Endocrine & Reproductive System Module 2024-2025 PDF
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This document is an endocrine and reproductive system module, covering topics like feedback mechanisms in the endocrine system, types of feedback mechanisms, and hormone action. It includes information about hormones, their functions, classification, and mechanisms of action.
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ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Feedback mechanism in the control of endocrine system Typical feed-back loop consists of: Gland A liberates hormone A, which will stimulates (+) gland B which lib...
ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Feedback mechanism in the control of endocrine system Typical feed-back loop consists of: Gland A liberates hormone A, which will stimulates (+) gland B which liberates hormone B. Horm one B in turn regulates the liberation of hormone A: Either I- stimulate hormone A which will stimulate hormone B. This is called positive feedback loop. or II- Inhibit hormone A which will inhibit hormone B. This is called negative feedback loop. N.B.: The purpose of this feedback is to control the plasma level of hormone B. Types of feedback mechanisms: I-Extrinsic feedback: A-Negative feed back: 1-Long-loop feedback: a- direct: hormonal/ or chemical b-indirect: hormonal or chemical) 2-Short feedback 3- Ultrashort (auto-feedback) B-Positive feed back: ▪ Long loop: a-Direct b-Indirect c. Auto-feedback II-Intrinsic (Intracellular) feed-back: Negative feedback at the cellular level. I- Extrinsic Feedback: A- Negative Feedback: 1-Long loop: between the target gland & the anterior pituitary or hypothalamus Direct negative (hormonal) feedback: between the target gland & the anterior pituitary. Example: - Anterior pituitary release TSH (thyrotropin)→ stimulate thyroid gland to secrete thyroxine. -Increased thyroxine→ decreases TSH, while decreased thyroxine→ increases TSH. Indirect negative (long loop): between target gland & hypothalamus (hypothalamusindirectly involved in regulation of target hormonal gland). Example: Increased thyroxine→ decrease TRF (from the hypothalamus) → decrease TSH (from anterior pituitary) → decrease thyroxine. 1 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 2- Short-loop negative feedback: between anterior pituitary & hypothalamus Example: Anterior pituitary growth hormone (Somatotropin) inhibits the release of somatotropin releasing factor from hypothalamus and stimulate release of somatostatin (growth hormone inhibiting factor). 3- Auto- negative feedback: Hormone of the target gland on itself. Example: Excess growth hormone → inhibits its own secreting cell from the anterior pituitary. B-Positive Feedback: It occurs when the hormone can stimulate directly or indirectly its own production. This exists between the female sex hormones. Long loop: 1. Direct positive (hormonal) feedback: Increased secretion of estrogen from ovary→ increase secretion of gonadotropin (LH) from the anterior pituitary. 2. Indirect Positive feedback: The feedback takes place at the hypothalamic level, increase in estrogen from ovary→ increases the release of the gonadotrophin-releasing hormone from the hypothalamus→ increases the secretion of gonadotropin from the anterior pituitary (LH) → increases estrogen. Auto Positive (self regulating) Feedback: Estrogen produced by a developing ovarian follicle→ increases the growth of that follicle directly→ producing more estrogen hormone. NB: Any positive feedback is intrinsically unstable; as once the concentration of the hormonehas reached a critical level it can trigger off a negative feedback mechanism which will then oppose the further rise in the hormone concentration. 2 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 II-Intrinsic (Intracellular) feed-back: It is negative feedback at cellular level Examples: Wolff-Chaikoff Effect: Large quantities of iodide inside thyroid cells exert an inhibitory influence on the thyroid hormone synthesis, and its release. Inhibition of 25-hydroxylation of cholecalciferol by previously formed 25- hydroxycholecalciferol in the liver cells. Negative feedback loop between cyclic AMP and intracellular calcium ion concentration in calcitonin-stimulated osteoblasts. Relation between the nervous system and endocrine system: Two systems control all function of the body: 1-Nervous system 2-Endocrine system Many interrelationship exist between them, but hypothalamo (nervous)-pituitary (endocrine) connection is of outstanding importance. NB: pituitary= hypophysis (Greek word). Hypothalamo-hypophseal (pituitary) connection 1- Direct nervous connection: Hypothalamus(nervous) secrete ADH & oxytocin hormones→ pass through hypothalamo-hypophysial nervous tract stored in posterior lobe of pituitary (endocrine)→ so called neurohypophysis. 2--Indirect vascular connection: Hypothalamus (nervous)control secretion of anterior pituitary hormones (Endocrine) by releasing several hormones (Releasing& inhibiting Factors) →reach the anterior pituitary via a vascular connection between them (hypothalomo-hypophysial portal circulation) to control secretion of anterior pituitary hormones (adenohypophysis) to control secretion of most endocrine glands of body. 3 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Hypothalamic releasing factors (hormones) according to their function : 1- Thyrotropin Releasing Factor (TRF) → stimulate the release of thyrotropin hormone (TSH) of anterior pituitary. 2- Corticotropin Releasing Factor (CRF) →stimulate the release of corticotropin (ACTH)hormone of anterior pituitary. 3- Somatotropin Releasing Factor →stimulate the release of growth hormone (somatotropin) of anterior pituitary. 4- Gonadotropin Releasing Factor (GRF)→ stimulate the release of gonadotropin hormone (FSH & LH ) of anterior pituitary. 5- Prolactin releasing Factor→ stimulate release of prolactin anterior pituitary hormone. Hypothalamic inhibitory factors according to their function : 1. Somatostatin (Growth hormone inhibiting factor) → inhibit the release of growth hormone of anterior pituitary. 2. Prolactin inhibitory Factor → inhibit release of prolactin anterior pituitary hormone 4 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Biochemistry and molecular base of hormonal action Hormones Classical definition : Substances produced by endocrine glands directly into the blood to act on distant target tissue. Broader definition : Any substance that carry signal to the tissue. Properties of hormones: Synthesized by endocrine glands. Acts at small concentration. Short half-life. Feed back regulation. Respond to physiological changes. Functions of hormones: 1- Regulatory functions 2- Growth 3- Reproduction 4- Homeostasis 5- keep the internal environment constant. Classification of hormones: 1-Classification according to chemical nature. 2-Classification according to solubility. 3-Classification according to mechanism of action. Classification according to chemical nature : 1-Proteins and glycoproteins : Insulin, growth hormone , prolactin , LH, FSH, and parathyroid hormone. 2-Peptides : Glucagon, oxytocin , ADH and hypothalamic hormones. 3-Amino acid derivatives : T3, T4 , epinephrine and norepinephrine. 4-Steroids : Glucocorticoids, mineralocorticoids, male sex hormones, female sex hormones, and 1,25 dihydroxycholecalciferol. Classification according to solubility : 1-Hydrophilic : Insulin and glucagon. 2-Hydrophobic : Steroid hormones and thyroxine. Classification according to mechanism of action : 1-Group I : Binds to cytoplasmic receptors. 2-Group II : Binds to cell membrane receptors Group I Group II Solubility Hydrophobic Hydrophilic Receptors Cytoplasmic Cell membrane Mediators Hormone-receptor complex Second messenger, cAMP, cGMP. 5 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Hormone receptors : Hormones do their action through specific receptors. All receptors have two domains: 1-Binding domain : binds to hormone. 2-Signal domain( transducing domain) : produces signals to control the intracellular functions. Hormone transport in the blood : 1. Most water-soluble hormone molecules circulate in the watery blood plasma in a “free” form 2. Most lipid-soluble hormone molecules are bound to transport proteins. 3. The transport proteins, which are synthesized by the liver, have three functions: 1.They make lipid-soluble hormones temporarily water soluble, thus increasing their solubility in blood. 2. They retard passage of small hormone molecules through the filtering mechanism in the kidneys, thus slowing the rate of hormone loss in the urine. 3. They provide a ready reserve of hormone, already present in the blood stream. In general, 0.1–10% of the molecules of a lipid-soluble hormone are not bound to a transport protein. This free fraction diffuses out of capillaries, binds to receptors, and triggers responses. As free hormone molecules leave the blood and bind to their receptors, transport proteins release new ones to replenish the free fraction. Mechanism of action of group I hormones : -Hormones of group I are lipophilic hormones doing its action through receptors present in the cytoplasm. -These hormones enter the cells by diffusion and bind with intracellular cytoplasmic receptors forming hormone receptor complex. -Hormone receptor complex passes from cytoplasm to the nucleus where it binds to specific area on DNA called hormone response element (HRE). Binding of hormone receptor complex to HRE results in stimulation of transcription of specific genes → protein (enzyme) synthesis. Examples of group I hormones : 1- Glucocorticoids 2- Mineralocorticoids 3- Male sex hormones 4-Female sex hormones 5- Retinoic acids 6- 1,25 dihydroxycholecalciferol. 