Menopause

Abbreviations

FMP Final Menstrual Period
ARI Absolute Risk Increase (ARI) = Absolute risk in treatment group - Absolute risk in control group = ART - ARC
ARR Absolute Risk Reduction (ARR) = Absolute risk in control group - Absolute risk treatment group = ARC - ART

NICE

NICE guideline [NG23] November 2015. Menopause: diagnosis and management

MHRA Drug Safety Alert August 2019.
Hormone replacement therapy (HRT): further information on the known increased risk of breast cancer with HRT and its persistence after stopping

MHRA link

HRT risk table

risk table pdf

Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. Collaborative Group on Hormonal Factors in Breast Cancer. The Lancet. August 29, 2019

Lancet article

LANCET PDF

Definitions

Final menstrual period (FMP) = cessation of menses
Onset of menopause = 12 consecutive months of amenorrhoea following FMP
Peri-menopause = Time pior to FMP and up to 12m after FMP; there is variable endogenous oestrogen production but no endogenous progesterone production
Post-menopause = More than 12m after FMP

Median age of FMP is 52.5y, and this is influences by BMI.

SUMMARY

A recently published meta-analysis, which included data from over 100,000 women between 1992-2018 (Lancet study) has shown the risk of breast cancer is increased with
All forms of systemic HRT
except vaginal oestrogens,
when used for longer than 1 year
The meta-analysis also showed that the risk:
increases further with longer duration of use
is higher for combined oestrogen-progestogen HRT (particularly continuous daily vs intermittent progestogen) than with oestrogen-only HRT
persists for more than 10 years after stopping HRT.
Only prescribe HRT to relieve post-menopausal symptoms (vasomotor or other symptoms) that are adversely affecting quality of life
Regularly (at least annually) review patients using HRT to ensure it is used for the shortest time and at the lowest dose
Remind current and past HRT users to be vigilant for signs of breast cancer and encourage them to attend for breast screening when invited
Transdermal estradiol is unlikely to increase the risk of VTE or stroke above that of non-users and is associated with lower risk compared with oral estradiol.
Limited evidence suggests that micronised progesterone and dydrogesterone may be associated with lower risk of breast cancer and venous thrombosis compared to other progestogens.
Women with premature ovarian insufficiency (POI) should be encouraged to use hormonal therapy at least until the average age of the menopause (age 50y)
HRT does not prevent coronary heart disease or protect against a decline in cognitive function and it should not be prescribed for these purposes.
For the treatment of menopausal symptoms the benefits of short-term HRT outweigh the risks in the majority of women, especially in those aged under 60 years or within 10 years of menopause onset.
HRT is not a contraceptive.

Hormones to consider

Synthetic
Ethinylestradiol
Medroxyprogesterone
Tibolone (oestrogenic, progestogenic and weak androgenic activity)
Dydrogesterone

Natural
Estradiol E2, Estrone E1, Estriol E3
Progesterone (micronised progesterone)
Dehydroepiandrosterone
Testosterone
Levothyroxine

Benefits of HRT

Short-to-medium term

Vasomotor symptoms: maximum hot flush reduction is not seen until approximately 3 months of HRT use
Musculoskeletal symptoms (for example, joint and muscle pain)
Mood (for example, low mood)
Urogenital symptoms (for example, vaginal dryness, atrophic vaginitis)
Sexual difficulties (for example, low libido)

Long-term

Bone mineral density and osteoporosis: HRT treatment (any), up to 5 years duration, may achieve ARR around 25 per 1000 (2.5%) fragility fractures.

Diagnosis

Clinical >45yr : peri-menopause and post-menopause diagnosis based upon clinical symptoms:
(irregular increasing/decreasing frequency periods OR absent periods>12m) AND vasomotor symptoms
Blood investigations
<45yr: use FSH test (false-negative if using COC or high-dose progestogen)
Exclude thyroid disease
Alternative prognostic test: may predict whether FMP is or is not imminent within a specified time frame
Very low level of antimüllerian hormone (AMH), a granulosa cell product released by early growing ovarian follicles, is suggestive of impending menopause.

Diagnosing premature ovarian insufficiency POI (<40yr)

Diagnose premature ovarian insufficiency in women aged under 40 years based on:

menopausal symptoms, including no or infrequent periods (taking into account whether the woman has a uterus) and
elevated FSH levels (FSH>30 IU/L) on 2 blood samples taken 4–8 weeks apart.

HRT can be given until the approximate age of natural menopause (i.e. until age 50 years). Alternatives to HRT should be considered if osteoporosis is the main concern.

