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The effect of oral contraceptives on antiaggregatory prostacyclin and proaggregatory thromboxane A2 in humans
The effect of oral contraceptives on antiaggregatory prostacyclin and proaggregatory thromboxane A2 in humans OLAVI
YLIKOKKAL.4,
JUKK4
PUOLAKKA,
LiZSSE
VIINlKK.4,
M.D. M.D. M.D.
Oulrr. Fiulctnd The effect of different types of oral contraceptives on the productions of antiaggregatoty prostacyclin (PGI,) and proaggregatory thromboxane A2 (TxA,) was studied by measuring the stable metabolites of these prostanoids, that is, 6-ketoprostaglandin F,,, (6-keto-PGF,,) and thromboxane B, (TxB,), respectively, from plasma. In addition, the capacity of the platelets to produce TxB, during spontaneous clotting was studied by measuring the TX& levels from the serum incubated at +37” C for 60 minutes. The material consisted of 48 women who had used estrogen-containing oral contraceptives for 2.0 2 1.9 years (mean 5 SD), 24 women using progestogen-only pills for 3.7 + 2.0 years, and 42 women of the same age using no oral contraceptives or intrauterine contraceptive device. The plasma concentrations of 6-keto-PGF,, in women with combined oral contraceptives (65.5 t 16.1 pg/ml, mean ? SD) was lower (p < 0.01) than that in the control subjects (77.4 t 26.4 pg/ml), whereas the use of combined oral contraceptives was associated with no changes in TxB, levels in plasma or serum. In women with progestogen-only oral contraceptives, the plasma levels of 6-keto-PGF,, and TxB, were normal, but the capacity of the platelets to release TxB, during spontaneous clotting was decreased (113.6 2 77.6 rig/ml versus 179.9 2 81.9 ngiml, p < 0.05). In a prospective trial on 11 women, who started using 30 pg of ethinyl estradiol and 150 pg of levonorgestrel, no changes in PGI, or TxA, were seen during the first 3 months of usage. The decrease in antiaggregatory PGI, during the prolonged use of estrogen-containing oral contraceptives may be associated with the increased risk of thromboembolism. (AM. J. OBSTET. GYNECOL. 142:573, 1982.)
II- IS well established that oral contraceptive users are subjected to the increased risk of’ thrombosis, but the fillal causati\.e mechanisms are not known.’ In the middle 1 SSOs, two prostanoids with opposing effects on the platelet-vascular interaction, which evidently is crucial in the fbrmation of’ the thrombosis,’ were discovered. Prostacyclin (PGI,), produced by the vascular wall, causes vasodilation and is the most potent inhibiFwm thr De,& rtmrn t.\ of Oh.\t&r\ uud Gyncrrroko,~~
tar of’ platelet
aggregation so far kno\+.n ,‘I whereas is the product of the platelets and characteri/.ed with ~asocolistrictor!. and proaggregatory properties.’ Both compounds are labile in php iologic pH and rapidI!, converted to the stable metabolites, PGI,! to 6-ketoprostaglandin F,, (6-keto-PGF,,)” and TxA,! to thromboxane Hi (TxB?).’ .4 decreased production of PGI, \vas recently reported f’rom a small series of oral contracepti\,e users.” 1n the present xvork lye ha\,c extended the material and measured, in addition to WI,, the circulating le\,els of”rsB, as well as the capacity of’ the platelets to produce TsB? during spontaneous clotting of’ the blood. thrombosane
A, (TxA,)
Material and methods Subjects. The srud!, consisted ot‘ two parts, from ;I cross-sectional study. where I 14 women were investigated (Table I), and from a prospective stud!, 011 11 573
574
Table
Ylikorkala. Puolakka, and Viinikka
I. Characteristics
of’ the study population
(mean rt SD)
“2.0 t 3.0
h0mc11 IK~\\~~cw 19 atid 2 \c;irs 01 age 12.110\\erc iI)\estigatd I~~lc~rc ;~tld alter I- 2nd 3-month use 0lor;rl (ontr;ice~~li\ei containing: 30 pg of cthin>l estradiol ;r~d 1 .iO E*R 01 le\onorgestrel. ITort\ -two \\‘omen itsing 110 01~1 contt~acrpti\~es or intrilLttcl~ille contt-aception \vei-c xt Litlietl x4 c.ontrol 9ut?jects. No \votnan had used drttgh I\IIOWII to intertere \vith the synthesis of’ prostaglillltlil1\
\$itllill
10
tl:l\S
kt’OW
the
SlLltl!‘.
