CHAPTER 2: Literature Review
2.1 Progestin-only injectable contraceptives
Progestin-only injectable HCs are a highly effective, long-acting and reversible method of contraception. They are exogenous hormones administered by injection, which contain a synthetic progestin hormone, similar to natural progesterone found in women. Currently, there are three types of injectable progestin-only HCs in wide use (Figure 2.1): DMPA (150mg dose in 1 ml injection, Figure 2.1c), depo-subQ provera 104™ (subcutaneous formulation of DMPA, 104mg dose in 0.65ml) and NET-EN (200mg dose in 1 ml; Figure 2.1d) (Bhathena, 2001; Elder, 1984; Fraser and Weisberg, 1981).
Figure 2.1 The chemical structures of (a) progesterone, (b) cortisol, (c) depot medroxyprogesterone acetate (DMPA) and (d) norethisterone enanthate (NET-EN). The structure of progesterone has 21-carbon precursor (C21H30O2) that are directly altered by enzymes within tissues resulting into different major classes of steroids (Wiebe et al., 2006). For example, the enzyme actions lead indirectly to the corticosteroids (cortisol, C21H28O5). DMPA (24-carbon precursor, C24H34O4) is a synthetic 17-hydroxyprogesterone derivative of progesterone (Fraser and Weisberg, 1981) while NET-EN is a 17C-alpha-ethinyl-17beta-heptanoyloxy-4esterene-3-one synthetic progesterone derivative (Zanartu and Navarro, 1968). Figure drawn by Sinaye Ngcapu.
DMPA and NET-EN differ in cost and frequency of administration, which has implications on budgeting in the health system and patient uptake, respectively. In South Africa and internationally, DMPA is substantially cheaper than NET-EN which is an important consideration from a public health perspective. According to the South African Department of Health Medicine Prices database from the 12th March 2015, a single dose of DMPA (150mg in a 1 ml injection) cost the government R25 (including value added tax) while NET- EN cost more than twice that at R58 per dose (200mg in 1 ml) (http://www.health.gov.za/index.php/single-exit-price-documents). In South Africa, both of these options are available free of charge at national primary health care facilities and are listed in the South African Essential Drugs List (Smit et al., 2001). Internationally, they are also extensively used in reproductive health programs, forming a large proportion of health system expenditure on contraception, especially in resource limited regions (Kaunitz, 1994;
Margulies and Miller, 2001). Both of these injectable HC formulations are given by intramuscular injection, and the progestin is then slowly released into bloodstream from the injection site over the course of months.
2.1.1 DMPA
DMPA is a synthetic 17-hydroxyprogesterone derivative of progesterone (Figure 2.1c), administered by intramuscular depot injection as an aqueous microcrystalline suspension (150mg/ml) every three months. It was developed by the UpJohn Company in the late 1950s and was approved as a contraceptive method in many countries in the late 1960s (Babcock et al., 1958; Fraser and Weisberg, 1981). DMPA binds with high affinity to the progesterone receptor expressed by epithelial cells, fibroblast and smooth muscle in the upper female reproductive tract, where it induces secretory transformation of the oestrogen-primed
endometrium, which is then shed (Hatcher et al., 2011).
DMPA gained popularity because of its prolonged 3-month duration of action, achieved by the progestin being slowly released (due to the low solubility of the microcrystals) into the bloodstream from the gluteal or deltoid muscles where it is injected (Mishell, 1996). DMPA can be detected in the bloodstream within 30 minutes after intramuscular injection and increases steadily to effective plasma levels >0.2ng/ml within 24 hours (Ortiz et al., 1977).
Plasma DMPA concentrations plateau between 1.0 to 1.5ng/ml for the 3 month duration of the contraceptive treatment but these plasma concentrations then gradually decline to
~0.2ng/ml during the fourth month (Ortiz et al., 1977). The active plasma concentrations of DMPA achieved vary between women, with some women having detectable plasma levels
>0.2ng/ml for more than 9 months after a single dose of 150mg/ml (Fraser and Weisberg, 1981; Mishell, 1996). DMPA is highly effective as a form of contraception, with an accidental pregnancy rate of 0.4 per 100 women, with lower efficacy generally only being seen because of inconsistent or incorrect use (Chinnatamby, 1971; Dodds, 1975; Powell and Seymour, 1971).
DMPA primarily provides contraceptive protection by suppressing levels of the follicle stimulating hormone and luteinizing hormone, which lead to inhibition of gonadotropin secretion, thereby inhibiting follicular maturation and ovulation (Hatcher et al., 2011;
Mishell, 1996; Mishell et al., 1968; Speroff and Darney, 2010). This action also results in a hypoestrogenic state (Mishell, 1996). DMPA also induces atrophy of the endometrium, by decreasing glycogen content needed to provide energy for the development of the blastocyst after the morula has entered the uterine cavity (Hatcher et al., 2011; Mishell, 1996; Mishell et
al., 1968; Speroff and Darney, 2010). Furthermore, DMPA causes thickening of cervical mucus, making it unfavourable for spermatozoa to migrate to the oviduct to fertilize the egg (Hatcher et al., 2011; Mishell, 1996; Mishell et al., 1968; Speroff and Darney, 2010).
DMPA is a reversible, coitally-independent method of contraception, which takes an average of 4 months for women to return to fertility after DMPA is discontinued (Pardthaisong, 1984). Studies have shown that the use of DMPA during pregnancy or breastfeeding does not adversely affect the duration of lactation, quantity or quality of breast milk or the health and development of nursing infants (Pardthaisong, 1984; Pardthaisong et al., 1992).
2.1.2 Norethisterone Enanthate (NET-EN)
NET-EN is a 17C-alpha-ethinyl-17beta-heptanoyloxy-4esterene-3-one synthetic progesterone derivative (Figure 2.1d), similar to DMPA, developed in 1966 (Zanartu and Navarro, 1968), and now commonly used for contraception. It is expensive compared to DMPA, resulting in more limited roll-out in limited-resourced countries (Smit et al., 2001). NET-EN is a long chain ester of norethisterone prepared in an oily solution that is effective for two months as a contraception (Fotherby et al., 1978; Goebelsmann et al., 1979). The usual dose administered contains 200mg/ml of NET-EN, with the plasma concentrations reaching a peak of 5.5 to 11ng/ml in about 10 days that gradually decreases to 0.8ng/ml at 8 weeks after intramuscular injection (Goebelsmann et al., 1979). NET-EN inhibits ovulation, coinciding with high levels of plasma progesterone (Fraser and Weisberg, 1981; Zanartu and Navarro, 1968). This is followed by premature luteolysis, the structural and functional degradation of the corpus luteum, together with peripheral fertility-inhibiting effect when ovulation-inhibiting effect wears off. The progestogenic effect also cause changes in cervical mucus, tubal function and
endometrium thereby reducing fertility (Fraser and Weisberg, 1981; Zanartu and Navarro, 1968). Like DMPA, the overall pregnancy rate for NET-EN is low, ranging from 0.01–1.49 per 100 women years (Kesseru-Koos et al., 1973). Like DMPA, NET-EN is a reversible method of contraception, but women take an average of 8 months to return to fertility after use (Banerjee et al., 1986). NET-EN use does not adversely affect lactating women but its administration is not advised in the first and early second trimesters of pregnancy (Fine et al., 1963; Karim et al., 1971).