Gynaecology Lecture 1 PDF

Female physiology & reproductive hormones (https://youtu.be/0h_fJRvoC-g) Female physiology (A) Regulation of reproduction The hypothalamus is the neural control center for reproductive hormones. Reproduction is controlled by : 2- The endocrine 1- The nervous system system A-Neural (nervous) regulation It translate or transduce external stimuli into neural signal which cause a change in reproductive organs, tissue Through 2-Neuro-endocrine reﬂex 1-Simple neural reﬂex (neurohumeral reﬂex) Require neuro-hormone Release their neuro- (substance released by transmitters (messengers) neuro-secretory cells) directly onto target tissues enter blood , act on target as ejaculation (glans penis) tissue Temperature sensitive as suckling reﬂex or ovulatory neurons located in the reﬂex in induced ovulation scrotum Neurotransmitters Hormones Released by nerve cells Released by endocrine glands Travel across the Travel through blood to synapse to act on act on distant target nearby cells cells Its effect is faster to act Its effect is slower to but shorter lasting build but longer lasting It is a part of nervous It is a part of endocrine system system Hormones: Chemical signal secreted into body ﬂuid (usually blood)communicates regulatory messages within body Forms of chemical signaling The main difference between the different categories of signaling is the distance that the signal travels through the organism to reach the target cell 1-Endocrine action Hormones travel the large distances between endocrine cells and their target cells via the bloodstream, 2-Paracrine action Hormone act locally by diffusing from its source to target cells in neighborhood 3-Autocrine action Hormone act on the same cell that produced it, This means the signaling cell and the target cell can be the same or a similar cell (a cell signals to itself), releasing a ligand that binds to receptors on its own surface. 4-Direct Signaling Across Gap Junctions (contact dependent signaling)(cell-cell contact) Gap junctions in animals, are connections between the plasma membranes of neighboring cells These water-ﬁlled channels allow small signaling molecules, called intracellular mediators, to diffuse between the two cells Signaling distances. Cell communication can be classiﬁed according to the distance between the signaling and responding cells One unique example of paracrine signaling is synaptic signaling, in which nerve cells transmit signals. This process is named for the synapse, the junction between two nerve cells where signal transmission occurs. -Neurocrine action (synaptic signaling) The neurotransmitters diffuse across the very small distances between nerve cells (synapses) allows the signaling cells (neurons) to release the chemical ligands, called neurotransmitters, a long distance from the cell body. chemical messenger is transferred to target cell via a synapse or neuromuscular junction N.B Neurotransmitter is a substance of small molecular weight that is released from the terminals of nerves that causes other nerves to ﬁre or causes contraction of smooth muscle that surrounds portions of the reproductive tract Hormones can be detected in blood, saliva, milk, urine, lymph, tears, and feces using radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) technology. 6-Solinocrine communication: these are hormones secreted directly into the lumen of the reproductive tract e.g., somatostatin and serotonin Somatostatin (growth hormone inhibiting hormone) present in the islets of Langerhans within the pancreas. Somatostatin is involved in the exocrine, endocrine, and CNS systems. Pheromones Pheromones are substances secreted to the outside of the body. They are generally volatile and are detected by the olfactory system (and perhaps the vomeronasal organ) by members of the same species. Mode of hormonal actions: Alternate target tissue metabolism Stimulate or depress secretory or synthetic activities of target organs Don`t direct change gene structure, but it activate or inhibit gene expression Reproductive hormones classiﬁed according to: Origin – Hypothalamus – Pituitary – Gonads – Uterus – Placenta Mode of action – Release of other hormones (releasing hormones) – Stimulate gonads (gonadotropins) – Sexual promotion (steroids) – Pregnancy maintenance – Luteolysis -Neuro-hormones Biochemical classiﬁcation – Peptides – Glycoproteins – Steroids – Prostaglandins A-According to glandular origin: 1-Hypothalamic hormones As GnRH, dopamine, CRH, growth H. release H 2-Pituitary hormones As FSH, LH, prolactin, ACTH, Oxytocin 3-Gonadal hormones -Ovary (E2,inhibin (GF)/ oxytocin, P4, relaxin(CL) -Testis (androgen, inhibin, estrogen) 4-Uterin & placental hormones (PG, eCG, hCG, P4) - Uterine hormone is prostaglandin F2 alpha (PGF2a). -Placental hormones include progesterone, estrogens, relaxin, equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG). The pituitary, a gland located in a bony depression (the Sella turcica) at the base of the brain The anterior lobe or anterior pituitary (also called adenohypophysis) The posterior lobe or posterior pituitary (also called neurohypophysis) 5-Pineal gland Melatonine 6-Liver Insulin like growth factors (IGF I,II) 7-Adrenal gland Mineralocorticoids, glucocorticoid, androgens, catecholamines, peptides B-According to mode of action: 1-Neuro-hormones as oxytocin An example is oxytocin that is synthesized by hypothalamic neurons, stored and released by the posterior lobe of the pituitary. 2-Releasing hormones as GnRH An example is gonadotropin releasing hormone (GnRH) that controls the release of FSH and LH from the anterior lobe of the pituitary. 