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Canad. Med. Ass. J. 1024 Rice-Wray and others: Oral Contracepttve Agent Nov. 12, 1966, vol. 95

Clinical Trial of a Combination of and (Lyndiol) as an Oral Contraceptive Agent EDRIS RICE-WRAY, M.D., CARMEN BECERRA, M.D., JULIO ESQUIVEL, M.D. and MANUEL MAQUEO, M.D., Mexico City, Mexico

Contraception with lynestrenol-mestranol (Lyndiol) was On a etudie le lynestrenol-mestranol (Lyndiol) comme studied in 332 Mexican women during a period of two contraceptif chez 332 mexicaines durant une periode and one-half years. Side effects were minimal or tran¬ de deux ans et demi. Les reactions secondaires ont ete sient. No pregnancies occurred in those who took the minima ou transitoires. Aucune grossesse n'est survenue medication according to instructions. The women were chez les femmes qui ont pris la medication conform£- followed with yearly pelvic examinations and Papa- ment aux instructions. Les femmes ont ete suivies au nicolaou smears, serial endometrial biopsies and exten¬ moyen d'examens pelviens annuels et de frottis de sive studies of blood, and glandular function. Com¬ Papanicolaou, de biopsies en serie de l'endometre et plete ophthalmological studies were done on 30 pa¬ d'etudes attentives du sang, du foie et de la fonction tients. No clinical or laboratory evidence of harmful glandulaire. Un examen ophthalmologique complet a effects could be demonstrated. Return to ovulation £te* effectue chez 30 femmes. On n'a constate, ni en (using pregnanediol and endometrial biopsies clinique, ni par les examens de laboratoire, d'effets as parameters) occurred in all of 22 women studied pernicieux du produit. Le retour a l'ovulation (les in the first three post-treatment cycles. Eight post- parametres utilises etant l'excr£tion de pregnanediol et treatment pregnancies and the resulting offspring were les biopsies de l'endometre) s'est produit chez les 22 normal. The first post-treatment cycle, as with other femmes observees, au cours des trois premiers cycles oral contraceptives, was unpredictable and tended to post-therapeutiques. Huit cas de grossesse post-the- be prolonged. It varied in length from 22 to 60 days. rapeutique et la progeniture qui en est resultee ont ete* normaux. Le premier cycle post-therapeutique, comme avec d'autres contraceptifs per os, est demeure the first field trials of norethynodrel with impre'visible et avait tendance a se prolonger. Sa SINCEmestranol in fertility control a decade ago,1 a longueur variait de 22 a 60 jours. variety of safe and effective compounds have been made to several available the public, including and disappears on changing to a different com¬ products studied by our group in Mexico City.2"6 Such considerations point to the rationale In the United States to a recent pound. alone, according of the continuing search for more oral contracep¬ report of the Food and Drug Administration, the tives and for lower effective number of women "the increased more contraceptive using pill" doses. This on a clinical evalua¬ than to some six in the last five paper reports 10-fold, million, tion of an oral a combina¬ in the in countries as far antifertility compound, years; elsewhere world, tion of and mestranol at two as and it is estimated that lynestrenol (Lyndiol), apart Egypt Argentina, dose levels and with two of administra¬ there are another to 10 million users. regimens eight Accept¬ tion. Part of the data set out here was ance of the agents has coincided presented antifertility in an earlier Ferin7, 23 and with a greater awareness on the part of religious publication.5 Lauweryns and political leaders everywhere of the disastrous and Ferin8 have also studied this contraceptive. consequences of a population explosion; it has been much favoured by the practical demonstration that Materials and Methods even the poorest classes can use this most con¬ A total of 332 women, over a span of two and venient method of family planning to maximum one-half years, were medicated with lynestrenol 5 benefit.26 mg. combined with mestranol 150 /xg. (Lyndiol Unpleasant side effects such as , , 5) and/or lynestrenol 2.5 mg. combined with nervousness, weight gain and intermenstrual bleed¬ mestranol 75 fig. (Lyndiol 2.5). The number of ing, though harmless and usually transient, previ¬ cycles followed with the 5-mg. was 1112, ously led to a fairly high initial discontinuance of and with