Hypothalamus and Anterior Pituitary Hormones Flashcards
What are the major functions of hormones?
- Regulation of energy storage, production, and utilization
- Adaptation to new environments or conditions of stress
- Facilitation of growth and development
- Maturation and function of the reproductive system
Posterior Pituitary Gland
Releases hormones synthesized in the hypothalamus
* Oxytocin
* Vasopressin
Oxytocin
- Causes contraction of the smooth muscles in the breast during lactation
- It also plays a role in uterine contraction during childbirth
Vasopressin
Essential for proper fluid balance and acts on the renal collecting ducts to conserve water
* can also stimulate ACTH
Anterior Pituitary
6 major peptide hormones of the anterior pituitary regulate peripheral endocrine glands (the thyroid, adrenals, and gonads) as well as growth and lactation
What are the five endocrine axes?
- Growth Hormone-releasing hormone (GHRH) & Somatostatin (SST)
- Corticotropin-releasing hormone (CRH)
- Thyrotropin-releasing hormone (TRH)
- Gonadotropin-releasing hormone (GnRH)
- Dopamine (DA)
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Growth hormone-releasing hormone (GHRH)?
- (+) Growth hormone (GH-somatotropin)
- Liver
- Insulin-like growth factor-1 (IGF-1) (somatomedin)
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Somatostatin (SST)?
- (-) Growth hormone (also called somatotropin)
- Liver
- Insulin-like growth factor-1 (IGF-1) (somatomedin)
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Corticotropin-releasing hormone (CRH)?
- (+) Adrenocorticotropic hormone (ACTH) also called corticotropin
- Adrenal cortex
- Corticosteroids
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Thyrotropin-releasing hormone (TRH)?
- (+) Thyroid-stimulating hormone (TSH) also called thyrotropin
- Thyroid
- Thyroid hormones
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Gonadotropin-releasing hormone (GnRH)?
- (+) Follicle-stimulating hormone (FSH) and Luteinizing hormone (LH) also called gonadotropins
- Gonads
- Estradiol, Progesterone, Testosterone
Name what anterior pituitary trophic (signal) factors, target organ, and target organ hormones comes from Dopamine (DA)?
- (-) Prolactin
- Mammary glands
- No target organ
T/F: ALL hypothalamic releasing hormones, except dopamine, are peptides
T
What are some considerations for exogenous hormone administration?
- Peptides and proteins are NOT absorbed intact from the GI tract (NOT by mouth-oral)
- Chemical instability, photo instability, physical instability
- Reconstitution increases instability
- Shorter shelf-life 12-18 months
- Many are stored refrigerated or protected from light
Thyrotropin releasing hormone (TRH, protirelin)
- Very simple—only 3 amino acids
- Used for diagnostic purpose (differentiate between primary and secondary problems with the axis)
- Interpretation relies on concept that TRH should increase TSH levels (but leave the interpretation to the endocrinologist)
Thyroid stimulating hormone (Thyrotropin alpha, rhTSH, Thyrogen)
- Recombinant (mimics human TSH) product generated from hamster cells
- Contains natural amino acid sequence—identical to native hormone
What is the indication for Thyroid stimulating hormone (Thyrotropin alpha, rhTSH, Thyrogen)?
- Diagnostic: Used to monitor for recurrence of thyroid carcinoma—give prior to radioactive iodine to “prime” active tissue—better detect “hot spots”
- Treatment: Used prior to high dose of radioactive iodine for more effective ablation of the thyroid cells
What are the pharmaceutical products of CRH for the adrenal axis?
- Human CRH, Corticoreline
- Sheep CRH, Corticoreline ovine, Acthrel
Sheep CRH, Corticoreline ovine, Acthrel
- Slightly different from human amino acid sequence
- Has a longer half-life (18 min), more potent, preferred
What are the indications of Sheep CRH, Corticoreline ovine, Acthrel?
Diagnostic to determine if ACTH release is normal
* Differentiate between a tertiary and secondary problem
What is ACTH1-24, Cortrosyn indication?
- Diagnostic
- Inflammatory disorders, infantile spasms
Tesamorelin (Egrifta)
- Growth hormone releasing hormone (GHRH) analog given SC
- FDA approved HIV-induced lipodystrophy
What are the GH secretagogues?
- Ghrelin
- Arginine, leucine
- Clonidine
- L-dopa
- Insulin-induced hypoglycemia
- Sleep, fasting, exercise, and stress
What are GH secretagogues used for?
