July 15, 1997. 1st year resident, Sung-Hee Oh, M.D.
I. Definition
Primary amenorrhea is defined as the absence of menses by 16 years of age in the presence of normal
secondary sexual characteristics or by 14 years of age when there is no visible secondary sexual
characteristic development.
Secondary amenorrhea is defined as absence of menstruation for three normal menstrual cycles
or 6 months.
II. Amenorrhea without secondary sexual characteristics
: Abnormal findings on physical examination may suggest certain enzyme deficiencies
A. Causes of primary amenorrhea
1. Hypergonadotropic hypogonadism
Table 24.1
Genetic abnormalities (30 %)
: Turner's syndrome and its variants represent the most common form of hypogonadism
in women structurally abnormal X chromosomes, mosaicism, pure gonadal dysgenesis,17α-
hydroxylase deficiency. Gonadotropin levels are elevated because of the lack of negative
estrogen feedback on the hypothalamic-pituitary axis.
Primary amenorrhea and lack secondary sexual characteristics
1) Genetic disorders
Gonadal dysgenesis (Turner's syndrome)
Gonadal deletions of the X chromosome: the phenotype is variable depending on the amout
and location of the missing genetic material
Mosaicism: 45X/46XY, vary in estrogen and gonadotropin production depending on the
number of follicles in the gonads. Spontaneous menstruation occurs in approximately 20%
of these patients
Pure gonadal dysgenesis: pheontypically female with sexual infantilism, have primary
amenorrhea with normal stature, and have no chromosomal abnormalities
2) Enzyme deficiencies
17α-hydroxylase deficiency: primary amerrhea, no secondary sexual charcateristics female
phenotypes, hypertension, and hypokalemia. reduction in cortisol production .
increase in adrenocorticotropic hormone (ACTH). excessive amounts of mineralocorticoid
are produced, resulting in sodium retention, loss of potassium and hypertension
17-20 desmolase deficiency: female phenotype. the uterus is absent, and sexual development
does not occur at puberty
2. Hypogonadotropic hypogonadism
Physiologic delay: most common, Levels of GnRH are functionally deficient in relation to
chronologic age, but normal in terms of physiologic development
Kallmann's syndrome: 2nd most common, insufficient pulsatile secretion of GnRH leads to
deficiencies in FSH and LH. Patients with isolated deficiencies of LH and FSH usually are a
normal height for their age whereas patients with physiologic delay of puberty are usually short
for their chronologic age but normal for their bone age
Central nervous system tumors: craniopharyngioma
3. Enzyme deficiencies
5α-reductase deficiency
XY,frequently experience virilization at puberty
testes(because of functioning Y chromosomes)
no mullerian structures due to functioning mullerian-inhibiting factor(MIF)
normal male differentiation of the urogenital sinus and external genitalia do not occur
normal internal male genitalia derived from the Wolffian ducts are present because this
development requires testosterone only
B. Diagnosis
P/E: short stature but consistent growth rate, a family history of delay puberty, and normal physical
finding may suggest physiological delay
Headaches, visual disturbances, short stature, symptoms of diabetes insipidus, and weakness of one
or more limbs suggest central nervous system lesions
Diagnostic workup
Assessment of the serum FSH level; differentiates hypergonadotropic and hypogonadotropic forms
.FSH increase --> Karyotype
Turner's syndrome:echocardiography, thyroid function studies
Karyotype is normal and the FSH is elevated
. 17α-hydroxylase deficiency
--> elevated serum progesterone(>3ng/ml) levels
a low 17α-hydroxyprogesterone(<0.2ng/ml) levels
elevated serum deoxycorticosterone level (DOS)
confirmed with an ACTH stimulation test
if the screening FSH level is low, the diagnosis hypogonadotropic hypogonadism is established
if the history suggests the presence of a central nervous system lesion or galactorrhea
: CT, MRI, suprasellar or intrasellar calcification in an abnormal sella is found in approximately
70% of patients with craniopharygioma
Physiologic delay is a diagnosis of exclusion that is difficult to distinguish from insufficient
GnRH secretion. X-ray showing delayed bone age, and the absence of a central nervous system
lesion on CT or MRI scanning
physiologic delay by their response to GnRH stimulation for their bone age
C. Treatment of primary amenorrhea
1. Hypergonadotropic hypogonadism
Cyclic estrogen and progestin therapy
0.625mg/day of conjugated estrogen or 1mg of estradiol
if the patient is short in stature, higher doses should not be used in an attempt to prevent
premature closure of the epiphyses. Higher estrogen does may be used initially and then
reduced to the maintenance doses after several months
Daily or 25 days per month and progestin(medroxyprogesterone acetate 5-10mg)should
be added 12-14 days every 1-2months to prevent unopposed estrogen stimulation of
the endometrium and breast
In patients with estrogen- free intervals , the progestin should be added during the last 12-14
days of each estrogen cycle
Alternatively, estrogen and progestin may be given daily
Individuals with mosaicism and gonadal streaks may ovulate and conceive either spontaneously
or after institution of estrogen replacement therapy
17α-hydroxylase deficiency: instituted with corticosteroid replacement as well as estrogen and
progestin
III. Amenorrhea with secondary sexual characteristics and anatomic abnormalities
A. Causes
1. Anatomic abnormalities
Blockage of the outflow tract or missing
Mayer-Rokitansky-Kuster-Hauser syndrome :15% have an absent kidney. 40% have a double
urinary collecting system. 5-12% have skeletal abnormalities
Asherman's syndrome : more common with secondary amenorrhea or hypomenorrhea ,
endometrial or cervical scarring such as a history of uterine or cervical surgery, infections
related to use of an intrauterine device, severe pelvic inflammatory dis.
