Dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are the most abundant circulating steroid hormones in humans. In animal studies, their low levels have been associated with age-related involuntary changes, including reduced lifespan. Extrapolation of animal data to humans turned DHEA into a 'superhormone' and an 'anti-aging' panacea. It has been aggressively marketed and sold in large quantities as a dietary supplement. Recent double-blind, placebo-controlled human studies provided evidence to support some of these claims. In the elderly, DHEA exerts an immunomodulatory action, increasing the number of monocytes, T cells expressing T-cell receptor gamma/delta (TCRγδ) and natural killer (NK) cells. It improves physical and psychological well-being, muscle strength and bone density, and reduces body fat and age-related skin atrophy stimulating procollagen/sebum production. In adrenal insufficiency, DHEA restores DHEA/DHEAS and androstenedione levels, reduces total cholesterol, improves well-being, sexual satisfaction and insulin sensitivity, and prevents loss of bone mineral density. Normal levels of CD4+CD25(hi) and FoxP3 (forkhead box P3) are restored. In systemic lupus erythematosus, DHEA is steroid-sparing. In an unblinded study, it induced remission in the majority of patients with inflammatory bowel disease. DHEA modulates cardiovascular signalling pathways and exerts an anti-inflammatory, vasorelaxant and anti-remodelling effect. Its low levels correlate with increased cardiovascular disease and all-cause mortality. DHEA/DHEAS appear protective in asthma and allergy. It attenuates T helper 2 allergic inflammation, and reduces eosinophilia and airway hyperreactivity. Low levels of DHEAS accompany adrenal suppression. It could be used to screen for the side effects of steroids. In women, DHEA improves sexual satisfaction, fertility and age-related vaginal atrophy. Many factors are responsible for the inconsistent/negative results of some studies. Overreliance on animal models (DHEA is essentially a human molecule), different dosing protocols with non-pharmacological doses often unachievable in humans, rapid metabolism of DHEA, co-morbidities and organ-specific differences render data interpretation difficult. Nevertheless, a growing body of evidence supports the notion that DHEA is not just an overrated dietary supplement but a useful drug for some, but not all, human diseases. Large-scale randomised controlled trials are needed to fine-tune the indications and optimal dosing protocols before DHEA enters routine clinical practice.

Dehydroepiandrosterone (DHEA): hypes and hopes.

Purpose
Diminished ovarian reserve (DOR) is characterized by poor fertility outcomes, and it represents a major challenge in reproductive medicine. Although consensus exists on the concept of DOR, its definition remains blurry. DOR has to be distinguished from premature ovarian failure (POF) and poor ovarian responders (POR), who are clearly defined.

Diminished ovarian reserve, premature ovarian failure, poor ovarian responder--a plea for universal definitions.

Background
Infertility is a condition affecting 10% to 15% of couples of reproductive age. It is generally defined as "the failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse". The treatment of infertility may involve manipulation of gametes or of the embryos themselves. These techniques are together known as assisted reproductive technology (ART). Practitioners are constantly seeking alternative or adjunct treatments, or both, in the hope that they may improve the outcome of assisted reproductive techniques. This Cochrane review focusses on the adjunct use of synthetic versions of two naturally-produced hormones, dehydroepiandrosterone (DHEA) and testosterone (T), in assisted reproduction.

DHEA and its derivative testosterone are steroid hormones proposed to increase conception rates by positively affecting follicular response to gonadotrophin stimulation, leading to greater oocyte yields and, in turn, increased chance of pregnancy.

Objectives
To assess the effectiveness and safety of DHEA and testosterone as pre- or co-treatments in subfertile women undergoing assisted reproduction.

Search methods
We searched the following electronic databases, trial registers and websites up to 12 March 2015: the Cochrane Central Register of Controlled Trials (CENTRAL), the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, MEDLINE, EMBASE, PsycINFO, CINAHL, electronic trial registers for ongoing and registered trials, citation indexes, conference abstracts in the Web of Science, PubMed and OpenSIGLE. We also carried out handsearches. There were no language restrictions.

Selection criteria
We included randomised controlled trials (RCTs) comparing DHEA or testosterone as an adjunct treatment to any other active intervention, placebo, or no treatment in women undergoing assisted reproduction.

Data collection and analysis
Two review authors independently selected studies, extracted relevant data and assessed them for risk of bias. We pooled studies using fixed-effect models. We calculated odds ratios (ORs) for each dichotomous outcome. Analyses were stratified by type of treatment. There were no data for the intended groupings by dose, mode of delivery or after one/more than one cycle.

