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  2. COURSE OUTLINES  Objectives  Introduction  Epidemiology  Pathogenesis  Risk factors  Clinical manifestations  Types of GTD  Staging  Investigations  Mgt  Post treatment surveillance 3/20/2023 2 BEKAN AND CHALTU
  3. OBJECTIVES  At the end of the session the students will able to:  Define gestational trophoblastic diseases  Discuss the pathogenesis of molar pregnancy  Differentiate types of GTD  Manage molar pregnancy 3/20/2023 3 BEKAN AND CHALTU
  4. INTRODUCTION  Gestational trophoblastic disease (GTD) is a proliferative disorder of trophoblastic cells.  It defines a heterogeneous group of interrelated lesions arising from the trophoblastic epithelium of the placenta.  All forms of GTD are characterized by a distinct tumor marker, the beta subunit of human chorionic gonadotropin (hCG).  The pathogenesis of GTD is unique because:  the maternal tumor arises from gestational rather than maternal tissue. 3/20/2023 4 BEKAN AND CHALTU
  5. INTRO…  There are several histologically distinct types of GTD.  Hydatidiform mole (complete or partial)  Persistent/invasive gestational trophoblastic neoplasia (GTN)  Choriocarcinoma  Placental site trophoblastic tumors  Complete and partial hydatidiform moles are noninvasive, localized tumors that develop as a result of an aberrant fertilization event that leads to a proliferative process.  They comprise 90 percent of GTD cases. 3/20/2023 5 BEKAN AND CHALTU
  6. INTRO…  The other three categories of GTD represent malignant disease because of their potential for local invasion and metastases.  Malignant GTD can develop from  Molar pregnancy or  Gestational experience:  spontaneous or induced abortion,  ectopic pregnancy, or  preterm and term pregnancy.  Malignant transformation of trophoblastic tissue is probably related to activation of oncogenes and inactivation of tumor suppressor genes. 3/20/2023 6 BEKAN AND CHALTU
  7. EPIDEMIOLOGY  The incidence of GTD varies widely in different regions of the world.  The incidence of hydatidiform mole ranges from 23 to 1299 cases per 100,000 pregnancies, while malignant GTD is less common.  North American and European countries tend to report low rates of disease (1 per 1000 to 1500 pregnancies),  The reason for this variation is that epidemiologic data on GTD are limited by the rarity of the disease and inaccurate ascertainment of the number of cases. 3/20/2023 7 BEKAN AND CHALTU
  8. PATHOGENESIS OF GTD  Gestational trophoblastic disease (GTD) — Lesions characterized by abnormal proliferation of trophoblast of the placenta.  This category is comprised of benign, nonneoplastic lesions including placental site nodule, exaggerated placental site and hydatidiform moles as well as malignant neoplasms.  Gestational trophoblastic neoplasia (GTN) —include: choriocarcinoma, placental site trophoblastic tumor, epithelioid trophoblastic tumor, and invasive moles that do not resolve spontaneously.  Disease diagnosed as a result of persistent elevation of hCG after evacuation of a molar pregnancy 3/20/2023 8 BEKAN AND CHALTU
  9. PATHO…  It is known that imprinting has a role in the development of GTD.  Paternal genes have more control over placental growth while maternal genes have more control over fetal growth.  With excess paternal genes, there is excessive placental or trophoblastic proliferation.  There is also a difference between the malignant potential of moles that are heterozygous (arising from two sperm) and homozygous (arising from a single sperm with duplication of DNA) 3/20/2023 9 BEKAN AND CHALTU
  10. PATHO…  Molecular pathways that might contribute to the development of GTD.  Somatic point mutations and instability of mitochondrial DNA  Amplification and overexpression of various oncogene products, such as c-erbB-2, c-myc, c-fms and mdm-2.  Epidermal growth factor receptor (EGFR)  Downregulation of tumor suppressor genes, including p53, p21 and Rb,  Telomerase activity and expression of cell-cell adhesion molecules,  Metalloproteinases, and tissue inhibitors of metalloproteinases 3/20/2023 10 BEKAN AND CHALTU
  11. RISK FACTORS  Extremes of age- older than age 35 and slightly increased in those under age 20.  History of previous GTD  Current smoking (>15 cigarettes per day),  Maternal blood type AB, A, or B,  History of infertility,  Nulliparity  Deficiency in vitamin A 3/20/2023 11 BEKAN AND CHALTU
  12. CLINICAL MANIFESTATIONS  Clinical manifestations of GTD include, in decreasing order of frequency:  Vaginal bleeding  Enlarged uterus  Pelvic pressure or pain  Theca lutein cysts  Anemia  Hyperemesis gravidarum  Hyperthyroidism  Preeclampsia before 20 weeks of gestation  Vaginal passage of hydropic vesicles 3/20/2023 12 BEKAN AND CHALTU
  13. TYPES OF GTD  There are various histologically distinct subtypes of GTD: 1. Benign nonneoplastic trophoblastic lesions  Exaggerated placental site  Placental site nodule 2. Hydatidiform mole  Complete hydatidiform mole  Partial hydatidiform mole 3. Gestational trophoblastic neoplasia (GTN)  Invasive mole (chorioadenoma destruens)  Choriocarcinoma  Placental site trophoblastic tumor  Epithelioid trophoblastic tumor 3/20/2023 13 BEKAN AND CHALTU
  14. TYPES….  Clinical classification of GTD 1. Benign gestational trophoblastic disease  Complete hydatidiform mole  Partial hydatidiform mole 2. Malignant trophoblastic disease  Invasive mole (chorioadenoma destruens)  Choriocarcinoma  Placental site trophoblastic tumor  Epithelioid trophoblastic tumor 3/20/2023 14 BEKAN AND CHALTU
  15. PATHOLOGIC AND CLINICAL CLASSIFICATIONS FOR GESTATIONAL TROPHOBLASTIC DISEASE PATHOLOGIC CLASSIFICATION CLINICAL CLASSIFICATION Hydatidiform mole *complete *incomplete Benign gestational trophoblastic disease Invasive mole Malignant trophoblastic disease Nonmetastatic Placental site trophoblastic tumor Metastatic Choriocarcinoma High risk Low risk 3/20/2023 15 BEKAN AND CHALTU
  16. TYPES…. I. BENIGN NONNEOPLASTIC TROPHOBLASTIC LESIONS.  Are frequently diagnosed only as an incidental finding in a pathology specimen after uterine curettage or hysterectomy. 1. Exaggerated placental site.  characterized by an extensive infiltration of the endometrium and myometrium by implantation site that occur in clusters or as single cells.  There is no destruction of the normal endometrial glands and stroma  It likely represents an excessive physiologic process rather than a true lesion;  the distinction between a normal placental site and an EPS is often subjective. 3/20/2023 16 BEKAN AND CHALTU
