Fertility Research Articles

Coenzyme Q10 Supplementation and Oocyte Aneuploidy in Women Undergoing IVF–ICSI Treatment

Bentov Y, Hannam T, Jurisicova A, Esfandiari N, Casper R.
Clinical Medical Insights: Reproductive Health 2014;8:3136.
This double blind randomized trial examined the effect of CoQ10 on oocyte aneuploidy in women undergoing IVF. 39 patients between ages 35 and 43 were given 600 mg of CoQ10 or a placebo for 2 months prior to IVF. Due to safety concerns, the study was terminated before reaching the target number of participants, therefore no significant differences in outcome were detected between the CoQ10 and placebo groups. Results showed that the rate of oocyte aneuploidy was 46.5% for the CoQ10 group and 62.8% for the placebo group, while the clinical pregnancy rates were 33% and 26.7% for CoQ10 and placebo groups, respectively. The study concluded that more research needed to study the effects of a longer duration of intake of CoQ10 on female reproductive function in women of various ages.

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).

The aging oocyte – can mitochondrial function be improved?

Bentov Y and Casper RF.
Fertil Steril 2013;99:18‐22.
This study reviewed the role of mitochondrial dysfunction and oxygen radicals in the process of reproductive aging in women. Age-associated natural declines in coenzyme Q10 levels were suggested as a contributing factor to loss of female fertility, and possible supplementation with CoQ10 was suggested.

The effect of coenzyme Q10 on sperm motility and function.

Lewin A, Lavon H.
Mol Aspects Med 1997;18:S213‐219.
This study looked at the effects of CoQ10 on sperm movement in IVF with intracytoplasmic sperm injection (ICSI). Semen samples were divided into 4 equal parts and incubated for 24 hours with four different media, including one supplemented with CoQ10. After incubation with CoQ10, a significant increase in sperm motility was observed in the sperm from asthenospermic men. In addition, patients with initial low fertilization rates after ICSI who were supplemented with oral CoQ1o 60 mg per day for a mean of 103 days. These patients demonstrated a significant improvement in fertilization rates after CoQ10 supplementaiton, from 10.3% to 26.3%.

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.

Effects of oral antioxidant treatment upon the dynamics of human sperm DNA fragmentation and subpopulations of sperm with highly degraded DNA.

Abad C, Amengual MJ, Gosalvez J, Coward K, Hannaoui N, Benet J, Garcia‐Peiro A, Prats J.
Andrologia 2012 [epub ahead of print].
In this study, sperm samples of 20 infertile patients with asthernoteratozoospermia were analyzed after the administration of an oral antioxidant treatment of l-Carnitine, vitamin C, CoQ10, vitamin E, zinc, vitamin B9 and B12, and selenium, over a 3 month period. DNA-degraded sperm decreased while DNA integrity improved, confirming that antioxidants could improve assisted reproductive technology’s outcomes.

The effect of coenzyme Q10 supplementation on partner pregnancy rate in infertile men with idiopathic oligoasthenoteratozoospermia: an open‐label prospective study.

Safarinejad MR.
Int Urol Nephrol 2012;44(3):689‐700.
This study evaluated the possible effects of CoQ10 supplementation on semen parameters and partner pregnancy rates. 287 participants underwent a CoQ10 treatment of 600 mg/day for 12 months. Sperm concentration, sperm motility and sperm morphology improved significantly, with positive effects on partner pregnancy rate, which was observed at 34.1%.

Effect of coenzyme Q10 supplementation on antioxidant enzymes activity and oxidative stress of seminal plasma: a double‐blind randomized clinical trial.

Nadjarzadeh A, Shidfar F, Amirjannati N, Vafa MR, MOtevalian SA, Gohari MR, Nazeri Kakhki SA, Akhondi MM, Sadeghi MR.
Andrologia 2013 [epub ahead of print].
This randomized, placebo-controlled trial examined the relationship between CoQ10 supplementation and antioxidant enzyme activity in seminal plasma. Sixty infertile men with idiopathic oligoasthenoteratozoospermia received 200 mg per day of CoQ10 or placebo for 3 months. Semen analyses conducted before and after treatment revealed that both CoQ10 levels and antioxidant enzyme activity markers increased in the CoQ10 group, suggesting that a 3-month supplementation with CoQ10 may reduce oxidative stress in semen plasma and improve semen parameters.

