ANSC 631
BAZER

TIRED
SLEEPY
CARDIOVASCULAR ISSUES
APPETITE
MAMMARY DEVELOPMENT
CHANGE IN LIBIDO

NAUSEAU AND VOMITING
• 4 to 6 weeks to 14-16 weeks of pregnancy
• Hyperemesis gravidarum severe nausea, vomiting, weight loss, and sometimes electrolyte disturbance, may require hospitalization for intravenous fluid and nutrition.
• Why
– Ho: adding spices to food inhibits growth of microorganisms and protects from diseases
– expelling or avoiding foods during early months of pregnancy protects mother and embryo from foodborne illnesses and toxins, especially when the fetal development is most sensitive to disruption.

American Scientist
89 (2) : 142
Protecting Ourselves from Food: Spices and morning sickness may shield us from toxins and microorganisms in the diet. Paul W. Sherman , Samuel M. Flaxman
SPECULATION
•Progesterone is analgesic with LD50 that may cause nausea by acting on nervous system like an anesthetic
•Changes in gut immune system response to food allergens, e.g., like some people respond to peanuts or shell fish

• STOMACH
–
HCl, PEPSIN, RENIN AND GASTRIC LIPASE
START PROCESS
• SMALL INTESTINE
– ENZYMES TRYPSIN, CHYMOTRIPSIN, ETC
DIGEST PROTEINS
– PROTEIN SOLUBILITY AND DIGESTIBILITY
– AMINO ACIDS ABSORBED
– CHYLE TO LACTEALS (LYMPH VESSELS) FOR
SURVEILLANCE
• LARGE INTESTINE
– ABSORPS WATER AND SALTS

Maternal nutrition and fetal development. J Nutr. 2004 134:2169-2172 W u G ,
Bazer FW , Cudd TA , Meininger CJ , Spencer TE .
Nutrition: intrauterine environmental factor altering expression of fetal genome with lifelong consequences ("fetal programming”) and "fetal origins of adult disease."
1) change structure, physiology, and metabolism of offspring predisposing individuals to metabolic, endocrine, and cardiovascular diseases as adults;
2) maternal undernutrition and overnutrition reduce placental-fetal blood flows and stunt fetal growth.
3) impaired placental NO (vasodilator/angiogenesis) and polyamines (DNA and protein synthesis) result in intrauterine growth retardation;
4) nutritional status alters epigenetic state through DNA methylation and histone modifications of fetal genome thereby impacting fetal programming and genomic imprinting.

MATERNAL CARDIOVASCULAR
SYSTEM
• 10-15% decrease in systemic arterial blood pressure
– Decreased vascular tone: systemic vascular resistance = mean arterial pressure cardiac output
PGE2, NO, PGI2 and decrease in alpha adrenergic receptor leads to vasodilation and decrease in mean arterial pressure

MATERNAL CARDIOVASCULAR
SYSTEM
• 25 to 60% increase in cardiac output
– Increase mostly after mid-gestation
– Cardiac output = heart rate X stroke volume
• Heart rate increase by 20 to 30%
• Stroke volume increase by 30-35%
• Increases in:
– Left Ventricle Mass
– Left Atrial Size
– End-Diastolic Dimensions
– Blood Volume Increase by 10 to 50%
– Highest percentages with multiple fetal-placental units

MATERNAL CARDIOVASCULAR
SYSTEM
• Red Blood Cell Mass (Hematocrit)
– Increases less than blood volume
– Increase in erythropoietin and erythropoiesis
– Physiologic Anemia of Pregnancy
• Blood Volume – Plasma Volume = Red Blood Cell Mass
• Vascular Reactivity Decreases
– Increased metabolic clearance of vasoactive agents such as norepinephrine and angiotensin II
– Decrease in alpha adrenergic receptors
– Increase in vasodilators – PGE2, PGI2, NO

MATERNAL CARDIOVASCULAR
SYSTEM
• Distribution of Cardiac Output
– Sheep – 3 to 4 Liters/min
• Uterus – 0.8 to 1.2 L/min
• Uteroplacental Blood Flow (Percent of Cardiac
Output
– Ewe: 8% at mid-gestation; 16% in late gestation; and 0.06% for nonpregnant uterus.
– Women: 17% at term
• Mammary Blood Flow: Increases from 0.2% in first trimester to 2% at term
• Skin Blood Flow – 100% increase over course of gestation

