Pharmacology of androgens Flashcards
1
Q
Where are androgens produced?
A
- testes, ovary and adrenal cortex secrete androgens - steroid sex hormones
- Testes (leydig cells) secrete testosterone, synthesised by cholesterol
- Secretions from the adrenal cortex is under the influence of ACTH - zona reticularis is site of production
2
Q
What is the HPG axis?
A
- Hypothalamic-gonadal axis
- GnRH released from the hypothalamuscauses the release of FSH and LH (gonadotrophins) from gonadotrophs in the anterior pituitary
- FSH acts on Sertoli cells, causing spermatogenesis, AMH release (regression of mullerian ducts) and inhibin B release.
- LH acts on Leydig cells, causing testosterone release, which acts on Sertoli cells, and is converted to DHT.
- FSH and LH are under the negative control of oestrogen and testosterone
- FSH and LH act synergisically
3
Q
What are the effects of FSH in males and females?
A
- Stimulates the growth and recruitment of immature ovarian follicles in the ovary in females
- In males in initiates and promotes spermatogenesis
4
Q
What are the effects of LH in females and males?
A
- Females, LH triggers ovulation and the development of a CL (temporary structure that secretes oestrogen and progesterone)
- Males, it stimulates the production of testosterone by Leydig cells
5
Q
How is FSH and LH release controlled?
A
- Controlled by the size and frequency of GnRH pulses, as well as by feedback from androgens, oestrogens and by factors released by sertoli cells.
- It is thought that low-frequency GnRH pulses = FSH release, a high frequency pulse = LH release
6
Q
What is inhibin B?
A
- Produced by granulosa cells in the ovary
- Suppresses synthesis and secretion of the FSH
- Probably produced in a specific pattern in response to gonadotrophin stimulation
- May play an important role in the regulation of the HPG axis during childhood and puberty
- Downregulates FSH synthesis and its secretion
7
Q
What happens when testosterone is aromatised?
A
- Converted to oestrogen
- DHT however cannot be converted by aromatase to oestrogen
8
Q
What is the mechanism of action of testosterone and DHT?
A
- Testosterone is converted in most target cells (except muscle) to DHT
- DHT and testosterone bind to the same receptor, however DHT has much higher avidity and so is 10x more potent - amplification of the actions of testosterone
- Nuclear receptor
- Once it binds, it can bind to the responsive element on DNA
9
Q
What are the effects of testosterone?
A
- Gonadotrophin and GnRH regulation
- Initiates and maintains spermatogenesis via sertoli cells
- Induces the differentiation of Wolffian duct structures (epididymis, VD, seminal vesicles, ejaculatory duct)
- Induces male secondary sex characteristics (deep voice, body hair, muscle bulk) - opposes action of oestrogen on breast growth
- Initially promotes bone growth by GH secretion, then subsequently stops growth by closing the epiphyseal growth plates
10
Q
What are the effects of DHT?
A
- External virilisation - enlargement of penis and prostate at puberty
- Sexual maturation at puberty - facial hair, acne, temporal hairline recession (in older age)
- Should be absent in females, so external genitalia develop into female form
11
Q
What are the two different types of 5a-reductase?
A
- Type I - scalp and skin
- Type II - genital skin and prostate
12
Q
What happens if there is a deficiency in 5a-reductase?
A
- Testes develop, but without a prostate
- External genitalia resemble those of a female (raised as girls until puberty)
- Mutation in type II causes male pseudohermaphroditism
13
Q
What is the mechanism of action of steroid hormones?
A
- Most hydrophobic steroids are bound to plasma protein carriers. Only unbound ones can diffuse into the target cell
- Steroid hormones are in the cytoplasm or nucleus
- The receptor-hormone complex binds to DNA and activates or represses one or more genes
- Activated genes create new mRNA that moves back to the cytoplasm
- Translation produces new proteins for cell processes
14
Q
Name some unwanted effects of testosterone/anabolic steroids
A
- Hypertension and oedema - calcium, sodium, water-retaining actions
- suppression of gonadotrophin release with testicular regression and reduced spermatogenesis
- Virilisation, hirsutism, acne, male pattern baldness
- Premature closure of long bone epiphyses in boys
- Gynaecomastia - conversion of testosterone to oestrogens by aromatase
15
Q
What can happen to men who use anabolic steroids long term?
A
- decreased testicular size and sperm count
- Changes in libido
- Increased aggression
- Hepatotoxicity with cholestasis, hepatitis or hepatocellular tumours
- increased LDL, decreased HDL, leading to vascular diseases
- weight gain
- acne
16
Q
What are two causes of a failure to develop normal internal and external genitalia?
A
- Androgen insensitivity syndromes - androgens are present, but receptors arent
- Congenital adrenal hyperplasia - 21-Hydroxylase deficiency
17
Q
What are androgen insensitivity syndromes?
A
- A mutation in androgen receptor gene causes androgen insensitivity
- XY male foetus will have female external genitalia and retained testes, but no female internal genitalia
18
Q
What treatments are there for AIS?
A
- Surgical removal of testes and then oestrogen therapy, if left can become malignant
- If mild with male-type external genitalia, give high dose testosterone to improve secondary characteristics
- Assign patient with gender they feel most comfortable with - will need hormone therapy dependent on which sex
19
Q
What is congenital adrenal hyperplasia?
