Human Reproduction Archives
Human Reproduction Archives
RESEARCH ARTICLE Assisted Reproduction

Evaluation of a new transdermal testosterone dosage used for 60 days prior to controlled ovarian stimulation in poor responders: preliminary results

Paula Luiza Muzetti De Chico, Vanessa Silvestre Innocenti Giorgi, Rui Alberto Ferriani, Paula Andrea Navarro

Downloads: 0
Views: 446


Objectives: Studies suggest a beneficial effect of transdermal testosterone (TT) used prior to controlled ovarian stimulation (COS) on reproductive outcomes in poor responders. Our aim was to evaluate the adverse effects and serum concentrations of testosterone, sex hormone-binding globulin (SHBG), and estradiol, following a new TT dosage associated with combined oral contraceptive (COC) before COS in poor responders. Methods: Pilot case-control study in which each patient was her own case-control. Women with poor ovarian response fulfilling Bologna Criteria were recruited and submitted to COS (Control Cycle - CC) to perform ICSI. Those who did not become pregnant were subjected to another COS with previous use of TT (25 mg/48 hours, for 60 days), associated with COC (Testosterone Cycle-TC). Blood samples were taken at the beginning of the first COS (D1); day of first oocyte retrieval (D2), first day of transdermal testosterone use (D3); 60 days after Testo-COC usage (D4); and day of second oocyte retrieval (D5). Adverse effects and serum concentrations of total and free testosterone, estradiol, and SHBG were analyzed. Results: Six women concluded both cycles. Testosterone was higher at D4 than D1 (p=0.009, p=0.041) and D3 (p=0.010, p=0.031). SHBG was higher at D4 than D1 (p=0.028). Estradiol was higher at D2 than D1 (p<0.001) and at D5 than D3 (p=0.001) and D4 (p=0.002). Mild adverse effects were observed. Conclusion: The TT dosage used before COS caused only mild adverse effects and resulted in significantly higher concentrations of total and free testosterone than in basal conditions.


Assisted Reproductive Techniques, Ovarian Stimulation, Testosterone, Poor Responder


1. Ubaldi F, Vaiarelli A, D’Anna R, Rienzi L. Management of poor responders in IVF: is there anything new? BioMed Res Int. 2014;352098. PMid:25136579. 

2. Oudendijk JF, Yarde F, Eijkemans MJ, Broekmans FJ, Broer SL. The poor responder in IVF: is the prognosis always poor?: A systematic review. Hum Reprod Update. 2012;18(1):1-11. PMid:21987525. 

3. Ubaldi FM, Rienzi L, Ferrero S, Baroni E, Sapienza F, Cobellis L, et al. Management of poor responders in IVF. Reprod Biomed Online. 2005;10(2):235-46. PMid:15823231. 

4. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26(7):1616-24. humrep/der092. PMid:21505041. 

5. Hillier SG, De Zwart FA. Evidence that granulosa cell aromatase induction/activation by follicle-stimulating hormone is an androgen receptor-regulated process in-vitro. Endocrinology. 1981;109(4):1303-5. PMid:6793349. 

6. Rodrigues JK, Navarro PA, Zelinski MB, Stouffer RL, Xu J. Direct actions of androgens on the survival, growth and secretion of steroids and anti-Müllerian hormone by individual macaque follicles during three-dimensional culture. Hum Reprod. 2015;30(3):664-74. PMid:25567619. 

7. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, et al. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab. 1998;83(7):2479-85. jcem.83.7.4917. PMid:9661631. 

8. Weil S, Vendola K, Zhou J, Bondy CA. Androgen and follicle-stimulating hormone interactions in primate ovarian follicle development. J Clin Endocrinol Metab. 1999;84(8):2951-6. PMid:10443703.

9. Vendola K, Zhou J, Wang J, Famuyiwa OA, Bievre M, Bondy CA. Androgens promote oocyte insulin-like growth factor I expression and initiation of follicle development in the primate ovary. Biol Reprod. 1999;61(2):353-7. PMid:10411511. 

10. Vendola KA, Zhou J, Adesanya OO, Weil SJ, Bondy CA. Androgens stimulate early stages of follicular growth in the primate ovary. J Clin Invest. 1998;101(12):2622-9. PMid:9637695. 

