Practice observed

Amanda is 39. I first saw her a year ago.

She had got to the end of her tether and had persuaded a locum general practitioner (GP) to refer her to the menopause clinic. Her regular GP had said this was not necessary as she could not possibly be menopausal, because she was too young. How often do we hear that?

Amanda had a hysterectomy three years before for fibroids which had caused intractable bleeding and pressure symptoms on her bladder. Her ovaries had been retained.

She told me that she has not felt herself since the operation and was surprised as she had been expecting to feel better. She had become tearful and struggled to cope with her job in a call centre as everyone she spoke to was complaining. She had left and taken a salary cut to start a shelf filling job in a supermarket where there was much less stress. Her GP had said that she was depressed and gave her a prescription for citalopram. She had been referred for counselling as he said that she was upset as she had never had children. She had not found this helpful.

Things had come to a head regarding sex. Her husband thought she did not love him anymore. She was adamant that this was not the case but she just was not interested. When she did agree the whole thing was uncomfortable and she did not get anything out of it.

The usual review revealed that she woke up at night but had been told and accepted that this was because she was depressed. When she woke up she was often hot but thought this was because her husband did not want the windows open. She was also hot during the day but put the blushing down to anxiety and embarrassment. She had some urinary urgency and frequency but thought that the bladder had not been able to recover from the effects of the fibroid. She ached all over but thought this was the physicality of her work. She had a whole gamut of estrogen deficiency symptoms but rationalised all of them except her loss of interest and response to sex. She felt that her marriage was on the line. Vaginal examination showed changes consistent with early atrophy.

There seemed little point in measuring follicle-stimulating hormone as she needed treatment but decided to do it anyway for the record. I was certainly not going to wait for two results in this instance. Helpfully, it was reported as 106.6 IU/L with a luteinising hormone of 56 IU/L which is consistent with ovarian failure (but not diagnostic).

Having talked through the options, Amanda elected to try a 50 µg/24 h estradiol patch to change twice a week with estradiol vaginal tablets 10 µg to use daily for two weeks then reduce to twice a week. While my intention was to stop the citalopram, it was too soon to do it at this stage. As a class effect, the selective serotonin reuptake inhibitors have a tendency to reduce sexual excitement and also to inhibit orgasm. This clearly would not help – though it might have taken the edge off the anxiety, sleep disturbance and hot flushes. I tend to change one thing at a time.

Ten weeks later she was much better. She was not as tearful but said that she had glimpses of her old self and was able to organise enough to book a holiday. She had learnt to recognise what were hot flushes and said that they were still happening though not as bad. Sleep had improved and she had managed to have sex without it being uncomfortable. However, her confidence and energy were still lacking and she had no interest in sex. She had given up on ever being able to orgasm again but this was not as important as being able to maintain her relationship. She said that her husband had noticed a difference and they were looking forward to the holiday.

The GP had already reduced the citalopram dose to 10 mg daily. So what next?

The estrogen patches were clearly helping but not enough; hence, I increased the patch strength to 75 µg/day. There was no adhesive irritation or other reason to change product so this stayed within the same product range. The vaginal estradiol was continued at twice a week and I explained that improvement could continue further. I advised how to progressively tail off and stop the citalopram over the next two months. I asked that if she was not right at that stage could she have the following blood tests:

Serum estradiol

Total testosterone

Sex hormone-binding globulin (SHBG)

This allows calculation of free androgen index – which is the relevant marker.

Three months later again she had had her holiday and felt better again in herself but was not quite right. The flushes had gone, she was sleeping better and sex was comfortable but she was still lacking energy, sexual interest and ached.

Her estradiol was 326 pmol/L – this is enough to be bone sparing but below physiological mean and would stand an increase.

Total testosterone 0.2 nmol/L (low)

SHBG 86.3 nmol/L (normal)

Free androgen index 0.23 – this is at the low end of the female range (my local laboratory quotes normal as 0.2–3.6). It does not prove that the symptoms are due to this but allows supplementation to see if it helps.

Given that I would be working outside of marketing authorisation in most instances, I ensure that I can justify my clinical decision. My personal rules (which are entirely empirical) for testosterone supplementation are that there should be:

Biological plausibility for deficiency (in this case disruption of the ovarian vascular supply during hysterectomy).

Symptoms consistent with androgen lack – particularly loss of sexual interest but also lethargy and myalgia.

Exclusion of relationship issues and other reasons for sexual difficulty.

Adequate estrogenisation – as the female genitalia need to be estrogenised to respond.

Low free androgen index.

These criteria having all been met I could then discuss the options available. I could have added Tibolone but did not feel that this would be potent enough in this young woman so discussed the use of 50 mg/5.0 g testosterone gel. Patches licensed for women are not marketed any longer in the UK. There are two such gel products licensed for men and the unit dose is approximately 10 times that required by women. I usually use Testim® (Ferring Pharmaceuticals Ltd., West Drayton, UK) on the basis that the tube has a screw cap and remaining gel more easily sealed than with the alternate product that uses a sachet that needs a bull-dog clip or similar. My advice was to use 1/10 of the tube daily – rubbed into the upper thigh (from where any excess hair growth can be easily removed). I repeat the same blood tests after eight weeks to ensure that she is not being over treated. Adjustment can then occur. In my experience, the dose required is typically 1/10 tube but can vary between ¼ and 1/20.

Amanda was warned that the product was being used off license and that the product information leaflet did not apply to her. What was important is that she understood what she was to do and why. She was told that the pharmacist would quite appropriately question the prescription. The patches were increased once more to estradiol 100 µg/24 h and the vaginal tablets continued.

I saw her recently. She was smiling broadly and gave me a bunch of flowers. She said that she had her life back and her husband had got back the woman he had married. She was looking for a new job which was more challenging. Sex was good, did not hurt and she generally forgot to use the vaginal tablets. As confirmation, her serum estradiol was 458 pmol/L, and her free androgen index was 2.0. This proved we were in the physiological range and not using an excessive dose: supportive of the clinical decision.

Amanda illustrates many points that may be encountered in everyday practice and is not overtly ‘complex’.

In young women, ovarian failure may require larger doses to supplement than in spontaneous menopause at a typical age.

Even if ovaries are conserved at surgery early failure can occur.

If there is compromise affecting the ovarian stroma, androgen production will be affected. This could be due to a number of causes including vascular, infective (e.g., mumps) and irradiation. In women, this can reduce androgens by up to about 50%. This may or may not cause symptoms but if it does testosterone supplementation can be justified.

Replacement should remain within the physiological range and then empirically will have a risk profile that is no different to that with normal ovarian function.