Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| Name | Class |
|---|---|
| Dutch Cancer Society | OTHER |
| Erasmus Medical Center | OTHER |
| Radboud University Medical Center | OTHER |
Not provided
Not provided
Not provided
Not provided
Risk-Reducing Salpingo-Oophorectomy (RRSO) at the age of 35 to 45 years is recommended for women with a high genetic risk for ovarian cancer. While this procedure decreases the risk of ovarian cancer by 80-96%, it also results in an immediate menopause. Current research on potential adverse effects of premenopausal risk-reducing salpingo-oophorectomy, such as increased risk of cardiovascular disease, compromised bone health, cognitive dysfunction and reduced quality of life, is limited, mostly due to short follow up.
The investigators will conduct a multicenter cross-sectional study nested in a cohort of BRCA mutation carriers from 8 Dutch centers for hereditary cancer. Eligible participants are women who underwent RRSO before the age of 45. The participants will be frequency-matched on current age with women above the age of 55 without RRSO or with RRSO after the age of 55. Participants will complete an online questionnaire containing various questions about lifestyle, medical history, risk factors for cardiovascular disease, bone health, cognition and quality of life. Participants will be asked to visit one of the participating hospitals for a blood test, a cardiovascular assessment and a DEXA scan for determining bone mineral density. Afterwards participants will be requested to perform the online Amsterdam Cognition Scale.
Rationale: Women at high genetic risk of ovarian cancer are advised to undergo risk-reducing salpingo-oophorectomy (RRSO) at ages 35-45 years. Currently, in the Netherlands ~500 women/ year opt for RRSO, which minimizes ovarian cancer risk and may decrease breast cancer (BC) risk as well, due to reduced gonadal hormone levels. Besides favorable effects of RRSO on ovarian cancer and, potentially, BC risk, RRSO induces immediate menopause, which may have unfavorable long-term health consequences. Early menopause has been associated with increased risks of cardiovascular disease (CVD), lower bone mineral density (BMD), cognitive impairment, and decreased quality of life. Current evidence regarding these health effects is mainly based on women with a natural early menopause, and it is unknown whether these results hold for women undergoing RRSO at early premenopausal ages.
Objective: The investigators will investigate long-term health effects of premenopausal RRSO on (subclinical) cardiovascular status, BMD, cognition and quality of life.
Study design: the investigators will assess long-term health effects of RRSO in a cross-sectional study, among 500 women who underwent premenopausal RRSO compared to 250 women of the same age without RRSO (or with RRSO after age 55). Eligible women will be invited to participate in a screening program assessing cardiovascular status, bone mineral density, cognitive functioning and quality of life.
Study population: Women are eligible for the premenopausal RRSO group if:
Primary study outcome: To study long-term effects of premenopausal RRSO on:
Secondary study outcome: To study long-term effects of premenopausal RRSO on:
Furthermore, the investigators will examine the influence of age at RRSO, time since RRSO, hormone replacement therapy (HRT), carrier ship of a BRCA1 or BRCA2 mutation and BC history on the outcome.
The obtained knowledge will assist physicians in counselling women with high ovarian cancer risk and help them to make well-informed decisions.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Early-RRSO |
|
| |
| Late-/non-RRSO group |
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CAC-score | Diagnostic Test | Testing for possible unfavourable health effects of early surgical menopause |
|
| Measure | Description | Time Frame |
|---|---|---|
| What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by coronary artery calcium scoring in agatston units | Due to the lack of estrogen we expect more atherosclerotic diseases. | 4 years |
| What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by pulse wave velocity in meters/second | Due to the lack of estrogen we expect more atherosclerotic diseases. | 4 years |
| What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by high-sensitive CRP in miligram/liter | Due to the lack of estrogen we expect more atherosclerotic diseases. | 4 years |
| What is the prevalence of atherosclerotic diseases in women with RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by high-sensitive cardial Troponine T in microgram/liter | Due to the lack of estrogen we expect more atherosclerotic diseases. | 4 years |
| What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by dual-energy X-ray absoptiometry in T- and Z-scores | Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts, The DXA-scan is corrected for age, with lower values representing a worse outcome | 4 years |
| Measure | Description | Time Frame |
|---|---|---|
| Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the SF-36 | How do women with a premenopausal RRSO experience their life. The SF-36 questionnaire ranges from 36 to 149, with higher values representing a worse outcome | 4 years |
| Measure | Description | Time Frame |
|---|---|---|
| What is the effect of premenopausal RRSO on risk of (contralateral) breast cancer and breast cancer-specific survival as assessed in a prospective setting within a well established cohort. | we will study the effect of RRSO on BC, contralateral breast cancer and ovarian cancer risk and prognosis after BC/ovarian cancer | 4 years |
Inclusion Criteria:
Exclusion Criteria:
Not provided
In order to be eligible the ovaries have been removed.
