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February 26, 2013

MENOPAUSE
Dr. Songco
Outline: I. II. III. IV. V. VI. VII. VIII. IX. X. Menopause The Age of Menopause Physiology of Menopause Pathophysiology of Menopausal Transition Stages of Reproductive Aging Workshop (STRAW) The Symptoms of Menopause Pathophysiology of Menopause Organ Changes Approach to the Woman in Menopause Treating the Woman in Menopause CHUCHU a. Premature Ovarian Failure (POF) b. Turner Syndrome c. Fragile X

PHYSIOLOGY OF MENOPAUSE Estrogen levels from Puberty to Post-menopause

MENOPAUSE
Permanent cessation of menstruation resulting from loss of ovarian follicular activity (WHO) FINAL menstrual period (not LAST menstrual period) 12 months amenorrhea without any other cause DEFINITION OF TERMS Perimenopause menopausal transition o Duration of 2-8 years (ave. 5 years) o Hot flushes, depressed mood, irritability Menopause Climacterium o Encompasses perimenopause, menopause, postmenopause Premature Ovarian Insufficiency/Failure (POF/POI) THE AGE OF MENOPAUSE
Too much estrogen from the ovaries

and

Average age Western countries Malay women Thai women Filipinas Genetically predetermined Early Smoking Low socioeconomic status Women at high altitudes Vegetarians/thinner women

51 y/o 51-52 y/o 45 y/o 49-50 y/o 47-48 y/o

negative feedback on the anterior pituitary release

Inhibin B release decreased FSH

Later Higher parity Prior use of OCP High BMI High alcohol consumption

The age at menopause appears to be genetically determined and is unaffected by race, socioeconomic status, age at menarche, or number of prior ovulations. Factors that are toxic to the ovary often result in an earlier age of menopause; women who smoke experience an earlier menopause (1), as do many women exposed to chemotherapy or pelvic radiation. Women who have had surgery on their ovaries, or have had a hysterectomy, despite retention of their ovaries, also may experience early menopause (2). Premature ovarian failure, defined as menopause before the age of 40 years, occurs in approximately 1% of women. It may be idiopathic or associated with a toxic exposure, chromosomal abnormality, or autoimmune disorder. [Berek and Novaks]

Androgen production from the ovary continues beyond the menopausal transition because of sparing of the stromal compartment. Androgen concentrations are lower in menopausal women than in women of reproductive age. This finding appears to be associated more with aging and decreased functioning of the ovary and adrenal glands over time rather than with menopause per se. Menopausal women continue to have low levels of circulating estrogens, principally from peripheral aromatization of ovarian and adrenal androgens. Adipose tissue is a major site of aromatization, so obesity affects many of the sequelae of menopause. The ovarianhypothalamicpituitary axis remains intact during the menopausal transition; thus, FSH levels rise in response to ovarian failure and the absence of negative feedback from the ovary. Atresia of the follicular apparatus, in particular the granulosa cells, results in reduced production of estrogen and inhibin, resulting in reduced inhibin levels and elevated FSH levels, a cardinal sign of menopause.

PATHOPHYSIOLOGY OF MENOPAUSAL TRANSITION

synthesis (such as gonadotropin-releasing hormone antagonists) helps to distinguish between the effects of aging and estrogen deficiency. These models are imperfect, though, and differ from natural menopause in many ways.

STAGES OF REPRODUCTIVE AGING WORKSHOP (STRAW)

Study this chart in detail, especially the last row, Endocrine! THE SYMPTOMS OF MENOPAUSE Vasomotor symptoms Sleep disturbance Depressed mood Skin and urogenital atrophy Decline in cognitive function Menstrual disturbances Osteoporosis/ostepenia Cardiovascular disease Sexual dysfunction

Study the chart in detail! The number of follicles is highest at 20 weeks of age. At birth,

there are 1-2 million follicles.


