Pituitary Dysfunction Flashcards
Pituitary Hormones
The Hypothalamus/Pituitary Gland-Master Gland, whose hormones affects, directly or indirectly, virtually every organ or tissue
a. Anterior Pituitary:
i. Thyroid Stimulating Hormone (TSH)
ii. Adrenocorticotropic hormone (ACTH)
iii. Growth Hormone
iv. Follicle Stimulating hormone (FSH) and Luteinizing hormone (LSH)
v. Prolactin
b. Posterior Pituitary
i. Oxytocin
ii. Anti-diuretic Hormone (ADH)
Pituitary Gland Regulation
Complex Integration Of Signals:
a. Higher CNS Centers
i. Thalamus
ii. Limbic System
iii. RAS
iv. Retina
b. Nutritional Status
c. Hormone Cross-Talk
Growth Hormone Regulation
a. Somatotropin (GH); most abundant pituitary hormone
i. 91 aa , 21kDa protein, Structurally similar to prolactin
ii. Half-life 20-25 minutes
iii. Multiple (6-8) discrete pulses/day
b. In youth, most pronounced with onset of sleep (children: 50-75% during phase 3-4 NREM sleep)
c. Stimulation
- Sleep
- Low glucose
- Exercise
- Stress
- Puberty
- High aa/protein
- GHRH
- Glucagon
- Alpha-adrenergic
d. Suppression
- Somatostatin
- High glucose
- Aging
- FFA
Excess and Deficiency of Pituitary Hormones
- GH
Excess: Acromegaly
Deficiency: GH Deficiency - PRL
Excess: Hypogonadism
Deficiency: Failed Lactation - FSH/LH
Excess: Rarely Clinically Evident
Deficiency: Hypogonadism - ACTH
Excess: Cushing’s Disease
Deficiency: Adrenal Insufficiency - TSH
Excess: Hyperthyroidism
Deficiency: Hypothyroidism - ADH
Excess: SIADH
Deficiency: Diabetes Insipidus
Assessment of Pituitary Hormones
a. Biochemical Evaluation requires assessment of Pituitary (Trophic) Hormones and their Target Gland Hormones
Pituitary Hormone and their Target Organ-Hormone
- TSH
i. Thyroid-T4 (+/- T3) - ACTH
i. Adrenal Gland-Cortisol and DHEA-S - Growth hormone (GH)
i. Liver-IGF - PRL
i. Breast - LH and FSH
i. Gonads-Testosterone (♂)
ii. Estradiol (♀)
Level of the Hypothalamic-PituitaryTarget
Organ Defect
a. Deficiencies are categorized as either central or Peripheral
b. Central Defect—> The hypothalamus or the Pituitary gland
i. If its the hypothalamus–> tertiary disorder (type of central disorder)
ii. If the disorder is the Pituitary–> Secondary disorder (type of central disorder/defect)
c. Peripheral defect—> mean that there is a primary disorder involving the target organ
Disorders of Pituitary Hormones
and their Target Glands
a. If the target organ has the disorder, it is a primary defect
b. If it is the hypothalamus (tertiary) or the pituitary gland (secondary) it is a central disorder
Dynamic Pituitary Testing
a. Utilizes Known Physiologic Stimulators and Suppressors of Pituitary Hormone Release.
b. Hormone Excess is assessed by a
Suppression Test (e.g., Oral glucose
tolerance test for GH suppression to
confirm acromegaly).
c. Hormone Deficiency is assessed by a
Stimulation Test (e.g., insulin tolerance
test to evaluate pituitary (ACTH and
GH) reserves.
Growth Hormone Regulation
a. Negative feedback regulation of Growth Hormone and IGF
b. GH and IGF will feedback onto the hypothalamus, this will cause there to be a decrease in GHRH release
Actions of Growth Hormone
a. Growth Hormone will increase the amount Insulin like growth factor to be created
i. requires high insulin for IGF to be created
ii. IGF will increase growing in bones, cell mass, protein synthesis
b. GH will also cause increased protein synthesis and fat breakdown (increase hormone sensitive lipase activity for higher serum FFA)
Problems of Growth Hormone Excess
a. GIGANTISM-Growth hormone excess before puberty (before closure of the growth plates).
b. ACROMEGALY-GH excess after puberty (after completion of linear growth).
