Menopause copy joannie

Menopause
Dr. Joannie Neveu (PGY-3)
Memorial University

Overview
• Definitions
• Physiological changes
• Diagnosis
• HRT: history and controversies
• Treatments
• Preventive health care

...
• Average age of menopause : 51.5 y/o
• Influential factors:
• Smoking ( 2 years)
• Chemotherapy
• Pelvic radiation
• Ovarian surgery

Definition
• Menopause:
1 year after the cessation of menses
• POF:
cessation of menses before 40 and associated
with an ↑FSH
• Menopausal transition:
begins w/ menstrual irregularity and extend
to 1 year after permanent cessation of menses

Definition
• Early menopausal transition:
• Regular cycle
• Variable length (> 7days different from N)
• FSH ↑, E may ↑ in early follicular phase
• Normal ovulatory cycle may be interspersed

Definition

• Late menopausal transition:
• Irregular cycle
• ≥ 2 skipped menses and 1 interval of
amenorrhea (≥ 60 days)

Overview
Hypothalamus-pituitary-ovarian axis change
Ovarian changes
Endometrial changes
Central thermoregulation changes
Bone metabolism and structures changes
Cardiovascular changes
Weight gain and fat distribution changes
Dermatologic, dental and breast changes
CNS changes
Psychosocial changes
Libido changes
Lower reproductive tract changes

Physiological
changes
Hypothalamus-Pituitary
Ovarian Axis Changes

The axis
• Arcuate nucleus release GnRH in a pulsatile
fashion
• GnRH binds to its receptors on the pituitary
• Stimulates cyclic LH and FSH release
• LH/FSH binds to receptors on ovaries
• Stimulates production of ovarian steroids:
Estrogen, progesterone, inhibin

Steroids production

• Granulosa ¢ : Estrogen , Inhibin
• Theca ¢ : Androgen
• Corpus luteum : Progesterone

The axis
• Reproductive year :
• Estrogen/Progesterone
➔ exert positive & negative feedback.
• Inhibin
➔ exert negative feedback.
• Feedback to :
➔ amplitude/frequency of GnRH release
➔ pituitary gonadotropin production

The Axis
menopausal transition
• Level of FSH rise slightly ➔ ↑ovarian follicular response
• ↑ # follicles in the cohort ➔ Higher E level
• Accelerated loss of follicles ➔ ↓ quality and capability of
aging follicles to secrete inhibin ➔ rising FSH ➔ supply
follicle is depleted

The Axis
menopausal transition

• Ovarian steroids release ceases ➔ negative feedback loop
is open ➔ GnRH is release at maximal frequency &
amplitude
• FSH&LH ↑ up to 4 fold higher than in reproductive years

Physiological
changes
Ovarian Changes

Ovarian changes

• Ovarian senescence begins in utero
(programmed oocyte atresia)

Variation
oocyte number & hormones

Ovarian changes
• From birth onward : primordial follicles are
continuously activated, mature partially and
then regress (independent of pituitary)
• More rapid deletion starts in late 30s early 40s
• Average women has ~ 400 ovulations in her
reproductive lifetime

Ovarian changes

• The process of atresia of the nondominant follicles
(independent of menstruation cyclicity) is the prime event
that leads to loss of ovarian activity and menopause

Adrenal steroids & SHBG
changes
Adrenal steroids level:
•↑ age = ↓ DHEAS, ↓ androstenedione
(regardless of menopausal status)
Sex-Hormone-binding globulin:
•SHBG ↓ after menopause ➔ ↑ free E, T

Physiological
changes
Endometrial changes

Endometrial changes

• Late menopausal transition : ↑ anovulation
• Endometrium display estrogen effect when
unopposed by progesterone
• Proliferative/disordered proliferative changes
are frequent findings on EMBx.

Menstrual disturbance
• Irregular cycle in > 50% of women in menopausal
transition
• DDx:
Anovulation (most common)
Endometrial hyperplasia
Endometrial polyp / fibroid (E-sensitive neoplasma)
Pregnancy
Infection
Endometrial CA

Endometrial Cancer
• Incidence:
• Menopausal transition : 0.1% per year
• Menopausal transition w/ AUB : 10%
• Malignant precursor are more prevalent:
• E.g. Complex Endometrial hyperplasia
(more common in menopausal transition)

Non cancerous
disordered proliferative changes of
endometrium
• From estrogen effects unopposed by
progesterone
• Premenopausal ➔ anovulation
• Postmenopausal ➔
• Extragonadal endogenous E production
(e.g. obesity)

• ↓ SHBG = ↑ unbound hormones
• Unopposed estrogen administration

Evaluation of AUB
Ultrasound: (endometrial thickness)
• Can be use to avoid EMBx
• EMBx not required if < 5mm (Speroff)
EMBx:
• Can be done in office vs D&C in OR
• <10% postmenopausal pt can’t be done in office most
often 2° to stenotic Cx
• Misoprostol 100 mcv PO night before or morning of

Evaluation of AUB

Hysterocopy and D&C
• Can be Dx and treatment
• Allows evaluation of focal lesions
• Misoprostol 100 mcv PO night before or morning
of

Physiological
changes

Central Thermoregulation
changes

overview

• Vasomotor symptoms
• Sleep dysfunction and fatigue

Central thermoregulation
Incidence :
• Most common complaint of perimenopausal pt:
Hot flushes/flashes & night sweats (60-80%)
• Hot flashes : (↓ with time)
• start 2y before FMP
• 85% of pt who experienced it will do for >1y
• 25-50% will experienced them for 5 years
• 15% may experienced them for >15 years

Hot Flushes
• Wave of heat over the body
• Last 1 to 5 minutes
• ↑ skin T° b/c peripheral vasodilatation
• Sweat primarily on the upper body
• ↑ systolic BP, ↑ HR (7-15 bmp)
• Skin temperature gradually return to N
• Significant contributor to sleep disturbance

Risk factors
• Surgical menopause (90% probability during 1st
year)
• Race/ethnicity ➔ black > white > asian
• BMI ? (SOGC obesity / Williams thinner lady)
• Early menopause
• Smoking
• SERMs
• Exposed to high ambient T°, hot drinks, R-OH

Pathophysiology

• Dysfunction of central thermoregulation
centers in the hypothalamus (narrowing of this
“thermoneutral zone” )
• Small changes in T° can evoke regulatory
response of sweating or shivering

Pathophysiology: Estrogen
• Play a vital role in the development of hot flashes.
Different hypothesis:
• ? Estrogen withdrawal
• ? Rapid fluctuation
• Not related to low level estrogen:
• Supported by: pt w/ Turner (lack N estrogen level)
don’t have hot flushes unless Tx and then withdrawn

Pathophysiology:
Neurotransmitters
• Norepinephrine:
• Primary NT responsible for lowering the
thermoregulatory set point (trigger heat loss
mechanism)
• Serotonin:
• Complex role

Pathophysiology:
Neurotransmitters

Hypothesis :
• ↓ and fluctuation of E ➔ ↓ presynaptic α2-receptors
• ↑ NE and serotonin ➔ lower the thermoregulatory
nucleus ➔ trigger heat loss mechanism

Perimenopausal &
postmenopausal

Treatment
• Estrogen is the most effective (see HRT section)
• ↓ by 75% hot flashes compared to placebo
• Transdermal patch : avoid first liver passage
• Progestin alone (see HRT section)
• Mild reduction in hot flashes (use when E contraindicated)
• Nonhormonal options that have shown some efficacy:
(but they have their own side effects…)
• Bellergal
• Clonidine
• SNRIs
• Gapapentin
• Zopiclone (sleep aids)
• Complementary and Alternative Medecine (acupuncture, naturopathy,etc.)

Treatment:
Non-Hormonal : SSRI
• Effexor, Prozac, Paxil, Pristiq : modest improvement in RCT compare to
placebo
• ↓ hot flashes:
• Effexor 37.5 mg/d ➔ 37%
• Effexor 75 mg/d ➔ 61%
• Effexor 150mg/d ➔ 61%
• Placebo ➔ 27%
• Paxil and Prozac also had ↓ in hot flashes
• When translated by event ➔ ↓ of ~1-2 hot flashes/d compare to
placebo.
• Need to balance against s/e : n°,d°,h/a,insomnia,fatigue,sexual dysfct

Treatment:
Non-Hormonal: clonidine
• Centrally active α2-adrenergic receptor agonist
• One study (1987)
Clonidine 0.1 mg/d transdermally x 8w
• 12/15 had ↓ vasomotor Sx vs 5/14 in placebo
group
• s/e : dry mouth, hypotension, dizziness,
constipation, sedation
• Low-dose clonidine is ineffective for many
women, and higher dose would magnify the s/e.

