combined oral contraceptive pill (OCP)

see also:

• gynaecology;
• contraception;
• flying and DVT risk with OCP

• the combined oestrogen/progesterone oral contraceptive pill is perhaps the most common form of contraception
• in 2025, a vaginal ring pessary (NuvaRing) which releases and oestrogen & progesterone over 3 weeks was approved by the Australian PBS - must be removed at 3 weeks then a normal menstrual period should ensue, has a 99.5 per cent efficacy rate with perfect use, and a 93 per cent rate with typical use (non-PBS cost is over $AU270/yr, but PBS subsidy will reduce this to ~$AU100/yr)

• risk of thrombotic stroke or AMI is mainly related to the dose of oestrogen ¹⁾
• the risk for VTE in users of low oestrogen dose (< 50 mcg ethinylestradiol) OCPs is 2-3x higher than for nonusers of OCPs who are not pregnant and remains lower than the risk associated with pregnancy and delivery.
• the relative risk of venous thromboembolism from using oral contraceptives with norethisterone, levonorgestrel, desogestrel, or gestodene decreased with decreasing oestrogen dose, whereas no difference was apparent between oral contraceptives with drospirenone and either 30 μg ethinylestradiol or 20 μg ethinylestradiol. Combined oral contraceptives containing the progestogens desogestrel, gestodene, cyproterone, or drospirenone confer about the same relative risk of venous thromboembolism, a risk that is about twice that from use of combined oral contraceptives with the same dose of oestrogen and levonorgestrel (ie. 4-6x risk compared with those not on OCP). ²⁾

• based on norethisterone as the progestogen, or norethindrone (NE), ethynodiol diacetate, or lynestrenol (LYN).

• eg. Norimin, Brevinor

• norethisterone 500 mcg, ethinyloestradiol 35 mcg (12 blue tabs: days 1-7 and 17-21); norethisterone 1 mg, ethinyloestradiol 35 mcg (9 white tabs: days 8-16); inactive: (7 orange tabs: days 22-28)
• Synphasic 28, Improvil 28

• eg. Norimin-1, Brevinor-1

• based on levonorgestrel as the progestogen which was introduced to the market in the 1970's
• reduced discontinuation rates compared to 1st generation OCP's (RR 0.79 (95% confidence interval [CI]: 0.69–0.91))
• improved cycle control comapred to 1st generation OCP's
• similar rates for contraceptive effectiveness, spotting, breakthrough bleeding and the absence of withdrawal bleeding compared to gestodene based OCP's, but more intermenstrual bleeding than with gestodene ³⁾
• half the risk of deep venous thrombosis (DVT) compared to 3rd generation OCP's containing the progestogens desogestrel, gestodene, cyproterone, or drospirenone ⁴⁾
• higher pregnancy rates with OCP's containing only 20mcg ethinyloestradiol

• lowest oestrogen dose and thus likely to have the least side effects other than menstrual, but the highest pregnancy rates
• may be suitable to help those with acne but needs strict compliance
• eg. Microgynon 20, Loette, Microlevlen ED

• progesterone dose increases throughout cycle while oestrogen dose peaks mid-cycle
• Triquilar ED, Logynon ED:
  • levonorgestrel 50 mcg, ethinyloestradiol 30 mcg (6 brown coated); levonorgestrel 75 mcg, ethinyloestradiol 40 mcg (5 white coated); levonorgestrel 125 mcg, ethinyloestradiol 30 mcg (10 ochre coated); inactive (7 larger white); lactose, sucrose;
• Triphasil ED, Trifeme:
  • levonorgestrel 50 mcg, ethinyloestradiol 30 mcg (6 brown tabs); levonorgestrel 75 mcg, ethinyloestradiol 40 mcg (5 white tabs); levonorgestrel 125 mcg, ethinyloestradiol 30 mcg (10 yellow tabs); inactive (7 red tabs); lactose, sucrose

• medium dose pill
• moderately higher risk of thrombotic stroke (RR 1.6 (1.4-2.0)) or AMI (RR 2.0 (1.6-2.5)) ⁵⁾
• eg. Microgynon 30 ED, Levlen ED, Nordette, Monofeme

