An update of clomiphene enclomiphen in male infertility evidence based, Dr. Abhishek Dr. Sharda Jain


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An update of clomiphene enclomiphen in male infertility evidence based, Dr. Abhishek Dr. Sharda Jain

  1. 1. An Update of CLOMIPHENE (Enclomiphene) in Male Infertility :Evidence Based DR. ABHISHEK SINGH PARIHAR DR. SHARDA JAIN
  2. 2. Causes
  3. 3. Causes of Male Infertility
  4. 4. 5% Psycological 15% Disorders of Sperm motility 50% due to disorders of 30% due to obstruction of ductus deferens. Causes spermatogenesis eg ↑ scortal tem
  5. 5. Early decline in testosterone……….. Male infertility Major link Testosterone deficiency
  6. 6. Testosterone deficiency Prevalence: 26.1% males in India are suffering from hypogonadism Causes: Andropause, Testosterone deficiency syndrome (TDS) and Ageing Indian J Urol. 2009 Apr;25(2):190-4.
  7. 7. Clomophene citrate is used left & right by infertility experts all over the country in India without much support by Cochrane review
  8. 8. 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
  9. 9. The uniqueness of SERMs The SERMs bind to testosterone receptors and have tissue-specific effects that allow them to function as testosterone agonists in some tissues and testosterone antagonists in other tissues
  10. 10. 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
  11. 11. Mechanism of action Enclomiphene
  12. 12. Hypothalamic-pituitary-testicular axis Enclomiphene Zuclomiphene ER antagonist ER agonist Induces hypothalamic GnRH release Opposes the action of Enclomiphene Increases LH & FSH levels Increases serum testosterone levels IDrugs 2009 Feb;12(2):109-19 Reduces testosterone levels
  13. 13. Enclomiphene in Male Hypogonadotropic Hypogonadism Associated with Infertility and Metabolic Syndrome EC has a theoretical advantage over testosterone replacement because gonadotropin levels, fertility, and testicular size are preserved, while testosterone secretion has a physiological, temporal pattern • In baboons who received 12 days of CC, EC, or ZC; EC: – – • In a phase IIb/III, double-blind trial in males with secondary hypogonadism, EC: – – • Increased serum testosterone > than CC (1144 ng/dL vs. 559 ng/dL; P=0.03) Decreased total cholesterol level Increased serum testosterone, LH, FSH, estrogen, FPG and cholesterol Levels were unchanged for placebo and testosterone gel SAFETY and TOLERABILITY: Similar to placebo; low frequency; mild-to-moderate (hot flashes, headache, nausea, vomiting) Hill S, et al. Idrugs. 2009. 12(2):109-119.
  14. 14. Animal study… contd. Study in baboons examined the effects of 12 days of treatment with clomiphene citrate, enclomiphene or zuclomiphene (all administered at 1.5 mg/kg/day) Zuclomiphene failed to increase testosterone levels 8-fold increase in testosterone levels with enclomiphene 5-fold increase in testosterone levels with clomiphene citrate Hill S, et al. Idrugs. 2009. 12(2):109-119.
  15. 15. LH & FSH level after 3 & 6 months Baseline Androxal Testosterone gel Androxal Testosterone gel After 3 months After 6 months
  16. 16. Comparing with Published data for Clomiphene citrate….
  17. 17. Enclomiphene 25 mg shows 2.5 times more LH rise than clomiphene 50 mg 458% 170% * European Journal of Endocrinology (2009) 161 163–169 Androxal® Data on File. ( #
  18. 18. Enclomiphene 25 mg shows more than 4 times FSH rise than clomiphene 50 mg 83% 354% *European Journal of Endocrinology (2009) 161 163–169 Androxal® Data on File. ( #
  19. 19. Enclomiphene shows significant improvement in LH & FSH levels than clomiphene citrate Increase in testosterone levels Increase in spermatogenesis Elevated sperm count
  20. 20. Significant improvement in testosterone levels 218% increased testosterone Androxal® Data on File. (
  21. 21. Enclomiphene Enclomiphene VS Current T Gels/ Cream Enclomiphene
  22. 22. Enclomiphene Indications & Dosage Treatment of Male Hypogonadism • Dosage: 1 capsule of Enclomiphene 25mg OD for 3-6 months
  23. 23. Lets Update ourselves on Medical treatment with clomiphene in male infertility
  24. 24. EC Stimulates Endogenous Production of Testosterone and Sperm Counts in Men with Low Testosterone • EC was compared as an alternative to topical testosterone in a proof-of-principle, randomized, open-label, phase IIB study in 12 men with secondary hypogonadism treated previously with topical testosterone. • After discontinuation of topical testosterone, morning total testosterone (TT) values averaged 165  ±  66  pg/dL. – After 3 months, there was a significant rise in TT that was sustained for 3 months. • • At 6 months, TT levels were 545  ±  268 and 525  ±  256  pg/dL for gel and EC groups, respectively. EC elevated sperm counts in all men at 3 and 6 months with sperm concentrations in the 75–334  ×  106/mL range. – At follow-up, only EC therapy was associated with elevated sperm counts. Kaminetsky L, et al. J Sexual Med. 2013; 10(6): 1628–1635.
  25. 25. Effect of clomiphene citrate on sperm density in male partners of infertile couples. Patankar et al 2007 Clomiphene citrate exerts its effect on spermatogenesis by raising the endogenous serum FSH, LH and testosterone levels to initiate and maintain gametogenesis . Researchers opined that this increase in endogenous gonadotrophins manifests itself in improving the sperm count, sperm motility and to certain extent morphology of the sperms, when there is no end-organ pathology.
  26. 26. COCHRANE Database syst Rev 2007 Jul 18;(4) Anti-oestrogens appear to have a beneficial effect on endocrinal outcomes, but there is not enough evidence to evaluate the use of anti-oestrogens for increasing the fertility of males with idiopathic oligo-asthenospermia. WITHDRAWN: Clomiphene or tamoxifen for idiopathic oligo/asthenospermia.
  27. 27. It is up to you to use The hidden facts of Enclomiphene In male infertility Shared in this presentation
  28. 28. CONCLUSION • Clomiphene is popular for treatment of unexplained idiopathic male infertility because it is inexpensive and safe • Management of secondary hypogonadism associated with obesity, metabolic syndrome . • Because efficacy of clomiphene is in DOUBT, prolonged courses of empirical antiestrogen therapy should not be used as a substitute for more effective modes of management.
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