Pharmacology of Oral Contraceptives

What are the main sex hormones?

Oestrone/estrone (less potent). Oestradiol/estradiol (17 beta-oestradiol). Oestriol/estroiol (least potent). Progesterone. Testosterone

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What is the main precursor for steroid hormones?

Cholesterol (rate limiting step - use of cholesterol desmolase enzyme to produce pregnenolone - synthesis of steroid hormones e.g. oestrogen, progesterone and testosterone)

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Describe features of glycoprotein hormones (1)

E.g. PH, FSH, hCG, TSH. All consist of alpha and beta chains (alpha chains common to all 4, beta chains responsible for specificity). LH/FSH/TSH from anterior pituitary, hCG from placenta

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Describe features of glycoprotein hormones (2)

Release of LH/FSH stimulated by GnRH (decapeptide from hypothalamus). Pulsatile release of GnRH (release LH/FSH). Sustained release of GnRH (inhibit LH/FSH)

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Describe features of glycoprotein hormones (2)

Amino acids: pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

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Outline the HPG axis (1)

Hypothalamus releases GnRH. Causes anterior pituitary to release FSH/LH to ovary (maturation of egg, graffian follicle, corpus luteum), causes release of oestrogen/progesterone. Oestrogen has negative feedback on anterior pituitary (inhibit FSH/LH)

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Outline the HPG axis (2)

Progesterone has negative feedback on hypothalamus (inhibit GnRH) and anterior pituitary (inhibit LH/FSH)

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What are the effects of gonadotropins on the ovary? (1)

LH acts on thecal cells (cholesterol converted to androgen). FSH acts on granulosa cells (aromatase used to convert androgen to oestrogen). Mid-cycle oestrogen causes positive feedback on gonadotrophs to increase sensitivity to GnRH

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What are the effects of gonadotropins on the ovary? (2)

LH surge causes ovulation. 0.5 degrees Celsius increase in body temperature at ovulation

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Outline the menstrual cycle (1)

Gonadotrophins (from anterior pituitary). FSH/LH remain high at the start of the cycle, oestrogen/progesterone remain low. Development of egg into follicle. Oestrogen levels increase to high levels (positive feedback on LH/FSH, LH surge), ovulation

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Outline the menstrual cycle (2)

High levels of oestrogen and progesterone. Corpus luteum formed. No fertilisation, oestrogen returns to normal levels and causes negative feedback on LH/FSH. Uterus lining breaks down (menstruation), cycle repeats

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Outline the steroid receptor mechanism (1)

Presence of steroid hormone causes hsp90 to unbind from ligand binding domain. DNA binding domain exposed. Results in altered transcription of specific genes (Er alpha activated transcription, Er beta inhibits transcription)

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Outline the steroid receptor mechanism (2)

Hormone-receptor complex translocated into the nucleus. Transcription, protein synthesis (RNA)

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What percentage of pregnancies in the UK were unplanned?

16%

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What is the most common method of contraception?

Oral contraceptives (user dependent) for females. Condoms for males. Proportion of females who choose long acting reversible contraceptives (e.g. implants) increases with age

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Describe features of the combined oral contraceptive pill (1)

Combination of an oestrogen and a progesterone. Either take for 21 days then 7 days with inactive pill or 7 pill free days. Withdrawal bleeding. Normal menstruation usually starts fairly quickly after cessation (within 2 cycles)

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Describe features of the combined oral contraceptive pill (2)

Effectiveness decreased by drugs which induce liver enzymes (e.g. antibiotics/rifampicin, anti-epileptic drugs/phenytoin/phenobarbital). Oral formulations (taken up in gut, hepatic circulation, secrete into bile/back into intestinal bacteria)

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Describe features of the combined oral contraceptive pill (3)

Need higher doses of oestrogen if the patient is taking other drugs which induce CYP450 enzymes

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What is the MOA for the combined oral contraceptive pill?

