Reproductive Physiology and Endocrinology
Reproductive Physiology and Endocrinology BMS 640
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PRIMER ON MEIOSIS Mammals sexual reproduction 2 components meiosis and fertilization Some nonmammalian vertebrates reproduce Via parthenogenesis no fertilization but still meiosis Some Species have no 0quot more later in course Meiosis occurs in gonads starts prebirth 5 mammal and at puberty 0quot Nomenclature mitosis and meiosis mo her father After the S phase this all duplicated sister chromatids identical compientary compl tary not identical Cells that will undergo meiosis meiocytes Produced by mitosis from gonial cells Gonia 1 meiocyte 2 meiocyte tid 2N 4N 2N 4N 2N N O W w Meiotic divisions vs mitotic l 2 divisions wonly 1 DNA syn 2 No or very short G2 after S phase MI 3 Chromosomes move differently and independently 4 Very long cell cycle weeks common years sometimes Have classical stages when cell divides as in mitosis interphase prophase metaphase anaphase telophase interphase Repeated for meiosis 11 Also sequences similar to mitosis appearance of chromosome breakdown nuclear envelope migration centrioles disappearance of nucleolus So the sequence of relevance is last G2 mitosis M gon1al cells S31 longish 62 absent Meiosis I M J Prophase This prophase very prolonged metaphase etc divided into 5 parts Classically Prophase described on basis of light microscopic observations leptotene adj zygotene pachytene diplotene diakinesis Start with preleptotene meiocyte at this point chromatin dif lse strands clumped Then prophase divided into 5 stages arti cial man made stages for continuum 1 leptotene Greek leptos for thread see highly attenuated long thin threadlike chromosomes 11139 ht 39 39 a 1g mlcrOSCOPy VleW Keywordthread Late leptotene chromosomes seem to stick to one side nuclear membrane ex bouquet formation in plants synizetic knot attach nuclear membrane near centriole 2 zygotene Greek for yoke adjoining pair homologous chromosomes come together in zipper like fashion point for point pairing each of homologous chromosomes is a pair chromatids can t recognize chromatids with light microscope at this Nothing like this occurs in mitosis 3 pachytene Greek for thick thickening amp apparent coiling of chromosomes Keyword thick 4 diplotene Greek for 2 see that each homologous chromosome is actually a pair chromatids Tetrad also see chiasmatas morphological correlate of genetic crossing over each homologous pair at least 1 chiasmata or apoptosis Keyword doubling Homologs seem to repel each other except at chiasmata I Is apparent actually Chromosomes go through diffuse stage many species doubled much earlier dyctiatate or dyctiotene Lampbrush chromosomes in some species 5 diakinesis Greek for across tetrads coil thicken shorten terminilization of chiasmata nuclear envelope disappears centrioles begin migration nucleolus disappears prometaphase prophase metaphase anaphase telophase somewhat like mitosis nuclear membrane forms at completion of MI in some species quick interkinesis no S phase GI and G2 are one phase and cells go through the rapid cell division of MII 9x Pairing of axial cores usually start ends of chromosomes on nuclear membrane bouquet formation ends at chromosomes where they attach nuclear membrane Is great debate over pairing of homologous chromosomes how it occurs See pairing light microscope at zygotene but it may occur earlier Some authors differentiate pairing from synapsis latter is more intimate version Some base pairing involved W Wao am W WVWW Wj wail 7 WA 73 A fjw w hwgt w Eff Aer mwJK LW ltQ3ltJgt ltLlt I r u u P L m I j H 1 u ltlt bk ltlt Are Oral Contraceptives Safe for Women MMeyers and B Spizziri History Hormones Hypothalamus and Pituitary Hormones 39Progestin and estrogen have feedback GnRH at hypothalamus 39FSH has an estrogen effect and LH has the progestin effect at the pituitary Types of Oral Contraceptives Combined Oral ContraceptiveCOC ProgestinOnly Oral Contraceptive MinipillPOC Hormones Involved in Combined Oral Contraceptives COCs Estradiol Synthetic Estr0gen Pr0gester0ne Antiestr0 gen effects Synthetic Pro ge stin Combined Oral Contraceptive Generations Progestin Derivatives 1st Generation 2nd Generation 3rd Generation Estr0gen Derivatives iMestranol iEthinyl