Blood zm~ples were obtained I)) ~~ni~~Llii~~ti~w without stasis in the sitting position belol-~ ;I ]x.l\ic cx;m~ination, il’ 1~cr~ortnrd. During 01-21 ~otitt~dcepti\r use, sampling Look place at least .5 dab ;tfter the tablet-f-cc iriterwl. For pi;isina, I~lootl was collected into icy-cold hr1JaGni0xl tubes containing ‘LO pni~~les/I. 01 xetylsalicylic acid ;IS ;I linal concentratic)n ;ttid ceklti-ittigetl illirnediatcl? I;or scrtttn, blood utllIJ~CS collected into rlr) tubes IX’CI‘Callowed to clot loI- 60 rnirlLitv\ ;11 :17”
samples.
(i-keto-I’(;[~,,,-bovine
serunl
albumi
and
,(y (spec-ilic
co~npouncls
tested. .I hc ret o\er\
PGF,, (50 to ‘LOO pgiml) xltletl to 1hm;t I O-+C/(and the coefficient5 of’ intra-assa\
of’ N-.ctoW:LS 84% to
ant1 interasY;I\ \;iriation\ lvere betlveen 6.K’;; antl H.ScG ;11ri1!I.:<‘; mtl 1 +.2V , respectively. Plasma 6-keto-MGF,, n~t’asuretnent as ;IJI index of %I2 production \\.;I$ tttrthcr validated b) demonstration ot ;I lincai. relationship (r = 0.96, p < 0.001, II = 24) betweeti infused P(;I, doses ( 1 to H ngikgimin) and the rises it] 6keto-PGF,, measurement. In addition, we could show that kuown PG synthesis inhibitors, such as acet$salicylic acid and indomethacin, inhibited in a concentration-dcpendent manner the release of’ radioimmunoassayable Cketo-PGF,, in various tissues in \-itro (to be puhlished) Measurement of Txa,. We detcrmineti tl1e .I x.‘i, production b\ measuring ‘I‘xB, coticeiltt.atioli~ in plasin;i and serum with a specific radioimrli~rnoas~~i~.~ ‘I’hr mtionale of‘ this approach b*iix to nieawre the ciwtilating T’xB, in vi\o and the capacit)~ of the platclcr to produce ~I‘xB2 during thrornbin-incluceti aggregation in spontaneous clotting. The amount of’ TsB2 produced during spontaneous clotting correlates closeh (I- > 0.9) with the amount of’I‘xB2 released f’rom pl,ttelets during induced aggregation iii platelet-i.icll plaslll;l.’
Statistical stLltlellt’s
analysis.
The
results
uc’rc’ tested bit11
t test.
(bl~‘)-6-keto-
dcti\.it! appiosi~natel~ 100 Ciirnniole, New Ikgiaritl Nuclear, Boston, Massachusetts). The cross rt*acti\it) of’the antibody was less than 0.1’92 at the 50’4 displacement levels with 22 prostaglandins and l’(ik
related
i 5 rt 2.0
Results Plasma
keto-PCF,, containing
of 6-keto-PGE,,. ‘I-he plasma ticoncentrations in women using estrogrrroral contraceptives were decreased (p C,
levels
Effect of oral contraceptives
on PGI, and TxA,
575
II. Concentrations (mean C SD) of &keto-PGF,, and TxB, in plasma and production of TxB, into serum during clotting of blood samples at 37” C for 60 minutes in women using various oral contraceptives and in control subjects
Table
Plarmn 6-kc-to-PW,, (pg.4
Cross-sectional
Serum TXB, (rl
65.5 2 I(i.l* (n = 48) 71.1 -c 20.8 (11= 24)
153.3 2 141.9 (n = 45) 114.0 2 57.7 (n = 24)
174.2 k 82.0 (n = ZX) 113.6 2 77.6 (n = 13)**
71.0 70.0 65.1 77.4
154.4 ” 98.8 (n = III 98.7 t 33.1 (n = 9) 131.5 2 65.6 (11= 42)
study:
Combined oral contraceptives Progestogen only Prospective
Y-d2 CPL!wJ
Study
study:
Before start of oral contraceptives After 1 mo use After 3 mo use Control subjects
2 k * 2
15.5 16.5 1x.x 26.4
(n = (n = (n = (11=
11) 11) 9) 42)
97.2
_t
56.0
(II
=
I1
1
17X.9 2 81.9 (n = 20)
*Significantly less than in control subjects, p < 0.0 1. **Significantly less than in control subjects, p < 0.05. 0.01) and those in women using minipills were normal in the cross-sectional stud) (Table 1 I). No cot-relation between the dose of‘ estrogen or the q)e of progestoThe plasma gen and plasma 6-keto-PGF,, was seen. ot‘ 60.2 * li.1 pg/ml (mean ? SD, 6-keto-PGF,, n = 13) in the smokers was not different f’rom that 01’ 66.6 t 16.1 pgiml in the nonsmokers (n = 5X). In the prospective study, no changes were seen in plasm;~ 6-keto-PGF,, (Table 11). Plasma or serum levels of TxB,. The use 01 combined oral contraceptives caused no changes in plasma or serum TxB, concentrations, hut the use 01’minipills signilicantl! suppressed the TxBf formation during spontaneous clotting (Table 11). This suppression \V;IS most prominent in women using le~onorgestrel, iti ~vhom the mean TxB, in serum was 66.1 ngiml.
