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Chapter 5 • Amenorrhea
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49
Table 5-1
Correlation of Ovarian and Endometrial Cycles (Ideal 28-Day Cycle)
EARLY
MENSTRUAL
(1-3 TO 5 DAYS)
OVARY
Involution of corpus
luteum
ESTROGEN
Diminution
PROGESTERONE
Absent Absent
ENDOMETRIUM
Menstrual desqua-
mation and
involution
PITUITARY SECRETION
Follicle-stimulating
hormone (FSH)
fairly constant
until just before
ovulation
Luteinizing hormone
(LH) fairly constant
until just before
ovulation
FOLLICULAR
(4 TO 6-8 DAYS)
Growth and
maturation
of graafian
follicle
Progressive
increase
Reorganization
and proliferation
Moderate
increase
just before
Marked
increase
just before
ADVANCED
FOLLICULAR
(9 TO 12-16 DAYS)
High concentra-
tion
Absent Appearing Rising Rising Decreasing
Further growth
and watery
secretion
Rapid decrease in previous levels
Rapid decrease in previous levels
OVULATION
(12-16 DAYS)
Ovulation Active
— Active secre-
EARLY LUTEAL
(15-19 DAYS)
corpus
luteum
Secondary
rise
tion and
glandular
dilation
ADVANCED
LUTEAL
(20-25 DAYS)
Accumulation
of secretion
and edema
PREMENSTRUAL
(26-32 DAYS)
Involution
of corpus
luteum
Decreasing
Regressive
Modified from Thompson JM, McFarland GK, Hirsch JE, Tucker SM: Mosby’s clinical nursing, ed. 4, St. Louis, 1997, Mosby.
It also aids in proper counseling and referral. Amenorrheic patients seeking pregnancy, who do not bleed after
androgen challenge tests, are most successfully treated
by an infertility specialist. Women seeking pregnancy
who are younger than 35 years of age and have been
unsuccessful after a year of unprotected sex, and those
over 35 years of age for 6 months, should be referred to
an infertility specialist.
Is this primary or secondary amenorrhea?
Key Questions
l
Have you ever had a menstrual cycle?
l
Have you started pubertal development? Can you
show me how your breasts and pubic hair (PH) look
compared with these pictures? Use Tanner stages of
development (Figures 5-2 and 5-3).
l
At what age did you start your periods?
l
When was your last normal menstrual period?
l
What is the nature of your periods (e.g., frequency,
duration, amount of ow)?
Onset of Menstruation
The age range for menarche in the United States is
9 to 17 years. If the woman has had established
menses at intervals of every 21 to 38 days, then the
classication of secondary amenorrhea would apply.
Established menses indicate that there is no outlet
ow problem, and that the HPO axis and endometrium
are functioning.
Pubertal Development
Female pubertal development begins with a growth
spurt 1 year before the development of breast buds
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Chapter 5 • Amenorrhea
M1—Tanner 1
(preadolescent). Only the
nipple is raised above the
level of the breast, as in the
child.
—Tanner 2. Budding
M
2
stage; bud-shaped elevation
of the areola; areola
increased in diameter and
surrounding area slightly
elevated.
—Tanner 3. Breast and
M
3
areola enlarged. No contour
separation.
M
—Tanner 4. Increasing fat
4
deposits. The areola forms a
secondary elevation above
that of the breast. This
secondary mound occurs in
approximately half of all girls
and in some cases persists
in adulthood.
—Tanner 5 (adult stage).
M
5
The areola is (usually) part
of general breast contour
and is strongly pigmented.
Nipple projects.
FIGURE 5-2 Five stages of breast development in females. (Growth diagrams 1965 Netherlands: Second
national survey on 0-24-year-olds, by J. C. Van Wieringen, F. Wafelbakker, H. P. Verbrugge, J. H. DeHaas.
Groningen: Noordhoff Uitgevers BV, The Netherlands.)
(thelarche) at around age 11 years. Growth continues
for 1 year until the peak height velocity is achieved.
Pubic hair appears (pubarche), followed by axillary
hair and the beginning of menarche. In the United
States, the average age of menarche for girls is 12 years
4 months. The length of time from thelarche to
menarche is 2 to 3 years.
