Biosynthesis and physiologic effects of estrogen and

pathophysiologic effects of estrogen deficiency: A review

Wulf H. Utian, MD, PhD
Cleveland, Ohio

Women are increasingly spending more years of their lives beyond the menopause, which places them at
risk for various health problems due to estrogen deficiency. Tissues and organs with estrogen receptors
such as the ovaries, endometrium, vaginal epithelium, hypothalmus, urinary tract. and skin are directly
affected by a lack of estrogen production. Other tissues in which estrogen receptors have not been
consistently identified, such as bone, are also affected by waning levels of estrogen. The postmenopausal
woman frequently experiences neuroendocrine changes (hot flashes) that often dissipate over time and a
steady rise in her risk of cardiovascular disease, which approaches that in men of comparable age. (AM J
OSSTET GVNECOL 1989;161 :1828-31.)

Key words: Estrogen deficiency, menopause

In 1980, men and women aged 65 years or older
represented 11.3% of the population, a percentage that
is expected to increase.' As the average life span of the
American population continues to increase, the num-
ber of women who live beyond the age of menopause
is growing significantly. Currently there are about 230
million people in the United States, of whom 118 mil-
lion (51 %) are women. About one third of these (39
million) are 45 years old or older, and almost 13.5%
(16 million) are 65 years old or older.
What do all these statistics mean? Simply stated, com-
pared with their ancestors, more women will live a sig-
nificantly increasing number of years beyond meno-
pause, placing them at risk for various health problems
that can be caused by ovarian failure and a lack of
estrogen production.
The current median age of menopause is 50 years.
However, approximately 8% of women undergo pre-
mature menopause before the age of 40 years! During
the time of the climacteric (the phase in the aging of
women that marks the transition from the reproductive
to the nonreproductive stage of life)/ several months
may pass between menstrual periods. This unpredict-
able perimenopausal menstrual pattern makes identi-
fying the onset of menopause difficult. Therefore, the
diagnosis of menopause is usually made retrospectively
after a women experiences her last menstrual period.
From the Departments of Obstetrics and Gynecology and Reproductive
Biology, Case Western Reserve Umvemty and University Hospuals
of Cleveland.
Reprint requests: Wulf Utian, MD, PhD, Department of Obstetrtcs
and Gynecology, Universtty H OSp!tats of Cleveland, Univemty Cir-
cle, Cleveland, OH 44106.
610116773
Table I. World Health Organization definitions'
Menopause: Permanent cessation of menstruation
resulting from loss of ovarian
function
Perimenopausal: Climacteric; the period immediately
before menopause and at least 5
years after menopause
Postmenopausal: The period dating from the meno-
pause, which can only be assessed
in retrospect
Table I provides the World Health Organization stan-
dard definitions of the terms menopausal, perimeno-
pausal, and postmenopausal.
Research has looked for factors that may influence
the age at which menopause occurs. For instance,
women who smoke may have lower serum estrogen
levels than nonsmokers and, on average, may also ex-
perience menopause at an earlier age. For the most
part, directly associating specific factors as a cause for
early or late menopause is difficult because so many
variables exist.
Physiology of menopause
As a woman ages, ovarian function begins to fail. The
number of follicles in the ovaries decreases, and less
estrogen is synthesized. A deficiency of follicular in-
hibin and estrogen leads to decreased negative feed-
back on the anterior pituitary gland, which results in an
increase in levels of follicle-stimulating hormone and
luteinizing hormone. In postmenopausal women, the
amount of follicle-stimulating hormdne present is
greater than the amount of luteinizing hormone,
which is the opposite of what is found in premeno-
pausal women. Feedback sensitivity on the hypothala-

1828
Volume 161 Pathophysiologic effects of estrogen defiCiency 1829
Number 6, Part 2

Table II. Potential problems of the

untreated climacteric'
• Hypothalamus

//1" 1
Target Organ PossIble symptom or problem

Vulva Atrophy, dystrophy, pruritus LRF, FSRF

vulvae
Vagina Dyspareunia, blood-stained dis-
charge, vaginitis
Bladder and urethra Cystourethritis, ectropion, fre-
quency and/or urgency, stress
incontinence
/
Uterus and pelvic
floor
Uterovaginal prolapse
/
/ CD Anterior Pituitary

Skin and mucous Atrophy, dryness, or pruritus;

