Gyne Menopause

Quid Refert, Dummodo non Desinas, Tardius Ire

Menopause

GYNECOLOGY

Dra. May C. Gabaldon

OUTLINE

AGE of MENOPAUSE: FACTOR affecting ONSET

 Definition of Terms  Menopause  Perimenopause  Climacteric  Straw Grading System  Hormonal Changes  Effects in various organ systems  CNS  Collagen  Genital Atrophy  Long-term effects  Bone  CVD  Therapy: Non-Drug & Drug  Hormonal  Non-hormonal

1.Genetics – primary determinant 2. Socioeconomic status 3. Smoking (1-2 years earlier) associated with early menopause because of decrease estrogen levels 4. BMI – the greater the BMI; the later the menopause. Asian people have earlier menopause. For Filipinos, the mean age of menopause is around 47-48 y/o. 5. Ethnicity (Asian – around 2yrs earlier) 6. Higher parity (experience later menopause), obese individual associated with late menopause 7. General health status 8. Geographic location  The primary determinant of age of menopause is genetic.  By age 58, 97% of women will have gone through menopause

MENOPAUSE

STRAW GRADING SYSTEM

 This is the permanent cessation of menstruation caused by failure of ovarian follicular development and estradiol production in the presence of elevated gonadotropin levels.  Defined by last menstrual period  Cessation of menses is variable  May occur prior to cessation of menses, seldom a precise time of this event  What are your gonadotropins?  FSH  LH  This is defined by your last menstrual period.  Usually kelan mo sasabihin menopause na ung patient? pag 1 year na siyang di dinadatnan ng mens.  Average age: 51 y/o  Filipino: 47-48 y/o

 Describe the endocrinologic events leading to menopause  Dapat 1yr hindi nag mens: POST-MENOPAUSE  Even before Perimenopaus: elevated FSH

PERIMENOPAUSE  Variable time beginning a few years before and continuing after the event of menopause.  Time between onset of irregular menses  When do you say it is perimenopausal transition? →This is the time usually 4 years before the actual time of menopause where in the patient is already experiencing irregular menses and eventually permanent cessation of your menses. That is the time of perimenopause.  So halimbawa ung patient mo nagiirregular bleeding, eventually di na siya dinatnan ng 8 months. Ano siya? Menopause or perimenopause?  Answer: Perimenopause. Pag higit isang taon na siya hindi dinatnan,

menopause na un. CLIMACTERIC  The physiologic period in a woman’s life during which there is regression of ovarian function  Time after the cessation of reproductive function  Time of ovarian follicular regression (pag 1 year or more na siyang hindi dinatnan, that is already considered as menopause, that’s from the last mens)  This is the physiologic period in a woman’s life during which there is already regression of the normal ovarian function.

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 When your patient arrives at the time of perimenopausal period, you have the early and the late. During the late perimenopausal period, your patient will now experience the signs and symptoms characteristic of your menopause particularly your hot flushes. And this is what you call your perimonopausal transition.  Mapapansin ninyo your perimnopause extends from the time that you have your regular bleeding upto around before 1 year na hindi ka dinadatnan.  After 1 year, that is already your post-menopausal period. This is characterized by your elevated FSH.  Usually you have your greatest number of follicles at around 20 weeks of AOG. You will have a regular rate of follicular atresia by the age of 37. So pagpatak mo ng edad na 37, regular rate na ung follicular atresia mo and by the age na nag 38 ka hanggang magmenopause there is already rapid decline in your ovarian follicle.

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THE MENOPAUSAL TRANSITION (PERIMENOPAUSE) 2 Phases:  Early  Late  These changes signify verying period of time during which rapid oocyte depletion to hypoestrogenism HORMONAL CHANGES during the PERIMENOPAUSE  Decreased ovarian inhibin production accompanied by an increase in pituitary FSH release  Inhibin – inhibits FSH production. So it decreases. Naturally, what will happen to your FSH? Your FSH will decrease.  Since decreased ang inhibin, your FSH will increase with concomitant increase in activin.  Increased in Activin  Activin – increase expression of FSH receptors that further increase in FSH  Reduction in ovarian estrogen production (major reduction occurs 6 months before menopause)  Very slow decrease in androgen status. Because ovary still continue to produce your androgens including also your adrenals to produce androgen and usually the decline is just secondary to the aging process.  Gametogenic failure (not discussed)  Marked diminution of reproductive capacity that precedes perimenopausal  Reduces early follicular phase inhibin secretion, rising serum FSH, marked reduction in fecundity, increase activin, reduction in estradiol production and androgen status.  Causes of increased FSH  Negative feedback detector between estradiol reduction and decreased ovarian inhibition.  Concerns during Perimenopause (not discussed)  Irregular bleeding o Treatment: short term use of oral contraceptive  Hot flushes o Treatment: Oral contraceptive/lower doses of estrogen  Inability to conceive o Treatment: requires more aggressive treatment due to decrease fecundity. Once FSH increase and AMH decrease poor prognosis for pregnancy