Not provided
Women are eligible if they underwent RRSO before age 45 and the RRSO was done 10 or more years ago (early RRSO group) and women are eligible as control group if they did not undergo RRSO, or underwent RRSO after age 55 while reaching natural menopause after the age of 50 years. The comparison group will be frequency-matched with the RRSO group on categories of calendar year of birth, and breast cancer history. For each patient with breast cancer, the investigators will perform individual matching accounting for age at breast cancer diagnosis and carrier status. For the early RRSO group the investigators select women who underwent RRSO at least 10 years ago and are currently older than 55 years because the investigators expect subclinical atherosclerosis not to manifest earlier.
Not provided
| Name | Affiliation | Role |
|---|---|---|
| Flora E van Leeuwen, Phd | NKI-AvL | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Netherlands Cancer Institute - Antoni van Leeuwenhoek | Amsterdam | 1066CX | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 41724092 | Derived | Beekman MJ, Terra L, Bleiker EMA, Heemskerk-Gerritsen BAM, van Doorn HC, de Hullu JA, van Dorst EBL, Mom CH, van Beurden M, Slangen BFM, Mourits MJE, Roeters van Lennep JE, Gaarenstroom KN, van Engelen K, van der Kolk LE, Collee JM, Wevers MR, Ausems MGEM, Berger LPV, Gomez Garcia EB, van Asperen CJ, Maas AHEM, van Leeuwen FE, Hooning MJ. Long-term outcomes of surgical menopause after risk-reducing salpingo-oophorectomy: results of the HARMOny study. Maturitas. 2026 Apr;207:108882. doi: 10.1016/j.maturitas.2026.108882. Epub 2026 Feb 14. | |
| 41045325 |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D002318 | Cardiovascular Diseases |
| D060825 | Cognitive Dysfunction |
| D016649 | Primary Ovarian Insufficiency |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D010049 | Ovarian Diseases |
Not provided
Not provided
| ID | Term |
|---|---|
| D001800 | Blood Specimen Collection |
| D015502 | Absorptiometry, Photon |
| ID | Term |
|---|---|
| D013048 | Specimen Handling |
| D019411 | Clinical Laboratory Techniques |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
Not provided
Not provided
Not provided
Not provided
Not provided
Optional for studyparticipants is to collect and store DNA in a blood Biobank.
| What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genetic risk of ovarian cancer with a natural menopause as assessed by instant vertebral assessment |
Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts |
| 4 years |
| What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genenetic risk of ovarian cancer with a natural menopause as assessed by beta-CTX in picogram/mililiter | Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts | 4 years |
| What is the prevalence of osteoporosis in women with a premenopausal RRSO compared to women with a high genenetic risk of ovarian cancer with a natural menopause as assessed by P1NP in miligram/liter | Loss of estrogen can result in more activity of osteoclasts and less activity of osteoblasts | 4 years |
| What is the prevalence of cognitive decline in women with RRSO compared to women with a natural menopause as assessed by the Amsterdam Cognition Scan | There are some studies suggesting that an early menopause has an influence on cognition | 4 years |
| Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the EORTC-QLQ BR23. | How do women with a premenopausal RRSO experience their life. We measure the body image using the EORTC QLQ BR23, with ranges from 2 to 8, with higher values representing a worse outcome | 4 years |
| Quality of life after a premenopausal RRSO compared to women from families with a high genetic risk of ovarian cancer with a natural menopause as assessed by validated questionnaires such as the FACT-ES | How do women with a premenopausal RRSO experience their life. The FACT-ES questionnaire ranges from 0 to 76, with higher values representing a worse outcome | 4 years |