Estradiol Estrogen and Progestin Binding Affinity Differs by progestin HalfLife Peak serum concentrations Combination Oral Contraceptive COC Ethinylestradi01 Dose 20 40 micrograms 2quotd and 3rd generation progestins oProgestin component D0se 01515 mg oNormal schedule is 21d on COC with a 7d gap Current COCS oLower Estrogen dose than 1960 s 50150 lpg vs 2040ug of estrogen oNew 2quot and 3rd generation progestins 10mg vs 01515mg Occurrence of serious side effects decreased due to lower dose of estrogen and progestin COCS Prevent Pregnancy 39Prevent ovulation Progestin effects Suppresses LH secretion olhickens cervical mucus preventinghindering sperm transport olhins endometrium preventing ovum implantation Interferes with secretoryperistaltic function inside fallopian tubes Estrogenic effects olnhibits ovulation by suppressing FSH and LH oAlters endometrium secretions Progestin only Oral Contraceptive o Minipills POC lower dose of progestin 28 day active hormone cycle Does not always supress GnRH Ovulation can occur Efficacy dependent on cervical mucus and endometrial effects 610 ectopic pregnancies among users Not as common Risk Factors Venous ThromboembolismV TE Highest risk in first year of use Highest risk with 3r generation progestins 50 fold increase of VTE if individual is a carrier for coagulation Factor V Leiden mutation when using 3rd generation COCs Duration of Use VTE risk decreased with decreasing estrogen dose 2quotd generation safer than 3rd generation Translates 12 additional casesyr 10000 users Highest risk associated with lSt generation users Myocardial Infarction MI Stroke 2 fold increased risk of Ischemic Stroke with any COC oCOCs with dose greater than 50ug Ethinyl estadiol have greatest risk oCon icting results between risks with 2quotd or 3rd generation COCS oCarriers of Factor V Leiden mutation had 13 fold increase risk Additional Risk Factors for MIStroke olncreased Risks with COCs Smoking Age gt30 23 fold Hypte1tension 10 fold Estrogen Level gt30 ug Hypercholesterolemia Obesity Migraines if over 35y oPOCs do not cause a risk of myocardial infarction or stroke Migraine Estrogens are vasodilators causing migraines in some women Migraines are thought to be associated with estrogen withdrawal period Dose and progestin generation does not in uence migraines Occurrence highest in women gt35y Migraines are linked to a stroke Bone Mass oCOC users lt18y may gain less BMD oDecreased estrogen exposure oLoss of bone mineral content olncreases risk of fracture oLimited studies in women under 30 Gall Bladder Disease Oral contraceptives have little effect on development of gallbladder disease Use of COCs can cause gall bladder attacks COC association is unknown Hormones may increase cholesterol saturation and decrease gall bladder motility Decreased motility causes gallstone formation Risk of Breast Cancer Increased risk if used lt45y 2040X Increased risk if 2029 or lt35 Greatest risk is in women lt35 with recent COCs Increased risk if used gt35y due to increase risk of breast cancer with age Con icting results for type or generation of progestin 50X higher risk with gt35 ug estrogen dose With breast cancer COC users have increased rate of tumor growth POCs have lower risk Fertility 39Fertility Problems 58 lst cycles are ovulatory Cycles can take up to one year to normalize 39Oral contraceptives do not cause permanent infertility Bene ts 39Prevention of 39Bone loss o12 increase in BMD vs control gt18y oGreatest protection with 210 yrs use oDue to estrogen dose 25ug 39Treatment of Acne Hirsutism 39COC regulate Irregular cycles Dysmenorrhea Menorrhagia Amenorrhea Pelvic in ammatory disease PID COCs increasing the thickness of cervical mucus Preventing bacteria from moving up the reproductive system Decreasing menstrual ow limiting the opportunity for bacteria to grow in the upper reproductive tract Ectopic pregnancy Less likely High contraceptive efficacy Ovarian cancer 10 to 12 percent decrease in risk after 1 year of use 50 percent decrease after 5 years of use Regardless of generation or dose Endometrial Cancer Decreases with length of use Protection continues after discontinuation Breast Cancer Bene ts Long term COC use reduces Benign breast disease BS640 Bott amp Gee Descent of Scrotal Testes and Temperature Regulation Importance