Assessment of a case of Amenorrhea

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					ASSESSMENT OF A CASE
OF   AMENORRHEA

     Dr. Mohammed Abdalla
     AMENORRHEA

Amenorrhea is the absence
 or abnormal cessation of
      menstruation.
          Primary amenorrhea
   is defined either as absence of menses by
    age 14 years with the absence of growth
    or development of secondary sexual
    characteristics .
    OR as absence of menses by age 16
    years with normal development of
    secondary sexual characteristics.
       Secondary amenorrhea
   defined as the cessation of
 is
 menstruation for at least 6 months
 or for at least 3 of the previous 3
 cycle intervals.
            PHYSIOLOGY
Circulating estradiol stimulates growth of the
  endometrium. Progesterone, produced by
  the corpus luteum formed after ovulation,
  transforms proliferating endometrium into
  secretory endometrium. If pregnancy does
  not occur, this secretory endometrium
  breaks down and sheds as a menstrual
  blood.
           PHYSIOLOGY
the age of the first menses varies by
  geographic location, as demonstrated by a
  World Health Organization study
  comparing 11 countries, which reported a
  median age of menarche of 13-16 years
  across centers.
           PHYSIOLOGY
 The number of primordial follicles in the
    human ovary peaks during the fifth
   gestational month at approximately 7
million. After this initial pool is in place, no
additional primordial follicles are formed. In
some cases, loss of menstrual regularity is
   an early sign of declining fertility and
   impending premature ovarian failure
             PHYSIOLOGY
by age 20 years, women have established
  regular and persistent patterns of menstrual
  cycle length with little variation .


on an individual basis Relatively stable and
  predictable menstrual cycle length continues
  until age 40 years.
                PHYSIOLOGY
   In the first year after menarche, the fifth
    percentile for menstrual cycle length is 23 days
    and the 95th percentile is 90 days.
   By the fourth year after menarche, the 95th
    percentile for cycle length has declined from 90
    days to approximately 50 days.
   by 7 years after menarche, cycles are more
    stable; the fifth percentile in cycle length is 27
    days, and the 95th percentile is 38 days.
              How common is it?
   Secondary amenorrhoea (prevalence about 3%)
   primary amenorrhoea (prevalence about 0.3%)
    Between 10 and 20% of women complaining of
    infertility have amenorrhoea [Franks, 1987].
   Up to 50% of competitive runners (training 80 miles
    per week) and up to 44% of ballet dancers have
    amenorrhoea [Balen, 1999a].
Etiology of PRIMARY
    amenorrhoea
            Secondary sexual
          characteristics present
   Pregnancy
   Constitutional delay
   Genito-urinary malformation, e.g. imperforate hymen,
    transverse vaginal septum, absent vagina with or
    without a functioning uterus
   Androgen insensitivity: XY female or testicular
    feminization
   Resistant ovary syndrome
               Secondary sexual
             characteristics absent
   Hypothalamic dysfunction, e.g. chronic illness, anorexia,
    weight loss, 'stress'
   Gonadotrophin deficiency, e.g. Kallman's syndrome
   Hydrocephalus
   Tumours of the hypothalamus or pituitary
   Hypopituitarism
   Hyperprolactinaemia
   Gonadal failure, e.g. ovarian dysgenesis/agenesis,
    premature ovarian failure
   Hypothyroidism
    Ambiguous external genitalia

   Congenital adrenal hyperplasia
   Androgen-secreting tumour
   5-Alpha-reductase deficiency
            Turner's syndrome
   Turner's syndrome is caused by either a
    complete absence or a partial abnormality of
    one of the two X chromosomes. About 50%
    have mosaic forms such as 45X/46XX or
    45X/46XY.
   Features :( short stature, web neck,
    lymphoedema, shield chest with widely spaced
    nipples, scoliosis, wide carrying angle,
    coarctation of the aorta, and streak ovaries.)
        Constitutional delay

