Introduction
Postponement of childbearing is a worldwide common practice because women prefer to pursue higher education and career advancement before making the decision to conceive. Consequently, there is a marked increase in the number of women with subfertility, who seek medical interventions to overcome the involuntary childlessness incurred as a result of ovarian aging. Ovarian aging, dictated by a decline in quantity and quality of oocytes within the ovaries, is accountable for the age-related decline in fertility, and of the age-related increase in adverse pregnancy outcomes such as miscarriage, and aneuploid pregnancies.
Women who suffer from ovarian aging are more likely to be fast-tracked towards assisted reproductive technology (ART) but yet are still at risk of having poor treatment outcomes due to diminished ovarian reserve leading to poor response to ovarian stimulation.
Poor ovarian response (POR) represents a significant challenge in assisted reproduction. It is encountered in 5% to 18% of women undergoing in vitro fertilization (IVF). It is increasing because of the delay to the first pregnancy; about 26.5 years old in 1977, between 29 and 31 in 2018 in most European countries.
Patients with POR have a very low successful pregnancy rate: 2% to 18%, depending on maternal age and number of oocytes retrieved. The fewer oocytes that are collected leads to lower pregnancy rates.
Over the years, many adjuvant therapies or protocols have been tested for POR to improve clinical pregnancy rates such as gonadotrophins-releasing hormone flare protocols, high dose gonadotrophins, antagonist protocol, arginine, testosterone, letrozole, luteal estradiol, or low dose aspirin.
What is DHEA?
Dehydroepiandrosterone (DHEA) is an endogenous steroid chiefly originating from the adrenal zona reticularis and ovarian theca cells in women. DHEA acts as an essential prohormone in the production of testosterone, which is believed to be involved in early folliculogenesis. Numerous studies and meta-analyses have shown its beneficial effects in POR, leading to an improved ovarian reserve, an increased oocyte yield and quality, and a higher pregnancy rate or live birth rate following in vitro fertilization (IVF) treatment. However, these studies used different definitions of POR, so the results were not clear evidence of DHEA effectiveness.
Casson and associates were the first to suggest therapeutic benefits from supplementation with DHEA in women with diminished ovarian reserve. They also suggested that, in micronized form, the androgens offer the potential for postmenopausal steroid replacement, adjunctive to estrogen; that its conversion may not be symmetrical, favoring androgens over estrogen, with testosterone increasing and estradiol remaining low; that DHEA has immunomodulatory effects, now therapeutically explored in autoimmune diseases, that vaginally administered DHEA, while delivering equivalent hormone, substantially diminishes bioconversion comparatively to oral micronized products, and that abnormally low adrenal DHEA secretion is potentiated by ovarian hyperstimulation with gonadotropins. They also reported that DHEA is well tolerated and increases IGF-1 levels.
Though demonstrating improvement in oocyte yields, their initial paper went unnoticed for years and initiated no follow-up studies.
Study Characteristics
This is the first systematic review to analyze the outcomes of embryo quality (searching for embryo score, ploidy, and miscarriage rates) in women with POR going through an intervention with oral DHEA compared to a control group. The importance in choosing as an outcome embryo quality instead of oocytes retrieved is that embryo quality is much more important for a successful IVF procedure to end on a positive pregnancy result.
In this study, we did a systematic review of the use of oral DHEA for POR patients who underwent an IVF procedure looking for outcomes related to the improvement of the quality of the embryos after an intervention giving oral DHEA.
In the majority of the studies(case-control and retrospective control) the DHEA group showed an improvement in embryo score and reduced rates of miscarriage and aneuploidy. (case-control were high risk of bias the retrospective cohort ones were high quality).
Why DHEA may be helping?
The actions of DHEA occur mainly via its conversion to androgen, which acts locally to regulate follicular and luteal function through an autocrine and/or paracrine effect. Androgen receptors are expressed in granulosa cells, theca cells, and oocytes in most follicular stages, especially in preantral and growing antral follicles. Androgen receptors decrease as follicles grow to the preovulatory stage. Indeed, androgens have been reported to be involved in the initiation of primordial follicle recruitment, in the stimulation of the early stages of follicular development by increasing FSH receptor expression, and in increasing the number of growing follicles by reducing follicular atresia.
Furthermore, active testosterone appears in the blood before exposure to its target tissues, while DHEA is converted to androgen intracellularly without significant release of active testosterone into the blood]. Therefore, DHEA supplementation seems to result in more precise actions and cause fewer adverse effects than testosterone supplementation in clinical practice.
Previous studies showed that DHEA might be associated with improvements in mitochondrial function and the regulation of mitochondrial dynamics and homeostasis.
