Abstract
Increasing medical specialization has undoubtedly resulted in better outcomes for patients with defined conditions. The converse to this is the lack of a generalist opinion for the presentation that is less obvious. One of the functions of the menopause clinic is to stand back and look at the bigger picture: to make an experienced analysis of a multisystem presentation. We routinely integrate risks and benefits affecting different bodily systems and in this respect differ from most other specialities.
Just under a year ago, I was asked by her general practitioner (GP) to think about Tracey who was 54. I was given selected hospital correspondence and results from the previous three years and Tracey had written reams about what had happened to her. I take the view that in such situations the more information the better.
From this I gleaned:
Twenty years previously, age 33, Tracey had developed menopausal flushes. Her mother had been prematurely menopausal in her 30s. No other explanation was identified and she was treated successfully with cyclical HRT.
Sixteen years before, age 37, Tracey had changed to continuous combined hormone replacement therapy (HRT) in the form of 2 mg estradiol +1 mg norethisterone (Kliofem®, NovoNordisk). This was also effective and she had no obvious flushes or other menopausal symptoms.
Three years before, age 51, Tracey had begun intermittently to bleed vaginally. This was more like discoloured discharge than a period but varied from pink to brown and occasionally red. The GP notes indicated that when examined her vagina had looked atrophic. Tracey had been advised to reduce the Kliofem and with that alteration, the blood loss had increased rather than reduced.
An ultrasound at the time had revealed a uniform and thin endometrium with no structural anomaly. A month later, a gynaecology out patient letter noted both the ultrasound result and that Tracey had an atrophic vagina. An endometrial biopsy had been taken and reported as scanty and atrophic. Tracey had been advised to use vaginal estradiol 25 µg tablets (Vagifem®, NovoNordisk) for six weeks and to plan to reduce the Kliofem. She had continued to use the vaginal tablets twice a week ever since and also to use the 2 mg combination daily as any attempt to reduce the HRT had resulted in an increase in bleeding.
At about the same time, Tracey had presented with symptoms of feeling hot and unwell, almost flu-like. She had developed low abdominal pain that varied but could be severe and debilitating. At one stage, this was bad enough that she had collapsed and an ambulance was called. When reviewed by her GP her urine had been positive for blood and leucocytes and she was treated for urinary tract infection though no positive culture was obtained on that or any other occasion since.
The urologists had been involved noting blood and leucocytes on dipstick testing and proposing a ‘semi-resistant bug’. Flexible cystoscopy was reported as normal, renal ultrasound was unremarkable and despite negative cultures prophylactic antibiotics were advised. After two years, she continued regularly to have symptoms summarized as back ache, suprapubic pain, a flu-like feeling but no dysuria. Bladder washes weekly for six weeks were tried without marked improvement.
Two years after the first attempt, a gynaecological review occurred in a postmenopausal bleeding (PMB) clinic. The discharge summary noted the absence of endometrium on ultrasound (no thickness measured) and that no endometrium was obtained on endometrial (Pipelle®) sampling. No management advice was offered.
As bleeding persisted, a third gynaecology appointment was considered as mention had been made of fitting a levonorgestrel IUS. Tracey had done her research and thinking there may be a link between her problems asked to come to the menopause clinic. Her GP agreed and provided me with information.
At that point her treatment consisted of generic estradiol 2 mg + norethisterone 1 mg with estradiol 25 µg vaginal tablets twice a week. She was using no complementary menopause therapies but emptied out a bag to show me packets of Cranberry tablets (Cysticlean®), Cod liver oil, Echinacea, multivitamins, Waterfall D Mannose and UVA Ursi that she was taking to try to help her bladder. Her only other medication was for asthma and hayfever.
As usual, I reviewed the full range of potential menopause-related symptoms and found out that Tracey had no flushes but complained of waves of nausea, headache and lacking energy. Her sleep was highly disturbed and she had night terrors but no significance had been attached to this. She was desperate to relieve her bladder symptoms but was not depressed. Other than some forgetfulness, she had no significant cognitive issues. She reported vaginal dryness and intermittent blood stained discharge (worse when stressed) and being too afraid to risk intercourse less the pain attributed to her bladder returned.
Tracey had cut out caffeine and was drinking two to three cups of peppermint tea daily. She neither drank alcohol nor smoked. We established that her mother had been menopausal at 38.
I noted that vaginal atrophy had been observed on several occasions. Endometrial atrophy had been noted on two scans and a Pipelle sample had failed to sample endometrium. Integrating these factors lead to the hypothesis that replacement had been suboptimal allowing urogenital atrophy slowly to develop over the intervening 20 years. Without replacement, it is most typically problematic at 5–10 years after menopause. With marked endometrial atrophy, angiogenic bleeding can occur from the superficial myometrium and this would be consistent with the bleeding described. I acknowledged that the cystoscopy had been thought to be normal but wondered if subtle signs were missed.
If this were the case, stopping estrogen would make bleeding worse (which it had) and a levonorgestrel IUS could make it much worse by exacerbating the atrophy. In this instance, it would not be the answer. The hypothesis would explain the urine dipstick findings and lack of positive culture results. I wondered if some if not all of the systemic symptoms of feeling hot and lightheaded and the sleep disturbance, were estrogen deficient in origin.
Having had such extensive negative investigation I advised Tracey for the time being to steer clear of further procedures and that we could try to adapt the HRT regimen by:
Changing the oral estradiol to transdermal and I suggested 0.1% estradiol (Sandrena®, Orion Pharma) 1.0 g sachets to use two daily. Changing the progestogen to micronized oral progesterone 100 mg capsules (Utrogestan®, Marlborough Phamaceuticals) one daily. This would be less potent than the norethisterone of the previous combination and I thought that intolerance would be unlikely given the lack of any previous premenstrual syndrome. Some women report sedation and it is my practice to advise use at night when this can be a positive benefit. Increasing the vaginal estrogen delivery by using the 25 µg vaginal tablets daily for the next month.
After a month, the bleeding had already stopped. By three months, this benefit was persisting and the bladder symptoms were settling.
As hoped but not promised Tracey was better in herself, she was not feeling as shivery and was sleeping better. Urinalysis was clear. We reduced the vaginal estrogen to 10 µg daily as the higher dose product was no longer available and no longer needed.
In the light of this observation I have negotiated a DEXA scan to ensure that bone density has been adequately preserved. This fortunately has been confirmed and illustrates the difference in requirement between tissues: bones do not seem to need as much to remain protected. This is consistent with the advice that, as we reduce dosages in older women, protective benefit will not be lost.
After a further four months all symptoms had resolved. Tracey had resumed a normal sexual relationship, was sleeping and coping better with life in general (including major family illness). With the benefit of the retrospectoscope (a marvellous instrument), Tracey was able to appreciate that she had had unrecognized systemic estrogen deficiency symptoms as well as the atrophy. There has been no need to further increase systemic dosage and will aim to review in a year or sooner if there are problems.
The conventional approach to bleeding on HRT would be to stop and then exclude disease. Often we will offer a levonorgestrel IUS. For many women, this may be the appropriate management option but Tracey illustrates how important it is to look at each woman individually. We should not dismiss information pertaining to body systems other than that causing the greatest problem.