of scrotal descent 0 Failure of testis descent into the scrotum is one ofthe two most frequent male reproductive pediatric complications Descent is essential for normal spermatogenesis Undescended testes leads to an increased incidence in testicular cancer Descent is essential for normal fertility as spermatogenesis can be greatly affected Phases of scrotal descent o lntraabdominal o lnguinoscrotal The gubernaculm and scrotal descent 0 Thick ligamentous structure comprised of condensed mesenchymal cells Peritoneal cells infiltrate the gubernaculum at the levels of the inguinal cannal Once the testes are in the inguinal region the first phase of testicular descent in complete The gubernaculum begins to regress This regression is the driving force pulling testes into the scrotum Gubernaculum penetrates the inguinal ring and grows rapidly from the distal end In 1973 scientists removed one or both testes from dogs and found abnormal gubernacular growth Testes or testis extract must be present to stimulate gubernacular growth in vivo and in vitro descendin lnsl3 Produced and secreted by Leydig cells priorto mesenchymal proliferation and gubernacular growth Transgenic INSL3 mice are cryptorchid with undeveloped gubernaculum LGR8 is a potential receptor for INSL3 Many labs have found implications for INSL3 in cryptorchidism Very few clinical cases of cryptorchidism have been linked to mutations in INSL3 or LGR8 Many other factors have been implicated in the 1st phase of scrotal descent especially other members ofthe insulin family Role of Androgens o Androgens have been implicated as the primary factors involved in the second phase of testis descent Androgens are important for gubernacular bulb development When given antiandrogens gubernaculum growth and testis descent is inhibited This is easily reversed by addition ofandrogens BS640 Bott amp Gee 0 Timing ofthe actions ofandrogens is critical Problems associated with testicular descent Cryptorchidism o Aetiology is multifactorial 0 Risk factors include low birth weight when adjusted for gestational age twinning maternal exposure to estrogen in 1st trimester May be heritable some breeds appear more at risk Surgical correction prevent loss of germ cells in humans Induced promotion of rapid lean muscle growth investigated as a form of contraception in humans Ectopic testes Inguinal hernia Thermoregulation and scrotal testes 0 Maintenance of testicular temperature of 2 7 C below body temperature is essential for spermatogenesis 0 Main anatomical features forthermoregulation Thin scrotal skin often hairless lots of sweat glands Tunica dartos and cremaster muscle Pampiniform plexus countercurrent heat exchange Absence of fat Testicular descent thermoregulation and exceptions Testicular descent allows testicles to be kept at lower than core body temperature essential for normal spermatogenesis Core body temperature is lethal for germ cells 0 Approximately 1500 species of mammals are nonscrotal 0 Most of these still have a transabdominal migration phase 0 Why is spermatogenesis still successful Some have testicles in a cooler position Some have specialized cooling systems Some have a low core body temperature Some we just don t know BS 640 LECTURE OUTLINE 7 PRIMARY SEX DETERMINATION 0 Primary vs Secondary sex determination Primary differentiation of bipotential genital ridge into ovary or testis Secondary differentiation male and female sexual phenotypes internal reproductive structures and external genitalia Primary SD has to occur for secondary SD to happen 0 Primary sex determination 9 Genetic mammals birds snakes amphibians or temperature dependent some reptiles crocodiles many turtles 0 History 515 BC side of the womb 9 males on right females on left Parmenides 500428 BC side of the farther s testis Anaxagoras 384322 BC goal semen is to produce males High temps 9 male cold temps 9 female Aristotle 19111 century environmental factors food impose the sex on the fetus 201h century sex determined by sex chromosomes Klinefelter XXY male and Turner X0 female 9 Y chromosome maleness o Genital ridge 9 bipotental gonad 9 ovary or testis What directs bipotential gonad to develop as ovary or testis 1970 s 9 HY antigen Histocompatibility antigen discovered in 50 s as male specific antigen that caused female