Lecture 18 - The Menstrual Cycle

Question 1

Menstrual Cycle

Answer 1

Menstrual cycle –regulated by fluctuating levels of sex hormones

Humans are nearly unique in having a menstrual cycle
Some apes and monkeys

Other species of mammals have estrous cycles

Menstrus = shedding of the lining

Question 2

Cycle basics

Answer 2

Low E and P mean no negative feedback therefore increased GnRH

GnRH stimulates FSH and LH during menstruation
Starts maturation of ova
Estrogen and progesterone

2 phases:
Follicular is when oocyte into ovum
Luteal following release of ovum

P comes from corp luteum

Corpus luteum degrades
Progesterone decline instigates menstruation

E2 and P: neg. feedback for HPG
Exception to this…

Question 3

Sex drive

Answer 3

E causes sex drive, not e and p as in rodents. P suppresses it. In rodents, E & P are close together, in humans when P arrives ovulation has occurred so no longer useful to have sex

Question 4

Hypothalamic Parts

Answer 4

GnRH Neurons

In the medial preoptic area (MPOA)
GnRH acts on anterior pituitary
FSH and LH release
Stimulate ovum which produces E2 and P

There are neurons in the arcuate nucleus which contribute to negative feedback of GnRH neurons

Question 5

FOLLICULAR PHASE

Answer 5

Between days 1 and 14 (interindividual variations)
late follicular phase = proliferative phase
ends with ovulation
Main hormone: estradiol

Question 6

STEP ONE

Answer 6

GnRH will stimulate pituitary as P and E2 drop during menstruation

Goes into portal veins and then FSH and LH are released

FSH + LH rise
Stimulate oocytes into ova

Question 7

STEP TWO

Answer 7

Step Two
Granulose cells around follicles proliferate
-increase FSH and LH receptors

Follicles start producing estrogen

• LH – acts on theca cells to produce T
• FSH activates aromatase to make E2

Question 8

STEP 3

Answer 8

As estradiol increases negative feedback on the pituitary and hypothalamus
-Lower GnRH, FSH and LH levels

Question 9

EVENTUALLY, ONE FOLLICLE GAINS DOMINANCE

Answer 9

More than one primordial follicle becomes a primary follicle. More than one of these keeps growing BUT

Near the end of follicular phase FSH is low due to inhibition by estrogen.
Only the follicle with the most FSH ad LH receptors can bind enough FSH to grow
Other follicles atrophy (atretic)

Selects for the most developed follicle

Question 10

The role of gonadotrophins in the follicular phase

Answer 10

Look at how gonadotropins (FSH and LH) stimulate follicle development

How does this differ in Invitro fertilization

In vitro uses external FSH
FSH sufficient for follicle growth
No LH (blocked GnRH) but still as large as during typical cycle

LH is needed only to make E, not to develop the follicle

In IVF have extended FSH because exogenous administration
Many follicles mature (fewer atretic)
When admin hCG multiple mature follicles for fertilization

Usually hCG is released after fertilization and is important to maintain it. In IVF we administer from harvesting until implantation to give the maximum chance of pregnancy

Regimes usually skip LH as this is not needed (though some add it at the end just so it can do whatever it does)

Question 11

STEP FOUR

Answer 11

The dominant follicle continues to secrete increasing estradiol
E2 reaches threshold
Causes LH spike (FSH too)
Ovulation

Basal body temp is higher at LH surge and this can be used to monitor for ovulation (0.3 degrees higher)

Question 12

Ovulation

Answer 12

Ovulation: The release of a mature ovum (egg) from the ovary

It varies in the individual, but typically occurs on days 11 to 16 of the menstrual cycle.

Question 13

How does the LH surge occur???

Answer 13

If E2 negative feedback on LH and FSH how does this spike in LH occur?
E2 threshold: once achieved E2 has positive feedback NOT negative
High levels stimulate different set of neurons….

GnRH Neurons
Gonadotrophin Releasing Hormone (GnRH) neurons in hypothalamus

Increase in the MPOA during puberty
Maintained throughout reproductive period

HPG axis
GnRH  FSH+LH  E2+P/T

What stimulates the GnRH system?
Start of GnRH Pulsatility: UNKNOWN!!!

(1) HPG axis activated at puberty
- Kisspeptin input from Arcuate

(2) GABA inhibits Kisspeptin in juvenile
Lack of Kisspeptin = no GnRH

(3) Late juvenile: glutamate stimulates Kisspeptin
Kisspeptin commences pulsatile GnRH

(4) Late puberty: females preoptic Kisspeptin
E2 activates these MPOA kisspeptin neurons for LH
This is not in the arcuate nucleus, it is its own thing in the MPOA

These give off excitation and activate the HPG axis causing the LH surge

Question 14

Positive Feedback and the Luteal Surge

Answer 14

Hypothalamus: axons of kisspeptin neurons from arcuate nucleus form synapses with MPOA GnRH neurons

Estrogens negative feedback on arcuate kisspeptin neurons

Reduce GnRH to reduce HPG axis

Just before ovulation: estrogen reaches threshold

• positive feedback on MPOA kisspeptin neurons
• GnRH peak to induce LH peak

The luteal surge causes estrogen peak
-Follicle bursts, releasing the egg into oviduct

