HRT suitable for certain women

HRT was commonly used in the late 1980s and the 1990s but availability of the therapy has lessened, Gary Culliton reports in his latest Clinical Update. This has followed a number of studies

Dr Jennifer Donnelly, Rotunda Hospital consultant obstetrician

Although professional bodies have moved away from hormone replacement therapy (HRT) based on data, in recent years the Royal College of Obstetricians and Gynaecologists has recommended that HRT might be considered for some groups of women who had previously been declined HRT.

A posited five-year “window of opportunity” should be borne in mind, Dr Jennifer Donnelly, Rotunda Hospital Consultant Obstetrician and Gynaecologist, told a recent Connolly Hospital GP Study Day. The lowest dose would be tried for relatively shorter periods of time.

Dr Donnelly spoke about HRT, which was commonly used in the late 1980s and the 1990s. Availability of the therapy lessened, following a number of studies. The NIH Women’s Health Initiative study (2002) followed the Heart and Estrogen/Progestin Replacement Study (HERS), the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial and the Million Women Study.

Initially, it had been thought that HRT had a secondary prevention effect in cardiovascular disease. These studies showed that this was not the case. As good data emerged (Burger et al., Climacteric, 2012), rates of HRT use dropped dramatically.

HRT emerged because it was a useful treatment for problems that had a significant effect on women’s quality of life. Reductions in the availability and use of HRT have been associated with an increase in the incidence of osteoporosis and fractures, research has shown. In terms of cardiovascular outcomes, the effects may not become apparent for another decade.

Often women who are on HRT are reluctant to come off the therapy. Yet there is also a reluctance to commence women on HRT and often women who would really benefit from HRT are not prescribed it.

Women who might get HRT include those with premature ovarian insufficiency and women commencing menopause before the age of 45, whether this was natural or surgically induced, Dr Donnelly suggested. Bilateral oophorectomies may be performed, for instance, as a result of early stage ovarian cancer or because of ovarian cancer risk — due to the presence of the BRCA 1 mutation.

HRT should also be considered for symptomatic women in their early 50s.

Acute menopausal symptoms, as well as long-term menopausal issues, are taken into consideration.

The menopause occurs a year after the last menstrual period. In the peri-menopausal period, there is a great deal of hormonal fluctuation. FSH (follicle stimulating hormone) and LH (luteinising hormone) levels can be normal, even though very significant vasomotor symptoms may be present, in up to 80 per cent of postmenopausal women.

These symptoms do not always disappear within the first year.

There can be connective tissue changes, dry hair, brittle nails, loss of collagen and urogenital prolapse as well as musculoskeletal symptoms — arthralgia, loss of muscle tone and general aches and pains.

Genitourinary symptoms are affected by the menopause and often worsen over time. Women may present with vaginal dryness, dyspareunia and vaginitis. This can have a huge impact on quality of life and relationships with partners. There may also be an association with other urinary symptoms.

There are many reasons besides the menopause, why women experience irritability, anxiety, tiredness and depression. But the hormonal fluctuations that occur during the peri-menopausal period can contribute.

HRT’s effect on cardiovascular disease was one of the reasons behind the reluctance to prescribe HRT widely. There is an increased incidence of ischaemic heart disease after the menopause, with the HERS study (1998) showing an initial increase in cardiovascular disease (it was stopped early).

In fact, there was an equal event rate among those receiving HRT and those not receiving it in years four and five of the study.

Another large study, the Women’s Health Initiative (WHI), was also stopped prematurely. Increased risk of cardiovascular disease, stroke, venous thromboembolism and breast cancer in some women was highlighted.

However, a number of factors need to be weighed. Conjugated equine oestrogen and medroxyprogesterone acetate HRT was used in the Women’s Health Initiative trial. The American women who participated in the WHI study had an average age of 63 and 21 per cent were over 70. Some 30 per cent were hypertensive entering the study, 30 per cent were in the obese range for BMI and 30 per cent of them were on statins. A total of 7 per cent had diagnosed pre-existing cardiovascular disease. In fact, systolic blood pressure increased very slightly over five years in the WHI study, Dr Donnelly said.

When the women in the study aged younger than 60 were considered, there was no increased risk of cardiovascular disease and stroke. There was a 30 per cent reduced risk of all-cause mortality among women in this population who received HRT. In the older group, there were additional deaths.

Identifying the women who could potentially benefit from HRT and who did not currently receive it, was key. It has been posited that a five-year “window of opportunity” exists and that oestrogen may be cardio-protective when the arterial endothelium is still intact. A number of papers support this (Grodstein, NHS, 2006; Hsia J, WHI 2006; Rousow et al.). Therapy would thus not be regarded as secondary prevention but might be started early.

