Pharmacology Infertility and Treatments

Secondary hypogonadism:

a pre-testicular infertility factor that causes low FSH and low LH, causing low testosterone and impaired spermatogenesis -caused by: obesity, alcohol, stress

Letrozole MOA:

aromatase inhibitor----Raises FSH -inhibits the aromatase enzyme, which converts androgen precursors into estrogens. By inhibiting the aromatase enzyme, letrozole reduces estrogen levels. decreasing feedback suppression of FSH and LH release, so FSH and LH levels raise, promoting follicle development and ovulation similar to clomiphene, raises FSH levels by preventing estradiol-mediated feedback inhibition of FSH release at the hypothalamus and pituitary

Why is letrozole preferred over clomiphene?

because it clears the body quicker (estrogen levels must be retained for ovulatory cycle)

Post-testicular factors for male infertility are defined as:

factors that affect the ability of sperm to travel from the site of production (testicle) to its leaving the body in the ejaculate

Pre-testicular factors for male infertility are defined as:

factors that affect the normal hormonal regulation of the testes -pre-testicular factors are usually effects at the pituitary

Increasing cGMP levels....

increase the length of an erection

Ovarian Induction methods tend to lead to....

multiple births (twins) -Clomiphene -Letrozole -Gonadotropin FSH especially, leads to triplets

Drugs that treat female infertility work to improve...

ovulatory dysfunction

Testicular factors for male infertility are defined as:

problems with the production and maturation of normal sperm are the most common cause of male infertility (ex: sperm abnormalities)

Clomiphene Citrate MOA

selective estrogen receptor modulator -antagonist on estrogen receptor -decreased estrogen, increases GnRH and thus FSH and LH levels -works on the hypothalamus, blocking the negative feedback effect of circulating endogenous estradiol (which stops ovulation) -this leads to increased hypothalamic GnRH pulse frequency, increased serum concentrations of FSH and LH, that in turn stimulates follicle development in the ovary

PDE5 inhibitors MOA:

to get an erection cGMP needs to be stimulated to relax smooth muscles in the penis to allow it to fill with blood -PDE5 inhibitors stop PDE5 from breaking down cGMP and terminating the erection. PDE5 inhibitor drugs increase cGMP levels and prolong the erection. -they mimic cGMP and competitively bind to PDE5 to prevent cGMP from binding and getting degraded

Bromocriptine and Cabergoline use:

treatment of hyperprolactinemia (decrease prolactin secretion) -hyperprolactinemia (high prolactin) suppresses GnRH secretion (as well as dopamine secretion) which in turn decreases FSH and LH from the pituitary, therefore disrupting the ovulatory cycles

The pituitary gland secretes _____ and _____ which impacts fertility:

FSH and LH

Follicle-Stimulating Hormone (FSH) MOA:

Gonadotropin ovarian stimulant -FSH stimulates development of follicles in the ovary -Human recombinant FSH is used as the drug

Chorionic Gonadotropin MOA:

LH activity -Human Chorionic Gonadotropin (hCG) is a glycoprotein hormone with activity like LH -hCG binds to the LH receptor and when given for fertility treatment, hCG mimics the LH surge

How do women test if they are ovulating?

LH appears in the urine about 12hr before surge -urine-based ovulatory test strips detect LH, based on immune detection after chromatography -test zone: detects LH antibodies -control zone: detects all antibodies

What triggers ovulation?

LH surge -ovulation occurs 24-36 hours after the surge

Sildenafil (Viagara), tadalafil (Cialis), and vardenafil (Levitra) are...

PDE5 inhibitors

Erectile Dysfunction therapies:

Phosphodiesterase type 5 inhibitors (PDE5 inhibitors)

Medications that can cause secondary hypogonadism:

-anabolic steroids: decrease FSH, LH, and testosterone -chronic treatment with glucocorticoids: these repress GnRH secretion -Continuous opioid administration: reduces FSH and LH release -------effect pituitary function

Medications, lifestyle, and environmental causes of testicular infertility:

-antineoplastic agents (impact spermatogenesis) -SSRI antidepressants (ex: sertraline (Zoloft) which is the most highly prescribed psychiatric drug in 2018): these drugs decrease libido, sperm quality, and impair ejaculation -trauma, mumps virus, and cigarette/marijuana smoking impair male fertility

How do the mechanism of clomiphene and letrozole overlap?

-clomiphene blocks the estrogen receptor at the hypothalamus and pituitary -letrozole prevents estradiol synthesis by inhibiting the enzyme aromatase, so there is no feedback inhibition Both medications raise FSH levels by preventing feedback inhibition by estrogen at the pituitary.

Why is purified hCG and synthetic recombinant hCG used instead of LH itself?

due to lifetime serum in the tube -hCG has a half-life of 24 hours, which LH only 20 mins

What drugs may cause male infertility?

-anabolic steroids -glucocorticoids -SSRI antidepressants (sertraline---Zoloft)

Bromocriptine and Cabergoline MOA:

bromocriptine and cabergoline are dopamine (D2R) receptor agonists and act like dopamine to inhibit prolactin release

Drugs for Ovulation Induction:

-Bromocriptine/cabergoline (suppress prolactin) -Clomiphene citrate -Letrozole -Follicle-stimulating hormone (FSH) -Chorionic gonadotropin (LH activity)

Post-testicular male infertility can be caused by:

-Cystic fibrosis: CF is associated with congenital absence of or block of the vas deferens -Infection or trauma that causes scarring and ductal blocking -Erectile dysfunction