   In this condition there is no anatomical
    abnormality and endocrine
    investigations show normal results.
   It is caused by immature Pulsatile release
    of gonadotrophin-releasing hormone;
    maturation eventually occurs
    spontaneously.
       Androgen insensitivity syndrome
                    (AIS)
   formerly known as testicular feminization,
   46XY
   failure of normal masculinization of the external
    genitalia in chromosomally male individuals. This
    failure of virilization can be either complete (CAIS) or
    partial (PAIS), depending on the amount of residual
    receptor function.
   affected individuals have normal testes with normal
    production of testosterone and normal conversion to
    dihydrotestosterone (DHT), which differentiates this
    condition from 5-alpha reductase deficiency.
        5-alpha-reductase deficiency
                   (5-ARD)
   inability to convert testosterone to the more
    physiologically active dihydrotestosterone (DHT).
    Because DHT is required for the normal
    masculinization of the external genitalia in utero,
   genetic males with 5-ARD are born with ambiguous
    genitalia (ie, male pseudohermaphroditism).
   The described clinical abnormalities range from
    infertility with normal male genital anatomy to
    underdeveloped male with hypospadias to
    predominantly female external genitalia, most often
    with mild clitoromegaly.
    5-alpha-reductase deficiency
               (5-ARD)
Measuring the clitoris is an effective method
 for determining the degree of androgen
 effect. The clitoral index can be determined
 by measuring the glans of clitoris in the
 anteroposterior and transverse diameter. A
 clitoral index greater than 35 mm2 is
 evidence of increased androgen effect. A
 clitoral index greater than 100 mm2 is
 evidence of virilization.
          Imperforate hymen
   Imperforate hymen represents the most common and
    most distal form of vaginal outflow obstruction.
   Clinical presentations range from an incidental finding
    on physical examination of an asymptomatic patient
    to discovery on an evaluation for primary amenorrhea
    or abdominal or back pain.
   The differential diagnosis of uterovaginal obstruction
    includes disorders of vaginal development, such as
    transverse vaginal septum or complete vaginal
    agenesis, Duplication anomalies of the uterovaginal
    tract often involve one tract that is decompressed and
    one that is obstructed.
Imperforate hymen
Etiology of secondary
     amenorrhoea
    No features of androgen excess present
   Physiological, e.g. pregnancy, lactation, menopause
   Iatrogenic, e.g. depot medroxyprogesterone acetate contraceptive
    injection, radiotherapy, chemotherapy
   Systemic disease, e.g. chronic illness, hypo- or hyperthyroidism
   Uterine causes, e.g. cervical stenosis, Asherman's syndrome (intra-
    uterine adhesions)
   Ovarian causes, e.g. premature ovarian failure, resistant ovary
    syndrome
   Hypothalamic causes, e.g. weight loss, exercise, psychological distress,
    chronic illness, idiopathic
   Pituitary causes, e.g. hyperprolactinaemia, hypopituitarism, Sheehan's
    syndrome
   Causes of hypothalamic/pituitary damage, e.g. tumours, cranial
    irradiation, head injuries, sarcoidosis, tuberculosis
    Features of androgen excess present

   Polycystic ovary syndrome
   Cushing's syndrome
   Late-onset congenital adrenal hyperplasia
   Adrenal or ovarian androgen-producing tumour
         Polycystic ovary syndrome

   This condition is characterized by hirsutism, acne,
    alopecia, infertility, obesity, and menstrual
    abnormalities (amenorrhoea in 19% of cases).
   Ultrasound examination of the ovaries typically shows
    multiple, small peripheral cysts. up to a third of women in
    the general population have polycystic ovaries on
    ultrasound examination [DTB, 2001].
   Endocrine abnormalities include increased serum
    concentrations of testosterone, prolactin, luteinizing
    hormone (LH) (with normal follicle-stimulating hormone
    [FSH] levels), and insulin resistance with compensatory
    hyperinsulinaemia.
       Premature ovarian failure

   Menopause/ovarian failure occurring before the
    age of 40 years is considered premature.
   Auto-immune disease is the most common cause;
    auto-antibodies to ovarian cells, gonadotrophin
    receptors, and oocytes have been reported in 80%
    of cases.
   Before puberty or in adolescents, ovarian failure is
    usually due to a chromosomal abnormality, e.g.
    Turner mosaic, or previous radiotherapy, or
    chemotherapy
       Ovarian failure (premature
             menopause)

    chromosomal                               autoimmune
     anomalies                                  disease



