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October 13, 2021

Menopause Part 13: Hormone Replacement Therapy (HRT)

Welcome to part 13 of the ODX Menopause Series. This post reviews the basics of hormone replacement therapy and its potential risks and benefits. Bioidentical hormone therapy will be addressed in a later post.

The ODX Menopause Series

  1. Menopause Part 1: A Quick Overview of a Slow Process
  2. Menopause Part 2: Biology and Physiology of Menopause
  3. Menopause Part 3: Increased Risk of Disease Associated with Menopause
  4. Menopause Part 4: Identifying Menopause: Signs and Symptoms
  5. Menopause Part 5: Laboratory Evaluation of Menopause
  6. Menopause Part 6: Cardiovascular Risk in Menopause
  7. Menopause Part 7: Beyond Hormone Testing in Menopause
  8. Menopause Part 8: Natural Approaches to Menopause
  9. Menopause Part 9: Diet and Nutrition Intervention in Menopause
  10. Menopause Part 10: Characteristic of Herbal Derivatives used to Alleviate Menopause Symptoms
  11. Menopause Part 11: Lifestyle Approaches to Menopause
  12. Menopause Part 12: The National Institute on Aging Addresses Hot Flashes
  13. Menopause Part 13: Hormone Replacement Therapy (HRT) in Menopause
  14. Menopause Part 14: North American and European Guidelines for Hormonal Management of Menopause
  15. Menopause Part 15: Bioidentical Hormone Therapy
  16. Menopause Part 16: Optimal Takeaways for Menopause
  17. Optimal The Podcast - Episode 10

Hormone replacement therapy (HRT), also known as menopausal hormone therapy (MHT), has been used as a primary approach to managing the vasomotor symptoms of menopause, especially within 10 years of menopause or for those under the age of 60:[1]

  • Systemic estrogen is most effective for vasomotor symptoms
  • Estrogen alone may be used following hysterectomy
  • Unopposed estrogen may increase risk of endometrial hyperplasia and cancer in those with an intact uterus
  • Concurrent progesterone is provided to reduce risk of uterine complications
  • Transdermal versus oral delivery may be reduce risk of venous thromboembolism

For those women under age 60 or within 10 years of menopause, the risk to benefit ratio is more favorable than those older than 60. Potential negative consequences from HRT include thrombosis, stroke, and cancer of the breast.[2] Ideally HRT is reserved for those with moderate to severe menopausal symptoms.[3]

The majority of postmenopausal women will have a serum estradiol level of 9.3 pg/mL (34 pmol/L) or less without hormone replacement therapy.[4] Hormone therapy may be initiated if no contraindications are present.[5] Low dose oral contraception with an intact uterus may also be effective. The transdermal form of estradiol may be preferred if CVD risk factors are present, including hypertension, obesity, smoking, or risk of venous thromboembolism. Progestin/progestogen therapy for 10-15 days per 28 days is recommended if the uterus is intact.[6]

Estrogen therapy reduces total and LDL-cholesterol and increases HDL-cholesterol. However, the oral form can increase triglycerides, leading to an EMAS recommendation to provide transdermal estrogen to women with hypertriglyceridemia.[7]

Research suggests that HRT can modulate the proinflammatory profile associated with menopause.[8] This pattern is characterized by elevations in TNF-alpha, IL-6, and CRP.[9]

Low Dosing

Research indicates that hormone replacement therapy may be best administered at a low dose with an adjustment in dosing dependent on clinical response. A clinical goal for estradiol of 60 pg/mL (220 pmol/L) would be required to reduce risk of osteoporosis and reduce hot flashes by 50%. Serum levels depend on dosing and form of therapy. The following serum levels were achieved using oral estrogen therapy:[10]