A thorough review of pediatric growth charts is
helpful in determining the young girl’s norm of growth
and development and the centimeters attained by her
latest growth spurt. Most adolescent girls have a mean
height gain of 29 cm (11.4 inches) and the growth spurt
lasts approximately 4 years. Adolescents who are overweight for height may be hypothyroid; adolescents
who are underweight may have deciencies in caloric
intake or systemic illnesses. Asking adolescents to
self-identify their Tanner stages, for breast and pubic
development maturity, provides very accurate staging
(see Figures 5-2 and 5-3). Additionally, it gives the opportunity for insight into their feelings about their body
and self-esteem.
Age of Menarche
The lack of menstrual periods and secondary sex characteristics by age 14, or the lack of menses by age 16
in the presence of secondary sex characteristics, is
considered primary amenorrhea. Fifty-six percent of
all adolescents start menses when PH development is
at PH stage 4 and 19% at PH stage 3 (see Figure 5-3).
If the adolescent is PH stage 4, but has not had a
Chapter 5 • Amenorrhea
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51
P1—Tanner 1
(preadolescent).
No growth of
pubic hair.
P3—Tanner 3.
Sparse, dark,
visibly
pigmented,
curly pubic hair
on labia.
P5—Tanner 5.
Lateral
spreading;
type and
triangle spread
of adult hair to
medial surface
of thighs.
P2—Tanner 2.
Initial, scarcely
pigmented
straight hair,
especially
along medial
border of the
labia.
—Tanner 4.
P
4
Hair coarse
and curly,
abundant but
less than adult.
P
—Tanner 6.
6
Further
extension
laterally,
upward, or
dispersed
(occurs in only
10% of
women).
FIGURE 5-3 Six stages of pubic hair development in females. (Growth diagrams 1965 Netherlands: Second
national survey on 0-24-year-olds, by J. C. Van Wieringen, F. Wafelbakker, H. P. Verbrugge, J. H. DeHaas.
Groningen: Noordhoff Uitgevers BV, The Netherlands.)
menses, then primary amenorrhea should be diag-
nosed. However, if the adolescent does not meet the
age and maturation criteria, then suspect she is experi-
encing delayed puberty, or is a so-called “late bloomer.”
She is likely to have a family history in her mother and
sisters of delayed menarche. Almost 80% of amenor-
rheic adolescents with intact female genitalia and
developed breasts have an inappropriate LH feedback,
anovulatory cycles, or high levels of androgenic hor-
mones. They will bleed after a PCT and should be
monitored for continued menses to avoid endometrial
hyperplasia.
Menstrual History
Absence of a menstrual period for the past 3 months
in females with established normal menstruation, or
9 months in females with previous oligomenorrhea
(menstrual periods occurring at intervals of greater
than 35 days, with only four to nine periods in a year),
is considered secondary amenorrhea. Sudden cessation
of menstruation is more likely to indicate pregnancy or
stress as a cause, whereas a gradual cessation suggests
polycystic ovarian syndrome (PCOS), or ovarian failure. Ovarian failure is considered premature in women
under age 40. Premature ovarian failure is also called
primary ovarian insufciency, and women may have
occasional periods. Women over age 40, who have not
had a period within the past 3 to 11 months, may be
considered perimenopausal.
Are there any constitutional delays causing the
amenorrhea?
Key Questions
l
Has there been a change in weight, percentage of
body fat, or athletic training intensity?
l
Are you under unusual stress at school, home, or
work?
l
Do you or anyone in your family have any congenital
disorders or chronic diseases?
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Chapter 5 • Amenorrhea
Change in Weight, Percentage Body Fat, and
Athletic Training Intensity
Underweight people typically have a low body fat–to–
lean muscle ratio. Body fat can be assessed using the
body mass index (BMI [weight in kilograms/height in
meters2]). The severe stress of anorexia nervosa can
produce prolonged amenorrhea. Exercise from various
sports—jogging, middle and long distance running,
ballet dancing, gymnastics, and track and eld events—
can lower body fat sufciently to cause menstrual aberrations. Long distance runners and ballerinas are more
apt to be amenorrheic than are swimmers; however,
even moderate exercise can cause one or two missed
periods a year. The mechanism of action on the HPO
axis is unknown, but is expressed by delayed puberty,
shortened luteal phase, anovulation, and amenorrhea.
Obesity can be the cause of amenorrhea or be a sign of
polycystic ovarian syndrome (PCOS). PCOS causes
ovarian dysfunction—elevated androgens, hirsutism,
low sex steroid binding globulin (SSBG), and an
elevated LH/FSH ratio.
Emotional State
The stress of athletic competition, family situations,
school performance, peer relations, and work can disrupt normal cyclic menses. The HPO axis of a teenager
is more sensitive to physical and psychological stress
than that of an adult female.
