Service evaluation project – Are local recommendations for onward referral to a specialist menopause clinic required to translate guidelines into practice?

Abstract

Objective

Referral audit – are local recommendations required to translate guideline to practice?

Study design

In total, 50 consecutive, anonymised referral letters reviewed during the initial consultation in a specialist menopause clinic; the reasons for referral along with the patient’s age and the source of referral were analysed.

Results

Several common reasons for referral were identified. Sexual dysfunction, including loss of libido and dyspareunia, resulted in 11 (22%) referrals. Ten (20%) women were troubled by persistent symptoms or side effects from HRT; 9 (18%) women were referred before hormone replacement therapy was discussed or commenced; 7 (14%) women seeking advice for their menopausal symptoms had a family or personal history of cancer; 5(10%) were migraineurs; 2(4%) women had premature ovarian insufficiency; 2(4%) were denied hormone replacement therapy because of concern about venous thromboembolism risk; and 4 (8%) had miscellaneous medical disorders. Over 25% of referrals were older than 60.

Conclusion

Menopausal symptoms are predominately dealt with in primary care where advice and support is needed. National Institute for Health Care and Excellence published guidance regarding onward referral to a specialist menopause clinic, which is vague and referral patterns are haphazard. Our audit highlighted areas of clinical uncertainty and formed the basis for providing local pre-referral information and advice. Some of the information provided is quite detailed and aimed at healthcare professionals with a special interest in menopause. Further training is now required to improve the quality of referrals. The diversity and complexity of some referrals illustrates the need both for a menopause specialist and clear pathways for further advice or referral within each region.

Keywords

Breast cancer estrogen HRT menopause urogenital atrophy vasomotor symptoms

Introduction

Menopause may have a profound impact on quality of life and some symptoms are difficult to treat, particularly in women affected by, or at increased risk of hormone-sensitive cancer. In November 2015, the National Institute of Health Care and Excellence (NICE) guidance on menopause care was published.¹ The guidelines suggested referral to a healthcare professional with expertise in menopause if:

treatments did not improve menopausal symptoms,

there are ongoing side-effects from treatment,

they have contra indications to hormone replacement therapy (HRT),

there is uncertainty about the most suitable treatment options for their menopausal symptoms and

premature ovarian insufficiency (POI) is suspected.

In addition, The Royal College of Obstetricians and Gynaecologists recommended that women, who become menopausal as a result of cancer treatment, should routinely be referred for specialist menopause care to optimise quality of life and prevent long-term sequelae. At present, access to clinics varies across the country and there is no consistent network of menopause services. Moreover, some menopause guidance is pragmatic and open to interpretation.

Method

To assess the need for further recommendations when considering onward referral to a specialist menopause clinic, information from 50 consecutive, anonymised referral letters was documented at the time the patient attended a consultant led menopause clinic. Data were collected regarding the reason for referral, age of patient and the source of the referral.

Results

Table 1 shows the reasons for referral and the numbers of patients referred in each age group. In total, 50 consecutive referrals were analysed. Two of the women referred with loss of libido also had POI; they were not referred because of POI and so not included in this group.

Table 1.

Reasons for referral to a specialist menopause clinic and number of patients referred.

	31–40 years n = 5	41–50 years n = 17	51–60 years n = 15	>60 years n = 13
Reasons for referral
Menopausal symptoms – general advice/HRT not discussed prior to referral, n = 9		3	3	3
Loss of libido/dyspareunia, n = 11		3	2	6
Persistent symptoms/side-effects on HRT or return of symptoms once stopping it, n = 10		2	7	1
Personal or family history of cancer – advice about HRT, n = 8	1	3	2	2
Migraineurs – advice about HRT, n = 5	2	2	1
POI, n = 2	2
VTE risk – advice about HRT, n = 2		2
Miscellaneous medical disorders, n = 3		2		1

HRT: hormone replacement therapy; POI: premature ovarian insufficiency; VTE: venous thromboembolism.

Forty-six patients were referred by general practitioners (GPs), 3 of whom specifically requested to see an expert and 4 by hospital consultants; 9 women were referred with menopausal symptoms before systemic HRT was discussed. The commonest reason for referral was loss of libido often associated with dyspareunia, n = 11. Ten women were referred with persistent symptoms despite HRT or had developed side-effects or recurrence of symptoms once HRT had been discontinued; 7 women were referred with either a personal or family history of cancer and advice about HRT; 3 had breast cancer of which 1 was a BRCA carrier and 2 had a strong family history of breast cancer; one woman had endometrial cancer and one had bowel cancer; 2 women, both requesting HRT, were referred because of concern about risk of venous thromboembolism (VTE); 13 women over 60 were referred showing the persistent nature of menopause symptoms.

Discussion

Menopause healthcare starts with an understanding of the impact of menopause along with encouragement to adopt a healthy lifestyle and provision of clear evidence-based information. Not every woman requires HRT but all should have access to the treatment options. In the audit, nine women were referred with severe menopausal symptoms before systemic HRT was discussed or offered. Subgroup analysis, of the albeit small numbers, showed all the women had tried either natural remedies including Sage and Black cohosh or non-hormonal therapies such as selective serotonin reuptake inhibitors (SSRIs) or gabapentinoid agents. Of interest, one woman had suffered hot flushes for over 10 years. SSRIs had failed to alleviate her symptoms. She was now 62 and her referring practitioner considered her too old to start HRT. Another woman, aged 54, was referred from the haematology department with sweats for which no cause could be found but a raised follicle-stimulating hormone level had been noted.

Of the nine women referred, eight chose to start HRT. The ninth woman continued with Sage.

Although the numbers are small, they illustrate the ongoing difficulty disseminating information about the options for managing menopause symptoms to both patients and practitioners.