- For diagnostic use
- Should induce Growth hormones
- FDA recommends 2 independent test
What are effects of growth hormone on lipid and carbohydrate metabolism?
- Anti-insulin effect
- Decreases utilization of glucose by peripheral tissues, increases lipolysis, and increases muscle mass
- Stimulates gluconeogenesis in hepatocytes, impairs post-receptor insulin action
Growth Hormone Axis
- Stimulate the formation of IGF-1 (mainly in the liver) which acts as direct stimulator of cell proliferation and growth
- Secreted in pulsatile fashion, wtih several short bursts that occur most at night
When is the secretion GH at its peak?
- At night
- At adolescence
What are the disorders of GH excess?
- Acromegaly
- Giantism/gigantism (very rare)
Acromegaly
a. Excess production of GH
b. Occurs after puberty (adults), AFTER growth plates close
c. Most often due to pituitary adenoma
Gigantism/gigantism
a. Excess GH
b. Occurs BEFORE epiphysial closure in children
What are the symptoms of acromegaly?
- Soft tissue overgrowth
- Growth of skeletal tree in THICKNESS (not length)
- Bones in adults CANNOT elongate, but they can get thicker—diagnosis by measuring circumference of middle finger
- Disfiguring appearance (jaw and fingers especially)
- Glucose intolerance or overt diabetes
Symptoms are gradual in onset
How do you diagnosis acromegaly?
- If high levels of insulin-like growth factor-1 (IGF-1), then get a glucose tolerance test
- Postprandial hyperglycemia should inhibit the secretion of GH for at least 1 to 2 hours. Therefore, an oral glucose load would be expected to suppress GH concentrations. However, patients with acromegaly continue to secrete GH during the OGTT
What are the drug therapy options for patients diagnosed with acromegaly?
- Somatostatic analogs
- Dopamine agonists
- GH receptor antagonist that acts on the liver
What are the mechanisms of the GH release inhibitory hormone agent (somastatin analog)?
a. Inhibits release GH
b. Inhibits release of intestinal and pancreatic peptides: gastrin, cholecystokinin, pepsin, renin, insulin, glucagon, etc.
c. Inhibits GI motility and bile flow
Octreotide (Sandostatin)
i. Longer acting 8 amino acid analog of somatostatin
ii. Given SC or IV, half life 1.5 hours (vs. 1.5 minutes for native hormone)
iii. Sandostatin LAR depot: IM, monthly (microspheres)
iv. Used as an alternative to radiation and surgery for acromegaly (adults)
v. Pharmaceutical product of GH release inhibitory hormone (GHRIH) Agents
What is Octreotide (Sandostatin) used for?
- carcinoid tumors
- vasoactive intestinal peptide-secreting tumors (VIPomas)
- GI fistulas
- variceal bleeding
- diarrheal states
- irritable bowel syndrome
What are the side effects of Octreotide (Sandostatin)?
- Nausea/vomiting
- Flatulence
- Gallstones
- Increases or decreases in blood glucose
Lanreotide
- (Somatuline depot) deep SC, monthly
- Octapeptide structure similar to octreotide
- For acromegaly
Pasireotide
- Pasireotide (Signifor LAR) monthly IM for acromegaly
- (another formulation—SC BID for Cushing disease)
- Broader affinity for SST receptor subtypes
Bromocriptine and Cabergoline
a. Paradoxical decrease in GH in patients with acromegaly
b. Only completely effective in about 10% of patients
c. Dopamine agonist
d. For acromegaly
What are the side effects of Bromocriptine and Cabergoline?
- CNS symptoms such as headache, lightheadedness, dizziness, nervousness, and fatigue
- GI effects such as nausea, abdominal, or diarrhea
Pegvisomant (Somavert)
i. Given SC, daily
ii. Blocks ability of GH to stimulate production of IGF-1 (levels of GH remain high, but there is reduction in IGF-1 concentrations) in the liver
iii. GH receptor antagonist for acromegaly
What are the side effects of Pegvisomant (Somavert)?
- Nausea and diarrhea
- Flu-like symptoms
- Elevations in hepatic aminotransferase
Dwarfism (children)
- Short stature–commonly defined by a physical height that is more than two standard deviations below the population mean for a given age, sex, and population
- Increased body fat, decreased muscle mass
What are the recombinant GH (somatropin) for dwarfism?
