`
`EXHIBIT 1015
`
`
`
`ORIGINAL RES.EARCH ARTICLE
`
`Changes in Androgens During
`Treatment with Four
`Low-Dose Contraceptives
`C.M.H. Coenen,* C.M.G. Thomas,*t G.F. Borm,:j: J.M.G. Hollanders,* and R. Rolland*§
`
`The aim of the present study was to compare changes in
`the endogenous androgen environment in healthy women
`while on low-dose oral contraceptives (OCs). One-hundred
`healthy women were randomized to receive one of four
`OCs during six months: 21 tablets of Cilest®, Femodeen®,
`Marvelon"'. or Mercil~m®. During the luteal phase of the
`pretreatment cycle, body weight and blood pressure were
`recorded and the following param eters were measured: sex
`hormone-binding globulin (SHBG), corticosteroid-binding
`globulin (CBG), testosterone (T), free testosterone {FT}. Sa·
`dihydrotestosterone (DHT}, androstenedione (A). dehydro(cid:173)
`epiandrosterone-sulpbate (DHEA-S) and Ila-hydroxy(cid:173)
`progesterone (l lOHP) while also the free androgen index
`(FAI) was calculated. Measurements were repeated during
`the 3rd week of pill intake in the 4th and the 6th pill
`m onth. There were no differences on body mass and blood
`pressure with the use of the four OCs. The mean serum
`DHEA-S decreased significantly in all groups though less in
`the Mercilon® group when compared to Giles~ and Mar(cid:173)
`velon® (approximately 20% vs 45 %}. Mean serum SHBG
`and CBG increased significantly in all four groups approxi(cid:173)
`mately 250% and 100%, resp?Ctividy. In each group CBG
`also increased significantly but less in women taking Mer(cid:173)
`cilon® (- 75%} as compared to the others (-100%). Current
`low-dose OCs were found to ha•·c similar impact on the
`endogenous androgen metabolism with significant de(cid:173)
`creases of serum testosterone, DHT, A, and DHEA-S. They
`may be equally beneficial in women with androgen related
`syndromes such as acne and hirsutism. CoNTRACEPTION
`1996;53: 171- 176
`
`KEY WORDS: androgens, oral contraceptives
`
`' Department of Obstetrics ano!l Gynecology, t Endocrinology and Reproduc tion
`Laboratory. +Deportment of Blootatistic::;. Univcroity Ho:;pitol Nijmcgcn St. Rod
`boud. Nijmegen. the Netherlands. and §IVF/Reproductive Endocrinology, King
`Fahad National Guard Hospital, P.O. Box 22490. Riyadh 11426, Saudi Arabia
`N:>m<> "nrl address for corresponr!PJV:f'!· r: M H . Coenen, M .D . , Dep,.rtmf>nl
`of Obstetric s and Gyneco~ University Hospital Nijmegen St. Radboud. P.O.
`Box 9101, 6500 HB Nijmege . the Netherlands. Tel: 31-24-3614748; Fax: 3 1-
`24-3541 194
`Submitted for publication ~gust 22, 1995
`Revised December 12,199
`Accepted tor publication D cember 18. 1995
`
`I
`
`@ 1996 Elsev ier Science lnc.IAII rights reserved.
`655 Avenue ol the Americas, New York, NY 10010
`
`Introduction
`
`O ral contraceptives (OCs) have been described
`
`as a risk factor for the development of cardio(cid:173)
`vascular disease (CVD). At first this pheno(cid:173)
`menon was attributed to the estrogenic component of
`the OC. ' ,?. Parallel with dose reduction of bolh the
`estrogenic and the progestogenic component and the
`introduction of new progestins, the incidence of CVD
`decreased significantly. At present there is doubt
`whether or not modem OCs increase the risk for car(cid:173)
`diovascular disease.3.4 The mechanism of a possible
`influence on CVD has also been attributed to the in(cid:173)
`trinsic androgenic potential of progestins used in
`OCs. This can at least in part be theoretically attrib(cid:173)
`uted to the influences on lipid metabolism.5
`The androgen environment in individual women
`taking oral contraceptives depends on the eventual
`androgenic effect of the utilized progestin, the anti(cid:173)
`gonadotropic effect of the estrogen-progestin combi(cid:173)
`nation altering ovarian androgen production and the
`effect of the OC on plasma proteins with sex steroid(cid:173)
`binding properties.
