MENOPAUSE

Dr. Lucero Premature Ovarian Failure/ Premature Ovarian

Insufficiency
July 17, 2013
- Permanent cessation of menses before age 40
Group 2 Causes of Premature Menopause
 Genetic
Menopause  Enzymatic
- Permanent cessation of menstruation caused by  Immune
ovarian failure  Idiopathic
- Considered to have occurred when there is  Ovarian insults
absence of menses for one full year in a woman  Gonadotropin defects
older than 40 years of age
- Average age of women’s final menstrual period: Menopausal Transition
 51.5 years – U.S. (Perimenopause/Climacterium)
 47-48 years – Philippines - Progressive endocrinologic continuum that takes
reproductive-aged women from regular cyclic,
Types of Menopause: predictable menses to a final menstrual period
1. Premature menopause associated with ovarian senescence
2. Surgical menopause – surgical removal of the - The time between the onset of irregular menses
ovaries or radiation therapy and permanent cessation of menstruation
3. Natural menopause – all women go through - Refers to the time period in the late reproductive
menopause usually between the ages of 45-55 years usually late 40s to early 50
Stages of Reproductive Aging Workshop (STRAW Report, 2001)

Influential Factors for Menopause  Ethnic background – Hispanics or blacks have

 Genetic factors – primary determinant of the age earlier menopause than whites
of menopause  Smoking – associated with menopause onset of
 Higher parity – associated with a later 1-3 years earlier
menopause  Chemotherapy
 Body mass index – greater BMI, later menopause  Pelvic radiation earlier onset of menopause
 Physical or athletic activity – associated with late  Ovarian surgery
menopause
What are the hormonal changes during menopause?
 - Steady decline in androgen levels
Female Reproductive Axis
HPO-Axis Changes during Menopausal Transition

Early Menopausal Transition

- Levels of FSH rise regularly: increased ovarian
follicular response  higher estrogen levels
- Inhibin regulates FSH through negative feedback
thus a decreased inhibin levels lead to elevated
levels of FSH
- Changing level of FSH can lead to fluctuating
levels of estradiol

Late Menopausal Transition

- Increased incidence of folliculogenesis and
increased incidence of anovulation
- Increased FSH levels – reflects reduced quality
and capability of aging follicle to secrete inhibin

Clinical Manifestations during Menopausal

Transition:

1. Menstrual Cycle Changes – reflects changes in

ovarian function and circulating levels of ovarian
and pituitary hormones
 Shortened cycle length – “ovulatory” cycle,
shortened follicular phase
 Prolonged cycle length – “anovulatory” cycle –
associated with DUB and oligomenorrhea
Endometrial neoplasia – hyperplasia/carcinoma
 Normal cycles

2. Other Manifestations:
- Hot flushes
Physiology of Menopausal Transition
- Headaches
- Psychological symptoms
A. Menopausal Transition
- Sleep disturbance
1. Ovary
Pathophysiology of Menopause
- Reduction in the number of follicles
- Remaining follicles less responsive to
gonadotropins Follicular Depletion

- Follicle maturation declines – ovulation becomes
Ovarian Failure
less frequent

- Follicular function vary from cycle to cycle
Estrogen deficiency

2. Endocrine Changes Decreased levels of estrogen is not sufficient to
- Reduced inhibin production induce endometrial proliferation
- Increased FSH levels 
- LH levels may not be affected Amenorrhea
- Fluctuating estradiol and progesterone levels Ovary
- Depleted follicular reserve
- Degeneration of granulosa and theca cells
- Absent FSH receptors

