Amenorrhea and

Spaniomenorrheas
Dr DOHBIT SAMA
Obs/Gyn
HGOPY – FMBS UNIYAO I
 Objectives
• At the end of this lecture, the student should
be able to:
1. Define and classify amenorrhea
2. State the common causes of amenorrhea at
the different levels
3. Discuss the diagnostic steps for amenorrhea
4. State the treatment principles of
amenorrheas.
 Plan
• Introduction
• Definition
• Etiology and pathogenesis
• Diagnosis
• Treatment
• Complications
• Prognosis
 Introduction
• Menstruation is a sign of female sexual
development,
• It is one of the most reliable signs of female
endocrine and reproductive tract maturation.
• Regular and spontaneous menstruation requires:
– (a) an intact hypothalamic–pituitary–ovarian
endocrine axis;
– (b) an endometrium competent to respond to steroid
hormone stimulation; and
– (c) an intact outflow tract from internal to external
genitalia.
 Introduction 2
• The menstrual cycle is susceptible to
environmental influences and stressors.
• Missing a single or occasional menstruation
rarely reflects a significant pathology.
• However, prolonged or persistent absence of
menses may be one of the earliest signs of
neuroendocrine or anatomic abnormality.
The Uterine cycle
 Introduction 3
• Amenorrhea should be diagnosed and treated
because of:
– The implications for future fertility;
– Risks of unopposed estrogen, including endometrial
hyperplasia and neoplasia;
– Risks of hypoestrogenism, including osteoporosis and
urogenital atrophy; and
– Impact on psychosocial development.
There is a significant overlap in etiology and treatment,
of primary and secondary amenorrhea
 Definition
• Amenorrhea is the absence of menses.
• Primary amenorrhea, seen in approximately
2.5% of the population, is clinically defined as
the absence of menses by age 13 years in the
absence of normal growth or secondary sexual
development; or the absence of menses by
age 15 years in the setting of normal growth
and secondary sexual development.
 Definition 2
• Traditionally, evaluation was usually initiated by
age 16 years or earlier if normal growth and
secondary sexual characteristics were present,
and at age 13 years if absent.
• At age 15 years more than 97% of girls should
have experienced menarche
• Evaluation should not be delayed in the setting of
neurologic symptoms (suggestive of
hypothalamic–pituitary lesion) or pelvic pain
(suggestive of outflow obstruction).
 Definition 3
• Secondary amenorrhea is clinically defined as
the 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.
 Causes of secondary amenorrhea
• Common causes:
– Pregnancy
– Hypothalamic amenorrhea
– Androgen disorders: polycystic ovarian syndrome,
congenital adrenal hypreplasia
– Galactorrhea-amenorrhea syndrome
• Less Common causes:
– Premature ovarian failure
– Asherman's syndrome
– Sheehan's syndrome
Causes of secondary amenorrhea 2
• Rare causes:
– Diabetes
– Hyperthyroidism or hypothyroidism
– Cushing's syndrome or Addison's disease
– Cirrhosis
– Tuberculosis
– Malnutrition
– Irradiation or chemotherapy
– Surgery
 Pathogenesis
• Pregnancy is the most common cause of
amenorrhea and must be considered in every
patient presenting for evaluation of
amenorrhea
• Nasah et al. Amenorrhea in every woman of
child bearing age is considered pregnancy
until proven otherwise
 Hypothalamic Defects
• Gonadotropin-releasing hormone (GnRH) secreting
neurons of the hypothalamus originate in the
olfactory bulb and migrate along the olfactory tract
into the mediobasal hypothalamus and the arcuate
nucleus.
• Under normal physiologic circumstances, the arcuate
nucleus releases pulses of GnRH into the hypophyseal
portal system approximately every hour.
• Discharge of GnRH releases luteinizing hormone (LH)
and follicle-stimulating hormone (FSH) from the
pituitary; LH and FSH, in turn, stimulate ovarian
follicular growth and ovulation.
 Hypothalamic Defects 2
• The ovarian hormones estradiol and
progesterone stimulate the development and
shedding of the endometrium, culminating in
the withdrawal bleeding of menses.
• Anovulation and amenorrhea occur as a result of
interference with GnRH transport, GnRH pulse
discharge, or congenital absence of GnRH
(Kallmann's syndrome with anosmia). Any of
these situations leads to hypogonadotropic
hypogonadism.