`The androgenic effect of progestins may be exerted
`in two different ways: first, through stimulating the
`binding of androgens to the androgenic receptors of
`the target organ and, second, to their affinity to sex
`hormone-binding globulin (SHBG) and other andro(cid:173)
`gen binding proteins, thus displacing testosterone (T J
`from SHBG binding and consequently increasing the
`proportion of free testosterone (FT).6 Therefore, the
`SHBG level is a useful parameler in the evaluation of
`the androgenicity of oral contraceptives.
`Literature data examining the new progestins norg(cid:173)
`estimate, desogestrel and gestodene concentrate on
`their possible influence on lipid m etabolism and clot(cid:173)
`ting. Surprisingly, few reports systematically assess
`the changes in sex s teroids exerting androgenic prop(cid:173)
`erties during treatment with OC.
`The aim of the present study was to compare the
`effects of four m odem low-dose OCs on sex steroids
`with androgenic properties and their binding proteins
`
`ISSN 0010-7824196/$15.00
`f>l! Soo 1 0-7824{96)()()()()6..6
`
`Petitioner Exhibit 1015
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 1
`
`
`
`172 Coenen et al.
`
`Contraception
`1996;53: 171- 176
`
`in serum. Therefore, the present study specifically
`evaluated changes brought about in plasma concen(cid:173)
`trations of SHBG, CBG, albumin (Alb), T, FT, dihy(cid:173)
`drotestosterone (DHT), androstenedione (A), dehydro(cid:173)
`epiandrosterone-sulphate (DHEA-S) and l7a(cid:173)
`hydroxyprogesterone II 70HP).
`
`Material and Method
`
`Study Design
`In an open randomised study, l 00 female volunteers
`were equally assigned to one of four different OC
`preparations during six cycles on therapy (Table 1 ).
`The healthy volunteers ranging in age between 18
`and 38 years, were not pregnant, not lactating, and
`had delivered at least six months before inclusion
`into the study. Their menstrual cycles had to be
`within a duration between 25 and 36 days.
`Obese women were excluded [Body Mass Index
`(BMl)= weight in kg/height in m2 > 28.0]. 7 The use of
`steroid-containing medication or medication possibly
`interfering with steroid metabolism was discontinued
`for at least two months prior to treatment and the use
`of medication known to alter liver enzyme function
`was not allowed. Also, the well known relative con(cid:173)
`traindications to the use of OCs such as a history of
`thromboembolic disorder, hyperlipoproteinemia,
`known or suspected estrogen-dependent neoplasia
`liver tumors and undiagnosed abnormal genital bleed~
`ing were reasons for exclusion. Finally, the volunteers
`were not allowed to smoke more than 10 cigarettes a
`day.
`Each subject was seen !before therapy during a con(cid:173)
`trol cycle between days 24- 27 (luteal phase) and while
`on therapy during pill cycle 4 and 6 (between days
`1 R- 21 of pill intake). At every visit, body weight and
`blood pressure were recorded and blood collected for
`measurements of SHBG, CBG, Alb, T, FT, DHT, A,
`DHEA-S and l70HP. Also, the free androgen index
`(FAI=Txl00/SHBG)8 was calculated. All blood
`samples were drawn between 08.00 and 10.30 am af(cid:173)
`ter a fasting period of at least 12 h. The blood was
`allowed to clot at room temperature, serum was col-
`
`Table 1. Composition of the four monophasic contracep(cid:173)
`tives tested
`
`Preparation
`
`Cilest®
`Femodeen®
`Marvelon®
`Mercilon®
`
`Ethinylestradiol
`per Tablet
`
`Progestagen
`per Tablet
`
`35 pg
`30 pg
`30 pg
`20 J..l&
`
`250 J.l& norgestimate
`75 pg gestodene
`150 ).lg desogestrel
`150 pg desogestrel
`
`lected after centrifugation at 2000xg and kept frozen
`at -20°C until assayed. The volunteers were in(cid:173)
`structed to take the first tablet on the first or second
`day of the menstruation following the control cycle
`visit. Then one tablet was taken daily at a fixed time
`for 21 days followed by 7 tablet-free days.
`The study was approved by the ethical committee
`of the hospital beforehand and was conducted accord(cid:173)
`ing to the guidelines for Good Clinical Practice.9
`Written informed consent was obtained from all sub(cid:173)
`jects at the beginning of the study.