mice to reject male skin Male specific antibodies detected in females with male skin rafts 9 serologically defined HY antigen SLIDE 1 Late 80 s 9 er mutant mice separated Tdy from HY era 9 XX males containing both Tdy AND HY antigen erb 9 gene fusion onfyl amp 2 deletes HY locus but leaves Tdy Also XX males 1990 9 discovery Tdy SRYSry XX mice transgenic for Sry 9 males Sry 9 HMG domain SLIDE 2 amp 3 0 Insight using transgenic mice 9 genes required for establishment genital ridge 0 Genetic control sex determination SLIDE 4 8 Sry Sox9 DaXl transcription factors 9 testis determination 9 AMH Wnt4 9 prevent 39J 39 vascular d 39 I 0 Anatomy of fetal gonadal differentiation Precursor somatic cells 9 Sertoli cells coelomic epithelium amp Leydig cells PGC s 9 oogonia enter meiosis amp spermatogonia enter mitotic arrest o Sry induces several pathways to initiate testis development SLIDE 9 amp 13 PreSCs proliferation Sertoli cell differentiation 9 Leydig cell differentiation Cell migration vascular endothelial cells peritubular myoid cells Development of testis specific vasculature 9 acitivin B Sox9 upregulation o Sry expression Mouse 24 hours vs humans into adulthood Expression pattern 9 center to poles Expression alone required but not sufficient XX Sox9 transgenic mice 9 male XYSry Sox9 transgenic mice 9 fertile male DaxlGata4Fog2 mutant B6 XY mice 9 Sry Sox9 9 ovaries 0 Do PGCs play a role in GSD PGCs important for ovarian NOT testicular development XX PGCs develop into spermatogonia in XY gonad XY PGCs develop into oogonia in XX gonad 9 hypothesis meiosis inhibiting substance secreted by XY gonad 0 Recent work by Koopman and Page 9 role of Retinoic Acid SLIDE 14 XY gonads metabolize RA thereby preventing PGC entering meiosis Intersex disorders Musculinized genetic females excess androgens Undermasculinized genetic males defects androgen synthesis resistance to androgens True hermaphrodites tesicular and ovarian tissue 9 mostly XX Free martins cows and sheep most frequent form of intersexuality in cattle 9 projector slide masculinzed XX female calf born as twin of XY male due to vascular connections between female and male fetuses 9 results in masculinization of female internal reproductive tract male hormones andor XY cells Humans 9 monozygotic twins of opposite sex Wachtel et al 2000 Both were 46 XY 46 XY female 9 normal external genitalia l undifferentiated gonad 46 XY male 9 1 normal developed testis l underdeveloped testis both intact Sry 46XY45X composition Mutation in downstream gene XXXY chimeras Tissue containing cells with different genotypes XXXY chimares 9 Sertoli cells predominantly XY True hermaphrodites SLIDE 15 Ovotestes 9 concordant with Sry expression pattern OT70TOT7TOT7007T Within gonad OTO OTT TTO Complete gonadal sex reversal XY females 20 explained by Sry mutations 9 streak gonads XX males 80 explained by Sry translocation Sexual Differentiation of the Brain Sexual Dilnorphism structural differences between the sexes Sexual dilnorphisms found in many regions of the brain We will focus on sexual differentiation of the hypothalamic pituitary axis and the role of steroid hormones in sexual differentiation In mammals the default is female with differentiation toward masculine patterns of gonadotropin secretion and behavior occurring in the male as a result of exposure to hormones of testicular origin during development In mammals differentiation includes 1 Defeminization suppression of female behavioral and cyclic pattern of gonadotropin secretion 2 Masculinization enhancement of male characteristics Landmark study Phoenix Goy Gerall and Young 1959 These authors proposed that testicular steroids could permanently alter the developing nervous system to make it more likely to display masculine behaviors and less likely to display feminine behaviors o This irreversible effect was organizational and not activational 0 Exposure of female guinea pigs to androgens in utero reduces their receptivity or female behavior in adulthood o What is different about males and females that cause them to behave differently Answer Brains are structurally different Aromatization hypothesis Aromatization hypothesis was originally developed through research with rats Observations 1 Soc DHT is less effective than either testosterone or estradiol to induce