Abstract
We have recently experienced another “HRT scare” and have been asked publically whether women should be prescribed HRT at all. The answer as always is that there can be few generalisations and an individual decision needs to be made by the patient. All women are different and while some have no or minimal symptoms, others are severely debilitated; concerns vary. In the clinic we should evaluate the profile and preferences of our women, look at how the evidence applies to their situation and offer options. There will be changes with time and it is important to start afresh on each review rather than simply continue a previous regimen.
Shirley is an example. She is now 67 and first took HRT nearly 20 years ago.
In 1996, aged 49, Shirley found that her periods were becoming less predictable and she was beginning to be troubled by flushes and sweats. She wanted symptom relief and was very concerned to avoid the osteoporosis that afflicted her mother. Her GP initiated a cyclical estradiol valerate/levonorgestrel combination (now discontinued). Shortly afterwards, a right-sided breast lump was identified which was identified as benign and aspirated but due to concern regarding her breasts she stopped HRT after about six months.
Five years later, aged 54, my opinion was sought by a new GP.
November 2001
Shirley explained that her periods had stopped altogether, her flushes had largely resolved but she was still very keen to protect her bones as her mother had had a miserable time in old age with both kyphosis and a hip fracture. She had had a bone mineral density (DEXA) scan which was reported as 5% above that anticipated for her age. She accepted that her mood was not great but attributed this to the stress of marital breakdown. She was known to be hypertensive, but was well controlled with atenolol and bendroflumethiazide. She had had no further breast symptoms and screening mammography was negative. Shirley worked as secretary but exercised in her spare time, had just about enough calcium in her diet, was not overweight, did not smoke but admitted to 14 units of alcohol a week. The primary reason at that point for her request was bone protection and she wanted HRT. This was 2001, before the scares and though the only significant risk was her maternal history we considered this entirely reasonable.
Shirley by this stage was not unduly troubled by her symptoms and was just postmenopausal – she was therefore prescribed a continuous combination of oral 1 mg estradiol with 5 mg dydrogesterone, to take one daily. Though lower in dose than her previous 2 mg product, it was believed to provide adequate estrogen to maintain bone density. At the time we thought it would probably offer cardiac protection but did not promise but explained that it would increase DVT risk. She was advised that there may be a small associated increase in breast cancer risk but that a low dose and continuous regimen was unlikely to aggravate benign breast symptoms. It was what she wanted and she understood the issues. She made the decision to take the product.
December 2004
This just goes to show how important it is to look at the numbers rather than rely on someone else’s analysis. While technically this can be considered as mildly osteopaenic at the lumbar spine and that loss had occurred this was less than the loss that would have been anticipated with no HRT (the Z score had improved).
In the interim, we had weathered the full force of furore in the wake of the initial publications from Women’s Health Initiative (WHI) and Million Women Studies (MWS). We were able to discuss what we thought we had learnt about risks of breast cancer, heart disease and DVT risk but could confirm reduced fracture risk and the possibility of fewer bowel malignancies associated with HRT usage. Bisphosphonates were not indicated by the DEXA results. Selective estrogen receptor modulators had already been shown to be less effective than estrogen with no effect on hip fracture. The decision was made to continue the same alternate day regimen (along with the vaginal estrogen) until the age of 60 by which time bone strength should be adequate to last her into old age and the systemic product could be stopped.
March 2007
Shirley, was nearly 60 and did not want to stop the HRT. She felt that this was keeping her going as well as protecting her bones. Her GP requested review of the risk benefit balance. She had no significant symptoms and felt very well. She was taking the same 1 mg product on alternate days with twice weekly vaginal 25 µg estradiol tablets. Her BMI was 23.6, her blood pressure was well controlled, she was taking an additional calcium tablet to ensure an adequate intake and had two further breast cysts aspirated. We discussed that the effect of HRT on breast cancer incidence appeared as a multiplication of baseline risk and that there was the suggestion that there was a dose effect. Evidence was emerging that age at initiation was relevant in respect of additional coronary artery disease and that having started in her early 50s this did not appear to be a problem. An increased effect on stroke was discussed but given that blood pressure was controlled and the dose low this was not unreasonable. Shirley was quite able to participate in the discussion regarding size of risk that was attributable and decide for herself that this could be accepted. She valued her well-being and bone protection and elected to continue.
February 2015
Shirley is now 67 and still taking the same oral HRT (1 mg estradiol plus 5 mg dydrogesterone) but the vaginal tablets available have reduced in strength and are now used at 10 µg twice a week. She has spontaneously increased the oral tablets to daily as she was not remembering every other day. This meant that she was taking 1 mg estradiol not an average of 0.5 mg daily. The option of a 0.5 mg product in the same combination had not been offered to her. Her blood pressure remains well controlled though she is now taking a sarten rather than a betablocker and diuretic and reports waking with panic some nights. She has no flushes or sweats but gets up five to six 6 times at night to pass urine. She stopped taking “bladder tablets” as they affected her memory. Despite this she feels generally well and if a new partner were to appear she would be interested! She has retired from work but provides full time child care for a granddaughter and is out every day with the pram or walking the dog. She admits to at least 15 units of alcohol a week and occasionally more. She has had no breast symptoms for years and screening is negative. There has not been a further DEXA scan. She still wants to continue her HRT.
There has been a subtle shift in her profile. While bone protection remains important to Shirley, benefit is perceived for wellbeing despite the breakthrough urinary symptoms. The effect of estrogen on breast risk is now thought to relate mainly to growth promotion rather than initiation and given that screening has been clear over so many years Shirley no longer has any great concerns. She has had no fractures or cardiovascular events. She continues to want bone protection though her fracture risk is now very low. She had not considered cardiovascular risk – despite the fact that her background risks will be rising as she is getting older and any multiplication will therefore have greater impact. We discussed recent evidence indicating that as the HRT was initiated at menopause, coronary artery disease may possibly have been mitigated through positive effects on atheroma. That is not the concern; the issue relates to risks of stroke and venous thromboembolic (VTE) risk which increase through the 60s. Given that these are further increased by a prothrombotic effect of oral estrogen, excess attributable risks have risen. The evidence of recent years is increasingly convincing that transdermal delivery at standard doses will have little if any effect on thrombogenesis. We therefore talked about patches and gel.
In the United States, a patch delivering 14 µg estradiol daily is licensed for bone maintenance in this age group. On the basis that she would not lose bone protection we have agreed a compromise. Shirley will try an estradiol/norethisterone combination patch – cut in half to deliver 25 µg estradiol daily (this is unlicensed but common in clinical practice). This will be applied to clean dry skin below the waist and changed twice a week. It is a comparatively simple routine, ensures opposition is maintained and should minimise the additional attributable risks that are now my concern.
The vaginal symptoms could be helped by increasing the vaginal estradiol frequency. This is reasonable as estradiol 10 µg five times a week will deliver a similar dose to the previous 25 µg product used twice a week (which had an indefinite license). No significant systemic effect has been demonstrated. A gradual increase was advised to three times a week initially.
Once again an informed decision has been made with the role of the clinician being to inform the patient and allow her to make a decision. We must optimise benefit and minimise excess risk. Women should understand that change occurs with time as a result of age and other aspects of their profile as well as in the evidence base. We must always be prepared to think again but as long as risks are reasonable the patient herself should be the final arbiter of what is right for her.