Renal 2 Pharmacology 2 Flashcards
Male Hypothalamic-Pituitary-Gonadal Axis
- release/secretion of hypothalamic and anterior pituitary hormone is pulsatile
- GnRH in hypothalamus stimulates pituitary to Release FSH and LH which stimulates sertoli cells and leydig cells
Anterior pituitary LH stimulates
Leydig cells testosterone biosynthesis and secretion
Testosterone + pituitary FSH stimulates
sertoli cells–>sperm maturation
Sperm maturation in Sertoli cells
- depends on FSH and testosterone, but also on precisely controlled estrogen levels
- Aromatase in sertoli cells uses testosterone to make estradiol
GnRH (LHRH)
- released by hypothalamus
- stimulates anterior pituitary to produce and secrete FSH and LH
FSH
- released by anterior pituitary
- stimulates sertoli cells and sperm maturation
LH
- released by anterior pituitary
- stimulates testosterone hormone synthesis and secretion by leydig cells
Continual high concentrations of LH result in
reduced secretion of testosterone due to down regulation of LH receptors in Leydig cells
Androgens, testosterone
- released by adrenals and testes
- stimulates Sertoli cells (other cells responsive to androgens, e.g. prostate epithelium)
Estrogens, estradiol
- released by adrenals and testes
- formed by aromatase catalyzed conversions of androgens to estrogens
Aromatase
-converts androstenedione to estrone and testosterone to estradiol
Synthesis of dihydrotestosterone
- androstenedione converted to testosterone by 17B-hydroxylase
- testosterone converted to DHT by 5a-reductase
Synthesis of estradiol in males
-estrone converted to estradiol by 17B-hydroxylase or testosterone converted to estradiol by aromatase
High concentrations of testosterone in the circulation
-inhibit the release of GnRH, FSH, and LH, by negative feedback control
When circulating concentrations of testosterone are low,
-higher levels of GNRH, FSH, and LH are released
Testicular levels of testosterone are
100-500x greater than those found in blood
An in crease in PSA level over time may indicate
prostate cancer
Androgens stimulate
prostate cancer cells to grow
- lowering androgen levels or stopping androgens from signaling in prostate cancer cells often makes tumors shrink or grow more slowly for a time.
- Androgen deprivation therapy alone does not cure prostate cancer
GnRH antagonist
Degarelix
GnRH agonist
Leuprolide
-Nafarelin (nasal)
Natural replacement of GnRH
Gonadorelin
Degarelix
- GnRH antagonist (blocks receptor on pituitary)
- reduces testosterone levels below detectable levels quickly (2-3 days)
- used to treat advanced prostate cancer
- given subcutaneously as a monthly injection
- counters reflex to try to produce more T because receptor is blocked
Degarelix Side effects
-problems at injection site (pain, redness, swelling) and increased levels of liver enzymes on lab tests
Continuous administration fo a GnRH agonist (Leuprolide)
-eventually desensitizes receptors for GnRH and LH after an initial ‘surge’ in androgen biosynthesis
Leuprolide
- causes circulating testosterone to surge initially, then drop later due to desensitization of GnRH and LH receptors
- cause testicles to shrink over time (chemical castration)
- other GnRH agonists include goserelin, triptorelin, and histrelin
How to manage testosterone flare that coincides with administration of GnRH receptor agonists
-concurrent administration of androgen receptor antagonists
Androgen receptor antagonists include
Bicalutamide
Flutamide
Nilutamide
Bicalutamide
- used with leuprolide or other GnRH agonists
- favored
- 1x a day
Flutamide
used with GnRH/LHRH agonists
Nilutamide
-used in combination with surgical castration
Non-steroidal (anti-androgens)–androgen receptor antagonists
- compete with testosterone and DHT for receptor
- No AR dimerization, transport
- No transcription
- suppress effects of residual adrenal testosterone, or testosterone flare from GnRH agonists
- palliative for metastatic prostate cancer: reduced bone pain, better performance status, increased sense of well being
GnRH antagonists and agonists halt
-androgen biosynthesis by testicles, but not other cells in the body
Abiraterone
- blockers enzyme CYP17, lowering tumor production of androgens
- CYP17 in testicular, adrenal and prostatic tumor tissues is required for androgen biosynthesis
- approved for advanced prostate cancer that is still growing despite low testosterone levels from a GnRH antagonist or agonists
- need to continue treatment with GnRH agonist or antagonist
- used with prednisone or other corticoids
CYP7 catalyzes 2 sequential reactions
- conversion of pregnenolone and progesterone to their 17a-hydroxy derivatives
- formation of DHE and androstenedione by C17,20 lyase activity
- these androgens are precursors of testosterone
- also deranges corticoid production by adrenals
Side effects of Abiraterone
- derives from its inhibition of cortisol biosynthesis and enhancement of aldosterone biosynthesis
- to avoid these problems, it is administered with prednisone or another comparable corticoid
Ketoconazole
- In high doses, blocks production of androgens, similarly to abiraterone
- most often used to treat men recently diagnosed with advanced prostate cancer
- lowers testosterone levels promptly
- can be tried if other forms of androgen deprivation therapy fail
- also blocks production of cortisol, thus, patients treated with this need to take a corticosteroid to prevent the side effects due to low cortisol levels
- has signifiant hepatotoxicity!
