24-03-23 - Drugs affecting reproductive function

Question 1

Learning outcomes

Answer 1

• Summarise the sources and effects of estrogens
• Identify the clinical uses of estrogens and anti-estrogens
• Describe the main effects of progestogens
• Summarise the clinical uses of progestins and anti-progestins.
• Explain the drugs used for contraception and the mode of action of these drugs.
• Identify the changes which occur after the menopause.
• Summarise the different types of HRT and know the major risks of the use of HRT regimens
• Summarise the effects of androgens and anabolic steroids
• Summarise the effects of gonadotrophin-releasing hormone analogues and gonadotropins

Question 2

Where are oestrogens synthesised?

How many endogenous oestrogens are there in the body?

Which is the most potent?

What is it secreted by?

Answer 2

• Oestrogens are synthesised by the ovary and the placenta and in small amounts in the adrenal cortex and testis.
• Oestradiol is the most potent and principal oestrogen secreted by the ovary.

Question 3

What is the main mechanism of action for oestrogens?

How can some oestrogen effects be initiated?

What are the effects of oestrogen dependent on?

What is the role of oestrogens in primary hypogonadism?

How can oestrogen be used in those with amenorrhea?

When are oestrogens given in relation to menopause?

Answer 3

• Main mechanism of action involves interaction with nuclear receptors (ERα and ERβ) to regulate gene transcription.
• Some oestrogen effects (rapid vascular actions) are initiated by interaction with membrane receptors (e.g. GPER)
• The effects of oestrogen depend on the state of sexual maturity
• In adults with amenorrhea, oestrogens can be given cyclically with progestogen, so they induce an artificial menstrual cycle
• Oestrogens can be given at or after the menopause, as they prevent menopausal symptoms and protect against bone loss but increase coagulability of blood and increase risk of thromboembolism

Question 4

What are 6 Therapeutic uses of oestrogens?

Answer 4

• 6 Therapeutic uses of oestrogens:

1) Replacement therapy in primary ovarian failure (Turner syndrome) to promote sexual maturation.

2) Replacement therapy for menopausal symptoms such as flushing, vaginal dryness and osteoporosis.

3) For the same reason they can be offered after gonadectomy

4) In contraception, they are used singly or in combination with progestogens.

5) Prostate and breast cancer.

6) When administered to males they cause feminisation.

Question 5

What are the various preparations of oestrogenic medication?

What kind of oestrogens do they include?

Where are they well absorbed?

What do oestrogens ind to in the blood?

What form are active oestrogens active in?

What are 4 side effects of oestrogens?

Answer 5

• There are many preparations for oestrogenic medications (oral, transdermal, intramuscular, implantable and topical)
• They include natural (e.g. estradiol, estriol) and synthetic (e.g mestranol, ethinylestradiol, diethylstilbestrol) oestrogens.
• They are well absorbed from the gut, across the skin and mucous membranes
• In the blood, oestrogens are bound to albumin and to a sex hormone-binding globulin (active estrogens are in the unbound state).
• 4 side effects of oestrogens:
  1) Breast tenderness
  2) Nausea
  3) Vomiting
  4) Increased risk of thromboembolism

Question 6

What are SERMs?

What are 3 examples of SERMs?

What is each one used for?

Answer 6

• Competitive antagonists or partial agonists of oestrogens are called selective oestrogen receptor modulators (SERMs).
• 3 examples of SERMs:

1) Tamoxifen is one such drug
* Used in oestrogen-dependent breast cancer (anti-oestrogenic action on mammary tissue).

2) Raloxifene
* Used to treat post-menopausal osteoporosis (antiestrogenic effects on breast and uterus but oestrogenic action on bone).

3) Clomiphene
* A pure estrogen antagonist at the hypothalamus and pituitary - acts to block negative feedback which leads to increased gonadotropin secretion, increased E2 and ovulation
* Used to treat infertility

Question 7

Progestogens.

Where and when is progesterone secreted?

What receptors does it act on?

How do oestrogen/progestogen affect the synthesis of each other’s receptors?

Why is progesterone not used therapeutically?

What is used instead?

What are 2 examples of natural progesterone derivatives?

What are 2 examples of testosterone derivatives?

What are 2 examples of newer progestogens?

Why might they be used instead of testosterone derivatives?

Answer 7

• Progestogens
• Progesterone is secreted by the corpus luteum late in the menstrual cycle and by the placenta during pregnancy.
• Progesterone acts on the progesterone receptor (PR) to regulate gene transcription in target tissues.
• Oestrogen stimulates synthesis of PR and progesterone inhibits the synthesis of oestrogen receptors.
• Progesterone is not used therapeutically due to rapid clearance by the liver
• Instead, synthetic derivatives are used – called progestins
• 2 examples of natural progesterone derivatives:
  1) Medroxyprogesterone
  2) Hydroxyprogesterone
• 2 examples of testosterone derivatives:
  1) Norethisterone
  2) Ethynodiol
• 2 examples of newer progestogens:
  1) Desogestrel
  2) Gestodene
• The newer progestogens may be used instead of the testosterone derivatives, as they have less androgenic activity

Question 8

What are 3 therapeutic uses of progestogens?

