Chapter 27. Amenorrhea

1
Chapter 27. Amenorrhea

• Berek Novaks Gynecology
• 14th edition (p 10351068)
• R3 Jung Mi Byun

2
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

3
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)
  

4
Overview

• Treatment
• ltGoal gt
• 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

5
Overview
Anterior suprachiasmatic nucleus
Posterior arcuate nucleus
Normal menstrual cycle
6
Overview

• Amenorrhea Mechanism
• any of the components nonfunctional
• ? bleeding cannot occur. (Amenorrhea)
• Amenorrhea 34 of reproductive age women, not
  pregnant.

hypothalamus, pituitary, ovary, outflow tract,
feedback mechanism
7
Decision tree for evaluation of amenorrhea.




Physical exam



) No Yes
)

High Normal

Karyotype Karllmans syndrome Physiology delay Disorders of low estrogen status before puberty
Karllmans syndrome Physiology delay Disorders of low estrogen status before puberty
XX Y line Turners (XO) Karllmans syndrome Physiology delay Disorders of low estrogen status before puberty
Secondary sexual characteristics
Absent
Present
HCG
HCG -
Normal
Absent uterus
Pregnancy
Primary

• 5a-reductase
• deficiency
• 17-20 desmolase
• deficiency
• 17a-hydroxylase
• deficiency (all with
• XY karyotype)

FSH level
8
Primary

No Yes

Secondary if risk of endometial scarring advise HSG culrutres to exclude Ashermans, cervical stenosis and infection Physical exam
Secondary if risk of endometial scarring advise HSG culrutres to exclude Ashermans, cervical stenosis and infection
Secondary if risk of endometial scarring advise HSG culrutres to exclude Ashermans, cervical stenosis and infection Normal Abnormal

TSH, PRL, FSH, Clinical evaluation of estrogen status Mullerian anomaly Androgen insensitivity True hermaphroite

Normal TSH Abnormal TSH

High PRL Hyperthyroidism Hypothyroidism

Normal PRL Hyperprolactinemia
9
Normal PRL

Normal FSH High FSH

Normal estrogen Low estrogen Ovarian failure- chromosomal radiaton chemotherapy infection autoimmune Galactosemia Savage syndrome Idiopathic
Ovarian failure- chromosomal radiaton chemotherapy infection autoimmune Galactosemia Savage syndrome Idiopathic
Chronic anovulatory Polycystic ovarian syndrome Idiopathic Ovarian neoplasm Grandulosa cell androgen- secreting Feedback disorders Obesity Cushing syndrome Androgen-secreting adrenal tumors Congenital adrenal hyperplasia Neurological exam CT/MRI, EEG Ovarian failure- chromosomal radiaton chemotherapy infection autoimmune Galactosemia Savage syndrome Idiopathic
Chronic anovulatory Polycystic ovarian syndrome Idiopathic Ovarian neoplasm Grandulosa cell androgen- secreting Feedback disorders Obesity Cushing syndrome Androgen-secreting adrenal tumors Congenital adrenal hyperplasia
Chronic anovulatory Polycystic ovarian syndrome Idiopathic Ovarian neoplasm Grandulosa cell androgen- secreting Feedback disorders Obesity Cushing syndrome Androgen-secreting adrenal tumors Congenital adrenal hyperplasia Normal Abnormal

Chronic disease pulmonary renal liver diabetes Addisons disease Hypothalamic dysfunction Anorexia Exercise-induced Stress Pseudocyesis Malnutrition Pituitary-hypothalamic lesions tumors infection infarction pituitary failure Sheehans Diabetic vasculitis Toxic-lead
10

• Amenorrhea
• without Secondary Sexual Characteristics
• Amenorrhea
• with Secondary Sexual Characteristics
• and Anatomic Abnormalities

11
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 .

