The Difference Between MHT and HRT: Key Facts
MHT treatment may offer significant protection against osteoporosis for some women.
Menopausal hormone therapy (MHT) is differentiated from hormone replacement therapy (HRT) by treatment goals related to the age of the individual. If used in consideration of individual risks, MHT could be beneficial in reducing osteoporosis and cardiovascular disease with little to no risk for breast cancer. A WCO IOF-ESCEO plenary presentation by Irene Lambrinoudaki, MD, Endocrinologist at the National and Kapodistrian University of Athens, Greece, summarized studies looking at how and when estrogen (and progesterone) have been used to treat women during perimenopause.
Menopausal Hormone Therapy (MHT) and Hormone Replacement Therapy (HRT)
In her presentation, Dr. Lambrinoudaki made an important distinction between MHT and HRT. MHT uses low doses of estrogen either as a monotherapy or in conjunction with progesterone to manage menopausal symptoms and osteoporosis. It is used in women who have transitioned to menopause or are in their 50s or older. In women who transitioned with the uterus intact, dual hormone therapy with progesterone is typically used. In transitioning women without a uterus, estrogen monotherapy is used. Common estrogen doses for MHT use are:
Standard age perimenopause
Estradiol (17b-E2)- oral 1 mg or 25-37 mg transdermal
Conjugated equine estrogen (CEE)- oral 0.3-0.45 mg
Menopause
Estradiol (17b -E2)- oral 0.25-1 mg or 14-37 mg transdermal
Conjugated equine estrogen (CEE)- oral 0.3-0.45 mg
HRT, as the name implies, is designed to replace estrogen. In addition to its use in treating girls and women with Turner’s syndrome, women who transition into menopause early (40s or younger) or who experience primary ovarian insufficiency (POI) may benefit from HRT. In young women or those with POI, HRT therapy increases estrogen levels to the pre-menopause state and treatment continues at this level until the age of natural menopause. For HRT, higher doses of estrogen are recommended:
Young age perimenopause
Estradiol (17b -E2)- oral 2 mg or 50 mg transdermal
Conjugated equine estrogen (CEE)- oral 0.625 mg
POI
Estradiol (17b -E2)- oral 2-4 mg or 50-100 mg transdermal
Conjugated equine estrogen (CEE)- oral 0.625-1.25 mg
Estrogen and Osteoporosis
Briefly, estrogen receptors are expressed on all classes of osteo-stem cells thus the hormone plays a role in the fine balance between bone formation and resorption. Estrogens inhibit osteoblast apoptosis and reduce osteoclastic differentiation and activity, thus favoring bone formation over resorption. With any decrease in estrogen, that balance swings in the other direction giving bone resorption the upper hand, leading to osteoporosis.
Summarizing data mostly collected by the Women’s Health Initiative (WHI, n>26,000 women), Dr. Lambrinoudaki showed that women 50-79 years old treated with either estrogen monotherapy (conjugated equine estrogen, CEE) or estrogen-progesterone combination had, compared their respective placebos, a reduced risk of total fractures (HR 0.70, 95%CI 0.63-0.79 and 0.76, 95% CI 0.69-0.85 respectively). The reduced risk extended to spine (HR 0.62 and 0.66) and hip fractures (HR 0.61 and 0.67). The general risk reduction in osteo-fractures by estrogen, either as a monotherapy or in combination with progesterone, was confirmed by the large meta-analysis from Gartlehner et al and by Zhu et al.
Dr. Lambrinoudaki also addressed the issue of stopping hormone therapy. Here the data is a little unclear but not necessarily unhopeful. In the early results of the Prospective Epidemiological Risk Factor (PERF) study, it was found that women who had taken hormone therapy for 2-3 years and then stopped had significantly higher bone mass density (BMD) measures than women on placebo at follow-ups 5, 11, and 15 years later. However, when these women stopped taking estrogen, the rate of bone loss resumed at a pace that matched those in the placebo group, but the placebo group still had a four-fold increase in fracture risk. By comparison, women who remained on estrogen therapy long term continued to benefit from the effects of estrogen on bone mass.
Alternatively, authors from the WHI study which focused on a 5-year follow-up of women who quit MHT, concluded that stopping MHT did not provide long term benefit from fracture risk, however, Dr. Lambrinoudaki suggests otherwise. She took a closer look at the numbers which suggests that there is a (non-statistically significant) difference between women previously treated with estrogen alone and those who were on an estrogen-progesterone therapy. Hazard ratios reported by Watts et al for women on estrogen alone seem to suggest a lower risk of fracture (HR 0.78, 95%CI 0.42-1.44) compared to those who had a dual hormone therapy (HR 1.13, 95%CI 0.72-1.78). It may not seem like a big difference but the addition of progesterone, as a diminishing factor on the effects of estrogen, seems to be part of a developing pattern on the downside of MHT.
Cardiovascular Disease, Breast Cancer, and Stroke Risks
Initial presentation of the WHI data suggested that in general MHT use was associated with increased risk of cardiovascular disease (CVD), stroke, and breast cancer, leading to a worldwide decrease in MHT use. However, the 18-year follow-up of women in the WHI study by Prentice et al suggests those negative effects of MHT were specific to women on dual hormone therapy – estrogen and progesterone.
For this 18-year follow-up study, only women who were originally 50-59 were included. During both the intervention and follow-up phases, those treated with an estrogen monotherapy had a lower risk of coronary heart disease, breast cancer, hip fracture, and all-cause mortality. When looking at stroke, these women were at higher risk during the intervention phase but with time, that risk dropped significantly. In comparison, women treated with estrogen and progesterone carried significant risk for coronary heart disease, breast cancer and stroke measured at both points in time. The authors concluded that the risks of estrogen-progesterone MHT outweighed any benefit, but that the risks of estrogen as a monotherapy could not outweigh its benefits.
Concluding Advice for Clinicians
MHT can be a beneficial tool for combating osteoporosis especially when initiated within the first 10 years of menopause in women at low to medium fracture risk. The benefits of estrogen are present regardless of oral or transdermal dosing. Transdermal dosing, though, could have fewer side effects than oral dosing because it sidesteps primary liver metabolism.
Prescribing physicians should take an individualized approach to MHT, considering a woman’s specific risk for breast cancer, heart disease, and osteoporosis. In terms of osteoporosis, an individual’s calcium and vitamin D intake should also be determined and adjusted as needed. If or when MHT is discontinued, one should be prepared to replace MHT with another bone-specific treatment especially in women with a high risk of fracture. In the end, Dr. Lambrinoudaki concluded that, “if properly individualized, MHT is a safe and effective treatment for the majority of peri- and postmenopausal women.”