Contraindications to HRT

History of breast cancer or oestrogen-dependent tumour
Undiagnosed vaginal bleeding, untreated endometrial hyperplasia
High-risk of cardiovascular disease (MI, CVA, TIA)
Arterial embolic or venous thromboembolic disease
Thrombophillic disorder
Liver disease with abnormal LFTs

LOCAL ERT (urogenital atrophy)

Menopausal atrophic vaginitis +/-recurrent UTIs may be treated by topical vaginal oestrogen preparation (Vagifem® pessary or estradiol intravaginal ring Estring®)
May be combined with systemic HRT if needed to achieve urogenital atrophy symptom control.
Alternaive option is to use non-hormonal vaginal moisturisers and lubricants.

SYSTEMIC HRT

Uterus present

Peri-menopause (prior to FMP or <12m after FMP)
Cyclical combined HRT
which incorporates cyclical progestogen (12d-14d of cycle)

Post-menopause (>12m after FMP)
Continuous combined HRT

Uterus absent

Oestradiol only preparation

Aim to avoid avoids first-pass metabolism and therefore does not increase levels of coagulation factors or hepatic-binding globulins.

Transdermal gel: Sandrena®, Oestragel®

Transdermal patch: Evorel®, Estraderm®, Estradot®, Progynova TS®);
patches are changed once or twice weekly

In women with a uterus, use combined oestradiol AND progestogen regimen to avoid unopposed uterine stimulation (endometrial hyperplasia, uterine cancer) or reactivation of endometriosis
Continuous HRT may cause erratic bleeding if given in peri-menopausal women owing to endogenous hormone production
Consider swapping from cyclical to continuous combined HRT no earlier than one year after commencing cyclical combined HRT.

Optimal HRT Regimens for women with a uterus

Transdermal oestradiol gel/patch
PLUS
(oral) micronised progesterone (Utrogestan)

Peri-menopause:
200mg orally, nocte, for last 2 out of 4 weeks, on a repeating basis, to trigger a bleed.

Post-menopause:
100mg orally, nocte, continuously

Oral fixed-dose combination of estradiol and progesterone (Bijuva®)

1 capsule=1mg oestradiol+100mg progesterone
1 capsule every evening with food

Transdermal oestradiol gel/patch
PLUS
LNG-IUS Mirena®

Used in peri-menopause or post-menopause

Manufacturer states 4yr license during ERT

Combined oestrogen AND progestogen

Cyclical patch
Evorel Sequi®, FemSeven Sequi®

Cyclical oral
Femoston®, Tridestra®, Elleste Duet®, Trisequens®

Continuous combined patch
Evorel Conti®, FemSeven Conti®

Continuous combined oral
Femoston Conti®, Elleste Duet Conti®, Kliofem®

Alternative options for treating vasomotor symptoms of HRT

Clonidine hydrochloride: may be used to reduce vasomotor symptoms

Fluoxetine, Paroxetine SSRI Selectively inhibit the re-uptake of serotonin; may be used to reduce vasomotor symptoms; contraindicated in women taking tamoxifen

Venlafaxine SNRI serotonin and noradrenaline re-uptake inhibitor; may be used to reduce vasomotor symptoms

Gabapentin may be used to reduce vasomotor symptoms

Other HRT treatment options

Oral Tibolone 2.5mg (Livial®) for post-menopausal women
Tibolone combines oestrogenic and progestogenic activity with weak androgenic activity; it is given continuously, without cyclical progestogen.

Alternative options for treating osteoporosis

Raloxifene hydrochloride: prevention of postmenopausal osteoporosis; does not reduce menopausal vasomotor symptoms

Bio-identical HRT

cBHRT: Compounded Bio-identical Hormone Replacement Therapy: NOT RECOMMENDED
Unregulated plant-derived hormonal combinations similar or identical to human hormones that are compounded by pharmacies to the specification of the prescriber.
These formulations do not follow the same MHRA regulatory pathway as conventional rBHRT
No clinical trial data support its safety or efficacy.

rBHRT: Regulated Bio-identical Hormone Replacement Therapy
Precise duplicates of endogenous hormones developed in a conventional way by the pharmaceutical industry and approved by MHRA (UK) or FDA (USA).

Dydrogesterone and micronised progesterone (D/MP), compared to androgenic progestogens, are associated with:

Lower risk of VTE: based upon observational data
Lower risk of cardiovascular disease: based upon observational data
Lower risk of breast cancer: based upon observational data
Possibly more breakthrough bleeding: based upon observational data
This could relate more to lack of compliance rather than biological efficacy.

