Repro Exam 4

Arguments in favor of universal PGT-A (PGS)

* Decreased termination due to aneuploidy
* Increased pregnancy rates
* Reduced miscarriage rates

PGT-A increases ongoing pregnancy rate

* Day 5 biopsy with or without CGH testing prior to transfer (only euploid aCGH embryos were transferred)
* Number of embryos transferred was not reported
* CGH increases pregnancy rate in every age group compared to non-CGH group

PGT-A decreases pregnancy loss rate

* Day 5 biopsy without or with a CGH testing prior to transfer (only euploid aCGH embryos were transferred)
* Number of embryos transferred was not reported
* CGH group has significantly less pregnancy loss in every age group. Most notable in older categories (38-40, 41-41, 42+)

Considerations for PGT (8)

1. Genetic counseling must include discussion of alternate strategies such as donor games or adoption
2. Diagnostic methodology may be expensive
3. Biopsy may damage embryo
4. Not all genetic abnormalities can be diagnosed
5. There may be no “unaffected” embryos to transfer
6. Controversial applications (e.g. gender selection, savior siblings, designer babies)
7. Misdiagnosis may result from mosaicism
8. Prenatal diagnosis (CVS or amniocentesis) is recommended for confirmation of PGS/PGD

What is a birth defect?

* Abnormality of sxr, fxn, or metabolism (body chemistry) present at birth that results in physical or mental disabilities or death
* About 120,000 babies (1 in 33) in the US are born each year with birth defects
* Birth defects are the leading cause of death in the first year of life

Congenital defect

* Any physical anomaly which is recognizable at birth

Causes of birth defects

1. Chromosomal defects
2. Single gene defects

Chromosomal Defect

Too many or too few chromosomes (aneuploidy)

* Trisomy 21 (down syndrome- mental retardation, characteristic facial features, and other problems)
* Trisomy 13 or 18 (multiple defects and often death in the first months of life)

Single gene defects

* Achondroplasia (form of dwarfism)
* Cystic Fibrosis (serious disorder of lungs and other organs, affecting mainly caucasians)
* Hemophilia (blood-clotting disorder)

What causes birth defects?

Environmental factors

* Teratogens (environmental substances that can cause birth defects)

Teratogens examples

Alcohol

* e.g. fetal alcohol syndrome- mental and physical birth defects

Certain drugs/ medications

* e.g. Acne medication isotrentinoin (Accutane)
* e.g. Cocaine

Infections

* e.g. STDs (untreated syphilis can result in stillbirth, newborn death, or bone defects)

How can risk of birth defects be reduced?

* Consult genetic counselor if birth defects are present in family history
* Avoid smoking, drinking alcohol, using drugs
* STD screening
* Take multivitamin with folic acid (recommendations vary from 400 micrograms to 4 mg)

Neural tube formation (general)

Occurs b/t 15-28 days of development (counting from fertilization)

* Often before a woman knows she is pregnant
* Defects attributed to environmental and genetic factors

Anencephaly

* Upper part of neural tube does not close all the way
* Baby is born without parts of brain and skull

Spina Bifida

* Can happen anywhere along spine where lower part of the neural tube does not close all the way
* Causes physical and mental disabilities that range from mild to severe

Neural tube formation (specific)

* Dorsal and transverse sections of 22 day embryo initiating neural tube formation Both anterior and posterior neuropores are open to amniotic fluid
* Dorsal view of embryo a day later. Anterior neuropore region is closing while posterior neuropore remains open
* Regions of neural tube closure postulated by genetic evidence superimposed on newborn body
* Anencephaly is caused by failure or neural plate fusion in region 2
* Spina bifida is caused by failure or region 5 to fuse or of posterior neuropore to close

Folic acid supplementation

* Folic acid is necessary for DNA synthesis, DNA repair, and DNA methylation and it acts as co-factor in biological reactions
* It is especially important for rapid cell division and growth, as in infancy and pregnancy
* Folic acid can help prevent some major birth defects of the baby’s brain and spine (anencephaly & spina bifida) by 50-70%

Folic Acid + public health

* ‘92 Public health service recommended that women of childbearing age increase consumption of folic acid to reduce spina bifida and anencephaly
* ‘96 FDA authorized that all enriched cereal grain products be fortified with folic acid
* Since ‘96, steady downward trend in rate of spina bifida in live births

How can birth defects be diagnosed before birth?