Comment The prolonged use of estrogen-containing oral contraceptives led to significantly decreased levels of’ in plasma. According to the present 6-!.eto-PGF,, knowledge, circulating 6-keto-PGF,, as the main mctaholite reflects PGI? producLion,” and consequentI! indicates decreased decreased plasma 6-keto-PGF,, production of PGI,. Because WI, is the most potent inhibitor of‘ platelet aggregation known so far:’ its decreased synthesis in women using combined oral COIP traceptives may he involved with the increased rate of thrombosis in these women.’ The risk of thrombosis it, oral contraceptive users seems to be related to the estrogen component of‘ the pill, ‘. +Jand indeed we fo~md no ICI, suppression in women using progestogen-onI!, oral contraceptives. Our assumption that synthetic estrogen is responsible for the PGI, suppression gains support from a recent report of‘ decreased release ot. vascular PGIZ and increased aggregation of’ the platelets in vivo in rabbits treated with ethinyl estradiol.“‘<)n
the other hand, our data are in contrast lvi[h some studies in \vliicli the treat mem \vith combined oral contracepti\.es has increased I’GI, s>.nthesis I,\ rat”. I” and liumati’~’ dissected \xcular tissue components, as assessed in in vitro production 01‘PGI,. The P(;l, synthesis in vi\0 is, however, ;I cornpIe?. process, where the endoperosides fix)tii source:, other than the ~asc-ulai will, fix example, tl~ni lhe platelets, ma\ he it) the ke! position.’ Therefixe, it is not knowt1 ho\;- ~~11, il at all, the producLion of’ PGI? 1)) ;I piece 01’\~ascula~-tissue in \.itro reflects the PGI, pi~oductioti in 1 il.0. In the prospecti\,e stud)., we did not find a significant decrease in prostaqclin. It is, ho\vever, iiote\vorth\ that pl;~sma 6-keto-PGF,, ;I tier ;I :l-month use of IOUestrogen coti~hined oral contraccptivcs \v;th alinost itlentital to that of’coml~ii~ecl oral c-ontracepti\~c users iti the cross-sectional st~itl!~. .l‘hus, the lack ot‘ significance might be due to tlie sample six; also the possibilit> that low-estrogen oral contraceptives deci-ease P(;l, productioii cannot he e\;clutied. \\‘e also present Iiwe the lirst e\,idence that the tise of’ c-omhitied oral contraceptives does not change the production ot I”.o;Lggt-egatot.\ TX;\,. Curiously enough, t he capxit! ot’the platelets to s!‘iit he&e 1‘sA: during clotting IY;IS decreased in ~votiien rtsing progestogeil-otil~ oral contraceptives. Tlieoi~eticall~ , it could result ill ;I .I‘his progrstogendecreased risk o! t hromhosia. induced suppressioti in ]“‘o;tggregatoi.~ TX& l’ormariot1 is compatible with Llie linding that noretliitidi.otle pre\ ented t lie increase ot platelet aggregation itiduced II) ctliin) I estradiol in rahhits iti \,i\ 0.“’ ~l‘li;~i ii0 -l‘aX, suppression \\as seeti iii ~ionien itsing progestogetis ill combination xritli ethiiq I cstradiol might suggest Lliat etliin! I estradiol cotinteracts this progcstogcii et tect. ~I‘hus, it seems Lllat progestogens alld ~SII-ogens ma)’ Iiavc opposing ef‘ltcts on platelets as on mail! otllei organs.
