Lecture 3 - Menstrual cycle I

Question 1

Menstrual cycle: what processes does it underdo?

Answer 1

• Maturation of the female gamete (oocyte) in the ovary and its transport to the site of fertilisation (uterine tube, aka Fallopian tube or oviduct)
• Preparation of the uterine endometrium as a suitable site for implantation of a developing embryo
• Menstruation if no embryo implanting occurs

Question 2

HPG axis: what is it and what is the process?

Answer 2

hypothalamic-pituitary-gonadal axis

• Kisspeptin neurons activate gonadotrophin-releasing hormone (GnRH) neurons in the hypothalamus
• Hypothalamus releases gonadotrophin releasing hormone (GnRH)
• GnRH causes Gn release (FSH/LH) from the anterior pituitary
• FSH/LH affect the ovaries and cause oocyte development and ovulation

Question 3

Menstrual cycle: what two parts of it are there?

Answer 3

• Uterine cycle
• Ovarian cycle

Question 4

Uterine cycle

Answer 4

• Menstrual phase - ~5 days
• Proliferative phase - ~9 days
• Secretory phase - ~14 days

Question 5

Ovarian cycle

Answer 5

• Follicular phase - ~14 days
• Luteal phase - ~14 days

Question 6

Why does the uterus lining break down?

Answer 6

The lack of circulating progesterone

Question 7

What follows the drop of circulating sex hormones?

Answer 7

FSH levels start to rise - this is due to the decreased amount of negative feedback on the hypothalamus and anterior pituitary

Question 8

FSH: what is it, what produced it, and what does it do?

Answer 8

Follicle stimulating hormone

The hypothalamus/anterior pituitary

Causes maturation of secondary follicles into tertiary follicles

Question 9

Follicles: what are they, how does their maturation work, and what hormone do they produce?

Answer 9

Small sacs found in the ovaries that contain eggs

• Ovaries enter the follicular phase as the uterus layer breaks down - results in maturation to secondary follicles
• Maturation to tertiary follicles arises in the presence of FSH

Oestrogen

Question 10

What causes the shift from the menstrual phase to the proliferative phase of the uterus?

Answer 10

Circulating oestrogen arising from tertiary follicles

Question 11

Circulating oestrogen: does it undergo negative or positive feedback and why?

Answer 11

It undergoes negative feedback unless a threshold is reached, at this point positive feedback occurs and a rise in FSH and LH occurs

Question 12

Follicular phase of the ovaries: how long does it last, what causes progression into this phase, and what does it do?

Answer 12

~14 days

Menstruation

Matures follicles until a dominant follicle is ready to be released

Question 13

Luteal phase of the ovaries: how long does it last, what causes progression into this phase, and what does it do?

Answer 13

~14 days

Release of the egg from the follicle

Produces oestrogen and large amounts of progesterone - builds up and maintains the uterus lining

Question 14

Menstrual phase of the uterus: how long does it last, what causes progression into this phase, and what does it do?

Answer 14

~5 days

Lack of fertilised egg binding to uterus

Breaks down the lining of the uterus, including many cell types

Question 15

Proliferative phase of the uterus: how long does it last, what causes progression into this phase, and what does it do?

Answer 15

~9 days

Circulating oestrogen produced by follicles

Builds up the lining of the uterus

Question 16

Secretory phase of the uterus: how long does it last, what causes progression into this phase, and what does it do?

Answer 16

~14 days

Circulating progesterone produced from the luteal phase of the ovaries

Endometrial secretions occur which support an embryo until it is ready for implantation

Question 17

Estrous cycle: what is it and how does it operate in animals and humans?

Answer 17

Behavioural strategy to ensure mating occurs at time of ovulation

Animals:
* Sexual stimulus
* Accept advances more readily
* Enticing behavioural gestures

Humans:
* Men prefer the smell of women in the middle of their menstrual cycle - sexual stimulus?
* Provocative movements potentially?
* Androstenone better tolerated

Question 18

Puberty: what controls it

Answer 18

• Genetic
• External factors - adiposity, endocrine disrupting chemicals, intra-family relationships, stressful events, etc

Question 19

Adiposity: why is it suggested to affect puberty age?

Answer 19

• Puberty age has decreased over time
• Countries with sub-optimal socioeconomic status have puberty later
• Delayed puberty in malnutrition and low weight
• Moderate obesity is associated with advanced puberty

Question 20

Adiposity: by what mechanisms may it affect puberty age?

