Endocrine and Reproductive Pharmacology

Endocrine and Reproductive Pharmacology : 

Endocrine and Reproductive Pharmacology Presented by: Dr. Dhiren B. Bhoi M.V.Sc. Veterinary Gynaecology and Obstetrics E. Mail:-drdhirenvet@gmail.com

Learning Objectives : 

Learning Objectives Review the physiology of the endocrine system, and know: The endocrine glands Control mechanisms of the system: + and - feedback What hormones are: endogenous and exogenous Be able to describe the neurohomonal reflex Be able to describe the location, function and hormonal products of various endocrine glands

Learning Objectives : 

Learning Objectives Know the uses and classes of gonadotropins, gonadal hormones, progestins, and prostaglandins used in Veterinary Medicine Know the uses and classes of drugs affecting the uterus and uterine contractility Be able to write a definition of pheromone and give and example

Learning Objectives : 

Learning Objectives Be able to describe the treatment for hypo and hyperthyroidism Know the endogenous sources of insulin and the metabolic effects of insulin Know the exogenous sources of insulin, and their characteristics Know the mechanism of action of growth promoters Know the clinical uses of anabolic steroids

OUTLINE : 

OUTLINE Introduction Anatomy and Physiology Review Hormones of reproduction Gonadotropins, gonadal hormones Prostaglandins Drugs affecting Uterine Contractility Pheromones

OUTLINE : 

OUTLINE Thyroid Hormones Hyperthyroidism Hypothyroidism Diabetes Mellitus treatment Insulin Hyperglycemic agents Growth promoters Anabolic Steroids Don’t forget to study definitions at the beginning of the chapter!

Introduction : 

Introduction Endocrine System Glands Groups of cells that secrete regulatory substances directly into blood stream Regulatory substances diffuse across cell membranes One of two major control mechanisms for the body (the other is the nervous system) Linked closely with the nervous system through the hypothalamus to allow adaptation of reproduction and survival to changes in the environment.

Introduction : 

Introduction Glands: Pituitary, adrenals, thyroid, ovaries, testicles, pancreas, kidneys Glands produce hormones: Be able to list the hormones produced by each gland! Hormones act on target organs influence the physiologic activity

Introduction : 

Introduction 2 reasons hormones are given to an animal: Correct a deficiency Cause a desired effect Is supplementation of a hypothyroid dog done through exogenous or endogenous hormone supplementation?

Anatomoy & Physiology : 

Anatomoy & Physiology Pituitary is the center Control of endocrine system Located in the base of the brain ventral to the hypothalamus. Bi-lobed: anterior (adenohypophysis) and posterior (neurohypophysis).

Anatomoy & Physiology : 

Anatomoy & Physiology Hypothalamus controls the anterior pituitary Releasing hormones Hypophyseal portal system Causes release of trophic hormones: TSH, ACTH, LH, FSH, Prolactin (LTH) and Growth hormone (GH) = indirect acting hormones

Anatomoy & Physiology : 

Anatomoy & Physiology Hypothalamus PRODUCES vasopressin and oxytocin Travel down the nerve fibers to the posterior pituitary STORED IN THE POST. PIT. = direct acting hormones

Anatomoy & Physiology : 

Anatomoy & Physiology CONTROL: Feedback mechanism: Plasma levels of a hormone affect its secretion by affecting the gland that produces the hormone. Negative or Positive NEGATIVE feedback: High plasma levels POSITIVE feedback: Low plasma levels

Anatomoy & Physiology : 

Anatomoy & Physiology Neurohormonal Reflex Release of oxytocin from the P.P. Stimulation of the udder by a nursing calf Stimulation of the uterus and vagina in parturition Stimulation of the cerebral cortex by sensory stimuli associated with nursing of the calf

Anatomoy & Physiology : 

