Reproductive Endocrinology Flashcards
Define GnRH
Gonadotrophin releasing hormone
Where does GnRH act?
On the gonadotroph cells of the anterior pituitary
What does the gonadotroph cell secrete?
LH and FSH
Which of LH and FSH has a pulsatile secretion pattern?
LH
Release of GnRH is pulsatile but cannot be measured in the blood. What is measured instead?
LH
Define Kallmans syndrome
Genetic defect resulting in no GnRH neurons in the hypothalamus. Results in reduced levels of sex hormones, no puberty and underdevelooment of gonads
True of false. GnRH agonists can be used to suppress ovulation
True
Release of LH is more rapid but of smaller amplitude during which phase of the cycle?
Follicular stage
FSH works with —? To stimulate the proliferation of granulosa cells
Estrogen
Explain the role of granulosa cells
They secrete inhibin
Define corpus luteum and its role
It is a temporary stage of the egg once ovulation has occurs. It secretes progesterone in preparation for pregnancy
Where does inhibin act?
Acts on the anterior pituitary to reduce FSH secretion
Why is it important that inhibin is secreted to reduce FSH secretion?
Because too much FSH would mean too much follicle maturation which would be a waste
Once the corpus luteum is formed, which hormones go up and which go down?
Inhibin and progesterone go up, which causes LH and FSH to go down
In which two cells does the estrogen synthesis pathway occur?
Theca and granulosa cells
Cholesterol uptake and androgen synthesis in theca cells is stimulated by which hormone?
LH
The conversion of androgens into estradiol in the granulosa cell is stimulated by which hormone?
FSH
Where does inhibin feedback to?
Anterior pituitary
Why is FSH needed after menstruation?
To stimulate estrogen production in the granulosa cells
What Happens to hormone levels as the corpus luteum dies off?
Inhibin secretion is reduced which increases FSH levels ready for the next follicular stage
If estrogen levels are low, which hormones do you want to increase?
LH and FSH
Explain the negative feedback involving progesterone
It inhibits the positive feedback of estrogen
Explain the role of progesterone in the uterus
Stimulates secretory and vascular activity of the endometrium preparing for implantation
When does estrogen negative feedback occur
During the follicular stage when estrogen levels are low
When does estrogen positive feedback occur
Towards the end of the cycle, when estrogen levels are high. Positive feedback = ovulation. Purpose of positive feedback is to stimulate the release of more LH and FSH, leading to the production of more estrogen
What does a surge in LH cause?
Triggers ovulation. LUTEINIZING hormone turns the follicle into the corpus luteum
FSH action?
Stimulates growth and maturation of eggs (follicles) during the follicular phase
Define menopause
Where the remaining follicles no longer respond to FSH. Results in reduced levels of estrogen and progesterone and no development of the endometrial lining
Explain negative feedback in menopause
Low estrogen levels causes negative feedback with the goal of trying to increase estrogen. GnRH, LH and FSH levels rise
In the absence of progestins (synthetic progesterone), what does estrogen do to the endometrium?
Causes hyperproliferation, increasing risk of cancer
Compare ethinylestradiol and estradiol
Estradiol is the endogenous estrogen. It is more potent than the modified ethinylestradiol, but not as orally active
Explain use of estrogen in HRT
Exogenous estrogen in HRT is used to induce negative feedback, meaning levels of GnRH, FSH and LH are reduced. This relieves many of the Sx
What is levonorgestrel
Synthetic progesterone
Explain how the pill affects FSH
High levels of estrogen due to the pill induce negative feedback and inhibit the secretion of FSH, meaning no follicle maturation and ovulation occurs
Explain how the pill affects LH
Increased estrogen and progesterone levels inhibit the synthesis of LH due to negative feedback. This means the surge of LH required for ovulation does not occur
Explain the action of progesterone in the pill
Thickens the cervical mucus which helps prevent sperm from getting in to uterus
Why should patients with a history of HT, stroke or DVT use the progestin only pill?
Because estrogen promotes blood clotting
Compare the concentration of levonorgestrel in Levonelle compared to regular pill
Regular = 0.15mg Levonelle = 1.5mg
Explain the MOA of Levonelle
Prevents the LH surge by inducing the negative feedback of progesterone. Only works if taken before this surge occurs
Compare EllaOne to Levonelle
EllaOne inhibits progesterone from binidng to its receptors, which prevents or delays ovulation. Levonelle works by increasing progesterone to induce negative feedback
What is the active ingredient in EllaOne
Ulipristal
What is mifepristone used for?
Pregnancy termination
Explain the MOA of mifepristone
Causes a breakdown of the decidua- the endometrium lining formed in preparation for pregnancy
What other pill needs to be given with mifepristone?
A prostaglandin pill. This induces uterine contractions
Explain the goal of therapy for estrogen dependent cancers
The goal is to either block estrogen synthesis, or block it from binding to its receptor
Which reaction does aromatase catalyse?
The conversion of androgens (like testosterone) into estradiol
Describe the MOA of letrozole or anastrozole
They are competitive antagonists for the androgen binding site on the aromatase enzyme
Name 2 aromatase inhibitors
Letrozole and anastrozole
Define ERE and its action
Estrogen responsive element.
This is the segment of DNA that the estrogen dimer binds to, which causes a conformational change which allows coactivators to bind to DNA and cause gene transcription.
What happens once estrogen passively diffuses into a cell?
It binds to the intracellular receptor. Once bound, the receptor undergoes a conformational change which allows it to form a dimer with another estrogen-bound estrogen receptor. It can then enter the nucleus
What is the drug tamoxifen used for?
Estrogen dependent cancers
Tamoxifen is activated by the liver to form what compound?
4-OH-Tam
Explain the MOA of tamoxifen / 4-OH-TAM
It enters the cell and competes for binding to the estrogen receptor. Once bound, it forms a dimer with another estrogen receptor bound to 4-OH-Tam. The dimer then enters the nucleus, binds to ERE but does not cause a conformational change, meaning no gene transcription occurs
With long term use, what is one serious issue with tamoxifen
Increases the risk of endometrial cancer
Benefits of tamoxifen?
Slows the growth of breast cancer