Hormonal Changes During Menopause

I. Ovarian Hormones – marked reduction of estradiol

and estrone
 Estrone – stable circulating reservoir of estrogen;
predominant estrogen in postmenopause
 Aromatase enzyme – converts androgens to
Consequences of Estrogen Deficiency
estrone; present in peripheral tissues,
 Age 45-50 – hot flushes, sweating, insomnia,
predominantly in adipose tissues
menstrual irregularities, psychological/mood
 Androstenadione, DHA and testosterone
disorders
production continues but at a decreased rate
 Age 55-60 – vaginal atrophy, dyspareunia, sexual
dysfunction, skin abnormalities, urge
II. Pituitary Hormones
incontinence
 Elevated FSH – 20-30x higher above
 Age 65-70 – osteoporosis, atherosclerosis
premenopausal years, plateaus 1-3 years after
(cardiovascular diseases), Alzheimer’s disease,
menopause
macular degeneration, stroke
 LH levels rise 2-3 fold after menopause, reflects
loss of negative feedback effect of estradiol
Hot flushes, hot flashes – hallmark feature of
declining estrogen levels in the brain
Declining Estrogen Levels have Special Effects on
Many Tissues:
Fatigue and Sleep Problems
 Urogenital tract
- Trouble getting to sleep
 Skin and soft tissue
- Waking up early
 Bones, teeth
- Difficulty of getting back to sleep after waking up
 Breasts
in the middle of the night
 Hair
 CNS Mood Changes
 Cardiovascular system - Moody
- Irritable
Life After Menopause - Depressed

Signs and Symptoms of Menopause Psychological and Mental Disturbances

- Loss of concentration
- Poor memory – forgetfulness

Effects of Estrogen on Brain Function:

 Organizational actions – effects on neuronal
number, morphology, and connection occurring
during critical stages of development
 Neurotrophic actions – neuronal differentiation,
neuritic extension, synapse formation,
interaction with neurotropine
 Neuroprotective actions – protection agains
apoptosis, antioxidant properties, anti-
Menopausal Symptoms Timeline inflammatory, augment cerebral blood flow,
enhance glucose transport
 Effects on neurotransmitters – acetylcholine,
noreadrenaline, serotonin, dopamine,
glutamate, neuropeptides, GABA
 Effects on glial cells
 Effects on proteins involved in Alzheimer’s
Disease – amyloid precursos protein, Tau
protein, Apolipoprotein E
Somatic Symptoms
- Headache
- Dizziness
- Palpations
- Joint aches, muscle stiffness and back pains
Urogenital Tract
- Dysuria, urinary frequency, urgency, urgency
incontinence, urinary stress incontinence
 Urinary Tract problems:
Urge incontinence – if you have trouble holding
urine when you feel the need to go the bathroom
Stress incontinence – is when you have trouble urine
when you sneeze, cough, run or step down
Long Term Effects of Menopause
Collagen: bone, skin, pelvic, and urogenital
structures
- Estrogen has a positive effect on collagen
- Serves as major support for the structures of the
pelvis and urinary system
- Almost 30% of skin collagen is lost within 5 years
after menopause; collagen decreases
approximately per year for first 10 years after
menopause
Vaginal Atrophy
- Dyspareunia – vaginal dryness, atrophic vaginitis
- Feelings about sex may change – decreased
libido
- Trouble becoming sexually aroused due to
hormonal changes
 On the other hand some women feel freer and
sexier during menopause, relieved that
pregnancy is no longer a worry.
 Remember after menopause, one can still get
sexually transmitted disease and HIV/AIDS.
Hair and Skin
- The skin may become dry, itchy, thin and more
wrinkled
- The hair may become thinner
- Facial hair may grow on the upper lip or chin
Body Changes
- Weight gain in the waist area
- Loss of muscle mass and increase in fatty tissue
- Breast – progressive fatty replacement and
atrophy of glands
Heart
- As estrogen levels go down during menopause,
older women may tend to have higher
cholesterol levels
- High cholesterol increases the chance of heart
disease and stroke and other diseases related to
the heart and blood vessels
- Estrogen favorably affects the lipid profile
- Estrogen increases coronary and cerebral artery
blood flow
- Estrogen favorably affects atherogenic plaque
formation
- Blood flow in all vascular beds decreases after
menopause due to decreased prostacyclin
production, reduced nitric oxide synthetase
activity, constrictive effect to acetylcholine
Osteoporosis
- Menopause can weaken your bones
- Can lead to fractures of hips, wrists, vertebrae,
sacrum
Bones
- Estrogen favors bone formation than bone
resorption
- Estrogen deficiency is associated with prolonged
bone resorption and shortened bone formation,
leading to bone loss
- Loss of trabecular bone (spine) is greater than
loss of cortical bone
- In a span of 4-8 years after menopause
 Bone loss: cancellous bone – 20-30%, cortical
bone – 5-10%
Common Osteoporotic and fracture sites:
 Wrist
 Hip
 Spine
Differential Diagnosis of Menopausal Symptoms:
 Hot flushes, vasomotor symptoms –
hyperthyroidism, febrile illness,
pheochromocytoma, anxiety and psychological
symptoms
 Vaginal dryness, dyspareunia – bacterial
vaginosis, pelvic pathology, marital discord, yeast
infection, poor vaginal lubrication
 Primary osteoporosis – osteomalacia, primary
and secondary hyperthyroidism, excess corticoid
therapy, increased calcium excretion Basal/Parabasal cells – menopause
 Abnormal uterine bleeding – endometrial cancer,
cervical cancer, endometrial hyperplasia,
endometrial polyps, uterine myoma