Treatment:
Non-Hormonal : Gabapentin
• 2003 Guttuso & associates :
• 900 mg PO/d for vasomotor Sx
• 45% ↓ hot flashes vs 29%↓ w/placebo
• s/e : somnolence
• 2006 Reddy & coworker RCT
• 60 pt in 3 groups ➔ x 12weeks
• Gabapentin 2400mg/d (↓ 71%)
• CEE 0.625mg/d (↓ 72%)
• Placebo (↓ 54%)
• S/E (25% of pt Tx w/ Gabapentin) : h/a, dizzy, disoriented

Treatment:
N n-Ho rm o na l : αlp ha -m e thy ld o p a
o

• NOT recommended ➔
significant s/e and modest improvement
• Aldomet 500-1000 mg/d ➔ 2x more effective than placebo
• S/e: dizziness, nausea, fatigue, dry mouth, ↓BP

Treatment:
Non-Hormonal : Bellergal
• NOT recommended : limited efficacy & significant s/e
• Sedative
• contains:
phenobarbital, ergotamine tartrate and belladonna
alkaloid
• RCT : modest to no reduction in Sx vs placebo
• >30% pt withdrew b/c of side effect and ineffectiveness
• Barbiturate are addictive and not recommended for longterm use

Complementary and
alternative medecine

Treatment:
• Acupuncture:
• RCT — multicenter, perimenopausal and postmenopausal
• Tx groups (10 or 12 sessions) vs control group.
• Significant ↓ hot flash frequency & intensity. BUT: Small study groups and had
data from only short-term therapy and follow-up.
• Adiposity
• 2 hypothesis:
• 1- aromatization of A ➔ E in body fat should lead to ↓ hot flash frequency.
• 2- High body fat should be associated with ↑ hot flashes from insulating effects.
• Thurston and colleagues (2008) found that ↑ abdominal adiposity was associated
with ↑ odds of hot flashes. Their suggestion is that fat loss and aerobic exercise
may improve the severity of hot flashes.

Treatment: Phytoestrogen
(isoflavone)
• Plant-derived compound that binds to ER —agonist & antagonist effect
• Found in soy product & Red clover
• Small studies evaluating their effectiveness for the Tx of hot flashes have noted no
efficacy or mixed results (Krebs, 2004).
• Soy product:
• Genistein & daidzein (isoflavone)
• Assumed to bound to ER ➔ shouldn’t assume that these dietary supplements are safe
for women w/ E-dependant cancer
• Albertazzi & col (1998) : 76 mg of isoflavone ↓45% hot flashes vs 30% w/ placebo
• Cheng & ass (2007) 60 mg of isoflavone daily x 3 months (↓57%)
• Levis & col (2011) Double-blind clinical trial w/ breast Ca survivor ➔ higher rate of
hot flashes compare to placebo
• Effect of soy protein in various food aren't bioequivalent.
Eg. processing in manufacture of tofu and soy milk remove the biologically active form.

(isoflavone)
• FLAXSEED
• (Linum usitatissimum) is rich in -linolenic acid, (omega-3 fatty acid)
• Use to ↓ inflam°, bone turnover, ♥ disease, cancer, DM, and cholesterol levels.
• For perimenopausal women, it also is purported to protect against breast cancer, hot flashes, and mood
disturbances.
• Data regarding efficacy for Tx of hot flashes are limited.
• Lewis and coworkers (2006)
• Double-blinded, RCT (87 pt in 3 group : soy, flaxseed, wheat).
• No significant difference in vasomotor symptoms among the three groups.
• Lemay and associates (2002) found 40 g of flaxseed as effective as 0.625 mg of CEE for the Tx of mild
menopausal symptoms in a randomized cross-over study comparing the two.
• RED CLOVER
• Trifolium pratense is a member of the legume family. Contains at least 4 estrogenic isoflavones a
• Several studies have failed to demonstrate an effect over placebo in the Tx of menopausal symptoms
• RCT: placebo over red clover : No significant change in hot flash frequency was reported (Tice, 2003).

(isoflavone)
• DONG QUAI
• Chinese herbal medicine (root of Angelica sinensis) and is the most commonly prescribed Chinese herbal
medicine for "female problems."
• Most herbal practitioners seem to agree that it is contraindicated during pregnancy and lactation.
• 1997 Hirata and coll. ➔ Double-blinded controlled clinical trial (daily dong quai dose of 4.5 g)
• Tx group and placebo group both reported a ↓ hot flashes (25%).
• Critics of the study have noted that the dose of dong quai was lower than that often used i
• Potentially toxic: conntains numerous coumarin-like derivatives (↑ bleeding or interactions with other
anticoagulants)
• Contains psoralens and is potentially photosensitizing, which ↑ concerns of sun exposure-related skin
cancers.
• BLACK COHOSH
• 2x RCT: did not ↓ frequency of vasomotor symptoms compared with placebo (Geller, 2009; Krebs, 2004).
• Few adverse effects have been reported BUT the long-term safety of these products is unknown.
•

.

Treatment:
phytoprogestin
• Extracts, tablets, and creams derived from yams are claimed to be
progesterone substitutes and are frequently sell as a natural source of DHEA.
• Sterol structures from the plant do not have inherent biologic activity.
• Plant sterol dioscorea CAN’T be converted in the body into progesterone.
• There is no human biochemical pathway for bioconversion of dioscorea to
progesterone or DHEA in vivo.
• Oral ingestion does not produce serum levels.
• Lack of bioavailability ➔ not to be expected to have efficacy.
• Wild yam extracts are neither estrogenic nor progestational,
• There are no published reports demonstrating the effectiveness of wild yam
cream for postmenopausal symptoms.

Treatment:
• Vitamin E :
(Barton 1998) 125 pt with a Hx of breast Ca
• ↓ 25% hot flashes vs ↓ 22% w/ placebo.
• ↓ one hot flash per person per day
• Environmental & life style:
• Fan, dressing in layer, cool shower temporarily help
• Relaxation techniques/meditation can ↓ Sx
• stop smoking, weight loss

1.Lifestyle modifications: ↓ core body T°, regular exercise, wgt management, smoking cessation, and avoidance of known
triggers such as hot drinks and R-OH may be recommended to ↓ mild vasomotor symptoms. (IC)
2.MD should offer HT (E alone or EPT) as the most effective therapy for the medical management of menopausal Sx. (IA)
3.Progestins alone or low-dose OCP can be offered as alternatives for the relief of menopausal Sx during perimenopause
(IA)
4.Nonhormonal Rx, including Tx w/ certain antidepressant agents, gabapentin, clonidine, and bellergal, may afford some
relief from hot flashes but have their own s/e. These alternatives can be considered when HT is CI or not desired. (IB)
5.Limited evidence of benefit for most complementary approaches foe hot flashes. W/o good evidence for effectiveness, and
in the face of minimal data on safety, these approaches should be advised with caution. Most approaches have not been
rigorously tested for the Tx of moderate to severe hot flashes, and many lack evidence of efficacy and safety. (IB)
6.Any unexpected PVB that occurs after menopause is considered PMB and should be investigated. (IA)
7.HT should be offered to pt with POF or early menopause (IA) and it can be use until the age of natural menopause (IIIC)
8.Estrogen therapy can be offered to pt who have undergone surgical menopause for the Tx of endometriosis. (IA)

Sleep Dysfunction
• Difficulty in sleep onset and maintenance are
common
• Sleep fragmentation is commonly associated
with hot flushes ➔ daytime fatigue, mood
lability, irritability, problem with short-term
memory
• As women age ➔ more likely to experience
lighter sleep

Sleep Dysfunction
• Lead to fatigue, irritability, depressive Sx and
cognitive dysfunction
• Relationship between vasomotor Sx and
impaired sleep (Hollander 2001)
• ↑ hot flushes = ↑ sleep disturbance
• Fatigue 2° to vasomotor Sx, difficulty sleeping
or independent risk factors (unresolved)

Fatigue prevention
instructions
• Obtain adequate sleep every night
• Exercise regularly to ↓ stress
• Avoid long work hour, maintain your personal schedule
• If stress is environmental :switch job, take vacation,etc.
• Limit intake of R-OH, drug and nicotine
• Eat healthy and well-balanced diet
• Drink adequate amount of water
(8-10 glasses in the early part of the day)
• Menopausal medecine

Treatment:
Sleep medication
• Indication : night sweats and sleep disruption
• Antihistamine, diphenhydramine
hydrochloride (cheap, over-the-counter)
• Insomnia Tx : Zopiclone ➔ improve sleep
and positively affect mood, QOL, next day
functioning, menopause-related Sx
— RCT 2006 (Soares)

Physiological
changes
Bone metabolism and
structural change

Bone metabolism change
• Peak bone mass is influenced by heredity and
endocrine factors
• Almost all bone mass in hip and vertebral bodies
is accumulated in young women by late
adolescence (peak)
• Bone reposition is couple with bone formation
(positive bone balance until bone maturity 25-35 y/o

• Thereafter : steady ↓ bone mass (0.4% year)
• ↓ ↓ during menopause

(2-5% per year for the first 5-10y then 1% per year)

Osteoporosis sequelae
• Fx are the most debilitating and $$ consequences
• Spine, hip and wrist are the most common
• Associated with significant M&M:
• Mortality hip Fx : 30%
• Only 40% of pt w/ hip Fx go back to their prefracture
level of independence

