1 GYNE 1 - Menopause

MENOPAUSE and CARE OF THE MATURE WOMAN

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 REFERENCES 1. Lecture Powerpoint 2. Lecture Recording

3. 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.

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

o 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

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

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,

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

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

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

 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

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

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

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 A. 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 B. NON-HORMONAL

 Protect women from increased destruction of bone mineral density2

 Selective estrogen receptors modulators (SERM)

 Biphosphonates

 Calcitonin

 Vitamin D

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

Figure 3. Timeline of the 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

BENEFITS OF HORMONE REPLACEMENT: MAGIC BULLETS?

Table 1. Benefits of HRT

RELIEF OF Early symptoms and intermediate physical changes Hot flushes Insomnia Irritability Mood disturbances Urogenital atrophy Skin atrophy

PREVENTION OF Late diseases 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.

1. Treatment of moderate to severe hot flushes and night sweats 2. 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 3. 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

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

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/ IMS

North American Menopause 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),



 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 MEDICATIONS

Clonidine, SSNRIs, Gabapentin

NONPRESCRIPTION MEDICATIONS Isoflavone, soy products, black cohosh, vitamin E

Lifestyle changes Reduce body temperature, maintain healthy weight, smoking cessation, paced respiration

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. Early stage

 Pallor, loss of rugae, denuded areas with petechial hemorrhages, funnel-like narrowing, thin discharge

2. 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 3. 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 Society/ IMS

North American Menopause Society/NAMS

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

 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

Figure 5. Cortical bone mass plotted by age and sex

 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

FRACTURE RATES IN WOMEN AFTER AGE 50

Figure 6. Incidence of all osteoporotic fractures increases with age.  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.

 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 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

 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.

GLOBOCAN 2000: COMPARISON OF BREAST CANCER INCIDENCE AND MORTALITY

Table 6. Incidence and Mortality of Breast Cancer COUNTRY INCIDENCE/100,000 AGE-STANDARD RATE MORTALITY/100,000: AGE-STANDARD RATE MORTALITY/ INCIDENCE 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

 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

Figure 8. Biological course of breast cancer.  PREMAMMOGRAPHIC (1 to 6.9 years)

 PRE-CLINICAL (7-10 years)

o Mammographic window, mammographic examination is

mandatory by the age of 40 since the breasts would be less dense

o Breast mass, size at least 1 mm

 CLINICAL (10.1 to 14 years)

o Breast tumor as large as 2.5 cm

RISK FACTORS FOR BREAST CANCER Table 7. Risk Factors for Breast Cancer

FACTORS BASELINE BREAST CANCERS PER 1,000 WOMEN ADDITIONAL CANCERS PER 1,000 WOMEN TOTAL CANCERS PER 1,000 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 (e.g. 2 drinks/day) 45 27 72

Lack of regular exercise (<4 hours/week)

45 27 72

Late menopause (10 year delay)

45 13 58

Body mass index (10kg/m2 _increase)

45 14 59

Weight gain after menopause (20 kg or

more)

45 45 90

 Baseline or basic risk applies to all women, and is due to factors that

cannot be controlled such as aging and gender.

 Hormone therapy use after 5 years or more increases the risk of

developing cancer2

 Alcohol use, lack of regular exercise, late menopause, high BMI and weight gain after menopaue further increase the risk of cancer2

EFFECTS ON SKIN

 Atrophy of dermis after menopause is due to decrease in collagen

content

 There is an inverse relationship between skin collagen and years since menopause

 30% collagen lost in first 5 years after menopause

 Average rate of loss of 2.1% per year after menopause

EARLY INTERVENTION WITH ESTROGEN PREVENTS COLLAGEN LOSS

 Deficiencies in skin collagen can be corrected by estrogen treatment

 Estrogens are of prophylactic value when initiated in the early postmenopausal years

 An increase in collagen with estrogen depends on the collagen content

at the start of treatment

HRT MAINTAINS SKIN THICKNESS IN POSTMENOPAUSAL WOMEN

 A study with 84 women on various hormone therapies was done wherein skin thickness was measured by high frequency ultrasound and computerized image analysis.