Anatomoy & Physiology Reproductive control (estrus) Proestrus, estrus, diestrus and anestrus Or… Follicular (Estrogen) and luteal (Progesterone) phases Hormones produced by the follicle vs the corpus luteum on the ovaries Hypothalamus: GnRH which acts on the A.P. A.P. releases FSH and LH

Anatomoy & Physiology : 

Anatomoy & Physiology FSH causes growth and maturation of the follicle which produces estrogen and inhibin (negative feedback to the hypothalamus) (Follicular phase) LH causes ovulation and CL formation(Luteal phase) CL produces progesterone which supports pregnancy Progesterone acts as negative feedback on the hypothalamus and GnRH release

Anatomoy & Physiology : 

Anatomoy & Physiology Prostaglandin secreted by uterus Lysis of the CL End of diestrus if not pregnant

Anatomoy & Physiology : 

Anatomoy & Physiology Parturition: hormones are also produced by the baby! ACTH Increased cortisol from the adrenal glands causes increased estrogen and prostaglandin release from the uterus. This allows the uterus to be primed to respond to oxytocin and contractions begin. Have to have a viable baby for this to occur correctly – if not…dystocia often results.

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Common in large animal practice Synchronize estrus Suppress estrus Induce estrus Treatment of cystic ovaries Termination of pregnancy

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Gonadotropins and Gonadal Hormones: Gonadotropins Estrogens Androgens Progestins Prostaglandins Dinoprost tromethamine Fenprostalene Fluprostanol Cloprostanol

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Drugs affecting Uterine contractility Oxytocin Ergot Prostaglandins Corticosteroids Pheromones Misc… Bromocriptine, leuprolide, melatonin, neutersol

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Gonadotropins Act like GnRH, LH and FSH Cause RELEASE of LH and FSH or cause activity like that of LH or FSH. LH: From pituitary extracts, pregnant woman urine (hCG) FSH: pituitary extracts, PMS between days 40 and 140 of pregnancy GnRH: synthetic

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Gonadotropins Examples: gonadorelin (GnRH) to treat cystic ovaries in cattle, chorionic gonadotropin (hCG), mimics LH in females, and in males, stimulates production of male hormones by the testicles. Used to treat nymphomania and cryporchidism FSH-P: pituitary extract of FSH, follicle stimulation, superovulation

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Estrogens: Synthesized by ovaries, testes, adrenal cortex, and placenta, or synthetic in origin Growth and development of female gonads and female characteristics Inhibit ovulation, increase uterine tone, proliferation of endometrium Uses: persistent CL, expulsion of retained fetal membranes, weight gain, urinary incontinence, induction of estrus during non-breeding season

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Estrogens: Examples: ECP, DES, implants Side effects/toxicity: Severe anemia, prolonged estrus, follicular cysts, cervical cancer and developmental anomalies in female offspring of women who take DES while pregnant (BANNED in food animals). Should not be given during pregnancy.

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Androgens: Male sex hormones produced in the ovaries, testicles, adrenal cortex. Growth and development of male gonads, characteristics and libido. Also promote tissue anabolism, weight gain, RBC formation Examples: Testosterone: C-III controlled substances Milberone: prevent estrus by blocking release of LH, no ovulation, weight gain

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Progestins Similar to progesterone Produced by CL Increased secretions by the endometrium, decreased contractility of uterus, increased development of mammary tissue Inhibit release of gonadotropins from the pituitary. Also have anti-insulin action, and suppress the adrenal gland.

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Progestins Uses: treat false-pregnancy, behavioral disorders, progestin-responsive dermatitis Examples: Megesterol acetate: synthetic progestin labeled for use in dogs. Its side effects include: hyperglycemia, adrenal suppression, endometrial hyperplasia, increased appetite. Medroxyprogesterone acetate (MPA): human drug Altrenogest (Regu-mate): for mares to suppress estrus and maintain pregnancy. SHOULD NOT BE HANDLED BY WOMEN

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Progestins Examples cont… Norgestromet: synthetic progestin implant in combination with estrogen for estrus synchronization in beef cows and NON LACTATING dairy cows.

