HRT hashem 2016.pptx
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Hormone replacement therapy in the menopause
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HRT hashem 2016.pptx
- 1. Hormone replacement therapyHormone replacement therapy in the menopausein the menopause
- 2. Outlines
- 3. Outlines
- 4. Menopause:Menopause: Definitions • ClinicallyClinically: Amenorrhoea of 12 months: Amenorrhoea of 12 months • WHOWHO: permanent cessation of menstruation,: permanent cessation of menstruation, resulting from the loss of ovarian follicular activityresulting from the loss of ovarian follicular activity • The Climacteric phases ?The Climacteric phases ? • Surgical menopause ?Surgical menopause ? • At 50 years (standard deviation + / - 4 years)At 50 years (standard deviation + / - 4 years) • Early menopause: before 45 years ~ risk factors ??Early menopause: before 45 years ~ risk factors ?? • Premature ovarian failure (POF): before 40 years ??Premature ovarian failure (POF): before 40 years ?? • Osteoporosis: reduced bone mass per unit volumeOsteoporosis: reduced bone mass per unit volume
- 5. FSH Ovary Hypothalmus Inhibin B + GnRH Normal Ovary Hormonal Changes The physiologic changes of MenopauseMenopause
- 6. FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Aging Ovary Hormonal Changes The physiologic changes of MenopauseMenopause
- 7. FSH Ovary Hypothalmus Estradiol / Inhibin B + GnRH Menopausal Ovary Hormonal Changes The physiologic changes of MenopauseMenopause
- 8. The physiologic changes of MenopauseMenopause
- 9. Symptoms associated with MenopauseMenopause • In about 70% of womenIn about 70% of women • Severely in about 20%Severely in about 20% • a median duration of 5.2 yearsa median duration of 5.2 years • 10% of women -> more than 10 years10% of women -> more than 10 years
- 11. ““The Menopausal Metabolic Syndrome”The Menopausal Metabolic Syndrome” Lipid TriadLipid Triad – HypertriglyceridemiaHypertriglyceridemia ↑↑ LDL CholesterolLDL Cholesterol Abnormalities in InsulinAbnormalities in Insulin – Insulin resistanceInsulin resistance ↓↓ insulin eliminationinsulin elimination – HT reduces onset of DM and improves insulin resistanceHT reduces onset of DM and improves insulin resistance Other FactorsOther Factors – Endothelial dysfunctionEndothelial dysfunction ↑↑ visceral fatvisceral fat ↑↑ uric aciduric acid ↓↓ HDL CholesterolHDL Cholesterol ↓↓ insulin secretioninsulin secretion HyperinsulinemiaHyperinsulinemia ↓↓ SHBGSHBG ↑↑ blood pressureblood pressure
- 12. Menopause:Menopause: Diagnosis • Healthy women aged over 45 years = > clinical symptoms,Healthy women aged over 45 years = > clinical symptoms, 1.1. vasomotor symptoms and irregular periodsvasomotor symptoms and irregular periods 2.2. Ammenorrhea at least 12 months and are not using hormonal contraceptionAmmenorrhea at least 12 months and are not using hormonal contraception • If without a uterus = > clinical symptomsIf without a uterus = > clinical symptoms • inin women aged 40 to 45 yearwomen aged 40 to 45 years with menopausal symptoms,s with menopausal symptoms, including a change in their menstrual cycle = >including a change in their menstrual cycle = >serum FSH andserum FSH and estradiaol is diagnostic (30iuml)estradiaol is diagnostic (30iuml) • in women aged under 40 years in whom menopause isin women aged under 40 years in whom menopause is suspected = >suspected = > serum FSH and estradiaol is diagnosticserum FSH and estradiaol is diagnostic • in women using combined oestrogen and progestogenin women using combined oestrogen and progestogen contraception or high-dose progestogen => ??contraception or high-dose progestogen => ?? NG23 ~ NICE 2015NG23 ~ NICE 2015
- 13. Outlines
- 14. Indications for HRT • Relief of menopausal symptoms (short-term) • Prevention/treatment of osteoporosis (long-term) • Premature ovarian failure •ACOG suggests not using MHT for theACOG suggests not using MHT for the preventionprevention of chronic disease (osteoporosis,of chronic disease (osteoporosis, CHD, or dementia) ,CHD, or dementia) ,but they now recommend bisphosphonates forthey now recommend bisphosphonates for osteoporosis treatment
- 15. Contraindications to HRT 1. Existing cardiac disease (AbsoluteAbsolute) 2. Active liver disease 3. Systematic lupus erythematosus 4. Previous breast cancer 5. Previous endometrial cancer 6. Undiagnosed vaginal bleeding 7. Previous personal/family history of venous thromboembolism
- 17. TipsTips • Estrogen , HRT vs cOCP ?!Estrogen , HRT vs cOCP ?! • Progestogen or micronised progesterone?! SixProgestogen or micronised progesterone?! Six months?months? • Orally or transdermally.Orally or transdermally. • Mirena ?Mirena ? Women who cannot tolerate oral progestinsWomen who cannot tolerate oral progestins • Supplemental testosterone ?!Supplemental testosterone ?! • Vaginal progesterone regimens ?Vaginal progesterone regimens ? • Conjugated estrogen/bazedoxifene ?Conjugated estrogen/bazedoxifene ?
