Dr. Ron’s Research Review – March 7, 2018

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This week’s research review focuses on micronized progesterone vs medroxyprogesterone.

Medroxyprogesterone

Use of hormone therapy for five years with estrogen plus medroxyprogesterone increases women’s risk of breast cancer, while estrogen alone does not have the same risk and may now be associated with reduced mortality from breast cancer in the longer term. (Shufelt and Bairey Merz, 2017)
The most valid evidence presently suggests that CEE-only treatment does not increase the risk of breast cancer and even may reduce it. But its combination with a synthetic progestogen (mainly medroxyprogesterone acetate) is a critical issue since it seems to be primarily associated with an increased incidence of breast cancer, however similar to or lower than that associated with some common lifestyle factors. Though not yet proven in a randomized, controlled trial, MHT continuously combining oral micronized progesterone with transdermal estradiol can presently be considered as the optimal MHT. It is not only safer than custom-compounded bioidentical hormones but also than oral conventional MHT and has the best breast profile; registered products for such optimal MHT are available around the world and must be preferred. (L'Hermite, 2017)

Micronized progesterone

Based on a systematic literature review on the impact of menopausal hormone therapy (MHT) containing micronized progesterone on the mammary gland, an international expert panel's recommendations are as follows: (1) estrogens combined with oral (approved) or vaginal (off-label use) micronized progesterone do not increase breast cancer risk for up to 5 years of treatment duration; (2) there is limited evidence that estrogens combined with oral micronized progesterone applied for more than 5 years are associated with an increased breast cancer risk; and (3) counseling on combined MHT should cover breast cancer risk - regardless of the progestogen chosen. Yet, women should also be counseled on other modifiable and non-modifiable breast cancer risk factors in order to balance the impact of combined MHT on the breast. (Stute et al., 2018) (Stute, 2014)

Dr. Ron


 

Articles

Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal.
            (L'Hermite, 2017) Download
The many advantages of registered bioidentical sex hormones over registered, conventional, non-bioidentical menopausal hormone therapy (MHT) are considered. The transdermal route of estrogen administration avoids excess venous thromboembolic and ischemic stroke events. There is some indication that conjugated equine estrogens are more thrombogenic and most likely induce some hypertensive responses; estradiol might also be superior to conjugated equine estrogens (CEE) in terms of global cardiovascular health. The most valid evidence presently suggests that CEE-only treatment does not increase the risk of breast cancer and even may reduce it. But its combination with a synthetic progestogen (mainly medroxyprogesterone acetate) is a critical issue since it seems to be primarily associated with an increased incidence of breast cancer, however similar to or lower than that associated with some common lifestyle factors. Though not yet proven in a randomized, controlled trial, MHT continuously combining oral micronized progesterone with transdermal estradiol can presently be considered as the optimal MHT. It is not only safer than custom-compounded bioidentical hormones but also than oral conventional MHT and has the best breast profile; registered products for such optimal MHT are available around the world and must be preferred.

Reassurance for many healthy women considering HRT.
            (Shufelt and Bairey Merz, 2017) Download
In Manson and colleagues’ new, age group analyses, women treated at age 50-59 had a greater reduction in all cause mortality than women treated at 70-79 years both during treatment (hazard ratio 0.61; 0.43 to 0.87) and after 18 years’ follow-up (0.87; 0.76 to 1.00). These findings are important because they align with current guidelines that support the use of hormone therapy by healthy and recently menopausal women for symptom control.Most notable in the new analyses are differences in mortality from breast cancer between formulations. During the original trials, breast cancer risk was increased in the oestrogen plus progestin arm (1.25; 1.07 to 1.46)8 but not in the oestrogen only arm (0.77; 0.57 to 1.01).9 Ten years after the trials ended, women who took only oestrogen had a significantly lower risk of breast cancer than the placebo group (0.77; 0.62 to 0.95).10 This difference can now be extended to breast cancer mortality. After 18 years of follow-up, women originally randomised to oestrogen alone had significantly lower breast cancer mortality than women randomised to placebo (0.55; 0.33 to 0.92).4 Women randomised to oestrogen plus progestin, however, had a moderate but non-significant increase in risk (1.44; 0.97 to 2.15). Use of hormone therapy for five years with oestrogen plus medroxyprogesterone increases women’s risk of breast cancer, while oestrogen alone does not have the same risk and may now be associated with reduced mortality from breast cancer in the longer term.

