Introduction to Endocrine System PDF

ENDOCRINE PHARMACOLOGY: HYPOTHALAMIC & PITUITARY Chapter 37: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 691-710) Chapter 42: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. Chapter 34: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 1446-54) ...

ENDOCRINE PHARMACOLOGY: HYPOTHALAMIC & PITUITARY Chapter 37: Basic & Clinical Pharmacology, Katzung, 15th ed. (pgs. 691-710) Chapter 42: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 13th ed. Chapter 34: Principles of Medicinal Chemistry, Foye, 8th ed. (pgs. 1446-54)  LECTURE OBJECTIVES - 1 1. Explain hypothalamic & pituitary hormones with respect to: a. Stimulation & inhibition of anterior pituitary hormones b. Secretion of posterior pituitary hormones c. Tissue effects and subsequent hormone secretion d. Conditions that arise  altered signaling of growth hormone 2. Explain significant aspects of drugs discussed in GH signaling a. Drugs that stimulate GH signaling (rhGH and rhIGF-1) b. Drugs that inhibit GH signaling (SST analogs, pegvisomant) c. Mechanism of action and pharmacokinetics d. Indications, contraindications, and adverse effects  LECTURE OBJECTIVES - 2 4. Explain specifics of drugs regulating water homeostasis a. List / differentiate agonists and antagonists b. Mechanism of action, pharmacokinetics, SAR c. Indications, contraindications, and adverse effects 5. Explain specifics of gonadotropin regulating drugs a. List / differentiate analogs, super-agonists, and antagonists b. Mechanism of action, pharmacokinetics, SAR c. Indications, contraindications, and adverse effects Harrison’s Principles of Internal Medicine, 18 th ed. HYPOTHALAMUS- PITUITARY- ENDOCRINE AXES 1. Hypothalamus produces (releasing) hormones / biomolecules to stimulate (+) or inhibits (-) the pituitary 2. Pituitary responds  synthesizes and releases specific hormones that enter the circulation 3. Circulating hormones act on specific endocrine glands/ tissues that respond by producing a biological effect HPA – hypothalamus – pituitary – adrenal HPT – hypothalamus – pituitary –  PHARMACOLOGICAL TREATMENTS  Various endocrine disorders can be treated with drugs that regulate the hypothalamic- pituitary axis (HP) by mimicking the endogenous hormone/regulatory substance or blocking its effects  Applications include:  Agonist at endogenous receptors (HRT)  Estrogen/progesterone or testosterone  Antagonism to block excess of pituitary hormones  Pegvisomant at GH receptors  Identifying endocrine abnormalities, i.e., diagnostic tools  ACTH stim. test  central or peripheral adrenal insufficiency Drugs that mimic or block the effects of hypothalamic and pituitary hormones have pharmacologic applications in three primary areas: (1)As replacement therapy for hormone deficiency states (2)As antagonists for diseases caused by excess production of pituitary hormones (3)As diagnostic tools for identifying endocrine abnormalities. Hormone Receptors Hormones that act predominantly via nuclear receptors to modulate transcription in target cells (e.g., steroid hormones, thyroid hormone, and vitamin D) Hormones that typically act via membrane receptors to exert rapid effects on signal transduction pathways (e.g., peptide and amino acid hormones) Classification of Hormones  Based on structure and/or type of receptor they activate.  Growth hormone (GH) and prolactin (PRL), single- chain protein hormones with significant homology (JAK/STAT)  TSH (thyrotropin), (FSH),(LH) (GPCR).  (ACTH), a peptide cleaved from a larger precursor, (GPCR) The control of metabolism, growth, and reproduction is mediated by a combination of neural and endocrine systems located in the hypothalamus and pituitary gland Quick overview Hypothalamic Hormone Clinical Uses Growth hormone-releasing hormone Used rarely as a diagnostic test for GH and (GHRH) GHRH sufficiency Thyrotropin-releasing- hormone (TRH, May be used to diagnose TRH or TSH protirelin) deficiencies; not currently available for clinical use in the United States Corticotropin-releasing hormone (CRH) Used rarely to distinguish Cushing disease from ectopic ACTH secretion Gonadotropin-releasing hormone (GnRH) May be used in a single dose to assess initiation of puberty (pubertal gonadotropin response) May be used in pulses to treat infertility caused by GnRH deficiency, Analogs used in long-acting formulations to inhibit gonadal function in children with precocious puberty, in some transgender/gender variant early pubertal adolescents (to block endogenous puberty), in men with prostate cancer and women undergoing assisted reproductive technology (ART) or women who require ovarian suppression for a gynecologic disorder Dopamine Dopamine agonists (eg, bromocriptine, cabergoline) used for treatment of Hormone Diagnostic Use Thyroid-stimulating- In patients who have been hormone (TSH; treated surgically for thyroid carcinoma, to test for cancer thyrotropin) recurrence by assessing TSH- stimulated radioactive iodine uptake and serum thyroglobulin level. Adrenocorticotropin (ACTH) In patients suspected of adrenal insufficiency, either central (CRH/ACTH deficiency) or peripheral (cortisol deficiency), in particular in suspected cases of congenital adrenal hyperplasia  PHARMACOLOGICAL AGENTS COVERED IN THIS SECTION 1 of 2 GH analogs / antagonists  mecasermin  somatropin ADH analogs /  lanreotide antagonists  octreotide  desmopressin  pegvisomant  vasopressin  conivaptan Prolactin regulators  bromocriptine  tolvaptan  cabergoline Oxytocin analogs  oxytocin  PHARMACOLOGICAL AGENTS COVERED IN THIS SECTION 2 of 2 GnRH analogs / agonists LH analogs  gonadorelin (GnRH)  Lutropin alfa (rLH)  goserelin  Menotropins (hMG)  leuprolide FSH analogs GnRH antagonists  Follitropin alfa  cetrorelix (rFSH)  degarelix  Follitropin beta  ganirelix (rFSH)  Menotropins (hMG) REGULATION OF GROWTH HORMONE  Figure 42-2; Goodman & Gilman; 13th ed. REGULATION OF GROWTH HORMONE  Growth-hormone releasing hormone (GHRH) acts at GPCRs in somatotropes of anterior pituitary  secrete growth hormone (GH)  GHRH receptors Gαs stimulate cAMP   iCa2+  stimulates synthesis and secretion of GH  Somatostatin actsLOF in GHRH receptors leads to short  at Gαi GPCRs (SSTR1-5) to inhibit stature adenylyl cyclase, activates K + channels and protein phosphatases, which inhibits the release of GH  Contrast: Dopamine, 5-HT, α2-adrenergic agonists, and ghrelin can stimulate GH secretion  GROWTH HORMONE  Splice variants of endogenous GH differentiate it from rhGH  ~50% GH bound plasma protein that contains extracellular GHR  Bound form is cleared slowly; t1/2 = 10X longer than free hormone  It can act as a reservoir  Obesity can  GH binding proteins  Secretion of GH is high in children, peaks in puberty, declines in adulthood  GH is secreted in irregular pulsatile manner with highest activity during sleep Figure 42-5; Goodman & Gilman;  GH receptors (GHR) are cytokine type13 ed. th  2 binding sites  receptor dimerization  Stimulates IGF-1 synthesis via JAK/STAT pathway  NATURAL GH / IGF-1 SIGNALING AGONISTS Growth hormone  191 amino acids (22.1 kDa) peptide hormone  Binds cell surface cytokine (JAK / STAT) receptors  ↑ IGF-1  Physiological effects:  Anabolic effects in many tissues (muscle, bone, and other organs)  Catabolic effects in adipose tissue  Reduces insulin sensitivity  t½ = 20 – 25 minutes Insulin-like growth factor 1 (IGF-1)  Inhibits insulin secretion and hepatic glucose production  Protein bound (IGFBP-3) in circulation  Tissue growth (skeletal, cellular, and organ)  Receptor tyrosine kinase is homologous to insulin receptor INCREASED GH SIGNALING BENEFITS …  Growth hormone deficiency  Pediatric patients treated with GH  Prader-Willi syndrome (genetic translocation/mutations)  Turner syndrome (missing or altered X chromosome)  Idiopathic short stature (ISS)  Growth failure