41. Endocrine and Metabolic Diseases

Question 1

What are the two embryologically distinct portions of the pituitary and what tissues do they derive from?

Answer 1

Adenohypophysis: invagination of the pharyngeal epithelium (Rathke’s Pouch) Neurohypophysis: Or pars nervosa is derived from neural tissue of the hypothalamus

Question 2

The adenohypophysis can be divided into?

Answer 2

The pars distalis, pars tuberalis, and pars intermedia

Question 3

What is the thought to be the main function of the pars tuberalis?

Answer 3

Believed to be involved in regulating the seasonal rhythm of reproductive hormone production. Rich in melatonin receptors

Question 4

What is the function of the pars nervosa?

Answer 4

Collection of nerve axons and terminals that origins in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus Oxytocin and ADH are produced in the PVN/SON and stored in and released from the pars nervosa

Question 5

What cell type is present in the par intermedia of the horse

Answer 5

Melanotropes

Question 6

Describe the innervation of the melanotropes in the pars intermedia

Answer 6

Innervated by nerve terminals of the paraventricular nucleus (PVN) dopaminergic neurons

Question 7

Describe the action of Dopamine on melanotropes in the pars intermedia

Answer 7

Interacts with Dopamine (D2) receptors and inhibits cell proliferation, transcription of POMC, and release of POMC-derived peptides

Question 8

What stimulates hormone release from melanotropes in the equine pars intermedia

Answer 8

Thyrotropin-releasing hormone (TRH)

Question 9

What are the cell types of the pars distalis

Answer 9

1. Corticotropes- release ACTH in response to CRH
2. Somatotropes- release GH in response to GHRH
3. Thyrotropes- release TSH in response to TRH
4. Gonadotropes- release FSH and LH in response to GnRH
5. Lactotropes- release prolactin in response to dopamine and somatostatin

Question 10

POMC in corticotropes is primarily processed into? And by what?

Answer 10

ACTH by Prohormone convertase 1

Question 11

POMC in melanotropes is converted to what? By what?

Answer 11

1. α-melanocyte stimulating hormone (α-MSH)
2. β-endorphin (β-end)
3. Corticotropin-like intermediate lobe peptide (CLIP
4. Small amount of ACTH

By Prohormone convertase I and II

Question 12

What is the most abundant form of β-end produced in the normal horse’s pars intermedia

Answer 12

Ac-β-end (No opioid activity)

Question 13

What is the most abundant β-end in horses with pituitary pars intermedia dysfunction (PPID)?

Answer 13

β-end, an opioid agonist

Question 14

What is the function of α-Melanocyte stimulating hormone? (3)

Answer 14

1. Pigmentation: through interaction with melanocortin receptor 1 (MC1R)
2. Energy homeostasis: MC3R and MC4R in the CNS particularly in the hypothalamus, where they function in the leptin-melanocortin pathway, regulating appetite-satiety balance and fat metabolism
3. Anti-inflammatory: Regulation of cytokine response

Question 15

Describe the pathophysiology of PPID

Answer 15

• Hypertrophy, hyperplasia, and microadenoma or macroadenoma formation in the pars intermedia with increased secretion of POMC peptides
• Compression of the adjacent pituitary lobes and hypothalamus with a decreased or loss of function of those tissues
• Signs of disease is from both increased pars intermedia products and from decreased pars tuberalis, distalis, nervosa, and hypothalamus products
• Loss of dopamine inhibition - there is dopaminergic neurodegeneration, so appears to be of hypothalamic origin rather than a spontaneously forming pituitary adenoma
• Possible causes of dopaminergic neurodegeneration: oxidative stress (dopaminergic neurons are particularly vulnerable to oxidative damage)

Question 16

Explain the muscle atrophy seen in PPID

Answer 16

Type 2 myofiber atrophy in horses with PPID, consistent with corticosteroid-associated muscle atrophy in other species

Question 17

What are the possible mechanisms for PU/PD in PPID

Answer 17

1. Compression of the pars nervosa resulting in decreased ADH production
2. Cortisol induced: Interferes with ADH secretion and may inhibit renin-angiotensin-aldosterone axis
3. Osmotic diuresis secondary to hyperglycemia and glucosuria (unlikely)

Question 18

What are the main tests for PPID?

Answer 18

1. Dexamethasone suppression test (DST)
2. ACTH
3. Thyrotropin-releasing hormone (TRH) stimulation test

Question 19

Discuss the Dexamethasone suppression test (DST)

Answer 19

• In the unaffected horse, IM dexamethasone decreases release of ACTH from the pars distalis, resulting in a serum cortisol concentration of less than 1 µg/dL 19 hours after dexamethasone.
• Only useful in identifying horses with end-stage disease

Question 20

Discuss ACTH measurement

Answer 20

Easiest to run in the field

Sensitivity 70% and specificity 80% so poor at identifying early disease

Question 21

Discus the TRH stim test

Answer 21

• Measure plasma ACTH concentration at time 0, 10, and 30 minutes after IV TRH (1 mg/horse or 0.5 mg/pony)
• 30 minute sample may not be needed
• Most accurate test
• Recommended to do in non-autumn seasons as TRH response can be very variable

Question 23

Discuss the use of pergolide in PPID

Answer 23

Dopamine agonist

Initial dose 0.002 mg/kg PO q24h

If clinical signs and diagnostic tests for PPID don’t normalize within 4 weeks then increase monthly by 0.001-0.002 mg/kg until normal

Repeat testing every 6-12 months

Question 24

Discuss Cyproheptadine in PPID

Answer 24

• Antiserotoninergic, antihistaminergic, and anticholinergic activity
• Dose 0.3-0.5 mg/kg PO q24h
• Was one of the original drugs used to treat PPID but has variable efficacy
• Can use along with pergolide in horses that require higher doses of pergolide (0.06mg/kg or higher)
• More $$$