Pituitary Primer for the Primary Care Physician

Educational Objectives

The goal of this program is to improve the diagnosis and management of pituitary abnormalities. After hearing and assimilating this program, the clinician will be better able to:

1. Describe the different manifestations of functional pituitary adenomas.
2. Screen for adrenal insufficiency in patients with pituitary adenomas.
3. Differentiate Cushing disease from polycystic ovary syndrome.

Summary

Anatomy and physiology: the hypothalamus produces releasing hormones that stimulate the anterior and posterior pituitary, which releases stimulating hormones to the end organs; prolactin controls lactation; gonadotropins (Gn) control menstruation and testosterone (T) production; thyrotropin (TSH) stimulates the thyroid, and adrenocorticotropic hormone (ACTH) stimulates the adrenal glands; growth hormone stimulates the liver to produce insulin-like growth factor 1 (IGF-1; affects bone and soft tissue); the posterior pituitary releases antidiuretic hormone (controls free water excretion) and oxytocin (involved in nursing and delivery)

Pituitary adenomas: 1937 autopsy series identified pituitary adenomas in >20% of individuals, with similar rates in men and women; adenomas can be subclinical or may secrete a hormone capable of producing clinical symptoms; Molitch (2008) found >10% of autopsies were positive for adenomas, with similar rates in men and women across all age groups; most incidentalomas were microadenomas; macroadenomas usually produce symptoms; ≤20% of computed tomography (CT) and >35% of magnetic resonance imaging (MRI) reveal irregularities (not all are adenomas); incidental macroadenomas are rare

Pituitary masses: usually adenomas (functional or nonfunctional); infarction, hemorrhagic, or apoplexy may be seen; craniopharyngiomas, Rathke cleft cysts, arachnoid cysts, and meningiomas are common; malignant causes are never incidental and include metastatic disease, lymphoma, or, rarely, primary pituitary cancer; infiltrative conditions include, eg, sarcoidosis, hemochromatosis, tuberculosis, fungal infection, pituitary inflammatory conditions (eg, autoimmune or drug-induced hypophysitis), physiologic hypertrophy (pregnancy, puberty, or untreated primary hypothyroidism), or normal variation

Assessment of pituitary adenomas: assess the effect on hormone production; functional adenomas may cause the pituitary to produce too much hormone; excess hormone production commonly involves prolactin and IGF-1, which is seen in acromegaly (rare but easily missed until major morbidity occurs); testing can be performed nonfasting at any time of day; test for Cushing disease (CD) only if clinically indicated; most adenomas are gonadotroph adenomas, but these are mostly clinically silent (ie, screening for Gn is not indicated); TSH-secreting adenomas are rare (test only in patients with clinical hyperthyroidism); hypopituitarism (HP) — larger masses are more likely to cause HP (panhypopituitarism or partial with one or two axes affected); screen for HP for masses >10 mm (regardless of symptoms) and screen based on clinical indications for masses 6 to 10 mm; screening is rarely needed for masses <6 mm

Gonadotropins: no tests are required for a premenopausal woman with normal menstrual cycles; Gn is low (indicating exogenous hormone use) in a woman taking birth control pills; testing may or may not be helpful for women with a progesterone-based intrauterine device; patients with low Gn and estrogen levels, as well as estrogen deficiency symptoms, need further workup; postmenopausal women should have high follicle-stimulating hormone (FSH) levels; for macroadenoma and nonelevated FSH levels, examine the other axes; however, tests are not helpful in postmenopausal women taking hormone replacement therapy; in men, check Gn and total (and possibly free) T

Growth hormone: random levels are not useful because of pulsatile release (too much overlap between deficiency, normal, and excess); test IGF-1 instead (low specificity for deficiency); obesity, type 2 diabetes mellitus (DM; T2DM), and insulin resistance can cause mildly low IGF-1 levels; use a stimulation test if considering replacement for growth hormone deficiency; thyroid hormones — TSH is not a useful test; an overtly low free thyroxine (T4) level or a significant drop from a known baseline may be relevant; prolactin — deficiency is rare and causes an inability to lactate; low prolactin is primarily seen in apoplexy or with certain medications (usually not from adenoma)

