Winter 2009 Notes for Lectures #19-20 Bio 75 Lecture #19: ENVIRONMENTAL BIRTH DEFECTS (Ch 13 Pinon) I. STATISTICS: for every 100 fertilized eggs only 48 healthy babies are born; 31% fail to implant and will therefore never produce a positive pregnancy test; another 14% result in miscarriages (often chromosomal aberrancies); 13% of newborns have some inborn defect II. CAUSES OF FETAL LOSS A. Intrinsic factor: means fetal loss is due to some defect in the embryo (often genetic anomalies) B. Extrinsic factor: means that fetal loss is due to some external factor, such as toxins C. Maternal factor: means that fetal loss is due to some defect in the maternal environment (malformation of the uterus, the placenta or maternal diseases that impair development of the fetus) D. Susceptibility: External factors have the most detrimental effects on the developing human during the 1st trimester, because all tissues and organs develop; later exposure during pregnancy often results in cognitive dysfunctions, because the brain continues to develop until birth. Statistically, brain abnormalities account for most human malformations at birth. III. TERATOLOGY A. Definition: study of developmental disorders (teratos = monster); Teratogens = environmental agents that affect development of the embryo/fetus (account for 10% of inborn abnormalities) B. Teratogens: biological (e.g. viral or bacterial infection), chemical (e.g. environmental toxins, such as mercury or DDT), drugs (prescription, recreational), radiation C. Effects: depend on time of exposure (e.g. early exposure to alcohol will affect heart development, while later exposure only affects brain development), dosage, and predisposition of the embryo/fetus (even with the same dosage and exposure time not 100% of the newborns will be affected the same way) IV. INFECTIOUS TERATOGENS A. Transmission: three modes of possible transmission from mother to infant: through placenta, during passage through birth canal, through breastmilk B. Rubella: virus; infection of mother during first trimester can be transmitted through placenta; results in cataract, heart defects and deafness in 20% of exposed babies; prevented by maternal rubella vaccination C. Chlamydia and Gonorrhea: 1. Incidence: Very common (20% of pregnant women have chlamydial and 7% gonococcal infection), especially among teenagers; recent epidemic in U.S. partly due to resistant strain Winter 2009 Notes for Lectures #19-20 Bio 75 2. Cause: Bacterium usually transmitted by intercourse (vagina, anus, mouth); other contact like wet towels but rare; to baby during birth mainly through eyes (usual prophylaxis is eye drops to neonate for gonorrhea), 3. Symptoms: a. in mother: after 2-6 d irritation & discharge local to site of infection; can then result in cloudy, yellow vaginal discharge, can spread to Fallopian tubes (15% of cases), also become PID (pelvic inflammatory disease), can cause infertility (Chlamydia is most common cause of infertility in women); 75% no symptoms!!!!! b. in newborn: pneumonia and conjunctivitis with risk of blindness 4. Prophylaxis and Treatment: Prenatal screening of all pregnant females; antibiotics to mother; if exposed antibiotics to neonate D. HIV infection 1. Incidence: estimated 1 M in U.S.; 40 M HIV+ in world; HIV can be transmitted to fetus in 25-50% cases 2. Cause: a. Virus: HIV-1 virus, also HIV-2; RNA retrovirus; infects mainly specific cell type of immune system; transmission through exchange of bodily fluids such as semen & blood; to baby through placental transfer, during birth (2/3 of transmissions), or through breastmilk; transmission is related to maternal viral load 3. Symptoms: a. in mother: ranges from asymptomatic HIV+ state to full spectrum of AIDS b. in newborn: infection in uterus results in growth retardation, microcephaly and facial anomalies; infected newborns have AIDS-related symptoms and usually die within first 2 years 4. Prophylaxis and Treatment: Pregnant women should be screened for HIV; if pregnant woman is HIV+ several interventions can reduce transmission to fetus: 1. reduce maternal viral load with antiretroviral therapy (reduces transmission rate from 30% to 2%); 2. C-section; 3. avoid breastfeeding V. NON-INFECTIOUS TERATOGENS A. Therapeutic drugs: 40 to 90 