- 20. EPT RegimenEPT Regimen EstrogenEstrogen ProgesteroneProgesterone Cyclic – sequentialCyclic – sequential Day 1-25Day 1-25 Last 10-14 days of ET cycleLast 10-14 days of ET cycle Cyclic- combinedCyclic- combined Day 1-25Day 1-25 Day 1-25Day 1-25 Continuous - sequentialContinuous - sequential DailyDaily 10-1410-14days every monthdays every month Continuous – long sequentialContinuous – long sequential Women who cannot tolerate oralWomen who cannot tolerate oral progestinsprogestins DailyDaily 1414days every 3-6monthsdays every 3-6months Continuous - combinedContinuous - combined DailyDaily DailyDaily TiboloneTibolone DailyDaily (estrogen plus a progestogen = EPT)(estrogen plus a progestogen = EPT)
- 21. Topical HRT: vaginal estrogenTopical HRT: vaginal estrogen • vulvovaginal atrophy (now referred to as “genitourinaryvulvovaginal atrophy (now referred to as “genitourinary syndrome of menopause” [GSM])syndrome of menopause” [GSM]) • Cornification and regeneration of the vaginal epithelium.Cornification and regeneration of the vaginal epithelium. • Improves lubrication and sexual function.Improves lubrication and sexual function. • Systemic absorption is insignificant.Systemic absorption is insignificant. • May reduce symptoms of urgency of micturition andMay reduce symptoms of urgency of micturition and recurrent urinary tract infections.recurrent urinary tract infections. • Additional systemic progestogen is not requiredAdditional systemic progestogen is not required • In such cases both topical and systemic may requireIn such cases both topical and systemic may require • Safety in breast cancer ??,Safety in breast cancer ??, The benefits to the genitourinary tract alongThe benefits to the genitourinary tract along with improved sexual intimacy may outweigh the risk.with improved sexual intimacy may outweigh the risk.
- 22. TiboloneTibolone • Steroid, Metabolites are activeSteroid, Metabolites are active • Selective tissue estrogenic activitySelective tissue estrogenic activity regulator.regulator. • Mildly, progestogenic and androgenicMildly, progestogenic and androgenic propertiesproperties • Unsuitable in perimenopausal women,Unsuitable in perimenopausal women, ↑ breakthrough bleeding.↑ breakthrough bleeding. • Breast cancer ?? No dataBreast cancer ?? No data
- 23. Side effects • Estrogen include:Estrogen include: 1.1. bloatingbloating 2.2. breast tendernessbreast tenderness 3.3. swellingswelling 4.4. nauseanausea 5.5. leg crampsleg cramps 6.6. headachesheadaches 7.7. indigestionindigestion 8.8. vaginal bleedingvaginal bleeding • ProgestogenProgestogen include:include: 1.1. breast tendernessbreast tenderness 2.2. swellingswelling 3.3. headaches or migrainesheadaches or migraines 4.4. mood swingsmood swings 5.5. depressiondepression 6.6. acneacne 7.7. tummy (abdominal) paintummy (abdominal) pain 8.8. back painback pain 9.9. vaginal bleedingvaginal bleeding
- 24. Outlines
- 25. What we know so far: theWhat we know so far: the main large studiesmain large studies A.A. The Heart and Estrogen/progestinThe Heart and Estrogen/progestin Replacement Study (HERS) I & IIReplacement Study (HERS) I & II • The first study to identify if HRT prevented recurrence of coronary heart disease (CHD) in women with established CHD • Randomised to conjugated equine estrogens (CEE)/medroxy progesterone • The treatment did increase the risk of venous thromboembolism (VTE) • A follow-up study of this cohort, the HERS II in 2002 concluded that this benefit did not persist and stated that HRT should not be used for secondary prevention in women with established heart disease.