  17. TYPES…. EPS  occur in a normal pregnancy or after a first trimester abortion or within current pregnancy.  The associated placenta is usually normal.  However, it occurs with increased frequency in molar pregnancies and thus can give a clue to diagnosis of these lesions.  The trophoblastic cells contain cytoplasm with hyperchromatic, irregularly shaped nuclei, but fail to show mitotic activity.  The lack of mitotic activity and association with chorionic villi is an important clue in diagnosis, between EPS and placental site trophoblastic tumor 3/20/2023 17 BEKAN AND CHALTU
  18. TYPES….PSN 2. Placental site nodule  Are found in uterine curettages and cervical or hysterectomy specimens in reproductive age patients.  40 % located in the endocervix, 56 % the endometrium, and 4 % found in the fallopian tube,  The intermediate trophoblastic cells of PSNs are likely derived from  the migratory intermediate (extravillous) trophoblasts of the placenta.  They represent the nonneoplastic counterpart of epithelioid trophoblastic tumors 3/20/2023 18 BEKAN AND CHALTU
  19. TYPES….PSN  They are occasionally found as multiple nodules or plaques.  They tend to have vacuolated cytoplasm and a somewhat degenerated appearance.  Mitotic figures are rare and usually absent.  Histologically, the nodules are well circumscribed and surrounded by a thin rim of chronic inflammatory cells. 3/20/2023 19 BEKAN AND CHALTU
  20. TYPES… II. HYDATIFORM MOLE  Is the most common form of GTD, representing 80 % of cases.  Moles may be complete, partial.  Complete and partial hydatidiform moles are differentiated by  karyotype,  gross morphology,  histologic appearance, and  clinical features  The development of GTN is significantly increased after a complete mole, but only slightly increased after a partial mole. 3/20/2023 20 BEKAN AND CHALTU
  21. TYPES…  The microscopic appearance of hydatidiform mole: • Hyperplasia of trophobasitc cells • Hydropic swelling of all villi • Vessles are usually absent. 3/20/2023 21 BEKAN AND CHALTU
  22. TYPES…  A sonographic findings of a molar pregnancy. The characteristic “snowstorm” pattern is evident. 3/20/2023 22 BEKAN AND CHALTU
  23. TYPES…  Color Dopplor facilitates visualization of the enlarged spiral arteriesclose proximity to the “ snow storm” appearance 3/20/2023 23 BEKAN AND CHALTU
  24. TYPES…MOLAR A. Complete mole  The chorionic villi of a complete mole are diffusely hydropic and surrounded by hyperplastic, often atypical, trophoblast  Fetal tissue is not typically present.  C/F-excessive uterine size for the expected "gestational age, elevation in serum hCG , theca lutein cysts; hyperemesis gravidarum; early development of preeclampsia and hyperthyroidism,  3/20/2023 24 BEKAN AND CHALTU
  25. TYPES…MOLAR  Complete hydatidiform mole demonstrating enlarged villi of various size 3/20/2023 25 BEKAN AND CHALTU
  26. TYPES…MOLAR  Hydatidiform mole: specimen from suction curettage 3/20/2023 26 BEKAN AND CHALTU
  27. TYPES…MOLAR  A large amount of villi in the uterus. 3/20/2023 27 BEKAN AND CHALTU
  28. TYPES…MOLAR Pathogenesis of complete mole  Most commonly has a 46,XX karyotype, with all chromosomes of paternal origin.  This results from fertilization of an "empty" egg (I e, absent or inactivated maternal chromosomes) by a haploid sperm that then duplicates (46,YY moles do not occur because this karyotype is lethal).  A small number (3 to 13 percent) of complete moles have a 46,XY chromosome complement; this is thought to occur when an empty ovum is fertilized by two sperm. 3/20/2023 28 BEKAN AND CHALTU
  29. TYPES…MOLAR  A few complete moles have a 46,XX karyotype but develop from fertilization of an empty ovum by two sperm,  Because the nucleus is entirely paternal in origin, a complete mole is actually a paternal allograft in the mother.  Rarely, complete moles are biparental and are associated with an autosomal recessive condition predisposing to molar pregnancy.  These patients often have recurrent hydatiform moles  This defect is likely due to dysregulation of genomic imprinting, and a mutation at the 1.1 MB region on chromosome 19q13.4 3/20/2023 29 BEKAN AND CHALTU
  32. TYPES…MOLAR Partial mole  They are usually (about 90 percent) triploid (69,XXX, 69,XXY, rarely 69,XYY) due to  the fertilization of an ovum (one set of haploid maternal chromosomes) by two sperm (two sets of haploid paternal chromosomes).  The fetal or embryonic tissue that is present with a partial mole will most commonly have a triploid karyotype. 3/20/2023 32 BEKAN AND CHALTU
  33. TYPES…MOLAR  Characterized by a marked proliferation of villous trophoblast associated with hydropic swelling of the chorionic villi.  These pregnancies are infrequently associated with  excessive uterine size, ovarian enlargement, preeclampsia, hyperemesis, or hyperthyroidism because:  hCG levels are generally lower than those observed with a complete mole. 3/20/2023 33 BEKAN AND CHALTU
  34. TYPES…MOLAR  Partial hydartidiform mole 3/20/2023 34 BEKAN AND CHALTU
  35. TYPES…MOLAR Pathogenesis  They are usually (about 90 percent) triploid (69,XXX, 69,XXY, rarely 69,XYY) due to:  the fertilization of an ovum (one set of haploid maternal chromosomes) by two sperm (two sets of haploid paternal chromosomes). 3/20/2023 35 BEKAN AND CHALTU
  37. COMPLETE VERSUS PARTIAL MOLE Feature Complete mole Partial mole Incidence 1/1500 pregnancies 1/750 pregnancies Karyotype Diploid: 46,XX (46,XY) Triploid: 69,XXX, 69,XXY (rarely 69,XYY) Embryonic/fetal tissue Absent Present Villi Diffusely hydropic Focal Trophoblastic proliferation Hyperplastic Less trophoblastic hyperplasia Immuncoytochemistry hCG*, rare PLAP hcG, PLAP, p57 Uterine size Often large for dates Often small for dates Theca lutein cysts Present in ≤25 percen Rare Persistent mole 15 to 20 percent 3 to 5 percent 3/20/2023 37 BEKAN AND CHALTU
  38. TYPES…MOLAR Diagnosis of Hydatidiform mole History and physical diagnosis • Quantitative beta-HCG( elaborates unique tumor marker for diagnosis & follow-up) • Ultrasound  The classic image is of a “snowstorm” pattern in complete mole  focal cystic spaces in the placental tissues and an increase in the transverse diameter of the gestational sac in partial mole(‘honeycomb’ like placenta)  Lutein cysts 3/20/2023 38 BEKAN AND CHALTU
  39. TYPES……GTN III.GESTATIONAL TROPHOBLASTIC NEOPLASIA  The group of true gestational trophoblastic neoplasia includes  Invasive mole  choriocarcinoma,  placental site trophoblastic tumor (PSTT), and  epithelioid trophoblastic tumor (ETT).  Each of these neoplasms can follow a normal pregnancy or a molar pregnancy. 3/20/2023 39 BEKAN AND CHALTU
