Reproduction 4

Question 1

What is 
PRIMARY AMENORRHEA?

What are common causes?

Answer 1

absence of menses in a phenotypic female by age 17

Common causes - disorders of sexual differentiation

• Turner’s syndrome
• Complete androgen resistance (Testicular Feminization)
• Hormonal disorders in ovaries, adrenals, thyroid, pituitary/adrenal/hypothalamic axis

Question 2

What is SECONDARY AMENORRHEA?

What are the most common causes?

Answer 2

cessation of menstruation for longer than 6 months

Most common causes – pregnancy, lactation, menopause

Others:
Prolactinoma- lactation can make HIGH levels of prolactin (prolactin inhibits GnRH) … so another reason some women do not have menstruation after birth

Panhypopituitarism- (lots of cell death in pituitary, including perhaps gonadotropes)

Question 3

What is OLIGOMENORRHEA?

What is the most common cause? Other causes?

Answer 3

infrequent periods (cycle length, greater than 35 days)

Most common – changes due to functional abnormalities in CNS mechanisms that regulate GnRH release including stress and illness

Changes in body fat composition – very low levels (athletes)

Intense exercise, extreme weight loss, anorexia nervosa – no consistent changes in plasma gonadotropins or ovarian steroids

-women under a lot of high control stress- cortisol will inhibit HPG axis
trouble conceiving, irregular menstrual cycles

• obese adults have high incidence of becoming infertile bc they become insulin resistant. (PCOS)
• any change in body fat- too much or too little can cause problems w HPG axis.

Question 4

What is DYSMENORRHEA?

What causes it? (At what phase of cycle)?

How can it be treated?

Answer 4

(painful menses)

Painful menses related to uterine contractions may involve pelvic pain radiating to back and thighs, nausea, vomiting, diarrhea. Prostaglandin synthesis is promoted by E2 followed by progesterone. (secretory phase)

Prostaglandins released during menses cause uterine contraction –may be severe enough to cause ischemia and pain.

Single most common cause of female work/school absenteeism.

Treatment – prostaglandin synthesis inhibitors, oral contraceptives, non steroidal anti-inflammatories to treat

Question 5

Describe PREMENSTRUAL SYNDROME and PREMENSTRUAL DYSPHORIC DISORDER.

At what phase does it occur?

What percent of women are affected?

Symptoms?

How is it related to progesterone?

Treatment?

Answer 5

OCCURS IN LATE LUTEAL PHASE

Both physical and behavioral symptoms that interfere with normal life.

Moderate to severe: 30% of females with normal cycles.

Symptoms: Abdominal bloating, extreme sense of fatigue, breast tenderness, labile mood – irritability, tension, depression

Cause not clear but related to cycle.
*No clear link to progesterone- for example, progesterone replacement doesn’t alleviate symptoms of PMS (or postpartum depression).
(happens at end of luteal cycle right when progesterone is low, right before endometrial lining will shed.. and progesterone replacement does not help.)

Vitamin supplements also not better than placebo

First-line treatment when socioeconomic dysfunction is present: SSRIs and oral contraceptives to suppress ovulation

Question 6

What is HIRSUTISM?

What are causes?

Answer 6

– inappropriately heavy hair growth in androgen sensitive areas
(beard area, inner thigh, back, lots of diff places NOT expected in female body type)

Causes:
Intake of exogenous androgens
Excessive androgen production by adrenals (adrenal hyperplasia, Cushing’s syndrome)
Idiopathic increases in sensitivity to androgens

Question 7

How could Cushing cause hirsutism?

Answer 7

can be caused by women w Cushing (high cortisol levels that could promote excessive DHEA prod. from zona-reticularis or tumor in adrenal gland)

Question 8

Describe Virilization.

Answer 8

includes hirsutism and more pronounced evidence of androgen stimulation – clitoral hypertrophy, deepening voice, temporal balding, male pattern skeletal muscle development
Causes: excessive androgen production

Question 9

What is PCOS?

Root cause?

