Fertility Research Articles

DHEA supplementation may improve IVF outcome in poor responders: a proposed mechanism

Hyman JH, Margalioth EJ, Rabinowitz R, Tsafrir A, Gal M, Alerhand S, Algur N, Eldar-Geva T.
Eur J Obstet Gynecol REprod Biol 2013;168:49-53.
This prospective study aimed to determine the mechanism of action of DHEA, and, specifically, the stage of folliculogenesis influenced by DHEA in poor IVF responders. Thirty-two women who were poor responders to IVF treatment were included in the study, which compared day 3 biochemical, ultrasound, ovarian reserve markers, and IVF treatment outcome before and after DHEA supplementation. The study found that DHEA influences ovarian response by rescue from antresia of small antral follicles (increased AFC).

Is there a role for DHEA supplementation in women with diminished ovarian reserve?

Fouany MR, Sharara FI.
J Assist Reprod Genet 2013;30:1239-1244.
This literature review examines the rationale for the use of DHEA in poor responders, citing several studies that have suggested an improvement in pregnancy rates with the use of DHEA. This review concludes that, while the role of DHEA is intriguing, evidence-based recommendations are lacking. It suggests that large randomized prospective trials are needed to better inform women with diminished ovarian reserve as to the benefits of DHEA supplementation.

Dehydroepiandrosterone supplementation improves predictive markers for diminished ovarian reserve: serum AMH, inhibin B and antral follicle count

Yilmaz N, Uygur D, Inal H, Gorkem U, Cicek N, Mollamahmutoglu L.
Eur J Obstet Gynecol Reprod Biol 2013;169:257-260.
This prospect study evaluated the effects of DHEA supplementation by measuring predictive markers in patients with diminished ovarian reserve (DOR). Forty-one DOR patients received 25 mg of DHEA, t.i.d., for at least 6 weeks. Researchers measured baseline ovarian reserve parameters before and after DHEA supplementation, and found significant differences in day 3 FSH, oestradiol, antral follicle count, AMH and inhibin B levels. The study concluded that DHEA supplementation is an effective option for patients with DOR.

A prospective study on role of dehydroepiandrosterone (DHEA) on improving the ovarian reserve markers in infertile patients with poor ovarian reserve

Singh N, Zangmo R, Kumar S, Roy KK, Sharma JB< Malhotra N, Vanamail P. Gynecol Endocrinol 2013;29:989-992. This study examined the role of DHEA supplementation on ovarian reserve markers in infertility patients who were poor responders in previous IVF cycles. 30 patients with a history of poor IVF response were administered 25 mg DHEA thrice daily for four months before ovarian stimulation. Results showed a significant increase in the serum Antimullerian hormone and Peak estradiol level on the day of human chorionic gonadotrophin administration, as well as a significant decrease in Day 2 follicle-stimulating hormone (FSH). The study concluded that DHEA has a significant effect in improving ovarian reserve.

Reduced quality and accelerated follicle loss with female reproductive aging - does decline in theca dehydroepiandrosterone (DHEA) underlie the problem?

Ford JH.
J Biomed Sci 2013;20:93.
This literature review examines how dehydroepiandrosterone (DHEA) supplementation effectively reverses the problem of oocyte quality. In females with normal fertility, pre-antral ovarian theca cells (the sole ovarian site of synthesis of DHEA) respond to stimulation by inhibin B to provide androgen-based support to developing follicles. With depletion of follicle numbers, inhibin B is reduced, reducing theca DHEA. In humans, DHEA synthesis occurs at about 70 days prior to ovulation thus effective supplementation needs to be undertaken about four months prior to intended conception.

DHEA supplementation positively affects spontaneous pregnancies in women with diminished ovarian function

Fusi FM, Ferrario M, Bosisio C, Arnoldi M, Zanga L.
Gynecol Endocrinol 2013;29:940-943
This study examines unexpected spontaneous pregnancies in women treated with DHEA supplementation prior to IVF. Researchers administered DHEA supplements to 39 women less than 40 years old and 38 women over 40 years for at least 12 weeks before starting a long stimulation protocol for IVF and found that spontaneous pregnancy rate significantly increased after DHEA treatment. Results show DHEA supplementation improves ovarian function in women over 40, suggesting that DHEA alone can raise fecundity and fertility treatment success.

