PATPHYSIOLOGY OF MENOPAUSE, AND ITS MANAGEMENT

PRESENTATION ON THE PHYSIOLOGY OF MENOPAUSE

1. PHYSIOLOGY OF MENOPAUSE By Chidiebere Agbo (Registrar, REF Unit) 24th August, 2022

2. Outline Introduction Relevant terminologies Epidemiology Menstrual cycle Physiology of menopause and clinical correlation Psychological and Sociocultural impact Conclusion References

3. YOUNGER WOMAN AND OLDER WOMAN

4. Introduction Greek words : Men os (month) & paus is (cessation) . End of monthly/menstrual cycle. Cessation of period following the loss of ovarian activity and absence of ovarian estrogen secretion

5. Introduction (cont’d) Begins after 12 months of amenorrhea after the final period. It marks the end of fertility when the woman will not be able to bear further child without any form of assisted methods of conception. It is a retrospective diagnosis Manifests by medical, psychological and emotional conditions 1887 menopause was documented as a cause of mental problems

6. Introduction cont’d) Menopause can be natural or induced (artificial) Natural- is a gradual process Induced (artificial)- Permanent cessation of ovarian function by artificial means Unlike menarche which is influenced by many biological and environmental factors, only a few factors such as smoking and malnutrition have been documented to be associated with early menopause

7. Relevant terminologies Commonly used interchangeable terminologies assumed to mean same but strictly two different entities are two stages in a woman’s life termed Climacteric and perimenopause.

8. climacteric Klimakter (Greek)- rung of ladder. Major movement on life’s ladder. It is the period of time during which a woman passes through reproductive to non reproductive stage.(45-55yrs) Wide variety of symptoms, signs, metabolic adjustment. Ultimate cause of which is a major reduction in level of circulating oestrogens

9. perimenopause It is 3-5 years preceding menopause with increase frequent irregular anovulatory bleeding followed by episodes of ammenorrhea and intermittent menopausal symptoms. It stops 1 year after menopause.

10. Premature menopause/premature ovarian failure Cessation of menses before 40 years of age – Cessation of menses and development of climacteric symptoms and complaints can occur as early as a few years after menarche Causes: Idiopathic Genetic – Turner’s syndrome Fragile x . FSH receptor polymorphisms

11. Early menopause Cessation of menses at < 45 years of age Majorly, iatrogenic

12. Delayed menopause Condition in which menstruation extends beyond 55 years. Late menopause occurs in women with estrogenic tumour of the ovary, women with endometrial cancer, high socioeconomic status. Often it is constitutional. Endometrial biopsy is required to rule out endometrial pathology

13. Epidemiology of menopause

14. Epidemiology of menopause (cont’d) African women: 3 studies 48.4(48.1-48.6) Nigerian and Ghanaian studies: 48-49.5

15. Brief embryology Oocytes Process begins in embryonic life. 20 weeks gestation - 6 - 7 million follicles. At birth - 1-2 million follicles Puberty: 300 000 – 500 000 Ovulation accounts for 500 with atresia of others with age Depletion of oocytes eventually leads to cessation of menstruation which is the cardinal sign of menopause

16. Embryology (cont’d) Follicular loss accelerates when the total number of follicles is ~25,000 When follicles are sufficiently depleted (<1000), menopause occurs There are 2 landmarks in ovarian failure process: Marked decline in fertility with no cycle dysfunction Cycle changes with shortened follicular phase, and luteal phase dysfunction

17. Menstruation Defined as a periodic cyclical shedding of the progestational endometrium accompanied by blood The menstrual cycle is the interval between two successive menstruation

18. HPO AXIS

19. Phases of female reproductive years

20. Endocrine changes in menopause Estrogens; Fall in estradiol & estrone Androgens; fall in androstenedione, testosterone, DHEA & DHEAS Progesterone falls Gonadotropin; Rise in LH & FSH Others; fall in AMH & Inhibin B

21. ENDOCRINE CHANGES (CONT’D) Estrogen The follicle is the basic functional unit of the ovary. It is composed of an oocyte, granulosa cells, and theca cells. The bulk of Estrogen in premenopausal women is Estadiol (E2)

22. ENDOCRINE CHANGES (CONT’D) Main postmenopausal oestrogen is estrone (E1) produced by peripheral fat from adrenal androgen by aromatization . Synthesis principally from androgens to E2 in granulosa cells. Aromatase enzymes promoted by FSH . At menopause dramatic decrease of estrogen→menstruation ceases and symptoms of menopause start.

