Menopause

1. By Dr Ufaque Batool Korai

2. MENOPAUSE The permanent cessation of menstruation that result from loss of ovarian follicular activity . Natural menopause is recognized to have occurred after 12 consecutive months of amenorrhea for which no other obvious pathological & physiological cause present. Menopause occurs with the final menstrual period only known with certainty 1 year after the event. No adequate biological markers exists. Women in the UK have their menopause between the ages of 45 and 55 years.

3. P remenopause It is refer to 1 to 2 years immediately before the menopause or to the whole of reproductive period , before the menopause. Currently this term is recommended to be used in the latter sense , e ncompassing the entire reproductive period from menarche to final menstrual period.

4. PERIMENOPAUSE is the phase surrounding the menopause . It is the time period from when the ovaries start to fail (and symptoms such as irregular periods or hot flushes may begin) until 12 months after the last menstrual period.

5. POST MENOPAUSE   s the time after the complete cessation of menstruation. It can only be known with certainty after 12 months of amenorrhoea .

6. PREMATURE OVARIAN INSUFFICIENCY Menstruation cessation before the age of 40 years  4 months of amenorrhoea and 2 FSH>=30 iu /ml at an interval of at least 1 month before the age of 40 years . The term premature ovarian failure suggests that the state of ovarian failure is irreversible , which is not strictly true . The ovarian follicular function fluctuates in about 50% of women with POF and 5–10% of women with the diagnosis may eventually conceive .

7. Causes of premature ovarian failure Primary Chromosome abnormalities FSH receptor gene polymorphism and inhibin B mutation Enzyme deficiencies Autoimmune disease Secondary Chemotherapy & Radiotherapy Bilateral oophorectomy , or surgical menopause Hysterectomy without oophorectomy Infection

8. PREVALENCE . The average age of menopause in the UK is 51 . However , this varies widely and 1 in 100 women experience premature ovarian insufficiency (menopause occurring before the age of 40 years ). Most women (8 out of 10) experience some symptoms, typically lasting about 4 years after the last period , but continuing for up to 12 years in about 10% of women

9. Physiology Menstrual cycle and hormone patterns begin to change many years prior to menopause. The following schematic shows the physiology of the menopause:

10. Physiology continues….. The number of primary ovarian follicles decreases markedly after the age of 40. This results in a decrease in serum estradiol (E2) levels and a decline in the secretion of inhibin B (a glycoprotein synthesized by granulosa cells in the ovary). FSH normally stimulates inhibin B synthesis, which then suppresses FSH via a negative feedback loop. After about age 45, however, inhibin B levels fall, perhaps due to the decreased number of ovarian follicles, causing a rise in FS Conti……..

11. The increased FSH levels stimulate increased estradiol release from the remaining follicles, and also prompt them to release the estradiol more rapidly, resulting in shorter cycles. About six to twelve months before menopause, the number of follicles is even lower, and higher FSH levels fail to increase estradiol production. At this point, the reduced estradiol levels can result in menopause-related symptoms. Conti……

12. During perimenopause , estrogen production by the ovary is erratic and estradiol levels fluctuate between normal, high, and low. Therefore, clinical history is more reliable than measurement of FSH and estradiol for diagnoses of perimenopause . Without a follicular source, the larger proportion of postmenopausal estrogen is derived from ovarian stromal and adrenal secretion of androstenedione , which is aromatised to estrone (E1) in the peripheral tissues (fat). E1 is biologically less active than E2. Testosterone levels also decrease with menopause but this decrease is not as marked as the decline in E2. Conti……

13. CLINICAL MANIFESTATION This section of the tutorial covers: acute  manifestations of menopause medium term  symptoms long term  implications.

14. SIGNS & SYMPTOMS This can last from a few months to several years and between three in ten and six in ten women (30% to 60%) experience physical and/or emotional symptoms during this time. The main symptoms include : • hot flushes and night sweats (the most common symptoms ) • vaginal dryness • tiredness and sleep disturbance • mood swings • forgetfulness or lack of concentration • loss of interest in having sex.

15. UROGENITAL ATROPHY Thinning and shrinking of the tissues of the vulva, vagina, urethra and bladder caused by oestrogen deficiency . This results in multiple symptoms such as vaginal dryness, vaginal irritation , a frequent need to urinate and urinary tract infections.

16. Vasomotor Symptoms Menopausal symptoms such as hot flushes and night sweats caused by constriction and dilatation of blood vessels in the skin that can lead to a sudden increase in blood flow to allow heat loss. These symptoms can have a major impact on activities of daily living .

