Hormone Replacement Therapy

What exactly is Hormone Replacement Therapy (HRT)?

Hormone Replacement Therapy (HRT) is a medication (or combination of medications) that is prescribed to women who are experiencing symptoms due to reproductive hormone imbalance. In most cases, this medication is a combination of hormones (estradiol and progestogen) that mimic the natural reproductive hormones known as estrogen and progesterone.7

Women go through hormone cycles throughout their lives that vary depending on age. As women age and reach what is called the end of their reproductive cycle (usually between ages 45 and 56),47 their hormone levels, particularly the two major hormones estrogen and progesterone, start decreasing in their bloodstream. This decrease is often accompanied by a series of symptoms.2

HRT is a treatment that can be prescribed to help women deal with these symptoms, and it is designed to replace the natural reproductive hormones that the body is producing in lesser quantities. Hence, the name, Hormone Replacement Therapy (HRT).

Estrogen, Menopause, and HRT

As women age and reach this “end of reproductive cycle” mentioned above, their levels of estrogen and progesterone decrease. The first stage of this decline in hormone levels is called perimenopause. During perimenopause, women’s hormone levels begin to decline, but they still have enough hormones in their bloodstream to continue having menstrual cycles. However, menstrual cycles become more irregular with time, until they completely stop. This is called menopause. In medical terms, once a woman has not had her period for an entire year (12 months), she has reached menopause. At this stage and beyond in a woman’s life, the hormone levels will continue to decrease. You can use this tool to find out whether you are in perimenopause or menopause.3

The hormones estrogen and progesterone have a variety of functions in the body. As their levels decrease, so do the functions where they are involved. One major function is the control of the menstrual cycle. 

There are several other functions where estrogen, particularly, is involved. 

• Regulates bone growth and bone density.4,46,56

• Interacts with the cardiovascular system and reduces coronary risks.5,1,6,46,56

• Interacts with the central nervous system and reduces the risks of developing Alzheimer’s disease46, as well as with brain regions that are crucial to higher cognitive functions and memory.50,56

• Prevents a decrease in skin collagen and maintains skin thickness,44 and it also has effects on skin aging, firmness, dryness, elasticity, and the depth and number of wrinkles.45

• Prevents vaginal atrophy, burning, and dryness.46,47,56

• Interacts with the hypothalamus and how the brain perceives temperature, causing vasomotor symptoms such as hot flashes and night sweats.47,48,56

• Reduces urinary incontinence.46

• Regulates the development and function of the immune system.49,56

• Level fluctuation affects mood and may trigger depression.51

• Interacts with the thyroid gland to affect mood regulation.52,53,56

• Can also regulate the expression (the behavior) of some genes.6

All in all, if the levels of estrogen decline, the functions where it is involved will be affected. For example, bone growth may change, which may result in a patient with weaker bones. Additionally, the cardiovascular system may not function properly if there is less estrogen in the bloodstream. And eventually, some genes may start acting abnormally if estrogen is not there to regulate their behavior. This is why for women going through a decrease of estrogen, it is recommended to take supplemental estrogen to counterbalance the lack of it, and to protect from the following potential negative things: 46,47,49,55,56

• Cardiovascular diseases

• Osteoporosis and bone loss

• Mood disorders, including depression and mood swings

• Alzheimer’s disease

• Urinary incontinence

• Memory loss and brain fog

• Vaginal dryness

• Skin dryness

• Hot flashes and night sweats

• Autoimmune diseases

• The deregulation of some genes

• Breast and colorectal cancer

Genetics and HRT

Some genetic variants, when not controlled properly, will misbehave and can allow the development of cancer. They are then considered pathogenic variants. When those genetic variants are inherited from your parents, they are called inherited genetic variants. If instead they were acquired during life, they are called acquired genetic variants. 

