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Chapter 27. Amenorrhea
Berek & Novak’s Gynecology
14th edition (p 1035~1068)
R3 Jung Mi Byun
Overview
 Primary amenorrhea
: absence of menses
– at age 13years when there is no visible secondary sexual
characteristic development
– at age 15years in the presence of normal secondary sexual
characteristics
 Secondary amenorrhea
– A woman who has previously menstruated
– absence of menstruation for three normal menstrual cycles
or 6 months
Overview
 Premature gonadal failure occurs in conjunction with primary
amenorrhea
– associated with genetic abnormalities (30%)
 Diagnosis
– History
– Physical examination
• 2nd sexual characteristics
• anatomic abnormalities (relatively few)
– Lab
• hCG
• FSH (differentiate between hypergonadotropic and
hypogonatropic forms of hypogonadism)
Overview
 Treatment
<Goal >
– correcting the primary cause of amenorrhea
– to initiate and maintain secondary sexual characteristics
– maintenance of bone mass
– Ovulation induction for patients desiring pregnancy
 Mehthod
– medical or surgical therapy
– hormone replacement
Overview
Anterior suprachiasmatic nucleus
Posterior arcuate nucleus
Normal menstrual cycle
Overview
 Amenorrhea Mechanism
– any of the components : nonfunctional
hypothalamus, pituitary, ovary, outflow tract, feedback mechanism
→ bleeding cannot occur. (Amenorrhea)
 Amenorrhea : 3~4% of reproductive age women, not pregnant.
Decision tree for evaluation of amenorrhea.
Secondary sexual
characteristics
Present
Absent
HCG -
Physical exam
Normal
FSH level
Absent uterus
•5α-reductase
) deficiency
•17-20 desmolase
deficiency
•17α-hydroxylase
deficiency (all with
XY karyotype)
High
Normal
Karyotype
Karllman’s syndrome
Physiology delay
Disorders of low
estrogen status
before puberty
XX
Y line
Turner’s (XO)
Primary
No
Yes
HCG +
Pregnancy
Primary
No
Yes
Secondary if risk of
endometial scarring
advise HSG &
culrutres to exclude
Asherman’s, cervical
stenosis and infection
Physical exam
Normal PRL
Normal
Abnormal
TSH, PRL, FSH,
Clinical evaluation
of estrogen status
Mullerian anomaly
Androgen insensitivity
True hermaphroite
Normal TSH
Abnormal TSH
High PRL
Hyperthyroidism
Hypothyroidism
Hyperprolactinemia
Normal PRL
Normal FSH
Normal estrogen
Chronic anovulatory
Ovarian neoplasm
Polycystic ovarian
syndrome
Grandulosa cell
androgensecreting
Idiopathic
High FSH
Low estrogen
 Feedback disorders
 Obesity
 Cushing’ syndrome
 Androgen-secreting
adrenal tumors
 Congenital adrenal
hyperplasia
Chronic disease
pulmonary
renal
liver
diabetes
Addison’s disease
Neurological exam
CT/MRI, EEG
Ovarian failurechromosomal
radiaton
chemotherapy
infection
autoimmune
Galactosemia
Savage syndrome
Idiopathic
Normal
Abnormal
Hypothalamic
dysfunction
Anorexia
Exercise-induced
Stress
Pseudocyesis
Malnutrition
Pituitary-hypothalamic
lesions
tumors
infection
infarction
pituitary failure
Sheehan’s
Diabetic vasculitis
Toxic-lead
 Amenorrhea
without Secondary Sexual Characteristics
 Amenorrhea
with Secondary Sexual Characteristics
and Anatomic Abnormalities
Amenorrhea
without Secondary Sexual
Characteristics
 Absence of secondary sexual characteristics
(breast development : 1st sign of estrogen exposure in puberty)
→ woman has never been exposed to estrogen stimulation
 Absence of a uterus suggests certain enzyme deficiencies and
indicate the presence of antimullerian hormone (AMH) in an XY
individual .
Cause of Primary Amenorrhea
 Hypergonadotropic Hypogonadism
– Genetic Disorders
– Enzyme Deficiencies
– Gonadotropin Receptor Mutation
 Other causes of Primary Ovarian Failure
 Hypogonadotropic Hypogonadism
 Genetic Disorders
 Other Hypothalamic / Pituitary Dysfunctions
Cause of Primary Amenorrhea
Table 27.1 Amenorrhea Associated with a Lack of Secondary Sexual Charateristics
Abnormal physical examination
5α-reductase deficiency in XY individual
17, 20-desmolase deficiency in XY individual
17α-hydroxylase deficiency in XY individual
Hypergonadotropic hypogonadism
Gonadal dysgenesis
Pure gonadal dysgenesis
Partial deletion of X chromosome
Sex chromosome mosaicism
Environmental and therapeutic ovarian toxins
17α-hydroxylase deficiency in XX individual
Galactosemia
Other
Hypogonadotropic hypogonadism
Physiologic delay
Kallmann’s syndrome
Central nervous system tumors
Hypothalamic/pituitary dysfunction
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
 LH, FSH ↑ : d/t decreased negative estrogen feedback.
 Associated with genetic abnormalities
(Approximately 30% of patients with primary amenorrhea)
 Syndrome of gonadal dysgenesis or Turner syndrome
 Other disorder :
– structurally abnormal X chromosomes,
– mosaicism,
– pure gonadal dysgenesis (46,XX and 46,XY with gonadal streaks),
– enzyme deficiencies that prevent normal estrogen production,
– Gonadotropin-receptor inactivating mutations
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Genetic Disorder
Gonadal Dysgenesis
 Turner syndrome(45,X)
:m/c chromosomal abnormality causing
gonadal failure and primary amenorrhea
P.Ex
– short stature, webbed neck
– shield chest,
– cubitus valgus
– short metacarpals,
– low hair line,
– high arched palate,
– multiple pigmented nevi,
– short fourth metacarpals
Study
– cardiac (30%: coarctaion of the aorta)
– renal (horseshoe kidney),
– autoimmune(thyroiditis)
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Genetic Disorder
 Abnormal X Chromosome
– 46, XX individuals with partial deletions of the X chromosome
: variable phenotypes depending on the amount and location of
the missing genetic material
– Deletion of the long arm of the X chromosome(Xq-) Xq13~Xq26
- sexual infantilism
- normal stature
- no somatic abnormalities, no streak gonads
- eunuchoid in appearance, delayed epiphyseal closure (some)
– Deletion of the short arm of the X chromosome (Xp)
: phenotypically similar to individual with Turner syndrome
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Genetic Disorder
 Mosaicism
– 45,X/46XX (m/c)
– Clinical finding :taller and fewer abnormalities than pure 45,X
– 20% : spontaneous menstruation (+)
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Genetic Disorder
 Pure Gonadal Dysgenesis
– Phenotypically female with sexual infantilism,
– primary amenorrhea,
– normal stature,
– no chromosomal abnormalities (46, XX or 46, XY)
– Gonads
: usually streaks, some development of 2nd sexual characteristics
< Swyer syndrome >
– mutations in the SRY (sex-determining region gene on the Y
chromosome) located at Yp11 result in XY females with
gonadal dysgenesis
– 15~20% of women (46,XY)
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Genetic Disorder
 Mixed gonadal dysgenesis
– XY
– Ambiguous genitalia with a streak gonad on one side and a
malformed testis on the opposite
– SRY gene mutation (small proportion )
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Enzyme deficiencies

