Pituitary Hormone replacement-What ’ s the big deal?

1. Theodore C. Friedman, M.D., Ph.D.Professor of Medicine-UCLAChairman, Department of Internal MedicineCharles R. Drew UniversityThe Ins and Outs of Pituitary Hormone Replacement MAGIC Adult Convention Las Vegas, NVApril 21, 2013

2. Pituitary Hormone replacement-What’s the big deal? • Pituitary disorders are common, but experts in treating them properly are not! • Small changes in replacement may make a big improvement in symptoms. • Many endocrinologists do not understand how to properly replace patients with hypopituitarism and do not understand (or don’t believe in) monitoring hormone levels. • We simply see the need to do more!

3. Hormonal Axes • Adrenal (corticotropes)=CRH-ACTH-Cortisol • Thyroid (thyrotropes)= TRH-TSH-T4/T3 • Gonads (gonadotropes)=GnRH-LH/FSH-Testosterone/estrogen • GH (sommatotropes) =GHRH-GH-IGF-1

4. Causes of Hypopituitarism • Anywhere along the hypothalamic-stalk-pituitary axis • Microadenomas! (Yuen, et al. Clinical Endocrinology 69:292-298, 2008

5. Pituitary Causes of Hypopituitarism • Pituitary Tumor (macroadenomas vs. microadenomas) • Pituitary Surgery • Pituitary radiation • Sheehan’s syndrome/ pituitary apoplexy • Hypophysitis • Pituitary infiltration • Empty Sella • Malnutrition/critical illness • Head trauma

6. Stalk/Hypothalamic Causes of Hypopituitarism • Craniopharyngioma • CNS malignancy • Surgery/radiation • Head trauma/accidents • Infiltrative diseases (histiocytosis X, hemachromatosis, sarcoidosis) • Infection • Drugs (steroids, dopamine analogues, somatostatin analogues)

7. Order of hormone deficiencies • GH • Gonadotropins (FSH, LH) • TSH • ACTH • Prolactin • Posterior pituitary hormones

8. Microadenomas and hypopituitarism (Yuen et al, 2008) • 38 patients with non-secreting pituitary microadenomas (mean tumor size 4.2 mm) and normal serum IGF-I levels were studied. • 19 patients (50%) were found to be GH-deficient, and had higher body mass index (BMI) than those that passed the GHRH-arginine test and healthy controls. • 19 patients (50%) had at least one other pituitary hormone deficit. • We concluded that a substantial number of patients with non-secreting pituitary microadenomas were GH-deficient despite normal serum IGF-I levels, and had at least one other pituitary hormone deficit, suggesting that non-secreting microadenomas may not be clinically harmless.

9. Microadenomas and hypopituitarism • Patients with low IGF-1 and a microadenomas are even more likely to be growth hormone deficient. • Many Endocrinologists test for hypopituitarism only if a patient has had prior surgery or radiation to their pituitary. • My approach is to measure pituitary hormones first and if it points to hypopituitarism, then get a pituitary MRI

10. Glucocorticoid Insufficiency-Diagnosis • Screen with 8 AM cortisol • If < 3 mg/dL-clear glucocorticoid insufficiency • If > 12 mg/dL and not severe stress, glucocorticoid insufficiency unlikely • 3-12 mg/dL-gray zone-do cosyntropin test (unless acute)

11. Glucocorticoid Insufficiency • Needs significant impairment of pituitary function • Classically, pituitary only affects cortisol, not mineralocorticoids (salt regulating hormones from the adrenals) • Can be life-threatening, but most patients do surprisingly well • Fatigue, lethargy, nausea, vomiting, joint pains, abdominal pain, weight loss, hypoglycemia (rare in adults), low sodium

12. Adrenal fatigue • Under stress, adrenals make more cortisol, not less. • Low cortisol needs to be either pituitary (associated with other pituitary hormone defects) of adrenal (high ACTH, low aldo, high renin) • “Adrenal fatigue” with the adrenals “petering out” makes no sense.

