Humn Reproution Vol.18, No.3 pp. 522±526, 2003 DOI: 10.1093/humrep/eg120 The risk of venous thromoemolism in women presrie yproterone ette in omintion with ethinyl estriol: neste ohort nlysis n se±ontrol stuy H.E.Semn 1, C.S.eVries n R.D.T.Frmer Deprtment of Phrmoepiemiology, Postgrute Meil Shool (University of Surrey), Stirling House, The Surrey Reserh Prk, Guilfor GU2 7DJ, UK 1 To whom orresponene shoul e resse. E-mil: h.semn@surrey..uk BACKGROUND: Cyproterone ette omine with ethinyl estriol (CPA/EE) is liense in the UK for the tretment of women with ne n hirsutism n is lso tretment option for polyysti ovry synrome (PCOS). Previous stuies hve emonstrte n inrese risk of venous thromoemolism (VTE) ssoite with CPA/EE ompre with onventionl omine orl ontreptives (COCs). We elieve the results of those stuies my hve een ffete y resiul onfouning. METHODS: Using the Generl Prtie Reserh Dtse we onute ohort nlysis n se±ontrol stuy neste within popultion of women ge etween 15 n 39 yers with ne, hirsutism or PCOS to estimte the risk of VTE ssoite with CPA/EE. RESULTS: The ge-juste iniene rte rtio for CPA/EE versus onventionl COCs ws 2.20 [95% on ene intervl (CI) 1.35±3.58]. Using s the referene group women who were not using orl ontreption, h no reent pregnny or menopusl symptoms, the se±ontrol nlysis gve n juste os rtio (OR j ) of 7.44 (95% CI 3.67±15.08) for CPA/EE use ompre with n OR j of 2.58 (95% CI 1.60±4.18) for use of onventionl COCs. CONCLUSIONS: We hve emonstrte n inrese risk of VTE ssoite with the use of CPA/EE in women with ne, hirsutism or PCOS lthough resiul onfouning y inition nnot e exlue. Key wors: ne/yproterone ette/ethinyl estriol/polyysti ovry synrome/venous thromosis Introution Ane is generlly ssoite with the onset of puerty n inrese seum proution from the hir folliles on the fe, hest n k. Propioniterium nes my proliferte within loke piloseeous units n use omeones n in me pustules. Sometimes ne is provoke y prolonge exposure to orl sterois. Conventionl tretments for ne t y reuing seum proution, unloking pores, elivering ntiiotis or suppressing the effets of nrogens. The ntinrogen yproterone ette (2 mg) omine with ethinyl estriol (35 mg) (CPA/EE) is liense in the UK for the tretment of women with severe ne tht is refrtory to prolonge orl ntiioti therpy n for moertely severe hirsutism. Although it is not liense s n orl ontreptive (OC) in the UK, CPA/EE is sometimes presrie for ontreption. Ane n hirsutism re ssoite with polyysti ovry synrome (PCOS) s re oesity, yslipiemi n insulin resistne, inepenent of oesity (Tylor, 1998; Solomon, 1999; Atiomo et l., 2000; Kelly et l., 2000). Thus women with PCOS hve n intrinsilly verse riovsulr risk pro le, s emonstrte y higher prevlene of ererovsulr n riovsulr moriity (Wil et l., 2000) n positive fmily history of thromoti isese in women with PCOS (Atiomo et l., 2000). Reent oservtionl stuies hve suggeste tht CPA/EE my e ssoite with n inrese risk of venous thromoemolism (VTE) ompre with onventionl omine orl ontreptives (COCs) (Frmer et l., 1999; Prkin et l., 2000; Vsilkis-Srmozz n Jik, 2001; Liegr et l., 2002). The use of CPA/EE in the UK more thn oule following the `pill sre' of 1995, possily euse women with nrogeni skin onitions were swithe to CPA/EE from COCs ontining less nrogeni progestogens (esogestrel n gestoene). Beuse the VTE risk pro le of women who hve nrogeni skin onitions (or PCOS) iffers from tht of other women of the sme ge, we onute ohort nlysis n se±ontrol stuy to estimte the risk of VTE ssoite with CPA/EE in suh women. Mterils n methos Our stuy use t from the Generl Prtie Reserh Dtse (GPRD). The GPRD ontins nonymous ptient reors for ~4% of the UK generl popultion. Routine emogrphi informtion is 522 ã Europen Soiety of Humn Reproution n Emryology
