6. Drugs affecting reproductive function Flashcards
Where are oestrogens synthesised?
Ovary and the placenta
Small amounts in adrenal cortex and testis
Clinical uses of oestrogens?
- Induce artificial menstrual cycle
- Contraception
- At or after menopause to prevent symptoms e.g. protect against osteoporosis, vaginal dryness and flushing
- Replacement therapy in primary ovarian failure (Turner’s syndrome) to promote sexual maturation
- Prostate and breast cancer
Side effect: Increase risk of thromboembolism, cause feminisation in Males
Oestrogen administration options?
Preparations: Oral, transdermal, intramuscular, implantable, topical (as it is well absorbed across the gut, skin and mucous membranes)
Options:
Natural e.g. Estragiol, estriol
Synthetic e.g. Menstranol, ethinylestradiol, diethylstilbestrol
Binding of eostrogens in the blood?
To albumin and to a sex hormone-binding globulin.
Thus making the oestrogens inactive
What does SERMs mean?
Selective Oestrogen Receptor Modulators
What are SERMs?
Competitive antagonists or partial agonists of oestrogens
3 examples of SERMs
Clomiphene
Tamoxifen
Raloxifene
Action of clomiphene?
Acts as an oestrogen antagonist in the hypothalmus and anterior pituitary to inhibit the negative feedback to induce ovulation.
Action of taxoxifen?
One such drug used in estrogen-dependent breast cancer. (anti-estrogenic action on mammary tissue)
Acton of raloxifene?
Used to treat and prevent osteoporosis (estrogenic action on bone).
3 oestrogens in the body are
Oestradiol **
Oestrone
Oestriol
Progesterone secreted by..
Corpus luteum in mentrual cycle follicular phase
Placenta during pregnancy
Relationship between progesterone, PR and oestrogen?
Progesterone acts on the PR (progesterone receptor) to regulate gene transcription in target tissues.
Oestrogen stimulates PR synthesis.
Progesterone inhibits oestrogen receptor synthesis
What are progestins?
Synthetic derivatives of progesterone (as progesterone is cleared rapidly so not used therapeutically)
3 examples of progestins?
Medroxyprogesterone
Hydroxyprogesterone
Norethisterone
Therapeutic uses for progestogens?
- Oral contraceptive pill alone or in combination with estrogen **
- Used as progesterone only injectable/ implantable contraception or as part of an intrauterine contraceptive.
- Combined with estrogen for estrogen replacement therapy in women, with an intact uterus, to prevent:
– endometrial hyperplasia
– carcinoma
– endometriosis
Danazol, what is it?
a modified progestogen used to treat sex- hormone dependent conditions including endometriosis, breast dysplasia and gynaecomastia
Action of danazol?
Via progesterone receptor to inhibit gonadotrophin production.
So… reduces oestrogen synthesis in women and androgen synthesis in men
Side effects of Danazol?
GI disturbances, weight gain, fluid retention, dizziness, headaches and menopausal symptoms
Has androgenic activity so is virilizing when given to women
Adverse effect of progestins?
acne, fluid retention, weight gain, depression, change in libido, breast discomfort, menstrual cycle irregularity and increased thromboembolism.
What is midipristone and what does it do?
It is an anti-progestogen
In combination with prostaglandin analogues = An effective medical alternative to surgical termination to early pregnancy
What is in the combined contraceptive pill?
Eoestogen in the form of: Ethinyloestradiol or mestranol
Progestogens in the form of: Noreethisterone, levonorgestrel, ethynodiol. Or in 3rd generation pills desogestrel or gestodene, these are more potent and have less andogenic action
Mode of action of the combined pill?
- Estrogen inhibits the secretion of FSH via negative feedback on the anterior pituitary and thus suppresses development of the ovarian follicle.
- Progestin inhibits LH secretion and prevents ovulation.
- Estrogen and progestin alter endometrium to discourage implantation.
- They may also interfere with the coordinated contractions of the cervix, uterus and fallopian tubes that facilitate fertilisation and implantation.
Side effect of the combined pill?
- 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.
- A small number of women develop reversible hypertension.
- A small increase in the risk of thromboembolism.
Progestin only contraceptive pill: Contents? Administration? MoA? Downside? Indications?
These pills include norethisterone, levonorgestrel or ethynodiol diacetate.
Taken daily without interruption.
MoA:
• On the cervical mucous which is made inhospitable to sperm.
• Hinders implantation through its effect on the endometrium and on the motility and secretions of the fallopian tubes.
Downside: Contraceptive effect is less reliable than the combined pill.
Indications:
-Women who can’t tolerate oestrogen-containing pills due to hypertension
Action of levonogestrel?
- Post-coital (emergency) contraception.
- Oral administration – levonogestrel alone or in combination with estrogen
- Effective if taken within 72 hours and repeated 12 hours later.
2 examples of long-acting progestogen only contraception?
- Medroxyprogesterone acetate can by 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.
What is the process of HRT?
Used when ovarian function decreases and oestogen levels fall.
Involves either cyclic or continuous administration of low dose oestrogens (estadiol, estriol) with or without progestogens.
Uses of HRT?
- Improves the symptoms cause by reduced estrogen such as hot flushes and vaginal dryness.
- Prevents and treats osteoporosis.
Drawnbacks of HRT
Withdrawal bleeding
Increased risk of breast cancer
Increased risk of endometrial cancer (if estrogens unopposed by progesterone)
Increased risk of thromboembolism.
Main androgen is..
testosterone
Testosterone synthesis?
By Leydig cells in testes and in smaller amounts in the adrenals and ovaries
LH stimulates androgen secretion
Clinical uses of androgens?
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.
Use of antiandrogens (e.g. flutamide and cryproterone)?
As part of the treatment of prostatic cancer as androgens promote cell division
Used of Dihydrotestosterone synthesis inhibitors such as finasteride?
In benign prostatic hypertrophy.
What anabolic steroid is used to increase protein synthesis and muscle development?
Nandrolone
Uses of anabolic steroids?
- Androgens can be modified to alter the balance of anabolic and other effects. Such steroids (nandrolone) increase protein synthesis and muscle development.
- Used in the therapy of aplastic anaemia and abused by some athletes.
Side effect of anabolic steroids?
Infertility, salt and water retention, coronary heart disease and liver disease (due to difficult metabolism).
Depresses HPG axis
Name 2 gonadotrophin-releasing hormone analogues
Gonadorelin: The same amino acid as the endogenous form but made synthetically
Nafarelin is a more potent analogue
Describe the administration and indications of gonadotrophin-releasing hormone analogies
Given in pulsatile fashion will stimulate release of the gonadotrophins (FSH and LH) and induce ovulation
Indications:
- 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).
Uses of gonadotropins e.g. LH and FSH?
- Infertility due to lack of ovulation (caused by hypopituitarism following failure of treatment with clomiphene)
- Male infertility d§ue to hypogonadotropic hypogonadism
Difference between progestogen and progestin?
Progestogen= Broad term including progestin and progesterone
Progestin= Synthetic analogue for progesterone
