1. Southwest Ohio Regional Updates in Internal Medicine 2018
Endocrinology: Pituitary Disorders
Ruchi Bhabhra MD PhD
Adjunct Assistant Professor
Division of Endocrinology
University of Cincinnati

2. Outline Pituitary anatomy and physiology Hyperprolactinemia
Managing a prolactinoma during pregnancy
Acromegaly
Pituitary hormone deficiencies
Pituitary incidentaloma

5. PRL
VASOPRESSIN
OXITOCIN
TSH GH
LH/FSH
ACTH
T4, T3
IGF-1
CORTISOL
TESTOSTERONE/ESTRADIOL

6. Feedback loop: Anterior pituitary (Except PRL)
Feedback loop: Prolactin

7. Hyperprolactinemia
Elevated prolactin level (reference ranges vary by the lab)
Usually found incidentally but sometimes during evaluation of hypogonadism in males/females

8. Symptoms of hyperprolactinemia
Mass effect: Headaches, peripheral vision changes
Males: Decreased libido, erectile dysfunction, gynaecomastia.
Females: menstrual irregularities, secondary amenorrhea, galactorrhea, infertility

9. Causes of hyperprolactinemia
Mild hyperprolactinemia (<50ng/mL): Difficult blood draw, exercise, sleep, food, stress, nipple manipulation, CKD, cirrhosis. Hyperprolactinemia in uncontrolled hypothyroidism: Mech: High TRH from hypothalamus increases prolactin by stimulating the lactotrophs, decreased renal clearance also contributes to high prolactin. Normalizing thyroid function by replacing levothyroxine will normalize prolactin

10. Medications and hyperprolactinemia
Prolactin level
expected
50-150ng/mL

11. Hyperprolactinemia + Pituitary adenoma ≠ Prolactinoma
A co-secreting tumor producing growth hormone and prolactin (acromegaly)
A pituitary tumor causing increased prolactin from compression of the stalk (stalk effect)

12. Prolactinoma size correlates with the prolactin levels
- Microadenomas (<1cm): Prolactin <200 ng/mL
Macroadenomas (>1-2cm): Prolactin ng/mL.
Macroadenomas >2cm: Prolactin >1000 ng/mL
Exceptions to the size rule - When prolactin level is lower than expected for the size of the tumor:
Necrosis/hemorrhage in the tumor
Stalk effect
Hook effect: Prolactin levels too high to be detected by the assays, needs serial dilutions to confirm true levels of prolactin

13. Hook effect
1:100 dilution

14. Macroprolactin
In the absence of symptoms and a mildly elevated prolactin, check a macroprolactin.
Macroprolactin is a polymeric form of prolactin which is detected as high prolactin on regular assays. With PEG precipitation it can be separated.
It is biologically inactive, therefore does not cause any symptoms and requires no treatment.

15. Management of Prolactinoma
Treatment of choice: Dopamine agonists: Cabergoline or Bromocriptine
Mech: Increase dopaminergic drive which decreases prolactin
START MEDICATIONS, NO SURGERY
Even if it’s a macroadenoma (>1cm), patient has optic chiasm compression, visual symptoms and visual field deficits
Goal of treatment:
Microadenoma: Treat hypogonadism, galactorrhea, infertility (risk of growth very low, seen in 10% cases)
Macroadenoma: Prevent tumor growth and normalize prolactin

16. Management of Prolactinoma
For premenopausal females, microadenoma (<1cm), no galactorrhea, no plans for pregnancy: Just OCPs
For postmenopausal females with microadenoma, no symptoms, continue to monitor
For asymptomatic males, mild increase in prolactin, normal testosterone – no treatment necessary, continue to monitor