- 26. What we know so far: theWhat we know so far: the main large studiesmain large studies B.B. The Women’s Health Initiative StudyThe Women’s Health Initiative Study • To evaluate the effect of HRT on healthy postmenopausal women with aTo evaluate the effect of HRT on healthy postmenopausal women with a particular interest in cardiovascular outcomes.particular interest in cardiovascular outcomes. • Randomised to CEE and medroxy progesterone acetate or placeboRandomised to CEE and medroxy progesterone acetate or placebo • Women who had had a hysterectomy were randomized to CEE only or placeboWomen who had had a hysterectomy were randomized to CEE only or placebo • In 2003 the combined arm of the study was closed -> Increase in breast cancer,In 2003 the combined arm of the study was closed -> Increase in breast cancer, heart disease, stroke and VTE events were reported, while a reduction inheart disease, stroke and VTE events were reported, while a reduction in fracture rate, bowel cancer and diabetes were the advantages gainedfracture rate, bowel cancer and diabetes were the advantages gained • The reanalysis of this study in 2007 demonstrated that giving HRT to womenThe reanalysis of this study in 2007 demonstrated that giving HRT to women within 10 years of the menopause was associated with fewer risks and awithin 10 years of the menopause was associated with fewer risks and a reduction in cardiovascular eventsreduction in cardiovascular events • ‘‘the window of opportunity’the window of opportunity’
- 27. What we know so far: theWhat we know so far: the main large studiesmain large studies C.C. The Million Women StudyThe Million Women Study • Women aged 50–64 years in the UK attending the NHSWomen aged 50–64 years in the UK attending the NHS breast screeningbreast screening programme were invited and subsequently followed by completion of aprogramme were invited and subsequently followed by completion of a questionnairequestionnaire.. • AA significant increased risk of breast cancer was seen in the women on combinedsignificant increased risk of breast cancer was seen in the women on combined HRT (estrogen and progestogensHRT (estrogen and progestogens) and less so with estrogen only and tibolone.) and less so with estrogen only and tibolone. • Problems:Problems: 1.1. the breast cancers already present at the time of entry into the study were notthe breast cancers already present at the time of entry into the study were not excludedexcluded 2.2. patients on HRT concerned for their wellbeing were more likely to attendpatients on HRT concerned for their wellbeing were more likely to attend 3.3. the rapid onset of the breast cancer development did not fit the biologicalthe rapid onset of the breast cancer development did not fit the biological course of the diseasecourse of the disease 4.4. significant amounts of data, such as menopausal status, time since menopause,significant amounts of data, such as menopausal status, time since menopause, age at menopause and body mass index changes were missing during the follow-age at menopause and body mass index changes were missing during the follow- up questionnaires.up questionnaires.
- 28. What we know so far: theWhat we know so far: the main large studiesmain large studies D.D. 2012 Cochrane Collaboration systematic2012 Cochrane Collaboration systematic reviewreview • Assessed the clinical effects of using HRT for 1 year or more • Twenty-three randomised double-blind studies were included involving 42 830 women aged 26–91 years. • Since 70% of the data were derived from the Women’s Health Initiative and HERS • The randomised studies included all estrogens, with or without progestogens • None of the studies focused on younger, recently diagnosed postmenopausal women. • the findings agreed with the large publications, with an increased risk of VTE, CVD, stroke, breast cancer, gall bladder disease and dementia in women over 65 years old. • the review concluded that there was no indication to use HRT for primary or secondarythe review concluded that there was no indication to use HRT for primary or secondary prevention of CVD or dementia or for protection of cognitive function.prevention of CVD or dementia or for protection of cognitive function. • There was a significant benefit and reduction in the risk of bone fracture after 5 years ofThere was a significant benefit and reduction in the risk of bone fracture after 5 years of useuse • The study had insufficient data to assess the risk of long-term HRT use in perimenopausal women or postmenopausal women younger than 50 years of age
- 29. Effect of HRT on CVS events inEffect of HRT on CVS events in recentlyrecently postmenopausal womenpostmenopausal women • A randomised study by Schierbeck et al. that was carried out in Denmark in 1990–1993, has been the first one to address the correct timing and the long-term effect of HRT on CVD in recently postmenopausal womenCVD in recently postmenopausal women • The number of patients was relatively small, with 502 patients randomly selected to receive HRT and 504 to receive no treatment. • The publication of adverse reports from other trials led to the discontinuation of the intervention at 11 years but follow-up was continued for a total of 16 years. • After 10 years, women on HRT were found to have had a significantfound to have had a significant reduction in mortality and CVD-related events, with no apparentreduction in mortality and CVD-related events, with no apparent increased risk of VTE, stroke or cancerincreased risk of VTE, stroke or cancer. The health benefits were seen for up to 6 years after stopping.
