Chapter 24. AMENORRHEA

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

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

  • 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

  • Iatrogenic causes : radiation, chemotherapy(cyclophosphamide), surgical interference with
    ovarian blood supply, infections

  • 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

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
    • 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

      : serum TSH, serum prolactin, FSH levels, estrogen status,
      pituitary & hypothalamic assessment as necessary

      1. TSH and prolactin levels

    • 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:

      • Androgen :hirsute patients(PCOS)
      • IGF-1 : coarse facial features,large doughy hands, hyperhidrosis(acromegaly)
      • Cushing's syndrome

    C. Treatment

    • 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
    • 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

      1. Oral contraceptives: decreasing ovarian androgen production, increasing circulating levels of
        sex hormone-binding globulin
      2. Spironolactone: decrease androgen production, limited diuresis, DUB.
      3. Cyproterone acetate (antiandrogen)

      2. Ovulation induction

      Patients may be advised that there is no increase in congenital anomalities in children born
      after ovulation induction

    • Clomiphene citrate

      • with adequate levels of estrgen and normal levels of FSH and prolactin
      • ineffective in hypogonadotropic patients who already have a poor estrgen supply
      • up 80% : ovulate
      • 40% : pregnancy rate
      • contraindication : pregnancy, liver disease, pre-existing ovarian cysts
      • 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
      • 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