MATERNAL PULMONARY SYSTEM

MATERNAL BLOOD COAGULATION INCREASES
FROM 3 MONTHS TO TERM
– Venous stasis – thromboemolic events
– Increase in platelet aggregation and formation of stable fibrin clots
• Intrinsic from Cell Injury and Collagen damage– increase in events beginning with Clotting Factor
XII to platelet phospholipids and Ca++ to
Fibrinogen and Clotting
• Extrinsic (Rapid from Tissue [placenta] thromboplastin to go from Clotting Factor VII to
Fibrinogen
– Clotting mechanism increase rapidly at term

– 24 year old woman – 56 kg
• Gain 12.5 kg in pregnancy
– 925 g protein
– 3.83 kg fat
– Fetus at term
• 3.44 kg
– 444 g fat
– 543 g protein

– Pulmonary Ventilation – increases 3 L/min
• 20% increase in maternal O2 absorption into blood
– Pregnant Uterus – 25 ml O2/min
– Pulmonary Muscles – 10 ml O2/min
– Heart – 9 ml O2/min
– Kidneys – 5 ml O2/min
– Mammary Glands – 2 ml O2/min
– Increasing Energy Intake Increases Appetite
• Increase of 50 kcal/day first 34 weeks to 300 kcal/day during last 30 days [basal diet is 2,100 kcal/day]
– Progesterone increases appetite
– Increase in fat increases leptin

– Poor Nutrition
• Smaller placentae by 20 to 30% and smaller babies by
200 to 300 g in first trimester
– Increase in Nutrient Absorption by 0 to 3%
• Increased pancreatic/biliary secretions
• Increased intestinal blood flow
• Decrease in gut motility
• Hypertrophy of gut epithelial lining
– Increase in villous height
– Increase in intestinal dilation
– Increase in epthelial hyperplasia
– Increase in Vitamin D and Ca++ aborption
– Increase in iron aborption
– Lactogenic hormones increase absorption of Vitamin D, Ca++ and H2O.

– Nutritional Priorities of Fetus and Mother
• Maternal
– Nervous System
Fetal Demands
Nervous System
Bone
Muscle
Fat
– Bone
– Muscle
– Fat

– Poor Nutrition
• Smaller placentae by 20 to 30% and smaller babies by
200 to 300 g in first trimester
– Increase in Nutrient Absorption by 0 to 3%
• Increased pancreatic/biliary secretions
• Increased intestinal blood flow
• Decrease in gut motility
• Hypertrophy of gut epithelial lining
– Increase in villous height
– Increase in intestinal dilation
– Increase in epthelial hyperplasia
– Increase in Vitamin D and Ca++ aborption
– Increase in iron aborption
– Lactogenic hormones increase absorption of Vitamin D, Ca++ and H2O.

– Physical Activity Decreases
• Progesterone
– Increase in sleep
– Decrease in Anxiety

Mammogenesis and Lactogenesis
• Mammogenesis – Growth of Mammary
Gland
• Lactogenesis
– Stage I – Milk Protein Synthesis
– Stage II – Milk Protein Synthesis and
Secretion
• Galactopoiesis – sustained milk production

MAMMOGENESIS AND LACTOGENESIS
Mammogenesis: Sex Steroid Hormones
Estrogen --Involved in lengthening and branching of ducts
Progesterone --Duct and ductule cell multiplication --Enlargement and/or widening --
Actually inhibits mammary growth at high levels
Progesterone + Estrogen -- Causes lobuloalveolar development
Initiation of Lactation (Lactogenesis)
Ovarian and/or placental steroids decrease (Progesterone inhibits)
Placental Lactogen disappears
Lactogenic Complex
Prolactin, Glucocorticoids. Insulin or IGF-I
Milk-Ejection Reflex Oxytocin/Neuroendocrine Reflex
Suckling or other teat/udder stimulation causes release of oxytocin from neurohypophysis
Maintenance of Lactation (Galactopoesis)
Galactopoetic Complex
Prolactin (Not Cattle), GH, Insulin, Thyroid Hormone, Glucocorticoids