SAR inhibitors in prostate cancer
-cause fewer tumors, but more mutations and such that allow more high grade (malignant) tumors
Male Infertility can be treated with
human chorionic gonadotrophin (hCG)
Secondary hypogonadism is associated with
- decreased secretions of the gonadotropins, LH and FSH, causing decreased testosterone secretion and sperm production
- testosterone replacement alone will not restore spermatogenesis
- testosterone secretion virtually always increases to normal after replacement of LH, and sperm production more often than not increases after replacement of LH alone or LH plus FSH
HCG
- LH analog
- heterodimeric protein with an alpha subunit identical to LH and FSH, and a unique B subunit
- has the biologic activity of LH but a longer half-life in the circulation
- Stimulates Leydig cells to synthesize and secrete testosterone
- hCG alone may suffice for stimulation of spermatogenesis
- FSH alone is not effective
- considerably less expensive than exogenous FSH preparations
Secondary Hypogonadism from taking exogenous androgens
- anabolic steroids
- including androstenedione, testosterone overexposure
- not pulsatile
- infertility, potential distortion of estrogen synthesis
- excess testosterone causes negative feedback
- can cause excess estradiol because excess testosterone converted to estradiol by aromatase
In the setting of secondary hypogonadism and infertility due to abuse or misuse of anabolic steroids,
- aromatase and estrogen receptors can add to the problem, thus drugs that modulate aromatase and estrogen receptors can sometimes have important uses
- use aromatase inhibitors or SERMS to hide the fact they are using exogenous androgens because these block conversion to estradiol
Selective estrogen receptor modulator (SERM)
-Clomiphene
Aromatase inhibitors
- anastrazole
- letrazole
Gonadal testosterone production is regulated by
a feedback loop which senses testosterone, other androgens, and also estrogen levels
During an anabolic steroid cycle,
- high androgen levels suppress the HPG axis
- for a few weeks this is tolerable, but extended anabolic steroid exposure can cause testicular atrophy
- HCG injection to limit typically fails after extended anabolic steroid use
Clomiphene
- SERM used for enhanced recovery of testosterone production after anabolic steroid cycles
- occupies the binding sites of estrogen receptors of cells, without activating them
- estradiol antagonist
- thus, it ‘tricks’ the hypothalamus to conclude that estrogen levels are low
- if androgen levels are not elevated, as indeed they should not be after an anabolic steroid cycle, the hypothalamus is then stimulated to produce LHRH.
- this will act to increase LH and restart natural testosterone production
- long half life–thus a loading dose is necessary for initial dose
In the presence of clomiphene, the body senses
low levels of estrogen, and 17-hydroxyprogesterone, androstenedione, and testosterone are up-regulated
- because of these hormone-receptor interactions, all aromatase inhibitors, including but not limited to, anastrozole, letrozole, exemestane, are banned substances in athletic competitors.
- selective estrogen receptor modulators, including but not raloxifine, tamoxifen and toremifene, clomiphene and the anti-estrogenic substances are also banned–but widely used