associated with chronic renal insufficiency  Growth hormone deficiency in adults  Chronic wasting diseases (AIDS, HIV)  Short bowel syndrome; dependent on TPN  Severe burns  SOMATROPIN (HUMATROPE®, NORDITROPIN®, GENOTROPIN®) Clinical Uses: Growth failure (pediatric), GH deficiency (adults), HIV- cachexia, and short bowel syndrome Recombinant human growth hormone (rhGH) 191 a.a. MOA: agonist at GH receptors in tissue   IGF-1 production Pharmacokinetics:  Absorbed slowly via SubQ or IM; t½ ~ 4 - 10 hrs; DOA = 18-20 hrs  Hepatic metabolism ( P450 ENZ activity) and renal elimination Side effects:  Pediatric – Otis media, hypertension, headache, nausea/ vomiting  Adults – peripheral edema, arthralgia, headache, diaphoresis Drug-Drug Interactions: 1. Diminishes hypoglycemic effects of anti-diabetic agents 2. GH inhibits 11-b HSD type 1,  activation of cortisone & prednisone  CONTRAINDICATIONS FOR USING GROWTH HORMONE THERAPY Contraindications - GH Use: Patients w/ acute critical illness due to following:  Complications after open-heart or abdominal surgery  Multiple accidental trauma  Acute respiratory failure As administration of GH resulted in  increased mortality Any evidence of neoplasm or malignancy  GH therapy  stimulate growth of tumor or neoplasm  Proliferative retinopathy  MECASERMIN (INCRELEX®) [ME KA SER MIN] Clinical Use: non-responsive to exogenous GH therapy  Patients with GH receptor mutations  GH gene deletions and positive for neutralizing GH antibodies Dose: 0.4 – 0.8 mg/Kg SubQ BID; must be w/in 20” meal or snack Mechanism of Action: agonist at IGF-1 receptors in liver, bone, etc. Pharmaco- dynamics / kinetics:  SubQ admin. only; IV is contraindicated; Half-life (t1/2 ) = 6 hrs Side effects: Hypoglycemia, lipohypertrophy  Other GH therapy side effects (hypertension, headache, etc.) Drug-drug Interactions:  enhances hypoglycemic effects of other diabetic agents Contraindicated in known cases of malignancies  INHIBITION OF GROWTH HORMONE RELEASE  Surgery is treatment of choice for GH over- secretion;  Pharmacological treatment is often needed for large adenomas or persistent GH secretion (giantism/ acromegaly)  Neurotransmitters that inhibit GH signaling  Somatostatin (endogenous hormone)  Drugs that inhibit or reduce GH signaling  Octreotide (Sandostatin) / Lanreotide (Somatuline)  Pegvisomant (Somavert)  General adverse effects of GH / IGF-1 antagonists Nausea and abdominal pain in 50% of patients  SOMATOSTATIN (SST) AND SYNTHETIC ANALOGS Somatostatin Figure 42-3; Goodman & Gilman; 13 th ed.  Cyclic peptide (14 amino acids); t = 3 ½ mins  Four residues (#7 – 10) crucial for activity:  Phe-Trp-Lys-Thr  Binds SST receptors to prevent GH release  SSTR1 – SSTR5 are all GPCR; SSTR2 & SSTR5  Analogs designed to ↑ half life and specificity  Octreotide  Lanreotide  OCTREOTIDE [OK TREE OH TIDE] (SANDOSTATIN®, SANDOSTATIN® LAR DEPOT) Modified Octa-peptide SST analog; Dose: 100 mcg SubQ or IM 3X/day; or 20 mg IM depot/4 wks MOA: agonist at somatostatin receptors (SSTR1-5)  Gi  inhibits cAMP;  K+ channels & pTYR  inhibit GH release; Pharmaco dynamics / kinetics:  25X more potent than SST; t½ = 100 minutes Adverse Effects: (depends on admin. / length of treatment)  Diarrhea, nausea, abdominal pain, biliary sludge, cholelithiasis;  Sinus bradycardia (~25%)  Hypothyroidism due to inhibition on TSH; Hyperglycemia Drug-drug Interactions:  Oral hypoglycemics, insulin  impaired glucose regulation  CCBs, QT prolong agent   risk prolong QT /cardiotoxicity  LANREOTIDE [LAN REE OH TIDE] (SOMATULINE®, SOMATULINE® DEPOT) Modified Octa-peptide SST analog; Lanreotide Dose: 90 mg SubQ depot 1X/month Tyr Val  monitor GH / IGF-1 levels MOA: Agonist at SSTR-2 and -5 Pharmacokinetics: t1/2 = 23 – 36 days Side effects, similar as octreotide:  Reduced gallbladder / biliary tract motility  Bradycardia and hypertension  Hypo- or hyperglycemia possible  Alterations in thyroid function (monitor