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Topic

Menopause and
Adrenopause
นศพ.วิกรม พงษ์ นะสุวรรณ์
นศพ.พสุ จันทร์ เพ็ญ
นศพ.ศิดาวัน อธิปัญจพงษ์
นศพ.จิรากร ไพชยนต์วิจิตร
STAGING REPRODUCTIVE
AGING
• Menopause
• Late reproductive stage
• Menopausal transition
• Post menopause
the Stages of Reproductive Aging
Workshop (STRAW)
Menopause
• After 12 month of amenorrhea following the final
menstrual period
• Without any other obvious pathological or
physiological cause
• Median age of 51.4 yrs
• Complete, or nearly complete, ovarian follicular
depletion
• Hypoestrogenemia and high follicle-stimulating
hormone (FSH) concentration
Late reproductive
stage
• Begin to notice changes in her menstrual cycles
• Subdivided into two substages (–3b and –3a)
• In stage –3b, periods remain regular without a
change in follicle-stimulating hormone (FSH) levels;
however AMH and antral follicle counts (AFC)
decline
• In stage –3a, shorter cycles begin and FSH levels
becomes more erratic.
Menopausal transition
• Defined by menstrual cycle and endocrine changes.
• Stages –2 (early) and –1 (late).
• Stage –2 is defined by a persistent difference in menstrual
cycle length of 7 days or more between consecutive cycles. It
also includes variable early follicular phase FSH levels and low
AMH and AFC.
• Stage –1 is manifested by the occurrence of amenorrhea of 60
days or longer. FSH levels are sometimes elevated into the
menopausal range and sometimes within normal limits for
earlier reproductive years.
• The menopausal transition ends with the final menstrual
period (FMP).
Postmenopause
• Stages +1 (early) and +2 (late) encompass the postmenopause.
• Stage +1a indicates the end of the 12-month period of amenorrhea
required to define that the FMP has occurred.
• Stage +1b includes the remainder of the period of rapid change in
FSH and estradiol levels.
• Stages +1a and +1b together are estimated to last about 2 years.
Menopausal symptoms are most likely to occur during this stage.
• Stage +1c represents the period of stabilization of high FSH and low
estradiol levels that is estimated to last 3 to 6 years.
• Stage +2 represents the period in which further changes in
reproductive endocrine function are more limited and processes of
somatic aging are the most concerning.
The hypothalamic pituitary gonadal
axis
• Ovarian senescence begins in utero and progresses
with primordial follicle activation, maturation and
regression
• Follicular phase of menstrual cycle decreases with
aging
• Menstrual cycles become irregular during early
menopausal transition because of fluctuant
anterior pituitary gonadotropins
The hypothalamic pituitary
gonadal axis
• Decreased inhibin B is the primary initiator of
menopause
• Decreases in early menopausal transition
• Normal function is to negatively inhibit the anterior
pituitary from secreting FSH early in the menstrual cycle
• As the female ages, the levels of inhibin B decrease due
to declining/poorly functioning follicle numbers →
decreased inhibin B causes increased early cycle FSH
because the negative inhibition has been removed
The hypothalamic pituitary
gonadal axis
• Ovaries respond to increased FSH by secreting estradiol
because the FSH has increased the number of recruited
follicles in each cohort → overall number of follicles
decreased but estradiol levels normal/high due to high
serum FSH and increase in aromatase activity
• Aromatase converts testosterone to estradiol
The hypothalamic pituitary
gonadal axis
• Progesterone further decreases during the luteal phase
of the cycle after inhibin B levels decrease
• When all follicles are depleted the ovary becomes
unresponsive to vastly increased FSH and estradiol levels
then decrease
• LH continues to stimulate the secretion of androgens
Pathophysiology
• Cardiovascular disease
• Estrogen is cardioprotective because it increases high
density lipoprotein levels and decreases low density
lipoprotein levels
• Post-menopausal women lack estrogen and their risk of
developing cardiovascular disease catches up to that of a
male counterpart at the age of 70
• Truncal obesity, an independent risk factor of cardiovascular
disease, is controlled by the relative proportion of androgens
• High androgen state is a risk factor → decreased estrogens +
insulin resistance can contribute to the state
• Risk can be managed by the normal preventative
strategies; use of hormone replacement is not
indicated
Pathophysiology
• Ovarian change
• Programmed ovarian senescence is accelerated as
the woman ages
• Post-menopausal women have marked anatomical
differences due to the senescence, including:
smaller volume, lack of follicular cysts, increased
atretic follicles, and persistent corpora albicans
Pathophysiology
• Endometrial change
• Endometrium responds to serum estrogen and
progesterone levels, which fluctuate depending on
stage of menopausal transition
• Early: fluctuant endometrial thickening in response to
estrogen levels and opposed by progesterone
