under the risk stratification for CAD (see

Dyslipldemias, M3)

• ischemic stroke (see Neurology, N53)

• risk of stroke in those with DM is approximately 2-3x higher for men and 2-5x higher for women

level of glycemia is both a risk factor forstroke and a predictor of a poorer outcome in patients

who suffer a stroke

• Ale level is a significant and independent predictor of the risk of stroke

• peripheral arterial disease (see Vascular Surgery, VS4)

manifests as intermittent claudication in lower extremities, intestinal angina,foot ulceration

• risk of foot gangrene is 30x higher in those with DM compared to age-matched controls

• risk of lower extremity amputation is 15x higher in those with DM

• screening: Ale every 3 mo, BP monitoring, lipid profile every 1-3 yr,resting ECG every 3-5 yr for highrisk patients

• treatment

• tight blood pressure control (<130/80 mmHg), especially for stroke prevention

• tight glycemic control in early DM without established CV D (refer to ACCORD, VA DT,

ADVANCE, DCCT, ED1C, UKPDS extension studies)

• tight LDL control (LDL <2.0 mmol/L) or >50% LDL reduction from baseline

• statin use in patients with clinical CVD, age £40, or either diabetes duration >15 yrand age >30,

or microvascular complications

ACE1 or ARB in high-risk patients

smoking cessation, healthy diet, physical activity, and maintenance of healthy weight goals

for adults with CVD who do not meet glycemic targets, recommended to add anti-hyperglvcemic

agent with demonstrated cardiovascular benefit (SGLT2I/GLP-I RAs) to reduce the risk of major

CV events

£ffectsol USAforPrimary Prevention in Persons

with Diabetes Hellitus

H EJM 2018:319:1529 1539

Study:Ml. 0

'

rded. with /.Ayr ol mean (ollow up

Population: 15480 patents Witt DU with no known

cardiovascular risk

Intervention: ASA lOOng once daily

Primary Outcome: Primary clhcacy outcome was

lirst instance of vascular event (composite outcome

ol non-fatal HI.nonfata!stroke,or transient ischemic

attack, or death from any vascular cause.

Results: the ASA grojp experienced a fewer nunher

ol vascular events(P*

0.01|but a greater number

ol major Weeding events|P'0.01)compaied to the

placebo group.

Conclusions: Currently. ASA is not recommended

for primary prevention in people with diabetes hut is

recommended loi secondary prevention

See

©

Landmark Endocrinology Trials for

more information on the EMPA REG

OUTCOME trial. It details the effects

of empagliflozin (SGLT2 inhibitor) on

cardiovascular risk in patients with

T2DM.

r T

L J

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E15 Endocrinology Toronto Notes 2023

Regular Review

• Assess glyccmic control,

cardiovascular and renal status

• Scroon for complications

(eye, foot, kidneys)

Review efficacy, side effects,

safety and ability to take current

medications

• Reinforce and support healthy

behaviour interventions

If A1C NOT at target

and/or

change in clinical status

Liraglutidc andCardioviscularOutcomes in12DM

NEJU 2016; 375:311 322

Rugose lo investigate whether liraglutidc (a ClP-1

analogue) has any effect on cardovascular risk in

patients with T 2DM whenadded to standardcare.

Study:Multi-centre,double-blind KUcompairq

liragtutide to placebo control:9340 patients (drug

n-4668.placebo n-46!2|.median obserratam 3.8 ft.

Outcome:Death from cardiovascular causes,

nonfatal Ml.or nonfatal stroke.

Resalts:Both groups concurrently received the

standard treatment for I20M Ihe lirag jt de

group had significantly louver rates of death from

cardiovascular causes than control|4.7Vvs.6%:

P“0.00?|.Ihe drug groupalso had lower all-cause

mortality|8.2% and 9.6V R'0.02). Bales olnonfatal

Ml.nonfatal stroke, and kospitaIllation lor heart

laBure were not signhcantly lower In Ihe litagliditfe

group.

Conclusion:Adding hraglutide to standard

treatment lor pabants with12DM radoced death from

cardiovascular cause and all-cause mortality when

compared to placebo.

Adjust or advance

therapy*

T

f ASCVD, CKO or HF OR age >60 with 2 CV risk factors J

f A1C above target and glucose lowering required ]

*

I

ADD or SUBSTITUTE AHA with demonstrated

cardiorenal benefits

ADD or SUBSTITUTE AHA" according to

clinical priorities'

"

Start insulin for symptomatic hyperglycemia and/or

metabolic decompensation

CV safety,

but NO proven

cardiorenal

benefit'

PROVEN

cardiorenal

benefit in

high-risk

populations"

Established cardiovascular RISK of HF

or renal disease

Risk

factors

>60 yr with

CV risk

factors'

ASCVD CKO HF

GLP1-RA Weight loss GLPI RA

exenatide ER.

lixisenatide

dulaglutide.

liraglutide.

semaglutide

SGL2T.

