Drugs Affecting Reproductive Function

Question 1

Where does the production of oestrogens occur?

Answer 1

Synthesised by the ovary and the placenta and in small amounts in the adrenal cortex and testis.

Question 2

What is oestradiol?

Answer 2

Oestradiol is the most potent and principal oestrogen secreted by the ovary.

Question 3

Describe the mechanism of actions and effects of oestrogens.

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).
• Effects of oestrogen depend on the state of sexul maturity.
• In primary hypogonadism oestrogens stimulate development of secondary sexual characteristics and accelerate growth.
• In adults with ameorrhea given cyclically with progestogen, they induce an artificial menstrual cycle.

Question 4

What are the effects of oestrogens if given after menopause.

Answer 4

Given at or after the menopause, they prevent menopausal symptoms and protect against bone loss but increase coagulability of blood and increase risk of thromboembolism.

Question 5

What are the therapeutic uses of oestrogens?

Answer 5

• Replacement therapy in primary ovarian failure (Turner syndrome) to promote sexual maturation.
• Replacement therapy for menopausal symptoms such as flushing, vaginal dryness and osteoporosis.
• In contraception, they are used in combination with progestogens.
• Prostate and breast cancer.
• When administered to males they cause feminisation.

Question 6

What are the different preparations of oestrogens?

Answer 6

• Many preparations:
  
  • Oral
  • Transdermal
  • Intramuscular
  • Implantable
  • Topical
• Well absorbed from the gut, across the skin and mucous membranes.
• They include natural (e.g. Estradiol, Estriol) and synthetic (e.g. Menstranol, Ethinylestradiol, Diethylstilbestrol) oestrogens.

Question 7

Describe the state of oestrogens in the circulation.

Answer 7

In the blood they are bound to albumin and to a sex hormone-binding globulin (active oestrogens are in the unbound state).

Question 8

What are the adverse effects of oestrogens?

Answer 8

• Breast tenderness
• Nausea
• Vomiting
• Anorexia
• Retention of salt and water with resultant oedema and increased risk of thromboembolism

Question 9

What are Selective Estrogen Receptor Modulators (SERMs)?

Give examples.

Answer 9

• Competative antagonists or partial agonists of oestrogens are called selective oestrogen receptor modulators (SERMs).
• Drugs that are selective oestrogen agonists in some tissues but antagonists in others are being developed.
• Tamoxifen is one such drug used in oestrogen-dependent breast cancer (anti-oestrogenic action on mammary tissue).
• Raloxifene is another such drug used to treat and prevent post-menopausal osteoporosis (antioestrogenic effects on breast and uterus but oestrogenic action on bone).
• Clomiphene is a pure oestrogen antagonist at the hypothalamus and pituitary - acts to block negative feedback which leads to increased gonadotrophin secretion and ovulation.

Question 10

Where are progestogens produced and when?

Where do they act?

Answer 10

• Progesterone is secreted by the corpus luteum late in the menstrual cycle and by the placenta during pregnancy.
• Acts on the progesterone receptor (PR) to regulate gene transcription in target tissues.

Question 11

Describe the antagonistic action of oestrogen and progesterone.

Answer 11

Oestrogen stimulates synthesis of PR and progesterone inhibits the synthesis of the oestrogen receptors.

Question 12

Why is progesterone not used therapeutically?

What is the alternative?

Answer 12

• Progesterone is not used therapeutically due to rapid clearance - it goes through first pass metabolism in the liver.
• Instead, synethetic derivatives are used - called progestins.

Question 13

Describe progestogens.

Give examples.

Answer 13

• Progestins are a derivative of natural progesterone.
• These include:
  
  • medroxyprogesterone
  • hydroxyprogesterone
• There are also testosterone derivatives
• These include:
  
  • norethisterone
  • ethynodiol
• With newer progestogens that have less androgenic activity:
  
  • desogestrel
  • gestodene

Question 14

What are the therapeutic uses of progestogens?

Answer 14

• Main therapeutic uses are in the oral contraceptive pill alone or in combination with oestrogen.
• Used as progesterone only injectable or implantable contraception or part of an intrauterine contraceptive.
• Combined with oestrogen for oestrogen replacement therapy in women, with an intact uterus, to prevent:
  
  • Endometrial hyperplasia
  • Carcinoma
  • Endometriosis

Question 15

What are the adverse effects of progestogens and use of anti-progestogens?

Answer 15

• Adverse effects of progestogens include:
  
  • Acne
  • Fluid retention
  • Weight gain
  • Depression
  • Change in libido
  • Breast discomfort
  • Menstrual cycle irregularity
  • Increased thromboembolism
• 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 16

Describe the combined oral contraceptive pill.

