Starting and resulting testosterone levels after androgen supplementation determine at all ages in vitro fertilization (IVF) pregnancy rates in women with diminished ovarian reserve (DOR)

Abstract

Purpose: To investigate whether androgen conversion rates after supplementation with dehydroepiandrosterone (DHEA) differ, and whether differences between patients with diminished ovarian reserve (DOR) are predictive of pregnancy chances in association with in vitro fertilization (IVF).

Methods: In a prospective cohort study we investigated 213 women with DOR, stratified for age (≤ 38 or >38 years) and ovarian FMR1 genotypes/sub-genotypes. All women were for at least 6 weeks supplemented with 75 mg of DHEA daily prior to IVF, between initial presentation and start of 1st IVF cycles. Levels of DHEA, DHEA-sulfate (DHEAS), total T (TT) and free T (FT) at baseline ((BL)) and IVF cycle start ((CS)) were then compared between conception and non-conception cycles.

Results: Mean age for the study population was 41.5 ± 4.4 years. Forty-seven IVF cycles (22.1 %) resulted in clinical pregnancy. Benefits of DHEA on pregnancy rates were statistically associated with efficiency of androgen conversion from DHEA to T and amplitude of T gain. Younger women converted significantly more efficiently than older females, and selected FMR1 genotypes/sub-genotypes converted better than others. FSH/androgen and AMH/androgen ratios represent promising new predictors of IVF pregnancy chances in women with DOR.

Conclusions: DOR at all ages appears to represent an androgen-deficient state, benefitting from androgen supplementation. Efficacy of androgen supplementation with DHEA, however, varies depending on female age and FMR1 genotype/sub-genotype. Further clarification of FMR1 effects should lead to better individualization of androgen supplementation, whether via DHEA or other androgenic compounds.

Figures

Fig. 1

Androgen conversion rates by age and FMR1 genotypes and sub-genotypes. Two-way ANOVA for pregnancy outcome and age group demonstrated significant interaction (P = 0.025). a There was also a significant interaction between pregnant and non-pregnant women (P = 0.015), independently observed in younger women only (P = 0.007). Amongst pregnant women, older women also demonstrated a significantly lower androgen conversion rate from DHEA to T (P < 0.001). b demonstrates that androgen conversion rates differ significantly between FMR1 genotypes and sub-genotypes (P = 0.021), between younger and older patients (P = 0.003), and in the interaction term between FMR1 and age (P = 0.057). *Post-hoc comparison (Holm-Sidack) demonstrated that sub-genotype het-norm/high converts androgens significantly more efficiently than het-norm/low (P = 0.003), and younger convert androgens more efficiently than older women (P = 0.003)

Fig. 2

Comparison of FSH at baseline and cycle start, and ratios between. FSH and AMH with androgens. a Pregnant and non-pregnant women differed significantly in FSHBL (P = 0.006) and AMHBL (P = 0.006) but only in AMHCS (P < 0.001). b In comparing androgens at baseline and cycle start only FTCS differed significantly between pregnant and non-pregnant women (P = 0.006). C1 and C2 demonstrate the large number of FSHBL/androgen ratios that demonstrated significant or almost significant differences between pregnant and non-pregnant women (for detail, see text). None of the FSHCS/androgen ratios proved different. D1 and D2 demonstrate a similarly large number of significant AMHBL/androgen ratios, and only one AMHCS/androgen ratio (for detail see text). Adjustment for age eliminated all significant ratios, except for AMHCS/DHEASCS., pointing at the age-dependency of most ratios

Fig. 3

Pregnancy chances per low, normal and high DHEA values. Predicted probabilities of pregnancy odds are presented as means and 1 SE from the mean. Different levels of DHEABL or of other baseline androgen levels did not affect pregnancy chances. As a demonstrates, in presence of low DHEACS, FTCS, however, significantly influenced odds of pregnancy (P = 0.009). With increasing DHEACS, the significance of FTCS, declines (normal DHEACS, P = 0.074). With high DHEACS, odds of achieving pregnancy were only significantly affected by DHEASCS (P = 0.002; data not shown). b summarizes significant changes in hormones between baseline and cycle start: With normal DHEACS, ΔFTBL to FTCS almost reached significance in affecting pregnancy chances (P = 0.053). With high DHEACS, the ratio of DHEASCS/DHEACS also affected pregnancy chances significantly (P = 0.005), though pregnancy odds barely changed (data not shown). c demonstrates associations after adjustments for age, oocyte numbers and length of DHEA supplementation: With low DHEACS, FTCS was still significantly associated with increasing odds of pregnancy (P = 0.028), and the same applied to rising DHEASCS (P = 0.004) and DHEASCS/DHEACS ratio (P = 0.006) in presence of high DHEACS, though pregnancy odds barely changed

Fig. 4

Pregnancy chances based on FMR1 genotypes and sub-genotypes. Predicted probabilities of pregnancy odds are presented as means and 1 SE of the mean. a demonstrates that increasing TTCS in women with het-norm/high FMR1 sub-genotype was associated with greater odds of pregnancy (P = 0.043). The collapsed hom genotype, overall, behaved differently from other FMR1 genotypes/sub-genotypes: Predicted probabilities for pregnant and non-pregnant groups in hom women were very similar, while other genotype and sub-genotypes demonstrated statistical trends. Rising FTCS also almost reached significance in het-norm/low (P = 0.060) and so, though to lesser degree, did other genotypes and sub-genotypes. As b demonstrates, in het-norm/low sub-genotypes, interaction between DHEACS and FTCS decreased odds of pregnancy (P = 0.056) and this conclusion remained valid after adjustments for oocyte numbers, age and length of DHEA supplementation (P = 0.064). Het-norm-high demonstrated a similar trend but not women with norm and hom genotype. Odds of pregnancy, however, did demonstrate a trend in norm women, based on ΔDHEASBL to DHEASCS (P = 0.062)

Fig. 5

FMR1 genotypes and sub-genotypes stratified by age. a demonstrates that in women ≤38 years Δ TTBL to TTCSFMR1 genotypes and sub-genotypes, overall significantly changed (P = 0.024). Post-hoc comparisons further demonstrated that this change in Δ of mean TT was significantly smaller for het-norm/low than het-norm/high (P = 0.028) or norm (P = 0.009) but mean ratio values between androgens did not differ. As b demonstrates, older women > age 38 behaved differently: DHEASCS differed significantly between FMR1 genotypes and sub-genotypes (P = 0.026), and post-hoc analysis confirmed that DHEASCS was significantly higher in hom than het-norm/high (P = 0.003) and het-norm/low women (P = 0.005). Older women, however, also demonstrated significant differences in mean androgen ratios: c demonstrates that DHEASCS/DHEACS differed significantly between FMR1 genotypes and sub-genotypes (P = 0.024), and post-hoc analysis suggested that hom women had a significantly higher ratio than het-norm/high (P = 0.003), het-norm/low (P = 0.005) and norm women (P = 0.013)