17. Bromocriptine Cabergoline
Half life
15h
63-69h
Dosing
Start low, – 1.25mg/d, tid dosing, upto mg/d
Start mg twice weekly
Side effects
GI, psychosis, headache, dyskinesias, postural hypotension
GI, headache, dizziness, Cardiac valve insufficiency (high dose)
Cost (30d supply)
2.5mg: $90
0.5mg: $150
50% tumor shrinkage ++
++++
PrL normalization
Non responders
Micro 20%, Macro 30%
Micro 10% ,Macro 20%

18. Prolactinoma during pregnancy
Increased pituitary volume (2X) is expected physiologically during pregnancy so prolactinoma carries a risk of enlargement
Risk of enlargement: 2.6% in microadenoma, 31 % for macroadenomas (especially if no h/o surgery or radiotherapy)
When patient is planning for a pregnancy switch from Cabergoline to Bromocriptine (more safety data in pregnancy)

19. Prolactinoma during pregnancy
As soon as pregnancy test is positive stop dopamine agonsists and monitor clinically
Educate patients on warning signs of headaches or vision changes so they can contact the physician
Macroadenomas may need resumption of medications if there is evidence of tumor growth clinically (headaches, vision changes) and with imaging.

20. Hypopituitarism Secondary adrenal insufficiency
Secondary hypothyroidism
Central diabetes insipidus (DI)
Secondary hypogonadism
Growth hormone (GH) deficiency

21. Hypopituitarism etiologies commonly tested on
IM boards:
Pituitary apoplexy: Pituitary hemorrhage and necrosis, presents with “worst or severe headache”, one or more hormone deficiencies, acute presentation
Traumatic brain injury (TBI): usually acute hypopituitarism
Pituitary surgery, irradiation

22. What else can cause hypopituitarism besides pituitary apoplexy?
Pituitary damage by tumors, surgery, radiation, brain trauma
Infections: Tuberculosis, histoplasmosis
Infiltrative diseases: Sarcoidosis, Langerhans cell histiocytosis, hemachromatosis
Sheehan’s syndrome: Postpartum hemorrhage
Lymphocytic hypophysitis

23. Lymphocytic hypophysitis:
Sheehan syndrome:
Associated with postpartum hemorrhage
Presents months/years later
Difficulty lactating or secondary amenorrhea
Can have GH, cortisol or free t4 deficiency in severe cases.
Lymphocytic hypophysitis:
Autoimmune, presents during late pregnancy (sometimes post partum)
Diffuse enlargement of pituitary on imaging, usually AI or hypothyroidism, severe headaches.
Labs will show one or more hormone deficiencies with a very high prolactin from pregnancy!

24. Secondary adrenal insufficiency is diagnosed by a low cortisol with low or normal ACTH.
Cortisol <3 confirms AI
Cortisol >15 rules out AI.
Cortisol 3-15 needs an ACTH stimulation test to diagnose AI, stimulation test not needed in urgent clinical setting and a known insult to the pituitary (surgery, trauma, hemorrhage etc)
Symptoms of adrenal insufficiency: Fatigue, nausea, vomiting, dizziness, hypotension, hypoglycemia.

25. Treatment of adrenal insufficiency in an acute setting:
Start with iv hydrocortisone 100mg X1 followed by stress dosing 50mg-100mg Q8h
Patient should be gradually tapered to maintenance doses of hydrocortisone 15-25mg per day in divided doses, a larger dose in the morning and another small dose in the afternoon.

26. Secondary hypothyroidism:
- Diagnosis: Low free T4 and a normal or low TSH
- Symptoms of hypothyroidism: Fatigue, weight gain, cold intolerance, constipation, edema, bradycardia
Central diabetes insipidus (DI):
Symptoms of DI: Excessive thirst, increased urine output ( >200cc/h) both during day and night
Serum Na is normal or high, serum osmolality is normal or high, urine osmolality is low, urine specific gravity is low
Treatment: Replace with iv/sc DDAVP starting with 1-2mcg dose at a time. Can transition to PO when patient can tolerate, usual dose is mg nightly or bid

