Download Amenorrhea_APGO

8th Edition APGO Objectives
for Medical Students
Amenorrhea
Quick Links:
Presentation
References
Clinical Case
Questions
Rationale
The absence of normal menstrual
bleeding may represent an anatomic or
endocrine problem. A systematic
approach to the evaluation of
amenorrhea will aid in the diagnosis and
treatment of its cause.
Objectives:
The student will be able to list:
a) Definitions of primary amenorrhea,
secondary amenorrhea and
oligomenorrhea
b) Causes of amenorrhea
c) Evaluation methods
d) Treatment options
Definitions
Primary:


No menses by age 14 yr. in the
absence of growth or
development of secondary sexual
characteristics
No menses by age 16 yr.
regardless of the presence of
normal growth and development
with appearance of secondary
sexual characteristics
Secondary:

In a woman who has been
menstruating, absence of
menstruation for a length of time
equivalent to a total of at least 3
of the previous cycle intervals, or
6 months of amenorrhea
Oligomenorrhea:

menses at intervals >35 days
Normal menstrual cycle
Causes
Anything that interferes with normal
sequence which culminates in
menstruation, i.e. disorders of the CNS
(hypothalamus), anterior pituitary, ovary,
uterus or outflow tract
Causes - Pregnancy

most frequent cause of amenorrhea
Causes - Hypothalamic dysfunction
(hypogonadotropic hypogonadism)



Suppression of GnRH pulsatile secretion -  Kallmann’s syndrome
 Amenorrhea with anosmia
second most frequent cause
 Caused by mutation of short arm of X
This causes low FSH and LH and, therefore,
chromosome that encodes a protein
also a low estrogen level and no withdrawal
responsible for functions necessary for
bleeding following progesterone challenge
neuronal migration
Stress - corticotropin-releasing hormone (CRH)
directly inhibits hypothalamic GnRH secretion  Cells that produce GnRH originate in
olfactory area and migrate during
(probably by augmenting endogenous opioid
embryogenesis along cranial nerves that
secretion)
connect nose and forebrain
 Weight loss - especially anorexia
 Effects 5 to 7 times more males than
 Excess exercise related both to percent
females
body fat and energy expenditure
 May be X-linked, autosomal dominant, or
 Severe emotional stress
autosomal recessive
 Chronic disease


CNS tumor - hamartomas
Other - sarcoidosis
Causes - Pituitary Dysfunction
hypogonadotropic, hypogonadism, i.e. low

FSH, LH and estrogen levels



Pituitary adenomas (benign adenomas
of lactotrophs)
Produce prolactin, elevated levels inhibit

pulsatile secretion of GnRH
Common



Found in 1/3% of women with secondary
amenorrhea
Only 1/3 of women with high prolactin
levels have galactorrhea
Almost never malignant (only 40 cases
of primary pituitary cancer in the world
literature through 1989) If large (>1 cm,
referred to as macroadenoma):

May compress optic chiasm causing
bitemporal hemianopsia and/or
headaches
Diagnosed via imaging studies (MRI
or CT) in patients with elevated
prolactin level
Treatment



Surgical - rarely used as complete
cure rate is low and recurrence
common
Medical - dopamine agonists
(bromocriptine or cabergoline) remember, inhibit pituitary prolactin
secretion
Surveillance - many
microadenomas (<10mm) regress
spontaneously or remain small.
Note: this does not treat patientﾕs
hypoestrogenic status
Causes - Pituitary Dysfunction
Hyperthyroidsm
 Elevated thyrotropin-releasing hormone levels
stimulate pituitary cells that secrete prolactin.
 In addition, thought to be associated with
declining hypothalamic content of dopamine
and, therefore, a removal of dopaminergic
suppression of prolactin secretion.
Causes - Pituitary Dysfunction
Lesions compressing the pituitary stalk causing
interference with delivery of hypothalamic
GnRH (all rare compared to pituitary
adenomas)

Other pituitary tumors - craniopharyngiomas,
meningiomas, gliomas, metastatic tumors,
chordomas
• May also cause optic chiasm compression even when
small