defeminization 2 The developing brain is a site of androgen to estrogen conversion 3 Inhibition of estrogen formation from androgen or the ability of estrogen to bind to the estrogen receptor iInpairs sexual differentiation of the brain 4 Estrogen is 1000 tilnes more potent than testosterone 5 A single injection of estradiol benzoate postnatally masculinizes the volume of the SDN POA of the female rat 6 Further evidence that the actions of androgens are not critical in the developing brain came from Tfm male rats These rats have 85 90 fewer androgen receptors than normal littermates yet gonadotropin release and sex behavior do differentiate with testosterone OH Testosterone 0 5a Reductase Ammatase OH HO 5 DHT Estradiol Critical Periods From MacLusky and Naftolin 1981 Critical Period Animal Gestation or Incubation after conception Rat 20 22 18 27 days Mouse 19 20 Postnatal Guinea Pig 63 70 30 37 days Sheep 145 30 90 days Rhesus monkey 146 180 40 60 days Zebra finch 12 14 posthatching Role of estrogen receptors in sexual differentiation With the identification of a second estrogen receptor beta in 1996 it was suggested that the processes of masculinization and defemenization could be regulated by selective activation of either the alpha or beta receptor It has been shown that these two processes are regulated via two different estrogen receptors Estrogen receptor alpha EROL masculinization Estrogen receptor beta ER defeminization EROLKO mice fewer numbers of males exhibit copulatory behavior ER KO mice No difference in male reproductive behavior in WT and KO mice Both WT and KO mice show copulatory behavior This indicates that their brains were masculinized Morphological Sex Differences The preoptic area POA of the anterior hypothalamus has been iInplicated in male sexual behavior Lesions in the FDA of rats caused males to lose interest in mating females Dr Gorski showed that the FDA was 5 6 tilnes greater in size in male rats compared to females 0 He termed this region sexually dilnorphic nuclei POA SDN FDA 0 Nucleus of the SDN POA is visible in rats at 20 days post fertilization No significant sex differences in the volume of the SDN POA until day of birth 3 days later 0 During the next 10 days there is a gradual increase in SND POA volume in the male 0 Castration of newborn rat produces a significant reduction in the volume of the SDN POA Administer testosterone the following day and the reduction in size can be prevented 0 Administration of testosterone to a newborn female rat will increase the volume of the SDN POA In humans this region is known as the third interstitial nucleus of the anterior hypothalamus INAH3 The volume of INAH3 is greater in males than females The INAH is larger due to greater number of neurons but these differences are not detected in children younger than 6 years of age In sheep the ovine sexually dimorphic nuclei oSDN is greater in size in males than females The SDN POA of the rat INAH3 of the human or oSDN of the sheep brain have all been speculated to in uence male sexual behaVior Specifically the SDN POA has been associated with male copulatory behaVior and sexual partner preference It is unknown if these nuclei in the brain are homologous among the spec1es Protection Hypothesis Alpha Fetoprotein rats and mice 0 A plasma glycoprotein produced by placenta and hepatocytes during fetal life AFP is in great amounts during fetal life and markedly decreases soon after birth That alpha fetoprotein binds specifically to estradiol and not testosterone led to the hypothesis the fetal female brain is protected from estradiol by alpha fetoprotein If estradiol were not bound by AFP estradiol would be free to enter the brain and cause masculinization and defemenization of the female brain 0 Afp female mice show no female sexual behaVior The Afp female mice do not exhibit lordosis behaVior However administration of an aromatase inhibitor to pregnant females beginning on day 12 of pregnancy restored female sexual behaVior in Afp female mice 0 Steroid hormone binding globulin primates and other mammals Effects of Sexual Differentiation in Gonadotropin Release 0 Males tonic LH release 0 Females LH surge o Androgenized Females treatment with testosterone in utero prevent the LH surge from occurring 0 Female rats exposed to