Hypothalamic and Pituitary Hormones

Hypothalamus and Pituitary

The output of the hypothalamus-pituitary unit regulates the function of the thyroid, adrenal and
reproductive glands and also controls somatic growth, lactation, milk secretion and water
metabolism.
Hypothalamic hormones are transported by hypothalamo-hypophyseal portal system to pituitary
can also stimulate or inhibit the release of anterior pituitary hormones, called RELEASING
HORMONES “RH” or INHIBITING HORMONES “IH”.

The Pituitary Gland

The Pituitary Gland is divided into 2 areas, with separate types of hormones.
The anterior pituitary synthesis and releases its hormones under regulation of the hypothalamus
Growth Hormone (GH), Thyroid-stimulating Hormone (TSH), Adrenocorticotropin (ACTH)
Follicle-stimulating Hormone (FSH) ), Leutinizing Hormone (LH), Prolactin

– The posterior pituitary stores and secretes hormones that are made in the hypothalamus:
Oxytocin and Antidiuretic hormone (ADH)
1- Growth Hormone Releasing Hormone (GHRH)

controls release of the GH from the anterior pituitary.

It is released from hypothalamus in a pulsatile fashion, with 5-9 major pulses detected per day.

GHRH release is enhanced by α2-adrenergic agonists (e.g. clonidine) and opioids.

GHRH release is also increased by extensive exercise.

Sermorelin (GHRH 1-29)

GHRH

Diagnostic Uses of GHRH

To test pituitary function in patients with GH deficiency.
GH deficiency could reflect either a hypothalamic or a pituitary defect.
If the primary defect is hypothalamic, as is most common, GHRH will elicit an increase in GH release.
If the defect is at the level of the pituitary, there will be no increase in GH following GHRH.

Therapeutic Uses of GHRH to enhance GH secretion

Pulsatile delivery of GHRH, mimicking the normal endogenous patterns (e.g. ~ every 3 hours) has
been used to stimulate GH release in patients with GH deficiency that is not of pituitary origin.
IV, SC, intranasal administration
Somatostatin

Somatostatin (Growth hormone-release inhibiting hormone (GHRIH)

Inhibits GH release and TSH from anterior pituitary.

Inhibits release of most GI hormones (mainly Gastrin) and pancreatic secretions (glucagon, insulin)
Somatostatin -- short half-life (<3 min); no clinical value,

Octreotide and Lanreotide (long acting analogs) – used to treat Acromegaly, Gastrinoma,
Glucagonoma, and esophagal varices bleeding
AEs : GI disturbances, postprandial hyperglycemia
2. Growth Hormone (GH; Somatotropin)
a single chain polypeptide.
secretion is controlled by GHRH and somatostatin
GH secretion is high in newborn, decreasing at 4 yr to an intermediate level, which is then
maintained until puberty, when there is further decline.
Significant differences in amino acid sequence between humans and other species prevent use of
non-human hormon

Physiological actions of Growth Hormone (GH; Somatotropin)

Growth -- almost all body tissues are stimulated to grow (GH receptor stimulation activates tyrosine
kinase that results phosphorylation of proteins and gene regulation in tissues).
Protein metabolism (increased nitrogen retention, amino acid transport into tissues, and
incorporation into protein)
Carbohydrate and lipid metabolism (promote usage of lipids as energy source instead of
carbohydrates)
GH has a hyperglycemic effect in diabetics
GROWTH HORMONE DEFICIENCY
Can have a genetic basis or can be acquired as a result of damage to the pituitary or
hypothalamus by a tumor, infection, surgery, or radiation therapy. In childhood: short
stature and adiposity, hypoglycemia. In adults : generalized obesity, reduced muscle
mass.

GROWTH HORMONE EXCESS

Mainly benign pituitary tumor. In adults causes acromegaly, If this occurred before the
long bone epiphyses close, it leads to the rare condition, gigantism.
Treatment of excess GH disorders: - Synthetic Somatostatin (Octreotide) - DA agonists
(Bromocriptine) / Surgical removal / Radiotherapy of the tumor - GH Antagonists
(Pegvisomant; a GH receptor antagonist, is now available to treat acromegaly in
patients who have not responded to other treatment).

Insulin-like growth factors (IGF, somatomedins)

peptides produced by liver and other tissues in response to GH; appear to mediate
many GH effects. rhIGF-1 available for treatment of growth failure in GH-resistant
patients
Clinical applications of GH

Recombinant human growth hormone (rh-GH) is used clinically.

There are two forms, Somatotropin and Somatrem.

Hypopituitary dwarfism – in children with insufficient GH secretion, GH will generally produce an

increased growth rate over several years. Recently, FDA approved use in children with
idiopathic, non-GH-deficient short stature.
Treatment of AIDS – associated wasting
Treatment of adult onset growth hormone deficiency
Turner’s syndrome

Problems associated with rh-GH therapy

intracranial hypertension and visual changes
type 2 diabetes and respiratory difficulties in patients with obesity
3- Gonadotropin releasing hormone (GnRH; Gonadorelin)
Stimulate the gonadotroph cells to produce and release LH and FSH
GnRH is used in the diagnosis & treatment (by pulsatile administration) of hypogonadal states in
females & males
In contrast, steady dosing inhibits gonadotropin release by causing down –regulation
(desensitization) of GnRH receptors in pituitary cells that normally cause release of gonadotropins

GnRH and analogs – drugs available include Gonadorelin (natural hormone) and
Long-acting analogs Buserelin, Histrelin , Leuprolide, Gosrelin, Triptoreline, and Nafareline.

