HRT Prescribing –Made Easy inCOVID pandemic

&Case discussions

Dr Manju Navani28th April 2021

Discussion • Why menopause matters ?

• HRT consultations during COVID

• Risk Assessment before prescribing HRT

• Basic Principles of HRT Prescribing

HORMONES

➢ Choosing the right HRT- Why Progestogen matters?

➢Body identical HRT – When & Why?

➢Local HRT preparations

➢Case Studies (including Metabolic Syndrome)

Take Home messages , resources

Q&A

Why Menopause matters ??Menopause is a CV risk factor

Consequences

➢CVD and Metabolic Syndrome1. Diabetes Mellitus2. Hyperlipidemia 3. Hypertension 4. Central obesity5. Prothrombotic state

➢Osteoporosis➢Anxiety and Depression ➢Dementia

Life style intervention

HRT Management during COVID

• www.mims.co.uk

• www.pcwhf.co.uk

• www.bms.org.uk

Tele-ConsultationHistory – New

Diagnosis of menopause – clinical > age 45

• Symptoms

• Menstrual Hx –Changes in cycles , Heavy periods ?

• Obstetric Hx / Gynaecological Hx – Hysterectomy , BSO , Endometriosis

• Does she need contraception?

• Life style factors- BP, BMI, Alcohol, exercise

• Indications for Transdermal HRT – Migraines +/- aura , BMI>30 , HT , Thyroxine , VTE risks etc

• Medical History – Personal/Family History - Why??

Why & What Risk Assessment? Personal & Family Hx

1. Migraines +/- aura

2. CVS & metabolic risk factors

3. Venous Thrombo-embolism ( VTE)

4. Cancer – Breast , Bowel , Uterine, Ovarian

5. Risk of osteoporosis, DEXA scan

Mental Health

Exclude other causes of symptoms ( FBC, TFT s if required)

www.bms.org.uk

www.menopausematters.co.uk

www.womans-health-concern.org.uk

Green Climacteric scale chart

Benefits outweigh risks 50-60 ( NICE Guidance)

BENEFITS of HRT

➢ Symptom Control

➢ Prevention and Rx of Osteoporosis ( under 60)

➢ Cardio –protection (window of opportunity in first 10 yrs)

➢Prevents metabolic Syndrome

➢May prevent Alzheimer's Disease (July 2020)

➢ Reduces risk of colorectal cancer

Rahman A, Schelbaum E, Hoffman K et al. First published June 14, 2020 Neurology Danish Osteoporosis Prevention Study (DOPS study) :2012, 17B E2 + NETA in early post menopausal yearsFinnish Study: Hodis HN et al. Vascular effects of Early v late post menopausal Rx with E . New Eng J of Med 2016;374(13)1221-31ELITE study, KEEPS trial www.bms.org.uk, NICE Clinical Guidance (2015) Menopause Diagnosis and Management

ibis.ikinopedia.com

Refer to iFamilial Breast Cancer - NICE Guideline (CG164)

• One relative– Female 1st degree with breast ca <40– Male 1st degree with breast ca at any age– Female 1st degree with bilateral breast ca <50 – 1st degree with breast and ovarian ca

• Two relatives– 1st/2nd degree with breast ca at any age– 1st/2nd degree with breast and ovarian cancer– With breast and/or ovarian cancer on paternal side

• Three relatives:– 1st or 2nd degree with breast cancer at any age

Other RISKS

Venous thromboembolism

➢Risk is increased with oral HRT 1 ( RR = 2)

➢Transdermal HRT has no greater risk than baseline risk 2

➢Risk depends on type of Progestogen : Micronised Progesterone (Utrogestan)

have lower risk of VTE compared with synthetic progestins2

Stroke

➢Risk increases with focal migraine, uncontrolled HT – consider transdermal HRT

➢Risk increases slightly over age 60 with oral HRT

Ovarian Cancer

➢1 /5000 per year 1. Canonico Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ 2008; 336 (ESTHER study)

2. Vinogradova Y et al. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the Qresearch and CPRM databases. BMJ 2019; 364:k4810 http://dx.doi.org/10.1136/bmj.k4810,

