Physiological Basis of Central Amenorrhea

1
Physiological Basis of Central Amenorrhea

• R. Jeffrey Chang, M.D.
• Department of Reproductive Medicine

2
PVN
MPO
GnRH Neuron System
AH
GnRH
Hypothalamus
AN
OVLT
Median Eminence
Superior Hypophysial Artery

Pituitary Stalk
GnRH
Portal Venous Plexus
Anterior Pituitary
LH, FSH
3
Pituitary Defects

• Anatomical
• Functional

4
Stalk
Optic nerve
Pituitary
Sella turcica
Sphenoid sinus
Sagittal View of the Sella Turcica
5
Pituitary Stalk
Optic Chiasm (Optic nerve)
Cavernous Sinus
Pituitary Gland
Cranial nerves (III, IV, V, VI)
Carotid Artery
Sphenoid Sinus
Sella Turcica
6
Clinical Presentation
36 year old woman wants to become pregnant but
hasnt menstruated in a year. Her main complaint
is headache which has grown worse over the past
several months. She also has fatigue. When asked
about vision, she says its like looking through
a tunnel with limited peripheral sight. Her
husband has fathered children in the past.
7
Anatomic Pituitary Defects

• Non-functional tumors
• Pituitary necrosis
• (Sheehans Syndrome)
• Empty sella syndrome
• Infiltrative diseases
• Head trauma and irradiation

GnRH
LH, FSH
8
Non-Functional Pituitary Tumors

• Microadenoma ( 10 mm)
• Usually asymptomatic
• May compress pituitary stalk
• Macroadenoma (gt 10 mm)
• Optic nerve compression
• Hypothalamic extension
• Infarction (headache)
• Destroy pituitary cells

9
Normal Pituitary Gland
Pituitary Gland
Pituitary Stalk
Sella Turcica
10
Pituitary Microadenoma
Microadenoma
Pituitary Stalk
Pituitary Gland
11
Large Pituitary Macroadenoma Lat View
12
Large Pituitary Macroadenoma AP View
13
Left Visual Field
Right Visual Field
RM
LM
LL
RL
Right eye
Left eye
Optic chiasm
Optic nerve
Brain
LL
RL
LM
RM
Optic Tract
14
Left Visual Field
Right Visual Field
RM
LM
LL
RL
Right eye
Left eye
Optic chiasm
Optic nerve
Pituitary Tumor
Brain
Narrowed or tunnel vision (bitemporal
hemianopsia)
LL
RL
LM
RM
Optic Tract
15
Sheehans Syndrome

• Acute necrosis of anterior pituitary
• Post-partum hemorrhage
• Failed lactation (? PRL)
• Fatigue (? TSH)
• Hypotension (? ACTH)
• Sexual hair loss (? LH/FSH)

16
Functional Pituitary Defects

• Hormone producing tumors
• Gonadotropin deficiency

17
Anterior Pituitary Hormone Secretion
TSH
ACTH
PRL
FSH, LH
GH
Growth Hormone
Thyroid
Cortisol
Estrogen
Prolactin
Acromegaly
Galactorrhea
Hyper-thyroidism
Cushings Syndrome
Uterine Bleeding
18
Clinical Presentation
23 year old woman recently noticed milky
discharge from her breast. She also confided that
her periods had been scant for several years
until complete cessation 9 months ago. There have
been no headaches, use of birth control pills, or
any other drugs. She is a graduate student in
otherwise good health. Her exam reveals
expressible milk from both breast and a normal
pelvic exam. She is 56 and weighs 135 lbs.
19
Clinical Presentation
The work-up reveals the following FSH 3
mIU/ml (2-10) E2 21 pg/ml
(30-250) TSH 2.5 µU/ml
(0.5-5.5) PRL 128 ng/ml
(3-24) MRI Pituitary microadenoma, 8 mm
20
Regulation of Prolactin Secretion
DA
GnRH
PRL
LH, FSH
Breast Ovary
21
Hyperprolactinemic Anovulation
DA
GnRH
DA
GnRH
LH, FSH
PRL
LH, FSH
PRL
Breast Ovary
Breast Ovary
22
Isolated Gonadotropin Deficiency Molecular
Mechanisms

• Subunit genes
• Inactivating mutations
• Receptor genes
• Inactivating mutations
• Polymorphisms

23
Isolated FSH Deficiency
FSH ?-subunit gene Women I amenorrhea,
hypogonadism FSH receptor gene Women Some
pubertal development, normal adrenarche,
follicles present, hypergonadotropic
24
Primary Amenorrhea Caused by Inactivating
Mutation of FSHß-subunit Gene

• Infertility, low FSH, and normal LH
• No menarche or thelarche, but normal adrenarche
  
• Altered aa sequence followed by premature
• stop codon
• Translatable protein truncated and unable
• to associate with common a-subunit to form
  bioactive hormone