Non-neoplastic intrasellar - gummas,
tuberculomas, fat deposits
Lesions near the pituitary- internal carotid artery
aneurysms, obstruction of the aqueduct of Sylvius
Causes - Pituitary Dysfunction
Empty sella syndrome
 Congenital incompleteness of sellar diaphragm
that allows an extension of subarachnoid space
into the pituitary fossa
 Found in 5% of autopsies, 85% are women,
incidence of 4-16% in patients who present with
amenorrhea/ galactorrhea 2
Causes - Pituitary Dysfunction
Pituitary infarction - Sheehan’s syndrome
 Acute necrosis of pituitary gland due to
postpartum hemorrhage, with hypotension,
decreased perfusion and shock
 Symptoms of panhypopituitarism seen early in
the postpartum period, especially failure of
lactation and loss of pubic and axillary hair
 Is life threatening
 Exceedingly rare in U.S.
Causes - Pituitary Dysfunction
Lactation
(physiologic hyperprolactinemia)
Causes - Premature Ovarian Failure
Premature ovarian failure  Etiologies
 Autoimmune - need to evaluate for
(hypergonadotropic
other autoimmune disorders,
hypogonadism) especially thyroid, adrenal
elevated FSH and LH
 Infection - such as mumps oophoritis
 Defined as ovarian
 Irradiation or chemotherapy
 Castration
failure at age <40 yr.
 Gonadal dysgenesis
 Due to early depletion
• Most common cause of primary
of ovarian follicles
amenorrhea
• Karyotype if age <30 yr.
 normal karyotype is
• May be abnormal karyotype (45, X; or
also linked to
mosaics) or may be normal
• If Y chromosome present, even in
neurosensory deafness
mosaic, gonads need to be removed
(Perrault syndrome)
to prevent tumor formation or
virilization
• Gonadal dysgenesis associated with
Causes - Chronic Anovulation
Chronic anovulation due to increased
androgens
 Cushing’s syndrome
 Congenital adrenal hyperplasia
 Polycystic ovarian syndrome
Causes - Disorders of Uterus
 Absence of uterus in normal (46,
Disorders of the uterus or
outflow tract - normal FSH, XX) female - Mayer- RokinatskyKuster-Hauser syndrome
LH and prolactin; no
• 2nd most common cause of
withdrawal with
primary amenorrhea
progesterone challenge
• Müllerian development with
congenital absence of uterus
 Müllerian anomalies
and/or vagina

Discontinuity by segmental
disruptions of the Müllerian
tube, i.e. obliteration of
vaginal orifice, complete
transverse vaginal septa,
absence of a cervix,
imperforate hymen
• Müllerian anomalies frequently
associated with urinary tract
anomalies, including ectopic
kidney, renal agenesis, horseshoe
kidney, and abnormal collecting
ducts (remember, genital and
urinary systems develop in close
proximity and timing during
embryogenesis.) May also be
associated with skeletal anomalies
Causes - Absence of Uterus
Absence of uterus in a phenotypic female but
genotypic male (46, XY) - called testicular
feminization - androgen insensitivity
Causes - Absence of Uterus





Male pseudohermaphrodite
3rd most common cause of primary amenorrhea
X-linked recessive disorder of the gene responsible for the androgen
intracellular receptor; therefore, despite normal male levels of
testosterone, there is a lack of testosterone action
Patients appear normal female at birth except for possible presence of
inguinal hernias. Growth and development are normal, except tend to be
eunuchoid (long arms, big hands and feet) and tall. (May commonly
become actresses!) Breasts are large with scant glandular tissue. Uteri
absent, and vagina is blind canal and usually short. Testes abdominal or in
an inguinal hernia
This is the one exception to removing X, Y gonads in a phenotypic female
as soon as diagnosed. These patients should have gonads removed after
puberty, as it allows for more normal development of puberty, and
testicular tumors in these patients have not been encountered prior to
puberty
Causes - Endometrial atrophy
Endometrial atrophy secondary to
prolonged progesterone administration
 Depo-Provera
 Oral contraceptives
 Norplant
Causes - Endometrial Damage

Asherman’s syndrome endometrial scarring



Generally result of
overzealous postpartum
curettage, but may also be
after other uterine surgery
Diagnosed with
hysterosalpingogram,
sonohysterogram or
hysteroscopy
Generally will not have a
withdrawal bleed from
Provera



May also present with
multiple miscarriages,
dysmenorrhea,
hypomenorrhea or
infertility
Treated by hysteroscopic
lysis of adhesions
Infection



Tuberculosis - common
cause of amenorrhea in
undeveloped countries
Schistosomiasis
IUD related infection or
severe PID
Treatment
A. Treat the cause, i.e. hypothyroidism,
pituitary adenoma, infection, stress,
outflow tract scarring or obstruction, etc.
Treatment
B. If anovulatory, need to give periodic
progesterone to prevent endometrial
hyperplasia


Desires conception - ovulation induction
(progesterone in pregnancy will, in essence,
prevent hyperplasia, as will the pregnancy itself)
Not desiring pregnancy at this time
•
•
Oral contraceptives
Cyclic progestins
Treatment
C. Hypoestrogenic anovulation - need to induce
estrogen production or give estrogen to prevent
bone loss. Then need to make sure patient also
has progesterone so they donﾕt have
“unopposed estrogen”causing endometrial
hyperplasia or carcinoma:



