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Repro > Pharmacology of androgens > Flashcards

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
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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
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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
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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
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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
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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
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7
Q

What happens when testosterone is aromatised?

A
  • Converted to oestrogen

- DHT however cannot be converted by aromatase to oestrogen

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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
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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
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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
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11
Q

What are the two different types of 5a-reductase?

A
  • Type I - scalp and skin

- Type II - genital skin and prostate

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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
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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
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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
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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
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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
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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
Q

What can Danazol be used for?

A
  • gynaecomastia
  • Breast pain/tenderness
  • Endometriosis and infertility
  • Menorrhagia
26
Q

What are some side effects of danazol?

A
  • 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
Q

What are hypogonadal syndromes?

A
  • 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
Q

Give an example of primary hypogonadism

A
  • 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
Q

Give an example of a secondary hypogondaism

A

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
Q

What is Cyproterone acetate? and what is it used for?

A
  • 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
Q

What is BPH?

A
  • Benign prostatic hypertrophy

- Enlargement of prostate in older men causing urinary obstruction

32
Q

How can BPH be treated?

A
  • 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
Q

What treatments are there for prostate cancer?

A
  • 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
Q

What causes erectile dysfunction?

A
  • Older age, Nerve damage, endocrine disease, depression, therepeutic/recreational drugs, atherosclerosis
  • insufficient blood flow to allow erection
35
Q

Why are androgens assumed to be involved with erectile dysfunction?

A
  • 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
Q

What is the reflex pathway in erection?

A
  • 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
Q

Give an example of a PDE5 inhibitor

A

Sildenafil (viagra)

38
Q

What is PDE5?

A
  • 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
Q

How do PDE5 inhibitors work?

A

Block cGMP hydrolysis by occupying its active site

- Prolongs cGMP-mediated smooth muscle relaxation, allowing erection for longer

40
Q

What are side effects of Sildenafil?

A

Headache, vasodilation, flushing, decreased BP, disturbance of colour vision due to inhibition of PDE6 in the retina
- low incidence of painful erection

41
Q

LOOK AT END OF WORD DOCUMENT FOR SBAS

A

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