- 30. Thrombosis riskThrombosis risk • the risk of venous thromboembolism (VTE) is increased by oral HRT comparedthe risk of venous thromboembolism (VTE) is increased by oral HRT compared with baseline population riskwith baseline population risk • the risk of VTE associated with HRT is greater for oral than transdermalthe risk of VTE associated with HRT is greater for oral than transdermal preparationspreparations • the risk associated with transdermal HRT given at standard therapeutic doses isthe risk associated with transdermal HRT given at standard therapeutic doses is no greater than baseline population risk.no greater than baseline population risk. • Consider transdermal rather than oral HRT for menopausal women who are atConsider transdermal rather than oral HRT for menopausal women who are at increased risk of VTE, including those with a BMI over 30 kg/m2.increased risk of VTE, including those with a BMI over 30 kg/m2. • Consider referring menopausal women at high risk of VTE (for example, thoseConsider referring menopausal women at high risk of VTE (for example, those with a strong family history of VTE or a hereditary thrombophilia) to awith a strong family history of VTE or a hereditary thrombophilia) to a haematologist for assessment before considering HRT.haematologist for assessment before considering HRT. ~GTG 2013~GTG 2013
- 32. Premature ovarian insufficiencyPremature ovarian insufficiency • ≤ 40 years + symptoms + elevated FSH levels on 2 blood samples taken 4–6 weeks apart. • Earlier onset of both CVD episodes and osteoporosis • ↓breast cancer risk compared with their menstruating peers. • it is strongly advised that these women should consider taking HRT, at least until the age of 50 ~ NICE 2015 • HRT may have a beneficial effect on blood pressure when compared with a combined oral contraceptive • BisphosphonatesBisphosphonates are not considered first-line treatment for preventionprevention of osteoporosis in younger women
- 33. Other benefits of HRTOther benefits of HRT • Improvement of low moodImprovement of low mood • Protection against loss of connective tissueProtection against loss of connective tissue • Reduction of bowel cancer in women using HRTReduction of bowel cancer in women using HRT • Neuroprotective, preserving cognitive function andNeuroprotective, preserving cognitive function and reducing the risk of Alzheimer’s disease.reducing the risk of Alzheimer’s disease. • Some protection against Parkinson’s DiseaseSome protection against Parkinson’s Disease ~The British Menopause Society & Women’s Health Concern recommendations on hormone~The British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause Int 2013replacement therapy. Menopause Int 2013
- 34. Non-hormonal treatmentsNon-hormonal treatments • Clonidine, selective serotonin reuptake (if not on tamoxifen) • Selective noradrenaline reuptake inhibitors for example, venlafaxinevenlafaxine, (unlicensed indication for vasomotor symptoms), mood lability or depressionmood lability or depression • Gabapentin ? • Aromatase inhibitors ?
- 35. HRT in survivors of gynaecologicalHRT in survivors of gynaecological and breast cancerand breast cancer
- 36. Outlines
- 37. Clinical approach: HistoryClinical approach: History 1. Age 2. Menstrual history 3. Menopausal symptoms 4. Mental state symptoms 5. Sexual history 6. Use of contraception 7. Urinary symptoms 8. Social history ( smoking, relationships…) 9. Medical history ( liver disease, SLE, migrane, CVD, VTE, or HTN) 10. Surgical history(gyne operations) 11. Family history ( cancers, CVD, or osteoperosis)
- 38. Clinical approach:Clinical approach: Physical examination 1. Blood pressure 2. Weight and hight 3. Breast palpation 4. Abdominal palpation 5. Vaginal examination 6. Pap smear
- 39. Clinical approach: Investigation 1. Pap smear 2. Urine analysis 3. Full blood count 4. Lipid profile 5. Thyroid function test 6. Liver and kidney function tests 7. Mamography ( all women, preferably before and annually) 8. Diagnostic hysteroscopy wih bx ( undiagnosed vaginal bleeding) 9. Bone density study 10. If diagnostic in doubt: serum FSH & Estradiol
- 40. Clinical approach: Differential diagnosis 1. Depression 2. Anemia 3. Thyroid dysfunction 4. Hyperparathyrodisim 5. Gynecological disorders - dysfunctional uterine bleeding
- 41. Practical guidance on HRTPractical guidance on HRT prescribingprescribing
- 45. Route / Starting estrogenRoute / Starting estrogen • Transdermal 17-beta estradiol → oral 17-beta estradiol →Transdermal 17-beta estradiol → oral 17-beta estradiol → conjugated estrogens.conjugated estrogens. • equally effective for symptom relief (and bone density).equally effective for symptom relief (and bone density). • metabolic effects differ (oral estrogens) :metabolic effects differ (oral estrogens) : 1.1. ↑↑ in serum triglyceridesin serum triglycerides 2.2. ↑↑ C-reactive proteinC-reactive protein 3.3. ↑↑ sex hormone-binding globulin (SHBG) ↓ free testosterone concentrations →→ a negative impact on libido and sexual function, but this has not been proven. 4.4. ↑↑ TBG and ↓ bioavailable T4TBG and ↓ bioavailable T4 5.5. ↑↑ cortisol-binding globulin (CBG), ↑ in total serum cortisolcortisol-binding globulin (CBG), ↑ in total serum cortisol • The risks of VTE and stroke appear to be higher with oral whenThe risks of VTE and stroke appear to be higher with oral when compared with transdermal estrogencompared with transdermal estrogen
- 46. DoseDose • oral 17-beta estradiol [0.5 mg/day]oral 17-beta estradiol [0.5 mg/day] • 0.025 mg of transdermal estradiol → 0.03750.025 mg of transdermal estradiol → 0.0375 mg → 0.05 mg (reassessment monthly)mg → 0.05 mg (reassessment monthly) • bilateral oophorectomybilateral oophorectomy: require higher doses up to 0.1 mg: require higher doses up to 0.1 mg transdermal estradiol for the first two to three years after surgery; thetransdermal estradiol for the first two to three years after surgery; the dose can subsequently be tapered down.dose can subsequently be tapered down. • Estrogen should be administered continuouslyEstrogen should be administered continuously • oral micronized progesterone (200 mg/day for 12oral micronized progesterone (200 mg/day for 12 days of each calendar month).days of each calendar month).
