HORMONE REPLACEMENT THERAPY (HRT)

• In general: use lowest effective MHT dose for relief of menopausal symptoms
  • except in early/premature menopause (<45 years)/ premature (<40 years) menopause:
    • High dose, long-term therapy required until at least the age of 50 (unlesscontraindicated). 
• Effectiveness monitored by self-reported symptom control.

BENEFITS	RISKS
– Reduces bowel cancer	– Increased endometrial Ca IF >5 YEARS!!
– Reduces osteoporosis	– Increased breast Ca (slight) – Risk decreases after cessation of MHT
– Reduces fractures	– Increased VTE
	– Increased CAD/CVA IF > 5 YEARS!!
	Note: Estrogen alone does not increase coronary heart disease or dementia

MHT and Cardiovascular Disease:

1. WHI Follow-Up Findings: Women who start MHT close to menopause show no cardiovascular harm and may even have a reduced cardiovascular risk.
2. Cochrane Review Findings: There is no strong evidence that MHT provides overall cardiovascular protection or harm, suggesting a neutral effect on cardiovascular outcomes.
3. Primary Prevention of CVD: MHT is not recommended for the primary prevention of cardiovascular disease.

MHT and Thromboembolic Disease:

1. Transdermal MHT (≤50mcg/24 hours): This form of MHT does not appear to increase the risk of venous thromboembolism (VTE).
2. Higher Transdermal Doses: The risk with higher doses of transdermal MHT is less clear but appears to be lower compared to oral oestrogen formulations.
3. Oral MHT: This form of therapy roughly doubles the risk of VTE, with a more significant risk increase for women with co-existing VTE risk factors such as smoking and obesity.

MHT and Endometrial Protection:

• Use of Progesterone: Women with an intact uterus must take progesterone alongside oestrogen to reduce the risk of endometrial hyperplasia and cancer.
• Risk of Unopposed Oestrogen: Without progesterone, the use of oestrogen can lead to a 5-10x increased risk of developing endometrial cancer.

MHT and Contraception:

• Hormone Replacement Therapy (HRT) Not as Contraception: MHT does not provide contraceptive protection. Women require contraception for at least one year after their last menstrual period to prevent unintended pregnancy.
• Use of Combined Oral Contraceptive Pill (COCP): In women without other risk factors, the COCP can be safely used for contraception up to the ages of 50-51 years.

CONTRAINDICATIONS HRT

ABSOLUTE	RELATIVE
– Estrogen dependent tumors (endo, breast) – Thrombophlebitis – Undiagnosed abnormal vaginal bleeding – Acute IHD – Recurrent thromboembolism	– History of CAD – Uncontrolled HTN – Active liver disease – Active SLE – Otosclerosis

Side Effects of HRT:

• Initial Oestrogenic Side Effects: During the first 2-3 months, women may experience some oestrogen-related side effects, which usually resolve or stabilize over time.
  • Premenstrual Symptoms: Consider decreasing the dose of progesterone or switching to an alternative type of progesterone.
  • Nausea and Breast Disorders: Lower the oestrogen dose to the starting level or consider using intravaginal oestrogen.
  • Heavy Bleeding: Lower the dose of oestrogen.
  • Breakthrough Bleeding: Increase the dose of progesterone.
  • Irregular Bleeding: Investigate further and consider endometrial sampling to rule out underlying issues.
  • No Bleeding: Reassure that this is not a cause for concern if no abnormal signs are present.
  • Leg Cramps: Lower the oestrogen dose.

Follow-Up After Commencing HRT:

• 3-Month Check-In: Conduct a review at three months after initiating therapy, which is also an ideal time for a mammography if not previously performed.
• Subsequent Reviews: Follow-up every six months thereafter, allowing for six months for therapy stabilization.

Duration of Treatment:

• General Treatment Duration: The aim is to use HRT for a maximum of 2 years initially, with regular reviews to assess its continued need. HRT use for up to 5 years may be appropriate, with trial discontinuation every 1-2 years to assess ongoing necessity.
• Discontinuation: When stopping HRT, taper oestrogen over a period of 6 weeks for mild symptoms or over 6 months for more severe symptoms.
• Risk Consideration: There is no significant increase in breast cancer or cardiovascular disease risk with HRT use for less than 5 years. Beyond five years, any slight increase in risk should be weighed against the potential benefits, such as improved quality of life, fracture protection, and a reduced risk of colorectal cancer.