Congenital or Chronic Diseases
Turner syndrome stigmata (see the discussion on performing a head and neck examination later in this
chapter), or similar physical ndings, suggest the probability of an abnormality of one or all components
(CNS, structural anomalies, or HPO axis) necessary
for menstruation. Most structural anomalies that would
prevent outow of the menstrual blood are detectable
on physical examination. Chronic diseases, such as
anorexia nervosa, diabetes mellitus, Crohn disease,
systemic lupus erythematosus, glomerulonephritis,
cystic brosis, pituitary adenoma, adrenal diseases,
and thyroid dysfunction, can cause amenorrhea.
Could this be thyroid dysfunction?
Key Questions
l
Have you noticed changes in the texture of your hair
or skin?
l
Are you bothered by hot or cold temperatures?
l
Have you had any changes in your energy level?
l
Have you had any changes in your bowel function?
Hair and Skin Changes and Temperature
Intolerance
Hypothyroidism and hyperthyroidism are expressed by
changes in hair and skin texture. Women with hypothyroidism may report dry hair along with thinning of hair.
Hyperthyroidism often makes women intolerant of the
heat, and this is sometimes confused with menopausal
syndrome symptoms. Cold intolerance is frequently
exhibited by people with a low-functioning thyroid.
Energy and Bowel Changes
Increased functioning of the thyroid causes restlessness
and diarrhea, whereas decreased functioning results in
constipation and fatigue. Even mild thyroid dysfunction
can cause menstrual irregularities, therefore a thyroid
function test is needed to assess the thyroid status.
Could this be caused by hyperprolactinemia?
Key Questions
l
Are you able to express a discharge or liquid from
your nipples?
l
Is there increased stimulation to your nipples?
l
Have you had any surgery or disease of the breasts or
chest wall?
Galactorrhea
A female patient may notice breast nipple discharge that
is not associated with breastfeeding or medications.
Causative medications are listed in Box 5-1 and include
primarily the dopamine antagonist agents and estrogens.
BOX 5-1
Drugs That May Cause
Amenorrhea
PROLACTIN INCREASE
• Antipsychotics: phenothiazines, haloperidol, pimozide,
clozapine
• Antidepressants: tricyclic antidepressants, monoamine
oxidase inhibitors
• Antihypertensives: calcium channel blockers, methyldopa,
reserpine
ESTROGENIC EFFECT
• Digitalis, marijuana, flavonoids, oral contraceptives
OVARIAN TOXICITY
• Busulfan, chlorambucil, cisplatin, cyclophosphamide,
fluorouracil
Modified from Kiningham RB, Apgar BS, Schwenk TL: Evaluation of
amenorrhea, Am Fam Physician 53:1186, 1996.
Chapter 5 • Amenorrhea
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53
Nipple Stimulation and Chest Wall Stimulation
Nipple stimulation from clothing irritation during jogging, from nipple manipulation or stimulation during
sexual activity, may cause galactorrhea. Surgical interventions such as lymph node dissection, or disease
processes such as herpes zoster, can also lead to galactorrhea, triggered by peripheral neural stimulation.
Could the amenorrhea be caused by medications?
Key Questions
l
What prescription medicines are you taking?
l
Have you used any street drugs? What kind of drugs
have you used?
Medication History
Some medications, such as phenothiazines or contraceptives, can cause amenorrhea. These drugs increase
prolactin levels, induce an estrogenic effect, or are
toxic to the ovaries (see Box 5-1). Use of illicit drugs,
such as heroin and methadone, also leads to menstrual
abnormalities.
Is a pituitary tumor causing the amenorrhea?
Key Questions
l
Have you experienced any visual changes?
l
Are you having an increased number of headaches?
Visual Changes and Headaches
A pituitary tumor could be responsible for the hyperprolactinemia. Enlarging pituitary tumors cause headaches. As the tumor grows out of the sella turcica, it
compresses the optic chiasm and nerves. The common
visual defect is bitemporal hemianopia, although other
defects can occur. Changes in visual elds are often
self-diagnosed when the patient recognizes vision
problems while reading or driving an automobile.
Clinical changes in vision warrant a referral to an
ophthalmologist and computed tomography (CT) or
magnetic resonance imaging (MRI) workup for a
tumor of the sella turcica. A high prolactin level
indicates a pituitary adenoma that presents with or
without galactorrhea.
Is this a problem of the HPO axis?
