Pharmacology of Hypothalamic and Pituitary Hormones

Introduction/Overview

The hypothalamic-pituitary axis represents the principal regulatory interface between the neural and endocrine systems, orchestrating a wide array of physiological processes including growth, metabolism, reproduction, stress response, and fluid balance. The pharmacology of hormones derived from or targeting this axis constitutes a cornerstone of endocrinology and therapeutics. These agents include both natural hormones and synthetic analogs, which are employed to either replace deficient hormones, suppress excessive secretion, or modulate endocrine pathways for diagnostic or therapeutic purposes. A thorough understanding of their pharmacodynamics and pharmacokinetics is essential for their safe and effective clinical application.

The clinical relevance of these pharmacological agents is profound, spanning the management of common conditions such as growth hormone deficiency, central diabetes insipidus, and infertility, to more complex disorders like acromegaly and Cushing’s disease. Furthermore, these hormones and their antagonists are critical tools in assisted reproductive technologies and oncology. The ability to precisely manipulate this axis has revolutionized the treatment of numerous endocrine disorders.

Learning Objectives

• Classify the major hypothalamic releasing/inhibiting hormones and anterior/posterior pituitary hormones based on their origin, structure, and primary function.
• Explain the molecular mechanisms of action for each major class of hormone, including receptor interactions and downstream intracellular signaling pathways.
• Compare and contrast the pharmacokinetic profiles of natural hormones and their synthetic analogs, relating these properties to their clinical dosing regimens.
• Identify the primary therapeutic indications, major adverse effects, and significant drug interactions for the principal agents discussed.
• Apply knowledge of special population considerations (e.g., pregnancy, renal impairment) to the selection and monitoring of hypothalamic and pituitary hormone therapies.

Classification

Hypothalamic and pituitary hormones can be classified according to their anatomical origin, chemical structure, and primary physiological role. This classification provides a framework for understanding their pharmacological profiles.

Hypothalamic Hormones (Releasing and Inhibiting Hormones)

These are peptides synthesized in hypothalamic neurons and secreted into the hypophyseal portal system to regulate anterior pituitary function.

• Gonadotropin-Releasing Hormone (GnRH): A decapeptide that stimulates the synthesis and release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH).
• Thyrotropin-Releasing Hormone (TRH): A tripeptide that stimulates thyroid-stimulating hormone (TSH) and prolactin release.
• Corticotropin-Releasing Hormone (CRH): A 41-amino acid peptide that stimulates adrenocorticotropic hormone (ACTH) release.
• Growth Hormone-Releasing Hormone (GHRH): A 44-amino acid peptide that stimulates growth hormone (GH) synthesis and secretion.
• Somatostatin (Growth Hormone-Inhibiting Hormone, GHIH): A 14- or 28-amino acid peptide that inhibits the secretion of GH, TSH, and several gastrointestinal hormones.
• Dopamine (Prolactin-Inhibiting Hormone, PIH): A catecholamine that tonically inhibits prolactin secretion.

Anterior Pituitary Hormones

These are peptide or glycoprotein hormones whose secretion is controlled by hypothalamic factors.

• Glycoprotein Hormones: TSH, LH, and FSH. Each is a heterodimer consisting of a common α-subunit and a unique β-subunit that confers biological specificity.
• Polypeptide Hormones:
  • Growth Hormone (GH, Somatotropin): A 191-amino acid single-chain polypeptide.
  • Prolactin (PRL): A 199-amino acid single-chain polypeptide structurally similar to GH.
  • Adrenocorticotropic Hormone (ACTH, Corticotropin): A 39-amino acid peptide derived from proopiomelanocortin (POMC).

Posterior Pituitary Hormones (Neurohypophyseal Hormones)

These are nonapeptides synthesized in hypothalamic neurons (supraoptic and paraventricular nuclei) and stored/released from the posterior pituitary.

• Oxytocin
• Vasopressin (Antidiuretic Hormone, ADH)

Chemical and Therapeutic Classification of Pharmacologic Agents

Pharmacologic agents include natural hormones extracted from human or animal sources, recombinant human hormones, synthetic analogs (agonists and antagonists), and hormone release inhibitors.