Adrenal insufficiency (AI): central AI occurs when the adrenal cortex is no longer stimulated by ACTH to produce cortisol or androgens; the renin-angiotensin-aldosterone axis is regulated separately, which allows normal mineralocorticoid production from the adrenal cortex (potassium is normal); with a regular sleep-wake cycle, cortisol peaks early in the morning and reaches its nadir 1 to 2 hr after going to bed at night; morning cortisol level is the screening test for AI; consider a cosyntropin stimulation test; for CD, use evening salivary cortisol, 24-hr urine, or a dexamethasone suppression test; repeat cortisol testing in patients with asymptomatic macroadenomas if initial results are in the “gray zone”

Additional workup: includes visual field testing (for all macroadenomas and smaller tumors abutting the optic nerve or chiasm) and a pituitary-dedicated MRI if CT was done initially; follow-up — depends on the adenoma's natural history; smaller adenomas at the time of diagnosis are less likely to grow

Indications for surgery: visual field deficits, neurologic compromise, and lesions contacting the optic chiasm; apoplexy (ie, presenting with acute sudden-onset nausea, vomiting, headache, low cortisol, and visual changes) requires urgent neurosurgical referral for decompression; consider surgery if the lesion is growing significantly, causing HP, or close to the optic chiasm in patients considering pregnancy (growth during pregnancy is common)

Treatment and surveillance: CD and acromegaly are treated surgically; hyperprolactinemia is treated with a dopamine agonist; check periodic MRIs in patients with clinically nonfunctional adenomas <1 cm; for adenomas >1 cm, rule out HP, and perform visual field testing and closer MRI surveillance; nonfunctional microadenomas can be followed by primary care providers

Hypogonadism (HG): prolactinomas are often diagnosed earlier in women as they cause menstrual irregularities or galactorrhea; men have less specific HG symptoms and are more likely to develop aggressive and treatment-resistant giant prolactinomas; treat with cabergoline unless vision is deteriorating rapidly (≤1 wk), then consider urgent neurosurgical evaluation; evaluation — always test prolactin in patients diagnosed with central HG; 2 to 3 morning fasting T samples are required; test total T (TT), and free T (FT) for borderline results or concerns about sex hormone-binding globulin (SHBG); check FSH and luteinizing hormone (LH) when HG is confirmed; factors — conditions affecting SHBG include T2DM, obesity, insulin resistance, and androgen and glucocorticoid use; if SHBG is low, TT may appear low, but FT can be normal; however, DM and obesity are risk factors for true HG (always confirm FT); aging, chronic liver disease, and smoking increase SHBG, making TT appear normal with low FT (more common) or high TT with normal FT

Primary HG: causes elevated FSH and LH and results from issues with the end organ; perform a thorough testicular history and examination, and consider karyotyping or ultrasonography (US)

Secondary HG: FSH is low or inappropriately normal when it should be high; check prolactin and ferritin for hemochromatosis; consider CD; consider pituitary MRI if there is evidence of HP, visual field changes, or TT below a certain threshold (<250 ng/dL in younger patients, <150 ng/dL in older patients)

Polycystic ovary syndrome (PCOS) vs CD: PCOS — caused by insulin resistance at the level of the ovary, causing excess male-hormone production, which results in irregular menstrual cycles, infertility, hirsutism, and acne; affects 6% to 10% of the population; CD — a functional tumor, causing excess ACTH production in the pituitary, excess cortisol production in the adrenal glands, or ectopic ACTH production; can also cause the above symptoms, plus other symptoms of excess glucocorticoids; rare; commonalities — increased risk for hypertension, cardiovascular disease, sleep apnea, and depression; proximal weakness, easy bruising, edema, fragility fractures, and kidney stones are specific to CD