576
Ylikorkala, Puolakka, and Viinikka
YLIKOKKAL.4,
JUKK4
PUOLAKKA,
LiZSSE
VIINlKK.4,
M.D. M.D. M.D.
Oulrr. Fiulctnd The effect of different types of oral contraceptives on the productions of antiaggregatoty prostacyclin (PGI,) and proaggregatory thromboxane A2 (TxA,) was studied by measuring the stable metabolites of these prostanoids, that is, 6-ketoprostaglandin F,,, (6-keto-PGF,,) and thromboxane B, (TxB,), respectively, from plasma. In addition, the capacity of the platelets to produce TxB, during spontaneous clotting was studied by measuring the TX& levels from the serum incubated at +37” C for 60 minutes. The material consisted of 48 women who had used estrogen-containing oral contraceptives for 2.0 2 1.9 years (mean 5 SD), 24 women using progestogen-only pills for 3.7 + 2.0 years, and 42 women of the same age using no oral contraceptives or intrauterine contraceptive device. The plasma concentrations of 6-keto-PGF,, in women with combined oral contraceptives (65.5 t 16.1 pg/ml, mean ? SD) was lower (p < 0.01) than that in the control subjects (77.4 t 26.4 pg/ml), whereas the use of combined oral contraceptives was associated with no changes in TxB, levels in plasma or serum. In women with progestogen-only oral contraceptives, the plasma levels of 6-keto-PGF,, and TxB, were normal, but the capacity of the platelets to release TxB, during spontaneous clotting was decreased (113.6 2 77.6 rig/ml versus 179.9 2 81.9 ngiml, p < 0.05). In a prospective trial on 11 women, who started using 30 pg of ethinyl estradiol and 150 pg of levonorgestrel, no changes in PGI, or TxA, were seen during the first 3 months of usage. The decrease in antiaggregatory PGI, during the prolonged use of estrogen-containing oral contraceptives may be associated with the increased risk of thromboembolism. (AM. J. OBSTET. GYNECOL. 142:573, 1982.)
II- IS well established that oral contraceptive users are subjected to the increased risk of’ thrombosis, but the fillal causati\.e mechanisms are not known.’ In the middle 1 SSOs, two prostanoids with opposing effects on the platelet-vascular interaction, which evidently is crucial in the fbrmation of’ the thrombosis,’ were discovered. Prostacyclin (PGI,), produced by the vascular wall, causes vasodilation and is the most potent inhibiFwm thr De,& rtmrn t.\ of Oh.\t&r\ uud Gyncrrroko,~~
tar of’ platelet
aggregation so far kno\+.n ,‘I whereas is the product of the platelets and characteri/.ed with ~asocolistrictor!. and proaggregatory properties.’ Both compounds are labile in php iologic pH and rapidI!, converted to the stable metabolites, PGI,! to 6-ketoprostaglandin F,, (6-keto-PGF,,)” and TxA,! to thromboxane Hi (TxB?).’ .4 decreased production of PGI, \vas recently reported f’rom a small series of oral contracepti\,e users.” 1n the present xvork lye ha\,c extended the material and measured, in addition to WI,, the circulating le\,els of”rsB, as well as the capacity of’ the platelets to produce TsB? during spontaneous clotting of’ the blood. thrombosane
A, (TxA,)
Material and methods Subjects. The srud!, consisted ot‘ two parts, from ;I cross-sectional study. where I 14 women were investigated (Table I), and from a prospective stud!, 011 11 573
574
Table
Ylikorkala. Puolakka, and Viinikka
I. Characteristics
of’ the study population
(mean rt SD)
“2.0 t 3.0
h0mc11 IK~\\~~cw 19 atid 2 \c;irs 01 age 12.110\\erc iI)\estigatd I~~lc~rc ;~tld alter I- 2nd 3-month use 0lor;rl (ontr;ice~~li\ei containing: 30 pg of cthin>l estradiol ;r~d 1 .iO E*R 01 le\onorgestrel. ITort\ -two \\‘omen itsing 110 01~1 contt~acrpti\~es or intrilLttcl~ille contt-aception \vei-c xt Litlietl x4 c.ontrol 9ut?jects. No \votnan had used drttgh I\IIOWII to intertere \vith the synthesis of’ prostaglillltlil1\
\$itllill
10
tl:l\S
kt’OW
the
SlLltl!‘.
