1. Hypothalamic & Pituitary Hormones
Dr Safaeian

2. Hypothalamus & Pituitary Glands
Pituitary is at the base of brain near optic chiasm, consists of an anterior lobe (Adenohypophysis) and a posterior lobe (Neurohypophysis).
It is connected to
overlying hypothalamus by
a portal venous system
that carries regulatory hormones from hypothalamus to
anterior pituitary.
روی استخوان زین ترکی

3. Hypothalamus & Pituitary Glands
Posterior lobe hormones are synthesized in hypothalamus and transported via neurosecretory fibers to posterior lobe and released into circulation.
Control of metabolism, growth, and reproduction is mediated by these glands.

4. Hypothalamus & Pituitary hormones: Pharmacologic Applications
As replacement therapy for hormone deficiency states
(2) As antagonists for diseases that result from excess production of pituitary hormones
(3) As diagnostic tools for identifying several endocrine abnormalities

5. Anterior Pituitary Hormones
Growth hormone (GH)
Prolactin (PRL)
Follicle-stimulating hormone (FSH)
Luteinizing hormone (LH)
Adrenocorticotropic hormone (ACTH, Corticotropin)
Thyroid-stimulating hormone (TSH, Thyrotropin)
Dimerization of two GH receptors is stimulated by a single GH molecule and activates signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs.
Adrenocorticotropic hormone (ACTH) is cleaved from a larger precursor that also contains the peptide –endorphin

6. Anterior Pituitary HormonesGH
PRL Janus kinase(JAK)/Signal Transducer and Activator of Transcription (STAT)
TSH
FSH LH
ACTH
Hypothalamic hormones
Activate JAK/STAT superfamily receptors
Activate G protein-coupled receptors
Dimerization of two GH receptors is stimulated by a single GH molecule and activates signaling cascades mediated by receptor-associated JAK tyrosine kinases and STATs.
Janus kinase (JAK) and Signal Transducer and Activator of Transcription
Adrenocorticotropic hormone (ACTH) is cleaved from a larger precursor that also contains the peptide –endorphin

7. Anterior pituitary hormones & their hypothalamic regulators
Pituitary hormones are under
control of hypothalamic peptides.
All are subject to feedback
inhibitory regulation by hormones
whose production they control.
Feedback regulation is critical to
physiologic control and in
pharmacologic treatments.

8. Hypothalamic-releasing hormones and actions of anterior pituitary hormones

9. Anterior pituitary hormones & their hypothalamic regulators
Growth hormone-releasing hormone (GHRH) → stimulates GH release, whereas Somatostatin (SST) inhibits GH production.
GH and its primary peripheral mediator, insulin-like growth factor-1 (IGF-1), inhibit GH release.
Gonadotropin-releasing hormone (GnRH)→ stimulates release of LH and FSH (Gonadotropins).
Gonadotropin and GnRH production is inhibited by Estrogen, Progesterone and Testosterone.

10. Anterior pituitary hormones & their hypothalamic regulators
Thyrotropin-releasing hormone (TRH)→ regulates TSH release.
TSH and TRH production is inhibited by thyroid hormones (Thyroxine and Triiodothyronine)
Corticotropin-releasing hormone (CRH)→ stimulates ACTH release.
ACTH and CRH production is inhibited by Cortisol.
Dopamine→inhibits Prolactin (PRL) production through D2 receptors (TRH can stimulate PRL release, particularly in primary hypothyroidism).
Hypothalamus does not produce a hormone that stimulates prolactin production.

11. Clinical uses of hypothalamic hormones
GHRH: Used rarely as a diagnostic test for GH responsiveness.
TRH, Protirelin: Used rarely to diagnose hyper- or hypothyroidism.
CRH: Used rarely to distinguish Cushing's disease from ectopic ACTH secretion.
Dopamine: Its agonists used for treatment of hyperprolactinemia
TSH: Diagnostic test for assessing recurrence of thyroid carcinoma after surgically treatment.
only a few pituitary and hypothalamic hormones are of major clinical importance. Because of the greater ease of administration of target endocrine gland hormones or their synthetic analogs.

12. Clinical uses of hypothalamic hormones
ACTH: Diagnostic test in patients suspected of adrenal insufficiency or suspected of congenital adrenal hyperplasia
GnRH: Used in pulses to treat infertility caused by hypothalamic dysfunction.
Long-acting formulations to inhibit gonadal function in children with precocious puberty, in men with prostate cancer, in women undergoing assisted reproductive technology (ART) or who require ovarian suppression for a gynecologic disorder.
May be used in pulses to treat infertility caused by GnRH deficiency
Nafarelin acetate (Synarel) 2 mg/mL solution (200 mcg/spray) Intranasal
Leuprolide acetate 1 mg/0.2 mL solution SC
only a few pituitary and hypothalamic hormones are of major clinical importance. Because of the greater ease of administration of target endocrine gland hormones or their synthetic analogs.

