Injectable hormonal contraceptives: an overview

Octavio Peralta
Department of Gynaecology and Obstetrics, San Borja Arriarán Hospital, Faculty of Medicine, University of Chile, Santiago, Chile

Hormonal depot contraceptives containing only progestogen administered by injection are the result of a series of studies initiated by Karl Junkmann in Germany in 1953 [1]. Almost simultaneously, Schering synthesised the injectable depot ester of the progestogen norethindrone, called norethindrone (or norethisterone) enanthate (NET-EN), which was marketed under the name Noristerat [2]. During this period, Upjohn in the USA developed medroxyprogesterone acetate in its injectable depot form (DMPA), known under its proprietary name Depo-Provera [2].

The initial clinical studies on progestogen-only injectables that analysed the efficacy and safety of the method were mainly carried out in Latin America by Zanartu in Chile [3], Coutinho in Brazil [4] and Kesserü in Peru [5], between 1963 and 1965. As a result of the outcomes of these clinical studies, NET-EN was put on the market in Peru in 1967 [6]. At present, worldwide experience with NET-EN as a contraceptive is based on more than 200,000 woman-years [2, 7] and it has been registered as a contraceptive in more than 60 countries [8].

The efficacy and safety of DMPA have been studied extensively worldwide both as a contraceptive and as a treatment for gynaecological disorders. More than 1000 publications describe its metabolism and safety [7, 9]. Numerous international health institutions supported its licence as a contraceptive, but not until October 1992 did the United States Food and Drug Administration approve its use as a contraceptive, 25 years after Upjohn first applied for approval.

DMPA is the most widely used injectable contraceptive formulation, having been marketed in more than 130 developed and developing countries. Since its introduction as a contraceptive, it has been used by more than 30 million women, more than 100,000 of whom have done so for longer than 10 years. At present it is estimated that approximately 13 million women worldwide are using it.

Combined once-a-month injectables contain a synthetic oestrogen in addition to progestogen. This allows them to keep the contraceptive effect of progestogen together with the added benefit of oestrogen to provide regular bleeding simulating menstrual bleeding. Different combined once-a-month injectable contraceptive formulations have been evaluated and used over the last four decades. In China and neighbouring countries, the so-called Injectable No. 1 has been developed, made up of 17a-hydroxyprogesterone caproate and estradiol valerate, and this has been used by approximately 1 million women [10]. Deladroxate, an injectable formulation made up of dihydroxyprogesterone acetophenide and estradiol enanthate, has been used for years in Latin America [11, 12]. It is known in different countries under the names of Perlutal, Unalmes or Agurin.

Table l: The two groups of injectable contraceptives.

Two new combined once-a-month injectable contraceptives have been studied by the WHO and other institutions during the last 20-30 years, namely Cyclofem (previously known as Cycloprovera) and Mesigyna (registered in some countries as Norigynon). Safety and efficacy studies for Cyclofem began in 1968 and the first clinical trials with Mesigyna started in 1974. Subsequent introductory studies of these two combined injectable contraceptives, carried out in different countries, confirmed the results of the clinical trials and supported their commercialisation. Cyclofem and Mesigyna have demonstrated benefits and advantages compared with other once-a-month injectables, as indicated by the multicentre studies carried out by the WHO, and they are currently being accepted by an ever-increasing number of countries as a good contraceptive option [2, 11, 13].

Composition and dosage
Injectable contraceptives can be divided into two main groups according to their hormonal composition (Table 1):

Progestogen-only injectables 
1. Depot medroxyprogesterone acetate (DMPA or Depo-Provera): 1 ml injection containing 150 mg DMPA in a microcrystalline aqueous suspension, administered intramuscularly every 3 months. 
2. Norethisterone enanthate (NET-EN or Noristerat):1 ml injection containing 200 mg NET-EN in castor oil, administered intramuscularly every 2 months.

Once-a-month combined injectables
1. Cyclofem/Cycloprovera: 25 mg medroxyproges terone acetate and 5 mg estradiol cipionate. 
2. Mesigyna/Norigynon: 50 mg NET-EN and 5 mg estradiol valerate.

Both preparations are administered by deep intramuscular injection. The first dose is administered during the first 5 days of menstrual bleeding and thereafter every 30 days, plus or minus 3 days. The pharmacokinetics of the different injectables are analysed in this issue by Josué Garza Flores and Teresa Navarrete.