If the woman is under 30, a
     karyotype should be          it is prudent to screen for thyroid,
 performed to rule out any              parathyroid, and adrenal
  mosaicism involving a Y                     dysfunction
        chromosome.
If a Y chromosome is found the   Laboratory evidence of autoimmune
gonads should be surgically      phenomenon is much more prevalent
excised.                         than clinically significant disease
autoimmune related dysfunction
   The most common association is with thyroid
    disease, but the parathyroids and adrenals can
    also be affected.
   Several studies have shown laboratory evidence of
    immune problems in about 15-40% of women with
    premature ovarian failure.
   In general, ovarian biopsy is not indicated in
    patients with premature ovarian failure since no
    clinically useful information will be obtained.
              Hyperprolactinaemia
   A prolactinoma is the commonest cause of
    hyperprolactinaemia (60% of cases).
   Other causes include non-functioning pituitary adenoma
    (disrupting the inhibitory influence of dopamine on prolactin
    secretion);
    dopaminergic antagonist drugs (e.g. phenothiazines,
    haloperidol, clozapine, metoclopramide, domperidone,
    methyldopa, cimetidine); primary hypothyroidism
    (thyrotrophin-releasing hormone stimulates the secretion of
    prolactin), or it may be idiopathic.
   Prolactin acts directly on the hypothalamus to reduce
    the amplitude and frequency of pulses of gonadotrophin-
    releasing hormone.
    Weight-related amenorrhoea

   A regular menstrual cycle is unlikely to
    occur if the body mass index (BMI) is less
    than 19 (normal range 20-25).
   Weight loss may be due to illness, exercise,
    or eating disorders, among which anorexia
    nervosa lies at the extreme end of the
    spectrum.
        Post-pill' amenorrhoea

   This is defined as absence of menstruation
    for 6 months following cessation of the
    combined oral contraceptive pill.
   It probably results from A transient inhibition
    of gonadotrophin-releasing hormone .
    Progestogen-associated amenorrhoea

   Depot medroxyprogesterone acetate inhibits the secretion of
    gonadotrophins and thus suppresses ovulation.
   After 1 year of use, 80% of women have amenorrhoea or very scanty,
    infrequent vaginal bleeding.
   There is partial oestrogen deficiency in women who use depot
    medroxyprogesterone acetate.
   The progestogen-only pill leads to reversible long-term
    amenorrhoea in a minority of women, due to complete suppression of
    ovulation.
   The levonorgestrel-releasing intra-uterine device commonly
    results in amenorrhoea after a few months. This is thought to be
    mainly a local effect, but suppression of ovulation can occur in some
    women (in some cycles).
ASSESSMENT of primary
     amenorrhea
                                      TSH                             elevated
                                                                      hypothyroidism
                          Normal
If puberty delayed                                                      delayed
                                 bone age
                                                                  constitutional delay
                            Normal

                  LH, FSH, and prolactin levels                          low or within
                                                                         reference range


                                              elevated                        head MRI

                                                                    •pituitary tumor or a
                                                                    brain lesion
 45,XO, the cause is gonadal dysgenesis                             •drug use, an eating
                                                         karyotype. disorder, athleticism,
                                                                    or psychosocial
46,XX, the primary cause is ovarian failure
                                                                    stress.
                           If the pregnancy test result is negative

   If puberty                                               elevated
   not delayed                 TSH and prolactin levels                   hypothyroidism and
                                                                          hyperprolactinemia
                   within reference range


                      -VE            progestin challenge     +VE
               E2/progestin challenge                               consider anovulatory cycles
                                                                               PCO
                       -         +
outlet obstruction                   obtain FSH and LH levels.


         low or within reference range                     high

                                                             karyotype
              head MRI.

exclude chronic disease,
anorexia nervosa, or                                              karyotype is normal (46,XX),
psychosocial stress.                      Turner synd.
                                                                  the cause is ovarian failure
genital tract
                                 karyotype
abnormalities


          If the karyotype is 46,XY              If the karyotype is 46,XX


           testosterone levels

                                                 müllerian agenesis
                                           (ie, Rokitansky-Kuster-Hauser
                                                     syndrome).
      male range            female range




                                      testicular regression
  androgen insensitivity.       or gonadal enzyme deficiency.
Breast development, pubertal growth spurt,
and adrenarche are delayed or absent
             in persons with




    hypothalamic pituitary
           failure.
 adrenarche occurs normally, while
estrogen-dependent breast development and the
  pubertal growth spurt are absent or delayed.




  isolated ovarian insufficiency
             or failure
Secondary Amenorrhea
               History