Clinical Presentation of Acromegaly
GH excess after puberty
Clinical Features of Acromegaly
1. Acral/Facial Changes +++ (>60%)
- Headaches +++
- Hyperhidrosis (increased sweating) +++
- Oligo/Amenorrhea +++
- Obstructive Sleep Apnea +++
- Hypertension ++ (20-50%)
- Dyslipidemia ++
- Paresthesias/Carpal Tunnel Syndrome ++
- Impaired Glucose Tolerance /Diabetes Mellitus ++
Growth Hormone Excess
Diagnosis
a. Clinical Features of GH excess (old pictures are helpful)
AND
b. Elevated IGF-1 level (age and gender
matched)-best screening test. Integrated
24 h secretion.
i. Long-half life.
c. GH levels fluctuate widely over 24 hrs and normal values can overlap with GH secreting tumors.
c. Check OGTT/GH levels for equivocal cases
d. Pituitary MRI-macroadenomas are detected in >80% of acromegaly
What is one of the most critical parts of diagnosing Growth Hormone Excess?
Elevated IGF-1 level (age and gender
matched)-best screening test. Integrated
24 h secretion.
i. Long-half life.
Acromegaly Treatment
a. A multi-modal and disciplinary approach from among a dedicated team of: Neurosurgeons, Endocrinologists,
Neuropathologists, Radiologists and Radiation/Oncologists.
b. Treatment Approach
i. Surgery
ii. Medical Therapies
iii. Somatostatin Analogs
iv. Growth Hormone Receptor Antagonist
v. Radiation Therapies
Growth Hormone Deficiency
a. GH/IGF-1 Levels Change with Age
i. Highest during puberty
ii. will naturally decrease each decade with adult life
b. Progressive Decline (14% per Decade) during Adult Lifetime
Wiki:
Growth hormone deficiency (GHD) is a medical condition, caused by problems arising in the pituitary gland, in which the body does not produce enough growth hormone (GH). Growth hormone, also called somatropin, is a polypeptide hormone which stimulates growth and cell reproduction.
Growth hormone deficiency has a variety of different negative effects at different ages; for example, in newborn infants, the primary manifestations may be hypoglycemia or micropenis, while in later infancy and childhood, growth failure is more likely. Deficiency in adults is rare, but may feature diminished lean body mass, poor bone density, and a number of physical and psychological symptoms. on.
The most common cause of GHD (representing two-thirds of cases) are pituitary and parasellar tumors. The origin of adult GHD may be congenital or acquired. Of those adult GHD that are acquired, roughly 15% are idiopathic, 50% are from pituitary tumors, 20% from extrapituitary tumors, and 5% from infiltrative or inflammatory lesions.
GH deficiency can be treated through growth hormone replacement, injections of growth hormone, or radiation or surgical treatment of tumors.
Manifestations of Adult Growth Hormone
Deficiency (GHD)
a. Body Composition
i. Increased Fat Deposition
ii. Decreased Muscle Mass, Strength and Exercise Capacity
b. Bone Strength
i. Increased Bone Loss and Fracture Risk
c. Metabolic and Cardiovascular Effects
i. Increased Cholesterol Levels
ii. Increased Inflammatory and Prothrombotic Markers (Creactive
protein) .
d. Psychological Well-Being
i. Impaired Energy and Mood
ii. Quality of Life (QoL)
Uses and Abuses of GH Therapy
a. Multi-Billion Dollar Industry
b. Numerous Web-Sites
- Ineffective (oral) Formulations
- Fraudulent Claims
c. Not FDA-Approved Uses
- Anti-Aging
- Obesity
- Chronic Fatigue Syndrome
Adult-Onset Growth Hormone
Deficiency (AoGHD)
a. GH replacement deficiency approved for use in Children-1985, Adults-1996
b. GH therapy-still somewhat controversial in adults regarding cost/benefit ratio
c. Studies in adult patients with severe GHD, albeit relatively short-term (<1 yr) have shown modest benefits in body composition, metabolic parameters
and QoL.
d. No hard end-points: reduced fracture, CV events or increased longevity.
