Treatment options for menopausal symptoms

The management of menopausal symptoms often presents a clinical challenge to prescribers. This could be because of concerns about breast cancer risk and initial data from the Women’s Health Initiative trial in 2002, which reported an increased risk in cardiovascular disease (CVD) and possible early harm in women receiving combined oestrogen and progesterone^[1]
. This resulted in reduced prescribing of menopause hormone treatment (MHT) in the UK. Subsequent follow-up data from the same study in 2013 showed no detrimental effect on CVD; therefore, with careful consideration of risks and benefits, there are now around one million women in the UK using treatment (including MHT) for their symptoms^[2]
.

Menopausal oestrogen deficiency is associated with irregular periods and multiple other symptoms — the most common being hot flushes and night sweats, vaginal dryness, mood changes, sexual dysfunction (including loss of libido), memory and concentration changes, headaches, joint and muscle complaints. Around 80% of women will experience symptoms, lasting an average of four years^[2]
.

In healthy women over the age of 45 years with menopausal symptoms, menopause and the perimenopause can be diagnosed without laboratory tests. Perimenopause is defined as irregular periods and vasomotor symptoms. Menopause is defined retrospectively as no periods for more than 12 months in the absence of hormonal contraception. In women without a uterus, menopause is diagnosed via symptoms alone^[2]
. Premature ovarian insufficiency (POI) is when menopause occurs before 40 years of age and affects 1% of women. The diagnosis of POI must take into account clinical history, such as previous surgery; however, it can be made in women under the age of 40 years who have infrequent or no periods and follicle stimulating hormone (FSH) levels >40IU/l on two occasions more than 4–6 weeks apart^[2]
.

Many women experience uncomfortable symptoms as they approach menopause and, therefore, will seek the advice of pharmacists and other healthcare professionals during the transition. This is a crucial time where risk assessment, combined with lifestyle and hormonal intervention, can minimise the effects of menopause and help reduce the risk of many long-term health conditions.

The management of menopausal symptoms must be individualised, taking into account the woman’s history and personal preferences. Options include complementary therapies, non-hormonal treatments and MHT. This article aims to support pharmacists and other healthcare professionals in recommending appropriate treatment options for women going through menopause so that they can make informed choices about how to relieve and manage their symptoms.

Managing the menopause without menopause hormone treatment

Lifestyle factors

Lifestyle and dietary changes can improve menopausal symptoms. Minimising caffeine and alcohol, maintaining a healthy weight and avoidance of smoking are all beneficial. Women should be advised to do at least 150 minutes of moderate intensity exercise per week. Two sessions of resistance training may provide additional benefit. Improved metabolic function, balance, muscle strength, cognition and quality of life are observed in women who are physically active. Additionally, cardiovascular events, breast and colon cancer, stroke and fractures are less frequent^[3]
.

Alternative therapies

There is some evidence that meditation, relaxation, controlled breathing, cognitive behavioural therapy and mindfulness training could play a role in reducing hot flushes, but adequately powered randomised trials are still needed^[4]
. Recent meta-analyses have also shown that acupuncture may be beneficial for vasomotor symptoms^[5]
.

Non-prescription treatments

National Institute for Health and Care Excellence (NICE) guidance advises that isoflavones and black cohosh may alleviate vasomotor symptoms; however, multiple preparations are available and their safety is unknown. St John’s wort is effective in relieving vasomotor symptoms; however, for women at high risk of, or who have, breast cancer, there is uncertainty regarding safe dosing, variation in the potency and nature of preparations. St John’s wort should also be used with caution because it can interact with other medications (e.g. anticoagulants, antidepressants and anticonvulsants)^[2]
.

Non-hormonal treatments

Some women will have contra-indications to MHT or choose not to use hormonal treatment. Non-hormonal treatments are less effective than MHT for vasomotor symptoms and will not help other symptoms of oestrogen deficiency, such as vaginal dryness, joint pain and low sexual desire (Box 1).

Clonidine is the only non-hormonal treatment licensed to treat vasomotor symptoms. It is an alpha-adrenergic agonist and works as an antihypertensive causing peripheral vasodilation. It interacts with hypertensive drugs and is, therefore, not suitable for patients with baseline low blood pressure.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressant medications. SNRIs (e.g. venlafaxine) inhibit the reuptake of serotonin and norepinephrine, whereas SSRIs act upon serotonin only. The benefit for vasomotor symptoms ranges from 20% to 60%.