In menopausal women, there is a low estrogenic environment that

1. 2. 3. 4. 5. 6. 7. 8. 9.

gives rise to a high androgenic environment. Thus, menopausal women may experience acne and hair growth. Anti-Mullerian Hormone (AMH) may be given anytime during the cycle. In the Philippines, it is very expensive, and only available at St. Lukes Global.
The menopausal transition is characterized by elevated FSH levels associated with variable cycle lengths and missed menses, whereas the postmenopausal period is marked by amenorrhea. The menopausal transition begins with variability in menstrual cycle length accompanied by rising FSH levels and ends with the final menstrual period. Menopause is defined retrospectively as the time of the final menstrual period followed by 12 months of amenorrhea. Postmenopause describes the period following the final menses The pathophysiologic consequences of menopause may be best understood by considering that the ovary is a women's only source of oocytes, her primary source of estrogen and progesterone, and a major source of androgens. Menopause results in infertility secondary to oocyte depletion. Ovarian cessation of progesterone production appears to have no clinical consequences except for the increased risk of endometrial proliferation, hyperplasia, and cancer associated with continued endogenous estrogen production or administration of unopposed estrogen therapy in menopausal women. The possible effects of declining androgen concentrations that occur with aging are an area of both controversy and active investigation. The major consequences of menopause are related primarily to estrogen deficiency. It is very difficult to distinguish the consequences of estrogen deficiency from those of aging, as aging and menopause are inextricably linked. Studying the effects of estrogen deficiency and replacement in young women with ovarian failure or of drugs that suppress estrogen
Apale,Aquino E., Aquino J. Arceo,

These are all due to follicular depletion and decreased estrogen. These women are secreting ESTRONE. Vasomotor Symptoms Hot flush o Starts from the chest, upwards o Occurs in the middle of the early mornings (a time that should be for deep sleep) Increase in awake and asleep SBP Increase in HR Loss of sleep Depressed Irritable Rapid decreases in estrogen levels (estrogen withdrawal) causes: o Increase norepinephrine stimulation
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Constantino

o Increase serotonin activation o Increase activity of central opioid peptides These factors added together causes narrowing of the thermoneutral zone in the thermoregulatory center o The upper threshold is decreased, which means smaller increases in core body temperature can trigger mechanisms to dissipate heat such as vasodilation and sweating o The lower threshold is increased, which means smaller decreases in core temperature can trigger mechanisms to preserve heat, such as shivers and chills Hot flushes start with core temperature rising above the narrow upper threshold vasodilation in the peripheral vasculature increase skin temperature increase systolic BP increase HR Can be accompanied by anxiety and palpitations o Reflex cooling from the improved skin surface heat dissipation causes chills after flash o Commonly occur at night, which leads to sleep dysfunction and reports of fatigue because of disruptive symptoms Estrogens effective for treatment of vasomotor symptoms o Systemic estrogen therapy is the most effective treatment available
for vasomotor symptoms and associated sleep disturbance

o Enhances cerebral blood flow 3 Thus, in menopause, there is decreased blood flow to CNS Menstrual Disturbances Anovulation o Perimenopausal women should NOT experience heavy menstrual bleeding Longer cycles in between, heavy bleeding Rule out organic pathology/neoplasia Cardiovascular Diseases

o Because vasomotor symptoms appear to be the result of estrogen


withdrawal, rather than simply low estrogen levels, if cessation of estrogen therapy is desired, the dose should be reduced slowly over several months Vasomotor symptoms affect up to 75% of perimenopausal women. Symptoms last for 1 to 2 years after menopause in most women, but may continue for up to 10 years or longer in others. Hot flashes are the primary reason women seek care at menopause and request HT. Hot flashes not only disturb women at work and interrupt daily activities but also disrupt sleep A central event, probably initiated in the hypothalamus, drives an increased core body temperature, metabolic rate, and skin temperature; this reaction results in peripheral vasodilation and sweating in some women.

Skin and Urogenital Atrophy Urogenital atrophy Vulvovaginal aging Lack of estrogen on the urogenital epithelium Dryness, itching, burning, dyspareunia Decreased blood flow, collagen, elastic fibers, vaginal elasticity Systemic estrogen therapy is effective for the relief of vaginal dryness,
dyspareunia, and urinary symptoms. For women who should not or choose not to use estrogen therapy, another option is topical application. Because systemic absorption is low, endometrial stimulation is minimal; thus vaginal estrogen therapy may be appropriate even for symptomatic women with breast cancer. Low doses of estrogen cream (Premarin, Estrace) (0.5 g) are effective when used only 1 to 3 times weekly (27). An estradiol vaginal tablet (Vagifem) (25 g) inserted twice weekly, which may be less messy and easier to use than estrogen cream, is available. An estrogen containing vaginal ring (Estring) (7.5 g/day), which is placed in the vagina every 3 months and slowly releases a low dose of estradiol, also is available