percent of women take at least one prescription drug during pregnancy, all drugs have been tested in animals for safety, but results sometimes do not apply to humans (e.g. thalidomide) 1. Anti-seizure drugs: Dilantin, Valproic acid cause mental retardation or facial defects in newborn 2. Thalidomide: was given for morning sickness in the early 60s, caused defect in limb development Winter 2009 Notes for Lectures #19-20 Bio 75 3. Tetracycline: antibiotic; causes stained teeth in newborn 4. Chemotherapy: destroys dividing cells and has severe effects on developing embryo 5. Accutane: anti-acne medication; causes neural tube defects B. Recreational drugs 1. Alcohol: 1-2 in 1000 newborns affected; most common cause of mental retardation; if exposed during 1st trimester while heart is forming, heart defects; damage to CNS neurons (causes neurons to die) throughout pregnancy; also facial anomalies and growth retardation of fetus 2. Cocaine: causes mental retardation, heart defects, kidney defects, intrauterine growth retardation and premature birth of fetus 3. Marijuana, LSD, methadone: can cause CNS dysfunction 4. Tobacco: causes decreased blood flow to placenta and in turn growth retardation of the fetus C. Environmental chemicals and toxins: heavy metals, polychlorinated biphenyls (PCB) and DDT can cause birth defects D. Radiation: high doses damage DNA and cause developmental defects; diagnostic doses are not teratogenic Lecture #20: INFERTILITY (Ch 16 Pinon) I. DEFINITION: Infertility is inability of a couple to conceive after one year of sexual intercourse without contraception. Normally, 85% of all couples with regular unprotected intercourse conceive after one year, after 2 years 93% have conceived. Fertility is age-dependent; in females fertility drastically declines after age 40; in males decline after age 55. II. CAUSES OF INFERTILITY Roughly, 1/3 of all infertility cases remain unexplained, 1/3 can be attributed to a female factor and 1/3 to a male factor. In females ovulatory failure and uterine tube defects are most common; more rare are defects of the endometrium that prevent implantation. In males sperm defects most common. III. DIAGNOSIS OF INFERTILITY Winter 2009 Notes for Lectures #19-20 Bio 75 A. in female: documentation of ovulation by determining basal temperature (least expensive method) or by measuring progesterone levels in second half of cycle (usually progesterone rises after ovulation); for tubal factor infertility laprascopy (done by inserting instrument with mirror through belly button) to visually inspect tubes or hysterosalpingography, where dye is injected through the vagina and uterus to visualize the uterus and tubes in an X-ray. B. in male: semen analysis for volume, sperm concentration, sperm shape, and sperm motility. IV. INTRINSIC FEMALE FACTOR INFERTILITY A. Ovulatory failure: often caused by gonadotropin hormone deficiency or imbalance of hormones; common cause of gonadotropin hormone imbalance is polycystic ovarian syndrome (PCO); PCO is the most common cause of ovulatory failure infertility; is characterized by little cysts that can be seen on ovaries in ultrasound; usually women with PCO do not menstruate regularly; can be associated with obesity and male hair pattern (hirsutism); caused by imbalance of FSH and LH. B. tubal factor infertility: mostly caused by prior pelvic inflammatory diseases (PID) (Chlamydia most common cause of PID), can also be caused by previous pelvic surgery, previous abortion if performed incorrectly, intrauterine devices (rare) or endometriosis. Endometriosis: characterized by endometrial tissue outside the uterus; since this tissue cylces just like the normal endometrium, women often suffer from severe abdominal pain during the second half of the cycle; if tissue grows in tubes, impaired transport of cleaving embryo to uterus results in infertility; treated mostly with hormones to relieve pain; in severe cases surgical removal of ectopic uterine tissue. C. implantation defect: can be caused by dysfunction of corpus luteum V. INTRINSIC MALE FACTOR INFERTILITY A. Cryptorchidism: is the failure of the testes to fully descend into the scrotum; if diagnosed in newborn mandates surgical treatment to pull down testes; if left untreated high risk of