`
`Assays
`SHBG was measured by a commercially available
`non-competitive coated-tube immunoradiometric as(cid:173)
`say (IRMA, Farmos Diagnostica, Orion Corporation,
`Turku, Finland) based on the method of Hammond et
`al. 10 The within-assay and between-assay coefficients
`of variation (CVw and CVb) ranged from 2.6%. to 2.9%
`and from 3.5% to 4.6%, respectively. Serum concen(cid:173)
`trations of CBG were measured with a commercially
`available direct competitive liquid-phase RIA (Tech(cid:173)
`land SA, Liege, Belgium); the CVw ranged from 3.2%
`to4.7% and the CVbfrom 8.6% to 8.8%. Serum T was
`measured after diethylether extraction by a specific
`charcoal RIA as described by Dony et al. 11; the CV w
`and the CVb were 5.6% and 6.9%, respectively. Se(cid:173)
`rum FT concentrations were assayed with a commer(cid:173)
`cially available direct competitive solid-phase RIA
`(Diagnostic Products Corporation, Los Angeles, CA,
`USA); CVw and CVb were 6.4% and 12.1 %, respec(cid:173)
`tively. DHT was measured with a specific in-house
`charcoal RIA. Purification of serum specimens by di(cid:173)
`ethylether extraction and column chromatography
`with Sephadex LH20 were as described by Van Du(cid:173)
`ren12; CV w and CVb calculated from a serum pool
`with a mean DHT level of 1.8 nmol/L were 6.5% and
`ll. 7%, respectively. Androstenedione was measured
`after diethylether extraction and Sephadex LH20
`chromatography by a charcoal RIA as described by
`Van Duren12; CVw was 3.6% and CVb was 7.0%.
`DHEA-S concentrations were measured with a highly
`specific charcoal RIA as described by Reijnders13
`;
`CVw and CVb were 3.7% and 6.9%, respectively. Con(cid:173)
`centrations of l?OHP in serum were determined after
`diethylether extraction followed by Sephadex LH20
`chromatography with a specific charcoal RIA as de(cid:173)
`scribed by Dony et al.ll; CVw and CVh were 3.7% and
`6.9%, respectively.
`
`Statistics
`All values are given as mean ± sd. P-values less than
`0.05 were considered significant. In order to remove
`
`Petitioner Exhibit 1015
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 2
`
`
`
`Contraception
`1996;53: 171-176
`
`Androgenicity of Four Low-Dose Contraceptives 173
`
`Table 3. Drop-outs according to pill cycle, subject num-
`ber, pill type and complaint(s)
`
`Pill
`Cycle
`
`Pill
`Subject
`Number Type•
`
`Complaint(s)
`
`heteroscedasticity and skewness, all parameters were
`log-transformed.
`In the primary analysis, changes from baseline in
`the four groups were compared using the Welch mul(cid:173)
`tiple range test. 14 In order to con troll the overall error
`rate per parameter, this was done in a stepwise man(cid:173)
`ner: first the changes over 6 months were evaluated,
`and only if these were !nominally) significant, the
`changes over the first 4 months were also evaluated
`!close testing procedure15
`). This method corresponds
`to the intuitive idea 1hat one first investigates if there
`are any long-term differences after 6 months and
`then, only if this is the case, one investigates whether
`the differences alrea<ily occur after 4 months.
`In a secondary analysis, the changes from baseline
`within the groups were evaluated. In order to control
`the overall error rate, a pooled t-test was carried out:
`the changes were evaluated for the four groups simul(cid:173)
`taneously in an ANOVA model with no intercept.
`Again changes over 4 months were tested, only if
`those over 6 months were found significant.
`
`Results
`Population Characteristics
`The characteristics of the study groups are given in
`Table 2.
`
`Dropouts
`Two women became pregnant during the control
`cycle and, therefore, dropped out prior to treatment.
`They were replaced according to the protocol.
`There were twelve true dropouts, the reasons for
`which are summarized in Table 3. Subject number 81
`(Ci-group) was not available during pill cycle 4, which
`is the reason why the second visit was planned during
`pill cycle 3. Subject number 85 (Fe-group) was not
`available during the third, fourth and fifth pill cycle;
`she was unable to attend the second visit. Hence, a
`total of 88 volunteers completed the study according
`to the protocol.
