Hormone Replacement Therapy: What You Should Know

Hormone Replacement Therapy: What You Should Know

What is hormone replacement therapy (HRT)?

Hormone replacement therapy (HRT) is exactly what it sounds like – replacing depleted hormone levels to an optimal amount. How exactly do hormones become dysregulated? Lifestyle choices are key influences on hormone balance. Nutrient-poor food, stress, toxins, and more are some of the responsible factors that lead to downstream effects that include hormone imbalance. We actually have a blog post and podcast talking more about female hormone balance! In addition to lifestyle factors, as we age our bodies make less and less of our sex hormones (estrogen, progesterone, and testosterone). In particular, sex hormone balance is greatly impacted in women that are reaching menopause. We also have a blog post talking about female hormones in mid-life and a podcast talking about menopause and hormones.

To be more precise, bioidentical hormone replacement therapy (BHRT) is something that many people are on for various reasons. According to the Cleveland Clinic, bioidentical hormones are designed to mimic the hormones the body makes. Most people who receive bioidentical hormone replacement therapy are being treated for symptoms caused by decreased levels of certain hormones. Common symptoms include hot flashes, vaginal dryness, night sweats, sleep disturbances, lower libido, painful sex, fatigue, confusion, and mood changes. Many of these hormones (i.e. estrogen, progesterone, testosterone) decrease as people age which can lead to adverse downstream effects to the body.¹ For many women, this comes to a head when menopause starts. Replacing these hormones can aid in decreasing the negative symptoms and improving overall health and well-being.

What are common hormones that are replaced? What do these do in the body?

There are several common hormones and proteins that are important to discuss::
-Estrogen
-Progesterone
-Testosterone
-DHEA (Dehydroepiandrosterone)
-Sex hormone binding globulin (SHBG)

Estrogen is a hormone that is largely associated with female reproductive organs and the development of female sexual characteristics. Estrogen found in the body has three different types: estrone (E1) estradiol (E2), and estriol (E3).²

-Estrone (E1): weaker form that is at its highest levels during a female’s first and last menstrual cycles; the body can convert estrone into other forms of estrogen if needed
-Estradiol (E2): strongest form; produced in both females and males; most common form use in hormone replacement therapy (HRT)
-Estriol (E3): weakest form; at its highest level right before giving birth

We have a blog post all about estrogen here.

Progesterone is a hormone that is secreted by the adrenal glands, the ovaries, or testes. Notably, it is the hormone that maintains the uterus during pregnancy. It is secreted by the ovaries during the first 10 weeks of pregnancy, then the placenta for the remainder of the pregnancy. It is generally considered to be a counter to estrogenic effects. For example, progesterone will thin the endometrial lining, which helps protect against developing endometrial cancer.³

If you are familiar with progesterone, you might also know that there are other forms called progestins. The biggest difference is that progestins are fully synthetic and have a different chemical structure. Progestins (i.e. medroxyprogesterone acetate, norethindrone, levonorgestrel, norgestimate, etc.) mimic progesterone by binding the same receptors, but they have slightly different side effects. Progestins are largely used in contraceptives and hormone replacement and are used for a variety of reasons.⁴

In deciding between a form of progesterone versus a progestin, there are some factors to consider. First, progesterone is the hormone that your body makes, while a progestin is synthetic and has a different structure. Safety and side effects are another important piece to consider. There are no current head-to-head studies comparing risk of breast cancer between regimens including progestins versus progesterone, but we have seen some sort of increased risk in women using estrogen and a progestin as opposed to estrogen alone. Additionally, the risk did not go up in women using transdermal estradiol and micronized progesterone.⁵

Both a type of estrogen and progesterone are prescribed together often for women in need of hormone replacement. This is to prevent the risk of endometrial cancer in women with in-tact uteruses that is often associated with estrogen-only regimens. There have been several large studies over the past few decades that demonstrated an association between the use of progesterone for less than 15 days a month in addition to estrogen. If the use is not consistent, there is a similar risk compared to those who are not adding in progesterone at all. Additionally, compared to individuals that do not take any hormones, there was no increased risk of endometrial cancer when taking both estrogen and progesterone together.⁶