Congenital Lipoid Adrenal Hyperplasia
– Autosomal recessive disorder
– Cholesterol → Pregnenolone
– Not defect of the P450scc gene
– 15 different mutations in the
steroidogenic acute regulatory
protein(StAR) : facilitates the
transport of cholesterol from the
outer to the inner mitochondrial
membrane.
– hypoNa, HyperK, acidosis in infancy
– XX, XY(m/c) – no uterus
– phenotype : female
– Genetic cluster : Japanes/Korean
and Palestinian Arab population
– Tx :mineralocorticoid and
glucocorticoid replacement
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Enzyme deficiencies

17α-Hydroxylase & 17, 20-Desmolase
Deficiency
– mutation in the CYP 17 gene
→ abnormalities in both the 17 αhydroxylase and 17, 20desmolase functions of the
protein
– Karyotype : 46, XX 46,XY
(no uterus)
– primary amenorrhea, no 2nd
sexual characteristic, female
phenotype, HTN, hypoK,
– ACTH ↑
– Meneralocorticoid production ↑
→ Na retension, K loss, HTN
– Primordial follicle
– Gonadotropin ↑
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Enzyme deficiencies


Aromatase Deficiency
– Autosomal recessive abnormality
Aromatizing
– Androgen
estrogen
– Most mother of affected children
: become virilized during pregnancy.
→ suspected before birth.
– At birth
: female child-clitoromegaly and
posterior labioscrotal fusion
– At puberty
: no breast development,
primary amenorrhea,
worsening virilization .
absent growth spurt,
delayed bone age,
multicystic ovaries
Tx : estrogen supply
Cause of Primary Amenorrhea
Hypergonadotropic Hypogonadism
Gonadotropin receptor Mutations
 Luteinizing Hormone Receptor Mutation
– Inactivation of LH receptors has been identified in XY
pseudohermaphrodites with primary amenorrhea in the
absence of secondary sexual characteristics
– caused by homozygous premature stop codon, deletions,
and missense mutations in the LHR gene located on
chromosome 2.
 Follicle-stimulating Hormone receptor Mutation
– Autosomal recessive
– single amino acid substitution in the extracellular domain of
the FSH receptor
– Primary or early secondary amenorrhea,
– variable development of secondary sexual characteristics
– high levels of FSH and LH
Cause of Primary Amenorrhea
Other Causes of Primary Ovarian Failure
 Irradiation
 Chemotherapy
with alkylating agents (e.g. cyclophosphamide)
 Combination of radiation and other chemothrapeutic agents
 Galactosemia
Cause of Primary Amenorrhea
Hypogonadotropic Hypogonadism
 Hypothlamus fails to secrete adequate amounts of GnRH
 Pituitary disorder associated with inadequate production or
release of pituitary gonadotropins is present.
Cause of Primary Amenorrhea
Hypogonadotropic Hypogonadism
 Physical Delay
 Kallmann Syndrome
 Central Nervous System Tumors
Cause of Primary Amenorrhea
Hypogonadotropic Hypogonadism
Physiologic Delay
 most common manifestation of hypogonadotropic
hypogonadism
 Amenorrhea
: result from the lack of physical development caused by delayed
reactivation of the GnRH pulse generator
 physiologic delay of puberty are usually short for their
chronologic age
 normal for their bone age
Cause of Primary Amenorrhea
Hypogonadotropic Hypogonadism
Kallmann Syndrome
 2nd most common hypogonadotropic hypogonadism
 insufficient pulsatile secretion of GnRH (Kallmann syndrome),
which has varied modes of genetic transmission
→ leads to deficiencies in FSH and LH
 caused by developmental or genetic defects, inflammatory
processes, tumors, vascular lesions, or trauma
 normal height for their age,
Cause of Primary Amenorrhea
Genetic Disorders
 5α-Reductase Deficiency
 Gnoadotropin-releasing Hormone Receptor Mutations
 Follicle-stimulating Hormone Deficiency
Cause of Primary Amenorrhea
Genetic Disorders
5α-Reductase Deficiency

XY , virilization at puberty,

Testes(+) : functioning Y chromosomes

No mullerian structure, d/t functioning AMH

Low gnoadotropin level

5 α-Reductase
Deficiency
D/Dx> androgen insensitivity
: not develop breasts at puberty

gonadotropin level: low

male differentiation of the urogenital sinus
and external genitalia : not

Normal internal male genitalia
(derived from the wolffian ducts using
testosterone)

Male pattern hair growth, muscle mass,
voice deepening
Cause of Primary Amenorrhea
Genetic Disorders
Gonadotropin-releasing Hormone Receptor Mutations
 GnRH receptor : G-protein-coupled receptor
 Abnormal GnRH function
 17% of sporadic cases of idiopathic hypogonadotropic
hypogonadism with normal olfaction
Cause of Primary Amenorrhea
Genetic Disorders
Follicle-stimulating Hormone Deficiency
 FSH deficiency
: treatment for delayed puberty and primary amenorrhea caused
hypoestrogenism.
 FSH↓ LH ↑ : distinguished from other hypoestrogenism
 Low serum androgen levels
: FSH-stimulated follicular development is prerequisite for thecal
cell androgen production
Cause of Primary Amenorrhea
Other Hypothalamic / Pituitary Dysfunctions
 Malnutrition
 Marijana
 Malabsorption
 Hypothyroidism
 Weight loss
 Polycystic ovarian syndrome (PCOS)
 Anorexia nervosa
 Cushing syndrome
 Excess ecercise
 Hyperprolactinemia
 Chronic disease
 infiltrative disorders of the central
nervous system
 Neoplasia
Amenorrhea
without Secondary Sexual Characteristics
Diagnosis
Treatment
Amenorrhea without Secondary Sexual
Characteristics
Diagnosis
 History
– short stature but consistent growth rate,
– a family history of delayed puberty,
– normal physical findings
(including assessment of smell, optic disks, and visual fields)
Physical delay
–
–
–
–
–
Headache,
visual disturbance,
short stature, symptoms of diabetes insipidus,
weakness of limbs
CNS lesion
Galactorrhea
 Physical Examination
Amenorrhea without Secondary Sexual
Characteristics
Diagnostic workup
History& P.Ex (-)
FSH
Coarctation of the aorta (30%)
Thyroid dysfunction
→
↑ Echocardiography
: every 3~5yrs
(Hypergonadotropic
hyporogonadism)
→ TFT : yearly
Evaluation for
Karyotype
hearing loss and hypertension
↓
(hypogonadotropic
hypogonadism)
•Serum Progesterone↑(>3.0)
Abnormal
 Turner syndrome
 Partial deletion of the X
chromosome,
 mosaicision,
 Pure gonadal dysgenesis,
 Mixed gonadal dysgenesis
Normal
17-α hydroxylase
deficiency
•17α-hydroxyprogesterone↓ (0.2ng/mL)
•Deoxycorticosterone (DOS)↑
→ ACTH stimulation test
: ACTH bolus administration
→S-progesterone↑
→17α-hydroxyprogesterone ( - )
Amenorrhea without Secondary Sexual
Characteristics
Diagnostic workup
 if galactorrhea, headaches, visual field defect (+)
→ CT, MRI