In women, it is known that breast cancer risk can be increased by the presence of certain inherited genetic variants, such as the pathogenic variants called BRCA1 and BRCA2. 8,41  And there are other inherited pathogenic variants that can increase the risk of breast cancer. One of them is called the inherited KRAS-variant9. This KRAS-variant not only is associated with an increased risk of breast cancer, it is also associated with an increased risk of lung, ovary, gallbladder, and lymphoma cancers.10,11,12,13,16,17,18

Remember that we said above that one of the functions of estrogen is to regulate the expression (or behavior) of certain genes? It turns out that the proper function of the KRAS-variant depends on estrogen levels in the bloodstream,42,43 and when there is less of it, the gene starts acting abnormally. Thus, lower levels of estrogen may increase the risk of breast,19,24 ovarian,20,21  and lung23,25 cancers. In other words, taking supplemental estrogen could be useful for cancer prevention for KRAS-variant patients.

Taking charge of your own health. What would be the next steps?

Ideally, cancers associated with the inherited genetic variants we discussed earlier, can be prevented.

The first step would be to do a genetic test in order to find out whether you have any of the genetic variants associated with cancer. Having a genetic variant does not mean you will necessarily develop cancer, it just means the risk is higher. Likewise, testing negative is not a guarantee that you will never develop any of the cancer types we discussed earlier. Unfortunately, with cancer there is never “zero” risk. 

Having said that, testing for the presence of cancer-associated genetic variants will always be helpful for planning a preventive path. With the testing results, you would be taking charge of your own health since you would be taking the first steps and decisions to help decrease your risk of cancer, or even prevent it. 55,56

Frequently Asked Questions

Are there any alternatives to HRT?

Yes, alternatives include lifestyle adjustments,30,34 non-hormonal medications for symptom relief,31 diet,55 exercise,56 and supplements,28,29,40 though these should be evaluated for efficacy and safety in the context of each woman's health. 27,34 However, none of these have been studied to act as a regulator of inherited genetic variants discussed earlier. Therefore, we don’t know if any of these alternatives would work as well as estrogen to regulate the KRAS-variant and to reduce cancer risk. 

Can you start hormone replacement therapy after menopause?

HRT can be started postmenopausally, particularly if symptoms persist and affect quality of life. However, starting HRT after the age of 60 may have some risks for some women, depending on their overall health.32,33,35 Women in their sixties and women who have had cancer should consult with their doctor before starting HRT.34,35

It is important to note, however, that the sooner you start HRT, the sooner you will tackle the low levels of estrogen in your body. In other words, the sooner you start, the greater the chance that you will avoid developing cancer if you have the KRAS-variant. 

Are there side effects with hormone replacement therapy?

Some side effects that may occur while taking HRT are vaginal bleeding, nausea, breast tenderness, migraine headaches, mood alterations, and abdominal bloating.38 Most of these symptoms can be curved with simple measures such as modifying the dose, replacing oral pills for skin patches (or vice versa), and changing the preparation.38 Another risk is the development of blood clots, and for this reason, women with a history of blood clots, or those at a known increased risk of clotting, are advised to not take HRT.54

What are the symptoms of having low estrogen levels or being perimenopausal?

There are a broad range of symptoms of low estrogen, but the most common include hot flashes, night sweats, vaginal dryness, dry skin, loss of libido, urinary incontinence, trouble falling asleep, sexual discomfort, bone loss, depression, and mood disturbances.39

What hormones are included in hormone replacement therapy?

HRT typically includes either estrogen alone or a combination of estrogen (called estradiol) and progesterone (called progestogen), depending on a woman’s specific needs.37 Women who have had a hysterectomy (removal of their uterus) typically only need estrogen, while women who still have their uterus will also need progesterone to protect their endometrial lining.

Is HRT a pill or a patch?

HRT is available in different presentations.36 There are pills/tablets to be taken by mouth, gels/creams to be inserted into the vagina or on the skin, skin patches, vaginal rings, and sprays.