Key Questions
l
Have you experienced any problems with infertility?
l
Do you have excess hair on your face or chest?
l
Are you having any menopausal symptoms (e.g., hot
ashes, vaginal dryness)?
l
Did you hemorrhage during childbirth?
Infertility
Many cases of infertility are caused by failure of ovulation. PCOS affects women between the ages of 15 and
30 years. Basal body temperature charts and endometrial biopsies can reveal anovulatory cycles. Vaginal
ultrasound shows enlarged ovaries with multiple small,
uid-lled cysts. Infertility can be caused by low or
high estrogen levels. Measurement of gonadotropins,
vaginal maturation index (MI), and progesterone levels,
provide insight into the functioning of the HPO axis.
Androgen Excess
About 50% of women diagnosed with PCOS are hirsute,
obese, and have difculty conceiving. Few other signs
of masculinization are present. Luteinizing hormone is
elevated with PCOS. Truncal obesity, acne, and male
pattern baldness can signify androgen excess.
Estrogen Deficiency
Amenorrhea can indicate a menopausal state. During
perimenopause, ovulation and menses occur irregularly because of uctuations in the hormones of the
HPO axis. Hot ashes or ushes, changes in mood, and
difculty sleeping are common menopausal symptoms
that women with low estradiol levels can experience.
A dry vagina is often accompanied by dyspareunia and
sometimes dysuria. The dysuria can be secondary to
the hypoestrogenic state of the urethra, and not be the
result of a urinary tract infection. Prolonged hypoestrogenic status leads to osteopenia, regardless of age.
EVIDENCE-BASED PRACTICE
Brambilla and colleagues (19 94) found that 3 to 11 months
of amenorrhea or irregular periods among women age 45
to 55 years were most predictive of menopause within
the followin g 3 years (sensitivity, 72%; specificity, 76%).
Reference: Brambilla DJ, McKinlay, SM, Johannes CB: Defining the perimenopause for application in epidemiologic investigations. Am J Epidemiol
140:1091-1095, 1994; Bastian LA, Smith C, Nanda K: Is this woman perimenopausal? JAMA 289:895-902, 2003.
Predictors of Menopause
A systematic review by B astian an d colleag ues (2003 )
showed that besides menstrual history, the strongest indicators of perimeno pause were hot flashes, night sweats, and
vaginal dryness.
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Chapter 5 • Amenorrhea
Hemorrhage at Childbirth
Amenorrhea can occur subsequent to a pregnancy
and delivery if there was severe hemorrhage at the
time of delivery. Obstetric hemorrhage causes pituitary ischemia and infarction and results in pituitary
insufciency. This pathological process is known as
Sheehan syndrome. In this instance, refer the patient
to an endocrinologist.
Is this a problem of the uterus?
Key Question
l
Have you had a miscarriage or abortion, uterine in-
fection, or any surgery or procedure involving your
uterus?
Gynecological Problem
Endometritis, incomplete abortion, or aggressive
curettage of the uterus can lead to denuding of the
endometrial layer, scarring, and Asherman syndrome.
The patient with Asherman syndrome will not bleed
after the PCT, nor will she bleed after the uterus is
primed with estrogen and challenged with DMPA.
The diagnosis can be made by performing weekly
serum progesterone tests to determine if any value is
within the ovulatory range (greater than 3 ng/mL),
yet there are no periods. The diagnosis can also be
made by the gynecologist via hysteroscopy, hysterosalpingography, or measuring endometrial thickness
by ultrasonography.
What symptoms support a structural outow problem?
Key Questions
l
Do you have cyclic abdominal bloating or cramping?
l
Have you been amenorrheic since you had a cervical
procedure?
Presence of Premenstrual Symptoms or
Dysmenorrhea
Cyclic symptomatology of dysmenorrhea, in the absence of menses, can be caused by an incomplete outow tract. Physical examination validates a vaginal
opening, imperforate hymen, intact uterus, or congenital imperforate cervical os. If there is no indication
of a uterus by examination or lower abdominal ultrasound, a karyotype is needed to determine the congenital disorder. A referral to an endocrinologist or
gynecological surgeon could be indicated for removal
of any abdominal male gonads, which would be a risk
for cancerous degeneration.
Amenorrhea Following Cervical Procedure
Stenosis of the cervical os can occur after gynecological ofce surgeries, such as cervical biopsies and
cryotherapy. However, it is more common after cone
biopsies of the cervix, such as the loop electrosurgical
excision procedure (LEEP) or carbon dioxide laser
treatment.
