Transcript Neuroendocrine Control of the Menstrual Cycle and Associated Disorders

Neuroendocrine Control of the Menstrual
Cycle and Associated Disorders
James H. Liu, M.D.
Arthur Bill Professor and Chair
Dept. of Reproductive Biology
Case Western Reserve University
University Hospitals of Cleveland
Components of the Reproductive System
Higher Neuronal Centers
Hypothalamic-Pituitary
Ovary
Uterus-Endometrium
Hypothalamic-Pituitary Compartment
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GnRH Pulsatile Administration
ACTION OF GnRH
Physiologic
Decreased GnRH
GnRH (pulsatile)
GnRH
LH
0
Time
(hr)
Decreased LH and FSH
8
Pump
Release of
LH and FSH
Gonads
Conn & Crowley, NEJM 324:93-103, 1991
Components of the Reproductive System
Higher Neuronal Centers
Hypothalamic-Pituitary
Ovary
Uterus-Endometrium
Ovarian Compartment
Follicle Unit
• Theca cell
– LH receptors
– Converts cholesterol to
androstenedione
• Granulosa cells
FSH receptors
LH receptors
Inhibin
HIGHER NEURONAL
SYSTEMS
HYPOTHALAMUS
GnRH
LH
SYNTHESIS OF
ANDROGEN
FSH
INHIBIN
STIMULATES SYNTHESIS OF
ESTRADIOL, PROGESTERONE,
AND INHIBIN
INHIBIN
FSH
RECEPTOR
LH
RECEPTOR
E2
E2
THECA
INTERNA
CELLS
E2
GRANULOSA
CELLS
E2
RECEPTOR
PROGESTERONE
Selection of the Dominant Follicle
Transvaginal Ultrasound
• Follicular cyst
• Premenopausal ovary
Transvaginal Ultrasound
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Regular cycles
L Ovarian Cyst
Dominant follicle
Doppler flow studies
Peripheral Blood flow
Transvaginal Ultrasound
• Corpus luteum cyst
• Folded internal
architecture
• Day 24 or 25 of 28 day
cycle
Hypothalamic-Pituitary Compartment
HIGHER NEURONAL
SYSTEMS
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Opiate system (-)
Noradrenergic system (+)
Dopaminergic system (+)
GABA system(-)
HYPOTHALAMUS
GnRH/DA/OPIATES
• Gonadotropin-releasing
hormone (pulsatile secretion)
• Pituitary Portal Transport
• Activin (+ FSH release)
• LH and FSH
Paracrine Regulation of FSH
HIGHER NEURONAL
SYSTEMS
Medial Basal Hypothalamus
GnRH/DA/OPIATES
LH
Activin
Follistatin
LH + FSH
FSH
Besecke et al. Endocrinology 137:3667, 1996
GnRH-LH Pulsatile Activity
Physiological Activation of the H-P Axis
20
Pubertal Pattern
Transitional Stage
LIGHTS OUT
Prepubertal Pattern
Apulsatile State
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15
10
10
LH IU/L
LH IU/L
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5
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20
LIGHTS OUT
15
LIGHTS OUT
Low Amplitude, Low Amplitude
State
15
10
Early Follicular Phase
Stage
LIGHTS OUT
10
LH IU/L
LH IU/L
5
5
0
20
0
0800
1200
1600
2000
2400
0400
CLOCK HOURS
Liu JH Am J Obstet Gynecol 1990
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0800
1200
1600
2000
2400
CLOCK HOURS
0400
0800
GnRH-LH Activation in Puberty
Boyar R. et al. N Eng J Med 287:582, 1972
Postpartum GnRH-LH Activation
Liu J and Park K J Clin Endocrinol Metab 66:839, 1988
Classification of Anovulation Associated with