Oestrogen inhibits FSH secretion (suppresses ovarian follicular development). Progesterone inhibits LH secretion (prevents ovulation, makes cervical mucus more hostile to sperm). Oestrogen/progesterone (alter endometrium to discourage implantation)

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Give examples of oestrogens

Ethinyl estradiol and mestranol

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Give examples of progestogens

Levonorgestrel and gestodene

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Give examples of the types of combined oral contraceptive pill (1)

Oestrogen (ethinylestradiol, 20-35 micrograms, sometimes mestranol). Progestin (synthetic progestogen) 1st/2nd generation - norethisterone or levonorgestrel, 3rd/4th generation - desogestrel, gestodene (3rd), nomegestrol/dienogest/dropspirenone (4th)

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Give examples of the types of combined oral contraceptive pill (2)

Less effect on lipoprotein levels but increased risk of thrombosis with 3rd/4th generation

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What are the side effects of the combined oral contraceptive pill?

Hypertension, increased risk of thromboembolism, increased risk of breast cancer, weight gain, nausea, depression or irritability, skin changes, amenorrhea on cessation

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What are the advantages of the combined oral contraceptive pill? (1)

Decreased menstrual problems. Used for irregular periods/intermenstrual bleeding. Decreases iron deficiency/anaemia. Decreases premenstrual tension. Decreases risk of benign breast disease. Decreases uterine fibroids

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What are the advantages of the combined oral contraceptive pill? (2)

Decreases incidence of ovarian cysts. Decreases risk of ovarian and endometrial cancer. Decreases risk of pelvic inflammatory disease

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What are the long term effects of the combined oral contraceptive pill? (1)

Use of pill associated with - decreased risk of endometrial (uterine) cancer/20,000 deaths per year reduction in high income countries. Decreased risk of ovarian cancer (50% reduction)

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What are the long term effects of the combined oral contraceptive pill? (2)

Increased risk of breast cancer/cervix (small risk, reduced with longer term use e.g. after 5 years, risk reduced). Decreases long lasting (20-30 years), increases short lasting

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What are the different types of dosing for the combined oral contraceptive pill?

Monophasic (fixed oestrogen and progestogen e.g. 24/4 nomegestrol/estradiol). Bisphasic (one or two doses of oestrogen but two different doses of progestogen). Triphase (one or two doses of oestrogen but three different doses progestogen)

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Describe features of the combined contraceptive patch (1)

E.g. Evra. 750 microgams of ethinylestradiol, 6 mg of norelgestromin. Delivers per day. 20 micrograms of ethinylestradiol, 150 micrograms of norelgestromin, each patch applied for 7 days. 3 patches (21 days) then 7 days drug free

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Describe features of the combined contraceptive patch (2)

(80% of drug still present at 7 days). Possible reason for reduced sperm count in males (high oestrogen levels in the environment, oestrogen patches flushed down the toilet instead of being returned to the pharmacist to be disposed properly)

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Describe features of the combined contraceptive vaginal ring

E.g. NuvaRing. 15 micrograms of ethinylestradiol, 120 micograms of etonogestrel. Applied for 21 days, new ring 7 days later (same effectiveness to COC pill)

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Describe features of the progesterone only pill (1)

Take daily. Progestogen. Desogestrel (75 micrograms). Etynodiol (500 micrograms). Levonorgestrel (30 micrograms). Norethisterone (350 micrograms). 3 hours POP (traditional POP - taken within 3 hours of same time each day)

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Describe features of the progesterone only pill (2)

12 hours POP (desogestrel POP - must be taken within 12 hours of the same time each day)

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What is the MOA for POP?

Inhibits LH secretion, prevents ovulation. Makes cervical mucus more hostile to sperm

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What are the common side effects of POP?

Effectiveness decreased by drugs which induce liver enzymes (e.g. antibiotics/rifampicin, anti-epileptic drugs/phenytoin/phenobarbitone)

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POP is suitable for which groups of patients?

