MCB 320 Exam 4 PDF

MCB 320 Reproductive Disorders Introduction to the Reproductive System Suggested Reading: Molecular Pathology, Chapters 22-23 Suggested Video: www.youtube.com/watch?v=eddh-AGV-6c 1...

MCB 320 Reproductive Disorders Introduction to the Reproductive System Suggested Reading: Molecular Pathology, Chapters 22-23 Suggested Video: www.youtube.com/watch?v=eddh-AGV-6c 1 ©Eric Bolton  Objectives Understand the anatomy and function of the reproductive system in males and females Understand gametogenesis in males and females Demonstrate understanding of the anatomy and function of the neuro-endocrine system Understand the regulation of male and female reproduction by the neuro-endocrine system 2 ©Eric Bolton  Why is Reproductive System Important to Human Health and Disease? Number % of All Rank Cause of Death of Deaths Deaths 1 Heart Diseases 702,880 21.4 · 2 Cancer (11% reproductive organs) 608,371 18.5 3 Accidents (unintentional injuries) 227,039 6.9 4 COVID-19 186,552 5.7 5 Cerebrovascular Diseases 165,393 5.0 Chronic Lower Respiratory 6 Diseases 147,382 4.5 7 Alzheimer Disease 120,122 3.7 8 Diabetes Mellitus 101,209 3.1 9 Kidney Diseases 57,937 1.8 10 Chronic Liver Diseases 54,803 1.7 Sources: Bray F et al. CA Cancer J Clin. (74) 2024; National Center for Health Statistics, Mortality in the United States, 2022, NCHS Data Brief 492, 2024. 3 ©Eric Bolton Anatomy of the Male Reproductive System 4 ©Eric Bolton  Male Reproductive System: 3 Accessory Glands Produce the Seminal Fluid Testosteron > - DHT induces growth of A Seminal Bladder Vesicles semen ↳ seminal fluid produce - which nourishes' protects sperm * Vas Prostate Deferens ↳ produces prostatic fluid which makes up sign. ↳ Transports sperm Portion of Seminal fluid epidydymis to * from creturn Urethra Bulbourethral Gland produces pre-ejaculate > - fluid which helps lubricate vreturn Epididymis ↳ stores > Matures sperm Testis Produce androgens ↳ specifically test - Sperm. 5 ©Eric Bolton  Functions of Seminal Fluid (Semen) Enhance transport of sperm to remall Composition ~3 mL per ejaculation ~1% spermatozoa (20 million or more sperm/mL) - ~99% accessory gland fluid (70% seminal vesicle, 28% prostate, 1% bulbourethral) - - ① supply for Survival Nutrient Substances released by accessory glands > - ProviMS nutrients moved emp for a Sperm -. Mob: Facilitate sperm mobility and - survival protection Enhance transport of sperm through the male and female reproductive tracts Creates environment for sperm in > - female reproduction system - survival for fertilization Protect the urinary and reproductive systems from - - pathogens that invade via the urethra intections > - ↓ Basic amine > - counteract acidic environment (female vaginal ↳ help protect DNA in spermatozod Sources: World Health Organization Laboratory Manual for the Examination of Human Semen and Semen-Cervical Mucus Interaction (4th edition) 2003. 6 ©Eric Bolton  -production ofsteroidnoromonef rom Productionper Steroidogenesis and Spermatogenesis - - Occur in the Testis Seminiferous tubule develop into sperm in speng space by sem tub. Spe. proved rest) Je outlines ↑ Stem Seminiferous tubules - alls spertmatogen Contain spermatogenic cells. spirgenupo and supporting Sertoli cells a Interstitial cells -turis Are surrounded by myoid cells Reside between the seminiferous tubules Leydig cells produce androgens (testosterone) - little estr) > 7 ©Eric Bolton  Steroidogenesis and Spermatogenesis Occur in the Testis 6Seminiferous tubule ② site where Seminiferous tubules > - spermatogen readin occurs the & Contain spermatogenic cells prod. Interstitial cells LeydigClls > - Reside between the seminiferous tubules and supporting Sertoli cells Are surrounded by myoid cells Support D developing * Nourish sperm alls resp. cells germ Leydig cells produce androgens (testosterone) for producing ; secrete horomoves to help * sperm Spermatogenesis reg. ↳ underg Mitosis * 7convery some test esa form spermatozon ©Eric Bolton meiosis to aromatase activity  ; Spermatozoa (Sperm) eabnormalfunctional not backwards d Normal healthy can't Head checking backwards for Nucleus – contains a haploid set of swimming = test to 23 condensed genetically inactive see if infertile chromosomes Acrosome – lysosome full of digestive enzymes used to penetrate the egg During fertilization > - Flagellar basal body – anchors the tail to the head caut Tail (flagellum) powerperm > Midpiece – contains - numerous mess seminal floid) mitochondria (ATP production) powers - > - movement s Principal piece – is longest portion of - L the tail (motility) > -crucial forpushing sperm thro longest - fluid works tog , midpiece w/ help to alls more forward portion Endpiece – tip of the tail , chstell > - 8 ©Eric Bolton  is where sperm produced via spermatogen. After being & Spermatogenesis Occurs in the - to produced sperm mon this where Seminiferous Tubules and Epididymis - tests- they complete differenticton storage for sperm prod in - Maturation > - - ↳ immature sperm alls that undergo Mitosis to prod. more ↓ support > - stem all pu key for - differentiate the meiosis imp is eventually to form sperm total) - ↓ formed from S Meiosis I & via spent Newbornimmature - Kapod23. mal sperm 2 Meiosis II & > - No mitotic activity T Each divide to Produce 2 Sperm inactive till data matures spermat. - during puberty grow read i in Spermatozoa/sperm - > - Epidynimus weeks where Epididymis > - Back of testis ~ 2 Spermis produced Consists of tightly coiled ducts that connect the - seminiferous tubules * to the ductus (vas) deferens tope that carries sperm out of testes > - Allows spermatozoa to complete differentiation/maturation 9 ©Eric Bolton  -occurs wi seministerous tobules of the testes Spermatogenesis ~ entive till puberty Before birth immaturecells sperm & - Adolescence for man 23X or y through adulthood 3 on spermatogonium produce 2 identical divides cells to 23 X all. for Em DNA replicates before Meiosis I TimingtosiSift (2 sets of 46 chromosomes) az > - chr. Formatio twounter chromatids ge he linked to em oMsal Segregation of homologous - chromosomes during Meiosis I x() - (2 sets of 23 chromosomes) - Separation of sister - 24 -11) chromatids - during Meiosis II 2x (1 set of 23 chromosomes) amettNA ↳ 23 single chromatids Eachgusevation for One primary spermatocyte creates 4 sperm 10 ©Eric Bolton  Neuro-Endocrine System > - Hypothalamus, pituitary gland , includes the HPG signaling axis - ginad (testes in Horomoves regulate Internal and external man , ovary in both reproduction in conditions eman) man a female noromones are s Sign Gonadotropin- d deteignal ke synsTon High levels of FSH CH inhibits releasing hormone - tuctprod. release of GnRtt (GnRH) Travels,d High levels of sex & horomones inhibits release & Of CH , FSH GnRH helps maintain homonal Balance in body ! Luteinizing -Mummmmm Follicle-stimulating Donenmakes s hormone (LH) hormone (FSH) have both test est dom iconads sorans ↳ Testis and Ovary ↳ produce in both mac ; feman > - ↳ Androgens (Testosterone) Estrogens (Estradiol) Progesterone and Inhibin Sources: Sadava D et al. Life: The Science of Biology (8th edition) 2007; Tortora GJ and Derrickson B Principles of Anatomy and Physiology (11th edition) 2006. 11 ©Eric Bolton  pulses Control of Spermatogenesis by the and insmal * levels Neuro-Endocrine System Androgensawa = downreg GURH receptors && Of In pit gland -d response in it > - No release FSHH Feedback. greversible Pulsatile secretion of release GURH AntagonistaingGonadotropin-releasing > - hormone (GnRH) nummngst ppoveants Follicle-stimulating D * sertoli * * hormone (FSH) -als reveuse For Luteinizing. A * ↳ Leyding alls hormone (LH) stimulates release alls andr. Sertoli cells Leydig cells to 12 ©Eric Bolton  Control of Spermatogenesis by the Neuro-Endocrine System Pulsatile secretion of Gonadotropin-releasing hormone (GnRH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Sertoli cells Leydig cells to 12 ©Eric Bolton  Review Question Which statement, about the control of spermatogenesis, is FALSE? A. Androgens always maintain negative feedback on FSH and LH release from the anterior pituitary. B. Spermatogenesis occurs in the seminiferous tubules of the testes with the support of Sertoli cells. * C. In males, the gonads become inactive after birth and do not resume mitotic/meiotic activity until puberty. O D. Spermatozoa complete differentiation/maturation in the seminiferous tubules before entering the epididymis. ↳ sperm only complete diffs mat in the epididymis, not th seem tup. 13 ©Eric Bolton Anatomy of Female Reproductive System 14 ©Eric Bolton Anatomy of Female Reproductive System - al ⑧ O Posterior view > attached - to OT. 15 ©Eric Bolton  in entero development aes emans Formation in Oogenesis G or · M overrives Diff be timing or Before birth Primordial germ cell in embryo * Mitosis' mosis in makes " temans d , Dorn wol primary oocytes (you have them since birth) is & gen Do terpe DNA replicates before Meiosis I => - (2 sets of 46 chromosomes) ~500,000 oocytes Adolescence to - keepsimpressurvival - Segregation of homologous menopause - > - chromosomes during Meiosis I Both have (2 sets of 23 chromosomes) 23up vacu a Sperm u er One primary oocyte produces Asymmetri, See only 1 egg Separation of sister Ospermlosthat has chromatids during Meiosis II (1 set of 23 chromosomes) 16 ©Eric Bolton  The Ovarian Cycle Follicular phase First ~14 days, but variable Jotist un Egg develops t in a follicle Stimulated by (Follicle Stimulating Hormone (FSH) released from pituitary gland Estrogens produced by surrounda - granulosa cells - Ovulation Luteinizing Hormone (LH) surge from pituitary triggers follicle rupture and - egg release into the abdominal cavity Fimbriae of the uterine tube collects the egg and channels it to the uterus Colteggt ↳ uterus 17 ©Eric Bolton  The Ovarian Cycle ⑧ ⑳ Luteal phase ↳ Postovulatory phase lasting ~14 days Corpus luteum- develops from ruptured follicle and starts producing progesterone in addition to estrogens Dominant nor, in this phase - > - Progesterone stimulates uterus in preparation for implantation No pregnancy è corpus luteum degenerates into corpus albicans - 18 ©Eric Bolton  Normal menst Life Cycle of an Ovarian Follicle cych No O Feedback = more Hypothalamus and noromones prevent Pituitary gland sutwe Nobred receives H normous Inhibin ac medi > - little - LH FSH Estradiol mod evels support foll > - stim Progesterone > - nuels "growth & Luteal Follicular -prod noromones aa - Estradiol Inhibin Progesterone FSH LH - 19 ©Eric Bolton  Maturation of the Secondary Oocyte (Granulosa cells) Oocyte develops the zona pellucida > - penetrated by sperm Glycoprotein coat (protective egg shell) estr Sperm must penetrate to fertilize the oocyte - convert androgen Surrounded by the corona radiata (granulosa epithelial cells) -sarom Theca stromal cells are stimulated by LH to synthesize androgens norted Granulosa cells are stimulated by FSH to convert androgens to estrogens ↓ - Clear liquid gathers to form fluid-filled antrum - Graafian follicles are fully mature and ready to ovulate 20 ↳ Fully mature follicle ©Eric Bolton Integration of Ovarian and Uterine Cycles FSH and LH are released by the pituitary. FSH stimulates follicle development and conversion of Androgens to Estrogens in granulosa cells. LH stimulates theca cells to produce Androgens 21 ©Eric Bolton Integration of Ovarian and Uterine Cycles FSH and LH are released by the pituitary. FSH stimulates follicle development and conversion of Androgens to Estrogens in granulosa cells. LH stimulates theca cells to produce Androgens Estrogens and Inhibin released by follicle and corpus luteum inhibit pituitary secretion of FSH Progesterone released by the corpus luteum inhibits pituitary secretion of FSH and LH and maintains the uterine secretory endometrium 22 ©Eric Bolton  Review Question Which statement, regarding the normal ovulatory cycle in a healthy female, is TRUE? * A. During the luteal phase the corpus luteum secretes high levels of testosterone and low levels of estradiol. hypothalamos * B. Ovulation is controlled by the = thalamus and through the release of hormones by the posterior pituitary gland. C. Estrogen - Testosterone L produced by ovarian granulose cells triggers * surge by positive feedback to the pituitary gland, an FSH resulting in ovulation. ⑧D. GnRH pulses by the hypothalamus control the release of LH and FSH by the anterior pituitary. 23 ©Eric Bolton  Summary The male gonad/testis is part of the reproductive and endocrine systems. The primary functions of the testes are to produce steroid sex hormones (testosterone) and to produce gametes (spermatozoa) by the process of spermatogenesis. Within the seminiferous tubules, germ/stem cells develop into spermatozoa through a series of cellular intermediates. The interstitial Leydig cells produce testosterone, which is important for sexual differentiation, spermatogenesis and fertility, as well as sexual behavior, libido, and erectile function. In the female reproductive cycle, pituitary and gonadal/ovarian hormones must coordinate ovarian and uterine cycles. Just before the beginning of each menstrual cycle, hypothalamic pulses of GnRH stimulate secretion of FSH and LH from the anterior pituitary. Under the influence of FSH, several follicles in the ovaries begin to mature. Theca cells are stimulated by LH and synthesize progesterone and androgens. In the neighboring granulosa cells, FHS stimulates aromatase activity, which converts androgens to estrogens. In the uterus under the influence of estrogens from the ovary, the endometrium begins to proliferate and regenerate. Immediately before ovulation, the high levels of estrogen, aided by the rising levels of progesterone, enhance pituitary responsiveness to GnRH. As a result, LH secretion surges and meiosis resumes in the developing follicle. Within 24 hours of the LH surge, ovulation occurs. After ovulation, the corpus luteum produces increasing amounts of progesterone and estrogen, which inhibit FSH and LH secretion. Progesterone is dominant in the luteal phase. If pregnancy does not occur, the corpus luteum degenerates into an inactive corpus albicans, and production of progesterone and estrogen drops, causing blood vessels in the uterine endometrium to contract and surface cells to die. 24 ©Eric Bolton  MCB 320 Reproductive Disorders Male Infertility Suggested Reading: Molecular Pathology, Chapter 22 1 ©Eric Bolton  Objectives Demonstrate understanding of impaired fertility in males Demonstrate understanding of the clinical features of Y chromosome microdeletion Understand the clinical features and endocrine dysregulation (primary hypogonadism) associated with Klinefelter syndrome