• Later: anovulation → estrogen no longer opposed by
progesterone → increased proliferation and disorganization
of endometrial tissue
• Estrogen derived from extragonadal aromatization of androgen to
estrogen because of obesity
• Decreased sex-hormone binding globulin (SHBG) increases the
levels of free, bioavailable estrogen
• Post-menopause: no estrogen → atrophy and cystic changes
Pathophysiology
• Urogenital tract change
• Estrogen and progesterone receptors throughout the
tract
• Lack of substrate leads to: decreased vascularity → decreased
muscle, decreased epithelial lining, increased fatty deposits
→ irritation, burning, itching and lack of lubrication
• Dyspareunia from the above changes and subsequent vaginal
atrophy leading to increased tissue trauma and bleeding
• Less glycogen and lactic acid → pH changes to a more alkaline
state (from ~4.5 to ~7) → increased susceptibility to infection
• Receptors on connective tissue can affect the laxity of
ligamentous structures of the pelvic floor → incontinence and
prolapse of pelvic structures into the vagina increases after
menopause
Pathophysiology
• Breast changes
• Ductal structures affected by estrogen
• Lobular structures affected by progesterone
• Decreased serum levels of both in the
postmenopausal period leads to loss of volume
• Replacement of dense breast tissue with soft adipose
Pathophysiology
• Vasomotor symptoms
• Normally, the body withstands a reasonable range of
core temperatures without triggering heat dissipation
mechanisms. The range of core temperatures is called
the thermoneutral zone, and it is controlled by the
thermoregulatory center in the medial preoptic area of
the hypothalamus.
• Rapid decreases in estrogen levels (estrogen
withdrawal) causes:
• ↑ norepinephrine stimulation
• ↑ serotonin activation
• ↑ activity of central opioid peptides
Pathophysiology
• Vasomotor symptoms
• These factors added together causes narrowing of
the thermoneutral zone in the thermoregulatory
center.The upper threshold is decreased, which
means smaller increases in core body temperature
can trigger mechanisms to dissipate heat, such as
vasodilation and sweating
• The lower threshold is increased, which means
smaller decreases in core temperature can trigger
mechanisms to preserve heat, such as shivers and
chills
Pathophysiology
• Vasomotor symptoms
• Hot flashes start with core temperature rising above
the narrow upper threshold → vasodilation in the
peripheral vasculature → ↑ skin temperature, ↑
systolic BP, ↑ heart rate
• Can be accompanied by anxiety and palpitations
• Reflex cooling from the improved skin surface heat
dissipation causes chills after the flash
• Commonly occur at night, which leads to sleep dysfunction
and reports of fatigue because of disruptive symptoms
• Estrogens effective for treatment of vasomotor
symptoms
Pathophysiology
• Bone changes
• Peak bone mass at age of 25-35 after which it declines
steadily
• Bone remodelling is done by osteoclasts (destruction of
bone matrix) and osteoblasts (building of lamellar
bone)
• Osteocytes = osteoblasts trapped in the matrix
• RANK and RANKL interactions promote the differentiation of
osteoclast precursors into mature osteoclasts
• OPG can bind to RANKL and interrupt this process
• Estrogen stimulates secretion of OPG by the osteoblast
• More factors at play but this is a simplification of the pathway
related to menopause
Pathophysiology
• Bone changes
• Osteoporosis typically affects trabecular bone → defect in
bone mineral density
• Menopause causes primary osteoporosis: estrogen decrease
→ increased osteoclast formation → bone resorption > bone
formation
• 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
• Vitamin D increases absorption of calcium in the kidney and the intestine as
well as stimulating osteoclasts
• With no estrogen, the bone now releases more calcium for the same amount
of PTH stimulation further weakening the structure
• Dental loss because of osteoporosis of the alveolar bone
and decreased salivary secretions which protect against
dental caries
Pathophysiology
• Bone changes
• Osteoporosis typically affects trabecular bone → defect in
bone mineral density
• Menopause causes primary osteoporosis: estrogen decrease
→ increased osteoclast formation → bone resorption > bone
formation
• 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
• Vitamin D increases absorption of calcium in the kidney and the intestine as
well as stimulating osteoclasts
• With no estrogen, the bone now releases more calcium for the same amount
of PTH stimulation further weakening the structure
• Dental loss because of osteoporosis of the alveolar bone
and decreased salivary secretions which protect against
dental caries
Pathophysiology
• Skin changes
• Difficult to differentiate from photoexposure
changes
• Thinning and loss of elasticity due to decreased
collagen content, dry due to decreased sebaceous
gland secretion and decreased vascularity.