3-Gonadotropins as FSH, LH hormones synthesized and secreted by specialized cells in the anterior lobe of the pituitary gland 4-Sexual promoters (steroids) are secreted by the gonads, to regulate the function of the hypothalamus and the anterior lobe of the pituitary as E, P, testosterone 5-Pregnancy maintenance hormones as P4, Placental lactogen 6-Luteolytic hormones as PGF2α 7- Metabolic hormone as thyroxin, growth H , adrenal corticoids Such hormones are thyroxin from the thyroid gland, the adrenal corticoids from the adrenal cortex and growth hormone (somatotropin) from the anterior lobe of the pituitary. C-According to biochemical structure Glycoproteins Polypeptide +carbohydrate (FSH,LH,inhibin) Bound to membrane receptors Steroids Contain cholesterol nucleus As E, P, T Bound to nuclear receptors Prostaglandins lipids consisting PGF2α 20 C unsaturated fatty acids Peptides small molecules with only a few amino GnRH, prolactin, acids joined by peptide bonds. oxytocin The quantity of carbohydrate on the surface of the protein is thought to determine the duration of the hormone's half-life of Glycoprotein hormones Glycoprotein hormones can be degraded easily by proteolytic enzymes in the digestive tract. Therefore, they are not effective when given orally. Protein hormones act via plasma membrane receptors / exert effects in the cytoplasm of the target cell, cannot given orally Steroid hormones act through nuclear receptors that regulate transcription factors that cause gene expression, can give orally Mechanism of action of protein hormone 1-Hormone diffuse from blood, bind to membrane receptor speciﬁc to hormone 2-HR Complex activate G-protein that activate membrane bound enzyme (adenylate cyclase) 3-ATP ad.cyc cAMP 4- cAMP cause activation of control enzymes in cytoplasm (pt. kinase), it activate these pts. allowing them to alter cell activity(cell function) Steps of Action for Protein Hormones Step 1 - Hormone-Receptor Binding Step 2 -Adenylate Cyclase Activation Step 3- Protein Kinase Activation Step 4 - Synthesis of New Products. For example, the gonadotropins (FSH and LH) bind to follicular cells in the ovary that results in the synthesis of a new product, estradiol. Mechanism of action of steroid hormone 1-Steroid H. are character by slow response 2-They travel from blood into plasma m.m of target cell (hormone receptor present in cytoplasm) 2-Move as hormone-receptor complex into nucleus (bind to nuclear receptors) 3-Hormone receptor complex activated by bind to speciﬁc region of DNA (this called hormone response element) 4-This binding effect has direct effect on level of transcription. Messenger RNA (mRNA) is produced, newly formed mRNA messenger leave nucleus ribosome to stimulate synthesis of speciﬁc protein. Steps of Action for Steroid Hormones: Nuclear Receptors ("Slow Response") Step 1 - Steroid Transport Steroids bind to a variety of plasma proteins in a nonspeciﬁc manner although some steroids have speciﬁc carrier proteins Step 2 - Movement Through the Cell Membrane and Cytoplasm. After the steroid molecule enters the cell, it diffuses through the cytoplasm and into the nucleus. Step 3 - Binding of Steroid to Nuclear Receptor. The steroid-receptor complex is referred to as a transcription factor and initiates DNA-directed messenger RNA synthesis (transcription). Step 4 - mRNA Synthesis and Protein Synthesis. The newly synthesized mRNA leaves the nucleus and attaches to ribosomes where it directs the synthesis of speciﬁc proteins Reproductive hormones characterized by: 1-They act in minute quantities Nano-gram (10⁻⁹) or pico-grams ( 10 ⁻¹²) per ml of blood 2-They have relatively short half lives Hormonal half-life is deﬁned as the time required for one-half of a hormone to disappear from the blood or from the body (the time it takes for the hormone to lose half of its physiological activity). 3-They bind to speciﬁc receptors to initiate a series of intracellular biochemical reactions 4-They regulate intracellular biochemical reactions Binding of the hormone with its speciﬁc receptor initiates a series of intracellular biochemical reactions. For example, estradiol (secreted by the ovary), causes the cells of the cervix to secrete mucus 5-They have feedback regulation when progesterone is high, GnRH neurons secrete only basal levels of GnRH. E GnRH (surge) LH surge (Ovulation) P4 GnRH FSH & LH=Incomplete follicular development Physiological activity of hormone depends on several factors: 1-Pattern, duration of hormone secretion -hormones under control nervous activity (have short duration of action) as oxytocin -hormones not directly linked to nervous activity (have long duration) as steroids H. 2-Half-life of hormone Longer half-life (eCG), more potent biological activity, very short half life (PGF2α)(secs) 3-Receptors density It depend on cell type, indirectly depend on animal condition or nutritional state 4-Receptor-hormone aﬃnity -The higher the degree to which a cell is populated with receptors, the higher potential for target cell responses. -Agonist (it analogue to hormone, it has same biological activity) (having a similar molecular structure) - Antagonist (it interfere in hormone action, it weak biological activity of native H)(have greater aﬃnity for the hormone receptor, but promote weaker biologic activity than the native hormone, Hormones disappear from the body because they are metabolized and then eliminated in the urine and feces. Pattern of hormones 1- Episodic (Fast) pattern which generally is associated with hormones under nervous control. When nerves in hypothalmus (ﬁre), neuro-peptides are released in sudden burst (episode), as pitutary Hs that release pulses, Pulsatile secretion is required for an animal to have a normal estrous cycle 2- Basal (tonic) (Background) pattern The hormone stays low, but ﬂuctuates with low amplitude pulses (GnRH secretion from tonic center of hypothalamus) 3- Sustained (Consistent) pattern Hormone remains elevated, but in a relatively steady, stable fashion for a long period of time (days to weeks). High progesterone during diestrus or pregnancy is an example 4-Circadian pattern/rhythm it is a pattern of hormone secretion which is normally set by the light–dark cycle e.g., melatonin. A-Peptide &protein hormones 1-Oxytocin (OXT) - a peptide of 9 amino acids(octapeptide)(neuropeptide), this may cause hypersensitivity for animals -secrete from post pituitary, ovary granulosa cell or CL luteal cell, testes leydig cell, cortex, medulla of adrenal gland in species other than horses The hypothalamus also produces oxytocin, this hormone is stored and secreted in the posterior lobe of the pituitary- -storage site is post.pit. Following IM oxytocin administration, the uterus responds within 3-5 minutes - Biological activities: (uterotonic hormone) 1-milk let down & ejection 2-contraction of myometrium 3-increase during parturition, induction of foaling 4-transportation of sperm, oocytes in tubular genetalia Oxytocin main actions Uterine contraction enhancement Milk letdown (neurohumeral control) Induction