HOW TO START

• Hormones to consider
  • Estrogen- for symptoms of menopause
  • Progesterone – for uterine protection
  • Testosterone – could be considered if libido doesn’t improve in premature menopause
• Regimes
  • Must given progestogen with oestrogen if the woman has a uterus

• Oestrogen Therapy
  • Effectiveness: Most effective for treating menopausal symptoms and preventing bone loss.
  • Endometrial Risk: Unopposed oestrogen therapy increases risk of endometrial hyperplasia and cancer in women with an intact uterus.
  • Progestogen Requirement: Women with an intact uterus should take progestogen for endometrial protection.
  • Post-Hysterectomy: No need for progestogen unless there’s symptomatic residual intra-peritoneal endometriosis.
  • Types of Oestrogens
    • Forms: Tablets, skin patches, gels.
    • Benefits: Patches or gels better for gut absorption issues, high triglycerides, or risk of venous thromboembolic disease (e.g., overweight, smokers).
    • Vaginal Oestrogen: Available as creams, pessaries, or tablets for vaginal dryness or dyspareunia.

• Combined Menopausal Hormone Therapy (MHT)
  • Cyclical Therapy:
    • Oestrogen daily, progestogen for 10-14 days/month.
    • Produces withdrawal vaginal bleeds.
    • Used for women in menopausal transition or recently postmenopausal.
  • Continuous Therapy:
    • Both oestrogen and progestogen daily.
    • Preferred by older women.
    • Early introduction close to menopause may cause irregular bleeding.
    • Unscheduled bleeding after six months should be investigated.
  • Combination Packs: Available to improve compliance and ensure reliable endometrial protection.
  • Mix and Match: Emphasize the need for sufficient progestogen exposure for endometrial protection.

• Progestogens
  • Oral – provera, primolut
  • Includes natural progesterone and synthetic preparations (progestins).
  • May have additional biological effects (e.g., androgenic, glucocorticoid, mineralocorticoid).
  • Can give for menopausal symptosm if estrogen dependent tumour
  • continuous or cyclical, risk of uterine hyperplasia
    • Use cyclical if perimenopausal
  • Forms: Mostly oral, except norethisterone in combined MHT patches.
  • Progesterone Creams: Not reliably absorbed, do not confer adequate endometrial protection.
  • Micronised Progesterone Capsules: Natural or “body-identical” progesterone, available in Australia and New Zealand.
  • Levonorgestrel Intrauterine System (Mirena): Delivers progestogen directly to the endometrium.
  • Inadequate Protection: Progesterone troches and creams do not provide adequate endometrial protection.

• Tibolone
  • Synthetic steroid hormone derived from the Mexican yam.
  • Metabolites have estrogenic, androgenic, and progestogenic effects.
  • Effects
    • Oestrogen-like effects:
      • Brain: Prevents hot flushes.
      • Bone: Prevents bone loss.
      • Vaginal tissue: Prevents dryness and soreness.
    • Progesterone-like effects:
      • Uterus: Prevents endometrial thickening and subsequent bleeding.
      • No need for additional progestogen if the uterus is intact.
    • Testosterone-like activity:
      • Enhances mood and libido, though response can vary.
  • When to Commence Tibolone
    • Suitable for women who have not had a natural period for at least 1 year (to avoid irregular bleeding).
    • Can start after the estrogen/progesterone phase for women using cyclical HT.
    • Postmenopausal women not on HT, or those who have had a hysterectomy, can start at any time.
    • Women on continuous combined HT can switch to Tibolone at any time.
  • Side Effects
    • Uncommon side effects: Headache, dizziness, nausea, abdominal pain, swollen feet, itching.
    • Slight bleeding or spotting may occur initially, typically subsiding after a few months.
    • Amenorrhea achieved in about 80% of women after the first month and over 90% after three months.
  • Long-Term Health Effects
    • Prevents bone loss and reduces spinal fractures.
    • Some studies suggest a potential increase in breast cancer risk, but high-quality trials do not show a significant change in breast cancer rates.
    • Does not increase breast density.

Duration of treatment

• Consider severity, response to treatment, long term aims (osteoporosis at least 10 years)
• Reasonable to start with 2 years, then review – consider extending to 5 years
• After 5-7 years breast cancer risk increases

IF <1 yr since last period (Menopausal Transition)

Option1	Low dose combined contraceptive (if low CVD risk & <50)
Option2	Continuous oestrogen	+	cyclical progestogen 10-14 days each month	+	contraception
Option3	Continuous oestrogen	+	levonorgestrel IUD for progestogen	+	contraception

IF >1 yr since last period (Postmenopause)

	Low dose combined contraceptive (if low CVD risk & <50)
Option1	Continuous oestrogen	+	continuous progestogen (if menopause >1-2 years ago)
Option2	Continuous oestrogen	+	cyclical progestogen(if menopause< 1 year ago)	+	cyclical progestogen
Option3	Tibolone (if menopause is >1-2 years ago) but not PBS funded = oestrogenic/progestogenic/androgenic effects. Not ax w increased risks of HRT but does drop HDL.
	Tissue-selective oestrogen complex (TSEC)

Continuous (can be cyclical but will have withdrawal bleed!!)