Diagnosis of AoGHD
(Adult-Onset Growth Hormone
Deficiency)
a. Provocative Testing for GH Reserve
i. Limited Reagents
b. Insulin induced hypoglycemia (gold standard).
i. Contraindications: Elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease.
c. GHRH-Arginine (second best test), although no longer available in U.S
d. Available tests: Arginine and glucagon stimulation tests
e. IGF-1 Level -Low (in the setting of multiple other pituitary hormone deficiencies).
i. Must be age/gender-matched.
Two major diagnosing paths to know for Adult-Onset Growth Hormone
Deficiency (AoGHD)
- Insulin induced hypoglycemia (gold standard).
i. Contraindications: Elderly, h/o seizure disorder, coronary artery disease or cerebrovascular disease. - IGF-1 Level -Low (in the setting of multiple other pituitary hormone deficiencies).
i. Must be age/gender-matched.
Hyperprolactinemia
PRL Level usually <150 ng/d
a. Physiological
i. Pregnancy, suckling, sleep, stress
b. Pharmacological
i. Estrogens (OCPs)
ii. Antipsychotics, antidepressants (TCAs),
antiemetics (reglan), Opiates
c. Pathological
i. Pituitary Stalk Interruption
ii. Hypothyroidism, chronic renal/liver failure, seizure
iii. Prolactinoma
Prolactinomas-The Basics
a. Most Common Functional Pituitary adenoma (30-40%)
b. Female:Male Prevalence-10:1, median age of diagnosis-34 yrs
Prolactinoma Diagnosis
a. Random PRL level (gender-based normative ranges)
b. Levels usually correlate with tumor size
i. >100-150 ng/dl with microadenomas
ii. >200-250 ng/dl with macroadenomas
c. Pituitary MRI (with/without contrast)
Prolactin Deficiency
a. Etiology: Severe pituitary (lactotrope) destruction from any cause (e.g., pituitary tumors, infiltrative diseases, infectious diseases, infarction, neurosurgery or radiation).
b. Clinical Presentation: Failed lactation in postpartum females, no known effect in males.
c. Diagnosis: low basal PRL level
Cortisol Physiology
a. A Catabolic “Stress” Hormone
i. Essential for Life
b. Primary Functions:
i. Gluconeogenesis
ii. Metabolism of Fat and Protein
iii. Control Inflammatory Reactions
c. ACTH acts on adrenal cortex
i. ZF, stimulates glucocorticoid production
ii. ZG, usually inactivated by 11-beta HSD2
- but can activate mineralcorticoid receptor in marked excess (HTN, hypokalemia)
iii. ZR, stimulates steroid hormone synthesis
The Complications of Chronic Cortisol
Excess
a. Changes in Carbohydrate, Protein and Fat Metabolism
i. Peripheral Wasting of Fat/Muscle
ii. Central obesity, Moon facies, fat pads
iii. Osteoporosis
iv. Diabetes
v. Hypertriglyceridemia
b. Changes in Sex Hormones
i. Amenorrhea/Infertility
ii. Excess hair growth (♀)
iii. Impotence
c. Salt and Water Retention
i. HTN and Edema
d. Impaired Immunity
e. Neurocognitive Changes
Cortisol Excess (Hypercortisolism)
Causes:
a. ACTH Dependent
i. Corticotrope Adenoma
(Cushing’s Disease)
ii. Ectopic Cushing’s
(ACTH/CRH tumors)
b. ACTH Independent
i. Adrenal Adenomas
ii. Adrenal Carcinoma
iii. Nodular Hyperplasia
(micro or macro)
Clinical Aspects of Cushing’s Disease
a. Incidence: 2-3 cases per 1 million/year.