/
71

membranes easily traumatized; loss of resi-
lience and pliability; dry hair
or loss of hair; minor hirsu-
tism of face; dry mouth
Vocal cords Voice changes (reduction in up-
per register)
Cardiovascular system Atherosclerosis. angina, and cor-
onary heart disease
Skeleton Osteoporosis with related frac-
tures, backache
Breasts Reduced size, softer consistency,
drooping
Neuroendocrine Hot flashes, psychologic distur-
system bances
mus and anterior pituitary glands may also decrease
(Fig. 1).
The predominant estrogen in premenopausal
women is estradiol, which is produced primarily by the
ovary. Estrone, a less active form of estrogen, is the
predominant form in postmenopausal women, Most
postmenopausal estrone is synthesized in the periphery,
predominantly in adipose tissue, by the conversion of
androstenedione to estrone (Fig. 2)".
As these hormonal changes occur, the amount of total
circulating estrogen may be reduced, with a potential
decline in menstruation usually around the age of 40
years. The decline manifests as irregular cycles with a
lighter menstrual flow, less frequent menses, and finally
a total absence of menstruation. If anovulatory cycles
occur, the absence of progesterone can result in irreg-
ularly heavy menstrual periods.
The tissues or organs directly affected by this relative
estrogen deficiency are those with specific estrogen re-
ceptors, such as the ovaries, endometrium, vaginal ep-
ithelium, hypothalamus, urinary tract, and skin. Other
tissues in which estrogen receptors have not been in-
consistently identified, such as bone,6.7 are nevertheless
affected by a lack of estrogen (Fig. 3). Table IP sum-
marizes the resultant symptoms or problems that may
occur when these various tissues and organs become
estrogen deficient.
Urogenital atrophy manifests as a loss of soft tissue
elasticity and a decrease in muscle tone and secretions.
Usually the uterus shrinks and the vagina undergoes
progressive thinning and shortening, with a loss of the
1
/
/ /
I / FSH, LH
I /
I I
I I
I
\ I
I
\ Ovary
\ \
\ \
\ \
,,\
,'-
-' ~
Estrogen
Fig. 1. Feedback control of the anterior pituitary and ovary
by the hypothalmus. LRF, Luteotropin (or luteinizing hor-
mone [LH]) releasing factor; FSRF, follicle stimulating re-
leasing factor; FSH, follicle stimulating hormone.
rugal pattern. These vaginal changes are a common
cause of pruritis in postmenopausal women and they
may be responsible for complaints of dyspareunia. Vag-
inal atrophy also puts the woman at increased risk of
vaginal trauma and infection. The increased risk of
infection is probably due, in part, to the slight increase
in vaginal pH associated with changes in the bacterial
flora.
Similar changes also occur in the urethra and the
trigone area of the bladder. Urethral atrophy may lead
to the "urethral syndrome," in which women have a
recurrent abacterial urethritis characterized by symp-
toms of dysuria, frequency and urgency of urination,
nocturia, and postvoid dribbling.
Other atrophic changes may also occur. The amount
of collagen in the skin decreases, and the skin becomes
thinner. The breasts also diminish in size, become sof-
ter, and may droop.
Systemic problems related to menopause
The risk of cardiovascular disease is higher in men
compared with age-matched women before the age of
1830 Utian December 1989
Am J Obstet Gynecol

EXTRAGLANDULAR
OVARY AROMATIZATION ADRENAL

{jJ).:~.:.'
.'
.t?1.. :..®,.~._ Androstenedione ~
Adipose
Androstenedione ,~

----+.~. ~
\~ ESTRADIOL ESTRONE
/'" ESTRONE

REPRODUCTIVE POSTMENOPAUSAL
LIFE LIFE

Fig. 2. Sources of estrogen during reproductive and postmenopausal life. (Reprinted with permission
from Carr BR, MacDonald PC. In: Stollerman GH, Harrington WJ , Lamont JT, eds. Advances in
internal medicine. Chicago : Year Book Medical Publishers, 1983.)

Table III. Psychologic complaints of

Brain peri menopausal and postmenopausal women
Decreased energy and Mood fluctuations
drive
Difficulty concentrating Tension
Irritability Depression
Aggressiveness Introversion
Nervous exhaustion Sense of internal frustration
and inadequacy
Intolerance of loneliness Anxiety
Marital troubles Headache
Antisocial behavior pat- Insomnia
Heart
terns
Breasts