Demonstrate understanding of how Klinefelter symptoms are treated Demonstrate understanding of the clinical features and treatment of secondary hypogonadism 2 ©Eric Bolton  Impaired Fertility Infertility – inability to conceive after 1 year of unprotected intercourse with the same partner Subfertility – ability to conceive after 1 year of unprotected intercourse with the same partner = 1 in 6 couples face impaired fertility (complications with conception) Fertility can be impaired by factors in either or both partners Fertility tests to determine whether the cause is structural or hormonal 3 ©Eric Bolton  Infertility Due to Reduced Sperm Count Spermatogenesis Declines with age Espermatogens a - At age 20-39, 90% of seminiferous tubules - - Mosman contain sperm ntogen - At age 40-69, [ 50% of seminiferous tubules > & contain sperm3- less spermatogenesis activity [ Deficits cause most male infertility3 Sources: David M. Phillips PR Science; Joyce Harper Welcome Images. 4 ©Eric Bolton  Y Chromosome Microdeletion (YCM) - ↳ condition where small sections genetic Clinical features of the y chromosomes are missing Chr. Y sections imp Many males exhibit no symptoms These for sperm production are ⑧ Nearly 20% of males with I can therefore read to intertility oligospermia (reduced sperm count) in med Azoospermia Factor Loci and azoospermia (lack sperm) have E (AZF) YCM location Molecular genetics of genes YCM is a family of genetic disorders required for spermatogen caused by deletions at three, called azoospermia factor loci (AZF), which contain genes involved in spermatogenesis YCM is passed directly from father to son (Y-linked inheritance) Sources: Foresta C et al. Endocrine Reviews (22) 2001. 5 ©Eric Bolton  Systemic Manifestations of Cystic Fibrosis Sources: Kliegman R and Kliegman RM Nelson Essentials of Pediatrics 2006. 6 ©Eric Bolton  Abnormal Sperm Morphology and Motility Sources: Sadler TW Langman's Medical Embryology (10th edition) 2006; David Becker Welcome Images. 7 ©Eric Bolton  Review Question Which statement best describes Y chromosome microdeletion (YCM)? A. YCM has been detected in ~20% of males with reduced sperm production. B. YCM is caused by deletions at azoospermia factor loci on the Y chromosome. C. YCM can be passed from father to daughter to grandson. D. A and B are correct. E. All of the above are correct. 8 ©Eric Bolton  Neuro-Endocrine System includes the HPG signaling axis Internal and external conditions Gonadotropin- releasing hormone (GnRH) Luteinizing Follicle-stimulating hormone (LH) hormone (FSH) Testis and Ovary Androgens (Testosterone) Estrogens (Estradiol) Progesterone and Inhibin Sources: Sadava D et al. Life: The Science of Biology (8th edition) 2007. 9 ©Eric Bolton Dysregulation of the HPG Signaling Axis Leads to Hypogonadism and Infertility Boonadissue - Pituitary or Primary Secondary Normal hypogonadism hypogonadism Hypothalamus issue HYPOTHALAMUS GnRH GnRH PITUITARY - Low levers to either & due hyp LH FSH * éLH ↳por éFSH êLH êFSH Testosterone Since LH' onadscan - FSH STIM T serthe & GONAD Androgens êAndrogens êAndrogens Inhibins and/or êInhibins êInhibins ↓ FSH causes Androge Examples: Klinefelter Kallmann syndrome ↳ zinviDins FSH secretion syndrome or brain tumor ↳ reduces test 10 prod ©Eric Bolton Klinefelter Syndrome 11 ©Eric Bolton  Klinefelter Syndrome Genetic condition in which a male is born with two or more X chromosomes XXY instead of XY 1 in 1,000 male births worldwide ↳ problems wi reprod health is noromou levels Major Signs and Symptoms Untreated males have a taller than average stature and a less masculine physical appearance egonass Primary hypogonadism (decreased testicular hormone - or endocrine function) results in low testosterone production and high FSH and LH levels Adults are generally infertile/subfertile 12 ©Eric Bolton Clinical Features of Klinefelter Syndrome Less muscular than other males Less facial/body hair Increased breast tissue (gynecomastia) Some difficulty using language to express themselves Increased risk of learning disabilities, breast cancer, autoimmune diseases, and osteoporosis (brittle bones) 13 ©Eric Bolton Regulation of Spermatogenesis and Male- Specific Differentiation by the HPG Axis Pulsatile secretion of Gonadotropin-releasing hormone (GnRH) Follicle-stimulating hormone (FSH) Luteinizing hormone (LH) Sertoli cells Leydig cells to 14 ©Eric Bolton  Effects of Primary Hypogonadism in Klinefelter Syndrome Pulsatile secretion of Gonadotropin-releasing hormone (GnRH) Follicle-stimulating ⑧ hormone (FSH) Luteinizing Lower levels of hormone (LH) androgens only weakly stimulate the development of male secondary sex characteristics and maturation of sperm cells Sertoli cells Leydig cells to 15 ©Eric Bolton  Diagnosis and Treatment of Klinefelter Syndrome Diagnosis Karyotype analysis can reveal multiple X chromosomes (47, XXY) No cure Hormonal Treatment Testosterone to increase masculine appearance and identity Hormone therapy can protect bones X Y from osteoporosis Assisted reproduction techniques may help males father children 16 ©Eric Bolton  Secondary Hypogonadism Can Cause Impaired Fertility Clinical features Normal testes (anatomy and function) Defect in the hypothalamus or pituitary decreases testis function Causes Kallmann syndrome – developmental defect in the hypothalamus Pituitary/brain tumors Medications – opiates or hormones Obesity Treatment – hormone supplements Sources: Mayo Foundation for Medical Education and Research. 