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice PROSTAGLANDINS: Naturally occurring, LCFA Used for regulation of activity and treatment of the female reproductive tract. Six classes: A, B, C, D, E & F – ONLY PGF2α is used. Lysis of CL, contraction of uterine muscles, relaxation of the cervix; uses: estrus synchronization, expulsion of pyometra/fetal tissues, abortion of feedlot cattle, induction of parturition

Hormones of reproduction used in practice : 

Hormones of reproduction used in practice Prostaglandins Examples: Dinoprost: labeled for cattle, horses and swine Fenprostalene: synthetic analog for use in cattle Fluprostenol: synthetic analog for use in mares Cloprostenol sodium: synthetic analog for use in cattle Side effects: Sweating in horses, colic, urination/defacation, dyspnea and panting, tachycardia, most effects are self-limiting. Can cause bronchoconstriction, increased blood pressure, and smooth muscle contraction in humans – PREGNANT WOMEN and ASTHMATICS SHOULD AVOID HANDLING THESE DRUGS!!!

Drugs affecting uterine contractility : 

Drugs affecting uterine contractility Induce abortion Induce labor Aid in delivery Involution of uterus CERVIX MUST BE DILATED BEFORE THE USE OF THESE DRUGS!!!

Drugs affecting uterine contractility : 

Drugs affecting uterine contractility Oxytocin Made in the __________________ and stored in the _________________________. Causes strong uterine myofibril contractions Uterus must be primed by progesterone and estrogen to respond to oxytocin Also affects milk letdown through stimulation of myoepithelial cells of the alveolar wall of the mammary glands

Drugs affecting uterine contractility : 

Drugs affecting uterine contractility Ergot: Fungus in rye grass Causes smooth muscle contraction Large enough doses from pastures can cause abortions in cattle Prostaglandins Also stimulate uterine smooth muscle

Drugs affecting uterine contractility : 

Drugs affecting uterine contractility Corticosteroids Can cause induction of labor in the last trimester of some species – cattle…mimics natural rise in the production of corticosteroids by the fetus as the time for delivery draws near Affects surfactant production in the fetus

Pheromones : 

Pheromones Odors released by animals that influence the behavior of other animals of the SAME species Used by Pet Spas, etc…to help make animals feel more comfortable…? Not FDA approved because…HOW DO YOU TEST THEM? Individual responses vary widely.

Misc…Reproductive Drugs : 

Misc…Reproductive Drugs Bromocriptine: dopamine agonist and prolactin inhibitor used for mismating in dogs and treatment of pseudopregnancy Leuprolide: synthetic analog of GnRH for treatment of adrenal disease in ferrets and inappropriate egg-laying in cockatiels Melatonin: Used for alopecia and sleep disorders in dogs and cats, and to improve early breeding and ovulation in sheep and goats Neuterosol: FDA APPROVED!!!  amino acid and zinc salt that can cause sterility when injected into the testicles of a puppy.

Thyroid Hormones : 

Thyroid Hormones Thyroid gland: Bi-lobed near the trachea anywhere from the larynx to the thorax – usually near the larynx. Follicles that when stimulated by the hypothalamus produce two active products: T3 and T4 Has to trap iodide, oxidize it to iodine, and combine with Tyrosine to form T3 and T4 T3 is considered the active form T4 is Thyroxine, converted to T3 once released.