We assessed the overall quality of the evidence for the main findings using the GRADE working group methods.

Main results
We included 17 RCTs with a total of 1496 participants. Apart from two trials, the trial participants were women identified as 'poor responders' to standard IVF protocols. The included trials compared either testosterone or DHEA treatment with placebo or no treatment.

When DHEA was compared with placebo or no treatment, pre-treatment with DHEA was associated with higher rates of live birth or ongoing pregnancy (OR 1.88, 95% CI 1.30 to 2.71; eight RCTs, N = 878, I² statistic = 27%, moderate quality evidence). This suggests that in women with a 12% chance of live birth/ongoing pregnancy with placebo or no treatment, the live birth/ongoing pregnancy rate in women using DHEA will be between 15% and 26%. However, in a sensitivity analysis removing trials at high risk of performance bias, the effect size was reduced and no longer reached significance (OR 1.50, 95% CI 0.88 to 2.56; five RCTs, N = 306, I² statistic = 43%). There was no evidence of a difference in miscarriage rates (OR 0.58, 95% CI 0.29 to 1.17; eight RCTs, N = 950, I² statistic = 0%, moderate quality evidence). Multiple pregnancy data were available for five trials, with one multiple pregnancy in the DHEA group of one trial (OR 3.23, 95% CI 0.13 to 81.01; five RCTs, N = 267, very low quality evidence).

When testosterone was compared with placebo or no treatment we found that pre-treatment with testosterone was associated with higher live birth rates (OR 2.60, 95% CI 1.30 to 5.20; four RCTs, N = 345, I² statistic = 0%, moderate evidence). This suggests that in women with an 8% chance of live birth with placebo or no treatment, the live birth rate in women using testosterone will be between 10% and 32%. On removal of studies at high risk of performance bias in a sensitivity analysis, the remaining study showed no evidence of a difference between the groups (OR 2.00, 95% CI 0.17 to 23.49; one RCT, N = 53). There was no evidence of a difference in miscarriage rates (OR 2.04, 95% CI 0.58 to 7.13; four RCTs, N = 345, I² = 0%, low quality evidence). Multiple pregnancy data were available for three trials, with four events in the testosterone group and one in the placebo/no treatment group (OR 3.09, 95% CI 0.48 to 19.98; three RCTs, N = 292, very low quality evidence).

One study compared testosterone with estradiol and reported no evidence of a difference in live birth rates (OR 2.06, 95% CI 0.43 to 9.87; one RCT, N = 46, very low quality evidence) or miscarriage rates (OR 0.70, 95% CI 0.11 to 4.64; one RCT, N = 46, very low quality evidence).

The quality of the evidence was moderate, the main limitations being lack of blinding in the included trials, inadequate reporting of study methods, and low event and sample sizes in some trials.

Authors' conclusions
In women identified as poor responders undergoing ART, pre-treatment with DHEA or testosterone may be associated with improved live birth rates. The overall quality of the evidence is moderate. There is insufficient evidence to draw any conclusions about the safety of either androgen. Definitive conclusions regarding the clinical role of either androgen awaits evidence from further well-designed studies.

/pdf/androgens-dehydroepiandrosterone-or-testosterone-for-women-59eini59tj.pdf

Androgens (dehydroepiandrosterone or testosterone) for women undergoing assisted reproduction

