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What Are The Risks and Benefits of Hormone Therapy?

Updated: Jan 30

Progesterone and estrogen therapies have long been used for treating symptoms of menopause, including: hot flashes, sleep, mood, weight gain, vaginal dryness, night sweats, chills, hair thinning and dry skin. However, hormone therapy is sometimes criticized because research has found that certain hormones in specific formulations have been associated with serious adverse effects in specific populations.[1] People often generalize these side effects and assume all forms of hormone therapy increase risk of stroke, blood clots, and certain cancers in all individuals. However, data suggests that many of these risks specifically come from synthetic oral forms of hormones and only occur at certain ages.


Natural Progesterone (Micronised Progesterone)


On the contrary, a 2018 study summarized current research and found that natural progesterone (micronised progesterone):[2]

● Did not affect risk of venous thromboembolism (blood clots)

● Reduced risk of breast cancer compared to synthetic progesterone[3]

● Had no impact on blood pressure


One of progesterone’s primary benefits is for those with (or at risk of developing) endometrial hyperplasia. A 2010 study summarized data from 24 studies and found that 66%-92% of those with endometrial hyperplasia who took progesterone had a reversal of hyperplasia back to normal endometrial lining.[4] A 2015 study found that those taking progesterone had one quarter the risk of requiring a hysterectomy compared to placebo.[5]


Natural Estrogen (Estriol & Estradiol)

Data suggests that some of the risks of estrogen are negated when used in a natural transdermal form (estriol or estradiol applied to skin). A 2013 study found that transdermal estrogen use was instead associated with a reduction in heart attacks rather than increase as seen in oral estrogen.[6] They also found reduced risk of diabetes and no impact on risk of stroke. Gallbladder disease and blood clots were also reduced in comparison to oral estrogen. However, there was still a slight increase in these risks compared to placebo/no treatment (for example, 1 in 331 women had gallbladder disease due to transdermal estrogen therapy).[7]


Benefits & Risks of Combination Therapies

In contrast to natural progesterone, synthetic combined estrogen + progesterone therapies generally have a number of risks associated with it at certain ages. The Women’s Health Initiative Trial is one of largest completed and they found that per 10,000 women on combined hormone replacement therapy each year there were:[8]

● 7 more cases of coronary heart disease (37 on combined HRT versus 30 on placebo)

● 8 more cases of strokes (29 vs 21)

● 18 more cases of blood clots (34 vs 16) and a twofold greater rate of total blood clots in the lungs and legs

● 8 more cases of invasive breast cancer (38 vs 30)

● 6 fewer cases of colorectal cancer (10 vs 16)

● 5 fewer cases of hip fractures (10 vs 15)


As shown above, hormone replacement therapy with a combination of synthetic hormones may increase some risks while simultaneously decreasing others. The study concluded that the risks overall outweighed the benefits in the group as whole.


Benefits Outweigh Risk in Young Menopausal Women

In contrast to the above, the Women’s Health Initiative Trial found that adverse effects were much less in those aged 50-59, and for this group total benefits were found to outweigh risks. In this group there were less cancers, fractures, and diabetes. They also had a higher rate of survival during the study period. So in this context, combination therapy of estrogen + progesterone is particularly beneficial.


Here are the numbers for those aged 50-59 years old:


Combined estrogen-progestin therapy – Number of cases (additional or fewer) per 1000 women per five years of hormone use when compared with placebo:[9]

● Coronary heart disease (CHD) – 2.5 additional cases

● Invasive breast cancer – 3 additional cases

● Stroke – 2.5 additional cases

● Pulmonary embolism – 3 additional cases

● Colorectal cancer – 0.5 fewer cases

● Endometrial cancer – No difference

● Hip fracture – 1.5 fewer cases

● All-cause mortality – 5 fewer events


Estrogen-alone therapy – Number of cases (additional or fewer) per 1000 women per five years of hormone use when compared with placebo:[10]

● CHD – 5.5 fewer cases

● Invasive breast cancer – 2.5 fewer cases

● Stroke – 0.5 fewer cases

● Pulmonary embolism – 1.5 additional cases

● Colorectal cancer – 0.5 fewer cases

● Hip fracture – 1.5 additional cases (of note, there was an overall decrease in all osteoporotic fractures in both the estrogen and combined estrogen-progestin groups)

● All-cause mortality – 5.5 fewer events


Although mixed with some medical conditions, the above data suggests overall net benefit whether using estrogen-only or a combination formula. As a side note - this data also suggests that estrogen appears safer than the combination therapy (progesterone + estrogen), suggesting that progesterone specifically carries the higher risk profile. However, this study used synthetic progesterone, and as mentioned before, data suggests that natural progesterone does not carry these same risks (stroke, blood clots, cardiovascular disease, etc). Furthermore, this study above unfortunately did not mention one of the most important risks of estrogen-only therapy: endometrial hyperplasia and endometrial cancer. Estrogen is stimulating to hormone-sensitive tissues when not given alongside progesterone. Data estimates around 20-50% of women using estrogen-only therapy develop endometrial hyperplasia within the first year.[11],[12] However, research suggests that by adding in progesterone alongside estrogen, that risk is eliminated and there is actually a trend towards reduced risk of endometrial cancer.[13]


Does Hormone Therapy Cause Weight Gain?