Thyroid Hormones : 

Thyroid Hormones Control Metabolic Growth Body temperature Heart rate Metabolism of nutrients Skin condition Immunity …? Hyper Hypo Diagnosis: measure serum T3 and T4 before and after TSH administration Goiter

Thyroid Hormones : 

Thyroid Hormones

Thyroid Hormones : 

Thyroid Hormones Hypothyroidism drugs: Thyroid hormone supplementation Levothyroxine Sodium (T4) (Soloxine) Liothyronine sodium (T3) (Cytobin) TSH (Dermathycin)

Thyroid Hormones : 

Thyroid Hormones Hyperthyroidism drugs: Goal of treatment: decreased circulating thyroid hormone levels (T3 and T4). Destroy or remove surgically the thyroid gland Block production Methimazole Carbimazole Ipodate Propylthiouracil Radioactive Iodine (I-131)

Thyroid Hormones : 

Thyroid Hormones Hyperthyroidism drugs: Methimazole: interferes with incorporation of iodine into the precursor molecules of T3 and T4 Doesn’t alter thyroid hormones released into the bloodstream Tapazole Side effects: anorexia, vomiting, skin eruptions Passed in milk from queen to kittens

Thyroid Hormones : 

Thyroid Hormones Hyperthyroidism drugs: Carbimazole Canadian methimazole Ipodate: Organic iodine compound which inhibits the conversion of T4 to T3 For use in cats that don’t tolerate methimazole Propylthiouracil Antithyroid drug, dangerous in cats – potential hematological complications Radioactive Iodine (I-131)

Scintigraphy of I-131 treated cat with hyperactive thyroid : 

Scintigraphy of I-131 treated cat with hyperactive thyroid

Drugs for D. M. : 

Drugs for D. M. Insulin Source: Pancreas Cells: islets of Langerhans or Beta cells Always produced with GLUCAGON (alpha cells) Action: decreases blood glucose levels by what mechanism? Also inhibits breakdown of fat, protein and glycogen into forms that can be used as energy Promotes synthesis of protein, fatty acids, and glycogen.

Drugs for D. M. : 

Drugs for D. M. Diabetes Mellitus Complex disease: inability of the beta cells to produce enough insulin, OR from altered insulin action on cells (altered or faulty insulin receptors). Inadequate secretion of insulin = TYPE I or insulin dependent Resistance of tissue to the effects of insulin = TYPE II or noninsulin-dependent Diabetes Mellitus (NIDDM) Both forms cause PU/PD, Polyphagia, and weight loss. Untreated progresses to Diabetic Ketoacidosis, metabolic acidosis and death

Drugs for D. M. : 

Drugs for D. M. Insulin Sources: beef or pork pancreas and purified preparations or a combination of beef and pork product. Pork insulin has closest structure to dogs and humans, Beef is closest in structure to cats. Most human products are recombinant DNA or synthetic in origin. Concentration measured in UNITS of Insulin /mL Human products are U-100

Drugs for D. M. : 

Drugs for D. M. Insulin administration: Use U-40 syringes with U-40 insulin and U-100 syringes with U-100 insulin…there are few U-40 insulin syringes, so if using U-40 insulin, PAY ATTENTION TO THE SYRINGE YOU ARE USING! ALWAYS STOP AND DOUBLE CHECK! AN INSULIN OVERDOSE MAY BE FATAL

Drugs for D. M. : 

Drugs for D. M. Handling insulin: DO NOT FREEZE, or heat Always check for precipitates and discoloration before giving Resuspend by GENTLY ROLLING the vial between the palms of your hands Always resuspend BEFORE drawing your dose Feed animal 30 minutes before giving insulin Rotate injection sites – have owners practice in office using saline.

Drugs for D. M. : 

Drugs for D. M. Insulin classifications: Duration of action: short acting, intermediate, and long acting. Short: regular crystalline, Semilente Intermediate: NPH and Lente Long-acting: PZI and Ultralente Combination products available Be familiar with the onset of effect and route of administration of different insulin preparations

Drugs for D. M. : 

Drugs for D. M. Short-acting Insulin: regular crystalline or semilente Made from zinc insulin crystals Clear solution – can be given IV, IM or SQ Used to treat diabetic ketoacidosis (DKA) until blood glucose levels are reduced and animal is stable. Then switch to long-acting formulation.