11. Massin N, Cedrin-Durnerin I, Coussieu C, Galey-Fontaine J, Wolf JP, Hugues JN. Effects of transdermal testosterone application on the ovarian response to FSH in poor responders undergoing assisted reproduction technique--a prospective, randomized, double-blind study. Hum Reprod. 2006;21(5):1204-11. PMid:16476678. 

12. Fábregues F, Peñarrubia J, Creus M, Manau D, Casals G, Carmona F, et al. Transdermal testosterone may improve ovarian response to gonadotrophins in low-responder IVF patients: a randomized, clinical trial. Hum Reprod. 2009;24(2):349-59. http:// PMid:19054777. 

13. Sipe CS, Thomas MR, Stegmann BJ, Van Voorhis BJ. Effects of exogenous testosterone supplementation in gonadotrophin stimulated cycles. Hum Reprod. 2010;25(3):690-6. PMid:20031956. 

14. Kim CH, Howles CM, Lee HA. The effect of transdermal testosterone gel pretreatment on controlled ovarian stimulation and IVF outcome in low responders. Fertil Steril. 2011;95(2):679-83. PMid:20801436. 

15. Kim CH, Ahn JW, Moon JW, Kim SH, Chae HD, Kang BM. Ovarian features after 2 weeks, 3 weeks and 4 weeks transdermal testosterone gel treatment and their associated effect on IVF outcomes in poor responders. Dev Reprod. 2014;18(3):145-52. PMid:25949183. 

16. Doan HT, Quan LH, Nguyen TT. The effectiveness of transdermal testosterone gel 1% (androgel) for poor responders undergoing in vitro fertilization. Gynecol Endocrinol. 2017;33(12):977-9. PMid:28562099. 

17. Saharkhiz N, Zademodares S, Salehpour S, Hosseini S, Nazari L, Tehrani HG. The effect of testosterone gel on fertility outcomes in women with a poor response in in vitro fertilization cycles: a pilot randomized clinical trial. J Res Med Sci. 2018;23:3. http:// PMid:29456560.

18. González-Comadran M, Durán M, Solà I, Fábregues F, Carreras R, Checa MA. Effects of transdermal testosterone in poor responders undergoing IVF: systematic review and meta-analysis. Reprod Biomed Online. 2012;25(5):450-9. rbmo.2012.07.011. PMid:22999555. 

19. Nagels HE, Rishworth JR, Siristatidis CS, Kroon B. Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2015;(11):CD009749. PMid:26608695. 

20. Vegunta S, Kling JM, Kapoor E. Androgen therapy in women. J Womens Health (Larchmt). 2020;29(1):57-64. jwh.2018.7494. PMid:31687883. 

21. Balaban B, Brison D, Calderon G, Catt J, Conaghan J, Cowan L, et al. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26(6):1270-83. PMid:21502182. 

22. Oatway C, Gunby J, Daya S. Day three versus day two embryo transfer following in vitro fertilization or intracytoplasmic sperm injection. Cochrane Database Syst Rev. 2004;(2):CD004378. PMid:15106249. 

23. Lawlor DA, Nelson SM. Effect of age on decisions about the numbers of embryos to transfer in assisted conception: a prospective study. Lancet. 2012;379(9815):521-7. PMid:22243709. 

24. Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999;84(10):3666-72. PMid:10523012. 

25. Hillier SG, Ross GT. Effects of exogenous testosterone on ovarian weight, follicular morphology and intraovarian progesterone concentration in estrogen-primed hypophysectomized immature female rats. Biol Reprod. 1979;20(2):261-8. http://dx.doi. org/10.1095/biolreprod20.2.261. PMid:454737. 

26. Billig H, Furuta I, Hsueh AJ. Estrogens inhibit and androgens enhance ovarian granulosa cell apoptosis. Endocrinology. 1993;133(5):2204-12. PMid:8404672. 

27. Franks S, Hardy K. Androgen action in the ovary. Front Endocrinol (Lausanne). 2018;9:452. fendo.2018.00452. PMid:30147675.

28. Morgante G, Massaro MG, Di Sabatino A, Cappelli V, De Leo V. Therapeutic approach for metabolic disorders and infertility in women with PCOS. Gynecol Endocrinol. 2018;34(1):4-9. PMid:28850273. 

29. Balasch J, Fábregues F, Peñarrubia J, Carmona F, Casamitjana R, Creus M, et al. Pretreatment with transdermal testosterone may improve ovarian response to gonadotrophins in poor-responder IVF patients with normal basal concentrations of FSH. Hum Reprod. 2006;21(7):1884-93. PMid:16517559. 