* Blood tests
* U/S
* Chorionic villus sampling
* Amniocentesis

Blood tests

* Non-invasive prenatal testing (NIPT); done as early as 7 weeks from LMP
* Cell-free fetal DNA
* Primary source in maternal circulation is thought to be apoptosis (programmed cell death) of placental cells (syncytiotrophoblast)
* Most reliably used for sex determination (sex-linked disorders)
* Potential for gender discrimination
* Most commonly used to diagnose Trisomy 13, 18, and 21 and single gene defects of paternal origin

U/S 1st Trimester

* Establish dates of pregnancy
* Detect heartbeat by 7 weeks from LMP
* Fetal movement can be detected by 7-8 weeks
* Determine number of fetuses
* Diagnose ectopic pregnancy or miscarriage

U/S 2nd Trimester

* Examine fetal anatomy for presence of abnormalities
* Discover sex of fetus (\~14 weeks)

U/S 3rd Trimester

* Monitor fetal growth
* Check amount of amniotic fluid
* Determine position of fetus and placenta

Chorionic villus sampling (CVS)

* Performed b/t 10-12 weeks fromLMP
* Placenta fully functional this time
* Sample of placental tissue is taken under u/s guidance
* Tissue contains same genetic material as fetus and can be tested for chromosomal abnormalities and some other genetic defects
* Does not provide information on the neural tube defects

CVS & fetal position

Fetus position in uterus determines which procedure is used

* Fetus facing internal organs = transcervical procedure
* Fetus facing externally (toward bellybutton) = transabdominal procedure

Amniocentesis

Performed b/t 15th & 20th weeks from LMP

* Volume of amniotic fluid is maximized relative to size of fetus

Sample of amniotic fluid that surrounds the fetus is taken under u/s guidance

* Amniotic fluid contains cells shed by the fetus (skin, digestive tract) & alpha-fetoprotein (indicator of neural tube defect)

Provides information about neural tube defects, chromosomal abnormalities, and some other genetic defects

Trisomy 18 cannot be detected by…

* 1st trimester u/s
* why?

The trophectoderm of a mosaic blastocyst has some cells that are 47, XY, +21 and some cells that are 46, XY. The inner cell mass is 46, XY. Later in the pregnancy, cells in the amniotic fluid will be…

* 46, XY
* why?

Risk-benefit ratio for CVS or amniocentesis

Chance of having a live-born baby with down syndrome increases greatly with age

* Less than 0.4% 20-24
* \~3.2% 45+

Approximate risk of CVS or amniocentesis causing miscarriage = \~0.3%

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Amniocentesis advised \~ age 36 (greater chance of having child with down syndrome than causing miscarriage

Arguments in favor of prenatal screening

* Pursue potential interventions that may exist
* fetal surgery for heart defects, urinary track blockage, spina bifida
* Begin planning for child with special needs
* Start addressing anticipated lifestyle changes
* Identify support groups and resources
* 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

How are birth defects diagnosed after birth?