  40. TYPES……GTN A. Invasive mole  Characterized by the presence of enlarged hydropic villi invading into the myometrium, into vascular spaces, or into extrauterine sites.  The abnormal villi penetrate deeply into the myometrium.  These lesions may be differentiated from choriocarcinoma in that they contain:  hydropic villi along with the marked trophoblastic proliferation. 3/20/2023 40 BEKAN AND CHALTU
  41. TYPES……GTN  Both invasive moles and choriocarcinoma may show:  invasion of the uterine vasculature and  the production of secondary metastatic lesions, particularly involving the vagina and lungs.  Invasive moles do not often resolve spontaneously.  it is usually only diagnosed histologically if a hysterectomy has been performed.  Invasion can be difficult to diagnose by curettage, as myometrium is often not present 3/20/2023 41 BEKAN AND CHALTU
  42. TYPES……GTN  Invasive hydatidiform mole infiltrating the myometrium 3/20/2023 42 BEKAN AND CHALTU
  43. TYPES……GTN B. Choriocarcinoma.  is a highly malignant epithelial tumor.  It can arise from any type of trophoblastic tissue (molar pregnancy, abortion, ectopic, preterm/term intrauterine pregnancy)  Consists of sheets of anaplastic cytotrophoblasts and syncytiotrophoblasts without chorionic villi.  Choriocarcinoma following a normal gestation is often comprised of biparental chromosomes identical to the fetus  Postmolar choriocarcinoma is often comprised exclusively of paternal DNA; and are aneuploid 3/20/2023 43 BEKAN AND CHALTU
  44. TYPES……GTN  Gross specimen of choriocarcinoma 3/20/2023 44 BEKAN AND CHALTU
  45. TYPES……GTN  Doppler image of choriocarcinoma 3/20/2023 45 BEKAN AND CHALTU
  46. TYPES……GTN  Most lesions begin in the uterus, although ectopic pregnancies provide extrauterine sites of origin.  When choriocarcinoma metastasizes, the most common sites are  lung, brain,  liver, pelvis, vagina,  spleen, intestine, and kidney.  Sometimes, when curettage is performed for an early pregnancy loss, immature gestational tissue without villi adjacent to regions of atypia may be encountered. 3/20/2023 46 BEKAN AND CHALTU
  47. TYPES……GTN C. Placental site trophoblastic tumors  is a rare, potentially malignant neoplasm originating from extravillous (intermediate) trophoblast cells  They can occur months to years after a pregnancy.  PSTTs most commonly develop after a term gestation, but also occur after any pregnancy  presents as a proliferation of extravillous or intermediate trophoblast in the myometrium or endomyometrium 3/20/2023 47 BEKAN AND CHALTU
  48. TYPES……GTN  Chorionic villi are rarely found and the typical dimorphic pattern of choriocarcinoma is absent  Instead, there is a characteristic pattern consisting of a relatively monomorphic population of predominantly mononuclear trophoblastic cells.  Scattered multinucleated trophoblasts are also present as are multinucleated syncytiotrophoblastic-like cells 3/20/2023 48 BEKAN AND CHALTU
  49. TYPES……GTN D. Epithelioid trophoblastic tumor.  ETT is a rare form of trophoblastic disease.  ETTs are clinically, pathologically and prognostically similar to PSTTs.  ETT primarily occurs in reproductive-age women up to 18 years following a prior gestation.  The majority of ETT occurs after a full-term pregnancy, but about one third arise following a spontaneous abortion or hydatidiform mole.  Vaginal bleeding is the presenting symptom in two-thirds of patients 3/20/2023 49 BEKAN AND CHALTU
  50. TYPES……GTN  Serum hCG levels are elevated, but usually do not exceed 2500 milli- international units/mL.  Gross inspection of ETT shows a solid to cystic, fleshy, and well- defined mass in the uterine wall, lower uterine segment, or endocervix.  Histologically ETT is nodular, with proliferation of smaller, more monomorphic trophoblastic cells in comparison to PSTT.  Molecular markers expressed on ETT by immunohistochemistry include  pancytokeratin, epithelial membrane antigen, cytokeratin 18,  inhibin-a, hCG, human placental lactogen, placental alkaline phosphate, and Mel-CAM 3/20/2023 50 BEKAN AND CHALTU
  51. TYPES……GTN  P63 is expressed in ETT, placental site nodule, and choriocarcinoma, but not in PSTT.  Epithelioid trophoblastic tumor can be confused with squamous cell carcinoma because of its frequent involvement of:  the lower uterine segment or endocervix, its epithelioid histologic appearance, and  expression of p63 and cytokeratins 3/20/2023 51 BEKAN AND CHALTU
  52. TYPES……GTN Diagnostic criteria for Gestational Trophoblastic Neoplasia (GTN)  Plateau of serum ß-hCG level (<10 % drop) for four measurements during a period of 3 weeks or longer.  Rise of serum ß-hCG ≥ 10 % during three weekly consecutive measurements or longer, during a period of 2 weeks or more.  The serum / urine hCG level remains detectable for 6 months or more.  Histological diagnosis of invasive mole, PSTT or choriocarcinoma. 3/20/2023 52 BEKAN AND CHALTU
  53. STAGING OF GTN  Stage I — All patients with persistently elevated beta-hCG levels and tumor confined to the uterus.  Stage II — The presence of tumor outside of the uterus, but limited to the vagina and/or pelvis.  Stage III — Pulmonary metastases with or without uterine, vaginal, or pelvic involvement.  Stage IV — All other metastatic sites (eg, brain, liver, kidneys, gastrointestinal tract). 3/20/2023 53 BEKAN AND CHALTU
  54. INVESTIGATIONS  CBC  Blood group and RH  Serum B-hCG (preferably) otherwise Urine hCG  LFT and RFT  Chest X-ray  Ultrasound: typical sonographic features. 3/20/2023 54 BEKAN AND CHALTU
  55. MANAGEMENT OF MOLAR PREGNANCY Immediate management.  Open an IV line and resuscitate as required.  Cross-match at least 2 units of blood  Arrange for evacuation of the uterus.  Get prepared for possible hemorrhagic shock.  If the cervix is closed and needs dilatation use cervical block or other analgesics.  NB: Evacuate the uterus by suction curettage in major OR if uterus is >14 weeks size. 3/20/2023 55 BEKAN AND CHALTU
  56. MANAGEMENT MOLAR,,,  Infuse oxytocin 20 units in 1 L normal saline or Ringer’s lactate at 60 drops / minute to prevent hemorrhage once evacuation is under way.  Provide prophylactic antibiotic  Administer Anti-D for RH negative patients  Submit the evacuated specimen for histo- pathologic examination 3/20/2023 56 BEKAN AND CHALTU
  57. MANAGEMENT OF MOLAR… Subsequent management and follow up;  Advice for use of combined oral contraceptive pill, implant or injectable for one year or tubal ligation if the woman has completed her family.  Get baseline ß-hCG within 48 hours of evacuation. 3/20/2023 57 BEKAN AND CHALTU