DIAGNOSTIC REASONING: FOCUSED
PHYSICAL EXAMINATION
Note General Appearance
The body morphology of the patient can provide
clues to the cause of amenorrhea; often disorders
can be diagnosed secondary to short stature, underweight, or overweight. A height less than 5 feet
(short stature) in a girl who is 14 years old or older
could indicate a congenital chromosomal problem.
Assess the woman’s general state of health to determine if there are signs of systemic, chronic, or
congenital disease.
Assess Nutritional Status and Plot Measurements
on Growth Chart in Adolescents
Assess nutritional status, looking for signs of undernutrition or overnutrition. Measure the height,
weight, and arm span of the adolescent. Plot on a
growth chart if delayed puberty is a consideration.
Anorexia nervosa is often found while evaluating
an adolescent who has short stature and is underweight.
Assess Sexual Maturity
Use the Tanner stages to assess and rate the stage of
breast and pubic hair development. A sexual maturity
rating (SMR) can be calculated by averaging the girl’s
stages of pubic hair and breast development. The stage
of breast and pubic hair development in the adolescent
girl is related to her chronological age, age at menarche, and evidence of growth spurt. The breasts often
develop at different rates, so some asymmetry is common. Menarche generally occurs at SMR 4 or breast
stage 3 to 4. Plot these physiological events on the
growth curve.
Screen for Eating Disorders
If you suspect anorexia nervosa or bulimia, administer
a screening instrument to help determine the diagnosis.
Refer to the DSM-5 for diagnostic criteria. About half
of the females with eating disorders will have short
stature.
Chapter 5 • Amenorrhea
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55
Calculate the Body Mass Index
Seventeen percent body fat is needed for most females
to be menarchal, and about 22% body fat is necessary
for ovulation. Calculate the BMI (Box 5-2). A BMI of
19 kg/m2 usually indicates about 17% body fat, which
can cause amenorrhea.
Obesity causes amenorrhea secondary to ovarian
dysfunction. A BMI of greater than 27 kg/m2 corresponds to being more than 20% overweight. Adipose
cell stroma convert androstenedione to estrogen (estrone) as the body fat increases. Obesity also increases
sex hormone binding globulin, thereby increasing free
steroid levels. Both processes can cause an imbalance
in the HPO axis and lead to amenorrhea.
Examine the Skin and Hair
Observe for signs of thyroid dysfunction or adrenal
excess. Features of hypothyroidism include dry,
coarse, aky skin; coarse hair that tends to break; and
thick, brittle nails. Hyperthyroidism is characterized
by ne, warm skin that is hyperpigmented at pressure
points. Nails will often separate from the nail plate
(onycholysis), and hair will be ne, thin, and limp.
Cushingoid features include truncal obesity, striae,
and “moon face.” Observe for other signs of androgen
excess, which include hirsutism, acne, and male
pattern baldness.
Perform a Head and Neck Examination
During the head and neck examination note any visual
changes, including visual eld defects that might indicate a pituitary tumor. Anosmia might denote a congenital absence of GnRH, resulting in no secretion of
LH or FSH from the pituitary. Without LH or FSH
BOX 5-2
BMI is helpful in assessing the nutritional status and
total body fat of the patient. You can use the BMI chart
in Appendix C to determine the BMI. You can also calculate
the BMI by using the following formula.
that number (product) and divide by the patient’s height in
inches. Once again, divide by the height in inches.
or 50 inches
Body Mass Index (BMI)
Multiply the patient’s weight in pounds by 704. Take
Example: Weight 5 75 pounds; height 5 4 feet 2 inches
75 3 704 5
52,800 4 50 5
1056 4 50 5
BMI
52,800
1056
21.12
21
5
production, there is no ovulation; anovulatory cycles
are amenorrheic. Also look for Turner syndrome
stigmata—webbed neck and low-set ears (other signs
are shieldlike chest and short fourth metacarpal).
Palpate the Thyroid Gland and Lymph Nodes
Palpate the thyroid gland for diffuse enlargement,
asymmetry, and nodules. Auscultate for thyroid bruits
and count the pulse rate. Assess for supraclavicular
and infraclavicular lymphadenopathy or carcinogenic
masses of the sternal notch and abdomen, which could
arise from a tumor of germ cell, adrenal, or pituitary
origin.
Perform Clinical Breast Examination
Physical examination veries sexual maturation level.
