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)
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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).
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.
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.
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.
KeywordsDiminished ovarian reserve Androgens Androgen deficiency Androgen supplementation Dehydroepiandrosterone (DHEA) Testosterone FMR1 gene Premature ovarian aging Follicle stimulating hormone (FSH) Anti-Müllerian hormone (AMH) Pregnancy rates In vitro fertilization (IVF) Adrenal insufficiency
Anti-Müllerian hormone receptor
Diminished functional ovarian reserve
Fragile X mental retardation 1
Functional ovarian reserve
Follicle stimulating hormone
Follicle stimulating hormone receptor
In vitro fertilization
Polycystic ovary syndrome
Premature ovarian aging
NG, AW and DHB have received research and grant support, travel funds and speaker honoraria from various pharmaceutical and medical device companies, none, however, related to here presented topics. NG and DHB are listed as inventors on two already awarded and other still pending United States patents, claiming beneficial effects on diminished ovarian reserve (DOR) and embryo ploidy from dehydroepiandrosterone (DHEA) or from other androgen supplementations. NG is owner of CHR, where this research was conducted. NG and DHB are also listed as co-inventors on a number of pending United States patents, claiming diagnostic relevance for the assessment of triple CGG repeats on the FMR1 gene in determining risk towards DOR and related issues. At time of this submission only two United States user patents with relevance to this manuscript, both DHEA-related, have been awarded (November 10, 2009; #7615544 and November 29, 2011; #8067400) The first claims benefits from supplementation of DHEA/androgens on ovarian reserve and IVF pregnancy rates in women with DOR; and the second claims decreased aneuploidy (and, therefore, miscarriage rates) and improved pregnancy rates. Among FMR1-related pending patent applications, one describes ovarian genotypes and sub-genotypes, as used in this manuscript, and claims that these genotypes and sub-genotypes reflect different ovarian aging patterns. All patent applications filed by researchers at CHR are 50 % owned by CHR and 50 % by the investigators who did the research that led to the application. A full list of all patent information can be provided on request.
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