Amenorrhea
Yousef R.Badran
Amenorrhea
• Amenorrhea is the absence of
menstruation.
• Primary:
– Absence of menses by age 16 with
normal secondary sexual characteristics.
– Absence of menses by age 14 without
secondary sexual development.
• Secondary
– Absence of menses for 3 cycles or 6
months in a previously menstruating
females.
• Oligomenorrhea
– Interval of more than 35 days between
periods
Events of Puberty
• Thelarche (breast development)
– Requires estrogen
• Pubarche/adrenarche (pubic hair
development)
– Requires androgens
Events of Puberty
• Menarche
Requires:
– GnRH from the hypothalamus
– FSH and LH from the pituitary
– Estrogen and progesterone from the
ovaries
– Normal outflow tract
P1
P2
P3
P4
P5
Epidemiology
Estrogen Production
Adrenal Hormones
Pathophysiology
Inadequate hormonal stimulation of
the endomerium “Anovulatory
amenorrhea”
- Euestrogenic
- Hypoestrogenic
Inability of endometrium to respond to
hormones “Ovulatory amenorrhea”
- Uterine absence - Utero-vaginal agenesis
- XY-Females ( e.g T.F.S)
- Damaged endometrium ( e.g Asherman’s syndrome)
Causes of 1ry Amenorrhea
• 1- Hypergonadotropic hypogonadism
(48.5% of cases)
• 2- Hypogonadotropic hypogonadism
(27.8%)
• 3- Eugonadism (pubertal delay with
normal gonadotropins; 23.7%).
Uptodate
• Chromosomal abnormalities causing gonadal dysgenesis
(ovarian failure due to the premature depletion of all
oocytes and follicles) — 50 %
• Hypothalamic hypogonadism including functional
hypothalamic amenorrhea — 20 %
• Absence of the uterus, cervix and/or vagina, müllerian
agenesis — 15 %
• Transverse vaginal septum or imperforate hymen — 5
percent
• Pituitary disease — 5 %
Causes of 2ry Amenorrhea
• 1-Disorders associated with a low or normal FSH, which
account for 66%
• 2-Disorders in which the FSH is high (12%)
• 3-Disorders associated with a high prolactin level comprise
13% of cases
• 4- Anatomic disorders (ie, Asherman syndrome) account for
7%.
• 5- Hyperandrogenic states as a cause of secondary
amenorrhea (2%)
Classification of Amenorrhea
• Outflow Tract Anomalies
• Ovarian amenorrhea
• Central Disorders:
– Hypothalamic amenorrhea
– Pituitary amenorrhea
Which is which???
Only 3 diagnoses are unique to primary
amenorrhea and never cause secondary
amenorrhea.
1- vaginal agenesis
2- androgen insensitivity syndrome
3- Turner syndrome (45,Xo)
Etiology: Outflow Tract Anomalies
• Mullerian Anomalies:
– Imperforate hymen
– Transverse vaginal septum
– Cervical Stenosis (2ry)
• Asherman syndrome (2ry)
• Mullerian Agensis:
– Vaginal and uterine aplasia-MayerRokitansky-Küster-Hauser
• Testicular feminization
Imperforate Hymen
• Intermittent abdominal pain
• Possible difficulty with micturition
• Possible lower abdominal swelling
• Bulging bluish membrane at the
introitus or absent vagina (only
dimple
Transverse Vaginal Septum
Mayer-Rokitansky-Kuster-Hauser Syndrome
(utero-vaginal agenesis)
• Mullerian Agenesis or Dysgenesis
• Complete vaginal agenesis and
absence of a uterus or partial vaginal
agenesis with rudementary uterus and
distal vagina.
• Karyotype 46-XX
• Ovaries present
Androgen Insensitivity
• Karyotype 46, XY
• X linked recessive
• Loss-of-function mutation in the
androgen receptor (AR) gene. This
AR gene has been localized to the
long arm of the X chromosome (ie,
Xq11-13).
• Undervirilization
• Normal breasts but no sexual hair
Androgen Insensitivity
• Phenotypical female
• Absent uterus and upper vagina
• Male range testosterone level
• 25% chance of developing benign
testicular tumors and a 4-9%
chance of malignancy.
• Treatment : gonadectomy after
puberty + HRT
Asherman Syndrome
Photograph of the hysteroscopic view of a uterine cavity with severe intrauterine
synechiae (Asherman’s syndrome) that occupied the bulk of the cavity. The
midline fundal location of the abnormal tissue is similar to that seen with a
uterine septum (the eccentric rotation of the scar tissue is not characteristic of a
uterine septum).
Ovarian Amenorrhea
• Hypergonadotrophic hypogonadism
Hypergonadotrophic
Hypogonadism
– Variants of Ovarian Dysgenesis
• Turner's Syndrome (XO)
– Gonadal Toxins (Chemotherapy/Radiation)
• Cytotoxic drugs (e.g. Chemotherapy)
• Glucocorticoids
– Enzyme defects
• 17 alpha hydroxylase deficiency
Hypergonadotrophic
Hypogonadism
– Miscellaneous
• Mumps
• Pelvic radiation
• autoimmune
– Gonadal failure (in adults)
• Hypogonadism in Women
– Menopause
– Premature Ovarian Failure
– Savage Syndrome: failure of response to
FSH and LH due to receptor defect
Turner’s
Sexual infantilism and short stature.