Answer 16

• Oestrogen in most combined pills is ethinyloestradiol or mestranol.
• The progestogen can be norethisterone, levonorgestrel, ethynodiol or in 3rd generation pills desogestrel or gestodene (more potent and have less androgenic actions).
• The oestrogen content is generally 20-50µg.
• Advice is to use the lowest dose that is well tolerated and gives good cycle control.
• Most COCP are taken for 21 consecutive days followed by 7 days pill free to allow a withdrawl bleed.
• Menstrual cycles return quickly after discontinuation.

Question 17

Describe the mechanism of action of the combined oral contraceptive pill.

Answer 17

• Oestrogen inhibits the secretion of FSH via negative feedback on the anterior pituitary and this suppresses development of the ovarian follicle.
• Progestin inhibits LH secretion and prevents ovulation.
• Oestrogen and progestin act in concert to alter the endometrium in such a way as to discourage implantation.
• They may also interfere with the coordinated contractions of the cervix, uterus and fallopian tubes that facilitate fertilisation and implantation.

Question 18

What are the adverse effects of the COCP?

Answer 18

• Mild nausea, flushing, dizziness and bloating.
• Weight gain, skin changes (acne or pigmentation), depression or irritability.
• Amenorrhea of variable duration after cessation of taking the pill.
• Serious withdrawl effects are rare.
• A small number of women develop reversible hypertension.
• A small increase in the risk of thromboembolism.

Question 19

Describe the progestin only contraceptive pill.

Answer 19

• Norethisterone, levonorgestrel or ethynodiol diacetate.
• This pill is taken daily without interruption.
• The mode of action is primarily on the cervical mucous which is made inhospitable to sperm.
• It probably also hinders implantation through its effect on the endometrium and on the motility and secretions of the fallopian tubes.
• They offer 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.
• Contraceptive effect is less reliable than the combined pill.

Question 20

Describe the use of post-coital (emergency) contraception.

Answer 20

Oral administration of levonogestrel alone or in combination with oestrogen is effective if taken within 72 hours and repeated 12 hours later.

Question 21

Describe long-acting progestogen only contraception.

Answer 21

• Medroxyprogesterone acetate can be given intramuscularly as a contraceptive. This is effective and safe.
• Levonorgestrel implanted subcutaneously - the capsules release their progestogen slowly over 5 years.
  
  • A levonorgestrel impregnated intrauterine device can last for 35 years.

Question 22

What are the symptoms of menopause?

Answer 22

Question 23

Describe the use of postmenopausal hormone replacement therapy.

Answer 23

• 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 oestrogens (estradiol, estriol) with or without progestogens.
• Improves the symptoms caused by reduced oestrogen, such as hot flushes and vaginal dryness.
• Prevents and treats osteoporosis.

Question 24

What are the drawbacks of postmenopausal hormone replacement therapy?

Answer 24

• Withdrawl bleeding
• Increased risk of breast cancer
• Increased risk of endometrial cancer (if estrogens unopposed by progesterone)
• Increased risk of thromboembolism

Question 25

What is the main androgen?

Where is this synthesised?

How is synthesis stimulated?

Answer 25

• Testosterone is the main androgen.
• 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 26

Describe the pharmacological use of androgens.

Answer 26

• Intramuscular depot injections or patches of testosterone esters are used for replacement therapy in male hypogonadism due to pituitary or testicular disease and female hyposexuality following ovariectomy.
• Mechanism of action is via nuclear receptors and control of gene expression.
• Effects depend upon age / sex and include development of male secondary sex characteristics in pre-pubertal men and masculinisation of women.
• Antiandrogens (e.g. flutamide, cyproterone) are used as part of the treatment of prostatic cancer.
• Dihydrotestosterone synthesis inhibitors such as finasteride are used in benign prostatic hypertrophy.

Question 27

Describe the pharmacological use of anabolic steroids.

Answer 27

• Androgens can be modified to alter anabolic and other effects.
• Such steroids (nandrolone) increase protein synthesis and muscle development.
• Used in therapy of aplastic anaemia.
• Abused by some athletes.
• Side effects can include infertility, salt and water retention, coronary heart disease and liver disease.

Question 28

Describe the pharmacological use of gonadotrophin-releasing hormone analogues.

Answer 28

• Gonadotrophin-releasing hormone is a decapeptide - analogues are used to manipulate the reproductive axis.
• Gonadorelin is the same amino acid sequence as the endogenous form but made synthetically.
• Nafarelin is a more potent analogue.
• Given in pulsatile fashion, it will stimulate release of the gonadotrophins (FSH and LH) and induce ovulation used in the treatment of infertility.
• Administration of GnRH 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 29

Describe the pharmacological use of gonadotrophins.

Answer 29

• Gonadotrophins (FSH and LH) preparations are used to treat infertility caused by lack of ovulation as a result of hypopituitarism following failure of treatment with clomiphene.
• Gonadotrophins are also used to treat men with infertility due to hypogonadotrophic hypogonadism.
• Gonadotrophins are made by recombinant DNA technology or extracted from urine of pregnant or post-menopausal women.

Question 30

Describe the regulation of FSH and LH release from the anterior pituitary.

Answer 30