Hormone Action and Regulation

Hormone Action

• Hormones function through nuclear receptor-mediated and membrane receptor-mediated actions.
• Steroid hormones use both mechanisms, affecting cells depending on receptor components.
• Understanding hormone receptors is important in drug development for clinical use.

Hypothalamic-Pituitary-Endocrine Axis

• Complex interactions between the hypothalamus, anterior pituitary, and target organs regulate classic endocrine hormones.
• Feedback mechanisms allow precise regulation of hormone levels within the hypothalamic-pituitary-endocrine axis.

Pituitary Hormone Regulation

• Anterior pituitary hormones are controlled by hypothalamic-releasing hormones.
• Posterior pituitary hormones, like oxytocin and vasopressin, regulate water balance and childbirth.
• Dopamine inhibits prolactin release, and other regulators include TRH and VIP.

Growth Hormone and Prolactin

• Growth hormone(GH) and prolactin (PRL) are in the somatotropic hormone family and use similar signaling.
• GH stimulates bone growth, muscle enhancement, muscle mass, and metabolism, while PRL is crucial for lactation.
• Feedback via IGF-1 and somatostatin regulates GH and PRL.
• GH impacts bone growth, muscle mass, and metabolism mainly through IGF-1.
• IGF-1 deficiency causes growth retardation but is GH unresponsive and IGF-1 responsive.
• PRL helps with lactation and mammary gland growth, as well as other functions.

Growth Hormone Secretion

• The hypothalamus regulates GH through GHRH (stimulates GH release) and somatostatin (inhibits GH release).
• IGF-1 inhibits GH release at the hypothalamus and pituitary.
• GH has direct effects on target tissues and indirect effects via IGF-1, which mediates growth.
• GHRH & SST are modes of GH action
• Daily GH secretion varies, peaking during puberty then declining with age, secreting with discrete, irregular pulses.
• GH secretion is stimulated by GHRH and ghrelin; feedback inhibition is subject to GH itself, SST, and insulin-like growth factor 1

Clinical Manifestations of GH Disorders

• Gigantism is caused by excess GH in children, causing excessive linear growth.
• Acromegaly is caused by excess GH in adults, causing enlarged hands, feet, facial bones, and organ enlargement.
• GH deficiency in children leads to growth failure and delayed puberty.
• GH deficiency in adults causes reduced muscle mass, increased fat, decreased bone density, and fatigue.

Prolactin Secretion

• Dopamine inhibits normal prolactin secretion.
• TRH and VIP stimulate prolactin under specific conditions.
• Hyperprolactinemia (excess PRL) in women leads to galactorrhea, amenorrhea, and infertility.
• Men with PRL excess will experience loss of libido and erectile dysfunction, as well as infertility.
• PRL deficiency results in failure of postpartum lactation.

Octreotide

• Octreotide and Pasireotide are somatostatin analogs to act on somatostatin receptors to reduce hormone secretion.
• Dosage of somatostatin analogs is titrated to reduce GH levels below 2.5ng/mL.
• The long-acting release form of octreotide is the standard type, given monthly.
• Pasireotide inhibits ACTH secretion and is FDA-approved for Cushing disease, which improves hypercortisolism.

Dopamine Agonists

• Dopamine agonists act on dopamine receptors (D2) to decrease prolactin secretion and prolactinoma size.
• Bromocriptine, an ergot derivative, interacts with D2 receptors to inhibit PRL release but does activate D1 receptors.
• Cabergoline is a long-acting dopamine D2 receptor agonist that is more effective and tolerable than bromocriptine.
• High doses of Cabergoline can cross-react at the 5HT2B receptor, causing cardiac valve abnormalities (not always seen when used for patients with prolactinomas)

Adverse Effects

• Gastrointestinal and cardiovascular side effects are concerns related to to somatostatin analogues.
• Pasireotide can cause hypocortisolism and worsen glucose tolerance, needing antihyperglycemic therapy.
• Bromocriptine, cabergoline, and quinagolide effectively reduce PRL levels, treat prolactin excess.
• Bromocriptine & Cabergoline decrease both PRL secretion and the size of the adenoma.