Answer 9

A root cause is insulin resistance, obesity (these are caused by and causes of PCOS).

High insulin stimulates androgen production (causing infertility), increased conversion to estrogens (weight gain).

Follicle development impaired, ovulation is not completed, follicles degenerate into cysts. Ovaries can double in size. -follicles grown, big antral-follicles growing, but they never ovulate, and these follicles just become a cyst

high insulin stimulating more androgen prod. in ovaries

Question 10

What are symptoms of PCOS? What are treatments?

Answer 10

Symptoms include sleep apnea, menstrual irregularity, obesity, acne, decreased HDL and increased triglycerides, hirsutism.

decreased HDL- direct action of T at liver!

treatment w metformin = metformin will inhibit gluconeogenesis in the liver but also increase peripheral insulin sensitivity (just fixing that insulin resistance issue is enough to make these women more fertile)

Treatments include weight loss, smoking cessation, metformin (for insulin resistance). Metformin alone is often sufficient to restore fertility. Clomiphene is also effective: 70% ovulation induction in PCOS cases.

Clomiphene- selective estrogen receptor modulators

Question 11

Describe the three types of estrogens.

Which form is higher after menopause? Which form is produced by placenta? Which form is higher during reproductive years? Which are weak?

Answer 11

E1 = estrone - produced in higher amounts after menopause; lower binding affinity for estrogen receptors

E2 – 17β-estradiol – primary circulating estrogen during reproductive years

E3 – estriol (weak) – produced by the placenta. Also converted from estrone in the liver

E1 and E3 weaker bc not as high affinity binding to estrogen receptor

High conversion in target tissues by aromatase .. high local concentrations

Question 12

How do estrogens travel in the blood?

Answer 12

TRANSPORT IN BLOOD:

38% bound to SHBG
60% bound to albumin
2-3% free

(these bound levels/free levels similar to T)

Question 13

Describe some positive effects of estrogen. Long term negative effects?

Answer 13

cardio-protective in pre-meno. women
neuro-protective (against Alt. and stroke) loss of estrogen thought to contribute to these diseases in older women (CV disease, osteoporosis, Alt. and stroke)

is because during rep. years estradiol is protective in all these tissues

in bone it stimulates OPG and prevents osteoclast from breaking down the bone

long term/life-long exposure to estrogens can increase risk for breast and uterine and ovarian cancers (bc estrogen has proliferative effects on these tissues, causes excessive growth)

highly tissue specific effects of estrogen. is pleiotropic hormone

Question 14

Describe the estrogen receptors. How does E2 bind

Describe the role of each. If you knocked out ERalpha what would occur? ERbeta?

How does expression change throughout life?

Why might post-meno. women eat more soy products?

Answer 14

E2 binds both receptors with equal affinity

ERα – mediate most reproductive effects of estrogens. ERα knock-out mice are infertile

ERβ – mediates non-reproductive effects (cardioprotection, neuroprotection, mood). ERβ knock-out mice are subfertile

ERβ has higher affinity than ERα for plant-derived estrogens (i.e. soy products) and some environmental estrogens

alpha- highly expressed during rep. years and goes away post-meno.
Beta- don’t change much during life time.

Question 15

What are SERMS – selective estrogen receptor modulators?

When might you give to women?

Answer 15

Synthetic compounds designed to specifically target the estrogen receptor

Can target ERα and/or ERβ

Can have tissue specific actions:

give to women to alleviate neg. symptoms following menopause.

Question 16

What type of medication is Tamoxifen? What is it used to treat? How?

Answer 16

SERMS – selective estrogen receptor modulators

e.g. Tamoxifen is an antagonist in breast and uterus, but an agonist in bone and brain.

Tamoxifen- used to be first line treatment in breast cancer. starting to go to aromatase inhibitors now but those are more expensive and need better insurance.
but Tamoxifen still major treatment for breast cancer… agonist in bone and brain (so get rid of effects of estrogen in breast where cancerous carcinoma but preserve beneficial effects in bone)

Question 17

What is CLOMIPHENE? What does it treat?