Pre-referral advice:

Improve ‘menopause awareness’ within the whole of the primary care team and identify a healthcare practitioner with a special interest in menopause care.

Provide all female patients with information about menopause care.

Good resource – Menopause Matters, https://www.menopausematters.co.uk/

Good resource – Women’s Health Concern, https://www.womens-health-concern.org/

Menopause and sexual dysfunction (n = 11)

Female sexual interest-arousal disorder is characterised by prolonged (greater than 6 months) distressing loss of libido, a key menopausal symptom and the commonest reason for referral accounting for 11 referrals. Four of the 11 women were systemic HRT users and 1 used vaginal estrogen alone. Of the four HRT users, one had a surgical menopause, another was taking an SSRI and two women reported additional vaginal dryness and dyspareunia. Six women had not been given any advice or treatment suggesting that sexual interest-arousal disorder may be an area of clinical uncertainty in primary care. Loss of libido is a symptom rather than a diagnosis and may have complex underlying cause(s) (hormonal, medication side-effects, psychological or relationship issues). In our study group, none of the women referred in to the clinic were found to have primary relationship issues.

Practitioners caring for women should be competent in managing sexual concerns as it is an essential component of menopause healthcare. Screening begins by establishing if the woman is currently involved in a sexual relationship and if there is a general loss in sexual interest or arousal, which is causing distress, or a local vulvo-vaginal problem or both. Enquiries should be made about relationship issues and possible comorbidities, particularly depression, anxiety, urinary incontinence, hypothyroidism, hyperprolactinaemia and the use of antidepressant or antipsychotic therapy.

Simple, open-ended questions enable assessment and normalises discussing sexual issues.²

Some post-menopausal women report vaginal dryness or soreness or that sensation is reduced during sexual activity. Do you have any concerns you would like to discuss?

Some women become distressed around the time of the menopause because they lose interest in sexual activity – have you encountered any problems in your relationship which you would like to discuss?

If there is concern, information should be provided about the aged-related physiological changes in sexual response and pelvic anatomy. Information about vaginal lubricants, the role of systemic HRT and vaginal estrogen is also valuable. This is basic information useful for every woman, even if the current problem is relationship based, in which case couples counselling may be required.

Menopause is associated with a decline in sexual interest, arousal and orgasm, which cannot solely be explained by declining testosterone levels, which happen gradually from about the age of 25. Only about 2% of testosterone is ‘free’ or biologically active, the rest is bound to sex hormone binding globulin (SHBG). Oral estrogen increases SHBG, thus decreasing free testosterone availability and potentially negatively influencing libido. So for women taking oral HRT, particularly conjugated equine estrogen, it may be worth considering switching to transdermal HRT, or tibolone for women under 60. Transdermal estrogen has no effect on SHBG. Alternatively, or in addition, if symptoms of vaginal dryness, soreness or reduced vulval sensation are present, vaginal estrogen should be offered.

There is some evidence that exogenous testosterone replacement may have a role in improving sexual response and thus desire.³ A trial of testosterone therapy (testogel 5 mg sachet per week, in divided doses) may be considered if estrogen alone fails to alleviate symptoms, particularly in women who had a surgical menopause or POI.¹ Prior to treatment, check SHBG (SHBG 15–75 nmol/L) and testosterone (T) levels (less than 2.8 nmol/L) to avoid testosterone misuse or overdose. Free testosterone assays are not always available and a free androgen index of less than 5% (<7% in women with POI) is an alternative test.

Prescribing testosterone is ‘off licence’ as long-term safety data is lacking⁴; however, no serious adverse side-effects have emerged.⁵ Possible reversible side-effects, acne, hirsuitism, alopecia and voice changes should be discussed. Physiological levels of transdermal testosterone (T less than 2.8 nmol/L) do not adversely affect cardiovascular function or the endometrium. Breast safety data are limited but trials of intra-vaginal testosterone in women with early breast cancer are now underway⁶ and there is some evidence to suggest it may have an anti-prolific effect on breast tissue. There is no upper age limit for testosterone use and treatment can be tried without estrogen therapy for those women wishing to avoid systemic HRT.⁷ Treatment may take 3 months to be effective and women must be aware that treatment is a trial. If no improvement after 6 months, discontinue treatment.

Pre-referral advice:

Provide patient information about age-related changes in sexual function, pelvic anatomy and where to access non-hormonal vaginal lubricants.

Good resource – The Women’s Health Concern, https://www.womens-health-concern.org/help-and-advice/…/focus…/sexual-problems/

Good resource – Jo Divine, https://www.jodivine.com/sexual-lubricants

Review medication side-effects and consider co-morbidities.

Discuss the roles of HRT, vaginal estrogen and lubricants.

Vaginal estrogen may be needed in addition to systemic HRT for vulvo-vaginal atrophy.

Consider switching from oral to transdermal estrogen or tibolone.

Follow local pathways to specialist level menopause service for

women requesting ‘off licence’ prescribing of testosterone therapy.

Persistent symptoms and side-effects (n = 10)

In total, 10 referrals had side-effects from HRT, usually an unacceptable bleeding pattern or ineffective symptom relief. Unscheduled vaginal bleeding occurs in up to 50% of women taking HRT, and it is the single most important factor deterring women from continuing HRT and concern that bleeding may reflect underlying malignancy often leads to invasive investigations.

For HRT users with a uterus, progestogen is essential to prevent endometrial hyperplasia or malignancy. Progestogen supplied sequentially for 12–14 days in a 28-day cycle, or continuously via an intra-uterine device (LNG 52 mg-IUS), is recommended for perimenopausal woman with less than 12 months’ amenorrhoea. When using a sequential regime, most women bleed for a few days near the end of the progesterone phase. Alternatively, for post-menopausal women, continuous combined estrogen/progestogen or tibolone may be used; over 80% of women will become bleed-free on a continuous combined regime.