Dose

Oral

Estrogen Form

Serum Estradiol

1 mg

Estradiol

30-65 pg/mL

110-239 pmol/L

2 mg

Estradiol

60-110 pg/mL

220-404 pmol/L

0.45 mg

Conjugated estrogen

60 pg/mL

220 pmol/L

0.625 mg

Considered standard dose,

Equivalent to 1-2 mg oral estradiol

Conjugated estrogen

76.8 pg/mL

282 pmol/L

Benefits and Risks

Women’s Health Initiative clinical trials provided postmenopausal estrogen therapy in the form of conjugated equine estrogens (Premarin from pregnant mare urine) or conjugated equine estrogens plus synthetic medroxyprogesterone acetate (PremPro). A one year analysis of a subset of 200 subjects found: [11]

  • Estrone levels increased by 4-fold in both therapy groups
  • Estradiol increased by 3-fold in both therapy groups
  • Bioavailable and free estradiol increased by 2-fold in both therapy groups
  • SHBG increased by 2.5-fold in both therapy groups
  • Progesterone decreased in the PremPro group (which was counterintuitive but possibly due to decreased endogenous production)
  • Researchers note variations in response to hormone therapy based on race, age, BMI, smoking status, baseline hormones, and reported vasomotor symptoms.

Researchers hope to target postmenopausal symptoms while minimizing systemic exposure to estradiol. Another option being researched is vaginal capsules of estradiol.[12]

Hormone therapy may reduce risk of future heart disease but should be combined with preventative measures for optimal effect. Management of menopause and perimenopause should focus on prevention of secondary complications and should include[13]

  • Evaluation and monitoring of heart disease risk
  • Blood pressure monitoring
  • Fasting lipid profile
  • Vitamin D status evaluation
  • Optimization of lifestyle habits including diet and activity

Many women report valuable benefits from HRT, including increased energy levels, better glucose regulation, healthier weight maintenance, and lack of hot flashes. Some decide that the benefits of therapy outweigh the risks for them.[14] That is a decision a woman should make in conjunction with her healthcare practitioner.

Potential Adverse Effects of Estradiol Therapy[15]

Cardiovascular

Edema, hypertension, thrombophlebitis, retinal thrombosis. 

Central Nervous System

Headache, depression, pain, dizziness, anxiety, migraine, nipple pain

Respiratory

Nasopharyngitis, flu-like symptoms, sinusitis, upper respiratory tract infection, headache, bronchitis, sinus congestion, pharyngitis, asthma exacerbation, cough 

Dermatologic

Skin rash, pruritus, erythema multiforme, erythema nodosum, urticaria

Skeletal

Arthralgia, weakness, back and neck pain, limb pain, myalgia, leg cramps

Endocrine

Weight gain or loss, hot flash, libido changes, hirsutism, menstrual changes, porphyria exacerbation, fluid retention, hypocalcemia, elevated triglycerides, galactorrhea

Gastrointestinal

Abdominal pain, constipation, heartburn, flatulence, bloating, nausea, vomiting, diarrhea, pancreatitis, gastroenteritis, carbohydrate intolerance 

Hypersensitivity

Anaphylaxis, angioedema, hypersensitivity reactions

Hepatic

Hepatic hemangioma exacerbation, jaundice

Ophthalmic

Conjunctivitis, steepening of the cornea, contact lens intolerance 

Infections

Fungal and other infections

Otic

Otitis media 

Contraindications to HRT

Significant medical history may be a contraindication to hormone replacement therapy. Hormone therapy contraindications include:[16] [17] [18] [19]

  • Antithrombin deficiency
  • Blood clots, DVT, pulmonary thromboembolism or risk of
  • Breast cancer history or risk of
  • Cardiovascular disease history or risk of
  • Endometrial cancer history or risk of
  • Endometriosis
  • Genital bleeding
  • Liver disease, active, with abnormal liver function tests
  • Migraine with aura
  • Obesity with excess lifetime exposure to estrogen
  • Pregnancy
  • Stroke
  • Thrombophilic disorders
  • Transient ischemic attack
  • Vaginal bleeding of unknown origin

References

[1] Neves-E-Castro, Manuel et al. “EMAS position statement: The ten point guide to the integral management of menopausal health.” Maturitas vol. 81,1 (2015): 88-92. doi:10.1016/j.maturitas.2015.02.003