Hypothalamic Defects 2
 Pituitary Defects
• As causes of amenorrhea are rare; most are
secondary to hypothalamic dysfunction.
• However, acquired pituitary dysfunction can
ensue from previous local radiation or surgery.
• Excess iron deposition due to
hemochromatosis or hemosiderosis may
destroy gonadotropes.
 Congenital Pituitary Dysfunction
• Congenital absence of the pituitary is a rare
and lethal condition.
• Isolated defects of LH or FSH production do
occur (rarely), resulting in anovulation and
amenorrhea.
 Acquired Pituitary Dysfunction
• Sheehan's syndrome; postpartum
amenorrhea, results from postpartum
pituitary necrosis secondary to severe
hemorrhage and hypotension and is a rare
cause of amenorrhea.
• Surgical ablation and irradiation of the
pituitary as management of pituitary tumors
also can cause amenorrhea.
 Acquired Pituitary Dysfunction 2
• Iron deposition in the pituitary may result in
destruction of the cells that produce LH and
FSH. This occurs only in patients with
markedly elevated serum iron levels (ie,
hemosiderosis), usually resulting from
extensive red cell destruction. Thalassemia
major is an example of a disease that causes
hemosiderosis.
 Acquired Pituitary Dysfunction 3
• Pituitary microadenomas and macroadenomas
also lead to amenorrhea because of elevated
prolactin levels, but the mechanism(s) underlying
this cause of amenorrhea are unclear.
• Isolated hyperprolactinemia in the absence of
adenoma is an uncommon cause of primary
amenorrhea. However, the diagnosis is strongly
suggested by a history of galactorrhea.
 Acquired Pituitary Dysfunction 4
• Diagnosis is readily made by evaluating a
serum prolactin level.
• Hypothyroidism may also lead to elevated
prolactin levels and thereby lead to
amenorrhea.
Ovarian and Ovulatory Dysfunction
Ovarian and Ovulatory Dysfunction
• A variety of gonadal disorders can result in
amenorrhea.
• The most common cause of primary amenorrhea
is gonadal dysgenesis.
• This group of disorders is usually associated with
sex chromosomal abnormalities, resulting in:
– streak gonad development,
– premature depletion of ovarian follicles and oocytes,
– and absence of estradiol secretion.
 Ovarian and Ovulatory Dysfunction 2
• Patients usually present with
hypergonadotropic amenorrhea regardless of
degree of pubertal development.
• Primary ovarian failure is characterized by
elevated gonadotropins and low estradiol
(hypergonadotropic hypogonadism).
 Ovarian and Ovulatory Dysfunction 3
• Secondary ovarian failure is almost always
caused by hypothalamic dysfunction and is
characterized by normal or low gonadotropins
and low estradiol (hypogonadotropic
hypogonadism).
 Ovarian Dysgenesis
• If the primitive oogonia do not migrate to the
genital ridge, the ovaries fail to develop.
• Streak gonads, which do not secrete hormones,
develop instead, and the result is primary
amenorrhea.
• Cytogenetic abnormalities of the X chromosome
account for the majority of abnormal ovarian
development and function, and studies show that
two intact X chromosomes are required to
maintain normal oocytes.
 Ovarian Dysgenesis 2
• Fetuses with 45,X karyotype demonstrate
normal oocyte number at 20–24 weeks'
gestation, but there is rapid atresia resulting in
absence of oocytes at birth.
• Similarly, women with deletions in either the
long or short arm of one X chromosome also
develop either primary or secondary
amenorrhea.
 Ovarian Dysgenesis 3
• Gonadal Dysgenesis with No Y Chromatin
• Turner's syndrome (45,XO or 45,XO,XX
mosaics) and 46,XX gonadal dysgenesis are
the most common karyotypes. Patients with
Turner's syndrome usually present with
primary amenorrhea. However, some patients
with mosaic abnormalities may menstruate
briefly and a few have conceived.
 Ovarian Dysgenesis 4
• Gonadal Dysgenesis with Y Chromatin
• Normal female sexual differentiation depends on
testicular secretion of antimüllerian hormone (AMH)
by Sertoli cells and testosterone by Leydig cells.
• AMH causes regression of müllerian structures,
whereas testosterone and its metabolite
dihydrotestosterone (DHT) promote differentiation of
male internal and external genitalia, respectively.