Diagnosis of Menopause
- Medical history
- Signs and symptoms
- Physical examination
- Laboratory studies Gonadotropin Levels
 Menopausal transition – normal to slightly
Physical Examination elevated FSH; normal LH
 Constitutional – height, weight, BMI, BP  Ovarian failure – FSH >40 mIU/ml, elevated LH
 Cognitive – forgetfulness and scattered thinking
 Psychosocial – depression, anxiety and sexual Estrogen Levels
functioning  Menopausal transition – normal, elevated or low
 Dermatologic – skin itching and wrinkling  Menopause – extremely low or undetectable
 Breast – breast tissue replaced by fatty tissue
Urinary and serum markers of bone resorption and
Laboratory Testing formation
 Vaginal pH - >5 Resorption Formation
 Pap smear Urinary Calcium Bone specific alkaline
 Maturation Index – predominance of parabasal Urinary hydroxyproline phosphatase
cells (100/0/0) Urinary piridinoline Osteocalcin
o Shift to the left - indicates predominance of Urinary deoxypiridinoline Procollagen I extension
Bone sialoprotein peptides:
parabasal and intermediate cells and denotes
Tartrate resistant acid Carboxy terminal (PICP)
low estrogen levels (60/40/0) phosphatase Amino terminal (PINP)
o Shift to the right – reflects an increase in the Crosslinks
superficial or intermediate cells which is - N-telopeptide
associated with higher estrogen levels - C-telopeptide
(0/40/60) - C-terminal
telopeptide of type
Superficial cells – estrogen effect 1 collagen

Bone Mineral Density (BMD)

Intermediate cells – progesterone effect
- Used for bone mass determination
- Dual-energy xray absorptiometry (DEXA) – most
accurate method to measure bone density
- Results are expressed as a T-score, which is the
number of standard deviations (SD) above or
below the young adult reference.
WHO Diagnostic Parameters for Low Bone Mass
 Status Hip Bone Mass Density  Known or suspected estrogen dependent
Normal BMD value within 1 SD of the young neoplasia
adult reference mean; T-score of -1  Active DVT, pulmonary embolism
or above  Arterial thromboembolic disease
Osteopenia BMD value more than 1 SD below  Liver dysfunction or disease
the young adult mean but less than 2  Hyepersensitivity to estrogen
SDs below this value; T-score lower
 Known or suspected pregnancy
than -1 and greater than -2.5
Osteoporosis BMD value 2.5 SDs or more below
the young adult mean; T-score of Risks of Estrogen Therapy
-2.5 or lower  Endometrial cancer
Severe BMD value 2.5 SDs or more below - When estrogen is used without progestins in
osteoporosis the young adult mean; T-score of women with intact uterus
-2.5 or lower, and presence of least - The risk is duration and dose dependent
one fragility fracture - Addition of progestin 10-14 days a month
reduces the risk
Risk Factors for Osteoporotic Fracture in  Uterine bleeding
Postmenopausal Women: - Return of periods especially with addition of
 History of prior fracture
progestins
 Family History of Osteoporosis
 Breast Cancer
 Caucasian race
- The fear of breast cancer is one of the most
 Dementia
 Poor nutrition common reasons women refuse to use estrogen
 Smoking after menopause.
 Low weight and molecular index - The risk of breast CA is related to dose of
 Estrogen deficiency estrogen as well as the duration of use
o Early menopause (age younger than 45 - Recent data showed that addition of
years) or BSO progestogen contributes to the increase risk of
o Prolonged premenopausal amenorrhea breast CA.
(>1year)
 Long term low calcium intake Risk and Benefit for Estrogen Therapy/Hormonal
 Alcoholism Therapy:
 Impaired eyesight despite adequate correction  More Benefit - For young asymptomatic women
 History of falls  More risk than benefit - For older asymptomatic
 Inadequate physical activity
women
 Patients should be individualized
Management of Menopause

