Amenorrhea / Amenorrhea is defined as either the absence or cessation of menses.
 It is a common symptom and may be : 1- anatomic (developmental or acquired) 2- organic 3- endocrinologic in nature.
 Amenorrhea may result from congenital or acquired disease or dysfunction at the level of the 1- genital tract 2- the ovary 3- the pituitary 4- the hypothalamus.
Genital Tract Abnormalities
Causes of 1ry amenorrhea
Female genital tract development involves :
 Medial-caudal migration and midlin fusion of the paired Mullerian ducts to form the tubes, uterus, cervix, &
upper 3/4 of vagina. (lower 1/4th of vagina develops by urogenital sinus)
 Downward migrating and fusion of ullerian duct system + with the fusion with urogenital sinus
forms : lower 1/4 of vagina & the introitus.
Outflow tract abnormalities that result from :
A) Failure of Mullerian duct development include: breast present + No uterus
1- Vaginal or Mullerian agenesis
- 46 XX karyotype € females ,
- Genetic defect results in unwanted exposure to intrauterine Anti-Mullerian hormone (AMH) €
failure of mullerian duct development .
- No Mullerian ducts € absence of tubes, uterus, cervix, & upper 3/4 of vagina € 1ry amenorrhea
- Normal development of ovaries from genital ridge € Intact hypothalamic-pituitary-ovarian axis
€ E2 production from ovaries € normal 2ry sexual character ( Breast & Pubic h ar present)
2- Androgen insensitivity syndrome (AIS) :
- They are males , with 46 XY karyotype. " Testicular feminization syndrome"
- But they develop phenotypically as females due to an x-linked inherited recessive disorder with
a defect in peripheral androgen receptors that renders them androgen resistant.
- Presence of developed testes in abdomen or inguinal region € normal testosterone level &
estrogen (estrogen from testes) € but androgen resistant€fail to develop 2ry ale sexual
characters€& estrogen dominates € (Breast is developed & pubic hear is absent ).
- Presence of Y chromosome € Mullerian inhibiting factor (MIF) gene € failure of Mullerian duct
development € absence of tubes, uterus, cervix, & upper 3/4 of vagina € 1ry a enorrhea
B) Failure of Mullerian duct fusion & canalization include: ( uterus present )
(causes of false amenorrhea "cryptomenorrhea" in which endometrial shedding occurs but ou flow obstruction
which result in accumulation of menstrual effluent above level of obstruction )
1- Imperforate hymen : Improper canalization of urogenital sinus
- Congenital condition € not vaginal orifices € accumulation of menstrual blood ehing hymen in
vangia (hematocolpos) at time of uberty
- 1ry menorrhea (most common cryptomenorrhea) + well developed 2ry sexual c aracters ( breast )
- Cyclic lower abdominal pain synchronous with time of menstrual period
- If neglected ,blood will accumulat in: endometrial cavity (hematometra) /Fallopian(Hematosalpinx)
2- Transverse vaginal septum : Improper fusion between urogenital sinus & Mullerian ducts
- Congenital condition € presence of one or more vaginal septae at any level between the hymeneal
ring & the cervix € occlusion of upper , middle or lowe segment of vagina
- The rest data as imperforate hymen.
3- Cervical atresia: Improper canalization of cervical canal
- The rest data as imperforate hymen.
Causes of 2ry amenorrhea
1- Asherman syndrome (Amenorrhea Trumatica)
Asherman syndrome results from intrauterine adhesions that obstruct or obliterate the endometrial cavity
as a consequence of inflammation (postpartum endometritis, retained products of conception) usually
coupled with surgical trauma (curettage).
2- Cervical stenosis , with complete outflow obstruction :
rare complication of cervical conization procedures or other surgical treatments for cervical
intraepithelial neoplasia.
Pituitary disorders
1- Pituitary adenomas
Pituitary tumors may cause amenorrhea by :
a- directly compressing pituitary gonadotrophs or
b- obstructing the portal venous network that delivers hypothalamic GnRH stimulation,
€ resulting in decreased FSH and LH secretion.
