1. Hypothalamic & pituitary hormones
By:
S.Bohlooli, PhD
School of Medicine, Ardabil University of Medical Sciences (ArUMS)

2. The hypothalamic-pituitary endocrine system
Figure The hypothalamic-pituitary endocrine system. Except for prolactin, hormones released from the anterior pituitary stimulate the production of hormones by a peripheral endocrine gland or the liver. Prolactin and the hormones released from the posterior pituitary (vasopressin and oxytocin) act directly on target tissues. Hypothalamic factors regulate the release of anterior pituitary hormones. (ACTH, adrenocorticotropin; ADH, antidiuretic hormone [vasopressin]; CRH, corticotropin-releasing hormone; DA, dopamine; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-releasing hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; PRL, prolactin; SST, somatostatin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.)

3. hypothalamic, anterior pituitary, and target organ hormone
Anterior Pituitary Hormone
Hypothalamic Hormone
Target Organ
Primary Target Organ Hormone or Mediator
Growth hormone (GH, somatotropin)
Growth hormone-releasing hormone (GHRH) (+) Somatostatin (-)
Liver, muscle, bone, kidney, and others
Insulin-like growth factor-1 (IGF-1)
Thyroid-stimulating hormone (TSH)
Thyrotropin-releasing hormone (TRH) (+)
Thyroid
Thyroxine, triiodothyronine
Adrenocorticotropin (ACTH)
Corticotropin-releasing hormone (CRH) (+)
Adrenal cortex
Glucocorticoids, mineralocorticoids, androgens
Follicle-stimulating hormone (FSH) Luteinizing hormone (LH)
Gonadotropin-releasing hormone (GnRH) (+)2
Gonads
Estrogen, progesterone, testosterone
Prolactin (PRL)
Dopamine (-)
Breast
(+), stimulant; (-), inhibitor.

4. Clinical uses of hypothalamic hormones and their analogs
Growth hormone-releasing hormone (GHRH)
Used rarely as a diagnostic test for GH responsiveness
Thyrotropin-releasing hormone (TRH, protirelin)
Used rarely to diagnose hyper- or hypothyroidism
Corticotropin-releasing hormone (CRH)
Used rarely to distinguish Cushing's disease from ectopic ACTH secretion
Gonadotropin-releasing hormone (GnRH)
Used rarely in pulses to treat infertility caused by hypothalamic dysfunction
Analogs used in long-acting formulations to inhibit gonadal function in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecological disorder
Dopamine
Analogs used for treatment of hyperprolactinemia

5. Diagnostic uses of thyroid-stimulating hormone and adrenocorticotropin
Thyroid-stimulating hormone (TSH; thyrotropin)
In patients who have been treated surgically for thyroid carcinoma, to test for recurrence by assessing TSH-stimulated whole-body 131I scans and serum thyroglobulin determinations
Adrenocorticotropin (ACTH)
In patients suspected of adrenal insufficiency, to test for a cortisol response.
In patients suspected of congenital adrenal hyperplasia, to identify 21-hydroxylase deficiency, 11-hydroxylase deficiency, and 3b-hydroxy-D5 steroid dehydrogenase deficiency, based on the steroids that accumulate in response to ACTH administration

6. Pharmacologic Applications of hypothalamic and pituitary hormones
Replacement therapy for hormone deficiency states
Antagonists for diseases that result from excess production of pituitary hormones
Diagnostic tools for identifying several endocrine abnormalities

7. GROWTH HORMONE (SOMATOTROPIN)

8. Introduction Peptide hormones
Important effects on lipid and carbohydrate metabolism
Its effects are primarily mediated via
insulin-like growth factor 1 (IGF-1, somatomedin C)
insulin-like growth factor 2 (IGF-2).

9. Chemistry & Pharmacokinetics
STRUCTURE:
is a 191-amino-acid peptide with two sulfhydryl bridges
rhGH
Somatropin has a 191-amino-acids
Somatrem has 192 amino acids

10. Pharmacodynamics
Mediates its effects via cell surface receptors of the JAK/STAT cytokine receptor superfamily
Has complex effects on
growth, body composition
carbohydrate, protein, and lipid metabolism
The growth-promoting effects are mediated through IGF-1
GH has anabolic effects in muscle and catabolic effects in lipid cells

11. Clinical Pharmacology
GROWTH HORMONE DEFICIENCY
PEDIATRIC PATIENTS WITH SHORT STATURE
Other Uses of Growth Hormone

12. Clinical uses of recombinant human growth hormone
Primary Therapeutic Objective
Clinical Condition
Growth
Growth failure in pediatric patients associated with:
Growth hormone deficiency
Chronic renal failure
Prader-Willi syndrome
Turner syndrome
Small for gestational age with failure to catch up by age 2
Idiopathic short stature in pediatric patients
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 AIDS
Improved gastrointestinal function
Short bowel syndrome in patients who are also receiving specialized nutritional support