Osteoporosis
• Definition: impairment in bone strength due to an
abnormal quantity or quality of bone, or both
• Quantity:
determined by BMD
• Quality:
determined by several factors; degree of
mineralization, connectivity of the bony
trabeculae, quality of the collagen fibres, and
health of the bone ¢

pathophysiology
• Primary osteoporosis:
• Bone loss associated w/ aging and
menopausal estrogen deficiency
• As E ↓ bone resorption ↑
(most rapid in early postmenopausal)
• Secondary osteoporosis:
• Caused by disease or medication

PTH response
• ↓ Ca intake or gut absorption ➔ low [ca] serum
• ↓ [Ca] ➔ ↑ production of PTH
• ↑ PTH = ↑ bone resorption to ↑ [Ca]
• Premenopausal pt : after ↑ in Ca, PTH quickly
return to N
• Postmenopausal pt : greater response to PTH *

Osteoporosis
risk factors
• Low BMD
• Fragility Fx :
• prior vertebral vex ↑ 4x risk of an other Fx
• 20% of pt have a second vertebral Fx in the following year
• Aging:
• ↑ 8x risk of Fx (from 45 to 85y/o)
• Race: Most common in caucasian
• Genetic: Maternal Hx of hip Fx is a key risk factor
• Risk of fall: ➔ reduce muscle strength, balance, visual acuity,R-OH,Rx
• Glucocorticoid: daily dose ≥ 7.5mg

Osteoporosis
risk factors
Osteoporosis risk factors
Major risk factor
Minor risk factors
> 65 y/o

RA

Vertebral compression Fx

PMHx hyperT4

Fragility Fx > 40 y/o

Chronic anticonvulsant Tx

Systemic glucocorticoid Tx >3months

Low diet Ca intake

Malabsorption syndrome

Smoking

Primary hyperPTH

Excess R-OH

Propensity to fall

Excessive caffeine

Osteopenia apparent x-ray

Weight less 57kg

Hypogonadism

> 10% wgt loss at 25 y/o

Early menopause (<45y/o)

Chronic heparin therapy

Screening (BMD)
• Women ≥ 65 y/o
• Women with 1 or more major risk factor
• Women with 2 minor risk factors
• Women who sustain fractures
• Women on treatment

Osteoporosis Dx
• BMD is the standard (reported in T-score)
• DEXA of lumbar spine, radius and hip
• Lumbar spine :
• Trabecular bone ➔ less dense, rapid remodeling
• Early rapid bone loss can be evaluate there
• Greater trochanter/femoral neck:
• Cortical bone ➔ more dense and compact
• Ideal for assessment of hip fracture risk

Osteoporosis Dx
BMD and T-scores:
• Reported and standard deviation : variance of an
individual’s BMD from that expected for a person of
the same sex at peak bone mass (25-30 y/o)
• Normal BMD: T-score between +2.5 and -1.0
• Osteopenia: T-score between -1.0 and -2.5
• Osteoporosis: T-score lower than -2.5

Osteoporosis Dx
• 2005 : Osteoporosis Canada recommended
identifying absolute fracture risk by
integrating key risk factors : age, BMD,
prior fracture, glucocorticoid usage
• 10 year Fracture Risk Assessment Tool
• FRAX (WHO)

(include also FmHx, smoking, RA, 2° causes of OP, R-OH >3/d)

Osteoporosis Dx
• 10 year Fracture Risk Assessment Tool & FRAX gives you
a percentage:
• High : >20%
• Moderate: 20-10%
• Low: <10%
• The additional effect of a pre-existing fragility Fx or glucocorticoid
use moves the patient 1 risk category higher
• Very high risk: Fx during antiresorptive Tx or significant bone loss
during Tx

Who needs treatment?
• High risk ➔ treatment (Raloxifene or biphosphonate PO or IV)
• Moderate risk ➔ management decision should be individualized
• Low risk ➔ r/o 2° causes and implement prevention strategies
VitD & Calcium
Exercise
↓R-OH (<2/d), ↓coffee (<4/d)
Smoking cessation
Biphosphonate : shown prevent bone loss in postmenopausal women with
osteopenia
HRT (if postmenopausal Sx) protect against OP and Fx
• Very high risk: should be considered for Tx with an anabolic agent ; ensure there
is no 2° causes and the patient is compliant.

Treatment
• Antiresorptive (anticatabolic):
• Inhibit osteoclast activity / ↓bone turnover ➔ ↓ Fx by 30-50%
• Act most quickly on bone w/ high trabecular content (rapid turnover) like vertebrae vs
hip (which is 50% cortical, 50% trabecular)
• Biphosphonates : ↓bone turnover/modest ↑ BMD
• Estrogen: link to E receptor , block the RANKL-induced osteoclast differentiation.
• Raloxifen (SERM): ↓ bone remodeling
• Calcitonin: inhibit osteoclastic bone resorption
• Vitamin D
• Anabolic therapy:
• ↑ production of bone matrix / enhance osteoblastic function
• ↓ Fx by 65% after 18 months Tx in Post-menopausal women w/ OP
• Teriparatide (recombinant PTH)
• ? Strontium ranelate

Treatment
Calcium/Vitamin D:
• WHI : 1000mg Calcium, 400UI vit D
•

29% reduction in hip Fx risk among the women taking 80% or more of their
calcium and vitamin D supplements.

•

A small, but significant, 17% ↑ in the risk of renal stones. So ensure that pts
aren’t using excessive calcium supplementation

• Not sufficient by itself for Tx of OP, it is recommended
as a mandatory adjunct to Rx
• Vit. D 800 IU daily or 10 000 IU weekly
• Calcium : 31-50y/o 1000g daily, >50y/o 1200 mg daily
(williams)

Treatment
HRT
• Estrogen:
• Block the RANKL/RANK interaction required for osteoclast recruitment and
activation ➔ ↓ bone loss ➔ ↑ BMD
• WHI : ↓ 30-39% Fx (E arm)
• Effect loss rapidly following discontinuation of HT

• Combined Estrogen&Progesterone:
• WHI: ↑hip BMD, ↓34% hip&vertebral Fx

• Low, ultralow dose HRT:
• Linear dose response of the skeleton
• RCTs: low dosage can prevent OP in postmenopaisal
• No Fx trial

Treatment
SERM
• Tissue-specific estrogen-agonist/antagonist effects
• Raloxifen is the only one approved for OP
• Most appropriate for Tx of vertebral disease
• MORE trial: Raloxifen 60-120mg daily x 4 y : ↓35-45% Vertebral Fx. Also
2° outcome : ↓ 65% RR breast Cancer. No ↑ CHD.
• STAR trial: ~20 000 pt at ↑risk breast CA : raloxifen 60mg = Tamoxifen
20mg daily. Both drugs ↓ breast CA by 50% but raloxifen had 36% less
uterine CA and 29% less DVT.
• S/E : (1) hot flushes (low incidente) and (2) ↑ VTE RR 1.78

Treatment
Biphosphonate
• Nitrogen containing biphosphonate (Alendronate, Risedronate,
zoledronic acid)
• Antiresorptive effect :
• Binds to hydroxyapatite crystal at site of bone resorption (where
bone matrix is expose).
• Biphosphonate is buried under newly form bone, where it lies
inert w/o skeletal effect.
• When there is bone resorption, the Rx is released and ingested
by osteoclast leading to their deactivation and apoptosis.
• Result in ↓ bone turnover and enhanced bone mineralization
• Compliance is necessary to achieve a ↓in Fx risk.

Treatment
Biphosphonate
• Advantage:
• Ease of administration and tolerability
• IV Rx have less frequent dosing, less GI s/e

• Disadvantage:
• Most common s/e : abdominal pain and dysphagia (but RCT doesn’t support
that)
• c/o : upper GI inflam°, ulceration, bleeding
• (Rare) Osteonecrosis of the jaw (ONJ) : limited mostly to oncology pt
• avascular bone necrosis
• most of the reports have been associated with frequent high-dose iv
• Many of these pt had risk factor: CxTx, RxTx

Treatment
Biphosphonate
• Alendronate:
• ↓risk of vertebral Fx in post-menopausal pt
(regardless of Hx of previous Fx)

Prevention of OP:
1)5mg daily
Treatment of OP:
1)10 mg daily
2)70 mg weekly

• ↓bone resorption and improve BMD
• ↑ BMD at the lumbar spine and hip continue through 10 years of Tx

• Risedronate:
• Maintain bone mass and preserve bone microarchitecture
• ↓ vertebral and non vertebral Fx
• 5 mg daily :
• ↓new Fx within 6 months, ↓ vertebral Fx within 1y
• ↑BMD at lumbar spine by >5% during 2y of Tx
• ↓ in vertebral Fx risk are independent of ↑ in BMD

Prevention&Tx of OP:
1) 5mg daily
2) 35mg weekly
3) 75mg x2d q month

Treatment
Biphosphonate
• Zoledronic acid:
• Most potent biphosphonate available
• 4mg IV doses : approved for prevention&Tx of
metastatic bone disease and hyperCa++ 2° malignant
disease
• 5mg IV annualy ➔ Tx Paget’s disease and
postmenopausal OP
• ↓ risk of vertebral Fx (3y) by 70% and hip Fx by 41%
• Improvement BMD and ↓ height loss

