Hormone Replacement Therapy for Menopause Treatment in Women with Down Syndrome

Key Points

• There have been many changes in recommendations regarding hormone replacement therapy over the last several decades.
• Hormone replacement therapy has not been specifically studied in women with Down syndrome.
• Some women with Down syndrome may benefit from treatment of menopausal symptoms with hormone replacement therapy with special considerations.

What is menopause?

Menopause is the time in a woman’s life when she no longer has menstrual cycles. A woman is in menopause when it has been a full year since her last menstrual cycle. After that, she is described as being in menopause or as post-menopausal. For more information, please see the article Menopause in Women with Down Syndrome.

What is hormone replacement therapy?

Women who are pre- or post-menopausal may experience symptoms like hot flashes, mood lability/depression, brain fog, vaginal dryness, and joint pain (1-2). Hormone replacement therapy (HRT) is one of the available treatments for some of the symptoms associated with menopause.

Controversy around HRT

There was a big study in the late 1990s called the Women’s Health Initiative studying hormone replacement therapy in menopausal women. At the time, the study ended early because the risks and dangers of hormone replacement therapy seemed too great. Over the last several decades, the data has been re-analyzed and found to be more complex and nuanced than originally reported (3-4). Newer studies suggest that hormone replacement therapy may be safe and effective when used in the right patient and the right context (5-6).

What hormones are in HRT?

Menopausal symptoms are caused by age-related changes in a woman’s natural levels of the hormone estrogen. Hormone replacement therapy primarily consists of taking estrogen to help relieve some of the symptoms of menopause.

If a woman is exposed to too much estrogen for too long, it can lead to thickening of the lining of the uterus. This can, in turn, lead to uterine cancer. Progesterone is another hormone in a woman’s body. This hormone can help thin the lining of the uterus. Studies have shown that when a woman takes progesterone and estrogen, the progesterone reduces the risk of developing uterine cancer (7). Therefore, if a woman being treated with estrogen still has her uterus, she requires progesterone in addition to the estrogen to reduce the risk of uterine cancer. If a woman undergoing treatment with estrogen for menopausal symptoms no longer has a uterus (i.e., she has had a hysterectomy), she does not need to take progesterone.

What types of HRT are available?

Estrogen is available in many different forms, including pills, patches, gels, and sprays.

If uterine protection is needed, progesterone is available in many forms including pills and vaginal inserts. There is also an intrauterine device (IUD) containing progesterone. It is approved for other reasons. It is sometimes used as a progesterone in hormone replacement therapy, but it is not approved by the Food and Drug Administration for this use.

There are different types of progesterone that are broken down into natural and synthetic progesterones. Studies are starting to look more closely at the side effects of progesterone and determining if certain side effects only apply to natural or synthetic progesterones as opposed to both. This is an area of active research.

Contraindications

Reasons why a women should not take hormone replacement therapy include: 

• Active breast cancer (or other hormone-sensitive cancers)
• History of myocardial infarction (heart attack) or stroke
• Undiagnosed vaginal bleeding
• History of deep vein thrombosis (blood clot in the veins). These individuals should especially avoid oral formulations (e.g., tablets).
• Porphyria (rare disorders caused by a buildup of natural chemicals needed to make heme, a part of hemoglobin)

HRT and blood clot risk

Blood clot risk has not been studied in adults with Down syndrome. One study found Down syndrome to be a risk factor for blood clots in children (8). People with Down syndrome may have other risk factors for blood clots, like autoimmune diseases.

Oral estrogen has been reported to increase the risk of blood clots in women without Down syndrome. However, a small but important study showed that transdermal estrogen patches did not increase the risk of blood clots in women without Down syndrome (5). These have not been studied in women with Down syndrome.

Some types of oral progesterone, like micronized progesterone (brand name Prometrium) and non pregnalone progesterones (like norethindrone), also do not increase blood clot risk (5).

Other oral progesterones, like megesterol (Megace) derivatives, do increase the risk of blood clots.

Larger studies are needed to understand blood clot risk with different formulations of estrogen and progesterone.

HRT and breast cancer

The Women’s Health Initiative study in the late 1990s/early 2000s suggested that estrogen and progesterone therapy increased the risk of breast cancer. Reanalysis of the data has shown the issue to be more complex. One reanalysis found (3):

• Estrogen alone actually decreased relative risk of breast cancer by 22%.
• Estrogen plus progesterone did NOT reach statistical significance for increasing breast cancer relative risk.

Other studies suggest that the type of progesterone and length of use might matter. One study found that micronized progesterone was not associated with increased risk of breast cancer (6).

It is interesting to note that women with Down syndrome have lower rates of breast cancer compared to women without Down syndrome (9). For more information on breast cancer in women with Down syndrome, please see the article Breast Cancer Screening for Women with Down Syndrome.

HRT and osteoporosis

Hormone replacement therapy is not an approved treatment for osteoporosis. However, estrogen given during menopause could help prevent future fracture risk. Hormone replacement therapy may help prevent osteoporosis (10). For more information on osteoporosis in people with Down syndrome, see the article Osteoporosis and Osteopenia: Low Bone Density.

