PSIO 469 Exam 4

mosaicism

mosaicism

presence of 2 or more genetically different cell lines in an individual who has developed from a single zygote (fertilized egg)

chimerism

when a single organism composed of 2 or more genetically distinct cell lines that originated from different zygotes

how can mosaicism arise from meiotic or mitotic errors?

mosaicism can arise from non-disjunction in both meiosis and mitosis

meiosis: homologous chromosomes don’t separate

mitosis: sister chromatids don’t separate

why is mosaicism a concern for PGT?

mosaicism may lead to a false positive of a chromosomal abnormality in PGT

proposed cellular mechanisms for insulin resistance with pregnancy and GDM

1. decreased phosphorylation of tyrosine residues

2. decreased IRS-1 protein (more of it is degraded in pregnancy)

3. increased hPGH and p85 (which inhibits PI3K activity + later PIP3, making more glucose available to fetus)

4. increased placental factors (TNFa + cytokines) cause increased IR pS (serine residues)

5. decreased adiponectin leads to increased mTOR activity (increases IR pS)

prevalence of PCOS

5-10% of women

why do PCOS and obesity decrease the glucose infusion rate observed during a hyperinsulinemic-euglycemia clamp?

these patients have elevated insulin levels but normal glucose levels

consequences of mosaicism arising late (in blastocyst stage)

if cell division error occurs later, chromosomal mosaicism may affect only specific tissues

why does the incidence of mosaicism decrease during embryonic development?

embryo self-correction may occur because euploid cells proliferate faster than aneuploid cells

mosaic embryos may half proliferation of abnormal cells

how is NGS used to diagnose aneuploidy?

next generation sequencing (NGS) allows a sample to undergo whole genome amplification and sequencing to compare and determine chromosomal copy number

this can detect 24 chromosome aneuploidy, mosaicism, and triploidy

arguments in favor of universal PGT

decreased termination due to aneuploidy

increased pregnancy rates

reduced miscarriage rates

congenital birth defect

any physical abnormality that is recognizable at birth

how common are birth defects?

1 in 33 babies in the US are born every year with birth defects

teratogen

environmental substance that can cause birth defects

actions taken to reduce the risk of birth defects

genetic counseling in families with history of birth defects

avoid smoking, drinking, drugs

STD screening

taking multivitamin with folic acid

why is folic acid necessary during pregnancy?

prevention of neural tube defects

folic acid is needed for DNA synthesis, repair, and methylation

very important for rapid cell division and growth

when does neural tube formation occur?

occurs between days 15-28 of development from fertilization (often before woman knows she is pregnant)

consequences of malformation

anencephaly and spina bifida

anencephaly

upper part of neural tube does not close all the way, causing the baby to be born without parts of the brain and skull

spina bifida

lower part of neural tube does not close all the way, causing physical and mental disabilities that range from mild to severe

4 basic methods for detecting birth defects during pregnancy

1. blood tests
2. ultrasound
3. chorionic villus sampling
4. amniocentesis

non-invasive prenatal testing (NIPT)

a prenatal diagnostic technique that analyzes genetic material released from the placenta that circulates in a pregnant woman's blood stream

cell-free fetal DNA

primary source in maternal circulation is thought to be apoptosis of placental cells (syncytiotrophoblast)

most reliably used for determining sex-linked disorders, potential for gender discrimination

can diagnose Trisomy 13, 18, and 21

goals of first trimester ultrasound

7 weeks: heartbeat
7-8 weeks: fetal movement

determines number of fetuses
diagnose ectopic pregnancy or miscarriage

goals of second trimester ultrasound

14 weeks: determine sex of fetus

examine fetal anatomy for presence of abnormalities

goals of third trimester ultrasound

monitor fetal growth
check amount of amniotic fluid
determine position of fetus and placenta

chorionic villus sampling

sample of placental tissue is taken under ultrasound guidance

this tissue contains the same genetic material as the fetus, so it will provide info about chromosomal abnormalities and other defects, but NOT neural tube defects

when is chorionic villus sampling done?