The Decision to use Estrogen

Management options for menopause
 Individual decision-carefully select patient
1. Hormonal therapy
o Symptoms
2. Nonhormonal therapy
o Risk factors
o Individual preferences
Precautions with Estrogen Administration
o Needs
- Estrogen should not be used in women with any
 If hormonal is chosen - flexible
of the following conditions:
 If nonhormonal - alternatives should be offered
 Undiagnosed abnormal genital bleeding
 Known, suspected or history of breast CA
Current Recommendations from the Global
Consensus Statement on Menopausal Hormone
Therapy (2013)
 MHT is the most effective treatment for
vasomotor symptoms associated with
menopause at age, but benefits are more likely
to outweigh risks for symptomatic women before
age 60 or within 10 years after menopause
 MHT is effective and appropriate for prevention
of osteoporosis related- fractures in at-risk
women before age 60 years or within 10 years
after menopause.
 Local low dose estrogen therapy is preferred for
women whose symptoms are limited to vaginal
dryness or associated discomfort with
intercourse.
 Estrogen as a single agent therapy is appropriate
in women after hysterectomy but additional
progeseterone is required in the presence of a
uterus.
 The risk of venous thromboembolism and
ischemic stroke increases with oral MHT but the
absolute risk is rare below age 60 years.
 Observational studies point to a lower risk with
transdermal therapy
 RCTs and observational data as well as meta
analysis provide evidencethat standard-dose
estrogen alone MHT may decrease coronary
heart disease and all cause mortality in women
younger tha 60 years of age and within 10 years
menopause. Data on estrogen+ progesterone
showed that in most RCTs there is no significant
increase or decrease in coronary heart disease.
 The option of MHT is an individual decision on
terms of quality of life and health priorities as
well as personal risk factors such as age, time
since menopause and th4e risk of venous
thromboembolism, stroke, ischemic heart
disease and breast cancer.
 The risk of breast CA in women over 50 years
associated with MHT is a complex issue. The
increased risk of breast CA is primarily
associated with the addition of progesterone to
estrogen therapy and related to the duration of
use. The risk of breast CA attributable to MHT is
small and the risk decreases after treatment is
stopped
 The dose and duration of MHT should be
consistent with treatment goals and safety
issues should be individualized
 In woman with premature ovarian insufficiency,
systemic MHT is recommended at least until the
average age of natural menopause
 The use of custom-compounded bio-identical
hormone therapy is not recommended
 Current safety data do not support the use of
MHT in breast CA survivors. These core
recommendations will be reviewed in the future
as new evidence becomes available
Hormonal Treatment Available for Postmenopausal
Women
A) Estrogens
Oral
- Oral CEE, 0 3, 0.45, 0.625, 0 9, 1 25 and 2.5mg
- Piperazine estrone sulfate, equivalent of 0.625
and 2.5 mg
- Esterified, 0.3, 0.625, 0.9, 1.25 and 2.5 mg
- Macronized estradiol, 0.5, 1 and 2 mg
Transdermal
- Estradiol patches, 0.014, 0.025, 0.0375, 0.05,
0.75 and 0.10 mg/d
- Estradiol gel, 1.5 and 3 mg
Vaginal
- Cream, CEE (0.0625%), estradiol (0.01%)
- Estradiol ring, 2mg, vaginal tablets, 25ug
Parenteral
- Intramuscular injections should be avoided
B) Progesterone
Oral
- Medroxyprogesterone acetate, 2.5,5 and 10mg
- Norethindrone Acetate, 5mg
- Micronized progesterone, 100 and 200 mg
Vaginal 4. Phytoprogestines
- Micronized progesterone, 100 mg 5. Vitamin E
- Progesterone gel, 4% and 8% 6. Environmental and lifestyle changes