17. Menopause diagnosis The average age of menopause is 51 years. Premature ovarian failure (also known as premature ovarian insufficiency) is diagnosed when menopause occurs before 40yrs of age. Menopause is diagnosed retrospectively when the last menstrual period has occurred 1 year earlier . Elevated FSH/LSH level predict the menopause. The climacteric defines the period (most symptomatic) around the menopause transition

18. DIAGNOSIS OF PERIMENOPAUSE AND MENOPAUSE 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.

19. Do not use the following laboratory and imaging tests to diagnose the perimenopause or menopause in women aged over 45 years: anti- Müllerian hormone inhibin A inhibin B Oestradiol Antral follicle count Ovarian volume

20. Do not use a serum follicle-stimulating hormone (FSH) test to diagnose menopause in women using combined oestrogen and progestogen C ontraception or high-dose progestogen. 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 suspected

21. Diagnosing premature ovarian insufficiency Diagnose premature ovarian insufficiency in women aged under 40 years based on : menopausal symptoms, including no or infrequent periods (taking into account whether the woman has a uterus) and elevated FSH levels on 2 blood samples taken 4–6 weeks apart .

22. Do not diagnose premature ovarian insufficiency on the basis of a single blood test . Do not routinely use anti- Müllerian hormone testing to diagnose premature ovarian insufficiency . If there is doubt about the diagnosis of premature ovarian insufficiency , refer the woman to a specialist with expertise in menopause or reproductive medicine .

23. hormonal contraceptive and continuing treatment until at least the age of naturalmenopause (unless contraindicated) that the baseline population risk of diseases such as breast cancer and cardiovas disease increases with age and is very low in women aged under 40 that HRT may have a beneficial effect on blood pressure when compared with acombined oral contraceptive that both HRT and combined oral contraceptives offer bone protection that HRT is not a contraceptive.

24. INFORMATION & ADVICE Give information to menopausal women and their family members or carers (as appropriate) that includes: an explanation of the stages of menopause common symptoms and diagnosis lifestyle changes and interventions that could help general health and wellbeing benefits and risks of treatments for menopausal symptoms long-term health implications of menopause.

25. What is HRT…??? HRT is a medical treatment for the menopause . It provides low doses of the hormone estrogen and sometimes other hormones (progestogens and testosterone ) which your body is no longer producing. HRT is available as tablets, skin-patches, gels or nasal spray . A cream, pessary , or vaginal ring containing estrogen can also be used to ease symptoms in the vaginal area.

26. Management Treatment should be targeted to individual women's needs Types of HRT Routes Benefits Risk Uncertainities CVS Dimentia Ovarian cancer Quality of life

27. Types of HRT

28. ROUTES of HRT Oral: usually first choice cost-effective acceptable beneficial effect on HDL-C, LDL-C, and total cholesterol high doses required variation in absorption all tablets contain lactose affects liver protein synthesis (increase in triglycerides).

29. Transdermal (Patch, gel, nasal spray) A voids gut and liver breakdown; so lower dose is required Generally more expensive Avoids bolus first-pass effect on the liver (less adverse effect on gallbladder disease and coagulation factors) Produces more physiological hormone levels than oral therapy Patch adhesive sensitivity/residue.

30. topical very little reaches systemic circulation and therefore avoids adverse systemic effects. Intrauterine system ( Mirena coil) for urogenital symptoms   licensed in the UK for delivering the progestogen part of HRT useful for persistent progestogenic side effects from systemic HRT useful when contraception is required along with HRT in the perimenopause useful when withdrawal bleeds on sequential HRT are heavy, after investigation if indicated.

31. Indication for non oral route patient preference poor symptom control with oral treatment side effects, e.g. nausea, with oral treatment history of migraine (when steadier hormone levels may be beneficial) risk of stroke , venous thromboembolism (when HRT should only be considered after full discussion and appropriate investigation) hypertriglyceridaemia current hepatic enzyme inducing agent, e.g. anticonvulsant therapy history of gallstones bowel disorder that may affect absorption of oral therapy lactose sensitivity.