VTE n yproterone ette/ethinyl estriol Tle I. Crue rtes n iniene rte rtio (IRR) for VTE (1992±1998) Age VTE (n) OWY/EWY VTE rte per 10 4 OWY/EWY (95% CI) Bseline rte <30 yers 96 458587 2.09 >30 yers 83 211485 3.92 All ges 179 670072 2.67 (2.28±3.06) Women expose to CPA/EE <30 yers 8 22698 3.52 >30 yers 15 5863 25.58 All ges 23 28562 8.05 (4.76±11.34) Women expose to onventionl COCs reore. Meil ignoses re oe to n OXMIS (Oxfor Meil Inexing System) or Re oe. Presriing informtion is ~95% omplete (Wlley n Mntgni, 1997). Other informtion relting to smoking hits, lohol onsumption, height n weight re inompletely reore. The vliity n utility of this tse for stuies of rug sfety hve een pulishe elsewhere (Vn St n Aenhim, 1994; Hollowell, 1997; Wlley n Mntgni, 1997; Lwrenson et l., 2000). The stuy popultion ws rwn from ohort of women who h ever h ignosis of ne, hirsutism or PCOS. Women with PCOS were ienti e s those with n unequivol ignosis of PCOS or the ienti tion of polyysti ovries y ultrsoun exmintion, n lso ny women with three or more mrkers for PCOS (ne, hirsutism/lopei, oesity, novultion/infertility, menorrhoe/ oligomenorrhoe or enorinologil mesures). From tht popultion we selete women who t ny time etween Jnury 1, 1992 n Deemer 31, 1998 were ge 15±39 yers. Women who h VTE (pulmonry emolism or eep vein thromosis) on rme y eviene of ntiogulnt therpy were ienti e n the `event te' tken s the te on whih the rst symptoms were reore. These symptoms inlue hemoptysis, shortness of reth, hest pin n swelling or reness of lim. Presriptions for onventionl OCs n CPA/EE were ienti e n use to mp rug use to eh y in the stuy perio (Frmer et l., 1999). We were thus le to sertin for eh se her OC exposure sttus on the VTE event te. Totl exposure to CPA/EE n onventionl OC prouts in terms of expose women yers ws use to lulte rtes of VTE strti e y ge. For the se±ontrol stuy, up to seven ontrols were rnomly selete from the stuy popultion mthe to the se y event (inex) te, generl prtie n yer of irth. The GPRD reors for ses n ontrols were reviewe n relevnt meil n rug exposure informtion reore. Women with hroni illness, whih inlue ietes, sthm, systemi lupus erythemtosus, Crohn's isese/ulertive olitis n thyroi n renl isese, were ienti e. The use of onventionl OCs n CPA/EE mongst ontrols ws esrie with referene to the inex te s efore. The perio of uninterrupte exposure prior to the event/inex te for eh se n ontrol expose to onventionl COC or CPA/EE ws lulte. Also, euse it ppere tht the use of CPA/EE in the UK inrese onsierly following the `pill sre' of 1995 (Semn et l., 2003), we prtitione the stuy popultion oring to whether the event/inex te ws prior to or fter 1995. IRR (95% CI): COCs versus CPA/EE <30 yers 36 109315 3.29 1.07 (0.43±2.34) >30 yers 16 30888 5.18 4.94 (2.27±10.67) All ges 52 140203 3.71 (2.70±4.72) 2.17 (1.27±3.61) Age-juste IRR 2.20 (1.35±3.58) OWY = oserve women yers; EWY = expose women yers. Differenes in the length of time ses n ontrols were registere with prties ontriuting to the GPRD oul hve ise our oservtions with regr to ssigntion of ne sttus. In orer to ress this potentil onfouning we performe