Newborn screening tests

* Every state routinely screens newborns before they 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 in some cases, death
* Except for hearing screening, all newborn screening tests are done using a few drops of blood from newborn’s heel

State of AZ newborn screening

Includes 31 disorders

* Endocrine disorders (2)
* Congenital hypothyroidism
* Congenital adrenal hyperplasia
* Amino acid disorders (6)
* e.g. PKU
* Fatty acid oxidation disorders (5)
* Organic acid disorders (9)
* Hemoglobin disorders (3)
* e.g. sickle cell anemia, beta-thalassemia
* Other disorders (6)
* Biotinidase deficiency
* Hearing loss
* Critical congenital heart defects

PKU

Babies cannot process phenylalanine (amino acid found in nearly all foods)

* Not problem during pregnancy since mother processes phenylalanine

PKU affects about 1 in 25,000 babies

W/o treatment, phenylalanine builds up in blood & causes brain damage & mental retardation

Treatment is low-phenylalanine diet that needs to be followed throughout infancy, childhood, adolescence, and generally, for life.

Gestational diabetes mellitus (GDM)

* Glucose intolerance with onset or first recognition during pregnancy
* Characterized by insufficient pancreatic B-cell function to meet body’s insulin needs
* Insulin resistance exits before pregnancy in women with history of GDM but worsens during gestation
* Most, but not all, women with GDM go on to develop diabetes outside of pregnancy

Potential causes for GDM

* Insulin resistance (progression to T2D)
* most common form
* Autoimmune disease (progression to T1D)
* less common form
* Monogenic causes (single gene defects)
* rare

How common is GDM?

* Incidence of GDM has doubled over the last 6-8 years and is paralleling the obesity epidemic
* 1990- majority of US 4-6%
* 2000- majority of US above 6%
* 2010- all of US above 10%

Possible explanations for rise in GDM

Increased screening during pregnancy

* More women are being screened
* Undiagnosed diabetes is being diagnosed first in pregnancy

Changes in diagnostic criteria

* Criteria in the 1990s resulting in inclusion of more women

Prevalence of GDM increasing over time (race)

Increasing for all races, but most prominent in Asian and Hispanic women

Blood glucose homeostasis

Maintained within narrow range

* normal range (fasting) is 70-99 mg/100 ml (3.9 - 5.5 mmol/L)

Hypoglycemia

< 2.5 mmol/L

* Confusion, drowsiness, coma, seizure

< 2.7 mmol/L

* Nervousness, intense hunger, trembling, weakness, irregular heart rate, difficulty speaking

Hyperglycemia

> 14 mmol/L

* Frequent urination, sugar in urine, frequent thirst, frequent hunger, ketoacidosis, coma

Blood-glucose homeostasis

Factors that increase blood-glucose

* Diet
* Mobilization

Factors that decrease blood glucose

* Utilization or storage
* Excretion (unusual)

Factors that increase blood-glucose

* Diet
* Glucose absorption from digestive tract
* Mobilization
* Hepatic glucose production:
* Through glycogenolysis of stored glycogen
* Through gluconeogenesis

Factors that decrease blood-glucose

Utilization or storage

* Transport of glucose into cells:
* For utilization for energy production
* For storage
* As glycogen through glycogenesis
* As triglycerides

Excretion (unusual)

* Urinary excretion of glucose (occurs only abnormally, when blood glucose level becomes so high it exceeds the reabsorbtive capacity of kidney tubules during urine formation)

Role of insulin in glucose homeostasis

Insulin decreases blood glucose

* only hormone capable of lowering blood glucose
* promotes cellular uptake of glucose form the blood
* promotes energy storage
* promotes utilization for energy production

Glucose-stimulated insulin release

* Pancreatic B-cells in islets of langerhans sense blood glucose levels
* When blood glucose rises B-cells secrete insulin into systemic circulation

Glucose-stimulated insulin release

* Insulin secretion by pancreatic B-cells is triggered by rising blood glucose levels
* Glucose follows its concentration gradient and enters the pancreatic B-cell via the GLUT-2 transporter
* Phosphorylation of glucose causes a rise in ATP:ADP ratio
* This rise in the ATP:ADP ratio inactivates (closes) the K-channel that depolarizes the membrane, causing the Ca-channel to open and allowing Ca ions to flow inward
* The ensuing rise in levels of Ca leads to the exocytosis of insulin from storage granules