Testosterone is the primary hormone that controls sex differentiation between males and females, male sexual characteristics, sperm production, and fertility. This hormone is primarily associated with people born male and the development of typical characteristics like facial hair, muscle growth, and a deepening of the voice. Although this is the case, it plays an important role in the female body. Testosterone can get converted to estrogen, which is vital for the female body.⁷

In menopausal women, studies have shown that adding some testosterone to a HRT regimen can improve sexual function.^8,9 One systematic review and meta-analysis saw improvement in several areas including desire, pleasure, arousal, and self-image.⁹

Dehydroepiandrosterone (DHEA) is a hormone that helps produce other hormones like estrogen and testosterone. DHEA is an androgen like testosterone. Peak levels of DHEA usually occur in young adulthood at approximately 25 years of age, then start to decrease. Since DHEA is a precursor to testosterone and estrogen, a deficiency could impact your levels of these hormones.⁷

DHEA supplementation has some evidence demonstrating positive effects and some showing no effects at all, but there are a variety of factors that could influence results. Supplementation can affect desire and arousal. Ultimately, reaching a balanced level is what the body needs to carry out its functions.

Sex hormone binding globulin (SHBG) is a protein in the body that can bind to estrogen and testosterone. It transports these hormones in your blood and controls what they target. If there is more sex hormone binding globulin, less of the actual sex hormones will be free in the blood.¹⁰

What are the benefits of hormone replacement?

Hormone replacement alongside lifestyle modifications will likely rebalance the sex hormones. As we have discussed, there are many factors that impact hormone balance. This rebalance will usually lead to an alleviation of symptoms like vaginal dryness, hot flashes, night sweats, etc.

In addition to reducing bothersome symptoms, there are positive benefits to maintaining adequate sex hormone levels. It is widely known that once a woman reaches menopause and no longer has an adequate amount of estrogen being released in the body, bones become weaker which can lead to osteoporosis.^11,12 There are a few studies that look at estradiol levels and how it related to bone mineral density. It is generally accepted that a serum estradiol level should target a minimum of 60 pg/mL to prevent bone loss.¹³ Even in premenopausal women, there was an association between having a serum estradiol level of <60 pg/mL and lower bone mineral density as opposed to women that were above 60 pg/mL.¹⁴

More potential benefits are linked to hormone replacement therapy in menopausal women. There is a link between hormone replacement therapy and cardiovascular disease outcomes. Cardiovascular disease (A.K.A heart disease) is the number one cause of death for women in the United States.¹⁵ In an article summarizing data from multiple studies, some data supports a reduction of all-cause mortality and cardiovascular disease in women who started on HRT at less than 60 years of age and/or less than 10 years post-menopause. In two specific meta-analyses, there was a 39% risk reduction in all-cause mortality compared to placebo (RR 0.61 [0.39-0.95], 95% CI, 5%-61%) from 30 RCTs, and a 32% risk reduction in coronary heart disease (CHD) (RR 0.68 [0.48-0.96], 95% CI, 4%-52%) from 23 RCTs.¹⁶ Current studies establish a benefit, but specific doses were not reported in many studies. All in all, the sooner a woman starts HRT to keep her sex hormones in balance, there appears to be a reduction in the incidence of heart disease.

There are also some possible cognitive benefits from HRT. Although there have been a variety of studies over the past few decades concerning this topic, there seems to be a timing component that can make an impact. As with cardiovascular disease, there is an association (β=0.55, P=0.048) between starting HRT within 5 years of menopause and better mini-mental state examination scores used to measure cognitive impairment. Also, women with a longer period of endogenous estrogen exposure (EEE) demonstrated better cognition in later life (β=0.03, P=0.054).¹⁷ The specific dosing strategies in this study were largely not reported, but some of the articles used for the meta-analysis used 0.625 mg of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate.

As we can see, balancing hormones not only can alleviate bothersome symptoms, but also can have an impact on bone health, as well as cardiovascular and cognitive outcomes.

What options are available?

