60. Hypothalamic and pituitary hormones

Last updated on November 23, 2019 at 13:22

The physiological hypothalamo-pituitary axis

Hypothalamic hormones:

Hormone

Receptor type Stimulatory/inhibitory Effect
Thyrotropin-releasing hormone (TRH) Gs-coupled Stimulatory

TSH↑

Corticotropin-releasing hormone (CRH)

Gq-coupled Stimulatory ACTH↑
Somatostatin (SST) Gi-coupled Inhibitory

GH↓, TSH↓, ACTH↓, GI hormones ↓

Growth hormone-releasing hormone (GHRH)

Gs-coupled Stimulatory GH↑
Gonadotropin-releasing hormone (GnRH) Gq-coupled Stimulatory

FSH, LH↑

Dopamine/prolactin-inhibiting hormone

Gi-coupled Inhibitory

Prolactin↓, GH↓

Pituitary hormones:

Hormone

Receptor type Stimulatory/inhibitory Effect
Growth hormone Receptor tyrosine kinase Stimulatory

Regulates growth, anabolic effect

Prolactin

Receptor tyrosine kinase Stimulatory Development of mammary tissue and milk production
Follicle-stimulating hormone (FSH) Gs-coupled Stimulatory

Stimulates growth of ovum and follicle, spermatogenesis

Luteinizing hormone (LH)

Gq-coupled Stimulatory Stimulation of ovulation and corpus luteum, stimulation of testosterone
Thyroid-stimulating hormone (TSH) Gs, Gq-coupled Stimulatory

Stimulates thyroid hormones

Adrenocorticotropic hormone (ACTH)

Gs-coupled Stimulatory

Stimulates adrenocortical hormones

Prolactin, TRH and TSH have no therapeutic usage.

Growth hormone

Preparations:

  • Growth hormone analogues
    • Somatropin
  • IGF-1 analogues
    • Mecasermin
  • Growth hormone antagonists
    • Pegvisomant

Treatment of growth hormone deficiency:

Growth hormone deficiency should be treated with hormone replacement therapy, most commonly with somatropin. It is given as a once-daily subcutaneous injection.

Treatment of IGF-1 deficiency:

Mecasermin.

Treatment of growth hormone excess:

In most cases this is due to a pituitary adenoma. Pharmacological treatment can be used while waiting for surgical removal or instead of it the tumor is inoperable.

In most cases a somatostatin analogue called octreotide is used. Bromocriptine (dopamine analogue) and pegvisomant can also be used. Like the name suggests pegvisomant is pegylated, so it has a long half-life.

Somatostatin

Preparations:

  • Somatostatin analogues
    • Octreotide
    • Lanreotide
    • Pasireotide

Indications:

  • Growth hormone excess
  • Oesophageal varices
  • Neuroendocrine tumours

Mechanism of action:

Somatostatin inhibits the release of growth hormone, TSH, insulin, glucagon and most GI hormones. It also indirectly vasoconstricts splanchnic blood vessels, making it useful in treating oesophageal varices. This vasoconstriction comes from decreased production of vasodilatory hormones like glucagon.

Dosage:

Somatostatin analogues are given intramuscularly or subcutaneously, depending on the type. They also exist in so-called long-acting release preparations, basically depot preparations.

Dopamine

Preparations:

  • Dopamine receptor agonists:
    • Bromocriptine

Indications:

  • Hyperprolactinaemia
  • Parkinson disease

Pharmacokinetics:

Bromocriptine is orally absorbed but undergoes significant first pass metabolism.

Adverse effects:

  • Nausea, vomiting
  • Hypotension
  • Cardiac and pleuropulmonal fibrosis

Fibrosis occurs after long-term use.

Gonadotropin-releasing hormone (GnRH)

Preparations:

  • GnRH agonist analogues
    • Buserelin
    • Goserelin
  • GnRH antagonist analogues
    • Degarelix

Indications:

  • Early puberty
  • Hormone-dependent prostate or breast cancer
  • Endometriosis
  • Uterine leiomyomas

Mechanism of action:

The synthetic GnRH agonists are many times more potent than endogenous GnRH. Giving GnRH agonists continuously causes an initial increase in FSH and LH, but after this the pituitary will downregulate GnRH receptors. This results in a decrease in FSH and LH secretion as long as the treatment continues. This is called medical or chemical castration.