23. ENDOCRINE CHANGES (CONT’D) Theca cells produce oestrogen from androgens stimulated by LH. 1 st sign of approaching menopause is decline in fertility in 4 th decade. 1 st endocrine change is fall in inhibin production by ovary Inhibin is a glycoprotein that inhibits production of FSH

24. ENDOCRINE CHANGES (CONT’D) Progesterone: Major source is the corpus luteum premenopause . Postmenopausal level is only 30% of young women during follicular phase. Level remains very low. Main source – adrenal gland. Mean level -0.4ng/ml (0.2 – 7) Measurement is of no clinical use.

25. ENDOCRINE CHANGES (CONT’D) Gonadotropins FSH → 10 – 20 fold increase > 40 lU /L . L H → 3 fold increase (Due to absent negative feedback effect of estradiol and inhibin) FSH rises earlier than LH N/B: Menopausal urine has become an important commercial source of gonadotropins. Later gonadotropin activity of anterior pituitary ceases and fall in FSH level eventually occurs.

26. ENDOCRINE CHANGES (CONT’D) Most significant change in the hormonal profile is the dramatic decrease in circulating estradiol Ovarian stromal and adrenal glands secrete androstenedione which is aromatized to estrone become source of estrogen

27. Endocrine changes (cont’d)

28. Endocrine changes (cont’d)

29. Effect of endocrine changes Shorter menstrual cycles <25 days due to a shortened follicular phase (e.g., 10 days rather than 14) but luteal phase remains fairly constant Transition to progressive periods of anovulation and unpredictable menstruation. Amenorrhea occurs once the follicular pool is depleted, at which point FSH levels remain persistently elevated for the remainder of the woman's life

30. menopausal CHANGES Nervous system (vasomotor changes) Reproductive system Urinary system Cardiovascular system Musculoskeletal system (bone metabolism and osteoporosis)

31. menopausal CHANGES (CONT’D) Skin and hair Breast Metabolic changes Cognitive dysfunction Psychological aspect Sociocultural impact

32. VASOMOTOR CHANGES The classical vasomotor symptom that has been observed in women is the hot flush Exact mechanism unknown Symptoms result from a defect in central thermoregulatory function Changes in CNS concentrations of norepinephrine and serotonin likely play an important role

33. VASOMOTOR CHANGES cont’d Close temporal association between the occurrence of flushing and the pulsatile release of LH has been demonstrated. Vasomotor symptoms are a greater annoyance than most physicians recognize.

34. Manifestation of hot flushes Reported in as many as 80% of women. Short-lived sensation of intense heat with sweating in the upper body. Associated with flushing, anxiety, and tachycardia and can be debilitating

35. HOT FLUSHES

36. CHANGES IN REPRODUCTIVE TRACT

37. CHANGES IN URINARY TRACT

38. CVS CHANGES

39. MUSCULOSKELETAL SYSTEM (BONE METABOLISM AND OSTEOPOROSIS) Increased receptor activator of nuclear factor- κB ligand (RANKL) levels Leads to osteoclast activation and increased bone resorption. Decreased production of osteoprotegerin (OPG), an osteoclast inhibitor compounded by general age-related changes in bone metabolism and remodeling Disturbed vitamin D and calcium homeostasis Less mechanical stimulation of bone turnover

40. OSTEOPOROSIS

41. MUSCULOSKELETAL SYSTEM (BONE METABOLISM AND OSTEOPOROSIS)

42. SKIN AND HAIR CHANGES Loss of elasticity Skin becomes thinner and wrinkles (around the mouth and eyes: the so-called “Purse string” and “Crow feet” respectively) become evident

43. CHANGES IN BREAST Regression of breast size during and after menopause This is psychologically distressing to some women Could be of benefit for those with cyclic symptoms of breast pain a nd cyst formation

44. Metabolic changes in menopause Higher prevalence of obesity in postmenopausal women Multifactorial process Reduced energy expenditure due to physical inactivity ( compounded by depression) Muscle atrophy and a lower basal metabolic rate Redistribution of body fat from the periphery to the trunk, which results in visceral adiposity.