Treatment:
Clinical capsule
Biphosphonate

• Poor bioavailability ➔ should be taken on a
empty stomach w/ adequate water for
proper dissolution and absorption
• Take in the morning with water
• No other intake for 30 minutes
• Remain upright (sit/stand) for 30 minutes

Treatment
Calcitonine
• Produced in thyroid gland
• Inhibit osteoclastic bone resorption
• Poor GI absorption ➔ subcutaneous or nasal
• 200 IU daily by nasal spray is approved for Tx
• BMD stabilizes at the lumbar spine and hip
• ↓ 21% vertebral Fx (failed to prove ↓ non vertebral Fx)
• Have analgesic effect ➔ useful in managing the pain of
acute vertebral compression Fx.
• s/e : 3% rhinitis, 8-10% nausea or gastric discomfort

Treatment
Denosumab (Prolia)
• Human monoclonal Ab against RANKL
• Prevent osteoclast activation (↓ bone resorption)
• Subcutaneous injection twice a year
• FREEDOM trial : ↓68% vertebral Fx, ↓ 40% hip Fx.
• ↓ bone turnover and ↑ BMD in OP and cancer pt
• Seem to be as effective as Forteo or Zolendronate and is
perhaps more effective than oral biphosphonate
• Because it’s an antibody ➔ its potential to affect the immune
system requires assessment

Treatment
Anabolic agent
• Teriparatide (PTH): - Forteo
• 20 mg SC x 21 months ➔ 9% ↑ in lumbar spine BMD and improved femoral-neck
and whole-body BMD.
• ↑ osteoblast # and activity.
• ↓ Risks for vertebral Fx (65%) and nonvertebral Fx (53%)
• Dramatic ↑thickness, density, # of trabeculae and ↑ cortical thickness & bone size.
• ↓ back pain has also been noted with teriparatide use.
• Well tolerated, with only minor s/e: n°, h/a, mild hyperCa++, leg cramp
• ATTENTION: dose & duration-dependent relationship between teriparatide and
osteosarcoma
• Osteosarcoma has not been seen in humans or in studies with monkeys. To date,
about 300 000 people have been treated with teriparatide, and 1 case of osteosarcoma
has occurred, which is comparable to the background incidence of osteosarcoma of 1
in 250 000.

Treatment
Anabolic agent
• Strontium ranelate
• antiresorptive effects + anabolic properties.
• Not associated with an ↑ risk of osteosarcoma.
• 9% ↓ new vertebral fractures at 1 year (2 g daily)
• 16% ↓ nonvertebral fractures
• 36% ↓ hip fracture
• S/e: n°, d°

Treatment
• Exercise ➔ small but statistically
significant ↑ BMD in pt doing aerobic
exercise and resistance training
• Fall prevention strategy
• ↓ caffein intake & sodium intake

Recommendation:
1. The goals of OP management include assessment of Fx risk and prevention of Fx and
height loss. (1B)
2. A stable or ↑ BMD = response to therapy in the absence of low trauma fracture or
height loss. Progressive ↓ in BMD, with the magnitude of bone loss being greater than
the precision error of the bone densitometer = lack of response to current therapy.
Management should be reviewed and modified appropriately. (1A)
3. MD should identify the absolute Fx risk in postmenopausal pt by integrating the key
risk factors for Fx; namely, age, BMD, prior fracture, and glucocorticoid use. (1B)
4. MD should be aware that a prevalent vertebral or nonvertebral fragility Fx markedly ↑
risk of a future fracture and confirms the Dx of OP irrespective of the results of the
bone density assessment. (1A)
5. Tx should be initiated according to the results of the 10-year absolute fracture risk
assessment. (1B)

Calcium and vitamin D
1. Adequate calcium and vitamin D supplementation is key to
ensuring prevention of progressive bone loss. For
postmenopausal pt (recommendation): (IB)
1. Total intake of 1500 mg/day of Ca2+ (food and suppl.)
2. Supplementation of 800 IU/d of vitamin D
2. Calcium and vitamin D suppl. alone is insufficient to prevent
Fx in pt with OP; however, it is an important adjunct to
pharmacologic intervention with antiresorptive and anabolic
drugs. (1B)

Hormone therapy
1. Usual-dosage HT should be prescribed for symptomatic postmenopausal women
as the most effective therapy for menopausal symptom relief (1A) and a reasonable
choice for the prevention of bone loss and fracture. (1A)
2. MD may recommend low- and ultralow-dosage E therapy to symptomatic women
for relief of menopausal symptoms (1A) but should inform their patients that
despite the fact that such therapy has demonstrated a beneficial effect in OP
prevention (1A), no data are yet available on reduction of Fx risk.
Biphosphonate
3. Should be considered to ↓ risk of vertebral, nonvertebral, and hip Fx (IA)
4. Etidronate is a weak antiresorptive agent and may be effective in ↓ risk of vertebral
fracture in those at high risk. (1B)

SERM
1. Tx with raloxifene should be considered to ↓risk of vertebral Fx.
(1A)
Calcitonin
2. Tx with calcitonin can be considered to ↓ the risk of vertebral Fx and
to ↓ pain associated with acute vertebral Fx. (1B)
PTH
3. Tx with teriparatide should be considered to ↓risk of vertebral and
nonvertebral Fx in postmenopausal women with severe OP. (1A)

Physiological
changes

Cardiovascular changes

Cardiovascular disease

• Coronary heart disease, congestive heart
failure, strokes
• Leading cause of death in men/women

Cardiovascular disease
Risk factors
• FMHx
• HTN
• Smoking
• DM
• DLPD
• Obesity
(worse w/ central ➔ ↑ total,LDL,TG and ↓ HDL)
• Age
• Stress

INTERHEART
study (RCT)
• Examining modifiable risk factor
• 94% of CVD is attributed to modifiable RF
•

Current smoking (OR 2.87)

•

Psychosocial stress (OR 2.67)

•

DM (OR 2.37)

•

HTN (OR 1.91)

•

Abdominal obesity (OR 1.62)

Effect of hormones on
cardiovascular function
1. Effect on lipid
2. Effect on hemostasis
3. Effect on carbohydrate metabolism
4. Modulation of blood vessel reactivity
(short-term - nongenomic)
5. Vascular structural remodeling (long term - genomic)

? HTR Cardioprotection

HERS:
• No benefit + early adverse events in pt w/ know CDV
who were randomly assigned to receive CEE & MPA.
Angiographic study :
• HT fails to delay the progression of CVD

? HRT Cardioprotection
Epidemiological and observational studies, clinical trials :
• Suggest possibility of a role for E in primary prevention of CVD
WHI (2002)
• EPT :↑ risk of MI/stroke
WHI (adjudicated findings)
• EPT : No statistically significant ↑ in CVD/death
• EPT : significant ↑ CV events in 1st year but not thereafter ( risk 21 /10 000) w/o ↑ in
CVD mortality
In the EPT arm of the WHI trial the RR for CAD was 1.68 in the first 2 years after the start of HT, 1.25
in years 2 to 5, and 0.66 beyond 5 years.

• E : no evidence of risk nor benefit ➔ suggestion of ↓CVD in pt aged 50-59 at baseline
(HR 0.63) & mortality (HR 0.70)
(*subgroup analysis)

? Cardioprotection
• Why does WHI have different result than clinical
trial ?
• ? Pt who seeks HT are better educated, higher SES; greater
access to health care (Tx for DM, HTN, etc.)
• ? Adhere to HT for disease prevention so they are more
likely to adhere to exercise program, be leaner, drink more
R-OH (affords a degree of ♥ protection)
• ? When they get sick they stop their HT so there is more
death in nonuser than current user of HT

? Cardioprotection
• Why does clinical trial have different result than WHI? Why are
WHI results challenged?
• Greater age of participant & time since menopause onset (loss of
ovarian E production)➔ Average 13y
• Time since menopause correlate w/ extent of subclinical atherosclerosis

• INTERHEARt risk factors were identified in their population
• 70% of women in WHI were > 60 y/o @ enrollment
• Likely that substantial proportion had subclinical CVD

• The ↑ in CVD event during first year is similar to the effect of HT
started in older women in the HERS

WHI (adjudicated findings)
• EPT : significant ↑ CV events in 1st year but not
thereafter ( risk 21 /10 000) w/o ↑ in CVD mortality
Lobo et al. (2 pivotal clinical trial, 4065 young health
menopause patients)
• No ↑ incidence of MI/stroke in the year after
initiation of Tx
• Not followed for long enough to determine whether
there might be longer=term benefit

? Cardioprotection

• KEEPS :

«Critical-window» hypothesis
• Dichotomous effect of HT :
HT at onset of menopause is cardioprotective whereas later
initiation could cause CV events
• 27-hydroxycholesterol (abundant in atherosclerotic lesion) acts as a competitive
antagonist of E receptor.
• Would account for loss of cardiovascular protection from vascular disease in older
women
Saltpeter et al. (meta-analysis w/ 23 RCT)
• HT significantly ↓CHD events in younger (OR 0.68) but not older (OR 1.03)
Saltpeter et al. (meta-analysis w/ 30 RCT)
• HT ↓ mortality when stated in younger group, but not in older group

Summary
• Saltpeter et al, Nurses’Health Study :
↓ incidence of CHD event when initiated younger
• Saltpeter et al, HERS, WHI:
Initiation of HT in older women is associated with ↑
incidence of adverse CHD in the first year only
• Rossouw et al. (2° analysis of WHI):
Didn’t identify any subgroup w/ ↓risk of CHD but
mortality was ↓ in 50 to 59 y/o group

Summary
• Carotid artery progression study:
↓ incidence of CHD event when initiated younger
• Carotid IMT has been followed as an early marker of
atherosclerotic disease
• Women who underwent H-BSO menopause had significantly ↑
IMT after 1 year compare to pt with just hysterectomy
• IMT ↑ among E nonuser and ↓ among E user in early menopause.
No benefit on progression in pt more remote from menopause

• Evidences that HT has no role in ↓ future risks
of CVD events in pt with established CAD.
• The absence of excess absolute risk of CHD
and the suggestion of reduced total mortality
in younger women offers some reassurance
that hormones remain a reasonable option for
the short-term treatment of menopausal
symptoms.”

