What is the role of trophic hormones, such as Thyroid-Stimulating Hormone (TSH), Adrenocorticotropic Hormone (ACTH), Follicle-Stimulating Hormone (FSH), and Luteinizing Hormone (LH), in the endocrine system and how are their deficiencies treated?

Trophic Hormones: Role and Management of Deficiencies

Overview of Trophic Hormones in the Endocrine System

Trophic hormones from the anterior pituitary—TSH, ACTH, FSH, and LH—regulate peripheral endocrine glands and are themselves controlled by hypothalamic releasing factors, with deficiencies requiring lifelong hormone replacement therapy targeting the affected peripheral glands. 1

Anterior Pituitary Trophic Hormones

The anterior pituitary secretes five major trophic hormones under hypothalamic control 1:

• Thyroid-Stimulating Hormone (TSH) regulates thyroid hormone production by controlling iodide uptake, thyroid peroxidase activation, T4 and T3 secretion, and thyroglobulin modifications 2
• Adrenocorticotropic Hormone (ACTH) stimulates cortisol production from the adrenal cortex 1
• Follicle-Stimulating Hormone (FSH) promotes follicular development in females and spermatogenesis in males 1
• Luteinizing Hormone (LH) triggers ovulation and corpus luteum formation in females, and testosterone production in males 1
• Growth hormone and prolactin also originate from the anterior pituitary, though their classification as purely "trophic" is debated 1

Plurihormonal Capacity

Normal anterior pituitary cells can co-express multiple hormones simultaneously, with prolactin co-expressing with ACTH, TSH, FSH, and LH; growth hormone co-expressing with ACTH, TSH, FSH, and LH; and TSH co-expressing with ACTH, FSH, and LH, though TSH shows the lowest co-expression coefficient at 1.0±1.3% 3

Diagnosis of Trophic Hormone Deficiencies

Clinical Presentation of Hypopituitarism

Patients with hypopituitarism commonly present with headache (85%) and fatigue (66%), while visual changes are uncommon 1. The median time from symptom onset to diagnosis is 8-9 weeks 1.

Diagnostic Algorithm

When hypopituitarism is suspected, obtain morning (8 AM) testing including TSH, free T4, ACTH, cortisol (or 1 mcg cosyntropin stimulation test), testosterone in men, estradiol in women, FSH, LH, and MRI of the sella with pituitary cuts—all before administering steroids. 1

Specific Testing Patterns

• Central hypothyroidism: Low TSH with low free T4, occurring in >90% of hypopituitarism cases 1
• Central adrenal insufficiency: Low ACTH with low cortisol, present in >75% of cases 1
• Hypogonadotropic hypogonadism: Low FSH/LH with low sex hormones, found in approximately 50% presenting with panhypopituitarism 1

Confirmatory Criteria

Diagnosis requires either ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 pituitary hormone deficiencies (TSH or ACTH deficiency required) in the presence of headache and other symptoms 1, 4

Imaging Findings

MRI abnormalities include pituitary enlargement, stalk thickening, suprasellar convexity, heterogeneous enhancement, and increased gland height compared to baseline 1. Pituitary enlargement commonly resolves within two months on follow-up scans 1.

Treatment of Trophic Hormone Deficiencies

Critical Treatment Principle

In patients with both adrenal insufficiency and hypothyroidism, always start corticosteroids before thyroid hormone replacement to prevent adrenal crisis—this is the single most important safety consideration in managing hypopituitarism. 1, 5, 4

Treatment Algorithm by Hormone Deficiency

Central Adrenal Insufficiency (ACTH Deficiency)

• Initiate hydrocortisone 20 mg in morning/10 mg in afternoon as physiologic replacement 4
• Start cortisol replacement at least 1 week before initiating thyroid hormone 4
• All patients must obtain and wear a medical alert bracelet 1, 4
• Provide education on "sick day" rules and emergency steroid use 4

Central Hypothyroidism (TSH Deficiency)

• Begin levothyroxine 50-100 mcg/day only after ensuring adequate cortisol replacement 4
• For patients <70 years without cardiac disease, use full replacement dose of approximately 1.6 mcg/kg/day 5
• For patients >70 years or with cardiac disease, start with 25-50 mcg/day and titrate gradually 5
• Monitor TSH and free T4 every 1-2 weeks initially, then every 6-8 weeks during titration 5, 4
• Once stable, recheck every 6-12 months or with symptom changes 5

Critical caveat: TSH cannot be used to monitor adequacy of replacement in central hypothyroidism—use free T4 levels to guide dosing, targeting mid-normal range 1

Hypogonadotropic Hypogonadism (FSH/LH Deficiency)

• Replace sex hormones (testosterone in men, estradiol in women) based on clinical need 1
• Monitor gonadal hormone levels (testosterone, estradiol) along with FSH and LH 1

Long-Term Management Considerations

Both adrenal insufficiency and hypothyroidism from hypopituitarism represent long-term sequelae requiring lifelong hormonal replacement in most cases 1. Resolution of pituitary enlargement on imaging does not indicate recovery of hormonal function 1.

Common Pitfalls to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency, as this precipitates adrenal crisis 1, 5, 4
• Do not rely on TSH levels to monitor thyroid replacement in central hypothyroidism—TSH remains inappropriately low despite adequate T4 replacement 1
• Avoid undertreating, which risks persistent symptoms, cardiovascular dysfunction, and impaired quality of life 5
• Avoid overtreatment with levothyroxine, which increases risk for atrial fibrillation, osteoporosis, fractures, and cardiac complications in 14-21% of patients 5
• Approximately 25% of patients are inadvertently maintained on excessive thyroid hormone doses that fully suppress TSH 5

Special Clinical Scenarios

Drug-Induced Hypophysitis

Hypophysitis incidence is highest with combination anti-PD(L)1/anti-CTLA-4 therapy (9-10%), followed by anti-CTLA-4 (2-6%) and anti-PD-1 (1%) therapy 4. High-dose steroids are reserved only for severe headaches, vision changes, or adrenal crisis—not for routine hormonal deficiencies 1.

Pregnancy Considerations

Women with central hypothyroidism planning pregnancy require more aggressive TSH normalization, as subclinical hypothyroidism during pregnancy associates with preeclampsia, low birth weight, and potential neurodevelopmental effects 5. Levothyroxine requirements typically increase 25-50% during early pregnancy 5.