6 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Mechanism of action of group II hormones : They are hydrophilic in nature and do their actions through cell membrane receptors. Hormone (first messenger ) binds to its receptors leading to formation of second messenger which in turn perform the biochemical function. According to the type of second messenger, these hormones are classified into : 1- Hormones use cAMP as second messenger 2- Hormones use calcium/phosphatidyl inositol as second messenger. 3- Hormones use cGMP as second messenger. 4- Hormones use kinase and phosphatase as second messenger. 1- Hormones use cAMP as second messenger These hormones do their action through receptors which contain protein called G protein. G protein: 1. It is a protein associated with the receptors. 2. It is called G protein because it combines with guanosine nucleotide. 3. G protein is composed of three subunits, α , β and γ. 4. α subunit binds to either GDP or GTP. 5. When hormone binds to its receptors , the GDP of α subunit is replaced by GTP. 6. α –GTP dissociates from β and γ subunits and becomes active. 7. The effect of α-GTP depends upon the specific type of G proteins. Types of G proteins : Gs stimulates adenyl cyclase Gi inhibits adenyl cyclase Gplc activates phospholipase C. The α subunits of all types contain GTPase , it hydrolyses GTP into GDP and Pi and returns inactive and bounds again to β and γ subunits. Effects of Gs : α-subunit activates adenyl cyclase present in cell membrane. Adenyl cyclase converts ATP to 3,5 cAMP which is the second 7 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 messenger for many hormones like epinephrine and glucagon. 3,5 cAMP activates protein kinase A enzyme. Protein kinase A is composed of 4 subunits; 2 regulatory proteins R , and 2 catalytic proteins C. 4 molecules of 3,5 cAMP are binded to the 2 R subunits leaving the 2 C , so protein kinase A becomes active. The active form of protein kinase A has two different actions : 1-Control the activity of enzyme or protein through phosphorylation. The active form of protein kinase A phosphorylates enzymes and cellular proteins though adding phosphate to OH of serine or threonine. This phosphorylation of enzymes either activates or inactivates the enzymes. -Phosphorylation activates glycogen phosphorylase. -Phosphorylation inhibits glycogen synthase. 2-Control gene expression of different proteins. The catalytic subunits of protein kinase A phosphorylate cAMP response element binding proteins (CREB) which pass from cytoplasm to nucleus to binds to cAMP response element (CRE) to affect gene transcription. Phosphodiesterases: -It cause hydrolysis of 3',5'cAMP to 5AMP , so terminate the action of hormones which use 3,5 cAMP as second messenger 3.5cAMP ------→ 5AMP 8 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Insulin hormone activates phosphodieaterase, while caffeine inhibits it. Effects of cholera toxins on Gs Cholera toxins ribosylate the α- subunit of Gs protein. This results in the inhibition of the GTPase activity and irreversible activation of G protein. Therefore, adenyl cyclase remains continuously active and keeps cAMP levels high resulting in a sustained PKA mediated phosphorylation of chloride channels. Hyperactivity of these channels will result in loss of sodium chloride with watery diarrhea. Effects of Gi : Gi inhibits adenyl cyclase by two mechanisms : 1-Hormone –receptor complex -----→ α-GTP is released causing direct inhibition of adenyl cyclase. 2-β, γ subunit of Gi binds to α-subunit of Gs ------→ inhibit the activation of adenyl cyclase. Hormones that use cAMP as second messenger include : -Glucagon -Epinephrine -LH 2- Hormones use calcium / phosphatidyl inositol as second messengers 1. -Hormone receptor complex activates a Gplc which activates phospholipase C(PLC) enzyme. 2. -Active PLC catalyzes the hydrolysis of phosphatidyl-inositol 4-5 biphosphate into diacylglycerol and inositol triphosphate (IP3). 3. -Diacylglycerol activates protein kinase C which in turn phosphorylate many enzymes and proteins at tyrosine residue. 4. -IP3 increases calcium release from endoplasmic reticulum, calcium binds to regulatory protein called calmodulin activating it. 5. -Calmodulin activates specific calmodulin dependent kinases which phosphorylates several enzymes and proteins. -Signal turn-off includes removal of Ca++ from the cytosol by action of Ca++-ATPase pumps, and degradation of IP3.Sequential dephosphorylation of IP3 (inositol- 1,4,5-trisphosphate) by enzyme-catalyzed hydrolysis yields inositol, which is a substrate for synthesis of phosphatidylinositol. -Hormones that use calcium as second messenger include: -Vasopressin -TSH - ATPase Calmodulin: 1. Calcium dependent regulatory protein. 2. It has 4 calcium binding sites. 3. Binding of 4 calcium molecules to calmodulin leads to conformational changes , which allow calmodulin to activate several calmodulin dependent kinases. 4. In addition, activated calmodulin activates actin-myosin complex and other microfilaments mediated cell motility, and mitosis. 9 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 3- Hormones use cGMP as second messenger : cGMP is produced from GTP by guanylyl cyclase enzyme. cGMP activates cGMP-dependent protein kinase G (PKG), which phosphorylates important effector proteins that can regulate calcium dependent contraction or motility through modulating calcium influx. Examples are smooth muscle myosin, leading to relaxation and vasodilatation. There are two forms of guanylyl cyclase enzymes; membrane bound forms and soluble forms. Atrial natriuretic factor (ANF) : ANF binds to transmembrane receptors containing guanylyl cyclase in its cytoplasmic domain resulting in increase in cGMP which in turn activates different protein kinase G → cause vasodilatation, diuresis, and natriuresis. Nitric oxide (NO) NO is the major activator of guanylate cyclase. NO in turn is produced by the action of NOS (Nitric oxide synthase) in tissues like vascular endothelial cells. NO can easily diffuse through the membrane and activate the soluble guanylate cyclase. The vasodilatation resulting from NO induced increase in cGMP has great physiological and pharmacological significance. The drugs that act via NO release are nitroprusside, nitrites (used in angina as coronary vasodilators) and sildenaphil citrate (Viagra). 10 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 4- Hormones use kinase and phosphatase cascade a) Insulin, and many growth factors like epidermal growth factor, and insulin like growth factor do its action through transmembrane receptors containing tyrosine kinase in its cytoplasmic domain. b) Binding of hormones to the extracellular domain of the receptors activate tyrosine kinase which results in activation of a cascade of protein kinases. A. Insulin signaling Insulin receptors : Insulin receptors are a good example for transmembrane receptors It consists of 4 subunits, 2 α subunits, and 2 β subunits. α- subunit is the extracellular domain, it binds to insulin hormone. β -subunit is the transmembrane and cytoplasmic domain. It contains tyrosine kinase, the function of β-subunit is signal transduction. Signal transduction of insulin : 11 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 1-Insulin binds to α -subunits 2-This binding activates the tyrosine kinase activity of the β- subunit, leading to autophosphorylation of β–subunit on tyrosine residue. 3-The phosphorylated insulin receptors next phosphorylate insulin receptor substrate ( IRS ) on tyrosine residues. There are different types of IRS e.g. IRS1, IRS2 and IRS3. IRS-1 appears to be involved in cell growth effects of insulin, IRS-2 is more involved in the metabolic effects of insulin, IRS-3 is important for glucose uptake by GLUT4. 4-Phosphorylated IRS binds to SH domains of a variety of proteins that are involved in mediating different effects of insulin. 5-In this way, the receptor activates several enzyme cascade like: -Phosphatidylinositol-3 kinase catalyzes phosphorylation of PIP2 to PIP3 which activates various protein kinases like PKB (akt), PKC leading to transcription of specific genes for key enzymes of glycogenesis and glycolysis and recruitment of GLUT-4 to cell membrane. -Activation of protein phosphatases. -Activation of serine/threonine kinases, which causes cell growth and new DNA synthesis. Insulin Resistance -Insulin resistance is defined as the reduced ability of insulin to lower plasma glucose, which reflects a failure of target organs (adipose tissues liver, skeletal 12 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 muscle) to respond normally to the action of insulin. -Insulin resistance is a hallmark of type 2 diabetes, obesity and metabolic syndrome and is associated with numerous other conditions, such as cystic fibrosis, uremia, septicemia and polycystic ovary. B-Growth factors signaling Growth factors play an important role in promoting cellular differentiation and cell division. They also play important roles in the tissues homeostasis and wound healing in the adult. Their activities are mediated via transmembrane receptors that contain cytoplasmic tyrosine kinase. Dysregulation of tyrosine kinase receptors has been found in a wide range of cancers, and it has been shown to correlate with the development and progression of cancers. Tyrosine kinase inhibitors and cancer. Tyrosine kinase inhibitors (TKI) are a class of chemotherapy medication that inhibit, or block the enzyme tyrosine kinase. TKI block the signaling of growth factors leading to stopping of cell growth and division.So ,TKI interferes with the progression of cancer. 