27. Secondary hypogonadism:
Symptoms:
Males: Decreased libido, fatigue, erectile dysfunction, decreased muscle mass and bone
Females: Irregular menstrual cycles or secondary amenorrhea, low bone density
Labs:
- Males: Low total and free testosterone (8AM) with normal or low FSH and LH.
- Females: Low estradiol with normal or low FSH and LH in females
Treatment: Testosterone replacement in males, Estrogen/Prog replacement in females

28. Adult growth hormone (GH) deficiency in panhypopituitarism
- When you have more than 3 pituitary hormone deficiencies always remember to check IGF1 to r/o GH deficiency
Diagnosis: low IGF-1 for the age specific reference range.
Gold standard test: Glucagon or insulin stimulation test
When >3 hormone deficiencies are present, IGF-1 alone
is good for diagnosis, stimulation test not necessary
- GH replacement is not urgent: Can be considered as outpatient

29. Hypopituitarism Symptoms:
Weight gain, increase in shoe size, ring size, enlarged tongue, acne, skin tags, diaphoresis, arthralgias, snoring/sleep apnea, carpal tunnel syndrome, worsening blood glucoses, insulin resistance, HTN
Exam findings:
Frontal bossing, macroglossia, thick and enlarged hands and feet, thickened nasolabial folds, acne, skin tags, acanthosis nigricans, sweaty palms

31. Arthropathy, OA, kyphoscoliosis, vertebral fx, synovitis
70%
Arrythmias, valve abnormalities, diastolic heart failure
60%
Macroglossia, nasal polyps, OSA
50-70%
Impaired glucose tolerance, insulin resistance
15-38%
HTN
33-46%
Risk of cancers NA
Risk of colon cancers 2X
Overall mortality
(duration, GH/IGF-1 level, size of tumor, h/o radiation, h/o HTN, age)
1.5X

32. Lab investigations for diagnosis of Acromegaly
IGF-1 is the first test of choice as its stable, non pulsatile, correlates with GH levels
Normal IGF1 rules out acromegaly
Factors that can increase IGF-1: adolescence, pregnancy
Factors that can decrease IGF-1: Liver disease, malnourishment, poorly controlled DM, hypothyroidism

33. Treatment of choice: Surgery!
75g OGTT for confirmation when IGF-1 mildly elevated, low clinical suspicion, GH levels do not match IGF1
75g glucose load (patient fasting), GH and glu at 0, 30, 60, 90, 120 min
Abnormal GH (>1 ug/ml or 0.4 ug/ml) at any time point
False +: obese, DM2, hyperglycemia, CKD, liver disease, malnutrition, estrogen therapy
Imaging: Once Acromegaly is biochemically diagnosed, pituitary imaging will be needed
Treatment of choice: Surgery!

34. Medical management of Acromegaly:
Somatostatin analogs:
Mech: Decrease GH production and decrease tumor size.
Side effects: GI symptoms, GB sludge: 25% patients.
Octreotide LAR 20-40mg im monthly
Lanreotide autogel mg im monthly
Pasireotide 20-60mg im monthly: worsens hyperglycemia!
Re-evaluate with IGF1 every 12 weeks and increase dose as tolerated

35. Medical management of Acromegaly:
Pegvisomant: Pegylated GH analog
Loading dose 40mg followed by 10-30mg sc daily, closely monitor liver function tests.
Excellent efficacy, normalizes IGF-1 in up to 97 % patients. Tumor growth risk minimal.
Cabergoline: Efficacy only 20-30% which decreases with time, therefore not the first option after surgery.
Usually reserved for combination therapy with other medical modalities for acromegaly.
Synergistic effect with somatostatin analogs. Usual dose 2-3mg/week

36. Pituitary incidentaloma

37. Pituitary Incidentaloma: An Endocrine Society Clinical Practice Guideline 2011, 96 (4) 894-904

38. The hormones to test for in pituitary incidentaloma
- Prolactin
IGF1 to rule out acromegaly
24h urine free cortisol or midnight salivary cortisol to rule out Cushing’s disease
Free T4, TSH to diagnose TSH producing adenoma (rare)
To r/o hypopituitarism: AM cortisol, ACTH, LH, FSH, testosterone (M), estradiol (F), free T4.

