contraceptives: an overview
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 . 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 .
During this period, Upjohn in the USA developed medroxyprogesterone
acetate in its injectable depot form (DMPA), known under its proprietary
name Depo-Provera .
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 , Coutinho in Brazil  and
Kesserü in Peru , 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
. 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 .
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 . 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):
1. Depot medroxyprogesterone acetate
(DMPA or Depo-Provera): 1 ml injection containing 150 mg DMPA in a
microcrystalline aqueous suspension, administered intramuscularly every
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
2. Mesigyna/Norigynon: 50 mg NET-EN and 5 mg
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
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].
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 
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
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 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
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
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. .
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.
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
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 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' . 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.
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