• high oestrogen dose pill
• eg. Microgynon 50 ED

• cyproterone is a synthetic steroidal antiandrogen drug with additional weak progestogen and antigonadotropic properties
• Dienogest is a semisynthetic, steroidal progestogen with antiandrogenic activity
• suitable for those with acne and hirsutism
• Combined oral contraceptives containing the progestogens desogestrel, gestodene, cyproterone, or drospirenone confer about the same relative risk of venous thromboembolism, a risk that is about twice that from use of combined oral contraceptives with the same dose of oestrogen and levonorgestrel. ⁶⁾

• eg. Yaz

• eg. Diane-35, Carolyn-35, Estelle-35, Juliet-35, Laila-35, Brenda-35

• mainly used for Rx of heavy and/or prolonged menstrual bleeding in women without organic pathology who desire oral contraception
• Qlaira
  • oestradiol valerate 3 mg (2 dark yellow tabs), oestradiol valerate 2 mg/ dienogest 2 mg (5 medium red tabs), oestradiol valerate 2 mg/ dienogest 3 mg (17 light yellow tabs), oestradiol valerate 1 mg (2 dark red tabs), placebo (2 white tabs); lactose; f-c

• containing 1 of 3 new progestins:
  • norgestimate 0.2mg
  • desogestrel 0.06mg
  • gestodene 0.04mg
• may have increased thrombogenic adverse effects, particularly with ethinyl-oestradiol doses of 30-40mcg
• users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel.⁷⁾

• higher risk of thrombotic stroke (RR 2.2 (1.8-2.7)) or AMI (RR 2.1 (1.5-2.8)) ⁸⁾
• eg. Marvelon 28
• eg. Gedarel 30/150

• moderately higher risk of thrombotic stroke (RR 1.8 (1.6-2.0)) or AMI (RR 1.9 (1.6-2.3)) ⁹⁾
• eg. Femoden ED

• Zoely is a new OCP introduced in 2011 which has nomegestrol 2.5mg + endogenous 17B-oestradiol 1.5mg
  • strong anti-gonadotropic activity, minimal antiandrogenic activity
  • only 4 placebo pills per cycle compared to usual 7 pills
  • slightly higher incidence of breakthrough bleeding and spotting
  • higher incidence of acne than with other OCPs (15% vs 7%)
  • the only advantage over other OCP's appears to be that menses may be shorter and lighter

• inhibits follicular development, ovulation, and, as a consequence, corpus luteum formation
• this is reflected in a marked reduction of ovarian estradiol secretion and the absence of progesterone production
• mechanism is via hypothalamic inhibition of GnRH secretion & thus inhibition of LH & FSH secretion:
  • either oestrogen or progestin alone is capable of inhibiting FSH and LH sufficiently to prevent ovulation. However, the combined administration of both compounds greatly increases their antigonadotropic and ovulation-inhibition effects
  • the progestin component of combined oral contraceptives is particularly effective in terms of ovulation inhibition, given its ability to block the midcycle rise in LH secretion
  • ethinyl estradiol in combined oral contraceptives potentiates the antigonadotropic effect of the progestin and prevents irregular shedding of the endometrium.
  • it has also been reported that important individual and ethnic differences in the biologic effects and metabolism of synthetic estrogens and progestins exist, which may also influence their contraceptive action.
  • the effect of combined oral contraceptives on FSH and LH secretion is prompt, lowering circulating FSH and LH levels within the first day of administration. However, at least 7 days of uninterrupted daily use of combined oral contraceptives is necessary to suppress follicular development.
  • combined oral contraceptives are administered for a 21-day cycle followed by a 7-day pill-free cycle, to mimic a 28-day menstrual cycle. FSH and LH secretion resume immediately after the last day of pill intake, which accounts for the risk of accidental pregnancy because of missed pills and for the rapid return of fertility on discontinuation of combined oral contraceptive use.
  • the development of new follicles starts during the 7-day pill-free interval.

• cervical mucus changes:
  • the cervical mucus remains scanty, thick, and highly viscous. In in vitro tests sperm penetration is inhibited as a result of the progestin's effect on mucus.
• endometrial changes:
  • the endometrium is altered such that implantation is unlikely to be successful, however, the clinical relevance of this is unlikely to be significant.