Prescribing HRT

Basic Principles

Check LIST for HRT prescribing

1. Uterus present - Oestrogen and Progestogens

2. Dose of Estrogen in HRT should be assessed & tailored on individual

patient circumstances (see following slides)

3. Type of Progestogen in HRT matters due to

CVS/Metabolic/ VTE/Breast cancer risks in individual patients

4. Transdermal HRT –Indications?

5 Regime: Sequential or Continuous Combined HRT ?

17 ℬ EstradiolOral : Tablets – 0.5 mg, 1mg , 2 mg

Advantages• Improves Insulin sensitivity>transdermal E2

• Lipid friendly

Disadvantages Higher risk of VTE >transdermal E2/no HRT ↑binding proteins : TBG, SHBG ↑TriglyceridesDrug interactions : Liver enzyme inducers

Transdermal (2/week, 1/wk )25, 37.5 mcg , 40 mcg , 50 mcg ,75 mcg , 80 mcg, 100 mcg

GelsOestrogel ™Sandrena™ gel

Spray Lenzetto ™(Estradiol1.53 mg/spray)

Considerations for transdermal HRT (17-ℬEstradiol)

❖Poor relief with oral HRT

❖Absorption problems

❖Migraines, +/-focal

❖Interacting medications

Thyroxine

Anti-epileptics ( liver enzyme inducers)

❖Gall Bladder disease, gall stones

❑Cardiovascular risk factors

( Metabolic syndrome)

BMI >30, Central Obesity

Hypertension

Dyslipidaemia

Diabetes

Hypertriglyceridemia

❑Hx of VTE, risk factors for VTE

(Transdermal is Thrombogenic neutral)

Estradiol Equivalent doses (Conversion /interchangeable formulation table)

LOW (50-60 yrs) STANDARD (40-50 yrs) HIGH (<40 yrs) POI

ORAL 1 mg 2mg 3-4 mg

PATCH 25 Ug 50 Ug 75-100Ug

GEL PUMP 1 measure 2 measures 3-4 measures

GEL SACHET 0.5, 1 mg

0.5mg 1 mg 1.5-2 mg

Estradiol spray Lenzetto

1 spray 20 Ug

2 sprays 29 Ug

3 sprays40 Ug

Practical Prescribing www.bms.org.uk

HRT, hormone replacement therapy; mg, milligram; µL, microlitre

1. Morton TL, et al. J Clin Pharmacol. 2009;49(9):1037–1046. 2. Lenzetto summary of product characteristics. 2018. Available from: https://www.medicines.org.uk/emc/product/11175. Accessed June 2020.2 Kovács G, et al. Climacteric. 2016;19(5):488–495.

What is Lenzetto?

Lenzetto2 1 spray21 mcg

2 sprays29 mcg

3 sprays40 mcg

Matrix Patch 2 25 mcg ug/d 37.5 mcg ug/d 50 mcg ug/d

Lenzetto® is a novel transdermal HRT spray, delivering metered doses of estradiol. Each spray or actuation delivers 90 µL of transdermal spray and consists of:1,2

1. Estradiol (1.53 mg)2. Octisalate (permeation enhancing)3. Ethanol

2. Invisible, no residue /irritation like with patches

Each Lenzetto device costs £6.90 and contains 56 sprays 2 min to

dry

X1- 3

Progestogens in HRT

1. PROGESTERONES

- Retroprogesterone: Dydrogesterone

- Micronised Progesterone : Utrogestan

2. PROGESTINS (Androgenic) Norethisterone (NET)

Medroxyprogesterone

acetate (Provera™)

3. Mirena™: Levonorgestrel (52mg)

Why Progestogen matters?

Type of Progestogen

PMS/ Androgenic effects

VTE Risks Metabolic effects1

Breast Cancer risk

Dydrogesterone

Utrogestan Lower Lower Neutral Lower

Norethisterone(oral)

MPA

Androgenic

Higher

Thrombogenic

Higher

Unfriendly (Neutralises beneficial effect of E2 on insulin , lipids)

Higher

LNG (MirenaTM )

Local effect , minimal

Local effect Local Effect Local effect (lack of safety data)

1. Stevenson J. Gray S. Hormone replacement therapy (HRT) shortage: switching to Femoston® (estradiol/dydrogesterone) from an alternative combination oral or transdermal HRT. Guidelines Nov 2019.