Summary

Menopause is a stage in every woman’s life. Being educated about the physical changes and symptoms that come during that journey, and the possible treatments available, arms each and every woman with the information they need to take charge of their own health. With the ongoing advancements in medicine and more personalized approaches to healthcare, HRT remains a meaningful option to be considered.

Sources

1. The North American Menopause Society 2017 Hormone Therapy Position Statement Advisory Panel. The North American Menopause Society (NAMS). 2018;24(7):728-753. 

2. https://www.nia.nih.gov/health/menopause/what-menopause#:~:text=Menopause%20is%20a%20point%20in,between%20ages%2045%20and%2055. 

3. https://mymenoplan.org/am-i-in-menopause/

4. Väänänen HK, Härkönen PL. Estrogen and bone metabolism. Maturitas. 1996 May;23 Suppl:S65-9. doi: 10.1016/0378-5122(96)01015-8. PMID: 8865143.

5. Knowlton AA, Lee AR. Estrogen and the cardiovascular system. Pharmacol Ther. 2012 Jul;135(1):54-70. doi: 10.1016/j.pharmthera.2012.03.007. Epub 2012 Mar 28. PMID: 22484805; PMCID: PMC5688223.

6. Lee HR, Kim TH, Choi KC. Functions and physiological roles of two types of estrogen receptors, ERα and ERβ, identified by estrogen receptor knockout mouse. Lab Anim Res. 2012 Jun;28(2):71-6. doi: 10.5625/lar.2012.28.2.71. Epub 2012 Jun 26. PMID: 22787479; PMCID: PMC3389841.

7. https://www.menopause.org/home 

8. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet 

9. McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB. Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle. 2015;14(13):2091-9. doi: 10.1080/15384101.2015.1041694. Epub 2015 May 11. PMID: 25961464; PMCID: PMC4614527.

10. Aran V. KRAS-variant4A: Lead or Supporting Role in Cancer Biology? Front Mol Biosci. 2021 Sep 15;8:729830. doi: 10.3389/fmolb.2021.729830. PMID: 34604308; PMCID: PMC8479197.

11. Weidhaas JB, Harris J, Schaue D, Chen AM, Chin R, Axelrod R, El-Naggar AK, Singh AK, Galloway TJ, Raben D, Wang D, Matthiesen C, Avizonis VN, Manon RR, Yumen O, Nguyen-Tan PF, Trotti A, Skinner H, Zhang Q, Ferris RL, Sidransky D, Chung CH. The KRAS-Variant and Cetuximab Response in Head and Neck Squamous Cell Cancer: A Secondary Analysis of a Randomized Clinical Trial. JAMA Oncol. 2017 Apr 1;3(4):483-491. doi: 10.1001/jamaoncol.2016.5478. PMID: 28006059; PMCID: PMC5470422.

12. Murugan AK, Grieco M, Tsuchida N. RAS mutations in human cancers: Roles in precision medicine. Semin Cancer Biol. 2019 Dec;59:23-35. doi: 10.1016/j.semcancer.2019.06.007. Epub 2019 Jun 27. PMID: 31255772.

13. Timar J, Kashofer K. Molecular epidemiology and diagnostics of KRAS mutations in human cancer. Cancer Metastasis Rev. 2020 Dec;39(4):1029-1038. doi: 10.1007/s10555-020-09915-5. PMID: 32725342; PMCID: PMC7680318.

14. Saridaki Z, Weidhaas JB, Lenz HJ, Laurent-Puig P, Jacobs B, De Schutter J, De Roock W, Salzman DW, Zhang W, Yang D, Pilati C, Bouché O, Piessevaux H, Tejpar S. A let-7 microRNA-binding site polymorphism in KRAS predicts improved outcome in patients with metastatic colorectal cancer treated with salvage cetuximab/panitumumab monotherapy. Clin Cancer Res. 2014 Sep 1;20(17):4499-4510. doi: 10.1158/1078-0432.CCR-14-0348. PMID: 25183481; PMCID: PMC4155520.