13 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Anatomy of Hypothalamus, pituitary & pineal gland Hypothalamus The hypothalamus is a part of the diencephalon, lying below the thalamus and its weight is about 4 gm weight, it is the link between the nervous system and the endocrine system via the pituitary gland. Pineal Gland (Epiphysis Cerebri) It is a part of epithalamus which is a part of diencephalon. It is a neuroendocrine gland that secretes melatonin hormone which modulates the sleep-wake cycle by controlling the circadian rhythm. Position and relations The pineal gland projects from the posterior wall of the 3rd ventricle below the splenium of corpus callosum. It is attached to the rest of the brain by the pineal stalk. Shape and measurements: The pineal gland is conical in shape and its weight is about 0.1 gm. Development: It develops at end of 4th week of prenatal life, as an outward projection from the posterior wall of the 3rd ventricle. Blood supply It is supplied by the posterior choroidal arteries (from the posterior cerebral artery) and drains into the internal cerebral veins. Pituitary Gland (Hypophysis Cerebri) The pituitary gland is a major gland of the endocrine system. It secretes hormones that control the actions of other endocrine organs. Position: 14 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 It lies within the hypophyseal fossa of the sphenoid bone, where it is covered superiorly by a reflection of the dura mater – the diaphragma sellae. The latter is pierced centrally by an aperture for the infundibulum (pituitary stalk) connecting it with the hypothalamus. Shape and measurements: It is a pea-sized oval structure, about 12 mm in transverse and 8 mm in anteroposterior diameter, and with an average adult weight of 500 mg. Relations: * Superiorly– diaphragma sellae, optic chiasma. * Anteriorly – tuberculum sellae * Posteriorly – dorsum sellae * Inferiorly – sphenoid air sinus * Laterally – cavernous sinus. Coronal (A) and sagittal (B) sections through the middle A cranial fossa showing relations of pituitary gland B Subdivisions and development: The pituitary gland is a ‘’two-in-one’’ structure consisting of the anterior pituitary and the posterior pituitary. These parts have different embryonic origins and function very differently. Anterior Pituitary (adenohypophysis): is derived from an upward growth of the roof of the primitive mouth called Rathke’s pouch. The lobe can be further divided into three parts: ✓ Pars distalis 15 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 ✓ Pars intermedia ✓ Pars tuberalis Posterior Pituitary(neurohypophysis): develops as a downgrowth from the floor of the diencephalon. It is connected with the hypothalamus by the infundibulum. Parts of hypophysis cerebri as seen in sagittal section Blood Supply: Hypothalamic-hypophysial Portal System This system connects the hypothalamus and the anterior pituitary gland. It consists of two capillary plexuses—one in the hypothalamus and the other in the anterior pituitary. In the hypothalamus there is a 1ry capillary plexus from which blood drains into a portal vein which enters the anterior pituitary to form a 2ry capillary plexus before draining into the venous circulation. This system allows the hormones-releasing factors released in the capillaries of the hypothalamus to be carried out to the anterior pituitary to stimulate it to release appropriate hormones. 16 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Arterial Supply The following branches of internal carotid artery supply the pituitary gland 1. Superior hypophyseal artery, one on each side. 2. Inferior hypophyseal artery, one on each side. Venous Drainage Short veins from the pituitary gland drain into neighboring dural venous sinuses (e.g., cavernous and intercavernous sinuses). The hormones pass out of the gland through venous blood to the target sites. Symptoms due to pressure of pituitary adenoma on adjacent structures: – Enlargement of hypophyseal fossa due to downward growth (intrasellar growth) of an adenoma. It is seen as ballooning of hypophyseal fossa (sella turcica) in plane radiograph of skull (lateral view). – Bitemporal hemianopia (loss of vision in right and left temporal fields of vision) due to the upward growth of adenoma pressing the central part of the optic chiasma. 17 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Histology of pineal gland and pituitary gland Pineal Gland (Epiphysis Cerebri) Histologically it is formed of: Stroma: o Capsule: The gland is enclosed by pia matter. o Trabeculae: A very thin connective tissue septa descend from the capsule subdividing the gland into indistinct lobules. o Reticular fibers: They form fine reticular fibers network. Parenchyma: o Two types of cells are forming the parenchyma of the gland: ▪ Pinealocytes. ▪ Interstitial cells. Pinealocytes: - The main cells contained in the pineal gland. - They are modified neurons. LM: - They are arranged in cords and clumps separated with blood vessels. - They are large branched cells. - Large spherical or lobulated nucleus with prominent nucleolus. - Pale basophilic cytoplasm. EM: - Many mitochondria. - Small Golgi complex, RER, SER and secretory vesicles. - Large numbers of cytoplasmic processes. Function: Secrete melatonin hormone. Interstitial cells - They are present among pinealocytes constitute about 5 of the cells. - They are modified astrocytes neuroglial cells. - They have long cytoplasmic processes. o In addition to the two cell types, the human pineal gland is characterized by presence of extracellular calcified concretions called brain sands or corpora arenacea. They increase in size and number with advancing age. Their significance is unknown. 18 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Physiology of Pituitary gland As mentioned before, Pituitary or hypophysis is a small gland about 1 cm in diameter. - Lies in the Sella Turcica at the base of the brain connected to the hypothalamus by the hypophyseal stalk. It is divided into anterior, intermediate & posterior parts. Functions of pituitary Gland: 1. Posterior Pituitary (Neurohypophysis): Posterior pituitary Hormones: - Vasopressin (Antidiuretic hormone, ADH) - Oxytocin 2. The Intermediate Lobe = PARS INTERMEDIA -The Intermediate lobe in human is rudimentary & no hormones is secreted in adults. - It secretes the Melanocyte stimulating hormone (MSH) which causes spreading of melanin pigment in melanocytes -ACTH causes the same effect as MSH (the cause of pigmentation in Addison's disease) 3. Anterior Pituitary (Adenohypophysis) -It is called “Master Gland” (makes & secretes various trophic hormones) -Trophic Hormones: act on other endocrine glands to stimulate release of their hormones Secretion of Hypothalamic factors: The neurons from various parts of the hypothalamus send fibres into the median eminence which secretes polypeptide hormones (hypothalamic hormones) that are absorbed into the hypothalamo-hypophyseal portal vessels to be carried to the adenohypophysis. They control the release of adenohypophyseal hormones. They are releasing or inhibitory factors according to their function : Thyrotropin Releasing Factor (TRF) Corticotropin Releasing Factor (CRF) Gonadotropin Releasing Factor (GRF) Somatotropin Releasing Factor (SRF) Somatostatin (Growth hormone inhibiting factor) Prolactin Inhibitory Factor (Leutropin inhibitory factor, LIF) 26 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Hormones of Anterior Pituitary 1- Thyroid Stimulating Hormone (TSH) 2- Adrenocorticotrophic Hormones (ACTH) 3- Gonadotrophic Hormones 4- Follicle Stimulating Hormone (FSH) 5- Luteinizing Hormone (LH) 6- Growth Hormone (GH) 7- Prolactin (PRL) Thyroid stimulating hormone (TSH, Thyrotropin) : Functions: 1- It stimulates the development of the thyroid gland, helps its growth and increases vascularity. 2 - It also stimulates the process of thyroxine formation. Adrenocorticotrophic hormone (ACTH) -Corticotropin : Functions: 1- It stimulates the development of the adrenal cortex. 2- It stimulates the formation and secretion of all the adrenal cortex hormones except aldosterone hormone. 3- It has a fat mobilizing effect 4- It has melanocyte-stimulating effect. Control: 1- Feedback mechanism : increase in adrenocortical hormones level in blood → inhibits ACTH secretion directly on the anterior pituitary and through inhibition of the hypothalamus. 2- Stress: emotional stress stimulate the hypothalamus to secrete corticotropin - releasing factor to stimulate ACTH secretion. 3- ADH : stimulates corticotrophin release Gonadotrophins: A- Follicle-stimulating hormone (FSH) B- Luteinizing hormone (LH) 27 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Anatomy of thyroid gland and parathyroid gland Thyroid gland The thyroid gland is the largest endocrine gland of the body. It secretes Triiodothyronine (T3), tetraiodothyronine (T4; commonly called thyroxine), and calcitonin hormones. Position: It is the only endocrine gland located superficially in the body. It lies in the lower part of the front and sides of the neck opposite C5, C6, C7, and T1 vertebrae. Measurements: The thyroid gland weighs about 25 gm. Each lobe is 5 cm long, 3 cm wide and 2 cm thick. The isthmus measures about 1/2 inch long and 1/2 inch wide. Parts and Extension: -It is H-shaped and consisting of conical right and left lateral lobes connected by an isthmus. -Each lateral lobe of the gland extends upwards to the oblique line of the thyroid cartilage and below up to the 5th tracheal ring. - The isthmus extends across the midline in front of the 2nd, 3rd, and 4th tracheal rings. - Sometimes a small pyramidal lobe projects upwards from the isthmus usually to the left of the midline. It may be connected to the body of the hyoid bone by a fibromuscular band called levator glandulae thyroideae. 38 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Capsule of the Thyroid Gland: The thyroid gland is invested by two capsules: an inner true capsule and an outer false capsule. 1. True capsule: It is formed by the peripheral condensation of the connective tissue of the gland. 2. False capsule: It is derived from the splitting of the pretracheal fascia enclosing the thyroid gland. On the medial surface of thyroid lobe, it thickens to form the suspensory ligament of Berry, which connects the lobe to the cricoid cartilage causing the gland to move with swallowing/deglutition. The dense venous plexus lies deep to the true capsule. Therefore, to avoid hemorrhage during thyroidectomy, the thyroid gland is removed along with the true capsule. 