Prolactinomas : (20% of 2ry amenorrhea)
 Commonest pituitary cause of hyperprolactenemia
 Amenorrhea occurs due to suppression of hypothalamic GnRH secretion by high prolactin level
 Microadenomas (<10 mm in size) is commonest which cause moderate elevation of prolactin
 all pituitary tumors are benign adenomas that may or may not be functional. Functional tumors may
secrete : prolactin, (GH), (TSH), or (ACTH).
 Primary malignant pituitary tumors are rare.
Other uncommon pituitary disorders :
2- Empty sella syndrome :
 The empty sella syndrome results from herniation of the arachnoid membrane (containing CSF), into the
sella turcica compressing the pituitary stalk & the gland.
 The sella contains spinal fluid but appears "empty" when viewed by (CT) or (MRI)
3- Sheehan syndrome (pituitary insufficiency) :
 Sheehan syndrome results from acute infarction & necrosis of the pituitary gland.
 Rare complication of shock due to obstetric hemorrhage.
 Depending on the extent of pituitary damage, clinical consequences may be :
 limited to disorders of reproductive function (failed lactation, amenorrhea) or
 multisystem failure due to panhypopituitarism.
The most common cause of amenorrhea results from absent or abnormal patterns of
pulsatile hypothalamic GnRH secretion € with consequences :
1- Low level of ( FSH & LH) 2- Absent
LH surge
3- Low level of E2
4- Chronic anovulation (hypogonadotrophic amenorrhea)
1- Congenital GnRH deficiency ( Kallmann's syndrome) :
 Rare syndrome , results from a defect in the Kalig-1 gene , associated with failure of
olfactory & GnRH neuronal migration during embryogenesis results in :
Anosmia - 1ry amenorrhea - Sexual infantilism (hypogonadotrophic hypogonadism)
2- Emotional, nutritional, or physical stress,may caue:
Both PCOS & hypothalamic amenorrhea due to dysfunctional secretion of gonadotropins,
but their pathophysiology and clinical presentations differ :
 Women with PCOS exhibit an :  Women with hypothalamic amenorrhea,
 increased frequency of pulsatile GnRH  lower frequency of pulsatile GnRH secretion
 increased LH synthesis,  results in inadequate pituitary gonadotropin release (FSH & LH),
hyperandrogenism,

 which is a failure to stimulate progressive follicular development.

impaired follicular maturation.
3- Hypothalmic tumors :
A- hypothalamic tumor (craniopharyngioma, meningioma, hamartoma, chordoma) may distort
tuberoinfundibular tract (pituitary stalk) with its portal venous network,
€ interfering with effective delivery of GnRH, resulting in € decreased FSH & LH secretion.
B- Alternatively, interference with hypothalamic dopamine delivery to pituitary lactotrophs € releases these
cells from tonic inhibition € resulting in hyperprolactinemia.
- Therefore, hypothalamic tumors, may result I (hypogonadotropic hypogonadism & amenorrhea)
4- Drug induced amenorrhea : €2ry amenorrhea can be causes by drugs :
- GnRH agonists € if given in high dose ( normally pulsating release ) € suppress FSH & LH
Progestins & OCP € will prevent the endometrial shedding & inhibit GnRH pulses
Ovarian disorders
Ovarian failure , occurs when :
No follicles capable of producing estradiol in response to pituitary gonadotropin stimulation
Follicular depletion may occur :
1- During embryonic life with no follicles remaining by infancy or early childhood.
 puberty may not occur
 When the depletion of follicles occurs prior to puberty, termed €Gonadal dysgenesis (Turner Syndrome) € 1ry
amenorrhea.
2- After puberty has begun but before menarche :
 puberty may begin normally but stop before the first menses 3- After menarche :
 Puberty may progress normally but menses stop prematurely before the
anticipated age of menopause (40 years of age) , it's termed€Premature ovarian failure (POF) € 2ry amenorrhea.
1- Gonadal dysgenesis(Turner Sundrome ): NO breast + uterus present
- It's chromosomal defect occurs in which an X chromosome will be missed
- It is the most common cause of 1ry amenorrhea (30% to 40%) and results
either from :
 Absence of ovarian follicles or
 Accelerated follicular depletion during embryogenesis or the first
few years of life before puberty.
