Pharmacology of androgens and anti-androgens Flashcards
1
Q
Where are androgens secreted from?
A
- testes, ovary + adrenal cortex secrete androgens - steroid sex hormones
2
Q
The testes (leydig cells of testes) secrete testosterone. What is it synthesised from in Leydig cells?
A
cholesterol
3
Q
Secretions from the adrenal cortex are under the influence from which hormone? Also where in the adrenal cortex are androgens made?
A
- ACTH
- androgens made in zona reticularis
4
Q
What does inhibin B do?
A
- produced by granulosa cells in ovary / sertoli cells in testes
- downregulates FSH synthesis
- inhibits FSH secretion
5
Q
What is FSH important for in males?
A
- sertoli cells
- spermatogenesis
- AMH -> regression of mullerian ducts
- -> inhibin B -> -ve feedback
6
Q
Describe the pathway of synthesis for testosterone
A
cholesterol -> pregnenolone -> progesterone -> androstenedione -> testosterone -> oestrogen
7
Q
Testosterone is converted to DHT in most target cells (by 5-a-reductase), except where?
A
except in muscle
8
Q
What is the difference in binding between testosterone and DHT to the receptor?
A
- DHT + testosterone bind to same receptor
- testosterone-receptor complex less stable
- DHT more potent
- DHT formation allows amplification of actions of testosterone
9
Q
What are downstream effects of testosterone binding to its receptor?
A
- gonadotrophin (LH + FSH) regulation
- initiates + maintains spermatogenesis
- sexual differentiation
- wolffian duct stimulation (internal genitalia)
10
Q
What additional downstream effects does DHT cause by binding to the testosterone receptor?
A
- external virilsation
- sexual maturation at puberty
11
Q
Treatment of what disease makes use of the testosterone mechanism of action pathway?
A
prostate cancer
12
Q
Why is male pattern baldness treated with 5a-reductase inhibitors?
A
DHT promotes hair loss
13
Q
Where is type I 5a-reductase found?
A
scalp + skin
14
Q
Where is type II 5a-reductase found?
A
genital skin + prostate
15
Q
What happens when there is a deficiency in 5a-reductase?
A
- testes develop
- without prostate
- external genitalia resemble those of females
- raised as girls until puberty
- some may adopt male role post-puberty (XY baby w female ext genitalia)
16
Q
What is “penis-at-12-syndrome”?
A
- clitoris enlarges
- at puberty inc testosterone causes development of external male genitalia + secondary sexual characteristics
- if the receptors are present
- inc LH and testosterone levels at puberty
17
Q
What would mutation in type II 5a-reductase lead to?
A
- male pseudohermaphroditisim
- comon in parts of Dominican Republic
- born w primary sex characteristics of one sex but develops secondary sex characteristics that are different from what woud be expected on the basis of the gonadal tissue (ovary or testis)
18
Q
What may inadequate metabolism of DHT cause?
A
- prostatic hyperplasia
- acne, hirsuitism
19
Q
What regulatory effects does testosterone exert?
A
- reduces secretion of GnRH
- inhibits secretion of LH
20
Q
Testosterone acts via sertoli cells to initiate and maintain spermatogenesis. What are the idfferent structures it induces via the Wolffian Duct?
A
- epididymis
- vas deferens
- seminal vesicles
- ejaculatory duct
21
Q
Testosterone induces male secondary sex characteristics. What does it do to oestrogen?
A
opposes action of oestrogen on breast growth
22
Q
What behavioural and physical changes does testosterone induce?
A
- provokes boisterous play
- may enhance sex drive
- aggressive behaviour
- virilisation - deep voice, body hair, muscle gmulk
23
Q
What actions does testosterone have on bone growth?
A
- anabolic
- induces bone growth
- cessation of bone growth
24
Q
What are the effects of testosterone and DHT on secondary characteristics in males compared to females?
A
- height: on avg males are taller than females
- muscularity: males are of greater muscularity, esp shoulder girdle than females
- bone growth: males have stronger bone growth, greater shoulder to pelvic girdle ratio (GH secretion) than females - heavier skulls, larger hands + feet
- deep voice: inc growth of larynx
- pubic hair - continuous with abdominal + chest hair
- prominent subcutaenous veins due to lack of subcutaneous fat
25
In many cases, several androgens (eg testosterone, nandrolone, oxymetholone etc) are used for prolonged periods and their continuous use can cause unwanted effects. What are some unwanted effects of testosterone?
* **hypertension + oedema**: testosterone + other anabolic steroids such as nandrolone, stanozolol have calcium, sodium + water-retaining actions
* **cholestatic jaundice**: anabolic steroids (nandrolone, stanozolol) may lead to liver cancer
* suppression of gonadotrophin release w/ testicular regression + **reduced spermatogenesis**
* virilisation; hirsuitism; male pattern baldness; acne
* premature closure of epiphyses of long bone in boys
* **gynaecomastia** - due to conversion of testosterone to oestrogens by aromatase
26
Why do body builders and athletes take steroids/testosterone?