—a

—i GIP1-RA SGLT2P

F or or GLP1-RA < SGini1

o GLPI RA 2

- QrtuQlrfloiin1

"*

ISGLT2i)

canagliflozm.

dapagliflozm.

SGLT2i

:

-Jempagliflozin

(ardlcwer

CVmonadtv

*

.E -

.t

SGLT2V SGLT2I SGLT2i

g '

—_ "Dm,

sitagliptm, linagiiplm, alogliptm

Acarbosc

E saxagliptin

O IDPP4H -

ts> |t

|S

2? 2

-s SGLT2T SGLTO' SGLT2J

Sylfonylurcas

Mcglitinidcs

Insulin

Hypoglycemia Weight gain

s i

Q

-

§

—i Thiarotidinediones

Highestlevelofevidence (GradeA (GiadeBj (CradaCorD)

Initiate only if eGFR >30 ml/min/1.73m‘

'

rixed dose combinations may be considered to reduce burden

Changes in clinical status may necessitate adjustment of glycemic targets and/or depresciibing

Tobacco uso; dyslipcdomio luso of lip< d modifying thorapy or o documented untreated low density lipoprote n ILDLI > 34 mmoVL or

high density lipoprotein chalastorolIHDL 0 cl.Ominol/lfor mon and <1.3 inmoVLfoc womon.or triglyceridos> 2.3mmolU;or hypertension

(use of blood pressure drug or untreated systolic blood pressure ISBPI >140 mmHg or diastolic blood pressure |0BP|>95 rnmHg)

All antihyperglycemic agents (AHAs) have grade A evidence for effectiveness to reduce blood glucose levels

"

Consider degree of hyperglycemia,costs and coverage,renal function,comorbidity,side effect profile and potential for pregnancy

~ In CV outcome trials performed in people with atherosclerotic cardiovascular disease IASCVDI.chronic kidney disease (CKO),heart failure

(HF) or at high cardiovascular (CV) risk

'

Vortis (CV outcome trial for ortuglifloMi) presented at Americon Oiabetes Association (ADA) Juno 2020 showed noninferiority for major

adverse CV events (MACE). Manuscript not published at time of writing

A1C - glycated hemoglobin; DPP4i- dipeptidyl peptidase 4 inhibitors;eGFR _ estimated glomerular filtration rate; GLP1 RA - glucagon like

peptide 1 receptor agonists;exenatide ER = exenatide extended release.HHF - hospitalization for heart failure. SGLT2i

- sodium- glucose

^

cotransporter 2 inhibitors

Figure 9. Treatment approach for patients living with diabetes

Microvascular Complications

Diabetic Retinopathy (see Ophthalmology, OP34 for a more detailed description)

Epidemiology

• diabetic retinopathy is the most common cause of incident blindness in people of working age

• among individuals with T1DM, limb amputation and vision loss due to diabetic retinopathy are

independent predictors of early death

Clinical Features

• macular edema: diffuse or focal vascular leakage at the macula

• non-proliferative (microaneurysms, intraretinal hemorrhage, vascular tortuosity, vascular

malformation) and proliferative (abnormal vessel growth)

• retinal capillary closure

r t

L j

Treatment and Prevention

• tight glycemic control (delays onset, decreases progression), tight lipid control, manage HTN,smoking

cessation

• ophthalmologic.il treatments available (see Ophthalmolcmv,OP35 for more details)

• annual follow- up visits with an optometrist or ophthalmologist to examine whether symptomatic or

not through dilated pupils(immediate referral after diagnosis of T2DM; 5 yr after diagnosis of'TlDM

for those >15 yr)

• interval for follow up should be tailored to severity of retinopathy

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El6 Endocrinology Toronto Notes 2023

Diabetic Nephropathy (see Nephrology, NP33 for a more detailed description)

Epidemiology

• DM-induced renal failure is the most common cause of renal failure in North America

. 20- 10"

,, of persons with T1DM (after 5-10 yr) and 4-20% with T2DM have progressive nephropathy

Screening

• serum creatinine for eGFR, random urine ACR

• ACR is used as albuminuria is considered the earliest clinical sign of diabetic nephropathy

(microalbuminuria); diagnosis requires persistent elevated urinary albumin (2 out of 3 urinary

samples required over 3 mo)