| What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the SAQ | Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The SAQ questionnaire scale has questions with different weights as described in Thirlaway et al. 1996 | 4 years |
| What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the UDI-6 | Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The UDI-6 questionnaire scale has a range from 0 to 18, with higher values representing a worse outcome | 4 years |
| What is the prevalence of urogenital problems in women with a RRSO compared to women with a natural menopause as assessed by validated questionnaires such as the IIQ-7 | Have women with a premenopausal RRSO more urogenital complaints due to longer duration of estrogen deficiency. The IIQ-7 questionnaire scale has a range from 0 to 24, with higher values representing a worse outcome | 4 years |
| What is the prevalence of cardiovascular risk factors in women with RRSO compared to women with a high genetic risk of ovarian cancer as assessed by a questionnaire. | Are some risk factors for cardiovascular disease more prevalent in women with a premenopausal RRSO | 4 years |
| Derived |
| Beekman MJ, Terra L, Stuursma A, Heemskerk-Gerritsen BAM, van Lennep JER, van Beurden M, van Doorn LC, de Hullu JA, van Dorst EBL, Mom CH, Slangen BFM, Mitea C, Slart RHJA, Snoeren MM, Stokkel MP, Verberne HJ, de Keizer B, Korse CM, Gaarenstroom KN, van Engelen K, van der Kolk LE, Collee JM, Wevers MR, Ausems MGEM, Berger LPV, Garcia EBG, van Asperen CJ, Hooning MJ, Maas AHEM, Mourits MJE, van Leeuwen FE, Zillikens MC. Long-term effects of premenopausal risk-reducing salpingo-oophorectomy on bone mineral density. Osteoporos Int. 2025 Nov;36(11):2307-2317. doi: 10.1007/s00198-025-07679-8. Epub 2025 Oct 4. |
| 40262388 | Derived | Beekman MJ, Terra L, Roeters van Lennep JE, Heemskerk-Gerritsen BAM, van Beurden M, van Doorn HC, de Hullu JA, van Dorst EBL, Mom CH, Slangen BFM, Mourits MJE, Gaarenstroom KN, van Engelen K, van der Kolk LE, Collee JM, Wevers MR, Ausems MGEM, Berger LPV, Gomez Garcia EB, van Asperen CJ, Hooning MJ, van Leeuwen FE, Maas AHEM. No increased arterial stiffness after premenopausal risk-reducing salpingo-oophorectomy (RRSO). Maturitas. 2025 Jun;197:108265. doi: 10.1016/j.maturitas.2025.108265. Epub 2025 Apr 11. |
| 36403862 | Derived | Terra L, Beekman MJ, Engelhardt EG, Heemskerk-Gerritsen BAM, van Beurden M, Roeters van Lennep JE, van Doorn HC, de Hullu JA, Van Dorst EBL, Mom CH, Slangen BFM, Gaarenstroom KN, van der Kolk LE, Collee JM, Wevers MR, Ausems MGEM, Van Engelen K, van de Beek I, Berger LPV, van Asperen CJ, Gomez Garcia EB, Maas AHEM, Hooning MJ, Aaronson NK, Mourits MJE, van Leeuwen FE. Sexual functioning more than 15 years after premenopausal risk-reducing salpingo-oophorectomy. Am J Obstet Gynecol. 2023 Apr;228(4):440.e1-440.e20. doi: 10.1016/j.ajog.2022.11.1289. Epub 2022 Nov 17. |
| 33480862 | Derived | Terra L, Hooning MJ, Heemskerk-Gerritsen BAM, van Beurden M, Roeters van Lennep JE, van Doorn HC, de Hullu JA, Mom C, van Dorst EBL, Mourits MJE, Slangen BFM, Gaarenstroom KN, Zillikens MC, Leiner T, van der Kolk L, Collee M, Wevers M, Ausems MGEM, van Engelen K, Berger LP, van Asperen CJ, Gomez-Garcia EB, van de Beek I, Rookus MA, Hauptmann M, Bleiker EM, Schagen SB, Aaronson NK, Maas AHEM, van Leeuwen FE. Long-Term Morbidity and Health After Early Menopause Due to Oophorectomy in Women at Increased Risk of Ovarian Cancer: Protocol for a Nationwide Cross-Sectional Study With Prospective Follow-Up (HARMOny Study). JMIR Res Protoc. 2021 Jan 22;10(1):e24414. doi: 10.2196/24414. |
| D000291 |
| Adnexal Diseases |
| D005831 | Genital Diseases, Female |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D000091662 | Genital Diseases |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D011677 | Punctures |
| D013514 | Surgical Procedures, Operative |
| D008919 | Investigative Techniques |
| D011859 | Radiography |
| D003952 | Diagnostic Imaging |
| D003720 | Densitometry |
| D010783 | Photometry |
| D002623 | Chemistry Techniques, Analytical |