BY DR Rajabu N.

TABLE OF CONTENTS

OVERVIEW

DEFINITIONS

FACTORS AFFECTING AGE OF MENOPAUSE

NORMAL MENSTRUAL CYCLE

ENDOCRINE CHANGES DURING MENOPAUSE

MENOPAUSAL SX & PROBLEMS

EVALUATION & WORK-UP

MANAGEMENT

Before menopause, estrogen & progesterone

are produced in the ovaries.
Estrogen works to regulate a womans
menstrual cycle & 2 sexual Characteristics, &
also prepare the body for fertilization &
reproduction.
Progesterone prepare the uterus for possible
implantation, prepare the breast for lactation.
As a woman reaches menopause the body
produces less & less estrogen & progesterone.

DEFINITIONS:
Menopause: Refers to complete / permanent
cessation of menstruation & is indicated by the
final menstrual period.
An interval of 6 - 12months of amenorrhoea is
necessary to establish the diagnosis of
menopause
Climacteric: Refers to the phase of the aging
process of women during which transition is
made from the reproductive stage of life to
non-reproductive stage.
This period usually becomes clinically apparent
over 2 to 5 yrs around the menopause.

CLASSIFICATION
PHYSIOLOGICAL MENOPAUSE Average age
about 50 years, less in Africa.
PREMATURE MENOPAUSE OR PREMATURE
OVARIAN CESSATION: If spontaneous
cessation occurs before 40 yrs of age.
ARTIFICIAL/INDUCED MENOPAUSE:
Cessation of menstruation that follows either
surgical removal of both ovaries or
iatrogenic ablation of ovarian function by
chemotherapy or radiation

The median age of menopause is 51.4yrs with

a range of 48 - 55yrs ( USA ). It is 47 in TZ,
range 43 - 51
If menopause occurs before age of 40yrs is
considered premature, if it occurs after 55yrs it
is late menopause
FACTORS AFFECTING THE AGE OF MENOPAUSE:
Early menopause:

Family history
Cigarette smoking ( number & duration)
Abnormal chromosome karyotype (turners
syndrome, gonadal dysgenesis)
Precocious puberty
Surgery (TAH & BSO)

Late onset of menopause:

- Obesity,
- High socioeconomic class

NORMAL MENSTRUAL CYCLE

Characterized by sequential growth,
maturation & sloughing of endometrial
mucosa, produced by cyclic release of
estrogen & progesterone.
Theres rise of FSH levels during the 1st 14
days of the cycle
This stimulates development of ovarian
follicles & subsequent estrogen production

LH levels rise slowly, abruptly peak on day 12 or

13 in response to rise estrogen levels.
Estrogen causes endometrial proliferation, LH
surge stimulates ovulation, & conversion of
ovarian follicles to Corpus Luteum which produce
estrogen + progesterone
Progestrone is produced only when ovulation
occurs. It converts the endometrium to secretory
phase in preparation for implantation if fertilization
occur
If no fertilization LH levels drop & Corpus Luteum
regresses, E + P levels drop, endometrium
deteriorate & is sloughed leading to bleeding.

ENDOCRINE CHANGES DURING MENOPAUSE:

Menopause is a hormone deficient state. The 1
alteration is in the ovary, which decreases
responsitivity to stimulation by pituitary
gonadotropins leading to further drop in
estrogen levels.

(a) Pituitary hormones:

Theres a gradual increase of circulating FSH
towards the upper limit of the normal menstrual
cycle during the peri-menopausal period.

Theres a decrease in serum estradiol. No

significant changes in LH level, & only a
slight decrease in progestrone levels.
Anovulatory cycles may be more
interspersed with ovulatory cycles, &
consequent anovulatory bleeding may occur.
Clinically:
Theres variaton & unpredictability in
amount of flow & in duration & timing of the
bleeding.
There can be periods of amenorrhoea, with
elevated serum FSH & LH levels followed by
few months of ovulatory cycles.

(b) Ovarian changes.

- Theres progressive loss of primodial
follicles from the ovaries during
intrauterine life, throughout reproductive
life & menopause.
- At the end of the 4th decade of life the
ovaries become increasingly less
responsive to stimulation by pituiary
gonadotropins.
Also recruitment & stimulation of follicles
to full maturity becomes increasingly
difficult.

Ovulation become irregular, infrequent

and finally stops
Mentsrual function stops because of
insufficient estrogen to stimulate
endometrial proliferation & growth.
Ovaries become smaller & fibrotic, with
atrophy of the cortex which contains the
premodial follicles.
The ovarian medulla become abundant
with active stromal cells which are
source of ovarian androgen.

