Eric L. Johnson, MD
Assistant Professor
Department of Family and Community Medicine
UNDSMHS
Assistant Medical Director
Altru Diabetes Center
Grand Forks, ND

• Understand basic principles of endocrine function
• Understand basic principles of endocrine dysfunction
• Understand management and referral of common endocrine diseases

• Disease state results from excess or insufficiency of hormone
• Clinical challenge is determination of the origin of excess or insufficiency, i.e., Hypothalamus
(tertiary), Pituitary (secondary) or target gland
(primary)

• Thyroid
• Adrenal
• Parathyroid
• Pituitary gland
• Gonadal
• Gout (uric acid)

Brain
Hypothalamus
Pituitary
Hypothyroid
Thyroid
Pancreas
Adrenal
Gonads

AVP = arginine vasopressin
CRH = corticotropin-releasing hormone
GHRH = growth hormone-releasing hormone
GnRH = gonadotropin-releasing hormone
SRIF = somatotropin release –inhibiting factor
(somatostatin)
TRH = thyrotropin-releasing hormone;
VIP = vasoactive intestinal polypeptide.
DA = dopamine
ACTH = adrenocorticotropic hormone
LH = lutenizing hormone
FSH = follicle-stimulating hormone
GH = growth hormone
TSH = thyroid-stimulating hormone
PRL = prolactin
Goldman: Cecil Medicine, 23rd ed. 2007

Anterior Pituitary Hormones
Hormone
Growth hormone (GH)
Target Gland
Multiple
Prolactin (PRL) Breast
Adrenocorticotropic hormone Adrenal
(ACTH)
Thyroid-stimulating hormone Thyroid
(TSH)
Luteinizing hormone (LH) Gonad
Follicle-stimulating hormone
(FSH)
Gonad

• TSH, ACTH, FSH, and LH hormones are tropic hormones that simulate other endocrine glands
• TSH-Thyroid
• ACTH- Adrenal Cortex
• FSH, LH- Gonads

• Vasopressin(ADH)- kidney, baroreceptors
(plasma osmolality, water retention, thirst)
• Oxytocin- breast, uterus
(no known function in males)
• Both are synthesized in specialized neurons in the hypothalamus
(neurohypophysial neurons)

• Pituitary adenomas may present with visual impairment, headache, or hormonal abnormalities
• Prolactinomas most common . Manifest with galactorrhea and gonadal dysfunction
• Laboratory testing: serum prolactin, creatinine levels and thyroid function tests
• MRI is the imaging modality of choice for the anatomic evaluation of the hypothalamus and pituitary gland

• Neoplasm
• Radiation
• Infiltrative/Infection
• Empty sella syndrome (herniation of subarachnoid tissue)
• Apoplexy (hemorrage)
• Sheehan’s syndrome (pregnancy)

• Acromegaly cause: growth hormone–secreting adenoma of the anterior pituitary
• Elevated serum levels of IGF-1 are found in acromegaly (best single test)
• The diagnosis of acromegaly is confirmed by a glucose tolerance test
• Transsphenoidal surgery to remove the pituitary adenoma is the initial treatment of choice in individuals with acromegaly

Acromegaly manifestations
• Increased hand/foot size
• Prognathism/teeth space widening
• Frontal bossing/coarsening of facial features
• Weakness/fatigue

Acromegaly manifestations cont’d
• Sweating
• HTN>>>cardiomyopathy
• Obstructive sleep apnea
• Insulin resistance

Treatment
• Surgical resection
Best if tumor small, 10-20% result in pan hypo pit
• Radiation
Slow to diminish GH, 50% pan hypo pit
• Bromocriptine
Blocks GH effect
• Octreotide
Lowers GH secretion, SC route w/frequent dosing

• Fatigue or hypoglycemia in the adult
• Dwarfism in child
Born normal length at birth but growth
“falls off curve”
• Diagnosis: IGF1 level (GH varies too much)
• Treatment: formerly used human pit gland extract, synthetic GH since late 80’s

• Deficiency of posterior pituitary hormone ADH
(aka vasopressin)
• ADH acts on kidney collecting duct to retain free water deficiency causes free water loss
• ADH maintains blood volume via: -
-Osmoreceptors in brain
-Stretch receptors in heart
-Baroreceptors in carotids and aorta

• Decreased urinary specific gravity (≤1.005)
• Decreased urinary osmolarity
(<200 mOsm/kg) even in the presence of high serum osmolality
• Hypernatremia, increased plasma osmolarity, hypercalcemia, hypokalemia
• Normal Serum osmolarity: 282 - 295 mOsm/kg
• Normal Urine osmolarity: 500 - 800 mOsm