`
`Vital Signs
`Changes in body weight and blood pressure (systolic
`and diastolic) registered in the control cycle and in
`
`Ta ble 2. Sample characteristics (mean ± sd)
`
`Ci
`
`Fe
`
`Ci
`
`Fe
`
`15
`
`85
`
`41
`43
`
`68
`
`76
`
`2t
`2t
`
`2t
`
`3
`
`Headache of unknown ori-
`gin
`Spotting/breakthroudt
`bleeding
`Me Mastopathy
`Tachycardiafhyperventila-
`Me
`tion
`Body weight and mood
`change
`Headache during pill-free
`week
`Pruritis vaginalis
`Ci
`81
`3t
`Sinusitis: antibiotics
`3
`4
`Fe
`Hepatitis A
`Ci
`16
`4
`Protocol violation
`Ma
`58
`4t
`Increase in migraine
`Me
`6
`4t
`Poor compliance
`Me
`98
`Unknown
`"Ci-Cilest*; Fe-Femodeen•; Ma-Marvelon•; Me-Mcrcilon•.
`tDrop·out aher pill day 21.
`
`the pill cycles 4 and 6 are shown in Table 4. None of
`these parameters significantly changed throughout
`the study period.
`
`Hormones and Binding Proteins
`All the steroidal serum parameters tested (T, FT,
`DHT, A, DHEA-S, 170HP, Alb) significantly de(cid:173)
`creased while on medication during 6 pill cycles {ratio
`of decrease between 1.3 and 3.0), irrespective of the
`OC preparation used {Tables 5 and 6). All changes
`were observed aheady after 4 pill cycles.
`Comparing the decreases of the above mentioned
`variables after 6 months between the 4 pill groups,
`the only significant difference observed concerned
`DHEA-S: the mean decrease of DHEA-S was 21±18%
`in the Me-group, significantly different compared to
`43±18% and 44±18%, respectively, in the Ci- and Ma(cid:173)
`group, while the Fe-group was in between with a de(cid:173)
`crease of 34± 14%.
`Significant increases were observed in the levels of
`steroid binding proteins. Both SHBG and CBG in(cid:173)
`creased significantly during pill-intake in all four
`
`Oral
`Conuaceptive
`
`Cilest•
`Femodeen•
`Marvelon•
`Mercilon•
`Overall
`·Body mass index.
`
`Age
`(Years)
`
`26.9 (4.2)
`26.3 (4.9)
`27.1 15.1)
`27 .• 3 (5 .. 3)
`26.9 (4.8)
`
`Cycle Length
`(Days)
`
`28.3 (l.S)
`28.8 (2.1)
`28.6 (2.1)
`29.0 (2.2)
`28.7 (2.0)
`
`Menses
`(Days)
`
`5.0 (0.8)
`4.7 (1.2)
`5.0 (1.0)
`5.4 (1.1)
`5.0 (1.1)
`
`BMI·
`(kg/m1 )
`
`22.2 (2.3)
`22.0 (2.4)
`22.0 (2.4)
`22.4 (2.2)
`22.1 (2.3)
`
`Petitioner Exhibit 1015
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 3
`
`
`
`17 4 Coenen et al.
`
`Contraception
`1996;53:171-176
`
`T•ble 4. Changes in body mass and systolic and diastolic
`blood pressure of the four preparations tested after six pill
`cycles (mean :t sd)
`
`Change in
`Body Mass
`(%)
`
`+0.5 (3.9)
`+1 .8 (3.9)
`+1.0 (2.8)
`+1.1 (2.8)
`
`Change in
`Systolic
`Blood
`Pressure
`(%)
`
`+1.6 (9.8)
`- 1.4 (6.6)
`+0.0 (7.6)
`-0.5 (7.7)
`
`Change in
`Diastolic
`Blood
`Press we
`(%}
`
`+3.9
`+0.5
`-2.4
`-1.0
`
`Cilest•
`Femodeen•
`Marvel on•
`Mercilon•
`
`groups. At six months on therapy, the mean increase
`of SHBG was 263% (±119%) and 94%(±26%1 in the
`case of CBG.
`Again, there were no differences between the dif.
`ferent pill groups except for CBG: this protein shows
`a significantly less increase in women taking Mer(cid:173)
`cilon411 (74±21 %) as compared to the three other con(cid:173)
`traceptives, Cilest• 96±31 %, Femodeen• 101±21%
`and Marvelon® 1 02±22%.