(c) Extraglandular estrogen

The principal circulating estrogen in the premenopausal period is ESTRADIOL primarily derived
from the ovary.
After the menopause ESTRONE becomes the
principal circulating estrogen derived mainly from
the adipose tissues, where androstenedione is
aromatised by the aromatase enzyme to estrone.
(d) Other hormones
- Serum testosterone levels are slightly lower than
in premenopausal state, however, theres still a
state of androgen excess compared to premenopausal levels.

MENOPAUSAL SYMPTOMS & PROBLEMS:

Most of the problems are due to

exclusively low estrogen levels /
prolonged estrogen deficiency.
(a) Psychoneuroendocrine effects
( Brain)

Hot flashes
Depression
Sleep disturbances
Inability to concentrate
Memory lapses
Headache
Tiredness, Lethargy, Anxiety, nervousness

(b) Cardiovascular diseases

Theres a marked increase in the incidence of CV
diseases in postmenopausal women after loss of
ovarian function.
Estrogen has protective effect vs ischemic heart
disease.
The risk of atherosclerosis is 3.4X greater in
postmenopausal women, the risk is 5.5X greater
in women who underwent bilateral oophorectomy
than in premenopausal women. (Witten et al)
3 lipids have been linked to CHD &
atherosclerosis; cholesterol, LDL (plaque
promoting) & HDL (plaque sparing)

After menopause theres considerable

increase in serum cholesterol. Theres
increase in LDL & significant decrease in HDL.
The lipids levels changes towards less cardioprotective pattern than before menopause.
When postmenopausal women are placed on
estrogen therapy theres increase in HDL, a
decrease in LDL & generally decrease in
cholesterol.

(c) Skin effects

Decrease estrogenic levels after

menopause reduces skin thickness 2
decreased epidermal collagen content.
skin is lax, more transparent, has readily
visible blood vessels, & is more easily
bruised.
Estrogen replacement Therapy(ERT)
increases skin collagen content, alter
vascularisation of the skin & increase
intracellular fluid content.

(d) Urogenital effects

- Reduced vaginal thickness, loss of rugae
- change of vaginal pH ( 3.5-4.5 to 6-8 )
- vagina becomes small & atrophic,
dyspareunia may
occur
-theres 30% drop in urethral closure
pressure
- theres diminished support to the pelvic
organs ie bladder & urethra
- atrophic urethritis may occur, characterized
by urgency, frequency, dysuria, suprapubic
pain..

(e) Bone effect

- Osteoporosis is one of the most significant
long term sequelae of menopause
- the skeleton is sufficiently compromised by
reduction in the mass per unit volume leading
to fracture even in the absence of trauma.
- trabecular bone is predominantly affected
than cortical bone
- most fractures seen are of vertebrae, ulna,
distal radius & neck of femur.
Mechanism:
-Estrogen deficiency results in declining levels
of Calcitonin, which opposes effect of
Parathyroid hormone.

Estrogen inhibits production of

prostaglandins ( PGE2) & interleukin both
of which increase bone resorption.

Estrogen increases formation of 1,25

(OH)2 D3

estrogen promotes renal tubular Ca++

reabsorption.

Thus ERT can block the decline in bone

mineral density & reduce fracture rates in
postmenopausal women

Risk factors associated with

postmenopausal osteoporosis:

positive familty history

low calcium intake
early menopause / oophorectomy
sedentary lifestyle
alcohol abuse
high sodium intake
cigarette smoking
high caffeine intake
2 loss( glucocorticoid therapy,
hyperthroidism).
Raloxifene, calcitonin & biphosphaphates can
Rx osteoporosis.

CNS effects
Normal aging induces a decline in certain
cognitive capabilities, lack of estrogen itself
may contribute to this process.
Current data suggest that women have higher
incidence of Alzheimer disease than men,
because this disease is primarily age related
condition.
ERT appears to reduce the relative risk of
developing this condition / delay its onset.

EVALUATION AND WORKUP

1. Complete history
- duration,severity,type of symptoms
- h/o liver dx, gallbladder dx, TAH & BSO

2. Physical examination
- BP, breast, thyroid

3. Investigation
- lipid profile - cholesterol, HDL, LDL, TGA

4. Endometrial evaluation
- for irregular vaginal bleeding Endometrial
Bx is advisable

5. Pituitary gonadotropins & estrogen levels.

Serum levels of FSH & LH need to be
evaluated if:
- the diagnosis of menopause is not clear
- theres irregular vaginal bleeding
/oligomenorrhoea/
-theres vasomotor symptoms without
amenorrhoea
6. Bone mass measurement using:
- Quantitative Computed Tomography of the lumber
vertebrae
- Dual-energy x-ray absorptiometry (DEX), a new
method for measuring bone density

7. Screening for ovarian cancer.

- palpation of the ovaries
- measurement of serum levels of CA-125
- Ultrasonography i.e vaginal uss.

