Reproductive senescence and energetic metabolism of human luteinized granulosa cells: is it all about ATP? A prospective cohort and critical view.

Mitochondria are known to play a key role in the regulation of reproductive capacity. Senescence is known to impair mitochondrial function and, ultimately, cellular energetic metabolism. Therefore, as women age, a deficient energy supply is likely to affect oocyte quality. The analysis of granulosa cells is considered a valuable noninvasive strategy to assess factors implicated in oocyte competence. Thus, we conducted an observational prospective cohort to evaluate the impact of aging on energy production by luteinized granulosa cells (LGCs). The control group comprised 13 young oocyte donors, whereas the comparison group included 13 infertile women over 38 years of age undergoing in vitro fertilization. Women with diseases that could potentially impact mitochondrial function were excluded. No differences were detected in the ATP levels in LGCs from young donors and infertile patients of advanced reproductive age (1.9 ± 0.99 picomoles in the control group vs. 2.1 ± 0.59 picomoles; p-value = .139). Likewise, the ATP levels in our series did not correlate with either oocyte number or maturity. Despite the similar ATP levels in LGCs, an age effect on the bioenergetic status cannot be excluded. Energy metabolism is very complex, and ATP does not seem to be the most important and reliable parameter.

DuoStim cycles potentially boost reproductive outcomes in poor prognosis patients.

AIM: To evaluate the overall performance and oocyte quality of follicular phase stimulation (FPS) vs. luteal phase stimulation (LPS) among patients undergoing double ovarian stimulation (DuoStim). MATERIALS AND METHODS: Observational retrospective two-center cohort study including 79 infertile women who underwent a total of 87 DuoStim cycles between January 2017 and May 2019. Besides assessing baseline characteristics in order to determine the patients' clinical profile, we analyzed the FPS and LPS regarding the total dose of gonadotropin received, the duration of stimulation, the number and maturity of oocytes, fertilization and blastocyst formation rates, and the number of blastocysts obtained. RESULTS: The patients' baseline characteristics were compatible with a diminished ovarian reserve and poor reproductive prognosis. While the luteal phase needed longer stimulation (12 days (5-19) vs. 11 (7-16), p < .001) and slightly higher gonadotropin doses (2946 ± 890 IU vs. 2550 ± 970 IU, p < .001), no significant differences were detected in the oocyte maturity, fertilization, and blastocyst formation rates. However, the number of oocytes retrieved (5 (0-16) vs. 4 (0-15), p = .006), mature oocytes (4 (0-15) vs. 3 (0-11), p = .032), and blastocysts obtained (70 vs. 53) were substantially greater after LPS. CONCLUSIONS: The DuoStim strategy in poor prognosis patients increases the number of oocytes and blastocysts available. Moreover, the number of oocytes and blastocysts obtained are higher after LPS when compared to FPS. Thus, it should be considered for selected patients in order to not only improve reproductive outcomes but also shorten the time to pregnancy.

Endometrioma and reproductive issues: a well-informed patient may be the driver for change.

Endometriosis affects a great proportion of women during their reproductive years and may impair female fertility in several ways. Ovarian endometrioma (OE) is the most frequent phenotype and growing evidence suggest an endometrioma-mediated damage to the ovary, ovarian reserve and oocyte quality. Traditionally, surgery has been the first-line treatment in cases of OE. Great advances in assisted reproduction and fertility preservation techniques opened new possibilities towards a more conservative approach. Herein we discuss multiple mechanisms responsible for the deterioration of the reproductive capacity in cases of OE as well as the pros and cons of different treatment options. The management of endometrioma-related subfertility remains controversial and it will depend on patient's intentions and priorities. In the "internet era" patients tend to be hyper-informed and more participative, but they are often misguided and misinformed. Thus, doctors should be able to convert these individuals into well-informed patients in order to facilitate the process of shared decision making, which is extremely relevant in the context of OEs.

