Amenorrhea

MEETING 6 LEC 2

Dr . Suzan Abd Elgani

 ESSENTIALS OF DIAGNOSIS
Amenorrhea is literally defined as the absence of menses. •

Amenorrhea

Primary (2.5% of the Secondary (incidence –

population) 3% in general population)
Primary amenorrhea
Remember two critical numbers:
• Absence of menses by age 13 years in the absence of normal growth
or secondary sexual development

or

• Absence of menses by age 15 years in the setting of normal growth

and secondary sexual development.

• The evaluation should begin at age 15 years, the age when more than
97% of girls should have experienced menarche.
Secondary Amenorrhea

• Absence of menses for more than 3 cycle intervals, or 6 consecutive

months, in a previously menstruating woman.

• The incidence of secondary amenorrhea can be quite variable, from

3% in the general population to 100% under conditions of extreme
physical or emotional stress.
Pathogenesis

• Regular and spontaneous menstruation requires:

1.Endocrine: functional hypothalamic–pituitary–ovarian endocrine
axis.
2. Anatomic: an endometrium competent to respond to steroid
hormone stimulation.
3. Outflow: an intact outflow tract from internal to external genitalia.
Pathogenesis
• Why it’s important to diagnose and treat amenorrhea?
Implications for future fertility:

1. risks of unopposed estrogen, including endometrial hyperplasia

and neoplasia;
2. risks of hypoestrogenism, including osteoporosis and urogenital
atrophy.
3. impact on psychosocial development
Pathogenesis

• Pregnancy is the most common cause of amenorrhea and must be

considered in every patient presenting for evaluation of amenorrhea.
Clinical Findings

Breast US
Axis Anatomy
+ + Anorexia/weight loss Physical Ex.
pregnancy/1st bleed History
Imperforate Hymen B-HCG
+ - Mullierian Agenesis (X,X), Normal Testosterone
AIS/testicular femiization (X,Y), elevated Testosterone
- + Kallmann’s Syndrome Low: LH, FSH
MRI
CranioPharyngioma Low: LH, FSH
Turner Syndome (X,O), elevated FSH, LH
Clinical Findings
A. Hypothalamic–Pituitary Dysfunction
• Secreting neurons of the hypothalamus originate in the olfactory bulb
and migrate along the olfactory tract into the mediobasal
hypothalamus and the arcuate nucleus.

• Anovulation and amenorrhea occur as a

result of interference with GnRH
transport, GnRH pulse discharge, or
congenital absence of GnRH
(Kallmann’s syndrome).
Clinical Findings
A. Hypothalamic–Pituitary Dysfunction
1. Defects of GnRH transport
• pituitary stalk compression/trauma/radiation/tumors
(CranioPharyngioma, germinoma, glioma, teratomas)/infiltrative
disorders (sarcoidosis, tuberculosis)

• Destruction of the arcuate nucleus.

Clinical Findings
A. Hypothalamic–Pituitary Dysfunction
2. Defects of GnRH pulse production
Any significant reduction little or no LH or
no ovarian no estradiol is the patient is
in the normal GnRH pulse FSH can be
follicles develop secreted amenorrheic.
frequency or amplitude released

This is the biochemical status in: normal prepubertal girls and those
with constitutional delayed puberty; such as in anorexia nervosa,
severe stress, extreme weight loss (at least 10% below ideal body
weight), or prolonged vigorous athletic exertion, and in
hyperprolactinemia, or Idiopathic phenomenon.
Clinical Findings
A. Hypothalamic–Pituitary Dysfunction
2. Defects of GnRH pulse production
• Functional or hypothalamic amenorrhea:
-Abnormal hypothalamic GnRH secretion in the absence of pathologic
processes.
-Serum FSH levels are usually in the normal range; the setting of high
FSH:LH ratio is consistent with prepubertal patterns

• Congenital GnRH deficiency – 60% sporadic. May be inherited.