performed between 10-12 weeks from the LMP

amniocentesis

procedure guided by ultrasound to take out about 10 mL of amniotic fluid

amniotic fluid contains fetal skin cells and alpha-fetoprotein, which is an indicator that there is a neural tube defect

what does it mean when alpha-fetoprotein is present in an amniocentesis procedure?

that there is a neural tube defect because it has not closed yet

when is amniocentesis done?

between 15-20 weeks from LMP (when there is the greatest ratio of amniotic fluid to the volume that is taken up by the fetus)

who are CVS and amniocentesis recommended for?

since CVS and amniocentesis have a low risk of causing miscarriage, younger mothers are recommended if these procedures are needed

after age 35, the risk of CVS or amniocentesis causing miscarriage increases dramatically

arguments for prenatal screening

pursue potential interventions that may exist

begin planning for child with special needs

start addressing anticipated lifestyle changes

make decision about carrying child to term

arguments against prenatal screening

parents should be accepting of results regardless of outcome

making decision about carrying child to term is not an option because of personal, moral, or religious reasons

testing may pose risk of harming developing baby

newborn screening

tests performed before newborns leave the hospital for certain genetic, metabolic, hormonal, and functional disorders

most birth defects have no immediate visible effects on a baby but, unless detected and treated early, can cause physical problems, mental retardation, and death

except for hearing screening, all tests are done using a few drops of blood from newborn's heel

what is phenylketonuria (PKU)? how is it treated?

a disorder where babies cannot process phenylalanine, which is an amino acid present in nearly all foods

without treatment, phenylalanine builds up in blood stream and causes brain damage

treatment may include low-phenylalanine diet that needs to be followed throughout infancy, childhood, and rest of life

what causes gestational diabetes mellitus (GDM)?

insulin resistance (progression to type 2 diabetes)

autoimmune disease (progression to type 1 diabetes)

monogenic causes (single gene defects)

incidence of GDM in the US

gestational diabetes has doubled over the last 6-8 years and is paralleling the obesity epidemic

possible explanations for the observed rise in GDM

increased screening during pregnancy

changes in diagnostic criteria

normal limits for fasting blood glucose

normal fasting range is 70-99 mg/ml

consequences of hypoglycemia

confusion
drowsiness
coma
seizure
weakness
irregular HR
difficulty speaking

consequences of hyperglycemia

frequent urination
sugar in urine
frequent thirst
ketoacidosis
coma

factors that increase blood glucose

diet (glucose absorption from digestive tract)

mobilization (hepatic glucose production: through glycogenolysis of stored glycogen or gluconeogenesis)

factors that decrease blood glucose

utilization or storage (transport of glucose into cells for energy production)

excretion (unusual -- occurs abnormally when blood glucose level becomes so high that it exceeds the reabsorptive ability of kidney tubules during urine formation)

role of insulin in glucose homeostasis

insulin decreases blood glucose

pathways stimulated by insulin

promotes cellular uptake of glucose from the blood

promotes energy storage

promotes utilization for energy production

when do pancreatic B-cells release insulin into systemic circulation?

when blood glucose rises

steps of insulin release from pancreatic B-cells

1. blood glucose levels rise

2. glucose follows its concentration gradient and enters the pancreatic B-cell via GLUT2 transporter

3. phosphorylation of glucose causes rise in ATP:ADP ratio

4. rise in ATP:ADP ratio inactivates (closes) the potassium channel that depolarizes the membrane, causing calcium channel to open and allowing calcium ions to flow inward

5. rise in levels of calcium leads to exocytosis of insulin from storage granules

C-peptide

cleaved off during processing and packaged along with insulin in storage granules, also released with insulin from B-cells

2 key tissues involved in insulin-stimulated glucose uptake

skeletal muscle
- principle site of whole-body glucose uptake (because there is a lot of this tissue)

adipose tissue
- takes up some glucose

role of GLUT-4 in glucose transport

the main insulin-responsive glucose transporter

expressed in skeletal muscle and adipose tissue

when insulin levels are low, GLUT-4 is stored in intracellular vesicles

steps of glucose uptake by cells after insulin rises in blood

1. GLUT-4 is stored in intracellular vesicles

2. insulin binds to the extracellular domain of its receptor in the membrane, resulting in phosphorylation of the intracellular portion of the receptor

