What types of Hormone Replacement Therapy are safe?

Tagged hormone replacement therapy, menopause, deep vein thrombosis; Comments 6 ; Posted 8 years ago by Andreas Obermair

This article is important for women who need their ovaries removed and who will become menopausal as a consequence. These are women who carry Lynch, BRCA 1/2, or who require surgery for gynaecological cancer or severe endometriosis at young ages.

Hormone Replacement Therapy (HRT) is used for management of menopausal symptoms such as hot flashes, dry skin and vulvovaginal atrophy. A well-documented risk of using HRT includes an increased risk of deep vein thrombosis (DVT), which may even lead to blood clots in the lungs (Pulmonary Emboli, PE).

Studies published in 2002 suggested that HRT can increase the risk of DVT and PE two- or threefold. New research suggests that the risk of blood clots depends on the type of HRT and how HRT is administered.

Menopausal women who still have a uterus are normally prescribed a combination of estrogen and progestin therapy. In these women the estrogen provides the HRT and the progestin reliably protects the uterus from developing endometrial cancer. Women who have undergone a hysterectomy (and do not have a uterus any longer) don’t require the progestin and will need estrogen only. 

Observational studies have suggested the DVT/PE risk is higher among users of estrogens plus progestogens than among users of estrogens only.

There is also a difference as to how HRT is administered. It can be administered as oral tablets, dermal patches, creams or suppositories. In the past it has been suggested that the risk of DVT/PE is higher with oral tablets compared to transdermal administration (through the skin). Currently all progestogen and estrogen therapy has a warning that they may increase clotting risk.

The latest research

A recent case-control study published in the reputable journal Menopause in July 2016 provides further evidence on the topic which I summarise here.

The aim of the study was to investigate if HRT increased the risk of DVT, if the route of administration influenced that risk, and it also wanted to clarify the effect of the progestin component on the risks of HRT.

The study was conducted in Sweden between 2003 and 2009 and included 838 cases of DVT and 891 controls (similar women without a DVT) with a mean age of 55 years. Women in the study were 18 to 64 years of age who had developed a DVT for the first time in the leg, pelvis or in the lungs. The researchers collected the following information from patients: hormone treatment within 90 days preceding the DVT, height, weight, menopause status, and any previous gynaecological surgery. Participants were asked if there was any immobilization or smoking during the three-month period before the DVT occurred. For patients on HRT, dose and route of administration were recorded.

Did HRT increase the risk of DVT?

Overall, yes. Current use of hormone therapy was reported by 237 cases with DVT (28.3%) and 191 (21.4%) controls. Current use of any hormone therapy was associated with a 72% increased risk of DVT, OR 1.72 (95% CI 1.34-2.20).

Was there a higher risk of DVT with combined estrogen and progestin therapy, compared to estrogen therapy only?

Yes. Use of combined hormone therapy (estrogen plus progestin) was associated with an almost threefold risk of DVT (OR 2.85, 95% CI 2.08- 3.90). Use of estrogen only was associated with a very small and imprecise increased risk increase.

Did route of administration increase risk of VTE?

Again, yes. Similar to previous studies, an increased risk of DVT was observed with the use of oral but not with transdermal estrogen patches. For users of orally administered estrogen there was a 65% increase on the risk of DVT, whereas for users of estrogen patches the risk was 10% lower than average.

What does this all mean for patients?

• Women who have to have a hysterectomy and removal of the ovaries can receive estrogen only replacement (without progestin) and should receive the estrogen as a skin patch. Their risk of DVT is not increased.
• For women who require a combination HRT with estrogen and progestin, they should avoid HRT as oral tablets. For these women an estrogen skin patch and a Mirena IUD might be a lot safer than the traditional tablets.

Estrogen tablets may exert a clotting effect through the liver first-passage effect (where the estrogens are quickly broken down by the liver). Therefore, there is increased plasma levels of Factor IX, prothrombin fragment 1+2 APC resistance, and C-reactive protein. It has been found that oral estrogen therapy decreases levels of tissue plasminogen activator antigen and plasminogen activator inhibitor activity, which are all blood clotting factors. Transdermal administration of hormone therapy as skin patches overcomes this first-passage effect on the liver.

• Numerous studies have shown that estrogen replacement therapy can be safely offered to women with a history of gynaecological cancer (e.g., endometrial, ovarian, cervical, vulval and vaginal cancer).

What do we learn from this research?

1. Hormone therapy is an effective treatment of menopausal symptoms.
2. The risk of a blood clots is lower for women who use estrogen only.
3. Transdermal estrogen (skin patches) and topical estrogen (vaginal pessary or cream) don’t seem not to be related to an increased risk of clotting.
4. HRT is safe for most women previously diagnosed with gynaecological cancer.

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