1 GYNE 1 - Menopause

Gynecology 1.1

MENOPAUSE and CARE OF THE MATURE WOMAN OUTLINE I. Menopause II. Pathophysiology of Menopause a. Reproductive Aging begins in utero b. Estrogen target tissues c. Accelerated disappearance of ovarian follicles begins at age 37.5 years d. Decline in number of oocytes from birth to menopause e. Perimenopausal transition f. Biological mechanisms III. Why should we be concerned with menopause? a. Consequences of estrogen deficiency b. Multiple, serious conflicting health needs c. Female life expectancy and onset of menopause d. Options in management of menopause e. Brief History of Hormone therapy f. Benefits of hormone replacement: magic bullets? g. FDA-approved indications of HRT IV. Management of Menopausal Symptoms a. Proportion of Women who experienced individual symptoms b. Vasomotor Symptoms c. Urogenital Atrophy d. Bone Loss 1. Bone Density and Bone loss in Early Menopause 2. Fracture Rates in Women after age 50 3. Calcium Supplementation 4. Postmenopausal Osteoporosis e. HRT and the Risk of Breast Cancer 1. GLOBOCAN 2000: Comparison of breast cancer incidence and mortality 2. Absolute Risk of Breast Cancer in the general population 3. Biological course of breast cancer 4. Risk factors for breast cancer f. Skin 1. Early intervention with estrogen prevents collagen loss 2. HRT maintains skin thickness in postmenopausal women 3. HRT improved Skin Parameters V. Identifying the Ideal Patient for HRT a. Early initiation of HRT: Benefits b. Principles governing current use of HRT c. Dose recommendations d. Route of Administration e. Transdermal Estrogen Preferable for women with metabolic syndrome f. Progestogen g. Duration of HRT use h. Monitoring HRT

Dra. Vera November 6, 2014

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Depletion of ovarian follicles render the ovary unresponsive to pituitary hormones, FSH and LH3 o Production of ovarian estrogen and progesterone cease3 Ovarian follicles which carries the egg is already active in utero at about 6-8 weeks2 After 6-8 weeks in utero, ovarian differentiation begins with rapid mitotic multiplication of the germ cells2 At 16-20 weeks, the maximal number of oocytes is about 6-7 million. From this point, the store of oocytes will irretrievably decrease, until finally will be depleted in some 50 years later. Average age of menopause is 51 years old2 o Age at menopause appears to be genetically determined, and is unaffected by race, socioeconomic status, age at menarche, or number of prior ovulations3 Early premature ovarian failure or early menopause can occur2 o Menopause before 40 years old, occurs in 1% of women3 o May be idiopathic or associated with toxic exposure, chromosomal abnormality, autoimmune disorder3  Toxic factors to the ovary such as smoking, chemotherapy, pelvic radiation  Common among women who had ovarian surgery, hysterectomy despite retention of ovaries Perimenopausal age starts at about 35 years of age2 Have your children early! Women can never replace the lost eggs from apoptosis and ovulation, whereas for the males the production of sperms is every 3 months2

REFERENCES 1. 2. 3.

Lecture Powerpoint Lecture Recording Berek and Novak’s Gynecology, Chapter 32, Menopause (italicized)

NOTE: Information that are underlined and bold, are important as consulted and may be possible exam questions, please remember these.

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MENOPAUSE The permanent cessation of menstruation, occuring at a mean age of 51 years old. Age of menopause has been constant despite a great increase in life expectancy in women3 After menopause, ovaries stop producing significant amounts of estrogen, therefore symptoms related to estrogen deficiency become important3 There are many conficting issues in regard to care of the woman of the menopause age2 End of the reproductive life of a woman2 Before you see the last menstrual or trickling of blood flow, which in a span of one year does not come back2

PATHOPHYSIOLOGY OF MENOPAUSE REPRODUCTIVE AGING BEGINS IN UTERO AND ENDS AT MENOPAUSE  Menopause is the reproductive aging. o It equates with the ability of ovaries to produce estrogen and progesterone which are the steroid hormones of your ovary2  Due to primary ovarian failure Group 9 | Nagtalon, Nartatez, Narvasa, Natanauan, Natividad

Figure 1. Ovarian differentiation after 6 to 8 weeks and a maximal oogonal content of 6-7 million by 16-20 weeks. 