Insulin structure

* Insulin is peptide hormone derived from proinsulin
* C-peptide is cleaved off during processing and packaged along with insulin in storage granules
* C-peptide is released along with insulin from pancreatic B-cells

Insulin-stimulated glucose uptake

* Skeletal muscle is principal site of whole-body glucose disposal (uptake)
* Less glucose is transported into adipose tissue than into skeletal muscle but adipose is still an important tissue for glucose uptake
* GLUT-4 is the main insulin-responsive glucose transported
* It is expressed in skeletal muscle and adipose
* When insulin levels are low GLUT-4 is stored in intracellular vesicles

Insulin stimulated glucose uptake (1-5 steps)

1. GLUT-4 is sorted in intracellular vesicles
2. Insulin binds to the extracellular domain of its receptor in the plasma membrane, resulting in phosphorylation of the intracellular portion of the receptor (a tyrosine kinase)
3. The activated tyrosine kinase phosphorylated insulin-receptor substrates (IRS)
4. These insulin-receptor substrates form complexes with docking proteins such as phosphoinoditide-3 kinase (PI-3K) at its regulatory 85-kd subunit (p85)
5. p85 is then constitutively bound to catalytic subunit

Insulin stimulated glucose uptake (6-8 steps)

6. Activation of PI-3K is a major pathway in the mediation of insulin stimulated glucose transport and metabolism


1. PI-3K phosphorylates membrane-bound PIP3 (not shown)
2. PIP3 activates phosphoionositide-dependent kinases that participate in the activation of protein kinases B (also known as Akt) and atypical forms of protein kinase C (PKC)
7. GLUT-4 is translocated to cell membrane, where is can facilitate glucose uptake
8. Exercise stimulates glucose transport by pathways that are independent of phosphoinositide-3 kinase that may involve 5’-AMP-activated kinase

____ cells are stimulated by an increase in blood ____ to release ____

Pancreatic beta, glucose, insulin

Glucose enters ____ via the ____ transporter in response to ____

1. Adipose, GLUT-4, elevated insulin
2. Pancreatic beta, GLUT-2, a concentration gradient

OGTT

Oral glucose tolerance test

* Screening conducted on otherwise healthy pregnant women
* Usually conducted in 24th-28th weeks of pregnancy (end of 2nd trimester)
* Measures levels of sugar (glucose) in the mother’s blood following ingestion of sugar drink (100 g dextrose)
* Abnormal glucose levels may indicate gestational diabetes

OGTT data

Controls- pregnant, glucose-tolerant GDM postpartum (3 months after delivery)

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No significant difference between groups for basal blood glucose concentration (time 0); (approximately 4.7-5.7 mmol/L)

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Blood glucose was significantly higher in GDM group than in controls at 1, 2, and 3 hours indicating inadequate insulin action (could be problem with secretion and/or resistance)

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Postpartum blood glucose in GDM group was similar to pregnant controls (inadequate insulin action resolves with delivery of baby)

Normal glucose regulation during pregnancy

* Normal pregnancy is characterized by 50% decrease in insulin-mediated glucose uptake (i.e. insulin resistance) and a 200-250% increase in insulin secretion to maintain euglycemia (normal blood glucose levels) in the pregnant mother
* Progressive insulin resistance begins near mid-pregnancy and progresses through 3rd trimester to levels that approximate insulin resistance seen in T2D
* Pancreatic B-cells normally increase insulin secretion to compensate for insulin resistance of pregnancy
* Changes in circulating glucose levels over course of pregnancy are quite small compared with large changes in insulin sensitivity
* Increased maternal adiposity
* Insulin-desensitizing effects of placental hormones (e.g. human placental lactogen \[also called human chorionic somatommaotropin\], and human placental growth hormone \[hPGH\])
* Rapid abatement of insulin resistance after delivery suggests major contribution from placental hormones

