ANSWER: Vasomotor symptoms (VMS) persist on average for 7.4 years after menopause, and for many women they may persist for more than 10 years. Vasomotor symptoms have a 50% chance of recurring when hormone therapy (HT) is stopped, independent of the woman’s age or how long she has been using hormones. Discussions about the risks of extended use are difficult, as the long-term follow-up data (especially with regards to breast-cancer risk) are complicated.

The 2017 North American Menopause Society (NAMS) guidelines highlight that ongoing use of systemic MHT by healthy women who initiated therapy within 10 years of menopause onset and without new health risks likely has a safety profile more favorable than for women initiating MHT older than age 65 years. It further states that HT does not need to be routinely discontinued at any arbitrary age or duration of therapy. It is recommended that there be annual re-evaluation, including reviewing comorbidities, and periodic trials of lowering or discontinuing MHT. There is lack of consensus as to whether stopping “cold turkey” or tapering is preferable.

For women considering continuation of MHT beyond the age of 65 years, consideration may be given to changing to low-dose transdermal estrogen to theoretically lower cardiovascular risk in this higher-risk population.

ANSWER: Primary ovarian insufficiency (POI) is the term used to describe the loss of ovarian hormonal function prior to the age of 40 years. Causes may be treatment-induced, surgical, chromosomal, or idiopathic. “Early menopause” describes the similar event in women aged 40-45 years. The basic issue for both groups of women is the same—the loss of ovarian hormonal function impacts quality of life and long-term health.

Associated with POI and early menopause are persistent VMS, early onset of bone loss, development of genitourinary syndrome of menopause (GSM), mood disorders, elevated risk of heart disease, dementia, stroke, Parkinson’s disease, ophthalmic disorders, and increased overall mortality.

For women with POI or early menopause who are free of contraindications, HT is recommended at least until the median age of menopause (52 years). Observational studies suggest that the benefits outweigh the risks for effects on bone, heart, cognition, GSM, sexual function and mood.

As most women with POI/early menopause still have a uterus, treatment with estrogen and progestogen is recommended. As natural estradiol levels at this age would average about 100 pg/ml, the treatment dose that would achieve this level is recommended. A three-year randomized controlled trial (RCT) suggested that transdermal estradiol 100 µg/day restores femoral neck bone mineral density (BMD). Appropriate endometrial protection must be instituted for those with a uterus. This regimen may be superior to oral contraceptive therapy in this subgroup of patients for restoring or maintaining BMD.

ANSWER: GSM is a new term which replaces the antiquated term, vulvovaginal atrophy. Use of the term GSM recognizes that in addition to genital symptoms, lower urinary tract symptoms can be due to estrogen deficiency.

Symptoms of GSM may include genital dryness, burning and irritation, pain with intercourse, urgency, dysuria, and recurrent urinary tract infections. These symptoms are caused by estrogen deficiency in the urogenital tissues. GSM symptoms tend to worsen with age and time since menopause.

Although estrogen therapy is the most effective treatment for GSM, some women may be fearful of using estrogen. Use of lubricants or vaginal moisturizers may ease some of the vaginal symptoms, but are ineffective for urinary tract symptoms, such as urgency or nocturia.

Low-dose vaginal estrogens (available as creams, tablets and rings) are effective and safe treatments. When used as directed, concomitant use of an endometrial protective agent is not indicated, although endometrial safety data beyond one year of use is lacking. Any vaginal bleeding in women using low-dose vaginal estrogens needs to be thoroughly investigated.

There is evidence that vaginal estrogen is beneficial for overactive bladder and recurrent urinary tract infections.

Low-dose vaginal estrogen products have minimal systemic absorption.

Many of the “black box” warnings applied to systemic estrogen may not apply to low-dose vaginal estrogen products. A recent analysis of more than 45,000 women in a Women’s Health Initiative (WHI) substudy showed no increased risk of heart disease, stroke, venous thromboembolic events, fractures or cancers (including breast and endometrial) in low-dose vaginal estrogen users compared to non-users.³ The decision to use vaginal estrogens in women with breast cancer should be made in conjunction with their oncologist. This is especially true for women on aromatase inhibitors.

ANSWER: The relationship between hormone use and breast cancer is complex and the answers are incomplete. There may be differences in breast-cancer risk depending on the choice of estrogen and the choice of endometrial protective agent (for those with a uterus), as well as duration of use.