Coenzyme Q10 treatment in infertile men with idiopathic asthenozoospermia: a placebo‐controlled, double‐blind randomized trial.

Balercia G, Buldreghini E, Vignini A, Tiano L, Paggi F, Amoroso S, Ricciardo‐Lamonica G, Boscaro M, Lenzi A, Littarru G.
Fertil Steril 2009;91(5):1785‐1792.
This double-blind randomized trial enlisted 55 interfile patients between 27 and 39 years and administered 200 mg of CoQ10 or placebo per day for 6 months. Both CoQ10 and ubiquinol levels increased significantly in seminal plasma and sperm cells after CoQ10 treatment, as well as sperm motility. Patients with lower baseline value for motility and CoQ10 levels showed a higher probability of responding to CoQ10 supplementation.

Effects of the reduced form of coenzyme Q10 (ubiquinol) on semen parameters in men with idiopathic infertility: a double‐blind, placebo controlled, randomized study.

Safarinejad MR, Safarinejad S, Shafiei N, Safarinejad S.
J Urol 2012;188(2):526‐531.
This study used 200 mg of ubiquinol (reduced form of CoQ10) and placebo over a 26 week period in 228 men with unexplained fertility, to assess CoQ10 administration’s effects semen quality. After the ubiquinol treatment, sperm morphology, sperm density, and sperm motility were improved, leading the authors to conclude that ubiquinol is an effective treatment for men with unexplained oligoasthenoteratozoospermia.

Efficacy of coenzyme Q10 on semen parameters, sperm function and reproductive hormones in infertile men.

Safarinejad MR.
Biofactors 2005;25:165‐174.
The study evaluated the efficacy of CoQ10 supplementation on sperm parameters, sperm function and reproductive hormone profiles in infertile men. 300 mg of CoQ10 or placebo was administered to 212 infertile men over a 26-week period, followed by a 30-week treatment-free period. During both timeframes, semen analyses were conducted on various sperm parameters. The results showed an improvement in sperm density, count, morphology and motility with CoQ10 treatment.

An update on coenzyme Q10 implications in male infertility: biochemical and therapeutic aspects.

Mancini A, De Marinis L, Littarru GP, Balercia G.
J Androl 1994;15(6):591‐594.
This study aimed to investigate the CoQ10 and quinone concentrations in seminal fluid and sperm cells after CoQ10 administration in infertile men. After CoQ10 administration, asthenozoospermic infertile men showed increased amounts of CoQ10 in both seminal plasma and sperm cells, ultimately improving sperm movement. Based on the strong correlation between CoQ10 concentration and sperm motility, the study suggested a cause/effect relationship between CoQ10 administration and improvements in sperm parameters.

Coenzyme Q10 concentrations in normal and pathological human seminal fluid.

Mancini A, De Marinis L, Oradei A, Hallgass ME, Conte G, Pozza D, Littarru GP.
J Androl 1994;15(6):591‐594.
In this study, 77 subjects underwent a semen analysis looking at seminal fluid and/or seminal plasma. A significant correlation was found between CoQ10 concentration and sperm count and sperm motility. Patients with varicocele, however, did not demonstrate the same correlation between CoQ10 concentration and sperm motility. The authors hypothesized a distinct CoQ10-related pathophysiology for varicocele patients. The study suggested a possible treatment with exogenous CoQ10 supplementation for patients with sperm problems.

Coenzyme Q10 levels in rat heart of different age.

Pignatti C, Cocchi M, Weiss H.
Biochem Exp Biol 1980;16:39‐42.
Examining the CoQ10 levels in rat hearts at different ages, this study showed that CoQ10 levels decline by about 20-30% with aging.

Mitochondria-related male infertility.