Etiology
-CNS insult -head trauma, surgery, tumor, infection
-Genetic
-MS, Metastatic Disease
-Drugs (lithium is classic)
Nephrogenic vs. Neurogenic vs. Psychogenic
Sx
–Thirst, polyuria, polydipsia (with a normal glucose)

• Diagnostic workup: decreased ADH or insensitivity to ADH?
• Water Deprivation Test:
-Baseline measurement of weight, ADH, plasma sodium, urine and plasma osmolarity
-Patient is deprived of fluids under strict medical supervision.
-Frequent (q2h) monitoring of plasma and urine osmolarity
• Test terminated when plasma osmolarity
>295 mOsm/kg or the patient loses ≥3.5% of initial body weight.
• Diabetes insipidus is confirmed if the plasma osmolarity is >295 mOsm/kg and the urine osmolarity is <500 mOsm/kg
(typical referral point)

• Nephrogenic vs. neurogenic
• Patient given 5 U of vasopressin (ADH), change in urine osmolarity is measured
• Significant increase (>50%) in urine osmolarity after administration of ADH is indicative of neurogenic diabetes insipidus.

Treatment
• Desmopressin
• Thiazides in mild neurogenic

• Hyponatremia
• Urinary osmolarity > serum osmolarity
• Normal BUN, creatinine,TSH,glucose

• Neoplasm
• Pulmonary disorders: pneumonia, emphysema , cystic fibrosis, status asthmaticus, respiratory failure
• Intracranial pathology: trauma , neoplasms, infections (meningitis, encephalitis, brain abscess)
• Postoperative period: surgical stress , ventilators with positive pressure, anesthetic agents
• Drugs: chlorpropamide, thiazide diuretics , chemotherapeutic agents carbamazepine, phenothiazines, MAO inhibitors, tricyclic antidepressants, narcotics, nicotine, clofibrate, haloperidol, SSRIs,
NSAIDs
• Other: acute intermittent porphyria, myxedema, psychosis, delirium tremens, ACTH deficiency (hypopituitarism), general anesthesia, endurance exercise

• Treatment
Fluid Restriction
Careful use of hypertonic saline IV
Resolution/Treatment of underlying problem

• Pituitary adenoma>>excess production of
ACTH>>excess cortisol production
• Distinguished from Cushing’s syndrome, which includes other causes of cortisol excess
(ectopic production of ACTH and CRH)
• Cushing’s disease causes 60-70% of excess cortisol disease states
• Occurs 8 times more often in women than men

• Classic Cushing's features : Centripetal obesity, moon facies, and ‘buffalo’ hump
• Striae are common
• Fine (lanugo) hair growth
• Muscle wasting
• Bone demineralization
• Hypertension
• IGT
• Psych

• Distinguish between:
• Cushings Disease
-Pituitary Causes
• Cushing’s Syndrome
-Adrenal causes of cortisol excess;
-Ectopic sources of ACTH or Ectopic
CRH (Cortisol Releasing Hormone)

• Serum Cortisol is elevated
• Abnormal tests can be seen in up to 30% of hospitalized and/or depressed patients
• 24 hour free urinary cortisol can be a useful adjunct
• Overnight Dexamethasone suppression test……

• Overnight Dexamethasone Suppression Test:
1 gram at 11pm, measure plasma cortisol at 8 am the next morning
• The normal response is suppression to less than
3mcg/dl
• If no suppression, they have ectopic or adrenal production
• If supression, they may have pituitary cause

• Can Measure ACTH
-ACTH low in Adrenal gland tumor
-ACTH high in ectopic or pituitary adenoma

• High serum or 24 hour urine cortisol
• Dexamethasone suppression
-No supression: Ectopic or adrenal
-Supression: Pituitary
• ACTH
-Low: Adrenal
-High: Likely pituitary or ectopic

• Can result in all loss of corticosteroid production if the adrenal cortex suffers destruction (primary)
• Can result from diminished ACTH production (secondary)

• Loss of cortisol:
-Loss of vascular tone and CV output
-Hypoglycemia-Cortisol important for
Gluconeogenesis
-Hypercalcemia (Loss of inhibition of intestinal absorption and renal reabsorption)
-Serum ACTH levels are usually used for initial screening (Low)

• Skin changes-Hyperpigmentation in
Palmar creases, scars, oral mucosa
• Longitudinal pigmented bands under nails
• Vitiligo in up to 15% of patients
• Decreased pubic and axillary hair in females
• Weakness, fatigue, nausea and vomiting, and a craving for salt

• Associated with other endocrine insufficiencies
(thyroid, parathyroid, type 1 DM, etc)
• Treatment is to replace adrenal hormones
• Case I’ve seen: Pt. also had Type 1 DM and hypothyroidism; died at age 27 from profound hypoglycemia