su-group nlysis inluing only those ses n ontrols with t lest 2 yers (760 ys) registrtion fter the inex te n t lest 1 yers (365 ys) registrtion prior to the inex te. Conitionl logisti regression moels were uilt to provie risk estimtes for VTE ssoite with CPA/EE juste for potentil onfouning. Results A totl of 179 women h VTE uring the stuy perio; none were ftl. Of these, 23 (13%) were expose to CPA/EE on the inex te giving rue VTE iniene rte of 8.05 ses/10 4 expose women yers. The rte of VTE inrese with inresing ge. The ge-juste iniene rte rtio for CPA/EE versus onventionl COCs ws 2.20 [95% on ene intervl (CI) 1.35±3.58] (Tle I). The 179 ses were mthe to 1076 ontrols. Chrteristis of ses n ontrols re shown in Tle II. Cses were more likely to hve history of VTE n to hve visite the generl prtitioner more frequently in the 6 months prior to the inex te. Pregnny, espeilly the intr/ postntl perio or post termintion of pregnny (TOP), hroni illness, reent surgery or trum n use of orl sterois were ll signi ntly ssoite with VTE. Using s the referene group women who were not using COCs n who h no reent pregnny or menopusl symptoms, exposure to onventionl COCs gve rue OR of 2.57 (95% CI 1.69±3.91) ompre with 6.86 (95% CI 3.71±12.69) for CPA/EE use. Cses n ontrols were similr in terms of oy mss inex (BMI) n smoking sttus. Amongst women in our stuy popultion who h een using onventionl COCs on the inex te, 90% h een using onventionl COC ontining the sme or smller ose of ethinyl estriol s ontine in CPA/EE (35 mg). The remining 10% h een using triphsi prouts. 523
H.E.Semn, C.S.e Vries n R.D.T.Frmer Tle II. Chrteristis of ses n ontrols Vrile Cses (n = 179) Controls (n = 1076) Crue OR (95% CI) n % n % VTE prior to 1992 8 4.47 12 1.12 4.04 (1.57±10.40) BMI <20 18 10.06 88 8.18 1.40 (0.79±2.46) 20±24 70 39.11 472 43.87 25±29 34 18.99 196 18.22 1.19 (0.77±1.85) 30±34 13 7.26 65 6.04 1.37 (0.71±2.63) 35+ 10 5.59 42 3.90 1.60 (0.77±3.33) Unknown 34 18.99 213 19.80 1.07 (0.67±1.72) Smoking sttus (losest to inex te) Non smoker 103 57.54 667 61.99 Smoker 45 25.14 252 23.42 1.19 (0.81±1.74) Unknown 31 17.32 157 14.59 1.29 (0.80±2.08) Numer of onsulttions with the generl prtitioner in the 6 months efore inex te None 13 7.26 274 25.46 1±2 30 16.76 327 30.39 1.92 (0.98±3.78) 3±9 83 46.37 389 36.15 5.29 (2.83±9.91) 10+ 53 29.61 86 7.99 20.43 (9.89±42.19) Reproutive sttus on inex te group 56 31.28 675 62.73 Antentl perio 21 11.73 53 4.93 5.72 (3.07±10.67) Intr/postntl perio or post-top 18 10.06 9 0.84 25.46 (10.56±61.40) Expose to onventionl COC 52 29.05 259 24.07 2.57 (1.69±3.91) Expose to POP 1 0.56 17 1.58 0.78 (0.10±6.01) Expose to CPA/EE 23 12.85 41 3.81 6.86 (3.71±12.69) Menopuse 8 4.47 22 2.04 3.86 (1.59±9.38) Chroni illness 49 27.37 169 15.71 2.10 (1.44±3.05) Reent surgery or trum 21 11.73 8 0.74 18.72 (7.49±46.76) Reent use of orl sterois 10 5.59 9 0.84 7.53 (3.06±18.54) Women for whom no urrent or reent pregnny n no urrent use of systemi orl ontreption ws pprent, n who were not menopusl/postmenopusl. Termintion of pregnny. Within the 6 week perio efore inex te. Tle III. Durtion of exposure in women expose to onventionl COC or CPA/EE Expose to onventionl COC on inex te Cses (n = 52) Controls (n = 259) Age-juste OR (95% CI) n % n % Durtion of exposure <6 yles prior to inex 32 61.54 108 41.70 2.17 (1.16±4.05) Durtion of exposure >6 yles prior to inex 20 38.46 151 58.30 Expose to CPA/EE on inex te Cses (n = 23) Controls (n = 