The growth spurt occurs before breast development
(thelarche), which is followed by the appearance of
axillary hair. Perform a breast examination and assess
breast maturity level using Tanner stages. More than
95% of adolescents are menarchal 1 year after they
reach a breast stage of 4. Check for galactorrhea (see
Chapter 6).
Perform a Pelvic Examination
Observe for maturation of the female genitalia and
secondary sex characteristics. Assign a Tanner stage
for pubic hair development. A congenital problem
might manifest as vaginal or uterine agenesis, and is
identied by the absence of a vagina, cervix, or uterus.
There could be a small invagination of the perineum
below the urinary meatus. It can be explored using a
cotton-tipped applicator and otoscope with a large ear
speculum or nasal speculum to determine the dimensions of the vault and presence of a cervix. A clitoris
larger than 1 cm is suggestive of androgen excess.
Assess for other outlet problems, including an imperforate hymen (painful, bluish bulging of the
perineum), stenotic cervix (bulging os, or inability to
pass a cotton-tipped applicator through the os), or a
transverse vaginal septum. The development of hematocolpos, hematometra, or hematoperitoneum from
menses behind an obstructed outow tract needs immediate intervention to prevent inammatory changes
and endometriosis. Needle aspiration is not recommended because it might potentiate infection. Refer to
a reconstructive gynecological surgeon for MRI, and
often, extensive surgery.
If the introitus is small, use a pediatric or other appropriately sized speculum or a Huffman vaginoscope.
Vaginal walls that are pale and dry, have few rugae,
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Chapter 5 • Amenorrhea
and are friable are estrogen decient. Low estrogen
levels cause scant cervical mucus. Vaginal cytology
reports for women exhibiting such symptoms show an
MI lacking or low in estrogen.
The bimanual examination can be performed with
only an index nger in the vagina if the vaginal vestibule is small. If the hymen is rigid, a rectal bimanual
examination can be completed instead of the usual
vaginal bimanual examination. On pelvic bimanual
examination, enlarged ovaries are palpated about half
the time in patients with PCOS. Assess for position,
size, shape, and consistency of the cervix, uterus, and
ovaries.
LABORATORY AND DIAGNOSTIC STUDIES
Pregnancy Test
Urine or serum testing for the beta subunit of the
human chorionic gonadotropin (b-hCG) is used to
identify or rule out pregnancy, and is an essential
test on all females presenting with amenorrhea.
Thyroid-Stimulating Hormone
A serum TSH test identies hypothyroidism. When
hormonal supplementation is provided, menses usually
resume for these patients. If the amenorrhea is associated with galactorrhea and hyperprolactinemia, the
prolactin level must be measured again after the thyroid
function levels become normal.
Prolactin Levels
About one-third of women with no obvious cause of
amenorrhea will have an elevated prolactin level.
When the patient’s fasting prolactin level is within
reference range, less than 50 ng/mL, a progesterone
challenge test is indicated. If the fasting prolactin level
is high, greater than 50 ng/mL, or if the patient has
galactorrhea, a cone-down view of the sella turcica is
taken to rule out a pituitary adenoma. A level greater
than 200 ng/mL, is highly suggestive of a prolactinoma. A prolactin elevation less than 100 ng/mL, but
higher than normal, is most frequently caused by prescribed or illicit drugs. The hyperprolactinemia usually
subsides a few weeks after stopping the offending
drug. Prolactin levels are normal in PCOS. Microscopic examination of breast discharge will reveal fat
globules and no red blood cells (see Chapter 6).
Serum Follicle-Stimulating Hormone Levels
Ovarian failure, which causes a low estradiol secretion,
will raise the FSH level higher than 40 milliunits/mL. If
both the FSH and LH levels are greater than 50 milliunits/
mL, then primary ovarian failure is established. If the
patient is older than 30 years, menopause is diagnosed; if
she is younger than 30 years, a karyotype should be
done. An FSH measurement of less than 40 milliunits/mL
denotes a hypothalamic-pituitary dysfunction and secondary ovarian failure.
Serum Luteinizing Hormone Levels
A serum LH level greater than 35 milliunits/mL is frequently seen in patients with PCOS. An LH:FSH ratio
higher than 2:1 is suggestive of PCOS, whereas a ratio
higher than 3:1 is considered diagnostic of PCOS.
Dehydroepiandrosterone Sulfate
Mildly elevated levels of dehydroepiandrosterone
sulfate (DHEA-S) are seen in women with PCOS. A
signicantly elevated level of DHEA-S, greater than
700 mg/dL, indicates congenital adrenal hyperplasia.