Great news! Different hormones can come in a number of formulations. There are pills, implanted pellets, creams, patches, gels, and intramuscular shots for many of the commonly replaced sex hormones. The goal is to relieve symptoms at the lowest dose possible for the shortest amount of time. Using a replacement option in conjunction with lifestyle modifications can help address the root cause of what may be leading to imbalances throughout your body. For some, lifestyle modifications may address the root cause. We have pharmacists that can partner with you to discuss the next steps you can take to learn more about your hormones!

If you are interested in checking out the blog posts or podcasts mentioned in this post, we have also linked them down below!

Check out our podcasts:
https://pharmtotable.life/podcast/035-hormone-balance/
https://pharmtotable.life/podcast/033-all-about-menopause-with-carrie-jones-nd/
Blog posts:
https://pharmtotable.life/2021/07/07/female-hormones-in-mid-life/
https://pharmtotable.life/2021/07/07/female-hormones-finding-balance/

Written by Katelynn Webster, PharmD
Edited by Lindsey Dalton, PharmD

References
1. Bioidentical hormones: Therapy, uses, Safety & Side effects. Cleveland Clinic. Accessed March 29, 2024. https://my.clevelandclinic.org/health/treatments/15660-bioidentical-hormones.
2. Delgado BJ, Lopez-Ojeda W. Estrogen. In: StatPearls. Treasure Island (FL): StatPearls Publishing; June 26, 2023.
3. Cable JK, Grider MH. Physiology, Progesterone. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 1, 2023.
4. Edwards M, Can AS. Progestins. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 10, 2024.
5. Collaborative Group on Hormonal Factors in Breast Cancer. Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Lancet. 2019;394(10204):1159-1168. doi:10.1016/S0140-6736(19)31709-X
6. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Combined estrogen-progestogen contraceptives and combined estrogen-progestogen menopausal therapy. IARC Monogr Eval Carcinog Risks Hum. 2007;91:1-528.
7. Nassar GN, Leslie SW. Physiology, Testosterone. In: StatPearls. Treasure Island (FL): StatPearls Publishing; January 2, 2023.
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9. Islam RM, Bell RJ, Green S, Page MJ, Davis SR. Safety and efficacy of testosterone for women: a systematic review and meta-analysis of randomised controlled trial data. Lancet Diabetes Endocrinol. 2019;7(10):754-766. doi:10.1016/S2213-8587(19)30189-5
10. Hammond GL. Diverse roles for sex hormone-binding globulin in reproduction. Biol Reprod. 2011;85(3):431-441. doi:10.1095/biolreprod.111.092593
11. Cheng CH, Chen LR, Chen KH. Osteoporosis Due to Hormone Imbalance: An Overview of the Effects of Estrogen Deficiency and Glucocorticoid Overuse on Bone Turnover. Int J Mol Sci. 2022;23(3):1376. Published 2022 Jan 25. doi:10.3390/ijms23031376
12. Porter JL, Varacallo M. Osteoporosis. In: StatPearls. Treasure Island (FL): StatPearls Publishing; August 4, 2023.
13. Reginster JY, Sarlet N, Deroisy R, Albert A, Gaspard U, Franchimont P. Minimal levels of serum estradiol prevent postmenopausal bone loss. Calcif Tissue Int. 1992;51(5):340-343. doi:10.1007/BF00316876
14. Huitrón-Bravo G, Denova-Gutiérrez E, Talavera JO, et al. Levels of serum estradiol and lifestyle factors related with bone mineral density in premenopausal Mexican women: a cross-sectional analysis. BMC Musculoskelet Disord. 2016;17(1):437. Published 2016 Oct 19. doi:10.1186/s12891-016-1273-7
15. Leading causes of death – females – all races and origins – United States, 2018. Centers for Disease Control and Prevention. March 3, 2022. Accessed April 8, 2024. https://www.cdc.gov/women/lcod/2018/all-races-origins/index.htm.
16. Hodis HN, Mack WJ. Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It Is About Time and Timing. Cancer J. 2022;28(3):208-223. doi:10.1097/PPO.000000000000059
17. Matyi JM, Rattinger GB, Schwartz S, Buhusi M, Tschanz JT. Lifetime estrogen exposure and cognition in late life: the Cache County Study. Menopause. 2019;26(12):1366-1374. doi:10.1097/GME.0000000000001405