Gonadotropins - typically used only for fertility
Pulsatile GnRH - typically used only for fertility
Oral contraceptives ･ HRT
Frequent sources of confusion
Post-pill amenorrhea
should be evaluated same as any other
amenorrhea if has been 6 mo. since
discontinuing OCPs or 12 mo. since last
injection of Depo- Provera
Frequent sources of confusion
Is it medically necessary for a woman to have a period
once a month?
No, but estrogen is necessary to build and maintain
bone mass, decrease risk of cardiovascular disease,
etc. Estrogen alone (unopposed estrogen)
significantly increases risk of endometrial hyperplasia
and adenocarcinoma. Progesterone counteracts
these risks. The combination of estrogen and cyclic
progesterone will produce a bleeding cycle. The two
hormones given together continuously (ex., taking
oral contraceptives without taking the placebo week)
creates amenorrhea without the adverse risks
discussed above
Frequent sources of confusion
If a woman is not menstruating, where does all
that blood go?
(A question often asked by patients, friends
and family) - depends on the cause of
amenorrhea. For example: if imperforate
hymen is cause, a hematometrium may
develop along with severe endometriosis. In
the case of continuous use of OCPs or DepoProvera, the endometrium is atrophic so
cannot “build up”
Frequent sources of confusion
If a woman is amenorrheic and doesn’t
want to have periods, should she be
evaluated?
Be treated? Yes, to rule out disease
processes and evaluate for bone loss
depending on length of time she was
amenorrheic. She may still be able to be
amenorrheic - for instance, if treated
with continuous OCPs.
Frequent sources of confusion
Can a woman who is amenorrheic
become pregnant?
Yes, depending on the cause of
amenorrhea
References
Speroff L et al. Clinical Gynecologic
Endocrinology and Infertility, 6th ed.
Williams and Wilkens: Baltimore, MD,
2000.
 Adapted from Association of Professors of
Gynecology and Obstetrics Medical
Student Educational Objectives, 7th
edition, copyright 1997

Clinical Case
Amenorrhea
Patient Presentation
A 26-year-old G2P2 woman with LMP= 6 months
ago presents with a concern regarding no
periods. She delivered two full term healthy
children vaginally and their ages are 5 and 3.
She stopped breastfeeding 2 years ago. She
has noted a persistent breast discharge, but no
breast masses. She is not using any
contraception, but parenting has taken a toll on
the husband-wife relationship and they
infrequently find the opportunity to have
intercourse.
Patient Presentation
Ob-gyn history
 G2 P2. 2 full-term vaginal
deliveries of a 6-0 pound
girl and a 7-8-pound boy.
Pap smears are up-todate and normal. No
STDs.
Past medical history
 Postpartum depression,
which resolved after one
year on an SSRI.
Past surgical history
 Cholecystectomy after
her first pregnancy
Social history
 Nonsmoker. Occasional
alcohol. No street drugs.
Married. Works as a
housewife.
Family history
 Noncontributory.
Patient Presentation
ROS
 Increased stress since the delivery of the
second child. Occasional hot flashes. Fatigue.
Headaches. Difficulty losing the pregnancy
weight gain.
Physical exam
 VS: BP= 120/80, P= 64, R= 18, Ht= 5’8”, Wt=
160 pounds
General: tired appearing Caucasian woman in
no apparent distress
Patient Presentation
HEENT: NC/AT









Neck: No thyromegaly palpable
Lungs: clear
CV: Regular rate, no murmurs
Breasts: bilateral milky white discharge with expression. No
masses, dimpling or retraction
Abdomen: non-tender, no distension, no masses, no
hepatosplenomegaly
Ext: Non-tender, no edema, DTRs 1+/= bilaterally
Pelvic exam: Normal external genitalia, moist vagina with
decreased rugae, no discharge, Cervix is multipara, nontender, and no lesions, uterus is non-tender, mobile and
normal size, adnexae are non-tender and no palpable masses
Allergies: None
Medications: Multi-vitamin
Patient Presentation
Laboratory/studies:






HCG= negative
FSH= 3.5 mIU/mL
TSH= 2.5 uIU/mL
Prolactin= 130 ng/mL; repeat on fasting, 100ng/mL
Breast discharge smear reveals multiple fat droplets
MRI of the head reveals a 0.8 cm mass in the anterior pituitary
Diagnoses



Amenorrhea
Galactorrhea
Prolactinoma (Pituitary microadenoma)
Treatment
This patient was treated with Cabergoline (a
dopamine agonist) on a weekly basis and the
dose was increased until her prolactin level was
in the normal range. She tolerated the
medication well. She had return of menses
within a few months time. Her galactorrhea
slowly resolved. She is now being followed on
an annual basis.
Teaching Points
1.
There are multiple causes of amenorrhea and
the student should become familiar with them.
This patient with her symptomatology could
have easily have been pregnant, had
hypothyroid disease, premature ovarian
failure or hypothalamic amenorrhea
associated with stress. It is important to
consider the entire differential diagnoses list
prior to treatment.
Teaching Points
2.
3.
Prolactinomas are the most frequent pituitary
tumor and these microadenomas tend to have
an indolent course.
The elevated prolactin levels produce
amenorrhea by inhibiting the pulsatile
secretion of GnRH and result in low
gonadotropins and estrogen levels.
Teaching Points
4.
5.
It is important to also evaluate both the TSH
and prolactin levels in these patients.
Hypothyroidism may be present with
increased prolactin levels since TRH can
stimulate both TSH and prolactin secretion.
Only 1/3 of women with high prolactin levels
will have galactorrhea.
Questions
Amenorrhea