Central Nervous System Imaging
If both FSH and LH levels are low, indicating a problem
of the pituitary, imaging of the CNS is warranted. Either
contrast-enhanced CT or MRI of the sella turcica can
determine whether there is an abnormality. If the prolactin level is greater than 100 ng/mL, or the cone-down
view of the sella turcica is abnormal, CT or MRI with
contrast enhancement should be obtained.
Pelvic Ultrasound and Vaginal Ultrasound
Pelvic and vaginal ultrasound studies are used to determine the presence of a uterus, the anatomical size and
endometrial thickness of a uterus, and whether broids
or other tumors exist. Ultrasound is used to measure
ovarian size, to identify cysts, and to evaluate follicular
development. In primary amenorrhea, ultrasound is
helpful in assessing müllerian agenesis and gonadal
dysgenesis, because there could be internal organs and
no conduit to the perineum. One-third of these patients
also have urinary tract abnormalities; therefore an
abdominal ultrasound can be obtained at the same time
to evaluate that system.
Progesterone Challenge Test
Also called the progesterone withdrawal test, the progesterone challenge test (PCT) consists of the administration of oral DMPA 10 mg daily for 7 to 10 days, or
parenteral progesterone in oil 200 mg intramuscularly.
The patient should respond to the medication within
2 to 7 days. If there is a positive PCT response, the
patient bleeds. This demonstrates that there are
Chapter 5 • Amenorrhea
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57
sufcient endogenous estrogens to prepare the endo-
metrium and conrms that there is a functioning
outow tract. It substantiates an intact HPO axis. Other
forms of progesterone can be used: micronized proges-
terone 400 mg orally daily for 7 to 10 days, or noreth-
indrone 5 mg orally daily for 7 to 10 days.
Estrogen/Progesterone Challenge Test
The estrogen/progesterone challenge test (E/PCT)
consists of the administration of conjugated estrogens
1.25 mg daily, or estradiol 2 mg daily for 21 days, fol-
lowed by progesterone as given in the PCT. If there is
no menstrual ow, administer the regimen a second
time. If there is no ow after both courses of therapy,
the cause is either the outow tract or the uterine
endometrium. The E/PCT is positive if there is men-
strual ow within 2 to 7 days. A positive test denotes
that there is inadequate estrogen production either
from inadequate functional ovarian follicles, or from
inadequate pituitary gonadotropic stimulation.
Chromosome Analysis (Karyotyping)
Karyotyping is done to delineate probable chromo-
somal abnormalities. It is used in the workup for
ambiguous genitalia, primary amenorrhea, oligomen-
orrhea, delayed puberty, or abnormal development at
puberty.
Endometrial Biopsy
Endometrial biopsy can be used to show the hormonal
response of the uterine endometrium.
Basal Body Temperature Charting
A woman can take her awakening body temperature
each day and chart it to determine if ovulation is oc-
curring. This test is based on the fact that progesterone
increases the body temperature by 0.5° F to 0.8° F for
11 days during the luteal phase. If this increase in
temperature occurs, ovulation has occurred and a
positive estrogen component is inferred.
Maturation Index
The maturation index indicates the degree of maturation
of the vaginal epithelium and provides an objective as-
sessment of vaginal hormone response as well as overall
hormonal environment. The sample is collected by scrap-
ing the vaginal wall near the cervix. The index is read
from left to right and refers to the percentage of parabasal,
intermediate, and supercial squamous cells appearing on
a smear, with the total of all three values equaling 100%.
For example, an MI of 0/40/60 represents 0% parabasal
cells, 40% intermediate cells, and 60% supercial
cells. Lack of estrogen effect is demonstrated by the
predominance of parabasal cells. Low estrogen effect is
demonstrated by the predominance of intermediate cells.
Increased estrogen effect is demonstrated by the predominance of supercial cells. Both increased and decreased estrogen effects can be reective of a hormonal
imbalance of the HPO axis.
Progesterone Levels
Serum progesterone levels collected at weekly intervals can establish whether ovulation has occurred. A
value greater than 3 ng/mL is found with ovulation.
DIFFERENTIAL DIAGNOSIS
Pregnancy
Pregnancy is the most common reason for amenorrhea in women of childbearing age. Determining the
pregnancy status of the patient is the rst step in the
amenorrhea workup.