A
- In the adrenal gland, cholesterol is converted to different androgens/oestrogens via various enzymes
- A deficiency in 21-hydroxylase leads to low levels of aldosterone and cortisol
- Other substances that don’t need the defectove enzyme is produced in excess, such as tesosterone
- Girls with have ambiguous genitalia and severe puberty
- Boys will have premature puberty - deep voice, enlarged penis, small testes, pubic and axillary hair will appear early
20
Q
Give an example of a synthetic GnRH
A
Gonadorelin - must be given intermittently to avoid desensitisation and down-regulation
21
Q
Give 2 examples of GnRh agonists
A
- Buserelin, Goserelin
- Desensitise after initial LH/FSH surge and act as antagonists
- cause reduction in testosterone in long term
- Useful for prostate and breast cancers and endometriosis
22
Q
Give 2 examples of GnRH antagonists
A
- Cetrorelix, Ganirelix
- Cause no initial surge in LH/FSH
- Used in IVF
23
Q
What are some uses of androgens/anti-androgens/
A
- Treating precocious/ delayed puberty
- Treating cryptorchidism
- Initiating spermatogenesis
- treating AIS
- Premature baldness - testosterone promotes hair growth, DHT is implicated in baldness
- Sex offenders - androgen antagonists to reduce libido
24
Q
What is Danazol?
A
- An androgen derivative, but not converted to oestrogen
- Feedback inhibition GnRH, reducing LH/FSH
- Inhibits testicular and ovarian function - stops ovulation
- Has antioestrogenic and antiprogesteronic effects
25
What can Danazol be used for?
- gynaecomastia
- Breast pain/tenderness
- Endometriosis and infertility
- Menorrhagia
26
What are some side effects of danazol?
- Acne, Oily skin, Deepening of voice, hirsutism, hair loss, vaginal dryness, amenorrhoea, hot flushes, mood swings, fluid retention, weight gain, liver cancer, breast getting smaller
27
What are hypogonadal syndromes?
- delayed piberty, testes fail to produce adequate testosterone in response to LH (primary) or when there is deficiency of pituitary hormones (LH/FSH) or pituitary dysfunction (secondary)
28
Give an example of primary hypogonadism
- Klinefelters (XXY)
- deficient negative feedback at Hypothalamus and pituitary, therefore high levels of FSH and LH
- Treat using testosterone and GH
- Continuous administration of testosterone leads to premature closure of long bone epiphyses, so low dose for short period.
29
Give an example of a secondary hypogondaism
Kallmans syndrome
- deficiency/absence of hypothalamic secretion of GnRH and hence low FSH/LH levels
- treatment is to give gonadorelin or LH and FSH - may take months for their effect on spermatogenesis to develop in post-pubertal patients
30
What is Cyproterone acetate? and what is it used for?
- inhibits peripheral androgen receptors
- Used for precocious puberty in boys, to suppress initial surge effects of goserelin and buserelin and in acne, hirsutism and virilisation in women
31
What is BPH?
- Benign prostatic hypertrophy
| - Enlargement of prostate in older men causing urinary obstruction
32
How can BPH be treated?
- 5a-reductase blocker - inhibit conversion of testosterone to DHT, shrinks prostate
- Finasteride has better utility as it inhibits type II 5a-reductase
- Dutasteride has unclear utility as it inhibits types I and II 5a-reductase
33
What treatments are there for prostate cancer?
- Cyproterone acetate - inhibits peripherla androgen receptors
- GnRH analogues - continuously given to suppress leydig cell function
- GnRH antagonists - block release of LH and FSH, causing regression of Leydig cells
- Oestrogens - decrease androgen-dependent prostate cancer
- Anti-androgens - compete with testosterone and DHT blocking their action
- 5-a-reductase inhibitors - suppresses prostate cancer cells
34
What causes erectile dysfunction?
- Older age, Nerve damage, endocrine disease, depression, therepeutic/recreational drugs, atherosclerosis
- insufficient blood flow to allow erection
35
Why are androgens assumed to be involved with erectile dysfunction?
- there is a decrease in serum testosterone with age (however doesnt always lead to ED)
- Castration causes a decline in sexual function
- erectile function is probably androgen-dependent
36
What is the reflex pathway in erection?
- Thoughts, emotions, smell and sight trigger CNS
- Input from penis mechanoreceptors
- Both cause increased activity of NO releasing parasymp neurons and reduce activity of symp neurons
- NO released, causing dilation of penis
- Compression of veins keeps erection
37
Give an example of a PDE5 inhibitor
Sildenafil (viagra)
38
What is PDE5?
- sexual stimulation releases NO
- NO activates guanylyl cyclase, producing cGMP
- This causes relaxation of smooth muscles lining the blood vessels
- PDE5 hydrolyses cGMP to GMP
- reduces cGMP and so causes loss of erection
39
How do PDE5 inhibitors work?
Block cGMP hydrolysis by occupying its active site
| - Prolongs cGMP-mediated smooth muscle relaxation, allowing erection for longer
40
What are side effects of Sildenafil?
Headache, vasodilation, flushing, decreased BP, disturbance of colour vision due to inhibition of PDE6 in the retina
- low incidence of painful erection
41
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