PPMC clinical cases

Background

AP is a 51-year-old charity worker, referred to a secondary care menopause service by her GP. She began experiencing vasomotor symptoms (VMS) aged 49 with severe hot flushes and night sweats, associated with insomnia. Her symptoms became particularly troublesome 18 months ago, around the time she experienced her last menstrual period. She is very motivated to follow a healthy lifestyle as her father died from a heart attack aged 36 (the only relevant family history). As a result, she follows a vegetarian diet and has never smoked, doesn’t drink alcohol, and attends the gym five times a week. She lives with her husband and enjoys her job in the charity sector; however, she is aware that the lack of predictability and severity of hot flushes is causing anxiety and embarrassment during work meetings – although working from home during the pandemic has made this slightly less problematic.

In relation to co-morbidities, she suffers from stress/tiredness-related migraines (with aura - flashing lights) which started during her university days; she was discharged from neurology ‘many years ago’. Each migraine attack lasts 24–36 h, and they are quite disabling, requiring bed rest to recover. She doesn’t recall any specific correlation between migraines and menstruation; she has never used any hormonal contraception. She has hypothyroidism which was diagnosed following pregnancy – she has one child, a 26-year-old daughter.

AP reports that recent routine blood tests (including cholesterol, blood glucose and thyroid function), carried out by her GP as part of a health check, were normal.

Her prescribed medicines are:

• Propranolol tablets, 40 mg twice daily (migraine prophylaxis)

She also takes a multivitamin and has no known drug allergies.

AP expressed a desire to try ‘something effective’ for her VMS, as her GP hadn’t offered any treatment. The only therapy she had tried so far for VMS is Black Cohosh from a health shop, a herbal remedy that has been shown to be effective for this indication in some studies. ¹ It can be associated with significant potential side effects including arrhythmia, hepatotoxicity and mania^1,2 and in this patient’s case proved ineffective. Her GP referred her to the hospital menopause service due to her history of migraine with aura and concerns about a potential associated increase in cardiovascular risk with hormone replacement therapy (HRT). AP reported that her GP advised that HRT was contraindicated in women with migraine.

During the consultation, AP reported no personal or family history of venous thromboembolism (VTE) and no personal or family history of breast, ovarian or endometrial cancer. She has an intact uterus. Her blood pressure was checked (127/77 mmHg) and BMI calculated (20.5 kg/m²) using her height (5 ft 6in) and weight (9st 1lb).

Menopause

Menopause can be diagnosed, without the need for blood tests, in otherwise healthy, symptomatic women over the age of 45, who and are not using hormonal contraception ³ ; AP fitted these criteria and as her last menstrual period was more than 12 months previously, she can be considered post-menopausal.

Vasomotor symptoms (VMS) result from the varied production of ovarian oestrogen at menopause, caused by failing ovarian function.^4,5 Two-thirds of women experience VMS, hot flushes and night sweats; one-third of affected women describe their symptoms as severe. VMS can start one to 2 years prior to menopause, persisting for a median of 7 years but up to 15 years in 20% of women. ⁶

Oestrogen-containing HRT is the first-line and most effective treatment for management of VMS^4,6,7; treatment should be considered for women whose symptoms are having a significant impact on sleep, their ability to function at home or work and on quality of life. ⁴

Women with an intact uterus require both oestrogen and a progestogen (unopposed oestrogen can increase the risk of endometrial cancer in this population in as little as 6 months). Hysterectomised women require oestrogen only therapy,^3,4,6 unless they have retained their cervix or surgery was to treat endometriosis. As AP has an intact uterus, HRT containing both oestrogen (to relieve VMS) and a progestogen (for endometrial protection) was recommended.

In addition to treating VMS, other oestrogen-responsive menopause symptoms include low mood and anxiety and joint pain. Urogenital atrophy (UGA) is another potential problem, causing vaginal dryness, itching, burning and dyspareunia; first line treatment, unless contraindicated, is with vaginal oestrogen, delivered as a cream, pessary or vaginal ring. ⁴ A progestogen isn’t required when vaginal oestrogen is used in non-hysterectomised women, due to minimal absorption – endometrial hyperplasia is not a risk ⁶ ; vaginal oestrogen therapy for UGA can also be used in addition to systemic HRT. ³ When specifically asked, AP reported no symptoms of UGA.