of maternal behavior Oxytocin is released in waves from hypothalmus Pressure on cervix , activate Receptors in uterus respond, sensory nerves uterine contraction -Act only on uterus pre-sensitized with estrogen -Uses: 1-Induce parturition in mare 2-Enhance uterine clearance in mare 3-Treat retention of placenta in mare 4-Help in milk let down in cow (agalactia) 5-Uterine inertia, weak birth pain 6-Uterine involution 7-Postoperative contraction of the uterus following a cesarean section and control of uterine hemorrhage N.B. Pharmacokinetics of oxytocin hormone - Oxytocin must be administered parenterally. - After IV administration, uterine response occurs almost immediately. - Following IM administration, the uterus responds generally within 3-5 minutes. The duration of action: Response in dog (i.v =13 min) – S/C or I.M (20 min) goat (22 min) Half life of oxytocin H in mare (6-9 min) so prefer give in multiple treatment It increases in the cyclic mares during late diestrus just prior to luteolysis N.B. Contra-indications of oxytocin use 1- Known hypersensitivity to oxytocin. 2- Dystocia due to abnormal presentation of fetus unless correction is made Commercial name Doses (1 ml/20 IU) For obstetrical use: U.S.P. Units ml Horses and Cows 100 (5 mL) Sows and Ewes 30-50 (1 1/2 to 2 1/2 mL) Dog /acc. To wt. 5-20 (¼-1 ml) Cat 2-5 Rabbit or experimental 0.2-3 animals For milk letdown: U.S.P. Units Cows 10-20 (1/2 to 1 mL) Bitch 0.5-1 2-Thyrotropin-releasing hormones (TRH) - Tripeptide H - It synthesized by hypothalamus, regulate thyrotrophic h from pit. gl - TSH necessary for production of T3,T4 from thyroid gland - TSH stimulate lactotropes from ant. Pituitary gland to release prolactin TRH TSH (ant.Pituitary) Thyroid Lactotropes from gland anter. pitutary T3,T4 Prolactin Uses -Treat agalactia -In diagnostic tests of thyroid gland disorders 3-Gonadotropin-releaseing hormone (GnRH) (Gonadoliberin) -It decapeptid H (10 a.a), hypothalmic H. -It stimulate, regulate gonadotropic hormones from gonads -It secreted from hypothalamus ant. Pituitary FSH, LH -If occur surge in level of GnRH peak in LH stimulate ovulation -If concentration of P or testosterone GnRH LH, FSH -Trade names: Receptal, Fertagyl, Gonadorelin, Factrel -Dose: 5 ml (cattle), 10 ml (mare) GnRH is character by short half life (2-4 min) Some substance affect on its level Norepinephrine ( GnRH) Dopamine,( GnRH) Estrogen also regulate secretion *In male surge center become inactivated during fetal life *In male, there are between 4-12 GnRH peak/day *Clinically GnRH analogs & agonist used: as deslorelin (synthetic analogue) 1-Initiate pit. gonadotrops that results in secretion of FSH, LH. However, on prolonged use they cause down regulation & inhibition of pit. gonadal axis Mares: To induce ovulation of a mature follicle 10 ml on the ﬁrst day on which the follicle has reached its maximum size (3-6 cm). -GnRH can be given approximately 6 hours prior to service to improve the pregnancy rate -GnRH antagonists Used for Pregnancy termination (by permanently decreasing P4 serum concentrations). Estrus suppression in pets as well as in contraception. As Detirelix, Cetrorelix, Ganorelix, acyline Uses:  Induced of ovulation in anestrous or transitional mares (between the anovulatory season and the ﬁrst ovulation of the year. This period is characterized by irregular estrus cycles and high incidence of regressing dominant follicles).  It hastens ovulation in mares exhibiting signs of estrus.  Treatment of ovarian inactivity in cattle and buffaloes.  Synchronization of estrus and ovulation in farm animals.  Indication of superovulation in ET & IVF techniques.  Treatment of cystic ovarian disease in dairy cattle  Reduce time interval from calving to ﬁrst ovulation  Improvement of post partum fertility(10-15 days post-calving) Commercial names: Natural Synthetic analogue analogue Cystorelin Receptal Ovuolant Gonazon Fertagil Buserelin Dose -Cattle natural (2 ml)& synthetic (2.5-5 ml) -Mare natural (2 ml) & synthetic (10 ml) -Rabbit 0.2 ml of synthetic analogue S/C at time of insemination or mating -In cattle (it used for treatment of follicular cyst, anestrum, delayed ovulation, improve pregnancy rate) -In mare (it induce ovulation of mature follicle to become mature enough for ovulation, improve pregnancy rate) N.B Neurons in the surge and tonic centers produce GnRH. Neurons in the paraventricular nucleus produce oxytocin Endocrine control is generally slower, but longer lasting than neural control These neuropeptides are called kisspeptins and are secreted by hypothalamic neurons in the periventricular, preoptic and arcuate nuclei. Kisspeptin is now recognized as an important regulator of sexual differentiation of the brain, the timing of puberty and adult regulation of gonadotropin secretion by gonadal steroids. Kisspeptins Kisspeptins are a family of neuropeptides secreted by hypothalamic neurons in the arcuate nucleus (Arc) and the anteroventral periventricular nucleus (AVPV) of the forebrain. Kisspeptins is a polypeptide/protein material composed of 398 amino acids that form seven transmembrane domains, like most G- protein coupled receptors. Kisspeptin is most notably expressed in the hypothalamus, but is also found in other areas of the brain including the hippocampus and in the adrenal cortex kisspeptin are mainly discovered in ovary and testis. GCs are the main cell which product Ovarian-derived kisspeptin, while Leydig cells are considered to product testicular kisspeptin. Kisspeptins are also found in other organs such as pancreas, liver, placenta, Gonads-derived kisspeptin might act directly in a autocrine- paracrine manner. kisspeptin is likely to act as an ampliﬁer of a series of GnRH secretion events, which are vital for normal puberty onset. Central and peripheral kisspeptins exert a role in various processes of female and male reproduction, maintaining the normal progress of follicular development, oocyte maturation, ovulation in female and spermatogenesis in male. 4-Corticotrophin-releasing hormone (CRH)& Adreno-cortico-tropic hormone (ACTH) CRH ACTH (Peptide H, 41 (35 a.a) a.a From paraventricular nucleus of From corticotropes of anterior hypothalamus & synthetized by pituitary gland which response for placenta which determine duration CRH stimulation of pregnancy Biological activity OF CORTRISOL: They