TSH, T4)  PEGVISOMANT (SOMAVERT®)[PEG VIH SO MANT] Pegylated peptide  enhances plasma circulation MOA: Competitive antagonist at GH receptors  Binds 1 receptor site (greater affinity) but not as well at second  dimerization without conformational change of GH receptor Dose: 10 mg SubQ 1X/day Pharmacokinetics: t½ = 3-6 days Side effects may include:  Elevated LFT (monitor); neutralizing antibodies  Diarrhea, nausea and altered glucose metabolism Drug-drug interactions:  SST analogs can increase risk for elevated liver  REGULATION OF PROLACTIN (I.E., LACTATION)  REGULATION OF PROLACTIN  Prolactin is the only anterior pituitary hormone that is not under stimulatory control; pseudo- constitutive activity  Dopamine inhibits prolactin release via D2 receptors on lactotropes and TRH can stimulate prolactin release  Prolactin levels remain low in males  PRL become elevated during normal menstrual cycle in females  REDUCING PROLACTIN SIGNALING Prolactin  Produced by anterior pituitary lobe; induces lactation  Excess production inhibits ovulation  No clinical preparations available for prolactin- deficiency Conditions that benefit from reducing prolactin secretion  Hyperprolactinemia from prolactinomas  Resulting from hypogonadism and infertility  Visual disturbances associated with tumor mass  Acromegaly (higher doses) General adverse effects of dopamine receptor  BROMOCRIPTINE (PARLODEL®) [BROE MOE KRIP TEEN] Clinical uses:  Hyperprolactinemia, hypogonadism, acromegaly Physiological effects: Suppress pituitary secretion of prolactin Dose: 2.5 – 15 mg PO/day (20 – 30 mg for acromegaly) MOA: slightly selective D2 receptor agonist Pharmacokinetics  Extensive 1st pass; metabolism via CYP3A4; t½ = 5-6 hours Side effects:  Orthostatic/postural hypotension, nausea &  CABERGOLINE (DOSTINEX®) [CA BER GOE LEEN] Clinical indications:  Hyperprolactinemia, idiopathic or due to pituitary adenoma  Dose: 0.25 – 1 mg PO 2X/week ( normal prolactin levels) MOA: agonist that has ↑ D2 selectivity Pharmacokinetics:  Extensive hepatic hydrolysis, not via CYP activity  t = 65 hours ½ Side effects:  Headache, dizziness, nausea; and orthostatic hypotension  Less severe nausea and vomiting; other ADE remain same DDIs: / β - adrenergic agonists and anti-psychotics  REGULATION OF GONADOTROPI N HORMONES Luteinizing Hormone (LH) Follicle Stimulating Hormone (FSH) Human Chorionic Gonadotropin (hCG)  BENEFITS OF INCREASED GNRH SIGNAL GONADOTROPIN HORMONE ANALOGS Benefits:  Follicular development and ovulation  Ovulation induction  Male infertility (spermatogenesis)  Prepubertal cryptorchidism Follicle stimulating hormone  follitropin alpha (Gonal-f); follitropin beta (Follistim)  urofollitropin (Bravelle) Luteinizing hormone: lutropin alpha (Luveris) Combined FSH/LH: menotropins (Menopur, Repronex) Chorionic gonadotropin  choriogonadotropin alpha (Ovidrel)  chorionic gonadotropin (Pregnyl, Profasi)  UROFOLLITROPIN (BRAVELLE)  Purified FSH from urine of menopausal women  Low levels of LH (2%) and no hCG  SC and IM; after 7 – 12 days results in follicular development  Follicular development monitored by ultrasound & E2 levels  Ovulation requires hCG when fully developed (mimics LH surge)  Contraindicated in pregnancy  CI: high levels of FSH (indicates primary ovarian failure)  CI: any other reason for infertility except anovulation  (GONAL-F) FOLLITROPIN BETA (FOLLISTIM) Recombinant FSH protein from CHO cells  Purified by immunochromatography using FSH antibodies  Follitropin-β: ≈ follitropin-α; different carbohydrate side chains  MOA: agonist at FSH receptors  Clinical indications:  Controlled ovulation and hyperstimulation in women  Infertility due to hypogonadotropic hypogonadism in men  Side effects:  Both sexes: headache, depression, and edema  Ovarian hyperstimulation syndrome; multiple pregnancies LUTEINIZING HORMONE ANALOGS lutropin alpha (Luveris)  Recombinant LH used in conjunction w/ follitropin