12
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

13
Table 27.1 Amenorrhea Associated with a Lack of
Secondary Sexual Charateristics
Cause of Primary Amenorrhea
Abnormal physical examination
5a-reductase deficiency in XY individual
17, 20-desmolase deficiency in XY individual
17a-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
17a-hydroxylase deficiency in XX individual
Galactosemia
Other
Hypogonadotropic hypogonadism
Physiologic delay
Kallmanns syndrome
Central nervous system tumors
Hypothalamic/pituitary dysfunction
14
Hypergonadotropic Hypogonadism
Cause of Primary Amenorrhea

• 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

15
Hypergonadotropic Hypogonadism Genetic Disorder
Cause of Primary Amenorrhea

• 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)

16
Hypergonadotropic Hypogonadism Genetic Disorder
Cause of Primary Amenorrhea

• 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-)
  Xq13Xq26
• - 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

17
Hypergonadotropic Hypogonadism Genetic Disorder
Cause of Primary Amenorrhea

• Mosaicism
• 45,X/46XX (m/c)
• Clinical finding taller and fewer abnormalities
  than pure 45,X
• 20 spontaneous menstruation ()

18
Hypergonadotropic Hypogonadism Genetic Disorder
Cause of Primary Amenorrhea

• 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
• lt Swyer syndrome gt
• mutations in the SRY (sex-determining region gene
  on the Y
• chromosome) located at Yp11 result in
  XY females with
• gonadal dysgenesis
• 1520 of women (46,XY)

19
Hypergonadotropic Hypogonadism Genetic Disorder
Cause of Primary Amenorrhea

• 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 )

20
Hypergonadotropic Hypogonadism Enzyme
deficiencies
Cause of Primary Amenorrhea

• 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

21
Hypergonadotropic Hypogonadism Enzyme
deficiencies
Cause of Primary Amenorrhea

• 17a-Hydroxylase 17, 20-Desmolase Deficiency
• mutation in the CYP 17 gene
• ? abnormalities in both the 17 a-hydroxylase and
  17, 20-desmolase 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 ?

22
Hypergonadotropic Hypogonadism Enzyme
deficiencies
Cause of Primary Amenorrhea

• Aromatase Deficiency
• Autosomal recessive abnormality
• 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

Aromatizing
23
Hypergonadotropic Hypogonadism Gonadotropin
receptor Mutations
Cause of Primary Amenorrhea

• 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

24
Other Causes of Primary Ovarian Failure
Cause of Primary Amenorrhea

• Irradiation
• Chemotherapy
• with alkylating agents (e.g.
  cyclophosphamide)
• Combination of radiation and other
  chemothrapeutic agents
• Galactosemia

25
Hypogonadotropic Hypogonadism
Cause of Primary Amenorrhea

• Hypothlamus fails to secrete adequate amounts of
  GnRH
• Pituitary disorder associated with inadequate
  production or release of pituitary gonadotropins
  is present.

26
Hypogonadotropic Hypogonadism
Cause of Primary Amenorrhea

• Physical Delay
• Kallmann Syndrome
• Central Nervous System Tumors

27
Hypogonadotropic HypogonadismPhysiologic Delay
Cause of Primary Amenorrhea

• 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

28
Hypogonadotropic HypogonadismKallmann Syndrome
Cause of Primary Amenorrhea

• 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,

29
Genetic Disorders
Cause of Primary Amenorrhea

• 5a-Reductase Deficiency
• Gnoadotropin-releasing Hormone Receptor Mutations
• Follicle-stimulating Hormone Deficiency

30
Genetic Disorders 5a-Reductase Deficiency
Cause of Primary Amenorrhea

• XY , virilization at puberty,
• Testes() functioning Y chromosomes
• No mullerian structure, d/t functioning AMH
• Low gnoadotropin level
• D/Dxgt 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)

5 a-Reductase Deficiency
31
Genetic Disorders Gonadotropin-releasing Hormone
Receptor Mutations
Cause of Primary Amenorrhea

• GnRH receptor G-protein-coupled receptor
• Abnormal GnRH function
• 17 of sporadic cases of idiopathic
  hypogonadotropic
• hypogonadism with normal olfaction

32
Genetic Disorders Follicle-stimulating Hormone
Deficiency
Cause of Primary Amenorrhea

• 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

33
Other Hypothalamic / Pituitary Dysfunctions
Cause of Primary Amenorrhea

• Malnutrition
• Malabsorption
• Weight loss
• Anorexia nervosa
• Excess ecercise
• Chronic disease
• Neoplasia