necessary for normal fetal development Stressors They required for adequate surfactant production, myelin, retinal, pancreases, mammary Hypothalamus development before parturition time CRH Pit. gl Uses ACTH Adrenal gl-cortex- -ve 1-Induction of parturition fetus 2-Prepare placental dropping in pre-term Cortisol application (glucocorticoids) 3-Allergies, inﬂammation cases CRH (hypothalamus) stimulate ant.pitutary ACTH stimulate adrenal gland -Adrenal Aldosterone Cortisone Male, female sex hormones Cortex Regulate conc. Of -Complex effect Similar to those Na, K in blood by on glucose, pt., secreted by ovary, control amount fat metabolism testes that are secreted -it increase or reabsorbed in metabolism kidney tubules Use for treat arthritic, rheumatic condition Adrenal medulla adrenalin Dose & therapeutic uses 1-Dexamethasone (quick release synthetic corticosteroid) -for induction of abortion In cattle (25 mg parenteral with 25 mg PGF2α later on after 150 days of gestation. -for induction of parturition (20-30 mg) In mare For induction of parturition (100 mg/ every day/4 day) resulted in parturition 6-7 days after the start of treatment. 2-Betamethasone (short acting synthetic corticosteroid) In cattle For induction of abortion (35 mg) 5-Prolactin (lactotrophic H)(LTH) -It is polypeptide (199 a.a), secrete by lactotrops or mammotrops cell of ant. Pit. gland -It has several forms of different molecular size -Prolactin secretion is pulsatile, it with sleep, pregnancy, chest wall stimulation, trauma -Normal fasting value (less than 25-30 ng/ml) -Origin: Lactotropic cells of ant. Pit. gl. -Biological activities: -In dog, rodent used for maintain CL (luteotropic) -Pigeon response for maternal feeding, nest building, pick up of scattered young, feeding behavior (crop milk) TRH, oxytocin stimulate lactotrope cell in ant. Pituitary prolactin Milk gland Milk synthesis -In human, prolactin H in male, female (cause galactorrhea or amenorrhea), that cause lowering fertility -Pituitary adenoma (diagnosed by measure blood prolactin H., treat by dopamine agonist (anti-prolactin H.) The normal values for prolactin are: Men: less than 20 ng/mL (425 µg/L) Non-pregnant women: less than 25 ng/mL (25 µg/L) Pregnant women: 80 to 400 ng/mL (80 to 400 µg/L) The actions of prolactin on luteal function depend on the species and stage of the estrous cycle. In rodents, prolactin acts as a luteotrophic hormone by maintaining the structural and functional integrity of the corpus luteum for 6 days after mating however, in the absence of mating prolactin is luteolytic (Freeman et al., 2000). Prolactin is a part of a luteotrophic complex in the dog. Half-life of prolactin is approximately 20 mins. Seasonal effects of reproductive cyclicity in goats, buffaloes and mares are considered to be partly mediated by prolactin (Its secretion affected by photoperiod, season) The chemical structures prolactin is similar to the structure of growth hormone and placental lactogen hormone Other factors that stimulate prolactin production include thyrotropin-releasing hormone (TRH), estrogen (pregnancy), and dopamine antagonists (antipsychotics) Males have characteristically low levels of prolactin. Abnormal elevation in males is suggestive of a potential underlying pathological process like a pituitary adenoma Prolactin release has an inhibitory effect on the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus Prolactin promotes the growth of mammary alveoli Prolactin secretion in response to different reproductive stimuli, such as estrogen-induced release, mating, pregnancy and suckling is detailed, Prolactin secretion is increased by various stressful stimuli and by strenuous exercise Prolactin suppress LH surge, ovulation. Prolactin inhibit by dopamine It is required for the initiation and maintenance of lactation in most species and thus also called lactotrophic hormone (LTH). Prolactin is a part of hormone complex that regulate milk secretion and maternal behavior. -Antiprolactins (dopamine)(Hypothalamus) (PRL-IH) (Bromocryptine, Cabergoline, metergoline)  For estrus induction (Suppression of prolactin secretion via dopamine agonists shortens the duration of anestrus and induces the estrus)  Pregnancy termination (suppresses luteal Functions, inhibit P4 secretion)  Pseudo pregnancy, treatment of hyperprolactinemic disorders Cabergoline has a slow clearance, which allows for a single oral daily administration. Furthermore, its action is longer than 48 hours due to its particularly long (minimum 48 hours) half-life at the hypophyseal level. Their administration for 4-5 days at pharmacological doses is effective in treating pseudopregnancy signs and reducing milk production. Bromocryptine mesylate inhibits PRL secretion during relatively short periods of time (half-life: ± 4-6 hours), bromocryptine should be administered at least twice a day Cabergoline (GalastopTM, CEVA-VETEM, a veterinary compound) bromocriptine (ParlodelTM, Sandoz, a human compound) are dopamine agonists (they increase the concentration of dopamine, a PRL-inhibiting factor) metergoline (ContralacTM, Virbac, a veterinary compound) is a serotonin antagonist (it lowers the concentration of serotonin). Antiprolactinic Daily dosage in the N° treatments/day bitch/queen Cabergoline 5 μg/kg 1 Bromocriptine 10-30 μg/kg (*) 2 Metergoline 500 μg/kg (*) 2 6-Relaxin It is polypeptide It belongs to insulin family (Insulin & IGF 1,2) Placenta in mare Ovary (CL) in other animals in It is origin from both pregnant, non pregnant Granulosa cells of follicle Male (prostate gland) 1-decrease collagen content I (remodeling)n extracellular matrix of pubic symphasis &cervix ( Activities: metalloproteinase enz.) 2-inhibit uterine contraction 3-play role in mammary gland development Relaxin is not present in the bovine placenta during any stage of gestation In bitches, relaxin hormone, which is produced from placenta, is a useful marker for early pregnancy diagnosis (as early as Day-20 post LH surge In male: relaxin is produced from prostate gland and plays an important role in sperm motility and oocyte penetration. 