- Genotropin
- Humatrope
- Norditropin
- Nutropin AQ
- Omnitrope
- Saizen
- Serostim
- Zomacitin
- Zorbtive
How is recombinant GH (somatropin) given to children with GH deficiency?
- Given IM or SC
- Initiate prior to onset of puberty and continued until a desirable height or decreased growth velocity after the pubertal growth spurt
What is the adverse events of recombinant GH (somatropin) for children with GH deficiency?
- Intracranial hypertenison
- Scoliosis
- Hypothryoidism
What are the adverse effects of recombinant GH (somatropin) for adults with AIDs associated with catabolism/weight loss, short bowel syndrome?
- Edema
- Myalgia
- Arthralgia
- Decreased insulin sensitivity
- Hyperglycemia and diabetes may develop
- Potentially increase promote of the growth various types of neoplasms
- Increase tumor recurrence rates in patients with a history of malignancy
SeroVital
- Do NOT have actual GH
rhlGF-1 and mecasermin (Increlex)
- Insulin-like growth factors–Somatomedins
- Some insulin activity (10%)
- Indicated for the treatment of growth failure in pediatric patients 2 years of age and older with severe primary IGF-1 deficiency or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH
-Other possible indications: HIV, severe insulin resistance
What are the actions of rhlGF-1, mecasermin (Increlex)?
- Growth promoting effects
- IGF-1 negative feedback primarily at anterior pituitary. GH negative feedback via SST and GHRH
- No negative feedback so patients would be expected to have high growth hormone levels
- IGF-1 increases insulin sensitivity (recall GH decreases insulin sensitivity)
What is a common side effect of rhlGF-1, mecasermin (Increlex)?
Hypoglycemia
The Prolactin Axis
- Secreted in a pulsatile fashion by lactotroph cells of the anterior pituitary
- Regulated by a short loop feedback–> prolactin itself stimulates the secretion of the inhibitory factor, dopamine
What makes the Prolactin Axis so unique?
- Hypothalamic regulation predominantly inhibitory, as opposed to stimulatory
- Involves a catecholamine neurotransmitter, dopamine, rather than the more typical peptide hypothalamic hormones involved in regulating all other pituitary systems
- Prolactin is only anterior pituitary hormone that does not have an endocrine target tissue, and therefore lacks a classical hormonal feedback system
What causes Hyperprolactinemia?
-Benign prolactin-secreting pituitary tumors (prolactinomas)
-Medications
What are some medications that cause Hyperprolactinemia?
- Dopamine antagonist: Antipsychotics
- Prolactin stimulators: Methyldopa, Reserpine
- Other: Verapamil
What are some signs and symptoms of hyperprolactinemia?
Headache and visual disturbances that result from tumor compression of the optic chiasm (causes tunnel vision)
What are the signs and symptoms of people with uterus for hyperprolactinemia?
- oligomenorrhea
- amenorrhea
- galactorrhea
- infertility
- decreased libido
- hirsutism
- acne
What are the signs and symptoms of people with testicles for hyperprolactinemia?
- decreased libido
- erectile dysfunction
- infertility
- reduced muscle mass
- galactorrhea
- gynecomastia
What are the laboratory test for hyperprolactinemia?
Prolactin serum concentrations at rest will be more than 25 mcg/L
What will prolonged suppression of estrogen with hyperprolactinemia lead to?
- decreased bone mineral density and osteoporosis
- the risk for ischemic heart disease may be increased with untreated hyperprolactinemia
What are the treatment options for Hyperprolactinemia?
- Clinical observation
- Dopamine agonists (Cabergoline is DOC)
- Radiation therapy
- Transsphenoidal surgical removal of the tumor
In people with ovaries, what does FSH and LSH do
- FSH directs follicle development
- FSH and LSH collaborate in the regulation of ovarian steroidogenesis
What are the ovulation induction protocols?
- Endogenous gonadotropin production is inhibited by administration of a GnRH agonist or antagonist
- Follicle development is driven by daily injections of a preparation with FSH activity (menotropins, FSH, or an FSH analog)
- Final stage of oocyte maturation is induced with an injection of LH or the LH analog human chorionic gonadotropin (hCG)
What does FSH and LH do in people with testicles?
