What is endocrinology and how does it relate to the diagnosis and treatment of endocrine disorders?

Overview of Endocrinology

Endocrinology is the medical specialty focused on diagnosing and treating disorders of hormone-producing glands and dispersed endocrine cells throughout the body, encompassing the thyroid, parathyroids, pituitary, adrenals, gonads, endocrine pancreas, and neuroendocrine cells in non-endocrine tissues. 1, 2

Historical Foundation and Scope

• The term "endocrinology" was introduced in 1909, though its conceptual origins trace to ancient organotherapy and the discovery of "internal secretions" in the 19th century 3
• The field emerged as a distinct scientific discipline between 1890-1905, following Claude Bernard's experimental studies, Thomas Addison's clinical observations, and Brown-Séquard's combined experimental-clinical work 3, 4
• The term "hormone" was coined by Starling in 1905 after the discovery of secretin as a chemical messenger 4

Cellular Classification and Pathophysiology

Endocrine cells are classified into three distinct families based on embryologic origin, morphology, and hormone synthesis pathways 1:

• Neuroendocrine cells: Produce peptide hormones and biogenic amines; found in traditional endocrine organs and dispersed throughout the gastrointestinal tract, lungs, thymus, breast, and prostate 1, 2
• Steroidogenic cells: Located in adrenal cortex, gonads, and placenta; synthesize steroid hormones from cholesterol 1
• Thyroid follicular cells: Unique iodine-concentrating cells producing thyroid hormones 1

Major Endocrine Disorders

Thyroid Dysfunction

• Primary hypothyroidism causes menstrual irregularities in a substantial proportion of affected women, with hyperprolactinemia occurring in 43% of frank hypothyroidism cases and 36% of subclinical cases 5
• Menstrual cycles normalize within 2-5 days of achieving adequate levothyroxine replacement 5
• Measure TSH and free T4 immediately when evaluating menstrual irregularities, as thyroid dysfunction is common and readily treatable 5
• Toxic goitre (hyperthyroidism) was recognized in 1884 as due to thyroid hormone excess 4

Pituitary Disorders

• Pituitary adenomas in children and young people under 19 years present unique challenges due to their rarity (1% of intracranial neoplasms before age 15), aggressive nature, and increased genetic predisposition compared to adults 6
• Hypophysitis is characteristic of ipilimumab immunotherapy, while thyroid dysfunction occurs more commonly with PD-1/PD-L1 inhibitors 6
• Hyperprolactinemia causes anovulation by inhibiting gonadotropin secretion via kisspeptin suppression, resulting in oligomenorrhea, amenorrhea, or polymenorrhea 5
• Check prolactin levels with morning resting samples to exclude hyperprolactinemia 5
• Dedicated pituitary MRI with pre-contrast (T1 and T2) and post-contrast-enhanced (T1) thin-sliced sequences, including post-contrast volumetric gradient echo sequences, should be performed for suspected pituitary adenomas 6

Adrenal Disorders

• Addison's disease (primary adrenal insufficiency) was described in 1855, with adrenalectomy proving fatal in animals 4
• Primary adrenal insufficiency from immunotherapy is rare but requires immediate recognition 6
• Evaluate morning ACTH (if >2-3× upper limit of normal) and cortisol (if <3 mg/dL), along with basic metabolic panel, renin, and aldosterone 6
• Initiate hydrocortisone replacement (15-20 mg in divided doses, maximum 30 mg daily) with endocrine consultation 6
• Most primary adrenal insufficiency cases require fludrocortisone (starting dose 0.05-0.1 mg/day) 6

Pancreatic Endocrine Dysfunction

• Diabetes mellitus, described in the first century, was recognized as resulting from absence of pancreatic islet internal secretion in the 19th century 4
• Type 1 diabetes from immunotherapy is rare but can occur, affecting the endocrine pancreas 6
• Acute pancreatitis has been observed with immune checkpoint inhibitors, with cases of recurrent pancreatitis on PD-1 inhibitor resumption 6

Gonadal and Reproductive Disorders

• Polycystic ovary syndrome (PCOS) affects 8-13% of reproductive-age women and is characterized by hyperandrogenism, insulin resistance, LH/FSH ratio >2, and anovulation 7
• Measure total testosterone, free testosterone, androstenedione, and DHEA-S to characterize androgen profile in suspected PCOS 5
• Obtain LH and FSH levels between cycle days 3-6, with LH/FSH ratio >2 suggestive of PCOS 5
• Hypothalamic amenorrhea presents with disturbed gonadotropin secretion, low LH levels, and amenorrhea/oligomenorrhea without hyperandrogenism 5
• Premature ovarian failure presents with amenorrhea and FSH >50 mIU/L in women under age 40 5
• Precocious puberty in girls is defined as breast development before age 8 or menarche before age 10, requiring comprehensive endocrine evaluation including bone age, LH, FSH, estradiol, and pelvic ultrasonography 8