1. Replacement Therapies: Recombinant human GH, desmopressin, vasopressin, levothyroxine (for secondary hypothyroidism), hydrocortisone (for secondary adrenal insufficiency).
2. Receptor Agonists: Long-acting GnRH agonists (leuprolide, goserelin), oxytocin agonists (carbetocin), GH secretagogues (tesamorelin).
3. Receptor Antagonists: GnRH antagonists (ganirelix, cetrorelix), vasopressin receptor antagonists (conivaptan, tolvaptan).
4. Release Inhibitors: Somatostatin analogs (octreotide, lanreotide), dopamine agonists (bromocriptine, cabergoline).

Mechanism of Action

The mechanisms of action for hypothalamic and pituitary hormones involve specific receptor binding, which triggers intracellular signaling cascades leading to altered cellular function. The pharmacodynamics of synthetic analogs are often modified to enhance stability, receptor affinity, or selectivity.

Hypothalamic Releasing/Inhibiting Hormones

These hormones act on specific G-protein-coupled receptors (GPCRs) on anterior pituitary cells.

• GnRH: Binds to the GnRH receptor, a GPCR coupled to G_q/11. Activation leads to phospholipase C (PLC) stimulation, generating inositol trisphosphate (IP₃) and diacylglycerol (DAG). IP₃ mobilizes intracellular calcium, while DAG activates protein kinase C (PKC). This cascade stimulates the synthesis and secretion of LH and FSH. Continuous administration of GnRH agonists causes receptor downregulation and desensitization, paradoxically suppressing gonadotropin release—a key therapeutic action.
• TRH: Activates a GPCR coupled to G_q/11, similarly activating the PLC pathway to stimulate TSH and prolactin secretion from thyrotrophs and lactotrophs, respectively.
• Somatostatin: Binds to one of five somatostatin receptor subtypes (SSTR1-5), all GPCRs primarily coupled to G_i/o. This inhibits adenylyl cyclase, reducing intracellular cAMP, and also modulates potassium and calcium channels. The net effect is a potent inhibition of hormone secretion (GH, TSH, insulin, glucagon) and cell proliferation.
• Dopamine: Acts on D₂ subtype dopamine receptors on lactotrophs, which are GPCRs coupled to G_i/o. This inhibits adenylyl cyclase and cAMP production, leading to decreased prolactin synthesis and secretion.

Anterior Pituitary Hormones

• Glycoprotein Hormones (TSH, LH, FSH): Bind to specific GPCRs on their target endocrine glands (thyroid, gonads). These receptors are unique in having a large extracellular hormone-binding domain. Receptor activation primarily stimulates the G_s-adenylyl cyclase-cAMP-protein kinase A (PKA) pathway, leading to increased hormone synthesis (thyroid hormones, sex steroids) and trophic effects on the target tissue.
• Growth Hormone (GH): Binds to the GH receptor, a single-pass transmembrane receptor belonging to the cytokine receptor superfamily. Dimerization of the receptor activates the intracellular tyrosine kinase JAK2 (Janus kinase 2), which phosphorylates signal transducers and activators of transcription (STATs), particularly STAT5b. This complex translocates to the nucleus to modulate gene transcription. GH actions are also mediated indirectly via insulin-like growth factor-1 (IGF-1) produced in the liver and other tissues.
• Prolactin: Binds to the prolactin receptor, also a cytokine receptor family member, activating JAK2-STAT signaling pathways (primarily STAT5) to promote mammary gland development and lactogenesis.
• ACTH: Binds to the melanocortin 2 receptor (MC2R), a GPCR coupled to G_s, on adrenal cortical cells. This stimulates adenylyl cyclase, increasing cAMP, which activates PKA. PKA phosphorylates key enzymes (e.g., cholesterol esterase, StAR protein) to accelerate the synthesis and secretion of glucocorticoids, mineralocorticoids, and adrenal androgens.

Posterior Pituitary Hormones

• Vasopressin: Exerts its effects through three GPCR subtypes: V_1a (vascular smooth muscle, hepatocytes, platelets), V_1b (anterior pituitary), and V₂ (renal collecting duct). The antidiuretic effect is mediated by V₂ receptors coupled to G_s. Activation increases aquaporin-2 water channel insertion into the apical membrane of collecting duct cells, enhancing water reabsorption. V_1a receptor activation, via G_q/11 and PLC, causes vasoconstriction.
• Oxytocin: Binds to the oxytocin receptor, a GPCR coupled to G_q/11. Activation of the PLC pathway increases intracellular calcium in uterine myometrial cells and myoepithelial cells of the breast, stimulating contraction during labor and milk ejection, respectively.