39. When is surgery indicated for pituitary incidentalomas?
Hypersecreting tumors other than prolactinomas
A visual field deficit or other vision abnormalities (CN III palsy)
Optic chiasm compression/encroachment
Pituitary apoplexy
Clinically significant growth of a known adenoma
Loss of endocrinological function
A lesion close to optic chiasm and a plan to become pregnant
Unremitting headache

40. Case 1
28 yo F with a h/o of hypothyroidism presents with oligomenorrhea.
Cycles irregular X 1 year. LMP 2 months ago.
Interested in pregnancy. Not using any contraception.
She has a milky discharge from her breasts. No headaches, no peripheral vision defects.
Exam: Unremarkable except for an enlarged goiter.
Labs: Elevated prolactin level at 110ng/mL( ), kidney function normal, CBC normal.

41. Case 1 Which one of the following would be the best next step in evaluation?
Pituitary MRI
Beta hCG
Repeat prolactin level
Check thyroid function
Get a detailed medication history

42. Case 1 Get a detailed medication history
Which one of the following would be the next step in evaluation?
Pituitary MRI
Beta hCG
Repeat prolactin level
Check thyroid function
Get a detailed medication history

43. Case 1 Pituitary MRI: Incorrect
In hyperprolactinemia, pituitary MRI will be helpful to look for the source. However it would be the next choice after you r/o pregnancy.
(B) Beta hCG: Correct
In female patients with hyperprolactinemia, pregnancy MUST be first ruled out since high prolactin and symptoms of hyperprolactinemia (menstrual irregularities/secondary amenorrhea, galactorrhea) can be seen physiologically during pregnancy.

44. Case 1 (C) Repeat prolactin level: Incorrect
This will be a good idea in a patient with mildly increased prolactin and low clinical suspicion. In her case she has all the symptoms of hyper-prolactinemia and modest elevation in prolactin.
(D) Check thyroid function: Incorrect
After pregnancy is ruled out, thyroid function should be checked in all hyperprolactinemia patients. In her case it is even more important as she has a h/o hypothyroidism.
(E) Detailed medication history: Incorrect
This is a key element in evaluating all hyperprolactinemia patients but will not be next step in evaluating the patient discussed in the question.

45. Case 2
54 yo male with a h/o HTN, HLD presents to the ED with a severe headache.
Intermittent headaches and blurred vision x 2 weeks. Worsening fatigue, weakness, nausea, and lightheadedness x 1week. Decreased libido x 2 months.
Exam: Wt 175lbs, Ht 5’8”, BP 90/60, HR 85, RR 20/min, 94% sat. Appears weak, tired and uncomfortable. Visual fields full to confrontation.
Labs: Na 125mEq/L, random cortisol 2.0ug/dL, free T4 0.4 ng/dL ( ), TSH 1.0 μIU/mL ( ), prolactin 40ng/mL ( ), total testosterone (8am) 198 ng/dL ( )
Brain MRI: A 2cm X 2.4cm heterogeneous sellar mass with suprasellar extension, encroaching the optic chiasm, with hemorrhage within the mass.

46. Case 2 What would be the first step in management of this patient?
Start hydrocortisone
Start levothyroxine therapy
Consult neurosurgery
Start DDAVP
Start testosterone replacement

47. Case 2 What would be the first step in management of this patient?
Start hydrocortisone
Start levothyroxine therapy
Consult neurosurgery
Start DDAVP
Start testosterone replacement

48. Case 2 Start hydrocortisone: Correct
This should be the first step in managing any patient with single or multiple pituitary hormone deficiencies related to apoplexy (hemorrhage into the pituitary gland) or any other cause of hypopituitarism.
(B) Start levothyroxine therapy: Incorrect
You would start levothyroxine eventually to address the central hypothyroidism but that should be the next step after replacing glucocorticoids and calling neurosurgery. Replacing thyroid hormone before glucocorticoids can worsen adrenal insufficiency.

