The relationship between premature ovarian insufficiency (FXPOI) and premutation in the FMR1 gene is well established. In recent years, though, a potential relationship between the latter and a low ovarian reserve has been suggested. To explore it, we conducted a retrospective study in an IVF program at a university tertiary referral center in Barcelona (Spain). Data were obtained retrospectively from a total of 385 women referred for FMR1 gene testing at our institution from January 2018 to December 2021. We compared the prevalence of FMR1 gene premutation between 93 of them, younger than 35 years, with a diminished ovarian reserve (DOR), characterized by levels of anti-Mullerian hormone < 1.1 ng/mL and antral follicle count < 5; and 132 egg donors screened by protocol that served as the controls. We found a higher prevalence of FMR1 premutation in the DOR group (seven patients (7.69%)) than in the control group (one patient (1.32%)), Fisher-exact test p-value = 0.012). We concluded that compared with the general population represented by young egg donors, the prevalence of FMR1 gene premutation is higher in young patients with a diminished ovarian reserve. Although these findings warrant further prospective validation in a larger cohort of patients within DOR, they suggest that, in clinical practice, FMR1 premutation should be determined in infertile young patients with DOR in order to give them adequate genetic counselling.

Female FMR1 (Fragile X mental retardation 1) premutation carriers are at risk for developing fragile X-associated primary ovarian insufficiency (FXPOI), a condition characterized by amenorrhea before age 40 years. Not all women with a FMR1 premutation suffer from primary ovarian insufficiency and nowadays there are no molecular or other biomarkers that can help predict the occurrence of FXPOI. Long non-coding RNAs (lncRNAs) comprise a group of regulatory transcripts which have versatile molecular functions, making them important regulators in all aspects of gene expression. In recent medical studies, lncRNAs have been described as potential diagnostic biomarkers in many diseases. The present study was designed to determine the expression profile of three lncRNAs derived from the FMR1 locus, FMR4, FMR5 and FMR6, in female FMR1 premutation carriers in order: (i) to determine a possible role in the pathogenesis of FXPOI and (ii) to investigate whether they could serve as a biomarker for the diagnosis of FXPOI. FMR4, FMR5 and FMR6 transcripts levels were evaluated in total RNA extracted from peripheral blood by digital droplet PCR and compared between FMR1 premutation carriers with FXPOI and without FXPOI. The diagnostic value of lncRNAs was evaluated by receiver operating characteristic (ROC) analysis. Results revealed a significant association between FXPOI and high expression levels of FMR4. No association was obtained for FMR5 or FMR6. ROC curve analysis revealed that FMR4 can distinguish FMR1 premutation carrier with FXPOI with a diagnostic power of 0.67. These findings suggest a potential role of FMR4 as a possible biomarker for FXPOI.

Endometriosis affects about 10% of reproductive-aged women, characterized by endometrial-like tissue outside the uterus, leading to chronic inflammation. The exact cause remains unknown, though genetic and epigenetic factors are increasingly recognized alongside traditional theories. The disease manifests in forms such as endometriomas, whether superficial or peritoneal, and deep infiltrating lesions, often causing chronic pain and infertility. Infertility affects nearly 50% of patients, requiring expensive treatments like in vitro fertilization. Oxidative stress plays a key role in endometriosis, with sirtuins, especially SIRT3, emerging as important regulators. SIRT3, located in mitochondria, helps manage oxidative stress and redox balance. Despite extensive research, no diagnostic biomarkers exist. This longitudinal study compares oxidative stress markers and SIRT3 levels in patients with different endometriosis types. While classic oxidative stress markers showed no significant differences, higher SIRT3 levels were observed in peripheral blood mononuclear cells of patients with deep endometriosis. Additionally, patients with prior surgeries had elevated SIRT3 levels, indicating a possible link between disease severity and SIRT3 expression. The findings suggest SIRT3 as a potential therapeutic target in endometriosis management.

Fertility preservation is increasingly offered to young women diagnosed with breast cancer. Although available clinical evidence suggests that controlled ovarian stimulation (COS) does not compromise oncological outcomes, its direct biological effect on tumor tissue remains poorly defined. In this single-center, longitudinal, prospective paired-biopsy study, 21 premenopausal women (age <40 years) with stage II-III breast cancer underwent paired diagnostic and post-COS tumor biopsies at the Breast Cancer Unit, Clínic BCCC (October 2020-September 2024). COS was carried out with recombinant follicle-stimulating hormone plus concurrent letrozole (5 mg/day) using a random-start protocol. After oocyte retrieval, a second core tumor biopsy was obtained within 24 to 48 hours. Immunohistochemistry [estrogen receptor (ER), progesterone receptor (PR), Ki-67, human epidermal growth factor receptor 2 (HER2,) tumor-infiltrating lymphocytes (TILs)] and PAM50 gene-expression profiling were carried out. Paired analyses evaluated changes in protein markers, gene-by-gene expression, intrinsic subtype, and risk of recurrence (ROR) score, applying a false discovery rate (FDR) <5% for significance. No significant differences were detected in ER (P = 0.962), PR (P = 0.562), Ki-67 (P = 0.768), or TILs (P = 0.172) after COS. Post-stimulation Ki-67 was not associated with stimulation duration (r = 0.047; P = 0.839), total gonadotropin dose (r = 0.026; P = 0.911), or peak estradiol levels (r = 0.121; P = 0.610). Transcriptomic analysis identified downregulation of 11/72 genes (15.3%), including proliferation-associated genes CDC6, CENPF, EXO1, and RRM2, although none met significance thresholds after FDR correction. PAM50 intrinsic subtype remained stable (luminal A 23.8%, luminal B 28.6%, HER2-enriched 19.0%, basal-like 23.8%), with only two borderline shifts between luminal A and luminal B. Five mild ROR variations were observed (four decreases and one increase), all small in magnitude on the continuous scale. COS with concurrent letrozole was not associated with short-term molecular changes in breast tumor tissue. These findings provide biological reassurance regarding the safety of COS for fertility preservation in young women with breast cancer.