39 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Relations: Relations of the Thyroid Lobe: Each lobe of the thyroid gland is roughly conical and presents apex, base, three surfaces (lateral, medial, and posterolateral), and two borders (anterior and posterior). Apex: The apex is directed upwards and extends up to the oblique line of thyroid cartilage. Base: The base extends up to the 5th or 6th tracheal ring. It is related to inferior thyroid artery and recurrent laryngeal nerve. Lateral (superficial) surface: It is convex and is covered by: Three strap muscles (sternothyroid, sternohyoid, and superior belly of omohyoid). Anterior border of sternocleidomastoid overlapping it inferiorly. Medial surface: It is related to: (a) Two tubes: trachea and esophagus. (b) Two muscles: inferior constrictor and cricothyroid. (c) Two cartilages: cricoid and thyroid. (d) Two nerves: external and recurrent laryngeal nerves. Posterolateral surface is related to: 1-Carotid sheath and its contents (common carotid artery, internal jugular vein, and vagus nerve). 2-The ansa-cervicalis is embedded in the anterior wall of the sheath 3-cervical sympathetic chain lies posterior to sheath. Anterior border: It is thin and separates superficial and medial surfaces. Posterior border: It is thick and separates the medial and the posterior surfaces. It is related to: Arterial anastomosis between superior and inferior thyroid arteries. Parathyroid glands. 40 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Relations of Isthmus: The isthmus is horizontal and presents two surfaces anterior and posterior and two borders: superior and inferior. * Anterior surface is related to strap muscles (sternohyoid and sternothyroid) and anterior jugular veins. * Posterior surface is related to: 2nd, 3rd, and 4th tracheal rings. * Superior border is related to: anastomosis between the anterior branches of two superior thyroid arteries. * Inferior border: Along this border inferior thyroid vein, thyroideaima artery. Transverse section of the anterior part of the neck at the level of thyroid isthmus, showing relations of the thyroid gland Blood supply of thyroid gland: Arterial supply: The gland is highly vascular and is supplied by the following arteries: 1- Superior thyroid artery: It is a branch of the external carotid artery. 2- Inferior thyroid artery: It is a branch of thyrocervical trunk from the first part of the subclavian artery. 3- Thyroidea ima artery (in 30% cases): It is a branch of the brachiocephalic trunk or may arise directly from the arch of aorta. 41 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Venous Drainge: The venous blood from the thyroid gland is drained by three set of veins: 1 Superior thyroid vein: It drains into the internal jugular vein. 2 Middle thyroid vein: it drains into the internal jugular vein. 3 Inferior thyroid vein/veins: They drain into the left brachiocephalic vein. Lymphatic Drainage: The lymph vessels draining the thyroid gland are arranged into two groups, upper and lower, and they follow the arteries: 1. The upper group drains into the prelaryngeal and upper deep cervical (jugulodigastric) lymph nodes. 2. The lower group drains into pretracheal and lower deep cervical (juguloomohyoid) lymph nodes. The upper lymphatics follow superior thyroid artery and lower lymphatics follow the inferior thyroid arteries. 42 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Nerve Supply: The thyroid gland is supplied by both sympathetic and parasympathetic nerve fibers: 1. The parasympathetic supply is derived from the vagus nerve. 2. The sympathetic supply is derived from the superior, middle, and inferior cervical sympathetic ganglia, but mainly from the middle one. Ligation of thyroid arteries during thyroidectomy: The superior thyroid artery and the external laryngeal nerve diverge from each other near the apex, the artery lies superficial and the nerve lies deep to the apex. Therefore, during thyroidectomy, the superior thyroid artery should be ligated as close to the apex of thyroid lobe as possible to avoid injury to the external laryngeal nerve. The recurrent laryngeal nerve lies very close to the inferior thyroid artery near the base of the thyroid lobe. Therefore, during thyroidectomy, the inferior thyroid artery should be ligated as away from the base of the thyroid lobe as possible to avoid injury to the recurrent laryngeal nerve. 43 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Parathyroid gland These are two pairs (superior and inferior) of small oval yellowish-brown endocrine glands, about 5 mm in diameter and located along the posterior borders of the thyroid lobes within the thyroid capsule. They secrete parathormone hormone. Location and development: The superior parathyroid lies at the middle of the posterior border of the thyroid lobe. They develop from the fourth pharyngeal pouch and hence also termed as parathyroid-IV. The inferior parathyroid lies on the posterior border of the thyroid lobe near its lower pole. They develop from the third pharyngeal pouch, hence also termed as parathyroid-III. Blood Supply: Arterial supply is chiefly via the inferior thyroid artery. Collateral arterial supply is from the superior thyroid artery and thyroid ima artery. Venous drainage is into the superior, middle, and inferior thyroid. Vein. 44 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Histology of thyroid & parathyroid gland THYROID GLAND Histological Structure: Stroma: o Capsule: The gland is enclosed by two layers of connective tissue capsule (highly vascularized): ▪ Outer layer of dense connective tissue which is continuous with pretracheal fascia. ▪ Inner adherent layer of loose connective tissue. o Trabeculae: Very thin descend from the capsule without any sort of lobulation o Reticular fibers: They form fine network around the thyroid follicles. Parenchyma (thyroid follicles) They are the structural unit of the thyroid gland. They are rounded structures mostly contain colloid with strong positive PAS reaction. The follicles are lined with simple cuboidal epithelium resting on prominent basement membrane. Each follicle is formed of two types of cells: 1- Principle follicular cells 2- Parafollicular cells. 1- Principle Follicular Cells LM They represent the majority of the follicular epithelium. They secrete thyroglobulin, a glycoprotein that is stored in the center of the follicle as colloid. They are simple cuboidal cells rest on basement membrane with central pale round nuclei and basophilic cytoplasm. 45 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 The shape of cells differs according the activity of the gland; columnar in hyperactive gland and squamous in inactive gland. EM: (protein synthesizing cell) Well developed supra-nuclear Golgi complex and basal RER. Elongated mitochondria. Free ribosomes and many lysosomes. Apical secretory vesicles and many microvilli. Tight junction between adjacent cells. Function: Synthesis of thyroid hormones. 2- Parafollicular Cells (C cells, Clear cells) LM: They are larger than the follicular cells Round or oval nucleus and pale cytoplasm. They occur single or in small clusters between follicular cells. They rest on the same basement membrane and do not reach the lumen. They are more numerous in the central region of the thyroid lobes. They are belonged to the diffuse neuroendocrine system (DNES). EM: (APUD cells) Few cisternea of RER. Elongated mitochondria. Large Golgi apparatus. Numerous granules contain hormone. Function: * They secrete calcitonin hormone. Calcitonin is an antiparathyroid hormone, lowers blood calcium levels and acts to inhibit bone resorption. * NB. Interfollicular cells are tangentially cut of the follicular cells (with occasional C- cells). * NB. APUD cells that also called DNES cells: DNES cells: are different group of endocrine cells (diffuse neuroendocrine cells) found throughout the body. They release their secretions into the blood or have a paracrine effect on neighboring cells. They are called also APUD cells; Amine Precursor Uptake and Decarboxylation means uptake of amine precursors and decarboxylase by enzymes for conversation of precursors to amines, to secrete peptide hormone. 46 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 FUNCTIONAL ULTRASTRUCTURAL OF FOLLICULAR CELLS ✓ Synthesis and storage of iodinated thyroglobulin: o Thyroglobulin (glycoprotein) synthesis starts on RER and glycosylation occurs in Golgi apparatus. o It is transported in small vesicles and discharged by exocytosis into the lumen of the thyroid follicles. o The cells uptake iodide from blood, oxidize into active iodine at villous surface and transport to the lumen Both the iodine and the thyroglobulin join each other in the lumen to form iodinated thyroglobulin that stored as colloid. ✓ Secretion of T3 and T4 hormones: o Upon stimulation of cell receptor, the colloid is taken again by endocytosis. o Lysosomes hydrolyze the iodinated thyroglobulin into thyroxin (tetra-iodothyronine, T4) and tri- iodothyronine (T3). o T3 and T4 are released from the basal surfaces of the follicle cell and enter the blood stream. 47 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 PARATHYROID GLANDS HISTOLOGY * They are four small glands embedded in the posterior surface of the thyroid gland. Stroma: 1- Capsule: thin connective tissue capsule. 2- Trabeculae: They are thin septa that divide the gland into incomplete lobules. 