Question 15

The Organizational-Activational Hypothesis

Answer 15

If females get androgens = masculanization

No ovulation, no sex behavior

When you masculinize a female, you are masculinizing LH production, like in men it it all about negative feedback sensitive, pulsatile release

in women LH surge

The change in masculinization is a lack of kisspeptin neurons in the PreOpticArea

Eg in CAH, polycist cos no LH surge therefore eventually cysts

Question 16

Anovulation

Answer 16

Anovulatory cycle = literally an absence of ovulation

Most often due to hormonal imbalance
-Polycystic ovarian syndrome (PCOS)

Can also occur due to stress, sudden weight loss, excessive exercise or drugs

Question 17

THE LUTEAL PHASE

Answer 17

Occurs after ovulation
-11-16 days
-Much more stable as this is fertilized ova takes 11 days to implant so cannot run late or early
-‘Begins with the formation of the corpus luteum – progesterone!!
Ends with either:
a) luteolysis
b) pregnancy

Question 18

The Corpus Luteum

Answer 18

Comes from what was around the ova

The corpus luteum continues to grow for some time, secreting progesterone and some estrogen

Progesterone makes the endometrial lining ready for implantation of an embryo

Estrogen helps make the cervical mucous ‘fertile’

Progesterone and estrogens keep FSH and LH levels low: negative feedback

Question 19

Luteolysis

Answer 19

Without FSH and LH the corpus luteum atrophies – luteolysis

Result of atrophy: drop in progesterone and estrogen

If pregnant progesterone remains high

Menstruation occurs + increase in FSH and LH to re-start the cycle

Question 20

Fertilization and the start of pregnancy

Answer 20

High progesterone and moderate amounts of estrogen thickened endometrium for zygote

Zone pellucida around egg
Acrosome of sperm binds to pellucida
First to fuse with ovum membrane

Implantation of egg: human chorionic gonadotropin (hCG)
Measured by pregnancy tests
hCG prevents luteolysis so corpus luteum maintains progesterone until placenta can take over

Question 21

Sperm and egg

Answer 21

Drills through zona peluza, digesting it

When it releases DNA, a cascade of Ca2+ hardens the shell so only one sperm fertilizes it

Question 22

hCG production surges immediately after fertilization

Answer 22

At 12 weeks, makes placenta
hCG decreases
Placenta exists which keeps progesterone going

Highest risk for pregnancy before this point therefore told not to tell people you are pregnant before

HCG causes nausea so when it goes away on the 2nd trimester, so does this

Question 23

Other hormones involved in pregnancy

Answer 23

Prolactin
necessary for lactation and some maternal behaviours

Increases steadily throughout pregnancy

Produces breast milk

Estradiol

Levels high across pregnancy, and rise only at the end

Augment effects of oxytocin which instigates labour

Question 24

Menstruation

Answer 24

Monthly bleeding, “menses”
Shedding of the endometrium because E2+P reach threshold low
Menstruation lasts anywhere between 2-7 days
The average loss of blood is 35ml during menstruation (range 10-80ml)

Is not a lot, just a shot at a bar

Question 25

Premenstrual syndrome (PMS)

Answer 25

A set of physical and psychological symptoms before the onset of menstruation
Symptoms of PMS are cyclic - begin up to 7 days before menstruation
End with menstruation

Spectrum disorder: Ranging from mild to severe
Premenstrual dysphoric disorder (PMDD) is most severe

Recognized in the DSM V now
PMDD only in 2-5% of women – must be severe to reach diagnostic criteria

Breast Tenderness
Headaches
Fatigue 
Bloating
Skin Blemishes 
Muscle Aches 
Cramping 

Appetite Changes
Mood Swings
Irritability
Crying Spells 
Depression 
Sleep Disorders
Anxiety

80% experience some symptoms
20-30% experience moderate to symptoms
2-5% experience most severe variant, PMDD

Question 26

PMS research: Study One

Answer 26

Two groups of women at same points in their cycle

Group 1: 6-7 days away from their period
Group 2: 7-12 days away from their period

6-7 days away reported worse PMS symptoms

Maybe this is because they were looking for them

Might be all psychological (according to feminist prof)

Question 27

PMDD research: Study Two

Answer 27

GnRH antagonists to eliminate menstrual cycle in PMDD
10 out of 18 women showed improvement

Estradiol and progesterone given to the 10 that showed improvement
PMDD symptoms reappeared after this treatment

The same study was done on women who do not have PMDD

After E2+P treatment they did not experience the PMDD symptoms

Hormone levels in both groups of women were equalized

Only women who had PMDD experienced PMDD symptoms with hormone

Hypothesis:
Hormone sensitive women (more receptors or different distribution of receptors/subtypes)

Not hormone levels but the sensitivity to the hormones
Similar to role of testosterone in male sexual behaviour

Question 28

PMDD: a modern phenomenon

Answer 28

Before contraceptives women were lactating or pregnant while in reproductive years
PMS more a byproduct of modern civilization
Similar arguments about changes in brain following pregnancy

Similar argument about our next topic which is menopause
A state that women rarely experienced from an evolutionary perspective….