- 47. Factors affecting oral estrogenFactors affecting oral estrogen metabolismmetabolism • Anticonvulsant drugs (phenytoin,Anticonvulsant drugs (phenytoin, carbamazepine) ?carbamazepine) ? • T4 replacement therapy?T4 replacement therapy? • Concurrent acute alcohol ingestion?Concurrent acute alcohol ingestion? • end-stage renal disease ?end-stage renal disease ?
- 48. • Duration of therapy:Duration of therapy: 1.1. short-term use → not more than five years or not beyond age 60 yearsshort-term use → not more than five years or not beyond age 60 years 2.2. recurrent, bothersome hot flashes → nonhormonal options → extended use ofrecurrent, bothersome hot flashes → nonhormonal options → extended use of hormone therapyhormone therapy • Monitoring with mammographyMonitoring with mammography ACOG Recommend annual mammogram , even in used short termACOG Recommend annual mammogram , even in used short term • Use of oral contraceptives during theUse of oral contraceptives during the menopausal transition:menopausal transition: 1.1. the ages of 40 and 50 years, desire contraception, need control of bleeding,the ages of 40 and 50 years, desire contraception, need control of bleeding, 2.2. OC containing 20 mcg of ethinyl estradiolOC containing 20 mcg of ethinyl estradiol 3.3. should be avoided in obese perimenopausal womenshould be avoided in obese perimenopausal women • Stopping hormone therapy& Tapering :Stopping hormone therapy& Tapering : 1.1. Tapering has not been proven to be more effective than stopping treatment abruptlyTapering has not been proven to be more effective than stopping treatment abruptly 2.2. ACOG suggests a gradual taper, one approach is to decrease the estrogen by oneACOG suggests a gradual taper, one approach is to decrease the estrogen by one pill per week every few weekspill per week every few weeks
- 49. Problems management • Persistent menopausal symptoms ?Persistent menopausal symptoms ? • Persistent breast tenderness ?Persistent breast tenderness ? • Heavy withdrawal bleeding ?Heavy withdrawal bleeding ? • Bleeding during progesterone therapy ?Bleeding during progesterone therapy ? • No bleeding ?No bleeding ? • Irregular bleeding ?Irregular bleeding ? • Intolerance of bleeding ?Intolerance of bleeding ? • Premenstrual symptoms ?Premenstrual symptoms ?
- 51. ReferencesReferences • Bakour SH, Williamson J. Latest evidence on using hormone replacement therapy in the menopause. The Obstetrician & Gynaecologist 2015;17:20–8. • Bregar A, Taylor K, Stuckey A. Hormone therapy in survivors of gynaecological and breast cancer. The Obstetrician & Gynaecologist 2014;16:251–8. • Green-top Guideline No. 19, 3rd edition | May 2011, Venous Thromboembolism and Hormone Replacement Therapy, RCOG • Marsden J. Hormone replacement therapy and breast disease. The Obstetrician & Gynaecologist 2010;12:155–163 • Arora P, Polson DW. Diagnosis and management of premature ovarian failure. The Obstetrician & Gynaecologist 2011;13:67–72. • Nonpharmacological treatment of postmenopausal symptoms. The Obstetrician & Gynaecologist 2013;15:19–25. • Menopause: diagnosis and management, NICE guideline, Published: 12 November 2015, nice.org.uk/guidance/ng23 • The British Menopause Society & Women’s Health Concern recommendations on hormone replacement therapy. Menopause Int 2013 • Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev 2012 • Commentary regarding recent Million Women Study critique and subsequent publicity. Menopause Int 2012
- 52. Hormone replacement therapyHormone replacement therapy in the menopausein the menopause
Editor's Notes
- Clinically defined as amenorrhoea of 12 months’ duration after the final menstrual period The average age of menopause is 51.4 years.1 Tobacco use, nulliparity, and family history are associated with earlier menopause When the menopause occurs before the age of 40 years, it is considered premature and is known as premature ovarian failure (POF)
- Inhibin made by the granulosa cells of the follicle Estradiol declines with involution of the CL FSH rises FSH stimulates follicular development and estradiol and inhibin B production Estradiol and inhibin B act at the level of the pituitary to supress FSH production Inhibin acts at the level of the pituitary
- No more follicles No inhibin b or estradiol production FSH rises Later LH will rise
- No more follicles No inhibin b or estradiol production FSH rises Later LH will rise
- Vasomotor symptoms (hot flushes and night sweats) are common, affecting about 70% of women (severely in about 20%), for a median duration of 5.2 years, but may continue for many more years in about 10% of women
- Diagnose the following without laboratory tests in otherwise healthy women aged over 45 years with menopausal symptoms: perimenopause based on vasomotor symptoms and irregular periods menopause in women who have not had a period for at least 12 months and are not using hormonal contraception menopause based on symptoms in women without a uterus. 1.2.2 Take into account that it can be difficult to diagnose menopause in women who are taking hormonal treatments, for example for the treatment of heavy periods. 1.2.3 Do not use the following laboratory and imaging tests to diagnose perimenopause or menopause in women aged over 45 years: anti-Müllerian hormone inhibin A inhibin B Oestradiol antral follicle count ovarian volume. 1.2.4 Do not use a serum follicle-stimulating hormone (FSH) test to diagnose menopause in women using combined oestrogen and progestogen contraception or high-dose progestogen. 1.2.5 Consider using a FSH test to diagnose menopause only: in women aged 40 to 45 years with menopausal symptoms, including a change in their menstrual cycle in women aged under 40 years in whom menopause is su
- Quality of life may be the deciding factor for women with contraindications, and in such circumstances a written statement from the woman is helpful and may avoid any future medico-legal complications.
