Lecture 17- Drugs Affecting Female Reproductive Endocrinology Flashcards
Control of female production
Puberty= increased output of the hormones of the hypothalamus + anterior pituitary stimulates secretion of oestrogenic sex steroids
Responsible for;
- maturation of the reproductive organs and the development of the secondary sexual characteristics
- phase of accelerated growth followed by closure of the epiphyses of the long bones
Oestrogens
Oestrogens are synthesised by the ovary + placenta and in small amounts by the testis and adrenal cortex
3 main endogenous oestrogens in humans;
Oestradiol= secreted by the ovary
Oestrone= metabolite of oestradiol
Oestriol= metabolite of oestradiol
Oestradiol= most potent and is the principal oestrogen secreted by the ovary
Actions of oestrogens
Act in concert with progesterone + induces synthesis of progesterone receptors in uterus, vagina, anterior pituitary and hypothalamus
Effects of exogenous oestrogen depend on the state of sexual maturity with the oestrogen administered;
- primary hypogonadism; oestrogen stimulates development of secondary sexual characteristics + accelerates growth
- adults with primary amenorrhoea; oestrogen given cyclically with progestogen, induces an artificial cycle
- sexually mature women= oestrogen (with progestogen) = contraceptive
- at/after menopause= oestrogen replacement prevents menopausal symptoms and bone loss
Actions of oestrogens
Have several metabolic actions including mineralcorticoid (retention of salt + water) and mild anabolic actions
Increase plasma concentrations of high-density lipoproteins
Produce dose-dependent increase coagulability of blood + increase the risk of thromboembolism
Oestrogen preparations
Many preps (oral, transdermal, IM, implantable + topical) of oestrogens are available for a wide range of indications
Preps include; natural (e.g. oestradiol, oestriol) + synthetic (e.g. mestranol, ethinylestradiol + stilbestrol) oestrogens
Oestrogens= presented either as single agents or combined with progestogen
Pharmacokinetics
Natural + synthetic oestrogens = well absorbed in the GIT but after absorption the natural oestrogens are rapidly metabolised in the liver whereas synthetic oestrogens are degraded less rapidly
Most oestrogens= readily absorbed from skin and mucous membranes. May be given topically in the vagina as creams/pessaries for local effect
Unwanted effects of oestrogens
Unwanted effects= include tenderness in the breasts, nausea, vomiting, anorexia, retention of salt and water with resultant oedema + increased risk of thromboembolism
Used intermittently for post menopausal replacement therapy, oestrogens cause menstruation-like bleeding
Oestrogens= cause endometrial hyperplasia unless given cyclically with a progestogen
Administered to males= oestrogens results in feminisation
Oestrogen administration to preg women= cause genital abnormalities in their offspring
Clinical uses of oestrogens
Primary hypogonadism;
- replacement therapy in oestrogen-deficient patients due to primary failure of development of ovaries, premature menopause, castration/ menopause
Post menopausal hormonal therapy (HRT)
- menopause- natural/surgically induced, ovarian function decreases + oestrogen levels fall
- HRT= improves symptoms, caused by reduced oestrogen; hot flushes + vaginal dryness
- HRT= used in prevention + treatment of osteoporosis
- oestrogens used in HRT can be given orally (conjugated oestrogens, oestradiol, oestriol) vaginally (oestriol) by transdermal patch (oestradiol) or by SC implant (oestradiol)
Contraception
Anti-oestrogens; Clomiphene
Clomiphene= inhibits oestrogen binding in the anterior pituitary -> prevents the normal modulation by negative feedback = increased secretion of GnRH and gonadotrophins
Inhibition of oestrogen binding= stimulation and enlargement of the ovaries and increased oestrogen secretion
Main effect of anti oestrogen action in the pituitary= induction of ovulation
Used in treating infertility caused by lack of ovulation
Selective oestrogen receptor modulators (SERMs)
Tamoxifen= first ‘selective oestrogen receptor modulator’ to be introduced
