Abstract
Rachel was referred in 2006. She was only 35 but already had a chequered gynaecological history. She had delivered four children (with depression in both antenatal and postnatal periods) but lost one from a cot death. She had a long history of pain attributed to pelvic inflammatory disease with removal of first one ovary and then attempted vaginal hysterectomy. Due to bleeding from iliac vessels an abdominal incision was needed. The remaining ovary was then removed.
Prior to referral she had been prescribed hormone replacement therapy (HRT). The initial hospital prescription was an estradiol 50 µg/24 hour weekly patch but this did not suppress sweating and she assumed that because of this the patches did not stick. She had improved with 100 µg/24 hour patches but continued to have problems with adhesion. Her general practitioner (GP) then tried estradiol valerate (branded as Progynova®) with which she complained of mood swings and was then changed to generic estradiol 2 mg, which she was still taking when I first met her.
‘Failure to settle on standard regimens’ is one of the referral criteria for the specialist menopause service and Rachel certainly met this. She was hot during the day and sweating with subsequent chills at night. Nights were very disturbed, she was tossing and turning, woken by the sweating and would frequently need to get up to pass urine. She was itchy and described moods that swung but were predominantly low. She was tearful, irritable and snapping at the family. Her concentration and memory were both poor and she survived by writing lists. Her vagina was dry and uncomfortable. She explained that all sexual interest and her sense of femininity had evaporated. In addition to vaginal discomfort she was slow to arousal. Sexual difficulty was the feature that most distressed her as she perceived it as threatening her relationship. Her breasts had shrunk and though she had lost the scourge of her periods she was generally tired and unhappy.
Rachel was slim and fit and her vascular and breast risk profile were unremarkable. The treatment recommendation at the end of a long discussion was to try non-oral delivery of estradiol once more but using a different patch in the hope that this would help adhesion. I asked her to try the 100 µg/24 hour dose again. In addition, we would add testosterone. Having lost her ovarian source of androgens, deficiency was a possibility and the symptoms described appeared consistent with this. At the time patches licensed for women were not available so testosterone 1% gel (Testogel®) was prescribed with advice to subdivide each sachet and use 1/7 daily such that each would last a week.
Four months later her sweats had reduced but not gone, sleep had improved but remained broken, she remained irritable though overall mood had lifted and concentration was not quite as bad. Sex had occurred on one occasion, which was not uncomfortable. Rachel felt that she was very slow to achieve arousal. There was still significant patch irritation but the higher delivery of estrogen seemed to have helped.
The next modification therefore was to stay with the non-oral route but change patches to gel in equivalent dose (Sandrena 1.0 g twice daily) and slightly increase the testosterone to 1/4 sachet daily.
Four months on Rachel was coping with life and concentrating well enough to hold down a job. She was still flushing during the day and waking 2–3 times at night. She had not had sex for six months as she still lacked inclination and genital response. At that point the dose of both estrogen and testosterone were increased but with the proviso that I would need serum estimation of both hormones if the response was insufficient.
By September 2007 (almost a year after we started to modify her HRT), Rachel was still experiencing daytime flushing. Her sleep was broken though not to the same extent. Her mood had lifted and she was more cheerful though still somewhat variable. Her urinary frequency was unchanged. Although she reported no vaginal dryness she remained disinterested in sex. As a positive element her skin irritation had settled.
Our laboratory needs precise information on its request form before agreeing to measure serum estradiol and did not process the GP request. They did report serum follicle stimulating hormone (FSH) of 60.5 IU/L. Serum testosterone was supraphysiological at 11.0 nmol/L. The learning point from this is that if contemplating androgen replacement using anything other than the low dose patches I would now measure initial levels and monitor at each stage of modification.
Clearly from Rachel's perspective, estradiol remained under-replaced despite 3 × 1.0 g sachets daily and we needed to reduce the level of androgens. After discussion we elected to use estradiol implants and with full informed consent Rachel had 2 × 50 mg estradiol (as a loading dose). She used no androgens for three months and then reverted to using each Testogel sachet over seven days.
Six months later, Rachel reported that her flushes had disappeared initially but were beginning to return. She was sleeping all night. Emotionally she was much more stable being neither irritable nor tearful and could concentrate again. She was not getting up at night to pass urine. There was very mild vaginal dryness but no soreness and she was aware of sensation returning and some responsivity. She had some interest in sex and could initiate.
Rachel had not remembered to have a blood test so was given a 25 mg implant as a top up and some estradiol vaginal tablets 25 µg to use twice a week.
When seen in October 2008, Rachel was well. She reported feeling feminine, emotionally stable and had no residual sexual problems. Her flushes had started to return in the previous four weeks. Again she had not been for her blood test so had a further 25 mg implant.
In April 2009, we finally had laboratory results showing a total testosterone of 2.9 nmol/L with an sex hormone-binding globulin (SHBG) of 92.3 nmol/L indicating that free androgens were approximately at the physiological mean (using Testogel over 7 days). The serum estradiol was 311 pmol/L though this was not known at the time of agreeing dosage. As Rachel had started to notice symptoms only in the previous month 25 mg was replaced.
This time, however, benefit started to be lost after four months and with a serum level of 310 pmol/L in October 2009 it was felt to be reasonable to use a higher dose but to wait longer before the next implant. 50 mg estradiol was used.
Eight months later, Rachel was very well with only a few breakthrough flushes. She had stopped using vaginal estrogens and only used testosterone occasionally. Both she and her partner reported their physical relationship to be good. A further 50 mg implant was provided.
Eight months later (February 2011), Rachel was really well using nothing other than the estradiol implants. Her serum estradiol was 433 pmol/L and her free androgen index at 0.5 (very low in the female range). Hindsight is a wonderful thing and I now wonder whether the benefit of the androgens she had previously had derived more from peripheral conversion to estrogen than their androgenic effects. Rachel had a further 50 mg estradiol implant.
In late October 2011, her serum estradiol was 527 pmol/L and Rachel had no symptoms at all. She was vibrant, happy and living life to the full. The change in this woman over the previous five years could not have been more marked.
The UK supply of estradiol implants had, however, been withdrawn. The ‘Dear Doctor’ letter had told us that there are alternatives or patches, gels and tablets that we could use. Not for this patient.
Appreciating the difference that effective estradiol replacement can make and that this is not always achievable with patches, gels or tablets we had arranged with the primary care trust (PCT) and hospital trust pharmacy departments that we would obtain implants from the unlicensed American source recommended by the British Menopause Society. Locally we were only able to obtain 25 mg implants initially and would therefore need two.
This was explained to Rachel ensuring that she understood the implications of an unlicensed product. She accepted this but was not prepared to go back to any other form of treatment. Rachel has therefore had 2 × 25 mg of the American product. We do not know how their pharmacokinetics will compare, but I will bring her back initially at eight months whereas I would have stretched the interval longer this time.
Estradiol is vital to the wellbeing of women. For some women with profound deficiency we really cannot manage their hormone therapy with any route of delivery other than implants. Rachel has asked that we tell her story to encourage the pharmaceutical industry to reconsider.