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Drugs For Pituitary & Hypothalamic Disease

  • The pituitary consists of an anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis). It is connected to the overlying hypothalamus by a stalk of neurosecretory fibers and blood vessels including a portal venous system that drains the hypothalamus and perfuse the anterior pituitary.
  • The portal venous system carries small regulatory hormones from the hypothalamus to the anterior pituitary. The posterior lobe hormones are synthesized in the hypothalamus and transported via the neurosecretory fibers in the stalk of the pituitary to the posterior lobe, from which they are released into the circulation.
Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas:
  1. As replacement therapy for hormone deficiency states;
  2. As antagonists for diseases caused by excess production of pituitary hormones;
  3. As diagnostic tools for identifying several endocrine abnormalities.
Link Between Hypothalamus, Anterior Pituitary And Target Organ
Hypothalamic Ant. Pituitary Target Organ Hormone/Mediator
Growth hormone-releasing hormone (GHRH) (+) Somatostatin (−) Growth hormone (GH, somatotropin) Liver, bone, muscle, kidney, and others Insulin-like growth factor-I (IGF-I)
Thyrotropin-releasing hormone (TRH) (+) Thyroid-stimulating hormone (TSH) Thyroid Thyroxine, triiodothyronine
Corticotropin-releasing hormone (CRH) (+) Adrenocorticotropin (ACTH) Adrenal cortex
Gonadotropin-releasing hormone (GnRH) (+) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Gonads Estrogen, progesterone, testosterone
Dopamine (−) Prolactin (PRL) Breast -
  • All of these hormones act through G protein-coupled receptors except growth hormone and prolactin, which act through JAK/STAT receptors
  • Endogenous GnRH, which is released in pulses, stimulates LH and FSH release. When administered continuously as a drug, GnRH and its analogs inhibit LH and FSH release through down-regulation of GnRH receptors.
Hypothalamic Hormones
  1. Growth hormone-releasing hormone (GHRH): Used rarely as a diagnostic test for GH and GHRH sufficiency
  2. Thyrotropin-releasing hormone (TRH, protirelin): May be used to diagnose TRH or TSH deficiencies
  3. Corticotropin-releasing hormone (CRH): Used rarely to distinguish Cushing’s disease from ectopic ACTH secretion
  4. Gonadotropin-releasing hormone (GnRH):
    1. May be used in pulses to treat infertility caused by GnRH deficiency.
    2. Analogs used in long-acting formulations to inhibit gonadal function in children with precocious puberty,
    3. in some transgender/gender variant early pubertal adolescents (to block endogenous puberty),
    4. in men with prostate cancer and
    5. women undergoing assisted reproductive technology (ART) or
    6. women who require ovarian suppression for a gynecologic disorder
  5. Dopamine: Dopamine agonists (e.g., Bromocriptine, cabergoline) used for treatment of hyperprolactinemia.
    Pituitary Hormones:
    Growth Hormone
    1. 191 amino acid peptide
    2. Important for growth and development.
    3. Structure is similar to that of prolactin and human chorionic
    4. Pharmacological actions are mediated by insulin like growth factors (IGF-1 & IGF-2). GH resembles to prolactin structurally. 


  1. Initially, it has insulin like actions after phase it has anti-insulin like actions.
  2. Growth hormone releasing hormone analogue named sermorelin is now available (Human grown hormone-hGH).
  3. However, it is not recommended to critically ill patients as it can increase mortality.
  4. Growth hormone release inhibiting peptides inhibit its release.
  5. GHRH receptors are G-protein coupled. Release of GH increases following use of GHRH. 
Indications For Growth Hormone:
Primary Objective Clinical Conditions
GROWTH Growth failure in pediatric patients associated with:
Growth hormone deficiency. Chronic renal insufficiency pre-transplant, Noonan syndrome, Prader-Willi syndrome, Short stature homeobox- containing gene (SHOX) deficiency, Turner syndrome, Small for gestational age with failure to catch up by age 2 years, Idiopathic short stature
Improved metabolic state, increased lean body mass, sense of well-being Growth hormone deficiency in adults
Increased lean body mass, weight, and physical endurance Wasting in patients with HIV infection
Improved gastrointestinal function
Short bowel syndrome in patients who are also receiving specialized nutritional support