Dyslipidemia Total and low density lipoprotein (LDL) cholesterol increase with age Accelerated by menopause High density lipoprotein (HDL) decreases Lead to increase rates of corononary heart disease, myocardial infarction and stroke in post-menopausal women CVD risk for menopausal women is higher than in men of equal age CVD is the most common cause of death in Filipino women o Withdrawal of estrogen dyslipidemia, which sets in at an increased rate, as compared to women of reproductive age Bone Issues: Osteopenia vs. Osteoporosis Those with osteopenia have a 10x increased risk of fracture Osteopenia leads to osteoporosis if undiagnosed or uncontrolled Estrogen is responsible for promoting osteoblast (bone-forming cell) activity. It also inhibits bone remodeling and balances osteoblast and osteoclast (bone-resorbing cell) activity. As levels of serum estrogen decline in menopause, there is an increase in the rate of bone loss Increase in bone turnover increases serum calcium Affects trabecular bone defect in bone mineral density Menopause causes primary osteoporosis : estrogen decrease Increased osteoclast formation Bone resorption > bone formation Bone turnover increases serum calcium Loss of estrogen also sensitizes bone to respond highly to parathyroid hormone When serum calcium becomes low, the parathyroid releases PTH to stimulate vitamin D production o Vitamin D increases absorption of calcium in the kidney and the intestine as well as stimulating osteoclasts o With no estrogen, the bone now releases more calcium for the same amount of PTH stimulation further weakening the structure Standard Tx: bisphosphonates, not calcium
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Skin Skin aging Lack of estrogen Decline in skin collagen Decline in Cognitive Function Estrogen is protective for the CNS o Estrogen protects against neuronal oxidative stress/cytotoxicity o Decreases the amount of amyloid protein deposits Alzheimers disease
Apale,Aquino E., Aquino J. Arceo,

Constantino

Bone mineral density (BMD) measurements may be used to diagnose osteoporosis, determine fracture risk, and identify women who would benefit from therapeutic interventions. Dual x-ray absorptiometry (DXA) of the hip and spine is the primary technique for BMD assessment. Women should receive 1,000 to 1,500 mg of calcium and 400 to 800 IU of vitamin D daily. Hormone therapy is effective in preventing and treating osteoporosis. In observational studies, estrogen therapy has been shown to reduce osteoporosis-related fractures by approximately 50% when started soon after menopause and continued long term. The World Health Organization (WHO) has established the following definitions: Normal BMD as a T-score > - 1 standard deviation of the mean Osteopenia as BMD between -1 and 2.5 SD Osteoporosis as a T-score < -2.5 SD The National Osteoporosis Foundation recommends testing in BMD: Women > age 65 years Post-menopausal women age 50-69 years with an increased risk profile Women > age 50 years with fracture Women with a medical condition (eg. Rheumatoid arthritis) or taking a medication (eg. Glucocorticoid > 5mg daily dose prednisone or equivalent for > 3months) that will pre-dispose to low BMD Women being considered for pharmacological therapy for osteoporosis Women being treated for osteoporosis, to monitor their progress Post-menopausal women discontinuing estrogen therapy PATHOPHYSIOLOGY OF MENOPAUSE ORGAN CHANGES

o o o o o

Urinalysis Liver enzymes Ultrasound DEXA Mammogram

TREATING THE WOMAN IN MENOPAUSE Vasomotor symptoms Lifestyle change Non-hormonal medications: phytoestrogens, SSRIs, gabapentin Estrogen replacement therapy o Give COMBINED estrogen/progesterone Otherwise, unopposed estrogen in endometrium will predispose one to having CA Osteopenia vs Osteoporosis 1. Bisphosphonates Alendronate (Fosamax) 10 mg daily tablet, 70 mg weekly tablet or liquid formation Risedronate ( Actonel) 5 mg daily tablet, 35 mg weekly tablet or 75 mg on 2 consecutive days tablets or 150 mg monthly tablet Ibandronmate (BOniva) 2.5 mg daily tablet, 150mg monthly tablet or 3 mg IV therapy every 3 months Zoledronic Acid ( Reclast) 5 mg IV thertapy yearly 2. SERMs Raloxifene HCl (Evista) 60 mg daily 3. Calcitonin Calcitonin Salmon (Miacalcin or Fortical) 200IU intranasal spray daily 4. MHT
Estrogen

5. PTH
Recombinant PTH(1-34) Teriparatide ( Forteo) 20 g SQ daily 6. Hormone replacement therapy 7. Conjugated equine estrogen 0.625 mg 8. Estrogen creams 9. Estrogen ring 10. Estrogen patch

PREMATURE OVARIAN FAILURE


Commonly referred to as premature ovarian failure (POF) but this is a misnomer as there is varying ovarian function in 50% of patients with POI Formal diagnoses made via history of amenorrhea for >4 months + 2 serum FSH levels gathered >1 month apart in a woman POI is ovarian failure with a high FSH level (primary hypogonadism) o Loss of oocytes lack of folliculogenesis lack of ovarian estrogen production o Clinical presentation is a per menopause when at the full end of the spectrum of insufficiency amenorrhea and estrogen deficiency symptoms Recommend karyotyping for relatives Women with POI tend to be smaller, and their ovaries go into atresia early on.