Physiologic delay
– distinguish from insufficient GnRH secretion
– history
– absence of a CNS lesion on CT or MRI
– X-ray : delayed bone age
 Gonadotropin-deficiency
– distinguished from physiologic delay
: response to GnRH stimulation
Physiologic delay
Gonadotropin-deficiency
LH : normal
LH and FSH ↓
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
All forms of gonadal failure
Hypergonadotropic hypogonadism
→ cyclic estrogen and progestin therapy
: to initiate, mature, and maintain 2nd sexual characteristics
prevention of osteoporosis (additional benefit of estrogen)
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
Initiation  conjugated estrogen 0.625mg/day
(Premarin R ) or
R
 estradiol 1mg/day (Progynova )
 estrogen +progestin
(medroxyprogesterone acetate)
R
(Provera ) daily or
 progesterone
to prevent unopposed estrogen stimulation
of the endometrium in patients with uterus
 short
stature : higher estrogen doses (x)
 normal stature : higher estrogen,
after then reduced to the
maintenance doses after
several months
Medrosyprogesterone acetate
 2.5mg daily or
 5~10mg for 12~14days every
1~2months
Oral micronized progesterone
R
(utrogestan )
 100mg daily or
 200mg for 12~14days every
1~2months
Progesterone suppositories
(progest R )
 50mg daily or
 100mg 12~14days every
1~2 months
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
 Mosaicism and gonadal streak
: ovulation (+), able to conceive either spontaneously or after
the institution of estrogen replacement therapy
 17α –hydroxylase deficiency
– corticosteroid and estrogen replacement
– If uterus(+) : progestin supply
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
 Aim of therapeutic measures
: correcting the primary cause of amenorrhea
– Craniopharyngiomas
: resected with a transphenoidal approach or during craniotomy depending on
the size of the tumor
– Germinomas
: radiosensitive ( surgery : rare indication )
– Prolactinomas and hyperprolactinemia
: dopamine agonists (bromocriptine or cabergoline)
– malnutrition, malabsorption, weight loss, anorexia nervosa,
exercise amenorrhea, neoplasia, and chronic disease
: specific therapies
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
 Aim of therapeutic measures
: correcting the primary cause of amenorrhea
– Hypogonadotropic hypogonadism of hypothalamic origin
- treated with long-term administration of pulsaile GnRH indwelling catheter
and a portable pump
- cyclic estrogen and progestin therapy at least until sexual maturity is
achieved
- hormone replacement to treat hypoestrogenic symptom
- nonestrogenic regimens
eg. Bisphosphomates
(for maintenance of bone mass and prevention of osteoporosis)
– Kallmann syndrome
: hormone replacement
– Physiologic delay
: reassurance that the anticipated development will occur eventually
Amenorrhea without Secondary Sexual
Characteristics
Treatment of Amenorrhea
 Karyotypes contain a Y cell line
(45,X/46, XY mosaicism, or pure gonadal dysgenesis 46, XY)
– Predisposed to gonadal ridge tumor,
such as gonadoblastomas, dysgerminomas, yolk sac tumors
→ remove gonads to prevent malignant transformation
Amenorrhea
with Secondary Sexual Characteristics
and Anatomic Abnormalities
 Causes
– Anatomic Abnormalities
– Androgen insensitivity
– True Hermaphroditismm
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Anatomic Abnormalities
Anatomic causes of Amenorrhea
Secondary sexual characteristics present
Mullerian anomalies
Imperforate hymen
Transverse vaginal septum
Mayer-Rokitansky-Kuster-Hauser syndrome (MRK syndrome)
Androgen insensitivity
True hermaphrodites
Absent endometrium
Asherman’s syndrome
Secondary to prior uterine or cervical surgery
Curettage, especially postpartum
Cone biopsy
Loop electroexcision procedure
Secondary to infections
Pelvic inflammatory disease
IUD-related
Tuberculosis
Schistosomiasis
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Anatomic Abnormalities
Mayer-Rokistanky-Kuster-Hauser(M.R.K.H.) syndrome
 XX, female
 result of the mullerian ducts failing to form properly early in embryonic
development, its underlying cause is unknown.
 associated with galactose metabolism
 characterized by congenital absence of the uterus and vagina
 associated with
– anomalies of the kidneys ranging from ectopic to congenital absence,
– skeletal abnormalities
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Androgen Insensitivity
 Gynotype : XY
 Phenotype : female
 Male pseudohermaphrodites
(Previously called testicular feminization )
 Defects in the androgen receptor
: gene located on the X chromosome
- absence of the gene that encodes for the androgen receptor
- abnormalities in the binding domains of the receptor
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Androgen Insensitivity
 Develop secondary sexual characteristics but not menses
 Testosterone : range of normal males
☜ antimullerian hormone: present and function (+)
 Internal female (mullerian) structure
(uterus, vagina, fallopian tube) : (-)
 Testes (+) in the abdomen or in inguinal hernias
: normally functioning genes on the Y chromosome
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Androgen Insensitivity