32. Benefits of HRT Vasomotor symptoms Estrogen is the most effective treatment for hot flushes. Improvement is usually noted within four weeks.  For all women, the lowest effective dose should be used for the shortest time. Mood or sleep disturbances HRT will often improve sleep by alleviating night sweats. It is not known whether HRT has a direct effect on mood, irritability, or anxiety, or whether these effects are due solely to the alleviation of hot flushes and sleep disturbances. HRT should not be used as monotherapy for depression. HRT is most likely to be useful if there are other menopausal symptoms   present

33. Urogenital symptoms Symptoms of urogenital atrophy such as vaginal dryness, soreness, superficial dyspareunia, and urinary frequency and urgency respond well to estrogens, which may be given either topically or systemically. Maximal benefit of HRT takes between one and three months of therapy, but may take up to one year of treatment. Symptoms can recur on cessation of therapy. Osteoporosis Evidence from randomised controlled trials (including  WHI ) show that HRT reduces the risk of spine and hip as well as other osteoporotic fractures. HRT is currently not recommended as a first line treatment for osteoporosis prevention. conti …….

34. . While alternatives to HRT use are available for the prevention and treatment of osteoporosis in elderly women, estrogen may still remain the best option, particularly in younger and/or symptomatic women. It is cheaper than other alternatives such as bisphosphonates. Unlike for HRT, there are no data suggesting that bisphosphonates reduce fracture risk in women with normal bone density . Colorectal cancer Results from the estrogen progestogen arm of the  WHI study  show that HRT reduces the risk of colorectal cancer by about one third.  There is no information about HRT in high risk populations, and current data do not allow prevention as a recommendation.

35. RISKS OF HRT

36. Breast cancer HRT with oestrogen alone is associated with little or no change in the risk of breast cancer HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer. Any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT .

37. Cardiovascular Disease Ensure that menopausal women and healthcare professionals involved in their care understand that HRT : does not increase cardiovascular disease risk when started in women aged under 60 years does not affect the risk of dying from cardiovascular disease . Be aware that the presence of cardiovascular risk factors is not a contraindication to HRT as long as they are optimally managed.

38. Osteoporosis HRT with oestrogen alone is associated with little or no change in the risk of breast cancer HRT with oestrogen and progestogen can be associated with an increase in the risk of breast cancer Any increase in the risk of breast cancer is related to treatment duration and reduces after stopping HRT .

39. Type 2 diabetes Explain to women that taking HRT (either orally or transdermally ) is not associated with an increased risk of developing type 2 diabetes. Ensure that women with type 2 diabetes and all healthcare professionals involved in their care are aware that HRT is not generally associated with an adverse effect on blood glucose control. Consider HRT for menopausal symptoms in women with type 2 diabetes after taking comorbidities into account and seeking specialist advice if needed .

40. Dementia Explain to menopausal women that the likelihood of HRT affecting their risk of dementia is unknown .

41. ENDOMETRIAL CANCER Unopposed estrogen therapy increases the risk of endometrial cancer in women with a uterus. Adding a progestogen to estrogen therapy (combined HRT) for at least 12 days per month greatly reduces this risk. Endometrial cancer risk is not completely eliminated with monthly sequential progestogen addition, especially when continued for more than five years and also with long cycle HRT . No increased risk of endometrial cancer has been found with continuous combined regimens. Tibolone has also been reported to increase the risk of endometrial cancer ( MWS ).

42. Venous thromboembolism Oral HRT has been associated with an increased risk of venous thromboembolism (VTE) (i.e., deep vein thrombosis or pulmonary embolism) in the first year of use. The level of risk may be lower with transdermal HRT even in women with predisposing factors. The risk is higher with combined HRT than with estrogen-only HRT. Limited data do not suggest an increased risk of thromboembolism with tibolone compared with combined HRT or women not taking HRT .

43. Gallbladder Disease HRT increases the risk of gallbladder disease; the risk might be lower with transdermal preparations. Gallbladder disease increases with ageing and with obesity.

44. Assessment prior to start HRT 1) Assess menopausal state and symptoms Stage of menopause (peri-, postmenopausal) Time of the last menstrual period Bleeding pattern Presence or absence of acute menopausal symptoms

45. 2) Current contraception – if the woman requires contraception Continue contraception for one year after the last menstrual period in women over 50 years old, or for two years in women under 50 years old Women taking HRT should use barrier methods, an intra-uterine device, or the levonorgestrel-releasing intra-uterine system (IUS) Women taking combined oral contraception do not need to have HRT added

46. 3) Check for contraindications Hormone-dependent malignancy (e.g. endometrial cancer, current or past breast cancer) Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction or stroke) Venous thromboembolic disease Current pregnancy Severe active liver or renal disease Uninvestigated abnormal vaginal bleeding Acute intermittent porphyria 4) Ask about family history of... Cardiovascular disease Osteoporosis Venous thromboembolism

