Lecture 9 – Reproductive and post reproductive health Flashcards
drug groups which target reproductive and post reproductive health
- Sex steroid hormones
- Inhibitors and antagonists
- Mixed agonists/antagonists
sex steroid hormones
- Oestrogens
- Progestagens
- androgens
Inhibitors and antagonists
- RU486
- Finasteride
Mixed agonists/antagonists
Selective oestrogen receptor modulators (SERMs) and selective progesterone receptor modulators (SPRMs)
sex steroid hormones are synthesised from
cholesterol
sex steroid synthesis
Steroid hormone receptors
- Classic nuclear receptor
- Exert effects through gene transcription (effectively transcription factors)
- But also a membrane receptor for oestrogen
major effects of oestradiol
stimulates growth of the endometriumna and breast
stimulates production of progesterone (PR)
major effects of progesterone
stimulates growth of the endometrium and breast
maintains pregnancy
inhibits production of oestrogen
major effect of testosterone
In men, it’s thought to regulate sex drive (libido), bone mass, fat distribution, muscle mass and strength, and the production of red blood cells and sperm. A small amount of circulating testosterone is converted to estradiol, a form of estroge
Recap of female reproductive endocrinology:
The menstrual cycle
-
28 day cycle
- Luteal phase always 14 days
- Ovulation occurs due to LH surge
- Oestrogen and progesterone have differing effects on endometrial tissue and on cervical mucus
oestrogen effect on cervical mucus and uterus
- thin cervical mucus- allows fertilisation
- endometrial and myometrial thickening
- glands are straight or moderately coiled
progestrone effect on cervical mucus and uterus
- Maintains endometrium and myometrium
- Causes glands to become highly coiled and secretory
- thick cervical mucus- act to block further sperm transport
Oestrogen and progesterone together
produce suppression of the HPO axis i.e. reduced production of LH and FSH from the AP
actions of oestrogen when used as a drug
- Mild anabolic
- Sodium and water retention
- Raises HDL, lowers LDL
- Decrease bone resorption
- Impaired glucose tolerance
- Increase blood coagulability
side effects of oestrogen when used as a drug
- Breast tenderness
- Nausea, vomiting
- Water retention
- Increased blood coag
- Thromboembolism
- Impaired glucose tolerance
- Endometrial hyperplasia and cancer
- Ovarian metaplasia and cancer
- Breast hyperplasia and cancer
actions of progesterone when used as a drug
- Secretory endometrium
- Anabolic
- Increases bone mineral density
- Fluid retention
- Mood changes
- Maintains pregnancy
side effect of progesterone when used as a drug
- Weight gain
- Fluid retention
- Anabolic
- Acne
- Nausea/vomiting
- Irritability
- Depression, PMS
- Lack of concentration
action of testosterone when used as a drug
- Male secondary sex characteristics
- Anabolic
- Acne
- Voice change
- Increased aggression
- Metabolic
- Adverse effects on lipid profiles particularly the HDL-c/LDL- C ration (increased risk of atherosclerotic disease in males)
Hormonal contraception- using steroid drugs to prevent pregnancy
Interruption of HPG axis..
- Endometrial and cervical mucus effects
- Inhibition of ovulation
- can have short acting reversible contraceptives and LARCs
- Routes of admin
- Oral
- Nasal
- Transdermal
- implants
types of hormonal contril
- Combined oestrogen and progesterone
- COCP
- patch
- ring
- progesterone only pill (POP)
- LARC
- progesterone depot and implant
uses of oestrogen as a drug
- As part of hormonal birth control (COCP)
- As part of menopausal hormone therapy
- Transgender hormone therapy
- Treatment of hormone sensitive cancers e.g. breast cancer and prostate
Pharmacokinetics of oestrogen as a drug
- Natural and synthetic oestrogens well absorbed in GI tract
- pills
- Also readily absorbed from skin and mucous membranes
- e.g. hormone patches
- Metabolised in the liver
- Excretion- in the urine as glucuronides and sulphates
Mechanism of action of oestrogen
- Lipophilic so can pass through cell membrane without receptor
- Bind to oestrogen receptors found within cell
- Regulate transcription of specific genes
Contraindications of oestrogen
- Estrogen hormone receptor sensitive malignancies including breast cancer, ovarian cancer, and endometrial cancers
- Hypertension
- Coronary arterial disease
- History of thromboembolism
- History of hypercoagulable disease (Factor V Leiden syndrome, Protein C or Protein S deficiencies and metastatic disease)
- History of ischemic stroke
- Migraine headaches (e.g. auras)
adverse drug response of oestrogen therapy
breast tenderness, bloating, nausea, headaches, leg cramping, and vaginal or “breakthrough” bleeding
drug drug interactions oestrogen
aromatase inhibitors, tamoxifen
st johns wort shouldnt be taken with COCP (induces CYP3A4)- reducing [plasma] conc
uses of progesterone as a drug
- birth control
- help restart menstrual periods that unexpectedly stopped (amenorrhea)
- treat abnormal uterine bleeding associated with hormonal imbalance
- symptoms of premenstrual syndrome (PMS).