Blind vaginal pouch and scant or
absent axillary and pubic hair

Abundant breast development at
puberty


nipples : immature
areolae : pale
 Eunuchoidal tendency
(long arms with big hands and feet)
Figure 27. 2
A : A well-developed patient with complete androgen insensitivity
Note the characteristic paucity of pubic hair and well-developed breast
B : Another patient with andtrogen insensitivity syndrome with a contrasting thin
body hiatus. This is a 17-uear-old twin 46,XY.
Cause of Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
True Hermaphroditism
 XX, XY and mosaic genotypes
 Both male and female gonadal tissue ( +)
 External genitalia : ambiguous
 Breast development (+)
 15% of XX true hermaphrodites : have SRY translocation
10% of XX true hermaphrodites : have Y chromosomal
mosaicisism within the gonad
Amenorrhea
with Secondary Sexual Characteristics
and Anatomic Abnormalities
Diagnosis
Treatment
Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Diagnosis
Imperforate hymen
Physical Examination
Others
presence of a bulging membrane
that distend during Valsalva
maneuver
USG or MRI : useful
skeletal malformation exam
IVP for renal abnormalities
Transverse septum or blind vaginal pouch in a male
complete absence of pseudohermaphrodite : difficult
the cervix and uterus to differentiate
in a female
karyotype determination
(Y chromosome)
Absent endometrium
not diagnosed by P.Ex
Evaluation of endocrine
abnormalities
(estrogen & progesterone
challenge test)
Asherman syndrome
not diagnosed by P.Ex
HSG,
saline infusion
USG
Hysteroscopy
Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Treatment
 Imperforate hymen
: making a cruciate incision to open the vaginal orifice
 Transverse septum : surgical remove
 Hypoplasia or absence of the cervix in the presence of a
functioning uterus
: surgery to repair the cervix : not successful
→ hysterctomy is required
 Vagina : absent or short
: progressive dilation is usually successful in making it
functional
Amenorrhea with 2nd sexual characteristics and Anatomic Abnormalities
Treatment
 Complete androgen insensitivity
: testes removed after pubertal development is complete to prevent
malignant degeneration
 Asherman syndrome
– removed using hysteroscopic resection with scissors or
electrocautery
– pediatric foley catheter : placed in the uterine cavity for
7~10days postop
– a 2-month course of high –dose estrogen therapy with monthly
progesterone withdrawal is used to prevent reformation of
adhesions
Amenorrhea
with Secondary Sexual Characteristics
and Nonanatomic Causes
Cause
Cause
 Ovarian failure
 Anorexia Nervosa
 Pituitary / Hypothalamic Lesions
 Exercise
 Altered Hypothalamic
Gonadotropin –releasing
Hormone secretion
 Stress-induced Disorder
 Weight Loss and Dieting
 Other Hormonal Factors
 Obesity
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Causes of Ovarian failure after Development of Secondary Sexual Chracteristics
Chromosomal etiology
Iatrogenic Causes
Radiation
Chemotherapy
Surgical alteration of on blood supply
Infections
Autoimmune disorders
Galactosemia (mild form or heterozygote)
Savage syndrome
Cigarette smoking
Idiopathic
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
 Normal : menopause
– Age of menopause : determined by genetic inheritance
 Premature ovarian failure
– ovarian failure <40years (1~5% of women)
– cause : decreased follicular endowment or accelerated
follicular atresia
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Cause
 Cigarette smoking
– Alters both gametogenesis and hormonogensis
– Inverse dose-response relationship with age of menopause
 Sex chromosome disorders
– Deletion of the X chromosome (Turner syndrome)
: associated with premature ovarian failure despite normal
development of the ovaries
– d/t accelerated atresia of the follicles
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Cause
 Fragile X carriers
– Cause of inherited (X-linked) mental retardation
– 4-5% of premature ovarian failure
– If premature ovarian failure is present in another family member, the
chance of finding a premutation increases to 15%
 Iatrogenic causes
– radiation,
sterility dose : 800cGy,
ovarian failure :150cGy in some pts. esp. >40yrs
– chemotherapy (esp. alkylating agents : cyclophosphamide)
– surgical interference with ovarian blood supply,
– infection
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Cause
 Infections
– Mumps
– Tubo-ovarian abscess
: follicular destruction and premautre ovarian failure
 Autoimmune Disorders
– Part of a polyglandular autoimmune syndrome
– Myasthenia gravis,
– Idiopathic thrombocytopenia purpura (ITP)
– Rheumatoid arthritis,
– Vitiligo,
– Autoimmune hemolytic anemia
– Diabetes mellitus
– Other autoimmune disorder
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Cause
Galactosemia
 Lack of functional galactose-1-phosphate
uridyl transferase (GALT)
 Galactose metabolites
: toxic effects on ovarian follicles causing
premature destruction
 associated cataracts, MR
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Ovarian Failure
Cause
 Savage syndrome
– Gonadotropin resistance,
– Likely d/t FSH receptor dysfunction
– High level of FSH and LH levels
– Biopsy : not advised
 Autosomal gene mutations
– Associated with hearing loss in Perrault syndrome
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Pituitary / Hypothalamic Lesions
Pituitary and Hypothalamic Lesions
Pituitary and Hypothalamic
Craniopharyngioma
Germinoma
Tubercular granuloma
Sarcoid granuloma
Dermoid cyst
Pituitary
Nonfunctioning adenoma
Hormone-secreting adenomas
Prolactinoma
Cushing’s desease
Acromegaly
Primary hyperthyroidism
Infarction
Lymphocytic hypophysitis
Surgical or radiologic ablations
Sheehan’s syndrome
Diabetic vasculitis
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Pituitary / Hypothalamic Lesions
Hypothalamic Tumors