45. Metabolic changes (cont’d) Abdominal obesity and menopausal oestrogen decline are associated with insulin resistance, a propensity to develop type 2 diabetes mellitus and dyslipidemia Dyslipidemia characterised by low (HDL) cholesterol levels and a high (LDL) particles. Altered adipokine secretion, which leads to chronic inflammation, is a possible mechanism that links abdominal obesity to its metabolic consequences

46. Metabolic changes

47. Cognitive dysfunction in menopause Estrogen increase cellular proteins, promote neuronal growth and survival, neural transmission and function, and synaptogenesis The menopausal transition has also been linked to changes in cognitive function CNS (prefrontal cortex, hippocampus and striatum) that control learning, registering and retrieving information, judgment, evaluation processes and language skills.

48. Cognitive changes (cont’d) Limitation of the inflammatory response in the CNS, which helps to avoid repeated inflammatory insults (dystrophy dementia). Aspects related to verbal memory and verbal fluency are most affected Simply a manifestation of depression Consequence of sleep having been disrupted by hot flushes

49. Psychological aspect of menopause Climacteric and menopause exemplify interplay between biological and social factors. Menopausal disorders are not yet recognized as an entity in clinical psychiatry Categorized under psychophysiological disorders group. Symptoms such as anxiety, despair, depression and estrangement.

50. Psychological aspect of menopause cont’d

51. Sociocultural impact Devalued or valued Myths and beliefs New marriages Marital discord

52. Sociocultural impact cont’d Value ; some communities place them on the same level as men and view them as being capable of taking decisions Devalued; setting aside by spouse as reproductive function ends Marital discord as a result of the woman’s belief that she shouldn’t engage in sexual activity Sexual intercourse with menopausal women sap the man’s energy, make them ill and weak Sexual intercourse causes abdominal distention as they believe there is no outlet for ejaculate New marriages by men once the older wives are menopausal

53. SUMMARY OF THE PATHOPHYSIOLOGY OF MENOPAUSE

54. Stages of reproductive aging workshop (STRAW) STRAW -This is Staging of Reproductive Aging Workshop. The STRAW staging system is widely considered the gold standard for characterizing reproductive aging through menopause First postulated in 2001 Revised in 2011 ( STRAW +10) more inclusive

55. Straw (cont’d) Goal provide consistent classification criteria for menopause  clinical and research agendas assessment of fertility, contraceptive needs, and healthcare decision making. To identify knowledge gaps that should be addressed by the research community

56. Straw (cont’d) The STRAW+10 added more criteria using endocrinological parameters such as FSH, AMH, Inhibin B, menstrual cycles, s ymptoms such as vasomotor, urogenital, fertility capability, ovarian imaging including AFC. There are both inclusion and exclusion criteria

57. Straw (cont’d) Exclusion criteria: - Women who had hysterectomy or endometrial ablation. - Women with chronic menstrual irregularity such as PCOS. -Women with chronic illness such as HIV/AIDS. -Women undergoing chemotherapy

58. Straw (cont’d) STRAW divided the female life into 3 broad phases: -Reproductive phase (3) -Menopause transition(2) - Postmenopause (2) The 3 phases contain 7 stages: 3 for the reproductive phase, 2 for the menopausal phase, and 2 for the postmenopausal phase.

59. Straw cont’d

60. CONCLUSION Menopause is a normal life event Knowledge of its physiology is crucial in enlightening our women This could be enough to allay fears in them.

61. THANKS FOR LISTENING

62. MANAGEMENT OF MENOPAUSE A PRESENTATION BY DR. OLANREWAJU PETER FATOKI REGISTRAR REF UNIT 24 TH AUGUST 2022

63. OUTLINE INTRODUCTION CLASSIFIACTION OF MENOPAUSE MANAGEMENT CONCLUSION REFERENCES

64. INTRODUCTION It is said that everything has a beginning and an end, so do physiological cycles It is only normal that females experience Menarche and Menopause and this presentation centers on Menopause Menopause is defined as the last menstrual period after a minimum of 12months amenorrhea. Regardless of if natural or induced, the signs and symptoms are the same . The age of occurrence is genetically predetermined, averagely by 51years but within the range of 45 – 55years. Nigerian and Ghanaian studies put it as 48 – 49.5years ( Kwawukume et al)