• A variety of disorders can result in the presentation of
amenorrhea in phenotypic females possessing Y
chromatin material
 Premature Ovarian Failure
• Menopause occurs when the ovaries fail
secondary to depletion of ova.
• If this occurs before age 40 years, it is
considered premature.
• It is marked by amenorrhea, increased
gonadotropin levels, and estrogen deficiency.
 Ovarian Resistance
(Savage's Syndrome)
• Patients with this syndrome have elevated LH
and FSH levels, and the ovaries contain
primordial germ cells.
• A defect in the cell receptor mechanism is the
presumed cause.
 Polycystic Ovary Syndrome
• One of the most common causes of secondary
amenorrhea is polycystic ovary syndrome (PCOS).
• PCOS is the most common cause of ovulatory
dysfunction in reproductive-age women.
• Diagnosis is based on the presence of at least two of
the following characteristics: (a) oligo- or anovulation;
(b) clinical and/or biochemical signs of
hyperandrogenism; (c) polycystic ovaries; and (d)
exclusion of other etiologies (congenital adrenal
hyperplasia, androgen-secreting tumors, Cushing's
syndrome).
Polycystic Ovary Syndrome
 Polycystic Ovary Syndrome 2
• Although the exact mechanism is unknown, it
appears that insulin resistance and
hyperinsulinemia play a permissive role.
• Abnormally elevated baseline insulin leads to
increased androgens via decreased sex hormone-
binding globulin, and stimulation of ovarian
insulin and insulinlike growth factor-I (IGF-I)
receptors.
• Increasingly, insulin-sensitizing agents such as
metformin and rosiglitazone are used as a sole or
adjuvant agent for ovulation induction in PCOS.
Anatomic Abnormalities causing
Amenorrhea
 Anatomic Abnormalities causing
Amenorrhea
• Müllerian Dysgenesis characterized by congenital
absence of the uterus and the upper two-thirds
of the vagina. Affected individuals have a 46,XX
karyotype.
• Vaginal Agenesis is characterized by failure of the
vagina to develop.
• Transverse Vaginal Septum results from failure of
fusion of the müllerian and urogenital sinus-
derived portions of the vagina.
• Imperforate Hymen: If the hymen is complete,
menstrual efflux cannot occur.
Anatomic Abnormalities causing
Amenorrhea
Anatomic Abnormalities causing
Amenorrhea
 Anatomic Abnormalities causing
Amenorrhea 2
• Asherman's Syndrome: amenorrhea is caused
by intrauterine synechiae.
• The usual cause is a complicated dilatation
and curettage (D&C) (eg, infected products of
conception, vigorous elimination of the
endometrium), but the syndrome can occur
after myomectomy, cesarean section, and
tuberculous endometritis.
 Amenorrhea in Women with 46,XY
Karyotype
• The sexually undifferentiated male fetal testis
secretes müllerian-inhibiting factor (MIF) and
testosterone.
• MIF promotes regression of all müllerian
structures: the uterine tubes, the uterus, and
the upper two-thirds of the vagina.
• Testosterone and its active metabolite DHT are
responsible for embryonic differentiation of
the male internal and external genitalia.
 Amenorrhea in Women with 46,XY
Karyotype 2
• Testicular Feminization: all müllerian-derived
structures are absent. The external genital
anlagen and mesonephric ducts cannot respond
to androgens, because androgen receptors are
either absent or defective.
• Affected individuals are therefore phenotypic
females lacking a uterus and a complete vagina.
• They produce some estrogen, develop breasts,
and are reared as girls, and therefore present
with primary amenorrhea.
 Amenorrhea in Women with 46,XY
Karyotype 3
• Pure Gonadal Dysgenesis
• If the primitive germ cells do not migrate to the
genital ridge, a testis will not develop, and a
streak gonad will be present.
• Affected individuals have normal female internal
and external genitalia, as neither MIF nor
androgens are secreted by the streaks.
• Because these individuals produce no estrogen,
they will not develop breasts.
• They are reared as girls and present clinically with
either delayed puberty or primary amenorrhea.
 Amenorrhea in Women with 46,XY
Karyotype 4
• Anorchia: If the fetal testes regress before 7
weeks' gestation, neither MIF nor
testosterone is secreted, and affected
individuals will present with a clinical picture
identical to that of pure gonadal dysgenesis.