3- Reticular fibers: They form reticular network. Parenchyma: * The cells of the parathyroid gland are arranged in cords and clumps separated by blood vessels. * There are two types of cells: a. Chief cells. b. Oxyphil cells. a. Chief Cells LM: - They are the most numerous cells type in the parathyroid glands. - They are polygonal cells with vesicular nuclei. - Pale stained cytoplasm due to large amount of glycogen. - With increasing age, they are replaced by adipocytes. EM: - Well developed Golgi apparatus and RER. - Many spherical mitochondria and abundant glycogen granules. - Irregular shape electron dense secretory granules contain the parathyroid hormone. Function: They secrete the parathyroid hormone (PTH) which release in response to low blood calcium. b. Oxyphil Cells LM: - They begin to appear at about the 7th year and increase in number with age. - They are larger than chief cells. - They are polygonal in shape with small dark stain nucleus. - Deeply stained acidophilic cytoplasm (due to numerous mitochondria). EM: - Numerous rounded mitochondria with many cristae. - Small Golgi complex and few RER. Function: Is not yet known (it may be stem cell for degenerated chief cells) 48 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Thyroid gland Biochemistry Thyroid hormones synthesis The Thyroid gland secretes 3 major hormones: 1.Thyroxine or T4: having 4 atoms of Iodine. (secreted in largest amount) 2. Triiodothyronine or T3: having 3 atoms of Iodine (secreted in lesser amount) 3. Calcitonin: which is an important hormone of calcium metabolism The thyroid secretes about 80 micrograms of T4, but only 5 micrograms of T3/ day. T3 has a much greater biological activity (about 10X)” ten times more active” thanT4. An additional 25 micrograms/day of T3 is produced by peripheral monodeiodination of T4. Steps of Synthesis of thyroid hormones Iodine Transport - Large amounts of Iodine are required for synthesis of physiological levels of thyroid hormones. - -To generate sufficient concentrations of Iodine, the ionic form of the atom, Iodide (I) is actively transported from the blood stream into the follicular lumen by the Follicular Epithelial Cells. - The transport of iodide into follicular cells is dependent upon a sodium/iodine cotransport system. - Consequently, Iodide is highly concentrated in the thyroid gland compared to the rest of the body. Thyroglobulin Synthesis - Thyroglobulin is a protein that contains large numbers of tyrosine amino acids that go on to become individual thyroid hormone molecules. - Thyroglobulin is synthesized within the follicular epithelial cell and secreted into the follicular lumen. - Initial Steps in Thyroid Hormone Synthesis: Thyroid Peroxidase Thyroid Peroxidase is an enzyme present in the acellular colloid of the follicular lumen and performs several key reactions. 49 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Thyroid Peroxidase first - generates I2 by oxidizing I ions present in the follicular lumen. Thyroid Peroxidase then "organifies" the generated I2 by covalently linking it with the tyrosine residues present in Thyroglobulin. This generates either single or doubly-iodinated species of tyrosine, termed "Monoiodotyrosine (MIT)" and "Diiodotyrosine (DIT)", respectively Peroxidase then combines MIT and DIT residues to generate T4 or T3 species within the thyroglobulin protein, a process termed "Coupling". T4 is generated by combining two DIT residues while T3 is generated by combining one DIT residue with one MIT residue. Importantly, peroxidase is much more efficient at combining of two DIT residues and thus generation of T4 occurs much more readily, explaining why the thyroid gland primarily produces T4 rather than T3. Release of T and T from Thyroglobulin 4 3 -Once endocytosed into the follicular epithelial cell, the thyroglobulin is broken down by lysosomes, thus releasing attached T4, T3, MIT, and DIT. -T4 and T3 are then transported out of the follicular epithelial cells and into the circulation. Conversion of T4 to T3 T3 has much greater biological activity than T4 A large amount of T4 (25%) is converted to T3 in peripheral tissues. This conversion takes place mainly in the liver and kidneys. The T3 formed is then released to the bloodstream. The T3 formed is then released to the blood stream. In addition to T3, an equal amount of “reverse T3” may also be formed. This has no biological activity. The conversion occurs by deiodinase enzyme. The deiodinases are selenium-containing enzymes, thus dietary selenium is essential for T3 50 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 production. 51 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Physiology of Thyroid Gland The functional unit of thyroid gland is the thyroid follicle, that contains two types of cells: 1-Follicular (A) cells that release thyroid hormones, T3(tri-iodothyronine)& T4 (thyroxine). T3 is 10 times more active than T4 2-Parafollicular (C) cells that release thyrocalcitonin Thyroid Hormones T3 & T4 mechanism of action ✓ Thyroid hormones (T3&T4) pass across the cell membrane and enter the cell. ✓ Most of T4 converted into T3 in cytoplasm of the cell, then enter the nucleus to bind to their receptors forming thyroid hormone nuclear receptor complex that stimulates synthesis of specific protein molecules with enzyme activity resulting in different actions of thyroid hormones ✓There are two types of human thyroid hormone receptors: Alpha: responsible for general metabolic function Beta: responsible for brain development and maturation & TSH release. Functions: 1) General metabolism: Calorigenic hormone, as it increases O2 consumption, heat production & BMR. Thyroid hormones stimulate diverse metabolic activities in most tissues, leading to an increase in basal metabolic rate. One consequence of this activity is to increase body heat production. 2) Special metabolism: -Increases blood glucose level: by stimulating glycogenolysis & gluconeogenesis& ++ glucose uptake by tissues. -decrease blood cholesterol level 52 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 -increase protein synthesis: Thyroid hormones increase protein synthesis and also increase protein breakdown ( in normal level of thyroid hormones it causes protein synthesis). An excess of circulating hormones induces a net protein deficit due to excessive catabolic activity while decreased hormone levels result in decreased protein anabolism. Therefore, in both hypo-and hyperthyroidism, growth development, and the maintenance of structural and other tissues are usually impaired 3) Convert Beta Carotene to Vit. A 4) CNS: essential for normal activity & development of CNS 5) CVS: -increase HR: through increasing oxygen consumption, rhythmicity and sensitivity of SAN to the circulating catecholamines by increasing the number of B-receptors. -increase cardiac output: through potentiating the chronotropic & inotropic effects of circulating catecholamines and also by direct action on the heart. -decrease peripheral resistance: due to peripheral VD This will result in increasing systolic ABP & decreasing or unaltered diastolic ABP. So, increase in pulse pressure (Water hummer pulse). 6) Blood: increase RBC’s formation 7) Respiratory system: increase pulmonary ventilation 8) Kidneys: -cause diuresis -increase excretion of K+ , Ca++ ,Po–in urine 9) GIT: increase motility & appetite 10) Gonads: -important for normal gonadal function -inhibit prolactin hormone production 11) Mammary glands: necessary for maintenance of milk production and secretion 53 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 during lactation. 12) Muscles: increase or decrease thyroid hormones cause muscle weakness (Myopathies). As, with high levels there will be increase in tissue protein breakdown& with low levels, there will be inhibition of protein synthesis 13) Growth, tissue maturation &differentiation: Thyroid hormones are very important for this function, through: Stimulation of growth hormone secreting cells in the anterior pituitary and helping its action. Stimulation of protein synthesis. Regulation: 1)-Thyrotropin-releasing hormone (TRH): from hypothalamus that stimulates the release of Thyroid – stimulating hormone (TSH) from anterior pituitary 2)-Thyroid-stimulating hormone (TSH): from anterior pituitary that stimulates synthesis and release of thyroid hormones from thyroid gland These two hormones play very important role in regulating thyroid hormone release through 2 negative feedback mechanisms: -Direct Feedback: increase in T3 & T4 levels directly suppresses further release of TSH from anterior pituitary, which in turns suppresses further synthesis and release of T3 & T4 from thyroid gland returning them to their normal levels. -Indirect Feedback: increase in T3 & T4 levels suppresses the release of TRH from the hypothalamus that will suppress the release of TSH from anterior pituitary, which in turns suppresses the synthesis and release of T3 & T4 from thyroid gland returning them to their normal levels. 3)-Long Acting Thyroid Stimulator (LATS): -Formed by lymphocytes, has long acting effect (while TSH is rapid and of short duration effect) -Related to antibodies &causes thyrotoxicosis 4)-Iodine supply: Excess iodine to: Normal person: stored in gland with no increase in thyroxine level Hypothyroid person:(with enlargement of thyroid gland due to increase TSH)→ the gland returns to normal condition and decreases the hyperplasia because iodine inactivates the TSH. Hyperthyroid person: decreases T4 formation due to inactivation of TSH& inhibition of biosynthesis of T4 [ Wolff-Chaikoff effect](inhibition of organification of trapped iodide by excess iodide or iodine administration). 5)-ANS: Sympathetic +++ stimulates thyroid secretion & effect 54 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 II- Thyrocalcitonin: It is a calcium lowering hormone, secreted by parafollicular C-cells of thyroid gland. Mode of action: Suppresses osteoclasts number & activity Increases excretion of Na+, Ca++ , and phosphate in urine Regulation: Simple feedback mechanism, when plasma calcium level rises, this stimulates its release Regulation Of Thyroid Hormone Levels Thyroid hormone synthesis and secretion is regulated by two main mechanisms: 1- An “autoregulation” mechanism, which reflects the available levels of iodine. 