65. Classification of Menopause Menopause can be classified based on cause into; Natural Menopause Premature menopause/Early Menopause/POI Induced Menopause

66. Causes of Non Induced Premature menopause/POI S/No Causes Examples 1 GENETIC Turner syndrome (XO 45) or mosaic turner (45X/46XX), Trisomy X (47XXX or Mosaic, FMR1 (fragile X Mental retardation 1) premutation Other chromosomal abnormalities: mutations of FOXL2, NR5A1, BMP15, FSHR and Gs alpha genes and of steroidogenic enzymes 2 METABOLIC Galactose-1-phosphate uridyltransferase deficiency Carbohydrate-deficient glycoprotein deficiency 17 alpha-hydroxylase 17,20 desmolase deficiency mutations of the aromatase gene 3 AUTOIMMUNE Polyglandular autoimmune syndrome, Hypothyroidism, Type1 Diabetes mellitus, Myaesthenia gravis, Systemic lupus erythematosus, Addison’s disease, Thrombocytopenic purpura, vitligo , Alopecia, pernicious anemia or autoimmue anemia, Rheumatoid arthritis, Crohn’s disease, sjogren’s syndrome, Primary biliary cirrhosis 4 INFECTIOUS Viral infections (HIV, Varicella), Tuberculosis, Shigellosis, Malaria 5 OTHERS Women of Chinese race or Hispanic origin

67. Causes of Induced Menopause Bilateral Oophorectomy Bilateral Ovarian cystectomies Chemotherapy: Primarily, alkylating agents and anthracyclines Radiation-external beam or intracavitary Environmental toxins (Tobacco, dioxins) Pelvic vessel embolization

68. General Overview of Management The management of menopause may be multidisciplinary sometimes and it more importantly entails; Taking a detailed history General and physical examinations Investigations Diagnosis Treatment

69. History Must be detailed. The use of a check list is helpful Important notes include Age Race/ethnicity/geographical location occupation Parity Presenting complaints - irregular menses, amenorrhea, hot flushes e.t.c Surgical history - TAH + BSO, Oophorectomy e.t.c Drug history Comorbidities

70. EXAMINATION A thorough examination is of the essence General and physical examination findings will help rule out possible differentials and comorbidities which may be associated with a menopausal state All systems are to be examined

71. INVESTIGATIONS General investigations Specific investigations others FBC/CBC Serum E/U/Cr Urinalysis Hormone profile (FSH, LH, estrogen, progesterone and AMH) Thyroid stimulating hormone 24hour urine calcium/ cr Serum lipids Abdominopelvic USS Electrocardiogram (ECG) Vaginal smears Endometrial/cervical smears

72. DIAGNOSIS The diagnosis of menopause is said to be retrospective Like earlier stated, a detailed history, general and physical examination and investigations help in the conclusion of such diagnosis ruling out all other differentials and comorbidities Once the diagnosis is made it informs treatment decisions/options

73. TREATMENT Following proper counselling, treatment options are: Counselling Non Pharmacological Pharmacological Hormonal Non-Hormonal

74. TREATMENT CONT’D T he first aspect of treatment is COUNSELLING. A vital process in the management of menopause It helps resolve some concerns of menopausal women without resorting to medications Requires patience , care, empathy and proper communication The focus is to educate the patient on the physiologic process, clarify doubts and myths P atient must be given the opportunity to enumerate what she has learnt in her own words C onsider the possibility of multiple visits.