Pathophysiology
• Psychological changes
• Controversy regarding the validity of claims that
menopausal transition affects cognition and/or
mood
• Leading thought centers on idea that high and erratic
estradiol levels relate to emotional distress
• Perceived symptoms may be a result of emotional distress over
menopausal symptoms as fluctuant estrogen levels are
correlated with menopausal symptom intensity
Signs& Symptoms
• Hot flash (vasomotor symptoms) → most common
• Atrophic changes → dyspareunia, pelvic organ
prolapse, atrophic cystitis, urinary incontinence
• Sexual dysfunction → vulvovaginal atrophy &
dryness
• Depression → increased risk 2.5x
• Cognitive change → anxiety & difficulty
concentrating
• Joint pain
Vasomotor Symptoms
• Affect ~80% women, mostly have mild symptoms
• 20-30% moderate to severe symptoms
• Typically last for 1-2 years after menopause
• Estrogen withdrawal (E2) → neurotransmitters
change in preoptic area of hypothalamus →
thermoregulatory dysfunction → decreased
thermoneutral zone (body core temperature range)
Vasomotor Symptoms
• Sudden onset

• Duration of few seconds to several minutes

• Reddening of the skin (head, neck & chest)

• Palpitation/tachycardia

• Feeling of intense body heat

• Perspiration

• More frequent & severe at night → sleep disturbances


Common Hot Flash
Triggers
• Cigarette smoke
• Stress
• Alcohol & Caffeine
• Spicy foods
• Heat & Tight clothing
Diagnosis
• Menopause = 12 months of amenorrhea in the
absence of other biological or physiological causes
• Age (STRAW) → typically ≥ 45 years old
• Menstrual history
• Menopausal symptoms
• R/O other causes of ovulatory dysfunction → especially
< 45 years old
Differential Diagnoses
• Hyperthyroidism
• Pregnancy
• Hyperprolactinemia
• Medications
• Pheochromocytoma
• Underlying malignancy
• Panic disorder
Long-term Consequences
of Estrogen Deficiency
• Osteoporosis → BMD loss (< -2.5 SD)
• Cardiovascular disease → change in lipid profile,
increased risk of CVD
• Dementia
Management
• Menopausal Hormonal therapy
• Non-Hormonal therapy
Menopausal Hormonal
Therapy (MHT)
Indications

• Vasomotor symptom
• High risk for osteoporosis
• Premature ovarian failure
Contraindications for MHT
• Pregnancy
• Know or suspected breast or endometrial cancer
• Undiagnosed abnormal uterine bleeding
• Cardiovascular disease
• Active liver or gallbladder disease
Risks vs Benefits
Risks Benefits
Cardiovascular disease Colorectal cancer

Venous thromboembolism Breast cancer (ET)

