Two different types of menopausal hormone therapy — estrogen alone and estrogen plus progestin — have opposite effects on breast cancer incidence that persist long after stopping treatment, according to over 19 years of follow-up of the landmark Women’s Health Initiative (WHI) released today.

The use of conjugated equine estrogens (CEE) alone significantly decreases breast cancer incidence and deaths from breast cancer, while CEE plus medroxyprogesterone acetate (MPA) significantly increases the risk of developing the disease.

In both instances, these effects linger for decades after discontinuation.

Women considering estrogen alone should know it’s safer and there may be a breast cancer benefit associated with its use.

Women considering estrogen plus progestin have a 20-year and maybe lifetime increased breast cancer risk although the absolute risk is very small.

In about meta-analysis of 58 observational studies, estrogen plus progestin and estrogen alone were both associated with a significantly increased risk of breast cancer

In the Million Women Study, both estrogen plus progestin as well as estrogen alone were associated with a significantly increased risk of dying from breast cancer.

WHI randomized controlled trials with more than 19 years of follow-up.

From 1993 to 1998, more than 27,000 postmenopausal women aged 50 to 79 years with no prior breast cancer enrolled in one of two randomized, placebo-controlled WHI trials implemented at 40 US centers, with follow-up through September 2016.

Women with an intact uterus received CEE (0.625 mg/day) plus MPA (2.5 mg/day) or placebo (n = 8102) for a median of 5.6 years.

Women with prior hysterectomy received CEE alone (n = 5310) or placebo (n = 5429) for a median of 7.2 years.

After about 19 years of follow-up, CEE alone resulted in a significant 23% reduction in breast cancer incidence.

Whereas CEE+MPA resulted in a significant 29% increased risk of breast cancer.

Taking estrogen/progestin for 5 years exposes a 20-year risk of increasing breast cancer risk.

In terms of deaths from breast cancer, there was 45% increase of borderline significance, with CEE+MPA and a significant 44% reduction with CEE alone.

Women with short-term estrogen exposure they are not at increased risk, and in fact, the data suggest there is decreased risk.

Vasomotor symptoms return in approximately 50% of women after discontinuation of hormonal therapy.

For recurrent hot flashes gradual taper of normal therapy over six months to one year is probably beneficial.

For women in with early surgical menopause the primary ovarian insufficiency show increased risk of cardiovascular disease, osteoporosis and fracture with high risk of affective disorder is Parkinson’s disease, cognitive dysfunction and sexual dysfunction in women in later menopause.

In the above patients hormone therapy is recommended at least until the expected age of natural menopause, approximately 51 years, to reduce long-term health risks.

The initiation of systemic hormonal therapy in women older than 60 years, in general, not recommended.

Hormonal therapy discontinuation is suggested after five years or by the age of 60.

Up to 8% of women continue to have hot flashes for 20 years or more after menopause and the decision to continue or stop hormone therapy includes assessment of its risk and benefits, which may include relief from hot flashes, protection against bone loss, and preservation of quality-of-life.

The risks of hormones increase with age, and duration of use.

The risk of stroke is increased with hormonal therapy, it is rare event in this age group, with an attributable risk of less than 0.5 additional cases per thousand women per year.

While there is increased venous thrombotic events with the use of oral estrogens, it was not identified as an increased risk with transdermal estradiol use.

In the WH I study the attributable risk of breast cancer with estrogen-progesterone therapy was low with less than one additional case per 1000 women per year, and no increase risk of breast cancer with short term estrogen-progesterone therapy or in women with estrogen alone.

Gallbladder diseases increases with oral estrogen use.

In the WHI study with over 18 years of cumulative follow-up, the use of estrogen-progestogen therapy for a median of 5.6 years with estrogen therapy for a median of 7.2 years was not associated with increased risk of all cause, cardiovascular, or cancer mortality.

The USPSTF recommends against the use of estrogen with or without progestin for prevention of chronic conditions such as coronary heart disease.

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