41) Durtion of exposure <6 yles prior to inex 12 52.17 18 43.90 1.05 (0.34±3.21) Durtion of exposure >6 yles prior to inex 11 47.83 23 56.10 Informtion on urtion of exposure in those women expose to onventionl COC or CPA/EE is presente in Tle III. In women expose to onventionl COC, ses were signi ntly more likely thn ontrols to e expose for <6 yles prior to the inex te. Tht reltionship ws not emonstrte in women expose to CPA/EE. A su-group nlysis of CPA/EE-expose ses n ontrols who, oring to the informtion ville, h not een expose to onventionl COC t ny time prior to the inex te inlue 13 ses (six expose for <6 yles n seven expose for >6 yles) n 16 ontrols (six expose for <6 yles n 10 expose for >6 yles). With referene to n exposure of >6 524 yles, the ge-juste OR for VTE ws 1.36 (95% CI 0.26±7.17). Stepwise onitionl logisti regression ws use to ientify vriles for the nl onitionl logisti moel (Tle IV). The strongest preitors of VTE were reent surgery or trum n the intr/postntl perio or post- TOP. Using s the referene group women who were not using orl ontreption n who h no reent pregnny or menopusl symptoms, use of CPA/EE gve n juste os rtio (OR j ) of 7.44 (95% CI 3.67±15.08) ompre with n OR j of 2.58 (95% CI 1.60±4.18) for users of onventionl COCs.
Tle IV. Conitionl multivrite logisti regression (numer of oservtions = 1255) Vrile OR j (95% CI) No reent surgery or trum Reent surgery or trum 28.62 (8.95±91.58) No prior VTE VTE prior to 1992 10.52 (2.58±42.85) No reent pregnny, OC use or menopusl symptoms Antentl perio 3.76 (1.83±7.72) Intr/postntl perio or post TOP 14.45 (5.41±38.62) Expose to onventionl COC 2.58 (1.60±4.18) Expose to POP 0.30 (0.03±3.30) Expose to CPA/EE 7.44 (3.67±15.08) Menopuse 1.64 (0.56±4.79) No onsulttions with the generl prtitioner e 1±2 onsulttions with the generl prtitioner 1.66 (0.82±3.36) 3±9 onsulttions with the generl prtitioner 3.24 (1.66±6.32) 10+ onsulttions with the generl prtitioner 11.18 (4.99±25.07) No reent use of orl sterois Reent use of orl sterois 9.36 (3.21,27.27) Within the 6 weeks efore the inex te. Termintion of pregnny. Comine orl ontreptive. e Within the six-month perio efore inex te. Tle V. Conitionl multivrite logisti regression restrite to ses n ontrols with t lest 2 yers GPRD registrtion fter the inex te n t lest 1 yer prior to the inex (numer of oservtions = 539) Vrile OR j (95% CI) No reent surgery or trum Reent surgery or trum 45.89 (4.85±434.28) No prior VTE VTE prior to 1992 44.09 (2.63±737.71) No reent pregnny, OC use or menopusl symptoms Antentl perio 2.40 (0.76±7.55) Intr/postntl perio or post-top 11.79 (1.92±72.48) Expose to onventionl COC 2.26 (1.13±4.56) Expose to POP 0.54 (0.01±39.09) Expose to CPA/EE 3.87 (1.13±13.30) Menopuse 1.40 (0.12±16.31) No onsulttions with the generl prtitioner e 1±2 onsulttions with the generl prtitioner 1.67 (0.62±4.50) 3±9 onsulttions with the generl prtitioner 2.70 (1.00±7.27) 10+ onsulttions with the generl prtitioner 10.41 (3.29±32.89) Teetotl 1±9 units of lohol per week 0.15 (0.07±0.31) 10+ units of lohol per week 0.16 (0.04±0.62) Unknown lohol intke 0.90 (0.38±2.14) Within the 6 weeks efore the inex te. Termintion of pregnny. Comine orl ontreptive. e Within the 6 month perio efore inex te. Our su-group nlysis ienti e 82 ses n 457 mthe ontrols with t lest 365 ys registrtion time prior to the inex te n 760 ys registrtion time fter the inex te. A totl of 77 ses (94%) h t lest four mthe ontrols. Stepwise logisti