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Androgens
Testes, ovary and adrenal cortex secrete androgens (= steroid sex hormones)
Testes (​Leydig cells​ of testes) secrete testosterone (which is synthesized from
cholesterol in Leydig cells) under the influence of LH
...

Different degrees of negative feedback inputs alter the secretions rates of FSH and LH
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FOR EXAM​ : know where testosterone comes from (ie
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​ Androstenedione
Testosterone gets metabolised to :
- Androsterone
- Etiocholanolone
→ those are essentially inactive
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Testosterone can get aromatised (by aromatase) to oestrogen
...

DHT and testosterone bind to the ​same​ receptor, but testosterone receptor complex is
less stable
DHT formation allows amplification of the actions of testosterone
...

Dihydrotestosterone
5alpha-reductase converts testosterone to DHT
- Type I 5alpha-reductase​ : scalp and skin
- Type II 5alpha-reductase​ : genital skin, prostate
DHT is required for masculinisation of external genitalia in utero
→ deficiency in 5alpha-reductase : testes develop, but without prostate; external
genitalia resemble those of females (raised as girls until puberty → puberty : they can
decide which sex they want to assume)
XY baby with female genitalia → Clitoris enlarged (penis at 12 syndrome)
At puberty, increased testosterone causes the development of external male genitalia
and secondary sexual characteristics - if the receptors are present
Increased LH and testosterone at puberty
Inadequate metabolism of DHT may cause prostatic hyperplasia (acne, hirsutism
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The tissues need the receptors to respond, otherwise testicular feminisation occurs ie
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​testosterone, nandrolone, oxymetholone​…) are
used for prolonged periods and their continuous use can cause :
- Hypertension and oedema : testosterone and other anabolic steroids such as
nandrolone, oxymetholone have calcium, sodium and water-retaining actions
- Cholestatic jaundice : anabolic steroids (eg
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Abuse of anabolic steroids cause the following :
- Decrease testicular size and sperm count
- Changes in libido, regression of testes with suppression of spermatogenesis
- Increased aggression
- Hepatotoxicity with cholestasis, hepatitis or hepatocellular tumours
- Increase LDL and decrease HDL → vascular disease
- Weight gain
- Acne
Causes and failure to develop normal internal & external genitalia
1
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21-hydroxylase deficiency​ as a common cause of congenital adrenal hyperplasia

You need 21-hydroxylase to produce cortisol and aldosterone
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Androgen resistant/insensitivity syndromes
→ ​mutation in androgen receptor gene reduces sensitivity to androgens
XY male foetus has female external genitalia (but short vaginal length) and retained
testes, but no female internal genitalia (eg
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Testes may be surgically removed and then patient put on oestrogen therapy at puberty
If mild with male type external genitalia, giving high dose testosterone helps to improve
secondary sexual characteristics
GnRH analogues, antagonists and androgens

Synthetic GnRH​ ​(gonadorelin)
Can be given, but administration must be by pump slowly and given intermittently to
avoid desensitisation and down-regulation
GnRH agonist analogues​ ​(Buserelin, Goserelin)
Densitise after an initial surge of LH and FSH release and act as antagonists
Cause reduction in testosterone in the long-term
Useful for prostate and breast cancers, and endometriosis
GnRH antagonists​ ​(Cetrorelix, Ganirelix)
Cause no initial surge in LH and FSH → better
Use of androgens and anti-androgens
- Precocious puberty or delayed puberty : significant deviations from pubertal age
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- Cryptorchidism (retained testes) : 97% of testes descend around birth and 99%
by 1 year
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Inhibition of 5alpha-reductase maintains testosterone levels, which can
result in regrowth of hair
Androgens to treat abnormalities of development of secondary characteristics
→ ​Testosterone​ : used for androgen deficiency, delayed puberty
→ ​Mesterolone​ : useful for male infertility associated with hypogonadism
→ ​Danazol​ : an androgen derivative, but not converted to oestrogen
- Feedback inhibition of pituitary gonadotrophin and GnRH → decreased release
of LH and FSH in both sexes
- Inhibits testicular and ovary function, directly stops ovulation
- Has antioestrogenic and antiprogestogenic effects
Danazol can be used for : gynaecomastia, mastalgia (breast pain), benign fibrocystic
disease (breast tenderness), endometriosis and infertility, menorrhagia
(increased/heavy and prolonged menstrual bleeding)

Uses of androgens, GnRH, gonadotrophins
Hypogonadal syndromes​ : delayed puberty (15-17yrs), testes fail to produce adequate
testosterone in response to LH (​primary​) or where there is a deficiency of pituitary
hormones (FSH/LH)or pituitary dysfunction (​secondary​)
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​Klinefelter’s (XXY) syndrome​ - deficient
negative feedback at hypothalamic-pituitary levels with consequent high levels of LH
and FSH
- Treatment : testosterone (and GH), puberty may take 2 years to reach
completion
→ continuous administration of testosterone can lead to premature closure of epiphyses
of long bones
Secondary​ : deficiency/absence of hypothalamic secretion of GnRH and hence low
levels or absence of pituitary FSH and LH (eg
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​Flutamide​ - competes with testosterone and DHT and
blocks their action → useful for prostate cancer
5a-reductase inhibitor eg
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​Sildenafil​ (active drug in viagra) :
- Release of NO during sexual stimulation
- NO activates guanylate cyclase which releases cGMP from GTP
- cGMP causes the relaxation of smooth muscles lining of blood vessels (inflow of
blood occurs)
- Generally without effect until stimulation begins
Side effects : headache, vasodilation, flushing, decreased BP, disturbances of colour
vision due to inhibition of PDE6 in the retina → can’t take with nitrate drugs
Sometimes, erection won’t go away (priapism) → if you take too much
Sildenafil is a potent and highly selective inhibitor of PDE5 :
- Blocks cGMP hydrolysis by occupying its active site
- Prolongs cGMP-mediated smooth muscle relaxation → erection, but
arousal/stimulation is important in its mode of action



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