When HRT is first started, irregular bleeding is common and usually settles within 3–4 months, although it may take up to 6 months for women using continuous combined HRT. It is important to inform HRT users about unscheduled bleeding, which may occur spontaneously or result from poor compliance, drug interactions and chronic gastro-intestinal diseases. Abnormal uterine bleeding is common in perimenopausal women. It is important to manage structural or histological causes of abnormal bleeding before starting HRT. This approach will avoid delay in the diagnosis of endometrial hyperplasia or cancer.

Generally, regimes containing a progestogen that is C19 testosterone derivatives, such as norethisterone, give effective cycle control because they were developed to have more focused endometrial potency compared to micronised progesterone. If unscheduled bleeding persists beyond 3–4 months doubling the progestogen dose, taking progestogen for longer (up to 21 days) or changing the progestogen class may be give better cycle control. Levonorgestrel-releasing intra-uterine system (LNG-IUS) may take up to 6 months to reach full effect and over that time women may experience irregular bleeding, which is usually light. LNG-IUS provides endometrial protection for 5 years, as well as contraception, and is the first-line treatment for heavy menstrual bleeding (HMB) which may coexist. Dienogest/estradiol valerate (Qlaira) is another option for healthy, non-smoking perimenopausal women; it also provides contraception and treatment for HMB (combined oral contraceptive rules apply). It has a European licence for control of HMB.

Continuous combined HRT is more likely to cause spotting rather than irregular bleeding. It reduces the risk of endometrial cancer below the background risk. If users experience persistent bleeding, management options include changing from transdermal or an oral regime with a C19 testosterone derivative, reducing the estrogen, or increasing the progestogen dose or changing the progestogen to LNG 52 mg-IUS (although this may cause prolonged spotting for several months). Tibolone is a useful alternative with a lower rate of unscheduled bleeding than continuous combined HRT. It has the additional advantage of improving libido, increasing energy levels with no effect on fibroid size or pre-existing endometriotic tissue. Occasionally, it may be necessary to change to a sequential regime for 6–12 months or stop HRT completely for 3 weeks allowing the bleeding to settle spontaneously.

Unscheduled bleeding with any regime may reflect endogenous hormone release; however, it should be investigated if it starts after 6 months of regular cycles with sequential HRT or if irregular bleeding persists after the first 6 months with continuous combined HRT. This is particularly important for women with a high body mass index (BMI) as they have a higher risk of developing endometrial hyperplasia and cancer because of unopposed extra ovarian estrogenic stimulation.

Pre-referral advice:

Encourage a healthy diet, ideal weight and regular physical activity to enhance symptom relief.

When discussing HRT, provide information about common side effects, including unscheduled bleeding.

Manage abnormal uterine bleeding before starting HRT.

Side-effects including unscheduled bleeding usually settle within 3–4 months.

If unscheduled bleeding persists on a sequential regime, increase progestogen dose, length of time it is taken or progestogen class.

Bleeding with continuous combined HRT may take 6 months to settle initially.

If bleeding with continuous combined HRT does not settle, the options are to increase or change progestogen, tibolone or change to a sequential regime for 6–12 months.

Follow local pathways to specialist level menopause service if

unscheduled bleeding persists beyond 6 months with continuous combined HRT, or starts after 6 months of good cycle control with sequential HRT and

in women with multiple treatment failures.

Menopause and cancer (n = 8)

Menopause care is inextricably linked to breast cancer management, both in its prevention and the side effects of treatment. Six women were referred with either a personal or family history of breast cancer, seeking advice about HRT for severe menopausal symptoms.

During a menopause consultation, it is relevant to take a family history of breast and/or ovarian cancer and calculate an approximate risk of breast cancer using a breast cancer risk tool.⁸ Genetic assessment may be indicated in accordance with NICE guidance shown in Table 2.⁹ Tools like BOADICEA or the Manchester scoring system are used in secondary care to calculate risk. The more accurate the information supplied about family history (age of cancer onset, site of cancer, Jewish ancestry), the more accurate the risk estimate.

Table 2.

Indications for referral to a service with specialist skills in estimating breast cancer risk.

Type of cancer	Relatives affected	Age at diagnosis	Referral for estimation of breast cancer risk
Female breast cancers only	1 First-degree relative	Under 40	Yes
	2 First-degree relatives	Any age	Yes
	1 First- and 1 second-degree relative	Any age	Yes
	3 First-degree relatives	Any age	Yes
	3 Second-degree relatives	Any age	Yes
Male breast cancer	1 First-degree male relative	Any age	Yes
Bilateral breast cancer	1 First-degree relative	Under 50 for diagnosis of first cancer	Yes
Breast and ovarian cancer	1 First-degree relative with breast cancer and 1 first-degree relative with ovarian cancer	Any age	Yes
	1 First-degree relative with breast cancer and 1 second-degree relative with ovarian cancer	Any age	Yes
	1 second-degree relative with breast cancer and 1 first-degree relative with ovarian cancer	Any age	Yes

Note: First-degree relatives include mother, father, daughter, son, sister and brother. Second-degree relatives include grandparent, aunt, uncle, niece, nephew, half-sister and half-brother.

The lifetime risk of breast cancer in the general population is about 12%.¹⁰ One in eight women will get breast cancer but seven out of eight will never be affected by breast cancer. The median age of breast cancer is 60.8, with peak incidence in the 64- to 69-year age group, so for most women menopause is well established when breast cancer first develops.

