The Nurses’ Health Study
The Nurses’ Health Study (NHS) has provided significant insights into the impact of hormone replacement therapy (HRT) on all-cause mortality. Here are the key findings related to HRT and all-cause mortality:
Hormone Replacement Therapy (HRT) and All-Cause Mortality
- Combined Estrogen and Progestin Therapy:
- The NHS indicated that long-term use of combined estrogen and progestin therapy was associated with an increased risk of certain conditions, such as breast cancer, heart disease, stroke, and blood clots. These increased risks contributed to a higher all-cause mortality rate in women who used combined HRT for extended periods.
- Estrogen-Only Therapy:
- For women who had undergone a hysterectomy, estrogen-only therapy showed a different risk profile. The NHS found that short-term use of estrogen-only HRT did not significantly increase the risk of breast cancer and was associated with a reduction in the risk of heart disease and all-cause mortality when compared to non-users. However, long-term use still posed risks, including an increased risk of stroke.
- Duration and Timing of HRT Use:
- The NHS highlighted the importance of the duration and timing of HRT use. Women who started HRT closer to the onset of menopause and used it for a shorter duration tended to have a lower risk of adverse effects and a lower all-cause mortality rate compared to those who started HRT later and used it for a longer period.
- Overall Mortality Impact:
- Overall, the NHS suggested that while HRT can offer benefits, particularly in managing menopausal symptoms and reducing the risk of osteoporosis, the associated risks can outweigh these benefits, especially with long-term use of combined HRT. The findings emphasized the importance of individualized risk assessment and careful consideration of the benefits and risks before starting HRT.
These insights from the NHS have contributed to a more nuanced understanding of HRT, leading to recommendations for more personalized approaches in its use, considering the individual’s health profile and risk factors.
The Women’s Health Initiative
The Women’s Health Initiative (WHI) was a major research program initiated by the National Institutes of Health (NIH) in the United States to address the most common causes of death, disability, and poor quality of life in postmenopausal women. The WHI included clinical trials and observational studies that focused on several key health issues, including hormone replacement therapy (HRT), dietary modifications, calcium and vitamin D supplementation, and their impacts on health outcomes.
Key Findings of the Women’s Health Initiative (WHI)
Hormone Replacement Therapy (HRT)
- Combined Estrogen and Progestin Therapy:
- The WHI found that combined HRT (estrogen plus progestin) increased the risks of breast cancer, heart disease, stroke, and blood clots.
- This therapy also increased the risk of dementia in women aged 65 and older.
- Despite these risks, combined HRT was found to reduce the risk of colorectal cancer and bone fractures.
- Estrogen-Only Therapy:
- For women who had undergone a hysterectomy, estrogen-only HRT showed a different risk profile. It was associated with a reduced risk of breast cancer compared to the combined therapy but still increased the risks of stroke and blood clots.
- Estrogen-only therapy also reduced the risk of bone fractures.
- All-Cause Mortality:
- The WHI found that HRT did not significantly affect all-cause mortality over the long term. The increased risks of certain diseases were somewhat balanced by reduced risks of others, but the net effect on overall mortality was neutral.
Dietary Modifications
- Low-Fat Dietary Pattern:
- The WHI examined the effects of a low-fat dietary pattern on health outcomes and found that it did not significantly reduce the risk of breast cancer, colorectal cancer, or heart disease.
- However, there was a modest reduction in the risk of developing invasive breast cancer among women who adhered to the low-fat diet.
Calcium and Vitamin D Supplementation
- Calcium and Vitamin D:
- The WHI study on calcium and vitamin D supplementation showed that these supplements did not significantly reduce the risk of hip fractures or colorectal cancer in the general population of postmenopausal women.
- There was a small benefit in bone density and a reduced risk of total fractures in women who adhered to the supplementation regimen.
Impact and Implications
The WHI’s findings have had a profound impact on clinical practice and public health guidelines, particularly regarding the use of HRT. The significant risks associated with combined HRT led to a more cautious approach to its prescription, emphasizing the importance of individualized risk assessment and the consideration of non-hormonal alternatives for managing menopausal symptoms.
The study also underscored the complexity of dietary interventions and the need for a holistic approach to diet and lifestyle in reducing the risk of chronic diseases.