testosterone fail to ovulate o Ovaries transplanted to the anterior chamber of the eye in male rats develop mature follicles but do not ovulate These follicles will ovulate if the male rat is gonadectomized at birth the critical period of sexual differentiation of the SDN POA o Aromatization of testosterone defeminizes the brain that a LH surge does not occur in either males or androgenized females TAKE HOME MESSAGE Testosterone from the fetal testis is aromatized to estradiol within the fetal brain During the critical period estradiol causes organization of the CNS The organizational effects which occur during fetal development in long gestation species or postnatally in short gestation species are permanent In contrast the activational effects of the hormones are transient and occur in adulthood ie puberty Exposure to testosterone estradiol during the fetal period masculinizes and defeminizes the brain Masculinization of the nuclei is essential for male typical adult behaviors Defeminization is the loss of adult female typical behaviors and suppression of estradiol to induce an LH surge Sertoli Cells Prepubertal Fill seminiferous tubule no lumen Secrete antiMullerian hormone in fetal life are preSertoli cells Postbirth but prepubertal there is a critical window weeks to months depending on species in which preSertoli cells divide to form the number of Sertoli cells that will be present in adults Numbers regulated by FSH secretion and FSH receptor numbers Also need GNRH LH testosterone If unilateral castration compensatory hypertrophy really mostly hyperplasia Get nearly doubling of Sertoli number in remaining testis mechanism FSHinhibin driven Only minor effect of unilateral castration in adult and no increase in cell numbers Testis size genetic component highly heritable about 60 genetic depends on FSH regulation of Sertoli cell numbers during the critical window Female relatives have the same mechanism but different endpoint larger testes earlier puberty in female relatives Sperm production directly correlated testis size about 15 germ cells per Sertoli in adult After critical period prepubertal Sertoli cells rarely divide if ever Very resistant to irradiation toxins hard to kill germ cells easy to kill very susceptible to insults Morphology Is an epitheliumbasement membrane in seminiferous tubules lumen into which uids sperm secreted Without germ cells Sertoli cells would fill seminiferous tubule Myoid smooth musclelike cells around outside of tubule Junctions between myoid cells Big species differences in numbers of layers myoid Leydig cells and infrastructure such as blood and lymph vessels between Sertoli cells Sertoli cell structure Euchromatic pleiomorphic nucleus much transcription Some species lots of smooth endoplasmic reticulum Many lysosomes vacuoles lipofuscin accumulates in older males Very elaborate junctions between Sertoli cells At ends of S tubules specialized Sertoli cells form tubuli recti valvelike entrance into rete testis D Bloodtestis barrier No blood cells get into S tubules in most species bathed in lymph Large molecules perfused in blood to testis do not get into S tubules Some smaller molecules get by the myoid cell junctions but get stopped by SertoliSertoli junctions These junctions divide S tubule into basal and adluminal compartments Adluminal part completely protected from blood Small molecules need to go through rather than between Sertoli cells to get from blood to adluminal compartment Slides of Sertoli cells diagrams light microscope scanning and transmission electron microscope Regulation of Sertoli cell function FSHFSH receptor Standard protein kinase A system cyclic AMP protein kinase A phosphorylation of key proteins regulation of transcription enzymes etc Effects FSH different prepubertal than post Pre stimulate mitosis cell proliferation differentiation Post glucose uptake metabolism protein synthesis secretion physiological function Hypophysectomy Sertoli cells and testis shrink Testosterone also key regulator very high concentrations androgen receptor 5a reductase converted to dihydrotestosterone Aromatase converted to estradiol 17 beta Species differences how much DHT E2 Permissive stimulators Vitamin A retinol is concentrated by Sertoli cells need retinol binding protein Vitamin E absolutely essential