Life Specialist Hospital Ltd. Nnewi Dydrogesterone Vs Vaginal micronized progesterone for Luteal support in IVF Cycles By Ikechebelu JI, Ibadin K, Joe Ikechebelu NN, Eleje GU, Nwaefulu K, Okwelogu SA, Oguanobi C, Life Specialist Hospital Ltd. Nnewi

Introduction Luteal phase support (LPS) is an essential component of every in-vitro fertilization (IVF) cycle Defective corpus luteum may produce low levels of progesterone insufficient for endometrial ripening, implantation or placentation.1 The standard of care for LPS in Nigeria is presently vaginal micronized progesterone pessary. It is expected that any oral formulation with similar outcome measures like the traditional vaginal formulation will be more acceptable to our women. This is the thinking behind this observational comparative study. 1. Engmann L & Benadiva C. Semin Reprod Med. 2010; 28(6):506-12;

Dydrogesterone vs. Vaginal Progesterone Tolerability: Women prefer to use oral formulations over vaginal ones2,3 Application of vaginal tablets requires a private clean room whereas tablets can be taken orally anywhere2 In a comparative study between dydrogesterone and vaginal micronized progesterone for luteal support4 Vaginal discharge or irritation Reported by 10.5% receiving vaginal progesterone No complaints in dydrogesterone group Satisfaction with the tolerability of the treatment was significantly higher with dydrogesterone than vaginal progesterone (p < 0.05) Women prefer to use oral formulation over vaginal one, even, in the case of mifepristone, when there are gastrointestinal side effects associated with the oral fomulation.1 Oral tablets can be taken anywhere; whereas, application of vaginal tablets requires a clean private room.1 The preferred route of administration of vaginal micronized progesterone or oral dydrogesterone was reported by a study of 430 women undergoing luteal support.2. There was no difference in the rate of treatment success (pregnancy and viable delivery) between the two treatment groups. However, significantly more patients in the oral dydrogesterone group were satisfied with the tolerability of their treatment (assessed by questionnaire) than in the vaginal micronized progesterone group).2 Vaginal discharge or irritation was reported in 10.5% of patients in the vaginal micronized progesterone group experienced compared to 0% of the oral dydrogesterone group. Satisfaction with the tolerability of the treatment was significantly higher with oral compared to vaginal application (p<0.05).2 References: 1. Arvidsson C, et al. Eur J Obstet Gynecol Reprod Biol 2005; 123(1): 87-91. 2. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5): 416-420. 2. Arvidsson C, et al. Eur J Obstet Gynecol Reprod Biol 2005; 123(1): 87-91. 3. Bingham JS. Br J Vener Dis 1984; 60(3); 175-177. 4. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5): 416-420.

Dydrogesterone versus Micronized Progesterone Receptor Selectivity Biological activity Dydrogesterone Progesterone Progestogenic + Anti-gonadotropic – Anti-estrogenic Estrogenic Androgenic Anti-androgenic ±* ± Glucocorticoid Anti-mineralocorticoid Dydrogesterone is selective for the progesterone receptor, avoiding other receptor‑related side effects1–4 There are several advantages to dydrogesterone over micronized progesterone. Dydrogesterone is very selective for the progesterone receptor, thereby avoiding other receptor-related side effects.1-4 In contrast to progesterone, dydrogesterone has no anti-gonadotrophic or glucocorticoid effects1 and has less pronounced anti-androgenic effects.4 Androgenic activity could result in the masculinization of a female fetus.5 However, progesterone, but not dydrogesterone or its major metabolite dihydrodydrogesterone, did exert an anti-androgenic effect by inhibiting 5α- reductase type 2 (an androgen-producing enzyme).4 Anti-androgenic activity could result in the inadequate masculinization of a male fetus, i.e. hypospadias.6 References: 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Dydrogesterone CCDS. 23 June 2015. 4. Rižner TL, et al. Steroids 2011; 76(6):607-615. 5. Kaňová N, Bičiková M. Physiol Res 2011; 60(2):243-252. 6. Wang MH, Baskin LS. J Androl 2008; 29(5):499-505. *Dydrogesterone has less pronounced anti-androgenic effects than progesterone; + effective; ± weakly effective; – not effective 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Dydrogesterone CCDS. 23 June 2015. 4. Rižner TL, et al. Steroids 2011; 76(6):607-615. Slide 68a

Dydrogesterone versus Micronized Progesterone Receptor Affinity Dydrogesterone has ~1.5 times better affinity to progesterone receptors than progesterone1 115% Medroxy-progesterone acetate Affinity to progesterone receptor1 75% Dydrogesterone 50% Progesterone Dydrogesterone is very selective for the progesterone receptor,1-3 and dydrogesterone also has ~1.5 times better affinity to progesterone receptors than progesterone.1 The metabolites of dydrogesterone also have progestogenic activity.1-3 References: 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Dydrogesterone CCDS. 23 June 2015. Dihydrodydrogesterone, the main metabolite of dydrogesterone, also has progestogenic activity1-3 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1): S3-S11. 3. Dydrogesterone CCDS. 23 June 2015. Slide 68b