7-Insulin-like growth factors (IGF) --It is polypeptide with high sequence similar to insulin H Biological activities: IGF-II (Modulation of fetal & placental growth) IGF-I (role in puberty) Stimulation of steroidogenesis via availability of steroid precursors & up regulation of steroidogenic enz. , expression & activity Selection of dominant follicles in mares The IGFs have a variety of effects on follicular and luteal cells, including stimulation of steroidogenesis, via increased availability of steroid precursors and up regulation of steroidogenic enzyme expression and activity. Follicular concentrations of IGF-1 increase in large equine follicles suggesting that intra-follicular IGF- may be involved in selection of dominant follicles in mares. In other species than equines, IGF- may play a role in puberty. IGF- is thought to be involved in normal fetal development B-Glycoprotein hormones (FSH, LH, Inhibin, Activin, TSH, eCG ) -FSH, LH, eCG (PMSG) -It present in vertebrate encoding in different gene -It consist from peptide part ( α, β subunits) &CHO (sugar)part 1-Follicle stimulating hormone (FSH)  Sugar part contains fructose , galactose, mannose  Sugar unit is response for interaction with FSH receptor  Oligosaccharide contain sialic acid that is critical for its biologic half- life of FSH, half life= 3-4 h.  Target tissues Sertoli cells (testes) Granulosa cells (ovary) Inhibin, androgen binding protein Estradiol synthesis Activity 1-Primary develop follicle for ovulation& LH effect and CL development 2-FSH facilitate granulosa cell development, E2 synthesis 3-Induction of aromatase enzyme activity promote follicular vascularity 4-Formation protease enz which weaken follicular wall prior to ovulation  Stimulate puberty in heifer  Super ovulation in dairy cow  Treat ovarian inactivity Biological sources:  Anterior pituitary extract (it is prepared from pituitary of sheep, horse, pig) {trade name=F.S.H.P diluent}  PMSG (eCG) Produced by pregnant mare during period from 40-120 day of gestation & only found in serum It is rich in FSH, low in LH Trade name (Pregnecol 6000- Folligon)  Human chorionic gonadotropin (hCG) or menopausal urine gonadotropin(MUG) -It is found in urine of post-menopausal women -Trade name (Epifasi 5000 iu, Pregnyl, Chorulon) -Dose: -Cattle, mare (3000-5000 IU) -Sheep, goat (500-800 IU) -Pig (1000 IU) -Dog (50-200 IU) 2-LH It is polypeptide, heterodimeric glycoprotein, known as lutropin It contain α, β subunits, β subunit responsible for interaction site with LH receptor It contain low or no sialic acid, produce by basophilic gonadotroph cell of anterior pit. Gl. LH surge around 6 h in cattle Activities 1-At the time of follicular maturation E2 via hypothalamic interaction (+ ve feed back) LH surge (ovulation, CL formation) 2-LH support theca cells in ovary that provide androgens, hormonal precursor for estradiol production 3-Final stage of follicle development, ovulation  Stimulate cell for histamine formation  Prepare endometrium for implantation  It stimulate granulosa cell PF2α  It stimulate theca cell E2  Stimulate ovarian parenchyma histamine  Ovulation CL -There is ratio between FSH & LH , is essential for initiation of ovulation and consequently length of estrus phase In mare, bitch In cow, buffalo (FSH is higher than LH) (LH is higher than FSH) (Long estrus) (Short estrus) (9 day) (12-18 h.) In males, LH is also known as Interstitial Cell Stimulating hormone (ICSH) and stimulates the production and secretion of testosterone from the testes via leydig cells. In females LH stimulates the production of oestrogens and progesterone from the ovary via theca interna cells and luteal cells. The biologic half-life of LH is 20 minutes, shorter than that of FSH (3–4 hours) and hCG (24 hours). FSH, eCG share a common receptor In male Hypothalamus LHRH ant. Pit. LH, FSH testes testosterone -LH is responsible for production of testosterone that exert both endocrine activity & intra testicular activity on spermatogenesis Uses: Induced ovulation Treat cystic ovaries Superovulation, embryo transfer Early embryonic loss due to low P4 production (it support P4 production) Delayed ovulation or an ovulation Prolonged estrus Improve libido in bull (stimulate testosterone production) -Biological sources: 1-Human chorionic gonadotropin (hCG) It is rich in LH, low in FSH Trade name: Pergonal / Follitropin-v Lutropin alfa 75 IU / Chorulon (eCG) Dose -Cattle , mare (3000-5000 iu, up to 10000 IU) -Sheep, goat (100-500 IU) -Dog (100-500 IU) -Cat (100-500 IU) 3-Inhibin It is glycoprotein It is a form of transforming growth factor family It contain from 2 subunit α, β Origin Luteal cell (in some animal as Granulosa cell (ovary) human, monkey, goat) Sertoli cell (testes) Biological activities: Female Male -ve feed back on FSH It slow-down spermatogenic process sensitivity of Inhibin is not in commercial a gonadotrophes GnRHR viable However, it used as biological biomarker for granulosa cell tumor In male, Inhibin inhibits FSH secretion, which together with decreased concentrations of LH and testosterone results in decreased spermatogenesis and therefore decreased sperm output and quality. In females inhibin inhibits FSH secretion. It does not have any effect on the secretion of LH but suppresses FSH secretion. 4-Activin It is a member of TGF family It consist of a dimers of 2 subunits β A + βA βB + βB Activin A is formed Activin B is formed -Source Placent Gonads Pituitary a female (granulosa cell) male (sertoli cell) -Activities:( FSH biosynthesis &secretion)  FSH binding & FSH induced aromatization in the follicle (in female)  It enhance spermatogenesis & participate in androgen synthesis, enhancing LH action in testes (male)  It regulate cellular proliferation, differentiation & promote neural survival The target tissue for activin in the male is the epididymis where it enhances spermatogenesis via increased FSH secretion. Activin also enhances the effect of LH on the testes. The increased concentrations of activin results in increased FSH binding on the female follicle and FSH-induced aromatization (increased synthesis of oestrogens). Activin also enhances the action of LH in the ovary Further non-reproductive role of activin is it's role in skin lesions where it is thought to stimulate keratinocytes. Part 2 of reproductive hormones Lecture for 4th class students Prepared by Dr/Al Shimaa Al Houssiney https://youtu.be/affVoMYTng0 3-Steroid H 1ry sex hormones, lipophilic compound, steroids bound to large carrier proteins (albumin, globulin) Basic structure 5 rings (A, B, C, D, E) 5 Group according to