(This chart is reproduced at the end of this trans) APPROACH TO THE WOMAN IN MENOPAUSE History and physical examination Appropriate laboratory tests o Pap smear o Lipid profile o FBS o FOBT o CBC
Apale,Aquino E., Aquino J. Arceo,

Constantino

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Ovarian failure occurs before 40 years of age in 1% to 5% of women and is considered pathologic (premature ovarian failure). Early failure may be caused by decreased follicular endowment or accelerated follicular atresia. If ovarian failure occurs before puberty, the patient's breasts will not develop (i.e., Turner syndrome), and gonadal agenesis results

ETIOLOGY AND PATHOGENESIS Two broad categories: 1. Follicle depletion lack of follicles due to inadequate initial pool of primordial follicles, increased expenditure, or destruction because of a follicle targeting toxin 2. Follicle dysfunction follicles present but non-functional in steroid production due to a pathological mechanism Follicle depletion Depletion due to genetics ( X chromosome disorders or somatic chromosome mutations), autoimmune cause, and ovarian toxins Turner syndrome Genotype is XO; can be a mosaicism with expected range of clinical presentation Turner fetuses contain normal number of primordial follicle germ cells up to week 12 of gestation with subsequent decease in number therefore it is accelerated atresia during the gestational period Ovaries described as streak gonads with extensive connective tissue infiltration and absent to few atretic follicles

Fragile X syndrome is the most common cause of inherited (Xlinked) mental retardation. It is caused by inactivation of the FMR1 gene located on Xq27.3 as a result of expansion of a CGG triplet repeat of more than 200 copies. The normal population has an average size repeat of 30. Female carriers of the disorder have between 60 to 200 repeats (premutations) and are not mentally retarded. Women who have premutations have a 15% to 25% chance of premature ovarian failure (91,92). Interestingly, women with full mutations are not at higher risk for premature ovarian failure. It is hypothesized that expression of abnormal FMR1 mRNA produced by patients with the premutation causes dysfunction in the ovary, which does not occur when the FMR1 gene is inactivated and not transcribed (91,92). Patients with premature ovarian failure have a 4% to 5% chance of having the premutation for fragile X . If premature ovarian failure is present in another family member, the chance of finding a premutation increases to 15%

END

You will never be happy if you continue to search for what happiness consists of. You will never live if you are looking for the meaning of life. Albert Camus Being sorry is the highest act of selfishness, seeing value only after discarding it. -Douglas Horton

FRAGILE X SYNDROME
X-linked form of severe intellectual disability affecting 5 untranslated portion of the FMR1 gene o Full mutation (affected): >200 CGG repeats in the FMR1 region No POI o Premutation: 55 200 CGG repeats Can expand to a full mutation in one generation of transmission Associated with POI increasing number of repeats decreases age at menopause o Gray zone: 40 CGG repeats Can be associated with POI When a female passes on her permutation it can increase the number of CGG repeats and develop into a full mutation, whereas in males the mutation can regress, expand (shy of a full mutation), or stay the same Mechanism for initiation of POI in permutations of Fragile X syndrome is unknown o Potentially increased FMR1 mRNA expression and decreased FMR1 protein Full mutation phase reduced Mean follicular phase FSH increased Inhibin B (follicular phase), inhibin A/progesterone (luteal phase) reduced Mechanism for initiation of POI in permutations of Fragile X syndrome is unknown o Potentially increased FMR1 mRNA expression and decreased FMR1 protein Full mutation phase reduced Mean follicular phase FSH increased Inhibin B (follicular phase), inhibin A/progesterone (luteal phase) reduced Women with intellectual disability at onset. Some have large breasts but with muscular dystrophies.
Apale,Aquino E., Aquino J. Arceo,

Hi IRG! Hi bears!!!

The reason a lot of people do not recognize opportunity is because it usually goes around wearing overalls looking like hard work.

Constantino

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Apale,Aquino E., Aquino J. Arceo,

Constantino

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