Hormone Receptor Blockers & Concerns

• Pegvisomant blocks the GH receptor, thus decreasing high GH levels and production of IGF-1 in acromegaly.
• SQ injections of Pegvisomant are given alone daily or weekly combined with somatostatin analogues.
• Concerns related to adverse hepatic effects may increase liver function tests
• It needs to be used cautiously in related concerns of hepatic impairment and hepatic function should be monitored during therapy
• Related concerns with benefits in glucose tolerance and the increase in GH secreting edenomas should be monitored regularly by pituitary MRI

Recombinant Pituitary Hormones

• Somatropin (Growth hormone) daily subcutaneous injection stimulates body growth via IGF-1.
• GH has indication in stimulating growth in childhood and replacing GH in GH deficienct adults
• GH can be used for Turner syndrome, Noonan syndrome, Prader-Willi, and idiopathic short stature in children.
• GH replacement therapy decreases fat mass, increases muscle mass and bone mass, thus improving quality of life in adults.
• GH side effects include peripheral edema, carpal tunnel syndrome, arthralgias, and myalgias

Insulin-like Growth Factor 1

• Mecasermin is used for severe IGF-1 deficiency due to GH receptor defects, GH insensitivity, or IGF-1 gene mutations.
• Mecasermin bypasses GH receptors and directly stimulates growth.
• Mecasermin subcutaneous injections should be given before meals to prevent hypoglycemia and rotate injection sites to avoid lipohypertrophy.
• Mecasermin adverse effects include hypoglycemia, lipohypertrophy, intracranial hypertension, and tonsillar hypertrophy.
• Active malignancy and closed epiphyses are contraindications

Growth Hormone-Releasing Hormone

• Tesamorelin
• It is a GHRH analog that stimulates GH and IGF-1 secretion but reduces visceral fat
• Tesamorelin is approved for HIV-associated lipodystrophy, reducing visceral adiposity with minimal impact on insulin resistance
• Injection site reactions, arthralgia, and peripheral edema are adverse effects
• Increased Injection rx, sterile water and Increased IGF-1 levels - monitor for potential long-term risks.

GNRH Analogues & Uses

• GNRH agonists (leuprolide, goserelin, nafarelin) continuously stimulate GnRH receptors, causing downregulation and decreasing LH & FSH secretion to treat:
  • Endometriosis (reduces estrogen) and precocious puberty (delays early puberty).
  • Hormone-sensitive tumors of breast & prostate (palliative treatment).
  • GNRH antagonists (degarelix, cetrorelix, ganirelix) directly block GnRH receptors, immediately decreasing LH & FSH secretion:
    • Prevent premature ovulation for assisted reproduction.
    • Suppress testosterone rapidly in advanced prostate cancer.

Gonadotropin-Releasing Hormone (GnRH)

• Goserelin is a GnRH agonist analogue.
• It is approved to treat endometriosis, endometrial thinning/ablation, advanced prostate and breast cancer.
• Histrelin is approved for central precocious puberty and advanced prostate cancer.
• Nafarelin is approved to treat precocious puberty and endometriosis.
• GNRH analogs includes Triptorelin used to treat prostate cancer
• GNRH antagonist includes Ganirelix & Cetrorelix
• Degarelix suppresses testosterone levels in advanced prostate cancer faster than GnRH agonists, while lowering prostate-specific antigen.
• Females: Must be 20 years old before being placed in menopause & Males: It is "medical castration"
• The effects includes change in Muscles, weight, and mood

Leuprolide

• It is a GnRH agonist that inhibits gonadotropin secretion, suppressing ovarian and testicular steroidogenesis with indications for:
• Palliative treatment of advanced prostate cancer
• Treatment of benign uterine diseases, like Endometriosis and uterine leiomyoma fibroids
• It is contraindicated in pregnancy and givem as intramuscular depot suspensions, as well as known to have side effects

Human Chorionic Gonadotropin

• Drug class: LH receptor agonist (mimics endogenous LH)
• Structurally similar with LH and binds with LH receptors on Leydig cells to stimulate testosterone production and supports spermatogenesis and testicular descent
• Indication: Male infertility r/t hypogonadotropic and hypogonadism
• Common used with FSH therapy to initiate sperm spermatogenesis.
• Contraindicated if underlying anatomical obstruction is present
• Adverse effect: Gynecomastia
• Other considerations:
  • Monitor testosterone levels with sperm counts
  • Peripheral conversion of androgens into estrogen will cause increased water rentention
  • Should also evaluate pituitary or hypothalamic dysfunction in hypogonadism casese