17 ©Eric Bolton  Review Question Which statement, regarding Klinefelter syndrome, is TRUE? A. Primary hypogonadism is due to decreased release of GnRH, which in turn increases FSH and LH levels. B. Primary hypogonadism results in decreased levels of testosterone and increased FSH and LH levels. C. Primary hypogonadism is due to decreased release of FSH and LH, which in turn increases testosterone levels. D. Primary hypogonadism results in decreased levels of testosterone and decreased FSH and LH levels. 18 ©Eric Bolton  Summary In males, the leading cause of infertility and subfertility is low sperm count, which can have many causes, including hormonal imbalance due to endocrine dysregulation, Y chromosome deletions, and exposures. Additional causes of impaired fertility include abnormal spermatozoa motility and morphology and autoimmune targeting of sperm for destruction. Y chromosome microdeletions (YCM) is a family of genetic disorders caused by deletions at 3 spermatogenesis loci (azoospermia factor loci) on the male Y chromosome. YCM has been detected in up to 20% of males with reduced sperm production and impaired fertility. Indeed, dysregulation of hormone production, release, or reception can lead to hypogonadism, meaning decreased gonadal hormone or endocrine function. In primary hypogonadism, which occurs in Klinefelter syndrome, a testicular defect may compromise steroidogenesis (testosterone production) and/or spermatogenesis and inhibin production. The absence of androgens and inhibins is unable feedback inhibit the release of LH and FSH from the pituitary, leading to systemic elevation of LH and FSH. In secondary hypogonadism, which occurs in Kallmann syndrome and in some patients with defects in the hypothalamus or pituitary (e.g., brain tumor), LH and FSH production is decreased. LH deficiency reduces androgen production by interstitial Leydig cells in the testes. In addition, FSH and androgen deficiency compromises spermatozoa and inhibin production in the seminiferous tubules. 19 ©Eric Bolton  MCB 320 Reproductive Disorders Female Infertility I: Uterine Disorders Suggested Reading: Molecular Pathology, Chapters 22-23 1 ©Eric Bolton  Objectives Demonstrate understanding of impaired fertility in females Understand the anatomy of the uterus and clinical features of uterine (endometrial and cervical) neoplastic disease Understand of the mechanisms of uterine (endometrial and cervical) neoplastic disease progression Understand the clinical features and treatment of endometriosis 2 ©Eric Bolton  Impaired Fertility Infertility – inability to conceive after 1 year of unprotected intercourse with the same partner egredocdlate Subfertility – ability to conceive after 1 year of unprotected intercourse with the same partner 1 in 6 couples face impaired fertility (complications with conception) Fertility can be impaired by factors in either or both partners Fertility tests to determine whether the cause is structural or hormonal 3 ©Eric Bolton Causes of Impaired Fertility in Females ovarian tomou Infertility or Pit. 30% · 30% O 10% ↳ complete obstruction of tobe ⑧ 15% tallopian ↳ Moplasia 10% ↳ anti-speim secretion 4 ©Eric Bolton  Anatomy of Female Reproductive System Posterior view Uterine/fallopian tubes Are ciliated tubes that channel ovum from the ovaries to the uterus - Flare into a trumpet shaped infundibulum with feathery projections (fimbriae) at the ovarian end > - in tubes Are where fertilization typically occurs (ova and sperm unite) OneO - 5 ©Eric Bolton  Anatomy of Female Reproductive System 3 layers Posterior view to narrower end connects Uterus - thick muscular chamber thatway ↳ harbors and nourishes the fetus (via the placenta) and contracts to expel the fetus during childbirth Perimetrium – external layer of simple squamous epithelium - - emuscold Myometrium – middle layer of spiraling smooth muscle (contraction) Thickest laye - - > - Endometrium – inner layer lined with simple columnar epithelium (attachment) = - ↳ mucosal 6 ©Eric Bolton  int niguly DY Buorom Hormonal. Control of the Endometrium Functions > - Endometrium as lining Simple columnar epithelium Inner glandular layer of Ut. Lined with simple Stratum functionalis (stroma) columnar epithelium stroma active upon the thick stroma Tissue with imbedded blood - rich blood > - - vessels and