receptor that bind with Glucocorticoid (21 C) Mineralocorticoid (21 C) Progesterone (21 C) Androgens (19 C) Estrogen (18 C) Natural steroid H is synthetized from cholesterol in the gonad & adrenal gland These form enter cell m.m quite easily as they are lipophilic nature Steroid H carry in blood to special carrier protein such as sex H binding globulin or corticosteroid binding globulin , further conversion & catabolism occur in liver as well as peripheral tissue 1-Estrogens Groups of steroid compound 1ry female sex H, The steroid 17-beta estradiol is the most potent and prevalent endogenous estrogen. It consist of 3 fractions {estradiol (more potent), estrone, estriol} The word estrogen was derived from the Greek word “oistros” meaning sex desire and “gen” meaning producer *Sources: Ovary (granulosa cells & luteal cells) (2 cell- 2 gonadotropin model) Testes (sertoli cell) Adrenal gland (cortex cell) Activities: 1-Response for behavioral signs of estrus, 2 female sexual characters nd 2-Stimulate follicular growth, maturation, induce pre-ovulatory LH surge 3-Proliferation of duct system of mammary gland, prepare uterus for parturition 4-Induced uterine, fallopian tube contraction 5-Keratinization of vaginal epithelium (especially in rate, bitch, queen) 6-Relaxation of cervical ms & increase cervical mucus secretion 7-Constitute pre-ovulatory LH surge 8-With inhibin decrease FSH secretion 9-During early pregnancy (estradiol + P4) prepare endometrium for implantation Part 2 of reproductive hormones Lecture for 4th class students Prepared by Dr/Al Shimaa Al Houssiney https://youtu.be/affVoMYTng0 3-Steroid H 1ry sex hormones, lipophilic compound, steroids bound to large carrier proteins (albumin, globulin) Basic structure 5 rings (A, B, C, D, E) 5 Group according to receptor that bind with Glucocorticoid (21 C) Mineralocorticoid (21 C) Progesterone (21 C) Androgens (19 C) Estrogen (18 C) Natural steroid H is synthetized from cholesterol in the gonad & adrenal gland These form enter cell m.m quite easily as they are lipophilic nature Steroid H carry in blood to special carrier protein such as sex H binding globulin or corticosteroid binding globulin , further conversion & catabolism occur in liver as well as peripheral tissue 1-Estrogens Groups of steroid compound 1ry female sex H, The steroid 17-beta estradiol is the most potent and prevalent endogenous estrogen. It consist of 3 fractions {estradiol (more potent), estrone, estriol} The word estrogen was derived from the Greek word “oistros” meaning sex desire and “gen” meaning producer *Sources: Ovary (granulosa cells & luteal cells) (2 cell- 2 gonadotropin model) Testes (sertoli cell) Adrenal gland (cortex cell) Activities: 1-Response for behavioral signs of estrus, 2 female sexual characters nd 2-Stimulate follicular growth, maturation, induce pre-ovulatory LH surge 3-Proliferation of duct system of mammary gland, prepare uterus for parturition 4-Induced uterine, fallopian tube contraction 5-Keratinization of vaginal epithelium (especially in rate, bitch, queen) 6-Relaxation of cervical ms & increase cervical mucus secretion 7-Constitute pre-ovulatory LH surge 8-With inhibin decrease FSH secretion 9-During early pregnancy (estradiol + P4) prepare endometrium for implantation 10-Hasten labor or abortion with oxytocin, PGF2α (ecbolic effect) 11-Estrone sulphate is used for diagnosis of pregnancy, indicator of fetal viability Practical uses 1-Delayed puberty in heifer 2-Initiation of ovarian activity in anestrum 3-Silent heat Large animal (5-20 mg) Small animal (3-10 mg) 4-Synchronization of estrus in cattle, buffalo 5-Cervical opening In closed pyometra, f. mummiﬁcation, maceration, failure of complete cervical dilatation at parturition, Uterine bleeding 1 mL (25 mg) Commercial preparation -Oral Ethinyl estradiol -Transdermal preparation Estraderm TTS Human -Ointment Estrogel -Estradiol & Stibrol (vet.) -E2is luteolytic in ruminants Luteotropic in sow, mare Natural E2 Synthetic E2 17 β estradiol, estrone, Estradiol esters , Estradiol estriol, conjugated equine valerate, estradiol acetate, estrogens, estrone estradiol cypionate, sulphate, estradiol benzoate, equilin diethylstilboestrol (DES) Dose of estradiol cypionate in animals Indication Dose in mg Dose in ml Cow Anestrus, persistent CL 3-5 0.75-1.25 Pyometra, retained 10 2.5 placenta, mummiﬁed fetus Heifer Anestrum 3 0.75 Mare Anestrum 5-10 0.25-2.5 Ewe Anestrum 0.5-1 0.125-0.25 Conjugated equine estrogens such as Premarin are produced from the urine of pregnant mares and consist of natural estrogens equilin, equilenin and estrone sulfate. Part 2 of reproductive hormones Lecture for 4th class students Prepared by Dr/Al Shimaa Al Houssiney https://youtu.be/affVoMYTng0 3-Steroid H 1ry sex hormones, lipophilic compound, steroids bound to large carrier proteins (albumin, globulin) Basic structure 5 rings (A, B, C, D, E) 5 Group according to receptor that bind with Glucocorticoid (21 C) Mineralocorticoid (21 C) Progesterone (21 C) Androgens (19 C) Estrogen (18 C) Natural steroid H is synthetized from cholesterol in the gonad & adrenal gland These form enter cell m.m quite easily as they are lipophilic nature Steroid H carry in blood to special carrier protein such as sex H binding globulin or corticosteroid binding globulin , further conversion & catabolism occur in liver as well as peripheral tissue 1-Estrogens Groups of steroid compound 1ry female sex H, The steroid 17-beta estradiol is the most potent and prevalent endogenous estrogen. It consist of 3 fractions {estradiol (more potent), estrone, estriol} The word estrogen was derived from the Greek word “oistros” meaning sex desire and “gen” meaning producer *Sources: Ovary (granulosa cells & luteal cells) (2 cell- 2 gonadotropin model) Testes (sertoli cell) Adrenal gland (cortex cell) Activities: 1-Response for behavioral signs of estrus, 2 female sexual characters nd 2-Stimulate follicular growth, maturation, induce pre-ovulatory LH surge 3-Proliferation of duct system of mammary gland, prepare uterus for parturition 4-Induced uterine, fallopian tube contraction 5-Keratinization of vaginal epithelium (especially in rate, bitch, queen) 6-Relaxation of cervical ms & increase cervical mucus secretion 7-Constitute pre-ovulatory LH surge 8-With inhibin decrease FSH secretion 9-During early pregnancy (estradiol + P4) prepare