  58. MANAGEMENT OF MOLAR,,, Follow-up:  Advise to come if she develops any or the combination of the following danger signs: cough, SoB, excessive vaginal bleeding, etc  Determine serum ß-hCG every 1-2 weeks until it falls to a normal level.  After three consecutive normal ß-hCG level is achieved, monitor monthly for six additional consecutive months, at which time surveillance can be discontinued safely. 3/20/2023 58 BEKAN AND CHALTU
  59. MANAGEMENT OF MOLAR…  Administer single agent chemotherapy (methotrexate or Actinomycin D) as a prophylaxis for high risk cases who may not avail themselves for follow up. A. Methotrexate  MTX: 0.4 - 0.5 mg/kg IV or IM daily for 5 days or  MTX: 30-50 mg/m2 IM weekly or  MTX- Leucovorin  MTX 1 mg/kg IM or IV on days 1,3,5,7  Leucovorin 15 mg PO days 2,4,6,8  High dose IV MTX / FA  MTX 100 mg/m2 IV bolus  MTX 200 mg/m2 12 hr infusion  Leucovorin 15 mg q 12 hr in 4 doses IM or PO beginning 24 hr after starting MTX 3/20/2023 59 BEKAN AND CHALTU
  60. MANAGEMENT OF MOLAR…. B. Actinomycin D  Table 1. Act D 10-12 mcg/kg IV push daily for 5 days or  Table 2. Act D 1.25 mg/m2 IV push q 2 wks  N.B: In places where there is no capacity to determine serum ß-hCG for surveillance, use urine hCG. 3/20/2023 60 BEKAN AND CHALTU
  61. MANAGEMENT OF GTN  Non-metastatic GTD  Low-Risk Metastatic GTD  High-Risk Metastatic GTD  Virtually all patients are potentially curable with chemotherapy, especially if correctly diagnosed and appropriate drugs are commenced early in the course of the disease 3/20/2023 61 BEKAN AND CHALTU
  62. MANAGEMENT OF GTN  Principles: 1) Chemotherapy 2) Surgery(resistant & persistent metastasis)- Liver, Brain, Lung, other 3) Radiotherapy 4) Hypogastric artery embolization 3/20/2023 62 BEKAN AND CHALTU
  63. MANAGEMENT OF GTN Treatment of Nonmetastatic GTD.  Hysterectomy is advisable as initial treatment in patients with non-metastatic GTD who no longer wish to preserve fertility  This choice can reduce the number of course and shorter duration of chemotherapy.  Adjusted single-agent chemotherapy at the time of operation is indicated to eradicate any occult metastases and reduce tumor dissemination. 3/20/2023 63 BEKAN AND CHALTU
  64. MANAGEMENT OF GTN  Single-agent chemotherapy is the treatment of choice for patients wishing to preserve their fertility.  Methotrexate(MTX) or Actinomycin-D  Treatment is continued until three consecutive normal hCG levels have been obtained and two courses have been given after the first normal hCG level. 3/20/2023 64 BEKAN AND CHALTU
  65. MANAGEMENT OF GTN Treatment of Low-Risk Metastatic GTD.  Single-agent chemotherapy with MTX or Actinomycin-D is the treatment for patients in this category  If resistance to sequential single-agent chemotherapy develops, combination chemotherapy would be taken  Approximately 10-15% of patients treated with single- agent chemotherapy will require combination chemotherapy with or without surgery to achieve remission 3/20/2023 65 BEKAN AND CHALTU
  66. MANAGEMENT OF GTN  Methotrexate: 1- 0.4mg/Kg IM/wk/5days, repeat Q2wks(10% failure rate). 2- 1mg/Kg/IM on days(1,3,5,7), alternate with folinic acid 0.1mg/Kg IM on days(2,4,6,8), after 24hrs of MTX 3- 50mg/M2 IM weekly(30% failure) 3/20/2023 66 BEKAN AND CHALTU
  67. MANAGEMENT OF GTN  Actinomycin-D: 1- 12mcg/Kg IV/day/5days repeat Q2 weeks(8% failure) 2- 1.25mg/M2 IV Q2weeks(20% failure) 3- MTX 250mg iv over 12hrs(EMA-CO regimen) – 30% failure 3/20/2023 67 BEKAN AND CHALTU
  68. MANAGEMENT OF GTN Treatment of High-Risk Metastatic GTD.  Multiagent chemotherapy with or without adjuvant radiotherapy or surgery should be the initial treatment for patients with high-risk metastatic GTD  EMA-CO regimen formula is good choice for high-risk metastatic GTD  MAC(MTX,Actinomycin-D, Cytoxan/chlorambucil)- alternative to EMA-CO(risk of leukemia) 3/20/2023 68 BEKAN AND CHALTU
  69. MANAGEMENT OF GTN  Resistant to EMA-CO: EMA-EP, EMA-PA  Resistant to EMA-EP: Taxol with cisplatin alternating with Taxol-etoposide or Taxol-5FU or ICE or BEP  Adjusted surgeries such as removing foci of chemotherapy-resistant disease, controlling hemorrhage may be the one of treatment regimen  Brain metastasis: Increase MTX dose in EMA-CO to1gm/M2, alkalinize urine by iv bicarbonate 3/20/2023 69 BEKAN AND CHALTU
  70. MANAGEMENT OF GTN  Radiotherapy: Brain & Liver metastasis Can be given with chemotherapy. 1- Brain:- 300 rads/day/5days/week X2weeks- 3000 rads total 2- Liver:- 200 rads/day/5days/week X 2weeks- 2000 rads total • Pelvic artery embolization- intractable hemorrhage 3/20/2023 70 BEKAN AND CHALTU
  71. POST TREATMENT SURVEILLANCE  Monitoring of patients with stage I, II, or III GTN consists of weekly beta-hCG measurements until the level is undetectable for 3 weeks, followed by monthly titers until the level is undetectable for 12 months.  Women with stage IV disease are followed for 24 months because of the greater risk of late relapse.  Patients are encouraged to use effective contraception during the entire surveillance period 3/20/2023 71 BEKAN AND CHALTU
  72. REFERENCES  William text book of obstetrics 26th edition, 2022.  FMOH management protocol on selected obstetrics topics for hospitals 2020.  William text book of gynecology 4th edition, 2020  DC Dutta text book of GYNECOLOGY 8th edition 2015 3/20/2023 72 BEKAN AND CHALTU
  74. COURSE OUTLINE  Objectives  Normal embrology  Mullerian anomalities  Cervical anomalities  Fallopian tube anomalities  DSD 3/20/2023 74 BEKAN AND CHALTU
  75. OBJECTIVES  At the end of the session the students will able to:  Differentiate different mullerian anomalities  Define DSD 3/20/2023 75 BEKAN AND CHALTU
  76. NORMAL EMBRYOLOGY  The urogenital tract is functionally divided into the urinary system and genital system.  The urinary organs include the kidney, ureters, bladder, and urethra.  The reproductive organs are the gonads, ductal system, and external genitalia.  The female urogenital tract develops from multiple cell types that undergo important spatial growth and differentiation.  Both the urinary and genital systems develop from intermediate mesoderm 3/20/2023 76 BEKAN AND CHALTU
  77. CONT…  During initial embryo folding,-  urogenital ridge-  longitudinal ridge and  develops along each side of the primitive abdominal aorta.  the urogenital ridge divides into the nephrogenic ridge and  the genital ridge(the gonadal ridge) 3/20/2023 77 BEKAN AND CHALTU
  78. CONT…  At approximately 60 days of gestation, the nephrogenic ridges develop into  the mesonephric kidneys and  paired mesonephric ducts(wolffian ducts.)  The mesonephric ducts connect the mesonephric kidneys to cloaca(opening into which the embryonic urinary, genital, and alimentary tracts join).  The paired paramaontphric ducts(the mullerian ducts), develop from invagination of the coelomic epithelium at approximately the sixth week. 3/20/2023 78 BEKAN AND CHALTU
