Evaluation and Management of Pituitary Failure. Dr S. Ali Imran MBBS, FRCP (Edin), FRCPC Professor of Medicine Dalhousie University, Halifax, NS

Evaluation and Management of Pituitary Failure Dr S. Ali Imran MBBS, FRCP (Edin), FRCPC Professor of Medicine Dalhousie University, Halifax, NS

Conflict of Interest None

Objectives Diagnostic approach to pituitary failure Common diagnostic pitfalls and how to avoid over-investigation Basics of pituitary replacement therapy

Fatigue and weight loss 46 yr old male with over 5 yr HO fatigue, weight loss of 7 lbs, night sweats and poor libido Cortisol = 212 nmol/l (120=620) TSH = 0.25 miu/l (0.35-5.50) T4 = 9.8 pmol/l (10-19) PRL = 6.7 ug/l (2.1-17.7) LH = 2.5 IU/L (1.5-9.3) FSH = 6.6 IU/L (1.4-18.1) Testosterone = 11.2 nmol/l (8.4-28.7)

What is the Hypothalamic Pituitary System? Hypothalamus is your body s main connection to the external world and it modulates your neuroendocrine and behavioural responses. Pituitary (from pituita or phlegm), is your master gland that modulates your major hormones through input from the hypothalamus

The Hypothalamic Pituitary System

Hypothalamo-pituitary hormones Important

Certain important concepts Pulsatile secretion of pituitary hormones and their effect Diurnal rhythm Positive and negative feedback Concept of stimulation and suppression tests Inappropriately normal hormone levels

Pulsatility matters!

Diurnal rhythm Variation in cortisol production during 24 hrs

Positive and Negative feedback

Traditional causes of hypopituitarism? Hypopituitarism is partial or complete loss of pituitary function leading to pituitary hormone deficiency.

Pituitary masses are common Prevalence: 107/100,000 in NS Aldahmani K et al,can J Neurol Sci 2015

Hypopituitarism is common in pituitary masses Aldahmani K et al,can J Neurol Sci 2015

Think of drug induced hypopit Hypopituitarism is partial or complete loss of pituitary function leading to pituitary hormone deficiency.

Now that you suspect hypopituitarism what questions to ask?

Is their any pituitary insufficiency? Prolactin Inability to breast feed GH Fatigue, increased adiposity and reduced exercise capacity Cortisol Weight loss, fatigue, muscle weakness, postural dizziness, salt craving

Is their any pituitary insufficiency? TSH Fatigue, weight gain, cold intolerance LH/FSH Amenorrhea, infertility, loss of sexual function, osteoporosis ADH Polyuria, polydipsia

CONSIDERING PITUITARY INSUFFICIENCY? RULE OUT THE BIG THREE FIRST

CONSIDERING PITUITARY INSUFFICIENCY WITH TUMOURS? RULE OUT THE BIG TWO FIRST Hypocortisolism, Hypothyroidism and DI

Test hormonal function between 0800-0900 if possible or within 2 hours of awakening (in case of shift workers)

Yip CE et al, 2013

Diagnosing hypocortisolism In symptomatic patients a random serum cortisol of < 130nmol/L is diagnostic. Check simultaneous ACTH and if either undetectable or normal (inappropriately) it confirms HP dysfunction. Basal 0900 cortisol of > 250 nmol/l (without critical illness) indicates normal HP reserve* Yip CE et al, 2013

Diagnosing hypocortisolism If cortisol is between 130-250 nmol/l adrenal stimulation test with either insulin induced hypoglycemia or synthetic ACTH is undertaken. An absolute peak response TO > 500-550 nmol/l to both is regarded as normal (It s not an increment*) Yip CE et al, 2013

Insulin stress test

ACTH stimulation test Serum cortisol is measured 30 and 60 minutes after injecting 250 mcg of ACTH. A value of >500 nmol/l means normal response. This test is false negative in 10-15% patients! Clayton RN, Clin Endocrinol, 1996

Steroid replacement simplified! Cortisol (HC) is the active hormone and the preferred replacement. 11 βhsd-1 Cortisone acetate Prednisone Dexamathasone Only serum cortisol is measured through the available assay. Other steroids can t be measured thus can t be adjusted.

Traditional steroid dosages Hydrocortisone is started at 20 mg A.M. and 10 mg P.M. Prednisone 5+2.5 mg DXM 0.5 + 0.25 mg HC 20 + 10

Recommended steroid dosages Hydrocortisone is started at 10 mg A.M. and 5 mg P.M. Prednisone 5+2.5 mg* DXM 0.5 + 0.25 mg* Most patients receive at least 50% larger dosage than needed

Emergency Management of hypoadrenalism Intamuscular: Hydrocortisone 100mg every 6 hrs. *An IV bolus is cleared quickly and shouldn t be used. Intravenous infusion: HC @ 3-4 mg/h No need to give fludrocortisone Supportive treatment like fluids, glucose management and management of the underlying illness.