Dydrogesterone versus Micronized Progesterone Bioavailability and Oral Administration Dydrogesterone has ~5.6 times better oral bioavailability than progesterone1–3 Oral bioavailability Oral dose 100–300 mg progesterone 28% dydrogesterone When comparing oral dydrogesterone to oral micronized progesterone, dydrogesterone has over 5.6 times better oral bioavailability and requires a 10–20 times lower oral dose, regarding endometrial transformation.1–3 Orally administered micronized progesterone shows a wide variation in absorption and bioavailability, even within a single individual.1 These differences with dydrogesterone translate into clinical benefits.4–6 References: 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Stanczyk FZ, et al. Endocr Rev 2013; 34(2):171-208. 4. Patki A, Pawar VC. Gynecol Endocrinol 2007; 23(Suppl 1):68-72. 5. Ganesh A, et al. Fertil Steril 2011; 95(6):1961-1965. 6. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5):416-420. <5% progesterone 10 mg dydrogesterone Dydrogesterone requires a 10–20 times lower oral dose than micronized progesterone,1–3 providing clear clinical benefits4–6 1. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 2. Schindler AE. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Stanczyk FZ, et al. Endocr Rev 2013; 34(2):171-208. 4. Patki A, Pawar VC. Gynecol Endocrinol 2007; 23(Suppl 1):68-72. 5. Ganesh A, et al. Fertil Steril 2011; 95(6):1961-1965. 6. Chakravarty BN, et al. J Steroid Biochem Mol Biol 2005; 97(5):416-420. Slide 68c

To summarize these findings: Dydrogesterone Is produced from a natural source1 like other progestogens Is very similar to progesterone, but has enhanced oral bioavailability2,3 Is highly selective and has a high affinity for progesterone receptors2,3 Is metabolized into compounds that are either progestogenic or inactive2,3 Has a fast onset of action and long, stable effect4 Is well tolerated and has a favorable safety profile in all approved indications, including pregnancy4–9 Note: the effectiveness and safety records of dydrogesterone are based on the body of evidence for treatment of threatened5,6,10,11 and recurrent miscarriage7 Dydrogesterone is produced from a natural source1 like other progestogens. It is very similar to progesterone, but has enhanced oral bioavailability, which means that dydrogesterone requires a 10–20 times lower oral dose than progesterone.2,3 Dydrogesterone is highly selective and has a high affinity for the progesterone receptors.2,3 The metabolites of dydrogesterone either have progestogenic activity or are inactive.2,3 Dydrogesterone has a fast onset of action and long, stable effect.4 Dydrogesterone is well tolerated and has a favorable safety profile in all approved indications, including pregnancy.4-9 The effectiveness and safety records of dydrogesterone are based on the body of evidence for treatment of threatened5,6,10,11 and recurrent miscarriage.7 References: 1. University of Maryland Medical Center. Complementary and Alternative Medicine Guide. Wild yam. http://umm.edu/health/medical/altmed/herb/wild-yam. Accessed 27 April 2015. 2. Schindler AE, et al. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 4. Dydrogesterone CCDS. 23 June 2015. 5. El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1):S43-S46. 6. Pandian RU. Maturitas. 2009; 65(Suppl 1):S47-S50. 7. El-Zibdeh MY. J Steroid Biochem Mol Biol 2005; 97(5):431-434. 8. Dutta DK. Asian J Obstet Gynae Pract 2001; 5(2):3-5. 9. Queisser-Luft A. Early Hum Dev 2009; 85(6):375-377. 10. Omar MH, et al. J Steroid Biochem Mol Biol 2005; 97(5):421-425. 11. Carp H. Gynecol Endocrinol 2012; 28(12):983-990. 1. University of Maryland Medical Center. Complementary and Alternative Medicine Guide. Wild yam. http://umm.edu/health/medical/altmed/herb/wild-yam. 2. Schindler AE, et al. Maturitas 2009; 65(Suppl 1):S3-S11. 3. Schindler AE, et al. Maturitas 2008; 61(1-2):171-180. 4. Dydrogesterone CCDS. 23 June 2015. 5. El-Zibdeh MY, Yousef LT. Maturitas 2009; 65(Suppl 1):S43-S46. 6. Pandian RU. Maturitas 2009; 65(Suppl 1):S47-S50. 7. El-Zibdeh MY. J Steroid Biochem Mol Biol 2005; 97(5):431-434. 8. Dutta DK. Asian J Obstet Gynae Pract 2001; 5(2):3-5; 9. Queisser-Luft A. Early Hum Dev 2009; 85(6):375-377. 10. Omar MH, et al. J Steroid Biochem Mol Biol 2005; 97(5):421-425. 11. Carp H. Gynecol Endocrinol 2012; 28(12):983-990. Slide 71

Study Objective To compare the pregnancy outcome with the use of oral dydrogesterone for luteal phase support to the present standard of care vaginal micronized progesterone pessary in In-vitro fertilization cycles.