Blood glucose remains elevated longer in women with GDM, indicating a problem with

either insulin resistance, or secretion

If we set blood glucose at a high level (9 mmol/l; fasting is 3.3-5.5 mmol/l), insulin secretion should

increase

Impaired insulin secretion with GDM

Controls- pregnant, glucose-tolerant GDM

ISR- insulin secretory rate (estimated from C-peptide kinetics)

* Both groups had blood glucose levels set at \~8.9 mmol/L during experiment (hyperglycemic clamp)
* As blood glucose increased so did ISRs in both pregnant and postpartum women
* ISRs are higher during pregnancy than after delivery (indicating IR during pregnancy)
* *During last 3 hours of study the ISR was ~19% lower in pregnant women with GDM; significantly different from controls*

What does it mean if women with GDM have a smaller increase in blood insulin after having their blood glucose set at 9 mmol/l?

A problem with insulin secretion

Insulin resistance with GDM

Controls- pregnant, glucose tolerant GDM

GIR- glucose infusion rate (measure of glucose uptake; rate of glucose replacement needed to maintain hyperglycemia)

* GIR is higher in pregnant controls than in women with GDM (need to add glucose at faster rate in controls than GDM group to replace glucose than is being taken up by muscle and adipose)
* *Lower GIR (~30-40% less) in women with GDM*
* Women who had GDM are still more insulin resistant postpartum

A higher glucose infusion rate (GIR) indicates:

Faster glucose uptake

Faster glucose uptake indicates

less insulin resistance

Abnormal glucose regulation with GDM

* Insulin secretion is inadequate to compensate for the IR, leading to hyperglycemia that is detected by routine glucose screening in pregnancy
* Gestational diabetes results from inability of pancreatic B-cells to make enough insulin to respond to tissue insulin demand
* Defective insulin secretion (in women with gestational diabetes) as well as in defective insulin action (i.e. resistance, in all pregnant women but even worse with GDM)

Proposed cellular mechanism (insulin stimulation of glucose transport) for non-pregnant women

1. Pathway for insulin stimulation of glucose transport in muscle involves activation of insulin receptor which phosphorylates IRS-1 and IRS-2 on tyrosine residues (pY)
2. IRS-1 recruits p85a regulatory subunit of PI-3 kinase (p85-p110) resulting in phosphorylation of membrane-bound phospholipids at 3’ position (PIP3)
3. Production of PIP3 is required for activation of Akt and aPKC and signaling for GLUAT4 translocation

Proposed cellular mechanism for IR in pregnancy

Similarities between non-pregnant and pregnant patients (with or without GDM)

* Same amount of IR protein
* Same amount of GLUT-4 intracellular stores

Differences between non-pregnant and pregnant patients

* Pregnant patients (with or without GDM) are insulin-resistant and have impaired glucose uptake

Proposed cellular mechanism for IR in pregnancy (without GDM)

1. Decreased IR pY (less tyrosine phosphorylation)
2. Decreased IRS-1 protein (increased degradation)
3. Increased hPGH increases amount of p85, which in turn inhibits PI3K activity (excess p85 association of PI3k (p85-p110) with IRS-1, thereby reducing PIP3 production); result is reduced glucose transport into skeletal muscle, which makes glucose more available to fetus
4. Increased placental factors (TNFa/ cytokines) act via increased PKC/JNK/NFkB serine kinase activity to increase IR pS and IRS-1 pS; leads to decreased glucose uptake
5. Decreased adiponectin (as a result of increased pregnancy-related adiposity) acts via decreased AMPK activity to permit increased mTOR activity, which increases IR pS and IRS-1 pS; leading to decreased glucose uptake

Proposed cellular mechanism for IR in pregnancy with GDM

1. Further decrease IR pY
2. Further decrease in IRS-1 protein(further increase in degradation)
3. Further decrease in adiponectin (as a result of increased adiposity), which acts via decreased AMPK activity to permit increased mTOR activity, which increases IR pS an IRS-1 pS, further decreases glucose uptake
4. Excess circulating nutrients (glucose, amino acids) stimulate mTOR activity, which further decreases glucose uptake