15. Chung CH, Lee JW, Slebos RJ, Howard JD, Perez J, Kang H, Fertig EJ, Considine M, Gilbert J, Murphy BA, Nallur S, Paranjape T, Jordan RC, Garcia J, Burtness B, Forastiere AA, Weidhaas JB. A 3'-UTR KRAS-variant is associated with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma. Ann Oncol. 2014 Nov;25(11):2230-2236. doi: 10.1093/annonc/mdu367. Epub 2014 Jul 31. Erratum in: Ann Oncol. 2015 May;26(5):1038-9. PMID: 25081901; PMCID: PMC4207729.

16. Chin LJ, Ratner E, Leng S, Zhai R, Nallur S, Babar I, Muller RU, Straka E, Su L, Burki EA, Crowell RE, Patel R, Kulkarni T, Homer R, Zelterman D, Kidd KK, Zhu Y, Christiani DC, Belinsky SA, Slack FJ, Weidhaas JB. A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk. Cancer Res. 2008 Oct 15;68(20):8535-40. doi: 10.1158/0008-5472.CAN-08-2129. PMID: 18922928; PMCID: PMC2672193.

17. Ratner E, Lu L, Boeke M, Barnett R, Nallur S, Chin LJ, Pelletier C, Blitzblau R, Tassi R, Paranjape T, Hui P, Godwin AK, Yu H, Risch H, Rutherford T, Schwartz P, Santin A, Matloff E, Zelterman D, Slack FJ, Weidhaas JB. A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk. Cancer Res. 2010 Aug 15;70(16):6509-15. doi: 10.1158/0008-5472.CAN-10-0689. Epub 2010 Jul 20. PMID: 20647319; PMCID: PMC2923587.

18. Kazmi HR, Chandra A, Kumar S, Satyam LK, Gupta A, Nigam J, Srivastava M, Mittal B. A let-7 microRNA binding site polymorphism in the KRAS 3'UTR is associated with increased risk and reduced survival for gallbladder cancer in North Indian population. J Cancer Res Clin Oncol. 2016 Dec;142(12):2577-2583. doi: 10.1007/s00432-016-2254-9. Epub 2016 Sep 12. PMID: 27620744.

19. McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB. Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle. 2015;14(13):2091-9. doi: 10.1080/15384101.2015.1041694. Epub 2015 May 11. PMID: 25961464; PMCID: PMC4614527.

20. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocr Rev. 2019 Aug 1;40(4):1048-1079. doi: 10.1210/er.2018-00242. PMID: 30994890; PMCID: PMC6693056.

21. Bulun SE, Wan Y, Matei D. Epithelial Mutations in Endometriosis: Link to Ovarian Cancer. Endocrinology. 2019 Mar 1;160(3):626-638. doi: 10.1210/en.2018-00794. PMID: 30657901; PMCID: PMC6382454.

22. Duffy MJ, O'Donovan N, Crown J. Use of molecular markers for predicting therapy response in cancer patients. Cancer Treat Rev. 2011 Apr;37(2):151-9. doi: 10.1016/j.ctrv.2010.07.004. Epub 2010 Aug 3. PMID: 20685042.

23. Caetano MS, Hassane M, Van HT, Bugarin E, Cumpian AM, McDowell CL, Cavazos CG, Zhang H, Deng S, Diao L, Wang J, Evans SE, Behrens C, Wistuba II, Fuqua SAW, Lin H, Stabile LP, Watowich SS, Kadara H, Moghaddam SJ. Sex specific function of epithelial STAT3 signaling in pathogenesis of K-ras mutant lung cancer. Nat Commun. 2018 Nov 2;9(1):4589. doi: 10.1038/s41467-018-07042-y. PMID: 30389925; PMCID: PMC6214980.

