Elena Labarta

STUDY QUESTION: Can natural cycles (NC) be effectively utilized in advanced maternal age (AMA) undergoing oocyte donation, without compromising live birth rates (LBRs) and miscarriage outcomes, when compared to artificial cycles (ACs)? SUMMARY ANSWER: In donor oocyte embryo transfer cycles, NC demonstrated superior outcomes in reproductive efficacy and obstetrical safety compared to AC, independent of the recipient’s age. WHAT IS KNOWN ALREADY: Previous studies have posited that NC may result in better outcomes when compared to AC embryo transfer, including a lower risk of miscarriage and hypertensive disorders of pregnancy. Recent studies support that NC-frozen embryo transfer (FET) decreases obstetrical and neonatal complications compared to AC-FET, even if LBR differences remain controversial in some general populations. There is limited research on the use of NCs in women of AMA. STUDY DESIGN, SIZE, DURATION: This retrospective, multicentre, cohort study included all single blastocyst embryo transfers following oocyte donation performed between January 2010 and December 2023, subdivided according to the type of endometrial preparation performed (NC or AC). The oocyte donation model was chosen to minimize the potential confounding effect related to poor oocyte competence in older women and the influence of ovarian stimulation performed during autologous IVF on endometrial receptivity prior to a fresh embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main objective of the study was to compare LBR. Secondary outcomes included hCG-positive pregnancy rate, clinical pregnancy rate, miscarriage rate, obstetric, and perinatal outcomes. Confounder-adjustment was performed using a multivariable generalized estimating equations model regression analysis, adjusting for multiple confounders. A sub-analysis compared results when the AC protocol was optimized with progesterone (P4) monitoring and rescue therapy. Additionally, an interaction variable was added to the final multivariable model to assess whether female recipient age may modify the effect of each type of endometrial preparation on LBRs. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 67 048 embryo transfers were analysed, including NC (n = 6922) and AC (n = 60 126). The NC group demonstrated consistent superiority over AC after adjustment for confounders across all transfers. NC was associated with a higher LBR (aOR 1.38, 95% CI 1.29–1.47; P < 0.01) and significantly lower miscarriage rate per hCG-positive pregnancy (aOR 0.68, 95% CI 0.61–0.76; P < 0.01). This superiority persisted even in optimized AC cycles with P4 monitoring and rescue therapy (LBR aOR 1.42, 95% CI 1.31–1.54; P < 0.01). Furthermore, NC was associated with significantly lower obstetrical risks in singleton pregnancies, including hypertensive disorders of pregnancy (aOR 0.72, 95% CI 0.56–0.94; P = 0.01), Caesarean delivery (aOR 0.86, 95% CI 0.77–0.96; P < 0.01), and large for gestational age (aOR 0.77, 95% CI 0.67–0.89; P < 0.01). The interaction between endometrial preparation method and female recipient age was not statistically significant (aOR 1.02, 95% CI 0.99–1.03). LIMITATIONS, REASONS FOR CAUTION: The retrospective nature of the study and the inherent risk of bias related to unmeasured confounding factors may have impacted the results. Another limitation is the low percentage of NC included in the study (10.32% of all cycles), which could be related to the low uptake to this treatment modality in real-life practice. WIDER IMPLICATIONS OF THE FINDINGS: NC may offer superior reproductive outcomes and is associated with lower obstetrical risks, with differences unlikely to be modified by female age. Therefore, it seems reasonable to suggest NC for older women, as they could benefit from the decreased risk of miscarriage and hypertension during pregnancy. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was obtained for this study. A.R.N. has received research grants (to institution) from Theramex; Consulting and Speakers′ fees and travel support from Organon and Merck KgaA; S.S.-R. has received consulting fees from Organon, IBSA, and Besins; Speakers′ fees and travel support from Organon, Ferring Pharmaceuticals, Theramex, IBSA, Gedeon Richter, Abbott, and Besins. He has also received travel support from Organon, Ferring, Theramex, IBSA, Gedeon-Richter, Abbott, and Besins. He holds stocks/shares with IVIRMA Lisboa. He is a member of the ESHRE Executive Committee and was the Senior Deputy of Safety and Quality for ESHRE. TRIAL REGISTRATION NUMBER: N/A.