Among the benefits identified in these large studies were reductions in colorectal cancer risk (information on newer transdermal products is not available in this regard), and significant reductions in hip and spine fracture risk. Benefits accrued in women who did not have a uterus.

In terms of outcomes, benefits were evident in younger women, the WHI study found. There were 10 fewer cardiovascular events in the younger population, and no difference in stroke events was seen. In that group, there was a slight increase in veno-thromboembolism , a reduction in colon cancer and a reduction in breast cancer.

Overall, there was no increase in breast cancer or myocardial infarction (MI) in the group, yet there was a significant reduction in mortality among women aged under 60 years, a meta-analysis of trials, involving 6,000 women showed (Salpeter, JGIM, 2004).

Another Danish study, (Schierbeck, BMJ, 2013) showed a reduction in MI and mortality in women on HRT up to the age of 58. No effect was seen in a study that considered carotid arterial thickness in women started on HRT within six years of the menopause (The Kronos Early Estrogen Prevention Study, KEEPS). Thus, according to the ‘window of opportunity’ theory, there were benefits to be gained by starting therapy early.

A trial considered women aged 42 to 59 over 48 months. Their interventions were conjugated equine oestrogen with transdermal estradiol or placebo and oral micronised progesterone. No negative effects on blood pressure were found, the carotid artery ultrasound and CT calcium scores were unaffected and there were no significant differences in adverse events. There has been a 79 per cent reduction in HRT use among women in their 50s.

Oestrogen may save lives, particularly among older women without a uterus (Am J Public Health, 2013).

There is a slightly increased breast cancer risk (JAMA 2002). Risks and benefits must be weighed, however: individual patient assessments must be carried out.

Women who were on oestrogen-only HRT had a lower number of breast cancer events, compared to those women who were on no HRT (Women’s Health Initiative). There is an increased incidence of endometrial cancer associated with oestrogen treatment alone (Lancet, April 2005).

A woman with a uterus should never be on (oral or transdermal) oestrogen-only HRT. However, low doses of vaginal pessaries such as estradiol hemihydrate 10mcg could be given to women without a uterus, without progesterone supplementation, said Dr Donnelly.

Where biologically equivalent — rather that synthetic — progesterones are used, that has a better effect on outcomes, evidence suggests.

The risk of veno-throm-boembolism increases with age. Risk is greatest in the first one or two years of HRT use and then it declines.

There did appear to be a slightly increased risk of ovarian cancer in women who used HRT compared to those who had never used HRT. There was one extra case per 2,500 users and one extra death per 3,300. (Nat Cancer Registry, NWS collaborators, Lancet, 2007). Advantages and disadvantages must be weighed — where symptoms may be having a significant impact on a woman’s life.

If there were not additional risk factors, HRT should be considered, Dr Donnelly said. The risk factors should be put in perspective, the woman should be given the information and she should make the decision on that basis.

The effect of combined hormone replacement therapy (HRT) in increasing a woman’s risk of breast cancer is likely to have been underestimated by a number of previous studies, according to a recent prospective study published in the British Journal of Cancer. Women taking combined HRT are 2.7 times more likely to develop breast cancer than non-users, with risk increasing with longer HRT use, the study found.

The new research was part of the Breast Cancer Now Generations Study — a major prospective study led by scientists at the Institute of Cancer Research, London. Some 39,000 women were identified and monitored for six years. During this time, 775 of these women developed breast cancer, with the researchers finding that women using combined HRT (for a median duration of 5.4 years) were 2.7 times more likely to develop breast cancer during the period of HRT use than women who had never used HRT.

This risk increased with duration of use, with women who had used combined HRT for over 15 years being 3.3 times more likely to develop breast cancer than non-users. However, in women using oestrogen-only HRT, there was no overall increase seen in breast cancer risk compared with women who had never used HRT.

Importantly, this increased risk level has been found to return to about normal once HRT use ends: after a year or two had passed since women stopped taking combined HRT, the scientists did not find a significantly increased risk of breast cancer, confirming the findings of previous studies.

Study leader Prof Anthony Swerdlow, Professor of Epidemiology at the Institute of Cancer Research, London, said the research showed that some previous studies were likely to have underestimated the risk of breast cancer with combined oestrogen-progestogen HRT. The findings indicated that current use of combined HRT increased the risk of breast cancer, depending on how long HRT had been used.