• 24 h urine collection for protein/albumin is the gold standard but is difficult to perform, inconvenient,

and often incorrect;random urine albumin is insufficient as albumin levels vary with urine

concentration

• begin screening annually at diagnosis for all T2DM, and >5 yr after diagnosis of T1DM for

postpubertal patients

Treatment and Prevention

• appropriate glycemic control

• appropriate BP control (<130/80 mmHg)

• use either ACPI or ARB to delay progression ofCKD (often used first line for CVD protection)

• use SGLT21 for nephroprotection

• limit use of nephrotoxic drugs and dyes

Diabetic Neuropathy

See Landmark Endocrinology Trials

for more information on the Steno-2

trial.It details the effects of intensive,

multifactorial interventions on the rates

of death in patients with T2DM and

microalbuminuria

LEFT

Epidemiology

• approximately 50% of patients within 10 yr of T1DM and T2DM onset

Pathophysiology

• can have peripheral sensory neuropathy, motor neuropathy, or autonomic neuropathy

• mechanism poorly understood

• acute cranial nerve (CN ) palsies and diabetic amyotrophy are thought to be due to ischemic infarction

of peripheral nerves

• the more common motor and sensory neuropathies are thought to be related to metabolic, vascular,

and possibly hormonal factors

Screening

• 128 Hz tuning fork or 10 g monofilament

• begin screening annually at diagnosisfor all T2DM, and >5 yr after diagnosis of IT DM for postpubertal patients

Clinical Features

o

o

° I

.c

3

CO

I

V

o s

Figure 10. Monofilament testing for

diabetic neuropathy Table 12. Clinical Features of Diabetic Neuropathies

PeripheralSensory Neuropathy Motor Neuropathy Autonomic Neuropathy

Paresthesias (tingling, itching), neuropathic Less common than sensory neuropathy end

pain, radicular pain, numbness,decreased occurslater in the disease process

tactile sensation

Postural hypotension, tachycardia,decreased

cardiovascular response to valsalva maneuver

Pharmacologic Interventionsfor Painful Diabetic

Neuropathy:An Umbrella Systematic Review

a ad Comparative Effectiveness Network MetaAnalysis

Ann Intern Med 2011;141:639-49

Purpose: focompare the efficatiesof rarionsoral

and topical anatges.esfor diabetic neuropathy.

Study Selection:RCIs that assessed pharmacologic

treatments lor pa nful diabetic peripheral neuropathy

in adults.

Results: 65 RCIs ,r

, a eg12632 patents were

included. Ibelolluwng pharmacological agents

demonstrated superiority over placebofor short-term

pain control:seroton:n and norep inepbrine reuptake

inhibitors (SNRIs)lstandaidired mean difference

(SMD).-1.36; 95% credible interval (Cil).|-1.77 to

0.9S1I, topkalcaps4ii,r (SMD, 0.91;Crl (MS

to-0.0811, tricyclic ante]epressants|ICAs|(SMD.

-0.78; Crl|-1.24 to -0.33]), and anticonvulsants

(SMD,-0.67:Crl[-0.97 to -0.37]).Spedfe agents

included:carbamaiep,-e (SMD. -1.57;Crl [-2.83 to

0.31[|, renlalaiine (SMD. 1.53:Crl( 2.41 to -0.6511.

dularetmelSMO. 1.33:Crl 1182 to 0 86)). arid

amitriptyline (SMD. -0.72:Crl (-1.35 tn -0.08'

J.

Conclusion:SNSIs. topical capsaicin. TCAs

and anticonvulsants are effective in short-term

nanagementdf painful diabetic neuropathy, but their

relative cflicacy compared to each other is unknown.

Delayed motor nerve conduction and muscle Gastroparesis and alternating diarrhea and

Bilateral and symmetric with decreased weaknesslatrophy constipation

perception ol vibration and pam'

tempcrature; May involve one nerve trunk (mononeuropalhy) Urinary retention and erectile dyslunclion

especially hue in Ihe lower evlremilics but 0

, m0It (mononeur,tis multiplex)

may also be present In Ihe hands

Decreased ankle reflex

Some ol the motor neuropathies

spontaneously resolve after 6-8 wk

Distal- predominant as the longest nerves are Reversible CN palsies:III (ptosis/

affected first ophthalmoplegia, pupil sparing).VI (inability

to laterally deviate eye), and VII (Bell 's palsy)