 Genital Atrophy  Genital dryness  Atrophic vaginitis  Dyspareunia CENTRAL NERVOUS SYSTEM  Brain is an active site for estrogen action as well as estrogen formation  Estrogen is basically neuroprotective. It has also neurotropic action to the CNS. Check table 14-3.  Activity in the brain is mediated via estrogen receptor alpha but predominantly beta in the frontal & parietal cortex.  Hot flush  HALLMARK FEATURE of estrogen decline  Refers to acute sensation of heat  Flash or vasomotor episode includes changes in the early perception of this event and other skin changes  Complaints: sleep disruption  Sudden, transient sensation of warmth to intense heat over face, chest, neck and head; concluded sometimes by profuse perspiration. Secondary to changes in hypothalamic response because of change in estrogen status.  Symptoms: Chills, nausea, anxiety, head or chest pressure, feelings of suffocation, inability to concentrate  Duration of few seconds to several minutes  Frequency: rare to recurrent every few minutes; more at NIGHT or during STRESS  Depressed mood (not discussed)  Although estrogen does generally improve depression, it should not be used for psychiatric disorder  Cognitive decline (alzheimer’s disease)  Estrogen has role in enhancing neurotransmitter function w/c is deficient in AD.  Treatment: early estrogen is beneficial but later treatment (after 65 y/o) has no benefit and may be detrimental. CNS is the active site for estrogen action and formation primarily via your estrogen receptor beta in the frontal and parietal cortex and cerebellum.

HORMONAL CHANGES with ESTABLISHED MENOPAUSE  Marked reduction in E₂ (estradiol) → more and E₁ (estrone) - peripheral aromatization  Elevated FSH and LH. Because there is further decrease in your ovarian inhibin production.  Decreased ovarian inhibin production  Serum E₂ is reduced to greater extent than E₁  What is the difference between the two?  Estradiol comes from ovarian estrogen production. Estrone is from the peripheral conversion in your adipocytes by aromatization  So that mas low ang decrease ng estrone amount of these patients.  Serum prolactin levels may slightly decreased. Because your prolactin secretion is also influenced by your estrogen.  Very slow decline in androgen status  Source of estrone: aromatization of androgen in the periphery EFFECTS of MENOPAUSE on VARIOUS ORGAN SYSTEMS  All of these are secondary to hypoestrogenism associated with your menopause  CNS  Hot flush  Disturbed sleep  Depressed mood  Cognitive decline  Dementia  Collagen

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COLLAGEN    

An important component of bone and skin Estrogen has positive effect on collagen 30% loss within the first 5yrs of menopause Without estrogen, there is a decrease in muscle tone, decrease elasticity so this will result to urinary incontinence, bladder symptoms, prolapse problem (Genitourinary problems)  The supportive effect of estrogen has implication also for bone homeostasis and for the pelvis  Genitourinary problem  Urinary incontinence and irritative bladder symptoms occur in 2040% in peri and post menopausal  Pelvic organ prolapse can happen  Treatment (not discussed) o Effects: restoration of bladder control o Decrease incidence of UTI o Important role in wound healing by enhancing TGF-beta GENITAL ATROPHY (Vulvar Atrophy)  Vaginal atrophy results in a loss of elasticity and reduced lubrication  Usual complaints of: 1. Pruritus 2. Discharge 3. Post-coital bleeding (lubricant: must be WATER based) 4. Dyspareunia 5. Burning on urination ESTROGEN DEFICIENCY results in