3. the activated tyrosine kinase phosphorylates insulin-receptor substrates (IRS)

4. insulin-receptor substrates form complexes with docking proteins such as PI3K at its regulatory subunit (p85)

5. p85 is then constitutively bound to the catalytic subunit (p110)

6. activation of PI3K phosphorylates PIP3

7. PIP3 activates PKC

8. GLUT-4 is translocated to the membrane and it facilitates glucose uptake

9. exercise can (independently of insulin) stimulate glucose transport into the cell

when and how is gestational diabetes mellitus (GDM) diagnosed?

it is recommended for all healthy pregnant females

usually conducted at the end of the 2nd trimester

a mother ingests 100g of dextrose (a sugary drink) and then has her blood glucose measured

normal blood glucose vs. GDM

blood glucose levels are significantly higher in GDM patients than normal patients, indicating an inadequate insulin action

postpartum blood glucose in the GDM group was ________________ to pregnant controls (normal patients)

similar, as inadequate insulin action resolves with delivery of baby

how is euglycemia (normal blood glucose) achieved in normal pregnant women?

through a combination of insulin resistance and increased insulin secretion (so the fetus has enough glucose too)

progressive insulin resistance begins near mid-pregnancy and progresses through 3rd trimester

pancreatic B-cells normally increase insulin secretion to compensate for insulin resistance of pregnancy

2 factors that may cause insulin resistance and increased insulin secretion in a normal pregnancy (non-GDM)

1. increased maternal adiposity

2. insulin-desensitizing effects of placental hormones

how can inadequate insulin secretion in females with GDM cause hyperglycemia?

without proper insulin secretion, blood glucose levels will not be regulated, and hyperglycemia may then be present

cellular mechanism for non-pregnant females for insulin stimulation

activation of insulin receptor which phosphorylates IRS-1 and IRS-2 on tyrosine residues (pY)

IRS-1 recruits p85a regulatory subunit of PI3K, resulting in phosphorylation of membrane bound phospholipids at the 3' position

production of PIP3 is required for activation of Akt and aPKC to signal for GLUT4 translocation

GLUT4 --> insulin-stimulated glucose transport in muscle

similarities between non-pregnant and pregnant patients in their cellular mechanisms

same amount of IR protein

same amount of GLUT4 intracellular stores

differences between non-pregnant and pregnant patients in their cellular mechanisms

pregnant patients (with or without gestational diabetes) are insulin-resistant and have impaired glucose uptake

tyrosine phosphorylation

activates insulin-stimulated glucose transport

serine phosphorylation

inhibits insulin-stimulated glucose transport

mTOR activation leads to what?

increase in serine residue phosphorylation in skeletal muscle, which in turn decreases glucose uptake

how is mTOR activated?

more adipose tissue (during pregnancy or obesity)

what is AMPK?

it is a sensor that tells the cell if there is a lot of energy or not (looks at AMP:ATP ratio)

low AMP relative to ATP inhibits AMPK activity

AMPK inhibition leads to increase in mTOR

risk factors for GDM

obesity
physical inactivity
high fat diet
smoking
advanced maternal age
family history of diabetes (only non-modifiable factor)

how does advanced maternal age increase the risk for GDM

after age 35, all ethnicities experience an increased risk for developing gestational diabetes

treatment for GDM

eat low-carb diet
exercise
maintain healthy pregnancy weight
monitor glucose levels
if needed, daily insulin injections

how does GDM affect offspring?

gestational diabetes leads to risks in the offspring

how can maternal hyperglycemia result in fetal hyperinsulinemia, increased fetal fat synthesis, neonatal hypoglycemia, and metabolic imprinting?

glucose crosses the placenta but insulin cannot

fetal insulin acts as a fetal growth hormone

metabolic imprinting (environmental influences on development) can lead to childhood obesity, glucose intolerance, and type 2 diabetes

how does fetal hyperinsulinemia lead to neonatal hypoglycemia?

once out of the mother, the baby's increased insulin levels will continue, but this will lead to low glucose levels because the baby is not longer in the presence of the placental glucose supply

macrosomia

abnormally large body seen in a newborn

visceromegaly

enlarged internal organs

what is PCOS?

polycystic ovarian syndrome

most common endocrine disease in women of reproductive age (5-10%)

symptoms associated with PCOS

hyperandrogenism (more androgens)
- male-pattern hair, acne, and hair loss

chronic anovulation (no ovulation)

polycystic ovaries (enlarged ovaries containing at least 20 follicles each)

diseases for which PCOS is a risk factor

type 2 diabetes
gestational diabetes
cardiovascular disease

what normally happens in a healthy female without PCOS in terms of LH + FSH levels?