pharmacokinetics of porgesterone
- oral, intranasal, transdermal, vaginal, rectal, intramuscular, subcutaneous, and intravenous injection.
- Injected progesterone is bound to albumin with some stored in adipose tissue
- Long acting
- Metabolised in liver
- Metabolised excreted in urine conjugated to glucuronic acid
MOA of progesterone therapy
The “classical” mechanism by which progesterone elicits its effects is via the progesterone receptor (PR), which, like the estrogen receptor (ER), has classically been described as a nuclear transcription factor, acting through specific progesterone response elements (PRE) within the promoter region of target genes to regulate transcription
adverse drug reaction : progesterone
- Spontaneous fetal abortion
- Ectopic pregnancy
- Headache
- Breast tenderness
- GI issues
Contraindications of progesterone
- Breast cancer, cervical cancer, endometrial cancer, endometrial hyperplasia, new primary malignancy, ovarian cancer, uterine cancer, vaginal cancer
- Infertility
- CVD risk
- hypertension
- Hepatic impairment
names of combined pills
Microgynon, Rigevidon and Ovranette are combined pills
pharmacokinetics of COCP and POP
- COCP and POP contraceptives are metabolised by CYP450
mode of action of COCP
- Main action- prevent ovulation – negative feedback of oestrogen and progesterone on LH surge
- Secondary action- reduce endometrial receptivity to implantation
- Thickens cervical mucus
Disadvantages of COCP
*
- User dependent
- No STI protection
- Medication interaction
- Contraindications
- Raised BMI
- Migraine and aura
- Breast cancer
mode of action of POP
- Low dose progesterone
- Main action – thickens cervical mucus
- Other actions
- Reduced cilia activity in fallopian tubes
- Ovulation not prevented
adverse drug response of COCP
- Side effects
- Menstrual irregularities
- Breast tenderness
- Mood disturbances
- Increased risk of CV disease, stroke, VTE, breast cancer and cervical cancer
- smoking increases risk substantially
- also long term use
Contraindications of COCP
- Migraines
- Cancer/ History
Drug-drug interaction of COCP
-
Oral contraceptive efficacy is reduced by enzyme (CYP450) inducing drugs- increasing the production of CYP450- therefore reduced plasma drug
- Antiepileptics such as carbamazepine or phenytoin
- Antibiotics e.g. rifampicin and rifabutin
- St Johns Wort
- Soya protein products enhance oestrogen absorption and reduce its storage in adipose and muscle so reduce half-life from 15 to 7 hours
menopause (no menstruation for 12 months)
- Ovarian follicle supply depleted
- Consequently ovarian sex steroid production stops
- End of female reproductive capacity
- Loss of oestrogen and progesterone leads to a range of systemic effects as symptoms of menopause
- Results in increased FSH
drug used to help with menopause
hormone replacement therapy
uses of hormone replacement therapy
- Manage symptoms of menopause
- E.g. hot flushes/sweats
- Osteoporosis
- Not effective for the prevention of heart disease
route of admin of HRT
- Oral
- Transdermal
- Transvaginal
- Nasal
mode of action of HRT
steroid action- binds to intracellular receptors and changes transcription
names of hormone replacement therapy
Adverse drug response of HRT
- Unopposed oestrogen (ERT) increases risk of developing endometrial and ovarian cancers
- Opposed oestrogen (HRT- Oes with prog) increases risk of breast cancer
-
Increased risk of venous thromboembolism
- Increases activated protein C resistance
- Increased thrombin activation
- Decreased anti-thrombin III activity
- Decreased protein S levels
- Decreased factor VII levels and decreased tissue factor pathway inhibitor
-
Increased risk of stroke
- Use of oral but not transdermal oestrogen is associated with a small increase in the risk of stroke
Contraindications of HRT
A history of breast cancer. *
A history of endometrial cancer. *
Porphyria.