Background Despite great advances in assisted reproductive technology, poor ovarian response (POR) is still considered as one of the most challenging tasks in reproductive medicine. Objective and rationale The aim of this systemic review is to evaluate the role of different adjuvant treatment strategies on the probability of pregnancy achievement in poor responders undergoing IVF. Randomized controlled trials (RCTs) comparing 10 adjuvant treatments [testosterone, dehydroepiandrosterone (DHEA), letrozole, recombinant LH, recombinant hCG, oestradiol, clomiphene citrate, progesterone, growth hormone (GH) and coenzyme Q10 (CoQ10)] were included. Search methods Relevant studies published in the English language were comprehensively selected using PubMed, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) until 11 July 2018. We included studies that investigated various adjuvant agents, including androgen and androgen-modulating agents, oestrogen, progesterone, clomiphene citrate, GH and CoQ10, during IVF treatment and reported subsequent pregnancy outcomes. The administration of GnRH analogs and gonadotrophins without adjuvant treatment was set as the control. We measured study quality based on the methodology and categories listed in the Cochrane Collaboration Handbook. This review protocol was registered with PROSPERO (CRD42018086217). Outcomes Of the 1124 studies initially identified, 46 trials reporting on 6312 women were included in this systematic review, while 19 trials defining POR using the Bologna criteria reporting 2677 women were included in the network meta-analysis. Compared with controls, DHEA and CoQ10 treatments resulted in a significantly higher chance of clinical pregnancy [odds ratio (OR) 2.46, 95% CI 1.16 to 5.23; 2.22, 1.08-4.58, respectively]. With regard to the number of retrieved oocytes, HCG, oestradiol and GH treatments had the highest number of oocytes retrieved [weighted mean difference (WMD) 2.08, 0.72 to 3.44; 2.02, 0.23 to 3.81; 1.72, 0.98 to 2.46, compared with controls, respectively]. With regard to the number of embryos transferred, testosterone and GH treatment led to the highest number of embryos transferred (WMD 0.72, 0.11 to 1.33; 0.67, 0.43 to 0.92; compared with controls, respectively). Moreover, GH resulted in the highest oestradiol level on the HCG day (WMD 797.63, 466.45 to 1128.81, compared with controls). Clomiphene citrate, letrozole and GH groups used the lowest dosages of gonadotrophins for ovarian stimulation (WMD 1760.00, -2890.55 to -629.45; -1110.17, -1753.37 to -466.96; -875.91, -1433.29 to -282.52; compared with controls, respectively). CoQ10 led to the lowest global cancelation rate (OR 0.33, 0.15 to 0.74, compared with controls). Wider implications For patients with POR, controlled ovarian stimulation protocols using adjuvant treatment with DHEA, CoQ10 and GH showed better clinical outcomes in terms of achieving pregnancy, and a lower dosage of gonadotrophin required for ovulation induction. Furthermore, high-level RCT studies using uniform standards for POR need to be incorporated into future meta-analyses.

/pdf/adjuvant-treatment-strategies-in-ovarian-stimulation-for-28fxrlu26r.pdf

Adjuvant treatment strategies in ovarian stimulation for poor responders undergoing IVF: a systematic review and network meta-analysis.

In the last decade, it has been revealed that androgens play a direct and important role in regulating female reproductive function. Androgens mediate their actions via the androgen receptor (AR), and global and cell-specific Ar-knockout mouse models have confirmed that AR-mediated androgen actions play a role in regulating female fertility and follicle health, development and ovulation. This knowledge, along with the clinical data reporting a beneficial effect of androgens or androgen-modulating agents in augmenting in vitro fertilization (IVF) stimulation in women termed poor responders, has supported the adoption of this concept in many IVF clinics worldwide. On the other hand, substantial evidence from human and animal studies now supports the hypothesis that androgens in excess, acting via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). The identification of the target sites of these AR actions and the molecular mechanisms involved in underpinning the development of PCOS is essential to provide the knowledge required for the future development of novel, mechanism-based therapies for the treatment of PCOS. This review will summarize the basic scientific discoveries that have enhanced our knowledge of the roles of androgens in female reproductive function, discuss the impact these findings have had in the clinic and how a greater understanding of the role androgens play in female physiology may shape the future development of effective strategies to improve IVF outcomes in poor responders and the amelioration of symptoms in patients with PCOS.

/pdf/androgens-and-ovarian-function-translation-from-basic-hstyh7hs82.pdf

Androgens and ovarian function: translation from basic discovery research to clinical impact.

Does dehydroepiandrosterone supplementation really affect IVF-ICSI outcome in women with poor ovarian reserve?

Background: Estradiol (E2) is required for follicular development and play an important role in embryo implantation. 

Objective: The aim of this study was to assess the impact of serum E2 levels on the day of hCG administration in IVF-ICSI patients who are performed controlled ovarian hyperstimulation (COH).

Materials and Methods: A total of 203 women who were undergone one time IVF cyclus were evaluated in this cross sectional study. All the patients were treated either with long protocol or with microdose flare protocol. The patients were categorized into five groups according to the serum E2 levels on the day of hCG administration.

Results: The mean number of the retrieved oocytes was (NRO) 10.6±6.7, mean fertilization rate was 55.7±24.8, and implantation rate was 9.0±19.2. Of 203 patients, 43 (21%) patients were pregnant. When the overall results are examined, the number of the retrieved oocytes and the number of transferred embryos were better in patients with serum E2 levels >4000 pg/ml and these values were statistically significant. There were no statistical difference in patients 37 years or older. In women ≤36 years old, the IVF-ICSI outcomes were better in patients with serum E2 levels >4000 pg/ml.

Conclusion: In spite of the lack of high quality evidence to support a positive association between serum E2 levels and IVF-ICSI outcomes, this study shows that high E2 levels during COH might be associated with an increased potential of pregnancy depending on better ovarian response. When the overall results are examined, the best scores were in patients with serum E2 levels >4000 pg/ml.