2- Regulation by the hypothalamus and anterior pituitary. Autoregulation Of Thyroid Hormone Production - The rate of iodine uptake and incorporation into thyroglobulin is influenced by the amount of iodide available: - low iodide levels increase iodine transport into follicular cells - High iodide levels decrease iodine transport into follicular cells. Thus, there is negative feedback regulation ofiodide transport by iodide. FEEDBACK REGULATION THE HYPOTHALAMIC-PITUITARY-THYROID AXIS Hormones derived from the pituitary that regulate the synthesis and/or secretion of other hormones are known as trophic hormones. Key players for the thyroid include: TRH - Thyrotropin Releasing Hormone TSH - Thyroid StimulatingHormone T4 /T3 - Thyroid hormones. Summary: Thyroid gland hormones -Maintain normal oxidative metabolism -Necessary for normal growth & maturation -Affect Calcium metabolism 55 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 ANATOMY OF SUPRARENAL GLAND Suprarenal gland (Adrenal gland) Ad (toward)- Ren (kidney)-Al (adj.) ; suprarenal glands Introduction: - Bilateral endocrine glands - In cut section, it consists of - Outer cortex: Zona glomerulosa (aldosterone) Zona fasciculata (Cortisol) Zona reticularis (Sex hormones) - Inner medulla: catecholamines (adrenaline & noradrenaline) Anatomy of adrenal glands: Site: Epigastrium, in front of the upper poles of each kidney weight: 4-5 gm Shape: Right: pyramidal, left semilunar (crescentic) Capsule: The gland has strong fibrous capsule and enclosed in renal fascia (Gerota’s fascia) in a special compartment 61 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Relations Right suprarenal gland Left suprarenal gland Anterior Small area covered by peritoneum of Large area covered by peritoneum of the liver lesser sac Medially: IVC Above: lesser sac and posterior surface of Laterally: right lobe of the liver stomach Middle: splenic artery Below: pancreas Posterior -Upper pole of right kidney (doesn't -Upper pole of left kidney (reaches the reach the hilum) hilum) -Right crus of diaphragm. -Left crus of diaphragm. Medially Right celiac ganglion Left celiac ganglion 62 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Blood supply: Arteries: each gland receives 3 arteries 1- Superior suprarenal artery 6.5 % 4-Random blood glucose : > 200 mg/dl. Biochemical disturbance of diabetes mellitus A- Carbohydrates metabolism: Insulin deficiency leads to decrease glucose uptake by tissues , decrease glucose oxidation, increase gluconeogenesis and glycogenolysis. This leads to: 1- Decrease intracellular glucose → hunger pain and polyphagia (excessive eating). 2- Increase blood glucose (hyperglycemia), This leads to increase in plasma osmolality which causes dehydration: a) Dehydration of brain cells causes hyperglycemic hyperosmolar coma b) Dehydration of body cells leads to sense of thirst and polydepsia. 3- Glucosuria: If the blood glucose level exceeds renal threshold (180 mg/dl), this leads to increase osmotic diuresis that causes: a) Excessive and frequent urination (polyuria) b) Loss of water soluble vitamins e.g. B1. c) Loss of minerals e.g. Na' and K+ 89 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 B- Protein metabolism: insulin deficiency leads to increase protein breakdown and stimulation of gluconeogenesis. this results in 1- Phosphate release that leads to hyperphosphatemia. 2- Excessive breakdown of tissue protein causing muscle wasting. 3- Decreased antibody formation causing low resistance and infection. 4- Delayed wound healing. C- Lipid metabolism: Insulin deficiency leads to excessive lipolysis in adipose tissue and mobilization of free fatty acids and glycerol to the blood , then to the liver and other tissues. This leads to: 1- Loss of weight. 2- Hyperlipidemia that may cause atherosclerosis. 3- Fatty liver. 4- Excessive ketone bodies formation which leads to ketonemia and ketosis which in turn cause diabetic ketoacidosis. Investigations of diabetes mellitus: 1- Fasting and Postprandial Blood Glucose: 1. Fasting plasma glucose level (8-12 hours after meal). i) Fasting blood glucose of 70 -110 mg/dl is considered normal blood glucose. ii) Fasting blood glucose of 110-126 mg/dl means impaired glucose tolerance. iii) Fasting blood glucose of >126 mg/dl, is considered diabetes mellitus. 2. Two - hours postprandial plasma glucose level. i. If concentration is 70- 140 mg/dl, it is considered normal blood glucose. ii. If concentration is 140- 200 mg/dl, it means impaired glucose tolerance. iii. If concentration is > 200 mg /dl, it is diabetes mellitus. 2 - Oral Glucose Tolerance Test (OGTT): Indications: ❖ Subjects with transient or sustained glucosuria but no symptoms of diabetes with normal fasting and random blood glucose levels. Subjects with symptoms of diabetes but with normal fasting blood glucose level and no glucosuria. Persons with strong family history of diabetes mellitus but no overt symptoms. Patients with glucosuria associated with thyrotoxicosis, infections and/or sepsis, liver diseases and pregnancy. Women with characteristically large baby. Patients with unexplained neuropathies, nephropathies or retinopathies. 90 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Patients with or without symptoms of diabetes mellitus but showing one abnormal value. Procedure: - Patient fast for 12 hours and blood sample is taken for measurement of blood glucose and urine sample for detection of glucose in urine. - Patient takes glucose orally 1gm/kg body weight, maximum 75 gm, - Blood samples and urine samples were taken after 0.5, 1, 2 & 2.5 hours after taken glucose. Normal oral glucose tolerance test: I. Fasting level: 65-110 mg/dl. II. The plasma glucose level reaches the maximum in 1 hour (120-150 mg/dl). The ascending limb of the curve represents glucose absorption. III. The plasma glucose returns to fasting level after 2 hours.The descending limb represents glucose utilization by the tissues in response to insulin secretion. IV. Normally, all urine samples contain no glucose. Diabetic oral glucose tolerance test: Fasting plasma glucose is greater than 126 mg/dl At least, one of the intermediate (0.5, 1, 1.5 hours) has plasma glucose greater than 200 mg/dl. Plasma glucose returns to normal level in more than 2 hours. If the rate of glomerular filtration of glucose exceeds that of tubular reabsorption in the kidney (renal threshold), glucose will appear in urine. Glucose tolerance curve of renal glucosuria: The curve is normal Glucose appears in some or all urine samples. Hypoglycemic glucose tolerance curve: Fasting level is below normal, maximum rise is below normal and returns to fasting level are very rapid. Lag storage glucose tolerance curve: 91 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Fasting blood glucose level is normal, then 30 minutes after glucose load, the level reaches above180 mg/dl. The curve falls sharply to the fasting level in less than 2 hours. This type of curve may occur in: 1. Thyrotoxicosis due to rapid absorption. 2. In severe liver disease, as all glucose enters directly to systemic blood and no glycogenesis. 3. After gastrectomy due to rapid passage of glucose into the intestine. Flat glucose tolerance test: Blood glucose levels fails to rise normally after glucose load. Occurs in myxedema and malabsorption. 3- Glycosylated hemoglobin (HbAlc): -It is hemoglobin to which glucose is bound. It is formed by non-enzymatic glycosylation of hemoglobin. It is used to monitor the long-term control of diabetes within 6-8 weeks. Normal HbA1c is < 6 %,controlled diabetes is 6 -7 % and uncontrolled is more than 7 %. The HbA1c is used now as a diagnostic tool for diabetes mellitus. Diabetes is diagnosed with an HbA1c of greater than or equal to 6.5%. Patients with values between 5.7 to 6.4 % are considered as prediabetics. 4-Fructosamine : 92 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 -Fructosamine is formed from the joining of fructose to protein molecules (mostly albumin) through glycation, a nonenzymatic mechanism. As the half-life of albumin is 14 - 21 days, fructosamine reflects the average blood sugar concentration over the prior two to three weeks. -Its normal level is between 2.4 - 3.4 mmol/L, this level is increased in uncontrolled diabetes. 5.Serum C-peptide: 1. C-peptide is secreted in equal molar ratio with the mature insulin. 2. C-peptide levels are better indicator of β-cell function than peripheral insulin concentration. 3. C-peptide assays do not measure exogenous insulin and do not cross-react with insulin antibodies, which interfere with the insulin immunoassay. 4. Fasting serum C-peptide level have a value in differentiating patients with Type-I diabetes from those with Type-II diabetes. 6- Other tests for monitoring diabetic patients: Microalbuminuria (for incipient diabetic nephropathy). Serum creatinine (in established renal disease). Lipids ( because of the risk of atherosclerosis). Acute complications of DM Hyperosmolar Diabetic ketoacidosis hyperglycemic state (DKA) (HHS) Blood glucose mg/dl >600 250-600 Blood ketones Negative Positive Urine ketones Negative Positive Arterial pH >7.3 15 < 15 (mEq/ L) Anion gap Normal >15 Chronic Complications of Diabetes Mellitus I. Microvascular complications: The damage of small blood vessels leads to a microangiopathy, which can cause one or more of the following: 1- Diabetic cardiomyopathy 2- Diabetic nephropathy 3- Diabetic neuropathy 4- Diabetic retinopathy 93 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 5- Diabetic encephalopathy II. Macrovascular complication: Accelerated atherosclerosis is the major contributor to many macrovascular complications such as: 1- Coronary artery disease, leading to angina or myocardial infarction. 2- Diabetic myonecrosis “muscle wasting”. 3- Stroke. 4- Peripheral vascular disease which contribute to intermittent claudication as well as diabetic foots. Pathogenesis of microvascular complications: 1) Aldose reductase “Polyol pathway” This pathway involves the conversion of glucose into sorbitol. High glucose levels increase the flux of sugar molecules through polyol pathway which causes sorbitol accumulation in cells exerting osmotic stress. Activation of polyol pathway leads to consumption of NADPH which acts as cofactor for glutathione reductase, which reduced oxidized glutathione into reduced glutathione. Also, the flux of glucose through the polyol pathway would increase advance glycation end products (AGE) formation. 