Hypoandrogenism in association with diminished functional ovarian reserve

Gleicher N, Kim A, Weghofer A, Kushnir VA, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH.
Hum Reprod 2013;28:1084-1091.
This study examined the associating between diminished functional ovarian reserve (DFOR) and low androgen levels. Investigators looked at women presenting with two forms of DFOR, premature ovarian aging/occult primary ovarian insufficiency (POA/OPOI), and physiologic diminished ovarian reserve (DOR), comparing them with a control group of infertile women with normal age-specific FOR. Dehydroepiandrosterone (DHEA), DHEA-sulfate (DHEAS), total testosterone (TT) and free testosterone (FT) levels were assessed for all three groups. DHEAS marginally varied between the three groups (P = 0.04), with older women with DOR actually demonstrating higher levels than controls (P = 0.03). TT differed between the three groups more profoundly (P = 0.005), with women with POA/OPOI demonstrating significantly lower levels than controls (P = 0.009).

Improvement in diminished ovarian reserve after dehydroepiandrosterone (DHEA) supplementation.

Gleicher N, Weghofer A, Barad DH
Reprod Biomed Online 2010;21:360-365.
To determine whether DHEA objectively improves ovarian reserve, this study investigated the AMH levels of 120 women supplemented with DHEA prior to IVF cycles. AMH levels significantly improved after DHEA supplementation over time. Women younger than 38 saw their AMH concentrations improve more than older females.

The impact of androgen metabolism and FMR1 genotypes on pregnancy potential in women with dehydroepiandrosterone (DHEA) supplementation.

Weghofer A, Kim A, Barad DH, Gleicher N.
Hum Reprod 2012 27;11:3287-3293
To assess whether the androgen concentration and FMR1 genotypes can explain the difference between those who get pregnant after DHEA supplementation and those who don’t, this study investigated 90 women with prematurely diminished ovarian reserve. In women with abnormal FMR1 genotypes, free testosterone levels after DHEA supplementation had a significant influence on the pregnancy potential. The study postulated that how androgens are metabolized after DHEA supplementation significantly influences IVF pregnancy chances in women with diminished ovarian reserve, with possible control by the FMR1 gene.

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).

Gleicher N, Kim A, Weghofer A, Shohat-Tal A, Lazzaroni E, Lee HJ, Barad DH.
J Assist Reprod Genet 2013 30;1:49-62
This cohort study investigated the androgen conversion process in women with diminished ovarian reserve (DOR) who took DHEA supplementation. Looking at the conversion from DHEA to testosterone (T), the study redefined DOR to be an androgen-deficiency state that can benefit from DHEA/androgen supplementation. Women who converted DHEA into testosterone more efficiently were more likely to conceive with IVF. The study suggests FHS/androgen and AMH/androgen ratios as promising new predictor of pregnancy chances with IVF.

DHEA supplementation improves follicular microenvironment in poor responder patients.

Artini P, Simi G, Ruggiero M, Pinelli S, Di Berardino O, Papini F, Papini S, Monteleone, P, Cela V.
Gynecol Endocrinol, 2012;28(9): 669-673
Aiming to understand the mechanism of DHEA action within the ovary, this study measured the levels of vascular endothelial growth factor (VEGF) and hyponix inducible factor 1 (HIF1) in the follicular fluid after 3 months of DHEA supplementation. HIF1 levels were significantly lower in follicular fluids after DHEA treatment. The study found a significantly higher number of mature oocytes retrieved in the DHEA group, as well as a relationship between the quality of oocytes and the levels of HIF1. The study suggests that the improvements in reproductive parameters after DHEA supplementation may be thanks to DHEA’s beneficial effects on the microenvironment within follicles.

The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment?

Gleicher N, Weghofer A, Barad DH.
Reprod Biol Endocrinol 2011;9(1):116.
Broadening the scope beyond human fertility and into published animal data, this extensive review of literature theorized that androgens, including DHEA, may play an essential role in the maturation of oocyte-containing follicles. At certain therapeutic concentrations, DHEA and other androgens may be capable of improving the early stages of folliculogenesis. The study presented the possibility that androgens like DHEA may be forerunners of a completely new class of ovulation-inducing medications that affect much earlier stages of follicle maturation than gonadotropins.

Dehydroepiandrosterone supplementation in diminished ovarian reserve (DOR).

Gleicher N, Barad DH
Reprod Biol Endocrinol 2011;9:67.
An extensive and detailed review of current best available evidence in this study confirmed that DHEA improves ovarian function, increases pregnancy chances and, by reducing aneuploidy, lowers miscarriage rates. Based on the improvement of oocyte/embryo quality after DHEA, this study introduced a new concept of ovarian aging, where ovarian environments, but not oocytes themselves, age. The study also suggested that DHEA may be the first pharmacological agent that beneficially affects aging ovarian environments.