Breast cancer (EPT) Coronary artery disease

Ovarian cancer Osteoporosis fracture

Endometrial cancer (ET) Vasomotor symptoms

Cerebrovascular disease Urogenital symptoms


Type and Forms of Hormonal
therapy
• Estrogen therapy (ET)
• Estrogen-Progestin therapy (EPT)
Estrogen
Progesterone
Combination Estrogen-Progesterone
Hormonal therapy
• กรณี ตดั มดลูกแล้ว
• ให้ ET รักษา โดยมี 2 แบบ
• Oral route
• Premarin (conjugate estrogen) 0.3 -
1.25 mg/d
• Estrofem (17-beta micronized
estradiol) 1 mg
• Progynova (estradiol valerate) 1 mg
• Transdermal
• Climara 50 (17-beta estradiol)
• 3.8 mg of estradiol
• Indications/Uses : relieve of menopausal and
postmenopausal symptoms. prevention of
postmenopausal osteoporosis.
• Apply to the skin on the trunk or buttock once weekly.
• Oestrogel
• Indications/Uses : relieve symptoms of menopause
caused by oestrogen deficiency. Prevention
postmenopausal bone loss.
• 1 measure of the ruler/day (2.5 g) for 24-28 days/mth
in combination w/ a progestogen for at least 12 days in
each cycle.
• Apply morning & evening on clean skin over the
abdomen, thighs, arms or lumbar region (except the
breasts).
• กรณี ยงั มีมดลูก
• ให้ EPT
• Cyclic EPT ให้ progestin เป็ นเวลา 10-14 วัน ทุก
เดือน
• Cyclic (sequential) regimens (CSR)
• Continuous EPT ให้ estrogen ร่ วมกับ
progestin ต่อเนื่องทุกวัน
• Continuous combined regimens (CCR)
Perimenopause or Early • Climen 28 : 2 mg estradiol valerate (21d) + 1 mg
postmenopause cyproterone (10d)
• E 21 d + P 10-14 d and no • Cycloprogynova : 2 mg estradiol valerate (21d) + 250 mg
hormone 7 d (withdrawal levonorgestrel (10d)
bleeding) • Femoston 1/10 : 2 mg estradiol (28d) + 10 mg
• E 28 d + P 12 d ท้าย and no dydrogesterone (15-28d)
hormone 4-5 d
Cyclic (sequential)
(withdrawal bleeding)
regimens (CSR)

Postmenopause • Premelle lite : Premarin 0.3 mg + MPA 2.5 mg


• E + P fixed dose daily • Activelle : estradiol 1 mg + 0.5 mg norethisterone acetate
• Breakthrough bleeding