75. Non-Pharmacological Lifestyle: Exposure to sunlight, smoking caesation , reduce alcohol and caffeine intake, increase number baths, wear light clothes, no weight-bearing, Exercise ; Brisk walking and jogging Dietary: F ortified diets (with calcium, vitamin D3 and protein), fruits, vegetables, proper daily hydration Soy protein: they are helpful in relieving vasomotor symptoms Flouride : used in conjunction with calcium supplements. (When used long term can lead to brittle bones)

76. Hormonal treatment/MENOPAUSAL HORMONE THERAPY (MHT) This refers refers to Menopausal Hormone T herapy (MHT) formerly HRT It refers to the use of estrogen or combination estrogen/progesterone treatment and androgens. For women who seek help for their menopausal symptoms, MHT is the most commonly prescribed treatment It helps to relieve symptoms by replacing estrogen levels that naturally fall during menopause It could be administered as tablets, skin patches or skin gels Patients are duly educated on the risks and benefits of MHT prior to commencement

77. Indications for MHT Women having climateric symptoms All asymptomatic high-risk women having Premature menopuse (surgical/spontaneous) Established osteoporosis on X-ray/B.M.D measurements Family history of osteoporosis Thin, small sedentary women Poor diet, excess alcohol, Corticosteroid and other medications High urinary calcium/creatinine, Low plasma estradiol Asymptomatic women with/without risk factors having no contraindications but who request MHT

78. Estrogen (MHT) T he minimum effective dose should be used and could be increased when required Despite this general consensus, it is important that the dose is high enough to fully alleviate symptoms. Higher doses of exogenous estrogen are associated with increased risk of breast cancer, VTE and stroke. D ose and route of administration of estradiol is tailored to the requirements of the woman to optimize benefits and minimize side effects and risks

79. Estrogen (MHT ) cont’d The starting doses of currently available systemic estrogen are as follows; 0.3mg oral conjugated equine estrogen 1mg oral micronized estradiol or estradiol valerate 25 -50ug transdermal estradiol Two metered doses of estradiol gel or 0.5-1.0mg estradiol sachets 25 – 50ug implanted estradiol (currently unlicensed for commercial use)

80. MHT – Estrogen CONt’D Prior to menopause, the estradiol/estrone ratio was 2:1 and this can be achieved if estradiol is delivered transdermally, by avoiding first-pass effect Oral estradiol preparations are partially metabolized to estrone by hepatic first-pass effect and so do not fully restore this ratio Sublingual tabs/wafer, nasal sprays are in the works. These provide room for improved bio-availability

81. VAGINAL ESTROGEN The most effective treatment for vulvovaginal atrophy (VVA) is local application of estrogen but the benefits only last whilst the preparations are used This is achievable through creams, tablets, rings delivering estriol and estradiol There is no significatnt systemic absorption of oestrogen from these formulations, therefore do not lead to endometrial hyperplasia or bleeding problems Hence endometrial protection with progestogens is not required

82. Vaginal estrogen cont’d VVA symptoms can be very distressing but are easily and safely alleviated with vaginal estrogen There is a license of 10ug of estradiol vaginal tablets which gives relief to urogenital symptoms. A year of exposure equates to 1.4mg of estradiol in total Some women require higher doses to fully alleviate their symptoms. This is indicated in the NICE guidelines but must be used judiciously

83. VAGINAL ESTROGEN (MHT) CONT’D Local vaginal estrogen options are; 0.01% estriol cream and pessaries 0.1% estriol cream 10ug per 24hours estradiol vaginal tablets 75ug per 24 hours estradiol-releasing silicone ring

84. New options for treatment of VVA Ospemifene it is a new option for treating VVA It is a Selective Estrogen Receptor Modulator that has estrogen-type activity in the urogenital tract Used for treatment of moderate to severe dysparunia For women who have a history of hormone receptor-positive malignancy whose menopause symptoms are often complicated by use of tamoxifen or aromatase inhibitors, the avoidance of estrogen may be of advantage in

85. CO2 laser & Erbium laser technology It is being used to rejuvenate atrophic vulval and vaginal tissue Done by facilitating the regeneration of collagen and eslatin through improved blood flow Still a work in progress

86. Progestogens – MHT cont’d This is required in women using systemic estrogen to minimize the risk of endometrial hyperplasia and carcinoma If the last menstrual period occurred less than 1year prior t o starting HRT, sequential combined regimen is recommended. ( i.e estrogen with progesterone for 12days per cycle) A progesterone challenge is required after 3months of estrogen alone in women who have had subtotal hysterectomy to check for residual endometrial tissue. An USS could be used Low dose progesterone is also used after endometrial ablation and pelvic radiotherapy. It’s considered for women following hysterectomy for severe endometriosis

