Comment on “Hormone Replacement Therapy in Gynecologic Cancer: Oncologic Safety and Alternative Therapies”

The estimated global incidence of gynecologic cancers of any type is >1.4 million as of 2022. Postmenopausal women are at the greatest risk, but about a quarter of malignancies occur in premenopausal women. Treatment of malignancy usually requires surgery, pelvic radiotherapy, chemotherapy, and/or anti-endocrine therapy, which can induce premature ovarian failure or iatrogenic menopause. Often, women who enter menopause due to cancer treatment experience more intense symptoms than those who enter menopause naturally, and these effects are long-term. Hormone replacement therapy (HRT) is an effective treatment for menopausal symptoms and for the prevention of risks associated with early menopause due to lower estrogen levels for prolonged periods. An obstacle to this treatment, however, is that most gynecologic cancers are hormone dependent, and the right treatment must be selected to balance the benefit of treatment with the risk of cancer recurrence. This article is a literature review designed to assess the oncologic safety of hormone replacement therapy for each type of gynecologic cancer, with an additional aim of reviewing hormonal and nonhormonal treatment options for patients where hormone replacement therapy is contraindicated. Literature search was performed using PubMed, MEDLINE, and Embase. Inclusion criteria for studies were all types of meta-analyses, prospective, retrospective, and systematic reviews, and Cochrane revisions. Exclusion criteria were gray literature, case reports, letters, and comments. Topics covered included ovarian preservation, hormone replacement therapy methods, including vaginal estrogen, vaginal dehydroepiandrosterone, tibolone, testosterone, and ospemifene, and the oncologic safety of hormone replacement therapy in endometrial, uterine, ovarian, cervical, vulvar, and vaginal cancers. Each type of hormone replacement therapy has different targets and benefits; vaginal treatments often target genitourinary symptoms of menopause in a local way, and do not systemically elevate hormone levels in the way oral medications do. Both vaginal estrogen and vaginal dehydroepiandrosterone may be suitable for selected candidates where systemic hormone therapy is contraindicated. Tibolone is generally avoided in hormone-sensitive cancer survivors, though it is effective for the treatment of menopausal symptoms. Testosterone has not yet been fully investigated in women, and there is very little safety data regarding its use in gynecologic cancer survivors. Ospemifene is another alternative to vaginal estrogen, as it can improve symptoms without systemic effects of estrogen. So far, research has not shown an increased risk of cancer recurrence with this medication. Evidence for hormone replacement therapy in endometrial cancer is quite limited, with 1 essentially unfinished randomized trial and 5 observational studies that all focused on early-stage cancer. The randomized trial did not show significant differences in cancer recurrence, but also did not assess overall survival or disease-free survival, nor did it specify the type and dose of hormone replacement therapy. Results of observational studies have shown consistently that the risk of recurrence, rates of disease-free survival, and rates of overall survival are not significantly different in patients using hormone replacement therapy. Though this evidence is encouraging, it is important to note selection bias for younger and early-stage patients, meaning that hormone replacement therapy is not recommended for high-risk or advanced-stage cancer. There are no studies that evaluate the safety of hormone replacement therapy in uterine cancers, so recommendations rely on hormone receptor status and tumor sensitivity. This is also true for vulvar and vaginal cancers, though most are not hormone sensitive; there is no contraindication to hormone replacement therapy theoretically, but caution should be exercised due to the lack of evidence. Studies on ovarian cancer show that hormone replacement therapy is likely safe and can possibly improve survival, particularly for high-grade serous carcinomas. Patients who should not use it include hormone-sensitive subtypes. Hormone replacement therapy has not been shown to increase recurrence or mortality in cervical cancer patients, and it has been shown to improve survival and sexual function. Current international guidelines recommend offering hormone replacement therapy to individuals with cervical cancer, though guidelines are often hesitant about other types of gynecologic cancer. Other factors to consider when weighing hormone replacement therapy as an option for patients include the timing of initiation, consistent follow-up, regular exams, and careful monitoring for cancer recurrence, depending on the type of cancer. Nonhormonal treatments are also available for patients where hormone replacement therapy is contraindicated or for patients who do not respond well to hormone therapy, though most of these treatment options have not been assessed for safety in gynecologic cancer survivors. Overall, hormone replacement therapy is considered safe and effective for most gynecologic cancer survivors. (Summarized from Luzarraga Aznar A, Elyashiv O, Dababou S, et al. Hormone replacement therapy in gynecologic cancer: oncologic safety and alternative therapies. Int J Gynecol Cancer. 2026;36(2):102809. doi: 10.1016/j.ijgc.2025.102809).