uterine supply Xanager mucus glands Stratum functionalis - Estrogen induces support proliferation in follicular phase - Progesterone adapts - it for implantation in luteal phase 2 - Completely shed during menstruation Stratum basalis - Never shed - Stratum functionalis in develops from it nonais 7 ©Eric Bolton Endocrine Control of the Uterine Cycle by Ovarian Hormones Ovarian connecting ve cycle: Follicular phase Ovulation Luteal phase Estrogen -Domoal Uterine activity L Progesterone levels,isis - · gar Estrogen Progesterone ·Uterine cycle: Menstruation Proliferative Cervical protects phase Secretory phase Menstruation mucus: Watery Thick twickensprint e d a 8 ©Eric Bolton  Estrogen Action through ERs Estrogen contrange L ER regulate ↳ Homoaimer ↑ binding +xV ot & aft to Progestins receptor. DNA - Progestnis genes rated reg DY pre-mRNA Deidifferentiation ER action regulates mRNA Gene Expression – PR Cell proliferation and survival - protein 9 ©Eric Bolton  more Endometrial Neoplasia and Type I adipocytes aromates ↳ move Carcinoma &Risk activity factors enchance endometrialcanara of Obesity (adipocytes can produce estrogen) - Increased estrogen exposure mismati repair Lynch syndrome (HNPCC) patients due to inactivating mutations in tumor suppressor genes involved in DNA mismatch repair Age * Doesn't work ton -tum %0 PTEN in 50 of abseEN - this Neoplastic disease progression Browning ↓ Endometrial hyperplasia è Endometrial f umt - intraepithelial neoplasia/dysplasia (EIN) 00 - è Endometrioid adenocarcinoma è ⑧ - Invasive endometrioid adenocarcinoma Prevention Healthy lifestyle – weight management through diet and physical activity -we uls Combine progestin with estrogen source (birth control/menopausal therapy) - Birth >minica luteal phase - control woromone evels Treatment Surgical - resection, hormone therapy (decrease estrogen and increase progesterone), radiation therapy, and systemic chemotherapy Sources: Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018; Horn LC et al. Ann Diagn Pathol. (11) 2007. 10 ©Eric Bolton  Progression of Endometrial Neoplasia - esogen abnormal eastrated of - ↑ lining growth - (microsatellite instability) contribution ② - > Tomor sopr. vinta pros - endometrioid adenocarcinoma mut- β-catenin - - guaeatment = - helpsreg survival - (Pi3 Kinase invasive endometrioid Y adenocarcinoma - progress cancer cells less you become -. 7 as con , estrogen receptor (ER) into invas of a dependent on progesterone receptor (PR) Cells exp receptor lose this Sources: Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018; Horn LC et al. Ann Diagn Pathol. (11) 2007. 11 ©Eric Bolton  Review Question Which statement, about type I endometrial carcinoma, is FALSE? - A. Endometrial cancer development is associated with an excess of systemic estrogen and a lack of progesterone. B. The tumor suppressor PTEN is frequently absent or inactivated in endometrial intraepithelial neoplasia (EIN). ⑨ C. Endometrial cancer development is associated with an excess of systemic progesterone and a lack of estrogen. D. PTEN is a lipid phosphatase that inhibits the PI3K-AKT- mTOR signaling pathway and cellular survival. - 12 ©Eric Bolton  Anatomy and Physiology of the Cervix goes in or out - controls what - Cervical functions Gateway between the -twin endocervix vagina and uterus wind) uterus transformation - zone · Produces mucus to - prevent or promote pregnancy cervix entranerus - > - Cervical histology Exocervix – faces the protect vagina ·. of vagina, lined with- thier external os stratified squamous alls > epithelium connectsectious exocervix ray. Endocervix – a tube ↑ - -through the cervix to Smucus prodsun) the uterus, lined with simple columnar epithelium and mucus glands - -Most common for detect of cancer loc & Transformation zone – border between the endocervix and ectocervix, e surrounding the external os (opening)trunstorm. -it rog - Physiologic squamous* metaplasia of columnar cells increases with age - Most cervical carcinoma develop here 13 ©Eric Bolton  34th most common cancer in women Cervical Neoplasia and Carcinoma > major risk Risk factors - factor HPV infection (20 million anogenital infections in US) - Multiple sexual partners > HPV risk - Neoplastic disease progression (75% squamous cell carcinoma, 20% adenocarcinoma, and 5% other) wilda ages esevere CIN1 CIN2 CIN3 Normal epithelium è Cervical -increasing -aspensi intraepithelial neoplasia (CIN1-3) è Cervical carcinoma in situ è Invasive cervical carcinoma è Metastatic cervical carcinoma Prevention S Basementpresistanc Basal cells Normal Mild – Moderate – Severe Carcinoma HPV vaccines (Gardasil O- 9/4) membrane now many squamous Dysplasia in situ epithelium reduce high-risk HPV infections HAV by 85% and cancerous changes genotypes &of the cervix by 40% Treatment Surgical resection, radiation, and uf ·. systemic chemotherapy Sources: Niederhuber JE et al. Abeloff’s Clinical Oncology 2020; Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018; Rosenblum HG et al. MMWR Morb Mortal Wkly Rep. (70) 2021; McClung NM et al. Cancer Epidemiol Biomarkers Prev. (28) 2019. 