2. EMAS Position statement on Diabetes

Odds ratio for VTE with different oral HRTs

1.Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies

using the QResearch and CPRD databases. BMJ 2019; 364: k4810.

Under 2 years

Which HRT?

Systemic HRT Local HRT

Has UTERUS – needs endometrial protection

YESE+P

Periods<1 yr

Sequential HRT (Period HRT)

E + IUS

Periods >1 yr or

age 54/55Cont Combined HRT-no period

TiboloneE+IUS

After 2 years – <50After 1 year – >50

Types of HRT

OestrogenEstrogenOnly( no uterus)

Oestrogen

17-28

(Sequential HRT)Monthly bleeds

Oestrogen Continuous combined HRT (CCHRT) but irreg bldg. x 6 monthsNo Bleed HRT

Estrogen

Progestogen

Progestogen Bleeddd

HRT Preparations ( Combined) E2 + P

1. SEQUENTIAL HRT

• Femoston ™ 1/10

• Femoston ™ 2/10

2. CONTINUOUS COMBINED HRT

• Femoston Conti ™ 1 mg

• Femoston Conti ™ 0.5 mg

ORAL ( FEMOSTON ™ )

E2 + Dydrogesterone

1. SEQUENTIAL HRT

• Elleste Duet ™ 1/10, NovofemTM

• Elleste Duet ™ 2/10

2. CONTINUOUS COMBINED HRT

• Elleste Duet Conti ™ 2 mg

KliofemTM KliovanceTM/

• Kliofem ( 1 mg )

ORAL(ELESTE DUET ™ )

E2+ Norethisterone (NET)

Oral

Tibolone

CONTINUOUS COMBINED HRT

● Oestrogenic, progestogenic,

androgenic effect

● Improves sex drive

● Endometriosis

● Increased risk of stroke above 60

(PATCHES ) E2+ NET

twice a week

1.Evorel Sequi ™ (50 Ug)

2. Evorel Conti ™

www.bms.org.uk. BMS update on HRT supply shortages (2021)

(PATCHES) E2+ LNG

once a week

1. Femseven Sequi ™ (50 Ug)

2. Femseven Conti ™

Tailor made HRT ( Mix& Match)

ESTRADIOL (Transdermal)

➕

MIRENA™MICRONISED PROGESTERONE

Estradiol patch Estrogel ™ Sandrena gel ™ Lenzetto spray™

Medroxy Progesterone acetate

➕ ➕Bioidentical HRT * Not licensed

for use as part of HRT

SEQUENTIAL HRT CONTINUOUS COMBINED HRT

• Transdermal E2 + Micronised Progesterone (Utrogestan)capsule

• 100mg x 2(200mg) for 12 days

• Licensed use – D15-D26

• E2 + MPA (medroxyprogesterone acetate)

• 10 mg for 2 wks x month

• Unlicensed use

• Transdermal E2 + Micronised Progesterone(Utrogestan) daily

• 100 mg (daily)

• Licensed use – D1-D25

• E2 + MPA ( 5 mg ) daily, if side effect can reduce to 2.5 mg daily monitor bleeding

• Unlicensed use

Oestrogen

Progestone

D1 D28

D14

Oestrogen

Progestogen

www.bms.org.uk

MIX & MATCH

Bio-identical HRT

BIO IDENTICAL HRT- Recommended Indications Transdermal E2 + Micronised Progesterone https://thebms.org.uk/publications/consensus-statements/bioidentical-hrt/

1. Patients with poor symptom control

2. Androgenic s.e with other HRT (PMS, acne, weight gain)

3. Can help with Insomnia 4. If shortages – of other HRT

History of focal migraines, aura 5

Cardiovascular risks , Stroke risks e.g. Q Risk score 5-10%, metabolic syndrome ,

Diabetes with BMI>304

Patients on hepatic enzyme inducing agents (e.g.

anticonvulsants)

VTE Risks 2, 3

Breast Cancer Risk factors1

Limited 5 yr data from

observational study

1.Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008; 107(1): 103-11

2. Vinogradova Y, Coupland C, Hippisley-Cox J. Use of hormone replacement therapy and risk of venous thromboembolism: nested case-control studies using the QResearch and CPRD databases. BMJ

2019; 364: k48103. Scarabin PY. Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. Climacteric 2018; 21(4): 341-5

4. Slopien R, Wender-Ozegowska E, Rogowicz-Frontczak A, et al. Menopause and diabetes: EMAS clinical guide. Maturitas 2018; 117: 6-10 ,KEEPS, ELITE study

5.Migraines and HRT. https://thebms.org.uk/publications/tools-for-clinicians/migraine-and-hrt/

When to Say No…..No to HRT?