GnRH antagonists cause pharmacological castration without the initial increase in FSH and LH.

Pharmacokinetics and dosing:

These drugs are not absorbed orally. They’re given as nasal spray multiple times a day or as a subcutaneous depot injection every couple of months.

Adverse effects:

Symptoms of sex hormone deficiency. For GnRH agonist a transient increase in tumor size and related symptoms may occur.

Gonadotropins (FSH, LH, hCG)

Preparations:

Gonadotropins exists in two types of preparations. The first type is extracted and purified from urine of pregnant or postmenopausal women. This is less used nowadays. The second type is recombinant gonadotropins.

  • Recombinant FSH – follitropin
  • Recombinant LH – lutropin
  • Recombinant hCG – choriogonadotropin

Indications:

  • Treatment of female infertility
    • Anovulation
  • Treatment of male infertility
  • Cryptorchidism

Dosing:

  • For treatment of female infertility
    • FSH and hCG
  • For treatment of male infertility
    • Androgens, FSH and hCG
  • For cryptorchidism
    • hCG

Mechanism of action:

hCG has LH-like effects and is often given instead of LH for these indications.

In female infertility FSH is used to initiate development of the ovarian follicle. After 7 days hCG is given, which initiates ovulation.

In male infertility androgens are used to induce sexual development. hCG is then administered to activate Leydig cells, and FSH is administered to activate spermiogenesis.

In cryptorchidism hCG stimulates the Leydig cells. The resulting testosterone production will stimulate testicular descent.

Adverse effects:

  • Treatment of female infertility
    • Multiple pregnancy
    • Ovarian hyperstimulation syndrome
  • Treatment of male infertility
    • Gynecomastia
      • FSH stimulates aromatase, which converts testosterone into estradiol

Ovarian hyperstimulation syndrome is a potentially life-threatening consequence of inducing ovulation with hCG. It occurs due to the formation of multiple ovarian follicles, which increases the levels of VEGF. VEGF increases capillary permeability and fluid to leak into the body cavities, including the abdominal and pleural cavities.

Corticotropin-releasing hormone (CRH) and ACTH

Indications:

  • CRH stimulation test
  • ACTH stimulation test

These tests are used to evaluate the function of the hypothalamic-pituitary-adrenal axis. They can also be used to determine at which level the problem lies. These tests are only of diagnostic use. There are no therapeutic applications for these hormones.

Oxytocin

Indications:

  • To induce labour
  • To augment labour if contractions are insufficient
  • To prevent postpartum uterine haemorrhage
  • To induce milk ejection

Mechanism of action:

Oxytocin induces rhythmic contractions of the uterus. During postpartum uterine haemorrhage this can contract the blood vessels, stopping the bleeding.

It also contracts the myoepithelium of the mammary gland.

Pharmacokinetics:

Oxytocin has a short half-life and so must be given as a continuous IV infusion.

Vasopressin/anti-diuretic hormone

Preparations:

  • V1 receptor selective
    • Ornipressin
  • V2 receptor selective
    • Desmopressin
  • Non-selective
    • Synthetic vasopressin

Indications:

  • Central diabetes insipidus
    • Vasopressin
    • Desmopressin
  • Oesophageal varices
    • Vasopressin
    • Ornipressin
  • Haemophilia A and von Willebrand disease type I
    • Desmopressin
  • Nocturnal enuresis
    • Desmopressin

Mechanism of action:

The vasopressin V1 receptor is located on vascular smooth muscle and mediates vasoconstriction.

The vasopressin V2 receptor is located in the renal collecting duct and increases aquaporin expression, which increases water reabsorption. Stimulation of V2 receptor also increases the level of factor VIII and von Willebrand factor in the plasma.

Pharmacokinetics:

Vasopressin itself has a very short half-life. The vasopressin analogues have longer half-lives.


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2 thoughts on “60. Hypothalamic and pituitary hormones”

  1. « Oxytocin has a slow half-life and so must be given as a continuous IV infusion.» —> short plasma half life (3-5minutes), but the uterine effect last for two to three hours

    1. Corrected the word error, but are you sure the uterine effect lasts that long? It doesn’t say so on the lecture and I’m not sure you would give it IV if it was true.

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