`
`Discussion
`Progestins, especially those with intrinsic androgenic
`activity, have an opposite effect on lipoprotein me(cid:173)
`tabolism as compared to estrogens. They especially
`stimulate hepatic lipase, thereby accelerating me(cid:173)
`tabolism and clearance of high density lipids (HDL)
`and lowering HDL levels. Low HDL levels are
`thought to increase the risk for CVD. 16
`The binding of a given progestin to SHBG is an
`important determinant of its androgenicity. The pro(cid:173)
`gestins used in this study may, in this respect, how(cid:173)
`ever, differ from othersY·18 These new progestins
`have been developed because of their small or absent
`
`intrinsic androgenic properties. Many studies have in(cid:173)
`deed indicated that they have no negative effect on
`lipid metabolism. In this study the suppression of
`plasma hormone concentrations in individuals on
`four different OCs has been evaluated.
`All androgen parameters investigated in the present
`study decreased while taking the new OCs regardless
`of the type. At the same time, the androgen binding
`proteins increased. The net effect of this was an even
`more substantial decrease of biologically active tes(cid:173)
`tosterone. The concentration of the most active an(cid:173)
`drogen in the human, Scx-dihydrotestosterone, is di(cid:173)
`rectly related to that of free testosterone. Therefore,
`during intake of these OCs the endogenous androgen
`environment changed in the ctirection of hypoandro(cid:173)
`genism. It is speculated that even if the applied pro(cid:173)
`gestins exert an intrinsic androgen action, this is neg(cid:173)
`ligible as concerned to the changes in the endogenous
`environment. It seems safe to postulate that all these
`four OCs are equally beneficial with regard to sebor(cid:173)
`rhoea, acne and hirsutism, but the clinical effects of
`the four preparations regarding to the skin have not
`bc:c:n invc:stigatc:u in our sLudy. They should also give
`rise to a favourable change in lipid metabolism and an
`increase in the high density/low density lipids (HDL/
`LDL) ratio has indeed been reponed for all of
`them.l9,20
`Norgestimate, desogestrel and gestodene all bind to
`progesterone and androgen receptors. The binding to
`the androgen receptor is significantly reduced, how(cid:173)
`ever, as compared to the older progestins. In view of
`our findings and the reports on HDL/LDL, therefore,
`a further attempt to reduce the progestin content of
`these OCs does not seem necessary. It may even be
`unwarranted, as a less effective cycle control may be
`the only achieved result.21 All OCs tested in the pre(cid:173)
`sent study decreased the concentration of DHEA-S
`
`T•ble 5. Serum concentrations of albumin (Alb), sex hormone-binding globulin (SHBG), and corticosteroid-binding globu(cid:173)
`lin (CBG); values are given as mean± sd
`
`Serum Variable
`
`Control Cycle
`(n • 100)
`
`Pill Cycle 4
`(n .. 90)
`
`47.40 [2.63)
`47.76(2.79)
`46.80 (2.53)
`47.60 (2.45}
`55 (20}
`5 l (17)
`61 (3 1)
`48 (20)
`44.0 (5.6)
`43.8 (4.5)
`41.2 (5.5)
`43.6 (3.0)
`
`42.73 (2.73}
`43.95 (2.50)
`42.56 (1.76)
`43.00 (2.56)
`173 (48)
`163 (49)
`201 (68)
`157 (52)
`85.5 (7.9) "
`86.2 (8. 1)"
`82.7 (6.4}"
`76.7 (8.1)
`
`Pill Cycle 6
`(n .. 88)
`
`43.10 (1.97}
`43.41 (2.91 )
`42.50 (2.02)
`43.43 (2.60)
`174 (64)
`162 (47)
`217 (88)
`156 (49)
`84.5 (7.9)•
`88.3 (7.9)"
`82.4 (9.6) "
`75.7 (8.6)
`
`Alb (g/L)
`
`SHBG (nmol/L)
`
`CBG (mg/LI
`
`Ci
`Fe
`Ma
`Mt:
`Ci
`Fe
`Ma
`Me
`C1
`Fe
`Ma
`Me
`'Sixroficantly different from Mcrcilon• with respect to ch.angc from baseline !dosed testing procedure).15
`
`Petitioner Exhibit 1015
`Petition for Inter Partes Review of U.S. Patent No. 7,704,984