Clinical use -- Gonadorelin is used for induction of ovulation.

Long acting analogs are used for treatment of Premenstrual Syndrome (PMS), endometriosis,
prostate cancer, and central -origin precocious puberty.
GnRH antagonists

GnRH antagonists

Ganirelix and Cetrorelix

Used to inhibit premature LH surges prior to harvesting eggs for in vitro fertilization

Abarelix – a GnRH receptor antagonist used to treat advanced prostate cancer.

AE : Danger of life-threatening allergic reactions in 4% of patients.
Gonadotropins

4. Luteinizing hormone (LH)

glycoprotein hormone
Physiological actions
Ovary – promotes ovulation and luteinization of ovarian follicles; stimulates synthesis and secretion
of estrogen and progesterone from corpus luteum.
Testis – stimulate Leydig cells to secrete androgens
Kits available to predict «time of ovulation» by measuring urinary LH

Clinical applications of LH
Infertility – Menotropins (a mixture of urinary LH and FSH) and Chorionic gonadotropin have been
used to induce ovulation. Recombinant human LH (lutropin alpha) is also available.
AEs : Hyperstimulation of ovary may occur
Gonadotropins

5. Follicle stimulating hormone (FSH)

glycoprotein with 2 peptide chains.

Physiological actions of FSH

Ovary – promote follicular development
Testis – stimulate testicular growth

Agents available are recombinant human FSH (follitropin), and urinary human FSH (urofollitropin)
These products are used in combination with other drugs to treat infertility particularly in women.
Gonadotropins

Chorionic gonadotropin (HCG)

glycoprotein with 2 polypeptide chains.
Synthesized by syncytiotrophoblasts of placenta.
not a pituitary hormone but is similar to the pituitary gonadotropins

Recombinant human HCG is used clinically.

Physiological actions – stimulate and sustain function of corpus luteum

Clinical application – induction of ovulation, promote descent of testes in cryptorchism
– presence of HCG in urine used to confirm diagnosis of pregnancy
6. Thyrotropin-Releasing Hormone (TRH)

stimulates release of thyrotropin (TSH) from anterior pituitary

is used in diagnosis of thyroid dysfunction
Protrelin i.v. administration

7. Thyrotropin (TSH)
glycoprotein with 2 polypeptide chains.
Physiological actions –increases function of thyroid gland, increases uptake of iodine by thyroid,
synthesis and release of hormone, and growth of gland.
Thyrotropin alpha and human recombinant TSH, is used clinically.

Clinical application
Increases uptake of radioactive iodine. Used as a diagnostic tool for serum thyroglobulin
testing or whole body scanning in the follow-up of patients with thyroid cancer.
8. Corticotropin-Releasing Hormone (CRH)
stimulates release of ACTH from anterior pituitary
diagnostic use

9. Corticotropin (Adrenal Cortex Trophic Hormone, ACTH)

natural hormone from anterior pituitary; a single chain polypeptide of 39 amino acids.
A synthetic form containing amino acids 1-24 (ACTH 1-24) is available.
Mechanism –activation of adenylate cyclase and synthesis of cAMP. cAMP activates enzymes
involved in steroid synthesis.
Physiological actions
stimulates adrenal cortex to synthesize and secrete cortisol, corticosterone, and aldosterone.
Clinical use
diagnosis of adrenal insufficiency
10. Prolactin - PRL
single chain polypeptide hormone from anterior lobe

Physiological actions
-- in males: involved in testicular function
Lactation – causes growth and development of breasts, and increased synthesis of milk proteins
-- decreases release or effectiveness of gonadotropins

Hypersecretion of PRL – hyperprolactinemia may cause galactorrhea, amenorrhea and infertility.

Bromocriptine, Pergolide, and Cabergoline are useful in suppressing PRL secreting tumors.

11. Prolactin-Inhibiting Hormone (PIH,dopamine)

Dopamine is the physiologic inhibitor of prolactin release.
Because of its peripheral effects, dopamine is not useful in the control of hyperprolactinemia.
Posterior Pituitary Hormones
Oxytocin

Oxytocin
is synthesized in the hypothalamus & transported to the posterior pituitary
It is an effective stimulant of uterine contraction
Induces the release of milk
Suckling sends a message to the hypothalamus via the nervous system to release oxytocin, which
further stimulates the milk glands
Clinical uses of oxytocin (i.v. or i.m.)
Induction of labor and control of postpartum bleeding
AEs :
uterine rupture, excessive fluid retention
Vasopressin (Antidiuretic Hormone, ADH)

Vasopressin (Antidiuretic Hormone, ADH)

ADH is synthesized in the hypothalamus & transported to the posterior pituitary

The function of ADH is to increase water conservation by the kidney
If there is high ADH secretion, the kidneys reabsorb water.
If there is a low level of ADH secretion, the kidneys release a dilute urine
ADH release increases if blood pressure falls or blood becomes too salty
ADH causes peripheral blood vessel constriction to help in elevation of blood pressure .

Clinical uses : Diabetes insipidus, Nocturnal enuresis (by decreasing nocturnal urine production)

AEs: hyponatremia and seizures

Synthetic ADH drugs– Vasopressin: IV, IM– Desmopressin: IV, IM. PO, intranasal
Actions and Regulation of ADH