Pregabalin and gabapentin can also be used to treat neurogenic pain, migraine and vasomotor symptoms.

Manging the menopause with menopause hormone treatment

MHT includes oestrogens, progestogens and combined preparations. It is licensed to treat menopausal symptoms and for osteoporosis prevention^[2]
. Choice of drug, combination and route is dependent on past medical history, menopausal status, uterine status and patient preference (Box 2). Oestrogen-only MHT has a significant risk of endometrial hyperplasia, which can result in malignancy; therefore, it must be combined with a progestogen in women with an intact uterus^[6]
.

Combined MHT takes two forms: sequential combined MHT (sc-MHT) and continuous combined MHT (cc-MHT). In the former, oestrogen is taken every day and progestogen is taken most commonly in the luteal phase (day 15–28) of the cycle. This is for women who are perimenopausal or still menstruating, and is usually taken until age 51 or for at least one year; cc-MHT, on the other hand, is daily oestrogen and progestogen, and is taken 12 months after the last period, after 51 years of age or 1 year after sc-MHT. MHT is usually prescribed within 5 years of menopause in women aged 50–59 years, but duration of use should be individualised and not based on arbitrary limits.

MHT can be administered via several routes including oral, transdermal (patches or gel), or subcutaneous implant. The choice of route will depend on several factors including past medical history and patient preference. The transdermal route avoids first-pass hepatic metabolism and, therefore, is not thought to be associated with any increased risk in venous thromboembolism (VTE).

Risks and benefits of menopause hormone treatment

Cardiovascular disease

In contrast to the initial Women’s Health Initiative data showing an increase in CVD associated with MHT, subsequent data have been much more reassuring. Large-scale randomised and observational data have shown that there is no increase in CVD risk in women under 60 years^[7]
. Furthermore, there are increasing data pointing to a ‘window of opportunity’ where the use of MHT within 10 years of the LMP is associated with reduced cardiovascular disease^[8],[9]
. A randomised controlled trial also showed a 30% reduced risk of all-cause mortality (13:10,000 fewer deaths) in the 50–59 year age group^[10]
.

Venous thromboembolism

The background incidence of VTE is around 1 in 1,000 in women aged 50 years^[11]
. Oral MHT (oestrogen alone or oestrogen plus progestogen) increases the risk of deep vein thrombosis and pulmonary embolism^[12]
. However, there is no significantly increased risk of VTE in women who are using transdermal preparations compared with non-users (either oestrogen alone or oestrogen with micronised progesterone)^[7]
. A meta-analysis showed pooled risk ratios for VTE were 1.9 (95% confidence interval [CI]: 1.3–2.3) and 1.0 (95% CI: 0.9–1.1) among oral and transdermal oestrogen users, respectively^[11]
. The risk of VTE with oral MHT is highest in the first year of use^[7]
and the increased risk disappears after the MHT is stopped^[7]
.

Osteoporosis

There is a decrease in incidence of all fractures, even in women who are not deemed high risk^[7]
. MHT is also the only treatment to have proven efficacy for reduction in osteopenia-related fractures.

Treatment for osteoporosis is indicated for women with a fragility fracture, a diagnosis of osteoporosis (T score of ≤–2.5) or osteopenia (T score of –1.0 to –2.5) with additional risk factors. NICE recommends MHT for second-line intervention for osteoporosis prophylaxis. MHT is of most benefit for the prophylaxis of postmenopausal osteoporosis if started early in menopause and continued for up to five years; however, bone loss resumes on stopping MHT^[7]
. Therefore, MHT is an option where other therapies are contra-indicated, cannot be tolerated, or if there is a lack of response.

Vitamin D is prescribed at 20,000IU/week for eight weeks for severe deficiency and 1,000IU/day for maintenance or mild vitamin D deficiency. Calcium is only indicated in women with proven deficiency up to a maximum of 1g/day. Other commonly used preparations are bisphosphonates, strontium ranelate and raloxifene.