Methodology Recruitment for self ovum cycle: Women with Day 2–5 follicle-stimulating hormone level of ≤10 iu/l Down regulation – Long Protocol with Buserelin 0.5mg daily from day 21 of previous cycle. Reduced to 0.25mg from day of stimulation. Stimulation Protocol – Menopour 150 – 300mg daily Follicle monitoring by transvaginal ultrasound [days 5, 8 and 11] Trigger – HCG 10,000 iu on day 11 or 12.

Methodology Luteal Phase Support: Women were allotted to 2 groups [computer generated random numbers] A : Dydrogesterone 20mg daily (10mg BD) B : Micronized Vaginal Progesterone 400mg daily from OCR day for 14 days post ET (day 3 transfer of 1-4 embryos) and continued to 14 weeks if pregnancy is confirmed. Pregnancy test performed with blood and urine on day 14 post ET Transvaginal ultrasound 4-6 weeks post ET to confirm pregnancy and fetal heart presence.

Results Table 1: Showing Pregnancy outcome in Dydrogesterone vs Micronized vaginal progesterone treated clients

Table 2: Cost Analysis Drug Cost per pkt (N) No of Tab per pkt Cost per tab (N) No. of Tab till 14d pET Cost of Tx till 14d pET In $ (US) Duphaston 2,200 20 110 34 3,740 12 Cyclogest 8,000 15 534 17 9,078 29 *all figures in Naira (Nigeria): Official exchange rate $1 (US) = N320 Price as at January 2017.

Summary of findings Improved pregnancy rate Dydrogesterone group= 33.3% Micronized vaginal progesterone group=19.2% Reduced cost of medications Duphaston treatment is 21/2 times less expensive. Acceptability by the clients The clients significantly preferred the oral route.

Oral dydrogesterone versus vaginal progesterone gel in the luteal phase support: RCT (2015) A total of 853 infertile women undergoing IVF/ICSI treatment in University Hospital Center “Sisters of Mercy”, Zagreb, Croatia. The on-going pregnancy rates were comparable between Crinone 8%® vaginal progesterone gel and oral dydrogesterone – Duphaston® (28.1% versus 30.3%; OR 1.11 (0.82–1.49 with 95% CI)). Overall satisfaction and tolerability were significantly higher in the dydrogesterone group than in the Crinone group. Vlatka Tomic, Jozo Tomic, Djurdja Zigmundovac Klaic, Miro Kasum, Krunoslav Kuna. European JOG & Repod.Biol. March 2015: Volume 186, Pages 49–53

Luteal phase support in IUI cycles BPR (%) (p) CPR (%) (p) LBR (%) (p) Erdem et al., 2009 25.1%-13.7% (0.002) 21.2%-12.7% (0.028) 17.4%-9.3% (0.016) Kyroue et al. 2010 7.3%-8.7% (NS) Ebrahimi et al.2010 13.5%-11.2% (NS) 11.5%-10% (NS) 7.5%-5.7% (NS) Maher 2011 37.1%-20.6% (0.004) 29.5%-19.8% (0.07) 18.9%-5.5% (<0.001) Agha-Hosseini et al. 2012 29%-21.8% (NS) 24.3%-14.1% (0.02) Khosravi et al. 2015* 25.7%-29.7% (NS) Based on the study results available in the literature, it appears to be beneficial to supplement the luteal phase in gonadotropin-stimulated IUI cycles that yield more than one follicle.

A comparative study of dydrogesterone and micronized progesterone for luteal phase support during in vitro fertilization (IVF) cycles. Gynecol Endocrinol. 2016;32(3):213-7. doi: 10.3109/09513590.2015.1110136. Epub 2015 Nov 20. Saharkhiz N1, Zamaniyan M1, Salehpour S1, Zadehmodarres S1, Hoseini S1, Cheraghi L2, Seif S3, Baheiraei N4. Abstract A total of 210 women (aged 20-40 years old) with a history of infertility, who underwent controlled ovarian stimulation for fresh intra-cytoplasmic sperm injection-embryo transfer cycles, were included in the study. Consequently, they were randomized to receive LPS with dydrogesterone 20 mg twice daily (n = 96) or micronized progesterone 400 mg twice daily at the day of oocyte retrieval (n = 114). The clinical success rate (31% versus 33%; p = 0.888), miscarriage rate (5.0% versus 3.0%; p = 0.721), ongoing pregnancy rate (30.0% versus 30.0%; p = 1.000), implantation (22.0% versus 24.0%; p = 0.254) and multiple pregnancy rate (5.30% versus 7.20%; p = 0.394) were comparable among the two groups. Serum progesterone levels were significantly lower among the patients receiving dydrogesterone than the control group (13.62 ± 13.83 ng/ml versus 20.66 ± 18.09 ng/ml; p = 0.001). However, there was no statistically significant difference regarding the patients' satisfaction (p = 0.825) and tolerability (0.790) between the two groups. Our results showed that oral dydrogesterone (40 mg/day) is as effective as vaginal micronized progesterone considering its clinical outcomes and patients' satisfaction and tolerability, for LPS among women undergoing IVF.

Conclusion Oral dydrogesterone for LPS has improved pregnancy rates at a reduced cost of medications when compared to vaginal micronized progesterone Dydrogesterone is safe, efficacious and cost effective for LPS in gonadotropin stimulated IVF cycles

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