in some species Numerous autocrine and paracrine regulators IGF l system testis speci c and non speci c growth factors 2 way communication Leydig and myoid cells germ cells G Sertoli cell secretions Over 100 proteins made and secreted secreted as made not stored species differences Main protein secreted androgen binding protein 80 secreted lumen 20 basal possibly used Sertoli cell itself goes into rete testis uid delivered to head of epididymis may function to deliver andro gens to epididymal epithelium in addition to transport Synthesis and secretion very FSH dependent Inhibin heterodimer of TGFbeta family Negative feedback to gonadotrope in anterior pituitary for FSH secretion Measurement confusing because homodimer is activin with Opposite function causes FSH secretion Transferrin and ceruloplasmin iron and copper binding proteins needed for protein function Retinol binding protein Vitamin A Plasminogen activator urokinase type proteolysis for spermatid remodeling release Most secretion into rete testis uids about 10 plh gm testis uid secretion also depends FSH H Sertoli cell functions Nurse cell regulate spermatogenesis and spermiogenesis Many genes are expressed only in the testis have testicular versions of many non testicular genes e g testis speci c lactate dehydrogenase The haploid late spermatid and sperm very dependent on Sertoli cell can t synthesize their own proteins Rete testis uid more like intracellular than extracellular uid very high potassium This uid also transports sperm which are non motile when spermiation occurs Maintain blood testis barrier Protection immune system post meiotic proteins not present when self non self established by immune system sperm very antigenic need protection from immune system if breached subfertilitysterility This happens with testicular damage vasectomy some diseases BT barrier also protects environmental toxins diseases etc to great extent Premeiotic cells in basal compartment postmeiotic in adluminal junctions between Sertoli cells open and close to let germ cells pass multiple sequential junctions I Sertoli cells in vitro Dif cult to maintain appropriate geometry Cells plate down and form at layer unless extracellular matrix such as Matrigel collagen hyaluronic acid etc Much learned isolated Sertoli Cells beginning to have successful in vitro spennatogenesis at least some steps J Pathologies Any derangement in gonadotropintestosterone secretion causes problem genetic or otherwise Injury irradiation stop spermatogenesis Sertoli cell tumors rare typical of nondividing cells Heat very damaging Descent of scrotal testes and temperature regulation Rebecca C Bott MS Erica K Gee BVSc PhD BS 640 Fall 2006 Failure of testis descent into the scrotum is one of the two most frequent male reproductive pediatric complications 3 mature male newborns up to 4596 1 in 1 year old boys I 30 prevalence in premature boys Importance of scrotal descent I Undescended testes leads to an increased incidence in testicular cancer I 15fold increase in unilateral crvtporchidism I 30fold increase in bilateral crvptorchidism I Descent is essential for normal fertility as spermatogenesis can be greatly affected Scrotal Animals Scrotal Swine Cattle Goats Sheep Felids Canines Primates Rodents Nonscrotal Birds Reptiles Elephants Dolphins Fish Comparative view of testes Testis development amp migration I Intraabdominal Inguinoscrotal Gubernacular development I I Thick ligamentous structure comprised of condensed mesenchymal cells I Peritoneal cells infiltrate the gubernaculum at the levels of the inguinal cannal E E mm mud W ch83 I g y Role of gubernaculum in descent I Once the testes are in the inguinal region the first phase of testicular descent in complete Visceral vaginal tunic i 7 L Vaginal cavity Parietal vaginal tunic Fully regressed gubernacu um n In 1973 scientists removed one or both testes from dogs and found abnormal gubemacular growth Testes or testis extract must be present to stimulate gubernacular growth in vivo and in vitro I descendln Role of INSL3 I Produced and secreted by Leydig cells prior to mesenchymal proliferation and gubernacular growth I Transgenic NSL3 mice are cryptorchid with undeveloped gubernaculum Many labs have found implications for lNSL3 In clyptorchldlsm Very few clinical cases of