Drugs for D. M. : 

Drugs for D. M. Intermediate-Acting Insulin: NPH (isophane)/lente Cloudy suspension of zinc insulin crystals and protamine zinc. Used for control of uncomplicated DM in dogs and cats. Lente doesn’t contain protamine Protamine is a protein derived from salmon testes that helps slow down the onset and extend the duration of action of NPH insulin. Once daily administration common.

Drugs for D. M. : 

Drugs for D. M. Long-Acting Insulin Protamine Zinc Insulin (PZI), ultralente, and glargine. Poor solubility and absorption from tissues = slow absorption and maintains blood levels for long time. Ultralente does not contain protamine Treatment of uncomplicated DM PZI is insulin of choice for cats…

Drugs for D. M. : 

Drugs for D. M. YOUR ROLE! You will often be put in charge of teaching clients how to give insulin injections, answering questions, and taking histories in which it is important to discern whether the owner is giving the right amount, the correct way, to the right animal! Counsel owners about diet and exercise of the Diabetic patient What to look for that indicates their pet is getting too much or too little insulin.

Drugs for D. M. : 

Drugs for D. M. Type II diabetes can be treated with oral hypoglycemic agents in HUMANS…no veterinary approved products. Cats may respond to these products Includes glipizide and metformin

Drugs that cause Hyperglycemia : 

Drugs that cause Hyperglycemia Corticosteroids Epinephrine Progesterone Diazoxide (Proglycem) Octreotide (Sandostatin) Treat hypoglycemia associated with insulinomas in dogs and ferrets

Growth Promotants : 

Growth Promotants Sex steroids, synthetic steroid analogs and Nonsteroidal analogs Strive to increase weight gain per pound of feed fed. Primarily estrogen (estradiol) Promotes water retention, increases protein synthesis, increases fat deposition, and increases release of endogenous growth hormone (Bovine somatotropin)

Growth Promotants : 

Growth Promotants Testosterone: Used in combination with estrogen for anabolic effects Progesterone can also be added: Slows the release of estradiol. Trenbolone: Synthetic anabolic agent Improves feed efficiency, weight gain in steers Zeranol: Analog of plant estrogen used to increase weight gain and feed efficiency

Growth Promotants : 

Growth Promotants Examples: Synovex C, H and S Compudose Implus-H and S Ralgro for calves and lambs Etc… Designed to last for a couple of months Residue????

Growth Promotants : 

Growth Promotants Growth Hormone: Bovine Somatotropin (BST) and Bovine Growth Hormone (BGH) Produced NORMALLY in the anterior pituitary gland Stimulates growth of the animal before puberty, and after puberty, stimulates anabolic activity. BST is a stimulator of milk production – as much as 20% boost in milk production What does this do to the feed bill???

Growth Promotants : 

Growth Promotants Recombinant BST (Posilac) is approved for use in Dairy cows to improve feed efficiency, decrease incidence of metabolic disease and increase milk production.

Anabolic Steroids : 

Anabolic Steroids Cause tissue building (anabolism) Testosterone, and many synthetic A.S. Causes positive nitrogen balance and reverses the breakdown of tissue. Increased appetite, weight gain, improved overall condition. Labeled for use in non-food animals for anorexia, weight loss, and debilitation. C-III controlled substances

Anabolic Steroids : 

Anabolic Steroids Examples: Stanozolol or Winstrol-V Do not use in pregnant animals, mares or stallions. BANNED IN FOOD ANIMALS Boldenone Undecylenate Horses – anabolic activity, little androgenic activity Equipose Caution: CAN CAUSE AGGRESSIVENESS

Next Week : 

Next Week Don’t forget the practice exam on Black board It will be available until Tuesday November 7th at 5 pm. Read Chapter 10 – Otic and Ophthalmic Drugs HAVE A GREAT WEEKEND! 