S4: Pharmacology of Androgens and Anti-Androgens

Question 1

What organs and tissues secrete androgens?

Answer 1

• Organs: Testes, Ovary and Adrenal Cortex. The testes are the primary synthesiser of androgens and it is the leydig cells that synthesis testosterone from cholesterol and secrete it. Other androgens include DHT and androstenedione. Secretions from the adrenal cortex is under the influence of ACTH. Secretions from the gonads are under the influence of FSH and LH which are under the influence of GnRH.
• Adipose tissue does secrete some androgens as well. Thus females do have some levels of androgens albeit much lower than in males.

Question 2

What is the role of inhibin B in the hormonal control of testes?

Answer 2

Sertoli cells release the peptide Inhibin B that acts on the anterior pituitary to reduce FSH release.

Question 3

What enzymes are used for the synthesise testosterone and oestradiol? What can be converted into mineralocorticoids?

Answer 3

• 5-alpha-reductase converts testosterone to DHT.
• Androstenedione and testosterone (androgens) can be converted to estradiol, by being aromatised. This occurs a lot in females and can also occur in males as Sertoli cells possess small amounts of aromatase.
• Progesterone may be converted to the mineralocorticoids. 17 -OH progesterone can be converted to glucocorticoids.

Question 4

Describe mechanism of action of testosterone

Answer 4

• When testosterone reaches its target cell as it is a steroid, it diffuses through and binds to its receptor in the cytosol. This is a nuclear receptor, which is a ligand activated transcription factor.
• Upon binding the complex will travel to the nucleus and cause changes in gene transcription. This causes the effects of testosterone that we see in downregulating the gonadotrophins, in stimulating Sertoli cells to maintain spermatogenesis and in early sexual differentiation by causing growth of Wolffian duct and thus internal male genitalia.

Question 5

Describe mechanism of action of DHT

Answer 5

• Testosterone is converted in most target cells (except in muscle) to dihydrotestosterone (DHT) using the enzyme 5a-reductase.
• DHT and testosterone bind to same receptor, but testosterone-receptor complex is less stable.
• DHT formation allows amplification of the actions of testosterone such as promoting hair loss.
• DHT is required for masculinisation of the external genitalia in utero.

Question 6

What may 5a-reductase inhibitors treat?

Answer 6

• Treatment of prostate cancer to block production of DHT, that is the principle androgen of the prostate.
• Male pattern baldness.

Question 7

What are the two types of 5a-reductase?

Answer 7

• Type I 5α-reductase is found on the scalp and skin.

- Type II 5α-reductase is found on the genital skin and in the prostate.

Question 8

List effects of testosterone in males

Answer 8

• It acts via Sertoli cells to initiate and maintain spermatogenesis.
• It reduces the secretion of GnRH from the hypothalamus.
• Inhibits LH secretion from anterior pituitary.
• In foetal life stimulates growth of Wolffian duct, inducing differentiation of epididymis, vas deferens, seminal vesicles and ejaculatory duct (male internal genitalia).
• Induces the male secondary sexual characteristics and opposes the action of oestrogen on breast growth.

Question 9

Describe effects of testosterone in males and females

Answer 9

• Testosterone provokes boisterous play, may enhance sex drive and aggressive behaviour.
• As for testosterones anabolic effects, it also induces bone growth and then causes cessation of bone growth once adequate length has been reached.

Question 10

Describe effects of testosterone and DHT on male secondary characteristics

Answer 10

• Testosterone and DHT are very important in the development of male secondary sexual characteristics (features that appear at sexual maturity that differentiate the two sexes). This occurs if the receptors are present. There is increased LH and testosterone levels at puberty.
• Testosterone as mentioned stimulates the development of the male internal genitalia (epididymis, vas deferens, seminal vesicles and prostate).
• DHT causes masculinisation of external genitalia in utero, this involves enlargement of penis and prostate at puberty, facial hair, acne and temporal hairline recession.
• Mutation in type II 5α-reductase leads to male pseudohermaphroditism and this is common in parts of Dominican Republic.
• Inadequate metabolism of DHT may cause prostatic hyperplasia; (acne, hirsutism).

Question 11

What happens if testosterone and DHT and their receptors isn’t present in development?

Answer 11

• In females these androgens are absent so the external genitalia develop into their female form.
• These tissues that the androgens are acting on require the testosterone receptors to respond, otherwise testicular feminisation will occur (genetic males appear female).

Question 12

What can cause a failure to develop normal Internal/External Genitalia?

Answer 12

A whole range of things can result in improper development of internal/external genitalia. These can be explained by the mechanism of action of testosterone/DHT.