cryptorchidism have been linked to mutations in INSL3 or its receptor Androgens have been implicamd as the primary factors involved in the second phase of testis descent Androgens are important for gubernacular bulb development I When given antiandrogens gubernaculum growth and testis descent is inhibimd This is easily reversed by addition of androgens I Timing of the actions of androgens is critical l HM l39 lll l lII3I39 I 3R1 w 3939I 71HHJJ1J Cryptorchldism Aetlology is multifactorial Risk factors include low birth weight when adjusted for gestational age twinning maternal exposure to estrogen In i t trimester May be heritable some breeds appear more at risk Surgical correction prevent loss of germ cells in humans induced promotion of rapid lean muscle growth Investigated as a form of contraception in humans Problems with testicular descent Ectopic testes I Inguinal hernia l Rabbits and rats have a patent inguinal canal throughout life Herniated Lac IIIf mast HE E Ingunnal n canal Ductus dcfcrcns Testicular artery Narmal Inguinal Anatomy Hernia Visceral vaginal tunic Maintenance of testicular temperature of 2H below body tern rature is essential for spennatogenes s Five main anatomical features for thermoregulation Thin scrotal skin often hairless low of sweat glands Tunlca dartos Pamplnlform plexus Cremester muscle Absence of fat Scrotum thermosensor cooler and protector Supports testes Bilobod sac 4 major layers l Skin sweat glands and thormosonsltlvo nerves Thermoregulation Scrotum has many sweat glands lnnervated by sympathetic nerves Hypothalamus is sensitive to increases in testis or core body temperature Stimulates sweat glands to provide ovaporatlvs cooling Respiration Figure 311 Proposed Scrotal Sweating and Thermal Polypnea This reflex pathway re sulting in polypnea is not activated until scrotal temperature reaches about 39 C Respiratory muscles Polypnea panting Thermosensitive neurons in scrotum Y Pathways in Rams Thermosensitive neuronsin hypothalamus Sweat glands Scrotal skin Waltes 1961 and 1962 Heating device for scrotum of ram Scrotal exposure to 40 0 for 30 minutes resulted in the ram panting up to 200 bpm and lowering core body temperature by 1 degree Heating other areas of the body had little in uence on respiratory rate Time Min 60 d 4 N a Z O u 6 h D U Q n lt 30 C gtlt 40 C Countercurrent exchange I Testicular artery is highly convoluted and passed through the spermatic cord and surrounds the testes ventromedial I Testicular veins are in close proximity to the tortuous testicular artery in spermatic cord I Pampiniform plexus is the spermatic venous network which has lots of fingerlike wrappings surrounding the spermatic artery This allows for countercurrent heat exchange of veins with the testicular artery Countercurrent exchange Blood from body Blood to body 39 C 39 C Blood to testis 33 C Blood from testis 33 C Thermoregulation I Tunica dartos smooth muscle in the scrotum I Capable of sustained contraction elevating testes in cold environmental temperatures I Cremaster muscle is continuous with internal abdominal oblique muscle I Capable of shortterm contraction I Short term elevation of testicles during fear or excitement I Contraction and relaxation acts as a pump on the pampiniform plexus Men and underwear Varicoeles lnguinal lipomas I Testicular IIIW39mtlclu to be kept at lower than core body temperature essential for normal spermatogenesls Core body temperature ls lethal for germ cells I But there are always exceptions I Approxirmtoly 1500 spool of mammals an i nonsru39otal I Most of those still have a transabdominal migration phase I Why is sponnatogonosis still successful I Some have much In a 39ooolor position I 53 uplr has subcutlnoous tactic I Some haw opociallud cooling syourm I Eg dolphin and vascular countercum hut chm dorsal fin and tall nukes I Sambawnlowoorobodytemponhrro I I Somewojustdon39tknow Questions If you would like copies of our slides or a list of our references we would be happy to share Please email rebeccabottcolostateedu Androgene may act by caloltonin gene related peptide CGRP CGPR localized in the genitofemoral nerve Potential neurotransmitter dictating growth of the tip of the gubemaculum and directed migration of the gubemaculum into the scrotum Role of key factors is still debatable