Growth hormone cotreatment for poor responders undergoing in vitro fertilization cycles: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of growth hormone (GH) supplementation in improving the in vitro fertilization (IVF) outcomes of poor responders. DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): Poor ovarian responders undergoing conventional IVF or intracytoplasmic sperm injection (ICSI). INTERVENTION(S): Randomized controlled trials (RCTs) of poor ovarian responders undergoing a single IVF/ICSI cycle with GH supplementation versus conventional controlled ovarian stimulation. This review was registered in the PROSPERO database before starting data extraction (CRD42020151681). MAIN OUTCOME MEASURE(S): Primary outcome was live birth rate. Clinical pregnancy rate, miscarriage rate, ongoing pregnancy rate, number of oocytes, number of mature (metaphase II [MII]) oocytes and the number of embryos available to transfer were considered as secondary outcomes. RESULT(S): Twelve RCTs were included; 586 women were assigned to the intervention group and 553 to the control group. The analysis revealed that patients receiving GH supplementation did not show an increased live birth rate, miscarriage rate, or ongoing pregnancy rate. However, GH supplementation in poor responders increased clinical pregnancy rate, number of oocytes retrieved (mean difference 1.62), number of MII oocytes (mean difference 2.06), and number of embryos available to transfer (mean difference 0.76). Sensitivity and subgroup analyses did not provide statistical changes to pooled results. CONCLUSION(S): The present meta-analysis provides evidence that GH supplementation may improve some reproductive outcomes in poor responders, but not live birth rates.

Impact of hypogonadotropic hypogonadism on ovarian reserve and response.

OBJECTIVE: To evaluate the hormonal profile, antral follicle count (AFC) and ovarian response of patients with hypogonadotropic hypogonadism (HH). DESIGN: Observational retrospective cohort including infertile women with HH undergoing assisted reproductive treatment (ART). SETTING: University-affiliated infertility center. PATIENT(S): Thirty-three women with HH who underwent ART between January 2007 and September 2018. The control group comprised 66 age-matched counterparts with tubal or male factor infertility. The patients with an abnormal karyotype, and those presenting primary or secondary amenorrhea due to other causes, were cautiously excluded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The primary outcome was serum levels of anti-Müllerian hormone (AMH) and AFC. We also investigated whether HH impacts ovarian response and reproductive outcomes. RESULT(S): Although AFC was similar between groups, HH patients showed significantly higher AMH levels (4.6 ± 2.7 ng/mL vs. 3.0 ± 1.9, p = 0.010) and lower basal FSH and LH. While the HH group needed longer stimulation [13 days (11-26) vs. 10 (7-14), p < 0.001] and higher gonadotropin doses [2700 IU (825-6300) vs. 2100 (425-5000), p = 0.038 ], no significant differences were detected in either the number or maturity of retrieved oocytes, or in the fertilization rate, number of embryos transferred, implantation rate, clinical pregnancy rate and live birth rate per cycle. CONCLUSION(S): HH patients present higher AMH levels, but similar AFC. Despite requiring longer stimulation and higher gonadotropin doses, ovarian response and reproductive outcomes seem unaffected.

Mitochondrial DNA copy number as a predictor of embryo viability.

The evaluation of embryo viability is typically based on morphologic and morphometric grading systems, which are known to be heavily affected by differences in subjective judgement. A significant proportion of euploid embryos do not implant even when the endometrium is normal, despite the wide incorporation of preimplantation genetic testing for aneuploidy. The need to improve reproductive outcomes following assisted reproductive treatments is culminating in the emergence of new research and technology with the potential to enhance embryo selection. The assessment of mitochondrial DNA content as a predictor of embryo viability has gained increasing attention among numerous promising approaches. As is common with new tools, this attention has led to both inflated expectations and serious disillusionment. Here we gather evidence to establish the true clinical applicability of this method. Controversy continues to surround this topic, adding both interest and confusion.

Endometrioma, fertility, and assisted reproductive treatments: connecting the dots.