Blood zm~ples were obtained I)) ~~ni~~Llii~~ti~w without stasis in the sitting position belol-~ ;I ]x.l\ic cx;m~ination, il’ 1~cr~ortnrd. During 01-21 ~otitt~dcepti\r use, sampling Look place at least .5 dab ;tfter the tablet-f-cc iriterwl. For pi;isina, I~lootl was collected into icy-cold hr1JaGni0xl tubes containing ‘LO pni~~les/I. 01 xetylsalicylic acid ;IS ;I linal concentratic)n ;ttid ceklti-ittigetl illirnediatcl? I;or scrtttn, blood utllIJ~CS collected into rlr) tubes IX’CI‘Callowed to clot loI- 60 rnirlLitv\ ;11 :17”
samples.
(i-keto-I’(;[~,,,-bovine
serunl
albumi
and
,(y (spec-ilic
co~npouncls
tested. .I hc ret o\er\
PGF,, (50 to ‘LOO pgiml) xltletl to 1hm;t I O-+C/(and the coefficient5 of’ intra-assa\
of’ N-.ctoW:LS 84% to
ant1 interasY;I\ \;iriation\ lvere betlveen 6.K’;; antl H.ScG ;11ri1!I.:<‘; mtl 1 +.2V , respectively. Plasma 6-keto-MGF,, n~t’asuretnent as ;IJI index of %I2 production \\.;I$ tttrthcr validated b) demonstration ot ;I lincai. relationship (r = 0.96, p < 0.001, II = 24) betweeti infused P(;I, doses ( 1 to H ngikgimin) and the rises it] 6keto-PGF,, measurement. In addition, we could show that kuown PG synthesis inhibitors, such as acet$salicylic acid and indomethacin, inhibited in a concentration-dcpendent manner the release of’ radioimmunoassayable Cketo-PGF,, in various tissues in \-itro (to be puhlished) Measurement of Txa,. We detcrmineti tl1e .I x.‘i, production b\ measuring ‘I‘xB, coticeiltt.atioli~ in plasin;i and serum with a specific radioimrli~rnoas~~i~.~ ‘I’hr mtionale of‘ this approach b*iix to nieawre the ciwtilating T’xB, in vi\o and the capacit)~ of the platclcr to produce ~I‘xB2 during thrornbin-incluceti aggregation in spontaneous clotting. The amount of’ TsB2 produced during spontaneous clotting correlates closeh (I- > 0.9) with the amount of’I‘xB2 released f’rom pl,ttelets during induced aggregation iii platelet-i.icll plaslll;l.’
Statistical stLltlellt’s
analysis.
The
results
uc’rc’ tested bit11
t test.
(bl~‘)-6-keto-
dcti\.it! appiosi~natel~ 100 Ciirnniole, New Ikgiaritl Nuclear, Boston, Massachusetts). The cross rt*acti\it) of’the antibody was less than 0.1’92 at the 50’4 displacement levels with 22 prostaglandins and l’(ik
related
i 5 rt 2.0
Results Plasma
keto-PCF,, containing
of 6-keto-PGE,,. ‘I-he plasma ticoncentrations in women using estrogrrroral contraceptives were decreased (p C,
levels
Effect of oral contraceptives
on PGI, and TxA,
575
II. Concentrations (mean C SD) of &keto-PGF,, and TxB, in plasma and production of TxB, into serum during clotting of blood samples at 37” C for 60 minutes in women using various oral contraceptives and in control subjects
Table
Plarmn 6-kc-to-PW,, (pg.4
Cross-sectional
Serum TXB, (rl
65.5 2 I(i.l* (n = 48) 71.1 -c 20.8 (11= 24)
153.3 2 141.9 (n = 45) 114.0 2 57.7 (n = 24)
174.2 k 82.0 (n = ZX) 113.6 2 77.6 (n = 13)**
71.0 70.0 65.1 77.4
154.4 ” 98.8 (n = III 98.7 t 33.1 (n = 9) 131.5 2 65.6 (11= 42)
study:
Combined oral contraceptives Progestogen only Prospective
Y-d2 CPL!wJ
Study
study:
Before start of oral contraceptives After 1 mo use After 3 mo use Control subjects
2 k * 2
15.5 16.5 1x.x 26.4
(n = (n = (n = (11=
11) 11) 9) 42)
97.2
_t
56.0
(II
=
I1
1
17X.9 2 81.9 (n = 20)
*Significantly less than in control subjects, p < 0.0 1. **Significantly less than in control subjects, p < 0.05. 0.01) and those in women using minipills were normal in the cross-sectional stud) (Table 1 I). No cot-relation between the dose of‘ estrogen or the q)e of progestoThe plasma gen and plasma 6-keto-PGF,, was seen. ot‘ 60.2 * li.1 pg/ml (mean ? SD, 6-keto-PGF,, n = 13) in the smokers was not different f’rom that 01’ 66.6 t 16.1 pgiml in the nonsmokers (n = 5X). In the prospective study, no changes were seen in plasm;~ 6-keto-PGF,, (Table 11). Plasma or serum levels of TxB,. The use 01 combined oral contraceptives caused no changes in plasma or serum TxB, concentrations, hut the use 01’minipills signilicantl! suppressed the TxBf formation during spontaneous clotting (Table 11). This suppression \V;IS most prominent in women using le~onorgestrel, iti ~vhom the mean TxB, in serum was 66.1 ngiml.