13. Growth Hormone (Somatotropin)
A 191-amino-acid peptide with two sulfhydryl bridges.
GH is required for attainment of normal size.
Important effects on lipid and carbohydrate metabolism, and lean body mass.
Its effects are mediated via:
Insulin-like growth factor 1 (IGF-1,
Somatomedin C)
Insulin-like growth factor 2 (IGF-2).

14. GH: Pharmacodynamics Somatropin: Recombinant form of human GH
Via cell surface receptors of JAK/STAT cytokine receptor superfamily:
Anabolic effects in muscle (↑muscle mass)
Catabolic effects in lipid cells (↓central adiposity)
Mixed effect on carbohydrate metabolism (↓insulin sensitivity and mild hyperinsulinemia )
In the past, GH was isolated from pituitaries of human cadavers and was contaminated with prions that could cause Creutzfeldt-Jakob disease.
Somatropin: Recombinant form of human GH
proteinacious infectious particle cause of the transmissible spongiform encephalopathies (TSEs).
in part because GH and IGF-1 have opposite effects on insulin sensitivity. GH reduces insulin sensitivity, which results in mild hyperinsulinemia. In contrast, in patients who are unable to respond to endogenous GH because of mutated GH receptors, IGF-1 acting through its own IGF-1 receptors and through insulin receptors lowers serum glucose and reduces circulating insulin
Creutzfeldt–Jakob disease (pron.: /ˈkrɔɪtsfɛlt ˈjɑːkoʊb/ KROITS-felt YAH-kohb)[1] or CJD is a degenerative neurological disorder (brain disease) that is incurable and invariably fatal.[2] CJD is at times called a human form of mad cow disease (bovine spongiform encephalopathy or BSE) even though classic CJD is not related to BSE;[3]

15. Somatropin: Clinical Applications
Replacement in GH deficiency
↑Final adult height in children with short stature (Chronic renal failure, idiopathic short stature,….): many years GH therapy result in ↑adult height of 4–7 cm.
Wasting in HIV infection (↑lean body mass, weight, and physical endurance)
Short bowel syndrome
A popular component of anti-aging programs
GH is one of drugs banned by Olympic Committee. used by athletes for ↑muscle mass and athletic performance.
Short bowel syndrome (SBS, also short gut syndrome or simply short gut) is a malabsorption disorder caused by the surgical removal of the small intestine more than two thirds , or rarely due to the complete dysfunction of a large segment of bowel.
در حالات کاتابولیک شدید و تحلیل تدریجی

16. Somatropin Pharmacokinetics: SC injection 3–7 x/wk, cleared by liver.
Toxicity:
Scoliosis, hyperglycemia, edema, gynecomastia, pancreatitis, myalgia, arthralgia, carpal tunnel syndrome, ↑CYP450 activity, hypothyroidism
so periodic assessment of thyroid function is indicated.,
Carpal tunnel syndrome (CTS) is a median entrapment neuropathy, that causes paresthesia, pain, numbness, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression of the median nerve traveling
through the carpal tunnel.[1]
خمیدگی و انحنا در ستون فقرات

17. Growth Hormone Inhibition
Somatostatin, a 14-amino-acid peptide is found in hypothalamus, CNS, pancreas, and GI.
Inhibits release of GH, glucagon, insulin, and gastrin.
Somatostatin has limited therapeutic usefulness because of its short duration of action and its multiple effects in many secretory systems.

18. Somatostatin analogs: Octreotide
The most widely used and longer-acting SST analogs
Inhibits production of GH (45 times more potent than SST), to a lesser extent, of glucagon, insulin, and gastrin
Clinical Applications:Acromegaly and other hormone-secreting tumors, Acute control of bleeding from esophageal varices
Toxicity: GI disturbances, gallstones, bradycardia
مهار گلوکاگون و سایر هورمونهای گوارشی با کاهش جریان خون مزانتر و پورت فشار واریسی را کم می کند.

19. Gonadotropins (FSH, LH) & Human Chorionic Gonadotropin
Produced by gonadotroph in pituitary and serve complementary functions in reproductive process.

20. FSH, LH & Human Chorionic Gonadotropin
In women:
FSH: directs ovarian follicle
development.
FSH and LH are needed for ovarian
steroidogenesis.
In follicular stage:
LH stimulates androgen production
FSH stimulates conversion of androgens to estrogens.
A coordinated pattern of FSH and LH secretion during menstrual cycle is required for normal follicle development, ovulation, and pregnancy.