endometrium for implantation 10-Hasten labor or abortion with oxytocin, PGF2α (ecbolic effect) 11-Estrone sulphate is used for diagnosis of pregnancy, indicator of fetal viability Practical uses 1-Delayed puberty in heifer 2-Initiation of ovarian activity in anestrum 3-Silent heat Large animal (5-20 mg) Small animal (3-10 mg) 4-Synchronization of estrus in cattle, buffalo 5-Cervical opening In closed pyometra, f. mummiﬁcation, maceration, failure of complete cervical dilatation at parturition, Uterine bleeding 1 mL (25 mg) Commercial preparation -Oral Ethinyl estradiol -Transdermal preparation Estraderm TTS Human -Ointment Estrogel -Estradiol & Stibrol (vet.) -E2is luteolytic in ruminants Luteotropic in sow, mare Natural E2 Synthetic E2 17 β estradiol, estrone, Estradiol esters , Estradiol estriol, conjugated equine valerate, estradiol acetate, estrogens, estrone estradiol cypionate, sulphate, estradiol benzoate, equilin diethylstilboestrol (DES) Dose of estradiol cypionate in animals Indication Dose in mg Dose in ml Cow Anestrus, persistent CL 3-5 0.75-1.25 Pyometra, retained 10 2.5 placenta, mummiﬁed fetus Heifer Anestrum 3 0.75 Mare Anestrum 5-10 0.25-2.5 Ewe Anestrum 0.5-1 0.125-0.25 Conjugated equine estrogens such as Premarin are produced from the urine of pregnant mares and consist of natural estrogens equilin, equilenin and estrone sulfate. Disadvantage & side effect: 1-Decrease milk yield, quality in milking animals 2-High doses is prohibited It produce relaxation of pelvic ligament, cause vaginal, rectal prolapse 3-Prolonged administration even at low doses Produce cystic ovary, nymphomania, mammary gland carcinoma, atrophy for ovary Antiestrogens (Estrogen receptor blockers) As Tamoxifen, Clomiphen Progesterone -It is steroid H (21 C), The physiologic half life of progesterone is short 22-36 min in the cow -It involved in female estrous cycle, pregnancy, embryogenesis of human & other species -P4 stored in adipose tissue Origin Ovary Adrenal gland Placenta CL High progesterone is also responsible for the so-called "progesterone block" that inhibits myometrial contractions. Progesterone increases in the blood of the pregnant female and peaks at different stages of gestation for different species In some species (ewe, mare and woman), the corpus luteum is not needed for the entire gestational period because the placenta takes over production of progesterone. For example, in the ewe the corpus luteum is responsible for initial production of progesterone, but the placenta assumes responsibility for its production after only 50 days of gestation. -In other species, (sow or rabbit), lutectomy (surgical removal of corpora lutea) will terminate pregnancy regardless of when this occurs during gestation. -Lutectomy in the cow up to 8 months of gestation will There is interaction between LH & luteal cells for P4 production LH surge during preovulatory intrafollicular proteolytic enz. time That cause weak for follicular wall Allow mature follicle to pass LH surge Luteinization of theca, granulosa Progesterone P4 cells, form CL LH act to mobilize cholesterol stored in the small to large luteal cells Activities: Proliferation of mammary gland alveoli Calm uterine contraction Assist in implantation, placenta formation Proliferation of uterine gland (uterine milk), These secretions include mucin, carbohydrates and speciﬁc proteins that are designed for nourishment of the embryo prior to implantation. It has anabolic effect (retention of salt, water) Form cervical plug, Progesterone also stimulates the remodelling of the endometrium and stabilizes smooth muscle cells to ensure that they do not contract during fetal development Play role in regulation of GnRH pulse frequency Response for maternal recognition of pregnancy This hormone has a central role in reproduction being involved in ovulation, implantation, pregnancy maintenance and lactation Progesterone prepares the uterus for reception of fertilized oocytes and is transported via the blood bound to plasma proteins Progesterone also prepares the mammary tissues for milk production as well as inhibits female reproductive behaviors during pregnancy Estrus suppression in dogs at dose 2 mg/kg/3-4 month Commercial preparation  Utrogestan (P4 oral tablet)  Depo-Provera(Medroxy progestrone acetate) (long acting inj.)(150 mg) human  Regu-Mate (Altrenogest) for equine, 0.22% oral progestin  Prontogest (P4 100 mg/ inj/ short acting/ human)  Luton 25 mg/ml-Geston ®  Most common is intravaginal device as (Synchromate B / CIDR)  Dose: Large animal (50 mg) Small animal (10-20 mg) Lutofolone injection contains Estradiol and Progesterone as active ingredients. Lutofolone injection works by inhibiting the ovulation; stimulates luteal actions, changes in uterus and vagina; Uses: Absence of a menstrual period Recurrent abortion Contraception Prevention of pregnancy Uterine bleeding Recurrent miscarriage Activities: Proliferation of mammary gland alveoli Calm uterine contraction Assist in implantation, placenta formation Proliferation of uterine gland (uterine milk), These secretions include mucin, carbohydrates and speciﬁc proteins that are designed for nourishment of the embryo prior to implantation. It has anabolic effect (retention of salt, water) Form cervical plug, Progesterone also stimulates the remodelling of the endometrium and stabilizes smooth muscle cells to ensure that they do not contract during fetal development Play role in regulation of GnRH pulse frequency Response for maternal recognition of pregnancy This hormone has a central role in reproduction being involved in ovulation, implantation, pregnancy maintenance and lactation Progesterone prepares the uterus for reception of fertilized oocytes and is transported via the blood bound to plasma proteins Progesterone also prepares the mammary tissues for milk production as well as inhibits female reproductive behaviors during pregnancy Estrus suppression in dogs at dose 2 mg/kg/3-4 month Commercial preparation  Utrogestan (P4 oral tablet)  Depo-Provera(Medroxy progestrone acetate) (long acting inj.)