- FSH is the primary regulator of spermatogenesis
- LH is the main stimulus for testicular androgen production
Leuprolide (Lupron, Eligard, Lupron depot)
- GnRH analog
- SC daily or IM injections every 1,3, or 6 months
Goserelin (Zoladex)
- GnRH analog
- Cylinders, 1-1.5 mm implanted SC in upper abdomen every 1 to 3 months
Histrelin (Supprelin)
- SC daily OR yearly implant
- GnRH analog
Nafarelin (Synarel)
- GnRH analog
- Nasal
Triptorelin (Trelstar)
- GnRH analog
- IM every 1, 3, or 6 months
What cells do the FSH act on to regulate spermatogenesis?
Sertoli cells
What cells does LH act on to secrete testosterone?
Leydig cells
What happens during stimulation of GnRH?
- Initial stimulation (1-2 weeks)
- EVENTUAL INHIBITION OF FSH AND LH RELEASE—ACT AS ANTAGONISTS IF GIVEN CONTINUOUSLY
- Decrease ovarian and testicular sex hormone production to postmenopausal and castration levels
- To prepare somebody for ovulation stimulation or to treat prostate cancer
GnRH analogs
- GnRH is a decapeptide (short peptide) that stimulates gonadotropin release when
- it is secreted in a pulsatile pattern by the hypothalamus
What are the indications for continuous GnRH agonist treatment?
- Suppresses endogenous gonadotropin secretion during ovulation induction with gonadotropins (prevent natural ovulation)—suppress LSH and FSH
- In gynecologic disorders that benefit from ovarian suppression (e.g. endometriosis, uterine leiomyomata)
- In advanced prostate cancer
- In early pubertal transgender adolescents (to block endogenous puberty prior to treatment with cross-gender gonadal hormones)
- In children with central precocious puberty
What are the side effects of GnRH analogs?
- Hot flushes, sweats, headaches
- risk of bone loss and osteoporosis
- decreased libido
- contraindicated during pregnancy
- In people with prostate cancer and children with central precocious puberty, the first few weeks of therapy can temporarily exacerbate the condition (cause a “flare”)
Ganirelix (Anatgon) and Cetrorelix (Cetrotide)
- Given SC
- Used during ovulation induction in place of GnRH agonist to suppress endogenous gonadotropin production
- Low doses decrease LH, and high doses decreases FSH
What are the advantages of Ganirelix (Anatgon) and Cetrorelix (Cetrotide) over GnRH agonist?
- Less ovarian stimulation, fewer side effects
- Shortens treatment time for in vitro fertilization from as many as 26 days to 5 days
Dagrelix and Relugulix (Orgovyx)
- SC monthly-Dagrelix
- Oral, given daily- Relugulix
- Approved for treatment of advanced practices
- Faster to achieve castration levels of testosterone compared with GnRH analogs (3 days vs 28 days)
What are the adverse effects of GnRH antagonists?
- Similar to continuous treatment of GnRH analogs except they do NOT cause tumor flares when used for treatment of advanced prostate cancer
- Less likely to cause the ovarian hyperstimulation syndrome when used for ovulation induction
Menotropins-hMG (human menopausal gonadotropins)
- Pergonal (IM), Repronex (IM), Menopur (SC)
- Purified from urine of post-menopausal women
- Contain FSH and LH-like hormones
- Used to treat infertility and delayed development (stimulate the follicle to produce an egg when we want it to be timed to produced)
Urofollitropin (Fertinex, Bravelle)
- Fertinex-SC
- Bravelle-IM, SC
- Primarily FSH from urine of post menopausal people
- Indications: PCOS and in vitro fertilization
Follitropin Alfa (Gonal-F)
- SC
- Human FSH preparation of rDNA origin
- Used to treat infertility
Follitropin Beta (Follistim)
- SC, IM
- Human FSH preparations of rDNA origin
What are the common adverse ovarian stimulation of Follitropins?
Excessive ovarian stimulation (multiple eggs being produced)
Human chorionic gonadotropins (hCG, Pregnyl, Novarel)
- IM
- LH analog
- Obtained from urine persons who are pregnant
- Used to induce ovulation (to trigger the release of the eggs when they are mature)
- What we look for when we’re doing a pregnancy test
What is the primary androgens that are produced by the adrenal cortex?
- DHEA and androstenedione
What is the backbone for ALL cortical steroids including sex hormones?
Cholesterol
Naturally occurring estrogen (C-18)
- Secreted primarily by the granulosa cells of the ovarian follicles, the corpus luteum, and the placenta
- Also synthesized in fat, liver, muscle, and brain
- Mostly bound to proteins (albumin, SHBG)
What is the principal source of estrogen in postmenopausal women?