47. 5) Check risk factors for coronary heart disease Hypertension, diabetes mellitus A family history of premature myocardial infarction or stroke Cigarette smoking, sedentary lifestyle, and obesity 6) Check risk factors for osteoporosis 7) What does the patient want? Does she want to take HRT? If not, what alternatives would she prefer? 8) Discuss healthy lifestyle options to prevent osteoporosis and cardiovascular disease

48. Follow up of a woman taking HRT   The recommended follow up schedule for HRT is: three months six months yearly – BP, breast examination, vaginal examination (three-yearly smears and three-yearly mammography aged 50–64 ).

49. Management of side effects with HRT Adverse effects account for almost 35% of HRT discontinuations. Women should be encouraged to persist with HRT for at least three months, as most adverse effects resolve with increased duration of use.

50. Bleeding as a side effect of HRT Nearly 50% of previous HRT users discontinue treatment because of bleeding problems. Unpredictable or unacceptable bleeding may be due to non-adherence to therapy, drug interactions, or gastrointestinal upset (or malignancy if not already excluded). Endometrial assessment is required if: for sequential regimens it is heavy or prolonged at the end of or after the progestogen phase, or occurs at any time (breakthrough bleeding) for continuous combined regimens if it occurs after the first six months of treatment (irregular breakthrough bleeding or spotting is common in the first 3–6 months), or it occurs after amenorrhoea .

51. Estrogen-related adverse effects Estrogen-related adverse effects tend to occur continuously or randomly through the cycle. They include fluid retention (more likely due to the progestin component), bloating, breast tenderness/enlargement, nausea, dyspepsia, headaches and leg cramps: leg cramps can improve with lifestyle changes, including exercise and regular stretching of the calf muscles nausea/gastric upset may be helped by taking with food or switching to transdermal preparations migraine triggered by fluctuating estrogen levels may respond to transdermal therapy as this produces more stable estrogen levels.

52. Progestogen -related adverse effects of HRT Progestogen -related adverse effects tend to occur in a cyclical pattern during the progestogen phase of cyclical HRT. The effects include fluid retention, breast tenderness, headaches/migraine, mood swings, depression, acne, lower abdominal pain, and backache. For persistent symptoms the following options can be considered: reduce the duration  – swapping from a 14-day to a 12-day product may provide benefit reduce the dosage  – but not below the recommended levels for endometrial protection change the type  – e.g.  from more androgenic ones to less androgenic ones change the route  – e.g. from oral to transdermal or intra-uterine progestogen change to continuous combined therapy  – as these products contain lower dosages of progestogen , but this option is only suitable for postmenopausal women. Fluid retention and headache may be related to either estrogen or progestin; modifying the progestogen first is usually the better strategy. Breast tenderness is more likely to be alleviated with lower estrogen dosages, although adjusting the progestogen may occasionally be effective if the symptoms seem to have a cyclic quality.

53. All women should be reviewed annually as the risks and benefits of HRT will alter with time. Women who choose to take HRT for more than five years should be counselled about the long term risks. Many women do not notice any symptoms even with abrupt cessation of HRT, while others will have recurrent vasomotor symptoms. However, there is insufficient evidence to support the assumption that tapering hormone therapy lowers the risk of recurrent symptoms. conti ……

54. If symptoms are severe after HRT is stopped, or persist for several months after stopping, the woman may wish to restart HRT after reassessment and counselling . Often a lower dose of HRT can be used (e.g. estradiol 1 mg) if HRT is restarted. The implications of stopping HRT, besides recurrence of menopausal symptoms, include resumption of bone loss. Therefore, risk factors for osteoporosis should be assessed and alternatives for preventing or treating osteoporosis (including diet and lifestyle advice) should be discussed at this time.

55. Stopping HRT   All women should be reviewed annually as the risks and benefits of HRT will alter with time. Women who choose to take HRT for more than five years should be counselled about the long term risks. Many women do not notice any symptoms even with abrupt cessation of HRT, while others will have recurrent vasomotor symptoms. However, there is insufficient evidence to support the assumption that tapering hormone therapy lowers the risk of recurrent symptoms . Conti…..