1. Androgen resistant syndromes.
2. 21-hydroxylase deficiency (type of cytochrome p450) as a common cause of CAH.

Question 13

Types of abnormal Internal/External Genitalia

Answer 13

• Deficiency in 5α-reductase: testes develop, but without prostate; external genitalia resemble those of females (raised as girls until puberty).
• Some may adopt normal male role post-puberty e.g. XY baby with female external genitalia.
• Clitoris enlarges (“penis-at-12-syndrome”).

Question 14

Compare DHT and testosterone on secondary characteristics in males and females

Answer 14

• Height: On average males are taller than females.
• Muscularity: Males are of greater muscularity, especially around the shoulder girdle.
• Bone Growth: Males have stronger bone growth, heavier skull, larger hands and feet.
• Deep voice: Causes growth of larynx resulting in males having deeper voice.
• Pubic hair: In males often continuous with abdominal and chest hair.
• Males also tend to have prominent subcutaneous veins due to the lack of subcutaneous fat. Also hair on the head recedes and baldness often occurs with increased hairiness elsewhere.

Question 15

What can unwanted effects can prolonged and continuous uses of androgens (testosterone, nadrolone, stanoxolol) cause?

Answer 15

• Hypertension and oedema: Testosterone and other anabolic steroids such as nandrolone, stanozolol have calcium, sodium and water retaining actions.
• Cholestatic jaundice: Anabolic steroids (nandrolone, stanozolol) may cause liver cancer.
• Intake of androgens (e.g. anabolic steroids) can lead to suppression of gonadotrophin release due to -ve feedback. This can result in testicular regression and reduced spermatogenesis. There can also be gynacomastia caused due to conversion of testosterone to oestrogen by aromatase.
• Androgens can also cause: virulisation, hirsuitism, male pattern baldness, acne. Virulisation is the development of male physical characteristics (e.g. deep voice, body hair, muscle bulk in a female or precociously in a boy due to excess production of androgens. However virulisation can also simply refer to changes that make a male body different from a female body.
• Sometimes testosterone is used to induce growth but they may cause premature closure of the epiphyses of long bones in boys.
• High androgens for prolonged periods may be drug induced, taken recreationally or may arise pathologically due to endocrine tumours.

Question 16

Anabolic effects of testosterone and steroids

Answer 16

• Anabolic steroids are structurally and functionally similar to testosterone and have androgenic and virulising properties. They are essentially synthetic androgens.
• Anabolic steroids are commonly used by body builders, large doses may be effective in increasing muscle mass/athletic performance in some individuals.
• However all anabolic steroids virilise and attempts to separate the anabolic effects from the virulising effects of anabolic steroids have been unsuccessful.

Question 17

Describe abuse of anabolic steroids effect (similar to unwanted effect of testosterone and androgens).

Answer 17

• Decreased testicular size (regression) and sperm count (decreased spermatogenesis).
• Hepatotoxicity with cholestasis, hepatitis or hepatocellular tumours.
• Increased LDL and decreased HDL levels leading to vascular disease.
• Changes in libido, increased aggression.
• Weight gain and acne.

Question 18

What is the difference between androgenic and anabolic steroid?

Answer 18

The main difference between androgenic and anabolic is that androgenic steroids generate male sex hormone-related activity whereas anabolic steroids increase both muscle mass and the bone mass.
- Testosterone is both in males.

Question 19

Describe Synthetic GnRH

Answer 19

Synthetic GnRH, that is identical to native GnRH (also called gonadorelin) can be given to people, but its administration must be via a pump and given in a pulsatile manner to avoid desensitisation and down-regulation. This is because continuous GnRH tends to desensitize the pituitary.

Question 20

Describe GnRH analogues

Answer 20

• GnRH agonist analogues (e.g. goserelin, buserelin) these cause an initial surge of LH/FSH but then stay bound to their receptors on gonadotrophs causing desensitisation. Thus they down-regulate gonadotrophin release.
  In the long-term therefore they decrease testosterone levels. They are very useful for prostate and breast cancers, as well as endometriosis.
• GnRH antagonists analogues (cetrorelix, ganirelix) cause no initial surge in LH/FSH, they just go and block the receptor with no efficacy. This makes it better in things like IVF where we want to control LH secretion.

Question 21

What are androgens?

Answer 21

• An androgen is any natural or synthetic steroid hormone that regulates the development and maintenance of male characteristics in vertebrates by binding to androgen receptors.
• Androgens increase in both boys and girls during puberty.
• The major androgen in males is testosterone. Dihydrotestosterone (DHT) and androstenedione are of equal importance in male development.
• Although androgens are commonly thought of only as male sex hormones, females also have them, but at lower levels: they function in libido and sexual arousal.
• Also, androgens are the precursors to estrogens in both men and women.

