60. Hypothalamic and pituitary hormones

The 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 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 which gives it a long half-life.

Treatment of IGF-1 deficiency (very rare)

Mecasermin.

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. 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 (argipressin)
  • Terlipressin

Ornipressin is not used anymore. It’s deregistered in Hungary and other countries.

Indications

• Central diabetes insipidus
  • Vasopressin
  • Desmopressin
• Shock where vasodilation is involved
  • Vasopressin
• Oesophageal variceal bleeding
  • Terlipressin
• Exclusive for desmopressin
  • Haemophilia A and von Willebrand disease type I
  • Nocturnal enuresis

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.

Terlipressin is a prodrug which is metabolised to lysine vasopressine (lypressine), which is identical to endogenous vasopressin except for one amino acid (lysine instead of arginine).

Pharmacokinetics

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