56. If symptoms are severe after HRT is stopped, or persist for several months after stopping, the woman may wish to restart HRT after reassessment and counselling . Often a lower dose of HRT can be used (e.g. estradiol 1 mg) if HRT is restarted. The implications of stopping HRT, besides recurrence of menopausal symptoms, include resumption of bone loss. Therefore, risk factors for osteoporosis should be assessed and alternatives for preventing or treating osteoporosis (including diet and lifestyle advice) should be discussed at this time.

57. What are alternatives to HRT..??? The alternatives to HRT can be broadly classified as: • Herbal medicine – a practice based on the use of plants or plant extracts to relieve symptoms – for example, evening primrose oil or St John’s Wort . • Alternative medicine – a range of therapies used instead of conventional medicine, such as acupressure, acupuncture and homeopathy . • Complementary therapy – interventions which tend to be used alongside conventional medicine, for example, aromatherapy with HRT . • Medical treatments – prescribed by your doctor, such as antidepressants.

58. Are these alternatives safe and do they work? Overall, the evidence shows that the alternatives to HRT discussed in this document are much less effective at easing the symptoms of the menopause compared with HRT. The best ones can reduce the severity of symptoms by 50% to 60%, compared with a reduction of 80% to 90% with HRT.

59. . Treatments that work and are safe There is evidence that the treatments below work and are safe: Lifestyle choices Regular aerobic exercise such as running and swimming . You should avoid infrequent, high-impact exercise as this may make your symptoms worse . Low-intensity exercise such as yoga may help hot flushes and general wellbeing . Reducing your intake of caffeine/caffeinated drinks and alcohol can help to reduce hot flushes and night sweats . Vaginal lubricants and moisturisers replace vaginal secretions and can help with vaginal dryness . St John’s Wort appears to be effective in treating depression during the menopause but it can interfere with other medications so it is important to speak with your GP before taking it. It has not been proven to help with hot flushes.

60. . Why would I choose an alternative to HRT? Not every woman chooses HRT for the menopause . For you, this may be because : • Your GP has advised you not to take HRT because of your own, or your family’s, medical history of (for example) breast cancer or deep venous thrombosis (blood clot in a deep vein ). • You want a treatment that works especially well for one particular symptom that you have . • You have concerns about the safety and side effects of HRT and believe that other treatments are safer . • You would prefer a non-medical treatment.

61. Treatments where more evidence is needed to know if they work and are safe More evidence is needed to know if the treatments below work, what the side effects may be and whether there are long-term risks. If there are safety concerns about a specific treatment

62. Non-prescribed treatments Acupuncture Black cohosh Chasteberry ( agnus castus ), selenium, vitamin C and herbs such as ginkgo biloba , hops, sage leaf, liquorice and valerian root Dehydroepiandrosterone (DHEA ) Homeopathy Magnetism in the form of bracelets/insoles

63. Phytoestrogens are plant substances that have similar effects to estrogen and are found in the following: foods such as soya beans, chickpeas, beans and peas. phytoestrogen supplements Soy products Red clover ( trifolium pratense ) Progesterone skin creams studies of whether these help with hot flushes and night sweats are conflicting and more studies are needed. Reflexology

64. Treatment prescribed by a DOCTOR NON-HORMONAL Antidepressants such as fluoxetine, paroxetine, citalopram and venlafaxine have been used to treat hot flushes and night sweats. More studies are needed to see whether they work since many of the studies only lasted a few weeks. However, venlafaxine appeared to have the most benefit. Antidepressants can cause nausea and other side effects. • Clonidine may help for hot flushes but the number of studies is small. Clonidine patches may be more effective than the tablets. Gabapentin, an anti-epileptic medication, appears to help hot flushes but may cause tiredness and other side effects. More studies are needed to confirm it helps and that it is safe.

65. Managing premature ovarian insufficiency Offer sex steroid replacement with a choice of HRT or a combined hormonal contraceptive to women with premature ovarian insufficiency , unless contraindicated (for example, in women with hormone-sensitive cancer ). Explain to women with premature ovarian insufficiency: the importance of starting hormonal treatment either with HRT or a combined that HRT may have a beneficial effect on blood pressure when compared with acombined oral contraceptive that both HRT and combined oral contraceptives offer bone protection that HRT is not a contraceptive . Continue…………

66. Give women with premature ovarian insufficiency and contraindications to hormonal treatments advice, including on bone and cardiovascular health, and symptom management Consider referring women with premature ovarian insufficiency to healthcare professionals who have the relevant experience to help them manage all aspects of physical and psychosocial health related to their condition.