Dehydroepiandrosterone (DHEA) supplementation in diminished ovarian reserve (DOR)

Abstract

Background: With infertility populations in the developed world rapidly aging, treatment of diminished ovarian reserve (DOR) assumes increasing clinical importance. Dehydroepiandrosterone (DHEA) has been reported to improve pregnancy chances with DOR, and is now utilized by approximately one third of all IVF centers world-wide. Increasing DHEA utilization and publication of a first prospectively randomized trial now warrants a systematic review.

Methods: PubMed, Cochrane and Ovid Medline were searched between 1995 and 2010 under the following strategy: [<dehydroepiandrosterone or DHEA or androgens or testosterone > and <ovarian reserve or diminished ovarian reserve or ovarian function >]. Bibliographies of relevant publications were further explored for additional relevant citations. Since only one randomized study has been published, publications, independent of evidence levels and quality assessment, were reviewed.

Results: Current best available evidence suggests that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. DHEA over time also appears to objectively improve ovarian reserve. Recent animal data support androgens in promoting preantral follicle growth and reduction in follicle atresia.

Discussion: Improvement of oocyte/embryo quality with DHEA supplementation potentially suggests a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. DHEA may, thus, represent a first agent beneficially affecting aging ovarian environments. Others can be expected to follow.

Figure 1

Oocyte and embryo counts in index patient. The patient underwent nine consecutive IVF cycles and increased oocytes and embryo yields from cycle to cycle, starting with one egg and embryo, respectively, and ending up with 17 oocytes and 16 embryos in her ninth cycle. Gonadotropin stimulation was reduced in her last cycle for concerns about possible ovarian hyperstimulation. The patients advised us of her DHEA supplementation only after her sixth cycle. The figure is modified from Barad and Gleicher, with permission, [10].

Figure 2

Cumulative pregnancy rates in women with DOR with and without DHEA supplementation. The figure demonstrates on the left side cumulative pregnancy rates in DHEA and control patients with POA (for definition see text). The right side of the figure demonstrates cumulative pregnancy rates in women above age 40 years. Both patient populations demonstrate similar treatment benefits for DHEA, though POA patients appear to have a slight pregnancy advantage, further confirmed in later data presentations. Modified with permission from Barad et al [17].

Figure 3

Age-stratified miscarriage rates in DHEA supplemented DOR patient in comparison to national U.S. IVF pregnancies. DHEA pretreated patients demonstrated significantly lower miscarriage rates at all ages. The difference was, however, relatively small under age 35 years and progressively increased after that age. Modified with permission from Gleicher et al [28].

Figure 4

Spontaneous pregnancy loss in spontaneous and IVF pregnancies at various AMH levels. The figure depicts at various AMH levels in the left column IVF pregnancies (IVF), as previously reported [Gleicher et al. (31)], and in the right column spontaneously conceived pregnancies (SP). Each column represents 100% of all pregnancies established, separated for live births (black section), voluntary termination of pregnancy (TOP; usually for aneuploidy) and spontaneous miscarriages (SAB). The figure demonstrates that at very low AMH levels (≤0.40 ng/mL) and at AMH ≥ 1.06 ng/mL. IVF pregnancies led to significantly higher live birth rates than spontaneously conceived DHEA pregnancies. Lowest pregnancy and live birth rates were observed with IVF and spontaneously between AMH 0.41-1.05 ng/mL, with no spontaneous DHEA pregnancies at all at AMH 0.81-1.05 ng/mL. While in IVF pregnancies miscarriage rates were clearly reduced at very low and at higher AMH, miscarriages appeared unaffected (~50%) in spontaneously conceived pregnancies.

Figure 5

AMH in POA and DOR patients over time of DHEA exposure. As the figure demonstrates, AMH increases significantly with length of DHEA treatment (------). This effect is more pronounce in young POA patients (- - -) than older DOR patients (......). Modified with permission from Gleicher et al [32].

Figure 6

Trends in patient characteristics of our center's IVF population. Panel A demonstrates mean ages for IVF patients between 2005 and year-to-date 2009. Panel B demonstrates proportional shift from younger patients (<39 years) to older women (≥ 40 years). Panel C demonstrates that this age shift is also accompanied by a significant fall in AMH levels in younger women (ages 31-35 years) and, therefore, increasing DOR in these younger (POA) patients. Combined, these data explain why in 2009 close to 90% of the center's population was affected by either POA or DOR.