The WHI study showed an increased risk of breast cancer for women who took conjugated estrogens with medroxyprogesterone acetate continuously, after 5.6 years of use. This resulted in one additional breast cancer diagnosed per 1,000 person-years of use. This increase in risk is similar to that seen with one daily glass of wine, being obese, or being physically inactive. This rare risk may or may not be generalizable to other doses, formulations or preparations. There is some observational data suggesting that micronized progesterone (MP) may have less impact on breast-cancer risk, but this has not been tested in a randomized trial. There is also some observational data that suggests that sequential estrogen-progestogen therapy may incur less risk than continuous combined regimens: this too has not been tested in large randomized trials.

The effect of duration of estrogen-progestogen use on breast-cancer risk is unclear. There is conflicting data from observational studies. In the WHI group, the increased risk of breast cancer was observed after 5.6 years of use.

The impact of estrogen-only therapy on breast-cancer risk is conflicting. The WHI trial showed that conjugated equine estrogens (CEE) alone either reduced or had a null effect on breast-cancer risk. This result may or may not be generalizable to other estrogen preparations. This reduced risk seen in the WHI was only observed in women who were hormone naïve at initiation and who were at least 80% compliant with therapy. There are no RCTs powered to assess effect of long-term estrogen-only therapy on breast-cancer risk. Observational studies on long duration of use are mixed, with some showing an elevated risk of breast cancer after five years of use, and others not.

Limited observational evidence suggests that the use of HT does not further increase the risk of breast cancer in women with a family history of breast cancer.

Different HT regimens may differentially affect breast density. Use of estrogen and progestogen increases breast density, while in trials of up to two years in duration, the combination of conjugated estrogen and bazedoxifene did not increase breast density compared to placebo. Increased breast density is considered an independent risk factor for breast cancer.

ANSWER: Both depressive symptoms and risk of clinical depression increase during the menopause transition. For post-menopausal women without clinical depression, the evidence is mixed with respect to the effects of HT on mood. While some short-term trials suggest that MHT early in the post-menopausal period improves mood, others showed no difference. In the KEEPS Cognitive and Affective study (an RCT on the effects of HT on mood and cognition), women treated with CEE 0.45 mg daily and MP 200 mg for 12 days per month showed significant improvement in mood in the realms of depression-dejection and tension-anxiety, compared to placebo. This was not seen in the transdermal estradiol/MP group.

Although HT might have a positive effect on mood and behaviour, it is not an antidepressant. As such, there is considered to be insufficient evidence to support its use as either a primary treatment for depression, or as an adjunct.

Longitudinal studies suggest that natural menopause may have a significant but small effect on some aspects of cognitive function. These effects may be time limited, and are thought to be not explained by menopausal symptoms such as sleep deprivation.

Estrogen therapy may have positive cognitive benefits when initiated immediately after early surgical menopause, but three RCTs on the use of HT in early naturally post-menopausal women have showed neutral effects of HT on cognition.

Observational studies have reported a reduced risk of developing Alzheimer’s disease among younger women initiating HT closer to menopause. Two hypotheses have been entertained, but not proven, to explain this finding. One, the “critical window hypothesis,” suggests that brain regions that are sensitive to estrogens may respond more favorably to early initiation of HT. The “healthy cell bias hypothesis” purports that estrogen therapy has a favourable effect in healthy neuronal cells and an unfavourable effect in unhealthy cells. This may explain why late initiation of HT (after age 65 years) has been associated with an increased risk of dementia in some studies.

In the absence of more definitive findings, HT cannot be recommended at any age to prevent or treat a decline in cognitive function or dementia.

References:

1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause 2017; 24(7):728-753.

2. Scientific Background Report for the 2017 Hormone Therapy Position Statement of The North American Menopause Society. Menopause 2017. Available at www.menopause.org. Accessed January 2018.

3. Crandall CJ, Hovey KM, Andrews CA, et al. Breast cancer, endometrial cancer, and cardiovascular events in participants who used vaginal estrogen in the Women’s Health Initiative Observational Study. Menopause 2018; 25 (1):11-20.

The answers above are informed by the 2017 NAMS guidelines. Readers are encouraged to refer to the full NAMS paper, available at www.menopause.org, for more detailed guidance, as well as the complete references cited by the NAMS authors.

Development of this article was made possible through the financial support of Pfizer Canada Inc. The opinions expressed herein are those of the author and do not necessarily reflect the views and opinions of Pfizer Canada Inc. The author had complete editorial independence in the development of this article and is responsible for its accuracy. The sponsor exerted no influence in the selection of content or material published.