* large doses may be effective in increasing muscle mass / athletic performance in some individuals
* all anabolic steroids virilise
* attempts to separate the anabolic from virilising effects of anabolic steroids have been unsuccessful
27
What are the effects of (abuse of) anabolic steroids?
* lower **testicular size** + sperm count
* changes in **libido**, regression of testes w/ suppression of **spermatogenesis**
* increased **aggression**
* **hepatotoxicity** w/ cholestasis, hepatitis or hepatocellular tumours
* increased LDL and decrease HDL -\> **vascular disease**
* **weight gain**
* **acne**
stanozolol, nandrolone + other anabolic steroids can be detected in the urine of atheletes abusing these drugs
28
Give an example of synthetic GnRH - how must this be administered?
* gonadorelin
* can be given but administration must be by pump
* and given intermittently to avoid densensitisation + down-regulation
29
Give examples of GnRH agonist analogues and their effects
* buserelin, goserelin
* desensitise after an initial surge of LH and FSH release + act as antagonists
* cause reduction in testosterone in long term
* useful for prostate + breast cancers, and endometriosis
30
Give examples of GnRH antagonists and what they're used for
* cetrorelix
* ganirelix
* cause no initial surge in LH and FSH
* so better used in IVF
31
What is cryptorchidism?
* retained testes
* 97% of testes descend around birth + 99% by 1 yr
* failure of testes to descend can potentially lead to testicular tumour formation + infertility
* drug treatment or surgical remedy
32
In which certain individuals are androgen antagonists used in?
* Sex offenders
* reduce libido to treat hypersexuality
* must get informed consent
* eg. cyprotorone acetate
33
What is mesterolone used for?
male infertility associated w hypogonadism
34
What is Danazol?
* androgen derivative, but not converted to oestrogen
* feedback inhibition on HPG -\> decrease release of LH/FSH in both sexes
* inhibits testicular + ovary function directly -\> stops ovulation
* has antioestrogenic and antiprogestogenic effects
* **used** for gynaecomastia, mastalgia, benign fibrocystic disease, endometriosis + infertility, menorrhagia
35
(primary problem) In chromosomal abnormalities such as Klinefelter's (XXY) syndrome there is deficient -ve feedback at hypothalamic-pituitary levels w/ consequent high levels of LH and FSH. What is the treatment for this?
* treat with testosterone (+ GH); puberty may take 2 years to reach completion
* note that continuous administration of testosterone -\> premature closure of epiphyses of long bones - so it's better to dose for 4-6 months, stop + assess growth to avoid reducing final height
36
What happens in Kallman's syndrome and what is the treatment?
* deficiency/absence of hypothalamic secretion of GnRH + hence low levels or absence of pituitary FSH and LH
* **treatment**: give gonadorelin or LH + FSH - it may take months for their effects on spermatogenesis to develop in post-pubertal patients
37
What is cyproterone acetate and its uses?
* _androgen antagonist_
* treat abnormalities of development of secondary sexual characteristics
* **inhibits peripheral androgen receptors**
* uses:
* precocious puberty in boys
* to suppress initial surge effects of goserelin and buserelin
* acne, hirsuitism, virilisation in women
38
What is benign prostatic hypertrophy and its treatment?
* enlargement of prostate in older men causes urinary obstruction
* **drug treatment:** 5a reductase blocker - stops DHT prod -\> shrinkage of prostate
* **Finasteride has better utility as it inhibits type II 5a-reductase**
* Dutasteride has unclear utility as it inhibits types I + II 5a-reductase
39
Testosterone and DHT stimulate the growth of prostatic cells. What is the drug treatment of prostate cancer?
* cyproterone acetate
* GnRH analogues (goserelin + buserelin)
* GnRH antagonists (cetrorelix + ganirelix)
* oestrogens (ethinyloestradiol + diethylstilbestrol)
* anti-androgens (flutamide)
* 5a-reductase inhibitors
40
For erectile dysfunction, treatment with exogenous androgens may produce clinical improvement in signs of hypogonadism but may not improve sexual function. What drug would be useful for treating erectile dysfunction?
* PDE5 inhibitors (eg. sildenafil) promotes following pathway:
* release of NO during sexual stimulation
* NO activates guanylate cyclase (GC) which releases cGMP from GTP
* cGMP -\> relaxation of sm mucles lining blood vessels
* -\> inflow of blood occurs
* tumescence (erection)
* generally without effect until stimulation begins
41
Side effects of sildenafil?
* headache
* vasodilation
* flushing
* decrease BP
* disturbances of colour vision due to inhibition of PDE6 in retina
* **do NOT take with nitrate drugs**
* incidence of priapism is low