Mechanism of action
Progestogen-only injectables
The main contraceptive effect is exerted through changes in the cervical mucus, making it hostile to the penetration of spermatozoa. They also inhibit ovulation and cause progestogenic changes in the endometrium [2, 7, 8].

Once-a-month combined injectables
The main effect is inhibition of ovulation. They also cause changes in the cervical mucus and in endometrial morphology [2, 8].

Efficacy
Both progestogen-only injectables and once-a-month combined injectables are highly effective, with pregnancy rates between 0.1 and 0.4 after 12 months [2, 8, 14]. The efficacy of the injectable methods depends on the timing of the first injection, adherence to the schedule, and on the injection technique. A study carried out in Thailand [15] shows that delaying the first injection from the fifth to the eighth day of the cycle, increases the pregnancy rate from 0.16 to 0.62 after 3 months of use. The maximum delay for the next DMPA injection should not exceed 2 weeks, 1 week for NET-EN and 3 days for the once-a-month injectables.

Non-contraceptive benefits
In addition to preventing pregnancy, injectable contraceptives also have other reported health benefits, having been shown to decrease menstrual blood loss, increase plasma haemoglobin, and decrease dysmenorrhoea and pelvic inflammatory disease [2, 7, 8]. Edith Weisberg and Ian Fraser discuss the non-contraceptive health benefits in this issue. Progestogen-only injectables decrease the risk of endometrial cancer and possibly also the risk of ovarian cancer. The relation between cancer and injectable contraceptives is reviewed in this issue by Ramiro Molina Cartes.

Use in the post partum period
Progestogen-only injectables have not shown any adverse effects on lactation with regard to quality of the milk, duration of lactation and infant growth [16-19]. However, the progestogen is present in maternal milk in the same concentration as in maternal plasma. DMPA reaches concentrations of 10 ng/ml in the first week after its administration, decreasing to 0.5 ng/ml in the third month. The concentrations of NETEN in maternal milk are lower than those of medroxyprogesterone because the 19-nor-derivatives are less soluble in milk. The estimated daily progestogen dose ingested by the infants of mothers using progestogenonly injectable contraceptives is 0.3-10 µg DMPA and 0.5-2.4 µg NET-EN. These amounts have been estimated by taking the concentrations in maternal milk and assuming that the infant ingests 600-700 ml milk a day [20, 21]. No health problems were found in children whose mothers had used these methods, but the possible long-term effects on neuroendocrine mechanisms regulating the reproductive process are not yet known [22, 23]. More studies and long-term follow-up are necessary to answer this question.
Oestrogen-containing once-a-month combined injectables would behave in the same way as the oral combined contraceptive pill and are therefore not recommended during this period due to their possible adverse effects on the duration of lactation and infant growth [24-26].

Side effects of injectable contraceptives
Irregular bleeding

Progestogen-only injectables
Irregular bleeding is the main side effect of progestogen-only contraceptive methods. The initial use of injectables may cause irregular, unpredictable bleeding, with or without intermittent spotting. Only 10% of women who use DMPA report normal cycles during the first year of use. Irregular bleeding is usual during the first 6 months, followed by delayed bleeding and/or amenorrhoea in the months thereafter.
Menstrual irregularities with NET-EN are similar but of a lower intensity. The rate of discontinuation after 1 year is estimated at 15% due to irregular bleeding and 12% due to amenorrhoea, but these figures vary considerably from one area to another [2, 7, 8].

Once-a-month combined injectables
There are no major differences between the bleeding patterns of Cyclofem and Mesigyna users. During 10-15 days after the first injection, most women have a bleeding pattern similar to menstrual bleeding, and then they will bleed every 30 days in a regular manner, differentiating once-a-month combined injectables from progestogen-only injectables. During the first 3-6 months of use, only 25% of women experience some form of irregular bleeding and 12% develop prolonged bleeding. The discontinuation rate due to irregular bleeding is between 5 and 12% per year [2, 27].

Other side effects

Progestogen-only injectables 
Most of the side effects associated with the use of progestogen-only injectables are subjective and difficult to quantify. Some users gain weight during the first year of use and some may subsequently continue to gain weight at the same rate [7, 8]. Between 3 and 19% of users report headaches or dizziness, a percentage similar to that seen in the general population; few women discontinue this method for these reasons.

Once-a-month combined injectables
Side effects are less common than those reported with progestogen-only injectables and are similar to those reported by the users of combined pills: headaches, dizziness, mastalgia, changes in body weight, etc. [28].
In their article, Edith Weisberg and Ian Fraser analyse in detail the beneficial and adverse effects and changes in uterine bleeding with the use of injectable contraceptives.