• Marijana
• Hypothyroidism
• Polycystic ovarian syndrome (PCOS)
• Cushing syndrome
• Hyperprolactinemia
• infiltrative disorders of the central nervous
  system

34
Amenorrhea without Secondary Sexual
Characteristics

• Diagnosis
• Treatment

35
Diagnosis
Amenorrhea without Secondary Sexual
Characteristics

• 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)
• Headache,
• visual disturbance,
• short stature, symptoms of diabetes insipidus,
• weakness of limbs
• Galactorrhea
• Physical Examination

Physical delay
CNS lesion
36
Diagnostic workup
Amenorrhea without Secondary Sexual
Characteristics
History P.Ex (-) History P.Ex (-) History P.Ex (-)

FSH FSH FSH

? (Hypergonadotropic hyporogonadism) ? (hypogonadotropic hypogonadism)

Karyotype

Abnormal Turner syndrome Partial deletion of the X chromosome, mosaicision, Pure gonadal dysgenesis, Mixed gonadal dysgenesis Normal 17-a hydroxylase deficiency Normal 17-a hydroxylase deficiency
Abnormal Turner syndrome Partial deletion of the X chromosome, mosaicision, Pure gonadal dysgenesis, Mixed gonadal dysgenesis Normal 17-a hydroxylase deficiency Normal 17-a hydroxylase deficiency
Abnormal Turner syndrome Partial deletion of the X chromosome, mosaicision, Pure gonadal dysgenesis, Mixed gonadal dysgenesis

• Coarctation of the aorta (30)
• Thyroid dysfunction
• ? Echocardiography
• every 35yrs
• ? TFT yearly
• Evaluation for
• hearing loss and hypertension

• Serum Progesterone?(gt3.0)
• 17a-hydroxyprogesterone? (0.2ng/mL)
• Deoxycorticosterone (DOS)?
• ? ACTH stimulation test
• ACTH bolus administration
• ?S-progesterone?
• ?17a-hydroxyprogesterone ( - )

37
Diagnostic workup
Amenorrhea without Secondary Sexual
Characteristics

• 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 ?
38
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics

• 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)

39
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics
Initiation conjugated estrogen 0.625mg/day (Premarin ) or estradiol 1mg/day (Progynova ) short stature higher estrogen doses (x) normal stature higher estrogen, after then reduced to the maintenance doses after several months
estrogen progestin (medroxyprogesterone acetate) (Provera ) daily or progesterone to prevent unopposed estrogen stimulation of the endometrium in patients with uterus Medrosyprogesterone acetate 2.5mg daily or 510mg for 1214days every 12months Oral micronized progesterone (utrogestan ) 100mg daily or 200mg for 1214days every 12months Progesterone suppositories (progest ) 50mg daily or 100mg 1214days every 12 months
R
R
R
R
R
40
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics

• Mosaicism and gonadal streak
• ovulation (), able to conceive either
  spontaneously or after
• the institution of estrogen replacement
  therapy
• 17a hydroxylase deficiency
• corticosteroid and estrogen replacement
• If uterus() progestin supply

41
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics

• 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

42
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics

• 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

43
Treatment of Amenorrhea
Amenorrhea without Secondary Sexual
Characteristics

• 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

44
Amenorrhea with Secondary Sexual Characteristics
and Anatomic Abnormalities

• Causes
• Anatomic Abnormalities
• Androgen insensitivity
• True Hermaphroditismm

45
Anatomic Abnormalities
Cause of Amenorrhea with 2nd sexual
characteristics and 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
Ashermans 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
46
Anatomic Abnormalities
Cause of Amenorrhea with 2nd sexual
characteristics and 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

47
Androgen Insensitivity
Cause of Amenorrhea with 2nd sexual
characteristics and Anatomic Abnormalities

• 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

48
Androgen Insensitivity
Cause of Amenorrhea with 2nd sexual
characteristics and Anatomic Abnormalities

• 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

49
Androgen Insensitivity
Cause of Amenorrhea with 2nd sexual
characteristics and Anatomic Abnormalities

• 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.
50
True Hermaphroditism
Cause of Amenorrhea with 2nd sexual
characteristics and Anatomic Abnormalities