In women referred for genetic assessment, the lifetime risk of developing breast cancer, starting from the age of 20 is categorised according to NICE guidelines⁹ as slightly higher than general population risk, or moderate risk (17%–29%,) or high risk (≥30%). Not all the women categorised as moderate or high risk will be tested for the BRCA mutation as genetic testing is only normally offered to affected family members (unless an affected member is unavailable).

Evaluating the need for genetic assessment is an important part of a menopause consultation as it may have a significant influence on subsequent management. Regional guidelines for women at moderate or high risk of breast cancer are now in place and outlined as follows:

Increased breast cancer surveillance

for high-risk women with a 30% or higher probability of being a BRCA or TP53 carrier – annual magnetic resonance imaging (MRI)/mammography from 40 to 59 years,

for high-risk women with a known BRCA1 or BRCA2 mutation – annual MRI/mammography from 40 to 69 years,

for moderate risk women – annual MRI/mammography from 40 to 49 years;

Chemoprevention for 5 years (instead of surgery) that

offers tamoxifen to premenopausal women at high risk of breast cancer who do not have thromboembolic disease or endometrial cancer as it has been shown to produce a significant reduction in breast cancer risk,

offers tamoxifen or raloxifene to postmenopausal women at high risk who do not have thromboembolic disease or endometrial cancer,

considers tamoxifen for both pre- and postmenopausal women at moderate risk of breast cancer who do not have thromboembolic disease or endometrial cancer;

Risk reducing mastectomy (RRM), this may be offered to women at high risk of breast cancer with suspected BRCA1/2 or TP53 mutation. For women with BRCA mutation, RRM decreases cancer risk by 90% (fourth decade of life is often the optimal timing).

Risk reducing bilateral salpingo oophorectomy (RRBSO), offered to women at high risk of breast cancer with suspected BRCA1/2 or TP53 mutation. Women with the BRCA1 mutation have a 55%–65% lifetime risk of breast cancer and 40%–60% lifetime risk of developing epithelial ovarian cancer (EOC). The risk is lower for a BRCA2 mutation (40% risk of breast cancer and 11%–17% risk of EOC). RRBSO reduces ovarian, fallopian tube and peritoneal cancer risk by about 80%, although there is still a 1%–4% risk of residual peritoneal cancer.¹¹ RRBSO has repeatedly been reported to reduce the risk of breast cancer among BRCA1 and BRCA2 mutation carriers (37% and 64% prospectively) when carried out in premenopausal women. However, a recent prospective cohort study, controlling for potential biases, suggested that no benefit in breast cancer risk reduction existed following RRBSO.¹²

The use of HRT to manage menopausal symptoms in women at high risk of breast cancer is largely influenced by the treatment option that has been chosen (as listed above). An early surgical menopause, following RRBSO, can cause symptoms of great severity lasting longer than a natural menopause and have detrimental effects on bone, heart and brain health. The short-term use of HRT does not appear to negate the benefit of surgery in women under the age of 51¹³ and is now recommended by NICE. Moreover, evidence from the Nurses Study did not show an increase risk of breast cancer in women taking HRT with a familial history of breast cancer.¹⁴ For women older than 51, HRT should be used with caution as safety data are lacking and even women who have undergone an RRM still have a small (1%–2%) risk of breast cancer. There is evidence from small studies that HRT may be safe in BRCA1 carriers over the age of 51 but further data are required to make this a recommendation.

For women taking tamoxifen as chemoprevention, HRT is not recommended outside trial conditions. Tamoxifen has a binding affinity for estrogen receptors (ERs) of greater than 99% and is not displaced by the presence of circulating serum estrogen. Evidence from chemoprevention trials that have permitted the use of HRT have found that the cancer preventing effect of tamoxifen is not observed for women on HRT.¹⁵

For women with a moderate risk of breast cancer the additional risk of taking HRT is not known.

For women with estrogen positive breast cancer

Breast cancer is a heterogeneous disease. The Cancer Genome Atlas Network recognises four intrinsic subtypes of breast cancer. About 75% of breast cancers express ER+ve and treatment often includes adjuvant anti-estrogenic therapy (AET) to eradicate occult micro-metastatic disease and reduce recurrence risk. The menopausal side-effects of breast cancer treatment are not to be underestimated and may impact greatly on quality of life, causing relationship problems and sexual dysfunction. Acute symptoms are often worst in younger women or those taking HRT at the time of breast cancer diagnosis. Complications, such as loss of libido, may persist even when AET is finished.¹⁶

UK follow-up pathways now promote ‘self-management’ after the initial treatment phase; however, all women affected by breast cancer should have an opportunity to discuss menopause-specific quality of life issues. Adverse effects are strongest during the first 3 to 6 months and for most women advice, reassurance, counseling and non-hormonal preparations (e.g. venlafaxine 37.5 mg od increasing to 75 mg daily or gabapentin 100 mg tds increasing gradually to 900 mg daily) may alleviate symptoms and maintain compliance. Some women develop intractable menopausal symptoms, which presents a significant clinical dilemma. There is good evidence from clinical trials¹⁷ that estrogen deprivation reduces breast cancer recurrence and increases breast cancer survivorship, so the use of HRT in women with breast cancer seems counterintuitive. NICE¹ suggests a pragmatic approach for women with intractable symptoms, and HRT may be prescribed after the risks are discussed and documented; however, this approach is difficult and the risk is that the limited ‘facts’ may be incorrectly applied.