• see post-coital emergency contraception
• regimen consists of 2 doses of combined OCP, each containing at least 100 µg of ethinyl estradiol and 0.5 mg of levonorgestrel, administered 12 hours apart, initiated within 72 hours of intercourse (most effective if within 24hrs)
• tendency to cause vomiting & thus in pill pack, provide anti-emetics such as metoclopramide & extra OCP's
• will not prevent pregnancy once implantation has occurred
• mechanism may involve a variety of actions depending on phase of menstrual cycle & includes:
• inhibition of ovulation (only is some women) - as for OCP
• suppressed or delayed LH surge
• shortened “dysfunctional” luteal phase
• endometrial changes - prevention of normal secretory endometrium
• inhibition of fertilisation
• inhibition of implantation 

• lowers androgen profiles improving hirsutism & acne:
  • increases sex hormone binding globulin 
  • decreases LH secretion & thus reduces ovarian androgen production
  • decreases adrenal androgen production
  • decrease conversion of testosterone to the biologically active 5 alpha-androstane-diol
• improves endothelial-dependent vasodilation
• some may raise HDL
• thrombogenic
• as tend to worsen insulin resistance, obesity is a relative C/I

• some may decrease sex hormone binding globulin & potentially nullify the oestrogen component's anti-androgenic effects, however, it appears all current low dose OCP's result in lowering of free testosterone levels, although some pts may have transient increase in acne on commencement of OCP perhaps due to transient release of testosterone from sex hormone binding globulin.
• 3rd generation have increased thrombogenic effects
• reduces risk of endometrial hyperplasia & possibly produces regular uterine withdrawal bleeding, thus helps reduce risk of uterine Ca
• anti-atherogenic thus decrease risk of IHD
• helps reduce risk of ovarian Ca

• altered hepatic metabolism of other drugs, eg.:
  • can double the half-life of caffeine
• altered serum levels of hormones:
  • oral estrogens raise corticosteroid-binding globulin (CBG) levels, leading to increased serum total cortisol concentrations
    • serum corticosteroid-binding globulin (CBG) and total cortisol levels decreased significantly and normalised by 4 weeks in women after discontinuation combined OCP¹⁰⁾
• seems each decade of OCP use results in 20-30% more plaque formation and thus increasing atherosclerosis and primary prevention
  • see http://www.abc.net.au/science/news/stories/2007/2085475.htm?health
• altered sense of smell
  • see http://www.abc.net.au/science/news/stories/s400532.htm
  • and perhaps inappropriate bonding to genetically incompatible partners - pheromonal mechanisms
    • although true species-specific pheromones have yet to be discovered in humans, humans do produce pheromone-like substances, and in women these change throughout the ovulatory cycle, and those at ovulation appear to have a favorable effect on males ¹¹⁾

• if 1 or more tablets are missed from the inactive tablets, no additional contraceptive precautions are necessary, thus continue taking as usual, ignoring missed tablets
• if all missed, and then the next pack is not started on time, start as soon as remembered, additional contraception must be used for next 7 days.

• delay < 12hrs then take ASAP & continue as usual
• delay > 12hrs then risk of contraceptive failure esp. if missed tablet is during 1st week or at end of pack
• take missed tablet ASAP, even if this means taking 2 at a time, but any earlier missed tablets are left in the pack
• continue taking remainder of pack as usual
• use additional contraceptive methods for next 7 days, if these extend into inactive section then skip the inactive section & start new pack in the active area on the next day instead

• hepatic enzyme inducing agents which increase metabolism of OCPs (usually via CYP 3A4 activity):
  • anticonvulsants such as:
    • carbamazepine, oxcarbazine, phenobarbitone, phenytoin
    • topiramate at doses > 200mg/d
    • NB. OCP's can increase clearance of lamotrigine and result in increased seizures!
  • rifampicin
  • St John's wort
  • modanafil
  • rifabutin
• griseofulvin
• antibiotics as these can cause vomiting or diarrhoea and thus decreased GIT absorption of OCP
  • NOTE HOWEVER, recent published guidelines from US and UK no longer recommend additional contraceptive precautions are needed when non-enzyme inducing antibiotics are taken UNLESS vomiting or diarrhoea occur, as the theory that oral antibiotics could interupt enterohepatic reabsorption of oestrogens has not been substantiated.
• sugammadex
  • used to reverse neuro-muscular blockers but decreases progesterone concentrations equivalent to missing a daily dose of OCP