EVENTS PRECEDING PARTURITION
• Final Maturation of Fetus and its Hypothalamic-
Pituitary-Adrenal Axis
• Initiation of Milk (Colostrum) Secretion
• Expansion of Birth Canal
• Nest Building (Prolactin)
• Aggression (Prolactin)
• Restlessness (Prolactin and Estrogen)
• Initiation of Uterine Contractions
• Parturition and Termination of Pregnancy
• Bonding Between Dam and Offspring (Prolactin and Oxytocin)

Fig. 14-14

Fig. 14-13

Fig. 14-15

• Controlled by fetus
• Congenital absence of Hypothalamic-Pituitary-
Adrenal Axis
• Ewe consumption of Veratrum californicum on
Days 14-15
– Delayed Parturition
• Lambs up to Day 175 and 20 pounds or more; some cases ewes died
• Piglets taken at Day 125
• Similar reports for calves taken by C-Section at very heavy weights, e.g., 200 lb

Parturition – Sheep Model
• Fetus
– Hypothalamus
• CRH
– Anterior Pituitary
• ACTH
• Prolactin
– Adrenal Gland
• Cortisol and Corticosterone
– Placenta
• Progesterone decreasing, estrogen increasing due to C-21 Steroid 17 alpha hydroxylase enzyme
• Maternal
– Corpus Luteum
• Progesterone and Relaxin (some species)
– Anterior Pituitary
• Prolactin and Growth Hormone
– Posterior Pituitary
• Oxytocin
– Uterus
• PGF2-alpha increasing

Hormonal Factors Associate with
Parturition
• Fetal Hypothalamic-Pituitary-Adrenal Axis
– A. CRH – Day 100 Fetal Life
– B. ACTH – Day 125 Fetal Life
– C. Cortisol Production – Dependent on Critical
Mass of Adrenal Tissue
– D. Cortisol – Increases most rapidly 2 to 3 days before onset of labor and parturition
– In pigs, adrenal weight increases along with circulating levels of cortisol most rapidly after Day 100 of the 114 day period of gestation

Hormonal Factors Associate with
Parturition
• Fetal Hypothalamic-Pituitary-Adrenal Axis
– E. Cortisol
• Stimulates rapid increase in C21 Steroid 17-alpha hydroylase enzyme for conversion of Progesterone to 17alpha hydroxy Progesterone when then is metabolized to androgens and estrogens
– P4 DECREASES RAPIDLY DUE TO CONVERSION OF
PROGESTERONE TO ESTROGENS
– Decrease sulfotransferase in endometrium so MORE
UNCONJUGATED ESTROGENS
– Stimulate PGF secretion

Hormonal Factors Associate with
Parturition
• Oxytocin
– Released in response to PGF and due to Ferguson
Reflex of fetal pressure on cervix
– Stimulates uterine contractions
– Stimulates bonding between mother and offspring

Hormonal Factors Associate with
Parturition
• Relaxin
Molecular Weight – 6,300 (6,000 to 10,000)
Pig – From CL
Other species – cow (CL, placenta), sheep (?), mare (placenta)
Cervical Relaxation
Acts with other hormones:
Estrogens
PGF and PGE
Oxytocin

Hormonal Factors Associate with
• Relaxin (continued)
Parturition
– Increases Keratin SO4 in cervical collagen
– Decreases Dermatin SO4 in cervical collagen
– With loss of Dermatin SO4 there is a decrease in crosslinking among collagen fibers and greater elasticity of connective tissue of cervix and pelvic ligaments to increase distinsibility of pelvic canal for birth of fetus
– Role in lactation by stimulating growth and development of teat and possibly lactation
– Ovariectomized pigs give birth, but don’t lactate normally, so is relaxin critical to parturition?