Phosphorylation of tyrosine residues on the insulin receptor will increase skeletal muscle glucose ____

uptake

Risk factors for GDM

* Obesity
* Physical inactivity
* Diet high in saturated fat
* Smoking
* Advanced maternal age
* Family history of diabetes (non-modifiable)

Advanced maternal age increases risk of GDM

* predominantly in asian/ hispanic women

Treatment of gestational diabetes

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

Risk to offspring of GDM mothers

Maternal hyperglycemia > fetal hyperglycemia (glucose crosses placenta, insulin cannot) > fetal islet cell hypertrophy and B-cell hyperplasia > fetal hyperinsulinemia > 1. Neonatal hypoglycemia, 2. Childhood: obesity, glucose intolerance, T2D (metabolic imprinting)3. Fetal substrate uptake (fat synthesis) > macrosomia + adiposity + visceromegaly (fetal insulin acts as fetal growth hormone)

What is PCOS

* Most common endocrine disease in women on reproductive age
* Prevalence estimated at 5-10%
* Often presents with IR
* Often, but not always associated with obesity
* Major risk factor for TD2, gestational diabetes, and CV diease

1991 NIH criteria for PCOS

* hyperandrogenism
* chronic anovulation
* exclusion of known disorders (e.g. pituitary disorders)

2003 Rotterdam criteria

2 of 3

* Hyperandrogenism
* Chronic anovulation
* Polycystic ovaries (enlarged ovaries containing at least 12 follicles each, updated to 20 follicles each in 2018)

What two cell types are involved in ovarian follicular steroidogenesis?

* Granulosa
* Theca

Follicular hormone production

Two cell, two gonadotropin model of follicular steroidogenesis

* LH stimulates production and secretion of androgens from cholesterol by precursor theca cells
* FSH stimulates estrogen production and secretion by granulosa cells
* Major end-product is estradiol

Tonic (basal) LH and FSH secretion

Negative feedback

* In follicular phase; estradiol > progesterone
* In luteal phase; progesterone > estradiol

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via ARC Kiss1 neurons

* GnRH release is pulsatile (continuous exposure causes down-regulation of GnRH receptors)
* Inhibin suppresses FSH synthesis and secretion, but not LH)

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(PCOS slide 6 if needed)

If you increase both LH and FSH, then the main steroid product of the follicle will be

estradiol

If you increase LH, but not FSH, then the main steroid product of the follicle will be

androstenedione/ testosterone

Ovarian hyperandrogenism

* Pulsatile GnRH release is essential for maintenance of gonadotropin secretion
* Frequency of GnRH pulses determines which gonadotropin hormone is preferentially synthesized
* Rapid GnRH pulse favors LH (decreases FSH)
* Normally prior to LH surge
* Slower GnRH pulses favor FSH (decreases LH)

Ovarian hyperandrogenism + rate

* PCOS patients have increased (faster) GnRH pulsatility
* Increased pulsatility favors LH over FSH (ratio of LH:FSH > 1)
* Increased LH:FSH ratio favors androgen production with less aromatization to estrogen by granulosa cells
* Ovaries overproduce androgens relative to estrogens

Consequences of androgen excess

* Hirsutism
* Dark, coarse, thick hair on face, chest, abdomen and back
* Acne
* Stimulated by androgens
* Androgenic alopecia
* Male-pattern hair loss
* Increased athletic performance?
* Not really…
* Normal male range testosterone: 8-29 nmol/l
* Normal PCOS range testosterone: 0.8-4.8 nmol/l
* Normal female range testosterone: 0.1-1.8 nmol/l

Chronic anovulation and polycystic ovaries

* Ovarian cysts are small fluid-filled sacs that develop in the ovary
* In an u/s image ovarian cysts appear black
* There are many different kinds of cysts- some are noncancerous and some are cancerous
* Follicular cysts are a noncancerous cyst that form when ovulation does not occur or when a mature follicle collapses on itself
* *Women with PCOS have large numbers of small follicular cysts*