Premature loss of ovarian
function
• Pt who had BSO had a ↑ risk for CAD
• WHI : pt who didn’t receive HT had 2x risk of
coronary artery calcium compare to pt who
received HT within 5 years of their Sx.
• Supports the need for E following premature
loss of ovarian function at least until the
natural age of menopause if estrogen is not CI
for other reasons

Stroke
Nurses’ Health Study: (observational)
• Dose–response relationship between the use of E and stroke
• Found an association between the use of P and stroke.
Lobo et al.
• No ↑ risk of stroke (4065 newly menopausal started HT : CEE w/ or w/o progestin
in 2 pivotal clinical trials)
WHI (2002)
• ↑ ischemic stroke across all age group
• E only : stroke risk appeared lower in 50-59 y/o then 60-69
• Conclusion cant be reached b/c of the small numbers in the younger group
WISDOM
• No excess incidence of CVA in women with EPT vs Placebo at 1 year

Stroke
• Absolute level of risk of ischemic stroke in
younger menopausal women is low
• Additional risk conferred by HTR : (WHI)
• 8/10 000 ( EPT)
• 13/10 000 (E)

Metabolic syndrome
• The results of large RCTs have suggested that HT ↓ incidence of
new-onset DM
• WHI : ↓ 21%
• HERS: similar ↓ than WHI
• Meta-analysis: 107 trials examining components of the metabolic
syndrome concluded that HT ↓: (in women w/o DM)
• Abdominal obesity
• Insulin resistance, new-onset diabetes
• Lipid levels
• Blood pressure in women without diabetes
• ***↓ insulin resistance and fasting glucose levels in pt w/ DM

DVT
• Oral HRT ↑ risk of VTE (greater in the first years)
• WHI: risk 4.0 (@1y) ↓ 1.04 (@6y)
• Data from WHI analyzed: other factors contribute
• 60-69 y/o had 2x risk of 50-59y/o
• 70-79 y/o had 4x risk of 50-59y/o
• Overweight (2x) obesity (3x)
• Highest risk: women who carries Leifen factor V

DVT
• Greatest risk factor : AGE
• Absolute incidence 2-3/10 000 at 50-54
• Absolute incidence 20-30/10 000 at 80
• ? Risk lower with Estrogen alone
• ? HT not synergistic with obesity and age
• ESTHER study : (case ctrl, multicentre)
risk of VTE ↑ with oral vs transdermal

Protection for CVD

• Premenopausal protection: Estrogen ➔ ↑ HDL
• This benefit disappear after menopause
• Risk of CVD ↑ exponentially for women as
they enter menopause and ↓ E

CVD prevention

• Physical activity
• Avoid gaining weight

Lipid profil
• ↑ total cholesterol
• Low HDL is a strong predictor for CVD
• Total cholesterol and LDL level can be
favorably reduced by :
• Diet modification
• Estrogen treatment*
• Lipid lowering Rx

Coagulation
• Change in clotting parameters occur w/ age:
• ↑ fibrinogen
• ↑ plasminogen activator-1
• ↑ factor VII
• Cause relatively hypercoagulable state

Summary cardiovascular
• First decade after menopause: cardiovascular risks from initiating
HT for distressing vasomotor symptoms are very small.
• Uncertainty remains about whether early initiation of estrogen
may even afford protection from atherosclerosis.
• HT should not be used for primary or secondary cardioprotection.
• Available evidence demonstrates that: initiation of HT should be
done with caution in women who are more than a decade after
menopause b/c it may be associated with an ↑ risk of adverse
cardiac events
• HT appears to slightly ↑ the risk of ischemic stroke

1.MD should not initiate or continue HT for the sole purpose of preventing CVD (IA)
2.MD should abstain from prescribing HT in women at high risk for VTE disease. (IA)
3.MD should initiate other evidence-based therapies and interventions to effectively reduce the risk of CVD
events in pt w/ or w/o vascular disease. (IA)
4.Risk factors for stroke (obesity, HTN, and smoking) should be addressed in all post-menopausal women. (IA)
5.If prescribing HT to older postmenopausal women, MD should address cardiovascular risk factors; low- or
ultralow-dose estrogen therapy is preferred. (IB)
6.MD providers may prescribe HT to diabetic women for the relief of menopausal symptoms. (IA)

Physiological
changes
Weight gain and fat
distribution

Weight gain
• ↑ age = ↓ metabolism = ↓ caloric requirement
• In exercise and diet don’t change = ↑ weight
• Weight gain is not an effect of hormonal changes
• Estrogen therapy doesn’t cause weight gain
(clinical trial and epidemiological studies)

↑ weight and its risk...

• Weight gain in menopause = ↑ abdominal fat
deposition = ↑ risk insulin resistance = ↑ risk of
DM and CVD

Physiological
changes

Dermatologic, dental and
breast changes

Dermatologic
• Intrinsic aging and photo-aging:
• Hyperpigmentation (age spot)
• Wrinkles
• Itching
• Hormonal aging:
• ↓ thickness of the skin (↓ collagen content)
• ↓ sebaceous glad secretion
• ↓ elasticity
• ↓ blood supply

Dental changes
• Buccal epithelium undergoes atrophy due to ↓
E ➔ ↓ saliva and sensation
• Bad taste in the mouth
• ↑ cavity
• ↑ tooth loss
•

Strongly correlated to smoking and hygiene

•

Correlated to osteoporosis

Breast changes

• ↓ E and P = reduction in breast proliferation
• ↓ in volume and % of dense tissue ➔ these
areas become replaced w/ adipose tissue

Treatment
• Skin aging:
• Avoid UV light
• Avoid tobacco
• Lmitation of R-OH intake
• ACOG : "there is insufficient evidence to
recommend estrogen treatment to increase skin
thickness and collagen content and thereby decrease
wrinkling in sun-exposed areas such as the face and
forearms."

Overview
• Hypothalamus-pituitary-ovarian axis change
• Ovarian changes
• Endometrial changes
• Central thermoregulation changes
• Bone metabolism and structures changes
• Cardiovascular changes
• Weight gain and fat distribution changes
• Dermatologic, dental and breast changes
• CNS changes
• Psychosocial changes
• Libido changes
• Lower reproductive tract changes

Physiological
changes
CNS changes:
Mood, memory, fatigue

CNS changes
• Memory decreases with advancing age
• No direct effect of lowered E on memory and cognition has been
determined yet
• High suspicion that there is a relationship
• Study 1995 (Hallbreich):
• Cognitive fct assessment in women in their forties vs
postmenopausal
• 40s: less likely to experienced cognitive decline
• Risk factor for ↓ perfusion and thinning of gray and white matter:
• TIAs, DLPD,HTN,smoking,excessive R-OH, male gender (?lack of
E)

Mood
• Evidence that depression can occur in the absence of
vasomotor symptoms and sleep disturbance.
• Recent systematic review of cohort studies failed to
detect a link between the menopausal transition and
new-onset depression
• They found contributory factors in additional to stage
of menopause that figure into the development of
perimenopausal depression (vasomotor symptoms, life
stress, Hx of depression in a family member,
postpartum blues, a high BMI, and sexual abuse)

Mood
• Limited clinical-trial data :
• Transdermal estrogen may be effective for Tx
major depressive episodes in perimenopausal
women, but not postmenopausal women.
• Psychotherapy and judicious use of
antidepressants will remain the mainstay of Tx
for depression; however, in cases of resistant
depression at the onset of menopause, HT may
be appropriate.

Memory
• Epidemiologic studies:
unable to document cognitive decline in women
throughout the menopausal transition.
• Spatial and semantic memory seem to be relatively
unaffected, whereas episodic memory and, in
particular, verbal fluency may show deterioration.
• having difficulties with word finding and recall.
• General lack of discernible cognitive impairment is
important and reassuring to women

Memory
• The WHIMS trials of EPT and E alone were 2 large RCTs
conducted in older postmenopausal women:
• HTR ↑ risk of cognitive decline.
• Various explanations:
(1) theory that memory is related to cardiovascular health and
that the cognitive decline mirrors the ↑ risk of CVA observed in
older postmenopausal women in the WHI.
(2) there may exist a critical window for neuroprotection.
• The clinical importance of these studies is that they showed no
benefit, and the potential for harm, in administering HT to older
postmenopausal women.