87. Progestogens – MHT cont’d Generation Progestin Estrogenic Progestational Androgenic First Norethindrone Ethynodiol diacetate Norgestrel Norethindrone acetate ++ ++ - ++ ++ +++ +++ ++ ++ + +++ ++ Second Levonogestrel - ++++ ++++ Third Norgestimate Desogestrel - +/- ++ ++++ ++ ++ Fourth Drospirenone - +/- -

88. Minimum doses of progesterone given orally in mhT as endometrial protection Progestogen type Sequential combined daily dosage Continuous combined daily dosage Testosterone-derived progestogens Levonorgestrel 75ug N/A Levonorgestrel intrauterine system N/A 20ug Norgestrel 150ug 50ug Norethisterone 5mg 0,1mg Progesterone-derived progesterons Crpterone 2mg 1mg Medroxyprogesterone acetate 5mg 2.5mg Micronized progesterone 200mg 100mg Cyclogest pessaries 400mg 200mg Crinone gel (8%) Alternate days/12days/cycle Twice weekly Spirinolactone -derived progestogens Drospirenone N/A 2mg

89. Progestogenic side effects The main factor for reduced compliance is that of progesterone intolerance Progestogens have numerous effects different from the one for which their use was intended Fluid retention - sodium retaining effect of the RAS triggered by stimulation of aldosterone 1 receptor Androgenic - Acne and hirsutism from testosterone-derived progestogen, stimulation of androgen receptors Mood swings - from stimulations of the CNS progesterone receptors PMS-like effect - from stimulation of CNS progesterone receptors

90. Progestogenic side effects – cont’d Minimizing the progestogen side effects is possible D ose can be halved and duration of progestogen use reduced to 7 -10days Natural progestogens can be used; have fewer side effects due to receptor specificity. MHT regimens with natural progesterone minimize metabolic impact and reduce risk of VTE LIUS; recommended for endometrial protection for up to 5years, minimizes systemic side effects by direct release of progesterone to the endometrium Drosperidone, a spironolactone analogue, also contains low dose estrogen. It is progesterone receptor specific and has anti-androgenic and anti-aldosterone effects.

91. Bio-identical MHT Estradiol, progesterone and testosterone exist in precise duplicates as synthesized by the human ovaries These are bio-identical hormones Manufactured from plant sources available in micronized oral tablets, transdermal patches, implants, gels

92. MHT CONT’d - Androgens Women with low sexual desire and tiredness should be counselled about the possibility of using androgen supplementation Trostan 2% gel, a testosterone male gel can be use on alternate days to achieve physiological levels 1% testosterone cream ( AndroFeme ) can also be used

93. MHT CONT’D - androgens In the administration of testosterone, the free androgen index should be kept within the physiological range (<5.0%). At this state there is rarely any side effects DHEA-S which is the sulfated form of DHEA which can be converted by tissues in the body is used to tackle the problems of ageing and has shown benefits on the skeleton, cognition, well-being, libido and the vagina

94. MHT CONT’D

95. Benefit –Risk Balance of MHT Coronary heart disease and overall mortality The Women Health Initiative (WHI) study earlier claimed that there was an increase risk in CVD, stroke, breast CA in women regardless of the age group Study was criticized due its design and age of subjects recruited for the study (63years) and many with obesity, hypertension and ore-existing CVD

96. Benefit –Risk Balance of MHT cont’d The recent evidence supports the fact that estrogen therapy may be cardioprotective if commenced around the window of opportunity( time of menopause) and may be harmful if commenced 10years after menopause A 13year follow up of women in the WHI study, with ages between 50 -59years showed reduction in CHD and MI Cochrane analysis shows that women within 10years of menopause had a reduction in all-cause mortality of 0.70 and cardiovascular mortality of 0.52

97. Benefit –Risk Balance of MHT cont’d Stroke The Incidence may be increased when HRT is initiated in women over 60years From the WHI study and cochrane analysis, Initiation of HRT in women less than 60years of age or less than 10years menopause has no effect on the risk of stroke The risk of ischaemic stroke with HRT is related only to standard-dose oral therapy, Low-dose transdermal therapy has a very low risk of ischaemic stroke