the 2.5-mg. tablet, 4634, for a total of the medication. It has been our experience that the 5746 cycles, representing 442 women-years of ex¬ incidence of these complaints had a direct rela¬ perience with the medication. A group of 120 tion to the amount of medication in the original women who started the project on the 5-mg. tablet compounds. With the new low-dosage compounds, were changed over to the 2.5-mg. tablet as it unpleasant side effects are notably less common, became available, without any break in the medica¬ while the pleasant side effects such as regularity of tion sequence. The distribution of medication cycles cycle, elimination of menorrhagia and relief of dys- is shown in Fig. 1; approximately two-thirds (218) menorrhea are maintained. Occasionally, the in¬ of the women completed 15 or more cycles, in¬ tolerance is related to an individual idiosyncrasy cluding 55 who finished 30 or more. The subjects were selected from the women who From the Centro de Investigacion de la Fisiologia de la Re- produccion. de la Asociacion Pro-Salud Maternal, A.C., come to one of our voluntary clinics in Mexico City Apartado Postal 7-1050, Mexico 7, D.F. for medical advice and assistance in This study was supported by a grant from Organon, Inc, family plan¬ West Orange, N.J., U.S.A. ning. They were chosen for the project according Canad. Med. Ass. J. Nov. 12, 1966, vol. 95 Rice-Wray and others: Oral Contraceptive Agent 1025

a separate group of 40 women who had been taking the medication for 30 or more cycles. Studies done for the liver profiles consisted of BSP, cephalin cholesterol, direct bilirubin, indirect bilirubin, SGOT, total protein, albumin, globulin, A/G ratio, and alkaline phosphate. Triiodothyronine (T-3) uptake by erythrocytes and radioiodine on two separate groups of 10 subjects before and during the first three post-treatment cycles was also de¬ termined. Whenever possible, laboratory studies yielding results outside the normal range were repeated several cycles later. On 50 subjects selected at random, slit-lamp examinations were performed initially and repeated IS fW5 30 K 30 3S 3T Tft£ATM£NT CYCLES after 18 cycles; 11 of these women were also Fig. 1..Duration of medication with lynestrenol-mestranol. examined in the interim period. A complete eye examination was carried out by an ophthalmologist to the usual criteria: 40 years old or less, proved on another group of 25 women who had received fertility with present marital partner, an apparently between 25 and 36 cycles of therapy. We were stable marriage, regular menstrual cycles, sufficient primarily interested in detecting possible cataract intelligence and motivation to continue on the formation. When Walsh et al.1* suggested possible medication, a domicile accessible to the social neuro-ophthalmological effects, complete eye ex¬ worker, and no steroid therapy in the preceding aminations were done. three months. An endometrial biopsy was taken in 204 women The subject population is composed of Mexican before the administration of the contraceptive. An¬ nationals in its entirety and is 98% Roman Catholic. other group of 215 biopsies were taken randomly The majority (68%) belong to the lowest economic in various cycles and days of cycle between 18 class, and the remainder to the lower middle class. and 36 cycles of medication. In yet another group Compared to the average Canadian woman, they of 34 subjects who had been taken off the 5-mg. are smaller in stature and are less well nourished. dose compound, serial endometrial biopsies were Their diet is low in protein and high in carbo- obtained at weekly intervals in the different wo¬ hydrates. Intestinal parasitosis is common. men, beginning one week after the first post-medi- Ages vary from 18 to 40 years, with an average cation menses and continuing for three cycles. of 32 years. Previous pregnancies average 6.0 for Pregnanediol determinations were obtained, dur¬ the group. The women come to the family planning ing and after discontinuing the medication, in this clinic usually as a result of information from a same group of 34 subjects, who had been taking friend and with the knowledge and consent of their the 5-mg. tablet for 13 to 25 cycles. The first deter¬ mates; most often because they cannot afford mination was carried out during the last treatment another child, less often for personal health reasons. cycle. The second