• Breast Cancer

• E2 dependent cancers- Endometrial Cancer beyond Stage 1

• Current thromboembolic disease/ IHD

• Active severe liver disease

• Migraine with aura • Hypertension. DM , Hyperlipidaemia• Past Hx of VTE/Family Hx of VTE• Endometriosis• Over 60 yrs

CAUTION

1. Sandra

• Age 52, Para 2 , actor, upset , tearful , mood worsened, insomnia, low self esteem, - 12 months

• Citalopram x 12 months , no effect

• Periods are irregular, every 2-3 months in last year

• Past Hx of PMS , Post natal depression , NIDDM on Metformin x 2 years

BP-120/80, BMI=26, non smoker

Drinks 10 units /week

She requests a blood test for menopause

Decides to start oral HRT Why Sequential HRT?

Oestrogen Oestrogen Oestrogen

17-28 Prog 17-28

😊 😡(E2 1mg + Dydrogesterone) (E2 + NETA) Elleste DuetTM

Why?1. Femoston™ 1/102. Mirena ™ and oral Estradiol tablet 1mg/ patches

1. Started Femoston- 1/10 ( 1mg E2 + 10 mg DG)

Contraception: add a mini pill (DSG/levonorgestrel), barrier

Month 1 Month 2 Month 3

Ref: https://thebms.org.uk/wp-content/uploads/2018/08/HRT-Practical-Prescribing-AUG2018.pdf ( for doses)

Follow up

FU-3 months • Still hotCheck BP

Femoston Conti 1 mg

Irreg bldgx 4 /12

Age 59-60Femoston Conti 0.5

mg

Femoston

2/10

• Age 54• Fed up

with periods

Benefit/Risk Analysis , Life style, Ca & Vit D

Age 52 Femoston

1/10

Can change from Seq to CCHRT after 1-2 yrs Sandra asks how long can I take HRT for?

Yearly FU, BP check , Review changes in Hx

Before starting HRT• Side effects • Benefits/Risks

Yearly FU

(Option 2) IUS + Estradiol

IUS + E2 from age 52-57. Advantages of IUS

• Unlicensed as part of HRT (x 5 yrs)

• Reduces heavy periods

• Local Hormonal effect with minimal side effects

• Data on Breast safety are sparse

At 57 , Remove IUS and change to Femoston Conti 1 mg ™

Mirena SPC: Bayer plc Lyytinen et al. A case control study on hormone therapy as a risk factor for breast cancer in Finland: IUS carries a risk as well. Int J Cancer.2010; 126:483-489

Daisy 51 yrs, very hot , insomnia, low mood tired , joint pains , gained weight – 2 years

No Periods – 1 year

Has tried herbal remedies – not seen much benefit

BP - 130/88 , BMI=32 , non - smoker

Alcohol 2-3 bottles of wine/week

Advise Life style interventions

1. Does she need contraception?

2. What are her HRT options ?? Personalise Risks and benefits

Evaluate her CVS risks before starting HRT – Q Risk score = 7%

If high risks – Alternatives to HRT

Choice of HRT preparation depends on BMI , CVS/VTE risk factors

Daisy has BMI= 32 , HT – Transdermal E 2 + Progesterone

No periods x 1 yr - CCHRT

CVS Risk factors Past Hx : PCOS, pre-eclampsia HT on Rx NIDDM- Metformin On statinNo auto immune disease VTE Risk factors BMI=32

Why Bioidentical HRT?