Nakada K, Sato A, Yoshida K, Morita T, Tanaka H, Inoue S, Yonekawa H, Hayashi J.
Proc Natl Acad Sci USA 2006;103:15148‐15153.
About half of infertility cases can be attributed to men due to mitochondrial genome mutations. This in-vivo mice study evaluated the possibility that mitochondrial respiration defects contribute to male infertility. Using wild type mice and those with mutant mtDNA, the study demonstrated that mitochondrial respiration defects, caused by accumulation of mtDNA damages, induced oligospermia and asthenozoospermia in the mice with mutant mtDNA, with most of their sperm carrying abnormalities in the middle piece and nucleus. The study concluded that normal mitochondrial function is necessary for healthy mammalian spermatogenesis.

Role of reactive oxygen species in the pathophysiology of human reproduction.

Agarwal A, Saleh R, Bedaiwy M.
Fertil Steril 2003:79;829‐843.
This literature review summarizes the roles that reactive oxygen species (ROS) plays in both male and female reproduction and fertility in relation to IVF, embryo toxicity and development. In the male fertility context, ROS is known to compromise the fluidity of the sperm plasma membrane and the integrity of DNA in the sperm nucleus. In the female fertility context, ROS has been implicated in endometriosis and unexplained infertility. Combined with their negative effects on female fertility, high levels of ROS are detrimental to fertility potential, both in natural and assisted conceptions.

Mechanisms of male infertility: role of antioxidants.

Sheweita SA, Tilmisany AM, Al‐Sawaf H.
Curr Drug Metab 2005;6(5):495‐501.
This review of antioxidants and male infertility suggested that identification of environmental and occupational risk factors to male infertility is needed, and proposed that a multi-faceted treatment approach involving supplementation with various antioxidants with proven efficacy, such as vitamin C, vitamin E and CoQ10, may improve male fertility via optimal sperm production and function.

Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa.

Aitken RJ, Gordon E, Harkiss D, Twigg JP, Milne P, Jennings Z, Irvine DS.
Biol Reprod 1998;59(5):1037‐46.
This study investigated how sperm reacted to different levels of oxidative stress. Analyzing sperm’s movement, sperm-oocyte interaction and DNA integrity, the study showed that when sperm was exposed to low level of oxidative stress, DNA fragmentation decreased and the rates of sperm-oocyte fusion were enhanced. Inversely, at high levels of oxidative stress, sperm DNA damage increased. Sperm movement and oocyte fusion were lost altogether.

Toxicology of male reproduction in animals and humans.

De Celis R, Pedron‐Nuevo N, Feria‐Velasco A.
Arch Androl 1996;37:201‐218.
This review lists environmental and occupational factors, such as heavy metals, organic compounds, alcohol, and cigarette smoking, that affect male fertility and reproduction.

The effect of age on the expression of apoptosis biomarkers in human spermatozoa.

Colin A, Barroso G, Gomez‐Lopez N, Duran E, Oehninger S.
Fertil Steril 2010;94:2609‐2614.
This cross sectional study examined the sperm of men ranging in age from 20 to 68 to determine how age influences the way sperm cells “die”. Advancing male age was found to significantly correlate with apoptosis biomarkers, and a clear trend for increased DHEA fragmentation in older male group was observed. The study confirmed that male age is associated with sperm death and resulting decrease in sperm concentration.

The effects of male age on sperm DNA damage in healthy non‐smokers.

Schmid T, Eskenazi B, Baumgartner A, Marchetti F, Young S, Weldon R, Anderson D, Wyrobek A.
Hum Reprod 2007;22:180‐187.
Eighty non-smoking men with no known fertility issues were evaluated for DNA damage and the production of genetically defective sperm. Older men were found to demonstrate increased sperm DNA damage in conjunction with single-strand DNA breaks. The study also identified caffeine intake as risk factor for sperm DNA damage: Men who consume caffeine daily, regardless of age, had increased double strand DNA breaks in their sperm.

Effects of age on DNA double‐strand breaks and apoptosis in human sperm.

Singh N, Muller C, Berger R.
Fertil Steril 2003;80:1420‐1430.
This study evaluated semen samples from 66 men between 20 and 57 years to investigate the relationship between a man’s age and DNA damage in the sperm, as well as the apoptosis (“death”) of sperm cells. The result showed a direct correlation between age and DNA damage: percentage of sperm with high degree of DNA damage, among other parameters, was significantly higher among men 36-57 years than those 20-35 years. Sperm motility was significantly better in the younger men. This study was also the first to show an age-related decrease in sperm apoptosis, indicating an age-related deterioration of healthy sperm cell selection process.