  79. CONT…  The cloaca is divided by formation of the urorectal septum by the seventh week and is separated to create the rectum and the urogenital sinus.  The urogenital sinus is considered in three parts: 1. The cephalad or vesicle portion, which will form the urinary bladder; 2. The middle or pelvic portion, which creates the female urethra;and 3. The caudal or phallic part, which will give rise to the distal vagina and the greater vestibular (Bartholin) glands and paraurethral glands. 3/20/2023 79 BEKAN AND CHALTU
  80. CONT… Gonadal Determination.  Mammalian sex is determined genetically.  Individuals with X and Y chromosomes usually develop as males, whereas with two X chromosomes develop as females  The epithelium proliferates, and cords of epithelium invaginate into the mesenchyme to create primitive sex cords.  In both 46,XX and 46,XY embryos, the primordial germ cells are first identified as large polyhedral cells in the yolk sac. 3/20/2023 80 BEKAN AND CHALTU
  81. CONT…  Sexual determination is the development of the genital ridge into either an ovary or testis.  This depends on the genetic sex produced at fertilization, when the X-bearing oocyte is penetrated by either an X- or Y-chromosome-bearing sperm.  In humans, the gene named the sex-determining region of that Y (SRY) is the testis-determining factor.  In the presence of SRY, gonads typically develop as testes.  Other genes are important for normal gonad development and include SOX9, SF-1, DMRTJ, GATA4, WNT4, WTJ, DAXJ, and RSPOJ. 3/20/2023 81 BEKAN AND CHALTU
  82. CONT…  Mutations in any of these genes may lead to abnormal sexual determination.  In males, cells in the medullary region of the primitive sex cords differentiate into Sertoli cells-form the testicular cord  Testicular cords are identifiable at 6 weeks and consist of these Sertoli cells and tighty packed germ cells.  During early development, Sertoli cells begin secreting antimullerian hormone (AMH), also called mullerian inhibitory substance (MIS). 3/20/2023 82 BEKAN AND CHALTU
  83. CONT…  This gonadal hormone causes regression of the ipsilateral paramesonephric (miillerian duct) system, and this involution is completed by 9 to 1 0 weeks' gestation.  In the female embryo, without the influence of the SRY gene, the bipotential gonad develops into the ovary.  The pathways regulating female sex determination have remained incompletely defined, but WNT4, WTI, FoxL2, and DAXJ genes are important for normal development  Development is first characterized by the absence of testicular cords in the gonad. 3/20/2023 83 BEKAN AND CHALTU
  84. CONT…  The primitive sex cords degenerate, and the mesothelium of the genital ridge forms secondary sex cords.  These secondary cords become the granulosa cells that band together to form the follicular structures that surround the germ cells.  Germ cells that carry two X chromosomes undergo mitosis during their initial migration to the female genital ridge. 3/20/2023 84 BEKAN AND CHALTU
  86. CONT… Ductal System Development  Sexual differentiation of the mesonephric (wolffian) and paramesonephric (mullerian) ducts begins in week 7 from the influence of gonadal hormones (testosterone and AMH) and other factors.  In the male, AMH forces paramesonephric regression, and testosterone prompts mesonephric duct differentiation into the epididymis, vas deferens. and seminal vesicles.  In the female, a lack of AMH allows mullerian ducts to persist. 3/20/2023 86 BEKAN AND CHALTU
  87. CONT…  During paramesonephric duct elongation, homeobox(Hox) genes determine developing duct.  HoxA9 is expressed at high levelsin areas destined to become the fallopian tube  HoxA10 and HoxA11 are expressed in the developing uterus  Mesonephric and paramesonephric duct systems become enclosed in peritoneal folds that later give rise to the broad ligaments of the uterus 3/20/2023 87 BEKAN AND CHALTU
  88. CONT..  Urogenital sinus is formed by fusion of the two distal portions of the mullerian ducts.  The fused ducts form a tube called the urovaginal canal.  By 12 weeks, mesonephric duct regress from lack of testosterone.  The uterine corpus and cervix differentiate, and the uterine wall thickens.  The vagina forms partly from the miillerian ducts and partly from the urogenital sinus 3/20/2023 88 BEKAN AND CHALTU
  89. CONT…  Specifically, the upper two thirds of the vagina derive from the fused mullerian ducts.  The distal third of the vagina develops from the bilateral sinovaginal bulb, which are cranial evaginations of the urogenital sinus. 3/20/2023 89 BEKAN AND CHALTU
  90. CONT… External Genitalia  By 6 weeks' gestation, three external protuberances have developed surrounding the cloacal membrane.  the left and right cloacal folds, which meet ventrally to form the genital tubercle  With division of the cloacal membrane into anal and urogenital membranes, the cloacal folds become the anal and urethral folds, respectively 3/20/2023 90 BEKAN AND CHALTU
  91. CONT…  Between the urethral folds, the urogenital sinus extends into the surface of the enlarging genital tubercle to form the urethral groove.  The genital tubercle elongates to form the phallus in males and the clitoris in females  In the male fetus, DHT forms locally by the 5a:-reduction of testosterone.  DHT prompts the anogenital distance to lengthen, the phallus to enlarge, and the labioscrotal folds to fuse and form the scrotum  Sonic hedgehog (SHH) is a gene that regulates urethral tubularization in males at 14 weeks' gestation 3/20/2023 91 BEKAN AND CHALTU
  92. CONT…  Specifically, DHT and SHH expression promote the urethral folds to merge and enclose the penile urethra.  In the female fetus, without DHT, the anogenital distance does not lengthen, and the labioscrotal and urethral folds do not fuse.  The genital tubercle bends caudally to become the clitoris, and the distal urogenital sinus becomes the vestibule of the vagina.  The labioscrotal folds create the labia majora, whereas the urethral folds persist as the labia minora. 3/20/2023 92 BEKAN AND CHALTU
  93. SUMMARY 3/20/2023 93 BEKAN AND CHALTU
  94. SUMMARY 3/20/2023 94 BEKAN AND CHALTU
  95. SUMMARY 3/20/2023 95 BEKAN AND CHALTU
  96. MÜLLERIAN ABNORMALITIES  are often asymptomatic and therefore unrecognized.  They may affect a young woman due to pain at the time of menarche, or a woman's obstetric and/or gynecologic health.  The incidence of congenital uterine anomalies is difficult to determine since  many women with such anomalies are not diagnosed, especially if they are asymptomatic.  Uterine anomalies occur in 2 to 4 percent of fertile women with normal reproductive outcomes. 3/20/2023 96 BEKAN AND CHALTU