E2: Improves Insulin sensitivity , lowers Cholesterol , primary prevention of CVD (Cochrane review 2014 1)

Moderate risk of CVD – Q Risk score is 5-10%

HRT can be used with caution

1. Transdermal E2- thrombogenic neutral cf oral E2

2. Micronised Progesterone : insulin & lipid neutral, doesn’t increase her risk of thrombosis, lower risk of breast cancer 2

Low dose transdermal E2 + Micronised Progesterone(Oral UtrogestanTM

100 mg daily (unlicensed use) OR MirenaTM

Counselling benefits & Risks, Ca and Vit D

FACT sheet on bioidentical HRT

https://thebms.org.uk/publications/consensus-statements/bioidentical-hrt/1. Boardman et al . Cochrane Database Syst Review 2015 . Hormone therapy for preventing CVD in post menopausal women .

2. An Endocrine Society Cl Practice Guideline . Wierman et al. JCEM2014, Climacteric, Maturitus 2/9/19

Effect of E2 HRT – in early and established atherosclerosis ( Menopause & CVD )

Menopause and CVD : Dr Louise Newson , Post Reproductive Health J, 17.01.2018

Bio-identical /Body identical (Regulated)

Unregulated

Oestrogel ™

1 measures daily

Sandrena gel™

(0.5 mg )

Lenzetto spray ™1 spray can ↑2 sprays in 4-6 weeks if required

Estradiol patches

(17B oestradiol)

25, mcg twice a week

Utrogestan™

(Micronised

Progesterone)

CONTIUOUS COMBINED

Licensed 100 mg cap D1-D25Unlicensed ( daily)

At bedtime, on empty stomach Vaginal insertion if s.eDrowsy, somnolence

Migraines and HRT

• 2 fold increased risk of ischemic stroke,

higher risk with oral E

• Diagnosis of migraine +/- aura

• Increased prevalence- fluctuating E levels, transdermal HRT advised

• HRT is not a CI – migraine with aura

• Continuous HRT preferred to cyclical

• Preferred Progestogens- MirenaTM, UtrogestanTM, transdermal norethisterone in combined patches

• Use lowest effective dose

www.bms.org.uk FACT sheet

• Anne MacGregor . Migraine, menopause & HRT . Post Reprod Health 2018 ; Vol 24(1) 11-18

When to refer for an Expert Opinion

• Multiple Rx failures

• Premature Ovarian Insufficiency ( POI) <40 yrs

• Complex medical problems - CVS/stroke etc

• Personal /Family Hx of VTE & Breast Cancer

• Safety concerns/Contraindications to HRT

• Abnormal bleeding on HRT

Genitourinary Syndrome of menopause ( GSM)

1. Johnston SL. Geriatrics & Aging. 2002;5(7):9-15. Adapted from Johnston 2002

2. Reiter S. International Journal of General Medicine 2013:6 153–158

Vagina before menopause Vagina after menopause

Non Hormonal Therapies

Lubricants

• Pjur Med ( silicone based)

• Yes: oil based , water based lubricant

• Water based – Sylk, not so effective

Moisturisers

• Regelle, Replens, Hyalofemme , Yes Vaginal Moisturiser

Laser Rx – CO2 , Erbium laser

Treatment OF GUS ( Genitourinary syndrome) • 17 B Estradiol

➢Vagifem TM (10 mcg) daily x2 w, foll by twice a week

➢Vagirux TM is therapeutically equivalent to Vagifem, single applicator, cheaper

➢Estring (trademark of Pfizer) ( 3 months)

• Estriol (weaker than Estradiol)

➢Cream – OvestinTM (0.1%- 500mcg /applicator)

➢Gel - BlisselTM (50 mcg) daily x 3 wks foll by twice a week

➢Pessary – ImvaggisTM (30 mcg)