Start at the lowest dose !!! Patches are the most common preparation

1. Continuous combined Menopausal Hormone Therapy (MHT) – Should be used if 12 months since LMP or after 12 months cyclical MHT

Low dose
Product	Presentation	Composition
Angeliq1/2*	tablet	1mg oestradiol/2mg drospirenone
Femoston-conti	tablet	1mg oestradiol/5mg dydrogesterone
Kliovance*	tablet	1mg oestradiol/0.5mg norethistrone
Bijuva*	capsule	1mg oestradiol/100mg micronised progesterone
Estrogel Pro*	Combination pack of oestradiol transdermal gel, with micronised progesterone capsules.	1 pump (0.75mg oestradiol) daily, and 1 capsule (100mg) micronised progesterone orally for 25 days out of a 28-day cycle^
Other Low dose hormonal options
Livial*, Xyvion*	tablet	2.5mg tibolone
Duavive* (oestrogen/ SERM combination)	tablet	0.45mg conjugated equine oestrogens / 20mg bazedoxifene
Medium dose
Kliogest*	tablet	2mg oestradiol/1mg norethistrone
Estalis continuous 50/140	transdermal patch	50mcg oestradiol/140mcg norethisterone acetate (twice weekly application)
Estalis continuous 50/250 (same oestrogen, more progestogen than Estalis continuous 50/140)	transdermal patch	50mcg oestradiol/250mcg norethisterone acetate (twice weekly application)
Estrogel Pro*	Combination pack of oestradiol transdermal gel, with micronised progesterone capsules.	2 pumps (1.5mg oestradiol) daily, and 1 capsule (100mg) micronised progesterone orally for 25 days out of a 28-day cycle^

2. Cyclic Menopausal Hormone Therapy (MHT)

Use continuous oestrogen and cyclic progestogen combinations at peri-menopause or if less than 12 months amenorrhoea

Low Dose
Product	Presentation	Composition
Femoston	tablet	1mg oestradiol/10mg dydrogesterone
Estrogel Pro*	Combination pack of oestradiol transdermal gel, with micronised progesterone capsules.	1 pump (0.75mg oestradiol) daily, and 2 capsules (200mg) micronised progesterone orally for 12 days out of a 28-day cycle
Medium dose
Trisequens*	tablet	1 and 2mg oestradiol/1mg norethisterone
Femoston	tablet	2mg oestradiol/10mg dydrogesterone
Estalis sequi 50/140)	transdermal patch	50mcg oestradiol/140mcg norethisterone acetate (twice weekly application)
Estalis sequi 50/250 (same oestrogen, more progestogen than Estalis sequi 50/140)	transdermal patch	50mcg oestradiol/250mcg norethisterone acetate (twice weekly application)
Estrogel Pro*	Combination pack of oestradiol transdermal gel, with micronised progesterone capsules.	2 pumps (1.5mg oestradiol) daily, and 2 capsules (200mg) micronised progesterone orally for 12 days out of a 28-day cycle

3. Continuous oestrogen

Only use these if patient has had a hysterectomy or in combination with a progestogen or Mirena if intact uterus 

Low dose
Product	Presentation	Composition
Estrofem*	tablet	1mg oestradiol
Progynova	tablet	1mg oestradiol
Premarin*	tablet	0.3mg conjugated equine oestrogen
Climara 25	transdermal patch	25mcg oestradiol (weekly application)
Estradot 25 or 37.5	transdermal patch	25 or 37.5mcg oestradiol (twice weekly application)
Estraderm 25 MX	transdermal patch	25mcg oestradiol (twice weekly application)
Estrogel*	gel	0.75mg oestradiol = 1 pump daily
Medium dose
Estrofem*, Zumenon	tablet	2mg oestradiol
Progynova	tablet	2mg oestradiol
Premarin*	tablet	0.625mg conjugated equine oestrogens
Climara 50	transdermal patch	50mcg oestradiol (weekly application)
Estradot 50, Estraderm 50 MX	transdermal patch	50mcg oestradiol (twice weekly application)
Sandrena	gel	1mg oestradiol daily
Estrogel*	gel	1.5mg oestradiol = 2 pumps daily
High dose
Climara 75	transdermal patch	75mcg oestradiol (weekly application)
Estradot 75, Estradot 100	transdermal patch	75 or 100mcg (twice weekly application)
Climara 100	transdermal patch	100mcg oestradiol (weekly application)
Estraderm 100 MX	transdermal patch	100mcg oestradiol (twice weekly application)
Estrogel*	gel	2.25mg oestradiol = 3 pumps daily or 3.0mg oestradiol = 4 pumps daily