- has anti-oestrogenic action on mammary tissue but oestrogenic actions on plasma lipids, endometrium and bone
- effective in some cases of hormone-dependent breast cancer + may have a role in preventing these cancers
- unwanted effects= similar to those experienced by women following the menopause
Selective oestrogen receptor modulators (SERMs)
Raloxifene; ‘selective oestrogen receptor modulator’= has anti-oestrogenic effects on breast + uterus but oestrogenic effects on bone, lipid metabolism and blood coagulation
Used for prevention + treatment of post-menopausal osteoporosis and reduces the incident of oestrogen receptor- positive breast cancer
Unlike oestrogen= does not prevent menopausal flushes
Progestogens
Natural progestational hormone= progesterone
- secreted by the corpus luteum in the second part of the menstrual cycle + by placenta during pregnancy
- prepares the endometrium for the potential of pregnancy after ovulation
- triggers the lining to thicken to accept a fertilised ovum
- prohibits the muscle contractions in the uterus that would cause the body to reject an ovum
- high levels of progesterone = blocks ovulation
- small amounts of= secreted by testis and adrenal cortex
Progestogens
Actions;
- oestrogen = stimulates the synthesis of progesterone receptors whereas progesterone inhibits synthesis of oestrogen receptors
Preps;
- progesterone- natural
- hydroxprogesterone- derivative
- medroxyprogesterone- derivative
- dyhydrogesterone- derivative
Testosterone derivatives; norethisterone, norgestrel + ethynodiol
Preps; oral administration, IM, administration via vagina/rectum
Progestogens
Unwanted effects;
- weak androgenic actions
- acne, fluid retention, weight change, depression, change in libido… slide 16
Clinical uses;
- contraception
- with oestrogen in combined oral contraceptive pill
- progesterone-only contraceptive pill
- injectable/implantable progesterone-only contraception
… slide 16
Oral contraceptives
2 main types;
- combination of oestrogen with a progestogen (combined pill)
- progestogen alone (progestogen-only pill)
Combined; extremely effective
Oestrogen- ethinylestradiol
Progestogen- norethisterone, levonorgestrel, ethynodiol… s17
COC- taken for 21 consecutive days followed by 7 pill free-days = withdrawal bleed
Combined pill
Mechanism of action;
- oestrogen inhibits secretion of FSH via negative feedback on the anterior pituitary + suppresses development of the ovarian follicle
- progestogen inhibits secretion of LH and prevents ovulation- makes the cervical mucus less suitable for the passage of sperm
- oestrogen + progestogen act in concert to alter the endometrium- discouraging implantation
Unwanted effects;
- weight gain, owing to fluid retention/anabolic effect
- mild nausea, flushing, dizziness, depression
- skin changes
^… slide 20
Progestogen-only pill
Norethisterone, levonorgestrel + ethynodiol
Progesterone only contraceptives= offer a suitable alternative to the combined pill for some women in who oestrogen is contraindicated + are suitable for women whose bp inc unacceptably during treatment with oestrogen
Pill = taken daily without interruption
Cervical mucus- made inhospitable to sperm
Progestogen- hinders implantation through its effect on the endometrium + on the motility and secretions of the fallopian tubes
POP; progestogen only pill
Disadvantages;
Less reliable + mainly a result of the alteration of cervical mucus
Irregular bleeding is common
Drug interactions
Combined + progestogen only oral contraceptives- metabolised by hepatic cytochrome P450 enzymes
- increase in clearance of oestrogen = result in contraceptive failure
- enzyme- inducing drugs= increase clearance of combined and POP
Rifampicin
Rima but in
Carbamazepine
Phenytoin
Griseofulvin
Control of female reproduction
At puberty= increased output of the hormones of the hypothalamus and anterior pituitary stimulates secretion of oestrogenic sex steroids
^responsible for;
- maturation of the reproductive organs and the development of the secondary sexual characteristics
- phase of accelerated growth, followed by closure of the epiphyses of the long bones