Answer 8

• 3 therapeutic uses of progestogens:

1) Oral contraceptive pill alone or in combination with oestrogen

2) Used as progesterone only injectable or implantable contraception or part of an intrauterine contraceptive.

3) Combined with oestrogen for oestrogen replacement therapy in women, with an intact uterus, to prevent:
* Endometrial hyperplasia
* Carcinoma
* Endometriosis

Question 9

What are 6 adverse effects of progestogens?

What can the anti-progestogen mifepristone be used for?

Answer 9

• 6 adverse effects of progestogens:
  1) Acne
  2) Weight gain
  3) Depression
  4) Change in libido
  5) Breast discomfort
  6) Menstrual cycle irregularity (if dose not high enough)
• The anti-progestogen, mifepristone, in combination with prostaglandin analogues is an effective medical alternative to surgical termination of early pregnancy (up to 9 weeks).

Question 10

The Combined Contraceptive Pill.

What substances are used in combined contraceptive pills?

What are the 2 oestrogens used in most combine contraceptive pill?

What are the 4 progestogens that can be used in the combined contraceptive pill?

What is the oestrogen content?

What is the frequency for taking the pill?

What happens after discontinuation?

Answer 10

• The Combined Contraceptive Pill
• Oestrogens and progestogens are used in combined contraceptive pills
• 2 oestrogens used in most combine contraceptive pills:
  1) Ethinyloestradiol
  2) Mestranol
• 4 Progestogens that can be used in the combined contraceptive pill:
  1) Norethisterone
  2) Levonorgestrel
  3) Ethynodiol or in
  4) Desogestrel or Gestodene (in 3rd generation pills)
• The oestrogen content is generally 20 – 50 ug (Advice is to use the lowest dose that is well tolerated and gives good cycle control)
• Most combined pills are taken for 21 consecutive days followed by 7 days pill free to allow a withdrawal bleed.

Question 11

What are 4 parts of the mode of action of the combined contraceptive pill?

Answer 11

• 4 parts of the mode of action of the combined contraceptive pill:

1) Oestrogen inhibits the secretion of FSH via negative feedback on the anterior pituitary and thus suppresses development of the ovarian follicle.

2) Progestin inhibits LH secretion and prevents ovulation.

3) Oestrogen and progestin act in concert to alter the endometrium is such a way as to discourage implantation.

4) They may also interfere with the coordinated contractions of the cervix, uterus and fallopian tubes that facilitate fertilisation and implantation.

Question 12

What are 11 adverse effects of the Combined Contraceptive Pill?

Answer 12

• 11 adverse effects of the Combined Contraceptive Pill:
  1) Mild nausea,
  2) Flushing
  3) Dizziness
  4) Bloating.
  5) Weight gain
  6) Skin changes (acne or pigmentation)
  7) Depression
  8) Irritability.
  9) Amenorrhea of variable duration after cessation of taking the pill.
  10) Serious withdrawal effects are rare.
  11) A small number of women develop reversible hypertension.
  12) A small increase in the risk of thromboembolism.

Question 13

Progestin Only Contraceptive Pill.

What are 4 Progestins that can be used in the Progestin Only Contraceptive Pill?

How frequency is the pill taken?

What are 3 parts in the mode of action in the Progestin Only Contraceptive Pill?

Who is it a suitable alternative for?

How reliable is it?

Answer 13

• Progestin Only Contraceptive Pill
• 4 Progestins that can be used in the Progestin Only Contraceptive Pill:
  1) Norethisterone
  2) Levonorgestrel
  3) Ethynodiol diacetate,
  4) Desogestrel
• The pill is taken daily without interruption.
• 3 parts in the mode of action in the Progestin Only Contraceptive Pill:

1) Reduces LH secretion (thru neg. feedback)

2) Makes the cervical mucous inhospitable to sperm

3) Hinders implantation through its effect on the endometrium and on the motility and secretions of the fallopian tubes.

• The progestin only pill is a suitable alternative to women in whom oestrogen containing pills are contraindicated and are suitable for women whose blood pressure rises unacceptably during treatment with the combined pill.
• Progestin contraceptives are as reliable as the combined pill.

Question 14

What are 2 Other drug regimens for contraception?

What are 3 examples of Long-acting progestogen only contraception?

How are they each administered?

Answer 14

• 2 Other drug regimens for contraception:

1) Post-coital (emergency) contraception.
* Oral administration of levonogestrel alone or in combination with oestrogen is effective if taken within 72 hours and repeated 12 hours later

1) Long-acting progestogen only contraception.