Continuous
combined regimens
(CCR)
Urogenital symptoms
• Local therapy if only have urogenital symptoms
• Premarin vaginal cream : conjugated estrogens 0.5 -1 g,
2-3 times weekly
• Vegifem : estradiol hemihydrate, Vg tablet, 1 tab
(10mcg), twice weekly
Non - Hormonal therapy
Non-Hormonal therapy
• Selective Tissue Estrogenic Activity Regulator
(STEAR)
• Tibolone (Livial)
• Structurally related to the 19-nortestosterone
progestins
• Synthetic steroid drug with estrogenic,
progestognenic, and weak androgenic action.
• Prevents bone loss in postmenopausal women
and relieve menopausal symptoms.
• Increased risks of breast cancer and
endometrial cancer
• Trandermal clonidine
• Natural therapies
• Phytoestrogen : have benefits of CVD, but no
significant difference between phytoestrogens
and placebo for relief vasomotor symptoms
• Isoflavones (soybean, lentils, chickpeas)
• Lignans (flaxseed, cereals, vegetables, fruits)
• Coumestans (sunflower seeds, bean sprouts)
• Antidepressant : Selective serotonins and
Norepinephrine reuptake inhibitors
• Paroxetine
• Venlafaxine
• Fluoxitine
• Anticonvulsants : Gabapentins (Neurontins),
Pregabalin (Lyrica)
• Dopamine antagonists : Veralipride
• Vaginal moisturizers and lubricants
Lifestyle changes
• Smoking cessation
• Reducing body temperature
• Maintaining a healthy body weight
• Relaxations response techniques
ANDROPAUSAL
DISORDER
DEFINITION
• A clinical and biochemical syndrome associated
with advance with advance age and characterised
by a deficiency in serum androgen levels with or
without a decrease in genomic sensitivity to
androgen
PHYSIOLOGY
PHYSIOLOGY
TESTOSTERONE ORGAN TARGET
CHANGE WITH AGE
• Serum total testosterone
• Serum sex hormone-binding globulin
• Serum free testosterone
• Change in spermatogenesis
• Change in gonadotropins
Serum total testosterone
• Decline of serum total testosterone concentration
with increasing age
Serum sex hormone-binding
globulin
• It binds testosterone with high affinity
• SHBG concentrations increase gradually as a
function of age
Serum free testosterone
• Serum free testosterone concentration decreases
with increasing age
• the percent fall in free testosterone was 2.8
percent per year
Change in spermatogenesis
• Decline in spermatogenesis
• Testiscular size is smaller in older age
Change in gonadotropins
• Serum gonadotropin concentrations increase
• Follicle-stimulating hormone (FSH) more than
luteinizing hormone (LH)
CAUSE
• Decrease rate of production by testis
• Reduction in size and weight of testis
• Critical illness
• Increased level of stress
• Testiscular trauma
• Genetic and metabolic disorder
• Chronic illness
• Medications
• Obesity
• Malnutrition
• Chronic substance abuse
• Physical stress
• Previous surgery
TESTOSTERONE DECLINE
• Sexual function
• Bone mineral density
• Muscle and fat mass
• Anemia
• Mood
• Cognitive function
• Metabolic cardiovascular parameters
SEXUAL FUNCTION
• Decline in sexual function
• Serum testosterone concentration less than
320 ng/dL will associate with 3 symptoms
• Poor morning erection
• Low sexual desire
• Erectile dysfunction
BONE MINERAL DENSITY
• BMD declines and their risk of fractures increase
• Risk was greatest in men with low bioavailable
estradiol and testosterone and high SHBG
MUSCLE AND FAT MASS
• Muscle mass declines and fat mass increases
• Aged 60 to 79 years have less muscle strength than
those aged 20 to 39 years
ANEMIA
• Anemia is also common in severe hypogonadism
and is readily corrected when testosterone is
replaced
• Testosterone treatment results in an increase in
hemoglobin when compared with placebo
MOOD
• Serum free testosterone concentrations below a
threshold were associated with depressive
symptoms
COGNITIVE FUNCTION
• The decrease in serum testosterone concentrations
that occurs with aging in men may be associated
with a decline in neuropsychologic function
METABOLIC CARDIOVASCULAR
PARAMETERS
• Low serum testosterone concentrations have been
associated with the subsequent development of
central obesity, higher insulin concentrations, the
metabolic syndrome, diabetes, high sensitivity C-
reactive protein, and increased mortality
EVALUATION OF
HYPOGONARDISM
TESTOSTERONE THERAPY
• Considering treatment with testosterone only if the
testosterone concentration is consistently less than
200 ng/dL (6.9 nmol/L), and only after discussion
with the patient of the potential benefits and risks
CANDIDATE FOR TESTOSTERONE
• Have symptom -> measuring the serum total
testosterone concentration in the morning -> less
than 300 ng/dL : suggest measuring it twice more
• Free testosterone should be measured only in men
who are obese
• total testosterone is less than 200 ng/dL should
evaluated for organic cause
CHOICE OF TESTOSTERONE
REGIMEN
• Oral preparations
• Parenteral testosterone
• Long-acting injections
• Extra-long-acting injections
• Transdermal/topical delivery
• Other
ORAL TESTOSTERONE
• Testosterone undecanoate (Andriol, Restandol), not
available in United States
• 40 mg capsules
• 40 to 80 mg twice a day after breakfast and dinner
• Gastrointestinal side effects
LONG-ACTING INJECTION
EXTRA-LONG-ACTING INJECTION
TRANSDERMAL PATCH
CONTRAINDICATON
ADVERSE EFFECTS
• Risk for prostate cancer
• Sleep apnea
• Erythrocytosis
• Venous thromboembolism
• Cardiovascular risk
• Skin irritation