Hormonal Factors Associated with Parturition
• Uterine Myometrial Contractions
– Coordinated and Rhythmic Contractions of Myometrium
– Involuntary Contractions of Abdominal Muscles
– Dilation and Softening/Distensibility of Cervix
– Myometrial Contractions
• Increased synthesis of gap junctions (e.g., Connexin 43) due to decreasing progesterone and increasing estradiol
Essential for strong coordinated contractions
• Increase in cAMP associated with increase numbers of gap junctions
• Increase in free Ca++ and its binding to calmodulin which activates myosin kinase:
– Myosin kinase → Myosin-PO4
– Myosin-PO4 + Actin = Contractions

Hormonal Factors Associate with
Parturition
• Uterine Myometrial Contractions (continued)
• Increase in free Ca++ and its binding to calmodulin which activates myosin kinase:
– Myosin kinase → Myosin-PO4
– Myosin-PO4 + Actin = Contractions
• Oxytocin lowers threshhold potential for action potential of myometrium and increases rate of Ca++ influx to stimulate contractions
• PGF increases intracellular free Ca++ and frequency of contractions

COOH cPLA
2
Phospholipids
Arachidonic Acid
(5, 8, 11, 14-eicosatetraenoic acid)
Nuclear receptor
PPAR

PPAR

PPAR

IP receptor cAMP
DP receptor cAMP
Relaxant Receptors cAMP
O
O
OH
O
Cox-1 Cox-2
O
O
9
10
11
8
12
7 4 2
6
14
5
15 16
13
OH
PGG
2
17
3
18
19
COOH
20
COOH
OH
PGI
2
Cox-1 Cox-2
PGI Synthase
O COOH
O
PGD Synthase
OH
PGH
2
PGE Synthase
TX Synthase
O
O
PGF Synthase
OH
TxA
2
OH
O
COOH
OH OH
OH
PGD
2 PGEM
PGDH
PGE
2
Inhibited at Parturition
COOH
9-keto-PGE reductase
COOH
TP receptor
Ca 2+ + IP
3
COOH
FP
A,B receptor
Ca 2+ + IP
3
OH
OH
PGF
2

PGDH
PGFM
Inhibited at Parturition
Constrictor Receptors
Ca 2+ / IP
3 or cAMP
EP
1
Ca 2+ /IP 3
EP
2 cAMP
EP
3a cAMP
EP
3b cAMP
EP
3c cAMP
EP
3d cAMP/
IP 3
EP
4 cAMP

11 β hydroxylase
11 β hydroxylase for corticosterone and cortisol

Ovine
Human
Fetal Hypothalamic Pituitary
Adrenal Axis
↓
Placental
Estrogens
← Fetal Glucocorticoid Production
Corticosterone and Cortisol
↓
→ Placental CRH
Intrauterine
Production of Prostaglandins

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
CRH is Produced by Human Chorion in response to cortisol from fetal adrenal
CRH stimulates Dehydroepianrosterone Sulfate
(DHAS) from fetal adrenal that is converted to estrogens by chorion
Glucocorticoids and estrogens stimulate increased expression of prostaglandins E and F and decreases
PGDF-15 that OTHERWISE inactivates PGs

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
Central Characteristics of Human Parturition
Increase in CRH and PGHS2 in chorion
Decrease in PGDH15
Increase in FP and EP prostaglandin receptors
Decreased sensitivity of uterus to progesterone
Increase in production of estrogens from
DHAS by chorion
Increase in myometrial contractions

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
Conversion of Progesterone to Estradiol and Loss of
Progesterone Influence
Increased Contraction Associated Proteins
Oxytocin Receptor
PGF Receptor
Connexion-43 Gap Junction Protein
Recent Suggestion that Increase in Progesterone
Receptor C Isoform Results in Loss of Progesterone
Responsiveness via PR Isoforms A and B in Human
Myometrium (Condon et al. 2006 Mol Endocrinol
20:764-775

• Efficient use of labor and facilities to reduce neonatal death losses
• Reduce length of gestation
• Increase opportunities for cross-fostering neonates in event of failure of dam to accept offspring, cannabilism or failure to lactate
• Convenience of producer
• In swine, uniformity of post-weaning estrus

Controlling Time of Parturition (continued)
• Swine: Corticoids Ineffective
– PGF-2 alpha – 200 ug cloprostenol or 10 mg Lutalyse at 7
AM and 7 PM with farrowing 24-26 h later.
– Should not be used prior to Day 112 of pregnancy due to decreased survival of neonate
• Cows; Corticoids, Estradiol and PGF are effective
– 20 mg dexamethasone to dam most commonly used. For maximal survival of calf, cows should be within 1 week of term. Some countries with wet and dry season induce parturition to coincide with rainy season, high nutrient availability and focus on milk production with calves having little economic value
• Retained placentae major issue

Controlling Time of Parturition (continued)
• Mare: Corticoids, PGF and Oxytocin
– 2.5 mg PGF (Lutalyse) every 12 hours causes birth/abortion in late gestation.
– 200 dexamethasone/day for 4 days with foals being born 72 to 96 h after end of treatment
– 20 IU to 200 IU Oxytocin administered with estradiol will cause cervical dilation and birth in some cases.