Quantitative effects of male age on sperm motion.

Sloter E, Schmid T, Marchetti F, Eskenazi B, Nath J, Wyrobek A.
Hum Reprod 2006;21:2868‐2875.
To address the lack of quantitative information on the risk factors that affect sperm quality, this study performed a linear regression analyses on 14 aspects of semen quality in a group of 90 men ranging from 22 to 80 years of age. Participants were non-smokers and had no history of infertility. The findings revealed age-associated declines in sperm motility and three quantitative aspects of sperm motion (linearity, straight line velocity, and average path velocity).

Paternal age and reproduction.

Sartourius G, Nieschlag E.
Hum Reprod Update 2010;16:65‐79.
It is already known that maternal age has a negative effect on fertility, in addition to contributing to adverse outcomes in pregnancy and offspring. This study was conducted to review the influence paternal age has on fertility and on the risk of poor outcomes. Though findings of deteriorated sperm quality and decreased sexual activity were associated with an increase in paternal age, the study concluded that paternal age, on its own, does not justify invasive procedures.

Effects of male age on semen quality and fertility: a review of the literature.

Kidd S, Eskenazi B, Wyrobek A.
Fertil Steril 2001;75:237‐248.
This study takes a look at research published on sperm quality from January 1, 1980 through December 31, 1999. In the analysis of stronger-evidence studies, a decrease in semen volume, motility and the percentage of normal sperm were observed when comparing 50-year-old men to 30-year-old men. Based on the majority of the evidence from the studies evaluated, this review proposes a decline in sperm quality as men age.

Decline in human fertility rates with male age: a consequence of a decrease in male fecundity with aging?

Matorras R, Matorras F, Exposito A, Martinez L, Crisol L.
Gynecol Obstet Invest 2011;71:229‐235.
This study sorted 454,753 newborns for the year 2004 by paternal and maternal age groups to evaluate human fertility based on male age. The grouping showed that male fertility declined at age 35-39 and continues to follow a constant slope, revealing a 21-23% decrease in fertility starting at age 39. The authors attributed the age-related decline in male fertility to deterioration in sperm quality.

Aging and male reproductive function: A mitochondrial perspective.

Amaral S, Amaral A, Ramalho‐Santos J.
Front Biosci 2013;S1:181‐197.
This study sought to provide an overview of how age affects the male reproductive system via mitochondrial function. The study proposes that oxidative stress on the mitochondria, changes in mitochondrial energy metabolism and mitochondrial-dependent testosterone production constitute a link between aging and male infertility.

Treatment of CoQ(10) deficient fibroblasts with ubiquinone, CoQ analogs, and vitamin C: time‐ and compound‐dependent effects.

Lopez LC et al.
PLoS ONE 2010;5:e11897.
This in vitro study evaluated the effects of CoQ10 and its various ubiquinone analogs within the mirochondria respiratory chain, and found that ubiquionone analogs cannot replace CoQ10 in cases of CoQ10 deficiency. The authors concluded that in cases of COQ10 deficiency, CoQ10 supplementation should be the preferred method of treatment, not ubiquinone supplementation.

Premature aging in mice expressing defective mitochondrial DNA polymerase.

Trifunovic A et al.
Nature 2004;429:417‐23.
With aging, mitochondrial DNA (mtDNA) deletions and mutations accumulate in tissues in the body. In this experimental study, knock-in mice with PolgA, a subunit of mtDNA, developed a phenotype increase of mutations illustrating that the rise of these mutations is associated with a variety of deficiencies related to age, including reduced fertility. The result shows a direct link between mtDNA mutations and ageing phenotypes in mammals.

The maternal age effect: a hypothesis based on oxidative phosphorylation.

Wilding M et al.
Zygote 2005;13:317‐23.
This study presented a hypothesis that free radicals negatively affect the efficiency of oxidative phosphorylation in the oocytes of older women, in the primordial stage. The authors suggested that oocyte quality depends on the level of oxidative phosphorylation.

The antioxidant role of coenzyme Q.