To date, all trials of HRT use in women with breast cancer have been prematurely discontinued because of safety issues.¹⁸ In women without breast cancer, the Women’s Health Initiative (WHI)¹⁹ and other studies suggest that it is the progestogen component of HRT and not estrogen that is more significant in any increase in breast cancer risk.²⁰ The Cancer Research Institute (CRI) recently published a large prospective trial showing the risk of breast cancer was 2.7 times baseline risk for current users taking combined HRT for 5 years, but no increased risk for women taking estrogen only HRT.²¹ However, the role of progesterone in breast cancer is poorly understood. Several small studies have demonstrated a different breast cancer risk associated with different progestogens; in some small studies, natural progesterone has been shown to have a lower risk than synthetic, androgenic progestins,²² and megestrol acetate has been demonstrated to have an anti-proliferative effect on breast tissue. Megestrol acetate (20 mg Megace) has been successfully used to treat hot flushes in breast cancer patients; however, it is not widely available and has no effect on vaginal dryness.²³ Robust safety data to recommend the use of LNG 52 mg-IUS is currently lacking.²⁴

So how can risk be accurately discussed and documented as NICE suggest?

Duavive is a new oral HRT licensed for the treatment of estrogen deficiency symptoms in women who cannot tolerate progesterone.²⁵ It combines low dose conjugated equine estrogen (CEE) and bazedoxifene (BDZ), a selective estrogen receptor modulator (SERM). BDZ down regulates ERs in the breast potently inhibiting cell growth.^26,27 Feasibility studies are currently underway to assess the use of Duavive in post menopausal women with ductal carcinoma in-situ and in the treatment of women with stage IV breast cancer.²⁸ So in women whose quality of life is severely affected by iatrogenic estrogen deprivation does a pragmatic approach include a discussion about the use of CEE with BDZ, which could be prescribed through the Early Access to Medicine scheme?²⁹

Management of intractable menopausal symptoms involves a quality of life discussion balancing risks and benefits, ideally avoiding estrogen therapy and involving the breast specialist team. Detailed documentation about the limited options and discussion about the possibilities of

– a tamoxifen holiday (up to 4 months if necessary),

– switching from tamoxifen to an aromatase inhibitor (AI) (post-menopausal women only) or from an AI to tamoxifen,

– CCE/BDZ (‘off licence’ after risks and limitations of scientific data documented and discussed),

– transdermal estrogen HRT for the shortest time and at the lowest dose possible, with micronised progesterone for women with a uterus (‘off licence’ after the risks and limitations of scientific data documented and discussed),

– vaginal estrogen therapy (Vagifem 10 µg pessaries once or twice weekly) has minimal systemic absorption and has not been shown to increase cancer recurrence risk; however, in women taking an AI baseline plasma, estrogen levels are often <1 pmol/ml, as AI block 95% of estrogen synthesis. Vagifem may temporarily increase estrogen levels above the therapeutic baseline which may theoretically reduce the efficacy of AI.³⁰ If vagifem is required, it is safer, therefore, to use it with tamoxifen rather than an AI.

– vaginal lubricants (Pjur Med, YES, SYLK), vaginal moisturisers (Regelle, which last 2–3 days) and emollients (e.g. Hydromol or Epaderm ointment) for vulval dryness,

– psychosexual counseling or specialist physiotherapy for persistent sexual dysfunction and

– vaginal testosterone therapy (intra-vaginal testosterone cream). Preliminary evidence suggests improvement in vulvo-vaginal symptoms and sexual dysfunction, safety data are limited to phase II trials which demonstrated that testosterone did not interfere with the ability of AI to suppress estradiol levels.⁹

For women with estrogen receptor negative (ER−ve) breast cancer

Twenty-five percent of breast cancers do not express the ER. These tumours are more likely to recur early and risk of recurrence later than 5 years is very small. HRT will not increase the risk of recurrence but it may increase the risk (6%) of a new breast cancer appearing in the contralateral breast.

Women more than 5 years post breast cancer

ER+ve (HER2 −ve) breast cancer recurrence may occur late after treatment.

Important factors influencing recurrence include axillary nodes metastasis found at operation, tumour size (>2 cm) and histological grade. HRT taken even 5–10 years after breast cancer diagnosis may influence the recurrence risk, which is about 1% by 10 years.³¹ Liaison with the breast cancer specialists before the menopausal consultation is important because cancer behaviour can be predicted, to some extent, using tumour prognostic factors and the adjuvant online tool http://www.predict.nhs.uk/predict.html, which may influence subsequent menopausal management.³²

For women with breast cancer, future research is required to establish the role/safety of

– CCE/BDZ in the management of intractable menopausal symptoms,

– transdermal or intra-vaginal testosterone for sexual dysfunction,

– LNG 52 mg-IUS for heavy menstrual bleeding particularly in women on tamoxifen and

– megestrol acetate for the treatment of hot flushes.

In addition, the safety of HRT following RRBSO in BRCA carriers beyond menopause age needs further investigation.

Early diagnosis and effective treatment have led to significant improvements in breast cancer survivorship, but for some women this has come at great cost. Future research must address the side-effects of iatrogenic estrogen deprivation resulting from treatment. Menopause management in women with or at increased risk of breast cancer is complex, involving a wide range of health issues. To promote research and avoid fragmentation of care, a coordinated, multidisciplinary team approach must be promoted.

Other cancers

Two women were referred following gynaecological cancer. Treatment of women with gynaecological cancers frequently results in acute loss of ovarian function and intense menopausal symptoms. HRT provides symptomatic relief and current scientific evidence does not show that HRT adversely affects the prognosis in the majority of gynaecological malignancies, including squamous cell carcinomas of the vulva or cervix, early stage endometrioid adenocarcinomas of the endometrium, stage 1 serous borderline ovarian carcinoma or any mucinous borderline carcinoma. In general, all women less than 45 who have mucinous or clear cell tumours should be advised to take HRT. Ovarian cancer is, however, a heterogeneous disease and a small subset will respond to estrogen suppression; establishing ER status will help to guide prescribing of HRT. For women with low-grade endometrial stromal sarcomas, the use of HRT is an absolute contraindication. In a woman with cranial meningiomas, HRT should be used with caution.