FSH production is favored over LH production

LH increases testosterone production, while FSH increases estradiol production

so overall, female will have more estradiol than testosterone

how is ovarian hyperandrogenism associated with PCOS?

LH levels are higher than FSH levels

so main product is androstenedione/testosterone, rather than estradiol

symptoms resulting from ovarian hyperandrogenism

hirsutism (dark hair on face, chest, abdomen, and back)
acne (stimulated by androgens)
androgenic alopecia (male-pattern hair loss)

why might mild hyperandrogenism confer a small advantage for female athletes with PCOS?

because increased testosterone levels may provide more physical advantage (although, male levels are still MUCH higher than a female with PCOS)

why does anovulation occur in women with PCOS?

arrest of follicular development occurs due to lower levels of FSH

higher androgen levels compared to estrogen levels decreases quality of oocyte that is developing

why is PCOS associated with infertility?

corpus luteum does not form, so progesterone remains low

why do women with PCOS have elevated AMH levels?

patients have small antral follicles that do not degenerate quickly, so AMH levels will remain elevated

hyperinsulinemia

high levels of insulin in the blood

euglycemia

normal level of glucose in the blood

why does insulin resistance in PCOS patients result in hyperglycemia and hyperinsulinemia?

despite there being high levels of insulin present, PCOS patients have resistance to this response and this leads to higher levels of glucose remaining in the blood

does faster glucose uptake (higher glucose infusion rate) indicate more or less insulin resistance?

less insulin resistance

why is insulin-dependent GLUT-4 glucose uptake lower in PCOS patients?

because there is increased serine phosphorylation of the insulin receptor and later IRS-1 (inhibits insulin activity)

consequences of PCOS-associated hyperinsulinemia for liver SHBG production

elevated levels of insulin in the blood inhibits SHBG output, which increases androgen levels

effect of insulin on theca cell androgen production

PCOS patients have increased GnRH pulsatility, favoring LH over FSH

theca cells become hypersensitive to amount of insulin (unlike skeletal muscle and adipose tissue, which become resistant)

effect of insulin on serine phosphorylation of 17a-hydroxylase

serine phosphorylation increases activity of 17a-hydroxylase in theca cells

upregulation of 17a-hydroxylase produces more precursor to create androgens

treatment for PCOS hirsutism and acne

oral contraceptives
- contain both estrogen and progestin (suppresses LH and FSH)

progestins with minimal androgenic properties
- norgestimate and desogestrel
- drospirenone

spironolactone
- aldosterone antagonist that blocks action of androgens

treatment of PCOS anovulation

oral contraceptives
- both estrogen and progestin to prevent endometrial hyperplasia

weight reduction
- restrict calories, exercise, low glucose diet

clomid
- estrogen antagonist to increase FSH for ovulation induction

exogenous FSH

treatment for PCOS insulin resistance

weight reduction

metformin
- interferes with carbohydrate absorption in GI tract, inhibits liver glucose output, increases peripheral glucose uptake

3 pathogens that cause STIs

bacteria
parasites
viruses

8 most common pathogens that cause STIs

4 curable:
syphilis
gonorrhea
chlamydia
trichomoniasis

4 incurable:
hepatitis B
herpes
HIV
HPV

STI vs. STD

STDs begin as infections, and may be originally asymptomatic

once the infection progresses into disease, it disrupts the body's normal functions and processes, causing symptoms

how can STIs be transmitted?

spread by sexual contact

some STIs can be transmitted through non-sexual blood contact or pregnancy/childbirth

why are untreated STIs and STDs a major health concern?

if untreated, the risk of acquiring another STI increases

HPV can cause cervical cancer

infertility due to pelvic inflammatory disease in women