HRT is associated with control of many menopausal symptoms and can be continued for as long as clinically necessary, provided benefits are deemed to outweigh risks. ⁸ The incidence of osteoporosis is reduced, with as associated reduction in the risk of fragility fracture for the duration of treatment; benefits may last longer if HRT is taken for a longer duration.^3,6

It is important in a menopause consultation, to consider adequate intake of dietary calcium (at least 700 mg/day), Vitamin D (10 mcg/day) and adequate weight-bearing exercise to further prevent against osteoporosis ⁹

If HRT is started prior to age 60 (as is AP’s case), the risk of cardiovascular disease is not increased. ³

In addition to the potential benefits associated with HRT, women should also be counselled on potential risks, depending on their individual circumstances, so that they can make an informed decision about treatment. There is an increased risk of stroke with oral (but not transdermal) estrogen. ³

Women who have migraine with aura have a higher baseline risk of stroke compared to those without aura. ¹⁰ There is an increase in migraine in women using HRT with oral oestrogen and transdermal delivery of oestrogen is preferable, as this is associated with more stable systemic oestrogen levels. ¹¹

Oral oestrogen also increases the risk of VTE relative to baseline. However, when delivered transdermally at standard doses, this risk is eliminated. ³ Transdermal delivery should therefore be used preferentially in women with risk factors for conditions such as stroke and VTE. ⁶

It is important in a menopause consultation to discuss the potential risk of hormone dependent cancers, particularly breast cancer, in association with use of HRT. There is controversy about the effect of HRT on breast cancer risk, with differing outcomes from large trials. ¹² Although oestrogen alone is not associated with an increased risk of breast cancer (i.e. the regimen used in hysterectomised women), combined HRT is thought to have a duration-dependent increase in risk of breast cancer, and this is likely to be affected by type of progestogen used – dydrogesterone and micronised progesterone are thought to be associated with a lower risk. However, overall, this risk is statistically small, especially when compared to the adverse effect of modifiable risk factors such as alcohol consumption, smoking and obesity on breast cancer. ⁶ The BMS ‘Understanding the risks of breast cancer’ pictogram ¹³ was shared with AP to help contextualise her risk and to support her to make an informed decision; it states that 23/1000 women aged 50–59 will be diagnosed with breast cancer over the next 5 years (i.e. baseline, without HRT). An additional four cases/year will be seen in women on combined HRT, but there will be four fewer cases in women on oestrogen-only HRT. In terms of lifestyle risks, in current smokers, there will be an additional three cases and an additional five cases in women who drink two or more units of alcohol/day. Irrespective of HRT, I encouraged AP to attend for breast screening with mammography when called, and to check her breasts regularly.

We also discussed other non-hormonal treatments for VMS, including using gabapentin off-label; 900 mg daily reduces VMS in 50% of women and this drug can also be used as a migraine prophylactic and therefore it has a further potential advantageous effect for this particular patient. ¹

However, AP was hesitant to try gabapentin as her friend had had a bad experience, with extreme drowsiness and a personality change. Antidepressants (off-label) are another option (the meaning/implications of ‘off-label’ explained to the patient). SSRIs are effective in 20–50% of cases, with paroxetine having the most evidence (50–60% of women report an improvement in VMS). The SNRI venlafaxine is effective in 20–66% of cases. ¹

The antihypertensive clonidine (licensed) is another option, but can cause significant side effects, for example, nausea and insomnia in 50% of people. ¹ Again, AP was hesitant due to the ‘stigma’ associated with antidepressants and she didn’t want to risk further disrupting her sleep pattern with clonidine.

Taking the above into account and following a discussion with AP in relation to her preferred transdermal treatment option, I prescribed the following HRT regime:

• Oestrogel® (estradiol 0.06%), two pumps (1.5 mg) daily, applied to clean, dry, unbroken skin on the shoulders, arms, or thighs (not the breast/vulva). She was advised not to cover the application site(s) with clothing for 5 minutes following use; to wash her hands after application and to avoid skin contact with others (especially males) for at least 1 hour ¹⁴

The Oestrogel® is the ‘therapeutic’ component of the HRT, to help control VMS; It is important that women understand why they are taking Utrogestan® and the need to use it consistently – whilst it won’t help her VMS, it is imperative that it is taken regularly to reduce the risk of endometrial proliferation/cancer. After discussion regarding the risks and benefits (including potential effects on co-morbidities, as discussed below), AP felt fully informed and was happy to proceed with the suggested HRT regimen.

Co-morbidities: Migraine

Migraine has a cumulative lifetime incidence of 43% in females (versus 18% in men), thought to be attributable to the differences in female and male sex hormones on migraine pathophysiology. ¹⁶

During perimenopause (i.e. the years/months leading up to and 12 months following the last menstrual period), migraine frequency can increase due to changes in estrogen and progesterone levels, and the resultant neuroendocrine response to the hormonal changes.^10,17 Following menopause, migraine attacks tend to reduce with time due to stabilisation of hormone levels. ¹⁰ AP recalled more migraine attacks during pregnancy, when estrogen levels are high, but did not consider menstruation as a causative factor pre-menopause. This indicates that her migraines might be somewhat sensitive to estrogen; however, intensity of VMS and symptoms such as insomnia and low mood can also aggravate migraine ¹⁰ and HRT may help reduce the frequency of migraines by reducing VMS.