14 ©Eric Bolton  HPV Proteins Target Tumor Suppressors ? Ubiquitin and Drive Cervical Neoplasia. - HPV16/18 E7 oncoproteins -uncontrolledent [Stimulate degradation of pRB tumor suppressor3è decreased - G1 cell cycle -restriction Point arrest è hyperplasia Increases genome instability and mutation - Cell HPV16/18 E6 oncoproteins - reg , Cycl Stimulates degradation of p53 tumor sensing ? > - suppressor è decreased G1 cell cycle ANA repairing damage arrest and apoptosis è hyperplasia Induces expression of - telomerase (hTERT) > protective è telomere maintenance è cellular - immortalization and survival capsound Tous Increases genome instability and mutation astmugetniunibitrept Sources: Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018; Niederhuber JE et al. Abeloff’s Clinical Oncology 2020; Lee RJ, Abramson JS and Goldsby RA Case Studies in Cancer 2019. 15 ©Eric Bolton  HPV Oncoproteins Alter Retinoblastoma (pRb) and p53 Tumor Suppressor Pathways Loss of a tumor supr. - requea ①require ⑧ entry trigger ↳an apoptosis at dame Sources: Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018. 16 ©Eric Bolton  Endometriosis Can Impair Fertility Epidemiology > - another common cause of impaired Affects ~5 million females in the fertility United States 30-40% of affected females are infertile, which accounts for ~10% of infertile couples > - sometimes Signs and symptoms Premenstrual bleeding Heavy, painful, and long menses Urinary urgency Painful intercourse or bowel movements Rectal bleeding 17 ©Eric Bolton  Endometriosis Clinical features Excessive proliferation and growth of endometrial tissue outside the uterus Growths (implants) respond to hormonal changes of the menstrual cycle -movingard Possible causes include retrograde menstruation, spread through vascular or lymphatic vessels of the circulatory system, or stimulation of multipotent/progenitor epithelial cells on the affected organs Treatment Endocrine therapy - Combined birth control pills with estrogen and progestin to induce pseudopregnancy - GnRH agonist to induce pseudomenopause Surgery to remove endometriosis and medications to control pain 18 ©Eric Bolton  Review Question Which statement best describes roles of HPV16/18 viral proteins in cervical carcinoma? A. HPV E7 oncoproteins inactivate the pRB tumor suppressor through proteasomal degradation, allowing the unrestricted transition of cells from G1 to S phase. B. HPV E6 oncoproteins inactivate the p53 tumor suppressor, allowing progression through cell cycle checkpoints and survival of genetically damaged cells. C. HPV E6 expression increases the expression of human telomerase reverse transcriptase, hTERT, which contributes to cellular immortalization and survival. D. B and C are correct. ① E. All of the above are correct. 19 ©Eric Bolton  Summary Ovulatory disorders (due to a pituitary or ovarian tumor, or polycystic ovary syndrome) account for 30% of female infertility. Uterine/fallopian tube disease, due to infections, fibrosis, or neoplasia, affect ~25% of infertile females. About 10% of infertile females have endometriosis. At least 10% of all cases of female infertility are caused by an abnormal uterus. Additional causes of infertility include antisperm secretions by the cervix and vagina and uterine neoplasia. Endometrial uterine cancer is the most common female reproductive cancer. Obese females tend to have high estrogen levels, because adipocytes produce some estrogen. The development of endometrial cancer is strongly associated with an excess of systemic estrogen and a lack of progesterone. This hyperestrogenic state is presumed to result in endometrial hyperplasia that progresses to dysplasia and eventually endometrioid adenocarcinoma. The tumor suppressor PTEN is absent or inactivated in ~50% of all EIN lesions. Cervical cancer is the third most common reproductive cancer, and it typically develops in females between the ages of 30-50. Persistent cervical infection with high-risk Human Papillomavirus (HPV) genotypes is necessary for the development of nearly all cervical cancer and its immediate precursor lesion, cervical intraepithelial neoplasia (CIN). HPV vaccines (Gardasil 9/4) reduce high- risk HPV infections by ~85% and cancerous changes of the cervix by ~40%. 20 ©Eric Bolton  MCB 320 10/23 Reproductive Disorders Female Infertility II: Turner Syndrome and PCOS Suggested Reading: Molecular Pathology, Chapters 22-23 1 ©Eric Bolton  Objectives Understand the clinical features of Turner Syndrome Demonstrate understanding of how Turner Syndrome symptoms are treated Understand the clinical features of Polycystic Ovary Syndrome (PCOS) Understand the pathophysiology and endocrine dysregulation of the ovarian cycle that occurs in PCOS Demonstrate understanding of how PCOS symptoms are treated 2 ©Eric Bolton  Turner Syndrome X chromosome > - abnormality Sources: Ehrmann D and Turgeon J Endocrine News. 2007. 