Additional evaluation for Premature

menopause:
Investigations include:
Abnormal sex chromosomes karyotype
( chromosomal karyotyping)
Polyglandular autoimmune disese &
autoimmune antibodies to the ovaries.

Levels of thyroid Antibodies should be determined

as thyrotoxicosis may mimic climacterics
symptoms especial if patient is menstruating.

HORMONAL REPLACEMENT THERAPY:

Treatment with HRT depends on patients

compliance, presence /absent of uterus,
severity of symptoms & type of symptoms.
The benefits of HRT should be discussed
with each patients before initiation of such
treatment

INDICATIONS OF HRT

Prevention of complications.

Relief of climacteric symptoms.

THERAPEUTIC REGIMENS
HRT may include;
Only estrogen
Estrogen & progestrones
Estrogen & androgens
Selective estrogen receptor modulators (SERM)

Types of estrogens;
Natural estrogens; estradiol, estrone, estriol
Semisynthetic estrogens; ethinyl estradiol
Synthetic estrogens; those with steroids;
mestranol or without steroids but derivatives of
diphenylene;stillbestrol

commonly used estrogen preparations;

Conjugate estrogen daily dosage 0.625 -1.25mg
Ethyinyl estradiol

5 - 10ug
Micronized estradiol

0.625 1.25mg
Estradial valerate

1 - 2mg
Estrogen can be given Orally, transdermally,
vaginally, subdermal.
The oral & transdermal route are the most
commonly used.

:Estrogen regimens:
Oral ERT can be summarized into 4
regimens:
Cyclic estrogen, given for 25 of the 30 days
with progestin added on the last 12 days,
and no medication for 5 days.( employed to
a woman with a uterus)
Cyclic estrogen, given for 30days with
progestrin during the first 12 days of the
month.( with/without a uterus)
Continous combined estrogen & progestrin
given daily & continously throughout the
month.(with/ without a uterus)
Continous estrogen given alone.( given only
if the woman doesnt have the uterus)

Adverse effects of ERT.

(a) Endometrial hyperplasia and neoplasia
- Prolonged unopposed estrogen increase significantly
the risk of endometrial hyperplasia & carcinoma.
- The Risk Ratio for Endo.Ca increases from 3 to 4
folds with use of postmenopause estrogen.
- The risk can be eliminated with progestrin
administration for 12 - 14days each month.

(b) Gallbladder disease

- Estrogen increases biliary cholesterol by enhancing
hepatic lipoprotein uptake & inhibiting bile acid
synthesis.
- Formation of bile stones is due to increased
cholesteral saturation in biliary secretion.

(c)Carbohydrate metabolism
In most studies, estrogen does not affect
blood glucose levels, but can impair glucose
tolerance.
(c) Breast cancer
Menopause is an important event that
influence the subsequent risk of breast
cancer.
The Risk may be increased after long-term
use of ER (10yrs or more).

Contraindications of estrogen
replacement therapy:
a) Known / suspected estrogen
dependent neoplasia:
- Breast cancer
- Melanoma
- Endometrial cancer

b) Thromboembolism
c) Myocardial infarction
d) Pregnancy
e) Undiagnosed genital bleeding
f) Active liver disease
g) Endometriosis
h) Active gallbladder disease

A follow-up visit at 6/12 after starting HRT

may help to identify side effects.

: ESTROGEN & ANDROGEN THERAPY:

Androgen offers a significant relief to those

with decreased libido & sexual satisfaction.
estrogen helps alleviate most sx &
complications of menopause

: TIBOLONE:
Is a tissue specific gonadomimmetic
which has estrogen, androgenic, &
progestogenic activity in different tissues
It is a synthetic steroid hormone which
displays estrogenic, progestogenic &
androgenic effect following oral
administration.

Dosage: 2.5mg/day to give optimum protection

to the bones as well as reduce incidence of
endometrial bleeding.
Toxicity: it does not affect liver/ renal function.
Estrogenic response: - on urogenital system &
vagina
- prevents osteoporosis
- on vasomotor symptoms
Progestogenic response - on endometrium
Androgenic response - decreases lipid fractions,
benefits mood & libido.

REFERENCES:
Danforths; Obst & Gyn. 7th edition. pg
771 - 788.
Copeland LJ; Text book of gynaecology.
Pg 619 - 637.
Online:

Hormonal replacement therapy(HRT).htm:

Lara mother health care centre
HRT.htm: A clinicians guideline to use in
menopausal women; Andrew M. Kauniz
The menopausal patients and HRT.1997: EJ
Mayeaux, Jr.