Histological :
Ovaries contain only stroma & grossly
appear as fibrous streaks (streak ovaries).
Types :
1- Classic type : associated with a 45,XO karyotype. (missed X chromosome)
2- Mosaic Turner (45,X0 /46,XX) :
These X chromosome anomalies may be present in all or only in some of the cells of the body
(mosaicism), depending on stage of postzygotic, embryonic, development when the defect
occurs.
3- Swyer syndrome (45,X/46,XX; 45,X/46,XY) : individuals with gonadal dysgenesis may have a
normal 46,XX or a 46,XY karyotype (Swyer syndrome) in all cells or in one or more cell lines
in mosaic individuals.
 Absence of Y chromosome € allow normal development of Mullerian duct € development of tubes , uterus ,
vagina.
 At puberty, streaks gonads fail to produce oestrogen, in spite of elevated FSH & LH levels € 1ry amenorrhea + NO
2ry sexual chara. (No Breast)
2- Premature ovarian failure (POF) : 1-5%
results in 2ry amenorrhea after completion of puberty and before 40 years of age.
Distinguishment from gonadal dysgenesis on basis of Histology :
 Instead of streak gonads, the ovaries in POF more closely resemble those of postmenopausal women
( showing corpora albicantes " no primordial follicles " ) .
The karyotype in individuals with POF:
 is most often €normal (46,XX)
 also may be € mosaic (e.g., 45,X/46,XX). Cause for early follicular depletion in POF:
 Inadequate germ cell migration during embryogenesis or accelerated atresia.
 Autoimmune disorders & in some cases (e.g., Addison disease) appears to result from an autoimmune
lymphocytic oophoritis
 Radiation & chemotherapy
 Galactosemia (rare):
There are primordial follicles presumably due to the cumulative toxicity of galactose metabolites on germ cell
migration & survival.
Clinical picture:
 2ry amenorrhea + high levels of FSH & LH ( no feedback inhibition by estrogen)
3- Other rare causes :
Unlike ovarian failure, the ovaries of individuals with these disorders contain follicles and oocytes BUT do not produce
estrogen.
A)17 alpha -hydroxylase deficiency
 The enzyme 17 alpha-hydroxylase mediates an early step in steroid hormone synthesis,
 Without it, progesterone cannot be converted to androgens and €
subsequently aromatized to estrogens.
B)Aromatase deficiency
 The enzyme aromatase mediates the conversion of androgenic precursors to € estrogens
 Individuals with aromatase deficiency generally exhibit :
1- Sexual ambiguity at birth, 2- Virilization at puberty,
3- multicystic ovaries (PCOS).
Poly Cystic Ovary Syndrome :
 A syndrome with chronic anovulation & hyperandrogenism.
 Commenst cause of 2ry amenorrhea
 Clinical picture:
 2ry menorrhea (or oligohypomenorrhea) + Hirsutism ,acne , androgenic alopecia , infertility and obesity
 LH/FSH ratio 3:1 (elevated LH level in relation to FSH) "n: 1.5/1"
 Elevated total & free testosterone level (high LH stimulate ovarian follicular
theca cells for production of androgens).--> hirsutism.
 Elevated DHEAS
 Some shows increased insulin resistence with hyperinsulinaemia.
 Acanthosis nigricans
 Transvagianl U/S: Ovaries are bilaterally enlarged by U/S due to(showing) :
 Stroma hyperplasia
 thickened ovarian capsule
 Peripherally arranged equal size small follicles ( string of pearls appearance) Androgen prevent normal follicular development by
inhibition FSH induction of LH receptors inducing premature follicle atresia.
C)Gonadotropin-resistant ovary syndrome: (Savage syndrome)
 It results from genetic mutations in the FSH or LH receptor or post- receptor signaling defects that prevent the
ovaries from responding normally to gonadotropin stimulation.
 So, ovarian follicles fail to develop beyond the early antral stage and
therefore produce little estrogen.
 Clinically: 2ry amenorrhea + high levels of FSH & LH.