regression ws use to ientify vriles for su-group onitionl logisti regression nlysis (Tle V). Reent surgery or trum, prior VTE, the intr- n postntl perio of pregnny or post-top n inresing numers of onsulttion with the generl prtitioner remine signi ntly ssoite with VTE. Exposure to onventionl COCs gve signi ntly rise OR of 2.26 (95% CI 1.13±4.56) n the OR for exposure to CPA/EE ws signi ntly rise to 3.87 VTE n yproterone ette/ethinyl estriol (1.13±13.30). Using exposure to onventionl COCs s the referene tegory, further nlysis revele tht the point estimtes for CPA/EE n onventionl COCs were not signi ntly ifferent [OR 1.71; (95% CI 0.49±5.96)]. There were 86 ses of VTE prior to 1995 n 62 ses fter 1995. Conitionl logisti regression nlysis revele no ifferene in the risk estimtes for VTE ssoite with CPA/ EE prior to, or fter, the 1995 `pill sre' (OR 7.22; 95% CI 2.10±24.82 versus 7.27; 95% CI 2.53±20.87). Disussion Our stuy popultion omprise group of women who were likely to hve n inrese risk of VTE. Tht risk ppere to e mpli e y exposure to CPA/EE. Previous work on CPA/ EE n VTE risk hs ompre the risk in users of CPA/EE with tht of onventionl COC users (Frmer et l., 1999; Prkin et l., 2000; Vsilkis-Srmozz n Jik, 2001; Liegr et l., 2002) lthough in only one pper ws the risk estimte juste for ne or PCOS (Vsilkis-Srmozz n Jik, 2001). In most ountries, CPA/EE is not liense s n orl ontreptive. Thus, we elieve it is pproprite to onsier the verse event risk pro le ssoite with CPA/EE longsie tht ssoite with other ne therpies. The verse retions ssoite with topil ne tretments inlue lol in mmtion n osionlly photosensitivity. The tetrylines hve een ssoite with vestiulr isturnes, hyperpigmenttion n photosensitivity n, more seriously, lupus-like retions n heptitis. The tretment options for women whose ne proves non-responsive to topil or orl ntiioti tretment inlue CPA/EE n orl retinois, lthough in the UK the use of isotretinoin requires speilist ermtologil supervision (British Ntionl Formulry, 2001). Isotretinoin is tertogeni n in women of hilering ge onomitnt use of omine estrogenprogesterone orl ontreptive is reommene. The potentil sie effets of isotretinoin use inlue hypervitminosis A-like symptoms, enign intrrnil hypertension, lopei, liver isese, elevte serum holesterol levels, photosensitivity n pnretitis (British Ntionl Formulry, 2001). More reently spontneous reports linking the use of isotretinoin with severe epression n suiie ttempts hve een ite (Wysowski et l., 2001) lthough there is urrently no epiemiologil eviene to support usl ssoition (Jik et l., 2000). We hve emonstrte n inrese risk of VTE ssoite with the use of CPA/EE in women with ne, hirsutism or PCOS. The estrogen omponent of the CPA/EE formultion in urrent use n use y women in our stuy rely exees tht of the mjority of onventionl COCs. To our knowlege no pulishe reserh hs ssoite CPA with VTE n s fr s we re wre there is no iologil plusiility for ny suh reltionship. The `epletion of suseptiles' priniple mintins tht ptients who remin on rug re those who n tolerte it whilst those who nnot re selete out of the popultion t risk (Yol n Aenhim, 1994). Thus risk per unit of time epens oth on history of prior exposure n on urtion of exposure. Whilst minful of the limittions impose y ensoring of t hel on the tse ( ptient's meil n rug exposure experiene prior to or fter perios 525