- Hormone replacement therapy (HRT) in which the estrogen is similar to natural ovarian production should not be confused with the potent ethinyl estradiol used in combined oral contraceptive regimens. The addition of a progestogen or micronised progesterone is essential if a woman still has a uterus to prevent endometrial hyperplasia and cancer. Estradiol can be delivered orally (micronised estradiol, estradiol valerate, estrone, estriol or conjugated equine estrogens), or transdermally (17b-estradiol). Topical vaginal administration of estrogen is used for localised symptoms. Various progestogens are used in combination with estradiol, either in a sequential cyclical regimen or as continuous combined therapy (CCT). Progestogens are mostly administered orally, with only two formulations being available transdermally. The levonorgestrel-releasing intrauterine system Mirena (Bayer Plc., Newbury, UK) is licensed for 4 years in the UK along with estrogen replacement. Tibolone is an oral synthetic steroid with estrogenic, androgenic and progestogenic actions that can be used as HRT in postmenopausal women. The role of supplemental testosterone will not be covered in this article. Women who cannot tolerate oral progestins — Some women are unable to tolerate any oral progestin, whether given in a cyclic or continuous regimen. In this case, we sometimes suggest off-label use of the lower dose levonorgestrel-releasing intrauterine device (IUD) (table 3). (See "Preparations for menopausal hormone therapy", section on 'Levonorgestrel-releasing intrauterine device'.) Other progestins that have been used include quarterly regimens (progestin administered only every third month). However, quarterly progestin administration is not considered to be standard therapy and cannot be recommended. Vaginal progesterone regimens have also been tried, but endometrial safety data are limited [24]. (See "Menopausal hormone therapy: Benefits and risks", section on 'Protective effect of progestins' and "Preparations for menopausal hormone therapy", section on 'Progestin preparations'.) Conjugated estrogen/bazedoxifene — Another option is the combination of bazedoxifene, a selective estrogen receptor modulator (SERM), with conjugated estrogen. This product is available in the United States for the treatment of menopausal vasomotor symptoms and osteoporosis prevention. In this combination, the SERM bazedoxifene prevents estrogen-induced endometrial hyperplasia so that administering a progestin is not necessary. Potential candidates include women with moderate-to-severe hot flashes who have breast tenderness with standard estrogen-progestin therapy (EPT) or women who cannot tolerate any type of progestin therapy because of side effects. Like other SERMs, the risk of VTE is increased with bazedoxifene. To date, no additive effect on VTE has been observed with the combination conjugated estrogen/bazedoxifene, but longer studies are needed to fully address this risk. (See "Menopausal hot flashes", section on 'Bazedoxifene/conjugated estrogen'.)
- We suggest transdermal 17-beta estradiol for many women starting MHT (Grade 2C). The transdermal route is particularly important in women with hypertriglyceridemia or risk factors for thromboembolism. However, the baseline risk of both venous thromboembolism (VTE) and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe. All types and routes of estrogen are equally effective for hot flashes. (See 'Starting estrogen' above.) ●For women who experience recurrent, bothersome hot flashes after stopping estrogen, we initially suggest nonhormonal options. However, if this approach is unsuccessful and symptoms persist, we resume MHT at the lowest dose possible in carefully selected women. (See 'Extended use of MHT' above.) ●For women with an intact uterus who choose ET, progestin therapy must be added to prevent endometrial hyperplasia and carcinoma. (See 'Adding a progestin'above.) ●We suggest micronized progesterone as our first-line progestin because it is effective for endometrial hyperplasia, is metabolically neutral, and does not appear to increase the risk of either breast cancer or CHD, although data are limited (Grade 2C). (See 'Adding a progestin' above.)
- Role of androgen therapy — The known decrease in ovarian androgen production rates and serum androgen concentrations has caused concern that menopause might be associated with a decline in libido. An age-associated decline in sexual desire has been observed in both men and women. However, it is unclear whether the decline in libido in women is age or menopause related, since studies in women have not shown a significant correlation between libido and the serum estradiol or testosterone concentration [51]. Clinical trials of exogenous testosterone replacement suggest modest benefits of testosterone therapy in some postmenopausal women. However, there are potential risks associated with androgen replacement, and the use of testosterone is limited by the lack of approved and commercially available products for women. Until the beneficial effects of androgen replacement are better established, it cannot be routinely recommended to postmenopausal women.