  97. MÜLLERIAN ABNORMALITIES  Classification of Müllerian anomalies according to the American Fertility Society classification system. 1) Type I: "Müllerian" agenesis or hypoplasia 2) Type II: Unicornuate uterus 3) Type III: Uterus didelphys 4) Type IV: Uterus bicornuate 5) Type V: Septate uterus 6) Type VI: Diethylstibestrol-related anomalies 3/20/2023 97 BEKAN AND CHALTU
  98. MÜLLERIAN ABNORMALITIES Müllerian Agenesis (Class I)  are caused by müllerian hypoplasia or agenesis.  These developmental defects can affect the vagina, cervix, uterus, or fallopian tubes  May be isolated or coexist with other müllerian anomalies. 3/20/2023 98 BEKAN AND CHALTU
  99. MÜLLERIAN ABNORMALITIES Vaginal Abnormalities.  The most profound and may be isolated or associated with other müllerian anomalies.  The Mayer- Rokitansky-Küster-Hauser (MRKH) syndrome, in which upper vaginal agenesis is typically associated with uterine hypoplasia or agenesis.  The obstetrical significance of vaginal anomalies depends greatly on the degree of obstruction. 3/20/2023 99 BEKAN AND CHALTU
  100. MÜLLERIAN ABNORMALITIES  With MRKH syndrome, a functional vagina can be created, but uterine agenesis proscribes childbearing.  However, ova can be retrieved for in vitro fertilization (IVF) and carriage by a surrogate mother.  Congenital septa may form longitudinally or transversely, and each can arise from a fusion or resorption defect.  Alongitudinal septum divides the vagina into right and left portions. 3/20/2023 100 BEKAN AND CHALTU
  101. MÜLLERIAN ABNORMALITIES  It may be complete and extend the entire vaginal length.  A partial septum usually forms high in the vagina but may develop at lower levels.  These septa are often associated with other müllerian anomalies.  A transverse septum poses an obstruction of variable thickness.  It may develop at any depth within the vagina, but most lie in the lower third.  Septa may or may not be perforate, and thus obstruction or infertility is possible. 3/20/2023 101 BEKAN AND CHALTU
  102. MÜLLERIAN ABNORMALITIES II. Uterine Abnormalities  Assessing an accurate population prevalence is difficult because the best diagnostic techniques are invasive.  The prevalence found with imaging ranges from 0.4 to 10 percent.  In a general population, the most frequent finding is arcuate uterus, followed in descending order by  septate,  bicornuate,  didelphic, and  Unicornuate 3/20/2023 102 BEKAN AND CHALTU
  103. MÜLLERIAN ABNORMALITIES Unicornuate Uterus (Class II)  General population estimates cite an incidence of 1 case in 4000 women.  only one uterine horn is present  Instead, an underdeveloped rudimentary horn may be present.  The rudiment may or may not communicate with the dominant horn and may or may not contain an endometrium-lined cavity.  With noncommunicating types, the rudiment may lie near the uterus or may lie anywhere along the embryological migration path of the paramesonephros. 3/20/2023 103 BEKAN AND CHALTU
  104. MÜLLERIAN ABNORMALITIES  Importantly, 40 percent of affected women will have renal anomalies.  Pregnancies developing in the main horn carry significant obstetrical risks. 3/20/2023 104 BEKAN AND CHALTU
  105. MÜLLERIAN ABNORMALITIES  Ectopic pregnancy, correctly termed a cornual pregnancy, can develop within a rudmentary horn.  The rudimentary horn pregnancy displays: 1. No continuity between the cervical canal and gestational sac, 2. Myometrium surrounding the gestation, 3. PAS-associated hypervascularity surrounding the gestational sac, and 4. A vascular pedicle connecting the main horn and the sac’s surrounding myometrium.  Treatment is surgical and removes the rudimentary horn and in situ pregnancy 3/20/2023 105 BEKAN AND CHALTU
  106. MÜLLERIAN ABNORMALITIES Uterine Didelphys (Class III)  This anomaly arises from incomplete fusion that results in  two entirely separate hemiuteri,  two cervices, and  usually two vaginas or a longitudinal vaginal septum 3/20/2023 106 BEKAN AND CHALTU
  107. MÜLLERIAN ABNORMALITIES  Uterine didelphys may be isolated or part of a rare triad with an obstructed hemivagina and ipsilateral renal agenesis (OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome.  it is considered in a fetus with renal agenesis and a cystic pelvic mass, which reflects hydrometrocolpos 3/20/2023 107 BEKAN AND CHALTU
  108. MÜLLERIAN ABNORMALITIES Bicornuate Uterus (Class IV)  This fusion anomaly results in two hemiuteri.  The central myometrium runs either partially or completely to the cervix.  A complete bicornuate uterus may extend to the internal cervical os  Have a single cervix (bicornuate unicollis) or reach the external os (bicornuate bicollis).  As with uterine didelphys, a coexistent longitudinal vaginal septum is common. 3/20/2023 108 BEKAN AND CHALTU
  109. 3/20/2023 109 BEKAN AND CHALTU
  110. MÜLLERIAN ABNORMALITIES Septate Uterus (Class V)  With this anomaly, a resorption defect leads to a persistent complete or partial longitudinal uterine septum.  In the rare, an asymmetric longitudinal septum creates a sequestered noncommunicating hemicavity that acts similar to a rudimentary horn 3/20/2023 110 BEKAN AND CHALTU
  111. MÜLLERIAN ABNORMALITIES Arcuate Uterus (Class VI)  This malformation is a mild deviation from the normally developed uterus.  Most consider this anomaly benign, but some have found excessive second-trimester losses, preterm labor, and malpresentation. 3/20/2023 111 BEKAN AND CHALTU
  112. MÜLLERIAN ABNORMALITIES Diethylstilbestrol-related Abnormalities (Class VII).  In the 1960s, a synthetic nonsteroidal estrogen—diethylstilbestrol (DES)— was used to treat threatened abortion, preterm labor, preeclampsia, and diabetes.  Moreover, women exposed as fetuses carry increased risks for vaginal clear cell adenocarcinoma, cervical intraepithelial neoplasia, and vaginal adenosis 3/20/2023 112 BEKAN AND CHALTU
  113. MÜLLERIAN ABNORMALITIES  Women exposed in utero can also show a cervix or vagina with a transverse septum, circumferential ridge, or cervical collar.  Uteri are potentially smaller or have a T-shaped cavity. 3/20/2023 113 BEKAN AND CHALTU
  114. CERVICAL ABNORMALITIES 3/20/2023 114 BEKAN AND CHALTU  Developmental abnormalities of the cervix include:  partial or complete agenesis,  duplication, or a longitudinal dividing septum.  Complete agenesis is incompatible with pregnancy.  surgical correction by uterovaginal anastomosis successfully relieves outlet obstruction