Answer 20

Leptin?
Adipose tissue may cause leptin secretion which binds to LepR in gonadotrophin releasing hormone (GnRH) neurones in the hypothalamus

This is wrong - GnRH neurones don’t express the leptin receptor

Kisspeptin?
This is regulated by leptin and fills the gap in the previous model - leptin stimulates kisspeptin neurones which secrete kisspeptin which binds to GnRH neurones which can then cause gonadotrophin release from the anterior pituitary

Question 21

Kisspeptin: what is it, where is it produced, what does it do, what is it regulated by, and what is its potential pathway for inducing puberty?

Answer 21

GPCR ligand

Produced in the hypothalamus:
* Arcuate nucleus - important in GnRH pulse generation
* Anteroventral periventricular nuclei - GnRH/LH surge and ovulation

Leptin

Leptin stimulates kisspeptin neurones which secrete kisspeptin which binds to GnRH neurones (GPR54) which can then cause GnRH release - this then reaches the anterior pituitary and causes Gn release

Question 22

What evidence suggests kisspeptin plays a role in puberty age?

Answer 22

Disruption of the gene results in failure of sexual maturation but treatment of juvenile rats with kisspeptin advances puberty timing

Question 23

GnRH: what is it, what is its structure, what does it do, and what types of GnRH release are there?

Answer 23

Gonadotrophin releasing hormone

Simple amino acid structure (10 aa’s)

Acts as a ligand for the GnRHR which signals through Gαq and PLC to result in transcription of Gonadotrophins

Pulses or surges

Question 24

GnRH pulses: why are they important and what do they do?

Answer 24

Promote the production of FSH

Question 25

GnRH surges: why are they important and what do they do?

Answer 25

Promote the production of LH

Question 26

FSH: what is it, what is its structure, what confers its specificity, what is its production stimulated by, where is it secreted from, and where is it packaged within the cell?

Answer 26

Follicle stimulating hormone Dimeric protein with both an α and β subunit (α identical in LH) β subunit Slow pulses of GnRH Anterior pituitary Secreted through the constitutive pathway - little storage within the cell

Question 27

LH: what is it, what is its structure, what confers its specificity, what is its production stimulated by, where is it secreted from, and where is it packaged within the cell?

Answer 27

Luteinising hormone Dimeric protein with both an α and β subunit (α identical in FSH) β subunit Fast pulses of GnRH Anterior pituitary Packaged in electron-dense granules, in association with storage protein secretogranin II

Question 28

How are FSH/LH secretions regulated?

Answer 28

* GnRH binds to GnRHR * Causes activation of Gαq * Gαq activates PLC * PLC activates protein kinase C - PKC activated MAPK, promoting βLH, βFSH, and FSH/LHα subunit production * FSH is dimerised then constitutively released * LH is packaged near to the PM, often on cells near capillaries- secretion is activated by Ca²⁺ ??????????

Question 29

GPCRs: what are they, what do they do, what is their structure, and how many domains do they have?

Answer 29

G protein-coupled receptors Bind with ligands, activating their attached G protein which can then do downstream signalling Long protein that passes through the membrane (7 times) and has extracellular/intracellular compartments Ectodomain (NH₂), transmembrane, and cytoplasmic domain (COOH)

Question 30

G proteins: what are they, what is their structure, how do they become activated, and how many α subunit families are there?

Answer 30

Guanine proteins Heterotrimer - αβγ subunits GPCRs induce a conformational change in the α subunit, causing a swap of GDP to GTP and α subunit dissociation Gαq - activates phospholipase C Gαs - activates adenylate cyclase Gαi - inhibits adenylate cyclase Gα12 - Rho family of GTPases

Question 31

PLC: what is it, what is its function, and what is its pathways?

Answer 31

Phospholipase C Causes downstream signalling after being activated by Gαq * Converts PIP₃ into PIP₂ and IP₃ which binds to receptors on the ER and Ca²⁺ * Activates PKC which causes activation of the MAPK pathway

Question 32

FSH/LH receptors: what G protein are they coupled to, what is activated, and what is the downstream signalling?

Answer 32

Gαs Activated adenylate cyclase * Causes conversion of ATP to cAMP * cAMP caused activation of PKA * PKA phosphorylates of Ser/Thr motifs