Oestrogen only vaginal therapy If prescribing vaginal oestrogen rather than systemic hormone therapy, a progestogen is not required.
Product	Presentation	Composition
Ovestin	cream	0.5mg oestriol = 1 application
Ovestin	pessary	0.5mg oestriol
Vagifem Low	pessary	10mcg oestradiol

4. Continuous Progestin = Suggested alternative doses for use with the oestrogen preparations above where fixed dose therapy is not suitable

Low dose for use with low dose oestrogen
Product	Presentation	Composition
Provera (1/2 of 5mg tablet)	tablet	2.5mg medroxyprogesterone acetate
Provera 2.5mg tablet*	tablet	2.5mg medroxyprogesterone acetate
Primolut N (1/4 of 5mg tablet)	tablet	1.25 mg norethisterone
Prometrium*	capsule	100mg micronised progesterone orally for 25 days out of a 28-day cycle^ or 200mg orally daily for 12 days out of a 28-day cycle
Mirena*(PBS indication for contraception/menorrhagia)	device(5 years)	20mcg levonorgestrel
Medium dose for use with medium dose oestrogen
Product	Presentation	Composition
Primolut N (1/4 of 5mg tablet)	tablet	1.25 mg norethisterone
Provera, Ralovera	tablet	5mg medroxyprogesterone acetate
Prometrium*	capsule	100mg micronised progesterone orally for 25 days out of a 28-day cycle^ or 200mg orally for 12 days out of a 28-day cycle
Mirena*(PBS indication for  contraception/menorrhagia)	device	20mcg levonorgestrel (5 years)
Higher dose (for use in cyclical therapy or continuous therapy with high dose oestrogen)
Product	Presentation	Dose
Primolut N (1/2 5mg tablet)	tablet	2.5mg norethisterone
Provera, Ralovera	tablet	10mg medroxyprogesterone acetate
Prometrium*	capsule	200mg micronised progesterone orally daily for 12 days out of a 28-day cycle. Safe continuous dose unknown due to insufficient data
Mirena*(PBS indication for contraception/menorrhagia)	device	20mcg levonorges

Mirena – eliminates bleeding, but not cyclical Symptoms 

Cyclical Progestin = given for the 1^st – 12^th day of the calendar month

• Oral
  • Provera (medroxyprogesterone acetate) = 5mg – 10mg
  • Primolut N (norethisterone) = 0.7mg – 2.5mg 

Special considerations

After hysterectomy	Continuous oestrogen or tibolone.
Cancers – breast/endometrial/ovarian (hormone-sensitive) cancer. OCP,	Liaise with treating oncologist/gynaecologist. In specific cases MHT/tibolone may be used +/- vaginal oestriol for vaginal/urinary symptoms
Cardiovascular disease (hypertension, diabetes, hypercholesterolemia)	Transdermal MHT.
Endometriosis	levonorgestrel IUD + oestrogen, tibolone, continuous combined MHTWith post-surgical menopause need to consider added progestogen/tibolone
Fibroids	MHT may increase size – less likely with tibolone or transdermal oestrogen and progestogen
Hirsutism	Oral oestrogen to increase SHBG: cyproterone, dydrogesterone, drospirenone or oral progesterone. Can also use spironolactone.
Low libido	Not OCP or oral oestrogen. Check other drugs affecting libido eg SSRI/SNRI. Use transdermal oestrogen to lower SHBG. Consider tibolone, or testosterone. (See Testosterone Therapy)
PV bleeding	Investigate to determine cause and exclude pathology prior to treatment – transvaginal ultrasound +/– hysteroscopy. If atrophic endometrium (
Testosterone therapy	Testosterone 1% cream (for women) is TGA approved for clinically diagnosed hypoactive sexual desire disorder (HSDD) or low sexual desire with distress, when all other causes are excluded. Total testosterone is measured with SHBG to exclude a high level and to monitor dosing
Liver disease, gallstones	Transdermal MHT
VTE/thrombophilia	Assess baseline risk; high risk if VTE recurrent, spontaneous, with pregnancy/ OCP, family history, smokers. Screen for inherited thrombophilia. If normal and low risk, use transdermal or tibolone. If high risk or inherited thrombophilia, avoid MHT unless anticoagulated. Seek specialist haematological advice re the use of transdermal MHT
Headaches	Hormonally sensitive migraine may worsen in perimenopause- fluctating estrogen levelsAll types of migraines are associated with increased risk of stroke – particularly if auraIf previous migraine – prefer transdermal estrogenIf progestgerone needed continuous may be better to decrease frequencyIf aura or headaches more significant – stop MHTConsider clonidine for hot flushes – also prevents migraine
Obesity/morbid obesity	Transdermal MHT