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ESTROGEN TARGET TISSUES Estrogen affects many target organs through estrogen receptors leading to a variety of actions in diverse tissues: o Brain o Eyes o Teeth o Vasomotor o Heart o Breast o Colon o Urogenital Tract o Bone Once you have menopause, or early premature ovarian failure, all these organs are effected2 When a woman complains of hot flashes, irritability, night sweats, insomnia and general body weakness which is increasing in frequency, suspect that she is reaching menopause2

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GYNECOLOGY 1.1 ACCELERATED DISAPPEARANCE OF OVARIAN FOLLICLES BEGINS AT AGE 37.5 YEARS  The accelerated disappearance of ovarian follicles begins at an early age of 37 years, but recent studies have shown that it starts to decrease at age of 352  The decline is almost like a “slide”. When a woman reaches 35, the decline is so fast that at 50 years old, the probability that she still have eggs is almost zero2  During a fixed window of 13 years before menopause   

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DECLINE IN NUMBER OF OOCYTES FROM BIRTH TO MENOPAUSE At birth, there are numerous number of oocytes2 At 25 years old, a woman displays only a minimum number of eggs2 At 50 years of age, sometimes the number of oocytes is only one and sometimes may not even functioning. The stromal area is dense compared to stromal area at birth2 PERIMENOPAUSAL TRANSITION: ALTERED PROFILES OF STEROID AND PITUITARY HORMONES Starts at 35 yo until she reaches menopause2 Speaks of different interplay of hormones2 Menopausal transition is characterized by elevated FSH levels with variable cycle lengths and missed menses, and it ends with the final menstruation period3 In contrast, menopause is defined retrospectively as the time of final menstrual period followed by 12 months of amenorrhea; and postmenopause describes the period following the final menses3

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BIOLOGICAL MECHANISMS OF OVARIAN AGING HYPOTHESES ON THE CAUSE OF OVARIAN FOLLICLE DEPLETION  Why do women have menopause? 1. Oxidative Stress o May cause cell damage from excessive accumulation of reactive oxygen species (superoxide anions, hydroxyl radicals, hydrogen peroxide) 2. Apoptosis (cell death) o Genes bax and bcl-2 are involved in ovarian follicle apoptosis in rats, and is ovarian follicle depletion was prevented in an aging bax knockout animal

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   Figure 2. Hormone levels in a study wherein 160 women monitored from pre- to post-menopause for 12 years 1. FSH (Follicle stimulating hormone) at the time a woman is about to have menopause, increases rapidly2  Ovarian-hypothalamic pituitary axis remains intact during menopausal transition. FSH levels rise in response to ovarian failure and absence of negative feedback from the ovary3  Atresia of granulosa cells reduce production of estrogen and inhibin, resulting in decreased inhibin and elevated FSH levels3 2. Estradiol/ 17-beta estradiol – the active form of estrogen, decreases2 3. LH (Luteneizing hormone) follows the decrease of estradiol, so does estriol2 4. Estriol is the passive form of estrogen which is converted from adrenals and fat cells to periphery)2  If I go into menopause, will I really have no more estrogen? You still have, but the passive form of estrogen which is estriol formed from peripheral conversion in the adrenal and fat cells2

Group 9 | Nagtalon, Nartatez, Narvasa, Natanauan, Natividad

Androgen production from the ovary continues beyond the menopausal transition due to sparing of the stromal compartment. Low levels of circulating estrogens come from peripheral aromatization of ovarian and adrenal androgens Adipose tissue is a main site of aromatization

WHY SHOULD WE BE CONCERNED WITH MENOPAUSE? CONSEQUENCES OF ESTROGEN DEFICIENCY FROM PERIMENOPAUSE TO ADVANCED AGE EARLY (at onset of menopause or 50 years old2) o Hot flushes o Sweating o Insomnia o Menstrual Irregularity o Psychological Symptoms INTERMEDIATE (after 55 years old2) o Vaginal Atrophy o Dyspareunia o Skin Atrophy o Urge-Stress Incontinence LATE (after 60-65 years old2) o Osteoporosis o Atherosclerosis o Coronary Heart Disease o Cardiovascular Disease o Alzheimer’s Disease REDUCED QUALITY OF LIFE throughout the different stages All these symptoms come when a woman is in menopause, and it is progressive2 Do not take it lightly when a woman in menopause complains of these problems. More often than not, she might have symptoms referable to an early stroke, because hypertension and DM clusters around the menopausal age2

THE MENOPAUSAL WOMAN HAS MULTIPLE, SERIOUS, CONFLICTING HEALTH NEEDS  Relief of climacteric symptoms  Enhancement of mood and libido  Treatment of urogenital atrophy  Prevention of cardiovascular disease  Protection of the breast  Protection of the endometrium  Prevention of cognitive decline  Prevention of bone loss  Improvement of quality of life  There is a need to address these needs because the quality of life of woman at this age is very different already. When she reaches her menopause, life expectancy is long, and she spends 30% of life at menopause2