- Atrophic vaginitis is treatable with topical estrogen, resulting in cornification and regeneration of the vaginal epithelium. This improves lubrication and sexual function. Systemic absorption is insignificant with low-dose topical estrogen. Additional systemic progestogen is not required. Vaginal estrogen may reduce symptoms of urgency of micturition and recurrent urinary tract infections. Vaginal symptoms can persist even when on adequate systemic HRT; in such cases both topical and systemic are required. The safety of topical vaginal estrogen has not been assessed in patients with breast cancer, where theoretically the risks are small. The benefits to the genitourinary tract along with improved sexual intimacy may outweigh the risk.
- Tibolone, a selective tissue estrogenic activity regulator, is effective in treating symptoms in postmenopausal women. The evidence of a reduced stimulatory effect on breast tissue compared with other HRT preparations meant that it was feasible to evaluate its safety in a randomised controlled trial in women with recently diagnosed breast cancer (LIBERATE study).43 Quality of life was improved in the treatment group, but a higher rate of breast cancer recurrence was seen only in the women with ER+ disease. There are no data on whether it is safe to use in disease-free survivors who still experience menopausal symptoms many years after their initial treatment.
- Administering HRTfor symptom relief during the early phase of the menopausal transition is now described as ‘the window of opportunity’ for treatment benefit.
- Abstract In the 1990s, two randomised clinical trials started in Scandinavia addressing whether hormone replacement therapy (HRT) is safe for women with previous breast cancer. We report the findings of the safety analysis in HABITS (hormonal replacement therapy after breast cancer--is it safe?), an open randomised clinical trial with allocation to either HRT or best treatment without hormones. The main endpoint was any new breast cancer event. All analyses were done according to intention-to-treat. Until September, 2003, 434 women were randomised; 345 had at least one follow-up report. After a median follow-up of 2.1 years, 26 women in the HRT group and seven in the non-HRT group had a new breast-cancer event. All women with an event in the HRT group and two of those in the non-HRT group were exposed to HRT and most women had their event when on treatment. We decided that these findings indicated an unacceptable risk for women exposed to HRT in the HABITS trial, and the trial was terminated on Dec 17, 2003. Breast cancer patients — Although women with breast cancer often experience early menopause due to adjuvant chemotherapy and may have vasomotor symptoms due to tamoxifen therapy, ET should not be prescribed. The epidemiologic data and clinical trial data have been inconsistent, but the increased risk of breast cancer recurrence with ET in one trial (Hormonal Replacement After Breast Cancer – Is It Safe? [HABITS]) is of great concern. We therefore do not recommend estrogen for women with a personal history of breast cancer. We suggest that other established means of controlling symptoms or preventing osteoporosis should be utilized before considering ET in these women. (See "Menopausal hormone therapy and the risk of breast cancer", section on 'Personal history of breast cancer'.)
- However, the baseline risk of both VTE and stroke is very low in otherwise healthy, young postmenopausal women. Therefore, if a patient prefers an oral preparation over a transdermal one (cost or personal preference), we consider oral estrogen to be safe. We typically choose oral 17-beta estradiol preparations although some clinicians prefer conjugated estrogens, a preparation that has been popular historically (and the preparation studied in the Women’s Health Initiative [WHI]). Details on the types of estrogen preparations are reviewed separately. (See "Preparations for menopausal hormone therapy", section on 'Estrogen preparations'.) All routes of estrogen administration appear to be equally effective for symptom relief (and bone density), but their metabolic effects differ: ●Oral estrogen has more favorable effects on lipid profiles, but there is no evidence that this results in long-term clinical benefit. On the other hand, oral estrogens are associated with increases in serum triglycerides and C-reactive protein. (See "Menopausal hormone therapy and cardiovascular risk", section on 'Lipids'.) ●Oral estrogens increase sex hormone-binding globulin (SHBG) more than transdermal preparations, which results in lower free testosterone concentrations. In theory, this could result in a negative impact on libido and sexual function, but this has not been proven. Similar effects on thyroxine-binding globulin (TBG) and bioavailable thyroxine (T4) occur with oral estrogen (increased TBG and lower bioavailable T4). Oral estrogens also increase cortisol-binding globulin (CBG), resulting in an increase in total serum cortisol. Interpreting serum cortisol values in a woman taking oral estrogen can therefore be misleading. (See 'Factors affecting oral estrogen metabolism' below.) ●The risks of VTE and stroke appear to be higher with oral when compared with transdermal estrogen. (See "Menopausal hormone therapy and cardiovascular risk" and 'Factors affecting oral estrogen metabolism' below.) In addition to oral and transdermal estrogen preparations, estrogen is available as a vaginal ring and as a topical spray, cream, or gel. The topical spray (Evamist) has been linked to adverse effects in children and pets exposed to the drug via skin contact. (See "Preparations for menopausal hormone therapy", section on 'Topical estradiol'.) The US Food and Drug Administration (FDA) now requires the adding of labels to all estrogen and estrogen-progestin products warning of the possible risk of heart disease, stroke, and cancer [13].