Matthews CH, Nat Genet, 1993
25
Isolated LH Deficiency

• LH ?-subunit gene
• Men Hypogonadotropic hypogonadism
• Women Luteal insufficiency and infertility
• LH receptor gene
• Men I hypogonadism to ambiguous
  genitalia
• Women I amenorrhea, normal breast,
  high LH, high normal FSH

26
External Genitalia in Mutated LH Receptor Gene in
a 46, XY Infant
Single nucleotide insertion in exon 11 (frame
shift) and premature termination of amino acid
translation Defective LH receptor led to Leydig
cell hypoplasia and insufficient T and DHT
synthesis. Normal female genitalia with testes.
Richter-Unruh A et al, Eur J Endocrinol, 2005
27
Hypothalamic Defects

• Anatomic
• Functional

28
Anatomic Hypothalamic Defects

• Tumors (Craniopharyngioma)
• Infiltrative diseases
• Trauma (pituitary stalk)
• Irradiation

29
Craniopharyngioma

• Common sellar neoplasm of children and 1/3
  occur in adults
• Derived from Rathkes cleft (origin of
• pituitary gland)
• Slow and aggressive growth (metastasize)
• Cyst formation is common and calcification is
  seen in 50

30
Craniopharyngioma
31
Functional Hypothalamic Defects

• Nutritional - weight loss
• Exercise
• Psychogenic stress
• GnRH receptor gene mutation
• Psychiatric disorders
• Familial disorders

GnRH
LH, FSH
32
Body Weight and Menstrual Function
40 - 30 - 20 - 10 - 0 -
Amenorrhea Prevalence ()
Integrity of menstrual function depends the
lean-fat ratio in body weight with at least 22
required for normal menses (Frisch and McArthur,
74)
45 50 54
58
Fat Thin
Total Water/Body Weight ()
33
Exercise and Menstrual Function
50 - 40 - 30 - 20 - 10 - 0 -
Runners (15 body fat)
Amenorrhea Prevalence ()
Swimmers (20 body fat)
0 20 40 60
80
Training (miles per week)
Sanborn et al, Am J Obstet Gynecol, 1982
34
Effect of Exercise on Menarche
Age at Menarche (years)
9 10 11 12 13 14 15 16
Training
Before
After
Controls
General Population (1976)
Frisch et al, J AM Med Assn, 1981
35
LH Pulse Secretion in Normal and Athletic
Amenorrheic Women
Normal









Serum LH, IU/L
Opiodergic
0800 1000 1200 1400 1600
1800 2000
GnRH
Athlete



Serum LH, IU/L
0800 1000 1200 1400 1600
1800 2000
LH, FSH
Clock Hour
36
Psychiatric Disorders

• Anorexia nervosa
• Pseudocyesis

37
Anorexia Nervosa

• Weight loss leading to body weight less than 85
  of
• that expected
• Intense fear of gaining weight or becoming fat
• Disturbance in the way ones body weight or
  shape is
• experienced or denial of the seriousness of
  low body
• weight
• Amenorrhea
• Types
• Restrictive type
• Binge eating/Purging type

38
Anorexia Nervosa
Symptom/Sign Percent Amenorrhea
100 Hypotension 86
Hypothermia 64 Constipation
62 Dry Skin 62
Lanugo 52 Bradycardia
26 Edema 26
Warren, Am J Obstet Gynecol, 1973
39
Anorexia Nervosa

• Extreme weight loss
• Amenorrhea
• Bulimia
• Low blood pressure
• Distorted body image

40
Deception and Distortion of Body Image?
41
Hypogonadotropic Hypogonadism

• Kallmans syndrome
• Laurence-Moon- Biedl syndrome
• Idiopathic hypogonadotropic hypogonadism

42
Kallman's Syndrome

• 27 year old
• Primary amenorrhea
• Hyposmia
• Lack of secondary
• sexual development
• Color blindness

43
ETIOLOGY OF KALLMAN SYNDROME GnRH neurons
originate in the olfactory epithelium (the
vomeronasal organ) in the nasal rudiment and
migrate to the hypothalamic region of the brain
during fetal development.
44
Kallmann Syndrome

• KAL1
• X-linked
• Familial transmission
• KAL1 (Xp22.3) mutation
• Anosmin-1

• KAL2
• Autosomal dominant
• Sporadic cases
• FGFR1 (8p12) mutation
• FGF receptor 1

45
Lawrence-Moon-BiedlBardet Syndrome

• Amenorrhea
• Retinitis pigmentosa
• Obesity
• Mental retardation

46
Lawrence-Moon-BiedlBardet Syndrome

• 31 year old female
• Primary amenorrhea
• Retinitis pigmentosa
• Legally blind
• Lack of secondary
• sexual development

47
Lawrence-Moon-BiedlBardet Syndrome
Retinitis Pigmentosa
48
Idiopathic Hypogonadotropic Hypogonadism

• Mutated Genes
• DAX 1
• (X-linked, adrenal hypoplasia congenita)
• Leptin/Leptin receptor
• (autosomal dominant)
• GnRH receptor (GPR54)
• (autosomal dominant)