Pathophysiology 5160 Reproduction 3 PDF
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CUSM
Dr. Maiyon Park
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This document discusses various disorders of sexual development. It covers topics such as SRY mutations, sex chromosome abnormalities, and congenital defects in hormone production. The document also contains learning outcomes and session summaries.
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Pathophysiology 5160 Reproduction 3 Dr. Maiyon Park CUSM - MBS COPYRIGHT NOTICE All materials found on CUSM’s course and project sites may be subject to copyright protection, and may be restri...
Pathophysiology 5160 Reproduction 3 Dr. Maiyon Park CUSM - MBS COPYRIGHT NOTICE All materials found on CUSM’s course and project sites may be subject to copyright protection, and may be restricted from further dissemination, retention or copying. DISCLOSURE I have no financial relationship with a commercial entity producing health-care related products and/or services. Session Learning Outcomes (SLOs) Students are able to describe following disorders of Sexual Development 1. SRY mutation in 46, XX MALE & Swyer Syndrome in 46, XY FEMALE 2. Disorders due to Inappropriate Number of Sex Chromosomes a. Klinefelter Syndrome – 47, XXY, MALE b. XYY Syndrome – 47, XYY, MALE c. Turner Syndrome – 45, XO, FEMALE 3. Kallmann Syndrome that has defect in GnRH producing cells 4. Congenital defects in Sex hormone production a. Congenital Adrenal Hyperplasia in FEMALE, Hirsutism/Virilization b. Androgen insensitivity syndrome c. 5-alpha reductase deficiency d. Aromatase deficiency 5. Cryptorchidism (Cryptorchism) 2 SLO 1: SRY gene and 46- XX Male Syndrome Sex-determining Region Y (SRY) gene Is located on the short branch of Y chromosome Initiates the development of male gonad, the Testis So called Testis Determining Factor Mutation of SRY or missing SRY on Y chromosome will lead to XY female Addition of SRY gene on X chromosome will lead to XX male 46, XX Male develops when there is abnormal crossing-over between tips of X & Y, leading to insertion of Yp on X- chromosome SRY gene is transferred to X upon translocation (46 XX male, SRY positive, 80%) No SRY gene is transferred to X upon translocation (46 XX male, SRY negative) Clinical symptoms present during adolescence or adulthood Infertility Small firm atrophic testis with small number of Leydig cells Azoospermia- absence of motile sperm in semen Gynecomastia (male breast enlargement) Low Testosterone, increased FSH, LH & Estrogen No Mullerian derived organ developed, fallopian tube, uterus, cervix & vagina SLO 1: Swyer Syndrome- SRY & other gene mutation Swyer syndrome is a rare disorder that fail to develop sex organs, testicles or ovaries People with Swyer syndrome have 46, XY genotype Develop vagina, uterus, fallopian tubes & external female genitalia Do not develop penis & scrotum Causes ~20% have mutations in sex-determining region Y (SRY) gene- non-functional SRY In other cases, SRY gene is unaffected but mutations in other genes are implicated Can be new mutation or can be inherited Clinical Presentation Phenotypically female with tall stature (~10 cm taller) Normal prepubertal development ~Normal Cognition/intelligence & Behavioral phenotype Sex development and fertility Primary amenorrhea Infertility due to non-functioning- Streak ovaries Decreased Estrogen production due to non-functional ovaries Can be pregnant with ova donation if uterus develops normally SLO 2b: Inappropriate Number of Sex Chromosome 47, XYY syndrome SUPERMALE, one more Y chromosome Paternal nondisjunction during meiosis II Incidence: 1 per 1,000 men Phenotypically tall & affected by severe acne Fertility is unaffected Klinefelter syndrome (47, XXY) Most common: 1 - 2.5 per 1,000 men 47, XXY: male externally & internally due to presence of Y & testes Paternal nondisjunction during meiosis I (X from father) Klinefelter syndrome causes Primary hypogonadism Hyalinization & dysgenesis of seminiferous tubules Clinical Presentation Root symptom: small testes, low testosterone Tall & long extremities (lack of testosterone to close epiphyseal plates) Female hair distribution, Gynecomastia, Infertility SLO 2c: Inappropriate Number of Sex Chromosome Turner Syndrome in FEMALE (45, X0) Female missing an X chromosome; 1 in 2,000 Short statue Short - webbed neck, low set ears & low hairline Cubitus valgus - angled out forearm, away from body Amenorrhea, infertility Streak gonad (ovary) Bicuspid aortic valve (normal tricuspid) Coarctation of aorta Horse-shoe kidney: 2 kidneys join (fuse) together at bottom and form a U shape like a horseshoe. SLO 3: Congenital defect in GnRH Producing Cells, Kallmann Syndrome Kallmann syndrome is present in Male (XY) and Female (XX) It is congenital hypogonadotropic hypogonadism, which is associated with dysfunction of olfactory bulbs, leading to anosmia or hyposmia Due to failed migration of GnRH producing neurons from the developing