Memory
• Henderson et al (2007) reanalyzed data from the
WHIMS trial:
• All-cause dementia was significantly less likely to
develop in women reporting prior HT
• Women’s Estrogen for Stroke Trial Estrogen
administrated for troke prevention
• No impact of E Tx, except in women with normal
function at baseline, who had less decline in
cognitive domains (RR, 0.46 [95% CI, 0.24 to 0.87])

Memory
• RCT(recent) for prevention of osteoporosis:
• Women randomized to HT had a ↓ risk of cognitive impairment
than those receiving placebo.
• Bagger et al.:
• Early administration of E was associated with significantly
improved performance in cognitive testing 5, 11, and 15 years
later; this study was limited by the absence of baseline cognitive
testing.
• Case-control studies:
• Women who underwent oophorectomy before menopause have
recently shown a small increase in the risk of dementia

What does it mean for our
patient?
• Women experiencing verbal memory changes at menopause can be
advised that there is no apparent association between verbal memory
change and global cognitive decline.
• For best preservation of memory and cognition: good overall health,
good cardiac and vascular health, exercise,maintenance of an active
mind, avoidance of excessive alcohol consumption, and measures to
reduce the risk of diabetes and hypertension.
• HT is not indicated for neuroprotection.
• Two clinical trials in progress may shed additional light on this question.
• Clinical studies support basic science research suggesting that ultralowdosage estrogen therapy may be sufficient for neuroprotection.

Recommendation:
1. Estrogen alone may be offered as an effective Tx for depressive disorders in
perimenopausal women and may augment the clinical response to
antidepressant, specifically with SSRIs (IB). The use of antidepressant
however, is supported by most research evidence (IA).
2. Estrogen can be prescribed to enhance mood in women with depressive
symptoms. The effect appears to be greater for perimenopausal symptomatic
women than for postmenopausal women. (IA)
3. Estrogen is not currently recommended for ↓ risk of dementia developing in
postmenopausal women or for retarding the progression of Dx Alzheimer’s
disease, although limited data suggest that early use of HT in the
menopause may be associated with ↓ risk of later dementia. (IB)

Physiological
changes
Psychosocial changes

Psychological changes
• Psychosocial and cognitive symptoms may
develop during menopausal transition and
include:
•

Depression

•

Mood changes

•

Poor concentration

•

Impaired memory

• Psychosocial factors may contribute:
•

Emotional stress from adolescents

•

Onset of major illness

•

Caring for aging parent

•

Career change

•

Retirement

• Hormonal fluctuation during early menopausal
transition are responsible for this affective instability
• Surgical menopause induces mood changes because of
the rapid hormonal loss at this time
• One placebo-controlled study w/ CEE 0.625mg per day
and it improved significantly sleep and hostility

Treatment
• First line treatment for menopausal women
presenting with depression would be a traditional
antidepressant e.g. SSRI.
• Tx with estrogen for pt with mild to moderate
depression may be an alternative
• Consideration to add HT to a fail response to SSRI

Physiological
changes
Libido changes

Libido
• Definitive data are lacking in regards of the
relationship between circulating hormones and
libido
•

Avis and co. (2000) study 200 women, postmenopausal status was
significantly related to a ↓ in sexual interest. However, after adjustment for
physical&mental health, smoking and marital satisfaction, menopause wasn’t
significantly related to ↓ libido.

•

Tungphasial (1991) study 100 naturally menopause women: ↓ sexual
thought, ↓ sexual activity compared to premenopausal status. They reported ↓
libido, dyspareunia and orgasme dysfunction (86% reporting no orgasms)

Treatment
• Estrogen replacement :
• RCT : significant positive effect of E on mood and
sexuality
• Testosterone:
• Controversial
• Study demonstrate effectiveness however very strong
placebo effect
• Off-label use ➔ s/e hirsutism, acne, △ lipid profile
• improve bone mass, muscle mass and ↓ hor flashes

Physiological
changes

Lower reproductive tract
changes

Lower reproductive tract
changes
• ↓ E ➔ vaginal loss of collagen, adipose tissues and
ability to retain water
• Vaginal walls shrinks, rugae flatten and vagina looks :
flat-walled, pale-pink
• Surface epithelium thins ➔ surface is friable and prone
to bleeding with minimal trauma
• Glandular secretions ↓
• The prepuce of the clitoris atrophies, exposing the gland
to irritation from clothing, prolonged sitting,etc.

Vaginal dryness
• Vaginal dryness ↑ progressively as women
approached and passed through menopause:
• 3% in premenopause
• 25% by 1 year
• 47% by 3 years after menopause
• Women who smoke have higher rates

Vaginal dryness : Treatment
• Local lubricants can alleviate dryness and discomfort but do not
reverse the histologic ∆.
• E.g. polycarbophil-based gel Replens ➔
- more sustained correction of vaginal dryness
- acidity of the gel lower vaginal pH to premenopausal level
• Intravaginal estrogen Tx can be used for vaginal dryness either alone
or in addition to systemic estrogen HRT.
• Cream, ring, tablet are all comparable
• Vagifem had less endometrial proliferation than CEE cream
• Vagifem and ring were more acceptable than cream
• Up to 40% of women receiving systemic Tx do not get an adequate
effect of estrogen on the vaginal mucosa.

Urogenital Treatment
• PV estrogen can have systemic effects if given
in sufficient quantity.
• In a low dose it may be transiently absorbed in
the first 7 to 14 days b/c the thinned
epithelium of the hypoestrogenic vagina
presents a minimal barrier to absorption.
• Generally after Tx for 1 to2 weeks the systemic
level of estrogen is once again at the
pretreatment level.

Urogenital Tx and Breast
Cancer
• Recent evidence: women with breast CA who have
endogenous E levels suppressed by use of an aromatase
inhibitor, systemic absorption of vaginal E, even though very
low, can be detected with conventional assays.
• Data on this finding are very limited at present.
• A large cohort study demonstrated no difference in the
outcome of breast CA for women choosing to receive local
vaginal estrogen therapy, although it is likely that few
women in this study were receiving aromatase inhibitors.
• This suggests caution in prescribing these products if the
intent of aromatase therapy is to completely suppress
endogenous estrogen.

Urinary incontinence
• Urgency incontinence affects:
• 10% of women by age 50
• 15% by age 60
• 25% by age 70
• 35% after age 80.1

• HERS trial: 4.2 years of HRT vs Placebo
• 64% of women assigned to HT vs 49% of those assigned to placebo reported
weekly incontinence (P < 0.001)
• Four years of HT caused an excess risk of 12% for weekly urge incontinence
and 16% for weekly stress incontinence.
• WHI :
• UI developed at a significantly higher rate among continent women taking
CEE alone or with MPA than among continent women taking a placebo.
• UI worsened in women taking CEE alone or with MPA compared with those
taking a placebo.
• Conclude: oral estrogen formulations used in the study ↑ risk of UI and
therefore should not be used to treat it.

• Basic science in this area is limited:
• Randomized clinical trial :
Pt receiving 2 mg of estradiol valerate PO x 6 months showed significant ↓ in total
periurethral collagen
• According to the authors, connective tissue is crucial to:
• the integrated action of the suburethral vaginal wall,
• the pubourethral ligaments,
• the pubococcygeus muscles
• the paraurethral connective tissues;
• consequently, its degradation contribute to the development of urethral hypermobility,
intrinsic urethral sphincter dysfunction, or both, thus setting the stage for stress urinary
incontinence.
• However, there is conflicting evidence:
Using Doppler imaging,they found that HT for 3 months improved periurethral vessel
number and blood flow, therefor improving urethral sphincter function and promote
continence, not worsen it.

Urinary incontinence:
Role of estrogen Tx
• Cochrane Review (2003):
15 small trials evaluating the role of E vs
placebo for the Tx of all UI.
• ~ 50% of the E-Tx women reported
improvement or cure compared with 25% of
those who received placebo.
• The effect was largest in the women with
pure urge incontinence.