  115. FALLOPIAN TUBE ABNORMALITIES  The fallopian tubes develop from the unpaired distal ends of the müllerian ducts.  Congenital anomalies include:  Accessory ostia,  Complete or segmental Tubal agenesis, and  Several embryonic cystic remnants.  The most common is a small, benign cyst attached by a pedicle to the distal end of the fallopian tube—the hydatid of Morgagni.  In other cases, benign paratubal cysts may be of mesonephric or mesothelial origin 3/20/2023 115 BEKAN AND CHALTU
  116. DISORDERS OF SEX DEVELOPMENT  Formerly, Disorders or differences in sex development (DSD} were subdivided as those: 1) associated with gonadal dysgenesis, 2) associated with undervirilization of 46,)CY individuals, and 3) associated with prenatal virilization of 46,XX subjects.  Proposed classification ofDSDs are: A. sex chromosome DSDs,  45,XTurne,.a  47,XXY Klinefelte,.a  45,X/46,XY Mixed gonadal dysgenesis  46,XX/46,XY Ovotesticular DSD 3/20/2023 116 BEKAN AND CHALTU
  117. CONT… B. (46,)CY DSDs, and  Testicular development  Pure gonadal dysgenesis  Partial gonadal dysgenesis  Ovotesticular  Testis regression  Androgen production or action  Androgen synthesis  Androgen receptor  LH/hCG receptor  AMH 3/20/2023 117 BEKAN AND CHALTU
  118. CONT… C. 46,XX DSDs  Ovary development  Ovotesticular  Testicular  Gonadal dysgenesis  Androgen excess  Fetal  Maternal  Placental 3/20/2023 118 BEKAN AND CHALTU
  119. CONT… Others  Hermaphroditism  Ambiguous genitalia 3/20/2023 119 BEKAN AND CHALTU
  120. SEX CHROMOSOME DISORDERS OF SEX DEVELOPMENT Turner Syndromes  usually caused by loss of part or all of an X-chromosome  occurs in approximately 1/2,500 live female births.  caused by de novo loss or severe structural abnormality of one X chromosome in a phenotypic female.  It is the most common form of gonadal dysgenesis that leads to primary ovarian insufficiency.  Most affected fetuses are spontaneously aborted.  Nearly all affected patients have short stature.  This results from lack of one copy of the SHOX gene(Short Stature Homeobox-containing Gene), which resides on the short arm of the X chromosome 3/20/2023 120 BEKAN AND CHALTU
  121. CONT… PATHOGENESIS  Maternal X is retained in two-thirds of patients with Turner syndrome and the paternal X in the remaining one-third.  More than one-half of all patients with Turner syndrome have a mosaic chromosomal complement (eg, 45,X/46,XX)  Mosaicism with a normal cell line in the fetal membranes may be necessary for adequate placental function and fetal survival 3/20/2023 121 BEKAN AND CHALTU
  122. CONT..,  The identification of mosaicism depends directly upon the method of ascertainment.  It varies from 34 percent with conventional cytogenetic techniques,  60 percent with fluorescence in situ hybridization techniques and  74 percent in a study in which reverse transcriptase polymerase- chain-reaction assays were used.  Some patients with Turner syndrome lack only part of one sex chromosome, and the Turner syndrome phenotype can be seen with of structural abnormalities, such as  isochromosomes, or  terminal deletions. 3/20/2023 122 BEKAN AND CHALTU
  123. CONT…  A rare but very informative class of Turner syndrome includes patients who have deletions of the Y chromosome that remove the testes-determining gene, SRY;  these individuals develop as females  Short stature is the only clinical finding invariably associated with the 45,X karyotype;  it also is the only phenotypic abnormality present in virtually 100 percent of patients.  Karyotypic abnormalities may also correlate with the presence of hypothyroidism 3/20/2023 123 BEKAN AND CHALTU
  124. CONT…  Some patients are not diagnosed until adolescence, when they present with short stature, prepubertal female genitalia, and primary amenorrhea.  The uterus and vagina are normal and are capable of responding to exogenous hormones.  Have a structural abnormality of the second X chromosome or have a mosaic karyotype, such as 45,X/46,XX.  More than half of the girls with this syndrome have chromosomal mosaicism 3/20/2023 124 BEKAN AND CHALTU
  125. CHARACTERISTIC FINDINGS OF TURNER SYNDROME  Height 142-147 cm  Micrognathia  Epicanthal folds  Low-set ears  Shield-like chest  Cubitus valgus  Renal abnormalities  Aorta coarctation  Diabetes mellitus  High-arched palate  Hearing loss  Webbed neck  Absent breast development  Widely spaced areolae  Short fourth metacarpal  Autoimmune disorders  Autoimmune thyroiditis 3/20/2023 125 BEKAN AND CHALTU
  126. CONT… CLINICAL MANIFESTATIONS Physical findings Skeletal growth disturbances  Short stature  Short neck  Short metacarpals Lymphatic obstruction  Webbed neck  Low posterior hairline  Rotated ears  Edema of hands/feet  Severe nail dysplasia 3/20/2023 126 BEKAN AND CHALTU
  127. CONT… Ovarian failure  The ovaries in Turner syndrome cxrsally consists:  small amounts of connective tissue and no follicles or  only a few atretic follicles ("streak gonads")  Most affected women have no pubertal development and primary amenorrhea,  Some develop normally and then have secondary amenorrhea,  While occasionally others have no morphologic defects and achieve normal stature.  The gonadal dysgenesis may be caused by accelerated apoptosis rather than abnormal germ cell formation. 3/20/2023 127 BEKAN AND CHALTU
  128. CONT.. Short stature  the most common clinical feature of Turner syndrome Renal anomalies  most commonly horseshoe kidney, followed by abnormal vascular supply  Anomalies associated with obstruction of the ureteropelvic junction can produce clinically significant  hydronephrosis or  pyelonephritis 3/20/2023 128 BEKAN AND CHALTU
  129. CONT… Cardiovascular disease  due to risk of cardiovascular malformations, renal abnormalities, and hypertension  coarctation, aortic valvular disease, aortic dissection, hypertension, Neck webbing Osteoporosis  due to both ovarian failure and possibly haploinsufficiency for bone-related X-chromosome genes 3/20/2023 129 BEKAN AND CHALTU
  130. DIAGNOSIS  Karyotype analysis  Y chromosome mosaicism  Serum thyrotropin (TSH)  Echocardiography or Magnetic resonance imaging  Blood glucose, serum creatinine, and urinalysis 3/20/2023 130 BEKAN AND CHALTU
  131. CONT… Management  Estradiol initiation at ages 11 or 12 years, the use of transdermal estradiol, and gradual dose increases over 2 to 3 years (International Turner Syndrome Consensus Group).  Progesterone is added after 2 years of treatment or with onset of breakthrough bleeding.  Ensure adequate calcium intake (1.2 g/day).  Encourage weight-bearing exercise.  Check bone mineral density every three to five years 3/20/2023 131 BEKAN AND CHALTU