PURPOSE OF REVIEW: Surgery has traditionally been the primary treatment option for endometriosis-related infertility of any phenotype. However, advances and refinements of assisted reproductive technologies (ART) permit a more conservative approach in many scenarios. This review summarizes the latest findings in the field of reproductive medicine, which have supported a paradigm shift towards more conservative management of ovarian endometrioma. RECENT FINDINGS: The presence of ovarian endometrioma per se is likely to impair ovarian reserve and alter ovarian functional anatomy. Conventional laparoscopic surgery is associated with significant risk of additional damage, and less invasive treatment approaches require further evaluation. With regard to infertile women with ovarian endometrioma who are scheduled for ART treatment, current data indicate that prior surgical intervention does not improve ART outcomes, and that controlled ovarian hyperstimulation (COH) does not affect quality of life or pain symptoms. SUMMARY: Reproductive medicine physicians frequently encounter patients with ovarian endometrioma. The current evidence does not support the postponement of infertility treatment in favour of surgery, except in cases with severe symptoms or to improve follicle accessibility. Although these patients may exhibit diminished ovarian response to COH, their endometrial receptivity, aneuploidy rates, and fertility outcomes are similar to healthy controls. Surgery for ovarian endometrioma provides no benefits in ART treatments.

A cohort study of functioning and disability among women after severe maternal morbidity.

OBJECTIVE: To assess functioning and disability related to severe maternal morbidity (SMM) via the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0). METHODS: In a retrospective cohort study, women with or without a history of SMM who delivered at a tertiary public hospital in Brazil between July 2008 and June 2012, completed the WHODAS 2.0 questionnaire by individual interview between August 2012 and November 2013. General WHODAS scores were evaluated by maternal and neonatal characteristics, and specific domain scores according to SMM event. RESULTS: Overall, 638 women were enrolled (315 with SMM and 323 without SMM). The mean general WHODAS score was higher among women with SMM (19.04±16.18) than among women without SMM (15.77±14.46; P=0.015). Domain scores were also higher in the SMM group for mobility (16.00±20.22 vs 11.63±17.51; P=0.003), household activities (26.79±30.16 vs 20.09±26.08; P=0.005), participation (23.55±21.72 vs 17.27±19.17; P<0.001), and work/school activities for women currently studying or working (20.52±26.64 vs 11.66±19.67; P=0.001). Excluding SMM, a parity of two or more was the only factor significantly associated with higher scores overall (P=0.013) and for domain 4 (getting along with people; P=0.017). CONCLUSION: By comparison with women without childbirth complications, SMM impaired self-reported functioning among women 1-5years after delivery.

Does Severe Maternal Morbidity Affect Female Sexual Activity and Function? Evidence from a Brazilian Cohort Study.

OBJECTIVE: to assess Female Sexual Function Index (FSFI) scores and delay to resume sexual activity associated with a previous severe maternal morbidity. METHOD: This was a multidimensional retrospective cohort study. Women who gave birth at a Brazilian tertiary maternity between 2008 and 2012 were included, with data extraction from the hospital information system. Those with potentially life-threatening conditions and maternal near miss episodes (severe maternal morbidity) were considered the exposed group. The control group was a random sample of women who had had uncomplicated pregnancy. Female sexual function was evaluated through FSFI questionnaire, and general and reproductive aspects were addressed through specific questions. Statistical analyses were performed using Mann-Whitney and Pearson´s Chi-square for bivariate analyses. Logistic regression was used to identify variables independently associated with lower FSFI scores. RESULTS: 638 women were included (315 at exposed and 323 at not exposed groups). The majority of women were under 30 years-old in the control group and between 30 and 46 years-old in the exposed group (p = 0.003). Women who experienced severe maternal morbidity (SMM) had statistically significant differences regarding cesarean section (82.4% versus 47.1% among deliveries without complications, p<0.001), and some previous pathological conditions. FSFI mean scores were similar among groups ranging from 24.39 to 24.42. It took longer for exposed women to resume sexual activity after index pregnancy (mean 84 days after SMM and 65 days for control group, p = 0.01). Multiple analyses showed no significant association of FSFI below cut-off value with any predictor. CONCLUSION: FSFI scores were not different in both groups. However, they were lower than expected. SMM delayed resumption of sexual activity after delivery, beyond postpartum period. However, the proportion of women in both groups having sex at 3 months after delivery was similar. Altered sexual response may be evaluated as one of possible long-term consequences after SMM episodes. Further studies on the growing population of women surviving severe maternal conditions might be worth for improvement of care for women.