In what scenarios is it used?

Answer 17

SERMS – selective estrogen receptor modulators

-Originally designed to treat women with oligomenorrhea

Selective for ERalpha – binds with very low affinity to ERbeta
Antagonist for ERalpha – specific to hypothalamus (blocks negative feedback)

• *Most highly prescribed drug to induce ovulation
• since blocks neg. feedback of estradiol. so get high stimulation of GnRH and gonadotropins and get increased fertility
• increases LH - LH stimulates steroidogensis, esp T… so also been used as drug of abuse for some athletes (endogenously increase levels of LH and steroid production)

Question 18

Describe progesterone.
Describe its receptors. What will upregulate these receptors?

Transport in serum?

Answer 18

Progesterone receptors A and B – E2 upregulates expression of these receptors. Nuclear steroid hormone receptor family

Transport: bound mostly to albumin; low affinity for SHBG

Question 19

What are the actions of progesterone (P4)?

Answer 19

Actions:
-Prepares endometrium for implantation of embryo (proliferation, synthesis of enzymes that lyse zona pellucida=coat that surrounds oocyte)

• Inhibits myometrial contractions – maintains pregnancy
• Stimulates mammary gland development – preparation for lactation
• Antagonizes actions of estrogen – important consideration for hormone replacement therapy

stimulates mammary gland development in prep for lactation. prevents lactation from happening too early. (in preg. breast prepares for lactation and start making milk but won’t lactate bc progesterone will stop that from happening

Question 20

Describe the levels of progesterone during pregnancy. What would happen if there was no progesterone? A lot of progesterone?

Answer 20

progesterone maintains quiescence of uterus so levels MUST be high throughout preg. to avoid premature birth/labor from occurring…action of progesterone that inhibits myometrial contractions

Inhibits myometrial contractions – maintains pregnancy

Question 21

Describe how hormones change in menopause and why.

Answer 21

Depletion of ovarian follicles results in reduced E2 and P4 production, and decreased inhibins

Loss of negative feedback = increased FSH and LH (FSH greater than LH)

Question 22

Describe the conditions that menopause women have increased risk for.

Answer 22

INCREASED RISKS FOR:
Osteoporosis – E2 normally stimulates OPG (protective for bone)
Cardiovascular disease – E2 protects against cardiac hypertrophy, reduces cholesterol
Vascular flushing (“hot flashes)” – increased gonadotropins result in increased core body temperature, reflex vasodilation
Dementia – E2 neuroprotective
Vaginal atrophy and dryness (decreased E2-induced cellular proliferation and decreased secretion of cervical mucus)

Question 23

After ovulation corpus luteum forms which makes lots of P and E. How does this align time wise with the uterus becoming receptive and fertilization of oocyte?

Answer 23

uterus starts to become receptive (this is day 20) fertilization can happen early as day 15 or 16 when second stage of meiosis complete and sperm fertilizes egg… so between day 16-20 newly made embryo hanging out in oviducts waiting bc uterine lining is not ready… get blastocytes come into uterus. blastocysts hatches (zona pellucid denigrates and allows to be implanted into uterine lining. rescuing of corpus lut. by HCG which is made by embryo and developing placenta. then get competition of implantation

Slide 31

Question 24

Gamete transport is the first step of fertilization.

SPERM:
150 million – 600 million sperm deposited into vagina
- 50-100 million reach ampulla of oviduct (site of fertilization)
Reach ampulla within 5 minutes – retained for 24-48 hours

Describe the factors that help the sperm reach its destination.

Answer 24

Helpers:

Vaginal secretions become more alkaline

Uterine and cervical contractions propel sperm forward

Prostaglandin in seminal plasma induce muscle contractility
Seminal “plug” – semen coagulates upon ejaculation
Vaginal mucus less viscous

Question 25

Where does fertilization usually occur?

Where is the oocyte released? What happens once it is released?

