lecture 45 Endocrine functions of the testis 2021

Education

1. Lecture 45 Endocrine functions of the Testes Dr Shamshad Majamaah University KSA

2. Objectives: Identify the different sex hormones secreted by tesits and contrast their biological activity. Describe the mechanism of action and the physiological effects of testicular androgens relating them to age .

3. Objectives: Identify the role of testosterone in male puberty. Discuss the role of hypothalamuo-hypophyseal -testiclar axis. Correlate this knowledge to the pathogenesis of the male hypogonadism.

4. Hormones secreted by Testes Androgens Others Testosterone Dihydrotestostereone:DHT Pregnenolone , Progestrone 17-OH progestrone Andosterndione Oestradiol Inhibin B and Activins Anti-Mullerian hormone (Mullerian -inhibiting substance,MIS) Insulin -Like factor 3

5. Androgens Androgens precursor : cholesterol Testosterone: P rimary testicular hormone In target tissues for further actions : Testosterone  (Active) Dihydrotestosterone (DHT)

6. Desmolase 3 -β-hydroxysteroid dehydrogenase 17 β-hydroxysteroid dehydrogenase 3 -β-hydroxysteroid dehydrogenase 17 β-hydroxysteroid dehydrogenase 3 β-hydroxysteroid dehydrogenase 17 β-hydroxysteroid dehydrogenase 17, 20-desmolase 17, 20-desmolase Aromatase Aromatase Pathways :Testosterone biosynthesis

7. 3x more potent than Testosterone

8. Steroid % Free % Bound to Corticosteroid Binding Globulin Gonadal Binding Globulin Albumin Testosterone 2 65 33 Androsterondione 7 8 85 Estradiol 2 38 60 Progesterone 2 18 80 Cortisol 4 90 6

9. Sex hormone binding globulin (SHBG) :Carrier protein SHBG has 3 fold higher affinity for testosterone Synthesized mainly in liver Regulated by the opposing actions of sex steroids Androgens inhibits SHBG synthesis Estrogen stimulates SHBG synthesis

10. Concentration of Androgen in normal male adult Plasma testosterone (Free & bound) Adult male Adult female ng / dL 300-1000 30-70 nmol /L 10.4-34.7 1.04-2.43

11. Functions : Testosterone Important sex hormone in male Development and functioning of the male phenotype Stages T estosterone Effect In utero :Fetal life Sex differentiation Puberty Virilization Adulthood Maintenance of the male phenotype Sexual function Anabolic effects

12. Fetal life : Prenatal sex differentiation Differentiation & Maturation of wolffian duct Suppresses formation of female genital organs in male fetus Development of penis,scrotum,prostate, seminal vesicle & male genital duct Descent of testis through inguinal canal into scrotum during last two months of gestation. Applied : Cryptorchidism (undescended testis ) Testosterone administration . If left untreated may lead to testicular cancers .

13. Target Functions Sex organs Virilization & development of testes,penis,epididymis,seminal vesicle & prostrate.Initiation & maintenance of spermatogenesis. Muscles Increase: M uscle mass, lean body mass, Anabolic effect on muscles Skin and hair Increase : sebaceous secretion , acne formation, male distribution of hair, temporal baldness

14. Skeletal organs Pubertal growth spurt : Increase : bone matrix thus bone density,Calcium salts deposition,Accelerate linear growth, closure of epiphysis of endplates of bone, Funnel shaped pelvis with narrow outlet,strengthening of pelvis Blood cells Erythropoiesis:Stimulate erythropoietin from kidney, stimulate stem cells, increase Hb synthesis Increase: production of clotting factors Decrease :Anti-inflammatory effect: suppression of humoral and cellular immunity

15. Liver Increases : fibrinogen, hepatic triglyceride lipase,alpha1 antitrypsin, haptoglobin Decreases: SHBG ,hormone binding proteins, transferrin, fibrinogen Lipids Increases: Plasma HDL concentration Decreases : Plasma cholesterol, LDL and triglycerides concentration. Proteins: Anabolic: Increases: Activities of all cells,enzymes production,BMR, protein synthesis

16. Electrolyte & water balance Reabsorption of sodium in distal tubules, water retention, Increases ECF and blood volume hence body weight Bl.glucose Decrease: Fasting blood glucose, HbA1c Brain Increases: sex drive, Libido,Improves cognitive function, socialization, confidence, concentration, neuroprotective actions,mood, spatial orientation,aggression,Male voice Decreases : anxiety,depression,verbal abilities.