• Cow
– Days 0-12 – Sloughing and Discharge of endometrial tissue and placenta
– Days 25-30 – Uterine Involution completed
– Days 40-45 – Uterus considered ready for next pregnancy
– Dairy – First estrus around Day 15 to 20 and breeding from Day 60
– Beef – First estrus between 60 and 100 days and breed during desired dates (spring or fall)

Post-Partum Period
• Sheep
– Uterus involuted by Days 25 to 30
• Breed in fall
• Pig
– Uterine involution completed by Days 21 to 28
– Breed at post-weaning estrus (3-7 days)
• Mare
Foal Heat – 5-15 days postpartum
Breed if no complications
Human
Highly variable and related to many factors
Suckling intensity, body condition, nutrition etc

Adjusting to Extra-Uterine Life

Fig. 14-14

Fig. 14-13

Fig. 14-15

• Ductus Arteriosis – Duct between Pulmonary
Artery and Aorta that allows most blood to be shunted past the Pulmonary Artery and into
Aorta. With increase in pO2 at birth, the Ductus
Arteriosis closes and blood is forced to go to the lungs for oxygenation.
• Foramen Ovale – Valve (flap-type) that closes when pressure in left side of heart increases upon closure of the Ductus Arteriosis.

ADULT
RIGHT HEART ► LUNGS ► LEFT HEART
↑
↑
LIVER ← ← ←
↓ AORTA
BODY
FETUS
Liver
Ductus
Venosus
Lung
RIGHT HEART ► FORAMEN OVALE ► LEFT HEART
↑
↑
AORTA
DUCTUS ARTERIOSIS
PLACENTA BODY OF FETUS

Gut
• Filled with Amniotic Fluid drunk at 500 ml/day
• Contains meconium – fecal material
• Absorbs amino acids, sugars and electrolytes
• Digestion of proteins, aborption of amino acids and incorporation into fetal tissues
• Colostrum – fluid phase pinocytosis and gut closure regarding absorption of immunoglobulins
– Passive Immunity – required for piglets and beneficial for offspring of all species
– Gut maturation
• IGF-I and EGF in colostrum stimulate gut maturation

• Normal fetus – 450 ml urine/day into amniotic sac with turnover of 300 to 600 ml/h of amnionic fluid
• Proteinuria in fetal life to closure of kidney tubules in neonate
• Absence or malfunction of kidneys leads to death or retarded development

Respiratory System
• Fetal breathing occurs in utero
• Allows development of intercostal muscles of chest and diaphragm associated with breathing

Fetal Adrenal Glands
• Norepinephrine
– Release of surfactant from epithelial cells of lung lobuloalveolar structures
– Absorption of liquid from lungs
• Glucocorticoids (Cortisol and Corticosterone)
– Lung maturation
– Lactogenesis
– Thyroxin to Triiodothyronine
– Glucose storage as glycogen
– Insulin secretion in response to glucose
– Transition from fetal hemoglobin to adult hemoglobin
– Closure of Ductus Arteriosis
– Parturition

Lung Maturation
• Synthesis and secretion of surfactant by lung alveolar epithelium
– Glucocorticoids – Synthesis (Transcription and
Translation) of surfactant and storage in cells
– Norepinephrine – Secretion of surfactant
• Surfactant essential for lung alveoli to maintain integrity and not collapse by providing high surface tension when stretched.
• Fetuses deficient in surfactant develop Hyalin
Membrane Disease and often die
• Now Pediatricians have artificial surfactant to decrease risk of Hyalin Membrane Disease

Respiration
• Umbilical Circulation
– pO2
• Artery – 15
• Vein - 25
– pCO2
• Artery – 55
• Vein – 40
• Maternal Uterine Circulation
– pO2
• Artery – 95
• Vein – 35
– pCO2
• Artery – 35
• Vein - 45

ADULT
RIGHT HEART ► LUNGS ► LEFT HEART
↑
↑
LIVER ← ← ←
↓ AORTA
BODY
FETUS
Liver
Ductus
Venosus
Lung
RIGHT HEART ► FORAMEN OVALE ► LEFT HEART
↑
↑
AORTA
DUCTUS ARTERIOSIS
PLACENTA BODY OF FETUS

Uterine Involution and Repair

).