  132. KLINIFELTER SYNDROME (47,XXY)  which occurs in 1 in 600 births or in 1 to 2 percent of all males.  are tall, undervirilized males with gynecomastia and small, firm testes.  They have significantly reduced fertility from hypogonadism due to gradual testicular cell loss that begins shortly after testis determination.  These men carty higher risks for germ cell tumors, osteoporosis, hypothyroidism, diabetes mellitus, breast cancer, and cognitive and psychosocial problems. 3/20/2023 132 BEKAN AND CHALTU
  133. CONT…  The 47,XXY karyotype results from nondisjunction of the sex chromosomes and can be maternal or paternal in origin.  Male newborns with the 47,XXY karyotype are phenotypically normal, with normal male external genitalia and no apparent dysmorphic features.  The major clinical manifestations of Klinefelter syndrome include tall stature, small testes, and infertility (azoospermia) that become noticeable after puberty. 3/20/2023 133 BEKAN AND CHALTU
  134. CONT…  Patients with Klinefelter syndrome are at increased risk for psychiatric disorders, autism spectrum disorders, and social problems. 3/20/2023 134 BEKAN AND CHALTU
  135. CHROMOSOMAL OVOTESTICULAR  Several karyotypes can create a coexistent ovary and testis, and thus ovotesticular DSD is found in all three DSD categories.  may arise from a 46, XX/46,XY katyotype.  an ovary, testis, or ovotestis may be paired  a picture of mixed gonadal dysgenesis shows a streak gonad on one side and a dysgenetic or normal testis on the other.  The phenotypic appearance ranges from undervirilized male to ambiguous genitalia to Turner syndrome stigmata. 3/20/2023 135 BEKAN AND CHALTU
  136. 46,XY DISORDERS OF SEX DEVELOPMENT  Insufficient androgen exposure of a fetus destined to be a male leads to 46,XY DSD, formerly called male pseudohermaphroditism.  The katyotype is 46,XY, and testes are frequently present.  The uterus is generally absent as a result of normal embryonic AMH production by Sertoli cells.  These patients are most often sterile from abnormal spermatogenesis and have a small phallus that is inadequate for sexual function.  Etiology of from abnormal testis development or abnormal androgen production or action. 3/20/2023 136 BEKAN AND CHALTU
  137. 46,XY GONADAL DYSGENESIS  Abnormal gonad underdevelopment includes  pure or complete, partial, or mixed 46,XY gonadal dysgenesis  These are defined by the amount of normal testicular tissue and katyotype. Pure gonadal dysgenesis( Swyer syndrome, )  results from a mutation in SRYor in another gene with testis- determining effects (DAXJ, SF-1, CBX2)  This leads to underdeveloped dysgenetic gonads that fail to produce androgens or AMH.  the condition creates a normalprepubertal female phenotype and a normal miillerian system due to absent AMH. 3/20/2023 137 BEKAN AND CHALTU
  138. CONT… Partial gonadal dysgenesis defines those with gonad development  intermediate between normal and dysgenetic testes.  Depending on the percentage of underdeveloped testis, wolffian and mi.illerian structures and genital ambiguity are variably expressed.  Mixed gonadal dysgenesis  One gonad is streak and the other is a normal or a dysgenetic testis.  Of affected individuals, a 46,XY katyotype is found in 15 percent  The phenotypic appearance is widen ranging as with partial gonadal dysgenesis 3/20/2023 138 BEKAN AND CHALTU
  139. ABNORMAL ANDROGEN PRODUCTION OR ACTION  In some cases, 46.XY DSD may stem from abnormalities in: 1) Testosterone biosynthesis, 2) Luteinizing hormone (LH) receptor function, 3) AMH function, or 4) Androgen receptor action.  The sex steroid biosynthesis pathway can suffer enzymatic defects that block testosterone production,  Depending on the timing and degree of blockade, undervirilized males or phenotypic females may result. 3/20/2023 139 BEKAN AND CHALTU
  140. CONT…  Abnormal action of 5α-reductase type 2 enzyme impairs conversion of testosterone to DHT and blunts virilization.  Second, hCG/LH receptor abnormalities within the testes can lead to Leydig cell hypoplasia and decreased testosterone production.  Disorders of AMH and AMH receptors result in persistent müllerian duct syndrome (PMDS).  Last, the androgen receptor may be defective and result in androgeninsensitivity syndrome (AIS). 3/20/2023 140 BEKAN AND CHALTU
  141. CONT…  Those with complete androgen-insensitivity syndrome (CAIS) are phenotypically normal females.  Girls often present at puberty with primary amenorrhea.  External genitalia appear normal; pubic and axillary hair are scant or absent; the vagina is markedly shortened; and the uterus and fallopian tubes are absent.  However, these individuals develop breasts during puberty due to conversion of androgen to estrogen 3/20/2023 141 BEKAN AND CHALTU
  142. 46,XX DSD  This DSD group may stem from abnormal ovarian development or from excess androgen exposure. 1. Abnormal Ovarian Development.  Disorders of ovarian development in those with a 46,XX complement include: i. Gonadal dysgenesis, ii. Testicular DSD, and iii. Ovotesticular DSD. 3/20/2023 142 BEKAN AND CHALTU
  143. 46,XX DSD  46,XX gonadal dysgenesis, similar to Turner syndrome, streak gonads develop.  These lead to hypogonadism, prepubertal normal female genitalia, and normal müllerian structures.  However, other Turner stigmata are absent.  46,XX testicular DSD, several genetic mutations lead to testis-like formation.  Most commonly, defects stem from SRY translocation onto one paternal X chromosome.  Less often, other genes with testis-determining effects are activated. 3/20/2023 143 BEKAN AND CHALTU
  144. 46,XX DSD  46,XX ovotesticular DSD, individuals possess a unilateral ovotestis with a contralateral ovary or testis, or bilateral ovotestes.  Anoverexpression of SOX genes, which are testis promoting, or deficient ovarian promoting genes are implicated.  Phenotypic findings depend on the degree of androgen exposure. 3/20/2023 144 BEKAN AND CHALTU
  145. 46,XX DSD 2. Androgen Excess.  The prior term was female pseudohermaphroditism.  In affected individuals, the ovaries and female internal ductal structures such as the uterus, cervix, and upper vagina develop.  The embryonic clitoris, labioscrotal folds, and urogenital sinus are commonly affected by elevated androgen levels.  Virilization may range from modest clitoromegaly to posterior labial fusion and a phallus with a penile urethra. 3/20/2023 145 BEKAN AND CHALTU
  146. REFERENCES  William text book of obstetrics 26th edition, 2022.  William text book of gynecology 4th edition, 2020  DC Dutta text book of GYNECOLOGY 8th edition 2015 3/20/2023 146 BEKAN AND CHALTU