Question 22

Uses of androgens and anti-androgens

Answer 22

• Precocious puberty, premature sexual development (e.g. testotoxicosis) or delayed puberty. Significant deviations from normal pubertal age onset (occurring too early or too late) must be investigated and treated. We can use androgens/anti-androgens to treat this. Give testosterone to help treat androgen deficiency, delayed puberty. Give Mesterolone (methyltesosterone) to help treat male infertility associated with hypogonadism.
• Cryptorchidism (undescended testes). In 97% of cases of cryptorchidism the testes end up descending around birth, with 99% by 1 year. Failure of testes to descend can potentially lead to testicular tumour formation and infertility. To prevent this, there is the option of drug treatment or surgical options.
• Initiate spermatogenesis. If spermatogenesis hasn’t occurred spontaneously at pubertal age, we can use androgens to help with this.
• Androgen-insensitivity syndrome. AIS impairs the masculinsation of the genitalia in XY males and also means secondary sexual characteristics fail to develop at puberty. If someone has complete insensitivity this will occur but in partial insensitivity we may consider giving DHT to help the individual develop male secondary sexual characteristics. DHT doesn’t undergo aromatisation like testosterone.
• Premature baldness. DHT is implicated in baldness, inhibition of 5α-reductase maintains testosterone levels that can result in regrowth of hair.

Question 23

Describe Androgen Antagonists to Treat Abnormalities of Secondary Sexual Characteristics

Answer 23

• Treat secondary sexual characteristics. Danazol is an androgen derivative but not converted to oestrogen. It decreases release of LH/FSH in both sexes by feedback inhibition. It also has antioestrogenic and antiprogestogenic effects so inhibits testiscular and ovary function direction (stops ovulation). It is very useful for gynaecomastia, mastalgia (breast pain) and benign fibrocystic disease (causes breast tenderness).
• Mesterolone (methyltestosterone): male infertility associated with hypogonadism.
• Cyproterone acetate: inhibits peripheral androgen receptors. It is used for precocious puberty in boys, to suppress initial surge effects of goserelin and buserelin, acne, hirsutism and virilisation in women.

Question 24

Describe Hypogonadal Syndromes

Answer 24

• Hypogonadal syndromes often results in delayed puberty (15-17yrs), caused by the testes failing to produce adequate testosterone in response to LH (this is primary (hypergonadotrophic) hypogonadism) or where there is a deficiency of pituitary hormones (FSH/LH) or pituitary dysfunction (secondary (hypogonadotrophic) hypogonadism).
• Primary Hypogonadism is caused by chromosomal abnormalities (e.g. Kinefelter’s Syndrome, 47XXY). Leads to low levels of testosterone resulting in low -ve feedback to hypothalamus/pituitary, leading to high FSH/LH levels; congenital testicular damage.
• Secondary Hypogonadism is caused by a deficiency at the hypothalamic/pituitary level, so there will be low levels of GnRH and also low levels of FSH/LH (e.g. Kallman’s syndrome).

Question 25

How is primary hypogonadism treated?

Answer 25

We give testosterone (and growth hormone), then puberty may take two years to reach completion. However do note that continuous administration of testosterone may cause premature closure of the epiphyses of long bones. Hence it is regarded as better to give testosterone for 4-6 months then stop and assess to avoid reducing the child’s final height.

Question 26

How is secondary hypogonadism treated?

Answer 26

To treat this we give gonadorelin (synthetic GnRH) or give LH and FSH. It may take months for their effects on spermatogenesis to develop in post-pubertal patients

Question 27

How can an enlarged prostate cause cancer?

Answer 27

An enlarged prostate can lead on to prostate cancer. Testosterone and DHT do stimulate the growth of prostatic cells this is largely to blame.

Question 28

Describe Treatment of Sex-Hormone Dependent Cancers e.g. prostatic cancer

Answer 28

• Cyproterone acetate: Inhibits peripheral androgen receptors, this can therefore stop the effects of testosterone and DHT on prostatic cells and be used to prevent prostatic hyperplasia or prostatic cancer.
• GnRH agonist analogues (goserelin and buserelin): Can be given to suppress Leydig cell function due to desensitising GnRH receptors, leading to down-regulating of LH/FSH. This can be used to treat and manage prostatic cancer as we are reducing the androgens from stimulating the cancerous cells.
• GnRH antagonist analogues (cetrorelix and ganirelix): work by blocking release of LH/FSH, causing regression of Leydig cells reducing testosterone.
• Oestrogens (ethinyloestradiol and diethylstilbesterol): These reduce androgen dependent prostate cancer (local and metastatic). The latter is more debated as a treatment.
• Anti-androgens: An example is flutamide, that competes (competitive antagonist) with testosterone and DHT for their receptor and thus blocks their action. It is useful for prostatic cancer.
• 5α-reductase inhibitors: Examples include finasteride, dutasteride. These stop production of DHT, that suppress prostate cancer cells. They also inhibit androgen-dependent prostatic cancers.