Pharmacokinetics

The pharmacokinetics of these peptide hormones are largely defined by their susceptibility to proteolytic degradation, which influences their route of administration, bioavailability, and elimination half-life. Synthetic analogs are frequently engineered to resist degradation, thereby prolonging their duration of action.

Absorption

With rare exceptions, peptide hormones are not administered orally due to extensive first-pass metabolism by gastrointestinal proteases and hepatic degradation. Parenteral routes are standard.

• Subcutaneous (SC) and Intramuscular (IM) Injection: Common for many hormones (e.g., GH, somatostatin analogs, GnRH agonists/antagonists). Absorption can be slow and variable, influenced by injection site and formulation (e.g., depot preparations).
• Intravenous (IV): Used for immediate effects (e.g., vasopressin in advanced cardiac life support, oxytocin during labor, diagnostic tests with CRH or GHRH).
• Intranasal: A viable route for small, stable peptides like desmopressin, which is absorbed through the nasal mucosa. Bioavailability via this route is approximately 10-20%.
• Oral: Limited to non-peptide agents (e.g., dopamine agonists bromocriptine and cabergoline) and the vasopressin antagonist tolvaptan.

Distribution

Distribution volumes for these hormones generally approximate extracellular fluid volume or total body water, as they are hydrophilic peptides. They do not readily cross the blood-brain barrier in significant amounts. Protein binding is typically low, though some hormones like GH may bind to carrier proteins in plasma (e.g., GH-binding protein).

Metabolism and Elimination

Metabolism occurs primarily via proteolytic cleavage by peptidases in plasma, liver, and kidneys. Renal and hepatic clearance are the major elimination pathways.

• Renal Elimination: Small peptides like vasopressin and oxytocin are filtered and degraded by renal tubular peptidases. Their plasma half-life (t_1/2) is very short, often 5-20 minutes.
• Hepatic and Systemic Metabolism: Larger peptides like GH and the glycoprotein hormones are degraded by systemic and hepatic proteases. Recombinant GH has a t_1/2 of 2-4 hours after SC injection.
• Engineered Analogs: Structural modifications dramatically alter pharmacokinetics. For example, desmopressin (1-deamino-8-D-arginine vasopressin) is resistant to peptidases, increasing its antidiuretic t_1/2 to 2-4 hours. Long-acting somatostatin analogs (octreotide, lanreotide) and GnRH agonists (in depot formulations) have elimination half-lives extending from hours to several weeks, permitting monthly dosing.

Key Pharmacokinetic Parameters

• Growth Hormone (somatropin): SC administration; bioavailability ~75%; t_1/2 ~3-4 hours; cleared by renal and hepatic metabolism.
• Octreotide: SC/IV; t_1/2 of immediate release ~1.5 hours; long-acting release (LAR) formulation administered IM every 4 weeks.
• Leuprolide (GnRH agonist): Depot IM/SC; sustained release over 1, 3, 4, or 6 months; t_1/2 of depot form is determined by polymer matrix, not the molecule itself.
• Desmopressin: Intranasal, oral, IV; intranasal bioavailability ~10%; t_1/2 2-4 hours; primarily renal elimination.
• Cabergoline (dopamine agonist): Oral; bioavailability ~50%; long t_1/2 ~65 hours; extensive hepatic metabolism via CYP3A4.

Therapeutic Uses/Clinical Applications

The clinical applications of these agents are diverse, reflecting the broad regulatory scope of the hypothalamic-pituitary axis.

Diagnostic Applications

Several hormones are used in dynamic function tests to assess pituitary reserve and diagnose endocrine disorders.

• TRH Stimulation Test: To assess TSH and prolactin reserve in suspected pituitary disease.
• CRH Stimulation Test: To differentiate Cushing’s disease (pituitary ACTH-secreting adenoma) from ectopic ACTH syndrome.
• GHRH and Arginine Stimulation Test: To diagnose adult GH deficiency.
• GnRH Stimulation Test: To evaluate gonadotropin reserve, though largely supplanted by basal hormone measurements.