Diabetic amyotrophy i.e. Bruns Garland

Syndrome:refers to pain,weakness,and

wasting ol hip flexors or extensors

Classic stocking- glove distribution

May result in neuropathic ulceration ol loot

Treatment and Management

• tight glycemic control

• for neuropathic pain syndromes: tricyclic antidepressants (e.g. amitriptyline), pregabalin, duloxetine,

anticonvulsants (e.g. carbamazepine, gabapentin ), and capsaicin

• foot care education

•|obst’fitted stocking and tilting of head of bed may decrease symptoms of orthostatic hypotension

• treat gastroparesis with dietary modification, domperidone and/or metodopramide (dopamine

antagonists), erythromycin (motllln receptor agonist)

• medical, mechanical, and surgical treatment for erectile dysfunction (see Urology, U33)

L J

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E17 Endocrinology Toronto Notes 2023

Other Complications

Dermatologic

• diabetic dermopathy: atrophic brown spots commonly in pretibia!region ( “tibia spots") secondary to

increased glvcosylation of tissue proteins or vasculopathy

• eruptive xanthomas secondary to increased triglycerides

• necrobiosis lipoidica diabeticorum:rare complication characterized by thinning skin over the shins

allowing visualization of subcutaneous vessels

Other Players in Glucose Homeostasis

These hormones act to increase:

Blood glucose levels

Glucagon

Epinephrine

Cortisol

Growth hormone

Bone and Joint Disease

• juvenile cheiroarthropathy:chronic stiffness of hand caused by contracture of skin over joints

secondary to glycosylated collagen and other connective tissue proteins

• Dupuytren'

s contracture

• increased fracture risk in both T1DM and T2DM due to decreased bone quality

• adhesive capsulitis (“frozen shoulder")

C-Peptide

A short peptide released into the

circulation when proinsulin is cleaved

to insulin

Cataracts

• subcapsular and senile cataractssecondary to glycosylated lens protein or increased sorbitol causing

osmotic change and fibrosis

Infections

• see Infectious Diseases. Diabetic Foot Infections.ID14

Use of C- pcptide Levels to Distinguish

between Exogenous and Endogenous

Source of Hypetmsulinemia

Increased endogenous

Decreased or normal = exogenous

Hypoglycemia

Etiology and Pathophysiology © • hypoglycemia occurs most frequently in people with DM receiving insulin or certain

antihyperglycemic therapies (insulin secretagogues)

• in people without DM, care must be taken to distinguish hypoglycemia that occurs in critically ill or

medicated patients from hypoglycemia that presents in individuals who are seemingly well

each invokes a separate DDx

the timing of hypoglycemia may also provide a clue to the diagnosis (e.g. individuals with

an insulinoma typically have fasting hypoglycemia whereas those with non -insulinoma

pancreatogenous hypoglycemia experience predominantly postprandial hypoglycemia )

must be distinguished from pseudohypoglycemia,defined assituations in which either BG >3.9

mmol/L with clinical signs of hypoglycemia (e.g.fatigue, headache, visual disturbances, or

lightheadedness) or BG <3.9 mmol/L but patient is asymptomatic.

Treatment of an Acute Hypoglycemic

Episode (Blood Glucose <4.0 mmol/L)

in the Awake Patient (e.g. able to

self

-treat)

1) Eat15 g of rapid acting carbohydrates

(e.g. 3 packets of sugar dissolved in

water;3/4 cup of juice)

«

2) Wait 15 min

«

3) Retest BG

«

4) Repeatsteps1-3until BG >5 mmol/L

«

Table 13. Causes of Hypoglycemia 5) Eat next scheduled meal. If next

meal is >1 h away, eat snack

including 15 g of carbohydrate and protein Insulin-Dependent Causes

Exogenous Insulin

Sulfonylurea or meglilmide

Pentamidine (possibly due to p cell destruction resulting in insulin

release)

Autoimmune hypoglycemia (autoantibodies to insulin or insulin

receptor)

Insulinoma

Non- insulinoma pancreatogenous hypoglycemia

Post- gastric bypass hypoglycemia

Insulin-Independent Causes

Hepatic failure

Renal failure

Inanition

Hormone deficiency (cortisol, glucagon, and epinephrine ininsulindeficient DM)

Non-islet cell tumours (typically the resultof mesenchymal tumour

overproduction ofIGF-2)

Inborn error of caibohydralc metabolism,glycogen storage disease.

gluconeogenic encymc

Alcohol

Drugs (e.g. quinine, indoinethacin.gatifloxacin,lithium, ACEI.

