Comments Dermatology 1992; I.S4:161-170
D. Lehucher Ceyrac ' D. Serfatyb H. Lefrancqc
Retinoids and Contraception
Dermatologic. Service du Pr. Puissant, et Centre de Fertilité. d’Orthogénie et de Régulation des naissances. I lôpital Saint-Louis. Paris. France; F. Hoffmann-La Roche. Basel. Switzerland
Key Words
Abstract
Retinoids Contraceptive pill Teratogenicity Intrauterine devices
The main side effect of the retinoids is teratogenicity. Every dermatologist has a moral obligation to ensure that this effect is avoided, and the present publication is aimed at helping prescribe these drugs. After a review of the key properties of each of the retinoids on the market, the different forms of contraception avail able and their indication in young patients undergoing retinoid treatment are discussed. Unless otherwise contraindicated, oral contraception with an estro gen-progestogen formulation is the contraceptive method of choice for women undergoing retinoid treatment. The intrauterine device (IUD) is of little or almost no relevance for young women undergoing treatment with a retinoid. IUDs are indicated in older multiparae who have practised this form of contra ception before starting retinoid treatment and who refuse to take the pill. Natu ral and local methods of contraception are totally unsuitable for women under going treatment w'ith retinoids. However, they may be used as an additional pre cautionary measure by IUD users.
Received: March 15. 1991 Accepted: September 13. 1991
essential that pregnancy should be formally excluded before the treatment begins. Selecting the form of contraception to be used and mon itoring its effectiveness are not necessarily routine tasks for the dermatologist. Wc therefore review specific aspects of contraception in women who require retinoid treatment for a skin disorder. First, however, the teratogenic effects of the retinoids, and the different oral contraceptives cur rently available, will be reviewed.
l)omink|uc Lchuchcr Ccyrac Consultante Dermatologie. Service du Pr. Puissant Hôpital Saint-Louis. L avenue Claude-Vcllcfuux 1**— 75745 Paris Cedex 10 (Prance)
1992 Karger A O. Basel 1018-8665/92/1843-0161 $ 2.75/t)
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
The retinoids are powerful drugs which may exert a spectacular effect; they nonetheless cause a number of adverse reactions which considerably limit their value in certain patients. One major limitation of the retinoids is their teratogenic effect. It is imperative that any woman of childbearing potential who is being treated w'ith an oral retinoid should take absolutely reliable contraceptive measures during the treatment and also afterwards for a period that varies according to the retinoid used. In addition, of course, it is
Table 1. Pregnancies occurring during treatment with retinoids and their outcome, as reported to the manufacturer between 1982 (for Roac cutane) or 1976 (for Tigason) and December 31. 1990 Tigason during treatment
Pregnancy Termination Normal infant In progress Malformations
world
USA
world
USA
world
USA
766 492 95 78 llll
533 315 78 5 88
83 47 16 18 15
12 8 2 7 2
123 42 53 18 1(1
8 1 6 1
Teratogenic Effects of Retinoids The teratogenic and embryotoxic effects of vitamin A and its derivatives were known from animal studies and became a particular focus of attention from the outset in the development of the retinoids. A number of events asso ciated with improper or poorly documented prescription of these drugs for women of childbearing potential [ 11 unfor tunately confirmed that the teratogenic effect also applies to human beings. Despite all the precautionary measures that were devised on the basis of the pharmacological, pharmacokinetic and clinical data and widely disseminated throughout the medical profession, the retinoids have sometimes been prescribed for pregnant women. In addi tion. a number of insufficiently informed patients have not adhered to the mandatory period of contraception follow ing withdrawal of treatment. These treatment errors have, in some eases, had drastic effects on the conceptus. Such events arc inadmissible: the available preclinical and clinical data have ensured from the outset that, if pre scribed according to rigorous criteria, with provision of information for the patient and strict medical and labora tory surveillance, the retinoids arc extremely safe drugs. Isotretinoin and Pregnancy Between the initial launch of isotretinoin in the USA in the summer of 1982 and December 31, 1990, 766 pregnan cies (533 of them in the USA) occurring in connection with administration of the drug in the countries in which it is marketed were reported spontaneously to the manufactur er (table 1). Of these pregnancies, 492 (315 in the USA) were termi nated voluntarily or spontaneously. In 95 women (78 in the USA) pregnancy resulted in the birth of a normal child. Seventy-eight women (52 in the USA) were still pregnant