alpha  Induce theca cells androgen secretion  Supports FSH-induced follicular development  Essentially equivalent cautions as FSH  Contraindicated during pregnancy menotropins (Menopur, Repronex)  Mixture of FSH and LH; from urine of menopausal women  Essentially equivalent caution as other LH & FSH analogs  Contraindicated during pregnancy  HUMAN CHORIONIC GONADOTROPIN (HCG) Endogenous analog of LH Clinical indications:  Initiation of ovulation during controlled ovulation hyperstimulation  Ovarian follicle development in women with hypogonadism  Male hypogonadotropic hypogonadism MOA: agonist at LH receptors Physiological effects: mimics effects of endogenous LH  PK: IM injection Side effects:  Both sexes: headache, depression, and edema  Ovarian hyperstimulation syndrome; multiple pregnancies in women  Gynecomastia in men  HUMAN CHORIONIC GONADOTROPIN (HCG) Choriogonadotropin alpha (Ovidrel)  Recombinant hCG; administered subcutaneous  Contraindicated during pregnancy  Ovulation induction when appropriately treated with FSH/LH  For use in prepubertal cryptorchidism Chorionic gonadotropin (Pregnyl, Profasi, others)  Isolated from urine of pregnant women; IM administration  Concern during pregnancy  Ovulation induction when appropriately treated  INHIBITING GNRH SIGNALING GnRH receptor super agonists  gonadorelin (Factrel) GnRH receptor  goserelin (Zoladex) antagonists  histrelin (Supprelin LA, Vantas)  ganirelix (Antagon)  leuprolide (Eligard, Lupron) cetrorelix (Cetrotide)  nafarelin (Synarel)   degarelix (Firmagon) triptorelin (Trelstar) Basic Adverse Effects GnRH super-agonists & antagonists  Gynecomastia in males  Depression and reduced libido  Contraindicated during pregnancy and breast feeding  Use Super-agonists over 6 months  risk of osteoporosis  GNRH ANALOGS gonadorelin: synthetic human GnRH Gonadorelin (agonist) and following analogs, (super- agonists) at GnRH receptors, exert similar MOA, physiological effects, clinical indications, and side effects as endogenous GnRH: goserelin histrelin nafarelin triptorelin  GNRH SUPERAGONISTS Gonadorelin (Factrel)  Acetate modification of native GnRH Goserelin, histrelin, leuprolide, nafarelin, triptorelin  GnRH analogs with D-amino acids at a.a. position six  Super agonists: more potent and longer half life  Agonist at GnRH receptor initially produce flare in hormones  Constant administration desensitizes, down- regulates GnRH receptors  Reduction in (LH/FSH) and gonadal steroid levels to post menopause & castration levels  Contraindicated during pregnancy  Clinical uses: IVF, endometerosis, gender transition Tx  LEUPROLIDE  MOA: agonist at GnRH receptors  Physiological effects:  Increased LH & FSH secretion w/ intermittent administration  Prolonged continuous administration reduced LH & FSH secretion and downstream decreased levels of gonadal steroids  Pharmacokinetics:  IV, SubQ, IM injection, intranasal; Depot formulation available  Side effects:  headache, nausea, light headedness  injection site reactions  hypogonadism with continuous administration  GANIRELIX (ANTAGONIST) AND ANALOGS  GnRH analog; several substitutions  MOA: Competitive antagonist at GnRH receptors  Confers binding affinity with loss of activity  Reduces endogenous production/secretion of LH & FSH; and, downstream gonadal steroids  Clinical indications: controlled ovarian hyperstimulation  Prevention of premature LH surges during controlled stimulation  Ganirelix can act in 5 days; Leuprolide may take up to 4 weeks; Relugolix : newly  Effects approved reverse non-peptide more quickly GnRH antagonist; than superagonists same MOA; orally administered; PK: metabolized via   POSTERIOR PITUITARY HORMONES: Vasopressin Analogs & Antagonists Oxytocin  POSTERIOR PITUITARY HORMONES  Peptides synthesized in hypothalamic neuronal cell bodies and transported to posterior lobe of pituitary via neuronal axons  Vasopressin (anti-diuretic hormone, ADH)  Oxytocin  