inumin mo araw araw. Dapat before kasi when a decade of your life, you have already achieved the maximum bone mass for yourself, because after that, especially at the time of menopause you will not anymore increase no matter how much calcium you take. Ang nagyari na lang dyan, lahat ng dineposito mo, unti-unting nagwiwithdraw. Just depends on the amount. Ibig sabihin, syempre kung naka calcium supplement ka, you have steady levels of calcium in the blood. The withdrawal process is more gradual as compared kung wala. Siyempre mas malaki ung withdrawal. But you do not expect to increase the bone mass just because you are taking the calcium supplement.  ESTROGEN: predominant importance for Bone Mass in both women & men  Gradual decrease of bone mass in menopause FUNCTION OF ESTROGEN in the BONE  Estrogen receptors are present in the osteoblast, osteoclast, & osteocyte  Estrogen deficicency → Bone density ↓more slowly in cortical than trabecular bone  Estrogen deficicency → Osteoporosis more rapidly in trabecular than cortical bone (tandaan)  Suppress bone turnover – estrogen decreases osteoclasts by increasing apoptosis and thus reduces their lifespan  Maintain rate bone formation - E₂ antagonizes glucocorticoid – induced osteoblast apoptosis  Molecular mechanism  Inhibit production of (IL)interleukin 1, IL 6, TNF-a, macrophage CSF, CSF-1 and PG E₂.  Up regulates TGF-b – inhibits bone resorption  RANKL ligand – this is the one that is responsible for osteoclast differentiation and action

 Moisture content is low 21-47% (Pruritus-akala fungal infection, dyspareuria 41%, post coital bleeding)  Discharge  Burning on urination (akala nila UTI lang lagi na pauilit ulit)  Dryness 21-47%  Thin (Atrophic changes) 15-55%  pH increases  mucosa may exhibit inflammation and small petechiae  paler vaginal mucosa Estrogen treatment (not discussed)  Increased number of superficial cell  Vaginal pH decreases  Vaginal blood flow increases  Electropotential difference across the vaginal mucosa increases LONG TERM EFFECTS of MENOPAUSE  Bones  Osteopenia  Osteoporosis  Fracture  CVD (risk of CVD during reproductive age is lesser among women compared to men, but at menopause it equalizes)  Cancer (take note daw)  Breast  Colon Di ba part of your preventive health maintenance ang mga menopausal patients ay ang pagpapa mammogram annually. Supposedly dapat nagpapa proctosigmoidoscopy, colonoscopy din. BONE  Loss of trabecular bone (spine) is greater with estrogen deficiency than loss of cortical bone (tandaan daw)  Attainment of peak bone mass in the late second decade is key to ensuring that the subsequent loss of bone mass with aging and estrogen deficiency does not lead to early osteoporosis (remember)  Di ninyo sasabihin na mag calcium supplement kasi menopause ka. HINDI na magiincrease and bone mass niyan kahit isang bote ng calcium ang

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DEFICIENCY of ESTROGEN    

Increase activity of remodeling units Prolong resorption Shortens the phase of bone formation Increase osteoclast recruitment ion bone multicenter unit

PHILIPPINE ORTHOPEDIC ASSOCIATION: Bone Mineral Mass Density Test METHOD Axial DEXA (central) Peripheral DEXA

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QUS

BODY SITE Hip, L1-L4, spine, total body Forearm, finger, heel Heel, shin

USES

PRECISION

RADIATION

DEFINITIVE DIAGNOSIS, treatment ∕follow up ∕Screening

1-2%

CXR

1-2%

CXR

Screening

1-2%

CXR

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WHY INCREASED RISK?

OSTEOPOROSIS: WHO Definition

Based on BMD of hip and spine measured by DEXA BMD (in relation to young adult ref.range) Diagnosis

T score

Within 1SD

1 to 2.5 SDs below (at either site)

>2.5 SDs below

>2.5 SDs below + fragility fracture

Normal

Osteopenia (mild to moderate bone deficiency)

Osteoporosis (marked bone deficiency)

Severe osteoporosis

-1 to -2.5

Below -2.5

Below -2.5

0 to 1

      

Take note only of Osteopenia, osteoporosis and severe osteoporosis. Pag nagbigay ng case, dapat alam ninyo kung anong T score and BMD for you to be able to classify. INDICATIONS for BMD TESTING  All post menopausal women > 65 years  All postmenauposal women < 65 years with risk factors or osteoporotic fracture  All patients >45 years with low energy fracture (no trauma, may fracture lang)  Patients on long term steroid therapy  Patients monitored for effective of therapy  Patients with primary hyperthyroidism or Iatrogenic hyperparathyroidism