Pre-referral advice:

Estimate personal breast cancer risk using risk assessment tool https://www.cancer.gov/bcrisktool/documentation.aspx.

Consider the need for formal genetic assessment using NICE guidance CG164.

Review regional breast cancer screening and prevention policy for women at increased risk of breast cancer.

Women with breast cancer

Discuss menopause-specific quality of life issues with breast cancer patients.

Provide practical advice to alleviate vasomotor symptoms.

Local vaginal estrogens may be prescribed for vulvo-vaginal atrophy after informed discussion – and with caution in women taking AIs.

Oestriol preparation (Ovestin) has less systemic absorption but shorter half-life than estradiol preparations (Vagifem 10 mcg pessaries and Estring) which are more convenient.

Venlafaxine 75 mg od and gabapentin 300 mg tds (starting at a low dose and increasing gradually) may be offered to control hot flushes.

Following risk reducing bilateral salpingo oophorectomy – HRT may be used until the age of natural menopause.

Follow local pathways to specialist level menopause service for

women at increased baseline risk of breast cancer,

breast cancer patients requesting HRT even in ‘remission’,

serous borderline ovarian cancer of stage 2 or above,

endometrial cancer stage 1 b or above and

cranial meningioma.

Menopause and migraine (n = 5)

Migraines are common and disproportionately affect women. In the peri- and early postmenopausal period, migraine frequency/severity often increases, especially following a surgical menopause or in women who have suffered menstrually related migraines. New onset migraine is also reported during this period. Fluctuating or declining levels of endogenous estrogen and prostaglandin are considered important triggers. Conversely, in susceptible women, increasing levels of estrogen may trigger migraine with aura and this might be seen when starting combined hormonal contraception or HRT.

Five women were migraineurs with severe menopausal symptoms for whom concern had been raised about prescribing HRT. None of the women referred used a monthly migraine diary although they often reported increased frequency and severity of migraines.

Objective assessment is best achieved using a symptom diary, available from the National Migraine Centre website³³; it is also useful for monitoring progress. For migraineurs with menopausal symptoms, maintaining a stable estrogen level with transdermal estrogen may reduce migraine frequency whilst controlling menopausal symptoms.³⁴ If progesterone is required, continuous transdermal delivery is best. LNG 52 mg-IUS may be used but the response is unpredictable. If an aura appears for the first time after the start of hormone therapy, reduce estrogen and consider changing route of delivery, aiming for the lowest effective dose to reduce vasomotor symptoms and migraine frequency.

Migraine is not a risk factor for stroke in perimenopausal women and is not a contraindication to HRT. If migraine symptoms deteriorate, venlafaxine 150 mg is an alternative treatment for vasomotor symptoms, which also provides migraine prophylaxis. Start venlafaxine at a low dose, as there may be an initial exacerbation of migraine in the first few weeks, which settles with continued use so it is important not to stop treatment early.³⁵ The ideal time to start preventative treatment is arbitrary as evidence from controlled trials is lacking. Once menopause is well established, up to 70% of migraineurs report an improvement in symptoms.

Pre- referral advice:

Headache diaries prior to referral help to clarify history, identify triggers such as poor sleep and monitor treatment response.

Offer transdermal HRT as it gives the least fluctuations in estrogen levels.

If an aura appears for the first time after starting HRT, reduce estrogen and consider changing route of delivery.

If progesterone is required, use continuous transdermal progesterone if possible or micronised progesterone.

Migraine is not a risk factor for stroke in perimenopausal women and is not a contraindication to HRT.

If non-hormonal treatment is requested for hot flushes, consider venlafaxine 150 mg daily.

Premature ovarian insufficiency (n = 2)

NICE recommends referral to a specialist clinic for all women with POI.¹ POI accounted for two referrals. Interestingly, two further women with POI who had hitherto been managed solely by their GPs, were referred in with loss of libido.

POI results in fluctuating ovarian activity. In over 80% of women with POI, the condition is idiopathic; about 10% of cases will have a genetic cause (Turner’s syndrome or the Fragile X mental retardation gene mutation 1 or premutation) and about 5% of cases can be attributed to auto immune disease (hypothyroidism, Addison’s and Coeliac disease).

Pre-referral advice:

Consider karyotyping women presenting < 35 years.

Check thyroid and adrenal auto antibodies.

Check ferritin, folate and B12 levels.

Check bone mineral density at the time of diagnosis of POI.

Provide information about the Daisy network http://daisynetwork.org.uk

Seek permission to register with the National POI register https://poiregistry.net

Follow local pathways to specialist level menopause service for

all women with premature ovarian insufficiency.

Menopause and VTE – when to involve the haematologist? (n = 2)

HRT increases the risk of VTE, although the absolute risk for a given patient is small. The risk is greatest soon after the initiation of HRT and returns to the baseline level when stopped. VTE risks multiply and predicting thrombotic risk becomes complicated if there is a personal or family history of VTE or inherited thrombophilia. Moreover, venous thrombosis has a polygenic inheritance with incomplete penetrance making genetic testing of uncertain value. Despite NICE suggesting that the risk of transdermal HRT is no greater than baseline population risk,¹ referral to a haematologist is still recommended for women at risk of VTE prior to starting HRT.

In the audit, two women (4%) were referred requesting HRT with haematological complications; neither had a personal history of VTE but one had a strong family history of VTE and the other was heterozygous for prothrombin G20210A gene mutation; so when is screening for thrombophilia indicated, who needs referral to a haematologist and how best to manage pro-thrombotic women requesting HRT? Table 3 considers risk factors for VTE, along with indications for selective thrombophilia screening and onward haematology referral.

