Anterior Pituitary Hormones

Introduction

The anterior pituitary gland, also known as the adenohypophysis, synthesises and secretes a group of polypeptide hormones that regulate a broad spectrum of physiological processes. These hormones, including growth hormone (GH), thyroid‑stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), luteinising hormone (LH), follicle‑stimulating hormone (FSH), and prolactin, are collectively referred to as anterior pituitary hormones. Historically, the concept of a “pituitary hormone cascade” emerged during the 19th‑century investigations of the hypothalamic‑pituitary axis, wherein early endocrinologists identified that removal of the pituitary gland led to profound systemic dysfunction, prompting the search for the mediators of this effect. The recognition that the pituitary is not merely an endocrine organ but also a hub of neuroendocrine communication has greatly influenced contemporary pharmacological practice, particularly in the management of endocrine disorders and in the development of targeted hormone‑modulating therapies.

Learning objectives for this chapter include:

• Describe the cellular composition and anatomical structure of the adenohypophysis.
• Explain the regulatory mechanisms governing the secretion of each anterior pituitary hormone.
• Identify the pharmacologic agents that modulate anterior pituitary hormone activity and their therapeutic indications.
• Apply knowledge of anterior pituitary hormone physiology to the interpretation of clinical cases involving endocrine dysfunction.
• Recognise the potential side‑effect profiles and drug interactions associated with hormone‑directed therapies.

Fundamental Principles

The adenohypophysis originates embryologically from Rathke’s pouch, a ectodermal invagination of the oral cavity, and is histologically composed of distinct endocrine cell populations: somatotrophs, thyrotrophs, corticotrophs, gonadotrophs, and lactotrophs. Each cell type expresses a unique set of transcription factors and hormone‑specific genes. For instance, the transcription factor Pit-1 is essential for the differentiation of somatotrophs, thyrotrophs, and lactotrophs, whereas SF-1 is required for gonadotroph development.

The secretion of anterior pituitary hormones is tightly controlled by hypothalamic releasing and inhibiting factors that act via the hypophyseal portal system. Hypothalamic hormones such as growth‑releasing hormone (GHRH), thyrotropin‑releasing hormone (TRH), corticotropin‑releasing hormone (CRH), gonadotropin‑releasing hormone (GnRH), and dopamine (the lactotroph inhibitor) enter the portal circulation, bind to specific G‑protein coupled receptors on pituitary cells, and trigger intracellular signalling cascades that culminate in hormone synthesis and exocytosis.

Key terminology that will recur throughout this chapter includes:

• Secretion – the process by which hormones are released into the bloodstream.
• Feedback inhibition – the suppression of hormone release in response to elevated target‑tissue hormone levels.
• Portal circulation – a short‑distance vascular system that conveys hypothalamic hormones directly to the anterior pituitary.
• Granulosa‑cell hyperplasia – a pathological response to chronic hormonal stimulation, often seen in endocrine tumors.
• Half‑life – the time required for plasma hormone concentration to decline by half, influencing pharmacokinetic considerations.

Detailed Explanation

Somatotrophs and Growth Hormone (GH)

Somatotrophs, located predominantly in the anterior lobe, secrete GH in a pulsatile manner. The secretion pattern is influenced by sleep, exercise, and nutritional status. GHRH stimulates GH release via a cAMP‑dependent pathway, whereas somatostatin (inhibitory) and growth hormone‑releasing peptide‑2 (GHRP‑2) modulate the process. GH exerts its effects by binding to the growth hormone receptor (GHR) on target tissues, initiating Janus kinase‑2 (JAK2) phosphorylation, and activating STAT5 signalling, which promotes protein synthesis, lipolysis, and glucose regulation. The mathematical relationship between GH pulse amplitude and downstream insulin‑like growth factor‑1 (IGF‑1) production can be approximated by a first‑order kinetic model: d[IGF‑1]/dt = k₁[GH] – k₂[IGF‑1], where k₁ and k₂ represent synthesis and clearance rates respectively.