• Aldosterone-a mineralocorticoid secreted by the adrenal glands
• Primary secretion affected by
Angiotensin II>renin (part of fluid and electrolyte balance)
• Increased aldosterone-increased sodium retention and increased potassium secretion by the kidney

• Primary-more common in women 3 rd to 5 th decade of life
• Presents with hypertension, weakness, fatigue, hypokalemia, polyuria, polydipsia
• Most cases are from benign adenomas
(Conn’s Syndrome)
• Screening: aldosterone:renin ratio of greater than 30
(off of anti-hypertensives, except Ca++ channel blockers)
• CT scanning for adrenal adenomas

• Usually occurs in edematous states-i.e.
CHF, cirrhosis or renal artery stenosis
• Causes intravascular volume depletion, stimulating renin production
• Elevated renin and aldosterone levels
• Can occur in Bartter’s syndrome (impaired chloride re-absorption)

• Sodium wasting and hyperkalemia
• May be up to 10% of hyperkalemia
• Hyper-reninemic hypoaldosteronism
(more common)
Defect is in aldosterone synthesis or angiotensin II action
Genetic, ACEI, ARB, heparin, Lead poisoning,
•
Severe Illness
Hyporeninemic
DM, HTN, renal insufficiency

• Lab:
Plasma renin
K+
Glucose
Kidney functions
Hyperchloremic metabolic acidosis

• Purpose
–Maintain serum calcium levels
• Target tissues
–Bone, kidney, intestine
• Feedback loop
–As Calcium rises, PTH lowers
–As calcium lowers, PTH rises

• Etiology
–Tumor (adenoma)
–Hyperplasia
–Drugs (lithium is classic)
–Ectopic PTH
• Secondary Hyperparathryroidism can occur in chronic renal disease

• Elevated PTH, Serum Ca++, urine Ca++
• Polyruia, Polydipsia
• Kidney stones
• Peptic ulcer disease
• Pancreatitis
• Nausea, vomiting or loss of appetite
• Osteopenia/porosis, leading to an increased risk of fractures
• Confusion or poor memory
• Muscle weakness or fatigue

• Treatment (loop diuretics, hydration)
• Observation
• Surgery

• Low PTH
(idiopathic, iatrogenic-thyroid surgery)
• Low Serum Ca++ (low Vit D?)
• Elevated Phosphorous
• Parasthesthias
• Alopecia/ vitiligo/ candidiasis
• Long Q-T on EKG
• Muscle cramps or tetany
Chvostek’s sign: facial twitch after a gentle tapping over the facial nerve
-Trousseau's sign: carpopedal spasm after inflation of blood pressure cuff above the patient's systolic blood pressure for 2 to 3 minutes

• Ca++ plus Vitamin D
• Low Phosphorous diet

• Incidence in the U.S. is about 1%
• Primary hypothyroidism accounts for 90-95% of all cases
• Autoimmune most common (Hashimoto’s)
• May or may not have enlarged (goitrous) thyroid
• End Stage Grave’s/treatment/can result in hypothyroidism
• Iatrogenic-surgical
• Iodine deficiency

• Decreased secretion of thyroid hormone from the thyroid gland. Most frequently reflects a disease of the gland itself
( primary hypothyroidism ) 95%
• Pituitary disease
( secondary hypothyroidism )
• Hypothalamic disease
( tertiary hypothyroidism )

• Generally leads to a slowing of metabolic processes
• Myxedema-occurs in severe diseaseaccumulation of of mucopolysaccharides in the skin (non-pitting edema)
• Congenital hypothyroidism is rare. Leads to developmental delay if not recognized and treated
• Can have bradycardia, CHF, coma in advanced cases

Symptomatology
• Patients may have no symptoms
• Common (Seen in >50% of Patients)
– Weakness, Fatigue, Lethargy, Decreased energy
– Cold intolerance
– Dry skin, Decreased sweating, Hair loss
– Inability to concentrate, Memory loss
– Constipation
– Weight gain
– Dyspnea
– Peripheral paresthesias

Symptomalotogy
Less common (Seen in <50% of Patients)
-Depression
-Anorexia
-Muscle cramps, Musculoskeletal pain,
Arthralgias,
-Infertility, Menorrhagia, anovulation
-Decreased hearing
-Carpal Tunnel Syndrome
-Impaired Glucose Tolerance

• Serum TSH sufficient for Screening for most Patients (elevated)
• Total T4 if clinically suspicious and
TSH normal
• If TSH elevated, Primary Hypothyroidism
• If TSH, T4, T3 all low, suspect pituitary/brain

• Synthetic thyroxine
• Start dose often 25 to 50 mcg daily
• Recheck TSH in about 4 to 6 weeks
• Titrate thyroxine based on symptoms, TSH