Craniopharyngiomas (m/c),
Germinomas,
Tubercular or sarcoid granulomas,
Dermoid cysts
→ prevent appropriate hormonal secretion
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Pituitary / Hypothalamic Lesions
Pituitary Lesions

Hypopituitarism : rare
: d/t large portion of the gland must be destroyed before decreased
hormonal secretion affects the patient clinically
– Gland destroyed by tumors (nonfunctioning or hormone secreting)
– Infarction
– infiltrating lesions such a lymphocytic hypophysitis,
granulomatous lesions, and surgical or radiologic ablations
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Pituitary / Hypothalamic Lesions
Pituitary Lesions
 Sheehan syndrome
– Associated with postpartum necrosis of the pituitary
resulting from a hypotensive episode
– Pituitary apoplexy : severe form
– Severe : retro-orbital headache or abnormalities in visual
fields and visual acuity
– Mild
: not lactate, lose pubic and axillary hair,
not menstruate after delivery
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Pituitary / Hypothalamic Lesions
Pituitary Lesions
 Diabetic vasculitis and sickle cell anemia
 Prolactinomas
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
Abnormalities Affecting Release of Gonadotropin-Releasing Hormone
Variable estrogen status
Euestrogenic states
Anorexia nervosa
Obesity
Exercise-induced
Hyperandrogenism
Stress-induced
Polycystic ovary syndrome
Pseudocyesis
Cushing’s syndrome
Malnutrition
Congenital adrenal hyperplasia
Chronic diseases
Androgen-secreting adrenal tumors
Diabetes mellitus
Androgen-secreting ovarian tumors
Renal disorders
Granulosa cell tumor
Pulmonary disorders
Idiopathic
Liver disease
Chronic infections
Addison’s disease
Hyperprolactinemia
Thyroid dysfunction
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
GnRH : Gonadotropin releasing hormone
TRH :Thyrotropin releasing hormone
CRH:corticotrophic releasing hormone,
ACTH adrenocorticotrophic hormone,
GHRH : Growth hormone releasing hormone
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
The pulsatile secretion of GnRH in the follicular
and luteal phases of the cycle

Pulsatile secretion of GnRH caries in
both frequency and amplitude
throughout the menstrual cycle and
tightly regulated