2. Androgen insensitivity
Secondary sexual characteristics but do not have menses
Male pseudohermaphrodites, XY
defect that prevents normal androgen receptor function,
total serum testosterone concentration is in the range of normal males
because antimullerian hormone is present and functions normally in these patients
internal female structures such as a uterus, vagina, and fallopian tubes are absent
Testes, blind vaginal pouch, scant or absent axillary and pubic hair, abundant breast
development at puberty
3. True hermaphrodites
Both male and female gonadal tissue is present in these patients in whom XX,XY and mosaic
genotypes have been found
Two-thirds of the patients : menstruate, ambiguous
B. Diagnosis
be diagnosed by physical examination
Imperforate hymen : by the presence of a bulging membrane (during valsalva maneuver)
ultrasound or MRI is useful to identify the mullerian anomaly
Androgen insensitivity is diagnosed when pubic and axillary hair is absent to confirm the
diagnosis, a karytype should be performed to determine whether a Y chromosome is present
Be suspected in patients with primary amenorrhea and normal secondary sexual characteristics
when the results of hormonal studies are normal and they do not bleed after withdrawal of
combined estrogen and progesterone replacement
Asherman's syndrome : performing hysterosalpingography or hysteroscopy if tuberculosis or
schistosomiasis is suspected, endometrial cultures should be performed
C. Treatment
Imperforate hymen : cruciate incision to open the vaginal orifice
Transverse septum : surgical removal
upper one- third of the vagina: 46%
middle one-third of the vagina : 40%
frank dilators should be used to distend the vagina until it is healed to prevent vaginal
adhesions
Hypoplasia or absence of the cervix in the presence of a functioning uterus is more difficult to
treat than other outflow obstructions
: surgery to repair the cervix has not been successful, and hysterectomy is required
If the vagina is absent or short, progressive dilatation is ususlly successful in making it
functional to maintain a functional vagina
In patients with complete androgen insensitivity, the testis should be removed after pubertal
development is complete to prevent malignant degeneration.
52% develop a neoplasia (gonadoblastoma:one-half of the testicular neoplasms are malignant -
dysgerminoma) but transformation usually does mot occur until after puberty
Ashermann's syndrome : hysteroscopic resection
foley cathter should be placed in the uterus cavity for 7-10 days postoperatively (broad
spectrum antibiotics)
2-month course of high-dose estrogen therapy with monthly progesterone withdrawal is used
to prevent reformation of adhesions.
IV. Amenorrhea with secondary sexual characteristics and nonanatomic causes
Pregnancy
The three major causes of amenorrhea with secondary sexual characteristics
ovarian failure
pituitary/hypothalamic lesions
abnormal hypothalamic GnRH secretion
A. Cause
1. Ovarian failure(before 40years of age-pathologic)
hot flashes and vaginal dryness(50%)
P/E : vaginal mucosal atrophy and no cervical mucus
Genetic disorders
Deletion of a portion of the X chromosome may be present in patients with premature o
ovairan failure(Xq26-28 region is critical), 47XXX karyotope
Autoimmune disorders: be part of a polyglandular autoimmune syndrome
92% of patients with premature ovarian failure had autoantibodies
only 20% of these patients exhibited signs of immunologic dysfunction, most frequently
a thyroid disorder
Galactosemia : galactose metabolites apper to have toxic effects on ovrian follicles causing
their premature their premature destruction
Savage syndrome: ovarian resistance, ovarian biopsy is the only way to distinguish these
disorders
2. Pituitary hypothalamic lesions
Hypothalamic tumors
Craniopharyngiomas(m/c), germinomas, tubercular or sarcoid granulomas or dermoid cysts
prevent appropriate hormonal secretion
exhibit neurologic abnormalities and abnormal secretion of other hypothalamic and pituitary
hormones
frequently cause headache and visual changes
the surgical and radiologic treatment
Pituitary lesions
tumors,infarction, infiltrating lesions such as lymphocytic hypophysitis,
granulomatous lesions and surgical or radiologic ablations
Sheehan's syndrome : localized severe retro-orbital headache or abnormalities in visual
fields and visual acuity, failure to lactate, loss of pubic and axillary hair, and failure to
resume menses after delivery
Altered hypothalamic GnRH secretion
Endogenous opioids, corticotropin-releasing hormones, melatonin, and a-aminobutyric
acid , : inhibit the release of GnRH
Catecholamines acetylcholine and vasoactive intestinal peptide : stimulate GnRH
chronic disease, malnutrition, stress, psychiatric disorders, and exercise inhibit GnRH
pulses, thus altering the menstrual cycle
Anorexia nervosa
5-10% of adolescent women in the U.S
as stated in the psychiatric diagnostic manual are refusal to maintain body weight above
15% below normal, an intense fear of becoming fat, altered perception of one's body image