P-adrenergic receptor blockers)

Hypoglycemia

©

Unawareness

(T1DM »> T2DM)

• Patient remains asymptomatic until

severe hypoglycemic levels are

reached

• Often occurs after repeated episodes

of hypoglycemia as the patient

develops blunted/minimal autonomic

response

• Causes:

• Decreased glucagon/epinephrine

response

• History of repeated hypoglycemia

or low A1c

• Autonomic neuropathy

• May not be safe for patient to d rive

• Suggest that patient obtain a

Medic-Alert"

bracelet if at risk for

hypoglycemia, especially with

hypoglycemia unawareness and

consider use of advanced monitoring

systems (continuous glucose monitor,

flash glucose monitor)

Clinical Features

• Whipple’s triad -suggests a patient’

ssymptoms are from hypoglycemia

1. serum glucose <4.0 mmol/L

2. neuroglvcopenic symptoms ( below)

3. rapid relief provided by administration of glucose

• autonomic symptoms(typically occur first; caused by autonomic nervoussystem activity)

palpitations,sweating, anxiety, tremor, tachycardia, hunger

• neuroglycopenic symptoms (caused by brain glucose deprivation)

dizziness, headache, clouding of vision, mental dullness, fatigue, confusion,seizures, coma

Investigations

• depend on a thorough history, physical exam, and available biochemical investigations as these may

provide clues to the etiology of hypoglycemia

for example, if suspecting insulin and insulin secretagogues in patients with diabetes, assess for

cortisol deficiency. In a patient with weight loss, hyperpigmentation, and hyperkalemia, consider

the possibility of 1G1 -2 mediated hypoglycemia. In an individual with a gastrointestinal stromal

tumour (GIST), think about renal/hepatic failure in the setting of critical illness

T

L J

© +

Refer to Diabetes Canada 2018

guidelinesfor advice around diabetes

and driving

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E18 Endocrinology Toronto Notes 2023

•when the cause of hypoglycemia is not evident,screen for oral hypoglycemic agents (ideally all

available sulfonylureas and glinides) and measure plasma glucose, insulin, proinsulin, C-peptide,

b-hydroxybutyrate, and insulin Ab during a spontaneous hypoglycemic episode or a supervised fast

of up to 72 h. If hypoglycemia occurs only in the postprandial state, evaluate the patient first with a

mixed meal test

•correct hypoglycemia with injection of 1.0 mg glucagon IV with measurement of plasma glucose

response.This will distinguish endogenous and exogenous hyperinsulinism from other causes of

hypoglycemia

Treatment

•for tumoural hypoglycemia, definitive treatment requires resection of the tumour. If that is not

possible certain medications can be helpful such as diazoxide for patients with insulinoma

for non-insulinoma pancreatogenous hypoglycemia and post-bariatric bypass hypoglycemia,

dietary changes including reducing the amount of carbohydrate intake and small frequent meals

may be helpful.For patients who do not respond to nutritional modification or have severe

symptoms, acarbose can be utilized

•see Emergency Medicine, ER34

•treatment of hypoglycemic episode in the unconscious patient or patient NPO

D50W 50 mL (1 ampule) IV in 1-3min or 1 mg glucagon SC or 1M (if no IV access is available)

may need ongoing glucose infusion once B(i >5 mmol/L

Metabolic Syndrome

• postulated syndrome related to insulin resistance associated with hyperglycemia, hyperinsulinemia,

HT'

N, central obesity,and dyslipidemia

• obesity aggravates extent of insulin resistance

• complications include DM, atherosclerosis, CAD, Ml, and stroke

• women with PCOS are at increased risk for developing insulin resistance, hyperlipidemia, and

metabolic syndrome

• not to be confused with syndrome X related to angina pectoris with normal coronary arteries

(Prinzmetal angina)

$

Obesity Features of Metabolic Syndrome

|-3 measures to make a Dx)

• see family Medicine.1-M9 Measure Men Women

Abdominal Obesity (derated Waist Circumference)

Canada. USA >102cm >88 cm

(40 inches) (35 inches)

Europid.Middle >94 cm >80 cm

Eastern,Sub- (37 Indies) (31.5 inches)

Saharan Africa.

Mediterranean

Pituitary Gland

Pituitary Hormones

>90cm >80 cm

Japanese. (35indies)

<31.5 Inches)

South (Central

America

TO level

Asian.