2) Advanced glycation end products (AGE) High glucose concentration can promote the non-enzymatic formation of advanced glycosylated end product. AGE can diffuse out of the cells and modify circulated proteins such as albumin. These modified proteins in the blood can bind to AGE receptors and activating them, thereby causing oxidative stress, production of inflammatory cytokines and growth factors. 3) Oxidative stress High glucose levels can stimulate free radical production which lead to cellular injury. 4) Growth factors and cytokines Several growth factors, cytokines and vasoactive agents have been implicated in the pathogenesis of microvascular complication especially diabetic nephropathy. Pathogenesis of Macrovascular Complications: 1- Atherosclerosis: Atherosclerosis is thought to result from chronic inflammation and injury to the arterial wall. In response to endothelial injury and inflammation, oxidised LDL accumulates in the endothelial wall of arteries. 94 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Monocytes then infiltrate the arterial wall and differentiate into macrophages, which accumulate oxidised LDL to form foam cells. 2- Increased platelet adhesion and hypercoagulability: Increased platelet adhesion may result from increased free radical formation, impaired NO formation, as well as altered calcium regulation. Elevated levels of plasminogen activator inhibitor type -1 may also impair fibrinolysis in patients with diabetes. The combination of increased coagulability and impaired fibrinolysis likely further increase the risk of vascular occlusion and cardiovascular events in type 2 diabetes. Insulin Resistance Insulin resistance is defined as the reduced ability of insulin to lower plasma glucose, which reflects a failure of target organs (adipose tissue, liver, skeletal muscle) to respond normally to the action of insulin. Insulin resistance is a hallmark of type 2 diabetes and of obesity. Glucosuria Definition: The presence of the detectable amounts of glucose in urine. Types: I-Hyperglycemic glucosuria In which blood glucose rises above the renal threshold and is filtered in urine as in: Diabetes mellitus Bronzed diabetes Adrenaline glucosuria: emotion , stress, pheochromocytoma. Excess secretion of diabetogenic hormones e.g. growth hormone, glucocorticoids, thyroid….etc. II-Normoglycemic glucosuria (Renal glucosuria) Blood glucose is within normal level, but there is decrease in renal tubular reabsorption as in: Diabetes innocens: A defect in renal tubular reabsorption, so the renal threshold is congenitally low. Pregnancy glucosuria: Occurs in 20% of normal pregnant women. It is due to increase in glomerular filtration rate by about 50% during pregnancy. Nephritis, nephrosis, or advanced renal tubular diseases 95 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 c. End Piece: It is formed by the tapering outer dense fibers and fibrous sheath caudally. It is about 5 µm in length It is formed of axoneme covered only by flagellar membrane becomes disorganized at its end NB.: Cell membrane forms an external covering of all parts of mature sperm (head, neck and tail with its three parts; a middle piece, a principal piece and an end piece). Sertoli Cells They are non-dividing epithelial cells of mesodermal origin with supportive function (Fig 4). LM: Tall columnar cells resting on basal lamina of seminiferous tubule and extend to their lumen. They are found between spermatogenic cells and span the entire thickness of the germinal epithelium. Highly irregular cells i.e. they have extensive lateral processes, so their outlines are not clearly defined and constantly changing to permit movement of spermatogenic cells. Nucleus: large basal oval and pale euchromatic with prominent nucleoli. Cytoplasm: pale acidophilic and contains a special crystalloid structure. EM: Numerous mitochondria. Prominent Golgi apparatus and RER Lipid droplets and well developed SER Well developed cytoskeleton of microtubules and microfilaments Lysosomes Euchromatic nucleus (high activity) The lateral cell membrane contains multiple pockets to enclose the proliferating spermatogonia. Tight junction (occludens junction) between their lateral membranes forming the blood testis barrier and dividing the tubular lumen into adluminal and basal compartments Function in brief: 1. Supportive function for all spermatogenic cells. 2. Nutritive function: they secrete a fructose rich fluid for nutrition of spermatogonic cells. 143 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 3. Phagocytic function: they phagocytose residual bodies resulting from the process of spermiogenesis. 4. Endocrine function: a. Androgen binding protein (ABP) which bind to testosterone stimulating spermatogenesis. b. Inhibin hormone which inhibit FSH and so inhibit spermatogenesis. c. Plasminogen activator d. Antimullerian hormone(during embryonic development) 5. Spermiation function: a process by which the mature spermatozoa are released actively from the protective Sertoli cells into the lumen of the seminiferous tubule with the help of their microtubules and microfilaments (cytoskeleton). 6. Responsible for blood testis barrier formation. Blood Testis Barrier It is formed by the tight (occluding) junctions between the lateral processes of the adjacent Sertoli cells (Sertoli- Sertoli junction) near their bases dividing the seminiferous tubule into two compartments (Fig 8): 1. Basal (outer) compartment: ( ) It contains basal group of cells including proliferating spermatogonia and blood capillaries. 2. Adluminal (inner) compartment: ( ) It contains adluminal group of spermatogenic cells that are away from blood stream and including primary spermatocytes, secondary spermatocytes, spermatids and sperms. Function: 1. It creates the suitable environment in which germ cells carry out the fundamental reproductive function of gamete production. 2. It prevents autoimmune reaction against the genetically different haploid cells. 3. It prevents exposure of spermatogenic cells to toxic substances in blood. 4. It selects and allows the passages of hormones and nutrients necessary for growth and development of sperms. 144 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Fig 8: Blood testis barrier Clinical Note: Defect in blood testis barrier formation leads to failure of spermatogenic cells and spermatozoa to remain isolated resulting in the production of sperm specific antibodies. These antibodies cause the sperm to agg-lutinate, prevent their movement and interaction with the ovum. Interstitial Tissue Seminiferous tubules are separated from one another by a loose areolar connective tissue stroma or interstitial tissue. This interstitial tissue contains clusters of endocrine Leydig cells which secrete testosterone. It also contains blood vessels, lymphatics and nerves. It contains myoid cells (contractile cells) to help sperm motility. Leydig Cells They are mesenchymal in origin, endocrinal in function (secrete androgens) and they differentiate in early fetal life. LM: Large cells occur in clusters within the interstitial tissue of the testis so called “Interstitial Cells of Leydig”. Shape: polyhedral. Nucleus: central rounded nucleus and may be binucleated with prominent one or two nucleoli. Cytoplasm: pale acidophilic. EM: (steroid-secreting cells) 145 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Lipid droplets and well developed SER Numerous mitochondria with tubular cristae. Well developed Golgi apparatus Lysosomes, peroxisomes and lipofuscin granules are evident. Small cytoplasmic inclusions called Reinke's crystalloids. Function: 1. In embryo: testosterone is responsible for the normal development of the gonads. 2. At puberty: testosterone is responsible for the initiation of sperm production, accessory sex glands secretions and development of secondary sex characters. 3. In adult: testosterone is essential for the maintenance of spermatogenesis, secondary sex characters, genital ducts and accessory sex glands. N.B Orchitis is acute or chronic inflammation of the testis frequently involves the ducts connecting this organ to the epididymis. Common forms of Orchitis are produced by infective agents and secondary to urinary tract infection or a sexually transmitted pathogen. II. MALE GENITAL DUCTS A. Intratesticular Ducts These ducts are found in the testis and connect the seminiferous tubules to the epididymis. 1. Tubuli Recti They are straight tubules as extension of seminiferous tubules. They are lined with Sertoli cells only at the 1st half and by simple cuboidal epithelium till its terminate. 2. Rete Testis They are a complex series of interconnecting channels within the mediastinum testis arise from anastomosis of Tubuli recti. They are lined with simple cuboidal or low columnar epithelium. The cells have a single apical cilium and few short microvilli. 3. Efferent Ductules (Ductuli Efferentes) They consist of five to six tubules that arise from the rete testis. They aggregate to form the head of the epididymis. They are lined with partially ciliated pseudostratified columnar epithelium. They are surrounded by a thin layer of circular smooth muscle with elastic fibers. 