Cancer

The baseline risk of breast cancer for women around menopausal age in the UK varies depending on presence of risk factors. Obesity, alcohol intake of >2 units/day and late menopause all carry a greater risk for breast cancer than MHT itself^[7]
. The increased risk of breast cancer is primarily related to the addition of a progestogen, as oestrogen-only MHT has little or no excess risk for breast cancer^[7]
. Combined MHT is associated with an increased risk of breast cancer estimated at less than 0.1% per annum or <1 per 1,000 women per year of use^[7]
. Any increase in breast cancer related to MHT is related to treatment duration and reduces when stopped^[2]
. There is evidence of a lower breast cancer risk with micronised progestogens or dydrogesterone compared with synthetic progestogens^[7]
.

Reduced incidence of bowel cancer has been shown in combined oestrogen/progestogen MHT^[13]
.

Unopposed oestrogen therapy increases the incidence of endometrial cancer; this risk is dependent on dose and duration, and is largely avoided by the use of combined oestrogen and progestogen therapy^[6]
. In fact, continuous combined regimens are associated with a signiï¬cantly lower risk of endometrial cancer than an untreated population^[14]
.

Side effects

Unscheduled vaginal bleeding is the most common side effect of cc-MHT and requires clinical review and investigation if it persists beyond three months^[15]
. Oestrogen-related side effects include bloating, breast tenderness, nausea, leg cramps, swelling and headaches. They are common in the first few weeks of treatment and frequently resolve. If persistent, a change in dose or route of administration can be tried. Progestogen-related side effects occur via activation of aldosterone and androgen receptors and include bloating, weight gain, breast tenderness, oedema, headaches, mood disturbance and acne (Box 3).

Additional treatments

Bioidentical hormones

These are precise duplicates of progesterone, testosterone, dehydroepiandrosterone, oestradiol, oestriol, and oestrone,  as synthesised by the human ovary and adrenal gland. They are often prescribed in combination with multiple serum and saliva tests; however, their use is not recommended because there is lack of regulation, rigorous safety testing, batch standardisation and purity measures^[16]
.

Androgen replacement

Androgens, including testosterone, play an important role in female sexual desire, energy levels and cognition. NICE recommends testosterone supplementation for menopausal women with low sexual desire if MHT alone is not effective. There is currently a lack of testosterone preparations designed for use in women and, therefore, off-label prescribing of male preparations is common. The most frequently used preparations are testosterone gels, usually prescribed so that a 50mg tube is used over 7–10 days. This aims to keep testosterone levels within the physiological range to minimise side effects (e.g. acne or hirsutism).

Vulval–vaginal atrophy/genitourinary syndrome of the menopause

In uncomplicated vulval–vaginal atrophy, local topical oestrogens can be used with moisturisers and lubricants. Local oestrogen improves vaginal tissue maturation, reduces pH and the route minimises the degree of systemic absorption with levels observed to be in the normal postmenopausal range (<20pg/ml)^[7]
. Local oestrogen may, therefore, be used concurrently with systemic MHT with no additional risks and minimal systemic side effects.

Treatment options for premature ovarian insufficiency

NICE recommends women with POI should receive either MHT or combined hormonal contraception; this should be continued until at least the average age of menopause (52 years). The aim of treatment is to control menopausal symptoms, maintain sexual function and to minimise the risk of cardiovascular disease, osteoporosis, and possibly reduce the risk of cognitive impairment associated with POI^[17]
. Calcium, vitamin D and lifestyle advice are also important.

POI patients typically require higher doses of oestrogen than older postmenopausal women, with the aim of achieving serum oestradiol levels equivalent to pre-menopausal mid-follicular levels (around 400pmol/l)^[18]
. Importantly, women with POI should be informed that MHT has not been shown to increase the risk of breast cancer before the age of natural menopause^[19]
.

Combined oestrogen/progestogen contraceptive pills (COCPs) may be used continuously until the expected time of the menopause but data are lacking on the impact on bone and CVD. There are also limited studies comparing MHT with the COCP; however, the COCP causes more suppression of FSH^[20]
and MHT is associated with beneficial effect on blood pressure^[21]
, less hyperinsulinaemia^[20]
, increased bone formation markers^[22]
and improved lumbar spine bone mineral density^[23]
. Thus, the small randomised trials suggest that metabolic and bone health are more effectively maintained with MHT, but this requires confirmation.

In women with POI, ovarian function can return intermittently and around 5% of women conceive naturally after the diagnosis. MHT is not contraceptive unless oestrogen is combined with a LNG-IUS; therefore, it may be more practical for the COCP to be used for the first few years following diagnosis of POI in those wishing to avoid pregnancy^[7]
.