- idiopathic hypogonadotropic hypogonadism when isolated phenomenon.
- Kallmann’s Syndrome when associated with anosmia.
- When inherited: autosomal dominant/X-linked recessive (like GnRH
receptor gene mutation.
Clinical Findings
B. Pituitary Defects
Rare •

Pituitary Defects

Congenital Acquired
Clinical Findings
B. Pituitary Defects
1. Congenital:
• absence of the pituitary is a rare and lethal condition.
• Isolated defects of LH or FSH production do occur (rarely).
Clinical Findings
B. Pituitary Defects
2. Acquired:
• Sheehan’s syndrome: postpartum amenorrhea, results from
postpartum pituitary necrosis secondary to severe hemorrhage – rare
• Surgical ablation and irradiation of the pituitary
• Iron deposition in the pituitary – hemosiderosis as in Thalassemia
major.
• Pituitary microadenomas and macroadenomas also lead to
amenorrhea because of elevated prolactin levels.
• Isolated hyperprolactinemia (may be drug induced – table)
• Hypothyroidism -> leads to hyperprolactinemia-> amenorrhea
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
• Various.
• Most common is gonadal dysgenesis.
• Usually associated with sex chromosomal abnormalities.
• Usually present with hypergonadotropic amenorrhea
Ovarian
failure

Primary Secondary
hypergonadotropic hypogonadism hypogonadotropic hypogonadism
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
1. Ovarian dysgenesis:
• primitive oogonia do not migrate to the genital ridge, the ovaries fail
to develop. Streak gonads, which do not secrete hormones, develop
instead. Mostly because of abnormalities of the X chromosome.

Ovarian
dysgenesis
typical early gonadal •
failure before testicular
*development (week 7)
Turner’s syndrome • with no y with y Swyer’s syndrome - do •
x46,XX gonadal dysgenesis • chromatin chromatin not secrete testosterone
or AMH
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
2. Premature Ovarian Failure - POF
• Failing of the ovaries secondary to depletion of ova before age 40
years - 1–5% of women.
• Should be tested for karyotype to rule out: sex chromosome
translocations, short arm deletions, or the presence of an occult Y
chromosome fragment, which is associated with an increased risk of
gonadal tumors.
• 16% of women having fragile X permutation experience POF.
• Iatrogenic causes : Surgery affecting the ovaries, chemotherapy, and
pelvic irradiation.
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
3. Steroid Enzyme Defects:
• Genetic females with defects in
enzymes 1–4 have normal internal
female genitalia and 46,XX
karyotype. However, they cannot
produce estradiol, and thus they
fail to menstruate or have breast
development.
Congenital lipoid adrenal hyperplasia:
- defects in the cholesterol transport from the outer to the inner
mitochondrial membrane.
- hyponatremia, hyperkalemia, and acidosis in infancy.
- Both XX and XY individuals are phenotypically female. Tx- Stero.+Minera.
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
4. Ovarian resistance (Savage’s Syndrome)
• A defect in the cell receptor mechanism – presumed cause
• elevated LH and FSH levels
• ovaries contain primordial germ cells
Clinical Findings
C. Ovarian and Ovulatory Dysfunction
5. Polycystic ovary syndrome
• The most common cause of ovulatory dysfunction in reproductive-age
women.
• Dx: at least 2 of the following:
- oligo- or anovulation
- clinical and/or biochemical signs of hyperandrogenism
- polycystic ovaries
• Mechanism: insulin resistance, hyperinsulinemia -> decreased sex
hormone-binding globulin -> increased androgens
• Thus metformin and rosiglitazone are used for ovulation induction in
PCOS (sole or adjuvant).
Clinical Findings
D. Anatomic Abnormalities Associated With Amenorrhea
1. Müllerian dysgenesis - congenital absence of the uterus and the
upper two-thirds of the vagina. may ovulate regularly, have normal
development of the secondary sex characteristic, and have a 46, XX
karyotype.
2. Vaginal agenesis
3. Transverse vaginal septum - failure of fusion of the müllerian and
urogenital sinus-derived portions of the vagina.
4. Imperforate hymen - If the hymen is complete
5. Asherman’s syndrome - The usual cause is a complicated dilatation
and curettage (D&C), but the syndrome can occur after
myomectomy, caesarean section, and tuberculous endometritis.
Clinical Findings
E. Amenorrhea in Women With 46, XY Karyotype
1. Testicular feminization – Uterus. X
Lower 2/3 vagia V
Testis V
Clinical Findings
E. Amenorrhea in Women With 46, XY Karyotype
2. Pure gonadal dysgenesis (Swyer Syndrome)
the primitive germ cells do not migrate to the genital ridge
Or
SRY gene is not functioning harboring a mutation

No testis  no MIF nor Testosterone

No estrogen  No breast

* Removal of the streak gonads should be done as soon as the

diagnosis – risk of malignancy
Clinical Findings
E. Amenorrhea in Women With 46, XY Karyotype
3. Anorchia
the fetal testes regress before 7 weeks gestation  neither MIF nor
testosterone is secreted  identical clinical picture to swyer.