Somatostatin

Dopamine CRH GHRH GnRH I

>1.7 mmol/L (150 mgfdL)

HDL-C level «1.0 mmol/L <1.3 mmol/l

(

-40 mg/dl) (

-50 mg/dl)

Blood Pressure ;130/8SmmHg

l I

If Prolactin ACTH GH FSH IH

It 1 I

fasting Glucose >5.6mmol/L (>100 mg/dl)

Level

H

Dtug treatment for any elevatedmarker isan alternate

indicator Adrenal

cortex

Liver Endocrine cells

of gonads

I I 1

Male Female

Somatomedins Androgens

(IGF-1) |

Cortisol Estrogens.

progesterone Anterior Pituitary Hormones SI

j

FLAT PIG i

FSH

si

r

Gonadal LH i

germ cells,

Multiple target organs

Breast Multiple target organs LJ

—as S' o

Figure 11. Hypothalamic-pituitary hormonal axes

ACTH

TSH

PPL

GH +

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Ely Endocrinology Toronto Notes 2023

Hypothalamic Control of Pituitary

• trophic and inhibitory factors control the release of pituitary hormones

• most hormones are primarily under trophic stimulation except FRL, which is primarily under

inhibitory control by dopamine. CiH and TSH are stimulated by GHRH and TRH respectively while

inhibition by somatostatin is less important for control

• transection of the pituitary stalk (i.e. dissociation of hypothalamus and pituitary) leads to pituitary

hypersecretion of PRL and hyposecretion of all remaining hormones

Anterior Pituitary Hormones

• FSH, LH , ACTH,TSH, CiH, PRL

• these hormones are produced,stored, and released from the anterior pituitary but regulated by

hormones produced by the hypothalamus

Posterior Pituitary (Hypothalamic) Hormones

• ADH and oxytocin

• peptides synthesized in the supraoptic and paraventricular nuclei of the hypothalamus

• although ADH and oxytocin are produced in the hypothalamus,these hormones are stored in and

released from the posterior pituitary

Table 14. The Physiology and Action of Pituitary Hormones

Hormone Function Physiology Inhibitory Stimulus Secretory Stimulus

IH/FSH Stimulate gonads via cAMP

Ovary:

LH:production o( androgens(thecal cells)

which are converted to estrogens(granulosa

cells):induces luteinization in follicles

FSH: growth ol granulosa cells in ovarian

follicle:controls estrogen production

lestes:

LH: production ol testosterone (leydig cells)

FSH: production olspermatocoa (Sertoli

cells)

Stimulates growth of adrenal cortex and

secretion of its hormones via cAMP

Polypeptide

Glycoproteins (same asubunit as TSH and hCG)

Secreted in pulsatile fashion

Estrogen

Progesterone

Testosterone

Inhibin

Continuous

(i.e.non - pulsatile)

GnRH infusion

Pulsatile GnRH (low frequency pulsation

•

fSH release, high frequency pulsation -

LH release)

Dexamethasone. cortisol, and other Corticotropin-Releasing Hormone

Melyrapone

hypoglycemia

Vasopressin

fever, pain,stress

ACTH Polypeptide

Circadian rhythm (highest in the morning, lowest glucocorticoids

at midnight)

Stimulates growth ol thyroid and secretion ol Glycoprotein

14 andT3viacAMP

thyroid hormones (14 and 13) and TRH

analogues, dopamine,somatostatin. AVP

cytokines, high dose glucocorticoids a adrenergic agonist

Dopamine (only pituitary hormone Sleep

under tonic inhibition of secretion) Stress, hypoglycemia

Pregnancy, breastfeeding

Mid-menstrual cycle

Sexual activity

TRH (primary hypothyroidism)

Drugs: anlipsycholics. tricyclic

antidepressants, metoclopramldc.

domperidone. verapamil, methyldopa,

opioids,high dose estrogen

GHRH

Insulin-induced hypoglycemia

Ghrelin

Exercise

REM sleep

Arginine, donidinc. propranolol. L- dopa

Sex hormones

Dopamine agonistsin normal individuals

Hypovolemia or a effective circulatory

volume

t serum osmolality

Stress, pain,fever,system

CNS disorders

TSH

Note: hCG can activate the TSH receptor and

therefore have thyroid-stimulating activity

Promotes mi Ik productionand breast tissue

development

Inhibits gonadotropin secretion

Polypeptide

Episodic secretion

PRL

GH Has direct effects on peripheral target cells

Needed (or linear growth and also has

metabolic effects to increase serum glucose

Stimulatessecretion of IGF-1 by the livec.a

potent growth and differentiation factor

Polypeptide

Acts indirectly through IGF-1|somatomedin-C)

synthesized in the liver and has direct effects

Serum GH undetectable lor most of the day and

suppressed alter meals high in glucose

Sustained rise during sleep

Glucose challenge

Glucocorticoids

Somatostatin

Dopamine D2 receptor agonistsin

some GH -secreting tumours

IGF -1 llong-loop)