CNS Hypothalamic-Pituitary System
• Functional Hypothalamic Anovulation
– Exercise-related factors
– Nutritional factors
– Psychogenic or stress factors
• Overlaps with anorexia nervosa or bulimia
• Physiological Anovulation
– Prepubertal phase
– Postpartum phase
– Breastfeeding phase
Classification of Anovulation Associated with
CNS Hypothalamic-Pituitary System
• Pharmacologic-Associated Anovulation
– Opiate agonist
– Dopamine receptor antagonist
• Psychiatric-Associated Disorders
– Pseudocyesis
– Anorexia nervosa
– Bulimia
Common Features of Psychogenic
Hypothalamic Amenorrhea
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Single marital status
Obsessive-compulsive habits
History of significant stressful life events
History of sexual abuse
History of prior irregular menstrual cycles
Tendency to use sedatives and hypnotic durgs
Involved in professional occupations
High intelligence
Expected Serum Hormonal Parameters in
Functional Hypothalamic Amenorrhea (FHA)
Hormone
FHA
Early Foll Phase
LH (IU/L)
8.5 ± 1.1*
11.6 ± 1.2
FSH (IU/L)
9.3 ± 0.5*
12.1 ± 1.0
PRL (ug/L)
12.2 ± 0.8*
17.1 ± 1.4
TSH (uU/L)
1.05 ± 0.33
1.33 ± 0.26
GH (ug/L)
6.7 ± 1.3
4.2 ± 0.7
Estradiol (pmol/L)
142 ± 15
156 ± 10
ACTH (pmol/L)
1.2 ± 0.2
1.3 ± 0.2
Cortisol (nmol/L)
230 ± 10*
170 ± 10
Testosterone (nmol/L
1.1 ± 0.2
0.9 ± 0.1
T3 (nmol/L)
1.19 ± 0.07*
1.48 ± 0.09
T4 (nmol/L)
59.2 ± 4.4*
79.2 ± 5.1
Hypothalamic Amenorrhea
H-P-Adrenal Axis
Suh B, Liu J, Berga S et al. J Clin Endocrinol Metab 66:733, 1988
Hypothalamic Amenorrhea
LH Secretion
Suh B, Liu J, Berga S. J Clin Endocrinol Metab 66:733, 1988.
Associated Neuroendocrine Abnormalities in
Hypothalamic Amenorrhea
• Increased daytime cortisol secretion
• Increased amplitude and duration of nocturnal
melatonin secretion
• Increased nocturnal secretion of GH
• Elevated CRH levels in cerebral spinal fluid
• Blunted elevation of PRL, ACTH, and cortisol
during the noon meal
Bulimia
• Disorder characterized by alternating episodes of
consumption of large quantities of food over a short time
interval (binge eating) followed by periods of food
restriction, self-induced vomiting, or excessive use of
laxatives or diuretics.
• 90-95% are females
• 4.5-18% incidence among high school and college
students
• Age 17-25 years
Common Features of Bulimia
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Food binge/purge cycles
Irregular menstrual cycles
Dental enamel erosion
Acute irritation of esophageal mucosa
Esophageal or gastric rupture
Hypokalemia
Aspiration pneumonia
Ipecac poisoning
Anorexia Nervosa
• Psychosomatic disorder characterized by the triad
of extreme weight loss (weight decrease of 25%
below ideal body weight; body image distortion;
and in intense fear of becoming obese.
• 0.64-1.12 per 100,000
• 90-95% female
• 12-30 years
• Mortality of up to 9%
Anorexia Nervosa
Liu J (unpublished)
GnRH-LH in Anorexia
Boyar et al. N Engl J Med 291:861, 1974.