Increases in levels of LDL-C Oxidation of LDL-C is also enhanced Decreased levels of VLDL and lipoprotein a Decreased in HDL-C levels The changes of weight, BP and blood glucose with aging BF in all vascular beds decreases after menopause Prostacyclin production decreases

 Beneficial effect of HRT if started early  Early kasi to, walang established atherosclerosis.  The problem here is that, if there is already an established atherosclerosis and then you give your HRT, there will be an altered biology of your HRT. Instead of all these beneficial effects, if HRT is started late there will be a:  reduction in estrogen receptor expression and function  decrease vasodilatation  increase inflammatory activation  Increase plaque instability  That’s why as early as possible, once menopause has already set in, usually if you are going to give it for the prevention of CVD, then you have to start it early.

MANAGEMENT of OSTEOPOROSIS         

Estrogen Progesterone SERM (Selective Estrogen Receptor Modulator) Tibolone Biphosphonates (Alendronate) Calcitonin Fluoride PTH Calcium  Food Sources of Calcium: dilis, sardines CARDIOVASCULAR EFFECT

 Normal Ovarian function is CARDIOprotective  For atherosclerotic changes, usually CVD rates in women develops 10 years than men, provided you have normal ovarian function.  When the possible reasons for the increase in cardiovascular disease are examined, the most prevalent finding is 1. an accelerated rise in total cholesterol in postmenopausal women. 2. changes in weight, BP, and blood glucose with aging, although important are not thought to be as important as the rate of rise in total cholesterol which is substantially different in women after menopause versus men.  Blood flow decrease in all vascular bed after menopause  Risk of cardiovascular disease increase  Possible reason  Accelerated rise in total cholesterol  Oxidation of LDL-C is enhanced  HDL-C level trend downward  Coagulation balance is not substantially altered  Blood flow in all vascular bed decreases after menopause  Prostacyclin decreases  Endothelin increase  Vasomotor responses to acetylcholine are constrictive, reflecting reduced nitric oxide synthase activity due to primarily to fairly rapid reduction of estrogen.  Vascular effect of estrogen  Increase circulating nitrates and nitrites

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Beneficial effects of HRT ↑vasodilation ↓Inflamm. activity ↑Nitric Oxide ↓CAMs ↓Endothelin ↓MCP-1, TNF-α ↑COX2 ↓lesion progression

HRT (Altered Biology) if started late ↓ ER expression, function ↓vasodilation ↑inflammatory activity ↑plaque instability

APPROACH to THERAPY Clinical treatment of women in the perimenauposae should address three general areas of concern:  Irregular bleeding – short term use of OCP (usually 20mcg ethynil estradiol) kasi malamang, kaya nagloloko ang mens nya kasi inadequate na ung production ng estrogen. But then you will not give your estrogen alone. You have to give it combined. Because unopposed estrogen can cause endometrial hyperplasia or CA.  Symptoms or early menopause such as hot flushes – OCP maybe an option if symptoms warrant therapy  Inability to conceive

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For Menopausal Women Concerns are:  Vasomotor and urogenital symptoms  Prevention of osteoporosis  Prevention of cardiovascular disease NON-DRUG THERAPIES      

Lifestyle changes Diet Nutritional supplements Exercise – helps to reduce the frequency of hot flushes Counseling Education DRUG THERAPIES HORMONAL

NON- HORMONAL  Alternative therapies for menopause  Phytoestrogens (eto lang sinabi niya about phytoestrogens)  Inconclusive evidence with regards to its efficacy GOVERNING PRINCIPLES  Hormonal therapy must be individualized and tailored according to symptoms and the need for prevention as well as personal and family history, results of relevant investigations the woman’s preferences and exceptions. Pretreatment Assessment

Additional investigations if needed

Re evaluation

History (potential indications and contraindications such as smoking & thromboembolic dse. for HRT) PE (with measurement of weight and BP) Mammography (d/c HRT for 2-4 weeks before test) → breast may appear nodular Vaginal UTZ and/or endometrial biopsy for abnormal vaginal bleeding Bone mineral density (based on local guidelines) Annual check up (reconsider indication/s and risk/benefit)

Reduce Frequency of occurrence of HOT FLUSHES: ↑ fluid intake Well-balanced diet Exercise

There is only one happiness in life, to LIVE and be LOVED..

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END Black – from power point Blue – trans from lecturer Red – from book

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