11 β hydroxylase
11 β hydroxylase for corticosterone and cortisol

Ovine
Human
Fetal Hypothalamic Pituitary
Adrenal Axis
↓
Placental
Estrogens
← Fetal Glucocorticoid Production
Corticosterone and Cortisol
↓
→ Placental CRH
Intrauterine
Production of Prostaglandins

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
CRH is Produced by Human Chorion in response to cortisol from fetal adrenal
CRH stimulates Dehydroepianrosterone Sulfate
(DHAS) from fetal adrenal that is converted to estrogens by chorion
Glucocorticoids and estrogens stimulate increased expression of prostaglandins E and F and decreases
PGDF-15 that inactivates PGs

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
Central Characteristics of Human Parturition
Increase in CRH and PGHS-2 in chorion
Decrease in PGDH-15
Increase in FP and EP prostaglandin receptors
Decreased sensitivity of uterus to progesterone
Increase in production of estrogens from
DHAS by chorion
Increase in myometrial contractions

Challis et al. J Obstetrics and Gynecology 31:492-499. Fetal
Signals and Parturition
Conversion of Progesterone to Estradiol and Loss of
Progesterone Influence
Increased Contraction Associated Proteins
Oxytocin Receptor
PGF Receptor
Connexion-43 Gap Junction Protein
Recent Suggestion that Increase in Progesterone
Receptor C Isoform Results in Loss of Progesterone
Responsiveness via PR Isoforms A and B in Human
Myometrium (Condon et al. 2006 Mol Endocrinol
20:764-775

• Efficient use of labor and facilities to reduce neonatal death losses
• Reduce length of gestation
• Increase opportunities for cross-fostering neonates in event of failure of dam to accept offspring, cannabilism or failure to lactate
• Convenience of producer
• In swine, uniformity of post-weaning estrus

Controlling Time of Parturition (continued)
• Swine: Corticoids Ineffective
– PGF-2 alpha – 200 ug cloprostenol or 10 mg Lutalyse at 7
AM and 7 PM with farrowing 24-26 h later.
– Should not be used prior to Day 112 of pregnancy due to decreased survival of neonate
• Cows; Corticoids, Estradiol and PGF are effective
– 20 mg dexamethasone to dam most commonly used. For maximal survival of calf, cows should be within 1 week of term. Some countries with wet and dry season induce parturition to coincide with rainy season, high nutrient availability and focus on milk production with calves having little economic value
• Retained placentae major issue

Controlling Time of Parturition (continued)
• Mare: Corticoids, PGF and Oxytocin
– 2.5 mg PGF (Lutalyse) every 12 hours causes birth/abortion in late gestation.
– 200 dexamethasone/day for 4 days with foals being born 72 to 96 h after end of treatment
– 20 IU to 200 IU Oxytocin administered with estradiol will cause cervical dilation and birth in some cases.

• Cow
– Days 0-12 – Sloughing and Discharge of endometrial tissue and placenta
– Days 25-30 – Uterine Involution completed
– Days 40-45 – Uterus considered ready for next pregnancy
– Dairy – First estrus around Day 15 to 20 and breeding from Day 60
– Beef – First estrus between 60 and 100 days and breed during desired dates (spring or fall)

Post-Partum Period
• Sheep
– Uterus involuted by Days 25 to 30
• Breed in fall
• Pig
– Uterine involution completed by Days 21 to 28
– Breed at post-weaning estrus (3-7 days)
• Mare
Foal Heat – 5-15 days postpartum
Breed if no complications
Human
Highly variable and related to many factors
Suckling intensity, body condition, nutrition etc