`Page 4
`
`
`
`Contraception
`1996;53:1 71-176
`
`Androgenicitv of Four Low-Dose Contraceptives 175
`
`Table 6. Serum concentrations of testosterone (T), free testosterone {Ff), free androgen index (F AI), 5a-dihydrotestosterone
`(DHT), androstenedione (A), dehydroepiandrosterone-sulphate (DHEA-S), 17a-hydroxyprogesterone I170HP); values are
`given as mean :1: sd
`
`Serum Variable
`
`Control Cycle
`(n = 100)
`
`Pill Cycle 4
`(n = 90)
`
`Pill Cycle 6
`(n = 88)
`
`T {nmol/ L)
`
`FT (pmol/L)
`
`FAI
`
`DHT (nmol/ L)
`
`A (nrnol/L)
`
`DHEA-S (nmol/ L)
`
`170HP (nmol/ L)
`
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`Ci
`Fe
`Ma
`Me
`'Significantly different from Mercilon" with respect to change &om baseline (closed testing procedurej. 15
`
`2.26 (0.85)
`2.43 (0.53)
`2.48 (0.85)
`2.50 (1.01 )
`5.79 (2.57)
`6.57 (2.11 )
`7.08 (2.46)
`7.12 (2.92)
`4.74 (2.41 )
`5.16 [1.67)
`4.73 (2.04)
`6.19 (3.55)
`0.89 (0.36)
`0.91 (0.30)
`1.00 (0.39}
`0.86 {0.44)
`5.97 (2.38}
`7.18 (2.61)
`7.72 (.i.lO}
`7.38 (3.59}
`7.88 (2.90)
`7.98 (2.35}
`8.42 (2.57)
`7.23 (2.49)
`4.81 (2.89)
`5.71 (2.39)
`5.60 [2.99)
`6.23 (2.80}
`
`1.81 (0.61 )
`1.94(0.44)
`2.05 (0.66)
`1.91 10.58)
`2.59 (0.80)
`2.70 (1.01 )
`3.02[1.63)
`2.95 (1.11 )
`1.14(0.53)
`1.30 [0.50)
`1.09 (0.39)
`1.36 (0.68)
`0.61 (0.32)
`0.61 (0.22)
`0.73 (0.29)
`0.64 (0.26)
`3.99 (1.58)
`4.15 (1.94)
`4.6.1 (1.92)
`4.29 (2.04)
`4.78 {2.48)
`5.17 {2.14)
`5.09 (2.32)
`5.10 (2.20)
`1.29 (0.87}
`1.52(1.41}
`1.55 (0.98)
`1.59 (1.30)
`
`1.70 (0.49)
`1.88 (0.41)
`1.98 [0.63)
`1.96 (0.64)
`2.61 [1.17}
`2.66 (0.76)
`2.88 (1.07)
`2.89 (1.09)
`1.28(1.30)
`1.27 {0.52)
`0.98 {0.36)
`1.36 {0.58)
`0.55 (0.22)
`0.61(0.19)
`0.73 (0.28}
`0.66 (0.29)
`3.92 (1.24)
`3.55 (1.36}
`4.64 (1.78)
`4.17(2.14)
`4.71 (2.65)*
`5.42(1.87)*
`4.90 (2.22).
`5.82(2.53)
`1.15 (0.66)
`1.49(1.02)
`1.51 (0.82)
`1.36 (1.03)
`
`significantly. This decrease is probably brought about
`by a suppression of the adrenocorticotropic hormone
`(ACTH).22 This effect is not only effected by dose and
`type of progestin but also by the ethinylestradiol (EE)
`content: Ma and Me differ only by their EE content
`and the effect of Me an DHEA-S was significantly less
`as compared to Ma. The lower EE content of Me ex(cid:173)
`plains, in our view, the significantly lower increase in
`CBG. From a clinit:al point uf view, th~ difference in
`Me on DHEA-S as compared to the others is possibly
`of little significance: DHEA-S is a weak androgen and
`the change seems minor when compared to the major
`decrease of free testosterone {and hence So:-dihydro(cid:173)
`testosterone), although this hypothesis needs further
`study.
`A profound decreJe in both total and free testos(cid:173)
`terone, and the abs nee of any negative effects on
`clinical variables su h as blood pressure and body
`mass are similar fo all four studied preparations.
`These OCs may the~fore be especially indicated for
`women with some sjigns of hyperandrogenism. The
`strong androgen-lowhing effect may also be disad-
`
`vantageous. Although thus far no data are reported in
`the literature, low androgen levels in the female may
`negatively interfere with libido and self-esteem.23 We
`therefore recommend that future research on new OC
`formulations should build into their protocols means
`to evaluate the tendency to hyperandragenism and
`eventual effects on libido and self-esteem.
`
`Acknowledgments
`The authors thank the staff of the Endocrinology and
`Reproduction Laboratory for expert technical assis(cid:173)
`tance.
`
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`Page 5
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`