Plasma Levels of Dydrogesterone and 20α-Dihydrodydrogesterone and Clinical Outcomes in FET

Table of Content


Dydrogesterone (DYD) is an oral, systemic alternative to vaginal progesterone for luteal phase support (LPS). The plasma concentrations of DYD and its metabolite, 20α-dihydrodydrogesterone (DHD) necessary to sustain implantation, in absence of endogenous progesterone is present, is not known. While DYD is widely used in fresh IVF cycles, the association of circulating concentrations of DYD and DHD on the day of embryo transfer (ET) with ongoing pregnancy rate in programmed anovulatory frozen embryo transfer (FET) is not known.


This study investigated the plasma levels of DYD and DHD on the day of ET in programmed FET cycles achieved by oral DYD thrice daily evaluated the inter and intraindividual variation of plasma levels and their association with treatment outcome.


Study Design

  • Prospective, clinical cohort study

Patient Profile

  • Infertile females aged 18-45 years (n=217) undergoing FET cycle following in-vitro fertilization (IVF) or intracytoplasmic sperm insemination (ICSI), who received 10 mg oral DYD (tid) and 2 mg oral estradiol (tid)
  • Serum and plasma samples were collected on day of FET and stored at -80°C for later analysis and in 56 patients, two or more FET cycles in the same protocol were performed.

Treatment Strategy

  • All women received oral E2 2 mg tid starting from day 1 of the menstrual cycle.
  • Absence of pre-ovulatory follicle and endometrial development was confirmed by ultrasound
  • Anovulation was confirmed after estimating serum progesterone levels
  • After intake of DYD 10 mg tid, the patients were scheduled for FET on day 3, 4 or 6 following ET on days 2, 3 or 5 respectively
  • From day of ET onwards, patients were assigned to apply transdermal 2.5mg E2 gel daily in addition to oral E2 2mg (tid) and oral DYD 10mg (tid).
  • Cohort was stratified by DYD and DHD plasma levels by percentiles (≤25th versus >25th) separately by day of ET

End Points

Primary Endpoints

  • Ongoing pregnancy rate at 10 weeks of gestation  

Secondary Endpoints

  • % having a clinical pregnancy
  • % having miscarriage
  • % with a preclinical pregnancy loss


  • Among 217 patients, 14 had serum progesterone level >1.0 ng/ml on the day of ET, indicating escape ovulation and  no LC-MS/MS results were available in n = 5 patients, so they were excluded from analysis
  • A total of 41 observations for cleavage stage ETs and 157 for blastocyst transfers were analyzed
  • The median (quartiles) of plasma levels of DYD and DHD as shown in the Table 1, indicating attainment of steady state on day 3
Table 1. Median quartiles of plasma levels




Day 2 or 3 (ng/ml)



Day 5 (ng/ml)



  • A weak association was seen between DHD plasma levels and body weight and BMI, and between DYD levels and body weight, but not BMI.
  • The 25th percentile of DYD and DHD levels were 0.71 ng/ml and 20.675 ng/ml on day of ET.
  • The ongoing pregnancy rate was significantly lower in patients in the lower quarter of DYD or DHD levels.
  • The comparison of outcomes of different DYD quarters are shown in Table 2.
Table 2. Outcomes of different DYD quarters


DYD <25th percentile (%)

DYD >25th percentile (%)

Positive pregnancy test



Preclinical pregnancy loss



Clinical pregnancy



Miscarriage in 1st trimester



Ongoing pregnancy



Live birth




  • There is considerable variation in the serum plasma concentration of DYD and DHD within women undergoing programmed FET cycles using 10 mg DYD (tid)
  • These variations are independent of body weight or BMI
  • Women with lower levels of DYD and DHD are less likely to have an ongoing pregnancy
  • DYD 10 mg daily tid in an artificial FET cycle is potentially a suboptimal dose for a proportion of the population.

Hum Reprod. 2022; 37(6):1183-1193.