A good history can reveal the etiologic
   diagnosis in up to 85% of cases of
              amenorrhea.
    If the history and physical
     exam are suggestive of a
          certain etiology :

  for the sake of efficiency and cost-
   effectiveness, the workup can
   sometimes be more directed according
   to history.
( in 85% of cases)
In patients that will not demonstrate any
  obvious etiology for their amenorrhea
   on history and physical exam. These
  patients can be worked up in a logical
    manner using a stepwise approach.
                How do I assess my patient with
                  secondary amenorrhoea?
    History
   Risk of pregnancy
   Associated symptoms, e.g. galactorrhoea, hirsutism, hot flushes, dry
    vagina, symptoms of thyroid disease
   Recent change in body weight
   Recent emotional upsets
   Level of exercise
   Previous menstrual and obstetric history
   Previous surgery, e.g. endometrial curettage, oophorectomy
   Previous abdominal, pelvic, or cranial radiotherapy
   Family history, e.g. of early menopause
   Drug history, e.g. progestogens, combined oral contraceptive,
    chemotherapy
               How do I assess my patient with
                 secondary amenorrhoea?
     Examination

   Height and weight: calculate body mass index if appropriate.
   Signs of excess androgens, e.g. hirsutism, acne
   Signs of virilization, e.g. deep voice, clitoromegaly in addition to
    hirsutism, and acne
   Signs of thyroid disease .
   Acanthosis nigricans: this hyperpigmented thickening of the skin folds
    of the axilla and neck is a sign of profound insulin resistance. It is
    associated with polycystic ovary syndrome (PCOS) and obesity.
   Breast examination for galactorrhoea.
   Fundoscopy and assessment of visual fields if there is suspicion of
    pituitary tumour.
   Pelvic examination .
                             -VE Preg.test


                           TSH ,PROLACTIN’,
                           Prog.challenge test


            withdrawal                              without withdrawal
             bleeding                                    bleeding


                                      hypoestrogenic                 compromised
                                                                     outflow tract.
        anovulation
                                     +ve.est,progest,                       +
                                      challenge test                 -ve.est,progest
                                                                      challenge test

                           FSH low       FSH>30-40
                                                                     Normal FSH
                    Repeat+serum, est.
                                           repeat
                          level
hypothalamic-                                               HSG OR hysteroscopy
pituitary failure                         PROF                   asherman
Raised testosterone/androgen level. This group includes women with
polycystic ovary syndrome (mildly raised level), and women with
androgen-secreting tumours of the ovary or adrenal gland, late-onset
congenital adrenal hyperplasia, or Cushing's syndrome.
Raised gonadotrophins (follicle-stimulating hormone [FSH] and
luteinizing hormone [LH]) with a low estradiol level. This group
includes women with premature ovarian failure and resistant ovary
syndrome.
Hyperprolactinaemia. This group includes women with prolactinomas
and hypothyroidism.
Low gonadotrophins (FSH and LH) with a low estradiol level. This
group includes women with amenorrhoea secondary to exercise, low
weight, and stress.
Normal or mildly raised gonadotrophin levels with normal estradiol
levels. This group includes women with polycystic ovary syndrome
(PCOS) or other mild disorders of gonadotrophin regulation or action.
      Complications and prognosis

   Osteoporosis: women with amenorrhoea associated with oestrogen
    deficiency are at significant risk of developing osteoporosis. This increased
    risk persists even if normal menses are resumed. Oestrogen deficiency is
    of particular concern in younger women as a desirable peak bone mass
    may not be attained
   Cardiovascular disease
         Young women with amenorrhoea associated with oestrogen deficiency
          may be at increased risk of cardiovascular disease


         Women with polycystic ovary syndrome have an increased risk of
          developing cardiovascular disease, hypertension, and type 2 diabetes
          [Hopkinson et al, 1998].
     Complications and prognosis
   Endometrial hyperplasia: women with amenorrhoea but
    no associated oestrogen deficiency are at increased risk of
    endometrial hyperplasia and endometrial carcinoma .
   Infertility: women with amenorrhoea generally do not
    ovulate.
   Psychological distress: amenorrhoea often causes
    considerable anxiety, Many women have concerns about
    loss of fertility, loss of femininity, or worry about an
    unwanted pregnancy. The diagnosis of Turner's syndrome,
    testicular feminization, or developmental anomaly can be
    traumatic for both girls and their parents .
Thank you

				
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