 HRT was found to maintain skin thickness among postmenopausal HRT users

Figure 9. Skin collagen decreases with time after menopause. Hormone replacement therapy protects against loss. Skin punch biopsies confirmed

that with estrogen, the collagen content in the body is maintained. LONG-TERM HRT DECREASED SKIN WRINKLES

 65 long term (≥5 years) hormone therapy users had menopause ≥5 years

 Visual assessment of severity of wrinkles at 11 facial locations using Lamperle scale by a plastic surgeon blinded to hormone therapy use

Table 8. Results of Wrinkle score (average Lamperle score)

HT Non-HT P value Horizontal forehead 1 1 NS Glabellar frowns 1 2.2 NS Cheek folds 1.5 2.1 NS Periauricular lines 1.7 2.5 NS Periorbital lines 2.1 2.3 NS Nasolabial folds 3 2 Upper lip lines 2 1 NS Corner of mouth lines 3 3 NS Marionette lines 1.3 2.7 NS Chin crease 2 2 NS Neck folds 3.2 4 NS AVERAGE SCORE 1.5 2.2 NS NS= not significant

HRT IMPROVED SKIN PARAMETERS

 A study of 40 postmenopausal women received ORAL sequential 2 mg

17β-estradiol/10mg dydrogesterone (Femoston) for seven, 28-day

cycles

 After 7 months of HT compared to baseline:

1. Elasticity increased at right ramus of mandible

2. Hydration tended to improve at inner side of right upper arm 3. Thickness improved

4. Surface lipids did not change

IDENTIFYING THE IDEAL PATIENT FOR HORMONE REPLACEMENT THERAPY  The use of hormone in early menopause and up to age 60 years has a

very minor potential for harm but may carry substantial benefits.

 Giving hormonal treatment is optimal when given before 60 years of

age and proximal to the menopause years2

BENEFITS OF EARLY INITIATION OF HORMONE REPLACEMENT THERAPY

 Cardiovascular System

o There are data to support the hypothesis that estrogen replacement in the early stages of estrogen deficiency will provide primary vascular benefits

 Central Nervous System

o There is a critical period, close in time to the menopausal transition during which hormone therapy confers optimal neuroprotection

 Skin

o By preventing the loss of collagen, estrogens are of prophylactic value when initiated in the early postmenopausal years

PRINCIPLES GOVERNING CURRENT USE OF HORMONE REPLACEMENT THERAPY

 HRT should be part of overall strategy for maintaining the health of postmenopausal women.

 HRT must be individualized and tailored according to symptoms and

need for prevention and the women’s history, preference and expectations

 Risk and benefits of HRT differ for women around the time of

menopause compared to those for older women (give before menopause and do not give after 60 year old2₎

HORMONE REPLACEMENT THERAPY: DOSE RECOMMENDATIONS

1. The lowest dose needed to relieve symptoms

 0.5-1 mg 17β-estradiol

 0.3-0.45 mg conjugated equine estrogens

 25-37 mg transdermal (patch) estradiol

 0.5 mg estradiol gel

 150 mg intranasal estradiol

2. Reassess symptoms after 8 to 12 weeks, adjust dose if necessary

ROUTES OF ADMINISTRATION OF HRT

Table 9. Routes of HRT Administration

NON-ORAL

To prevent aggravation f the condition

For women with:

Hypertriglyceridemia Liver disease Migraine headache

Increased risk of venous thrombosis

LOW-DOSE VAGINAL ESTROGEN For women with:

Urogenital symptoms alone

Urogenital symptoms despite systemic therapy

TRANSDERMAL ESTROGEN PREFERABLE FOR WOMEN WITH METABOLIC SYNDROME

 A study was conducted on 50 obese postmenopausal women with metabolic syndrome on oral estradiol 1mg/d or transdermal estradiol 0.05mg/d for 3 months