21. FSH, LH & Human Chorionic Gonadotropin
In women:
In luteal phase:
Estrogen and progesterone
production is primarily under
control of LH.

22. FSH, LH & Human Chorionic Gonadotropin
In pregnancy:
Estrogen and progesterone production is under control of human chorionic gonadotropin (hCG).
hCG: A placental protein nearly identical with LH; its actions are mediated through LH receptors.

23. FSH, LH In men: FSH: Primary regulator of spermatogenesis.
LH: Main stimulus for production of testosterone by Leydig cells.
FSH: Stimulates production of androgen-binding protein and conversion of testosterone to estrogen by Sertoli cells.

24. FSH, LH, hCG All are commercially available
administered by SC or IM injection.
Act through G protein-coupled receptors.
Menotropins: human menopausal gonadotropins (hMG):The first commercial gonadotropin product, extracted from urine of postmenopausal women, which contains both FSH and LH activity.
HCG در درمان کریپتورکیدیسم (پائین نیامدن بیضه ها) در پسران در نزدیکی سن بلوغ بکار میرود.

25. FSH
Urofollitropin (uFSH): A purified preparation of human FSH, extracted from urine of postmenopausal women.
2 recombinant forms of FSH (rFSH):
Follitropin alfa and follitropin beta: With shorter half-life and considerably more expensive.
They differ from each other and urofollitropin in the composition of the carbohydrate side chains.
Follitropin alfa and follitropin beta. have a shorter half-life than preparations derived from human urine

26. LH Lutropin alfa: recombinant form of human LH,
Approved for use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency.
It has not been approved for use with the other preparations of FSH nor for simulating the endogenous LH surge that is needed to complete follicular development and precipitate ovulation.

27. hCG
Produced by human placenta and excreted into urine→ extracted and purified→ IM injection
Choriogonadotropin alfa (rhCG): recombinant form→ SC injection

28. FSH, LH & Gonadotropins: Clinical Pharmacology
Ovulation Induction
In anovulation secondary to hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causes→ who fail to respond to other forms of treatment (eg, clomiphene).
For controlled ovarian hyperstimulation in assisted reproductive technology procedures: in vitro fertilization (IVF)
باروری در محیط برون تنی

29. FSH, LH & Gonadotropins: Clinical Pharmacology
Ovulation Induction: Protocol:
Daily injections of FSH preparations (hMG, urofollitropin) from day 3 of menstrual cycle, continued for 7–12 days.
Appropriate follicular maturation → FSH discontinued.
Following day, hCG is administered (IM) to induce final follicular maturation and ovulation → insemination in ovulation and oocyte retrieval in assisted reproductive technology procedures.
تلقیح اسپرم به تخمک

30. FSH, LH & Gonadotropins: Clinical Pharmacology
Male Infertility
Conventional therapy in hypogonadism:
Initial treatment for 8–12 weeks with hCG several times/week.
Then, hMG is injected 3 times/week.
4–6 months treatment for sperm to appear in ejaculate.
In men with hypogonadal hypogonadism, it takes an average of 4–6 months of such treatment for sperm to appear in the ejaculate.

31. FSH, LH & Gonadotropins: Toxicity
Ovarian hyperstimulation syndrome: ovarian enlargement, ascites, hydrothorax, hypovolemia, sometimes shock, fever, and arterial thromboembolism.
Multiple pregnancies: 15–20%
Gynecomastia in men
Headache, depression, edema in both sexes 
تجمع‌ مايع‌ در حفره‌ جنب‌
چندقلویی