Purpose of review: Progesterone plays a pivotal role in implantation and ongoing pregnancy. In the context of assisted reproductive technology (ART), and in particular frozen embryo transfer (FET), increasing evidence suggests that serum progesterone levels strongly influence reproductive outcomes. This review summarizes the latest findings regarding the optimal range of serum progesterone concentrations and their implications across different endometrial preparation protocols. Recent findings: Observational and interventional studies have consistently shown that suboptimal mid-luteal serum progesterone levels are associated with lower implantation and live birth rates in FET cycles. The need for exogenous supplementation varies according to the type of endometrial preparation, with hormone replacement therapy cycles being particularly sensitive to inadequate progesterone exposure. Emerging data support the concept of individualized luteal support, including serum-guided adjustments or alternative routes of administration in cases of suboptimal serum progesterone levels. Summary: Adequate serum progesterone concentrations are critical for optimizing outcomes after FET. Evidence supports a paradigm shift from empirical supplementation to precision medicine approaches based on serum thresholds and patient characteristics. Future research should aim to define universally accepted cutoff values, clarify the role of endometrial versus systemic progesterone, and refine strategies for tailoring luteal phase support in ART.

Previous studies have linked the microbiome of distinct body habitats to obesity and infertility; however, the often-divergent results observed have left the role of the so-called “second genome” in obese infertile patients incompletely explored. Here, we present a prospective observational multicenter study of oral, gut, endometrial, and vaginal microbiota of infertile patients classified according to BMI. Patients collected saliva/fecal samples, while vaginal/endometrial fluid samples were collected in the clinic. Total bacterial DNA was extracted, and microbiota profiles were analyzed by 16S rRNA gene sequencing. Our results showed no differences in the Bacteroidetes/Firmicutes ratio (proposed obesity hallmark) in the gut microbiota between patients with obesity and normal weight; however, a tendency for higher levels of genera such as Escherichia-Shigella in normal-weight patients was observed; in comparison, patients with obesity possessed increased numbers of Parasutterella and Roseburia. In the reproductive tract, vaginal samples possessed a similar microbiota to endometrial fluid, both largely colonised by Lactobacillus, Gardnerella, and Streptococcus, supporting the hypothesis that uterine colonisation proceeds from vaginal bacteria ascension. Additionally, higher prevalence of a Streptococcus-dominated (>50%) endometrial microbiota was observed among patients with obesity. This first description of the human digestive and reproductive tract microbiota in infertile women with obesity may explain their poor reproductive outcomes.

Infertility affects 15% of the population in developed countries, and its prevalence is increasing. Fertility can be influenced by different factors. Although key factors like maternal age cannot be changed, there is growing evidence that other modifiable factors, such as diet, can have an impact on fertility. Diet has become increasingly important in recent years for a number of reasons: the new trend toward a healthy lifestyle, the higher prevalence of certain digestive disorders, a lack of time that leads people to consume more prepared and processed food, and personal choice to not eat meat, among others. To meet these needs, several diets have recently become popular, such as the Mediterranean diet, known as the gold standard of health; the DASH diet, known for preventing hypertension; the Western diet, characterized by processed food; the ketogenic diet, characterized by low carbohydrate intake; and the vegetarian diet, which is the choice for people who do not eat meat or animal by-products. Diets present a unique composition characterized by the presence or absence of specific nutrients, which have also been associated with male and female fertility individually. This review assesses the impact of these diets and of macro- and micronutrients on both female and male fertility.