Therapeutic Applications

Replacement Therapy for Hormone Deficiency

• Growth Hormone Deficiency: Recombinant human GH (somatropin) is standard for children and adults with documented deficiency. In children, it normalizes growth velocity. In adults, it improves body composition, lipid profile, and quality of life.
• Central Diabetes Insipidus: Desmopressin, a selective V₂ receptor agonist, is the treatment of choice for ADH deficiency. It reduces polyuria and polydipsia.
• Hypopituitarism: Deficiencies of TSH and ACTH are treated with target gland hormone replacement (levothyroxine, hydrocortisone), not with the pituitary hormones themselves, due to practical and safety considerations.

Suppression of Hormone Excess or Pathologic Processes

• Acromegaly and Gigantism: First-line medical therapy often involves somatostatin analogs (octreotide, lanreotide) to suppress GH secretion. GH receptor antagonists (pegvisomant) are used if somatostatin analogs are ineffective.
• Prolactinomas: Dopamine agonists (bromocriptine, cabergoline) are first-line therapy to lower prolactin levels, shrink tumors, and restore gonadal function.
• Central Precocious Puberty: Long-acting GnRH agonists (leuprolide, histrelin) suppress the pituitary-gonadal axis, halting premature sexual development.
• Hormone-Sensitive Cancers: GnRH agonists are used for androgen deprivation in prostate cancer and for creating a hypoestrogenic state in premenopausal breast cancer. Octreotide is used for symptom control in neuroendocrine tumors expressing somatostatin receptors.
• Cushing’s Disease: Pasireotide, a somatostatin analog with high affinity for SSTR5, is approved to reduce ACTH secretion in patients not candidates for surgery.

Stimulation of Endocrine Function

• Infertility: Gonadotropins (recombinant or urinary FSH, LH, hCG) are used for controlled ovarian stimulation in assisted reproduction and for induction of ovulation or spermatogenesis in hypogonadotropic hypogonadism.
• Induction of Labor and Postpartum Hemorrhage: Oxytocin is administered IV to induce or augment uterine contractions during labor and to prevent or treat uterine atony after delivery.
• Vasodilatory Shock: Vasopressin or its analog terlipressin is used as a vasopressor in septic shock, acting via V_1a receptors to increase vascular resistance.

Other Uses

• Nocturnal Enuresis: Desmopressin is used for its antidiuretic effect to reduce nighttime urine production.
• SIADH and Hyponatremia: Vasopressin receptor antagonists (vaptans: conivaptan, tolvaptan) promote aquaresis (excretion of free water) to correct euvolemic or hypervolemic hyponatremia.

Adverse Effects

Adverse effects range from extensions of the hormones’ physiological actions to immunogenic reactions and complications related to chronic hormonal manipulation.

Common Side Effects

• Growth Hormone: Fluid retention (edema, arthralgias, carpal tunnel syndrome), insulin resistance, myalgias, headache. In children, slipped capital femoral epiphysis and progression of scoliosis are monitored.
• GnRH Agonists (initial flare phase): Transient increase in gonadotropins and sex steroids can cause tumor pain (“flare” in prostate cancer), vaginal bleeding, or worsening of symptoms in endometriosis. Chronic use leads to hypogonadal effects: hot flashes, decreased libido, osteoporosis, mood changes.
• Somatostatin Analogs: Gastrointestinal effects are most common: nausea, abdominal cramps, diarrhea, steatorrhea (due to inhibition of pancreatic exocrine secretion). Gallbladder abnormalities (sludge, stones) occur with long-term use due to inhibition of gallbladder contractility and bile secretion. Hyper- or hypoglycemia can occur due to modulation of insulin and glucagon.
• Dopamine Agonists: Nausea, vomiting, orthostatic hypotension, headache, nasal congestion. Less commonly, psychiatric effects (hallucinations, impulse control disorders) and, with ergot-derived agents (bromocriptine), pleuropulmonary and retroperitoneal fibrosis.
• Desmopressin: Headache, flushing, and hyponatremia/water intoxication if fluid intake is not restricted, particularly in pediatric or elderly patients.
• Oxytocin: Nausea, vomiting, and, at high doses, water intoxication due to its weak antidiuretic activity. Excessive uterine stimulation can lead to hypertonicity, fetal distress, or uterine rupture.
• Gonadotropins (FSH, LH/hCG): Ovarian hyperstimulation syndrome (OHSS) is a serious risk, characterized by ovarian enlargement, ascites, and hemodynamic instability. Multiple pregnancies and injection site reactions are also common.

