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HRT advice and troubleshooting guide for GPs in primary care

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Definitions

DiagnosisDefinition
Menopause Age 45–55 with outliers above 55
Early menopause Age 40–45
Perimenopause Change in cyclical menstrual pattern with or without psychological or physical symptoms (including depression, anxiety, low libido). Often affecting quality of life.
Postmenopause  12 months of amenorrhea, average age 51
Premature ovarian insufficiency (POI) Elevated FSH with oligomenorrhea or amenorrhea diagnosed under age of 40
Premenstrual syndrome Usually psychological symptoms, but may be physical, having and adverse effect on quality of life
Premenstrual dysphoric disorder (PMDD) Severe psychological symptoms  having an adverse effect on quality of life, often misdiagnosed as bipolar disorder

Hormone related disorders—clinical considerations

  • Post menpausal
  • Osteopenia, osteoporosis
  • Hormonal (catamenial) depression and anxiety—in perimenopausal or postmenopausal women
  • Progesterone intolerance
  • PMS and PMDD
  • Irregular bleeding on a sequential combined HRT (intact uterus)
  • Postmenopausal bleeding (PMB) or breakthrough bleeding on a continuous combined HRT (intact uterus)
  • Unresolved menopause symptoms
  • Symptomatic on HRT 
  • Vaginal atrophic symptoms
  • Under age 45—uncertain diagnosis

Hormone replacement therapy (HRT)

  • HRT choice is based on a number of factors: Patient choice, patient adherence, safety and efficacy 
  • Over the counter (OTC) supplements and alternative therapies may be encouraged although, there is no validated evidence of efficacy but there is reported anecdotal evidence.
  • HRT is licenced for all women who present with symptoms consistent with the menopause that are having a significant impact on their quality of life. 
  • HRT provides immediate symptom relief of menopause symptoms both psychological and physical, as well as long-term protection against osteoporosis, cognitive decline including Alzheimer’s disease and cardiovascular risk reduction. Risk data is available via the British Menopause Society (BMS).
  • In POI or early menopause there is a risk of insufficient circulating estrogen to protect against osteoporosis and cardiovascular disease before the average age of the menopause at 51. A baseline BMD is advised to ensure bone density is protected and adequate estrogen replacement continued until at least the age of 51. The reversal of low bone density is achievable over time with adequate estrogen replacement, with the goal of restoring normal bone density.
  • Until menopause status is confirmed pregnancy risk remains and contraception should be advised, for some women up until at least the age of 55. 
  • There is no definitive duration of use or age cut off for HRT use, as this should be individualised and risks assessed on a patient by patient basis. Persistent symptoms or need for bone protection are indicators for on-going treatment.

Good clinical practice points (HRT)

  • HRT choice is based on a number of factors: Patient choice, patient adherence, safety and efficacy 
  • Most women can effectively be managed in primary care, with the use of NICE guidelines to inform clinical decision making
  • Only women only the age of 45 required FSH/LH and estradiol to aid diagnosis
  • Women diagnosed with POI should have HRT until at least the age of 51
  • Always recommend transdermal estrogen which has a non-significant risk for MI, CVA, Stoke, VTE in any age group
  • For women with and intact uterus, always recommend natural bioidentical progesterone due to its non-significant breast cancer risk
  • Discuss contraceptive needs
  • Only recommend licenced products
  • Only refer high risk women for specialist opinion prior to initiating HRT

Understanding HRT

  • Synthetic hormones: 100% synthesised, manmade.
  • Natural bioidentical hormones: Licenced hormones e.g. all estradiol preparation and Utrogestan. Base molecule derived from either soy or plants and modified to be identical to ovarian Estradiol, progesterone or testosterone
  • Compounded bioidentical hormones: Unlicensed natural bioidentical hormones
Routes of administrationEstrogen preparationsProgestogen, progesterone preparations
Oral-Systemic

All reversible
Estradiol only pill or combined pill

Cyclical or non-bleed options 
Micronised progesterone

Synthetic Progestogen

Combined tablet with synthetic Progestogen, variable dose ranges available

The POP is not licensed for combined HRT use
Transdermal-Systemic

All reversible: except sub-dermal implants
Estradiol only patch or gel, available in variable doses

Combined patch, only 50mcg dose available  
Combined patch, one dose strength only available

Seven day patches are not recommended due to poor skin adherence and increase sensitivity reactions

There is no licensed transdermal progesterone cream for HRT
Uterine-Systemic

Reversible
None Mirena: levonorgestrel (LNG) IUS

No other long term reversible progestogen is licensed for combined HRT use
Vaginal

Reversible
Estrogen: Pessaries and creams (local effect) Natural bioidentical progesterone: Pessaries and cream (systemic effect, off label use) 