Premature ovarian failure and dehydroepiandrosterone.

Mamas L, Mamas E.
Fertil Steril 2009;91:644-646.
This study reported on the experience of a center utilizing DHEA supplementation in patients with premature ovarian failure (POF). Systematically utilizing DHEA in patients with POF undergoing ART cycles, the center observed a decline in FSH levels. All patients achieved pregnancy.

Addition of dehydroepiandrosterone (DHEA) for poor responder patients before and during IVF treatment improves the pregnancy rate: a randomized prospective study.

Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A.
Hum Reprod 2010;25:2496-2500.
While small, this Israeli study was the first randomized controlled trial evaluating the effects of DHEA supplementation on IVF outcomes. Compared to the control group, DHEA group had a significantly better embryo quality and higher live birth rates (23.1%, compared to 4.0% in control group). The study concluded that DHEA supplementation can have a beneficial effect on ovarian reserve in patients with poor response to IVF treatment.

Dehydroepiandrosterone supplementation improves ovarian response and cycle outcome in poor responders.

Sönmezer M, Özmen B, Cil AP, Özkavukcu S, Taşçi T, Olmus H, Atebekoğlu CS.
Reprod Biomed Online 2009;19:508-513.
In this 2009 study, 19 patients with previous poor response to ovarian stimulation received DHEA supplementation for at least 3 months. After DHEA supplementation, IVF cycle cancellation rate dropped to 5.3% from 42.1%, while pregnancy rate per embryo transfer improved dramatically to 44.4% from 0%. While uncontrolled, this study confirmed previous reports that DHEA supplementation can significantly improve IVF pregnancy rates and reduce cycle cancellation rates in women with poor ovarian response.

Dehydroepiandrosterone supplementation augments ovarian stimulation in poor responders: a case series.

Casson PR, Lindsay M, Pisarksa MD, Carson SA, Buster JE.
Hum Reprod 2000;15:2129-2131.
In this small case series, five women with previous poor responses to ovarian stimulation received DHEA supplementation for two months. After DHEA supplementation, their responses to ovarian stimulation significantly improved even after controlling for gonadotropin dosage, resulting in a twin delivery. This early report ultimately led to the more systematic investigation and utilization of DHEA supplementation for women with diminished ovarian reserve by the Center for Human Reproduction in the mid-2000s.

Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation in women with diminished ovarian reserve: a case control study.

Gleicher N, Ryan E, Weghofer A, Blanco-Mejia S, Barad DH
Reprod Biol Endocrinol 2009;7:108.
CHR and another fertility center based in Toronto, Canada, jointly conducted this study. Women on DHEA supplementation had significantly lower miscarriage rates at both centers, compared to those for the general IVF population. Both centers reported an identical miscarriage rate for DHEA-supplemented women. The improvement was more pronounced among women over 35. The miscarriage rates in women on DHEA supplementation were comparable to miscarriage rates in normal, fertile patients, despite their DOR status, suggesting that DHEA may reduce embryo aneuploidy.

Update on the use of dehydroepiandrosterone supplementation among women with diminished ovarian function.

Barad DH, Brill H, Gleicher N.
J Assist Reprod Genet 2007;24:629-634.
In this case-control study, 190 women with DOR were divided into DHEA-supplemented group and control group. Women who received DHEA supplementation had more than double the pregnancy rates of women without DHEA (28.4%, compared to 11.9%).

Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo and cell number in IVF.

Barad D, Gleicher N.
Hum Reprod 2006;21:2845-2849.
In this case-control study, 25 patients underwent IVF cycles both before and after supplementation with DHEA. After DHEA treatment, patients had more oocytes that fertilized and more normal embryos on day-3. More embryos were transferred, and average embryo grades were significantly higher (better), confirming the earlier hypothesis that DHEA supplementation may have beneficial effects on the ovarian functions of women with DOR.

Increased oocyte production after treatment with dehydroepiandrosterone.

Gleicher N, Barad DH.
Fertil Steril 2005;84(3):756.
This was the first case report on the effects of DHEA on oocyte production. Describing the stunning increase in oocyte production after supplementation with DHEA in a 42-year-old patient with severe DOR, the report (correctly, as it turned out,) speculated that "ovarian function may be salvaged, even in women of advanced reproductive age."