• Basically :
• the influence of hormone factors on urethral and bladder
function is still poorly understood
• Data are conflicting
• unlikely that estrogen Tx has a significant role to play in the
treatment of UI
• Aim to optimize risk factors : obesity, amount and type of fluid
intake, smoking, major depression, and the use of certain Rx
• ↓ of 5% in BMI showed an improvement in symptoms

Recurrent UTI

• Recurrent UTI and vaginal infections are more
likely in estrogen-deficient women.
• Both systemic and local estrogen Tx will
correct vaginal health, but only local Tx ↓
frequency of recurrent UTI

Urogenital concerns:
1. Conjugated estrogen cream, intravaginal estradiol ring, or estradiol vaginal
tablets are recommended as effective Tx for vaginal atrophy. (IA
2. Routine progestin cotherapy is not required for endometrial protection in pt
receiving vaginal E (N dose) (IIIC)
3. Vaginal lubricants may be recommended for subjective symptom
improvement of dyspareunia. (IIIC)
4. MD can offer polycarbophil gel (a vaginal moisturizer) as an effective Tx for
symptoms of vaginal atrophy, including dryness and dyspareunia. (IA)
5. As part of management of USI, pt should try nonsurgical optionsuch as
↓weight, pelvic floor physic (±biofeedback), weighted vaginal cones,
functional electrical stimulation, and/or vaginal pessary (II-1B)

Urogenital concerns:
5. Lifestyle modification, bladder drill (II-1B), and anti-muscarinic Tx
(IA) are recommended for the Tx of urge UI
6. Estrogen therapy should not be recommended for the Tx of
postmenopausal urge or USI but may be recommended before
corrective surgery (IA)
7. Vaginal estrogen therapy can be recommended for the prevention of
recurrent UTI in postmenopausal women. (IA)
8. Following treatment of adenocarcinoma of the endometrium (stage
1) estrogen therapy may be offered to women distressed by
moderate to severe menopausal symptoms. (IB)

Sexual concerns:
10.A biopsychosexual assessment of preferably both partners (when appropriate),
identifying intrapersonal, contextual, interpersonal, and biological factors, is
recommended prior to Tx of women’s sexual problems. (IIIA)
11.Routine evaluation of sex hormone levels in post-menopausal women with
sexual problems is not recommended. Available androgen assays neither reflect
total androgen activity, nor correlate with sexual function. (IIIA)
12.Testosterone therapy when included in the management of selected women
with acquired sexual desire disorder should only be initiated by clinicians
experienced in women’s sexual dysfunction and with informed consent from
the woman. The lack of long-term safety data and the need for concomitant
estrogen therapy mandate careful follow-up. (IC)

Herbal remedies
• WHI 2002 ➔ MD abandoned prescription of HT for
vasomotor Sx
• Pt have turned to unproven and untested complementary
therapies
• Multi-billion $ business and only a few have met rigorous
testing criteria required of pharmaceutical products by US
FDA.
• Pharmaceutical regulatory requirement : pt in study
must have average of 7 hot flashes/d or 50/week,
• Most reported study of hebal product: open label and in
women with as few as 1 or 2 hot flashes per day.

Herbal remedies
• Caution about potential adverse safety profiles
• Cautions about interaction w/ pharmaceutical &
anesthetic agents
• New canadian legislation : January 2004
• Removed herbal product from food category
and placed them into a special drug category
(to allow regulation of manufacturing, labeling
and indications)
• Very few accomplished in the regulation so far

Herbal remedies
• Several systematic review :
• No single complementary therapy have been
proven efficacious for moderate to severe
hot flashes
• Same efficacy than placebo
• Direct head-to-dead : HT vs black cohosh,
soy or multibotanical showed only HT to be
more efficacious than placebo.

Historical
studies
- PEPI
- HERS
- WHI

PEPI

Postmenopausal E/P interventions trial
• 1980s E were prescribed not only for vasomotor Sx but also for prevention of
other condition
• PEPI : ~900 pt, Mean age 56 y/o and 5 group, x 3 years
(1)

Placebo

(2)

E

(3)

E + cyclic MDPA

(4)

E + micronized progesterone

(5)

E + continuous MDPA

• 1995 PEPI trial results were published:
• LDL ↓ & HDL ↑ in group 2-5
• Fibrinogen was ↑ in placebo group
• no difference in systolic BP and glucose intolerance
• clinical event : 2 x MI, 1x cardiac arrest, 2 x strokes (all in HRT groups)

Hers
• Published in 1998
• 2800 patients w/ pre-existing ♥ disease receiving E
as secondary prevention Vs placebo group
• 1st year: ↑MI in pt EPT
• After 4y: no difference between the groups OR 0.99

• Started to question the cardioprotective effect of
HRT
• June 2002 ➔ HERS II : Showed that HT wasn’t
beneficial in secondary prevention of heart disease
after 6.8 years

WHI
• Before the result of PEPI & HERS
• WHI was launch in 1993
• Compare EPT vs Placebo in ~16 000 healthy postmenopausal
women aged 50-79. Outcomes:
• Coronary heart disease
• Breast CA
• VTE
• Colon CA
• Bone Fx
• Concurrently they had a E only arm (pt w/o uterus) vs Placebo

WHI
• After 5.2 y the EPT arm was halted b/c risk exceeded benefits
• July 2002 ➔ result released to media prior to publication of the data and education to health care
provider
• 2007 (Rossouw & Colleague) did secondary analysis go WHI data
• Pt started HRT closer to menopause had ↓ risk of CHD vs pt more distant from menopause
• < 10 y from menopause : OR 0.76
• 10-20y from menopause: OR 1.10
• >20y from menopause : OR 1.28
• Pt younger at start of HRT had lower risk of CHD
• 50-59y/o : OR 0.93 (↓ 2/10 000)
• 60-69 y/o : OR 0.98 (↓1/10 000)
• 70-79 y/o : OR 1.26 (↑19/10 000)
• HRT ↑ risk of stroke (OR 1.32) and it didn't vary by age or time since menopause
• WISDOM trial (started 1999) was halted after the WHI result ➔ data collected showed ↑ risk of
CHD & VTE when started many years after menopause

Summary risks
• ↑ risk of CHD in older menopausal women
• ↑ risk Breast Ca ( w/ >5y use)
• ↑ Stroke
• ↑ VTE
• ↑ cholescystitis
• ↑ Ovarian Ca (w/ > 10y use)
• 2 studies showed that (Danforth 2007, Lacey 2006)
• Other studies haven’t confirmed this

Summary benefits
• ↑ BMD
• ↓ rate of Fx
• ↓ colorectal Ca
• Effect on mortality (metanalysis OR 0.98)
• HRT ↓ mortality in <60y/o (OR 0.61) vs
> 60 (OR 1.03)
• Suggest: once CHD is establish, HRT has
no effect in reversing progression

Summary of indications
• Tx of vasomotor Sx & vaginal atrophy
• Tx or prevention of osteoporosis
• Re-evaluation of the need of HRT q 6-12months
• Prescribed in lowest dose for the shortest period
• Bone specific agent would be more appropriate for long-term OP
prevention or Tx
• Use continuous or cyclic progestin (cyclic is useful while in
transition)
• Mirena can be use for progestin
• Low-dose OCP can be useful in transitional period (younger
patient, provide contraception for the occasional ovulation)

Summary of contraindication
• Contraindicated:
� Known/suspected/Hx Breast CA
� Known/suspected/Hx E-dependant CA
� Undiagnose AUB
� Known or suspected pregnancy
� Active/Hx of VTE
� Active or recent (<1y) MI or stroke (Arterial thromboembolic)
� Liver disease
� Known allergy to any component
• Used with caution:
� Dementia
� Gallbladder disease
� Hypertriglyceridemia
� Prior cholestatic jaundice

SOGC’s Canadian Consensus
Conference on Menopause (2006) :
• ↑risk of breast CA detection after 5 years of EPT, with
an RR ~ 1.3 over many clinical trials
• Unopposed E appears to be slightly lower than that
after EPT
• Most women using HT for symptomatic relief use it for
< 5 years
• Risk of breast CA returns to N shortly after d/c of HT
Consensus has been that short-term use of HT for relief of disruptive
vasomotor symptoms carries little appreciable risk for the average woman
entering menopause. Longer-term is a matter for discussion w/ the pt.

WHI
• Women w/ prior HRT had ↑ risk after 3y EPT
• Women w/o use of HRT had no ↑ during the 5 y
• No ↑ risk of invasive breast CA up to 2.4y after WHI
• The ↑ risk of breast CA detection reported for combined
HT in the WHI : HR, 1.24
• The 24% ↑ risk of breast CA translated into an absolute ↑
risk of only 8 additional cases/10 000 hormone users
per year in the older age-mix of the WHI.

WHI
• Factors that modify breast CA risk to a similar/greater degree:
(all HR ~ 1.3)
• Early menarche
• Late menopause
• Post-menopausal obesity
• Delaying pregnancy until after 30
• No breastfeeding
• No exercise
• Consuming excessive amounts of alcohol
• Shift work*(not 1.3)

WHI

• Major risk factor:
• Positive family history (HR 3)
• Past breast Bx with atypic (HR 5)
• Premenopausal women w/ BRCA mutation (HR 200)

WHI

• E only arm : no ↑ in breast CA
but population mostly overweight, and pt obese have an ↑
risk of breast CA so it’s a possibility that there were only a
little added risk when exposed to HT.