Severe active liver disease.
Hypertriglyceridemia.
Thromboembolic disorders.
Undiagnosed vaginal bleeding.
Endometriosis.
osteoporosis (as a result of menopause) treatment
Bisphosphonates (stable analogues of pyrophosphates)
name a drug under the class Bisphosphonates (stable analogues of pyrophosphates)
alendronic acid
Pharmacokinetics of bisphosphonates (alendronic acid)
- Long biological half life
- Poor gut absorption
- Absorption affected by food (must be taken on an empty stomach)
Uses of alendronic acid (bisphosphonates)
*
- Prophylaxis and treatment of osteoporosis
- Other uses include management of other disease involving bone
- Paget’s disease of bone
- malignancy
Mechanism of action of Bisphosphonates (stable analogues of pyrophosphates)
Drug names: Alendronic acid
- Reduce bone turnover by controlling osteoclast activity
- Have an effect on osteoclast membrane meaning they cant bind to bone
Adverse drug response of bisphosphonates
- Upper GI effects
- Oesophagitis (must stay seated or standing 30 mins after taking)
- Hypocalcaemia
- Check calcium and Vit D levels prior to initiating treatment
2 broad classes of inhibitors and antagonists
- Mifepristone (RU486)
- Finasteride
name a drug under the class of RU486
Mifepristone
use of RU486 (mifepristone)
Termination of pregnancies
MOA of RU486 (mifepristone)
- Progesterone and glucocorticoid receptor antagonist
- Therefore = anti-progesterone
- Sensitising the myometrium to prostaglandin- induced contractions
Used for termination of pregnancy
contraindications of RU486
contraindicated in patients with a confirmed or suspected ectopic pregnancy because MIFEPREX is not effective for terminating ectopic pregnancies
finasteride uses
Finasteride is in a class of medications called 5-alpha reductase inhibitors.
- Finasteride treats BPH by blocking the body’s production of a male hormone that causes the prostate to enlarge.
- Finasteride treats male pattern hair loss by blocking the body’s production of a male hormone in the scalp that stops hair growth.
MOA of Finasteride
nhibiting 5α-reductase and thus preventing DHT (more potent testosterone)production
mixed agonists and antagonists
SERM- selective oestrogen receptor modulator
SPRM- selective progesterone receptor modulators
examples of drugs under the class SERM- selective oestrogen receptor modulator
Drug names: Tamoxifen, Raloxifene, Clomiphene
MOA of SERM- selective oestrogen receptor modulator
- Pure agonists and pure antagonists
- Varying effects in different tissue
uses of clomiphene
- anovulation
mechanism of action of clomiphene
- Competes with oestrogen for ER binding
- Leads to ovulation induction through increased production of anterior pituitary hormones (LH)
uses of tamoxifen
breast cancer
Mechanism of action : tamoxifen
- pro-drug
- little affinity for ER
- metabolised in the liver to active derivatives
- some isoform of enzymes will not produce active derivative
- need genotyping before commencing treatment
- tamoxifen active metabolites compete with oestrogen for bind to ER
Adverse drug response: tamoxifen
Adverse drug response
- Acts as a SERM
- converse effects in breast and endometrial tissue
- in endometrium = ER agonist
- in breast = ER antagonist
- cell cycle arrest
- converse effects in breast and endometrial tissue
name a drug under the class Selective progesterone receptors modulators
Ulipristal acetate (e.g. ellaOne)
Ulipristal acetate (e.g. ellaOne) uses
- Emergency contraception
- Uterine fibroids
Mode of action: Selective progesterone receptors modulators
- Selective progesterone receptor modulator
- Delays ovulation
summary
- Many sex steroid pharmaceutical preparations available
- Indicated for contraception, emergency contraception termination of pregnancy
- In post-menopausal women main indication is for relief of vaso-motor symptoms and symptoms of genital atrophy
- Mostly well tolerated
- Risks associated with hormonal contraceptives low
- ERT risks – ovarian and endometrial cancer
- HRT – breast cancer and thromboembolism