DHEA supplementation could increase mitochondrial mass and mitochondrial dehydrogenase activity, reduce mitochondrial reactive oxidative species generation and diminish the loss of mitochondrial membrane potential in human cumulus cells or human HO23 granulosa cells. Additionally DHEA treatment restores mitochondrial morphology fission and mitophagy in human cumulus cells.
Its mechanism of action on the ovary remains hypothetical. Different hypotheses have been described over the years. It may increase the bioavailability of IGF-1, as reflected by an increase in IGF-1 and a decrease in IGFBP-1 levels. IGF may potentiate gonadotrophins actions. Gleicher et al. reported that DHEA created polycystic ovary (PCO) like characteristics during stimulation. It had indeed been used to induce PCO-like ovarian phenotypes in rats and mice. An increased level of androgens characterizes this PCO situation. And androgens had previously been reported to suppress apoptosis. Hyman et al. suggest that DHEA does not influence the early state of folliculogenesis but antral follicles representing the recruitable follicles cohort that has escaped from atresia.
Casson et al, 2000, who was the first to report the beneficial effects of DHEA on ovaries with diminished reserve, demonstrated a transient increase in IGF-1 inpatients undergoing exogenous gonadotrophin ovulation induction after pretreatment for only 8 weeks of DHEA. Such a transient increase in IFG-1 may have been due to either increased production of androgen effect on the liver producing decreased IGF-1-binding hormone.
Furthermore, DHEA significantly increased the activities of superoxide dismutase, catalase, and peroxidase, and decreased the loss of mitochondrial membrane potential and the level of reactive oxygen species in the Leydig cells. Patel et al. indicated that DHEA treatment can improve oxidative energy metabolism by promoting ATPase activity and mitochondrial dehydrogenase activities in the mitochondrial in rats.
Mitochondrial mass in cumulus cells (CCs) from the POR remarkably increased following DHEA supplementation.
Taken together DHEA treatment may ameliorate IVF outcomes partially through improving mitochondrial function and reducing apoptosis in CCs.
Low androgen levels can be of ovarian and or adrenal etiology. Since DHEA-S is almost exclusively produced by adrenals, it is generally accepted that low DHEA-S reflects an adrenal cause for low androgen levels. Therefore, Chyi-Uei Chern et al study would suggest that DHEA supplementation was especially effective if androgen deficiency was of adrenal origin. Gleicher et al. demonstrated that patients with secondary ovarian insufficiency induced by adrenal hypoandrogenism dramatically improved in ovarian function after DHEA supplementation.
Studies on women with the polycystic ovarian syndrome (PCOS) demonstrated that elevated androgen concentrations both in serum and follicular fluid were associated with an increased number of preantral and small antral follicles, along with increased responsiveness to gonadotrophin induction.
Since a majority of miscarriages are believed to be a consequence of aneuploidy, it is possible to hypothesize that a decreased aneuploidy rate should be translated into decreased spontaneous pregnancy loss. It is unlikely that this effect may be restricted to infertile women with POR, as in their study a reduced miscarriage rate was also observed in women without POR administered with DHEA, with respect to patients undergoing placebo treatment.
Probably DHEA is able to improve fertility in patients with advanced reproductive age seeking pregnancy. Although additional larger studies using different DHEA protocols are required to support these findings, Tartagni et al 2015 is the first randomized, placebo-controlled study suggesting the potential beneficial effects of DHEA administration in women with infertility and advanced reproductive age, but with still normal ovarian reserve.
Their results showed a higher embryo quality in DHEA group (77,3% vs 48.2%) than the placebo control group. Also in Tartagni et al study, they showed a lower miscarriage rate in the DHEA group (0 vs 5) than in the placebo group.
Despite worldwide utilization of DHEA supplementation in women with DOR; the lack of enough controlled studies is still regretful with the small study by Wiser et al and Narkwichean et al representing the only prospective clinical trials (Level I evidence). Studies of more substantial size are all based on lower levels of evidence and, therefore have to be interpreted cautiously. This fact is reemphasized by most publications coming from only a small number of centers.
Purists may argue that no treatments should be routinely applied in clinical practice unless based on prospectively randomized studies. Recognizing that Level I clinical trials may, at times, be too costly and/or too difficult to conduct, such an approach has, however, recently been questioned in the academic community.
Conclusions
Even with the negative outcomes that the only randomized highest quality study showed, we think it’s worth performing additional randomized placebo studies with a larger number of patients to reassure if the use of DHEA as a protocolized treatment for POR women in all fertility clinics can be useful.
Why do we think it’s worth performing additional high-quality studies is because we could find a new treatment that could help POR women that don’t want to accept an ovodonnation, and because of its simplicity of use and lack of harmful side effects.
Its mechanism of action is probably due to an increase in androgens levels that have been reported to be involved in the initiation of primordial follicle recruitment increasing IGF-1, an improved mitochondrial function by increasing antioxidants, and also an anti-apoptotic effect.