Answer 25

Fertilization:
Just 1 oocyte is released from ovary into peritoneal cavity. Cumulus cells help fimbriae “capture” oocyte and direct towards oviduct

Usually occurs in ampulla
First stages of embryonic development occur – development of blastocyst (stays about 3 days)

Question 26

Describe the transport of sperm.

Answer 26

Slide 34

Question 27

What step is necessary in order for the sperm to penetrate the oocyte?

Where does this occur?

Once this happens, what is then possible?

Answer 27

Sperm capacitation

Final step of sperm maturation

Allows sperm to penetrate zona pellucida surrounding oocyte

Involves removal of protective protein coat (of acrosome)

protein coat around acrosome that has to degraded and removed, occurs in vaginal tract and sperm become capacitated and can bind to receptors on oocyte, ZPE3 receptors.

Question 28

Describe the acrosomal reaction.

Answer 28

Sperm binds to ZP3 receptor (glycoprotein)

Triggers increased calcium in sperm cell – leads to exocytosis of hydrolytic enzymes

Sperm and oocyte membranes fuse – acrosome reacted sperm bind to ZP2 proteins

so now sperm head stuck in there kinda sidewise and binds to ZP2 receptors (glycoprotein receptors made by oocyte that the sperm have to be able to bind to)

Question 29

Describe the cortical reaction.

Answer 29

Acrosomal reaction (Ca being released inside the sperm)
Cortical reaction ( Ca being released inside the oocyte) 

Cortical Reaction:
Calcium-mediated release of cortical granules

Enzymes in these granules prevent ZP3 and ZP2 binding

Prevention of polyspermy – triploid cells are not viable
“hardening” of z. pellucida

ortical granules released from oocyte that cause these receptors to internalize and z. pellucida will harden and no more sperm gets in. (if more got in would be tripled cell which is not viable

Question 30

What will intracellular Ca release in oocyte trigger in addition to ZP3 and ZP2 receptors being internalized? (What reaction is this)?

Answer 30

now sperm can move inside of here, and intracellular Ca release will also trigger completion of Meiosis II. now thats complete and get extrusion of the second polar body. so have female pro-nucleus (male pro-nucleus bc sperm now mature) and the 2 can now combine.

(cortical reaction)

Question 31

At what phase of fertilization do you have a female and male pro-nucleus?

Answer 31

cortical reaction of (Sperm penetration of oocyte)

Question 32

Describe the completion of meiosis.

What kind of chromosomes are present in oocyte?

Answer 32

cortical reaction.

Decondensation of sperm DNA

Oocyte is released from metaphase II arrest and completes meiosis II

Second polar body is extruded – oocyte has haploid, unduplicated chromosomes

once combines get recombination and development of zygote.

Question 33

Describe the embryo implantation.

Describe function of the following cells:

Trophoblast cells
Blastocyst
Cytotrophoblast
Syncytiotrophoblast

Answer 33

“Hatching” of embryo – dissolution of zona pellucida by trophoblast cells

Blastocyst at implantation - trophoblast differentiates into cytotrophoblast and syncytiotrophoblast

Cytotrophoblast – (initially) feeder for continually dividing cells (penetrating) nutrients prod. feed zygote dividing rapidly.

Syncytiotrophoblast – 3 functions: adhesion, invasion, and endocrine

Question 34

In embryo implantation, which cells are first to enter endometrium?

Describe role of this cell.

Answer 34

syncytio- first get in there, so adhere to external part of endometrium, then go through invasion where they push way in, then they become an endocrine component, helping to form placenta.

Syncytiotrophoblasts secrete adhesive surface proteins (cadherins and integrins)

Question 35

What is osteopontin?
Where is it released from? What stimulates its release?

Describe its purpose.

Answer 35

E2-dependent secreted by uterine glands

-bridging molecules

E causes secretion of osteopontin- forms bridge that allows it to stick to outside of endometrium.

important for EMBRYO ADHESION

Question 36

What happens to stromal cells upon implantation/ embryo adhesion?

Answer 36

Stromal cells form decidua and secrete nutrients. Later this structure becomes a barrier and endocrine organ.

stromal to decidua- now can secrete lots of nutrients used for invading embyro.