Considering risks

  • Risks of HRT are determined by patent age at starting HRT and past medical history
  • Refer to secondary care before initiating HRT, where risks appear to outweigh benefit
Past medical historyHRT choices—decision-makingComment
MI, CVA, Stoke, VTE Transdermal estradiol does not significantly increase event risk

Transdermal estradiol always recommend if women with a pre-existing risk history

Oral estradiol increases risk event and not recommended unless there are no other pre-existing risk factors

Norethisterone (NET) may be associated with significant increased VTE risk
Oral estradiol is contraindicated in MI, CVA, Stoke, VTE history

Suspected coagulopathies should be assessed by a haematology specialist with an interest in HRT

NET not recommended as a first line progestogen
Migraine with aura Transdermal estradiol does not significantly increase event risk

Transdermal estradiol is always recommend in women with a pre-existing risk history 
Oral estradiol is contraindicated in history of migraine with aura 
Breast Cancer or other hormonal cancer Natural bioidentical progesterone has a non-significant breast cancer risk with HRT

Medroxyprogesterone (MPA) may be associated with significant increased breast cancer risk
Utrogestan, natural bioidentical progesterone is hormone of choice

MPA not recommended as a first line progestogen

Troubleshooting

  • Common problems with HRT are: uncontrolled symptoms, suboptimal estrogen replacement or irregular bleeding
  • Where problems cannot be resolved after trying alternative options, refer to a menopause specialist or appropriate clinical pathway 
ProblemConsiderActions
Osteopenia, Osteoporosis The younger the women at diagnosis the greater the risk of developing osteoporosis and increased morbidity

Confirmed low bone density should be actively treatment with a therapeutic estrogen replacement dose

Encourage Vitamin D, magnesium, Vitamin K supplements and weight bearing exercises 
Regular bone scans per guidance or as directed by the specialist

A serum estradiol of at least 250pmol/l is required to promote bone metabolism and reversal of bone loss – change estradiol dose and brand as required

Refer to rheumatology if HRT is optimised but bone health not improving

Refer to menopause clinic if HRT is not optimised and bone health not improving
Hormonal (catamenial) depression and anxiety in perimenopausal or postmenopausal women Antidepressants are not recommended as first line treatment in the NICE guideline

Effective HRT will alleviate hormonal depression by replacing stable physiological hormone levels and equilibrium

Endogenous depression should be managed separately
Hormonal depression is best relieved with good stable estrogen replacement

The effective dose replacement is individual and the maximum licensed dose and alternative brands should be tried

High estrogen levels are often required, between 400-600pmol/l and referral to secondary care indicated if off licences dose of estrogen needed
Progesterone intolerance The development of progestogenic side effects often describe as PMS

A common limiting factor with the HRT, COCP, POP and IUS

There is usually at least 1 progestogen replacement that will be tolerated

Utrogestan is least likely to case side-effects and may be used off label per vagina to limit this effect 
Due to their synthetic nature, the COCP or POP are not usually effective, often worsening depressive symptoms

Androgenic progestogens eg NET are more likely to precipitate side effects and reduce adherence

Natural bioidentical progesterone is least likely to precipitate side effects and can be used per vagina (off label)

The Mirena (licenced use) or Jaydess and Kyleena (off label) are excellent options due to low systemic effects

Contraception needs must be advised
PMS and PMDD See:

Hormonal (catamenial) depression and anxiety – in perimenopausal or postmenopausal women

Progesterone intolerance
Refer to the National Association of Premenstrual Syndrome guidelines (NAPS). A national support network for women with PMS/PMDD with evidence base treatment guidelines and patient support

Resistant PMS may require cycle suppression with GnRHa or ultimately surgery

Women with a history or mental health disorders must have had a recent review to assess their suicidal risk, prior to referral
Irregular bleeding on a sequential combined HRT(intact uterus) A sequential combined HRT is only suitable for women who are perimenopausal or still having regular menstrual cycles

The licenced dose and duration of use should be adhered to when taking progestogen or progesterone

A lower dose or shorter duration increases the risk of irregular bleeding and potential for endometrial hyperplasia

Missing doses causes irregular bleeding as may undiagnosed pathology

Some women will have been advised to use an off label regimen by the specialist and may develop irregular bleeding

All irregular bleeding should be investigated if continues beyond 4-6 months
A timed ultrasound scan after an induced bleed is advised

The endometrial result should about 5mm or less although there is no standard in menstruating women

Any abnormal pathology eg endometrial polyp, should be followed up according to your local care pathway

Changing to a more androgenic progestogen eg NET, or the Mirena is recommended

Any  persistent abnormal irregular bleeding, should be followed up according to your local care pathway
Postmenopausal bleeding (PMB) or breakthrough bleeding on a continuous combined HRT(intact uterus) Initiating HRT or changing from a bleed to non-bleed HRT can provoke bleeding for up to 4-6 months and is considered normal