Serious/Rare Adverse Reactions

• Increased Mortality: Recombinant GH therapy in critically ill patients is associated with increased mortality.
• Benign Intracranial Hypertension (Pseudotumor Cerebri): Reported with GH therapy, especially in children.
• Second Malignancies: A potential concern with GH therapy, though evidence is not conclusive; ongoing surveillance is recommended.
• Severe Allergic Reactions: Possible with any protein therapeutic, particularly older preparations derived from animal sources.
• Hepatotoxicity: A black box warning exists for tolvaptan due to the risk of serious and potentially fatal liver injury.

Black Box Warnings

• Growth Hormone (somatropin): Contraindicated in patients with active malignancy or acute critical illness due to increased mortality risk. Therapy should be discontinued if evidence of tumor growth or recurrence occurs.
• Tolvaptan: Risk of serious and potentially fatal liver injury; requires monitoring of liver function tests.

Drug Interactions

Interactions can occur through pharmacokinetic mechanisms (e.g., altered metabolism) or pharmacodynamic mechanisms (additive or opposing physiological effects).

Major Pharmacodynamic Interactions

• Glucocorticoids: Antagonize the growth-promoting and insulin-sensitizing effects of GH. High doses can also suppress the pituitary-adrenal axis, confounding the management of ACTH deficiency.
• Insulin and Oral Hypoglycemics: GH can induce insulin resistance, potentially increasing insulin requirements in diabetic patients. Somatostatin analogs can alter glycemic control by suppressing insulin and glucagon.
• Other Vasoactive Agents: Vasopressin’s pressor effects may be potentiated by other vasoconstrictors and attenuated by vasodilators. Desmopressin may enhance the pressor effect of norepinephrine.
• Drugs Affecting Prolactin Secretion: Dopamine antagonists (typical antipsychotics, metoclopramide) counteract the effects of dopamine agonists and can cause hyperprolactinemia.
• Diuretics: Concomitant use with desmopressin increases the risk of hyponatremia. Loop diuretics may reduce the risk of hyponatremia with vaptans.

Major Pharmacokinetic Interactions

• Enzyme Inducers/Inhibitors: Cabergoline is metabolized by CYP3A4. Strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) can increase cabergoline plasma levels and toxicity, while inducers (e.g., rifampin) may reduce its efficacy.
• Drugs Affecting Gastric Motility and pH: May alter the absorption of orally administered agents like bromocriptine and cabergoline.

Contraindications

Contraindications are often specific to each agent but generally include:

• Hypersensitivity to the drug or its components.
• Active malignancy (for GH therapy).
• Pregnancy (for many agents, particularly GnRH agonists/antagonists, due to potential fetal harm).
• Severe renal or hepatic impairment for drugs cleared by these pathways (e.g., dose adjustment required for GH in renal failure, contraindication for tolvaptan in anuric patients).
• Uncorrected electrolyte imbalances (e.g., hyponatremia for vaptans).
• Conditions where the drug’s physiological effect would be dangerous (e.g., desmopressin in patients with habitual or psychogenic polydipsia, oxytocin in situations of fetal distress or cephalopelvic disproportion).

Special Considerations

Use in Pregnancy and Lactation

Most hypothalamic and pituitary hormones are classified as Pregnancy Category B or C, indicating that human data are limited. A risk-benefit analysis is always required.

• Contraindicated/Generally Avoided: GnRH agonists and antagonists are typically contraindicated as they suppress sex steroid production, which is vital for maintaining pregnancy. Dopamine agonists are usually discontinued once pregnancy is confirmed in prolactinoma patients, though cabergoline has not been associated with increased teratogenic risk in limited data.
• Used with Caution: GH is not recommended during pregnancy. Desmopressin, being a synthetic analog, has a low risk of crossing the placenta and may be used if clearly needed for diabetes insipidus. Oxytocin is used routinely during labor and delivery.
• Lactation: Many peptide hormones are unlikely to be excreted in significant amounts into breast milk due to their size and potential degradation. However, dopamine agonists suppress lactation. Oxytocin is released naturally during breastfeeding.

Pediatric Considerations

Dosing is typically weight-based or body surface area-based. Monitoring is crucial due to effects on growth and development.