• 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

51
Amenorrhea with Secondary Sexual Characteristics
and Anatomic Abnormalities

• Diagnosis
• Treatment

52
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Anatomic Abnormalities
Physical Examination Others
Imperforate hymen presence of a bulging membrane that distend during Valsalva maneuver USG or MRI useful skeletal malformation exam IVP for renal abnormalities
Transverse septum or complete absence of the cervix and uterus in a female blind vaginal pouch in a male pseudohermaphrodite difficult to differentiate 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
53
Treatment
Amenorrhea with 2nd sexual characteristics and
Anatomic Abnormalities

• 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

54
Treatment
Amenorrhea with 2nd sexual characteristics and
Anatomic Abnormalities

• 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 710days postop
• a 2-month course of high dose estrogen therapy
  with monthly progesterone withdrawal is used to
  prevent reformation of adhesions

55
Amenorrhea with Secondary Sexual Characteristics
and Nonanatomic Causes

• Cause
• Ovarian failure
• Pituitary / Hypothalamic Lesions
• Altered Hypothalamic Gonadotropin releasing
  Hormone secretion
• Weight Loss and Dieting

• Cause
• Anorexia Nervosa
• Exercise
• Stress-induced Disorder
• Obesity
• Other Hormonal Factors

56
Ovarian Failure
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
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
57
Ovarian Failure
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Normal menopause
• Age of menopause determined by genetic
  inheritance
• Premature ovarian failure
• ovarian failure lt40years (15 of women)
• cause decreased follicular endowment or
  accelerated
• follicular atresia

58
Ovarian FailureCause
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

59
Ovarian FailureCause
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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.
  gt40yrs
• chemotherapy (esp. alkylating agents
  cyclophosphamide)
• surgical interference with ovarian blood supply,
• infection

60
Ovarian FailureCause
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

61
Ovarian FailureCause
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
Galactosemia

• Lack of functional galactose-1-phosphate
• uridyl transferase (GALT)
• Galactose metabolites
• toxic effects on ovarian follicles causing
• premature destruction
• associated cataracts, MR

62
Ovarian FailureCause
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

63
Pituitary / Hypothalamic Lesions
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
Pituitary and Hypothalamic Lesions
Pituitary and Hypothalamic
Craniopharyngioma
Germinoma
Tubercular granuloma
Sarcoid granuloma
Dermoid cyst
Pituitary
Nonfunctioning adenoma
Hormone-secreting adenomas
Prolactinoma
Cushings desease
Acromegaly
Primary hyperthyroidism
Infarction
Lymphocytic hypophysitis
Surgical or radiologic ablations
Sheehans syndrome
Diabetic vasculitis
64
Pituitary / Hypothalamic Lesions
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Hypothalamic Tumors
• Craniopharyngiomas (m/c),
• Germinomas,
• Tubercular or sarcoid granulomas,
• Dermoid cysts
• ? prevent appropriate hormonal secretion

65
Pituitary / Hypothalamic Lesions
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

66
Pituitary / Hypothalamic Lesions
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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
  

67
Pituitary / Hypothalamic Lesions
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Pituitary Lesions
• Diabetic vasculitis and sickle cell anemia
• Prolactinomas

68
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
Abnormalities Affecting Release of
Gonadotropin-Releasing Hormone
Variable estrogen status Euestrogenic states
Anorexia nervosa Obesity
Exercise-induced Hyperandrogenism
Stress-induced Polycystic ovary syndrome
Pseudocyesis Cushings 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
Addisons disease
Hyperprolactinemia
Thyroid dysfunction
69
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
GnRH Gonadotropin releasing hormone TRH
Thyrotropin releasing hormone CRHcorticotrophic
releasing hormone, ACTH adrenocorticotrophic
hormone, GHRH Growth hormone releasing hormone
70
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion

• 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

The pulsatile secretion of GnRH in the
follicular and luteal phases of the cycle
71
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