24. Gupta GK, Collier AL, Lee D, Hoefer RA, Zheleva V, Siewertsz van Reesema LL, Tang-Tan AM, Guye ML, Chang DZ, Winston JS, Samli B, Jansen RJ, Petricoin EF, Goetz MP, Bear HD, Tang AH. Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies. Cancers (Basel). 2020 Aug 24;12(9):2392. doi: 10.3390/cancers12092392. PMID: 32846967; PMCID: PMC7565566.

25. Deng S, Ramos-Castaneda M, Velasco WV, Clowers MJ, Gutierrez BA, Noble O, Dong Y, Zarghooni M, Alvarado L, Caetano MS, Yang S, Ostrin EJ, Behrens C, Wistuba II, Stabile LP, Kadara H, Watowich SS, Moghaddam SJ. Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer. Carcinogenesis. 2020 Nov 13;41(11):1529-1542. doi: 10.1093/carcin/bgaa064. PMID: 32603404; PMCID: PMC7896112.

26. https://www.ncbi.nlm.nih.gov/books/NBK493191/ 

27. https://www.menopause.org/docs/default-source/for-women/menonote-deciding-about-ht-2017.pdf 

28. https://www.webmd.com/menopause/ss/slideshow-menopause 

29. https://www.liebertpub.com/doi/10.1089/jwh.2005.14.634?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub++0pubmed

30. https://www.peoplespharmacy.com/articles/menopause 

31. https://www.peoplespharmacy.com/articles/veozah-is-a-new-non-hormonal-drug-for-hot-flashes 

32. https://www.mayoclinic.org/diseases-conditions/menopause/in-depth/hormone-therapy/art-20046372

33. https://www.breastcancer.org/research-news/nams-updates-hrt-position-statement 

34. https://www.cancer.gov/about-cancer/causes-prevention/risk/hormones/mht-fact-sheet

35. https://www.medscape.com/viewarticle/892071_24

36. https://www.nhs.uk/medicines/hormone-replacement-therapy-hrt/types-of-hormone-replacement-therapy-hrt/#:~:text=There%20are%20different%20types%20of,may%20also%20sometimes%20prescribe%20testosterone)

37. https://www.mayoclinic.org/diseases-conditions/menopause/in-depth/hormone-therapy/art-20046372#:~:text=If%20you%20haven't%20had,the%20risk%20of%20endometrial%20cancer.

38. Evans MP, Fleming KC, Evans JM. Hormone replacement therapy: management of common problems. Mayo Clin Proc. 1995 Aug;70(8):800-5. doi: 10.4065/70.8.800. PMID: 7630222.

39. https://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/five-solutions-for-menopause-symptoms

40. https://www.menopause.org/for-women/menopauseflashes/menopause-symptoms-and-treatments/natural-remedies-for-hot-flashes

41. https://www.cancer.gov/about-cancer/causes-prevention/genetics/brca-fact-sheet#:~:text=A%20harmful%20variant%20in%20BRCA1%20or%20BRCA2%20can%20be%20inherited,all%20cells%20in%20the%20body.

42. McVeigh TP, Jung SY, Kerin MJ, Salzman DW, Nallur S, Nemec AA, Dookwah M, Sadofsky J, Paranjape T, Kelly O, Chan E, Miller N, Sweeney KJ, Zelterman D, Sweasy J, Pilarski R, Telesca D, Slack FJ, Weidhaas JB. Estrogen withdrawal, increased breast cancer risk and the KRAS-variant. Cell Cycle. 2015;14(13):2091-9. doi: 10.1080/15384101.2015.1041694. Epub 2015 May 11. PMID: 25961464; PMCID: PMC4614527.

43. Jung SY, Malhotra P, Nguyen KC, Salzman D, Qi Y, Pak EH, King J, Vlashi E, Ann D, Weidhaas JB. The KRAS-variant and its impact on normal breast epithelial cell biology. Cell Death Differ. 2019 Dec;26(12):2568-2576. doi: 10.1038/s41418-019-0320-y. Epub 2019 Apr 1. PMID: 30932013; PMCID: PMC7224195.