The current progesterone or progestogen dose could be doubled to stop bleeding or the Mirena IUS recommend

The recent smear history should be checked and repeated if indicated
Bleeding beyond 4-6 months is a red flag and should be investigated under the 2WW pathway for hysteroscopy +/- Mirena (gold standard)

A serum estradiol is useful to further interpret the USS result as a thin endometrium <5mm can be indicative of suboptimal estrogen replacement cause bleeding
Unresolved menopause symptoms—symptomatic on HRT  Unresolved symptoms often reflects with poor adherence or lack of effective absorption

This is one of the few occasions performing FSH/LH and serum estradiol have clinical value as other gynaecological disorders may present similarly
Symptoms generally resolved when serum estradiol >200pml/l. There is no upper limit but generally not >800pmol

If symptomatic on HRT use the full licensed dosing range, change brand or change route of administrations; with oral estradiol the last option (unless contraindicated)
Vaginal atrophic symptoms Systemic HRT does not always resolve vaginal atrophic symptoms, but suboptimal replacement should be addressed

Local estrogen can be used to relieve symptoms whether or not systemic HRT is being used

HRT risks are not increased by using both systemic and local estrogen together

Any regular over the counter vaginal lubricants (for intimacy) and moisturiser (for daily rehydration) is advised in addition to or instead of local estrogen
A year of Vagifem 10mcg use is equivalent to one oral table of estrogen

Previous evidence based used of 25mcg Vagifem twice weekly is still extant. Therefore, Vagifem 10mcg can be used 4-5 times per week if symptoms persist

Where other vulval pathology is suspected a referral to dermatology vulval clinic is advised

Persistent recurrent UTI or vaginal infection to be referred to the respective specialist clinics
Under age 45—uncertain diagnosis  NICE guideline advise this is the only indication for using FSH/LH to aid diagnosis to aid exclusion of other gynaecological disorders that may present similarly

Ensure contraception issues discussed due to risk of random ovulation or  unplanned pregnancy
Refer women under the age of 40 with POI to a specialist POI clinic, with baseline investigations, USS and BMD where possible

Early menopause may be treated as for all menopause women, but with greater consideration for effective estrogen replacement for long-term bone, heart and brain health and continued until at least age 51

Good clinical practice points (troubleshooting)

  • Prescriptions should be continued on a repeat basis
  • Prescription generically unless specifically required
  • To achieve symptom relief, Oestradiol doses may be increased up to the maximum licensed dose. 
  • Outside of this chart, off-label doses may be prescribed from clinic where it is clinically indicated to achieve optimum serum Oestradiol and symptom relief. 

Comparative dose prescribing

Also see BMS website for current availability.

 Serum Oestradiol  Aim for mid-follicular range: 200-600pmolRoutine testing not requiredMost women will be symptom free within this rangeTesting indicated in treatment resistant womenIncrease dose or change product / route if symptomatic
Opt Oestrogens(Bioidentical) Low dose Intermediate dose Standard dose Intermediate dose High dose
1. Oestradiol PO 0.5mg daily   1.0mg daily   2.0mg daily 
2. Sandrena Gel 0.5mg daily   1.0mg daily 1.5mg daily 2.0mg daily (off-label)
3. Oestrogel 0.06% X1 measure daily   X2 measures daily X3 measures daily X4 measures daily
4. Patches (most tolerated: Estradot) 25mcg biweekly 37.5mcg biweekly (Estradot or ½ Evorel 75mcg) 50mcg biweekly 75mcg biweekly 100mcg biweekly
Opt Progestogen  Continuous HRT (non-bleed)   Cyclical HRT (with bleed)¥     
5. Utrogestan capsule PO (Bioidentical) 100mg capsule nocte  daily    2x100mg capsule nocte     
6. Utrogestan oral capsule per vagina (off-label use) or Lutigest 100mg pessary (off-label use) 100mg oral capsule nocte used PV (no applicator)        
7. Utrogestan 200mg pessary (off-label use)     200mg pessary nocte (with applicator)    
8. Norethisterone (synthetic) 5mg daily   10mg daily     
9. Provera-MPA (synthetic) 5mg daily   10mg daily    
Opt Testosterone (off-label)          
10. Tostran Gel 2% (Not Testogel 16.2mg/ml) X1 measure per 2-3x per week
Titrated to efficacy and side effects
Supply x1-should last 6 months Cautions: acne, alopecia, hirsute    
11. Testim gel 50mg/5mls or Testogel 50mg/5mls (off-label) 1/7th to 1/14th of the tube per day, dependent upon response  Supply 1 box 30 sachets (6 months’ supply-cost effective) Apply to thighs, pubic hair or inner wrists. Rotate sites Cautions: acne, alopecia, hirsute  

Clinical resources