Studies on use of HRT in migraine are scarce and have provided inconsistent results. ¹⁷ A cross-sectional questionnaire carried out in 6700 post-menopausal women, 2375 of whom were past/current users of HRT, found a significant association between headache, including migraine, and current oral or topical HRT use. ¹⁸ Conversely, 64% of 120 women attending a headache clinic reported improvement/remission of headache, versus 13% reporting worsening headache and 22% no change with HRT. ¹⁹ It is therefore difficult to predict what will happen for an individual patient.

In terms of guidance, the British Menopause Society (BMS) advise that migraine with aura isn’t a contraindication to HRT; however, it is possible for aura to worsen with HRT, or even develop as a new symptom, but this is thought to be a dose-dependent effect related to oral estrogen administration. ¹⁷ Topical body identical estrogen formulations such as Oestrogel® are preferred to oral treatment in migraine sufferers as this delivery route provides more stable systemic levels, and the lowest effective dose should be used.^10,17 The manufacturer of Oestrogel® advises that it should be used with caution in women with migraine. ¹⁴ With respect to the progestogen component, continuous regimens are advised (versus cyclical, which can aggravate migraine due to hormone fluctuation); suggestions are the levonorgestrel intrauterine system (IUS, Mirena®), transdermal norethisterone or micronised progesterone continuously.^10,17 AP is post-menopausal, therefore, a continuous-combined regimen is recommended. Irregular spotting and bleeding are possible for four-six months following initiation of treatment. ⁵ For women with migraine who do not wish to use or have contraindications to estrogen, escitalopram or venlafaxine (out of product license) are an alternative treatment option for VMS.

HRT can be taken concomitantly with preventative and acute migraine treatments, ¹⁰ with no expected drug interactions in this patient’s case .^{10,15,20–23}

Co-morbidities: Hypothyroidism

Hypothyroidism is up to 10 times more common in females than it is in males; prevalence increases with age. ²³ The recommended treatment is levothyroxine, initially in a dose of 1.6 micrograms/kg in adults under 65; the dose is then titrated according to symptom control and the results of blood tests (thyroid stimulating hormone). ²³

Thyroid replacement therapy isn’t a contraindication to HRT, but the dose of levothyroxine may need to be increased when oral estrogen is used due to hepatic induction of thyroid-binding globulin, which binds and decreases levels of free serum thyroxine. This effect doesn’t occur with transdermal oestrogen, thus transdermal delivery is preferable in hypothyroid patients. ¹⁰

AP’s GP was advised that consideration should be given to monitoring thyroid function if she feels symptomatic at any point following initiation of HRT (e.g. increased tiredness, low mood, weight gain); however, there are no set guidelines for this monitoring post-HRT initiation – clinical judgement is needed.

Monitoring

I counselled AP on the most common adverse effects of each preparation, Table 1 provides a suggested monitoring schedule.

OPEN IN VIEWER

Table 1.

Suggested monitoring schedule.

Parameter	Rationale	Frequency	Action
Abatement of VMS (patient-reported)	Evaluate Oestrogel® effectiveness	Next review 3/12; at least annually thereafter 8	Increase dose, as per SPC, if necessary
Adverse effects (patient-reported)	To evaluate adverse effects of Oestrogel®/Utrogestan®	Next review 3/12; at least annually thereafter 8	Reduce dose or change therapy, depending on nature/implication of adverse effect
Blood pressure	To evaluate cardiovascular health	Next clinic review 3/12; at least annually thereafter	Oestrogel® should be withdrawn if there is a ‘significant’ increase in blood pressure 14 (clinical judgement required)
BMI	BMI >30 kg/m2 is a risk factor for VTE	Next clinic review 3/12; at least annually thereafter	Caution required if BMI >30 kg/m2; encourage weight loss
Migraine frequency (patient-reported)	Increased frequency could indicate adverse impact of HRT	Next review at 3/12 (sooner if necessary)	Withdraw/change therapy if suspected HRT contributing to increased migraine frequency
Symptoms of hypothyroidism (patient-reported)	Increased symptoms could indicate adverse impact of HRT	Next review at 3/12 (sooner if necessary)	GP to monitor for signs of hypothyroidism; otherwise annually

Transfer of care

Oestrogel® and Utrogestan® are green on the Pan–Mersey Formulary, ²⁴ thus AP’s GP can prescribe them in primary care. However, she will be reviewed in 3–4 months’ time, likely by telephone, to evaluate efficacy and adverse effects of her regimen, and to modify treatment as appropriate (e.g. if VMS symptoms have not fully abated, the dose of Oestrogel® can be increased; if Utrogestan® is making her intolerably drowsy, there is the option of changing to the levonorgestrel IUS, Mirena®. The effect of HRT on migraine severity/frequency will be evaluated and a review of any other significant health changes undertaken. AP will be asked about any new menopause symptoms e.g. low libido, symptoms of UGA, with consideration of additional treatment options as appropriate.

Blood pressure and BMI will be checked. Depending on the outcome of the review appointment at 3-4 months, AP could be discharged from the service for on-going GP management or reviewed again if needed. Once stable, the GP should review HRT annually to determine the on-going need for treatment. ⁸