Table 3.

Risk factors for VTE in women aged 50–59, selective screening and when to seek haematology opinion.

Risk factor(s)	Thrombophilia screen indicated	Consider haematology opinion	Women with distressing menopausal symptoms requesting HRT
Obese BMI > 30 kg/m², or heavy smoker, varicose veins, inflammatory disorders	No	No	Consider TD HRT with MP or LNG 52 mg-IUS (IUS) if progestogen required
Personal history of VTE – major provoking factor identified, no FH of VTE	No (other factors are better predictors of recurrent VTE risk)	No	Ensure no other risk factors have developed Offer TD with MP or IUS
Personal history of unprovoked VTE, no FH of VTE		Yes	Consider TD ± MP or IUS
Personal history of unprovoked VTE + strong FH of VTE or thrombophilia		Yes	Probably already under haematologist, joint management. Is current or additional thromboprevention required? Consider TD ± MP/IUS.
No personal VTE, + strong FH of unprovoked VTE/thrombophilia	Controversial	Yes	Consider other factors, BMI, smoking, obstetric history, type of thrombophilia – offer TD+/MP/IUS

FH: family history; HRT: hormone replacement therapy; MP: micronized progesterone; TD: transdermal; VTE: venous thromboembolism.

In women with a VTE history for which a major provoking factor has been identified and no family history of VTE, thrombophilia testing is not recommended.³⁶ However, more than 50% of VTE patients do not have a major provoking factor and the risk of recurrent VTE is up to 10% in the first year after stopping anticoagulants, 5% in the subsequent year and 30% at 8 years.³⁷ Recurrent VTE is fatal in 3.6% of cases. If the woman was young at the time of the unprovoked VTE or had a strong family history of VTE it is likely screening for inherited thrombophilia will have been carried out to decide the duration of anticoagulation. In such women taking long-term anticoagulants, a specialist menopause service may offer transdermal HRT to manage debilitating menopausal symptom.³⁸ If anticoagulant therapy has been discontinued, the current risk of a further deep vein thrombosis (DVT) will need to be re-assessed with the haematologist if HRT is to be considered. Oral HRT should be avoided.

In women with no personal but a strong family history of VTE, routine screening is not recommended because testing for heritable thrombophilia provides an uncertain estimate of VTE risk.³⁶ However, selective screening for women requesting HRT, from thrombosis prone families or with a high-risk thrombophilia, may modify clinical practice and should be discussed with the haematologist even though a negative result does not exclude increased risk of VTE; oral HRT should be avoided. It is worth noting that more severe pro-thrombotic conditions usually develop complications before menopause age and factors such as a successful pregnancy or oral contraceptive use provide some degree of reassurance. Further research is required to assess the effect of transdermal estrogen and the different classes of progestins in the ‘increased VTE risk’ group_.

Table 4 shows the inherited thrombophilic VTE risk and effect of HRT.³⁶ Data from large case-controlled, observational studies showed no increased relative risk of VTE from transdermal HRT³⁹; however, the limitations of the evidence must be explained to patients.

Table 4.

Thrombophilia, risk of VTE and influence of HRT.

Thrombophilia	VTE risk without HRT (Odds Ratio)	VTE risk with HRT (Odds Ratio)	TD HRT +MP considered on an individual basis
Prothrombin G20210A gene mutation heterozygous – common present in about 4% of Caucasian population. There are no data available for the homozygous mutation	3 (about the same as a long distance flight)	13–25	Some observational studies have shown no increased risk with TD HRT
Factor V leiden – the most common mutation 5% of Caucasian population heterozygous	5	13–25	Some observational studies have shown no increased risk with TD HRT
or homozygous	10	No data	Discuss with haematologist on a case by case basis
Prothrombin G20210A mutation, heterozygous + factor V Leiden mutation heterozygous	4–15	No data
Congenital protein S deficiency	5–11	No data
Congenital protein C deficiency	3–15	No data
Congenital antithrombin deficiency	4–50 depending on type 1 or 2	No data
Factor VIII elevation	5–8	No data
Antiphospholipid antibodies	2–16 depending on titres/combination	No data

HRT: hormone replacement therapy; MP: micronized progesterone; TD: transdermal; VTE: venous thromboembolism.

Pre-referral advice:

The risk of VTE is about 1 per 1000 person-years for a woman in her 50 s.

Observational, case-controlled studies suggest the relative risk of both first and recurrent thrombotic event is not increased with transdermal estrogen, LNG 52 mg-IUS or micronised progesterone.

Relative risk does not change, only absolute risk changes.

The absolute risk of VTE is increased in women with past-unprovoked VTE and inherited thrombophilia.

As the safety data regarding transdermal estrogen are observational, consensus regarding the use of transdermal estrogen therapy is lacking and current advice is to assess each woman at increased risk of first or recurrent VTE on a case-by-case basis.

In women of menopause age with no personal VTE history but with a family history of VTE, or heterozygous for Factor V leiden, low dose (50 mcg estradiol) transdermal estrogen or estrogel is probably safe (particularly for a non-smoking woman with a low BMI and history of uncomplicated pregnancy or oral contraceptive use). Other risk factors must be considered (general health, life style) and women must be informed that there are only observational data on which to base the advice.

Transdermal HRT may be used with anticoagulant therapy if considered necessary.

Inform all HRT users about the symptoms of VTE and the increased VTE risk following trauma, immobility, long-distance flights or illness.

Follow local pathways to specialist level menopause service for

women with a history of unprovoked DVT requesting HRT and

women taking anticoagulant therapy.

Age and HRT (n = 13)

In total, 13 women were over 60, suggesting age is a factor causing clinical uncertainty, presumably because older women are outside the scope of the NICE guideline.