Follicular phase
: frequency and amplitude of pulses↑

luteal phase
: frequency ↓ and amplitude↑↑↑
– pulse frequency ↓
: LH secretion ↓& FSH ↑
– Important aspect of enhancing
FSH availability in late luteal phase
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
 Abnormal secretion of GnRH : 1/3 of patients with amenorrhea
 Chronic disease, malnutrition, stress, psychiatric disorders,
exercise
: inhibit GnRH pulses → altering the menstrual cycle.
 Hyperprolactinemia, Cushing disease (excess ACTH),
acromegaly (excess GH),
: secreted excess pituitary hormones
→ inhibit GnRH secretion
GnRH pulsatility ↓ : severe amenorrhea
Less severe alterations in GnRH pulsatility : anovulation
Slight defects in the pulsatility : luteal phase defect
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
 Leptin
– hormone secreted by adipocytes that is involved in energy
hemostasis
– Receptors : in the hypothalamus and bone
– correlate with nutritional changes and body mass index
– Leptin level ↓
: associated with hypothalamic amenorrhea
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Weight Loss and Dieting
Loss of 10% body mass in 1year
: associated with amenorrhea
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Anorexia Nervosa
 Eating disorder : affects 5% ~ 10% of adolescent women in the US
 Criteria for diagnosis
(Diagnostic and Statistical Manual of Mental Disorders -DSM-IV-)
– Refusal to maintain body weight above 15% below normal
– An intense fear of becoming fat
– Altered perception of one’s body image
(ie. Patients see themselves as fat despite being underweight)
– Amenorrhea
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Anorexia Nervosa
 Attempt to maintain their low body weight by food restriction,
induced vomiting, laxative abuse, and intense exercise.
 Mortality rate : 9%
 Combinations of restrictive and binge eating
 Binge eating : associated with bulimia consisting of vomiting,
laxative abuse, and diuretics to control weight.
 Signs of bulimia : tooth decay, parotid gland hypertorph
(chipmunk jowls), hypokalemia, metabolic alkalosis
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Exercise
 Decreased in the frequency of GnRH pulses
 Assesed by measuring a decreased frequency of LH pulse
 Hypoestrogenic state
 Runners and ballet dancers > swimmer (high risk)
(differences in body-fat content have been used to explain the different rates of
amenorrhea by sport)
– minimum of 17% of body fat is required for the initiation of menses
– 22% body fat for the maintenance of menses
 Higher-intensity training, poor nutrition, stress of competition,
and associated eating disorders increase an athlete’ risk for
menstrual dysfunction
–
Female athlete triad
• amenorrhea,
• osteoporosis,
• eating disorder
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Stress-induced Disorders
Caused by abnormalities in neuromodulation in hypothalamic
GnRH secretion
(similar to those that occur with exercise and anorexia nervosa )
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Obesity
 >8.4% in women above 75% ideal body weight : menstrual disorder
 Obese women
– Excess number of fat cells in which extraglandular
aromatization of androgen to estrogen occurs
– Lower circulating levels of sex hormone-binding globulin
: allows a larger proportion of free androgens to be converted to
estrone
– Excess estrogen : risk for endometrial cancer for these women.
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Other Hormonal Factors
 PCOS
– irregular bleeding rather than amenorrhea
– one of the most common causes of amenorrhea
– result of peripheral alteration in IGF-1, androgen, estrogen
levels, which leads to hypothalamic dysfunction
 Elevations in androgens (eg. Sertoli-Leydig, hilus and lipoid cell
tumors) and estrogens (e.g. granulosa cell tumors) by ovarian
tumors
: lead to abnormal menstrual patterns, including amenorrhea
 Excess secretion of GH, TSH, ACTH and prolactin from pituitary
gland
: cause abnormal feedback inhibition of GnRH secretion leading to amenorrhea
Amenorrhea
with Secondary Sexual
Characteristics and Nonanatomic