Adipose tissue stroma, where estrone is synthesized from dehyroepiandrosterone (DHEA) secreted by the adrenal cortex
Progesterone (C-21)
- Secreted by the corpus luteum, the placenta, and (in small amounts) the granulosa cells of the ovarian follicles
- Mostly bound to proteins
- Short half life
What is the menstrual cycle controlled by?
Intermittent, pulsatile release of GnRH and Gonadotropins
What are the effects of estrogen?
- Reproductive developmental
- Genital structures
- Secondary sexual characteristics
- Neuroendocrine actions involved in the control of ovulation
- Metabolic effects
What are the metabolic effects of estrogen?
- Modifies serum protein levels
- Enhances the coagulability of blood
- Reduces bone resorption
- Increases TGs, reduces LDL, and increases HDL
What are the clinical uses of estrogen?
- Contraception
- Estrogen deficiency resulting from premature ovarian failure, menopause, or surgical removal of the ovaries
- Hypogonadism in young people
Synthetic estrogens
- Oral, transdermal patch, vaginal cream, or IM injections
- Ethinyl estradiol is the most common estrogen used in hormone contraceptives
- Micronized estradiol also has increases oral bioavailability–used in HRT
- Long-acting esters of estradiol-IM injection
- Mixtures of conjugated estrogens from biologic sources (e.g. Premarin) are used orally for HRT
What is the ADE of estrogens?
- Nausea
- Breast tenderness
- Increased risk of migraine headache
- Thromboembolic events
- Gallbladder disease
- Hypertriglyceridemia
- HTN
- Increased risk of endometrial cancer
- In postmenopausal people, small increase in risk of breast cancer and cardiovascular events
Estrogen Receptor Modulators (SERMS)
- “Tailor-made” estrogens that have selective effects
- Goal of these drugs is to produce beneficial estrogenic actions in certain tissues but antagonist activity in tissues such as breast and endometrium
Which SERMS are used for the treatment of breast cancer?
- Tamoxifen and Toremifene
Which SERMS are used for the prevention and treatment of osteoporosis and to reduce the risk of invasive breast cancer in high-risk postmenopausal people?
Raloxifene
Which SERMS is used in combination with estrogen to treat severe menopausal vasomotor symptoms and prevent osteoporosis?
Bazedoxifene
Which SERMS is used to treat postmenopausal dyspareunia?
Ospemifene
What are the antiestrogens?
Clomiphene and Fulvestrant
Clomiphene
Approved for the treatment of infertility due to no ovulation (anovulatory)
* Selectively blocks estrogen receptors in the pituitary to reduce negative feedback and increase FSH and LH output (i.e., stimulates ovulation)
Fulvestrant
- Used for the treatment of estrogen-sensitive breast cancer with disease progression after tamoxifen
What are the aromatase inhibitors that are used to treat breast cancer?
- Anastrozole
- Letrozole
- Exemestane
What are the clinical uses for progestins?
- Contraceptives
- Used in combination with estrogen in HRT
- Used in assisted reproductive technology methods to promote and maintain pregnancy
Medroxyprogesterone
- A 17alpha-hydroxyprogesterone derivative and is most common HRT progestin used in the US
- Used in place of progesterone because of its longer half life
Drospirenone
- Fourth generation progestin structurally similar to spironolactone (aldosterone-receptor antagonist)
- Synthetic progestin with both anti-androgenic and anti-aldosterone properties
What are the ADE of Progestins?
- Irritability
- Weight gain
- Bloating
- Headache
- “Premenstrual-like” symptoms (mood swings, bloating, fluid retention, sleep disturbances)
- Increase blood pressure and decrease HDL
What are some effects of long term use of high doses of Progestins?
- Reversible decrease in bone density
- Delayed resumption of ovulation after termination of therapy
Mifepristone
- Antiprogestin
- Used as an abortifacient in early pregnancy (up to 49 days after last menstrual period)
- Prevent conception, induce labor, and treat endometriosis, meningiomas, and breast cancer
Androgen Receptor Antagonist
- Used with GnRH agonist to treat metastatic advanced prostate cancer
- Androgen receptor antagonist block all androgens, including those synthesized in the adrenal
- Together provide maximal androgen blockade
What are the products of androgen receptor antagonist?
- Bicalutamide
- Flutamide
- Nilutamide
- Enzalutamide