/pdf/association-between-serum-estradiol-level-on-the-hcg-3q9z5eicm1.pdf

Association between serum estradiol level on the hCG administration day and IVF-ICSI outcome

Background: Estradiol (E2) is required for follicular development and play an important role in embryo implantation. Objective: The aim of this study was to assess the impact of serum E2 levels on the day of hCG administration in IVF-ICSI patients who are performed controlled ovarian hyperstimulation (COH). Materials and Methods: A total of 203 women who were undergone one time IVF cyclus were evaluated in this cross sectional study. All the patients were treated either with long protocol or with microdose flare protocol. The patients were categorized into five groups according to the serum E2 levels on the day of hCG administration. Results: The mean number of the retrieved oocytes was (NRO) 10.6±6.7, mean fertilization rate was 55.7±24.8, and implantation rate was 9.0±19.2. Of 203 patients, 43 (21%) patients were pregnant. When the overall results are examined, the number of the retrieved oocytes and the number of transferred embryos were better in patients with serum E2 levels >4000 pg/ml and these values were statistically significant. There were no statistical difference in patients 37 years or older. In women ≤36 years old, the IVFICSI outcomes were better in patients with serum E2 levels >4000 pg/ml. Conclusion: In spite of the lack of high quality evidence to support a positive association between serum E2 levels and IVF-ICSI outcomes, this study shows that high E2 levels during COH might be associated with an increased potential of pregnancy depending on better ovarian response. When the overall results are examined, the best scores were in patients with serum E2 levels >4000 pg/ml.

Short communication Association between serum estradiol level on the hCG administration day and IVF-ICSI outcome

Oocyte retrieval under transvaginal ultrasonographic guidance has been used for in vitro fertilization-intracytoplasmic sperm injection. Despite considerable advances in the assisted reproductive techniques, the efficacy of follicular flushing during egg collection remains controversial. The aim of this study was to compare the follicular aspiration only and aspiration + flushing methods in terms of retrieved oocyte number and clinical pregnancy rates. A total of 200 patients were randomly divided into the intervention and control groups. All the patients underwent long protocol. Oocyte retrieval was performed when the dominant follicle reached 17 mm. Aspiration was performed using a single- or double-lumen catheter. Follicular flushing was performed after follicular aspiration in 100 patients of the intervention group. In the control group, only follicular aspiration was performed. There were no detected differences in the retrieved oocyte number. Although the clinical pregnancy rate in the intervention group was higher than the control group (40 vs. 33 %), the difference was not statistically significant. Cycle cancelation rate was lower in follicular flushing group (8 %) than control group (11 %) but, this difference was not statistically significant. Metaphase I (MI), germinal vesicle numbers were higher in group 1 than in group 2 and the differences were not statistically significant, either. Total operation time was longer in aspiration + flushing group (group 2) than aspiration only group (group 1) and the difference was statistically significant (p = 0.02). In conclusion, our results indicate that follicular flushing during oocyte retrieval does not improve the retrieved oocyte number or clinical pregnancy rate but, it significantly increases the duration of procedure.

Is follicular flushing really effective? A clinical study

Background: The latest studies reported that local endometrial injury is a useful method to improve the success of IVF-ICSI outcome.

Objective: To assess whether local endometrial injury occurred by Pipelle in the spontaneous cycle could improve implantation rate, cleavage rate, and pregnancy outcome in the subsequent IVF-ICSI cycle in patients who had recurrent IVF failure.

Materials and Methods: An endometrial biopsy was performed on day 21st in 41 patients as intervention group in this retrospective cross-sectional study. The control group contained 42 women.

Results: Implantation rate was 22.5% and 10.5% in intervention and control group, respectively and this difference was found to be statistically significant (p=001). Pregnancy rate was 43.9% in the intervention group and this parameter was significantly lower in control group (21.4%) (p=0.03).

Conclusion: Local endometrial injury in the nontransfer cycle increases the implantation rate and pregnancy rate in the subsequent IVF-ICSI cycle in patients who had previous failed IVF-ICSI outcome.

Mustafa Kara

Papers

Does dehydroepiandrosterone supplementation really affect IVF-ICSI outcome in women with poor ovarian reserve?

Association between serum estradiol level on the hCG administration day and IVF-ICSI outcome

Short communication Association between serum estradiol level on the hCG administration day and IVF-ICSI outcome

Is follicular flushing really effective? A clinical study

Efficacy of the local endometrial injury in patients who had previous failed IVF-ICSI outcome.