13. Standard (1 hr) Cosyntropin Test • 250 mg of IV cosyntropin (ACTH1-24) • plasma cortisol at time 0, 30 and 60 minutes • any value over 20 mg/dL is normal • if peak response is less than 10 mg/dL, glucocorticoid replacement is required • if peak response is between 10 and 20 mg/dL, glucocorticoid replacement is recommended during stresses, otherwise replacement needs to be individualized

14. 1 mg vs. 250 mg cosyntropin test • 250 mg is supraphysiological, will miss subtle glucocorticoid insufficiency • Mild ACTH deficiency, like mild hypothyroidism exists and the consequences of misdiagnosis may be severe. • Why do the test? • My philosophy-I want as many patients to know they have borderline HPA function and as few patients as possible on replacement steroids • Needs better cut-offs, but I use 18 mg/dL for 1 mcg and mg/dL for 20 mcg

15. Daily cortisol production rate in man • Esteban et al. (JCEM, 72: 39, 1991) measured daily cortisol production rates in normal volunteers with a stable cortisol isotope method. • 9.9 +/- 2.7 mg/day, 5.7 mg/m2 day. • Not all of oral cortisol is absorbed, need to take 12-15 mg/day • Most glucocorticoid replacement is supraphysiological. • Leads to osteoporosis, glucose intolerance and increased infections. • True physiological replacement is likely to be fairly benign

16. Glucocorticoid Replacement • Most patients are over-treated • Earliest manifestation of excess treatment is easy bruising • Weight gain, central obesity, etc. • Earliest manifestation of inadequate treatment is joint pain. • Reasonable to mimic circadian rhythm with most or all cortisol given first thing in the morning • Want to avoid nighttime administration as it could lead to sleep disturbances, • But, some patients need a bit of cortisol at night to go into deep sleep (Garcia-Borreguero, D. (2000) J. Clin. Endocrinol. Metab. 85:4201-4206) • No studies comparing different treatment regimens

17. Glucocorticoid Replacement (2) • My approach is to use hydrocortisone mainly in AM-aim for dose between 10 and 20 mg/day in a women and slightly higher in a man. • Decrease dose slowly until some symptoms develop, then go back a dose. • Small changes make a big difference • Increase dose with illness, short term its better to err on giving more, long term its better to give less • Can take a bit more (1.25-2.5 mg before heavy exercise)

18. Monitoring glucocorticoid replacement • Signs and symptoms • 24 hr urine for 17-hydroxysteroids (17-OHS) • UFC tends to be high during replacement • In replacement, most of UFC excretion occurs right after taking the cortisol, as high doses are not bound to CBG and exceeds reabsorption by the kidney. • 17-OHS (corrected for creatinine excretion in g/day) reflects cortisol metabolism and is more integrated throughout the day.

19. Monitoring glucocorticoid replacement • LW: Sheehan’s syndrome-very athletic and health conscious • HC tapered from 20 mg/day to 17.5 mg/day (12.5 mg in AM, 5 mg in PM)-less bruising, slight weight loss • On 17.5 mg a day-UFC 191 mg/day (10-34) • 17-OHS 4.7 mg/day (2-6) • 17-OHS/gm Cr 3.5 mg/day (1.6-3.6) • Went down to 15 mg/day of HC, had an adrenal crisis when had the flu

20. Steroid coverage for illnesses or surgery • Short-term give more, but keep duration short • Moderate illness in hospital • 50 mg of hydrocortisone twice a day • Severe illnesses • 100 mg of IV hydrocortisone Q 8 hours • Minor procedures without anesthesia • No extra coverage • Moderately stressful procedures (endoscopy or arteriography • Single 100 mg IV dose of hydrocortisone prior to procedure • Major surgery • 100 mg of IV hydrocortisone before anesthesia and Q 8 hours

21. Steroid coverage for illnesses or surgery • Exercise-can add 2.5-5 mg before major exercise. • Flus and colds-could add 5-10 mg if fever • Pneumonias, sinus infection, urinary tract infections-double the dose-but for as short as possible

22. Central Hypothyroidism • Common, even with small tumors • Mild cases may be more manifest clinically more than “subclinical hypothyroidism” due to actual low thyroid hormones in central hypothyroidism • Similar signs/symptoms as in primary hypothyroidism. • Low free T4 in the face of lowish TSH. • In mild cases, free T4 between 0.7 and 1.0 ng/dL • Measuring free or total T3 not helpful