Metabolic effects
Progestogen-only injectables tend to cause mild changes in carbohydrate metabolism. DMPA has a slight diabetogenic effect and should therefore be used with caution in diabetic women. Both types of injectables may induce changes in lipid metabolism, reducing HDL cholesterol and decreasing the HDL:LDL cholesterol ratio [29-31]. The metabolic effects of injectable contraceptives are reviewed by Luis Bahamondes.

Return to fertility
After discontinuation of progestogen-only injectables, there is generally a delay in the return to fertility in comparison with the combined pill or with non-hormonal methods. The extent of this delay varies between different regions, communities and women. After discontinuing use of DMPA, 50% of women became pregnant in the 9 months following the last injection. After discontinuing once-a-month combined injectables, ovarian function recovers quickly: 39% of women ovulated within the first 3 months and 78% within 6 months after discontinuing the method. The return to fertility is considerably shorter with these injectables, most women becoming pregnant during the first 6 months after discontinuing treatment [2, 7, 8, 13, 32]. This subject is reviewed in this issue by Susana Bassol Mayagoitia.

Interaction with other drugs
Drugs inducing liver enzymes, especially when used for prolonged periods of time, may reduce the efficacy of hormonal contraceptives. This category of drugs includes some antibiotics (rifampicin, griseofulvin), anticonvulsants and barbiturates. To date there is insufficient knowledge with regard to the possible interactions between these drugs and injectable contraceptives, and therefore it is recommended that women who need these types of drugs for prolonged periods of time use other contraceptive alternatives.

Counselling
Counselling is an essential element for any couple visiting a family planning centre to select a contraceptive method. Women choosing an injectable contraceptive must be given clear information about the advantages and disadvantages of the method, side effects, costs and comparisons with other contraceptive methods. The differences between the two types of injectables must be explained, especially with regard to menstrual irregularity and return to fertility.

Eligibility criteria for using injectable contraceptives
The WHO has taken special care to revise and reach consent on the medical criteria concerning recommendations for use of the different contraceptives. Attempts have been made to standardise medical eligibility criteria to ensure that the suggestions made during medical counselling are adequately supported by scientific evidence. Accordingly, four categories have been established for each alternative contraceptive method, with the aim of ensuring a certain margin of safety in the indication and of trying to eliminate the term 'contraindications' [33]. The eligibility criteria for the injectable contraceptives are reviewed extensively by Laneta Dorflinger; the acceptability of the method is discussed by Pablo Lavin; while indications in special circumstances such as adolescence, post partum and during perimenopause, are described by Mamdouh M. Shaaban.