98. Venous thromboembolism (VTE) During the first year of estrogen use, with or without progestogen, the incidence of VTE is higher Initiation of hormone therapy in older women and continued use of such therapy is associated with an increased risk compared to non-users According to the WHI study there is a slightly higher risk of VTE in women aged 50 – 59years who used estrogen—progestogen than those who use just estrogen, though both are far less than the risk of VTE in normal pregnancy Transdermal estrogen does not increase the risk of VTE

99. Benefit –Risk Balance of MHT cont’d Cognitive function and dementia If HRT is commenced post onset of dementia, it doesn’t improve cognition or slow down disease HRT commenced after midlife increases the risk of dementia HRT commenced during midlife reduces the risk of dementia and Alzheimer's disease (some form of prevention when commenced during the window of opportunity)

100. Benefit –Risk Balance of MHT cont’d Breast Cancer The relationship between breast cancer and HRT is still very debatable The WHI estrogen and progestogen trial and several observational studies have reported an increased risk after at least 5years of use, suggesting a possible promoter effect on tumours a meta-analysis of data by the NICE guideline group says the degree for estrogen and progestogen combined was an extra 5 per 1000 women over 7.5year period HRT using estrogen alone has a neutral impact on breast cancer risk according to most studies and a possible reduction in risk

101. Benefit –Risk Balance of MHT cont’d Ovarian Cancer There are controversies as to whether HRT increases the risk of ovarian cancer A meta analysis of data from 52 studies involving women age 50 – 54years; The absolute risk was 1 per 1000women per year of use A base rate of 1.2 per 1000 per 5years Absolute excess of 0.55 per 1000 per 5years Further good quality data still needed for definitive statements.

102. Benefit –Risk Balance of MHT cont’d Osteoporosis MHT decreases the incidence of all fractures, even in women with high risk of fractures It is the only therapy available with proven efficacy of fracture reduction in women with osteopenia Age at initiation of MHT is key for its efficacy W omen 50 – 60years or within 10years after menopause, the benefits of MHT outweighs risk and can be considered as first line therapy For those over 60years, bisphosphonates should be considered. If MHT is to be considered, then the minimum effective dose should be used with estrogen delivered transdermally

103. Contraindications to HRT Women with active Cardiovascular Disease , active liver disease Women with recent Stroke Women with Venous thromboembolism (though transdermal route may be considered) Women with known or suspected estrogen-sensitive malignant conditions Recent or active Arterial thromboembolic disease (angina, myocardial infarction) Porphyria cutanea tarda Undiagnosed genital bleeding

104. Pharmacological (Non-Hormonal Treatment) Selective estrogen receptor modulators (SERM): improve bone mineral density and reduce the risk of endometrial and breast cancers. they increase the risk of VTE Clonidine: centrally acting alpha-2 agonist, indicated for hot flushes Gabapentin: decreases hot flushes but may cause sedation Thiazides: reduces calcium secretion from the kidneys

105. Pharmacological (Non-Hormonal Treatment) Tibolone : synthetic steroid with estrogenic, progestogenic and androgenic properties. Improves sexual function/libido Vitamin E suppository: Indicated for vaginal atrophy Bisphosphonates : Risendonate , etidronate . Used for postmenopausal osteoporosis. Not useful as single therapy Phytoestrogens: lower the incidence of vasomotor symptoms, osteoporosis and cardiovascular diseases

106. Conclusion A good knowledge of Menopause and its associated challenges is of utmost importance. Every woman deserves complete physical, mental, social wellbeing even at this phase of life. Improving our skill in the care of these women will do well to improve their life expectancy

107. References D. Keith Edmonds MB, Christoph Lees MD, Tom Bourne PhD, 2018, Dewhurst’s Textbook of Obstetrics & Gynaecology , 9 th Edition, Blackwell Publishing Ltd (8e, 2012), Wiley Blackwell E Y Kwawukume , B A Ekele , K A Danso , E E Emuveyan , 2017, Comprehensive gynaecology in the tropics, 2 nd Edition, G-Pak Ltd National Institute for Health and Care Excellence, 2015, Information for the public, Published 12 November, 2015 Alan H. Decherney I Lauren Nathan, Neri Laufer I Ashley S. Roman, CURRENT Diagnosis & Treatment; Obstetrics and Gynaecology UPDATE COURSES www.nice.org.uk