Inhibitors of Steroidogenesis

• Includes Ketoconazole, Metyrapone, Etomidate, and Mitotane from chap 50 -Ketoconazole inhibits adrenal and gonadal steroidogenesis due to CY17 inhibition
• Metyrapone selectively inhibits CYP11B1, which reduces cortisol production
• Etomidate and Mitotane treats treatment hypercortisolism and inoperable adrenocortical carcinoma

Thyroid Disorders

• T4 normal levels is 4.5 to 11 µg/dL, with T3 at 1/100 of that
• T4 acts as T3 after converting in circulation to regulate with a negative feedback loop

Thyroid Hormones

• Crucial for amphibian metamorphosis and brain development regarding growth.
• Childhood hypothyroidism decreases linear growth and delays in skeletal bone age.
• Childhood thyrotoxicosis accelerates bone maturation and can affect final height.
• They also influences hepatic LDL receptor expression and apolipoprotein B levels, plus regulates resting energy expenditure and metabolic rate regarding thermogenesis

Thyroid Hormones: Metabolization

• Deiodination converts T4 into T3 (active) – Ether cleavage conjugates glucuronidation/sulfation and oxidative decarboxylation
• T4 & T3 metabolization influenced from half lives in relationship to hyper and hypothyroidism

Thyroid Hormones & TBG

• TBG and clearance is influenced in relationship with pregnancy, estrogen use, and liver disease.
• Those and drugs such in phenytoin, the salicylates all display TA from the TBG

Hypothyroidism & Treatment

• Levothyroxine or Thyroxine (T4): Levoxyl, Synthroid, Unithroid
• Synthroid goal: euthyroid TSH level
• Maintenance of 75-150 mcg/day & increased every 4-6 weeks, and recheck serum 6-8 weeks after with long half life of 7 days
• Should consider other comorbidities

Levothyroxine

• Action
  • T4 is converted to T3, which has more potent indications
• Indication
  • hypothyroidism
• Side effects
  • resembles hyperthyroidism
  • nervousness, anxiety, tremor, heat intolerance, weightloss, and arrhythmias

Liothyronine

• T3 treats hypothyroidism, while also being a diagnostic agent that binds to the nuclear thyroid hormone receptors and regulates gene expression
  • Contraindications w/ cardiovascular disease.
• Has rapid onset with a rapid half life
• Should be given at more intervals
• A concern with Desiccated thyroid extract is a contraindication use in pregnancy, and to use alternate drugs

Formulation Variability

• Note: It is crucial to be aware of formulation variabilility and to consistently switching of brands

Hyperthyroidism Goals

• Restore individuals to the euthyroid state, to eliminate risks linked with hyper state or chronic
• Treatment is not always for the persons lifespan
• Should consider to be careful and monitor medications of Propylthiouracil when pregnant

Treatment of Hyperthyroidism

• Is best treated patients that are 40 y.o and is useful to administer anti thyroid drugs younger in younger patients
• Propylthiouracil inhibits the organification of iodine and blocks D1 enzyme to reduce T4

Thyroid-PTU (Propylthiouracil)

• PTU- Thioamide drug that inhibits thyroid to decrease synth
  • is mostly preferreable during preganancy
  • Risk factor Pregnancy Category D, breastfeed, with associated common edema
• Methimazole will prevent thyroid, and inhibit iodine organification

Hyperthyroidism Treatment

• Methimazole will need to monitor PTU, and liver hepatotoxicity, as well has monitor the T3 levles
• Can have side effect rash or liver heptaic issues and the bone narrow status should always be monitored
• The response to such treatment can improve with weeks as its administered

Hyperthyroidism: Adjunctive treatments

• Max effects of iodine may occur thyroid concentration after 10 days of treatment.
• Contraindication of pregnancy-jodine can cause that goes through the placenta & can cause feta goiters
• use only the follow-Potassium lodide Contraindications, lugol solution.
• S/S treatment
• The drugs mentioned are B adrenergic receptor, Calcium channel blockers.

Diabetes Mellitus

• Glycemic control assessed using both short term and long – Desired outcomes • Reduce the risk for micro or Maro issues and improve overall quality of life.