49. Case 2 (C) Consult neurosurgery: Incorrect (D) Start DDAVP: Incorrect
Surgical intervention is indicated in pituitary apoplexy but its not the first thing you would do, this would be the second step after replacing glucocorticoids.
(D) Start DDAVP: Incorrect
Patient does not have symptoms or lab findings to suggest central diabetes insipidus (DI) so DDAVP will not be indicated.
(E) Start testosterone replacement: Incorrect
Not urgent in acute setting, certainly needs to be addressed as an outpatient. This patient has symptoms of hypogonadism and a low total testosterone at 8AM.

50. Case 3
32 yo female at 12 weeks gestational age presents for a routine prenatal visit.
She has a h/o microprolactinoma diagnosed 2 years ago.
She was on Cabergoline 0.25mg twice a week pre-pregnancy but she stopped when she found she is pregnant.
She c/o worsening headaches for the past week and has noticed blurred vision. No peripheral vision changes.

51. Case 3 Which of the following will be the next best option in her management?
Pituitary MRI
Restart Cabergoline
Check a prolactin level
Ophthalmology referral

52. Case 3
Which of the following will be the next best option in her management?
Pituitary MRI
Restart Cabergoline
Check a prolactin level
Ophthalmology referral

53. Case 3 Pituitary MRI: Incorrect
MRI pituitary is not routinely recommended during pregnancy unless patient has evidence of tumor growth. If visual field defects & headaches are present then imaging can be done to confirm.
(B) Restart Cabergoline: Incorrect
Dopamine agonists are held during pregnancy but can consider restarting if tumor growth is evident clinically and then confirmed with imaging
(C) Check a prolactin level: Incorrect
Prolactin level measurement is not recommended during pregnancy and lactation. Cannot distinguish physiological increase in prolactin (10X) with prolactin from a pituitary tumor

54. Case 3 (D) Ophthalmology referral: Correct
This will be the next best option in evaluation of this patient. Her symptoms of headache and blurred vision while concerning for growth of prolactinoma, do not prove tumor growth.
Formal visual field test is needed to look for deficits, that will confirm tumor growth.
If visual deficits present, next step is imaging (MRI without contrast)

55. Case 4
45 yo male with a h/o HTN, HLD, and obstructive sleep apnea presented with complaints of numbness and tingling in both hands, increase in the size of his gloves and shoes, excessive sweating and acne.
Exam: BP 156/85, HR 78, RR 18, Wt 180lbs, Ht 5’11”. Well built male, thick and enlarged feet and hands, sweaty palms, skin tags on neck, enlarged tongue, coarse facial features with frontal bossing and thickened nasolabial folds.
Labs: GH 43ng/mL (0-10), IGF1 723 ng/mL (78-270), prolactin 43 ng/mL ( ), rest of the pituitary function normal.
Brain MRI: A 1.8 x 2.1 cm pituitary macroadenoma, approaching the optic chiasm, with cavernous sinus invasion.
He underwent a trans-sphenoidal surgery. Post op IGF1 was 550ng/mL and GH was 23ng/mL.

56. Case 4 Which of the following will be the next best option in normalizing his IGF-1 levels?
Repeat trans-sphenoidal surgery
Start Octreotide
Start Cabergoline
Gamma knife radiation

57. Case 4
Which of the following will be the next best option in normalizing his IGF-1 levels?
Repeat trans-sphenoidal surgery
Start Octreotide
Start Cabergoline
Gamma knife radiation

58. Case 4 Repeat trans-sphenoidal surgery: Incorrect
Not a good choice for this patient as he has cavernous sinus invasion. This residual tumor is not accessible for resection.
Repeat surgery is only indicated as the first option if a bulk of the tumor is still remaining/recurs and is removable by the surgeon.
(B) Start Octreotide: Correct
Somatostatin analogs are the first choice for medical management of persistently high IGF1 and GH after surgery.