23. Central Hypothyroidism-Confirmation • TRH test (hard to get)-can show blunted TSH response to TRH • nocturnal TSH test (TSH should rise at least 1.5-fold between 5 PM and midnight) in normals, but not in patients with central disease-not easy to get blood at midnight • Usually base on baseline free T4 and TSH

24. Central Hypothyroidism-Treatment • Thyroid gland makes both T4 and T3. • T3 is the active hormone, but has a short-half life; T4 has a long half life • L-thyroxine in most cases, but just as some patients with primary hypothyroidism do better on T4/T3 combinations (see next slide, some patients with central hypothyroidism may also do better on T4/T3 combinations). • GH deficiency can lead to impaired T4 to T3 conversion, so T3 may be especially beneficial in central hypothyroidism • Monitor by aiming for free T4 in upper-normal range (1.5-1.7 ng/dL). • TSH will be suppressed and is usually not worth measuring after starting treatment. • Patients with both primary hypothyroidism and a central component should also be monitored with free T4 and not TSH measurements.

25. Central Hypothyroidism-Treatment • Many options for thyroid hormone replacement. • L-T4 alone (Levothyroxine, Synthroid, Levoxyl, Tirosint, Unithroid) • L-T3 alone • L-T4/L-T3 combinations • Desiccated thyroid (Armour, NaturThroid, Erfa)-from pig thyroid • Desiccated thyroid/L-T4 combinations • Proper treatment needs to be individuals (not one blood pressure medicine). • Multiple studies have shown poor quality of life among patients on L-T4 replacement • About 16% of patients have a polymorphisms (change in DNA) in their type 2 deiodinase that converts T4 to T3 (Panicker et al, JCEM, 2009, 94:1623-1629). These patients did better with T4/T3 combinations.

26. Central Hypothyroidism-Treatment-Armour • Armour thyroid is made by Forest Labs and concern about variability of preparations and lack of standardization are unfounded. • Armour has a higher T3/T4 ratio than the human thyroid. Most patients on Armour alone have high fT3, low fT4 and low TSH • L-T3 has a short half-life and L-T3 or Armour should be given twice a day • There may be other components of thyroid missing in synthetic preparations. • I usually give Armour in a twice a day dose with extra L-T4 supplementation, especially in patients with a poor quality of life on L-T4 alone. • Another option is a higher L-T4 dose with a low Armour dose • For hypopit patients, I aims for a fT4 and fT3 in upper normal range, with a suppressed TSH. • My patients do not have a problem with the “new” formulation of Armour

27. Central Hypothyroidism-L-T4/L-T3 treatment • Some but not all studies show a benefit of L-T4/L-T3 treatment over L-T4 alone. • Large study in Italy (Gullo, PLoS One, 2011, 6:e22552) found that in patients without a thyroid given L-T4 replacement, 15% had a low serum fT3 level, but normal TSH levels. • This suggests that certain patients have a different setpoint for TSH secretion and that some patients need L-T4/L-T3 treatment to achieve normal freeT3 and freeT4 levels. • It supports measuring freeT3 and freeT4 in patients on treatment.

28. Central Hypothyroidism-L-T4/L-T3 treatment • Celi et al. (JCEM, 2011, 96:3466-74) found that patients on L-T3 alone had lower weight and better lipid profiles than those on L-T4 alone. • I often give L-T4/L-T3 combination therapy (or Armour/L-T4) to patients who don’t do well on L-T4 alone, but these studies suggest that many patients should be on combination therapy (I recently added a low dose of Armour twice a day to my L-T4 treatment). • If give T3 alone, T4 goes to 0, I don’t think that is good to have a major hormone 0 and it gives no reserve if you miss a dose. • I usually do not give L-T3 alone treatment as I like the long acting “reservoir” of the L-T4 along with the shorter acting “boost” L-T3 effect.

29. Central Hypothyroidism-L-T4/L-T3 treatment • In general, take thyroid medicine first thing in AM on an empty stomach • If on twice a day treatment, take 2nd dose in mid- afternoon • Avoid taking with • Iron • Calcium • Vitamins with iron or calcium • Proton pump inhibitors, carafate, oral bisphosponates (Fosamax), orlistat, cholestyramine • Minor effect of soy

30. Central Hypothyroidism-selenium • Selenium increases T4 to T3 conversion and reduces TPO antibody levels. • Patients with untreated GH deficiency have decreased T4 to T3 conversion, so they are likely to benefit from selenium (but also benefit from GH treatment) • Selenium appears to increase the rate of diabetes. • I am cautious about giving selenium in those patients with prediabetes or diabetes or those with a family history of diabetes.