A study completed an analysis on 22 studies and found that there was a slight trend towards increased weight gain (about 1 pound) in those who used estrogen-only hormone therapy. In contrast to estrogen-only, they found a slight trend towards decreased weight in those who used progesterone containing preparations.[14] Furthermore, a 2021 study found that women with excess weight tend to be deficient in progesterone, while women at more healthy weights tend to have higher levels of progesterone.[15] Altogether, these studies suggest that by correcting progesterone imbalance, people may see a small improvement in weight.


Which Ones Are Synthetic and Natural?

  • Synthetic progesterones: medroxyprogesterone, nomegestrol acetate, levonorgestrel

  • Natural (bioidentical) progesterone: micronized progesterone, prometrium

  • Synthetic estrogens: ethinyl estradiol, estradiol valerate, estropipate, conjugate esterified estrogen, quinestrol

  • Natural estrogens: estradiol, estriol


Conclusion

summary of risks of hormone therapy
Fig. 1 Summary

In general, for both estrogen and progesterone options (synthetic or natural), the benefits generally appear to outweigh risks for the first several years after menopause (50-59 year old individuals). However, by using natural forms of hormones we keep most of the benefits to symptoms, osteoporosis, and cancer risk reduction, while avoiding some of the more serious side effects that come along with synthetic options (eg. cardiovascular, breast cancer). Furthermore, transdermal preparations (hormone creams) appear to improve safety profiles even more. At our clinic we complete a comprehensive assessment that includes a hormone blood work panel, so that we can determine the best dose of natural progesterone and/or estrogen.


References

[1] Schneider C, Jick SS, Meier CR. Risk of gynecological cancers in users of estradiol/dydrogesterone or other HRT preparations. Climacteric. 2009 Dec;12(6):514-24. doi: 10.3109/13697130903075352. PMID: 19905903. [2] Newson LR, Lass A. Effectiveness of transdermal oestradiol and natural micronised progesterone for menopausal symptoms. Br J Gen Pract. 2018 Oct;68(675):499-500. doi: 10.3399/bjgp18X699353. PMID: 30262631; PMCID: PMC6146001. [3] Hamoda H, Panay N, Pedder H, Arya R, Savvas M. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health. 2020 Dec;26(4):181-209. doi: 10.1177/2053369120957514. Epub 2020 Oct 12. PMID: 33045914. [4] Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. 2010 Dec;203(6):547.e1-10. doi: 10.1016/j.ajog.2010.07.037. PMID: 20934679. [5] Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. 2015 Oct;213(4):469-78. doi: 10.1016/j.ajog.2015.03.037. Epub 2015 Mar 19. PMID: 25797236. [6] L'Hermite M. HRT optimization, using transdermal estradiol plus micronized progesterone, a safer HRT. Climacteric. 2013 Aug;16 Suppl 1:44-53. doi: 10.3109/13697137.2013.808563. PMID: 23848491. [7] Liu B, Beral V, Balkwill A, Green J, Sweetland S, Reeves G; Million Women Study Collaborators. Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study. BMJ. 2008 Jul 10;337:a386. doi: 10.1136/bmj.a386. PMID: 18617493; PMCID: PMC2500203. [8] Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523. [9] Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523. [10] Manson JE, Chlebowski RT, Stefanick ML, Aragaki AK, Rossouw JE, Prentice RL, Anderson G, Howard BV, Thomson CA, LaCroix AZ, Wactawski-Wende J, Jackson RD, Limacher M, Margolis KL, Wassertheil-Smoller S, Beresford SA, Cauley JA, Eaton CB, Gass M, Hsia J, Johnson KC, Kooperberg C, Kuller LH, Lewis CE, Liu S, Martin LW, Ockene JK, O'Sullivan MJ, Powell LH, Simon MS, Van Horn L, Vitolins MZ, Wallace RB. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA. 2013 Oct 2;310(13):1353-68. doi: 10.1001/jama.2013.278040. PMID: 24084921; PMCID: PMC3963523. [11] Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. The Menopause Study Group. Am J Obstet Gynecol. 1994 May;170(5 Pt 1):1213-23. doi: 10.1016/s0002-9378(94)70129-6. PMID: 8178840. [12] Schiff I, Sela HK, Cramer D, Tulchinsky D, Ryan KJ. Endometrial hyperplasia in women on cyclic or continuous estrogen regimens. Fertil Steril. 1982 Jan;37(1):79-82. doi: 10.1016/s0015-0282(16)45981-9. PMID: 6277698. [13] Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, Liu J, McNeeley SG, Lopez AM; Women's Health Initiative Investigators. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA. 2003 Oct 1;290(13):1739-48. doi: 10.1001/jama.290.13.1739. PMID: 14519708. [14] Norman RJ, Flight IH, Rees MC. Oestrogen and progestogen hormone replacement therapy for peri-menopausal and post-menopausal women: weight and body fat distribution. Cochrane Database Syst Rev. 2000;(2):CD001018. doi: 10.1002/14651858.CD001018. PMID: 10796730. [15] Whynott RM, Summers KM, Jakubiak M, Van Voorhis BJ, Mejia RB. The effect of weight and body mass index on serum progesterone values and live birth rate in cryopreserved in vitro fertilization cycles. F S Rep. 2021 Feb 18;2(2):195-200. doi: 10.1016/j.xfre.2021.02.005. PMID: 34278354; PMCID: PMC8267385.



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