Thyrotrophs and Thyroid‑Stimulating Hormone (TSH)

Thyrotrophs produce TSH, a glycoprotein composed of α‑ and β‑subunits. TRH stimulates TSH secretion via a phospholipase C pathway, whereas somatostatin and dopamine inhibit the process. The primary target of TSH is the thyroid gland, where it upregulates the sodium‑iodide symporter and thyroglobulin synthesis, ultimately increasing circulating triiodothyronine (T3) and thyroxine (T4). A common pharmacologic manipulation involves levothyroxine therapy, which provides negative feedback to suppress TSH secretion. The relationship between TSH and free T4 follows a sigmoidal curve, often modeled by the Hill equation: TSH = TSH_max / (1 + (T4/K_d)^n), where K_d is the dissociation constant and n is the Hill coefficient.

Corticotrophs and Adrenocorticotropic Hormone (ACTH)

Corticotrophs release ACTH in response to CRH and, to a lesser extent, vasopressin. The downstream effect is the stimulation of cortisol synthesis in the adrenal cortex. The ACTH–cortisol axis follows a classic negative‑feedback loop: elevated cortisol inhibits CRH release from the hypothalamus and ACTH from the pituitary. The 24‑hour cortisol rhythm is governed by a circadian oscillator, which may be perturbed by exogenous glucocorticoids or stressors. The pharmacologic agent metyrapone, used diagnostically, inhibits 11‑β‑hydroxylase, thereby reducing cortisol synthesis and indirectly increasing ACTH secretion, a hallmark of the feedback relationship.

Gonadotrophs and Luteinising/Hypogonadotropic Hormones (LH/FSH)

Gonadotrophs synthesize LH and FSH in response to pulsatile GnRH. The pulsatility frequency dictates whether LH or FSH release predominates; a high frequency favours LH, whereas a low frequency favours FSH. These gonadotropins act on the gonads, stimulating sex steroid production and gametogenesis. The feedback from sex steroids (estrogen, progesterone, testosterone) modulates GnRH pulse frequency and amplitude. Pharmacologic manipulation of this axis includes GnRH agonists (e.g., leuprolide) that initially stimulate but subsequently downregulate GnRH receptors, leading to decreased LH/FSH and sex steroid production; and GnRH antagonists (e.g., cetrorelix) that immediately suppress gonadotropin release.

Lactotrophs and Prolactin

Lactotrophs produce prolactin, whose secretion is primarily inhibited by dopamine, the hypothalamic “prolactin inhibitor.” Prolactin acts on mammary epithelial cells to promote milk synthesis and also has immunomodulatory roles. Stress, estrogen, and TRH can stimulate prolactin release. Dopamine agonists (cabergoline, bromocriptine) bind to D₂ receptors on lactotrophs, inhibiting prolactin secretion and thus providing a therapeutic strategy for prolactinomas and hyperprolactinaemia. The prolactin–estrogen feedback is complex, with estrogen upregulating prolactin receptor expression and amplifying prolactin’s effects.

Clinical Significance

Anterior pituitary hormones are central to a multitude of clinical conditions. Dysregulation can lead to growth disorders (e.g., acromegaly, gigantism), thyroid dysfunctions (e.g., hypo‑ or hyperthyroidism), adrenal insufficiency, hypogonadism, and lactation abnormalities. Pharmacologic agents that modulate these hormones are widely employed in both therapeutic and diagnostic settings.

For instance, GH therapy (somatropin) is indicated for GH deficiency in children and adults, whereas somatostatin analogues (octreotide) are used to treat GH‑secreting pituitary adenomas. Levothyroxine remains the cornerstone of hypothyroidism management, with TSH suppression therapy employed in differentiated thyroid carcinoma to reduce recurrence risk. Glucocorticoid replacement (hydrocortisone, prednisone) addresses primary adrenal insufficiency, and exogenous ACTH (cosyntropin) is used diagnostically to assess adrenal responsiveness. GnRH analogues are integral to assisted reproductive technologies, while dopamine agonists treat prolactinomas and certain Parkinsonian syndromes.

