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Endocrine Control of Male Reproduction. William Walker 383-8634 walkerw+@pitt.edu. Objectives 1. Understand the functions of the testis A. Secretion of testosterone B. Production of spermatozoa 2. Understand the endocrine and paracrine regulation of the testis.
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Endocrine Control of Male Reproduction William Walker 383-8634 walkerw+@pitt.edu
Objectives 1. Understand the functions of the testis A. Secretion of testosterone B. Production of spermatozoa 2. Understand the endocrine and paracrine regulation of the testis
Human Semen Abnormalities Azoospermia No spermatozoa in the ejaculate Oligospermia Sperm concentration < 20 million/ml Asthenozoospermia Less than 50% of spermatozoa have normal mobility or less than 25% have any motility Teratozoospermia Less than 30% of spermatozoa have normal morphology One or more of these abnormalities are found in 90% of infertile males. Treatments: In vitro fertilization Intracytoplasmic sperm injection
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport
Testis Cross Section Showing The Spermatogenic and Steroidigenic Units
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport
Binding of Testosterone by TEBG Testosterone levels: Peripheral blood- 4 ng/ml Testis- 100-600 ng/ml
Physiological Actions of Androgen In utero: External genitalia development Wolffian Duct development Pubertal: External genitalia Hair growth Linear growth Accessory sex organs Voice Pyche (aggressive attitudes, sexual potency) Muscle mass increase Initiation of spermatogenesis Adult: Hair growth, baldness Phyche (sexual potency) Maintenance of bone mass Maintenance of spermatogenesis
The Androgen Signaling Pathway Testosterone h s p 9 0 + A R h s p 7 0 C o a c t i v a t o r C o m p l e x A R A R S R C - 1 RNA Pol I I DHT A R A R A R E A A A A Testosterone A l t e r e d P r o t e i n C e l l u l a r F u n c t i o n Target tissues: Testosterone- muscle, testis DHT-external genitalia, reproductive tract, skin
Testicular Feminization (tfm) Androgen Insensitivity
DHT and Estrogen Synthesis Growth regulation Bone mass maintenance
Estrogen Regulates the Pubertal Growth Spurt in Men
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport
Regulation of the Hypothalamic-Pituitary-Testis Axis Negative Feedback (GnRH) Negative Feedback (LH) Negative Feedback (FSH)
A c R C G s R C CREB cAMP dependent kinase LH Binding to Receptors on Leydig Cells Induces the cAMP-Dependent Protein Kinase Signaling Pathway Leydigcell CYTOPLASM NUCLEUS R LH ATP cAMP P TRANSCRIPTION TGACGTCA downstream effector genes
Regulation of the Hypothalamic-Pituitary-Testis Axis Negative Feedback (GnRH) Negative Feedback (LH) Negative Feedback (FSH)
Kallmann’s Syndrome (GnRH deficiency) Symptoms: Hypogonadotropic, hypogonadal, aspermic, cryptorchid, absence of puberty, Defective sense of smell Defective KAL locus on X chromosome that encodes the anosmin protein Anosmin is a neural adhesion molecule Required for the correct migration of GnRH neurons Therapy: Androgen replacement-virilization Gonadotropin therapy-restore fertility
Pulsatile GnRH secretion is required for FSH and LH production
Serum LH concentrations in normal and hypogonadal men Normal ng/ml Hypogonadal ng/ml
Testosterone Treatment Decreases LH Secretion Frequency In Hypogonadal Men
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport
Human Spermatogenesis Spermatogonia Spermatocytes Meiosis Spermiogenesis Spermiation Time to complete =70 days
Cell Divisions During Human Spermatogenesis Spermatogenesis potential Human: 1 type A spermatogonia = 8 spermatids Rat: 1 type A spermatogonia = 4,096 spermatids?
Germ Cells Form Cytoplasmic Bridges Due to Incomplete Cytokinesis Result: Clonal development of germ cell cohort Synchronization of germ cell maturation
Cell Divisions During Human Spermatogenesis 3 phases of Spermatogenesis Stem Cell Renewal Proliferation of spermatogonia and spermatocytes Spermiogenesis Spermatogenesis requires 70-75 days in humans
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport
Sperm production: 800 million /day 5 million/10 minutes Regulation of Sperm Output: 1. Apoptosis 2. Toxic chemicals 3. Nutrition (Vit A) 4. Sertoli cell number 5. Testosterone and FSH
Sertoli cells are the targets for testosterone and FSH regulation of spermatogenesis Sertoli cells form a blood-testis barrier Nothing larger than 1 kDa can pass into the seminiferous tubule The germ cells develop in a protected microenvironment Sertoli cells must provide all growth factors and nutrients for germ cells FSH and testosterone regulate Sertoli cell gene expression and protein production
A c R C G s R C CREB cAMP dependent kinase FSH Binding to Receptors on Sertoli Cells Induces the cAMP-Dependent Protein Kinase Signaling Pathway CYTOPLASM NUCLEUS R FSH cAMP ATP P TRANSCRIPTION TGACGTCA Sertoli cell downstream effector genes
FSH Activated Genes In Sertoli Cells Transferrin Androgen Binding Protein Pyruvate dehydrogenase Lactate dehydrogenase Androgen Receptor Inhibin
Effects of Decreased FSH Action 1. Mouse FSHb gene knockout Sperm number reduced 75% Motile sperm reduced 45% 2. Mouse FSH receptor gene knockout 33% lower litter size Delayed sexual maturity Sperm number decreased 36% 2.6-fold increase in aberrant sperm 3. FSHb mutation in men 3 of 3 have azoospermia- infertile 4. FSH receptor mutation in men (C566T) Oligozoospermia (<1 x 106/ml) 1 of 3 are childless
Testosterone can maintain spermatogenesis after hypophysectomy 1 0 0 7 5 % of normal sperm count 5 0 2 5 0 FSH T FSH + T
FSH and Testosterone Synergy Testosterone concentration
Spermatogenesis is Regulated by Testosterone and FSH Testosterone and FSH act through Sertoli cell receptors. Testosterone: Can independently maintain spermatogenesis Required to complete meiosis Induces protein secretion from Sertoli cells Mechanism is unknown FSH: Not essential to maintain spermatogenesis Increases spermatogenesis efficiency Increases the number of Sertoli cells Induces factors supporting spermatogenesis
Paracrine Factors Produced by Sertoli and Germ Cells Stem Cell Factor Activin IL-1 Nerve growth factor IGF-1 TNF-a Sertoli cell Germ Cell
Do Sertoli cells or germ cells determine the timing of germ cell development? Use the info that rat and mouse germ cells mature at different rates. Experiment: Use drugs or radiation to eliminate only germ cells in mouse testis. Transplant rat spermatogonia to mouse testis. Do rat germ cells mature on a rat or mouse schedule?
Lecture Outline Testis structure Testosterone production and action Regulation of testosterone secretion Germ cell development (spermatogenesis) Regulation of sperm output Sperm transport