Diagnosis: 2 of 3 Rotterdam criteria (2003) are needed to diagnose PCOS, ie, irregular cycles, hyperandrogenism, and polycystic ovaries (anovulation) on US; rule out, eg, thyroid disease, elevated prolactin, nonclassic congenital adrenal hyperplasia, premature ovarian insufficiency; CD — hypercortisolemia is detected on 24-hr urine cortisol, overnight suppression test, or evening salivary cortisol (can be done at home); CD screening is not necessary in all patients with PCOS; cortisol (a stress hormone) increases with physical or emotional stress; high cortisol levels are common in obesity, T2DM, PCOS, and chronic pain, which can make the diagnosis confusing (nontumoral hypercortisolism); diagnostic clues — PCOS symptoms typically start around puberty or teenage years and progress gradually; CD progresses over months to a few years; proximal weakness manifests as difficulty standing from a chair, climbing stairs, and keeping arms above the head; presents with tiredness, trouble focusing, and irritability; fragility fractures, nephrolithiasis, dark striae, poor wound healing, facial rounding, and supraclavicular fullness are possible; however, the dorsocervical fat pad is not specific to CD (common in obesity of any cause); a family history is common in PCOS, T2DM, and insulin resistance

Testing cortisol in PCOS: if cortisol is slightly high, monitor over time for development of CD

Immune checkpoint inhibitor (ICI)-induced HP (hypophysitis): ICIs can cause thyroiditis; hypophysitis occurs in 5% to 10% of users, most of whom develop permanent AI; patients rarely develop type 1 DM (highest rates with combination therapy); adverse events (AEs) occur in first weeks to months of starting ICIs; other immune-related AEs include skin, rheumatologic, and gastrointestinal symptoms, which correlate with improved oncologic outcomes; AI persists even after stopping the drug (eg, ipilimumab, nivolumab, pembrolizumab)

Acromegaly: symptoms are typically present 8 to 15 yr before a diagnosis is made; early diagnosis improves morbidity, mortality, and quality of life; untreated mortality rates are twice that of the general population; mortality returns to normal with treatment; diagnosis — made using nonfasting IGF-1 levels; low IGF-1 is not specific, but high IGF-1 levels indicate acromegaly (puberty and pregnancy are other causes and easy to rule out); common symptoms include carpal tunnel syndrome, T2DM (with no family history), and sleep apnea; other symptoms include new hot flashes, worsening arthritis pain, hypertension with left ventricular hypertrophy, dental malalignment, increased sweating, increase in shoe size and ring size, and enlargement of the jaw and forehead

Readings

Brzana J, Yedinak CG, Hameed N, et al. Polycystic ovarian syndrome and Cushing's syndrome: a persistent diagnostic quandary. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2014 April;175:145-148; Chalif EJ, Morshed RA, Young JS, et al. Pituitary adenoma in the elderly: surgical outcomes and treatment trends in the United States. Journal of Neurosurgery. 2022 April 29;137(6):1687–1698; Husebye ES, Pearce SH, Krone NP, et al. Adrenal insufficiency. The Lancet. 2021 February 13;397(10274):P613-629; Kim SY. Diagnosis and treatment of hypopituitarism. Endocrinol Metab (Seoul). 2015 Dec;30(4):443–455; Li C, Ford ES, Li B, Giles WH, et al. Association of testosterone and sex hormone–binding globulin with metabolic syndrome and insulin resistance in men. Diabetes Care. 2010 Jul;33(7):1618–1624; Molitch ME. Nonfunctioning pituitary tumors and pituitary incidentalomas. Endocrinol Metab Clin North Am. 2008 Mar;37(1):151-71, xi. doi: 10.1016/j.ecl.2007.10.011. PMID: 18226735; Zahr R, Fleseriu M. Updates in diagnosis and treatment of acromegaly. Eur Endocrinol. 2018 Sep;14(2):57–61.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Wolf was recorded at Riding the Waves of Primary Care 2023, held November 6-10, 2023, on Kohala Coast, Waimea, HI, and presented by Providence Regional Medical Center Everett. For information on future CME activities from this presenter, please visit https://cmetracker.net/prov. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

IM711801

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.