Bentinger M et al.
Mitochondrion 2007;7(Suppl):S41‐50.
This study investigated the function of coenzyme Q (CoQ) as an antioxidant that protects cellular membrane. The only lipid-soluble antioxidant synthesized in the body, CoQ is the most abundant antioxidant in the body and protects lipids, proteins and DNA. The study suggested that re-establishing normal levels of CoQ in cases of deficiency due to genetic mutation or aging is of therapeutic interest.

Mitochondrial DNA in the oocyte and the developing embryo.

May‐Panloup P et al.
Curr Top Dev Biol 2007;77:51‐83.
This review examined recent studies on the important roles mitochondria play in the reproductive process. Driving cellular energetic metabolism, mitochondria greatly influence the quality of human eggs and assist in the process of egg fertilization and early embryo development.

The effects of oxidative stress on female reproduction: a review

Agarwal A et al.
Reprod Biol Endocrinol. 2012 Jun 29;10:49.
This extensive review focused on the effects of oxidative stress (OS) on various aspects of infertility, including PCOS, endometriosis and unexplained infertility. The study found conflicting animal and in vitro reports on the potential use of antioxidants for infertility associated with OS. The study concluded that despite evidence that OS compromises sperm, egg and embryo quality in assisted reproductive technologies settings, further studies are needed to validate possible benefits of antioxidant supplementation to treat infertility.

The contribution of mitochondrial function to reproductive aging.

Bentov et al.
Genet 2011;28:773‐83.
Against a backdrop of increasing number of women ages 36-44 trying to conceive, this study reviewed available data on the possible role that mitochondria plays in reproductive aging. The review concluded that while the factors responsible for low-quality oocytes still need to be elucidated, mitochondrial dysfunction appears to play a role in reproductive aging.

Coenzyme Q10 in submicron‐sized dispersion improves development, hatching, cell proliferation and adenosine triphosphate content of in vitro‐produced bovine embryos.

Stojkovic M et al.
Biol Reprod 1999;61:541‐7.
In this study, CoQ10 was tested as a supplement for IVF culture of bovine embryos to show whether or not the CoQ10 supported the embryo in the culture system. Embryos showed high cleavage rate and the significantly more blastocysts hatched with the administration of CoQ10, proving that CoQ10 does support embryo development of bovines.

Coenzyme Q10 content in follicular fluid and its relationship with oocyte fertilization and embryo grading.

Turi A et al.
Arch Gynecol Obstet 2012;285:1173‐6.
The study was the first to investigate the presence and functions of CoQ10 in human follicular fluid. CoQ10 levels were significantly higher in mature oocytes than dysmorphic oocytes, and significantly higher in better-quality embryos than lower-quality embryos. The study proposed administration of CoQ10 for women with infertility to evaluate its reproductive functions.

The use of mitochondrial nutrients to improve the outcome of infertility treatment in older patients.

Bentov Y et al.
Fertil Steril 2010;93:272‐5.
The study proposed the hypothesis that mitochondrial dysfunction plays a significant role in reproductive senescence, and suggested supplementation with mitochondrial nutrients, including CoQ10, to treat older patients with infertility.

Why do older women have poor implantation rates? A possible role of the mitochondria.

Bartmann AK et al.
J Assist Reprod Genet 2004;21:79‐83.
Mitochondria provide energy for spindle formation during meiosis II, facilitating fecundation. Because it is passed on maternally, integrity of oocyte mitochondria is crucial for embryonic development. This opinion piece proposed a model to explain the poor implantation rates of older women by age-related DNA mutations in mitochondria.

Reproductive aging is associated with decreased mitochondrial abundance and altered structure in murine oocytes.

Kushnir VA et al.
Fertil Steril 2005;84(3):756.
This study was conducted to test the hypothesis that dysfunction in oocytes due to a decrease in mitochondrial abundance is linked to reproductive aging. The study measured conception and litter size in young and aged mice. Older mice took significantly longer to conceive than younger mice, and had fewer surviving pups. The oocytes of older mice had 2.7-fold less mtDNA compared to the younger mice, proving the association of reproductive aging and the decrease in the amount of mitochondria in oocytes.

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."