Chronic anovulation and polycystic ovaries - infertility

* Arrest of follicular development (red X) can anovulation can be caused by abnormal secretion of gonadotropins (Lh > FSH), androgen excess, genetic factors
* Androgens promote early (small antral) follicle growth
* Elevated androgen: estrogen ratio decreases quality of developing oocyte in follicle
* Low FSH is not sufficient to stimulate follicle development
* Corpus luteum doesn’t form so progesterone remains low
* = infertility

AMH

* (same AMH that causes regression of mullerian ducts in male fetus)
* Infertile = 0-0.8
* Normal = 2-6
* Risk of PCOS = 6+

IR with PCOS

* Skeletal muscle (and adipose) are principal sites of glucose disposal (uptake)
* Skeletal muscle glucose uptake is determined by insulin, exercise, and genetic factors
* PCOS patients are insulin resistant resulting in elevated blood glucose
* Elevated blood glucose stimulates more insulin secretion from pancreatic B-cells in effort to stimulate glucose uptake
* PCOS patients exhibit elevated blood insulin

IR with PCOS - glucose infusion rate

* GIR in the last 30 min of a 120 min hyperinsulinemic-euglycemic clamp
* Plasma glucose maintained at 5 mmol/l (normal is 3.9-5.5)
* Lean BMI

Higher glucose infusion rate (GIR) indicates

faster glucose uptake

Faster glucose uptake indicates

less insulin resistance

IR in skeletal muscle PCOS

* Insulin stimulates glucose uptake under normal conditions
* Increased serine phosphorylation of IR and IRS-1/2 with PCOS
* *PCOS: ^ insulin >> decrease PI3K >> decrease glucose uptake*

Consequences of IR in PCOS

Elevated blood insulin:

* Inhibits liver SHBG output which increases circulating free androgens
* Stimulates release of free fatty acids from liver which increases adipose tissue growth (excess glucose is stored as fat in adipose)
* Obesity results in further IR

Insulin activity in theca cells in PCOS

* PCOS patients have ^ GnRH pulsatility which favors LH over FSH
* Increased LH:FSH fatio causes ovaries overproduce androgens relative to estrogens
* While most tissues (skeletal muscle and adipose) become IR with PCOS, theca cells remain responsive or become hypersensitive to insulin (i.e. selective IR)

Selective IR

*Serine phosphorylation inhibits insulin signaling in skeletal muscle*

* Serine phosphorylation stimulates the activity of P450c17 enzyme (17a-hydroxylase; encoded by gene CYP17) in theca cells

Estrogen biosynthesis

1. Cholesterol > progestagens (key regulatory step)
2. Progestagens + 17-a-Hydroxylase > 17-OH version
3. > androgens (DHEA)


1. + 5a-reductase > DHT
4. Androstenedione + testosterone + aromatase (FSH; absent in theca cells) >
5. E1, E2, E3

Treatment of PCOS

Major lifelong effects on reproductive, metabolic, and CV health

Treatment focuses on:

* Hirsutism + acne
* Anovulation
* IR

Treatment of hirsutism + acne

* Oral contraceptives containing both estrogen and progestin
* Suppress LH and FSH
* Suppress ovarian androgen production
* Increase liver SHBG production
* Progestins with minimal androgenic properties are preferred
* Norgestimate and desogestrel are virtually nonandrogenic
* Drospirenone is anti-androgenic
* Spironolactone (aldosterone antagonist - antidiuretic)
* Blocks action of androgens and androgen receptor

Treatment of anovulation

* Oral contraceptives containing both estrogen and progestin to prevent endometrial hyperplasia
* Weight reduction
* Caloric restriction
* Dietary modification (restrict simple carbs; e.g. low glycemic index)
* Exercise - increase muscle glucose uptake
* Clompihene citrate (clomid)
* Estrogen antagonist to increase FSH for ovulation induction
* Exogenous FSH administration