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FEMALE LIFE EXPECTANCY AND ONSET OF MENOPAUSE From 1900 to 2000, as a woman goes to menopause, her life expectancy increases as long as you protect her lifestyle and QOL during her menopause age OPTIONS IN THE MANAGEMENT OF MENOPAUSE I. DRUG THERAPY Hormonal Long randomized controlled well defined studies were stopped because women given these hormones (estrogen and progestins) were dying because of stroke along with an increased incidence of breast cancer2 Women’s health initiative studies had to be stopped due to increase in events of death from cardiovascular diseases and invasive breast cancer2  Estrogens + progestins  Low-dose estrogens + progestins o Progestin counteracts the effects of estrogen to endometrium (which proliferates the endometrium) otherwise it can cause endometrial cancer2  Tibolone o Tissue specific steroid2  Low-dose oral contraceptives NON-HORMONAL  Protect women from increased destruction of bone mineral density2  Selective estrogen receptors modulators (SERM)  Biphosphonates  Calcitonin  Vitamin D

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BENEFITS OF HORMONE REPLACEMENT: MAGIC BULLETS? Table 1. Benefits of HRT RELIEF OF Early symptoms and Hot flushes intermediate physical Insomnia changes Irritability

II. NON-DRUG THERAPY Lifestyle Changes o Nutrition o Exercise o Smoking Cessation - may aggravate risk of fractures2 Counselling Education III. ALTERNATIVE THERAPY Phytoestrogen (tofu2 ) Traditional Alternative Therapy may have no effect, will not increase bone density or improve vasomotor symptoms2 BRIEF HISTORY OF HORMONE THERAPY

1942 - FDA approved estrogen for treatment of menopausal symptoms (hot flushes, mood swings, irritability, headache2) OCPs or oral contraceptives pills are associated with increased incidence of blood clot formation and heart attacks Observation studies show benefits are greater than the risks o Estrogen use showed a higher BMD or Bone Mineral Density, lower heart disease, higher breast cancer risk 1965 - CDP: Conjugated Equine Estrogen or CEE in men, blood clots, heart attacks 1975 - Uterine cancer 1980’s, estrogen preparations were modified2. Progestins were added to protect uterus 1995 - PEPI trial, Estrogen>EP (MPA, MP) o In the PEPI trial, it was shown that there is a higher risk for use of estrogen alone than the use of estrogen with progestin2 o From 1960, the use of estrogen was well seen in the population but suddenly dropped in the 1980 then went up again2 o In the WHI study, the use of estrogen together with progestin has dropped down2 o Lesson: giving of hormones may not be beneficial2  Benefits may be less than the risk but it’s not a 100% risk because there is still an window period that you can give the hormones, not after menopause but in the proximal years prior to menopause2  Give it at lowest dose and in the lowest number of years before menopause2

Mood disturbances Urogenital atrophy PREVENTION OF

Late diseases

Skin atrophy Osteoporosis Cardiovascular disease Alzheimer’s dementia

FDA-APPROVED INDICATIONS FOR HORMONE REPLACEMENT THERAPY The media reacted that Hormone replacement therapy is riskier than advertised. What’s a woman to do? (Time Magazine, 22 July 2002)  The FDA responded by creating guidelines for the use of HRT. 

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Figure 3. Timeline of the history of Hormone Therapy

Group 9 | Nagtalon, Nartatez, Narvasa, Natanauan, Natividad

Treatment of moderate to severe hot flushes and night sweats Treatment of moderate to severe vaginal dryness o When prescribing solely to treat symptoms of vaginal atrophy, topical products should be considered o Give vaginal moisturizer if you are treating vaginal dryness only2 Prevention of osteoporosis o When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk and non-estrogen medications should be carefully considered. o Estrogen is the best management to prevent osteoporosis o If not amenable to estrogen, the patient can be given other drugs such as bisphosphonates such as alendronate2

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GYNECOLOGY 1.1 MANAGEMENT OF MENOPAUSAL SYMPTOMS PROPORTION OF WOMEN WHO EXPERIENCED INDIVIDUAL MENOPAUSE SYMPTOMS Table 2. Individual Menopause Symptoms SYMPTOMS PERCENTAGE (%) Body or Joint Aches or Pains 86.3 Decline in Memory 80.1 Nervousness/Irritability 71 Insomnia 68.7 Malaise 66.4 Mood Swings 64.7 Hot Flushes 64.5 Loss of concentration 62.3 Skin Texture Changes 61.5 Loss of Interest in Intimacy 59.6 Hair Texture Changes 56.6 Vaginal dryness or irritation 55.7 Night sweats 52.7 Palpitations 51.9 Feeling bloated 42.3 Vaginal itching 39.7 Painful urination or urgency 37.4 Painful Intercourse 29.9  Note that they vary from 29.9 to 86.2 (highest). So it seems that hormone treatment has a place in the menopause complaints of patients2   

