A review of the benefits of triphasic combined oral contraceptives when compared to today’s low-dose monophasic alternatives.
Since their introduction in 1961, oestrogen-progestogen combined oral contraceptive (COC) pills have provided women with an effective and effortless means of contraception for 50 years . Taken by 17% of all women of reproductive age, they are amongst the most widely prescribed drugs in the U.K. today. Hitherto, earlier COC formulations have been associated with harmful dose-dependent side effects . In time, however, a collective scientific effort has successfully improved the safety of COC’s by developing preparations that contain the minimum hormonal concentrations required to inhibit ovulation. Today COC’s contain 80-90% less oestrogen and progestogen than the earliest preparations and an in some types the newer, less androgenic, progestogens also . In comparison to earlier COCs, the safety profile of current low-dose preparations is markedly superior.
Accompanying these therapeutic advances has been the evolution of COC administration towards multiphasic dosing regimens, in which progestogen concentrations are sequentially increased over two (biphasic) or three (triphasic) phases. In some preparations the dose of oestrogen is also increased over one of these phases . Owed to such dose alterations, the phasic regimen has allowed further reductions in total monthly hormone exposure and more closely mimics the dynamic hormonal picture of the female menstrual cycle. During its conception, scientists hypothesised that such physiologically appropriate lower doses would afford triphasic COC’s fewer side-effects, whilst maintaining contraceptive efficacy and satisfactory cycle control [7-8].
Of the currently available multiphasic agents, triphasic COCs have almost replaced biphasic COC’s and contain up to 40% lower progestogen concentrations than their monophasic counterparts [8-9]. However, as many of the mentioned hypotheses of the benefits of triphasic COC’s were formed in the 1970s, a time when monophasic COC’s were not the low-dose preparations we identify with today, a worthwhile assessment of triphasic-benefit can only be made when they are compared to these newer low-dose monophasics. Such comparisons, on the basis of contraceptive efficacy, cycle control, side-effects and risk of cardiovascular complications, are made in this review.
Mechanism of action:
The combined administration of oestrogen and progestogen achieves contraception by employing the negative feedback mechanisms of the hypothalamic-pituitary-ovarian axis. More specifically, exogenous delivery of oestrogens and progestogen reduce the frequency of gonadotrophin-releasing hormone release from the hypothalamus, which stops follicle stimulating hormone release and the luteinizing hormone surge from the anterior pituitary gland. In tandem, this inhibits the development of ovarian follicles and prevents ovulation. Also, the progestogen component augments this contraceptive effect by making cervical mucus too viscous for sperm penetration and rendering the endometrium less amenable to blastocyst implantation . As triphasic COC’s contain increasing concentrations of progestogen and in some types a mid-phase rise in oestrogens, they are said to more closely recapitulate the peaks in endogenous hormones that occur in the menstrual cycle (see fig. 1).
Figure 1 – Endogenous and exogenous hormonal concentrations over a 28-day menstrual cycle. Stimulated by gonadotrophin-releasing hormone (GnRH) release from the hypothalamus, the anterior pituitary gland begins the menstrual cycle by secreting follicular stimulating hormone (FSH) (purple line). FSH leads to the development of 6-12 ovarian follicles; one of which eventually reaches maturation. During this time, the cells surrounding the follicle release increasing levels of...