• Hypothyroid in Pregnancy -Require more frequent monitoring. Check TSH at beginning of pregnancy, end of first trimester, optional again at end of second trimester
• Down Syndrome -high incidence-check annually
• Type 1 Diabetes -higher incidence than general population. Check regularly

• Graves' Disease
60-90% of all cases
• Toxic multinodular goiter
• Solitary ‘hot’ nodule
• TSH secreting pituitary tumor
• Molar pregnancy
• Choriocarcinoma

• Common (Seen in >50% of Patients)
-Nervousness, Irritability, Hyperactivity,
Hand tremor
-Insomnia
-Hand tremor
-Excessive sweating
-Palpitations, tachycardia, arhythmias
-Weight loss

-Increased appetite
-Heat intolerance
-Pruritus
-Hyperdefecation
-Oligomenorrhea or amenorrhea

• Less Common (Seen in <50% of Patients)
-Nausea and vomiting, Dysphagia
-Decreased libido
-Impotence
-Dyspnea on exertion
-Periodic paralysis
-Exacerbation of angina
Loose nails (Plummer’s nails)

• Diffuse nodular Goiter is classic finding, along with opthalmopathy
• TSH is suppressed,elevated T4
• If T4 is normal, check serum T3-patient may have a
T3 thyrotoxicosis

• Toxic multinodular goiter
• Functional autonomy of thyroid independent of TSH stimulation
• Disease of the elderly (usually)

• Radioactive Iodine (RAI131) is ablative, and is definiitive
(not used in children or pregnancy)
• Hypothyroidism develops in
80% of patients

• Propylthiouracil –blocks thyroid hormone synthesis
• Propanalol –blocks hormone effects, inhibits conversion T3 to T4
• Surgery can be done for large goitersmany are then hypothyroid

• Thyroid Storm
• Preciptated by ‘medical crisis/stress’
• Extreme irritability, delirium, coma, fever, tachycardia, hypotension, vomiting
• Treatment: Antithyroid agents, beta blocker, steroids, supportive measures

• Usually from a viral infection
• Can be suppurative
• Presentation is a tender thyroid with fever and malaise
• Can have transient thyroid test abnormalities
• If transiently hyperthyroid (mild), sometimes managed with beta-blockers
• Usually managed symptomatically

• Premature Ovarian failure
-Occurs before age 40
-Genetic
-Autoimmune
-Infectious
-Iatrogenic
-Idiopathic

• Polycystic Ovarian Syndrome
-Prediabetes Syndrome
-Hirsuitism
-Amenorrhea/infertility (may start with dyfunctional uterine bleeding)
-Obesity
-6 to 7% of reproductive age women

• PCOS
-Clinical diagnosis: progesterone withdrawal test (5 days- bleeding)
-Lab: Elevated LS/FSH ratio >2.5
Elevated PRL in 25%

• PCOS
-Lab: Glucose every 6mos-2 yrs
Lipids/LFT’s every 6mos-2yrs
Serum testosterone
(may be tumor)

• PCOS:
Lab
TSH
17-hydroxyprogesterone
(rule out congenital adrenal hyperplasia)
Cushing’s testing
Ovarian Imaging

• PCOS
Treatment
-Surgical (Ovarian wedge resection)
TZD’s, Metformin
-Oral contraceptives
-Spironolactone
-Weight loss

• Many causes
• Many settings
• In adult men, reduction of spermatogenesis, erectile dysfunction, fatigue, weight gain
• Treated easily with testosterone replacement (should monitor PSA)

Etiology
• Purines (from proteins) metabolized to uric acid
• Serum level > 7.0 urate exceeds solubility and precipitates

• Increased production of uric acid
–Lympho/myeloproliferative dz
–Hemolysis
–High level exercise/rhabdomyolysis
–Alcohol
• Decreased elimination
-EtOH,NSAIDS, Down Syndrome, renal

• Signs/symptoms
–Monoarticular, acute, inflammatory arthritis
Great toe classic, can be any joint
–Tophi (finger joints, achilles tendon, ears)
–Urolithiasis
-Renal damage
(deposition in renal parenchyma)

Exacerbation ‘Attack’
• Red, swollen, inflamed, painful joint(s)
• 90% monoarticular
• Acute onset, worst at 24 –48 h
• Resolves in 7 –10 days

• Diagnosis
-Exam
-Joint aspiration- crystals visible in polarizing microscopy (don’t always need aspirate for clinical decision)
-Serum uric acid level

• Treatment
-NSAIDS (Indomethacin-classic) 1 st line
-Corticosteroids may be considered
-Colchicine
• Preventive
-Colchicine
-Allopurinol
-Probenicid

• QUESTIONS?
• Diabetes is next……