59. Case 4 (C) Start Cabergoline: Incorrect
Only indicated for mild IGF-1 elevation, in this patient IGF-1 is modestly elevated.
(D) Gamma knife radiation: Incorrect
It can be complementary to the medical management but not the mainstay of treatment for residual tumors. It has very slow response over years. Can worsen vision changes, can cause hypopituitarism

60. Case 5
43yo male presented to the ED after fall from a ladder while working in his backyard. He hit his head but had no neurological symptoms.
He c/o mild headaches after the fall, no double vision or blurred vision. He was alert and oriented. CT head showed no hemorrhage but a 0.9cm pituitary adenoma was discovered.
No significant past medical history, not on any medications.
He denies any sexual dysfunction, fatigue, weight changes and is overall asymptomatic.
Brain MRI showed a 0.9cm x 0.7cm pituitary adenoma with no suprasellar extension, no optic chiasm compression and no cavernous sinus invasion.
Physical exam unremarkable. Visual field tests are normal.

61. Case 5 What would be the next best step in management?
Refer to a neurosurgeon
Measure prolactin
No intervention needed
Repeat MRI in 1 year

62. Case 5 What would be the next best step in management?
Refer to a neurosurgeon
Measure prolactin
No intervention needed
Repeat MRI in 1 year

63. Case 5 Refer to a neurosurgeon: Incorrect
For pituitary adenoma, surgery is not always the first choice. This
patient does not have vision changes, is asymptomatic.
(B) Measure prolactin: Correct
The first thing to check in any pituitary incidentaloma (macro or micro) is
to look for pituitary hyperfunction or hypofunction. This will be the
correct choice as it is measuring one of the pituitary hormones.
(C) No intervention needed: Incorrect
Patient will need pituitary hormone workup so this is not the
correct choice.
(D) Repeat imaging in one year: Incorrect
This would be the correct choice only after the hormonal workup has been completed and is normal AND vision abnormalities have been ruled out.

64. References # Case 1:
Melmed S et al, JCE&M, Diagnosis and treatment of hyperprolactinemia: An endocrine society clinical practice guideline
Mancini et al, Endocrin metab Clin n Am Hyperprolactinemia and prolactinomas
Vilar L et al, Arq Bras Endocrinol metab Challenges and pitfalls in the diagnosis of hyperprolactinemia
Ajmal A et al, psychosomatics Psychotropic induced hyperprolactinemia: a clinical review

65. References # Case 2:
Fleseriu M et al, JCE&M Nov 2016, 101 (11), Hormonal replacement in hypopituitarism in adults: An Endocrine society clinical practice guideline.
Ascoli P et al, Pituitary 2006; 9(4). Hypopituitarism
Albany A et al, Int J of Endocrinol Multidisciplinary management of pituitary apoplexy

66. References # Case 3:
Melmed S et al, JCE&M, Diagnosis and treatment of hyperprolactinemia: An endocrine society clinical practice guideline
Maiter D, Ann Endocrinol, 77 (2), June Prolactinoma and pregnancy: From the wish of conception to lactation
Witek P etal, Minerval Endocrinol, 38 (4), Dec Management of prolactinomas during pregnancy

67. References # Case 4:
Katznelson L et al, JCE&M Nov (99). Acromegaly: An endocrine society clinical practice guideline
Melmed S, J Clin Invest, Nov 2009; 119 (11). Acromegaly pathogenesis and treatment
Melmed S, NEJM, Dec Acromegaly Review

68. References # Case 5:
Freda PU et al, JCE&M 2011; 96 (4). Pituitary incidentaloma: An endocrine society clinical practice guideline
Orija IB etal, 2012; 26 (1). Pituitary incidentaloma, Best Pract Res Clin Endocrinol Metab