• Individuals whose testes regress between 7
and 13 weeks' gestation present with
ambiguous genitalia.
 Amenorrhea in Women with 46,XY
Karyotype 5
• Testicular Steroid Enzyme Defects: Affected
individuals have female external genitalia and
no müllerian structures.
• They will be reared as girls and present
clinically with either delayed puberty or
primary amenorrhea.
 Diagnosis
• Any patient with amenorrhea who has a
uterus should be tested for pregnancy and for
serum levels of thyroid-stimulating hormone
(TSH) and prolactin.
• Galactorrhea should be identified or ruled out
by physical examination
 Diagnosis of Primary Amenorrhea
• Pelvic examination should be done to establish
the presence of a vagina and uterus and no
vaginal septum or imperforate hymen that might
account for the failure of appearance of menses.
• In adolescent girls pelvic ultrasound or
examination under anesthesia may be required to
establish the presence of a uterus.
• If no uterus is present, serum testosterone levels
should be measured and karyotyping done to
differentiate between müllerian agenesis and
testicular feminization.
 Amenorrhea Associated with
Galactorrhea-Hyperprolactinemia
• Patients with primary hypothyroidism have
elevated thyroid-releasing hormone (TRH)
levels.
• TRH acts to stimulate the release of prolactin
and may thereby lead to galactorrhea-
amenorrhea syndrome.
• TSH is also elevated and easier to measure
and thus is the screening test for
hypothyroidism.
 Amenorrhea Not Associated with
Galactorrhea-Hyperprolactinemia
• The first step is the progestin challenge
• Asherman's syndrome can be ruled out by
administration of conjugated estrogen, 2.5 mg
orally daily for 25 days, plus
medroxyprogesterone acetate, 10 mg orally
on days 16 through 25.
• Patients with Asherman's syndrome do not
bleed following this regimen.
 Amenorrhea Not Associated with
Galactorrhea-Hyperprolactinemia 2
• In a patient who does not have Asherman's
syndrome and who does not respond to the
progestin challenge, ovarian dysfunction may be
of hypothalamic or ovarian origin.
• The distinction is based on the FSH level.
• Primary ovarian dysfunction resulting in low
estradiol secretion is associated with high serum
FSH.
• Values vary in different laboratories, but in
general an FSH level higher than 40 mIU/mL
indicates primary ovarian failure
 Amenorrhea Caused by Primary
Ovarian Failure
• Karyotyping is indicated for all women who
present with premature menopause,
particularly if their amenorrhea is primary.
• Patients with primary amenorrhea may have a
steroid enzyme defect.
• Autoimmune oophoritis is a reversible cause
of ovarian failure that must be investigated.
 Treatment
• Management of Patients Desiring Pregnancy—
Ovulation Induction with or without Pituitary
Macroadenoma:
– Bromocriptine or carbegoline
– Dopamine agonist
 Treatment 2
• Ovulation Induction in Patients with
Hypothyroidism frequently respond to thyroid
replacement therapy
• Ovulation Induction in Patients with Primary
Ovarian Failure: Donor oocytes for IVF
• Hormone replacement therapy for those not
desiring pregnancy
 Complications
• The complications of amenorrhea can be
numerous, including:
– infertility and psychosocial developmental delays with
lack of normal physical sexual development.
– Hypoestrogenic patients can develop severe
osteoporosis and fractures, the most hazardous to life
being femoral neck fracture.
– The complications associated with amenorrhea in
patients who respond to progestin challenge are
endometrial hyperplasia and carcinoma resulting from
unopposed estrogen stimulation.
 Prognosis
• The prognosis for amenorrhea is good.
• It is not usually a life-threatening clinical event, as with
proper evaluation, tumors can be recognized and
treated.
• Many patients with hypothalamic amenorrhea will
spontaneously recover normal menstrual cycles.
• Virtually all amenorrheic women who do not have
premature ovarian failure can be made to ovulate
with a dopamine agonist, clomiphene citrate, insulin-
sensitizing agents, and gonadotropins.
 Conclusion
• All cases of amenorrhea require careful
investigation
• Correct diagnosis is needed for adequate
therapy
• Clinical diagnosis is very essential in our
setting where resources are very limited
Thank you