Is breast cancer risk the same for all progestogens
            (Stute, 2014) Download
The population-based case–control study CECILE investigated the impact of various menopausal hormone therapy (MHT) products on breast cancer (BC) risk in 1,555 postmenopausal women [1]. The case group (n = 739) included incident cases of in situ (!) or invasive BC in postmenopausal women. The control group (n = 816) included women from the general population within predefined quotas by age and socio-economic status (SES). While quotas by age were applied to obtain similar distributions by age among controls and among cases, quotas by SES in control women were applied to reflect the distribution by SES of women in the general population in the study area. Data of participants were obtained by a structured questionnaire during in-person interviews, and from pathology reports if applicable, respectively. Women were divided into current and past MHT user. MHTs were classified in estrogen-only therapy (ET), estrogen combined with progestin therapy (EPT) and tibolone. EPT was subdivided in three subtypes according to the progestogen constituent: natural micronized progesterone, progesterone derivatives, and testosterone derivatives. In comparison to never MHT users, any current or past MHT use (ET, EPT, tibolone) was not associated with an increased BC risk. However, in subanalysis BC risk was significantly increased for current use of EPT for 4 or more years (n = 73 cases and n = 56 controls, adjusted OR 1.55; 95 % CI 1.02–2.36). Within the group of current EPT users for 4 or more years, 14 cases had used estrogens combined with micronized progesterone (n = 17 controls), and 55 a combination with a synthetic progestogen (n = 34 controls), respectively. Compared to never MHT use, current use of EPT containing a synthetic progestogen for 4 or more years was associated with a significantly increased BC risk (adjusted OR 2.07; 95 % CI 1.26–3.39), but EPT containing micronized progesterone was not (adjusted OR 0.79; 95 % CI 0.37–1.71). 73 % of current MHT users started treatment within the first year of onset of menopause. Early EPT (n = 52 cases and n = 38 controls, adjusted OR 1.65; 95 % CI 1.02–2.69), but not early ET, starters had a significantly higher BC risk compared to never MHT users. In contrast, MHT initiation beyond 1 year after menopause was not associated with an increased BC risk. The authors concluded that: (1) ET and EPT containing natural progesterone did not increase BC risk whereas, (2) BC risk was increased in users of tibolone or EPT containing a synthetic progestogen, respectively, and that (3) MHT use early after onset of menopause was associated with an increased BC risk as compared to women who delay MHT beyond 1 or more years.


 

The impact of micronized progesterone on breast cancer risk: a systematic review.
            (Stute et al., 2018) Download
Postmenopausal women with an intact uterus using estrogen therapy should receive a progestogen for endometrial protection. The debate on bioidentical hormones including micronized progesterone has increased in recent years. Based on a systematic literature review on the impact of menopausal hormone therapy (MHT) containing micronized progesterone on the mammary gland, an international expert panel's recommendations are as follows: (1) estrogens combined with oral (approved) or vaginal (off-label use) micronized progesterone do not increase breast cancer risk for up to 5 years of treatment duration; (2) there is limited evidence that estrogens combined with oral micronized progesterone applied for more than 5 years are associated with an increased breast cancer risk; and (3) counseling on combined MHT should cover breast cancer risk - regardless of the progestogen chosen. Yet, women should also be counseled on other modifiable and non-modifiable breast cancer risk factors in order to balance the impact of combined MHT on the breast.

 

References

L’Hermite, M (2017), ‘Bioidentical menopausal hormone therapy: registered hormones (non-oral estradiol ± progesterone) are optimal.’, Climacteric, 1-8. PubMed: 28301216
Shufelt, C and CN Bairey Merz (2017), ‘Reassurance for many healthy women considering HRT.’, BMJ, 359 j4652. PubMed: 29030494
Stute, P (2014), ‘Is breast cancer risk the same for all progestogens’, Arch Gynecol Obstet, 290 (2), 207-9. PubMed: 24838289
Stute, P, L Wildt, and J Neulen (2018), ‘The impact of micronized progesterone on breast cancer risk: a systematic review.’, Climacteric, 1-12. PubMed: 29384406