 Results are as follows:

Table 10. Comparison or Oral and Transdermal Estrogen

PARAMETER ORAL E2 TRANSDERMAL

E2

Baseline insulin Increased No change

Quantitative insulin-sensitivity check index

Decreased No change

Homeostasis model assessment Increased No change

HDL – cholesterol Increased No change

Leptin Increased No change

Adiponectin Decreased Increased

Leptin-adiponectin ratio Increased No change

Resistin Increased No change

Goserelin Decreased Decreased

 Some women prefer transdermal estrogen, especially those with metabolic syndrome, however most of the transdermal estrogen as

compared to orally taken estrogen shows no change in the symptoms being treated

PROGESTOGEN

 In general, progestogen should be added to prevent endometrial

hyperplasia and cancer

 Some progestins have specific beneficial effects that could justify their use beside the actions on the endometrium

DURATION OF HORMONE REPLACEMENT THERAPY USE

 There are no reasons to place mandatory limitations on the length of treatment. Whether or not to continue therapy should be decided at the discretion of the well-informed hormone user and her health professional.

 FDA 2003, recommends the shortest duration and lowest dose

consistent with treatment goals.

 ACOG 2004, recommends the lowest effective estrogen dose should

be used for the shortest possible time to alleviate symptoms

 NAMS 2004, recommends the duration and dose consistent with treatment goals

MONITORING HORMONE REPLACEMENT THERAPY 1. PRETREATMENT ASSESSMENT

 History

 Potential indications and contraindications

 Physical examination

 Measure weight and blood pressure

2. ADDITIONAL INVESTIGATION IF NEEDED

 Mammography

 Discontinue HRT for 2-4 weeks before test

 Vaginal ultrasound and/or endometrial biopsy

 For abnormal vaginal bleeding

 Bone mineral density

 Based on local guidelines

3. RE-EVALUATION

 Annual checkups

o Women taking HT should have at least an annual

consultation to include a physical examination, update of

medical history, relevant laboratory and imaging

investigations and a discussion on lifestyle. Especially when the patient is taking estrogen alone.

 Review indication(s) and risk/benefit equation

“Always consider the particular patient, the particular time in the patient’s life and the patient’s particular constitution.” – Doctrine of treatment

MENOPAUSE and CARE OF THE MATURE WOMAN

OPTIONS FOR TREATMENT AND PRVENTION OF OSTEOPOROSIS3

BISPHOSPHONATES Alendronate 37-70 mg/wk,

Risedronate 35 mg/week, Ibandronate 150 mg/month

No additional potential benefits; potential risks: esophageal ulcers; Side effects include GI distress,

arthralgias, myalgias

HORMONE THERAPY Estrogen or Estrogen/Progestin Therapy Additional potential benefit: treat vasomotor symptoms and urogenital atrophy; Potential risks include breast cancer, gallbladder

disease, venous thromboembolic events, CVD, stroke;

Side effects include vaginal bleeding and tenderness

SELECTIVE ESTROGEN RECEPTOR MODULATORS Raloxifene 60 mg/day Add’l pot’l benefits: reduced risk of breast cancer; Potential risks: venous thromboembolic events;

Side effects include vasomotor symptoms, leg cramps

CALCITONIN 200 IU/day intranasally or 100 IU/day

subcutaneously or IM

Add’l pot’l benefits: none; Potential risks: none; Side effects include rhinitis,back pain

TERIPARATIDE 20 ug/day SQ Add’l pot’l benefits: none;

Potential risks: osteosarcoma after long term use in rodents; hypercalcemia

Side effects include leg cramps

Appendix B

CONTRAINDICATIONS TO HORMONE THERAPY3 _{RELATIVE CONTRAINDICATIONS}3

Known or suspected breast cancer or endometrial cancer Undiagnosed abnormal genital bleeding

Active thromboembolic disorders Active liver or gallbladder disease

Heart disease Migraine headaches

History of liver or gallbladder disease, Endometrial cancer, Thromboembolic events