Continuing Education Activity

Hormone replacement therapy (HRT) replenishes women with ovarian hormones lost during the menopausal transition to alleviate associated symptoms. Traditional HRT typically includes estrogen and progesterone, mimicking hormones produced by the ovaries. Various estrogen replacement methods, including naturally occurring estradiol and estriol, as well as conjugated equine estrogen (CEE), are prevalent in the United States. Women with an intact uterus require progesterone supplementation to protect the endometrium from cancer. HRT is United States Food and Drug Administration-approved for treating moderate to severe vasomotor symptoms of menopause and preventing osteoporosis. Available estrogen therapies include ethinyl estradiol, CEE, synthetic conjugated estrogens, and micronized 17β-estradiol. Progesterone and progestins protect the uterus from endometrial hyperplasia or malignancy. HRT can be administered orally or transdermally, with each route having distinct benefits and risks.

Participants in this educational activity gain enhanced competence in understanding the indications, risk-benefit ratio, and management of HRT. The course covers the various types of estrogen and progesterone therapies, their administration methods, and the importance of individualized treatment plans. Emphasizing a collaborative approach highlights how working with an interprofessional team, including gynecologists, endocrinologists, and primary care physicians, enhances patient outcomes. This collaboration ensures comprehensive care, informed decision-making, and personalized management strategies, ultimately improving the quality of life for women undergoing HRT.

Objectives:

• Identify the symptoms of menopause that are appropriate for treatment with hormone replacement therapy.

• Differentiate between the various types of estrogen and progesterone therapies available for hormone replacement therapy.

• Apply current clinical guidelines and best practices in managing menopausal symptoms using hormone replacement therapy.

• Apply interprofessional team strategies to improve commmunication and care coordination and outcomes in patients using hormonal replacement therapy.

Indications

Hormone replacement therapy (HRT) is a treatment approach used to manage vasomotor and vaginal symptoms in women during the menopausal transition. To relieve vasomotor symptoms associated with menopause, conventional HRT includes an estrogen and a progesterone component to mimic hormones created by the human ovary. See our companion StatPearls reference article on "Male Hypogonadism" for male hormone replacement therapy.[1]

Hormonal therapy is Food and Drug Administration (FDA) approved for first-line treatment of moderate to severe vasomotor symptoms due to menopause as well as for prevention, not treatment, of osteoporosis. Available estrogen therapies include ethinyl estradiol, conjugated equine estrogen (CEE), synthetic conjugated estrogens, and micronized 17β-estradiol. Conjugated equine estrogen is a mixture of conjugated estrogens from pregnant mares' urine. Synthetic conjugated estrogens are a blend of substances, including estrone sulfate, estradiol sulfate, and equilin sulfate. Micronized 17β-estradiol is identical to the estradiol produced from the ovaries. Ethinyl estradiol is a synthetic estrogen used primarily in contraceptive preparations.[2] The indications for hormonal therapy in menopause include:

• Treatment of moderate to severe vasomotor symptoms of menopause
• Treatment of genitourinary syndrome of menopause (ie, vaginal and vulvar atrophy)
• Osteoporosis prevention

Progestogen refers to the hormones progesterone, made by the human ovary, and progesterone-like substances, also known as progestins. A woman with an intact uterus who desires HRT must have a progestogen in addition to estrogen therapy for endometrial protection from endometrial hyperplasia or malignancy, as estrogen therapy alone will cause the endometrial lining to grow unopposed. Progestogens prevent the lining from proliferating abnormally. However, if a woman has had a hysterectomy, progestin is unnecessary. Progesterone, though, is different as it can also provide symptom relief from sleep disturbance and mood instability, and increasing evidence supports that it offers tissue protection to the breast.[3][4][5] FDA-approved indications for progestogens include:

•  Amenorrhea (primary or secondary)
•  Assisted reproductive technology treatment
•  Endometrial hyperplasia
•  Dysfunctional uterine bleeding

Administration

Numerous estrogen and progestogen formulations are available for treating menopausal vasomotor symptoms. The various formulations of hormone replacement therapy have comparable efficacy for treating vasomotor symptoms. They may be administrated orally or transdermally through creams, sprays, patches, vaginal rings, or subdermal pellets. Available dosages vary based on the route and formulation. Furthermore, the dosage used should be individualized according to the lowest effective dose.[6] Each route of administration has unique benefits and risks.[2] 

Estrogen Formulations

Any estrogen administered orally increases activated protein-C resistance, increasing the risk of a blood clot. Oral estradiol also induces the hepatic formation of matrix metalloprotease 9, which decreases the formation and rupture of atherosclerotic plaque. Conversely, transdermal estrogen bypasses the hepatic metabolism that produces activated protein-C resistance, negating the risk of blood clotting.[2] 

Progestogen Formulations

Progestin administration is usually via the oral route, although a few are available in combination with estrogen in patch forms. Progesterone is available in an oral form that can also be used vaginally for non-FDA-approved uses.[2]

Compounded Formulations

Specialized pharmacies make compounded estrogen and progesterone creams, sublingual troches, and vaginal inserts, but these are not FDA-approved and are not included in this article. Compounded bioidentical hormone therapy is minimally regulated, may easily be under or overdosed, and lacks safety and efficacy data.[2]

Vulvovaginal Therapy

Estrogen is FDA-approved for the treatment of moderate to severe symptoms of vulvovaginal atrophy and dyspareunia, but local estrogen is preferred over systemic therapy for this treatment. FDA-approved therapies for dyspareunia due to menopause include local estrogen, vaginal dehydroepiandrosterone, and an oral selective estrogen receptor modulator called ospimiphene.[2]

Adverse Effects

Women's Health Initiative Trial

When studying the potential adverse events of HRT, the most referenced information in the United States comes from the Women's Health Initiative (WHI).[7][8][9] The WHI was a multifaceted trial, including 2 double-blind, placebo-controlled, randomized trials of postmenopausal hormone therapy.[10] The first arm included CEE at 0.625 mg and medroxyprogesterone acetate (MPA) at 2.5 mg daily. The second arm studied patients with prior hysterectomies and only treated with CEE 0.625 mg.

