Hypothalamic & anterior pituitary

Endocrine system Dr. Entisar Al-Mukhtar

• Pituitary & hypothalamus control the neuroendocrine system by transmitting messages between individual cells & tissues.
• Nervous system communicates locally by electrical impulses & neurotransmitters. Nerve impulses generally act within milliseconds.
• The endocrine system releases hormones (chemical messengers) into the blood stream, from which they reach their target cells.
• Response time to hormones may be seconds - days, or longer.
Note: response to hormones may last for weeks or months.
• In several instances, the release of hormones is stimulated or inhibited by the nervous system, & some hormones (Hs) can stimulate or inhibit nerve impulses.

Hypothalamic & anterior pituitary hormones
• Peptides or low-molecular-weight proteins.
• Bind to specific receptor sites.
• Hypothalamus produce releasing or inhibiting factors (or Hs), which regulate the anterior pituitary (AP) Hs.
Note: hypothalamic-releasing hormones (RHs) are primarily used for diagnostic purposes, e.g., CRH is used to differentiate between Cushing syndrome & ectopic ACTH-producing cells.
Anterior & posterior pituitary Hs are administered either IM, SC, or intranasally, but not orally (destructed by the proteolytic enzymes).


Adrenocorticotropic hormone (ACTH) or Corticotropin
• ACTH synthesized & released from the AP under the influence of CRH.
• ACTH is released in pulses with a diurnal rhythm, highest concentration occurring at 6 AM & lowest in the late evening.
• Stress stimulates ACTH secretion, whereas cortisol suppresses it (via negative feedback).
Mechanism of action:
Binding of ACTH to its receptors ? activate G protein ? ? cAMP ? + conversion of cholesterol to pregnenolone (a rate -limiting step in the adrenocorticosteroid synthesis) ? synthesis & release of adrenocorticosteroids & adrenal androgens.
Hypothalamic and Anterior
Pituitary Hormones
Choriogonadotropin alfa OVIDREL
Corticotropin H.P. ACTHAR
Cosyntropin CORTROSYN
Follitropin alfa GONAL-F
Follitropin beta FOLLISTIM
Goserelin ZOLADEX
Histrelin VANTAS
Human chorionic gonadotropin
PREGNYL
Lanreotide SOMATULINE
Leuprolide LUPRON
Menotropins MENOPUR,REPRONEX
Nafarelin SYNAREL
Octreotide SANDOSTATIN
Pegvisomant SOMAVERT
Somatropin HUMATROPE
Urofollitropin BRAVELLE
Uses:
1. To differentiate between primary adrenal insufficiency (Addison disease) & secondary adrenal insufficiency.
ACTH preparations are either from domestic animals or synthetic human ACTH like Cosyntropin which is preferred for the diagnosis of adrenal insufficiency.

2. Infantile spasm (West syndrome) treatment.

Adverse effects:
• Toxicities are similar to those of glucocorticoids (osteoporosis, HT, edema, hypokalemia, emotional disturbances & increased risk of infection).
• Abs against ACTH from animal origin.

Growth hormone (GH) or Somatotropin
• Large polypeptide released by the AP.
• Somatostatin (from hypothalamus), inhibits GH secretion.
• Highest levels of GH is released during sleep.
• With increasing age, GH secretion decreases, being accompanied by a decrease in lean muscle mass.
• Somatropin is a human GH synthesized by recombinant DNA technology, administered as SC or IM injection, (note: GH from animal sources is ineffective).

Mechanism of action:
• Many physiologic effects of GH are exerted directly at its targets, others are mediated by somatomedins—insulin-like growth factors I & II (IGF-I and IGF-II) (note: In acromegaly, IGF-I levels are high, reflecting elevated GH).
Uses:
(1) GH deficiency in children (dwarfism ).
(2) growth failure due to Prader-Willi syndrome
(3) management of AIDS wasting syndrome
(4) GH deficiency in adults to increases lean body mass, bone density, and skin thickness, whereas adipose tissue is decreased. [note: GH has been off-label used by older individuals and athletes].
GH adverse effects ? pain at the injection site, edema, arthralgias, myalgias, flu-like symptoms, and risk of diabetes.
• Somatropin should not be used if there is closed epiphyses, diabetic retinopathy, or obesity in patients with Prader-Willi syndrome.

Somatostatin (GH -inhibiting hormone)
• Suppress GH & TSH release.
• It also found in neurons, intestine & pancreas.
• It also inhibits release of, insulin, glucagons & gastrin.

Octreotide and Lanreotide ? synthetic somatostatin analogs with longer half- life (given once every 4 weeks), used to treat acromegaly, diarrhea and flushing associated with carcinoid tumors.
Octreotide IV infusion ? used to treat bleeding of esophageal varices.

Octreotide adverse effects ? flatulence, diarrhea, nausea & steatorrhea. Gallbladder empting is delayed & long-term therapy may cause asymptomatic cholesterol gallstones.

Pegvisomant ? GH receptor blocker used to treat acromegaly that is refractory to surgical, radiologic, or pharmacologic intervention.

Gonadotropins – releasing hormone ( GnRH )
• Its pulsatile secretion is essential for gonadotropins (FSH & LH) release.
• Continuous administration of synthetic GnRH analogs (receptors agonists) such as leuprolide, goserelin, nafarelin & histrelin inhibits gonadotropin release ( due to down-regulation of the GnRH receptors) thus, reduce androgens & estrogens production [note: several of these agents are available as implantable formulations].
• GnRH analogs are used to treat prostatic cancer, endometriosis & precocious puberty.
• In women GnRH analogs may cause hot flushes, sweating & diminished libido, depression & ovarian cysts.
• Contraindication ? pregnancy & lactation.
• In men, they initially cause a rise in testosterone that can result in bone pain, hot flushes, edema, gynecomastia & diminished libido.

Gonadotropins:
• FSH & LH are glycoproteins that are produced in the AP.
• Regulate gonadal steroid hormones secretion.
• Used to treat infertility in men and women.

Menotropins ( Human menopausal gonadotropins "hMG"): Obtained from the urine of postmenopausal women, it contain both FSH & LH.

Urofollitropin: FSH obtained from postmenopausal women.

Follitropin alfa & Follitropin beta: Human FSH produced by recombinant DNA technology.

Human chorionic gonadotropin (hCG): Placental hormone, excreted in the urine.
• hCG and choriogonadotropin alfa (made by recombinant DNA technology) are identical to LH.
All of these hormones are injected IM or SC.
• hMG or FSH injected over a period of 5 to 12 days causes ovarian follicular
growth & maturation, then subsequent injection of hCG induce ovulation.
• In females adverse effects ? ovarian enlargement & possible ovarian hyperstimulation syndrome (may be life threatening) & multiple births.

Prolactin (PRL)
• Peptide hormone secreted by the AP.
• Dopamine (at D2 receptors) inhibit PRL secretion [Note: dopamine antagonists e.g. metoclopramide & antipsychotics like risperidone increase PRL secretion].
• PRL decreases sexual drive & reproductive function.
• D2 receptor agonists eg. bromocriptine & cabergoline are used to treat hyperprolactinemia (galactorrhea & hypogonadism) & pituitary microadenomas, bromocriptine is also indicated to treat type 2 DM.
• Their adverse effects ? nausea, headache & psychiatric problems.