Immunotherapy-Related Endocrinopathies

Incidence and Timing

• Combination immune checkpoint inhibitor therapy carries the highest risk of endocrinopathy, with hypothyroidism incidence up to 13.2% versus 3.8% with ipilimumab alone 6
• PD-1 inhibitors confer significantly greater hypothyroidism risk compared to ipilimumab (OR 1.89,95% CI 1.17-3.05) 6
• Hyperthyroidism risk is higher with PD-1 versus PD-L1 inhibitors (OR 5.36,95% CI 2.04-14.08) 6
• Median time to onset of endocrinopathy ranges from 1.4 to 5 months depending on the immunotherapy regimen 6

Management Principles

• Endocrinology specialists play a critical role in managing immune-related adverse events, particularly severe or complex cases, as symptoms may overlap with malignancy or other acute illnesses 6
• Differentiate between central (pituitary) versus primary (thyroid, adrenal) endocrine dysfunction to tailor management appropriately 6

Thyroid Toxicity Management

• Check TSH every 4-6 weeks for routine monitoring in asymptomatic patients on immunotherapy 6
• For thyrotoxicosis, use beta-blockers (atenolol or propranolol) for symptomatic relief 6
• Monitor thyroid function every 2-3 weeks after thyrotoxicosis diagnosis to detect transition to hypothyroidism, the most common outcome 6
• For persistent thyrotoxicosis beyond 6 weeks, refer to endocrinology for additional workup and possible medical thyroid suppression 6
• Hold immunotherapy for grade 2-4 thyrotoxicosis until symptoms return to baseline 6

Critical Diagnostic Approach

Initial Evaluation

• Obtain pregnancy test in all reproductive-age women regardless of reported contraceptive use 5
• Measure TSH and free T4 immediately to exclude thyroid dysfunction 5
• Check morning resting prolactin levels 5
• Assess for medication-induced endocrine dysfunction, particularly antiepileptic drugs, antipsychotics, and depot medroxyprogesterone acetate 7

Imaging Protocols

• 3-Tesla MRI enhances anatomical definition for surgical planning and may improve completeness of resection without altering complication rates 6
• Standard pituitary protocol uses 2 mm slice spin echo T1-weighted sequences before and after contrast, with fast/turbo spin echo T2-weighted sequences pre-contrast 6
• Functional imaging may aid diagnosis when MRI is negative or equivocal, particularly for corticotroph adenomas not visible on standard MRI 6

Common Pitfalls and Caveats

Medication-Induced Endocrinopathy

• Valproate is particularly problematic, with 45% of women on monotherapy experiencing menstrual irregularities and increased PCOS risk 5, 8
• Enzyme-inducing antiepileptic drugs (carbamazepine, phenobarbital, phenytoin) affect hormone metabolism and may influence pubertal development 8
• Consider alternative antiepileptic drugs when valproate causes reproductive endocrine dysfunction 8

Immunotherapy Considerations

• Infliximab is not recommended for steroid-refractory hepatotoxicity due to liver toxicity concerns, though it has not been tested in this setting 6
• Corticosteroids are the primary treatment for immune checkpoint inhibitor-mediated hepatotoxicity, with mycophenolate or cyclosporine reserved for steroid-refractory cases 6
• Tacrolimus may be effective for refractory immune checkpoint inhibitor-related hepatitis based on case report data 6

Pediatric Considerations

• Pituitary adenomas in children often present late due to occult symptoms during development, such as pubertal delay, amenorrhea, or rapid growth velocity 6
• Large and giant adenomas (>4 cm) are more prevalent in children than adults, with mass effects more common at presentation 6
• Coordinated management between pediatric neurology and pediatric endocrinology is essential for children with both epilepsy and precocious puberty 8

Multidisciplinary Care Requirements

• Consultation with endocrinology specialists with pituitary expertise is key for interpreting complex hormonal results 6
• Close interaction between pediatric and adult endocrine services is required for transition planning, which may be variable due to potential developmental delays 6
• Surgery for pituitary adenomas should be performed in specialist centers with multidisciplinary discussion at local and national levels 6
• Collection of long-term outcome data on endocrine, vascular, neurocognitive, metabolic, and quality of life parameters should be mandatory for treatment protocols 6