- All types and routes of estrogen are effective for relieving menopausal symptoms, particularly, hot flashes. (See "Menopausal hot flashes", section on 'Menopausal hormone therapy'.) In a meta-analysis of 24 trials of MHT in 3329 women, the frequency of hot flashes decreased more in those receiving MHT (weighted mean difference -18 hot flashes per week compared with placebo; 95% CI -22.86 to -12.99; 75 percent reduction) [14]. The severity of hot flashes also decreased more with MHT compared with placebo. In a second meta-analysis, conjugated estrogen 0.625 mg/day and 17-beta estradiol (oral 1 mg/day or transdermal 0.05 mg/day) appeared to be equally effective for the treatment of hot flashes [15]. These doses eliminate hot flashes completely in about 80 percent of women and reduce the frequency and severity in the remainder [14]. In the past, a “one-size-fits-all” approach to estrogen dosing was used, with oral conjugated estrogen (0.625 mg/day) or its equivalent oral 17-beta estradiol (1 mg/day), or transdermal 17-beta estradiol (0.05 mg [50 mcg]), prescribed to most women. If symptoms were relieved, the same dose was continued indefinitely. However, the current approach is to start with lower doses, such as transdermal estradiol (0.025 mg) or oral estradiol (0.5 mg/day), and titrate up to relieve symptoms. Lower doses are associated with less vaginal bleeding and breast tenderness [16]. Lower doses are also associated with fewer effects on coagulation and inflammatory markers, and a possible lower risk of stroke and VTE than standard-dose therapy [17,18]. Based upon available data, we suggest starting with lower doses of estrogen (oral 17-beta estradiol [0.5 mg/day] or 0.025 mg of transdermal estradiol) unless the patient has severe symptoms. If hot flashes are still present after one month, we increase transdermal estradiol to 0.0375 mg and reassess one month later. If symptoms are still not relieved, we increase further to 0.05 mg. An exception to this approach is the patient with severe symptoms; we start with a transdermal dose of 0.05 mg to achieve more rapid relief of symptoms. “Standard” doses of estrogen given daily (conjugated estrogen 0.625 mg or its equivalent) are adequate for symptom relief in the majority of women [14,15,19]. An exception is younger women after bilateral oophorectomy. They often require higher doses (eg, up to 0.1 mg transdermal estradiol) for the first two to three years after surgery; the dose can subsequently be tapered down. The lowest available transdermal estradiol dose is 0.014 mg; it is approved for prevention of bone loss. However, about 50 percent of women derive some benefit for hot flashes. [20]. Progestin doses may be lowered with low-dose estrogen, but there is no consensus on optimal regimens. (See 'Adding a progestin' below.) Estrogen should be administered continuously; past regimens where estrogen was administered days 1 to 25 of the calendar month are considered to be obsolete. Women will often get hot flashes during the days off, and there is no known advantage to stopping for several days each month.
- Factors affecting oral estrogen metabolism — There are several situations in which the metabolism of exogenous estrogen is altered and therefore a change in the dose may be needed. Increased metabolism may result in lower serum estrogen concentrations, while decreased metabolism can result in higher serum concentrations. ●The above dosing suggestions (see 'Dose' above) may need to be increased in women taking anticonvulsant drugs (phenytoin, carbamazepine), which increase the hepatic clearance of estrogens and other steroid hormones. However, there is no way to predict how much more estrogen is needed [21]. In this situation, a transdermal estrogen may be better than oral estrogen since it avoids the first-pass hepatic metabolism. (See "Overview of the use of estrogen-progestin contraceptives", section on 'Drug interactions'.) ●Oral estrogens increase TBG more than transdermal preparations, which results in lower bioavailable T4. Therefore, in women receiving T4 replacement therapy, the addition of oral ET may increase T4 requirements. (See "Treatment of hypothyroidism".) ●Concurrent acute alcohol ingestion with oral estradiol has been found to cause a threefold rise in serum estradiol concentrations, apparently by slowing the metabolism of estradiol [22]. While it would be difficult to alter the medication dose based upon these findings, women taking exogenous estrogen should be encouraged to limit alcohol intake. ●Women with end-stage renal disease have higher serum estradiol concentrations after an oral dose of estrogen than do normal women [23].
- Extended use of MHT — Both the North American Menopause Society and the American College of Obstetrics and Gynecology agree that use of MHT should be individualized and not discontinued solely based upon patient age. They suggest that extended use of MHT (beyond age 60 or even 65 years) may be reasonable when the clinician and patient agree that the benefits of symptom relief outweigh the risks [40,41]. As noted, over 40 percent of women ages 60 to 65 years have persistent hot flashes that can impair sleep and quality of life. For women who choose extended use of MHT (more than five years or beyond age 60 years), we restart estrogen at the lowest dose possible and make plans for a future attempt to stop the estrogen. Monitoring with mammography — Routine mammograms and breast exams are recommended in women taking MHT, even when used short-term. In the WHI, the risk of breast cancer with combined EPT did not increase until the fourth year. However, abnormal mammograms were more common with both ET and EPT (although more common with EPT). The majority of abnormal mammograms in the WHI represented requests for additional views. Of note, stopping therapy for one to two months before a mammogram does not reduce recall rates.