Comment The prolonged use of estrogen-containing oral contraceptives led to significantly decreased levels of’ in plasma. According to the present 6-!.eto-PGF,, knowledge, circulating 6-keto-PGF,, as the main mctaholite reflects PGI? producLion,” and consequentI! indicates decreased decreased plasma 6-keto-PGF,, production of PGI,. Because WI, is the most potent inhibitor of‘ platelet aggregation known so far:’ its decreased synthesis in women using combined oral COIP traceptives may he involved with the increased rate of thrombosis in these women.’ The risk of thrombosis it, oral contraceptive users seems to be related to the estrogen component of‘ the pill, ‘. +Jand indeed we fo~md no ICI, suppression in women using progestogen-onI!, oral contraceptives. Our assumption that synthetic estrogen is responsible for the PGI, suppression gains support from a recent report of‘ decreased release ot. vascular PGIZ and increased aggregation of’ the platelets in vivo in rabbits treated with ethinyl estradiol.“‘<)n
the other hand, our data are in contrast lvi[h some studies in \vliicli the treat mem \vith combined oral contracepti\.es has increased I’GI, s>.nthesis I,\ rat”. I” and liumati’~’ dissected \xcular tissue components, as assessed in in vitro production 01‘PGI,. The P(;l, synthesis in vi\0 is, however, ;I cornpIe?. process, where the endoperosides fix)tii source:, other than the ~asc-ulai will, fix example, tl~ni lhe platelets, ma\ he it) the ke! position.’ Therefixe, it is not knowt1 ho\;- ~~11, il at all, the producLion of’ PGI? 1)) ;I piece 01’\~ascula~-tissue in \.itro reflects the PGI, pi~oductioti in 1 il.0. In the prospecti\,e stud)., we did not find a significant decrease in prostaqclin. It is, ho\vever, iiote\vorth\ that pl;~sma 6-keto-PGF,, ;I tier ;I :l-month use of IOUestrogen coti~hined oral contraccptivcs \v;th alinost itlentital to that of’coml~ii~ecl oral c-ontracepti\~c users iti the cross-sectional st~itl!~. .l‘hus, the lack ot‘ significance might be due to tlie sample six; also the possibilit> that low-estrogen oral contraceptives deci-ease P(;l, productioii cannot he e\;clutied. \\‘e also present Iiwe the lirst e\,idence that the tise of’ c-omhitied oral contraceptives does not change the production ot I”.o;Lggt-egatot.\ TX;\,. Curiously enough, t he capxit! ot’the platelets to s!‘iit he&e 1‘sA: during clotting IY;IS decreased in ~votiien rtsing progestogeil-otil~ oral contraceptives. Tlieoi~eticall~ , it could result ill ;I .I‘his progrstogendecreased risk o! t hromhosia. induced suppressioti in ]“‘o;tggregatoi.~ TX& l’ormariot1 is compatible with Llie linding that noretliitidi.otle pre\ ented t lie increase ot platelet aggregation itiduced II) ctliin) I estradiol in rahhits iti \,i\ 0.“’ ~l‘li;~i ii0 -l‘aX, suppression \\as seeti iii ~ionien itsing progestogetis ill combination xritli ethiiq I cstradiol might suggest Lliat etliin! I estradiol cotinteracts this progcstogcii et tect. ~I‘hus, it seems Lllat progestogens alld ~SII-ogens ma)’ Iiavc opposing ef‘ltcts on platelets as on mail! otllei organs.
576
Ylikorkala, Puolakka, and Viinikka