HRT and Alzheimer’s disease

One study showed that an early age of menopause in women with Down syndrome is associated with an earlier diagnosis of Alzheimer’s disease (11).

In women without Down syndrome, the presence of nighttime vasomotor symptoms (hot flashes) may be a sign of increased risk of developing Alzheimer’s disease in the future (12).

The Women’s Health Initiative initially found an elevated risk of Alzheimer’s in women over age 65 taking estrogen and progesterone hormone replacement therapy (13). However, studies have also found that beginning hormone replacement therapy within 5 years of menopause led to a 30% reduction in Alzheimer’s disease, especially if it was used for 10 or more years (14). It has been suggested that the timing of the hormone replacement therapy (how close to the start of menopause it is initiated and for how long it is given) may influence how protective it is (15). This is an area that needs more research.

Because the risk of developing Alzheimer’s disease is so high for women with Down syndrome, the potential connections to hormone replacement therapy are interesting. However, at this time, more research is needed to understand if hormone replacement therapy may impact Alzheimer’s disease in women with Down syndrome.

HRT dosing

There are many available hormone replacement therapy dosing regimens. The following is one of many approaches.

Because transdermal estrogen does not appear to be associated with increased risk of blood clots, it is often the preferred form of estrogen. It is often prescribed as:

• Transdermal estrogen (for example, Mylan estradiol transdermal patch, apply one patch twice weekly)

If progesterone is needed to protect the uterus, micronized progesterone is often used because it appears to not be associated with an increased risk of breast cancer (6).

• There are two standard approaches to dosing of micronized progesterone (16):
  • 100 mg daily (continuous dosing)
  • 200 mg daily for 12-14 days per month (sequential dosing)

Resources

Down syndrome

Breast Cancer Screening

Menopause

Osteoporosis and Osteopenia

General

Porphyria (Mayo Clinic)

References

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2. Maki PM, Jaff NG. Menopause and brain fog: How to counsel and treat midlife women. Menopause. 2024;31(7):647-649. doi:10.1097/GME.0000000000002382

3. Goldman JA. The Women’s Health Initiative 2004 – Review and critique. MedGenMed. 2004;6(3):65.

4. Rossouw JE, Prentice RL, Manson JE, et al. Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA. 2007;297(13):1465-1477. doi:10.1001/jama.297.13.1465

5. Canonico M, Oger E, Plu-Bureau G, et al. Hormone therapy and venous thromboembolism among postmenopausal women: Impact of the route of estrogen administration and progestogens: The ESTHER study. Circulation. 2007;115(7):840-845. doi:10.1161/CIRCULATIONAHA.106.642280

6. Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: A case-control study among post-menopausal women in France. PLoS One. 2013;8(11):e78016. doi:10.1371/journal.pone.0078016

7. Chlebowski RT, Anderson GL, Sarto GE, et al. Continuous combined estrogen plus progestin and endometrial cancer: The Women’s Health Initiative randomized trial. J Natl Cancer Inst. 2015;108(3):djv350. doi:10.1093/jnci/djv350

8. Journeycake JM, Brumley LE. Down syndrome as an independent risk factor for thrombosis in children. Blood. 2006;108(11). doi:10.1182/blood.V108.11.1489.1489

9. Hasle H, Friedman JM, Olsen JH, Rasmussen SA. Low risk of solid tumors in persons with Down syndrome. Genet Med. 2016;18(11):1151-1157. doi:10.1038/gim.2016.23

10. Stevenson J; medical advisory council of the British Menopause Society. Prevention and treatment of osteoporosis in women. Post Reprod Health. 2023;29(1):11-14. doi:10.1177/20533691221139902

11. Schupf N, Lee JH, Pang D, et al. Epidemiology of estrogen and dementia in women with Down syndrome. Free Radic Biol Med. 2018;114:62-68. doi:10.1016/j.freeradbiomed.2017.08.019

12. Thurston RC, Maki P, Chang Y, et al. Menopausal vasomotor symptoms and plasma Alzheimer disease biomarkers. Am J Obstet Gynecol. 2024;230(3):342.e1-342.e8. doi:10.1016/j.ajog.2023.11.002

13. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: The Women’s Health Initiative Memory Study: A randomized controlled trial. JAMA. 2003;289(20):2651-2662. doi:10.1001/jama.289.20.2651

14. Shao H, Breitner JC, Whitmer RA, et al. Hormone therapy and Alzheimer disease dementia: New findings from the Cache County Study. Neurology. 2012;79(18):1846-1852. doi:10.1212/WNL.0b013e318271f823

15. Guo H, Liu M, Zhang L, et al. The critical period for neuroprotection by estrogen replacement therapy and the potential underlying mechanisms. Curr Neuropharmacol. 2020;18(6):485-500. doi:10.2174/1570159X18666200123165652

16. Flores VA, Pal L, Manson JE. Hormone therapy in menopause: Concepts, controversies, and approach to treatment. Endocr Rev. 2021;42(6):720-752. doi:10.1210/endrev/bnab011