162
2 years after treatment
at the time of writing (March 1991 ). In the other cases, the offspring had anomalies but no malformations, or the patients were lost from sight. Malformations of the neonates or. if pregnancy was ter minated. of the fetuses were observed in 101 patients (88 in the USA). The data show that, as far as births connected with iso tretinoin treatment are concerned, the number of normal children and that of children with malformations were more or less equivalent. A study by Chen [3] drew attention to several important points: The malformations arc all found in infants whose mothers took isotretinoin during the first 3 months of preg nancy. There is no significant difference between the children with malformations and the normal children in respect of the length of exposure of the fetus to the drug and the daily dose taken by the mother. The malformations mainly concern the central nervous system, the craniofacial region (ears) and the cardiovascu lar system (large vessels). Of the patients whose obstetric history has been recon structed in detail, more than one third appear to have already been pregnant before isotretinoin was prescribed. A similar proportion of these women were not taking con traceptive precautions at the time of prescription. Finally, one third w'ere using unreliable contraceptive measures (local or mechanical). The mechanism underlying this teratogenic effect has not been elucidated. It is possibly connected with a harmful effect of isotretinoin on cell migration from the neural crest, which is ultimately manifested as craniofacial malfor mations [4|.
Lchuchcr Ccyrac/Serfaty/Lcfrancq
Retinoids and Contraception
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
Roaccutane
Contraception and Retinoids Any estimate of the number of women treated with reti noids throughout the world can only be very approximate. For etretinate, the number is virtually impossible to calcu late because the drug is a symptomatic and not a causal treatment for disorders of kcratinization: since these disor ders often recur, each patient has to undergo periodic treat ment at irregular intervals. With regard to isotretinoin, if each patient received a total cumulative dose of 10 g. the number of people treated throughout the world in 1990 may be put at 250.000. Many of these patients are women of childbearing potential. They arc. in fact, all the more likely to become
pregnant because the skin disease from which they are suf fering will have been an immense social and emotional handicap for them and their physical appearance may be considerably improved by treatment. Hence the extreme importance of informing them of the risks inherent in any treatment with isotretinoin. Since the introduction of the retinoids, enormous efforts have been made in all countries - with the support of the health authorities - to inform doctors and medical staff about the risk of malformations occurring in connection with retinoid treatment. Despite these efforts, however, the figures reported above show that the information campaign has not had the desired impact. Pregnancies are still occurring during reti noid treatment. Since most modern methods of contracep tion and birth control have proved effective, it has to be admitted that the pregnancies in question were the result of mistakes made either by the patient or by the prescribing doctor. There are two conclusions to be drawn from this: ( I) it is essential that the information campaign should be continued and even stepped up: (2) since retinoids are usu ally prescribed by dermatologists, who arc not necessarily aware of the latest progress in contraceptive techniques, specific information on the subject should be compiled and disseminated. Hormonal Contraception: The 'PUT Epidemiological Aspects. Oral contraceptives (the 'pill') combining an estrogen and a progestogen are currently the most effective and most widespread method of birth con trol throughout the w'orld. According to the WHO journal Progress (No. 14. 1990). 55 million women the world over use oral contraceptives. In the USA. 13.2 million women aged 15-44 years, i.e. 32% of women of childbearing potential, were taking the pill in 1987 (table 2) [5]. In the EC countries [unpubl. data], the pill is the most popular method of contraception among women of childbearing potential aged 15-44 years, i.e. 38% of women in the UK. 36% in Denmark. 33% in the FRG and 31% in France [69]. In France, the pill is the principal method of contracep tion. being used by 32% of women aged 18-49 years |7|. Different Types o f Oral Contraceptives. The different types of oral contraceptives currently available are listed in table 3. Their effectiveness can be estimated with the help of Pearl's formula for calculating the number of unwanted pregnancies per 1.200 months of use. i.e. 12 months of use in 100 women (100 woman-years): Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
Etretinate and Pregnancy Etretinate tends to be indicated in older patients, and therefore the problem of contraception is less acute than with isotretinoin. This is probably the reason why fewer pregnancies have been reported in connection with etreti nate. Between 1976 (when etretinate was introduced for the first time, in the UK), and December 31. 1990. 83 pregnan cies (12 in the USA) resulting from conception during treatment with etretinate were reported spontaneously to the manufacturer (table I). Of these pregnancies. 47 (8 in the USA) were termi nated voluntarily or spontaneously. In 16 women (2 in the USA), pregnancy resulted in normal offspring. In 6. preg nancy is still underway at the time of writing (March 1991). or the children were born with anomalies but no malforma tions. One woman was lost from sight. Malformations were observed in the offspring of 15 women (2 in the USA). As with isotretinoin, the number of infants exhibiting malformations was more or less equivalent to that of nor mal children. The malformations observed mainly concern the skel etal system, craniofacial region, limbs and central nervous system. During the same period. 123 pregnancies (8 in the USA) were reported in connection with conception occurring during the 2 years following withdrawal of treatment with etretinate. Of these pregnancies. 42 (1 in the USA) were terminated voluntarily or spontaneously. In 53 women (6 in the USA) pregnancy resulted in normal offspring. For 18 women, pregnancy is still in progress at the time of writing, or the children were born with anomalies but no malforma tions. Malformations were observed in the offspring of 10 women (I in the USA).
i ¡IK|CX„ number of pregnancies x 1.200 number of months of exposure
Combined estrogen-progestogen oral contraceptives arc available in a number of forms but have the same mech anism of action: blockage of ovulation as a result of their gonadotropic effect and peripheral changes affecting the endometrium and the cervical mucus. Higher-dose formulations contain 50 ¡.tg of estrogen and a variable amount of progestogen. These formulations are the most effective; their failure rate is 0.2% per 100 woman-years. Low-dose formulations contain less than 50 pg of estro gen and come in three forms: monophasic formulations, in which the same content of estrogen and of progestogen is used for the entire calendar pack; biphasic formulations, in which two levels of estrogen and progestogen content are used: triphasic formulations, in which three levels of estro gen and progestogen content are used. This type of formu lation has the advantage of being very well tolerated. In addition, disturbances of the menstrual cycle appear to occur more rarely than under low-dose monophasic formu lations while offering much the same level of protection against pregnancy. The pregnancy rate varies according to the combined estrogen-progestogen formulation used: the Pearl preg nancy index is 0-0.1 for the higher-dose formulations. 0-0.18 for the monophasic low-dose formulations. 0-0.01 for the biphasic formulations and 0.10-0.18 for the tripha sic formulations (table 2). Sequential estrogen-progestogen oral contraceptives arc designed so that estrogen alone is administered for 7-15 days at the beginning of the cycle, and a combination of estrogen and progestogen the rest of the time. They act mainly by blocking ovulation and arc slightly less effective than the combined formulations. Their efficacy varies according to the progestogen used: the Pearl index is between 0.9 and 3. Low-dose progestogen-only formulations (‘minipill’) arc designed so that very small amounts of a progestogen on its own arc administered continuously and without interrup tion. These formulations act by modifying the cervical mucus, while their effect on the pituitary-suprarenal axis, endometrium and tubes varies. According to the Pearl index calculated for the different oral contraceptives, the combined estrogen-progestogen formulations appear to be the most effective, followed by sequential oral contraceptives and then the low-dose pro gestogen formulations.
164
Table 2. Estimated number and percentage distribution of women aged 15—14 years in the USA: breakdown by exposure to risk of unwanted pregnancy, form of contraception used and percentage dis tribution of women aged 15-44 years exposed to risk Exposure and method used
Number of users (millions)
All women %
Women exposed to risk. %
Users exposed to risk Sterilization Women Men Pill Condom IUD Diaphragm Spermicide gel Suppository Impregnated tampons Periodic abstinence Withdrawal Vaginal douche Nonusers exposed to risk
38.0
66
02
13.8 5.7 13.2 6.0 l.l 1.7 0.6 0.6 1.1 1.7 2.3 0.6 3.3
24 10 23 12 2 3 1 1 2 3 4 1 6
33 14 32 17 3 4 1 1 3 4 6 1 8
From Forrest and Fordyce [2|. quoted by Mishell |5j.
Other progestogen formulations with an antigonadotropic effect, e.g. certain derivatives of 19-nor-progesterone (nomegestrol and promegestone) and of 17-hydroxy progcstcronc (chlormadinonc acetate), may be used on their own as contraceptives from day 5 to day 25 of the menstrual cycle if there is a compelling contraindication for estrogens, even though this indication is not universally accepted by the authorities. Side Effects. Vascular complications are the main risk associated with estrogen-progestogen formulations. The risk of venous thromboembolism is 3-5 times higher than in nonusers; the risk of coronary artery complications is 3^4 times higher and that of cerebrovascular accidents 4-9 times higher junpubl. data]. The incidence of venous thromboembolism has shown a marked decline as a result of the reduction in the estrogen content of the formulations and the more rigorous criteria applied to users. The pathogenesis of these vascular complications of the pill has not been fully elucidated. Very probably, classic risk factors of vascular disease such as high blood pressure, diabetes, obesity, blood lipid disorders and, above all. tobacco abuse increase the risk inherent in the two compo nents of the pill, estrogen and progestogen |8|.
I .clincher Ceyrac/Serfaty/Lefrancq
Retinoids and Contraception
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
p
Table 3. Different oral contraceptives Type of oral contraceptive
Definition
Combined EP pills
Higher dose E =50 pg/day
E -5 0 ug/day + P variable
Low dose E 5(1 ug estrogen
D. Lehucher Ceyrac ' D. Serfatyb H. Lefrancqc
Retinoids and Contraception
Dermatologic. Service du Pr. Puissant, et Centre de Fertilité. d’Orthogénie et de Régulation des naissances. I lôpital Saint-Louis. Paris. France; F. Hoffmann-La Roche. Basel. Switzerland
Key Words
Abstract
Retinoids Contraceptive pill Teratogenicity Intrauterine devices
The main side effect of the retinoids is teratogenicity. Every dermatologist has a moral obligation to ensure that this effect is avoided, and the present publication is aimed at helping prescribe these drugs. After a review of the key properties of each of the retinoids on the market, the different forms of contraception avail able and their indication in young patients undergoing retinoid treatment are discussed. Unless otherwise contraindicated, oral contraception with an estro gen-progestogen formulation is the contraceptive method of choice for women undergoing retinoid treatment. The intrauterine device (IUD) is of little or almost no relevance for young women undergoing treatment with a retinoid. IUDs are indicated in older multiparae who have practised this form of contra ception before starting retinoid treatment and who refuse to take the pill. Natu ral and local methods of contraception are totally unsuitable for women under going treatment w'ith retinoids. However, they may be used as an additional pre cautionary measure by IUD users.
Received: March 15. 1991 Accepted: September 13. 1991
essential that pregnancy should be formally excluded before the treatment begins. Selecting the form of contraception to be used and mon itoring its effectiveness are not necessarily routine tasks for the dermatologist. Wc therefore review specific aspects of contraception in women who require retinoid treatment for a skin disorder. First, however, the teratogenic effects of the retinoids, and the different oral contraceptives cur rently available, will be reviewed.
l)omink|uc Lchuchcr Ccyrac Consultante Dermatologie. Service du Pr. Puissant Hôpital Saint-Louis. L avenue Claude-Vcllcfuux 1**— 75745 Paris Cedex 10 (Prance)
1992 Karger A O. Basel 1018-8665/92/1843-0161 $ 2.75/t)
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
The retinoids are powerful drugs which may exert a spectacular effect; they nonetheless cause a number of adverse reactions which considerably limit their value in certain patients. One major limitation of the retinoids is their teratogenic effect. It is imperative that any woman of childbearing potential who is being treated w'ith an oral retinoid should take absolutely reliable contraceptive measures during the treatment and also afterwards for a period that varies according to the retinoid used. In addition, of course, it is
Table 1. Pregnancies occurring during treatment with retinoids and their outcome, as reported to the manufacturer between 1982 (for Roac cutane) or 1976 (for Tigason) and December 31. 1990 Tigason during treatment
Pregnancy Termination Normal infant In progress Malformations
world
USA
world
USA
world
USA
766 492 95 78 llll
533 315 78 5 88
83 47 16 18 15
12 8 2 7 2
123 42 53 18 1(1
8 1 6 1
Teratogenic Effects of Retinoids The teratogenic and embryotoxic effects of vitamin A and its derivatives were known from animal studies and became a particular focus of attention from the outset in the development of the retinoids. A number of events asso ciated with improper or poorly documented prescription of these drugs for women of childbearing potential [ 11 unfor tunately confirmed that the teratogenic effect also applies to human beings. Despite all the precautionary measures that were devised on the basis of the pharmacological, pharmacokinetic and clinical data and widely disseminated throughout the medical profession, the retinoids have sometimes been prescribed for pregnant women. In addi tion. a number of insufficiently informed patients have not adhered to the mandatory period of contraception follow ing withdrawal of treatment. These treatment errors have, in some eases, had drastic effects on the conceptus. Such events arc inadmissible: the available preclinical and clinical data have ensured from the outset that, if pre scribed according to rigorous criteria, with provision of information for the patient and strict medical and labora tory surveillance, the retinoids arc extremely safe drugs. Isotretinoin and Pregnancy Between the initial launch of isotretinoin in the USA in the summer of 1982 and December 31, 1990, 766 pregnan cies (533 of them in the USA) occurring in connection with administration of the drug in the countries in which it is marketed were reported spontaneously to the manufactur er (table 1). Of these pregnancies, 492 (315 in the USA) were termi nated voluntarily or spontaneously. In 95 women (78 in the USA) pregnancy resulted in the birth of a normal child. Seventy-eight women (52 in the USA) were still pregnant
162
2 years after treatment
at the time of writing (March 1991 ). In the other cases, the offspring had anomalies but no malformations, or the patients were lost from sight. Malformations of the neonates or. if pregnancy was ter minated. of the fetuses were observed in 101 patients (88 in the USA). The data show that, as far as births connected with iso tretinoin treatment are concerned, the number of normal children and that of children with malformations were more or less equivalent. A study by Chen [3] drew attention to several important points: The malformations arc all found in infants whose mothers took isotretinoin during the first 3 months of preg nancy. There is no significant difference between the children with malformations and the normal children in respect of the length of exposure of the fetus to the drug and the daily dose taken by the mother. The malformations mainly concern the central nervous system, the craniofacial region (ears) and the cardiovascu lar system (large vessels). Of the patients whose obstetric history has been recon structed in detail, more than one third appear to have already been pregnant before isotretinoin was prescribed. A similar proportion of these women were not taking con traceptive precautions at the time of prescription. Finally, one third w'ere using unreliable contraceptive measures (local or mechanical). The mechanism underlying this teratogenic effect has not been elucidated. It is possibly connected with a harmful effect of isotretinoin on cell migration from the neural crest, which is ultimately manifested as craniofacial malfor mations [4|.
Lchuchcr Ccyrac/Serfaty/Lcfrancq
Retinoids and Contraception
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
Roaccutane
Contraception and Retinoids Any estimate of the number of women treated with reti noids throughout the world can only be very approximate. For etretinate, the number is virtually impossible to calcu late because the drug is a symptomatic and not a causal treatment for disorders of kcratinization: since these disor ders often recur, each patient has to undergo periodic treat ment at irregular intervals. With regard to isotretinoin, if each patient received a total cumulative dose of 10 g. the number of people treated throughout the world in 1990 may be put at 250.000. Many of these patients are women of childbearing potential. They arc. in fact, all the more likely to become
pregnant because the skin disease from which they are suf fering will have been an immense social and emotional handicap for them and their physical appearance may be considerably improved by treatment. Hence the extreme importance of informing them of the risks inherent in any treatment with isotretinoin. Since the introduction of the retinoids, enormous efforts have been made in all countries - with the support of the health authorities - to inform doctors and medical staff about the risk of malformations occurring in connection with retinoid treatment. Despite these efforts, however, the figures reported above show that the information campaign has not had the desired impact. Pregnancies are still occurring during reti noid treatment. Since most modern methods of contracep tion and birth control have proved effective, it has to be admitted that the pregnancies in question were the result of mistakes made either by the patient or by the prescribing doctor. There are two conclusions to be drawn from this: ( I) it is essential that the information campaign should be continued and even stepped up: (2) since retinoids are usu ally prescribed by dermatologists, who arc not necessarily aware of the latest progress in contraceptive techniques, specific information on the subject should be compiled and disseminated. Hormonal Contraception: The 'PUT Epidemiological Aspects. Oral contraceptives (the 'pill') combining an estrogen and a progestogen are currently the most effective and most widespread method of birth con trol throughout the w'orld. According to the WHO journal Progress (No. 14. 1990). 55 million women the world over use oral contraceptives. In the USA. 13.2 million women aged 15-44 years, i.e. 32% of women of childbearing potential, were taking the pill in 1987 (table 2) [5]. In the EC countries [unpubl. data], the pill is the most popular method of contraception among women of childbearing potential aged 15-44 years, i.e. 38% of women in the UK. 36% in Denmark. 33% in the FRG and 31% in France [69]. In France, the pill is the principal method of contracep tion. being used by 32% of women aged 18-49 years |7|. Different Types o f Oral Contraceptives. The different types of oral contraceptives currently available are listed in table 3. Their effectiveness can be estimated with the help of Pearl's formula for calculating the number of unwanted pregnancies per 1.200 months of use. i.e. 12 months of use in 100 women (100 woman-years): Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
Etretinate and Pregnancy Etretinate tends to be indicated in older patients, and therefore the problem of contraception is less acute than with isotretinoin. This is probably the reason why fewer pregnancies have been reported in connection with etreti nate. Between 1976 (when etretinate was introduced for the first time, in the UK), and December 31. 1990. 83 pregnan cies (12 in the USA) resulting from conception during treatment with etretinate were reported spontaneously to the manufacturer (table I). Of these pregnancies. 47 (8 in the USA) were termi nated voluntarily or spontaneously. In 16 women (2 in the USA), pregnancy resulted in normal offspring. In 6. preg nancy is still underway at the time of writing (March 1991). or the children were born with anomalies but no malforma tions. One woman was lost from sight. Malformations were observed in the offspring of 15 women (2 in the USA). As with isotretinoin, the number of infants exhibiting malformations was more or less equivalent to that of nor mal children. The malformations observed mainly concern the skel etal system, craniofacial region, limbs and central nervous system. During the same period. 123 pregnancies (8 in the USA) were reported in connection with conception occurring during the 2 years following withdrawal of treatment with etretinate. Of these pregnancies. 42 (1 in the USA) were terminated voluntarily or spontaneously. In 53 women (6 in the USA) pregnancy resulted in normal offspring. For 18 women, pregnancy is still in progress at the time of writing, or the children were born with anomalies but no malforma tions. Malformations were observed in the offspring of 10 women (I in the USA).
i ¡IK|CX„ number of pregnancies x 1.200 number of months of exposure
Combined estrogen-progestogen oral contraceptives arc available in a number of forms but have the same mech anism of action: blockage of ovulation as a result of their gonadotropic effect and peripheral changes affecting the endometrium and the cervical mucus. Higher-dose formulations contain 50 ¡.tg of estrogen and a variable amount of progestogen. These formulations are the most effective; their failure rate is 0.2% per 100 woman-years. Low-dose formulations contain less than 50 pg of estro gen and come in three forms: monophasic formulations, in which the same content of estrogen and of progestogen is used for the entire calendar pack; biphasic formulations, in which two levels of estrogen and progestogen content are used: triphasic formulations, in which three levels of estro gen and progestogen content are used. This type of formu lation has the advantage of being very well tolerated. In addition, disturbances of the menstrual cycle appear to occur more rarely than under low-dose monophasic formu lations while offering much the same level of protection against pregnancy. The pregnancy rate varies according to the combined estrogen-progestogen formulation used: the Pearl preg nancy index is 0-0.1 for the higher-dose formulations. 0-0.18 for the monophasic low-dose formulations. 0-0.01 for the biphasic formulations and 0.10-0.18 for the tripha sic formulations (table 2). Sequential estrogen-progestogen oral contraceptives arc designed so that estrogen alone is administered for 7-15 days at the beginning of the cycle, and a combination of estrogen and progestogen the rest of the time. They act mainly by blocking ovulation and arc slightly less effective than the combined formulations. Their efficacy varies according to the progestogen used: the Pearl index is between 0.9 and 3. Low-dose progestogen-only formulations (‘minipill’) arc designed so that very small amounts of a progestogen on its own arc administered continuously and without interrup tion. These formulations act by modifying the cervical mucus, while their effect on the pituitary-suprarenal axis, endometrium and tubes varies. According to the Pearl index calculated for the different oral contraceptives, the combined estrogen-progestogen formulations appear to be the most effective, followed by sequential oral contraceptives and then the low-dose pro gestogen formulations.
164
Table 2. Estimated number and percentage distribution of women aged 15—14 years in the USA: breakdown by exposure to risk of unwanted pregnancy, form of contraception used and percentage dis tribution of women aged 15-44 years exposed to risk Exposure and method used
Number of users (millions)
All women %
Women exposed to risk. %
Users exposed to risk Sterilization Women Men Pill Condom IUD Diaphragm Spermicide gel Suppository Impregnated tampons Periodic abstinence Withdrawal Vaginal douche Nonusers exposed to risk
38.0
66
02
13.8 5.7 13.2 6.0 l.l 1.7 0.6 0.6 1.1 1.7 2.3 0.6 3.3
24 10 23 12 2 3 1 1 2 3 4 1 6
33 14 32 17 3 4 1 1 3 4 6 1 8
From Forrest and Fordyce [2|. quoted by Mishell |5j.
Other progestogen formulations with an antigonadotropic effect, e.g. certain derivatives of 19-nor-progesterone (nomegestrol and promegestone) and of 17-hydroxy progcstcronc (chlormadinonc acetate), may be used on their own as contraceptives from day 5 to day 25 of the menstrual cycle if there is a compelling contraindication for estrogens, even though this indication is not universally accepted by the authorities. Side Effects. Vascular complications are the main risk associated with estrogen-progestogen formulations. The risk of venous thromboembolism is 3-5 times higher than in nonusers; the risk of coronary artery complications is 3^4 times higher and that of cerebrovascular accidents 4-9 times higher junpubl. data]. The incidence of venous thromboembolism has shown a marked decline as a result of the reduction in the estrogen content of the formulations and the more rigorous criteria applied to users. The pathogenesis of these vascular complications of the pill has not been fully elucidated. Very probably, classic risk factors of vascular disease such as high blood pressure, diabetes, obesity, blood lipid disorders and, above all. tobacco abuse increase the risk inherent in the two compo nents of the pill, estrogen and progestogen |8|.
I .clincher Ceyrac/Serfaty/Lefrancq
Retinoids and Contraception
Downloaded by: University of Connecticut 132.174.250.220 - 6/13/2018 6:41:06 AM
p
Table 3. Different oral contraceptives Type of oral contraceptive
Definition
Combined EP pills
Higher dose E =50 pg/day
E -5 0 ug/day + P variable
Low dose E 5(1 ug estrogen