and amenorrhea with a mortality rate as high as 9% follow the weight loss,multiple
hormonal patterns are altered
Exercise and stress induced disorders
There is a decrease in the frequency of GnRH pulses, which is assessed by measuring a
decreased frequency of LH pulses, usually hypoestrogenic
Minimum of 17% body fat is required for the initiation of menses and 22% body fat for the
maintenance of menses
Inappropriately low caloric intake during strenuous exercise is more important than body fat
Stress related amenorrhea can be caused by abnormalities in neuromodulation in
hypothalamic GnRH secretion, similar to those occur with exercise and anorexia nervosa
Obesity
More than 8.4% in women(menstrual disorders), above 75% ideal body weight
Decrease in sex hormones-binding globulin
Increase in free androgen levels,
Hirsutism can develop
Other hormonal imbalances
Excessive or deficiencies of thyroid hormone, glucocorticoids androgens and estrogens can
cause menstrual dysfunction
Polycystic ovarian syndrome : irregular bleeding bur may cause amenorrhea
Ovarian tumors may lead to abnormal menstrual patterns including amenorrhea
B. Diagnosis
Pregnancy test
If the results of the pregnancy tests are negative, the evaluation of amenorrhea is as follow
If elevated TSH and prolactin levels are found, the hypothyroidism should be treated before
hyperprolactinemia is treated
Often the prolactin level will normalize with treatment of hypothyroidism because TRH, which
is elevated in hypothyroidism, stimulate prolactin secretion
2. FSH levels
Circulating FSH level of >40mlu/ml indicated on at least samples is indicative of
hypergonadotropic amenorrhea
Hypergonadotropism
chemotherapy or radiation therapy,
galactose-1 phosphate uridly transferase level
less than 30years (karyotype)
autoimmune workup (antinuclear antibodies, rheumatoid factor, and ESR)
In hypergonadotropic amenorrhea, ovarian biopsy-not advised (even if oocytes are found,
there is not a good method of stimulating those oocytes to ovulate)
3. Assessment of estrogen status
By giving medroxyprogesterone acetate , either 5mg or 10mg for 10days to determine whether
the patient bleeds after withdrawal of the medication (usually 2-10days after the last dose)
100-200mg progesterone in oil is given intramuscularly
Vaginal dryness
Estrogen response - the presence of superficial cells
Higher than 40pg/ml is considered adequate
4. Assessment of the pituitary and hypothalamus
Hypoestrogenic and the FSH level is not high
Complete neurologic examination
Either CT or MRI scanning
The patient's history of weight changes, exercise, eating habits , body image and career or
school achievements are important factors in differentiating anorexia nervosa, malnutrition ,
obesity, or exercise-induced or stress- induced menstrual disorders
Patients with appropriate clinical finding should undergo screening for other hormonal
alterations as follows:
The underlying disorder should be treated whenever possible
When thyroid abnormalities are discovered , thyroid hormone, radiocative iodine, or antithyroid
drugs may be administered as appropriate
Hyperprolactinemia - discontinuation of contributing medications, treatment with
bromocriptine, rarely, surgery for particular large pituitary tumors
Ovarian failure - prescribed for protection against cardiac disease as well as prevention of
osteoporosis
Gonadectomy is required when a Y cell line is present, surgical removal, radiation therapy, or a
combination of both is generally advocated for treatment of central nervous system tumors other
than prolactinomas
1. Hirsutism
After ruling out androgen secreting tumors and congenital adrenal hyperplasia,
treatment may be aimed at decreasing course hair growth
Oral contraceptives: decreasing ovarian androgen production, increasing circulating levels of
sex hormone-binding globulin
side effects : hot flashes, poorly understood visual symptoms
multiple gestation : 6.25-12.3%
50mg daily for 5 days (begining on MCD 5th days) ->100mg ->150mg
hMG
fail to ovulate with clomiphene citrate,hypogonadotopic hypoestrogenic anovulation
pregnancy rate up to 90%
75-150 IU/day by IM for 2-4days
ovulation is triggered by intramuscular injection of 5000-10,000IU hCG once the lead
follicle reaches 16-20mm in diameter based on ultrasound assessments (36hours after hCG
administration)
luteal phase support is sometimes given with additional injections of hCG or with
progesterone supplementation
multiple pregnancy : 10-30%
ovarian hyperstimulation syndrome
: numerous follicles, estradiol levels approaching or exceeding 2000pg/ml may be canceled
by withholding the ovulatory dose of hCG
GnRH
chronic anovulation associated with low levels of estrogen and gonadotropins
functional ovary and pituitary gland must be present
pulsatile fashion either intravenously or subcutaneously by a programmable pump
relatively low incidence of ovarian hyperstimulation and multiple births
after ovulation, luteal phase support is necessary and may be provided with hCG,
progesterone, or continuation of the GnRH therapy