Hormone Replacement Therapy and the Breast

The CEE/MPA arm was discontinued earlier than expected due to an increased incidence of invasive breast cancer of 24% (hazard ratio [HR], 1.24). The CEE-only arm was not discontinued early; it was completed in 2004, and extended follow-up of patients has continued for 11.8 years. CEE use for 5 to 9 years is associated with a statistically significant reduction in breast cancer by 23% (HR, 0.77). Those in the CEE arm also had decreased mortality from breast cancer by 63% compared to those not on CEE, and 38% fewer died from all other causes after breast cancer was diagnosed. The conclusions are vastly different and unequal when examining evidence from European studies, which usually use estradiol derivatives rather than CEE and non-MPA progesterone or progestins. Transdermal estradiol alone increased the risk of breast cancer by 10%, but estradiol with progesterone decreased the risk by 10%.

Hormone Replacement Therapy and the Heart

In the WHI CEE/MPA arm, the overall incidence of coronary heart disease increased by 24% over 5 years of use, with the most substantial elevation in risk within the first year, with an increase of 81% (HR, 1.81).[11][12] This evidence requires cautious interpretation due to the following:

• The average age of the patients treated in this study was 62 years. In women who started therapy within 10 years of menopause, there was a risk reduction of coronary artery disease (CAD) of 11% (HR, 0.89), but this was not statistically significant.
• In those women who continued CEE/MPA for over 6 years, the risk of CAD dropped by 30% (HR, 0.70).

These risks do not apply to estradiol and progesterone-based treatments. Basic science studies show several mechanisms through which estradiol (not CEE) is cardioprotective. These include stabilizing atherosclerotic plaques, reducing carotid intima-media thickness, and decreasing coronary artery calcium scores. Numerous subsequent studies in Europe and the United States show that cardiovascular disease and death are prominently reduced when HRT commences within the first 4 years of the menopause transition. The "timing hypothesis" refers to the theory that when starting HRT closer to the menopause transition, a cardiovascular benefit is seen compared with later initiation.

Hormone Replacement Therapy and Risk of Stroke

Stroke incidence increased in both arms of the WHI trial by 31% in the CEE/MPA arm and 39% in the CEE arm. Studies using oral estradiol are conflicted, showing a similar stroke risk, but the incidence of fatal stroke is unchanged.[13]

Hormone Replacement Therapy and the Risk of Venous Thromboembolism

Venous thromboembolism, comprised of deep venous thrombosis and pulmonary embolism, was increased by 2-fold (HR, 2.06) in the WHI CEE/MPA arm. Numerous European studies have evidenced that transdermal estradiol does not confer the same thromboembolic risk. The ESTHER study from France showed an overall risk of 0.9 for a blood clot, which is a decreased risk.[14] Subsequent studies looking at other transdermal estradiol doses and routes confirm these findings, with at least a null effect for blood clotting risk.

Contraindications

Contraindications for oral or transdermal estrogen-based therapies include:

• Known, suspected, or history of breast cancer
• Known or suspected history of other estrogen-based cancer (ie, uterine cancer); women who have had a hysterectomy and have no remaining evidence of disease are still candidates for HRT
• Active deep venous thrombosis (DVT) or a history of DVT or pulmonary embolism 
• History of blood clotting disorder, the most common being Factor V Leiden mutation carriers
• Active or history of arterial thrombotic diseases (eg, myocardial infarction or stroke)
• Chronic liver disease or dysfunction
• Migraine with aura [6]

Conditions that increase the risk of stroke, including uncontrolled blood pressure (≥180/110) and triglycerides (>400 mg/dL), are relative contraindications for HRT.[6] These contraindications do not apply to transvaginal-based estrogen therapies, as the serum concentration of estrogen from this route is extremely low. The North American Menopause Society has recommended that the black-box warning that applies to conventional HRT not be applied to transvaginal estrogen treatments.

Monitoring

Hormone levels of estradiol and progesterone are not traditionally measured for monitoring purposes. Instead, the relief of menopausal symptoms and the absence of adverse effects signify an adequate medical response. Adverse side effects may include:

• Abnormal uterine bleeding
• Fluid retention
• Breast tenderness
• Headaches
• Mood changes [6]

No scientific evidence links HRT with significant weight gain. Additionally, androgen therapies (eg, testosterone) should be monitored with serum testing but are not considered conventional HRT.

Enhancing Healthcare Team Outcomes

Patients undergoing menopause require comprehensive management from an interprofessional team, including physicians, advanced practitioners, nurses, and pharmacists. Patients should be informed about the benefits and risks of HRT. Pharmacists play a crucial role by consulting with prescribers on the appropriate agent and dosing while reviewing the patient's medication history. Nurses must be vigilant for signs of adverse events, closely monitor patients during follow-up visits, and promptly inform the clinician of any concerns. Effective interprofessional communication and coordinated care ensure patient-centered care, enhance safety, improve outcomes, and boost team performance related to HRT.