• Growth Hormone: Dosing is weight-based. Regular monitoring of growth velocity, bone age, and IGF-1 levels is essential. The diagnosis of GH deficiency must be unequivocal.
• Desmopressin for Enuresis: Fluid intake must be strictly limited in the evening to prevent water intoxication and hyponatremia, to which children are particularly susceptible.
• GnRH Agonists for Precocious Puberty: Monitor for suppression of the hypothalamic-pituitary-gonadal axis via LH, FSH, and sex steroid levels, and for catch-down growth and bone age progression.

Geriatric Considerations

Age-related declines in renal and hepatic function can alter drug clearance. Comorbidities are common.

• Renal Impairment: May reduce clearance of GH and desmopressin, necessitating dose reduction. GH is contraindicated in end-stage renal disease. Vaptans require careful monitoring in renal impairment.
• Increased Sensitivity: Elderly patients may be more sensitive to the fluid-retaining effects of GH and the hyponatremic effects of desmopressin. They are also more prone to orthostatic hypotension from dopamine agonists.
• Bone Health: Long-term use of GnRH agonists in elderly men for prostate cancer significantly accelerates bone loss, requiring assessment of fracture risk and consideration of bone-protective therapy.

Renal and Hepatic Impairment

• Renal Impairment: Clearance of peptides metabolized renally (e.g., vasopressin, desmopressin, GH) is reduced. For desmopressin, the risk of hyponatremia is markedly increased. Dosing intervals may need to be extended. Vaptans are contraindicated in anuric patients.
• Hepatic Impairment: May affect the metabolism of agents like cabergoline and the clearance of GH. The liver is a major site of IGF-1 production, so hepatic disease can profoundly affect the GH-IGF-1 axis, complicating therapy. Somatostatin analogs are metabolized hepatically; caution is advised in liver disease.

Summary/Key Points

• The hypothalamic-pituitary axis is a critical neuroendocrine interface, and its pharmacological manipulation is central to treating disorders of growth, metabolism, reproduction, and fluid balance.
• Agents include natural hormones, recombinant proteins, and synthetic analogs designed as agonists, antagonists, or release inhibitors, each with tailored pharmacokinetic profiles to suit clinical needs.
• Mechanisms of action predominantly involve binding to specific cell surface GPCRs or cytokine receptors, activating intracellular signaling cascades (e.g., cAMP/PKA, PLC/PKC, JAK/STAT) that alter gene transcription and cellular function.
• Due to peptide nature, most agents require parenteral administration (SC, IM, IV), with elimination primarily via proteolytic degradation and renal/hepatic clearance. Synthetic analogs are engineered for prolonged half-lives.
• Major therapeutic applications encompass hormone replacement (GH, desmopressin), suppression of hormone excess (somatostatin analogs for acromegaly, dopamine agonists for prolactinomas), control of reproductive function (GnRH agonists/antagonists, gonadotropins), and modulation of vascular tone and renal water handling (vasopressin, oxytocin, vaptans).
• Adverse effects are frequently extensions of pharmacological action (e.g., fluid retention with GH, hypogonadism with GnRH agonists, GI upset with somatostatin analogs). Serious risks include hyponatremia with desmopressin, ovarian hyperstimulation with gonadotropins, and hepatotoxicity with vaptans.
• Significant drug interactions are often pharmacodynamic, such as glucocorticoids antagonizing GH or dopamine antagonists counteracting dopamine agonists. Careful consideration of contraindications and special population adjustments (renal/hepatic impairment, pediatrics, pregnancy) is mandatory for safe use.

Clinical Pearls

• The “flare” phenomenon upon initiating GnRH agonist therapy can cause serious complications in metastatic prostate cancer (e.g., spinal cord compression); pre-treatment with an antiandrogen is often employed to block this effect.
• When monitoring desmopressin therapy for diabetes insipidus or enuresis, serum sodium should be checked periodically, as symptomatic hyponatremia can occur even with standard doses, particularly in children, the elderly, or with concomitant illness.
• In acromegaly, the goal of therapy with somatostatin analogs is not only to normalize serum IGF-1 but also to achieve a GH nadir of <1.0 µg/L after an oral glucose tolerance test, which is associated with reduced mortality.
• For patients with prolactinomas, cabergoline is generally preferred over bromocriptine due to its superior efficacy, tolerability, and twice-weekly dosing, though cost may be a limiting factor.
• When using gonadotropins for ovulation induction, careful ultrasound and estradiol monitoring are essential to minimize the risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies.

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