Oxytocin receptor agonists  Oxytocin (Pitocin)  Stimulates uterine contraction  Up-regulation of receptors late in pregnancy  Stimulates lactation in breast tissue  OXYTOCIN (PITOCIN) Nonapeptide similar to vasopressin peptide MOA: agonist at oxytocin receptors (Gαq)  PLC; iCa2+ Clinical indications: Induction/augmentation of labor  Maternal diabetes, preeclampsia, Rh problems, ruptured membranes  Control of post-delivery uterine hemorrhage  PK: IV infusion or IM injection ; Serum t½ of 5 minutes  Side effects:   ARGININE TyrCys VASOPRESSIN Phe CysProArgGly –NH2 GluAsn 9 a.a. peptide synthesized by hypothalamus, transported to posterior pituitary and released in response:  ↑ osmolality or ↓ blood pressure Administered: either IV or IM  Actions of AVP include:  Vasculature: vasoconstriction and ↑ arterial pressure  V receptors  vasoconstriction 1  V receptors  vasodilation & H O reabsorption via 2 2 upregulation of aquaporin channels  Deficiency in vasopressin  diabetes insipidus  Pharmaco-dynamics/kinetics: Half-life ~ 15 - 30 minutes;  Desmopressin TyrMod-Cys (DDAVP) Phe CysProD-ArgGly –NH2 GluAsn ([1-deamino-D-Arg]vasopressin) peptide analog MOA: relatively selective agonist at V2 receptors  Physiological effects:  Decrease H2O excretion in renal collecting duct cells  Extra-renal: stimulates V2 receptors to increase Factor VIII & VWF  Pharmaco-dynamics/kinetics:  Low bioavailability (1-5%) Oral; IV, SubQ or intranasal admin.  t1/2 = 1-3 hrs (> 30 mins due to a.a. modifications)  Side effects:  Hyponatremia, headache, GI disturbances, allergic reactions  conivaptan (Vaprisol) MOA: antagonist at V1a / V2 receptors Physiological effect:  renal excretion of H2O in collecting duct PK: IV infusion; sensitive CYP 3A4 substrate DDI: CYP3A4 inhibitors / substrates Side effects:  Infusion site reactions (related to route of admin.) Tolvaptan (Samsca®; non-peptide; orally active)  Selective V2-R antagonist; blocks effects from excess vasopressin  Same physiological effects and DDIs as conivaptan  PEARLS: HYPOTHALAMUS & PITUITARY ENDOCRINE SYSTEM 1. Peptide hormones of the anterior pituitary are essential for the regulation of growth and development, reproduction, response to stress, and intermediary metabolism. 2. Synthesis and secretion of the pituitary hormones are controlled by hypothalamic hormones and by hormones from the peripheral endocrine organs. 3. Most striking physiological effect of GH is the stimulation of the longitudinal growth of bones. 4. GH excess is treated with the SST analogs octreotide and lanreotide. 5. GH deficiency is treated w/ recombinant human GH (somatropin). 6. Analogs of GnRH are used predominantly to treat advanced prostate cancer; endometerosis,. 7. Diuresis regulation (vasopressin analogs / antagonists)  HYPOTHALAMIC – PITUITARY – ORGAN PATHWAYS Anterior Target Hypothalamic Pituitary Target Organ Hormone or Hormone Hormone Mediator Growth hormone-releasing Growth Hormone (GH; Liver, bone, muscle, hormone (GHRH) stimulates somatropin) kidney, and others Decreased Somatostatin inhibits Decreased effects effects Thyrotropin-releasing hormone Thyroid-stimulating Thyroid (TRH) stimulates hormone (TSH) Corticotropin-releasing Adrenocorticotropin Cortisol hormone (CRH) stimulates (ACTH) Gonadotropin-releasing hormone (GnRH) pulsatile Gonads Estrogen stimulation Gonadotropin-releasing Progesterone (f) hormone (GnRH) pulsatile Gonads Testosterone (m) stimulation Dopamine inhibits Breast  REFERENCES 1. Basic & Clinical Pharmacology, 15th Ed. (2020) by Bertram G. Katzung. McGraw-Hill Medical (accessed via AccessPharmacy) 2. Foye’s Principles of Medicinal Chemistry, 8th Ed. (2019) by Victoria F. Roche, S. William Zito, Thomas L. Lemke, and David A. Williams. Lippincott Williams & Wilkins 3. Goodman & Gilman’s Pharmacological Basis of Therapeutics, 13th Ed. (2018) by L.L. Brunton, J.S. Lazo, and K.L. Parker. McGraw-Hill (accessed via AccessPharmacy)