Summary
Hysterectomy, oophorectomy, and tubal ligation are common surgical procedures; however, reports linking cardiovascular disease (CVD) risk after these surgeries have basically focused on oophorectomy with limited research on hysterectomy or tubal ligation. Recently, Farland et al. [1] reported on data of participants of the Nurses’ Health Study II (n = 116,429) who were followed from 1989 to 2017. Self-reported gynecologic surgery was categorized as follows: no surgery, hysterectomy alone, hysterectomy with unilateral oophorectomy, and hysterectomy with bilateral oophorectomy; the authors separately investigated tubal ligation alone. The primary outcome was CVD based on medical-record confirmed fatal and non-fatal myocardial infarction, fatal coronary heart disease, or fatal and nonfatal stroke. Secondary outcome expanded CVD to include coronary revascularization (coronary artery bypass graft surgery, angioplasty, stent placement). The authors used Cox proportional hazard models to calculate hazard ratios (HR) and 95% confidence intervals (CIs), a priori adjusted for confounding factors. Differences by age at surgery (≤50, >50) and menopausal hormone therapy usage was analyzed. Average age of participants at baseline was 34 years. During 2,899,787 person-years, the investigators observed 1,864 CVD cases. Hysterectomy in combination with any oophorectomy (unilateral or bilateral) was associated with a greater risk of CVD in multivariable-adjusted models. Hysterectomy alone, hysterectomy with oophorectomy (unilateral and bilateral), and tubal ligation were also associated with an increased risk of combined CVD and coronary revascularization (HR 1.19; HR 1.29; HR 1.22, and HR 1.16, respectively). The association between hysterectomy/oophorectomy and the risk of CVD and coronary revascularization varied by age when surgery was performed, with the strongest association observed if surgery was before age 50. The authors finally conclude that hysterectomy, alone or in combination with oophorectomy (any type), as well as tubal ligation, seems to be associated with a higher risk of CVD and coronary revascularization; indicating that these findings extend previous research finding that oophorectomy is associated with CVD.
Commentary
The Nurses’ Health study (NHS) was, and still is, an iconic name in the temple of menopause medicine. It started to collect important clinical data in 1976, and produced results based on long-term follow-up of a large cohort of postmenopausal nurses from the US who were interviewed periodically. This study was observational, but the high number of participants, all providing reliable information being medical aspects, allowed to obtain presumably better perspectives on menopause-related physical, mental, and emotional alterations. It also served as a fantastic source of data on the consequences of menopausal hormone therapy (MHT). While the official indications for MHT are menopause symptoms and osteoporosis, the NHS also addressed other end points, such as cardiovascular health. The NHS demonstrated a 46% risk reduction in major coronary events in current hormone users [2]. This clear message, strengthening the results of previous trials, was translated in the last years of the previous century into recommendations by medical societies and organizations that were in favor of taking MHT as part of preventive medicine throughout the entire postmenopausal period of life [3]. These recommendations were even stronger in the case of early menopause, either natural or after oophorectomy. But in 2002 a new player entered, the WHI study, a randomized, double-blind trial [4]. The preliminary data were surprising and alarming, and the conclusions this time were that MHT is dangerous and perhaps better to be avoided. Later-on it became clear that the WHI results were partially misinterpreted, and the advantages of MHT as a preventive therapy were put back on the table, although with a more cautious and restrictive phrasing [5]. Nevertheless, the hype over MHT was in fact over, and the NHS was almost forgotten.
The new release of data from the NHS is a sort of a revival [1]. It demonstrates again the huge number of participants (116,400) and the very long follow-up (1989-2017) which characterize this unique trial. The focus of the current publication was the after-effect of hysterectomy with or without oophorectomy on the future risk of cardiovascular events. As expected, the surgical procedures increased the risk, pointing out at the importance of considering MHT post hysterectomy as a preventive measure. Indeed, a large study from Australia demonstrated such protective effect [6], and later-on, an even larger study based on the British Bio Bank data found that women who underwent hysterectomy before age 40 had a higher risk of cardiovascular mortality when compared to those with natural menopause at the age of 50-52 [7]. Furthermore, MHT users had a lower risk of cardiovascular mortality following hysterectomy at ≥50 years.
The recent review of Cho et al. [8] entitled “Rethinking Menopausal Hormone Therapy” signifies the renewed interest in implementing the vast data that has accumulated throughout many decades into clear guidelines that consider the benefits and risks of MHT in various clinical situations, taking into account the age factor and the individual medical profile. The bottom-line message is clear: don’t hesitate to use MHT when appropriate.
Amos Pines, MD
Sackler Faculty of Medicine, Tel-Aviv University, Israel
References
- Farland LV, Rice MS, Degnan WJ 3rd, Rexrode KM, Manson JE, Rimm EB, Rich-Edwards J, Stewart EA, Cohen Rassier SL, Robinson WR, Missmer SA. Hysterectomy With and Without Oophorectomy, Tubal Ligation, and Risk of Cardiovascular Disease in the Nurses’ Health Study II. J Womens Health (Larchmt). 2023 May 8. doi: 10.1089/jwh.2022.0207.
https://pubmed.ncbi.nlm.nih.gov/37155739/ - Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133(12):933-941.
https://pubmed.ncbi.nlm.nih.gov/11119394/ - Guidelines for counseling postmenopausal women about preventive hormone therapy. American College of Physicians. Ann Intern Med. 1992;117(12):1038-1041.
https://pubmed.ncbi.nlm.nih.gov/1443972/ - Rossouw JE, Anderson GL, Prentice RL, et al.; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
https://pubmed.ncbi.nlm.nih.gov/12117397/ - Lobo RA, Pickar JH, Stevenson JC, Mack WJ, Hodis HN. Back to the future: Hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis. 2016;254:282-290.
https://pubmed.ncbi.nlm.nih.gov/27745704/ - Chen L, Mishra GD, Dobson AJ, Wilson LF, Jones MA. Protective effect of hormone therapy among women with hysterectomy/oophorectomy. Hum Reprod. 2017;32(4):885-892.
https://pubmed.ncbi.nlm.nih.gov/28184451/ - Xu Z, Chung HF, Dobson AJ, Wilson LF, Hickey M, Mishra GD. Menopause, hysterectomy, menopausal hormone therapy and cause-specific mortality: cohort study of UK Biobank participants. Hum Reprod. 2022;37(9):2175-2185.
https://pubmed.ncbi.nlm.nih.gov/35690930/ - Cho L, Kaunitz AM, Faubion SS, et al.; ACC CVD in Women Committee. Rethinking Menopausal Hormone Therapy: For Whom, What, When, and How Long? Circulation. 2023;147(7):597-610.
https://pubmed.ncbi.nlm.nih.gov/36780393/
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