Women with history or risk of VT (related to oestrogen levels, POP more suitable), smokers, older women, higher blood pressure with COC

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Describe features of postcoital (emergency) contraception (1)

Levonorgestrel up to 72 hours after intercourse (preferably within 12 hours). Levonelle One Step - single 1.5 mg pill. 85% successful if taken within 72 hours (<1% of women experience nausea)

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Describe features of postcoital (emergency) contraception (2)

Levonelle-2, 2 x 750 micrograms. ellaOne (ulipristal, 30 mg). 90% successful if taken within 120 hours. Selective progesterone receptor modulator (SPRM)

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Describe features of postcoital (emergency) contraception (3)

Available in pharmacies, walk-in centres, minor injuries units. 1 in 20 women aged 16-49 use emergency contraception. 50% obtained pills from pharmacy. Most commonly used by 25-34 year olds

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Describe features of postcoital (emergency) contraception (4)

Intrauterine device (IUD) also works up to 5 days after intercourse (0.09% failure rate). Ulipristal (1.4% failure rate). Levonorgestrel (2-3% failure rate)

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Describe features of long acting contraceptives (1)

Levonorgestrel/ethinylestradiol (150 micrograms/30 micrograms, Seasonale), 84 days active pill, 7 days placebo, only 4 periods per year

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Describe features of long acting contraceptives (2)

Levonorgestrel/ethinylestradiol (90 micrograms/20 micrograms, Lybrel, Amethyst), active pill every day, 28 pills in each pack, no periods

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Describe features of long acting contraceptives (3)

Annovera, segesterone acetate/ethinylestradiol (103 mg/17.4 mg). Re-usable for 1 year. Insert for 3 weeks, remove for 1 week then re-insert

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Describe features of long acting contraceptives - IM injection

Medroxyprogesterone (Depo-Provera), every 12 weeks. Norethisterone (Noristerat) every 8 weeks. (Not reversible)

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Describe features of long acting contraceptives - implants

Etonogestrel (Nexplanon). Subcutaneous implant effective for 3 years

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Describe features of the intrauterine devices (IUD)

Copper containing device which interferes with implantation. Effective for 3-5 years. More suitable for older women. Also have IUD impregnated with levonorgestrel (Mirena)

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What are the main side effect of IUD?

Pelvic inflammatory disease (can lead to infertility)

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What is the effect of E2 oestradiol on the pituitary?

Negative feedback (inhibit LH/FSH)

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What is the effect of inhibin on the pituitary?

Negative feedback (inhibit FSH). Alpha beta A, alpha beta B

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What is the effect of activin on the pituitary?

Positive feedback (stimulates FSH), bAbA , bBbB and bAbB

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Give examples of male contraception (1)

Condoms, vasectomy, intra-vas device (IVD). Reversible inhibition of sperm under guidance, vasalgel and NES/T gel

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Give examples of male contraception (2)

Androgen (testosterone) weekly injection/implants. Androgen + progesterone, weekly injection/daily oral progesterone. Androgen + GnRH antagonist (weekly injection androgen/daily inject antagonist). Testosterone/norethisterone (inject every 8 weeks)

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Give examples of male contraception (3)

Takes up to 8-12 weeks for maximum suppression of spermatogenesis (azoospermia <1million sperm/mL)

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Describe results from male contraception studies (1)

Testosterone implant every 4 months, medroxyprogesterone (IM) every 3 months). No pregnancies in 55 couples over 1 year. Organon + Schering, etonogestrol (Implanon), testosterone undecanoate (Nebido) every 12 weeks, treated for 42-44 weeks

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Describe results from male contraception studies (2)

Mean recovery time for sperm count 15 weeks. WHO funded study on 390 men - 200 mg norethisterone enanthate, 1g testosterone undecanoate (IM) every 8 weeks. 96% azoospermatic within 24 weeks, 1.5 pregnancies/100 men

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Describe results from male contraception studies (3)

96% normal sperm count after 52 weeks. Still no oral formulation but now testing testosterone + segesterone gel (NES/T)

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Describe results from male contraception studies - knock out of alpha 1A and P 2x1 receptors (1)

Double KO mice. 29 male mice didn't produce any pregnancies. Sperm from mix fertilised control ova in vitro implantation of fertilised ova in foster families produced normal litters

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Describe results from male contraception studies - knock out of alpha 1A and P 2x1 receptors (2)

Possible use of alpha 1 A and P 2x1 receptor antagonists as non-hormonal contraceptives

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Pharmacology of Oral Contraceptives

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