Drug interactions can arise due to shared metabolic pathways. For example, CYP3A4 inducers (rifampin, carbamazepine) may accelerate the clearance of levothyroxine, necessitating dose adjustments. Likewise, somatostatin analogues can inhibit insulin secretion, potentially leading to hyperglycaemia in patients with diabetes. Therefore, a comprehensive understanding of anterior pituitary hormone physiology is indispensable for safe and effective pharmacotherapy.

Clinical Applications/Examples

Case 1 – Acromegaly Caused by GH‑Secreting Adenoma

A 45‑year‑old male presents with acral enlargement, facial coarsening, and joint pain. Serum IGF‑1 is markedly elevated, and MRI confirms a pituitary macroadenoma. The therapeutic approach may include first‑line surgery, but in cases where surgical resection is incomplete or contraindicated, octreotide LAR (30 mg intramuscularly every 28 days) is administered. Octreotide binds to somatostatin receptor subtype 2, inhibiting GH secretion. Monitoring of IGF‑1 and tumour size guides dose adjustments. Potential side effects such as cholelithiasis and gastrointestinal disturbances are considered in follow‑up.

Case 2 – Primary Hypothyroidism with TSH Suppression Therapy

A 60‑year‑old woman with differentiated thyroid carcinoma undergoes total thyroidectomy. Post‑operative levothyroxine therapy is initiated at 1.6 µg/kg/day, aiming to suppress TSH below 0.1 mU/L to reduce tumour recurrence. Serial TSH and free T4 measurements are performed monthly. Inadequate suppression prompts dose escalation, while overtreatment, evidenced by suppressed TSH below 0.1 mU/L and elevated free T4, may lead to atrial fibrillation; dose reduction is then implemented. The pharmacokinetic variability of levothyroxine necessitates individualized titration.

Case 3 – Hyperprolactinaemia Due to Prolactinoma

A 28‑year‑old woman reports galactorrhoea and amenorrhoea. Serum prolactin is 250 ng/mL, and MRI reveals a 1.2 cm pituitary adenoma. Cabergoline is initiated at 0.5 mg twice weekly. The dopamine agonist reduces prolactin secretion and often causes tumour shrinkage. The dose is titrated to a maximum of 3.5 mg weekly, with monitoring for orthostatic hypotension and nausea. If cabergoline is ineffective, bromocriptine may be considered as an alternative, albeit with a higher risk of gastrointestinal side effects.

Case 4 – Hypopituitarism Following Traumatic Brain Injury

A 35‑year‑old man sustains a severe head injury and develops fatigue, weight loss, and hypotension. Hormonal assays indicate deficiencies in GH, ACTH, TSH, and gonadotropins. Replacement therapy is instituted: hydrocortisone 15 mg in the morning and 10 mg in the afternoon, levothyroxine 75 µg daily, and recombinant GH 0.2 mg/kg/week. Gonadotropin replacement is deferred until the patient achieves stable glycaemic control. Monitoring of adrenal function involves periodic cosyntropin stimulation tests, and adjustments to hydrocortisone dosing are guided by serum cortisol and clinical status.

Summary/Key Points

• Anterior pituitary hormones are produced by distinct endocrine cell types and regulated by hypothalamic releasing and inhibiting factors.
• Negative‑feedback loops involving target‑tissue hormones are central to maintaining homeostasis and are exploited pharmacologically.
• Pharmacologic agents such as dopamine agonists, somatostatin analogues, levothyroxine, glucocorticoids, and GnRH modulators directly target anterior pituitary hormone pathways.
• Clinical management requires careful dose titration, monitoring for therapeutic efficacy, and vigilance for drug interactions and side‑effect profiles.
• Understanding the mathematical models of hormone kinetics aids in predicting pharmacodynamic responses and tailoring individualized therapy.

References

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