Common Behavioral Features of
Anorexia Nervosa
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Preoccupation with handling of food
Bulimic behavior
Calorie counting
Distortion of body self-image
Hyperactivity, obsessive-compulsive personality
Increased incidence of past sexual abuse
Amenorrhea
Constipation
Common Features of Anorexia Nervosa
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Coarse, dry skin
Soft, lanugo-type hair
Hypothermia with defective thermoregulation
Mild bradycardia
Cardiac arrhythmias
Hypotension
Hypokalemia secondary to laxative abuse
Osteopenia
Increased beta-carotene levels
Anemia/leukopenia
Elevated hepatic enzymes
Neuroendocrine Abnormalities
Associated with Anorexia Nervosa
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Diminished GnRH-LH pulsatile frequency and amplitude
Low blood LH and FSH levels
Impaired ACTH response to CRH stimulation testing
Resistance to dexamethasone suppression
Increased ACTH levels
Increased 24 hour urinary free cortisol levels
Low prolactin levels
Low TSH levels/ high reverse T3 and low T3 levels
Elevated GH levels
Decreased IGF-1 levels
Diabetes insipidus
Hypothesis: Stress on GnRH
Secretion
Potential Mechanism(s) for Functional Hypothalamic Amenorrhea, Anorexia, Exercise Amenorrhea
GnRH Neuron
Environmental
Beta Endorphin (-)
Stress (-)
Neuron
CRH
Dopaminergic (-)
CRH
Neurons
GnRH Neuron
Noradrenergic (+)
Neurons
ACTH
Cortisol
Cushing’s Disease and
GnRH-LH Secretion
Liu JH et al. J Clin Endocrinol Metabl 1987
Organic Defects of the HypothalamicPituitary Unit: Hypogonadotropic
Hypogonadism
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Kallmann syndrome
Isolated gonadotropin deficiency
Pituitary tumors
Sheehan syndrome
Pituitary apoplexy
Empty sella syndrome
Inappropriate prolactin secretion
Infection (HIV, tuberculosis)
Head trauma
Post-radiation effects
Tanner Stage I Breast
Tanner Stage II or III Pubic
Hair
Isolated Gonadotropin Deficiency
• Other pituitary functions are normal
• Low LH and FSH and therefore failure to undergo
puberty and secondary sexual development
• Eunuchoid features (tall, slender, long limbs)
• Primary amenorrhea
• Infertile
• Defective sense of smell (Kallmann syndrome)
• Long term treatment is replacement sex hormone therapy
• Short term treatment is pulsatile GnRH or injectable
gonadotropins.
GnRH Pulsatile Administration
Summary
Activation of the H-P Axis:
•Requires GnRH pulse activity every 60-120 minute.
•Characterized by sleep-associated rise in LH/FSH.
•Preferential secretion of FSHb, i.e. puberty, postpartum.
Reproductive Dysfunctions:
•Reduction in endogenous GnRH secretion
•Stress, exercise, and anorexia are characterized by
decrease in GnRH pulse activity and increases
in ACTH/cortisol secretion.
Menotropins
Hormone
recFSH
Urinary
LH/FSH
recLH
hCG
P
Tradename Route of
Administration
Gonal F
Subcutaneous
Follistim
Pergonal
Intramuscular
Humagon
Intramuscular
Repronex
IM or SC
Lhadi
Subcutaneous
Profasi
Pregnyl
Novarel
Intramuscular
Injectable Gonadotropins
• Production of urinary gonadotropins requires
menopausal urine donors
• 1 ampule 75 IU of Pergonal requires 1-2 liters of
urine (3.8 liters=1 gallon)
• Serono had 250,000 donors
– 35 worldwide collection centers
– 64 million liters of urine 1997
GnRH Analogues
• Originally derived from the brain hormone
gonadotropin-releasing hormone (GnRH)
• GnRH agonists (Lupron and Synarel) initial
stimulates the pituitary to release LH and FSH,
then induces desensitization.
• GnRH antagonists (Antagon) immediately
inhibits LH and FSH pituitary secretion
Fertility Drugs: GnRH analogues
• Antagon (ganarelix); Cetrotide
– Injection
– GnRH antagonist
• Nafarelin (Synarel)
– Intranasal spray twice per day
– GnRH agonist
• Leuprolide acetate (Lupron)
– Daily subcutaneous injection
– Depot 30 day injection
– GnRH agonist
ACTION OF GnRH AND LONG-ACTING AGONIST
ANALOGUES
Physiologic
Pharmacologic
GnRH agonist daily
GnRH (pulsatile)
GnRH
LH
Agonist
phase
Desensitised
phase
LH
0
Time
(hr)
0
8
Pump
Time
(wk)
4
GnRH agonist
Release of
LH and FSH
Gonads
Conn & Crowley, NEJM 324:93-103, 1991
LH and FSH IU/L
Early
Follicular
Phase
15
10
5
0
20
LH and FSH IU/L
20
15
After
GnRH agonist
antagonist
10
5
0
20
0800
1200
1600
2000
2400
CLOCK HOURS
0400
0800
Applications of GnRH Analogs