Cyclic Menopausal Hormone Therapy (MHT)
Use continuous oestrogen and cyclic progestogen combinations at peri-menopause or if less than 12 months amenorrhoea
| Low Dose | ||
| Product | Presentation | Composition |
| Femoston | tablet | 1mg oestradiol/10mg dydrogesterone |
| Estrogel Pro* | Combination pack of oestradiol transdermal gel, with micronised progesterone capsules. | 1 pump (0.75mg oestradiol hemihydrate) daily, and 2 capsules (200mg) micronised progesterone orally for 12 days out of a 28-day cycle |
| Medium dose | ||
| Trisequens* | tablet | 1 and 2mg oestradiol hemihydrate/1mg norethisterone |
| Femoston | tablet | 2mg oestradiol/10mg dydrogesterone |
| Estalis sequi 50/140) | transdermal patch | 50mcg 17β oestradiol/140mcg norethisterone acetate (twice weekly application) |
| Estalis sequi 50/250 (same oestrogen, more progestogen than Estalis sequi 50/140) | transdermal patch | 50mcg 17β oestradiol/250mcg norethisterone acetate (twice weekly application) |
| Estrogel Pro* | Combination pack of oestradiol transdermal gel, with micronised progesterone capsules. | 2 pumps (1.5mg oestradiol hemihydrate) daily, and 2 capsules (200mg) micronised progesterone orally for 12 days out of a 28-day cycle |
Continuous combined Menopausal Hormone Therapy (MHT)
Should be used if 12 months since LMP or after 12 months cyclical MHT
| Low dose | ||
| Product | Presentation | Composition |
| Angeliq1/2* | tablet | 1mg oestradiol hemihydrate/2mg drospirenone |
| Femoston-conti | tablet | 1mg oestradiol/5mg dydrogesterone |
| Kliovance* | tablet | 1mg oestradiol hemihydrate/0.5mg norethistrone |
| Bijuva* | capsule | 1mg oestradiol/100mg micronised progesterone |
| Estrogel Pro* | Combination pack of oestradiol transdermal gel, with micronised progesterone capsules. | 1 pump (0.75mg oestradiol hemihydrate) daily, and 1 capsule (100mg) micronised progesterone orally for 25 days out of a 28-day cycle^ |
| Other Low dose hormonal options | ||
| Livial*, Xyvion* | tablet | 2.5mg tibolone |
| Duavive* | tablet | 0.45mg conjugated equine oestrogens / 20mg bazedoxifene acetate |
| Medium dose | ||
| Kliogest* | tablet | 2mg oestradiol hemihydrate/1mg norethistrone |
| Estalis continuous 50/140 | transdermal patch | 50mcg 17β oestradiol/140mcg norethisterone acetate (twice weekly application) |
| Estalis continuous 50/250 (same oestrogen, more progestogen than Estalis continuous 50/140) | transdermal patch | 50mcg 17β oestradiol/250mcg norethisterone acetate (twice weekly application) |
| Estrogel Pro* | A combination pack of oestradiol transdermal gel with micronised progesterone capsules is needed. | 2 pumps (1.5mg oestradiol hemihydrate) daily, and 1 capsule (100mg) micronised progesterone orally for 25 days out of a 28-day cycle^ |
^Can be given daily if adherence is an issue
Oestrogen-only therapy:
Only use these if the patient has had a hysterectomy or in combination with a progestogen or Mirena if an intact uterus
| Low dose | ||
| Product | Presentation | Composition |
| Estrofem* | tablet | 1mg oestradiol hemihydrate |
| Progynova | tablet | 1mg oestradiol valerate |
| Premarin* | tablet | 0.3mg conjugated equine oestrogens |
| Climara 25 | transdermal patch | 25mcg oestradiol (weekly application) |
| Estradot 25 or 37.5 | transdermal patch | 25 or 37.5mcg oestradiol (twice weekly application) |
| Estraderm 25 MX | transdermal patch | 25mcg oestradiol (twice weekly application) |
| Estrogel* | gel | 0.75mg oestradiol hemihydrate= 1 pump daily |
| Medium dose | ||
| Estrofem*, Zumenon | tablet | 2mg oestradiol hemihydrate |
| Progynova | tablet | 2mg oestradiol |
| Premarin* | tablet | 0.625mg conjugated equine oestrogens |
| Climara 50 | transdermal patch | 50mcg oestradiol (weekly application) |
| Estradot 50, Estraderm 50 MX | transdermal patch | 50mcg oestradiol (twice weekly application) |
| Sandrena | gel | 1mg oestradiol daily |
| Estrogel* | gel | 1.5mg oestradiol hemihydrate = 2 pumps daily |
| High dose | ||