30. Bosdou JK, Venetis CA, Dafopoulos K, Zepiridis L, Chatzimeletiou K, Anifandis G, et al. Transdermal testosterone pretreatment in poor responders undergoing ICSI: a randomized clinical trial. Hum Reprod. 2016;31(5):977-85. humrep/dew028. PMid:26956551. 

31. Bercaire L, Nogueira SM, Lima PC, Alves VR, Donadio N, Dzik A, et al. ANDRO-IVF: a novel protocol for poor responders to IVF controlled ovarian stimulation. JBRA Assist Reprod. 2018;22(1):52-5. PMid:29303236. 

32. Davis SR, Moreau M, Kroll R, Bouchard C, Panay N, Gass M, et al. Testosterone for low libido in postmenopausal women not taking estrogen. N Engl J Med. 2008;359(19):2005-17. PMid:18987368. 

33. Panay N, Al-Azzawi F, Bouchard C, Davis SR, Eden J, Lodhi I, et al. Testosterone treatment of HSDD in naturally menopausal women: the ADORE study. Climacteric. 2010;13(2):121-31. PMid:20166859. 

34. Roche. Reference Interval Study for children and randomly selected adults. Elecsys® Fertility Tests. Germany: Roche; 2015. 

35. Ata B, Seli E. Strategies for Controlled Ovarian Stimulation in the Setting of Ovarian Aging. Semin Reprod Med. 2015;33(6):436- 48. PMid:26562286. 

36. Cheng G, Weihua Z, Mäkinen S, Mäkelä S, Saji S, Warner M, et al. A role for the androgen receptor in follicular atresia of estrogen receptor beta knockout mouse ovary. Biol Reprod. 2002;66(1):77-84. PMid:11751267. 

37. Bahceci M, Ulug U, Turan E, Akman MA. Comparisons of follicular levels of sex steroids, gonadotropins and insulin like growth factor-1 (IGF-1) and epidermal growth factor (EGF) in poor responder and normoresponder patients undergoing ovarian stimulation with GnRH antagonist. Eur J Obstet Gynecol Reprod Biol. 2007;130(1):93-8. PMid:16720073. 

38. Frattarelli JL, Gerber MD. Basal and cycle androgen levels correlate with in vitro fertilization stimulation parameters but do not predict pregnancy outcome. Fertil Steril. 2006;86(1):51-7. PMid:16716312. 

39. Qin Y, Zhao Z, Sun M, Geng L, Che L, Chen ZJ. Association of basal serum testosterone levels with ovarian response and in vitro fertilization outcome. Reprod Biol Endocrinol. 2011;9(1):9. PMid:21247501. 

40. Rivera-Woll LM, Papalia M, Davis SR, Burger HG. Androgen insufficiency in women: diagnostic and therapeutic implications. Hum Reprod Update. 2004;10(5):421-32. PMid:15297435. 

41. Kriplani A, Periyasamy AJ, Agarwal N, Kulshrestha V, Kumar A, Ammini AC. Effect of oral contraceptive containing ethinyl estradiol combined with drospirenone vs. desogestrel on clinical and biochemical parameters in patients with polycystic ovary syndrome. Contraception. 2010;82(2):139-46. PMid:20654754. 

42. Garnett E, Bruno-Gaston J, Cao J, Zarutskie P, Devaraj S. The importance of estradiol measurement in patients undergoing in vitro fertilization. Clin Chim Acta. 2020;501:60-5. PMid:31705856.

43. Guo J, Zhang Q, Li Y, Huang J, Wang W, Huang L, et al. Predictive value of androgens and multivariate model for poor ovarian response. Reprod Biomed Online. 2014;28(6):723-32. PMid:24745840. 

44. Sfakianoudis K, Pantos K, Grigoriadis S, Rapani A, Maziotis E, Tsioulou P, et al. What is the true place of a double stimulation and double oocyte retrieval in the same cycle for patients diagnosed with poor ovarian reserve? A systematic review including a meta-analytical approach. J Assist Reprod Genet. 2020;37(1):181-204. PMid:31797242. 

45. Cohen J. Statistical power analysis for the behavioral sciences 2nd ed. Hillsdale, NJ: Lawrence Erlbaum Associates; 1988.

Submitted date:

Accepted date:

63af0ea1a953952df259fa83 hra Articles
Links & Downloads

Hum Reprod Arch

Share this page
Page Sections