Acts at renal collecting ducts on V2 receptors Octapeptide

to cause insertion of aquaporin channels

and increases water reabsorption thereby

concentrating urine

ADH a serum osmolality

Secreted by posterior pituitary

Osmoreceptors in hypothalamus detect serum

osmolality

Contracted plasma volume detected by

baroreceptors is a more potent stimulus than i

osmolality

Causes uterine contraction

Breast milk secretion

EtOH Suckling

Distention ol female genital tract during

labour via stretch receptors

Oxytocin Nonapeplide

Secreted by posterior pituitary

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E20 Endocrinology Toronto Notes 202J

Growth Hormone

GH Deficiency

• cause of short stature in children (see Paediatrics. P13)

• adults exhibit increased fat and decreased lean body mass, decreased bone mineral density, and

fatigue

• diagnosis made with low serum l

(il;

-l levels in individuals with deficiencies in three or more pituitary

axes, or by failure to increase GH with a provocative test (see above under GH secretory stimulus);

insulin tolerance test to induce hypoglycemia is the gold standard dynamic test

• Tx:GH replacement is not alwaysindicated after max linear height and peak bone mass is reached;

consider in an adult patient with childhood onset irreversible GH deficiency (some children who are

diagnosed with idiopathic GH deficiency will have normal GH responses when tested as adults and

do not require GH treatment). GH replacement can also be provided to patients with adult onset GH

deficiency who do not have an active malignancy and prefer treatment after a discussion about its

potential benefits, adverse effects, and cost

GH Excess

Etiology

• GH secreting pituitary adenoma, neuroendocrine tumourssecreting ectopic GH or GHRH (very rare)

Pathophysiology

• normally GH is a catabolic hormone that acts to increase blood glucose levels

• in GH excessstates,secretion remains pulsatile but there isloss of hypoglycemic stimulation, glucose

suppression, and the nocturnal surge

• proliferation of bone, cartilage,soft tissues, organomegaly

• insulin resistance and 1GT

Risks Associated with GH Excess

• Cardiac disease (e.g.

cardiomyopathy, valvulopathy.

arrhythmias, CAD) in 1/3ol patients.

Two-fold increase in mortality in

acromegaly due to acromegalyassociated complicationssuch

as HTN, diabetes,CVD, and

cerebrovascular disease

. HTN in1/3of patients

• Increased risk of cancer (particularly

colon cancer)

Clinical Features

• leads to gigantism in children (before epiphyseal fusion)

• leads to acromegaly in adults(after epiphyseal fusion)

• dermatologic (thickening of skin, increased sebum production,sweating, acne, sebaceous cysts),

musculoskeletal (enlargement of hands and feet, coarsening of facial features, thickening of

calvarium, prognathism, carpal tunnel syndrome, osteoarthritis), cardiometabolic (HTN, DM,

acanthosis nigricans, cardiomyopathy),sleep apnea,sexual (low libido)

Investigations

• first line test:serum 1GF-1 (expected to be elevated)

• glucose suppression test is the mostspecific test (75 g of glucose PO suppresses GH levelsin healthy

individuals but not in patients with acromegaly)

• O'

, MKI. or skull x-rays may show cortical thickening, enlargement of the frontal sinuses, and

enlargement and erosion of the sella turcica

• MKI of the sella turcica is needed to look for a tumour

Treatment

• surgery is the recommended initial therapy for the majority of patients with acromegaly;second line

options include somatostatin analogue (octreotide), dopamine agonist (cabergoline), GH receptor

antagonist (pegvisomant), radiation

« radiation may be considered in patients whose disease is not controlled by surgery or medical

treatment

Prolactin

Hyperprolactinemia

Etiology

• prolactinoma:most common pituitary adenoma

• sellar masses,disease with pituitary stalk compression,or damage causing reduced dopamine

inhibition of PKL release

• primary hypothyroidism (increased TRH), PCOS, acromegaly

• decreased clearance due to CKD orsevere liver disease (PRL is metabolized by both the kidney and

liver)

• medications with anti-dopaminergic properties are a common cause of high PRL levels: antipsychotics

(common), antidepressants, antihypertensives (verapamil/methyldopa), bowel motility agents

(metoclopramide/domperidone), H2-blockers, opiates (morphine), estrogens(e.g.oral contraceptives)

• macroprolactinemia (high molecular weight PRL also known as big-big PRL) that has no action but

results in falsely elevated serum prolactin

• physiologic causes: pregnancy,stress,sleep, nipple stimulation, factors affecting the chest wall

