Abstract Study question To compare the most effective duration of pre-treatment with transdermal testosterone gel in improving IVF outcomes using GnRH antagonist protocol in poor prognosis patients. Summary answer Pre-treatment with testosterone gel for 28 days had higher clinical pregnancy rate, more mature oocytes in lesser days and lower total dose of gonadotropins. What is known already Poor prognosis patients undergoing IVF exhibits subnormal ovarian response resulting in higher IVF cycle cancellation and lower clinical pregnancy. Amongst various adjuvants regimens use of androgen supplementation improves clinical pregnancy and probability of live birth in such patients. Androgen stimulates early stages of follicular growth, increase the number of primary, pre-antral and antral follicles. It increases FSH receptor expression in granulosa cells, in turn leading to better oocyte yield and pregnancy rate. We aim to compare the most effective duration of pre-treatment with transdermal testosterone gel in improving IVF outcomes using GnRH antagonist protocol in poor prognosis patients. Study design, size, duration A prospective, randomised controlled trial was carried out from 1st September 2021 to 31st August 2022 at a tertiary infertility centre in India. 100 poor prognosis patients POSEIDON group 3 and 4 (age 21-40 years, AFC <5 and AMH ≤1.2 ng/ml) were enrolled. They were randomized into 4 groups of 25 each by computer based program. Participants/materials, setting, methods Group 1, control received no pretreatment, Group 2, Group 3 and Group 4 received 1% TTG one actuation (12.5mg testosterone daily) for 2, 3 and 4 weeks respectively before start of ovarian stimulation. Patients received a starting dose of HP HMG dose 300 IU and dose was adjusted. Inj. Cetrorelix 0.25 mg started when lead follicle was 14 mm and Oocyte retrievals were performed 35 hours after 250 mcg r-HCG trigger. Main results and the role of chance All groups were comparable with regards to baseline FSH, AFC and AMH levels. Only one cycle was cancelled in control group because of lack of response to gonadotropins till day 5 of stimulation. Requirement of total days (9.68 Vz 8.95 days) and total dose of gonadotropins was significantly lower in group 4 as compared to control group 1. This showed that cases with pre-treatment of transdermal testosterone gel for longer duration, required less amount of gonadotropin (2826 IU Gp 1 Vz 2329 IU Gp 4) treatment (p < 0.01) and also the mean number of mature oocytes retrieved (0.80 Gp 1 Vz 3.38 Gp 4) were significantly higher (p < 0.01). Day 3 fresh embryo transfers were performed for all. Incidence of clinical pregnancy rate was 4.2%, 8%, 12% in group 1, 2, and 3 respectively which increased to 20% in group 4 (p-0.33). Miscarriage rate was 4.2% , 4%, 12% and 4% in group 1 ,2, 3 and 4 respectively (p-0.71). Ongoing pregnancy rate was 4% in group 1, while it was 7.7 %, 10.6 % and 19.2% in group 2,3 and 4 respectively (p-0.33). Limitations, reasons for caution The study was done at a single centre with small sample size, replication with more subjects and in different centers is needed. The long term effects of testosterone pretreatment requires further studies. Wider implications of the findings Pre-treatment with testosterone gel in poor prognosis patients improves response to gonadotrophin, reducing amount and days to complete stimulation and results in higher number of mature oocytes and improved clinical pregnancy rates. Transdermal testosterone treatment is advantageous as it is not first metabolized in the liver, convenient to the patient. Trial registration number CTRI/2022/03/040793
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