• High FSH and LH levels.
• Bilateral streaked gonads.
• Karyotype - 80 % 45, X0
- 20% mosaic forms (46XX/45X0)
• Treatment: HRT
Turner’s Syndrome
(Classic 45-XO)
Mosaic (46-XX / 45-XO)
Typical features of Turner Syndrome
Gonadal Dysgenesis
• Progressive loss of primordial germ cells. This loss
leads to hypoplastic and disfunctioning gonads mainly
composed of fibrous tissue, streak gonads.
• Absence of MIF and testesterone
• Regression of Wolffian ducts due to absence of
testosterone.
• Absence of MIF will allow Mullerian ducts to
differentiate into oviducts and uterus
• Genotypically male yet will with female like internal
and external reproductive characteristics
Pure Gonadal dysgenesis
• Swyer syndrome:46 XY, no functional gonads.
• Mutation of SRY gene
• Absence of breasts
• Presence of uterus and pubic hair.
• High risk of malignancy(eg.Gonadoblastoma)
• Surgical removal,HRT
Enzyme deficiencies, tricky tricky!!
Central Disorders
Hypothalamic amenorrhea
• GnRH release:
– Kallmann syndrome
• GnRH transport: compression or
destruction of pituitary stalk or arcuate
nucleus
–
–
Tumor mass effect
trauma
–
Sarcoidosis
–
Tuberculosis
–
Irradiation
Central Disorders
Hypothalamic amenorrhea
GnRH Pulsatility:
– Psychological stress
– Anorexia nervosa, weight loss
– Increased exercise levels
– drug-induced amenorrhea
– Hyperprolactinemia
– Hypothyroidism
– Space-occupying lesion of CNS
Central Disorders
Pituitary amenorrhea
• Tumors
• Infiltration
• Surgery/Irradiation
• Empty sella syndrome
• Sheehan syndrome
• Hemosidrosis
Important notes for Diagnosis
• Breast development
depends on:estradiol
• Uterus Presence: Absence
of MIF
Diagnosis
• History
• Physical examination
– Physical examination begins
with vital signs, including
height and weight, and with
sexual maturity ratings
• Laboratory evaluation
Hormonal Assays
• Estrogen
• FSH/LH level
• Thyroid function tests
• Karyotype
• Bone age
• Prolactin
• Testosterone, DHEAS,17-OHPRog, androstenedione
• Pelvic US, imaging
• Routine blood work looking for chronicillness
Hormonal Assays
• Prolactin: prolactinoma, Psychotropic
drugs, hypothyroidism, stress, and
meals
• FSH, ovarian insufficiency
• LH, 17,20 lyase deficiency, 17hydroxylase deficiency, and premature
ovarian failure.
• Estradiol,
• Thyroid hormones
• Androgens.
Diagnostic Evaluation
• When to investigate?
• No menarche by 15.5-16 years
• Investigate earlier if:
– Galactorrhea
– Short stature
– Dysmorphic features
– Virilisation
– Abnormal pubertal development
– Out of keeping with family historyof menarche
– Symptoms or signs of hypothalamic-pituitarydisease
– Parent/adolescent concerned
Evaluating 1ry Amenorrhea
Amenorrhea-Galactorrheahyperprolactenemia
Progesterone Challenge rationale
2ry Amenorrhea/Progesterone
Challenge
The 2-Question approach
• Has puberty occurred?
• “No” then, normal stature or short?
“yes”, then
Feminizing or virilizing
Has puberty occurred?
• No
• Normal or tall
• GnRH deficiency
( FSH low)
• Pure FSH deficiency
(FSH low)
• Pure gonadal dysgenesis (High FSH)
Has puberty occurred?
• No
• Short=something else is
going on
– Hypopituitarism
– Turner’s
– Hypothyroidism
– FSH slightly high, TSH high
Has Puberty occurred?
• Yes
• Virilizing
• 46 xx ( Virlizing female intersex,
congenital adrenal hyperplasia)
• 46 xy (Virilizing male intersex ,
Partial androgen insensitivity
syndrome, Leydig cell hypoplasia)
Has Puberty occurred?
• Yes
• Feminizing
• 46,xx: Idiopathic delay,
Mullerian agenesis
• 46, xy : Complete androgen
insensitivity syndrome
Has Puberty occurred?
• Uterovaginal agenesis
• Low transverse vaginal septum
• Complete androgen insensitivity
• All the entities of secondary
amenorrhea
Treatment
• treatment varies depending upon the
causes of the amenorrhea. Treatment
options include:
– Dietary changes, including an increase in
fat and calories in order to stimulate
estrogen production.
– Counseling for eating disorders.
– Using stress reduction techniques to
help regulate the period.
– Hormonal supplements, like the birth
control pill or patch, or hormone
replacement therapy.
– Surgery to remove cysts, fibroids or
tumors