Dose adjustment by UFC and day curve Maintain UFC values within mid-normal range. Perform day curve 600 nmol/l 500 nmol/l 400 nmol/l 300 nmol/l 200 nmol/l 100 nmol/l 0900 sample 1230 sample Morning dose at 0800 1700 sample

A steroid bracelet must be worn!

Diagnosing 2 0 hypothyroidism TSH = 2.3 and T4 = 7.8 TSH alone is not sufficient for diagnosing secondary hypothyroidism. You need T4 too! Normalization of TSH is not the goal of replacement therapy. Although debatable, the goal is achieving mid-normal T4 level. It is also suggested that optimum dose is 1.6 mcg/kg* (Bunevicius, et al, 1997,Sawka, et al., 2003,Zimmerman, 2003)

T4 replacement is variable Cross sectional analysis of 354 patients with SH from Halifax, NS and Leicester, UK. T4 levels based on weight. mcg/kg T4 Dose 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 0 100 200 300 Daily Thyroxine Dose Brandsema J et al, CSEM 2004 Quebec, October 27-30.

Managing 2 0 hypothyroidism TSH = 0.21 and T4 = 12.4 As with primary hypothyroidism, start T4 replacement at a small dose and gradually build up the dose to keep T4 around the mid-normal range. If patient develops symptoms of hyperthyroidism, start cutting the dose back until symptoms resolve.

Diagnosing GHD

Effect of GH replacement Improvement in QOL Increased lean body mass, bone mass and low fat Increased cardiac and muscle oxygen uptake Improved cardiac systolic and diastolic function Although GH deficiency is associated with higher mortality but does GH treatment reverse that---- Not clear.

Gonadotropin deficiency or central hypogonadism Diagnosis of hypogonadism is made through low serum testosterone/estradiol and low/inappropriately normal LH and FSH

Gonadotropin deficiency or central hypogonadism Loss of body hair Gynecomastia Testicular shrinkage Excessive fat deposition Osteoporosis Amenorhea Breast shrinkage Vaginal dryness Osteoporosis

Association of Low T Levels with Aging

Biochemical Evaluation of Serum T Circadian rhythm influences serum T 1 Ratio 1.2 1.15 1.1 1.05 1 0.95 0.9 0.85 0.8 0.75 0.7 8 9 10 11 12 13 14 15 16 Time (hours) Age (yrs) 80 70 60 50 40 30 Circadian rhythm effect decreases with age Obtain serum sample between 7 and 11 am 2 1. Brambilla DJ, et al. J Clin Endocrinol Metab. 2009;94:907-913. 2. Wang C, et al. Eur J Endocrinol. 2008;159:507-514.

Daily Variability in T Subject 10 Up to 50% of young healthy men have temporary T levels below the normal range in a 24-hour period. 1 Testosterone (ng/dl) Testosterone (ng/dl) Subject 7 900 700 500 300 100 900 700 500 300 100 10:45 18:00 24:00 6:00 10:10 18:00 24:00 6:00 Time (clock hours) 1. Spratt DI, et al. Am J Physiol. 1988;254:E658-666.

Testosterone Replacement Therapy Under 50: 200 mg IM q 2 weekly Over 50: 100 mg IM q 2 weekly Not recommended s Androgel: 5-10 g daily Testim: one tube daily s

Female Hormone Replacement Therapy Goals: Symptom improvement Replacement of physiological levels Several safe and effective formulations available s

Diabetes Insipidus Presents with polyuria and polydipsia. Ask about the amount and frequency of urine.

A fasting serum osmolality > 600 mosmol/kg excludes DI

Practical tips for DI The first step is to confirm polyuria and polydipsia. If 24-h urine volume is < 2.5 L and serum Na is normal, it is very unlikely that the patient has DI. If early morning serum osmolality is high normal and urine osmolality is > 600 mosmol/kg, DI is unlikely. If in doubt still, get a water deprivation test but do NOT start DDAVP since treatment of DI is WATER.

Water deprivation test Measure AVP

Management of DI DDAVP with SC, PO or intranasal. Adjust the dose till patient becomes asymptomatic. Fine tune the dose to normalize serum electrolytes. Avoid over-replacement which is diagnosed through hyponatremia

Canada s Ocean Playground