(150 mg) human  Regu-Mate (Altrenogest) for equine, 0.22% oral progestin  Prontogest (P4 100 mg/ inj/ short acting/ human)  Luton 25 mg/ml-Geston ®  Most common is intravaginal device as (Synchromate B / CIDR)  Dose: Large animal (50 mg) Small animal (10-20 mg) Lutofolone injection contains Estradiol and Progesterone as active ingredients. Lutofolone injection works by inhibiting the ovulation; stimulates luteal actions, changes in uterus and vagina; Uses: Absence of a menstrual period Recurrent abortion Contraception Prevention of pregnancy Uterine bleeding Recurrent miscarriage Uses  Habitual abortion in human  Synchronization of estrus  Vaginal prolapse by counteract estrogen effect  Prevent mare from coming into estrus during training or exhibition  Estrus suppression in the dog at the dose rate of 2 mg/kg every 3-4 months  Estrus suppression (100-200mg Single SC /IM injection; Promone E, Upjohn) in beef heifers for 120 days. N.B. In mares: The appropriate dose is 1 ml Regumate per 50 kg B.wt. (i.e.,0.044 mg altrenogest per kg) per day for. 15 consecutive days. In cows: Melengestrol acetate (MGA) is a steroidal progestogen used as a feed additive to synchronize estrus in heifers at a dosage of 0.5 mg/head/day for 14 days. -Anti p4 Mifepristone (used in pregnancy termination in bitch 2.5 mg/kg/4-5 d begin at day 32 d of pregnancy. -Aglepristone (twice/daily s/c 10 mg/kg) Antiandrogens Lower production Receptor blocker Other Abarelix Cyproterone acetate, Ketoconazole, Goserelin ﬂutamide Medroxyprogestron e acetate 4-Prostanoids (Eicosanoids) -It consist from polyunsaturated fatty acids (arachidonic acid) precursor -It produce by many cell types, produce within ut. Endometrium & vesicular gl. -There are several PG types (A, B, E, F) Activities PGE2 PGF2α Decrease myometrium activity -Increase myometrium It enhances progesterone activity secretion by the C.L. -Lutolytic action Ovulatory uterine corpus luteum follicles myometrium For maintenance of pregnancy prostaglandin secretion should be blocked There are two main factors involved in the regulation of uterine secretions of PGF2α oxytocin secretions from the corpus luteum Molecules secreted by the developing embryo that facilitate the maternal recognition of pregnancy PGs are effective in inducing estrus when administered between Day 5-15 of estrus cycle in cattle and buffaloes. In mares they are effective when administered after Day 5 of ovulation and in the presence of a follicle greater than3 cm in diameter Clinial uses Uterine evacuation, metritis, pyometra, mucometra, endometritis and retention of placenta Estrus synchronization, estrus induction and induction of parturition in cows, buffaloes, goats, dogs, camels and pigs. Natural analogs Synthetic analogs Cloprostenol , Dinoprost prostalene Trade Dose name Cattl Natural Lutylase 25-35 mg (5-7 ml) e PGF2α Synthetic Estrumate 500 μg (2 ml) PGF2α Synthetic Prosolvin 15 mg (2 ml) PGF2α Mare Lutalyse 1-2 ml Estrumate 0.5-1 ml Prosolvin 1 ml It used in small dose as it induce increasing in intestinal motility & fetal colic Shee 62.5-125 μg at 144 days of gestation deliveries will peak at 30 p, -35 h. after inj (to induce delivery of fetus) goat Melatonin Melatonin (N-acetyl-5-methoxytryptamine) is synthesized in the pineal gland which takes up the amino acid, tryptophan, from the circulation and converts it to serotonin. The photoperiod inﬂuences the secretion of melatonin via neuroendocrine. The secretion of melatonin presents circadian rhythm, it is reduced during daylight hours and rises during darkness. Synthesis/metabolism of melatonin Two steps in the metabolism of serotonin are under neural control. The ﬁrst is the conversion of serotonin to N acetylserotonin, which is followed by the conversion N acetylserotonin to melatonin. The second step involves the melatonin forming enzyme, hydroxy indole O methyltransferase (HIOMT). Biological activity of melatonin Synthesis and secretion of melatonin is greatly elevated during darkness. Long daily periods of elevated secretion of melatonin are probably responsible for the induction of ovarian cycles in ewes and the inhibition of cyclicity in mares. In contrary, in spring and summer, there is less melatonin secretion in mares, and the hypothalamus secretes gonadotropin-releasing hormone (GnRH) to induce gonadotropins secretion: (FSH, follicle- stimulating hormone, and LH, luteinizing hormone) in the anterior pituitary and stimulates the ovulatory function. Melatonin is secreted by the pineal gland in two phases: photophase (daytime) and scotophase (night time). It therefore demonstrates a circadian secretion, with the highest levels of secretion being evident during the scotophase. Clinical uses of melatonin Exogenous melatonin regulates ovine gonadal activity; continuous melatonin administration effectively induces breeding activity in acyclic ewes around midsummer. Melatonin treatment 36 hours after CIDR withdrawal increased the pregnancy rate and number of lambs. Melatonin implants increased the number of lambs born per ewe in a late-autumn mating season, and the effect was greatest if it was given in combination with PGF2α administration at ram introduction. Dose: 5 mg oral per ewe or a subcutaneous melatonin implant containing 18 mg melatonin, Melovine®) at the base of the left ear Other reproductive hormones Hormones Source Biological activities 1-Melatonin Pineal gland 1-Cue to breeding, mating in season 2-Regulating sleeping cycles 2-Testesteron Leydig cell Male sex H 3-PMSG (eCG) Mare endometrial Stimulate follicle development that cups 40-85 d of consequently ovulate & form accessory CL pregnant to maintain pregnancy(have quite long half -lives) 4-hCG Syncytiotrophoblas Maternal recognition of pregnancy t It has LH like action Cells of human placenta as soon as 8 days, reaching a maximum value at about 2.5 months 5-Follistatin Follicular ﬂuid of Inhibit pit. release of FSH graﬃan follicle Binding, neutralizing of activin 6-Bradykinin Follicular ﬂuid of -Relaxation of SMs ﬁber in fallopian tube G.F -Help in egg trapping by infundibulum Hormone Source Activity Placental lactogen placenta 1-Regulate maternal (somatomammotropi nutrient to fetus n) 2-Prepare milk in the ewe ovine letdown in pregnant (chorionic placental lactogen animal somatotropin) similar (oPL) has a more to growth h. potent lactogenic -similar to growth activity than hormone, thus somatotropic activity. promoting the growth A similar condition of the fetus. exists in humans, but not in the cow. Protein B placenta Maternal recognition of pregnancy

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