31. Growth Hormone Deficiency • Patients with hypopituitarism have increased mortality, suggested, but not proven to be due to GH deficiency • Growth hormone deficiency in adults results in: • Decreased bone formation • Increased fat mass (central obesity) • Decreased muscle mass • Lipid abnormalities • Increased thickness of blood vessels • Increased inflammatory markers • Impaired quality of life • Increased number of sick days • Impaired exercise tolerance • Most symptoms are corrected by treatment

32. Growth Hormone Deficiency-Diagnosis • Screen with IGF-I: • If in top 75% of normal range for age and sex (> 150 ng/mL)-GH deficiency less likely • If empty sella, history of head trauma, headache and low blood pressure after delivery (Sheehan’s syndrome), history of pituitary surgery or radiation or pituitary tumor (micro or macro adenoma)=GH deficiency more likely • If < 75 ng/mL-GH deficiency likely • Stimulation testing • Glucagon stimulation test is preferred- GH deficient if GH is < 5 ng/mL (cutoff is unclear) • ITT- GH deficient if GH (by RIA) is < 5 ng/ml • I use glucagon unless need to use ITT for adrenal insufficiency workup

33. Growth Hormone Deficiency-Diagnosis • I don’t agree that “mild’ growth hormone deficiency should not be treated. • Stimulation tests are non-physiological, but gold-standard, maybe more important is day to day GH/IGF-I axis than with stimulation. • Unclear what to do with patient with hypopituitarism and lowish IGF-I and normal stimulation testing.I often use a supplement called D-trans-tropin which stimulates the hypothalamus to secrete more GHRH and is available at compounding pharmacies.

34. Adult Growth Hormone Treatment • 10% of dose/body weight than that of children. • Don’t need to adjust for body weight. • Women, especially on oral estrogens, need higher doses than men. • Start at 0.4 mg/day in women, 0.2 mg/day in men. • Final dose varies widely and can not be predicted. • Titrate upwards with IGF-I measurements monthly. • Aim for IGF-I in upper 1/3 of normal range (200-300 ng/mL). • Usually not much improvement in symptoms until in this range. • Too much GH-joint (hand mainly) swelling and pain.

35. Estrogen Replacement-Women • Amenorrhea or oligomenorrhea indicates gonadotropin deficiency • Irregular periods may be an early sign of pituitary dysfunction • WHI and HERS studies were on post-menopausal women not previously on estrogen (average age in WHI-63) and used oral estrogen preparations • Younger women who are hypogonadal are likely to benefit from estrogen replacement. • Young women ‘feel better” on higher estrogen preparations and may require higher doses than post-menopausal women.

36. Estrogen Replacement-Women (2) • Oral, but not transdermal estrogens inhibit the action of GH at the liver, leading to higher GH and lower IGF-I levels (Wolthers et al, AJP-Endo, 2001, 281:E1191).-I avoid oral estrogens or birth control pills for patients on GH. • I like an estrogen patch (Climara or Vivelle) or estroGel (cream). • Titrate dose so that estradiol is in the upper normal range for the follicular period (50-100 pg/mL). • Progesterone (Prometrium is my preferred choice) in women with a uterus and can probably be given every 3 months to induce a period. • Give Prometrium at night as it is sedating. • If a women stops oral estrogens or birth control pills and stays on the same dose of GH, her IGF-1 will rise dramatically and she will likely get hand swelling and joint pain

37. Androgen Replacement-Men • Symptoms include low libido, erectile dysfunction, fatigue, decreased muscle mass • Soft testes may be the earliest sign of gonadotropin deficiency • Small testes or gynecomastia may be seen and helpful in borderline testosterone levels • Measure free (by equilibrium dialysis) and total testosterone levels. If total Testosterone < 200 ng/dL, testosterone deficiency likely. • If 200-350 ng/dL- borderline result, use clinical judgment plus free testosterone. • LH/FSH helpful only to exclude primary hypogonadism.

