The goal of this clinical trial is to find out whether removing the fallopian tubes at the time of hysterectomy leads to an earlier menopause. The study includes women under 55 years of age who previously underwent hysterectomy as participants in the HOPPSA trial, where they were randomly assigned to either removal of the fallopian tubes or no removal.

The main question is:

• Does removing the fallopian tubes at the time of hysterectomy lead to an earlier menopause? Researchers will compare women who had their fallopian tubes removed during hysterectomy with women who had hysterectomy alone to see whether menopause occurs earlier after tube removal. Age at menopause will be estimated by measuring follicle-stimulating hormone (FSH) in small blood samples collected on a paper card.

Participants will:

• Collect 4-5 drops of blood using a finger prick
• Place the drops on a paper card and mail it to the researchers
• Complete an online questionnaire These steps will be done twice, one year apart.

Opportunistic salpingectomy, defined as removal of the fallopian tubes during gynaecologic surgery performed for another indication, has been proposed as a strategy to reduce the risk of ovarian cancer. This approach is supported by accumulating evidence that many high-grade serous ovarian cancers originate in the distal fallopian tube. Although short-term surgical safety has been evaluated in randomized and observational studies, uncertainty remains regarding possible long-term effects on ovarian function.

The HOPPSA randomized trial was initiated to evaluate outcomes after hysterectomy with or without salpingectomy in women undergoing surgery for benign conditions. Previous analyses from this cohort have focused on perioperative safety and patient-reported outcomes. However, the effect of salpingectomy on the timing of menopause has not yet been determined. This question is clinically important because epidemiologic evidence shows that earlier menopause is associated with increased risks of cardiovascular mortality and all-cause mortality, with approximately a 2% relative increase in risk per year earlier menopause. Earlier menopause has also been associated with increased risks of osteoporosis, neurocognitive symptoms, sexual dysfunction, and reduced quality of life. Even modest shifts in menopausal timing could therefore have clinically meaningful long-term health implications.

The relevance of this knowledge gap is underscored by the relatively low lifetime risk of epithelial ovarian cancer in the general population, estimated at approximately 1.3-2%. Modelling studies suggest that between 96 and 148 opportunistic salpingectomy procedures may be required to prevent one ovarian cancer case. Consequently, even small changes in menopausal timing, if present, could influence the overall balance of benefits and risks associated with preventive salpingectomy.

Assessment of menopausal timing after hysterectomy presents methodological challenges because menstrual history cannot be used. Biochemical markers are therefore required. Follicle-stimulating hormone (FSH) is a well-established indicator of ovarian aging and menopausal transition, reflecting declining ovarian follicular activity. Measurement of FSH in blood samples enables estimation of menopausal timing independent of menstrual data.

Capillary blood sampling using self-collected dried blood spots enables biologic measurements in large populations without requiring clinic visits. This approach has been validated for hormone analyses and facilitates long-term follow-up with reduced logistical constraints, thereby supporting high participation and minimizing attrition in longitudinal studies, an important consideration for unbiased estimation of long-term outcomes.

The MISSION-O study uses extended follow-up of participants previously enrolled in the HOPPSA randomized trial to determine whether salpingectomy influences age at menopause. By leveraging a randomized surgical cohort with long-term biologic assessment, this study aims to generate robust evidence regarding the endocrine safety of opportunistic salpingectomy. The findings are expected to inform clinical counselling, individualized risk-benefit assessment, and future clinical guidelines regarding preventive salpingectomy at the time of gynaecologic surgery.

Inclusion Criteria:

• Having had hysterectomy for a benign indication
• Less than 55 years at surgery
• Was included in the ITT population of the HOPPSA register-based randomised controlled trial (R-RCT) of opportunistic salpingectomy
• Informed consent

Exclusion Criteria:

• Ongoing systemic hormonal treatment using sex steroids
• Bilateral oophorectomy
• Cancer treatment affecting ovarian function
• Other treatments with major effects on ovarian function

Under Swedish law, individual-level health data containing potentially identifiable and sensitive patient information cannot be shared publicly. Metadata will be published in a research data repository. Researchers may request access to the data; such requests will be subject to a formal secrecy assessment in accordance with the Swedish Act on Public Access to Information and Secrecy (2009:400) and applicable ethical approvals.

Masking is attempted to participants, but cannot be guaranteed due to the legal framework. Follicle-stimulating hormone will be measured with laboratory personnel unaware of participant allocation.