sustained one or more fractures of the proximal femur,

Genitourinary Tract
Bone
----1r--- Skin
Fig. 3. Tissues and organs affected by estrogen deficiency.
40 to 45 years. During the perimenopausal period, the
risk of cardiovascular disease in women begins to in-
crease to a rate similar to that in men (Fig. 4).8 The
decrease in estrogen production is thought to be re-
sponsible for this acceleration of risk.
After cardiovascular disease, the most significant
problem related to estrogen deficiency is osteoporosis.
By the age of 80 years, about 25% of all women have
vertebrae, or distal radius. Hip fractures are associated
with high morbidity and mortality rates. The manage-
ment of hip fractures constitutes a large public health
care expense and carries with it about a 20% mortality
rate within the first year.
Neuroendocrine problems are also relatively com-
mon in perimenopausal and postmenopausal women.
Hot flashes, which can begin several years before the
actual menopause, occur in 75% to 85% of climac-
teric women. One postulated mechanism is that the
temperature-regulating set point of the hypothalamus
may be reset downward. Most women describe a sud-
den onset of warmth and vasodilation, often visible as
a red flush that is most apparent over the face and
chest. The flush usually lasts from 30 seconds to 5 min-
utes and may occur every few minutes or only once or
twice a week. Other vasomotor symptoms include nau-
sea, dizziness, weakness, headaches, palpitations, dia-
phoresis, and night sweats. Women who experience hot
flashes may also complain of sleep disturbances, char-
acterized by an increased number of awakenings and
increased fatigue.
Volume 161
l\umber 6, Part 2
Rate
per
1000
/ . women . . men
200
100
0+-------~------~-------+------_+------_4------~
30-34 35-39 40-44
Age at Entry
Fig. 4. Incidence of coronary heart disease based on age and sex. (Reprinted WIth permission from
Castelli WP. Am] Med 1984;76(2A):4-12.)
Many other psychologic changes associated with
menopause have been reported and studied, These
changes are probably due to the interactive effects of
endocrine changes, sociocultural effects. and psycho-
logic factors in each individual. The complaints are
usually multiple. vague. and nonspecific. They may be
related to vasomotor symptoms and a lack of sleep.
Table III lists a variety of complaints that perimeno-
pausal and postmenopausal women report. The sever-
ity of psychologic complaints during the menopausal
years are usually mild. not continuous. and tend to
fluctuate.
Women may associate menopause with old age and
feelings of asexuality. Hopefully. women's attitudes, as
well as society's. are changing today to shatter the myth
that women past the age of menopause lose their sex-
uality.
Summary
A woman who is 50 years old today can expect to
live to 89 years of age, By the year 2000, more women
will be spending a larger percentage of their life beyond
the age of 40 years, The numbers alone dictate ad-
dressing the issues that surround menopause, There
are still many myths to dispel and facts to discover that
could promote a healthier. more productive life-style
for women in this age group, Meanwhile. what we do
know is that the benefits of estrogen replacement ther-
apy can improve the quality of life for postmenopausal
women.
Pathophysiologic effects of estrogen deficiency 1831
45-49 50-54 55-59 60-62
REFERENCES
I. Schneider J. Forward. Med Clin North Am 1987;71:ix-xi.
2. Coulam CB, Anderson SC, Annegen ]F. Incidence of pre-
mature ovarian failure. Obstet Gynecol 1986;67:604-6.
3. Utian WHo Menopause in modern perspective. New York:
Appleton-Century-Crofts, 1980.
4. Research on the menopause. Geneva: WHO Technical Re-
port Series, 1981 :670.
5. Carr BR, MacDonald PC. Estrogen treatment of post-
menopausal women. In: Stollerman GH, Harrington W],
Lamont ]T, eds. Advances in mternal medicine. ChIcago:
Year Book Medical Publishers, 1983.
6. Komm BS, Terpening CM, Benz DJ. et al. Receptor mRNA,
and biologic response in osteoblast-like osteosarcoma cells.
Science 1988;241 :81-4.
7. Eriksen EF, Colvard DS, Berg NJ, et al. Evidence of estro-
gen receptors in normal osteoblast-like cells. Science 1988;
241 :84-6.
8. Castelli WP. EpidemIology of coronary heart disease: the
Framingham Study. AmJ Med 1984;76(2A):4-12.
SUGGESTED READING
An additional list of references is provided for those interested
m a review on pathophysiology.
Barbo DM, ed. The postmenopausal woman. Med Clin North
Am 1987;71:1.
Gambrell RD ] r, ed. The menopause. Obstet Gynecol Clin
North Am 1987;14:1.
Mlshell DR. Menopause: physiology and pharmacology. ChI-
cago: Year Book Medical, 1987.
Studd, JW, Whitehead MI. eds. The menopause. Oxford:
Blackwell Scientific, 1988.
Utian WHo Menopause in modern perspective: a guide to clin-
ical practice. New York: Appleton-Century-Crofts. 1980.
Utian WHo Overview on menopause. AM J OBSTET GY:'oJECOL
1987;156:1280