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VASOMOTOR SYMPTOMS Vasomotor symptoms affect up to 75% of perimenopausal women3 Symptoms last for 1-2 years after last menopause in most women, but may continue up to 10 years or longer in others 3 Hot flashes are the most common complaint 3 o Central event initiated in the hypothalamus drives an increased core body temperature, metabolic rate and skin temperature o This results in peripheral vasodilation and sweating They are the consequence of estrogen withdrawal, not merely deficiency3 o If cessation of estrogen therapy is desired, the dose should be reduced slowly over several months o Patient’s symptoms should be the basis in guiding the pace at which she discontinues therapy

Table 3. Comparison of HRT and Estrogen therapy in treating Vasomotor symptoms International Menopause Society/ North American Menopause IMS Society/NAMS Hormone therapy  remains to be the most effective therapy for vasomotor symptoms  Other menopause related complaints such as joint and muscle pains, mood swings sleep disturbances and sexual dysfunction may improve with hormone therapy

Estrogen therapy  with or without the use of progestogen, is the most effective treatment for menopause-related vasomotor symptoms (hot flashes and night sweats), and their potential consequences (diminished sleep quality, irritability, reduced quality of life),

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If you are going to treat the vasomotor symptoms of the woman, give estrogen. No other drug can treat these except estrogen2 But if the woman has an intact uterus, to prevent her from developing endometrial carcinoma, give progestogen together with estrogen2

Table 4. Options for Treatment of Vasomotor Symptoms3 HORMONE THERAPY Estrogen therapy, combination estrogen-progestin therapy, progestin NONHORMONAL PRESCRIPTION Clonidine, SSNRIs, Gabapentin MEDICATIONS NONPRESCRIPTION MEDICATIONS Isoflavone, soy products, black cohosh, vitamin E Lifestyle changes Reduce body temperature, maintain healthy weight, smoking cessation, paced respiration

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MANAGING UROGENITAL ATROPHY Urogenital atrophy results in vaginal dryness and pruritus, dyspareunia, dysuria, and urinary urgency3

Figure 4. Stages of Urogenital Atrophy in Menopause 1.

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Early stage  Pallor, loss of rugae, denuded areas with petechial hemorrhages, funnel-like narrowing, thin discharge Advanced stage  With extensive adhesion, to the point that the woman feels so dry and she has vaginitis but it is of the atrophic vaginitis type2 Histology of the vagina after menopause  Loss of the active vaginal glands which produce the secretions for lubrication of the vaginal canal.

Table 5. Comparison of HRT and Estrogen therapy in treating Urogenital Atrophy International Menopause North American Menopause Society/NAMS Society/ IMS Hormone therapy  remains to be the most effective therapy for estrogen deficient urogenital symptoms

Estrogen therapy  most effective treatment for moderate to severe symptoms of vulvar and vaginal atrophy such as vaginal dryness, dyspareunia, and atrophic vaginitis.  When Hormone Therapy is considered solely for this indication, local vaginal estrogen therapy is generally recommended

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Group 9 | Nagtalon, Nartatez, Narvasa, Natanauan, Natividad

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GYNECOLOGY 1.1 

When estrogen is considered solely for this indication, local vaginal estrogen is generally recommended. It consists of creams and moisturizer. You do not give the systemic estrogen2 MANAGING BONE LOSS BONE DENSITY AND BONE LOSS IN EARLY MENOPAUSE

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You cannot give estrogen anymore after 60 years old. There is almost no benefit but risk still increases tremendously. CALCIUM SUPPLEMENTATION The study, “Effect of Calcium on bone mineral density and fractures in postmenopausal women”, conducted 15 randomized controlled trials with a population of 1806, with a follow up of 2-3 years. Percent change from baseline of bone mineral density are as follows o Total body – 2.05% o Lumbar spine – 1.66% o Hip – 1.60% o Distal Radius – 1.91% Results show that the total body, lumbar spine, hip and distal radius will really have some form of a baseline of the bone mineral density2 If a woman is > 60 yo this baseline increases. So, calcium and vitamin D should be given. Calcium without vitamin D is useless2 MANAGEMENT OF POSTMENOPAUSAL OSTEOPOROSIS