17. Epiphyseal plate closure: Mediated by estrogen Testosterone → estrogen via aromatase In testes, Sertoli cells express aromatase enzyme

18. Mechanism of action Testosterone binds to an intracellular receptor;Ex : NR3C4 Facilitating transcription of various genes. 1: Negative Gonadotropin regulation 2: Wolffian duct stimulation : sexual differentiation Sexual maturation at puberty Spermatogenesis ;gene regulation 3: External Virilization: sexual differentiation ;Gene regulation

19. G enomic and non-genomic effects of testosterone. Unbound bioactive testosterone interacts with the cytoplasmic androgen receptor (AR). AR is also activated by dihydrotestosterone in a similar way. Ligand binding induces conformational changes of the receptor. T-AR complex forms dimers and acts as a functional transcription factor. Activated AR recognizes the androgen response element in the nucleus due its specific structure. Coactivators (CA) and RNA polymerase II are recruited for transcription initiation. Gene expression produces a pool of specific proteins that can affect cell characteristics, metabolism and activity. The non-genomic response is mediated via receptor-tyrosine-kinases (RTK) or G-protein coupled receptors. Subsequently, downstream signaling cascades are activated, that can result in genomic effect (activation of various transcription factors, protein activation or new protein synthesis). G-protein coupled receptors can activate phospholipase C and cause an increase of intracellular Ca 2+ . All these processes are linked with changes in cell activity.

20. Degradation and Excretion of Testosterone Conjugated either to Glucuronides or Sulfates Conjugated metabolites are excreted F rom Gut through liver bile Or Kidneys through urine.

21. Testosterone Regulation

22. Human Chorionic Gonadotropins: hCG Fetal life : Secreted by placenta Stimulates testosterone secretion by the fetal testes Testosterone is helps in formation of male genital organs in fetus.

23. Inhibin Glycoprotein Molecular weight : 10k-30k From Sertoli cells in males & granulosa cells in females Action : Potent inhibitory feedback effect  Ant pituitary gland (FSH) Important Negative feedback mechanism  control of spermatogenesis

24. Heterodimers stimulates FSH Details not known Found in brain, bone marrow & other tissues Actions : In Bone marrow helps WBCs development. In embryonic life;involved in mesoderm formation. Activins :

25. Class Activity Complex Dimer subunits 1 2 Inhibin Inhibits FSH secretion Inhibin A α β A Inhibin B α β B Activin stimulates FSH secretion Activin A β A β A Activin AB β A β B Activin B β B β B

26. Follistatin: A Pituitary autocrine glycoprotein Inhibits secretion of FSH Kisspeptins : Family of neuropeptides localized ; Arcuate nucleus (brain) Stimulators of GnRh secretion. GnIH: Upstream of GnRh Operates at the testes: autocrine regulators of steroidogenesis

27. Hypogonadism : Nonfunctional testes During male fetal life :No male characteristics develop Instead female sex organs formed. B efore puberty : Eunuchism : Infantile sex organs Sex characters with tall height. Castrated after puberty : Secondary sexual character not affected Decreased sex desire,impotence & sterility Gradual dysfnction of accessary sexual organs FSh & Lh increased due to negative feedback mechanism

28. Adiposgenital dystrophy syndrome (Frohlich’s syndrome ) Rare disorder Characterized by: decreased GnRH production Obesity, Mental ,growth and genital organ retardation Associated with tumors of hypothalamus or hypothalamic eunchism develop

29. Klinefelter’s syndrome Kallmann's syndrome

30. Primary Hypogonadism Secondary Hypogonadism Site Testes Pituitary gland, hypothalamus Serum Testosterone Decreased Decreased FSH & LH Increased No changes, or decreased Causes Klinefelter’s syndrome Kallman’s syndrome

31. Primary: prepubertal onset:Eunuchoidism Causes: Klinefelter's syndrome Chromosomal abnormalities Mutation of gonadotropin receptors genes Cryptorchidism Congenital anorchia Lack of adult male hair distribution High pitched voice Infantile genitalia Increased fat deposition