Typically occurring between the ages of 45 and 55 years, menopause marks a significant natural reduction in ovarian estrogen production. This decrease in estrogen results in the cessation of menstrual periods, low serum estradiol levels, vasomotor symptoms (VMS) such as hot flashes and night sweats, and genitourinary syndrome of menopause (GSM) involving vulvovaginal atrophy, vaginal dryness, and dyspareunia (Martin & Barbieri, 2023). Other symptoms of perimenopause and menopause include difficulty sleeping, mood changes, depression, and joint pain, all significantly impacting quality of life. Menopause is inevitable. The treatment is controversial. Patients with severe symptoms have sought hormone replacement therapy for relief, but is it safe?
 

The Controversy

It's a polarizing issue, stemming in part from the landmark studies conducted by The Women’s Health Initiative (WHI). The WHI Hormone Therapy Trials were developed to test the effects of postmenopausal hormone therapy (HT) on a female’s risk for coronary heart disease (primary analysis), hip and other fractures, and breast cancer (secondary analysis). In 1993, individuals between the ages of 50 and 79 years at baseline were enrolled in a randomized controlled trial to receive either combined hormone therapy involving 0.625 mg of conjugated equine estrogen (CEE) with 2.5 mg of medroxyprogesterone acetate (MPA) daily or placebo. Females who had a hysterectomy at baseline were randomized to either estrogen alone (no progesterone) or placebo. A 2002 study safety review found that combined estrogen and progestin therapy was associated with an increased risk of breast cancer, some increased risk of cardiovascular disease, and more harm than benefit overall. The estrogen-alone trial was stopped in 2004 after data showed an increased risk of stroke and no benefit to coronary heart disease. A follow-up study of the WHI conducted by Chlebowski (2024) found CEE alone increased ovarian cancer incidence and ovarian cancer mortality, while CEE plus MPA did not. On the contrary, CEE plus MPA significantly reduced endometrial cancer incidence.
 
Following the publication of the WHI results, healthcare provider use of menopausal hormone therapy (MHT) dropped precipitously (Martin & Barbieri, 2023). However, further analysis of the data by age group has shown the increased risk for coronary heart disease applied primarily to females who initiated HR after age 60 or a decade after menopause. In addition, long-term follow-up found the incidence of total cancer mortality was not different between the HT and placebo groups. Furthermore, studies such as the Kronos Early Estrogen Prevention Study (KEEPS) and the Early Versus Late Intervention Trial with Estradiol (ELITE) both support the safety of hormone therapy when started early in menopause (Mehta, Kling & Manson, 2021).
 
The 2022 hormone therapy position statement from the North American Menopause Society states that “hormone therapy remains the most effective treatment for vasomotor symptoms and genitourinary syndrome of menopause and has been shown to prevent bone loss and fracture.” The advisory panel cautions that the treatment should be individualized and periodically reevaluated to weigh the benefits and risks of continued therapy. Their main recommendations include:

• For females younger than 60 years or who are within ten years of menopause onset and have no contraindications, the benefit-risk ratio is favorable for the treatment of VMS and the prevention of bone loss.
• From females who begin hormone therapy more than ten years from menopause onset or who are older than 60 years, the benefit-risk ratio is less favorable due to an increased risk of coronary heart disease, stroke, venous thromboembolism, and dementia.

 

Administration of MHT (Martin & Barbieri, 2023)

In general, menopausal VMS requires systemic estrogen, administered by pill, transdermal, or topical (gel, lotion, spray). GSM symptoms alone are treated with low-dose vaginal estrogen. All females with an intact uterus should be prescribed a progestin with their systemic estrogen, known as combined estrogen-progestin therapy (EPT), to prevent endometrial hyperplasia and potential uterine cancer. Females who have undergone a hysterectomy do not require progestin and may take estrogen-only therapy (ET). Dosing begins low and is titrated up to relieve symptoms. Once symptoms subside and the patient tolerates MHT, the medication regimen continues for three to five years before a taper is attempted. MHT is typically discontinued by the age of 60 when the risks outweigh the benefits. However, The Menopause Society and the American College of Obstetrics and Gynecology recommend that MHT be individualized and not stopped based only on patient age.
 
For individuals who cannot take estrogen, medications such as selective serotonin receptor inhibitors (SSRIs) (e.g., paroxetine) and other antidepressants such as venlafaxine and desvenlafaxine may alleviate hot flashes (Casper, 2023). Other non-hormonal strategies that may help reduce menopausal symptoms include stress management, relaxation, and yoga.
 
As always, an open conversation between provider and patient is essential to develop a personalized plan for relief during this transition phase. Check out Lippincott NursingCenter’s pocket card on Hormone Replacement Therapy for Menopause for more information on indications, contraindications, adverse effects, and administration tips.

References
Casper, R.F. (2023, October 24). Patient education: Non-estrogen treatments for menopausal symptoms (Beyond the Basics) [Online]. In UpToDate. Accessed September 2024 via the Web at www.updtodate.com  
 
Chlebowski, R. T., Aragaki, A. K., Pan, K., Haque, R., Rohan, T. E., Song, M., Wactawski-Wende, J., Lane, D. S., Harris, H. R., Strickler, H., Kauntiz, A. M., & Runowicz, C. D. (2024). Menopausal Hormone Therapy and Ovarian and Endometrial Cancers: Long-Term Follow-Up of the Women's Health Initiative Randomized Trials. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, JCO2301918. Advanced online publication. https://doi.org/10.1200/JCO.23.01918
 
Martin, K. A. & Barbieri, R. L. (2023, November 20). Treatment of menopausal symptoms with hormone therapy [Online]. In UpToDate. Accessed September 2024 via the Web at www.updtodate.com  
 
Mehta, J., Kling, J. M., & Manson, J. E. (2021). Risks, Benefits, and Treatment Modalities of Menopausal Hormone Therapy: Current Concepts. Frontiers in endocrinology, 12, 564781. https://doi.org/10.3389/fendo.2021.564781 
 
“The 2022 Hormone Therapy Position Statement of The North American Menopause Society” Advisory Panel (2022). The 2022 hormone therapy position statement of The North American Menopause Society. Menopause, 29(7), 767–794. https://doi.org/10.1097/GME.0000000000002028
 
The Women’s Health Initiative. (n.d.) Hormone Therapy Trials (HT) [Online]. In Women’s Health Initiative Intranet Site. Accessed September 2024 via the Web at https://sp.whi.org/about/SitePages/HT.aspx

 

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