Causes
Diagnosis
Treatment
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnosis
 Pregnancy test (urine or S-hCG)
 Pregnancy (-)
– Serum TSH
– Serum prolactin
– FSH levels
– Estrogen status
– Imaging of the pituitary and hypothalamic assessment as
necessary
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnostic work-up
Pregnancy test (-)
Both normal
Progesterone challenge test
• medroxyprogesterone acetate, (MPA)
Check TSH &
5mg or 10mg for 10dsys po prolactin
level
100~200 mg progesterone in oil IM
→ withdrawal bleeding within 2~10days
Normal PRL
after the last dose
abnormal TSH
• Serum estradiol > 40pg/mL
Progesterone
challenge test
Normal TSH
Abnormal PRL
Thyroid disease
Withdrawal bleeding (+)
Withdrawal bleeding(-)
Normogonadotropic
hypogonadism
Estrogen /Progesteron
challenge test
Withdrawal
bleeding (+)
•2.5mg conjugated PRL < 100pg/mL
estrogen or 2mg
micronized estradiol,
for 25days with 5~10mg
of MPA for the last
Consider others
10days
Outflow
obstruction
FSH>20IU/L
LH > 40IU/L
FSH&LH<5 IU/L
Hypergonadotropic
hypergonadism
MRI to evaluate for
pituitary tumor
Normal MRI
Hypogonadotropic
hypogonadism
Perform MRI to evaluate
for prolactinoma
MRI (-)
Consider others
Withdrawal
bleeding(-)
Check FSH &
LH level
PRL >100pg/mL
Asherman syndrome
confirmed by showing filling
defects on HSG or by
visualizing adhesions with
hysteroscopy
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnosis
Follicle-stimulating Hormone Levels
 S-FSH > 25~40mIU/mL (on at least two blood samples)
: hypergonadotropic amenorrhea
 Dx for cause of ovarian failure
– History : chemotherapy, radiation therapy
– Galactose 1 phosphate uridyl transferase (GALT) level
– Fragile X carrier status
– Karyotype (<30years of ages) : presence of a Y cell line
– autoimmune disorder
– Ovarian biopsy : not advised
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnosis
Follicle-stimulating Hormone Levels
 Extent of an autoimmune workup required for a patient with
ovarian failure
– Screening with nonspecific test (ANA, RA, ESR)
– Normal PTT : exclude lupus anticoagulant
– Serum electrolytes, calcium, phosphorus concentrations
: evaluate possibility that parathyroid autoantibodies are active
– TSH, antithyroglobulin antibodies, antimicrosomal antibodies
– 24hr urinary free cortisol
: detect the presence of antiadrenal antibodies
– Parietal cell antibodies, islets of Langerhans antibodies and
antiadrenal antibodies : unclear
→ repeated yearly d/t transient nature of autoimmune disorders
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnosis
Assessment of the Pituitary and Hypothalamus
 Hypoestrogenic & FSH level : not high
→ pituitary and hypothalamic lesions should be excluded
– A complete neurologic examination
– CT or MRI
– After anatomic lesions have been excluded, the patient’s history
of weight changes, exercise, eating habits, body image, and career or
school achievements are important factors in differentiating anorexia
nervosa, malnutirition, obesity or exercise-induced or stress-induced
menstrual disorders.
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Diagnosis
 Hypothalamic dysfunction caused by chronic disease, anorexia
nervosa, stress, and malnutrition
– may be more severe or
– may exist for a more prolonged time in hypoestrogenic
patients than in euestrogenic patients.
 Appropriate clinical findings
– Androgen levels (hirsutism…)
– IGF-1 levels : Acromegaly
– 24hr urinary cortisol
: Cushing syndrome ( truncal obesity, hypertension,
erythmatous striae)
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
 Thyroid abnormalities
: thyroid hormone, radioactive iodine, antithyroid drugs
 Hyperprolactinemia
: dopamine agonists (bromocriptine or cabergoline)
 Surgery for particularly large pituitary tumors
 Ovarian failure : hormone replacement
 Y cell line(+) : Gonadectomy
 Surgical removal, radiation therapy, or a combination of both is
generally advocated for treatment of central nervous tumors
other than prolactinoma
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Treatment of amenorrhea associated with hypothalamic dysfunction