  1. Recombinant human IGF-I
  2. Mecasermin is recomb. human IGF-I alone, while mecasermin rinfabate is a complex of recombinant human IGF-I (rhIGF-I) and recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3).
  3. USES: Growth failure due to mutations in the GH receptor and in the GH receptor-signaling pathway, neutralizing antibodies to GH, and IGF-I gene defects.
Growth Hormone Antagonist


  1. Peptide known as “universal hormone inhibitor”.
  2. Inhibits release of hypothalamic, pituitary gastrointestinal hormones.
  3. Octreotide or lanreotide are a synthetic analogues
  4. Octreotide is DOC :  Acromegaly,  VIPoma and GIPoma.
  5. Cabergoline is the initial drug in acromegaly. Later, pegvisomant (GH antagonist) can be used.
    1. Earlier, bromocriptine was used as an initial drug of choice
    2. Not preferred now due to short duration of action and lot of side effects     
  6. Cabergoline is the best-tolerated dopamine agonist in patients with PD or acromegaly.
    1. Should be given at night to minimize side effects
  • Pegvisomant is a GH receptor antagonist used to treat acromegaly.
  1. This is a tripeptide and is short acting.
  2. TRH infusion increases release of prolactin. Therefore, hyperprolactinemia is accompanied by increase in its release.
  1. Derivative of proopiomelanocortin.
  2. Increases release of ACTH and beta-endorphin.
  3. 41 amino acid and is given intravenously.
  4. It is used to differentiate between Cushing’s disease and ectopic ACTH production.
  1. This is a small peptide hormone (1-24 for activity and 24-39 for specificity) and it increases synthesis and release of glucocorticoids.
  2. Used in Infantile Spasms


  1. Decapeptide synthesized and released from arcuate nucleus of hypothalamus.
  2. Natural GnRH has a short half life of few minutes
  3. Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH.
  4. Sustained non-pulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary in both women and men, resulting in hypogonadism.
  5. Its analogue act for a longer duration. By acting on pituitary gonadotrophins, the drug increases the release of LH and FSH.
  6. Gonadorelin is an acetate salt of synthetic human GnRH. Synthetic analogs of GnRH include Goserelin, Histrelin, Leuprolide, Nafarelin, And Triptorelin
  7. GnRH analogs can be administered subcutaneously, intra- muscularly, via nasal spray (nafarelin), or as a subcutaneous implant.
The physiologic actions of GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty. This is not surprising in view of the complex role that GnRH plays in normal reproduction, particularly in female reproduction.
Pulsatile GnRH release occurs and is responsible for stimulating LH and FSH production during the fetal and neonatal period. Subsequently, from the age of 2 years until the onset of puberty, GnRH secretion falls off and the pituitary simultaneously exhibits very low sensitivity to GnRH. Just before puberty, an increase in the frequency and amplitude of GnRH release occurs and then, in early puberty, pituitary sensitivity to GnRH increases, which is due in part to the effect of increasing concentrations of gonadal steroids. In females, it usually takes several months to a year after the onset of puberty for the hypothalamic-pituitary system to produce an LH surge and ovulation.
By the end of puberty, the system is well established so that menstrual cycles proceed at relatively constant intervals. The amplitude and frequency of GnRH pulses vary in a regular pattern through the menstrual cycle with the highest amplitudes occurring during the luteal phase and the highest frequency occurring late in the follicular phase. Lower pulse frequencies favor FSH secretion, whereas higher pulse frequencies favor LH secretion. Gonadal steroids as well as the peptide hormones activin and inhibin have complex modulatory effects on the gonadotropin response to GnRH.