About 40% of women aged 60–65 have persistent menopausal symptoms and are thus reluctant to stop HRT. The effects of HRT on most organ systems, however, do vary with age and time since last exposure to hormones, so how are women over 60 best advised about HRT?

The main areas of age-related clinical concern include VTE, cardiovascular disease (CVA) and breast cancer, as risk for these conditions increases with age. Both VTE and stroke risk depend on dose, route of administration of HRT and progestin class whereas breast cancer risk seems to be influenced largely by duration of use. At present, data to provide absolute risk figures for women taking HRT above the age of 60 are lacking; a pragmatic approach is to consider individual risk.

Table 5 shows a population risk of VTE, with and without oral HRT.⁴⁰

Table 5.

Absolute risk of VTE in peri- and postmenopausal women with and without oral HRT – WHI annual rate/1000 person years.

Age	Absolute risk of VTE without HRT	Absolute risk of VTE with HRT (oral estrogen + progestin)
50–59 years	0.8	2.27
60–69 years	1.9	4.28
70–79 years	2.7	7.46

HRT: hormone replacement therapy; VTE: venous thromboembolism.

Risk increases maximally in the first year of taking HRT so consideration must be given to the timing of starting HRT. The VTE risk is minimized by the use of transdermal estrogen with micronised progesterone if progestin is needed.⁴¹ A personal risk of VTE can be calculated using http://qthrombosis.org, which demonstrates that HRT has little effect on risk unless the BMI is >29 kg/m². Importantly, HRT users must be informed about the factors, which may increase VTE risk and when to seek urgent medical advice.

Cardiovascular disease, increases with age. A personalized 10-year chance of developing cardiovascular disease can be calculated using the QRISK2 calculator, https://qrisk.org; the Endocrine Society suggest non-hormonal therapies for women at high risk (>10% 10-year risk).⁴² In addition, stroke risk may be calculated using QStroke risk calculator http://qstroke.org.

Both calculations are useful for counseling and discussion provides an opportunity to encourage healthy life style changes (smoking cessation, increased physical fitness) and optimise medication (e.g. warfarin may reduce stroke risk by 50%–67%). Evidence from the Cochrane data analysis (2017), long-term follow-up from the WHI⁴³ and observational data⁴⁴ suggest HRT started at menopause onset or initiated more than 10 years after the menopause does not increase cardiovascular risk or death.

However, the risk of stroke increases with oral HRT RR 1.21, (95% CI 1.06–1.38). The risk is minimized using transdermal 17 β-estradiol used in conjunction with daily-micronised progesterone if progestogen is needed. Therefore, in women aged 60–65, for whom stroke risk is a concern, a 25 -µg patch may be considered and a 12.5 µg patch for women over 65; avoid tibolone and oral estrogen preparations.

Breast cancer risk increases with age; a personalized risk can be calculated using https://www.cancer.gov/bcrisktool/documentation.aspx. The additional risk of breast cancer posed by prolonged use of combined HRT is complex; the most recent data suggest women who took combined HRT for over 15 years are 3.3 times more likely to develop breast cancer than non-users.⁴⁵ However in women using estrogen-only HRT, evidence from the WHI showed a statistically significant reduction in invasive breast cancer occurring for all participants 50–79 years of age.⁴⁶ Any increased risk falls once HRT is stopped; by about 2 years, it has returned to background individual level.

The use of HRT should be individualised not be discontinued solely on the basis of age alone. Provided the woman has been adequately counseled and has clinical supervision, HRT may be continued beyond 60 using the lowest effective dose to control symptoms.⁴⁷

Pre-referral advice:

Re-enforce life style changes that may alleviate symptoms, promote healthy living and optimise medication to reduce CVA and VTE risk.

Discuss personal baseline risk of VTE, CVA and breast cancer using adjuvant tools if indicated:

http://qthrombosis.org

http://qstroke.org.

https://www.cancer.gov/bcrisktool/documentation.aspx.

Age is not a contraindication to starting or restarting HRT – if required, offer low dose transdermal estrogen, with daily-micronised progesterone if progesterone is needed.

Avoid tibolone and oral estrogen in women over 60.

Conclusion

Access to a specialist menopause service varies across the country and current referral guidance is limited. Investigating the reasons for referral revealed areas of clinical uncertainty suggesting that access to problem-specific information and pre-referral advice should be provided. Some of the available advice is detailed and aimed at healthcare professionals with a special interest in menopause. Many women with complex conditions including breast cancer sufferers with intractable menopausal symptoms, women with high-risk cancer genes or multiple treatment failures need local pathways for further advice and referral to a menopause specialist. The audit provides evidence for Clinical Commissioning Groups that more training and support is required for primary care doctors. Each referral costs to secondary care costs approximately £160 and if pre-referral advice was available, at least 25 referrals would have been prevented saving an estimated £4000. Many of the women in the study provide clinical scenarios that illustrate the need for a specialist menopause service. A menopause specialist is able to assess patients holistically and consider therapeutic approaches that may not be specified in guidelines thus providing the individualised care recommended by NICE.

Footnotes

Acknowledgements

The author thanks Dr C Marfleet who came up with the idea of the project, collected the data and provided expertise. The findings were published as a poster at the British Menopause Society’s 27th Annual Conference.

Contributorship

Anne Marie C Neill, MB, ChB, MRCOG, is the principal contributor to this work. Caroline Marfleet, MB, ChB, Consultant in Family Planning and Reproductive Health (now retired from Colchester hospital), suggested a service evaluation project and was involved with data collection.

Declaration of conflicting interests

The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.

Ethical approval

Ethical approval was not sought as evaluation is routine practice.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Guarantor

Anne Marie C Neill is the guarantor having composed the manuscript.

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