146 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 The transport of sperms in these ductules is affected by ciliary action and contraction of fibro-muscular layer. Most of the fluid secreted in the seminiferous tubules is reabsorbed in these ductules. B. Extra testicular Ducts These are the epididymis, ductus deferens and ejaculatory duct. 1- Ductus Epididymis The ductus epididymis or epididymis is a crescent shaped highly convoluted tubular structure about 6m in length. It lies along the superior and posterior surfaces of the testis. It connects the efferent ductules to vas deferens. It is divided into head, body and tail, histologically formed of mucosa, musculosa and adventitia: (Fig 9) Mucosa: a) Epithelial lining: Pseudostratifid columnar epithelium with stereocilia rest on a clear basement membrane. The epithelium is formed of two types of cells: 1. Principal cells: LM: ▪ Tall columnar cells with acidophilic cytoplasm, basal oval nuclei and apical brush border. EM: ▪ Apical stereocilia (long microvilli), supranuclear Golgi apparatus, numerous cisternae of rough endoplasmic reticulum, coated vesicles, multivesicular bodies and lysosomes. Function: ▪ They reabsorb the excess luminal fluid leaving the testis. ▪ Phagocytose remnants of spermatogenic cells which are not removed by Sertoli cells. ▪ Synthesize a glycoprotein to inhibit capacitation of the sperms until they reach the female genital tract. 2. Basal cells: ▪ Short pyramidal cells with rounded heterochromatic dense nuclei. ▪ The cytoplasm is clear, scanty and acidophilic and contains few organelles. ▪ They are considered as stem cells of the principal cells. b) Lamina propria: ▪ It is surrounded by a thin delicate vascular layer of connective tissue 147 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Musculosa: ▪ In the head and most of the body a smooth muscle coat of a thin layer of circular smooth muscle. ▪ In the rest of the body and in the tail, inner and outer longitudinal layers are present and middle circular. ▪ Contractions of this muscle layer help conduction of spermatozoa to the ductus deferens. Adventitia It is an external layer of connective tissue invests the musculosa. Function of the epididymis: 1. Absorption: the principle cells absorb the excess fluid secreted in the seminiferous tubules. 2. Secretion of certain substances by principal cells to aid sperms maturation as glycerophosphocholine, sialic acid and glyoproteins. 3. Phagocytosis: for the residual bodies and degenerated sperms that are not phagocytized by Sertoli cells. 4. Capacitation and decapacitation functions: a. Decapitation: sperms acquire a decapitation factor in their heads from epididymal fluid which acts temporarily until they reach the female genital tract; this factor is inactivated just before fertilization. b. Capacitation means that sperms acquire motility and ability for ovum penetration (fertilization) during their in female genital tract. 5. Contraction to move and push the sperms during ejaculation. Fig 9: Section in epididymis 148 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 2- Ductus (Vas) Deferens The vas deferens is the longest part of the extratesticular ducts. It is a fibromuscular tube connecting the tail of the ductus epididymis with the prostatic urethra. It ascends along the posterior border of the testis as direct continuation of the duct of epididymis and then enters the abdomen as a component of spermatic cord by passing through the inguinal canal. After leaving the spermatic cord, it descends in the pelvis behind urinary bladder where it dilates and forms the ampulla of the vas. The ampulla joins the seminal vesicle duct to form the ejaculatory duct. Its wall formed from: (Fig 10) Mucosa: a) Epithelial lining: Pseudostratifid columnar epithelium with stereocilia. b) Lamina propria It contains abundant elastic fibers. Musculosa: The muscular wall of the vas is thick in proportion to the diameter of the lumen. The muscle is organized indistinctly into three layers: inner and outer layers of longitudinal smooth muscle fibers and a middle layer of circular fibers. Adventitia: It is an external layer of connective tissue invests the musculosa. Function: transports the spermatozoa from tail of epididymis to ejaculatory ducts Spermatic cord The spermatic cord contains 5 structures surrounding by C.T coverings: (Fig 10) 1. Vas deferens. 4. Cremastric muscle. 2. Testicular artery and vein. 5. Lymphatic vessels and nerves. 3. Pampiniform plexus of veins. 149 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Fig 10: Structure of vas deferens and spermatic cord 3- Ejaculatory Duct It is formed by joining the ampulla of vas with the duct of seminal vesicle. It penetrates the prostate gland to open in prostatic urethra. The wall of ejaculatory duct is formed of simple columnar epithelium with the underlying lamina propria. It has no muscular layer. III. ACCESSORY GLANDS All the accessory glands (Fig 11) help in nutrition, protection and easy transport of sperms. Fig 11: Accessory male glands 150 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Physiology of Male reproduction Hypothalamic-hypophyseal testicular axis 1-Gonadotropin- releasing hormone (Gn-RH): - Decapeptide secreted by the hypothalamus →to the anterior lobe of the pituitary gland, through the hypophyseal portal circulation → release of FSH and LH hormones. - The secretion of Gn-RH is continuous in male not cyclic as in female. This known as sexual differentiation of the hypothalamus. - Gn-RH stimulates the release of gonadotropic hormone through cyclic AMP. Control of Gn-RH: (A) Feedback control 1. Long loop between testosterone , hypothalamus and anterior Pituitary gland. 2. Short loop between FSH and LH and the hypothalamus (negative feedback). (B) Nervous factors: e.g. emotional and physical stress act on the hypothalamus leading to decrease Gn-RH secretion →decreased secretion of pituitary gonadotropin and decrease fertility in men. 2- Pituitary gonadotropin (FSH & LH): LH: tropic to Leydig cells → stimulates testosterone secretion. So called ICSH. FSH: tropic to Sertoli cells → stimulates spermatogenesis, maintains high concentration of testosterone in seminiferous tubular fluid, and stimulates secretion of inhibin and estrogen. LH and FSH are glycoproteins. They exert their effects on their target tissues in the testes mainly 156 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 by activating cyclic AMP, which in turn activates specific enzyme systems in the respective target cells. High testosterone blood level → negative feedback inhibition of LH secretion at both hypothalamic and pituitary levels, and vice versa. High inhibin blood level → negative feedback inhibition of FSH secretion from the anterior pituitary, and vice versa. 1- Spermatogenesis 2- Endocrine (hormonal ) function Spermatogenesis requires about 64 – 74 days in man, Steps: (see before page 151) Role of the Sertoli cells in spermatogenesis ❖ Responsible for blood testis barrier formation (protective) ❖ They provide a special environment for germinal cells development. ❖ They secrete a fluid that provides nutrients for the developing sperm. ❖ They phagocytose residual bodies resulting from the process of spermiogenesis ❖ Spermiation or conversion of the spermatid to mature sperm (it secrete digestive enzymes that remove most of the cytoplasm of spermatids). ❖ Play a physical role in shaping the head & tail of the sperm. ❖ Secrete some hormones: o Mullerian inhibitory factor (MIF) during fetal development to inhibit the formation of fallopian tubes from mullerian ducts in male fetus. o Estradiol, as one of the stimulatory factors in spermatogenesis. o Androgen–binding protein (ABP), that maintain a high, stable supply of androgen in the tubular fluid. o Inhibin, has a negative feedback effect on the anterior pituitary gland to prevent over secretion of FSH. o Activin, follistatin, IGF-1, transferrin & cytokines (Plasminogen activator). 157 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 Histology of female reproductive system It includes: (Fig. 1) 1) Internal genitalia consist of: A. Paired ovaries. B. Paired fallopian tubes. C. The uterus. D. The vagina. 2) External genitalia consist of: A. Clitoris. B. Labia majora. C. Labia minora. Fig. 1: General structure of female genital system INTERNAL GENITALIA A. OVARIES They are the primary sex organs that consist of paired almond-shaped glands approximately 3 x1.5 x 1 cm and located intraperitoneally (Fig.1). Function: The ovaries perform three main functions: 1. Produce immature female gametes or oocytes. 2. Secrete female sex hormones, including estrogens and progesterone. 3. Secrete inhibin, involved in the feedback control of pituitary FSH production. Development of gametes (oocytes) (oogenesis): (Fig. 2) 181 ENDOCRINE & REPRODUCTIVE SYSTEM MODULE 2024-2025 1. Around the first month of embryonic life, a small population of primordial germ cells migrates from the yolk sac to the gonads where they divide by mitosis then differentiation into oogonia 2. Oogonia contain diploid number of chromosome (2n) and diploid amount of DNA (2c). 3. At third month, oogonia divide by mitosis and differentiate into primary oocyte. 4. Primary oocyte duplicate their DNA before entering the first meiotic division (S phase). Therefore, each primary oocyte contain diploid number of chromosome (2n) and tetraploid amount of DNA (4c). 5. At fifth month, primary oocyte enter the prolonged prophase of the first meiotic division and stop. They do not complete this division until puberty, just before ovulation at each menstrual cycle. 6. After birth, many primary oocytes are lost through a degenerative process called atresia. 7. At puberty, the ovaries have about 600,000 primary oocytes. 8. Primary oocyte completes its first meiotic division shortly before ovulation to produce secondary oocyte. 9. Secondary oocyte contain haploid number of chromosome (1n) and diploid amount of DNA (2c). 10. One secondary oocyte is liberated in each menstrual cycle (average duration, 28 days) and as the reproductive life of a woman lasts about 30-40 years, only about 450 oocytes are liberated. All others degenerate through atresia. 11. Immediately after ovulation, the secondary oocyte enters the second meiotic division (without DNA duplication) and arrested at metaphase. It will be completed if fertilization occurred forming mature ovum (haploid number of chromosome (1n) and haploid amount of DNA (1c). 12. Fig. 2: Oogenesis 182 ENDOCRINE & REPR