brain There is lack of GnRH production leading to low FSH, LH, Testosterone, Progesterone & low Sperm (male) & Egg (female) count Clinical symptoms include Anosmia (inability to smell) or Hyposmia Failure to start or fully complete puberty Poorly defined secondary sexual characteristics Lack of testicle development in male Primary amenorrhea in female Infertility in male & female During the development of the fetal brain, GnRH producing cells are in the area of the brain known as the olfactory placode. Around 6 to 8 wGA, the cells migrate into their final position in hypothalamus. The movement of the GnRH releasing cells is dependent on the presence of olfactory tract to allow passage of the cells to the hypothalamus. SLO 4a: Genetic Mutations in Sex Steroid Hormone Production Congenital adrenal hyperplasia (CAH) in FEMALE Due to lack of 21 hydroxylase, 11 or 17 hydroxylase Deficiency in 21 hydroxylase or 11 hydroxylase leads to excessive androgen production in female utero (Hirsutism & virilization- female masculinization) Both show high 17-hydroxyprogesterone XX female have ovaries with ambiguous genitalia & clitoromegaly, an abnormal enlargement of clitoris 21 hydroxylase CAH: hypotension & hyperkalemia 11 hydroxylase CAH: hypertension & hypokalemia due to mineralocorticoid nature of deoxycorticosterone Deficiency in 17 hydroxylase Decreased production of glucocorticoids & androgens Increased production of mineralocorticoid (aldosterone) & precursors (deoxycorticosterone & corticosterone) SLO 4a: Genetic Mutations in Sex Steroid Hormone Production Androgen Insensitivity syndrome in MALE Due to Mutation in Androgen receptors Normal/Elevated testosterone levels, defective testosterone receptors in pituitary or hypothalamus (no negative feedback) but high LH level (due to lack of response to androgen in body) The nuclear Receptors cannot bind to any androgens, Testosterone & DHT Normal appearing female with male genotype Genotypically 46, XY Have normal female external genitalia & develop secondary female sex characteristics Have Short, rudimentary vagina but no uterus or sexual hair is present Have undescended testes and Identified when patients fail menarche SLO 4c: Genetic Mutations in Sex Steroid Production 5-α-reductase deficiency in MALE Autosomal recessive defect in 5-α-reductase in XY male There is Impaired conversion of Testosterone to Dihydrotestosterone (DHT) Testosterone is produced in this patient, and the patient is born with male internal genitalia, but testes are undescended DHT is important for differentiation/development of external genitalia Due to lack of 5-α-reductase & DHT, the external genitals typically have female appearance at birth, but partially masculinized Phenotypically female-appearing male until puberty During puberty, there is virilization due to high levels of testosterone that changes the genitals The penis grows, the testes descends, and body become more masculine SLO 4c: Genetic Mutations in Sex Steroid Hormone Production Aromatase deficiency in Male and Female Rare autosomal recessive disorder Mutations in CYP19A1 gene cause aromatase deficiency Decreased aromatase activity leading to reduced levels of the female sex hormone estrogen Increased levels of the male sex hormone testosterone. Symptoms Hyperglycemia due to insulin resistance in both sexes (impaired response to insulin), fatty liver, tall stature Estrogen plays a role in regulating glucose metabolism and insulin sensitivity Female Lack of menstruation and lack of breast growth Ambiguous genitalia in female infants Acne and hirsutism in female adult Male Abnormal sperm production in adolescence Cryptorchidism Abnormal bone growth SLO 5: Cryptorchidism Cryptorchidism (Undescended testicle) Cryptor (hidden) & Orchis (testicle) Not be able to see or feel testicle in scrotum Failure of testes to descend into the scrotum unilaterally or bilaterally Associated condition Common in premature baby (Prematurity) Kallmann's syndrome Cystic fibrosis Testicular feminization The testes may descend by 3 months after birth If natural descent does not occur by 3 months, it must be removed surgically by 2 years old because patients with cryptorchidism have increased risk of testis cancer Decreased sperm count and low level of Inhibin due to the higher temperature of testis inside the body Summary of Reproduction Lecture- 3 1. SRY mutation in 46, XX MALE & Swyer Syndrome in 46, XY FEMALE 2. Disorders due to Inappropriate Number of Sex Chromosomes a. Klinefelter Syndrome – 47, XXY, MALE b. XYY Syndrome – 47, XYY, MALE c. Turner Syndrome – 45, XO, FEMALE 3. Kallmann Syndrome that has defect in GnRH producing cells 4. Congenital defects in Sex hormone production a. Congenital Adrenal Hyperplasia in FEMALE, Hirsutism/Virilization b. Androgen insensitivity syndrome c. 5-alpha reductase deficiency d. Aromatase deficiency 5. Cryptorchidism (Cryptorchism) 13 THANKS and BEST WISHES Final Exams, MCAT Testing, MD and other Application, Future Goals and Life