infertility and testicular cancer B. Genital tract obstructions: can be due to prior STDs, trauma or inborn C. Gonadotropin hormone deficiency: just as in females, where LH and FSH from the pituitary induce ovulation and estrogen/progesterone production, FSH and LH in males stimulate sperm generation and testosterone production; low gonadotropin levels result in low sperm counts D. Coital disorder: impotence, retrograde ejaculations or failure to ejaculate can cause infertility VI. EXTRINSIC FACTORS OF INFERTILITY Infertility can be caused by external factors such as extreme exercise; being under or overweight, recreational drugs (chronic alcohol consumption, marijuana, cocaine), some therapeutic drugs Winter 2009 Notes for Lectures #19-20 Bio 75 (mainly antidepressants and antipsychotics); all these external factors cause hormone imbalances which lead to ovulatory failure in females and sperm defects and often impotence in males. VII. MANAGEMENT OF INFERTILITY A. Induction of ovulation: 1. Clomid (taken orally) acts as an estrogen antagonist and blocks the effects of estrogen on the pituitary; since estrogen normally blocks FSH/LH release from the pituitary, FSH and LH are increased in response to Clomid; FSH/LH stimulate follicle growth in ovary; induces ovulation and pregnancy in 40% of women with anovulation. 5% of all Clomid-induced pregnancies are multiple gestations 2. Gonadotropins (FSH,LH,HCG): needs to be injected in specific regimen; induces ovulation more efficiently than Clomid, but rate of multiple gestations also much higher; requires close monitoring of women and follicle growth in ovaries by ultrasound B. Intrauterine insemination: Procedure: The female's ovaries are stimulated hormonally with gonadotropins to induce ovulation; the male partner's semen is processed to select the highest quality sperm; the physician will then inject this sperm via a catheter through the vagina and cervix, into the uterus Indication: can help infertility in cases of male and female infertility, but NOT when tubes are blocked, because fertilization still happens in tubes!!! C. In vitro fertilization (IVF): Procedure: The female's ovaries are stimulated hormonally with gonadotropins to induce ovulation; oocytes are retrieved via transvaginal ultrasound; the male partner's sperm is processed to isolate highest quality sperm; approximately 5hrs after the oocyte retrieval, the oocytes and sperm are put together in a petri dish and placed in an incubator; 2-3days after oocyte retrieval, the embryos (blastocyst stage) are transferred into the uterus of the woman using a special catheter; hormonal treatments are given for the following 3 weeks, after which a pregnancy test is scheduled; any excess embryos not transferred may be cryopreserved for later use Indication: can help infertility in cases of male and female infertility, also helps in cases of tubal blockage D. GIFT: Gamete Intrafallopian Tube Transfer: sperm and 3 eggs are transferred into the fallopian tube; ZIFT: Zygote Intrafallopian Tube Transfer; fertilization in vitro and transfer of zygote into the fallopian tube; otherwise similar to IVF; has in some cases better success rate than IVF; does not work in cases of tubal blockage Winter 2009 Notes for Lectures #19-20 Bio 75 E. ICSI: Intracytoplasmic Sperm Injection: Process whereby a single sperm is injected directly into the cytoplasm of the egg; used in cases of severe male factor infertility; however, since low sperm counts in males are associated with genetic defects in the germ cells, ICSI also increases the risk of the fetus to have developmental abnormalities VIII: ISSUES ASSOCIATED WITH ASSISTED REPRODUCTIVE TECHIQUES A. To be successful, multiple blastocysts need to be implanted in IVF or ZIFT; increased incidence of multiple pregnancies (twins, triplets, quadruplets) B. Sperm can be frozen, but oocytes (eggs) need to be harvested fresh with each IVF; sperm or egg can come from a donor if one partner has non-treatable infertility; if oocytes are donated, donor needs to undergo hormone treatment before eggs can be harvested. C. More blastocysts are produced in the dish than implanted back into women; what should be done with these frozen blastocysts?
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