Regression between weeks 7 and 13  ambiguous genitalia

4. Testicular steroid Enzyme Defects

 Differential
Diagnosis
-
Primary
amenorrhea
 Differential
Diagnosis
-
Secondary
amenorrhea
 Differential
Diagnosis
-
galactorrhea-
hyperprolactin
emia
Differential
Diagnosis
-
progestin
challenge
positive
 Differential
Diagnosis
-
hypogonadotropic
hypogonadism
 Differential
Diagnosis
-
hypergonadotropic
hypogonadism
Complications
• Infertility

• psychosocial developmental delay with lack of normal physical sexual

development

• Hypoestrogenic patients -> severe osteoporosis and fractures ->

femoral neck fracture

• Patients who respond to progestin challenge -> endometrial

hyperplasia and carcinoma (due to unopposed estrogen stimulation).
Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
1. amenorrhea-galactorrhea WITH pituitary MACROadenoma
• Dopamine agonist drugs cabergoline and bromocriptine
• Surgical therapy— transsphenoidal or frontal removal of the pituitary
adenoma or the entire gland—may be required if
- tumor size or secretion are resistant to dopamine agonists.
- the lesion is rapidly enlarging or causing symptoms*
- women with giant adenomas (>3 cm) who wish to discontinue
agonist treatment for conception and the duration of pregnancy.
• Approximately half of surgically treated patients will menstruate normally
after this procedure.
Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
2. amenorrhea-galactorrhea WITHOUT pituitary MACROadenoma
• Dopamine agonist drugs cabergoline and bromocriptine: Lowest dose
needed to maintain normal prolactin levels.

• Once pregnancy has been achieved, the agent can be discontinued.

• Patients with macroadenomas may need to continue therapy throughout
pregnancy to avoid further growth of the lesion.
• Patients taking drugs that raise the prolactin level should discontinue
them if possible, but continued use of such drugs is not a contraindication
to therapy.
Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
3. Hypothyroidism

• Thyroid replacement therapy - Eltroxin , Euthryox

Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
4. Primary ovarian failure:
• Patients with reversible ovarian failure include those with
autoimmune oophoritis*, who can be successfully treated with
corticosteroids.
• Otherwise, cannot be made to ovulate.
• In vitro fertilization (IVF) with donor oocytes is the only way they can
have children.
• Any patient with a Y chromosome should undergo oophorectomy* to
prevent tumor development.
Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
5. hypoestrogenic hypothalamic amenorrhea (progestin-challenge
negative)

• Injections of exogenous gonadotropins (hMG – Human Menopausal

Gonadotropin)
• a single course of clomiphene citrate (an antiestrogen), 150 or 250 mg
daily for 5 days, on the chance that ovulation will occur. (to cancel the
negative feedback of the remaining estrogen on gonadotropins, even
though patients are hypoestrogenic)
• Combination.
Treatment
• Is she desiring pregnancy?
Yes: Ovulation induction in patients with:
6. progestin-challenge positive

• clomiphene citrate (an antiestrogen), The starting dose is 50 mg orally

daily for 5 days. This can be increased to a maximum of 250 mg orally daily.
Ovulation occurs 5–10 days after the last dose.
• clomiphene citrate & Oral hypoglycemic agent in Patients with elevated
androgens who do not respond to clomiphene citrate.
• Not effective -> gonadotropin therapy may be attempted carefully so they
won’t be hyperstimulated
• Laparoscopic ovarian drilling* in PCOS
Treatment
Is she desiring pregnancy? •
Yes: Ovulation induction in patients.

hypoestrogenic
Positive progestin No:
Hyper-prolactinemia
challenge
• Combination of • occasional progestin • periodic prolactin
estrogen and administration. measurements
progesterone. • OCT / P for 10-13 days • radiographic cone views
• OCT / E (day 1-25)+ P every month or other of the sella turcica to
(day 16-25) month rule out the
• To maintain bone • to prevent the development of
density and prevent development of macroadenoma.
genital atrophy endometrial hyperplasia
and carcinoma