13. Toxicity & Contraindications
A rarely reported side effect is intracranial hypertension, which may manifest as vision changes, headache, nausea, or vomiting

14. MECASERMIN Is a complex of For treatment of severe IGF-1 deficiency
recombinant human IGF-1 (rhIGF-1)
recombinant human insulin-like growth factor-binding protein-3 (rhIGFBP-3)
For treatment of severe IGF-1 deficiency
The most important adverse effect is hypoglycemia

15. GROWTH HORMONE ANTAGONISTS
Somatostatin
It inhibits the release of GH, glucagon, insulin, and gastrin
has limited therapeutic usefulness
Octreotide
reduces symptoms caused by a variety of hormone-secreting tumors
acromegaly; the carcinoid syndrome; gastrinoma; glucagonoma; nesidioblastosis
the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and diabetic diarrhea.

16. Amino acid sequence of somatostatin and its analog

17. Pegvisomant Is a GH receptor antagonist
Useful for the treatment of acromegaly
The polyethylene glycol (PEG) derivative of a mutant GH, B2036,

18. THE GONADOTROPINS FSH LH human Chorionic Gonadotropin (hCG)
Are dimers that share
an identical  chain
in addition to a distinct  chain

19. Chemistry & Pharmacokinetics
MENOTROPINS
FOLLICLE-STIMULATING HORMONE
Urofollitropin,
follitropin alfa and follitropin beta
LUTEINIZING HORMONE
Lutropin,
HUMAN CHORIONIC GONADOTROPIN

20. Pharmacodynamics
Effects through G protein-coupled receptors

21. The menstrual cycle
Figure The menstrual cycle, showing plasma levels of pituitary and ovarian hormones and histologic changes.

22. Clinical Pharmacology
OVULATION INDUCTION
to induce ovulation in women with anovulation due to:
hypogonadotropic hypogonadism
polycystic ovary syndrome
obesity
MALE INFERTILITY

23. Controlled ovarian hyperstimulation
Figure Controlled ovarian hyperstimulation in preparation for an assisted reproductive technology such as in vitro fertilization. Follicular phase: Follicle development is stimulated with gonadotropin injections that begin about 3 days after menses begin. When the follicles are ready, as assessed by measurement of serum estrogen concentration and ultrasound measurement of follicle size, final oocyte maturation is induced by an injection of hCG. Luteal phase: Shortly thereafter oocytes are retrieved and fertilized in vitro. The recipient's luteal phase is supported with injections of progesterone. To prevent a premature luteinizing hormone surge, endogenous gonadotropin secretion is inhibited during the follicular phase with either a GnRH agonist or a GnRH antagonist. In most protocols, the GnRH agonist is started midway through the preceding luteal cycle.

24. Toxicity & Contraindications
ovarian hyperstimulation syndrome
multiple pregnancies
Headache, depression, edema, precocious puberty

25. GONADOTROPIN-RELEASING HORMONE & ITS ANALOGS
Pulsatile GnRH secretion is required to stimulate the gonadotroph cell to produce and release LH and FSH
Sustained, nonpulsatile administration of GnRH or GnRH analogs inhibits the release of FSH and LH by the pituitary

26. Chemistry & Pharmacokinetics
STRUCTURE
GnRH is a decapeptide found in all mammals
Gonadorelin is an acetate salt of synthetic human GnRH
Synthetic analogs include goserelin, histrelin, leuprolide, nafarelin, and triptorelin.
PHARMACOKINETICS
GnRH analogs can be administered subcutaneously, intramuscularly, via nasal spray or as a subcutaneous implant

27. Pharmacodynamics
GnRH exhibit complex dose-response relationships that change dramatically from the fetal period through the end of puberty.

28. Clinical Pharmacology
STIMULATION
Female infertility
Male infertility
Diagnosis of LH responsiveness
SUPPRESSION
Controlled ovarian hyperstimulation
Endometriosis
Uterine leiomyomata (uterine fibroids)
Prostate cancer
Central precocious puberty
Other
advanced breast and ovarian cancer

29. Toxicity Headache, light-headedness, nausea, and flushing
Contraindications to the use of GnRH agonists in women include
pregnancy and breast-feeding

30. GNRH RECEPTOR ANTAGONISTS
Ganirelix and cetrorelix
Pharmacokinetics
absorbed rapidly after subcutaneous injection
Clinical Pharmacology
preventing the LH surge during controlled ovarian hyperstimulation
Toxicity
nausea and headache

31. PROLACTIN Is a 198-amino-acid peptide hormone
Its structure resembles that of GH

32. DOPAMINE AGONISTS
Bromocriptine , cabergoline, pergolid and Quinagolide
Pharmacokinetics
All available dopamine agonists are active as oral preparations
Clinical Pharmacology
HYPERPROLACTINEMIA
PHYSIOLOGIC LACTATION
ACROMEGALY
Toxicity & Contraindications
nausea, headache, light-headedness, orthostatic hypotension, and fatigue