38. Androgen Treatment-Men • Testosterone gel or patch is easier. • Injections often give better results with erectile dysfunction. • New option is subcutaneous (in the stomach) shots twice a week • HCG is another possibility and making a come-back (does not cause testicular shrinkage). It is similar to LH from the pituitary. • Clomiphene (clomid)-blocks feedback inhibition by estradiol on the pituitary, which increases LH and testosterone. • It’s a pill-50 mg every other day is a good dose-main side effect is gynecomastia. • Good short term solution as it stimulates HPG axis

39. Androgen Treatment-Men • Aim for total testosterone levels in the upper normal range. • Androderm patch 5 mg- may need 2 patches to achieve appropriate levels-lots of skin irritation • AndroGel 1% 5 G delivers 5 mg, may also need higher doses (7.5 or 10 G) • Testosterone subcut 50 mg twice a week

40. Androgen Treatment-Women • Women with hypopituitarism have low testosterone levels-due to LH (on the ovaries) and low ACTH (on the adrenals). • Measuring testosterone (and bioavailable testosterone) by a good laboratory can be a clue to hypopituitarism. • Bioavailable testosterone is more accurate than free testosterone in women

41. Androgen Treatment-Women • Our study (still unpublished) on testosterone levels in women with hypopituitarism and normal volunteers found that low testosterone levels were highly correlated with subjective measures including low libido, low arousal, low mood, depression and fatigue • Objective measures of sexual function including genital sensation and genital blood flow were not correlated with testosterone levels. • However, in a small number of patients treated with a testosterone gel, these deficiencies did not improve with treatment.

42. Androgen Treatment-Women • Testosterone deficiency in women with hypopituitarism leads to impairment in subjective, but not objective sexual function. • Testosterone more likely affects central (brain) rather than peripheral processes. • Genital sensation and genital blood flow are probably not testosterone-mediated.

43. Androgen Treatment-Women • I still recommend testosterone replacement in women with hypopituitarism with a low total (< 10 ng/dL in a good assay) with testosterone cream. • Compounding pharmacies (Bellevue Pharmacy) have reliable and safe preparations. • In almost all my patients treated with testosterone cream go from low testosterone levels to high-normal levels with minimal side effects. • Side effects include acne, extra hair growth, rage, and oily skin

44. Diabetes Insipidus • Excessive urination and thirst • Mild cases are probably common and worthy of treatment • Chronic polyuria may lead to bladder/kidney problems • How many times are you waking up at night?

45. Diabetes Insipidus (2) • I screen by having the patient collect urine for 24 hours and measure the volume. • Greater than 3 L indicates diabetes insipidus is likely • I confirm with a 12 hour fast (no water!) and collect an 8 AM serum and urine osmolality. • DI-High serum osmolality (>300 mOsm/kg), low urine osmolality (<500 mOsm/kg) and low AVP < 1pg/mL). • Formal water deprivation test probably not needed.

46. Diabetes Insipidus (3) • DDAVP pills are probably the best; most Endocrinologists still recommend nasal puffs. • Take most of the dose at night to prevent waking up at night. • Should have a period of “break-through” urination. • Treatment is pretty benign.

47. What’s the problem? • Most patients are on : • Too much cortisol • Not enough thyroid medication • Not enough growth hormone • Not on testosterone • Leads to weight gain and depression. • Get your doses adjusted!

48. Hormonal Interactions • Treating a patient with adrenal insufficiency and hypothyroidism with thyroid hormone increases the breakdown of cortisol and may lead to an adrenal crisis. • Thyroid hormone may also increase catabolism of other hormones (GH, testosterone) and lead to increased requirements when thyroid dose is increased. • Treating with GH may increase T4 to T3 conversion, so the dose of T3 (if on T3) may need to be reduced.

49. Hormonal Interactions (2) • Oral, but not transdermal estrogens, increase the need for L-thyroxine in women with hypothyroidism (Arafah, BM, NEJM, 344:1743). • Oral, but not transdermal estrogens, increase the need for GH replacement. • Stopping oral estrogens leads to an elevated IGF-1 (hand swelling). • Patients on GH replacement should probably not be on oral estrogens.

50. Hormonal Interactions (3) • Treating adrenal insufficiency may unmask diabetes insipidus • Testosterone raises IGF-1