[2] Kim, Soo-Min et al. “Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women.” Scientific reports vol. 11,1 3585. 11 Feb. 2021, doi:10.1038/s41598-021-81201-y

[3] De Franciscis, Pasquale et al. “A Nutraceutical Approach to Menopausal Complaints.” Medicina (Kaunas, Lithuania) vol. 55,9 544. 28 Aug. 2019, doi:10.3390/medicina55090544

[4] Marchand, Geneviève B et al. “Increased body fat mass explains the positive association between circulating estradiol and insulin resistance in postmenopausal women.” American journal of physiology. Endocrinology and metabolism vol. 314,5 (2018): E448-E456. doi:10.1152/ajpendo.00293.2017

[5] Hale, Georgina E et al. “The perimenopausal woman: endocrinology and management.” The Journal of steroid biochemistry and molecular biology vol. 142 (2014): 121-31. doi:10.1016/j.jsbmb.2013.08.015

[6] Hale, Georgina E et al. “The perimenopausal woman: endocrinology and management.” The Journal of steroid biochemistry and molecular biology vol. 142 (2014): 121-31. doi:10.1016/j.jsbmb.2013.08.015

[7] Anagnostis, Panagiotis et al. “Menopause symptom management in women with dyslipidemias: An EMAS clinical guide.” Maturitas vol. 135 (2020): 82-88. doi:10.1016/j.maturitas.2020.03.007

[8] Vrachnis, Nikolaos et al. “Effects of Hormone Therapy and Flavonoids Capable on Reversal of Menopausal Immune Senescence.” Nutrients vol. 13,7 2363. 10 Jul. 2021, doi:10.3390/nu13072363 [R}

[9] Honour, John W. “Biochemistry of the menopause.” Annals of clinical biochemistry vol. 55,1 (2018): 18-33. doi:10.1177/0004563217739930

[10] Kim, Soo-Min et al. “Serum estradiol level according to dose and formulation of oral estrogens in postmenopausal women.” Scientific reports vol. 11,1 3585. 11 Feb. 2021, doi:10.1038/s41598-021-81201-y

[11] Edlefsen, Kerstin L et al. “The effects of postmenopausal hormone therapy on serum estrogen, progesterone, and sex hormone-binding globulin levels in healthy postmenopausal women.” Menopause (New York, N.Y.) vol. 17,3 (2010): 622-9. doi:10.1097/gme.0b013e3181cb49e9

[12] Hariri, Lana. and Anis Rehman. “Estradiol.” StatPearls, StatPearls Publishing, 13 February 2021. This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (),

[13] Hale, Georgina E et al. “The perimenopausal woman: endocrinology and management.” The Journal of steroid biochemistry and molecular biology vol. 142 (2014): 121-31. doi:10.1016/j.jsbmb.2013.08.015

[14] Gupte, Anisha A et al. “Estrogen: an emerging regulator of insulin action and mitochondrial function.” Journal of diabetes research vol. 2015 (2015): 916585. doi:10.1155/2015/916585 This is an open access article distributed under the Creative Commons Attribution License.

[15] Hariri, Lana. and Anis Rehman. “Estradiol.” StatPearls, StatPearls Publishing, 13 February 2021. This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (),

[16] Hickey, Martha, Rebecca A. Szabo, and Myra S. Hunter. "Non-hormonal treatments for menopausal symptoms." bmj 359 (2017).

[17] Hariri, Lana. and Anis Rehman. “Estradiol.” StatPearls, StatPearls Publishing, 13 February 2021. This book is distributed under the terms of the Creative Commons Attribution 4.0 International License (),

[18] De Franciscis, Pasquale et al. “A Nutraceutical Approach to Menopausal Complaints.” Medicina (Kaunas, Lithuania) vol. 55,9 544. 28 Aug. 2019, doi:10.3390/medicina55090544

[19] Lauritsen, Clinton G et al. “Current Treatment Options: Headache Related to Menopause-Diagnosis and Management.” Current treatment options in neurology vol. 20,4 7. 6 Mar. 2018, doi:10.1007/s11940-018-0492-7

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