b. ~10-15% of Functional Pituitary adenomas
c. Female, Middle-aged predominance
Non-Specific Signs/Symptoms of
Cushing’s Syndrome
Obesity Fatigue Menstrual Irregularities Hirsutism HTN
Glucose Intolerance/DM Dyslipidemia Acne Anxiety/Depression Peripheral Edema Metabolic Syndrome
Screening Guidelines for Cushing’s Syndrome
Screening indicated in patients with
multiple and progressive “high discriminatory” features of Cushing’s
Syndrome.
Specific Signs of Cushing’s Syndrome 1. Plethoric/moon facies 2. Wide (>1 cm), violaceous striae (abdominal, axillary) 3. Spontaneous Ecchymoses 4. Proximal Muscle Weakness 5. Early/Atypical Osteoporosis (atraumatic rib fx)
Specific Signs of Cushing’s Syndrome
- Plethoric/moon facies
- Wide (>1 cm), violaceous striae (abdominal, axillary)
- Spontaneous Ecchymoses
- Proximal Muscle Weakness
- Early/Atypical Osteoporosis
(atraumatic rib fx)
Cortisol Rhythms
a. Episodic ACTH/cortisol secretions daily
b. Major ACTH/cortisol burst in the early morning (before
awakening) .
c. Cortisol Nadir 11-12 pm (assuming a normal sleep-wake cycle)
Cortisol Binding
a. Most cortisol is bound to transcortin (cortisol binding globulin-CBG).
b. 10-15% bound to albumin (less tightly)
c. 5% Unbound (Free cortisol)
Screening Tests for Cushing’s Syndrome
a. Disrupted Circadian Rhythm
i. Midnight Salivary or Serum Cortisol
b. Increased Filtered Cortisol Load
i. 24 hr Urine Free Cortisol
c. Attenuated Negative Feedback
i. Low Dose (1 mg) Dexamethasone
Suppression test (11-12 p.m.)
Confounding Issues in Cushing’s
Diagnosis
a. “Pseudo-Cushing’s Disease”
overactivation of the HPA axis, without
tumorous cortisol hypersecretion
b. Conditions that can give false negatives for Cushing’s (lead to high cortisol)
i. Severe Depression/Anxiety/OCD
ii. Severe Obesity
iii. ?Obstructive Sleep Apnea
iv. Alcoholism
v. Poorly-controlled DM/hypoglycemia
vi. Physical Stress (acute illness,
surgery, pain)
Cushing’s Disease Work-up
- ACTH LEVEL
• Plasma ACTH levels are usually high-normal to mildly elevated in Cushing’s disease - IMAGING
• Pituitary MRI (~80% microadenomas, 50% identified on MRI) - INFERIOR PETROSAL SINUS
SAMPLING
• For a negative/equivocal MRI
Central Adrenal Insufficiency (AI)
low cortisol
a. Etiologies of Primary AI-separate lecture
b. Etiologies of Secondary/Tertiary AI—> Suppression of the HPA axis
i. S/p tumor resection for Cushing’s Syndrome (pituitary, ectopic or adrenal)
ii. Supraphysiologic exogenous glucocorticoid use (most common) > 5-7.5 mg prednisone (or equivalent
glucocorticoid dose) for >1 month
iii. Drugs: Opioids and megace
c. Hypothalamus/Pituitary Diseases and/or their treatments.
d. Other-Isolated ACTH deficiency (very rare)
Central Adrenal Insufficiency
Clinical Presentation of secondary/tertiary
adrenal insufficiency (AI)
1. Fatigue
2. Anorexia, nausea/vomiting and weight loss
3. Generalized malaise/aches
4. Scant Axillary/Pubic hair (DHEA-S dependent in females)
5. Hyponatremia and Hypoglycemia