72
Altered Hypothalamic Gonadotropic-releasing
Hormone Secretion
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

73
Weight Loss and Dieting
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Loss of 10 body mass in 1year
• associated with amenorrhea

74
Anorexia Nervosa
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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 ones body image
• (ie. Patients see themselves as fat despite
  being underweight)
• Amenorrhea

75
Anorexia Nervosa
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

76
Exercise
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Decreased in the frequency of GnRH pulses
• Assesed by measuring a decreased frequency of LH
  pulse
• Hypoestrogenic state
• Runners and ballet dancers gt 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

77
Stress-induced Disorders
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Caused by abnormalities in neuromodulation in
  hypothalamic
• GnRH secretion
• (similar to those that occur with exercise and
  anorexia nervosa )

78
Obesity
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• gt8.4 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.

79
Other Hormonal Factors
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

80
Amenorrhea with Secondary Sexual Characteristics
and Nonanatomic Causes

• Diagnosis
• Treatment

81
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Pregnancy test (urine or S-hCG)
• Pregnancy (-)
• Serum TSH
• Serum prolactin
• FSH levels
• Estrogen status
• Imaging of the pituitary and hypothalamic
  assessment as necessary

82
Diagnostic work-up
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess
Pregnancy test (-)

Check TSH prolactin level

Both normal Normal PRL abnormal TSH Normal TSH Abnormal PRL

Progesterone challenge test Thyroid disease
PRL lt 100pg/mL PRL gt100pg/mL
Withdrawal bleeding () Withdrawal bleeding(-)

Normogonadotropic hypogonadism Estrogen /Progesteron challenge test Consider others Perform MRI to evaluate for prolactinoma

Withdrawal bleeding () Withdrawal bleeding(-) MRI (-) Consider others

Check FSH LH level Outflow obstruction

FSHgt20IU/L LH gt 40IU/L FSHLHlt5 IU/L

Hypergonadotropic hypergonadism MRI to evaluate for pituitary tumor

Normal MRI Hypogonadotropic hypogonadism

• Progesterone challenge test
• medroxyprogesterone acetate, (MPA)
• 5mg or 10mg for 10dsys po
• 100200 mg progesterone in oil IM
• ? withdrawal bleeding within 210days
• after the last dose
• Serum estradiol gt 40pg/mL

• 2.5mg conjugated estrogen or 2mg micronized
  estradiol, for 25days with 510mg of MPA for the
  last 10days

Asherman syndrome confirmed by showing filling
defects on HSG or by visualizing adhesions with
hysteroscopy
83
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Follicle-stimulating Hormone Levels
• S-FSH gt 2540mIU/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 (lt30years of ages) presence of a Y
  cell line
• autoimmune disorder
• Ovarian biopsy not advised

84
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

85
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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
  patients 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.

86
Diagnosis
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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)

87
Treatment
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

88
Treatment
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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
• Exerciseinduced amenorrhea
• improve with moderation of activity and
  weight gain, when appropriate
• Anorexia nervosa demands a multidisciplinary
  approach

89
Treatment
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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)

90
TreatmentHirsutism
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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
• 5a- reductase inhibitors
• Eflornithine hydrochloride (topical cream)

91
TreatmentOvulation Induction
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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

92
TreatmentOvulation Induction
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• Clomiphene citrate 1st choice for ovulation
  induction
• Contraindication
• pregnancy, liver disease, pre-existing
  ovarian cysts
• Side effects
• hot flashes(gt11 of pts), poorly understood
  visual symptoms
• Incidence of multiple gestation 6.2512.3
• Regimen
• 50mg daily for 5days
• beginning on the 3rd5th day of menstrual or
  withdrawal bleeding

93
TreatmentOvulation Induction
Amenorrhea with 2nd sexual characteristics and
Nonanatomic causess

• 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 (1030)
• GnRH
• chronic anovulation associated with low
  levels of estrogen and
• gonadotropins
• Ovarian failure and desire pregnancy oocyte
  donation

94
Thank you for your attention
95

• Continual pulsatile secretion of GnRH is
  necessary
• d/t extremely short half life (only 24 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