Goals of Therapy DM and Medications

• Medications such as
• -Metformins – sulfonylureas
• Type 1 and 2
• Gestational
• A1-C, preprandials, capillary, blood pressure, weight and CGM goals

ADA 2022

• Adapted from ADA
• -Consider other coor morbidities.
• -Consider to monitor lipid control.

Hypoglycemia

• Follow general rules -Should be instructed how to treat hypoglycemia and what to do the use of Glucagon

Types of Insulin

• There were 2 types listed -Insulin -Biguanides

Mechanism of Action

• Rapid or peak or short action
• The onset, peak are always changing
• When to take in considerations

1.Insulin Lispro, Aspart, and Glulisine:

• differs on the rapid distribution to dissociate into monomers under subcutaneous.

2.Long-Acting Insulins:

-NPH insulin: more suspenation related after gradual disollution or injection Glargine with pH solution or aggregation occurs Detemir: modified with fatty acid, promotes less hypoglycmia Degludec: multihermatic complex to less hypoglycmia again

Drugs To Be Aware

• 1. stable combinations that helps on injections

2. a more rapid inhalation

Name + Concentration

• Insulin 0-500 regular
• Humalog-200 bolus
• Toujeo-300 basal
• Tresbia-200 basal

Type 1 and 2

-Type 1 = the patient will dose the insulin with body wait

• Patients tend to get higher if those are pregnant of obese etc

Appropriate Agent 1 DM

• Administer and monitor A1-c 3 months Second line, increase insulin Third 3: adjust monitors

Therapy for T2DM

• Intensive lifestyle changes a cornerstone for treatment like intensive lifestyle changes, or micro and macrovasucalr
• Use 9 classes of injection and oral injectables.
• Pt will go under symptomatic issues if diagnosed with symtopic.

Treatment algorithm

• DM educ and patient with glucose issues should get diagnosed
• Metformin the first one and should do it at time. If not reaching 7 then give second or third with the second agent

Drugs And Names

• -K-ATP Channel Modulators: Sulfonylureas Glimepiride (Amaryl) Glipizide (Glucotrol, Glucotrol XL) Glyburide (DiaBeta, Micronase)

1-With Chronic Use-

levels starts to decline but the maintenance is always with lower plasma glucose .

• -Also to always consider what they can take and contraindications and what's the risk of liver kidney disease Side effects-Pregnalncy, renal

-Repaglinide (Prandin) or Nateglinide (Starlix)

• Controls and indicates postprandial with better outcomes
• side effects- Hypoglycemia of hypoglycemia w/s
• Biganuidies = less

Metformin (Glucophage, Glucophage

• Liver production and the AMP Interfers wit ahsroption
• With alcohol
• And the patient with an better African
• thiazolidinedones- reduces resistance

thiazolidinediones TZD

• With the aid of insulin and increasing skeletal muscles
• And with out with stimulating what's a great way.
• • and what has increase and what can decrease

Person With Disbetes -

a sign of TZD. Because actions. These days weeks action.With the rosi A supplement with metformin and sulfona

-Alpha-Glucodise inhibitors = Accerose.

FDA approved - has to decrease the amplitude post prandias in diabetics.

Side Effects:

• Always note and use

-Contraindiation-

Aline should cause contraion or with that

-GLPO-1 Agonists (Glucagon)

Hormones that releases. After meal Stimulates the increase

Contraindications-

Allergic Nuasuea, etc

• Semaglutide. May have effects

###-Dipeptide peplase peptidase = Inhibitors

• -Mechsnism
• This also increase to glucongen and glyp and good action with fasting issues for both with diabetes for second and first genrations

-2nd, 3rd and -Glipos

• Side effect
• Doseages
• indications
• interactions

-Na+-Glucose Transporter 2 Inhibitors

It inhibits the effects related from excretion of plasma to low bloods S2G2 reducers = cause excretion in ptoximat and also the rates

• Potentially Beneficial Side Effects =
• weight/ blood pressure/ osmic
• SiderEffects: all the same sides
• A1-0.
• G2LT expression and glucose and amino acids Most FDA

Amilyn AGONISTS = Symllin

• CNS hypothalamus
• satiery
• glucoogonn

Bile

• Bile is to keep gLp1 regualated

SGI =

• Affect S GI. Tract with no effect or drug has side note . With what

• Table

• Medeications

• And the type of HBA

• What actions is that and advantages and side notes