32. GnRH & Its Analogs
Pulsatile GnRH secretion → stimulate gonadotroph cell to produce and release LH and FSH.
Amplitude and frequency of GnRH pulses vary in a regular pattern through menstrual cycle.
Sustained nonpulsatile administration of GnRH or GnRH analogs inhibits release of FSH and LH → hypogonadism (due to receptor down-regulation and changes in signaling pathways activated by GnRH).
During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare. شعله ور شدن
All the clinical methods share in common the delivery of the pulsatile GnRH via a small, portable, programmable infusion pump. Multiple routes of GnRH administration are available. Absorption occurs after IV, subcutaneous (SC), intramuscular (IM), nasal, and sublingual administration.
The pulse frequency of endogenous GnRH in normal women during regular ovulatory menstrual cycles ranges from approximately 95 minutes in the early follicular phase to approximately 60–70 minutes in the periovulatory period.31, 32, 33 Luteal-phase pulses are of decreasing frequency but higher amplitude.
In an effort to mimic the physiologic pulsations of GnRH in the normal menstrual cycle, some centers use a varying pulse frequency. A regimen using a 90-minute pulse frequency in the first week of folliculogenesis, followed by an increase in frequency to every 60 minutes in the midfollicular phase of the induced cycle, followed by a return to slower pulse frequency in the luteal phase, has been well described.27 The literature to date supports a follicular-phase pulse frequency of 90 minutes or less to achieve maximum spontaneous ovulation rates, and further studies need to be performed to determine whether there is an added benefit to cycle-specific, nonfixed frequency regimens.
Pulse dosage
Ovulation can be effectively induced over a range of GnRH doses. The optimal dose depends somewhat on the route of administration, because the SC route requires higher doses than the IV route. Thus, we recommend a starting dose for IV therapy of 75 ng/kg/pulse (approximately 3.5–5.0 μg/pulse). For women who do not respond to this pulse dose, the dose can be incrementally increased up to 10–20 μg/pulse. We administer our pulses in a 0.9% sodium chloride solution containing 10 μg/mL GnRH and 30 units of heparin/mL. When tailoring optimal dosage regimens, allowances should be made for considerable individual differences in GnRH requirements. Obese patients and those with PCOS may require much higher doses than average.

33. GnRH & Its Analogs GnRH is a decapeptide.
Gonadorelin: acetate salt of synthetic GnRH (IV, SC).
Synthetic Analogs:
Goserelin Nafarelin
Buserelin Triptorelin (Decapeptyl ®)
More potent and longer-lasting than native GnRH and gonadorelin [SC, IM, nasal spray (nafarelin), SC implant→ depot forms: 1, 4, 6, or 12 months].
دکا=10
range of durations of action from several hours (for daily administration) to 1, 4, 6, or 12 months (depot forms).

34. GnRH & Its Analogs: Clinical Pharmacology
Stimulation of gonadotropin production:
Female Infertility
Male Infertility
GnRH agonists are occasionally used for stimulation of gonadotropin production.
They are used far more commonly for suppression of gonadotropin release.

35. GnRH & Its Analogs: Clinical Pharmacology
Suppression of gonadotropin production:
Controlled Ovarian Hyperstimulation
Endometriosis
Uterine Leiomyomata (Uterine Fibroids)
Prostate Cancer, Advanced Breast and Ovarian Cancer
Central Precocious Puberty (onset of secondary sex characteristics before 8 years in girls or 9 years in boys).
In controlled ovarian hyperstimulation that provides multiple mature oocytes for assisted reproductive technologies, it is critical to suppress an endogenous LH surge that could prematurely trigger ovulation. This suppression is most commonly achieved by daily SC injections of leuprolide or daily nasal applications of nafarelin.
Endometriosis is a syndrome of cyclical abdominal pain in premenopausal women that is due to the presence of estrogen-sensitive endometrium-like tissue outside the uterus. The recommended duration of treatment with a GnRH agonist is limited to 6 months because ovarian suppression beyond this period can result in decreased bone density (depot or nasal twice daily )
A leiomyoma (plural is 'leiomyomata') is a benign smooth muscle neoplasm that is very rarely (0.1%) premalignant.
Treatment with a GnRH agonist is generally continued to age 11 in females and age 12 in males.
Uterine leiomyomata are benign, estrogen-sensitive, fibrous growths in the uterus that can cause menorrhagia, with associated anemia and pelvic pain. Treatment for 3–6 months with a GnRH agonist

36. GnRH & Its Analogs: Toxicity
Headache, light-headedness, nausea,
Injection site reactions
Symptoms of hypogonadism with continuous treatment (typical symptoms of menopause)
the typical symptoms of menopause, which include hot flushes, sweats, and headaches. Depression, diminished libido, generalized pain, vaginal dryness, and breast atrophy

37. GnRH Receptor Antagonists
Ganirelix
Cetrorelix
Synthetic decapeptides competitive antagonists of GnRH receptors inhibit secretion of FSH and LH.
Approved for use in controlled ovarian hyperstimulation procedures.

38. Prolactin Responsible for lactation. Milk production is stimulated by
A 198-amino-acid peptide hormone
of anterior pituitary resembles GH.
Responsible for lactation.
Milk production is stimulated by
prolactin during appropriate levels
of estrogens, progestins,
corticosteroids, and insulin.

39. Prolactin
A deficiency of prolactin is rare→ No preparation of prolactin is available for use.
Hyperprolactinemia: is more common → Amenorrhea and galactorrhea in women, and loss of libido and infertility in men (result from inhibition of GnRH release)
Inhibition of prolactin secretion can be achieved with dopamine agonists.

