Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage.

Effects of virtual reality on pain during intrauterine device insertions: A randomized controlled trial.

OBJECTIVES: The trial aimed to compare the pain perceived by women during intrauterine device (IUD) insertion, with or without virtual reality (VR) therapy. Furthermore, anxiety during the insertions, pain after the insertions, and satisfaction with the insertions were compared. METHODS: The trial was designed as a prospective, bi-centric, randomized, open-label interventional trial. All adult women that chose an IUD during a contraceptive consultation, and who provided informed consent were eligible. Women under legal guardianship, not affiliated to a national social security system, and with pre-existing dizziness, severe facial wounds, or epilepsy were not eligible. Eligible women were randomly allocated either standard care without VR therapy (Control group) or with VR therapy (Experimental group). Pain, anxiety, and satisfaction were measured using a 10-cm numerical scale. RESULTS: Between September 2020 and April 2022, 100 women were randomized: 50 to each group. The mean pain scores during IUD insertion were 5.4 cm in the Control group versus 5.1 cm in the Experimental group (p = 0.54). Mean anxiety during insertion were 4.8 cm in the Control group versus 4.2 cm in the Experimental group (p = 0.13). While mean pain perceived after insertions were 2.4 cm in the Control Group and 2.4 cm in the Experimental group (p = 0.98). Mean satisfaction with the insertions was 9.6 cm in both groups (p = 0.87). Anxiety before IUD insertion, as well as anticipated pain, were significantly correlated with pain perceived during insertions. CONCLUSIONS: VR therapy performed during the procedure did not alleviate perceived pain in women undergoing IUD insertions.

Ovarian response to stimulation for fertility preservation in women with hematologic cancer.

PURPOSE: To compare the ovarian response to controlled ovarian hyperstimulation (COH) in patients with hematologic malignancies treated for fertility preservation (FP) and healthy subjects (oocyte donors (OD)). PATIENTS AND METHODS: Retrospective cohort study comparing 41 women (18-37 years) who underwent COH for oocyte vitrification prior to gonadotoxic treatment for hematologic cancer (FP group) from January 2014 to February 2019 and with 117 women undergoing COH as part of an OD protocol (OD group) during the same period. The number of frozen mature oocytes, number of oocytes retrieved, total dose of rFSH, maximal estradiol levels, percentage of maturity, number of dominant follicles >14 mm, days of stimulation were evaluated. Results were adjusted for age, body mass index (BMI), anti-Mullerian hormone (AMH) and rFSH starting dose. RESULTS: Patients in the FP group were younger and had a lower BMI than those in the OD group. rFSH starting dose was higher in the FP group (median 225UI (125;450) vs 150UI (87.5;337.5), p < 0.0001). After adjusting for age, BMI and starting rFSH dose according to ANCOVA, more frozen mature oocytes (median 10 (0;45) vs 8 (0;22] p = 0.0055) and retrieved oocytes (median 12 (0;49) vs 11 (0;29) p = 0.0468) were found in the FP group. Other outcome measures did not differ between the groups. CONCLUSION: Ovarian response after COH in women with a hematologic cancer is similar to that in the general population. A higher number of mature oocytes were collected in the FP group after strong COH.