• Prasterone 6.5 mg : IntrarosaTM (DHEA)daily

• Ospemifene TM (SERM) Oral tablet 60 mg daily

1. NICE Guidelines NG23; 2. BMS Consensus Statement 2018-Urogenital Atrophy

2. Public Assessment Report: Vagirux 10 micrograms vaginal tablets PL 04854/0184. October 2020. 2. Novo Nordisk. VAGIFEM (estradiol 10 microgram) vaginal tablets. Summary of Product Characteristics. September 2018. 3. Gedeon Richter. VAGIRUX (estradiol 10 microgram) vaginal tablets. Summary of Product Characteristics. 4. Gedeon Richter Plc. Data on File: Vagirux 2 – Therapeutic equivalence and systemic exposure study. September 2020. 5. Sturdee DW, Panay N, on behalf of the IMS Writing Group. Climacteric 2010;13:509–22. 6. NHS Sustainable Development Unit. Reducing plastic in the NHS. Available at: https://www.sduhealth.org.uk/nhs%20long%20term%20plan/single-use-plastics/reducing-plastic-in-the-nhs.aspx (Last accessed: November 2020).

Applicators and packaging as suppliedVagirux packaging1

£11.341 applicator sealed in foil and

24 tablets in a blister pack

With 24-tablet packs of Vagirux and a reusable applicator per pack, this could save 15.6 million plastic applicators

from landfill.†1,4,5

Vagifem packaging2

£16.724

24 applicator sealed in individually sealed foil and24 tablets in a blister pack

✓ Vagirux tablets are packed in blister pack, accompanied by a CE-certified applicator for multiple use, giving:

Vagirux has an environmentally sustainable design

Up to 24 uses before disposal of the applicator1

Less waste than single use applicators1,2

A positive user experience, with handling rated as “problem-free” by the majority of users in a focus group*3

*In 12 of 13 participants.3 †Calculation based on 24-tablet pack sizes. Also supplied as 18-tablet packs where marketed.1. Gedeon Richter. VAGIRUX (estradiol 10 microgram) vaginal tablets. Summary of Product Characteristics. 2. Novo Nordisk. VAGIFEM (estradiol 10 microgram) vaginal tablets. Summary of Product Characteristics. 3. Gedeon Richter Plc. Data on File: Vagirux 2 – Therapeutic equivalence and systemic exposure study. September 2020. 4. NHS Business Services Authority. Drug Tariff. November 2020. Available at: https://www.nhsbsa.nhs.uk/sites/default/files/2020-10/Drug%20Tariff%20November%202020.pdf (Last accessed: November 2020). 5. NHS Digital (UK) GP Practice Prescribing Presentation-level Data. Organisation Data Service, Health and Social Care Information Centre, licensed under the Open Government Licence v3.0 (Last accessed: November 2020).

Duration & F/U of systemic HRT

• POI - until age 51 at least

• >51 yrs : Informed choices, No arbitrary time limit Discontinue gradually-makes no difference

• Individualise Rx & Risks:

- 50-60 = Benefits outweigh risk

- 60-70 Benefits = risk

- Over 70 Risk outweigh benefits

1 At 3/12, followed by Annual review (QS4)

2. BP, BMI

3. Check Bleeding pattern, symptom control

4. Risk Benefit Analysis

5.Any changes in Medical History

6. Dose reduction with age

Take Home Messages

1. Menopause is a CV risk factor - Life style intervention

2. Over 45 : No need for Blood test (FSH)

3. HRT within 10 years of menopause or under 60 – benefits outweigh risks, cardioprotective

4. Oestrogen matters : Consider dose, Transdermal : BMI>30, HT , Thyroxine, Migraines , VTE /CVS risk factors

5. Progestogen matters : Advantages of Dydrogesterone and Utrogestan in DM, CVS risks , VTE Risk factors, Breast cancer risk factors

6. Local E2 for GSM – can be added to systemic HRT

Training

• BMS Principles & Practice Menopause care www.bms.or.uk

• http://www.pcwhf.co.uk/(Primary

Primary Care Womans Health Forum)

• www.menopauseacademy.co.uk

• www.emas-online.org

• IMPART online learning

www.imsociety.org

www.ims.org ( Excellent webinars)

• mywayhub.co.uk - webinars

• BMJ learning

• Management of The Menopause- 6th

edition -BMS

• Patient info leaflet ( NICE)

• Menopause & me leaflet

• www.menopausematters.co.uk

• www.womens-health-concern.org.uk

• www.bms.org.uk

• www.managemymenopause.co.uk

• www.menopausedoctor.co.uk

• www.nice.org.uk

Thank you for your attention

Continue to Stay Safe International menopause society