C) Androgens Fatigue and Sleep Problems

- If unable to sleep well during the night, take a
Oral nap during the day
- Estimated estrogen and methyltestosterone - Reduce caffeine intake
0.025/1/25mg and 1.25/2.5mg
Osteoporosis
Transdermal - getting plenty of calcium and vitamin D, before
- Patch, 150ug/300ug in development and after menopause can lower the risk of
osteoporosis
Selective Estrogen Receptors Modulators - Milk and dairy products such as butter and
- Raloxifene 60mg
cheese are good source of calcium and vitamin D
- Others for osteoporosis
- Tibolone 2.5mg (not approved in the USA)  Exercise may keep muscles and bones strong
- Human parathyroid hormone 1-34; 20ug  taking estrogens may also prevent bone loss
subcutaneously daily  other drugs for osteoporosis such as raloxiphene,
alendronate, calcitonin
Bisphosphates
- Alendronate 5 and 10mg daily; 35 and 70mg
Treatment of Osteoporosis:
weekly
Non-hormonal Antiresorptive Agents
- Risedronate – 4mg; 35mg weekly
- Ibandronate – 150mg monthly  Bisphosphonates - Risedronate and Alendronate
- Etidronate – 200mg (intermittent)  Calcitonin
Nonpharmacologic Therapy
Indications for Hormonal Replacement Therapy  Calcium
(FDA and Phil. Society of Climacteric Medicine)
 Vitamin D
1. Treatment of moderate to severe hot flashes and
night sweats  Diet
2. Urogenital atrophy  Physical Activity
3. Osteoporosis
Heart Disease
Coping with Menopause - The following tips will help you keep your chance
of heart disease down:
Hot Flushes
 Eat low fat foods such as ruits, vegetables, and
- Go to a cool place
whole grains
- Remove a layer of clothing
- Get a cold drink of water or juice  Do not smoke
- Use a portable fan (airconditioned room does  Maintain a healthy weight
not affect)  Exercise regularly
 Vitamins C, A, E, B complex
Treatment of Vasomotor Symptoms
1. Hormonal Therapy
- Estrogen Problems with Sex
2. CNS agents - to ease vaginal discomfort during sexual
- SSRI intercourse, use water based lubricants such as
3. Alternative medicine K-Y Jelly, Ultraglide, Felina
- Phytoestrogens, soy products, black cohosh
- Other creams and medications are also used to
alleviate these problems.
Hair and Skin
 Using sunscreen and not smoking and limitation
of alcohol intake can help reduce wrinkles
 Unwanted hairs may be removed by a variety of
methods
 Exercise
 Use moisturizers
 Vitamins

Incontinence
 limit caffeine
 exercise pelvic muscle
 train bladder to hold more urine
 talk to your doctor

Body Image
 regular exercise
 eat low fat foods
 skin care (suncreen & moisturizers)

Summary
- Menopause is a normal stage in a woman's life.
- During menopause, women go through physical,
mental, and emotional changes

Sources:
Dr. Lucero’s powerpoint
William’s Gynecology
Current Dx and Tx
Google (pictures)
Proofreader: Sameon