References
1. Junkmann K. Ober protrahiert wirksame Gestagene. Naunyn Schmiedeberg's Arch Exp Pathol Pharmakol 1954; 223: 244-53.
2. Lande RE. Popul Rep 1995; 23(2).
3. Zanartu J. A new approach to fertility control: long-acting injectable progestogens. Adv Fertil Control 1968; 3: 41-3.
4. Coutinho EM, Carlos de Souza J. Conception control by monthly injections of medroxyprogesterone suspension and long-acting oestrogen. J Reprod Fertil 1968; 15: 209-14. 
5. Kesseru E, et al. Fertility control with norethindrone enanthate, a long-acting parenteral progestogen. Acta Eur Fertil 1973; 4:203-321. 
6. Kesserü-Koos E, Larrañaga-Legufa A, Hurtado-Koo H, Scharff JJ. Nuevas perspectivas Para los anticonceptivos inyectables. Adv Contracept 1994; 10 (suppl 1): 69-77.
7. Liskin LS, Blackburn MS. Hormonal contraception: new long acting methods. Popul Rep Ser K 1987; 3.
8. Declaration of IMAP on injectable contraception. IPPF Med Bull 1999; 33(2).
9. Hall P, Garza Flores J. Anticonceptivos inyectables de acción prolongada. In: Perez Palacios G, Garza Flores J, Hall P, eds. Avances recientes en regulación de la fertilidad. Vol 1. Mexico: Editorial Piensa SA de CV, 1987.
10. Sang GW, Shao QX, Ge RS, et al. A multicentred phase III comparative clinical trial of Mesigyna, Cyclofem and Injectable No. 1 given monthly by intramuscular injection to Chinese women. Contraception 1995; 51: 185-92.
11. Newton JR, D'Arcangues C, Hall PE. Once-a-month combined injectable contraceptives. J Obstet Gynecol 1994; 14 (suppl 1): 41-53.
12. Facts about once-a-month injectable contraceptives: memoran dum from a WHO meeting. Bull WHO 1993; 77: 677-89.
13. Garza Flores J, Hall P Anticonceptivos inyectables mensuales. In: Perez Palacios G, Garza Flores J, Hall P, eds. Avances recientes en regulacidn de la fertilidad. Vol 1. Mexico: Editorial Piensa SA de CV, 1987.
14. Koetsawang S. Once-a-month injectable contraceptives: efficacy and reasons for discontinuation. Contraception 1994; 49: 387-96.
15. Gray RH, Pardthaisong T, McDaniel EB, et al. The timing of the first injection of Depoprovera. IPPF Med Bull 7975; 9(5).
16. Zanartu J, Aguilera E, Munoz G, Peliowski H. Effect of a longacting contraceptive progestogen on lactation. Obstet Gynecol 1976; 47:174-6.
17. Toddywalla VS, Joshi L, Virkar K. Effect of contraceptive steroids on human lactation. Am J Obstet Gynecol 1977; 127: 245-9.
18. Karim M, Ammar R, el-Mahgoub S, et al. Injected progestogen and lactation. Br Med J 1971; 1: 200-3. 
19. Peralta O, Diaz S, Croxatto HB. Planificación familiar durante el período de lactancia. Rev Chil Pediatr 1989; 60 (2 suppl): 19-23.
20. Koetsawang S, Nukulkarn P, Fotherby K, et al. Transfer of contraceptive steroids in milk of women using long-acting gestagens. Contraception 1982; 25: 321-31.
21. Saxena BN, Shrimanker K, Grudzinskas JG. Levels of contraceptive steroids in breast milk and plasma of lactating women. Contraception 1977; 16: 605-13.
22. Jimenez J, Ochoa M, Soler MP, Portales P. Long-term follow-up of children breast-fed by mothers receiving depot medroxyprogesterone acetate. Contraception 1984; 30: 523-33.
23. Koetsawang S, Boonyaprakob V, Suvanichati S, et al. Longterm study of growth and development of children breast-fed by mothers receiving depoprovera during lactation. In: Zatuchni GI, Goldmith A, Shelton JD, Sciarra JJ, eds. Long-acting contraceptive delivery systems. Philadelphia, PA: Harper and Row, 7984; 378-87.
24. Diaz S, Peralta O, Juez G, et al. Fertility regulation in nursing women: III. Short-term influence of a low-dose combined oral contraceptive upon lactation and infant growth. Contraception 7983; 27: 1-11.
25. Croxatto HB, Díaz S, Peralta O, et al. Fertility regulation in nursing women: IV Long-term influence of a low-dose combined oral contraceptive initiated at day 30 post partum upon lactation and infant growth. Contraception 1983; 27: 13-25.
26. Peralta O, Díaz S, Juez G, et al. Fertility regulation in nursing women: V. Long-term influence of a low-dose combined oral contraceptive initiated at day 90 post partum upon lactation and infant growth. Contraception 1983; 27: 27-38.
27. Fraser IS. Vaginal bleeding patterns in women using once-a month injectable contraceptives. Contraception 1994; 49: 399-1120.
28. Hall PE. The introduction of Cyclofem into national family planning programmes: experience from studies in Indonesia, Jamaica, Mexico, Thailand and Tunisia. World Health Organization Task Force on Research on Introduction and Transfer of Technologies for Fertility Regulation. Contraception 1994; 49: 489-507.
29. Fraser IS, Weisberg E. A comprehensive review of injectable contraception with special emphasis on depot medroxyprogesterone acetate. Med J Aust 1981; 1 (1 supply: 3-9.
30 Haiba NA, el-Habashy MA, Said SA, et al. Clinical evaluation of two monthly injectable contraceptives and their effects on some metabolic parameters. Contraception 1989; 39: 619-32.
31. Giwa-Osagie OF. Metabolic effects of once-a-month combined injectable contraceptives. Contraception 1994; 49: 421-33.
32. Bassol S, Garza Flores J. Review of ovulation return upon discontinuation of once-a-month injectable contraceptives. Contraception 7994; 49: 441-53.
33. World Health Organization. Improving access to quality care in family planning. Medical eligibility criteria for initiating and continuing use of contraceptive methods. Geneva: WHO, 1996.