H.E.Semn, C.S.e Vries n R.D.T.Frmer of registrtion with ontriuting prtie re unknown) n the smll numers of expose ses, we foun tht, ompre with long-term use (>6 yles), there seeme to e n inrese risk for VTE in short term users (<6 yles) of onventionl COCs ut not users of CPA/EE. Thus we i not n eviene to support the possiility tht the inrese VTE risk in women using CPA/EE ws ssoite with epletion of suseptiles, even when we restrite the nlysis to CPA/EE-expose ses n ontrols who h no eviene of prior orl ontreptive use. The growth of the GPRD in longituinl t will llow us to explore further the urtion of exposure issue in future work. The oservtion tht the use of CPA/EE in the UK inrese onsierly following the `pill sre' of 1995 shoul e onsiere in n ssessment of VTE risk in women presrie CPA/EE. As prt of the nlysis, therefore, the t were prtitione oring to whether the VTE ourre prior to or fter 1995Ðonitionl logisti regression nlysis revele no ifferene in the risk estimtes for VTE ssoite with CPA/EE efore or fter the `pill sre'. Women with n ne ignosis t ny time in the meil reors ontriute to our stuy popultion. Thus it ws possile tht if the time registere with prties ontriuting to the GPRD iffere for ses n ontrols is oul e introue into the nlysis with regr to ne sttus. We hve esrie n `ne perio' for ptients with ne ignoses on the GPRD (Semn et l., 2003). Tht theoretil perio egn 2 yers prior to ptient's rst ne ignosis n ene 1 yer fter the lst ne ignosis. Bse on tht resoning, to relily ssign ne sttus to ses n ontrols we performe sugroup nlysis inluing only those ses n ontrols with t lest 2 yers (760 ys) registrtion fter the inex te n t lest 1 yers (365 ys) registrtion prior to the inex te. The results of the su-group onitionl logisti regression inite sttistilly signi nt ssoition etween VTE n exposure to CPA/EE (OR 3.87) n exposure to onventionl COCs (OR 2.26). Thus it ppers tht t lest prt of the signi ntly elevte risk estimte for VTE in women presrie CPA/EE my e ounte for y resiul onfouning with regr to ne sttus. The ifferene in risk etween CPA/EE n onventionl COCs ws not signi nt, unlikely to e ssoite with ethinyl estriol ose n oul e hne ning. The ge-juste IRR for VTE ssoite with CPA/EE use versus use of onventionl COCs ws 2.2 n fter justment in the su-group se±ontrol nlysis this rtio ws reue to 1.7. Thus if omplete justment for onfouning oul e hieve it is possile tht no ifferene in risk etween onventionl COCs n CPA/EE woul remin. Our stuy popultion omprise women with ne, hirsutism or PCOS. It is possile tht the moriity ssoite with more severe symptoms in suh women my inlue n elevte VTE risk. We nnot etermine isese severity using routinely ollete t suh s tht ville on the GPRD n further work is plnne to explore the unerlying risk pro les of CPA/ EE users. In onlusion, it is likely tht onfouning y isese severity is n importnt omponent of the elevte VTE risk ssoite with CPA/EE exposure in women with ne, hirsutism or PCOS. Our nings suggest tht CPA/EE remins 526 vile tretment option for women with hirsutism or ne whih hs prove unresponsive to other rugs. In ition the nings of this stuy suggest tht, ompre with other estrogen-ontining prouts of similr ose, CPA/EE oes not inrese womn's seline VTE risk. Creful onsiertion shoul e given to the risks ssoite with CPA/EE versus other tretment options. Aknowlegements This stuy ws supporte y n unonitionl reserh grnt from Shering AG. The ompny ws not involve in the investigtions t ny point. 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