Hormonally active ovarian tumors : surgical removed

Obesity, malnutrition or chronic disease, Cushing syndrome and
acromegaly : specially treat

Pseudocyesis and stress-induced amenorrhea
: respond to psychotherapy

Exercise–induced amenorrhea
: improve with moderation of activity and weight gain, when
appropriate

Anorexia nervosa : demands a multidisciplinary approach
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Treatment of amenorrhea associated with hypothalamic dysfunction
 Chronic anovulation or PCOS : treated after identifying the
desires of the patient (menstruation, hirsutism or infertility)
– endometrium should be protected from the environment of
unopposed estrogen
– oral contraceptives or progestin
– Estrogen +progestin replacement for successful menstrual
regulation and prevention of osteoporosis
Medroxyprogessterone acetate (10mg for 10days/month)
 Congenital adrenal hyperplasia
: glucocorticoid administration (ie. Dexamethasone 0.5mg at bedtime)
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Hirsutism
 R/O androgen-secreting tumors, congenital adrenal hyperplasia
 Aim of treatment : decreasing coarse hair growth
– Oral contraceptives
– Antiandrognes
• Spironolactone Flutamide
• Cyproterone acetate (strong progestin)
– GnRH Agonist
• Add-back therapy
– 5α- reductase inhibitors
– Eflornithine hydrochloride (topical cream)
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Ovulation Induction
Clomiphene citrate : 1st choice for ovulation induction
 Relative safety, efficacy, route of administration (oral), relatively
low cost
 Indication
– adequate levels of estrogen and normal FSH and prolactin,
– inappropriate gonadotropin release
(an increased LH-to-FSH ratio ie. PCOS)
 Pregnancy rate : 40%
 Rate of expected ovulation : 80%
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Ovulation Induction
Clomiphene citrate : 1st choice for ovulation induction
 Contraindication
: pregnancy, liver disease, pre-existing ovarian cysts
 Side effects
: hot flashes(>11% of pts), poorly understood visual symptoms
 Incidence of multiple gestation : 6.25~12.3%
 Regimen
– 50mg daily for 5days
– beginning on the 3rd~5th day of menstrual or withdrawal
bleeding
Amenorrhea with 2nd sexual characteristics and Nonanatomic causess
Treatment
Ovulation Induction
 Longer courses of clomiphene citrate
: adjunctive therapy with glucocorticoids and hCG
 PCOS : insulin resistance – insulin sensitizing agents
(biguanide metformin and thiazolidinediones)
 Injectable gonadotropins
– FSH
– Complication : multiple pregnancy (10~30%)
 GnRH
: chronic anovulation associated with low levels of estrogen and
gonadotropins
 Ovarian failure and desire pregnancy ; oocyte donation
 Continual pulsatile secretion of GnRH is necessary
 d/t extremely short half life (only 2~4 minutes) – rapid
proteolytic cleavage
 Continual infusion : gonadotropin secretion (-) downregulation
 - the number of gonadotroph cell surface GnRH receptor ↓
 Palsatile pattern : led to physiologic secretion patterns and
follicular growth, upregulate or autoprime
 - The gonadotroph to increase its number of GnRH receptors
 Pulsatile secretion of GnRH caries in both frequency and
amplitued throughout the menstrual cycle and tightly regulated
 Follicular phase : increase in both frequency and amplitude of
pulses
 During luteal phase : progressive lengthening of the interval
between pulses and amplitude higher