Question 37

EMBRYO INVASION

*most invasive of all placental mammals

How is it ensured that the embryo does not implant too deeply in the endometrium?
Describe the cells crucial in maintaining this balance.

Answer 37

Embryo completely burrows into superficial layer of endometrium

Balance between decidual cells (defense) and trophoblast migration (offense). Matrix metalloproteinases (MMP) from trophoblasts vs. inhibitors of MMP from decidual cells; IGF-2 Secreted from trophoblasts vs IGF-binding proteins (secreted from decidua).

This balance prevents invasive trophoblasts from penetrating too deeply.

IGF-2 - acts like insulin and promotes growth, is secreted by tropho.
but endometrium secretes IGF binding proteins and when it is bound to those binding proteins, its inactive and can’t do anything.
whole balance allows embryo to penetrate far into endometrial lining but not go too far.

Question 38

What is lacuna?

What forms the chorionic villus?

Answer 38

Lacuna = fluid filled spaces in the syncytium make contact with the maternal blood vessels

Cytotrophoblasts proliferate and invade the syncytiotrophoblast – form the chorionic villus

Question 39

Describe the placental formation.

Answer 39

have zygote, its completely invaded endometrial lining and completely surrounded now by endometrial tissue.

initial trophoblast cells diff. into 2 types: cyto. and syncytio. these form 2 sep. barriers between fetus and mother.
syncytio. on invading side… pushing into endometrium.
cytotropho-still feeding prolif. cells

syncytium will grow and be filled with these fluid filled spaces called lacuna. those will merge w maternal vessels coming in from endometrium… these all coming from those spiral arteries deeper in, protrude out and come in contact w lacuna and spread out

cytotropho- start forming villi, chorionic villus (finger like projections that protrude into syncytium) …form barriers here where maternal blood coming in and pooling and surrounding these villi to allow for nutrient transfer between maternal blood and placenta

Lacuna = fluid filled spaces in the syncytium make contact with the maternal blood vessels

Cytotrophoblasts proliferate and invade the syncytiotrophoblast – form the chorionic villus

Mature villus = fetal tissue protruding into maternal blood
“brush border” of syncytiotrophoblast faces maternal blood

Question 40

Describe mature villus.

Answer 40

Mature villus = fetal tissue protruding into maternal blood
“brush border” of syncytiotrophoblast faces maternal blood

part facing the maternal blood is brush border

Question 41

Describe the vascular remodeling at the site of implantation. How do vessels change?

What will failure to develop vasculature result in?

Answer 41

Vascular remodeling at site of implantation is critical for fetal life: conversion of high resistance, low capacity to low resistance, high volume vessels

Spiral arteries increase in diameter; muscular and elastic components are lost – increases perfusion of the placenta

Failure to develop vasculature results in relative placental ischemia.

if doesn’t develop properly then placenta starts to become relatively ischemic and this can get much worse and cause Pre-eclampsia eclamsia…

Question 42

Describe PREECLAMPSIA-ECLAMPSIA

Leading cause of maternal death in developed countries

What are the hallmark symptoms?
Describe the pathophysiology.

Which women are more at risk for developing this?

Answer 42

Hallmark symptoms:
Hypertension
Proteinuria
Edema

Pathophysiology –
Relative placental ischemia leads to oxidative stress and endothelial cell damage

Damaged endothelial cells decrease vasodilators and increase vasoconstrictors – results in worsening placental hypoperfusion

Endothelial cell barrier between platelets and basement membrane is breached – thrombosis (blood clot) …causes capillary leak…edema and proteinuria

if vasculature does not remodel property to allow proper perfusion of ischemia, then this relative ischemia will lead to oxidative stress, cause endothelial cells to react and start trying to vaso- constrict those vessels even more, causes it to potentiate and hypo perfusion worse and endothelial cells start to die, barrier in breakdown, leakage across capillaries, proteins leak out into urine and edema builds up in interstitial space

if women already have hypertension going into preg. more at risk for developing this.