3 ©Eric Bolton  Turner Syndrome - typically thio deletions Genetic condition where a female is born with a portion or all of one X chromosome missing or altered ↳ only 1 normal X chr. 1 in 2,500 female births worldwide Absence = more symptoms Mutations/partial = milder Symptoms Major Signs and Symptoms Short stature (average height of an untreated female with Turner Syndrome is 4 8 ) is partially due to short stature s homeobox (SHOX) transcription factor deficiency esteroid hormones Ovaries fail to produce hormones and ova (eggs) sex develop d > - bone do - Less long growth you Adults are generally infertile/subfertile - puberty que alloid this 4 ©Eric Bolton  Clinical Features of Turner Syndrome Short webbed neck - - Low hairline at the neck - Broad chest - -Arms/legs that turn out => at the elbow/knee joints e short term birth ater S Swollen hands => risic f and feet or obstru IncreasedNabnormalities stem of the heart and kidney, - middle ear infections, = -- hearing loss, diabetes, cataracts, osteoporosis -- 5 ©Eric Bolton  Diagnosis and Treatment of Turner Syndrome Diagnosis Karyotype analysis can reveal a missing (45,X) or short mutated X chromosome -No cure reverses -partially symptoms Hormonal treatment Growth hormone to increase stature age young - Estrogen for breast development ↳ brithepones X Estrogen and progesterone to provide regular menstrual cycles X & Hormone therapy until age 50 to protect Strengthen bones from- T- osteoporosis Brittle pores Assisted reproduction techniques may - help females become pregnant - 6 ©Eric Bolton Who are they? 7 ©Eric Bolton Which Spice Girl is this? Posh Spice (Victoria Beckham) At age 20, she was diagnosed with the most common endocrine disorder in females of reproductive age PCOS Which endocrine disorder? 8 ©Eric Bolton  Polycystic Ovary Syndrome (PCOS) Most common endocrine disorder in females of reproductive age Affects 5-10% of females of reproductive age sunderdiagn 5 million females in the US (many are undiagnosed) - A leading cause of infertility/subfertility we don't main Molecular Genetics Familiaorder know - cause Family history (genetic predisposition) ~50 genes have demonstrated association with PCOS None are causative of PCOS pathogenesis Sources: Knockenhauer ES et al. J Clin Endocrinol Metab. (83) 1998; Azziz R et al. J Clin Endocrinol Metab. (89) 2004; Coleman WB and Tsongalis GJ Molecular Pathology 2009, 2018. 9 ©Eric Bolton  Polycystic Ovary Syndrome (PCOS) Symptoms described by Stein and Leventhal (1935) Discovered Amenorrhea (absence of menses) Normal menstral Hirsutism (male pattern of body hair) cycle after ovary Obesity biopsy Polycystic appearance of enlarged ovaries Current diagnosis requires 2 of 3 symptoms Polycystic ovaries detected using ultrasound Elevated levels of androgens in serum Amenorrhea or oligomenorrhea (< 9 menses/year) dabsesses Sources: Stein IF and Leventhal ML Am J Obstet Gynecol. (29) 1935; Azziz R J Clin Endocrinol Metab. (91) 2006. 10 ©Eric Bolton  Life Cycle of an Ovarian Follicle eFuviation >16 mm E2 acumotion toll'icca E2 + P Estrogen (Estradiol,E2) and Progesterone (P) production 11 ©Eric Bolton  International Consensus Definition of Polycystic Ovary (PCO) Atret'1 A polycystic ovary contains 12 or more small follicle carsing accum follicles - measuring 2-9 mm in diameter and/or ↑ in size I swelling an increased ovarian volume (>10 cm )3 Sources: Norman RJ et al. MJA. (180) 2004; Azziz R J Clin Endocrinol Metab. (91) 2006. 12 ©Eric Bolton  Fertility Problems Associated with PCOS - NoughT X. E2 oul Triggers Chion' OU. ↑ X a X cycles Quizing E2 + P m · No estrogen (estradiol, E2) increase follicles do not No LH surge wo & est > - No H = causing. > - EZ co oculation mature properly levels to not ↑ like they should - No corpus luteum (no E2 or progesterone, P) ↓ levels (but try > - Cycle) mmnst. reg > - Excess androgens increase follicular arrest and atresia a death13 follicles stop dcrelping properly Force ©Eric Bolton  Review Question Which of the following is NOT a symptom of PCOS? A. Elevated levels of androgens in the circulation B. Polycystic ovaries detected using ultrasound C. Swollen abdomen due to edema D. Amenorrhea or oligomenorrhea 14 ©Eric Bolton  Clinical Features of PCOS: Hyperandrogenism Acne Hirsutism Androgenic alopecia ↳ male pattern hairloss 15 ©Eric Bolton  Clinical Features of PCOS: Metabolic Syndrome ! Acanthosis Nigricans She due to insulin resistance - d Central Obesity Thickening of hyperpiga 16 ©Eric Bolton  Metabolic Disorders Associated with PCOS Clinical Condition PCOS Patients Affected Hyperinsulinemia and · Insulin resistance 50-70% Central obesity 50-70% Dyslipidemia (high triglycerides and low 50-70% HDL-cholesterol) Hyper