Utrogestan (micronised progesterone, 100mg and 200mg capsules)
Derived from plants, including yam, a root vegetable.
Identical to endogenous progesterone

Side-effects with Utrogestan

Unscheduled bleeding in first 3 months (but if persisting beyond 3 months mandates urgent 2-week-wait gynaecological cancer referral)
Sedation, drowsiness
Low mood (through GABA stimulation)
Breast pain; constipation; diarrhoea; dizziness; drowsiness; jaundice cholestatic; skin reactions; vomiting

Drug interactions

Oestrogens and progestins are metabolized partly by CYP3A4 enzymes.
CYP3A4 inhibitors such as erythromycin and grapefruit juice could increase concentrations of HRT hormones and their risk of adverse effects.
Taking a CYP3A4 inducer such as St. John’s wort or rifampin concomitantly could lower serum concentrations of HRT hormones and decrease their efficacy.

Contraception

Contraception is NOT required if <50y and amenorrhoeic for >2yr OR >50y and amenorrhoeic for >1y
If contraception indicated, consider Mirena IUS, Cu-IUD, progestogen-only contraception (tablet, implant, injection), barrier methods.
Stop hormonal contraception once age 55yr and above.

Monitoring

Monitor symptom control, side-effects, breakthrough bleeding (common when initiating continuous combined HRT)
Assess whether there is an indication to continue HRT treatment (and thereby justify its cessation), or opportunity to lower the dose of HRT (to maximise safety)
Consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective.
Check BP, BMI and breast/cervical screening is up-to-date
Vaginal Utrogestan administration (off-license) may be considered in women who cannot tolerate side-effects of oral progesterone.
Furthermore, vaginal administration may improve endometrial protection through uterine first pass effect.
Investigate unscheduled persistent/abnormal bleeding beyond 3 months
If no worrisome uterine pathology, consider:
Switching back from continuous combined to cyclical regime for 12m
Increasing dose and duration of micronised progesterone
Switching to alternative progestogen- either micronised progesterone or IUS

RISKS OF HRT

HRT increases the risk of

Breast cancer
Ovarian cancer
Endometrial cancer (effectively eliminated by concurrent cyclical or continuous progestogen)
Venous thromboembolism (DVT/PE)
Coronary heart disease (if starting combined HRT more than 10y after the menopause)

Risk of breast cancer

In the UK, 63 per 1000 (6.3%) never-users of HRT will be diagnosed with breast cancer between age 50-69y

For women of average weight who start using systemic HRT in their 40s or 50s, and continue for 5 years, the risk of breast cancer by age 69y is estimated to be:

Oestrogen plus daily progestagen preparations 83 per 1000 (ARI 20 per 1000, 2%) 1 extra case in every 50 HRT users
Oestrogen plus intermittent progestagen preparations 77 per 1000 (ARI 14 per 1000, 1.4%) 1 extra case in every 70 HRT users
Oestrogen-only preparations 68 per 1000 (ARI 5 per 1000, 0.5%) 1 extra case in every 200 HRT users

The number of extra cases up to age 69 years is approximately double these values for women who use systemic HRT for 10 years compared with those who use HRT for 5 years

Risk of ovarian cancer

Long-term use of combined HRT or oestrogen-only HRT is associated with a small (ARI 1 / 1,000) increased risk of ovarian cancer.
This excess risk disappears within a few years of stopping HRT.

Risk of venous thromboembolism

Compared to oral oestrogen, transdermal oestrogen does not appear to increase the risk of VTE.
Avoid HRT in women with VTE risk factors: personal or family history of deep vein thrombosis or pulmonary embolism, severe varicose veins, obesity, trauma, or prolonged bed-rest.
Consider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.
Combined HRT, used for five years, increases the risk of VTE by ARI 7 / 1,000 .
Micronised progeterone appears to be safest progestogen, but more data is needed.

Risk of Stroke

Oral (but not transdermal) oestrogen is associated with a small increase in the risk of stroke
Combined HRT or oestrogen-only HRT, used for five years, increases the risk of stroke by ARI 1 / 1,000

Risk of coronary heart disease

HRT does not prevent coronary heart disease and does not increase cardiovascular disease risk when started in women aged under 60 years.
There is an increased risk of coronary heart disease in women who start combined HRT more than 10 years after menopause.

Dr Rajesh Varma9 June 2020menopause, HR