Pulsatile Stimulation                    Continuous Suppression
Female Infertility (Assisted Ovulation)
Male Infertility
Diagnosis Of Delayed Puberty (Due To Hypogonadotrophism)
Controlled Ovarian Hyperstimulation
Prostate Cancer
Central Precocious Puberty
Advanced Breast/Prostate Cancer
PCOD (For Treatment Of Infertility And Amenorrhea)
Early Pubertal Transgender Adolescence
Thinning Of Endometrium (For Ablation Procedures)
  1. Hot flushes are common side effects. Prolonged use can lead to osteoporosis.
  2. Decrease libido, infertility, ovarian cyst
  3. Depression
  1. Ganirelix, cetrorelix, and degarelix
  2. Ganirelix and cetrorelix are approved for use in controlled ovarian hyperstimulation procedures, whereas degarelix is approved for men with advanced prostate cancer.
  1. Milk production is stimulated by prolactin when appropriate circulating levels of estrogens, progestins, corticosteroids, and insulin are present.
  2. Hyperprolactinemia produces a syndrome of amenorrhea and galactorrhea in women, and loss of libido and infertility in men.
  3. Dopamine agonist are DOC for hyperprolactinomas

Gonadotrophins (FSH, LH) and Beta-hCG

  1. Glycoprotein hormone and acts via cAMP. 
  2. FSH association with LH, it regulates gonadal function. LH is responsible for gonadal hormone production.
  3. In males, LH increases production of testosterone from Leydig’s cells.
  4. In females, maturation of follicles and induction of ovulation are main functions of LH.
  5. During luteal phase, it stimulates production of progesterone and androgens.  
  6. LH is not used clinically. Instead, hCG is used clinically as it has LH like actions.
  7. Earlier, MENOTROPINS (hMG): from urine of menopausal women with FSH like properties.
  8. FSH PREP: Urofollitrophin, purified preparation of human FSH extracted from the urine of postmenopausal women. Two recombinant forms of FSH (rFSH) are also available: follitropin alfa and follitropin beta.
  9. Lutropin alfa, the recombinant form of human LH
  10. Choriogonadotropin alfa (rhCG) is a recombinant form of hCG.
  11. USES: Ovulation induction, male infertility.
  12. S/E: Multiple pregnancies, Ovarian Hyperstimulation Syndrome
  1. Peptide hormone secreted by the posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating women.
  2. Oxytocin is a 9-amino-acid peptide with an intra-peptide disulfide cross-link
  1. Induction Of Labour: In Case Of Rh Incompatibility, Maternal Diabetes, Preeclampsia, Ruptured Membranes Etc
  2. Augmentation Of Labour: In Case Of Protracted Or Arrest Labor
  3. Immidiate Post-Partum: To Control Uterine Hemorrhage After Delivery
  4. 2nd Trimester Abortion
  5. Oxytocin Challenge Test: The oxytocin challenge test measures the fetal heart rate response to a standardized oxytocin infusion and provides information about placental circulatory reserve. An abnormal response, seen as late decelerations in the fetal heart rate, indicates fetal hypoxia and may warrant immediate cesarean delivery.
Dosage: For induction of labor, an initial infusion rate of 0.5–2 mU/min is increased every 30–60 minutes until a physiologic contraction pattern is established. The maximum infusion rate is 20 mU/min.
For postpartum uterine bleeding, 10–40 units are added to 1 L of 5% dextrose, and the infusion rate is titrated to control uterine atony. Alternatively, 10 units of oxytocin can be administered by intramuscular injection after delivery of the placenta.
  1. Peptide hormone released by the posterior pituitary in response to rising plasma tonicity or falling blood pressure.
  2. Vasopressin possesses antidiuretic and vasopressor properties. A deficiency of this hormone results in diabetes insipidus
  3. Desmopressin is a long-acting synthetic analog of vasopressin with minimal pressor activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin.
Vascular smooth muscle cells and mediates vasoconstriction via the coupling protein Gq. Renal tubule cells and reduces diuresis through increased water permeability and water resorption in the collecting tubules via Gs. Regulate the release of coagulation factor VIII and von Willebrand factor.
  1. Vasopressin and desmopressin are treatments of choice for pituitary (central) diabetes insipidus.
  2. Bedtime desmopressin therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing nocturnal urine production.
  3. Desmopressin is also used for the treatment of coagulopathy in hemophilia A and von Willebrand’s disease
  4. Vasopressin infusion is effective in some cases of esophageal variceal bleeding and colonic diverticular bleeding.
Vasopressin Antagonist:
  • Conivaptan and tolvaptan are approved by the FDA for intravenous administration in hyponatremia.
  • Conivaptan has high affinity for both V1and V2 receptors.
  • Tolvaptan has a 30-fold higher affinity for V2 than for V1 receptors.

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