• 3 examples:

1) Levonorgestrel (Norplant) subcutaneous implant (5 years)
* A levonorgestrel impregnated intrauterine device (IUS) can last for 35 years.

2) Etonogestrel (Nexplanon) subdermal implant (3 years)

3) Medroxyprogesterone acetate can by given intramuscularly as a contraceptive. - This is effective and safe.

Question 15

Possible Possible side effects with hormonal contraceptives

Answer 15

Question 16

What are 7 symptoms of menopause?

Answer 16

• 7 symptoms of menopause:
  1) Hot flushes
  2) Night sweats
  3) Vaginal dryness and discomfort during sex
  4) Difficulty sleeping
  5) Low mood or anxiety
  6) Reduced sex drive (libido)
  7) Problems with memory and concentration

Question 17

How is ovarian function affected in menopause?

How can this be treated?

What does HRT involve?

What does it improve?

What does it prevent and treat?

What are 4 drawbacks of HRT?

Answer 17

• At menopause ovarian function decreases and oestrogen levels fall - can be treated with HRT
• HRT normally involves either cyclic or continuous administration of low dose estrogens (estradiol, estriol) with or without progestogens.
• HRT improves the symptoms cause by reduced estrogen such as hot flushes and vaginal dryness.
• HRT prevents and treats osteoporosis.
• 4 Drawbacks of HRT:
  1) Withdrawal bleeding
  2) Increased risk of breast cancer
  3) Increased risk of endometrial cancer (if estrogens unopposed by progesterone),
  4) Increased risk of thromboembolism.

Question 18

What is the main androgen?

Where is testosterone synthesised?

What does GnRH act on?

What does LH stimulate?

Answer 18

• The main androgen is testosterone
• Testosterone is synthesised by Leydig cells in testes and in smaller amounts in the adrenals and ovaries
• GnRH acts on the anterior pituitary to release both FSH and LH
• LH stimulates androgen secretion

Question 19

How is testosterone in hormone replacement therapy administered?

In what people can it be administered?

What is the mechanism of action?

What do the effects depend on?

What are anti-androgens used for?

What are 2 examples of anti-androgens?

What are Dihydrotestosterone synthesis inhibitors used for?

What is an example?

Answer 19

• Intramuscular depot injections or patches of testosterone esters are used for replacement therapy
• It can be administered in male hypogonadism due to pituitary or testicular disease and female hyposexuality following removal of ovaries
• The mechanism-of-action is via nuclear receptors and control of gene expression.
• Effects depend on age/sex - include development of male secondary sex characteristics in pre-pubertal men and masculinisation of women
• Anti-androgens are used as part of the treatment of prostatic cancer
• 2 examples of anti-androgens:
  1) Flutamide
  2) Cyproterone
• Dihydrotestosterone synthesis inhibitors such as finasteride are used in benign prostatic hypertrophy
• An example is finasteride

Question 20

How can androgens be modified?

What is an example of this?

What affects does this lead to?

What can these steroids be used for?

What are 4 side-effects of anabolic steroids?

Answer 20

• Androgens can be modified to alter anabolic and other effects
• Such steroids (nandrolone) increase protein synthesis and muscle development (anabolic steroids)
• Anabolic steroids can be used in the therapy of aplastic anaemia (and abused by some athletes)
• 4 side-effects of anabolic steroids:
  1) Infertility
  2) Salt and water retention
  3) Coronary heart disease
  4) Liver disease

Question 21

What kind of compound is GnRH?

What can analogues of GnRH be used for?

What are 2 examples of GnRH analogues?

How does administration of GnRH analogues in a pulsatile and continuous fashion alter their effects?

When might these be used?

Answer 21

• Gonadotropin-releasing hormone (GnRH) is a decapeptide
• Analogues of GnRH are used to manipulate the reproductive axis
• 2 examples of GnRH analogs:

1) Gonadorelin
* Same amino acid sequence as the endogenous form but made synthetically.

1) Nafarelin is a more potent analogue.

• Given in pulsatile fashion, GnRH analogues will stimulate release of the gonadotropins (FSH and LH) and induce ovulation, used in the treatment of infertility.
• Administration of GnRH analogues in a continuous regimen will induce gonadal suppression. This is used in sex hormone-dependent conditions (e.g. prostate and breast cancers, endometriosis and large uterine fibroids).

Question 22

What are Gonadotropins (FSH and LH) preparations used for in women and men?

What are 2 ways gonadotropins are made?

Answer 22

• Gonadotropins (FSH and LH) preparations are used to treat infertility in women caused by lack of ovulation as a result of hypopituitarism following failure of treatment with clomiphene
• Gonadotropins are also used to treat men with infertility due to hypogonadotropic hypogonadism
• 2 ways gonadotropins are made:

1) Recombinant DNA technology

2) Extracted from urine of pregnant or post-menopausal women.

Question 23

Regulation of FSH and LH release from the anterior pituitary diagram

Answer 23