Does ovarian stimulation with highly purified (hp)-HMG protect from elevated progesterone in the follicular phase compared to recombinant FSH (r-FSH) cycles through a different regulation of follicular steroidogenesis? hp-HMG enhanced the Δ₄ pathway from pregnenolone to androstenodione leading to lower serum progesterone at the end of the cycle, while r-FSH promoted the conversion of pregnenolone to progesterone causing higher follicular phase progesterone levels. Elevated progesterone in the follicular phase has been related to lower clinical outcome in fresh IVF cycles. Progesterone levels are positively correlated to ovarian response, and some studies have shown that when r-FSH alone is used for ovarian stimulation serum progesterone levels on the day of triggering are higher than when hp-HMG is given. Whether this is caused by a lower ovarian response in hp-HMG cycles or to a difference in follicular steroidogenesis in the two ovarian stimulation regimens has not been well characterized A randomized controlled trial including 112 oocyte donors undergoing ovarian stimulation with GnRH antagonists and 225 IU/day of r-FSH (n = 56) or hp-HMG (n = 56) was carried out in a university-affiliated private infertility clinic. Subjects were recruited between October 2016 and June 2018. The women were aged 18–35 years with a regular menstrual cycle (25–35 days) and normal ovarian reserve (serum anti-Müllerian hormone (AMH) = 10–30 pMol/l) undergoing ovarian stimulation for oocyte donation. FSH, LH, estradiol (E₂), estrone, progesterone, pregnenolone, 17-OH-progesterone, androstenodione, dehidroepiandrostenodione, and testosterone were determined on stimulation Days 1, 4, 6, and 8 and on day of triggering in serum and in follicular fluid. Samples were frozen at −20°C until assay. Total exposures across the follicular phase were compared by polynomic extrapolation. Subjects in both groups were comparable in terms of age, BMI, and AMH levels. Ovarian response was also similar: 17.5 ± 7.9 (mean ± SD) versus 16.5 ± 7.5 oocytes with r-FSH and hp-HMG, respectively (P = 0.49). Serum progesterone (ng/ml) on day of trigger was 0.46 ± 0.27 in the hp-HMG group versus 0.68 ± 0.50 in the r-FSH group (P = 0.010). Differences for progesterone were also significant on stimulation days 6 and 8. The pregnenolone: progesterone ratio was significantly increased in the r-FSH group from stimulation day 8 to the day of trigger (P = 0.019). Serum androstenodione (ng/ml) on day of trigger was 3.0 ± 1.4 in the hp-HMG group versus 2.4 ± 1.1 in the r-FSH group (P = 0.015). Differences in adrostenodione were also significant on stimulation Day 8. The pregnenolone:androstenodione ratio was significantly higher in the hp-HMG group (P = 0.012) on Days 6 and 8 and trigger. There were no other significant differences between groups. Follicular fluid E₂, FSH, LH, dehidroepioandrostenodione, androstenodione, and testosterone were significantly higher in the hp-HMG than r-FSH group. No differences were observed for progesterone, estrone, 17-OH-progesterone, and pregnenolone in follicular fluid. All women included in the study were young, not infertile, and had a normal BMI and a good ovarian reserve. The findings might be different in other patient subpopulations. Hormone analyses with immunoassays are subject to intra-assay variations that may influence the results. Stimulation with hp-HMG may prevent progesterone elevation at the end of the follicular phase because of a different follicular steroidogenesis pathway, regardless of ovarian response. This should be considered, particularly in patients at risk of having high progesterone levels at the end of the follicular phase when a fresh embryo transfer is planned. Roche Diagnostics provided unrestricted funding for all serum and follicular fluid hormone determinations. J.L.R., M.M., and A.P. have nothing to declare. E.B. has received consulting fees from Ferring, Merck, Gedeon Richter, and Roche and has participated in a research cooperation with Gedeon-Richter. In addition, the author has participated in speakers’ bureau and received fees from Ferring, Gedeon Richter, Merck, and Roche. P.A. has received consulting fees from MSD and has participated in speakers’ bureau and received fees from Ferring. P.A. also declares travel/meeting support from MSD. E.L. has received consulting fees from Ferring and MSD. In addition, the author has participated in a research cooperation with Gedeon-Richter. Also, the author has participated in speakers’ bureau and received fees from Ferring and IBSA, as well as travel/meeting support from IBSA and Gedeon Richter. E.B., P.A., and E.L. also own stocks in IVIRMA Valencia. NCT: NCT02738580. 19 February 2016. 03 October 2016.

The February ESHRE Journal Club discussion focused on a study by Maignien et al. (2022), the novel clinical variables accounting for low progesterone levels on day of FET in patients undergoing HRT and the difficulties of defining an ideal luteal phase support in these patients. FET: frozen embryo transfer; HRT: hormone replacement therapy; P4: progesterone.

Mitochondria transfer techniques were first designed to prevent the transmission of diseases due to mutations in mtDNA, as these organelles are exclusively transmitted to the offspring by the oocyte. Despite this, given the crucial role of mitochondria in oocyte maturation, fertilization and subsequent embryo development, these approaches have been proposed as new potential strategies to overcome poor oocyte quality in infertile patients. This condition is a very common cause of infertility in patients of advanced maternal age, and patients with previous in vitro fertilization (IVF) attempt failures of oocyte origin. In this context, the enrichment or the replacement of the whole set of the oocyte mitochondria may improve its quality and increase these patients’ chances of success after an IVF treatment. In this short review, we will provide a brief overview of the main human studies using heterologous and autologous mitochondria transfer techniques in the reproductive field, focusing on the etiology of the treated patients and the final outcome. Although there is no current clearly superior mitochondria transfer technique, efforts must be made in order to optimize them and bring them into regular clinical practice, giving these patients a chance to achieve a pregnancy with their own oocytes.