Constitutional Problems
Delayed Puberty
A pituitary adenoma must be ruled out for all patients
with delayed puberty. Yearly prolactin levels should be
performed for those with delayed puberty because of
the possibility of occult pituitary adenomas.
Anorexia Nervosa and Bulimia
Anorexia nervosa and bulimia are disorders that are
psychiatric in origin. Affected women have such a fear
of being fat that they do not eat or they purge after
eating. Often these women are overachievers and have
low self-esteem. The majority are adolescents, with
a mean age of 13 to 14. Amenorrhea is caused by
extreme weight loss and/or cachectic state.
Exercise-Induced Amenorrhea
This amenorrhea is common in competitive athletes,
but exercise can also cause skipped menses in the casual trainer. Gymnasts, ballerinas, and long distance
runners are at high risk, especially if they started their
training at a very early age. Body fat of 17% is needed
for menarche, whereas 22% body fat is necessary for
ovulation. The BMI estimates the level of body fat.
Congenital or Chronic Disorders
Turner Syndrome
Turner syndrome causes primary amenorrhea because
of ovarian agenesis. The typical features are short
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Chapter 5 • Amenorrhea
stature, webbed neck, shieldlike chest, and delayed
secondary sex characteristics.
Cushing Syndrome
Cushing syndrome is caused by an excess secretion of
adrenocorticotropic hormone (ACTH) from a pituitary
or adrenal adenoma. Classically, patients present with
a moon face, acne, hirsutism, kyphosis, purplish striae
of the abdomen, and hypertension. A CT scan can
reveal pituitary or adrenal adenoma.
Thyroid Dysfunction
Amenorrhea from thyroid dysfunction subsides as
soon as serum thyroid levels return to normal. Hypothyroidism frequently causes amenorrhea and is characterized by fatigue, constipation, cold intolerance,
and dry skin.
Polycystic Ovary Syndrome
In PCOS, the patient typically is obese, hirsute, has
oligomenorrhea, and large cystic ovaries. However,
women with chronic anovulatory cycles and hyperandrogenemia meet the criteria for PCOS even if they are
slim and without hirsutism. The LH/FSH ratio is
greater than 3:1. The level of DHEA-S is elevated.
Uterine and Outflow Tract Problems
Imperforate Hymen
The woman with an imperforate hymen could present
with a painful, bulging perineum. There is lack of an intact outow tract, which causes the primary amenorrhea.
Cervical Os Stenosis
Stenosis of the cervical os can be the cause for either
primary, or secondary amenorrhea. Stenosis is often
caused by therapeutic procedures of the cervix such
as cryotherapy or cone biopsies. These procedures
cause scarring and stenosis of the os, obstructing the
outow tract.
Asherman Syndrome
Asherman syndrome occurs when the uterine endometrial lining is denuded or scarred, usually by infection
or curettage. The patient does not respond to either a
PCT or an E/PCT.
Hypothalamic-Pituitary-Ovarian Axis Problem
Ovarian Failure
Menopause occurs when the ovaries fail, secondary to
depletion of ova. The average age of menopause in the
United States is 51 years. It is a state of hypoestrogenemia. The gonadotropin levels rise (FSH greater than
40 milliunits/mL), and the estradiol levels fall (less than
15 pg/mL). Clinical symptoms are hot ashes, night
sweats, insomnia, mood changes, and amenorrhea
for 12 months. If this occurs before age 40 years, it is
considered premature. Common causes of premature
ovarian failure include genetic and enzyme disorders,
immune disturbances, and chemotherapy.
Sheehan Syndrome
Sheehan syndrome is activated by severe obstetrical
hemorrhage, which causes pituitary ischemia and infarction. The pituitary gland becomes dysfunctional.
Medications
Prescription and illicit drugs can increase prolactin levels, which in turn promote galactorrhea. Offending drugs
are primarily dopamine antagonist agents, estrogens, and
marijuana.
Chest Wall or Nipple Stimulation
Prolactin inhibits the pulsatile secretion of GnRH,
unbalancing the HPO axis and possibly causing
amenorrhea. The higher the prolactin level, the
greater the likelihood that the patient will be amenorrheic.
Pituitary Adenoma
Pituitary macroadenomas and microadenomas should
be suspected if the prolactin level is greater than
100 ng/mL, or if there are any abnormalities of the
cone-down view of the sella turcica. Patients with
pituitary adenomas should be referred to an endocrinologist. Patients with prolactin levels exceeding
1000 ng/mL probably have an invasive tumor.
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