| Climara 75 | transdermal patch | 75mcg oestradiol (weekly application) |
| Estradot 75, Estradot 100 | transdermal patch | 75 or 100mcg oestradiol (twice weekly application) |
| Climara 100 | transdermal patch | 100mcg oestradiol (weekly application) |
| Estraderm 100 MX | transdermal patch | 100mcg oestradiol hemihydrate (twice weekly application) |
| Estrogel* | gel | 2.25mg oestradiol hemihydrate = 3 pumps daily or 3.0mg oestradiol = 4 pumps daily |
| Oestrogen only vaginal therapy If prescribing vaginal oestrogen rather than systemic hormone therapy, a progestogen is not required. | ||
| Product | Presentation | Composition |
| OvestinOvestin | creampessary | 0.5mg oestriol = 1 application0.5mg oestriol |
| Vagifem Low | pessary | 10mcg oestradiol hemihydrate |
Progestogen
Suggested alternative doses for use with the oestrogen preparations above where fixed dose therapy is not suitable
| Low dose for use with low dose oestrogen | ||
| Product | Presentation | Composition |
| Provera (1/2 of 5mg tablet) | tablet | 2.5mg medroxyprogesterone acetate |
| Provera 2.5mg tablet* | tablet | 2.5mg medroxyprogesterone acetate |
| Primolut N (1/4 of 5mg tablet) | tablet | 1.25 mg norethisterone |
| Prometrium* | capsule | 100mg micronised progesterone orally for 25 days out of a 28-day cycle1 or 200mg orally daily for 12 days out of a 28-day cycle |
| Mirena*(PBS indication for contraception/menorrhagia) | Intrauterine system | Levonorgestrel 52mg (approx. 20mcg daily over 5 years) |
| Medium dose for use with medium dose oestrogen 2 | ||
| Product | Presentation | Dose |
| Primolut N (1/4 of 5mg tablet) | tablet | 1.25 mg norethisterone |
| Provera, Ralovera | tablet | 5mg medroxyprogesterone acetate |
| Prometrium* | capsule | 100mg micronised progesterone orally for 25 days out of a 28-day cycle^ or 200mg orally for 12 days out of a 28-day cycle |
| Mirena*(PBS indication for contraception/menorrhagia) | Intrauterine system | Levonorgestrel 52mg (approx. 20mcg daily over 5 years) |
| Higher dose (for use in cyclical therapy or continuous therapy with high dose oestrogen)2 | ||
| Primolut N (1/2 5mg tablet) | tablet | 2.5mg norethisterone |
| Provera, Ralovera | tablet | 10mg medroxyprogesterone acetate |
| Prometrium* | capsule | 100mg micronised progesterone orally for 25 days out of a 28-day cycle1 or 200mg orally for 12 days out of a 28-day cycle |
| Mirena*(PBS indication for contraception/menorrhagia) | Intrauterine system | Levonorgestrel 52mg (approx. 20mcg daily over 5 years) |
Notes
- Can be given daily if adherence is an issue
- There are insufficient data for the need to increase the dose of micronised progesterone with higher oestrogen doses, or safety of higher doses. Therefore, the current recommendation is 200mg of progesterone for 12 days on a cyclical regimen or 100mg per day on a continuous regimen. This may not be enough in terms of unscheduled bleeding with higher doses of oestrogen.
- Patients commenced on continuous combined MHT should not bleed after the first 6 months of use. If they do bleed, they need to be investigated.
- Those using combined cyclic therapy should have a withdrawal bleed around the end of the progestogen phase and if they bleed out of cycle, too long or too heavily, they also need an ultrasound.
- If investigation of unscheduled or out-of-cycle bleeding discloses no endometrial abnormality, it may be appropriate to increase the dose of progestogen to 200mg daily for women using high-dose oestrogen on a continuous regimen and to 300-400mg for 12 days per month for those using high-dose oestrogen on a cyclic regimen.
- The use of oestrogen plus progestogen is intended to reduce the risk of endometrial cancer to the level seen in an untreated population and not to zero. Consequently, women and their doctors should be aware of the importance of investigating any postmenopausal bleeding.
HRT and Factor V Leiden
Observational studies have not shown an increased risk of DVT in postmenopausal women using transdermal oestrogen