40. Dopamine Agonists
Ergot derivatives with a high affinity for dopamine D2 receptors:
Bromocriptine
Cabergoline
Oral and Vaginal preparations, eliminated by metabolism.
Half-life: Cabergoline=65 hrs, bromocriptine =7 hrs.

41. Dopamine Agonists: Clinical Pharmacology
Hyperprolactinemia
Physiologic Lactation: were used in the past to prevent breast engorgement when breast-feeding was not desired. Not commended because of toxicity.
Acromegaly: GH release is reduced although not as effectively.
Parkinson's disease

42. Dopamine Agonists: Toxicity
GI disturbances
Orthostatic hypotension
Headache
Psychiatric disturbances
Vasospasm
Pulmonary infiltrates in high doses
Cabergoline → less nausea than bromocriptine

43. Posterior Pituitary Hormones
Vasopressin
Oxytocin
Synthesized in neuronal cell bodies in hypothalamus and transported via their axons to posterior pituitary, where they are stored and then released into circulation.

44. Oxytocin A 9-amino-acid peptide Its amino acid sequence
differs from vasopressin at
positions 3 and 8.
Participates in:
Labor
Milk ejection in lactating women.
Its amino acid sequence differs from that of vasopressin at positions 3 and 8.

45. Oxytocin IV for initiation and augmentation of labor.
IM for control of postpartum bleeding.
Not bound to plasma proteins.
Eliminated by kidneys and liver.
Circulating half-life: 5 mins.

46. Oxytocin: Pharmacodynamics
Acts through G protein-coupled receptors and phosphoinositide-calcium → to contract uterine smooth muscle and myoepithelial cells surrounding mammary alveoli (milk ejection)
Stimulates release of PGs and LTs → ↑uterine contraction.
At high concentrations → weak antidiuretic and pressor activity (via vasopressin receptors).

47. Oxytocin: Clinical Pharmacology
Induction of labor for conditions requiring early vaginal delivery (Rh problems, maternal diabetes, preeclampsia)
Control of uterine hemorrhage after vaginal or cesarean delivery
Toxicity: Fetal distress, placental abruption, uterine rupture, fluid retention, water intoxication, hyponatremia, seizures, and death.
Bolus injections → hypotension
کندگی جفت

48. Vasopressin (Antidiuretic Hormone, ADH)
A nonapeptide hormone with
arginine at position 8
Released by posterior pituitary
during ↑plasma tonicity or ↓BP.
Possesses antidiuretic and
vasopressor properties.
Deficiency → Diabetes insipidus (polyuria, polydipsia, or hypernatremia)
IV or IM injection, with renal and hepatic metabolism
نونا=9

49. Vasopressin: Pharmacodynamics
Activates 2 G protein-coupled receptors:
V1: on vascular smooth muscle cells
→ Vasoconstriction
V2: on renal tubule cells → ↓diuresis through ↑water permeability and water resorption in collecting tubules.
Extrarenal V2-like receptors regulate release of coagulation factor VIII and von Willebrand factor.

50. Vasopressin analog: Desmopressin acetate (DDAVP)
DDAVP: 1-desamino-8-D -arginine vasopressin
Long-acting analog with minimal V1 activity and an antidiuretic-to-pressor ratio 4000 times that of vasopressin.
IV, SC, intranasally, or orally.
Nasal bioavailability of desmopressin is 3–4%, whereas oral bioavailability is less than 1%.

51. Vasopressin and desmopressin: Clinical Pharmacology
Treatments of choice for pituitary diabetes insipidus (intranasal or oral)
Vasopressin infusion for esophageal variceal bleeding and colonic diverticular bleeding
Desmopressin for treatment of coagulopathy in hemophilia A and Von Willebrand's disease
Toxicity: GI disturbances, headache, hyponatremia, allergic reactions 
esophageal varices (or oesophageal varices) are extremely dilated sub-mucosal veins in the lower third [1] of the esophagus. They are most often a consequence of portal hypertension, commonly due to cirrhosis;
A diverticulum (plural: diverticula) is the medical or biological term for an outpouching of a hollow (or a fluid-filled) structure in the body. تشكيل كيسه هاي توخالي
Diverticulitis is a common digestive disease which involves the formation of pouches (diverticula) within the bowel wall. This process is known as diverticulosis, and typically occurs within the large intestine, or colon, although it can occasionally occur in the small intestine as well. Diverticulitis results when one of these diverticula becomes inflamed.
deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion.