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`the Wo1d
`
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`
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`
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`
`iti
`
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`
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`
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`
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`
`deetve Medtuee
`
`OC Practice Guidelines
`Minimizing Side Effects
`
`Philip
`
`Darney M.D M.Sc
`
`Department
`
`of Obstetrics Gynecology
`
`ProlessormnResidenee
`
`and Reproductive Sciences
`School of Medicine
`
`of California San Francisco
`University
`San Francisco Califwnia US
`
`breast
`
`of
`
`of oral contraceptives OCs can be minimized by appropriate OC selection
`ASTRACT The side effects
`themselves physicallye.g
`that manifest
`Side effects
`side effects
`or perceived
`weight gain breakthrough
`tenderness mood swings acne
`bleeding I3TB nausea headache
`and hirsutismare the most corn
`mon causes
`of oral contraception ihe relative androgenicity
`the progestin
`of premature discontinuation
`in selecting OC formulations Several
`has become an important differential
`of combination OC.s
`component
`that preparations with less androgeirie potential can minimize some of
`studies have
`the physi
`indicated
`Acne and hir
`cal side effects
`and adverse metabolic effects
`traditionally associated with oral contraception
`autism common pre-existing conditions that are clearly related
`of
`the progestin
`to the androgenicity
`or improved by use of OCs with low androgenic
`activity Many women pen
`can be eliminated
`component
`that OCs cause weight gain although weight gain is to some extent
`androgen related most studies
`ceive
`low-androgenic OCs with medium- or high-androgenic preparations
`have
`found
`little or no
`comparing
`few mnths is related to
`regardless of formulation BTB which usually
`in weight
`subsides within
`change
`in the OC formulation Low.estxogen-dose O2s
`and ratio of
`and progestin
`the estrogen
`the dose potency
`arc associated with bleeding patterns
`S35 pg cthinyl estradiol
`less androgenie
`contaimng
`progestins
`as
`fonnulations The same analysis
`found that smoking
`as older
`cigarettes pro
`acceptable
`low-estrogen-dose
`in women who use OCs There is no convincing evidence
`the use of one progestin
`motes
`that
`or
`is ies likely to cause or exacerbate
`sometimes
`however changing preparations
`another
`headache
`the mcidence Women with persistent
`interval may benefit
`from longer
`headaches during the pill-free
`cycle of OC treatment
`woman
`Nausea
`and breast
`effects
`tendernesa
`are primarily
`estrogen-related
`nausea switching to an OC formulation containing
`20 pg EE may be appropriate
`experiences
`persistent
`cautioned that ETE is more likely Mood changes arc
`common highly
`the patient
`subjectwe
`long as
`relationship to DC use is hard to assess Concerns about
`complaint whose
`the potentially deleterious
`of combination OCs on lipid/lipoprotcin
`metabolism have
`and carbohydrate
`been substantially diminished
`low
`by new epidemiologic findings
`relative to cardiovascular
`as by the development
`as we-Il
`lower LDL cholesterol
`and
`progestiris Formulations containing
`increase l-IDL
`these progestins
`metabolism as much as older more androgenic formulations
`they do not affect
`l158-469
`
`BTI3
`
`androgenic
`
`cholesterol
`
`Jut
`
`carbohydrate
`1997
`
`disease
`
`reduces
`
`if
`
`as
`
`effects
`
`of
`
`KEY WORDS oral contraceptives
`
`side effects androgenicity
`
`estrogen progestin
`
`INTRODUCTION
`
`WIDE VARIETY OF EFFECTIVE AND
`safe oral contraceptive OC formulations
`As
`is currently available
`general rule
`combination OC with the lowest dose
`that will maintain contra
`and estrogen
`
`of
`
`progestin
`
`158
`
`and meet
`ceptive protection minimize side effects
`should be pre
`the individual
`needs of
`the patient
`scribed The present article
`on issues per-
`focuses
`taming to unwanted OC side effects
`and how they
`by appropriate OC selection
`may be minimized
`with particular
`on those that manliest
`emphasis
`themselves in ways
`that are perceptible
`
`to users
`
`________________________
`
`IntfFexOi42
`
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`Csa Pku 11$O4P TJB
`Ho 12vO2I2-JP.TJB
`
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`
`_____ _______ OC Practice GukJUns
`
`159
`
`number of studies have
`these phys
`that
`suggested
`ical side effects are the most common cause of
`premature discontinuation
`of oral contraception
`The androgenicity
`of progcstin has received
`considerable
`attention
`
`in recent years particularly
`of combination OCs contain
`with the introduction
`ing progestins with relatively low andrngenic
`ity Accordingly much of
`discussion
`the following
`role of
`is devoted to the potential
`these newer
`mulations in reducing 00 side effects
`
`activ
`
`for
`
`SIDE EFFECTS DiScONTINUATION
`AND PATIENT COMPLIANCE
`
`Clinicians
`the potential effects
`are well aware of
`of OCs on lipid/lipoprotein and
`carbohydrate
`and hemostatis
`metabolism blood pressure
`Women who use OCs however
`are usually more
`concerned with avoiding physical problems such
`bleeding BTB
`as weight gain breakthrough
`and mood
`headache nausea breast
`tenderness
`changes Acne and hirsutism although
`rarely caused
`by modern low-estrogendose 35 jrg EE OCs are
`in 00 selec
`nonetheless
`important considerations
`to be related to
`
`they are often perceived
`
`tion because
`OCs These
`be dramatically
`side effects
`in fact
`can
`reduced by certain formulations Although physical
`to health they are fre
`pose no threat
`side effects
`causes of 00 discontinuation
`and probably
`subsequent unplanned pregnancy
`
`quent
`
`initiation
`
`these
`
`Some 25% to 50% of women who start oral
`con
`and sale
`discontinue
`using this effective
`traception
`method within the first 12 months
`alter
`12 An analysis
`by Pratt and Bachrach
`of data
`of Family Growth
`from the 1982 National
`Survey
`indicated that most women aged
`to 44 who
`15
`using OCs did so on their own initiative1
`stopped
`had been
`advised
`only about one-third
`doctor
`by
`use Almost all former users of
`to discontinue
`older 00 formulations which
`very often contained
`than are used today identi
`higher doses of estrogen
`fied some physical problem connected with OC use
`for quitting the method Figure
`reason
`as
`reasons why women
`The
`two most common
`stopped taking OCs on their own initiative were
`weight gain 11.4% and nausea 10.2% Headache
`and menstrual abnormalities
`also were frequently
`cited 6.4% and 6% respectively Concern
`about
`t3.2% and high blood
`blood
`clots or heart disease
`pressure 1.2% were given
`as additional
`reasons
`for
`figures do not necessarily
`discontinuation These
`but in many cases proba
`reflect existing conditions
`the safety of OCs
`fears about
`bly indicate patients
`such as acne and weight
`side effects
`Androgenic
`gain have also been reported to be major cause
`00 discontinuation
`It has been
`calculated
`that
`25% of women who stop OCs do so
`approximately
`both of
`because of weight gain
`or acne
`Addition
`which
`are associated with androgenicity
`analyzing OC use in sample
`recent study
`ally
`of 6676 women between the ages of 16 and 30 found
`
`of
`
`12
`
`10
`
`Discontinuing
`on Own
`
`Weight
`Ga
`
`Nausea
`
`Headache
`
`Bleeding
`
`Blood
`
`Clot/
`
`Aboornalities
`
`Heart
`
`12
`
`High
`
`Blood
`
`are the main reasons women aged 15 to 44 discontinue use
`FIG Physical problems
`of OCs Based on data from Pratt Bachrach
`
`Disease
`
`Pressure
`
`Intl Fertil 42
`
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`
`Darney_._
`
`same study
`associated with
`
`this
`
`that when hirsutism another androgenic phe
`as an actual or per
`was present whether
`nomenon
`the likelihood of poor compliance
`ceived
`side effect
`with OC regimens was approximately
`doubled
`Consistent with numerous
`previous
`reports
`found that poor compliance was also
`routine for
`lack of an established
`and understand written
`pill-taking failure to read
`come with the OC package and
`materials that
`information about OCs from
`inadequate
`receiving
`their health care provider Thus in addition
`to
`selecting DC formulations that help minimize
`coun
`unwanted
`and providing
`effects
`appropriate
`and gener
`that
`is important to ensure
`ally transient nature it
`of DC
`the basic mechanics
`new users understand
`These
`are particularly
`important
`usage
`aspects
`since the data from Pratt and Bachrach
`indicated
`former DC users did not adopt any
`19% of
`method after discontinuing
`oral contraception
`
`seling regarding their possible occurrence
`
`that
`
`MINIMIZING
`
`PHYSICAL SIDE EFFECTS
`
`the OC formula
`To minimize physical
`side effects
`tion with the lowest doses of progestin and estrogen
`the individual needs of
`that will meet
`the patient
`should be prescribed
`for the relatively
`Except
`use of an OC con
`unusual circumstance in which
`taining 50 jag estrogen may be warranted most DC
`users are and should be taking low-estrogen-dose
`formulations i.e containing 35 pg EE 40 jag EE in
`Europe The relative androgenity
`the progestin
`has become
`an issue in selecting among
`component
`formulations because several
`have
`these
`studies
`that OCs with less androgenie
`indicated
`side effects
`the physical
`can minimize some
`of
`adverse metabolic effects
`
`potential
`and
`
`traditionally associted
`
`of
`
`with oral contraception
`conference
`consensus
`
`fore
`
`countries
`
`was convened there
`based on the
`to develop
`guidelines
`practice
`of various OC formulations
`available
`androgenicity
`in the United States
`and some other
`In European
`OCs
`low androgenic
`greater variety of
`those
`is available
`including
`containing
`gestodene
`and dienogest DC formulations
`were categorized
`on the basis of
`low- medium- or high-androgenic
`the progestin
`activity of
`component Table
`The factors that were taken into account
`in gener
`included the degree
`to
`bind to androgen
`
`ating these
`which
`
`classifications
`
`different
`
`progestins
`
`TABLE
`U.S formulation selections
`
`progestin androgenic
`
`activity
`
`Low
`
`Medium
`
`High
`
`Norgestimate
`
`Levonorgestrel
`
`triphasic
`
`Norgestrel
`0.3 mg
`
`Desogestrel
`
`Norethindrone
`
`Norethindrone
`
`1.0 mg monophasic
`or triphasic
`
`acetate
`152.5 rug
`
`Norethmdmo cc
`04 0.5 mg
`monophasic
`
`Norethindrone
`10 rug
`
`acetate
`
`Levonorgestrel
`015 mg
`
`Ethynodiol
`1.0mg
`
`diacetate
`
`Adapted
`
`with permission from Mishell
`
`combination OCs containing these
`increase levels of sex hormone binding
`globulin SHBG and
`bind
`different progestins
`to SHBG thereby displacing testosterone
`the signs and symptoms probably
`Among
`threeacne hir
`attributable to androgenic
`effects
`sutism and weight gainhave been emphasized
`is known
`about
`the literature Less
`the relation
`and BTB
`ship if any between androgenicity
`and mood
`headache nausea breast
`tenderness
`the impact
`these
`of
`swings Further study of
`variables
`on various physical
`androgenic
`associated with the use of OCs is needed
`
`receptors
`
`progestins
`
`effects
`
`in
`
`side
`
`ACNE HIRSUTISM AND WEIGHT GAIN
`
`Acne and hirsutism are clearly related to the andro
`Several cliii
`of the progestin component
`genicity
`that OC use decreases
`ical studies have
`indicated
`OCs may
`
`pre-exis.ting
`
`acne and that
`benefit hirsute women
`by Palatsi and colleagues
`scores
`compared acne
`of DC use in
`at study entry and after
`cycles
`women with pre-cxisting acne who were treated
`with two different monophasic OCs one containing
`0.15 rng and the other dcsogestrel
`levonorgestrel
`0.15 mg with the same dose of RE 30 jag Acne
`
`low-androgenic
`randomized
`
`clinical
`
`trial
`
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`
`was
`
`scored
`
`equaled
`
`severe
`
`serum free testosterone
`
`scale ranging from to
`on
`few small
`clear skin or
`lesions
`acne The results showed
`that by the
`equaled
`sixth cycle of use the acne
`had improved
`signifi
`in both treatment groups but
`the improve
`candy
`ment was much greater with the less androgenic
`Even
`progestin desogestrel Figure
`though
`fell 60% in both treatment
`showed
`groups only the dcsogcstrel/EF
`group
`increase in SHBG which may account
`nificant
`scores Other studies have also
`the difference in acne
`
`OC Practke Gudenes
`
`161
`
`documented
`
`the effectiveness
`
`of desogestrel/EE
`
`in
`
`observed in
`
`ter
`
`trial of
`
`improving pre-existing acne
`2j
`on preexisting acne was
`beneficial
`effect
`European multicen
`noncomparative
`formulation containing
`monophasic
`01 41913
`norgestimate/EE 0.25 mg/35
`iag
`women aged 30 years who were enrolled 4438
`cycles of OC
`11% had acne at study entry After
`these 4438 women 37.7% no longer
`use 1675
`had
`acne Figure
`In addition among the total
`only 1% 439 reported either the
`
`of
`
`study population
`
`where
`
`and
`
`sig
`
`for
`
`LNG/EE N15
`DSO/EE NlB
`
`2.00
`
`1.50
`
`1.00
`
`0.50
`
`Acne
`
`Score
`
`0-3
`
`Baseline
`
`Cycle
`
`FIG
`
`Acne
`
`scores
`
`in
`
`comparison
`
`trial of
`
`clear
`
`or
`
`few small
`
`lesions
`
`severe
`
`levonargestrel/EE and desogestrel/EE
`tP.01 J-.OUl Based
`on data
`acne
`
`from Palatsi ci al
`
`5000
`
`4000
`
`No of
`
`3000
`
`Patients
`
`2000
`
`1000
`
`Baseline
`
`Incidence
`
`Acne No Longer
`Present
`
`Newly Emerged
`Acne
`
`Cycle
`
`monophasic UC in women aged 30
`FIG
`Acne changes with
`norgestimate/bE
`years At baseline 11% of subjects
`had acne Adapted
`with permission
`4438/41913i
`from Anderson FD Selectivity and minimal androgenicity
`in
`of norgestimate
`and
`oral contraceptives Acta ObsU3t Cynecol
`Scand 71 Suppl
`inonophasic
`triphasic
`1561521 1992 1992 Munksgaard International
`Publishers Ltd Copenhagen
`Den
`on data from Cniriwald et al 14
`mark Based
`
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`
`162
`
`PDarfley
`
`of acne or worsening of existing
`first appearance
`cycles of use In an open-label
`study of
`acne
`over
`the norgestimate/35 jig liE formulation in 42022
`women over
`cycles the incidence of acne was
`to 9% after
`from 12% pre-treament
`reduced
`1151 Only 1% of patients who
`treatment
`acne before treatment
`the
`reported
`
`cycles of
`did not have
`
`about weight gain prior to starting
`cate patients
`them on OCs so that
`if they do gain weight
`attribute it to the OC
`will not automatically
`
`they
`
`BREAKTHROUGH BLEEDING
`
`of acne during the sixth cycle
`appearance
`of OC progestins
`The effects
`on hirsutism have
`been most
`thoroughly studied for desogestrel
`large study of desogestrelcontaining OCs 499 of
`11605 women had hirsutism before being
`on
`placed
`cycles of OC use the
`After
`this preparation
`of women with preexisting
`number
`or newly
`emerged hirsutism was almost halved Several other
`have documented
`similar
`studies
`noncomparative
`treatment with desogestrel
`on hirsutism after
`effects
`to 24 months
`OCs for periods ranging from
`Many women especially
`believe
`adolescents1
`that weight gain is caused by the use of OCs and
`oral
`the reason
`often give this as
`for discontinuing
`contraception OC progestins
`SHBG and reduce
`concentrations might
`androgen
`be expected to increase body weight
`the least
`studies of OCs containing
`Noncomparative
`117 have
`and dcsogestrel
`indeed
`timate
`shown that weight
`gain is rare in women using
`mean weight gain of
`formulations with
`these
`Most stud
`of use
`whole year
`low-androgenic OCs with medium-
`have
`however
`or high-androgenic
`preparations
`in body weight
`found little or no change
`regardless
`of which formulation is used Two
`studies compar
`norgestrel OCs versus monophasic
`ing monophasic
`norgestimate did show that discontinuation
`rates
`due
`gain were slightly higher
`to weight
`than in the norgcstimate
`groups
`1.0%
`and 1.Sl% versu
`groups1.l% versus
`0.84%
`these findings are difficult
`to
`that diet age and other
`affect body weight are difficult
`to control
`cal trials With
`
`Tn
`
`that most
`
`increase
`
`forges
`
`only
`
`lb after
`
`ies comparing
`
`norgcstrel
`
`interpret given
`
`in the
`
`factors that
`
`in clini
`
`parison of
`
`for example
`
`corn
`
`regard to age
`triphasic preparation
`containing
`desogestrel OC
`and
`monophasic
`levonorgestrel
`found that significant weight gain approximately
`but only in
`kg occurred with both formulations
`women under age 20
`The preponderance
`of evidence
`sug
`therefore
`gests that OCs cause either no or only slight
`weight gain The fact
`that many women have quite
`perception makes it important
`to edu
`differet
`
`as
`
`BTB according
`to the data
`by Pratt and
`reported
`common cause of OC cliscontinu
`Bachraeh
`is
`ation BTB usually
`time goes by and in
`subsides
`or months of OC use does not
`the first
`require
`The
`in formulation
`investigation or
`change
`woman just starting OCs should be apprised of
`and should be instructed
`these
`to take
`the
`points
`pills at approximately the same
`time each
`dayand not
`pillsince there is some
`to skip
`if OC ingestion
`that BTB can occur
`evidence
`is
`few hours With new-start
`delayed by even
`BTB is often associated with poor compli
`patients
`ance To anticipate
`this problem clinicians must
`patient which requires
`counsel
`each
`individual
`and poor
`that predict
`good
`as well as an understanding
`of
`the
`
`knowledge
`
`of
`
`factors
`
`compliance
`
`decision-making processes
`patients
`BTB is related to the dose potency
`and ratio of
`and progest-in in the OC formulation
`the estrogen
`as well
`to individual
`physiologic
`response
`information about different OC prepara
`However
`tions and how they affect menstrual problems has
`been
`is due to
`the diffictilty
`Part of
`
`as
`
`confusing
`
`reported
`
`of
`
`differing study populations cultures
`study designs
`and
`the manner in which
`data were collected
`and
`The use of
`fixed reference
`periods for
`and severity
`the incidence
`of vagi
`quantification
`nal bleeding is clearly important when comparing
`different OC formulations
`123
`that OCs containing
`Published studies
`suggest
`low estrogen
`less androgenic progestins and
`dose are associated with bleeding patterns as
`50 jig Eli
`as older
`acceptable
`low-estrogen-dose
`In comparative American
`formulations
`studies
`of 1473 women using either norgestimate/EE or
`of BTB and spot
`the daily incidence
`norgestrel/EE
`ting was similar with the two treatment
`regimens
`Another study which
`desogestrel OC with
`triphasic lcvonorgestrel
`found
`to be equally
`cycle control
`mulation
`The performance
`for the two preparations
`the gonane progestins desogestrel
`gestodene
`and norgestrel with regard to BTB
`norgestimate
`may be related
`td their relatively
`least in part
`
`compared
`
`monophasic
`for
`
`good
`
`of
`
`at
`
`lot
`
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`

`
`has been
`
`dose
`
`decreases
`
`if any
`
`It
`
`et al
`
`the norgestimate
`
`long half-lives which maintain serum concentra
`tions in patients who take
`their OCs at
`the same
`time every day
`of BTB and
`The frequency
`spotting
`shown to increase as the estrogen
`to what extent
`is unclear however
`the small difference among preparations
`containing
`30 and 35 .ig EE in the trials analyzed
`by Rosenberg
`1241 might have
`contributed
`to the apparent
`formulation There
`superiority of
`30 pg EE
`is evidence
`between
`that
`the difference
`in terms of BTB In
`and 20 pg EE is meaningful
`two OC
`double-blind
`multicenter
`trial comparing
`formulations both containing
`0.15 mg desogestrel
`but with either 20 pg or 30 pg hE Ackerlund and
`found that ETB or spotting was sig
`colleagues
`nificantly more frequent with the 0.15
`pg
`combination in about
`two-thirds
`the
`of cycles over
`1-year course of the study In addition more women
`pg combination discontinued
`the
`on the 0.15 mg/20
`about continuing
`study or were less positive
`at the end of the trial
`0.15 mg/20
`pg preparation
`months with heavy
`If BTB persists beyond
`flow that bothers
`the patient
`the first step is to
`determine if she takes her pills regularly Other fac
`tors that should be considered include
`infection
`endometrial polyps submueous myoma or cervi
`cal cancer Although combination OCs reduce
`the
`disease P11 it is
`incidence
`of pelvic inflammatory
`an infectious
`still possible to have
`of irreg
`etiology
`
`nrg/20
`
`the
`
`OC Prctke Guidene
`
`183
`
`In the lat
`
`PJD or cervicitis
`ular bleeding whether
`data documented
`high preva
`ter regard recent
`infection among OC
`lence
`of cervical
`chiamydial
`users who reported
`intermenstrual spotting
`studied 65 women who had used
`The investigators
`OCs for more than months and who had spotting
`of no readily demonstrable cause They were com
`controls who were taking
`pared with 65 matched
`OCs without
`and
`intermenstrual
`spotting
`who were tested for Chiamydia trachomatis em
`and 65
`because of one or more risk factors
`vicitis
`The
`matched controls seeking contraception
`that 29% of the women taking OCs
`results showed
`for more than months and experiencing
`spotting
`tests for
`compared
`trachomatis
`had positive
`with Ii 0/ of controls who were also on OCs but
`and
`intermenstrual
`were not experiencing
`6% of the controls who were screened
`tion of contraception
`use infection and
`ruling out
`incorrect
`After
`problems in the woman with persis
`nonhormonal
`com
`tent BTB most clinicians alter
`the progestin
`additional
`before providing
`estrogen It is
`ponent
`not clear why switching to
`different progestin
`If BTB still per
`sometimes
`improves cycle control
`if the bleeding is midcycle adding
`week during the time of ETB
`more estrogen
`few
`20 pg EE or 1.25 mg conjugated
`estrogens
`months often controls the problem As
`and
`has no risk factors
`the patient
`
`spotting
`
`before initia
`
`for
`
`last
`
`for
`
`sists especially
`
`for
`
`resort
`
`if
`
`Proportion
`
`with
`
`Spotting
`
`or
`
`Bleeding
`
`0.6
`
`0.6
`
`0.4
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Cycle
`
`FIG Proportion of OC users with spotting or bleeding by smoking status Adapted
`ML Waugh MS Stevens CM Smoking and cycle
`with permission from Rosenberg
`control among oral contraceptive users Am Obstet Gynecol
`
`l974628632
`
`1996
`
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`1611
`
`narney
`
`124
`
`three
`
`is
`
`the clinician might want
`to consi.er
`thrombosis
`to an OC containing
`50 pg EE
`switching
`that smoking
`There is growing evidence
`BTB and spotting
`in women
`promotes
`cigarettes
`who use OCs In their analysis
`of data from three
`large multisite trials Rosenjerg and associates
`one-third
`of
`that approximately
`the
`ascertained
`women smoked cigarettes The proportion of
`smokers who reported
`ranged from 59%
`bleeding
`23% over
`in cycleJ to 14% in cycle
`averaging
`slightly lower proportion
`the
`cycles Figure
`reported these events 52% in cycle
`of nonsmokers
`19% over
`9% in cycle
`the
`averaging
`cycles
`of OC use
`for recent use and consistency
`Adjusting
`smokers were 47%
`and the progestin
`component
`spotting or bleeding than
`more likely to have
`of OC use The fre
`nonsmokers over
`cycles
`or bleeding increased as the
`of spotting
`quency
`increased
`the likeli
`of smoking
`By cycle
`level
`hood of spotting or bleeding was almost
`times as great among women who smoked 16
`cigarettes per day The findings
`are consistent with
`prior studies suggesting that cycle control
`impaired by smoking
`The investigators
`by which
`smoking
`catabolism of estro-
`increased
`cycle may involve
`gen which would diminish the extent of endome
`leading to an increased
`trial support thereby
`or bleeding The findings
`are
`tendency
`for spotting
`because OC users who experi
`of particular concern
`or bleeding are more likely to discon
`ence spotting
`tinue OC use than are women with good
`cycle
`These women often do not adopt another
`control
`method of contraception
`or select
`less effective
`method
`
`theorize
`
`the mechanism
`interferes with the menstrual
`
`that
`
`HEADACHE
`
`the
`
`is
`
`difficult
`
`it is
`
`The relationship between OCs and headache
`cause of OC discontinuation
`third leading
`common subjective
`to study because
`complaint among women whether
`or not
`they at-c
`numerous
`steroids Although
`taking exogenous
`causal mechanisms have
`been proposed
`it is not
`headache when they use
`clear why women develop
`OCs It is known
`that migraine and
`tension-type
`seem to be different with regard to
`headache
`number of endogenous
`and exogenous factors
`In
`study of 80 patients
`suffering from tension-type
`
`and colleagues
`
`to influence
`
`neither
`
`survey
`
`drugs
`
`as
`
`1311
`
`of
`
`found that OC
`headache Mraz
`the frequency
`use appeared
`nor
`and it has been
`the intensity of headache
`attacks
`recommended that OCs riot be withheld in cases of
`tension headache
`based on
`However
`to the WHO Collaboration
`Centre
`10506 reports
`Drug Monitoring found that OCs
`International
`for
`were among the most commonly implicated
`in migraine 32j Although the causal
`relationship
`between migraine and OCs is somewhat controver
`impression is that OCs can change
`the general
`sial
`the character
`and frequency of migraine attacks
`OCs can
`be used in women with common
`symptoms
`focal neurologic
`migraine without
`symptoms do not worsen
`long as headache
`sonic women actually
`experience
`lessening
`migraine symptoms when they take
`combination
`OCs However women who have classic migraine
`with focal symptoms are generally not good can
`didates for oral contraception since they may be at
`thrombotic stroke and most
`increased
`risk of
`find
`that OCs make the migraine condition worse
`In the absence of
`history of classic migraine
`women should be encouraged
`to continue taking
`OCs for at
`least months to determine if headaches
`will subside as they often do Headaches
`that con
`interval are prob
`sistently occur during the pill-free
`ably due to estrogen withdrawal
`The fall
`in
`that occurs with menstruation may trigger
`estrogen
`menstrual migraine whereas the sustained high
`levels
`of estrogen during pregnancy
`frequently
`result in headache
`In this connection it
`relief
`has been
`that headaches occurring
`observed
`during
`interval may resolve with the use of
`combination OCs long-cycle
`daily continuous
`he used in this set
`phasic OCs cannot
`treatment
`ting because the variation in steroid levels may
`cause BTB There is nothing special about
`the 21-
`day cycle and most women can take combination
`weeks sometimes
`for up to
`longer
`preparations
`irregular bleeding and need
`before they experience
`to stop continuous pill-taking on that account 34
`the frequency of
`there is no improvement or if
`nonhormonal
`headaches increases
`method should be considered
`Very few controlled
`comparison
`been performed to determine whether
`the incidence
`varies by OC formulation
`of headache
`.g depot medroxy
`and Norplant
`are
`of headache
`than
`
`the pill-free
`
`If
`
`or severity
`
`Progestin-only
`
`contraceptives
`
`progesterone acetate
`associated with higher
`
`incidence
`
`contraceptive
`
`studies
`
`have
`
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`
`headache
`
`beneficial
`
`results of
`
`in Italy
`
`preparations
`
`In these
`
`placebo
`
`clinical
`
`and the other
`
`to illustrate
`
`the
`
`arc combination OCs
`Thcrc is no convinc
`the use of one OC progestin
`ing evidence
`that
`or
`another
`is less likely to cause or exacerbate
`but sometimes
`changing preparations
`is
`probably because of
`effect The
`multicenter
`twp noncomparative
`trials one conducted
`in Germany
`are shown in Figure
`effect of OCs on the incidence
`of headaches
`placebo
`two monophasic OC
`in women taking either of
`low-androgenic
`containing
`progestins
`13% and 9.9% of women respec
`studies
`tively reported headache
`prior to use of either
`The incidence
`norgestimate/EE or desogestrellEE
`declined steadily as the women contin
`of headache
`9.9% and 69% of
`ued to take the OCs at cycle
`the women respectively reported headache It
`these women attributed
`likely that many of
`seems
`their headaches to OC use Those who did not have
`them by cycle
`headaches at baseline and developed
`were probably dissatisfied with their OC and
`diminution of symptoms
`might experience
`if switched to another for
`through placebo effect
`mulation Counseling patients
`about
`during cycle
`diminishing would be
`the probability of headache
`6.2% and 2.8%
`because by cycle
`important
`reported headache
`
`respectively
`
`NAUSEA/BREAST
`
`TENDERNESS
`
`Nausea
`
`gen-related
`
`and breast
`tenderness
`are primarily estro
`effects They arc infrequent with OCs
`
`OC Practc Guidelines
`
`165
`
`containing less
`within the first
`
`than 50 pg EE and usually
`months
`of use It has been
`or
`
`abate
`
`if
`
`rather
`
`nausea and
`observed
`that
`patient
`experiences
`result she may develop
`skips some pills as
`ular bleeding which
`can lead to discontinuation
`of
`Women who repeatedly
`nau
`OCs
`experience
`sea can be instructed
`to take the pill
`inunediately
`after meal
`than at bedtime on an empty
`stomach
`side
`Because
`nausea
`is an estrogenic
`switching to an OC formulation
`effect
`20 pg EE may be appropriate
`long the patient
`as
`is
`irregular bleeding is more likely
`cautioned that
`with this preparation
`
`irreg
`
`containing
`
`MOOD SWINGS
`
`reported
`
`Mood changes are
`common highly subjective
`complaint whose relationship to OC use is difficult
`and
`to assess As recently
`pointed out by Patten
`study designs would be
`Love
`sophisticated
`role for medica
`to confirm an etiological
`required
`for depression but adequate
`tions as risk factors
`conducted Mood changes
`studies have
`rarely been
`by OC users may be positive rather
`than
`that examined
`in one study
`negative In fact
`the relation between OC and changes in positive
`in 50 women the results indi
`and negative
`that OC users experienced
`cated
`level of
`higher
`the pill or men
`over
`the course
`positive
`atten
`strual cycle than did nonusers
`Considerable
`in the CC literature to
`tion has been devoted
`determining how mood may vary depending on the
`
`affect
`
`affect
`
`of
`
`40
`
`35
`
`30
`
`25
`
`20
`
`15
`
`10
`
`Cases
`
`Basolino
`
`Cycle
`
`Cycle
`
`FIG
`
`Effects
`
`studies Based
`
`of monophasic OCs on headache
`from Grunwald et al
`on data
`
`in two noncomparative
`in Runnebaum
`
`as cited
`
`multicenter
`
`and
`
`Bilotta
`
`Favilli
`
`mi Perth
`
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`
`166
`
`P.Darney
`
`progestin-only
`which
`
`patterns
`
`have
`
`suggests
`
`that
`
`impact
`
`the cycle but no consistent
`phase of
`emerged from these studies
`Mood changes seem to be more common with
`especially DMPA
`contraceptives
`in high serum concentrations
`of pro
`result
`Data on symptom variation by OC or
`gestin
`are scant and inconclusive
`mulation
`However1
`some evidence
`todays low-estrogen-
`dose 35 rg EE OCs have minimal
`on
`mood
`The relationship of progestins
`to central
`nervous
`remains unexplained
`system symptoms
`as yet
`trial evidence
`that progestins
`Clinical
`suggests
`with low androgenicity
`are not more likely to
`cause mood changes than arc other progestins
`and
`the former are more asso
`that
`there is no evidence
`ciated with changes
`in libido than are the older
`
`preparations
`Some OC users who complain of
`change
`or of vague amriety may
`feelings of well-being
`their
`benefit by being switched to
`formulation contain
`the problem is severe
`different progestin If
`ing
`e.g profound depression and persistent
`switching
`nonhormonal method such as an intrauterine
`to
`device or barrier method should he considered
`
`in
`
`METABOLIC ALTERATIONS
`
`been
`
`concerned
`
`about
`
`effects
`
`ease
`
`Women and clinicians have
`of combination
`deleterious
`the potentially
`and carbohydrate
`OCs on
`lipid/lipoprotein
`on cardiovascular dis
`metabolism and their effects
`In recent years these concerns have been
`diminished
`evi
`by epidemiologic
`substantially
`that OCs are not associated with increased
`dence
`mortality from cardiovascular
`disease
`as well as by
`of ow-androgen
`the development
`
`progestins
`
`The changes in lipid and lipoprotein values
`in OC users are related to the androgenicity
`and the estrogen/progestin
`component
`progestin
`ratio Whether
`these alterations are clinically sig
`healthy women is not known
`nificant
`in otherwise
`Older OCs containing
`relatively high doses of pro
`gestin with high androgenie
`activity are associated
`in HDI
`with decreases
`and increases in
`cholesterol
`LUL cholesterol
`Contrary to earlier
`it now appears
`that
`assumptions however
`these
`changes do riot increase cardiovascular
`undesirable
`risk among OC users On the other hand low
`have opposite
`and clearly
`androgenic progestins
`slight decrease
`desirable metabolic
`in
`increasing I- cholesterol
`LDL cholesterol
`and
`which
`have
`
`seen
`
`of
`
`the
`
`effects
`
`cardio
`
`to decrease
`the potential
`this effect has yet
`risk however
`demonstrated
`familial lipoprotein abnormal
`Women who have
`ities who are hyperandrogenic or who are at risk
`tolerance e.g those who have
`of abnormal
`glucose
`demonstrated abnormal
`tolerance
`during
`glucose
`
`vascular
`
`to be
`
`pregnancy might
`
`ence cardiovascular
`
`likely to experi
`be particularly
`from the use of OCs
`The path of
`
`benefits
`
`contaiiiing low-androgenic progestins
`today lies in the direction of
`research
`
`increasing
`
`the benefits rather
`than
`the already negli
`reducing
`gible risks associated with modern OCs
`have
`Several
`studies
`indicated
`like older
`that
`combination OCs formulations containing pro
`are associated with
`gestins with low androgenicity
`levels but
`to cause clinical problems
`in women who already have
`400 mg/dLi
`levels
`of combination OCs
`the estrogen
`component
`to be responsible for raising triglyceride lev
`women who have marked
`pre-existing
`may not be good candidates
`any estrogen-containing OC preparation
`
`these elevations
`
`are
`
`increased
`
`triglyceride
`not high enough
`
`except
`
`perhaps
`
`extremely
`
`high triglyceride
`
`Since
`
`appears
`
`els
`
`hypertriglyceridemia
`
`for
`
`Lipid/Lipoprotein Changes
`
`of
`
`an increase in high-density
`Estrogens induce
`and may pro
`lipoprotein HDT
`cholesterol
`values
`lipoprotein LDL
`mote the uptake
`low-density
`by cells However both of
`cholesterol
`these desir
`able actions are potentially overcome by the andro
`This
`genie actions of
`the progestin component
`impact on lipoprotein levels was one of
`progestin
`pharmaceutical chemists
`the factors that prompted
`
`to develop
`
`less androgenic
`
`progestins
`
`Carbohydrate Effects
`
`of OC use oil carbohydrate
`The effects
`and their relationship to cardiovascular
`be