Other research
• Other research supports the fact that the effect of
estrogen alone on breast cancer is small and is
usually undetectable with short-term exposure:
• Finish study:
• E for > 4 years resulted in 2 to 3 extra cases of breast
CA per 1000 women followed over 10 years
• No ↑ if treated for less than 5 y
• Harvard’s Women Health study:
• No ↑ in women using CEE after a mean of 10y

2 meta-analasis post-WHI

• Strong statistical evidence that EPT
carries a statistically significant risk for
breast cancer greater than the risk
attributable to estrogen alone

The Million Women Study
• 1 084 110 women (1996 and 2001)
• No ↑ breast CA in past user, regardless
of time since discontinuation and
duration of use
• Current HTR showed ↑RR 1.3 (E) and
↑RR 2.0 (EPT)
• Consistent with WHI

Facilitated detection vs de
novo breast tumor
• Is HTR facilitating the detection of pre-existing small
carcinomas b/c of a more rapid growth ?
• Is HTR causing the development of new malignant
breast tumors by an ↑ frequency of initiating mutation?
• Studies that report the rapid appearance of breast CA
after initiation of HTR ➔ support the hypothesis that
HTR is speeding up the growth and detection of preexisting tumors.
• In support of this hypothesis are data indicating better
outcomes for women whose cancers were detected while
on HTR.

Return to Breast CA risk
shortly after d/c

• Return of the breast CA risk to baseline
shortly after d/c HTR has been
consistently reported in observational
studies

Difference between
progestins
• Many studies have been unable to distinguish
between the progestins used (b/c of low
numbers of users of products different than
MPA)
• E3N cohort study (France): 80 377 pt
• Incidence of breast CA wasn’t ↑ in pt taking E
and progesterone (OR, 1.0)
• Incidence of breast CA was ↑ in pt taking E and
other progestogens (OR, 1.69)

Breast density
• ↑ breast density is an independent risk
factor for breast CA. However, even though
breast density can be ↑ by the use of E with a
progestin, it has never been shown that an
acquired ↑ density (2° hormonal Tx) ↑ breast
cancer risk.
• Estrogen alone and low-dose or transdermal
combination therapy appear to have a lesser
impact on breast density.

Random
• There is no consistent evidence to favor
either continuous or cyclic sequential
regimens for estrogen and progestin.
• Women using EPT had an 11% greater risk
of an abnormal mammogram after 5 years
• There remains no consensus on whether
cancers detected in women using HT are
more or less advanced.(WHI had
contradictory findings)

Random
• Pt choosing to use HT for relief of symptoms need
to understand that short-term HTR use is unlikely
to appreciably alter their personal risk of breast
cancer
• The risk of breast CA appears to be : EPT > E alone.
• Insufficient evidence to support progesterone over
various progestogens, but there is both clinical and
basic science evidence accumulating to suggest it.
• Risk of breast cancer has been found to return to
baseline after cessation of HTR

Random
• Singletary:
• HT had about the same risk as early
menarche, late menopause, excessive
alcohol consumption and failure to
exercise.

HTR IN WOMEN
WITH A PFHx OF BREAST CANCER
• Pt w/ a single 1stdegree relative (mother, sister, or
daughter) in whom breast CA was Dx > 50y have little ↑
in risk over the approximately 12% risk of the general
population
• Pt w/ two 1stdegree relative doubles a woman’s lifetime
risk (to approximately 24%).
• Pt w/a single 1stdegree relative in whom breast CA was
Dx <50y have a risk of 24%.
• Pt w/ two 1stdegree relative doubles a woman’s lifetime
risk (to approximately 48%).

HTR IN WOMEN
WITH A PFHx OF BREAST CANCER

• One study: HTR in pt w/ positive family hx didn’t
have any ↑ in the overall risk but ↓mortality
• Similar conclusion with a collaborative reanalysis
• Why ? The influence of genetic is so important that
it generally overshadows any small potential
increment resulting from lifestyle or HRT.

HRT IN BREAST CA SURVIVORS
WITH VASOMOTOR SYMPTOMS
• The HABITS trial found that women who used HT after a
Dx of breast CA had a ↑ ↑ recurrence risk than did pt w/
placebo.
• Owing to the adverse findings in the HABITS trial the
Stockholm Trial was prematurely closed, even though it
had failed to find any adverse effect of HT
• Possible explanations for the discrepant findings of these
2 RCTs include the fact that more node-positive tumours
were evident in the HABITS trial, more women in the
Stockholm Trial were treated with tamoxifen, and
different progestin regimens were used in the 2 trials.

HRT IN BREAST CA SURVIVORS
WITH VASOMOTOR SYMPTOMS
• What should we say to the patient?
• Women who wish to consider HT for improved
quality of life after a Dx of breast CA should
understand that a definitive answer to the question
of when HT will influence Px is lacking. The results
of observational studies, which are fraught with
potential biases, have been reassuring; however, a
single RCT suggested that HT had an adverse effect
on recurrence rates.

SERM AND BREAST CA
• Raloxifene : Tx and prevention of osteoporosis
+ approved in US to prevent breast CA
• MORE trial : pt on raloxifene had ↓72% risk of
breast CA at 4 years.
• STAR trial: raloxifene was as effective as
tamoxifen in reducing risk of invasive breast
CA. Raloxifen has ↓risk of VTE

1. MD should periodically review the risks and benefits of
prescribing HT to a menopausal woman in light of the
association between duration of use and breast cancer risk.
(IA)
2. MD may prescribe HT for menopausal symptoms in
women at increased risk of breast cancer with appropriate
counseling and surveillance. (IA)
3. MD should clearly discuss the uncertainty of risks
associated with HT after a diagnosis of breast cancer in
women seeking treatment for distressing symptoms. (IB)

Progestin preparation
Trade name

Strength

Apo-Medroxy

2.5, 5, 10

Gen-Medroxy

2.5, 5, 10

Medroxy 2.5

2.5

Medroxy 5

5

Novo-Medrone

2.5, 5, 10

PMS-Medroxyprogesterone

2.5, 5, 10

Ratio-MPA

2.5, 5, 10

Provera

2.5, 5, 10, 100

Provera Pak

5, 10

Comment

Oral (mg)
Medroxyprogesterone acetate

Provera Pak 5 mg contains 14 tablets
Provera Pak 10 mg contains 10 tablets

Megestrol

40, 160

Nu-Megestrol

40, 160

Linmegestrol

40, 160

Megace

40, 160

Megace OS

40 per mL (liquid)

Prometrium

100

Micronor

0.35

Norlutate

Norethindrone

40, 160

Megestrol-40 Megestrol-160

Micronized progesterone

Apo-Megestrol

5

Depo-Provera

50 per mL (5 mL)

Injectable
Medroxyprogesterone acetate

150 per mL (1 mL)
Progesterone

Progesterone Injection

50 per mL (10 mL)

Implanon

40 g/d

Minera Intrauterine
System (IUS)

52 mg per IUS

Implant
Progestogen
Intrauterine
Levonorgestrel

Approval pending

Nonhormonal osteoporosis medications
Regimen
Treatment
Alendronate (Fosamax)

10 mg daily
70 mg once weekly

Cyclical etidronate* (Didrocal)

400 mg daily for 2 weeks followed by 500 mg
calcium daily for 76 days in a 3-month kit (Didrocal)

Fosavance 70/2800

70 mg/2800 IU vitamin D3

Fosavance 70/5600

70 mg/5600 IU vitamin D3

Nasal calcitonin (Miacalcin NS)

200 IU daily, intranasally via alternating nostrils

Parathyroid hormone

20 µg subcutaneously daily

Raloxifene ( Evista)

60 mg daily

Risedronate (Actonel)

5 mg daily
35 mg once weekly

Risedronate plus Calcium carbonate
(Actonel plus calcium)

35 mg once-a-week + 1250 mg calcium carbonate

Teriparatide (Forteo)

20 µg injectable daily

Prevention
Alendronate (Fosamax)

5 mg daily

Cyclical etidronate* (Didrocal)

400 mg daily for 2 weeks followed by 500 mg
calcium daily for 76 days in a 3-month kit (Didrocal)

Raloxifene ( Evista)

60 mg daily

Risedronate (Actonel)

5 mg daily

*Etidronate alone (Didronel) is only available as a 200 mg tablet.

FDA approved product
• Definition: therapy similar in chemical
composition to that made in human
body ➔ 17-E2 and/or progesterone
• Products are regulated and monitored
by the FDA. They have proven efficacy
at relieving menopausal symptoms and
have published endometrial safety
profiles ➔ See next slides table

Non-FDA approved
• Topical regimens (estrogen) :
• Tri-est (80 % estriol, 10 % estrone, 10 % estradiol) ➔ 1.25 to 2.5 mg
• Bi-est (estriol 80 % & estradiol 20 %) ➔ 1.25 to 2.5 mg
• These estrogens are compounded w/ micronized progesterone:
• Dermabase ➔ 10 to 50 mg daily,
• Eucerin➔ 10 to 50 mg daily
• Some pharmacy individualized to pt based on salivary hormone testing
• Lack of correlation w/ serum hormone level
• Not undergone rigorous RCT for safety and efficacy
• Educate patient regarding potential risks & benefit
• FDA : "Other doses of CEE and MPA, and other combinations and dosage forms of estrogens and
progestins were not studied in the WHI clinical trials, and in the absence of comparable data, these
risks should be assumed to be similar.”
• Compounded hormone can’t assumed to be safer than conventional E and progestin and it is very
important that adequate endometria protection is provided if compounded E are prescribed.

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