44. Shah MG, Maibach HI. Estrogen and skin. An overview. Am J Clin Dermatol. 2001;2(3):143-50. doi: 10.2165/00128071-200102030-00003. PMID: 11705091.

45. Stevenson S, Thornton J. Effect of estrogens on skin aging and the potential role of SERMs. Clin Interv Aging. 2007;2(3):283-97. doi: 10.2147/cia.s798. PMID: 18044179; PMCID: PMC2685269.

46. Palacios S. Current perspectives on the benefits of HRT in menopausal women. Maturitas. 1999 Nov;33 Suppl 1:S1-13. PMID: 10661610.

47. Crandall CJ, Mehta JM, Manson JE. Management of Menopausal Symptoms: A Review. JAMA. 2023 Feb 7;329(5):405-420. doi: 10.1001/jama.2022.24140. PMID: 36749328.

48. https://www.cedars-sinai.org/blog/why-hot-flashes-occur-and-how-to-treat-them.html

49. Moulton VR. Sex Hormones in Acquired Immunity and Autoimmune Disease. Front Immunol. 2018 Oct 4;9:2279. doi: 10.3389/fimmu.2018.02279. PMID: 30337927; PMCID: PMC6180207.

50. Cutter WJ, Norbury R, Murphy DG. Oestrogen, brain function, and neuropsychiatric disorders. J Neurol Neurosurg Psychiatry. 2003 Jul;74(7):837-40. doi: 10.1136/jnnp.74.7.837. PMID: 12810759; PMCID: PMC1738534.

51. Wharton W, Gleason CE, Olson SR, Carlsson CM, Asthana S. Neurobiological Underpinnings of the Estrogen - Mood Relationship. Curr Psychiatry Rev. 2012 Aug 1;8(3):247-256. doi: 10.2174/157340012800792957. PMID: 23990808; PMCID: PMC3753111.

52. Santin AP, Furlanetto TW. Role of estrogen in thyroid function and growth regulation. J Thyroid Res. 2011;2011:875125. doi: 10.4061/2011/875125. Epub 2011 May 4. PMID: 21687614; PMCID: PMC3113168.

53. Kuś A, Kjaergaard AD, Marouli E, Del Greco M F, Sterenborg RBTM, Chaker L, Peeters RP, Bednarczuk T, Åsvold BO, Burgess S, Deloukas P, Teumer A, Ellervik C, Medici M. Thyroid Function and Mood Disorders: A Mendelian Randomization Study. Thyroid. 2021 Aug;31(8):1171-1181. doi: 10.1089/thy.2020.0884. Epub 2021 May 26. PMID: 33899528; PMCID: PMC7612998.

54. Abou-Ismail MY, Citla Sridhar D, Nayak L. Estrogen and thrombosis: A bench to bedside review. Thromb Res. 2020 Aug;192:40-51. doi: 10.1016/j.thromres.2020.05.008. Epub 2020 May 11. PMID: 32450447; PMCID: PMC7341440.

55. Chlebowski RT, Aragaki AK, Pan K. Breast Cancer Prevention: Time for Change. JCO Oncol Pract. 2021 Dec;17(12):709-716. doi: 10.1200/OP.21.00343. Epub 2021 Jul 28. PMID: 34319769; PMCID: PMC8677965.

56. Manyonda I, Sinai Talaulikar V, Pirhadi R, Ward J, Banerjee D, Onwude J. Could Perimenopausal Estrogen Prevent Breast Cancer? Exploring the Differential Effects of Estrogen-Only Versus Combined Hormone Replacement Therapy. J Clin Med Res. 2022 Jan;14(1):1-7. doi: 10.14740/jocmr4646. Epub 2022 Jan 29. PMID: 35211211; PMCID: PMC8827222.