Clinical Features

• galactorrhea (secretion of breast milk in women and, in rare cases, men), infertility, hypogonadism,

amenorrhea,oligomenorrhea, erectile dysfunction

&

Approach to Nipple Discharge

• Differentiate between galactorrhea

(fat droplets present) vs. breast

discharge (usually unilateral, may be

bloody or serous)

• If galactorrhea, determine if

physiologic (e.g. pregnancy,

lactation) vs. pathologic

• If abnormal breast discharge,must

rule out a breast malignancy

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E21 Endocrinology Toronto Notes 2023

Investigations

• serum PRL, l

'

SH,liver enzyme tests,creatinine, hCG in all women of reproductive age

• macroprolactin level in patients with hyperprolactinemia but no symptoms of PRL excess

• MRI of the sella turcica when a secondary cause is not identified or when PRL levelssuggest that there

may be underlying tumoural hyperprolactinemia

Diagnosis and Treatment of

Hyperprolactinemia:An Endocrine

Society Clinical Practice Guideline

J Clin Endocr Mctab 2011:96:273 88

• Indications to treat:

• Symptomatic patients.

in particular those with

galactorrhea, hypogonadismamenorrhea.low libido,or

infertility

• Adenomas >1cm or any size

causing structural compression

• For patients with symptomatic

prolactinomas,dopamine agonist

therapy should be used to lower

prolactin levels, decrease tumour

size, and restore gonadal function

• Cabergoline should be preferentially

used due to higher efficacy in

normalizing PRL levels and shrinking

pituitary tumours

. For symptomatic patients with

treatment

-resistant prolactinomas,

increase the dose to maximal

tolerable dose before referring for

surgery

• Most women with prolactinomas

should discontinue dopamine agonist

therapy immediately if they become

pregnant (except for patients with

large invasive tumours)

Treatment

• first line: dopamine agonists (bromocriptine, cabergoline, quinagolide)

• surgery ± radiation (rare)

• PRL-secreting tumours are often slow-growing; treatment may not be necessary in the setting ofsmall

tumours associated with hyperprolactinemia which does not result in hypogonadism or bothersome

galactorrhea

• if medication-induced, consider stopping medication if possible

• in certain cases if microprolactinoma and not planning on becoming pregnant, may consider OCP

Thyroid Stimulating Hormone

. see '

thyroid,£24

Adrenocorticotropic Hormone

• tee AdrenalCortex, £33

Luteinizing Hormone and Follicle Stimulating Hormone

Hypergonadotropic Hypogonadism

• hypogonadism due to impaired release of PSH and LH

Etiology

• congenital: Kallmann syndrome, CHARGE syndrome, GnRH insensitivity

• secondary: CNS or pituitary tumours, pituitary apoplexy, hypothalamic- pituitary radiation,

drugs (GnRH agonists/antagonists,glucocorticoids, narcotics, chemotherapy, drugs causing

hyperprolactinemia, opioids),functional deficiency due to another cause (hyperprolactinemia,

chronic systemic illnesses, eating disorders, hypothyroidism, DM,Cushing’s disease),systemic

diseases involving the hypothalamus/pituitary (hemochromatosis,sarcoidosis, histiocytosis)

Clinical Features

• amenorrhea,low libido, decrease in energy, erectile dysfunction (see Urology. U33),loss of body hair,

thin skin, testicular atrophy,decrease in muscle mass, and failure of pubertal development

Treatment

• treat underlying cause if present

• combined l

'

SH/LH hormone therapy, hCG, recombinant l

'

SH,or pulsatile GnRH analogue if fertility

desired

• symptomatic treatment with estrogen/testosterone

hypergonadotropic Hypogonadism

• hypogonadism due to impaired response of the gonads to ESH and LH

Etiology

• congenital:

chromosomal abnormalities (Turner'

ssyndrome, Klinefelter syndrome, XX gonadal dysgenesis)

enzyme defects ( I7a-hydroxylase deficiency, 17,20-lyase deficiency)

gonadotropin resistance (Leydig cell hypoplasia, ESH insensitivity, pseudohypoparathyroidism

type 1A)

• acquired:

gonadal toxins (chemotherapy,radiation)

drugs(antiandrogens, alcohol)

• infections (S'

l

'

ls, mumps)

gonadal failure in adults(androgen decline and testicular failure in men, premature ovarian

insufficiency and menopause in women)

Clinical Features

• amenorrhea,erectile dysfunction (see Urology, U33),loss of body hair,fine skin,testicular atrophy,

failure of pubertal development,low libido, decrease in energy, and infertility

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