Figure 5. Cortical bone mass plotted by age and sex 

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To prevent bone loss associated with menopause which is usually at the cortical bone mass, you will have to give estrogen, but if it use only for the prevention of bone loss you can use the other drugs which are bisphosphonates or alendronate2 Bone mineral density assessment is done through Dual X-ray Absorptiometry (DXA) of the hip and spine3 o Recommended for women above 65 years old, regardless of risk factors; and for young premenopausal women with 1 or more risk factors3 o BMD is expressed as the T-score (number of standard deviations from the mean for a young, healthy woman) 3  Above -1 is normal  Between -1 and -2.5 denotes osteopenia  Below -2.5 indicates osteoporosis

Figure 7. After 60 years old, do not give hormone replacement treatment. Drugs that can be given are Raloxifine, bisphosphonates, parathyroid hormone, calcium WITH vitamin D2 

FRACTURE RATES IN WOMEN AFTER AGE 50

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 Vertebral fractures are the most common Decrease in bone loss of a woman in her menopausal age is equated to fracture2 Accelerated bone loss after age 60 o Fracture rates after age 50 depending on different parts especially in the hips, wrist and vertebrae increases rapidly after 60 years of age2 To prevent fractures, put rails in their homes for support. Even a little imbalance can cause fracture.

Group 9 | Nagtalon, Nartatez, Narvasa, Natanauan, Natividad

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Imperative to treat since risk increases with 1. Increasing age 2. Declining Bone Mineral Density (BMD) 3. Prior fracture 4. Family history of osteoporosis 5. Risk factors for bone loss a. Corticosteroid therapy, b. Immobilization c. Hyperparathyroidism d. Chronic illness 6. High levels of bone remodeling markers If you want to treat her decreased bone mineral density before menopause, you can do that 5 years or even in the years proximal to the menopause2 Counsel regarding altering modifiable risk factors3 o Women should receive 1000 to 1500 mg of Calcium and 400 to 800 IU of Vitamin D daily3 OPTIONS FOR OSTEOPOROSIS PREVENTION AND TREATMENT (See Appendix A) 3 HRT AND THE RISK OF BREAST CANCER No clear link between HRT (hormone replacement therapy) and breast cancer We have over 50 studies, and we have lack of agreement, lack of uniformity, lack of consistency.

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GYNECOLOGY 1.1 GLOBOCAN 2000: COMPARISON OF BREAST CANCER INCIDENCE AND MORTALITY Table 6. Incidence and Mortality of Breast Cancer COUNTRY INCIDENCE/100,000 MORTALITY/100,000: MORTALITY/ AGE-STANDARD AGE-STANDARD INCIDENCE RATE RATE RATIO WORLD 35.7 12.5 0.35 USA 91.4 21.2 0.23 AUSTRALIA 82.7 19.7 0.24 SINGAPORE 47.1 15.6 0.33 PHILIPPINES 44.8 20.4 0.46 MALAYSIA 41.9 18.8 0.45 HONGKONG 34.4 9.3 0.27 JAPAN 31.4 7.7 0.24 VIETNAM 17.4 7.9 0.45 CHINA 16.4 4.5 0.27 THAILAND 15.9 7.2 0.45     

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Some studies showed a decrease in breast cancer but there are randomized controlled trials which showed increased in invasive breast cancer2 Philippines has a 31.4 increase in breast cancer. Incidence of mortality secondary to breast cancer is 0.46 (PH data). It is higher than Vietnam2 Decreasing incidence rate from USA to Thailand Highest mortality rates are 1) USA, 2) Philippines and 3) Australia. The lowest being China. The Philippines has the highest mortality/incidence ratio (0.46), and the lowest being USA with 0.23 ABSOLUTE RISK OF BREAST CANCER IN THE GENERAL POPULATION Each 50-year-old woman has ~2.8% chance of developing breast cancer by age 60 years Risk of breast cancer by 60 years old after 5 years of hormone therapy use o Hormone Replacement Therapy for breast cancer of 1.24 after 5 years of Hormone Therapy use (24% increase in risk) o Absolute increase of 3.47 per 100 Hormone therapy users (0.67 additional women over baseline risk) BIOLOGICAL COURSE OF BREAST CANCER

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RISK FACTORS FOR BREAST CANCER Table 7. Risk Factors for Breast Cancer FACTORS BASELINE ADDITIONAL TOTAL CANCERS BREAST CANCERS PER 1,000 CANCERS PER 1,000 WOMEN PER 1,000 WOMEN WOMEN No HRT use (baseline) 45 0 45 5 years of HRT use 45 2 47 10 years of HRT use 45 6 51 15 years of HRT use 45 12 57 Alcohol consumption 45 27 72 (e.g. 2 drinks/day) Lack of regular exercise 45 27 72 (