherally Increased cervical mucus Short half-life of 24 hrs Less Resistance in patients Endometrial thickening Reproductive Biomedicine Online; vol. 15;No.2. 2007, 134-148 Usadi, R, Fritz, M, Glob. libr. women's med., (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10337 Endocrinology. 1983 Feb;112(2):442-8 Middle East Fertility Society Journal; Vol. 13, No. 1, 2008;52-56
  14. 14. Zuclomiphene peripheral disadvantages Peripheral antiestrogenic Endometrium Cervix Endometrial thinning Poor cervical mucus Decreased implantation J. Biosci., Vol. 7, Number 2, March 1985, pp. 161– 173. Middle East Fertility Society Journal; Vol. 13, No. 1, 2008;52-56
  15. 15. Drawbacks of ZC : Benefits of EC Enclomiphene scores over the cisisomer in terms of: Good follicular growth  Induces ovulation Endometrial thickness  Builds up endometrial lining  No abnormal luteal phase morphology Zu Clomiphene (Cis-Isomer) Good quality of cervical mucus (thin) which is desirable for better sperm transport Short T1/2 (24 hrs): Gets eliminated from the body faster Teramoto S, Kato O. Reproductive BioMedicine Online. 2007; 15(2): 134-148. .
  16. 16. What literature has to say… Zuclomiphene gets accumulated for a longer time in the body Is detectable in the circulation even after 1 month of treatment and may actually accumulate over consecutive cycles of treatment Human Reproduction Vol.20, 2005 Enclomiphene disappears rapidly from the circulation (less than 24 hrs) CURRENT SCIENCE, VOL. 80, 2001 Zuclomiphene is unable to induce ovulation due to its estrogenic nature Hum Reprod.1989 Apr;4(3):252-6.
  17. 17. • Twenty-six normoprolactinaemic women • Women treated with 100 mg clomiphene citrate daily from day 2 of the first cycle for 5 days • Following a ‘washout’ cycle were then randomized to receive 50 mg either the En or the Zu isomer daily from day 2 of the third cycle for 5 days.
  18. 18. Enclomiphene 50 mg comparable to Clomiphene citrate 100 mg p < 0.01 p <0.05 Hum Reprod.1989 Apr;4(3):252-6.
  19. 19. EC is the Isomer Active in Inducing Follicular Development Parameter CC cycles Spontaneous ZC Normoprolactinemic women (N=26; mean age=32 yrs) with EC regular menstrual cycles (mean ± SEM) patent fallopian tubes being treated with donor insemination cycles and Serum oestradiol Day 0 3388±530** 1022±141 2595±500* 1176±171 Serum oestradiol Day 1 3772±614** 1236±158 3262±638** 1232±151 Serum progesterone 95±14** 43±4 95±15** 44±8 Mean number of follicles>16 mm 2.4±0.3** 1.2±0.3 2.1±0.3 1.2±0.2 Day of LH peak 14.9±0.4 13.9±0.6 15.2±0.3 13.3±0.4* Spinbarkeit of the endocervical mucus was significantly reduced in CC-treated cycles and EC-treated cycles but there was no reduction in the ZC-treated cycles Glasier AF, et al. Human Reproduction.1989;40(3): 252-256.
  20. 20. Lets recap the clomiphene cycle and Monitoring
  21. 21. 50 mgm of Enclomiphene = 100 mgm of clomiphene Day of start of clomiphene cycle does not improve the pregnancy rate (day 2, 3, or 5) Increasing the dose of clomiphene does not increase the chances of ovulation If ovulation has been documented with 50 mgm dose , continue with the same dose
  22. 22. Each cycle needs to be monitored • Minimum monitoring • Better monitoring • Best monitoring LH kit TVS TVS + LH kit With positive 2 lines following 2 days should be
  23. 23. Usually started from Day 8 - 10 • If CC started from D5 • Monitoring from D12 • Ovulation expected by D 16 – 17
  24. 24. HCG Trigger • GT 18 – 20 mm • CC 22 – 24 mm
  25. 25. How many inseminations 2 or 1 Male factor Low monitoring TWO
  26. 26. HOW MANY CYCLES We at lifecare 6 (including of all ) Cummulative success rate 50 %
  27. 27. Luteal phase support is needed in all cases of cc Method Pregnancy Rate (%) for unexplained infertility Intercourse (Timed) 4 IUI 6 CC 6 CC+IUI 8 FSH / HMG 7.7 CC / FSH /IUI 9-12 3 FSH/ HMG/IUI 17 – 20 % 5 In vitro fertilization 20 to maximum 30 2 Natural Intercourse is NOT Prohibited During Monitoring
  28. 28. For ovulatory disorders Treatment should begin with a low dose, 50 mg daily for 5 days. (1 tablet of Enclomiphene) • The dose should be increased only in those patients who do not ovulate in response to 50 mg of Enclomiphene.
  29. 29. Enclomiphene generally is very well tolerated Side effects are rarely persistent or severe enough to threaten completion of treatment.
  30. 30. Side Effects (2% -10% of women) • Vasomotor flushes (hot flushes) • Mood swings • Visual disturbances: Blurred,double vision, scotoma • Isolated reports of optic neuropathy • If visual disturbances identified, it is prudent to stop treatment and consider alternative methods of ovulation induction • Breast tenderness • Pelvic discomfort • Nausea Practice Committee of the American Society for Reproductive Medicine. FERTILITY AND STERILITY.2013; 100(2):341-348.
  31. 31. KEY TO SUCCESS Patient selection ! Proper stimulation Right timing to IUI Luteal support
  32. 32. Dr ALKA KRIPLANI & Dr P. GUPTA
  33. 33. Improves Cervical Mucus quality Unlike clomiphene Purest isomer Of Clomiphane Ultra-short Acting (24 hrs), Unlike Clomiphane Enclomiphene Improves Endometrial Thickening Unlike Clomiphene Improves Follicular Development Like Clomiphene
  34. 34. Enclomiphene is the main player for ovulation induction and its short half-life can effectively cancel the positive feedback at the hypothalamic level Enclomiphene is the one primarily responsible for the ovulation-inducing actions of CC Reproductive Biomedicine Online; vol. 15;No.2. 2007, 134-148 Usadi, R, Fritz, M, Glob. libr. women's med., (ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10337
  35. 35. The need of the hour for Ovulation Induction is… • Take only the positive effects of Enclomiphene • Remove the negative effects of Zuclomiphene The end result would be… Maximum efficacy Highest Safety
  36. 36. Thank you

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