determination was done on 24- At the onset of the study, every subject is given a hour from day 22 of the next cycle, the first gynecologie examination and an examination of without therapy. Subsequent determinations were breasts and rectum; a Papanicolaou smear is also carried out at weekly intervals until the onset of taken at this time, along with a biopsy of any menstruation. If no ovulatory level of urinary preg¬ Schiller-positive areas of the cervix; all of which nanediol was obtained during the first menstrual is repeated at yearly intervals. cycle without medication, the whole procedure On 100 subjects selected at random, the follow¬ was repeated in the following cycle and, if neces¬ ing laboratory studies were carried out initially sary, in a third cycle. Only those determinations and then repeated at approximately three, six, 12 obtained for days -2 to -10, counting back from and 18 cycles: fibrinogen, recalcified (plasma) the onset of menstrual bleeding, were considered clotting time, clotting time, Quick prothrombin relevant to a possible ovulatory event. The study time, partial thromboplastin generation, complete was completed satisfactorily in 22 women. In an¬ blood count (including platelets), LE cells, total other group of 76 women pregnanediol determina¬ protein, cephalin flocculation, alkaline phosphatase, tions were obtained before therapy; 160 determina¬ serum glutamic pyruvic transaminase, bromsul¬ tions were carried out in these same women phalein excretion, bilirubin, serum , blood between treatment cycles 2 and 23. urea nitrogen, protein bound iodine, urinalysis, The women were protected by alternate contra¬ pregnanediol excretion, urinary , 17- ceptive means during control cycles, in the course and 11-oxysteroids. of preliminary studies. Two regimens were fol¬ The few women who objected to the taking of lowed with the 2.5-mg. presentation. Up to August repeated blood samples, and for this reason were 1965, the standard administration method of 20 dropped from the study, were replaced by new days of medication per cycle was followed.2 Since subjects. Liver profiles were also obtained for that time the regimen of 22 days of medication per Canad. Med. Ass. J. 1026 Rice-Wray and others: Oral Contraceptive Agent Nov. 12, 1966, vol. 95 cycle has been followed, in which each subject is TABLE II..Side Reactions in Total Cycles instructed to take one tablet for 22 and Lynestrenol 5 mg. Mestranol 0.150 mg. 1112 cycles daily days Lynestrenol 2.5 mg. Mestranol 0.075 mg. 4634 cycles then go for six days without medication, repeating Menstruation 5 mg. 2.5 mg. this sequence regularly every cycle. Cycles % Cycles % occurs during the six days of each cycle in which no medication is taken. The of this Delayed menses advantage (amenorrhea). 71 method, which works to produce regular 28-day Intermenstrual spotting. 22 menstrual cycles, is primarily one of personal con¬ Headache. 18 venience. When used in this manner, each series of Nausea, gastric distress.. 9 Pelvic cramps. 9 22 tablets begins and ends on the same day of the Abdominal fullness, week and the patient is not required to count the bloating. 8 has the Nervousness. 7 requisite cycle days. Moreover, she option Vomiting. 5 of choosing the most convenient time for menstrua¬ Leg cramps. 4 tion by initiating treatment on the appropriate day. Dizziness. 3 Anxiety or depression... 3 The subject returns to the clinic routinely at the Breast tenderness or time of her menses for a monthly supply of tablets enlargement.2 on occasions the social Backache. 2 and is interviewed these by . 2 worker and, when warranted, by the physician in Unusual fatigue.1 of the Careful records are of . 1 charge project. kept Urticaria. 1 the date of the menses, tablet omission, intermen¬ Chloasma (by number of strual spotting and bleeding, and unpleasant side patients). 1 0.1 16 0.3 effects, only voluntary complaints being noted. All the for what¬ subjects discontinuing project, let with the ever reason, are followed up for future contracep¬ compared 2.5-mg. lynestrenol-mestranol tive methods used, future pregnancies and de¬ tablet. liveries, and future children. The side effects occurring in more than 1% of the subjects were headache, breakthrough bleeding Results and delayed menses.the latter 6.3% of 5-mg. Acceptability tablet users only. The small number (six women) who withdrew Weight Change from the for medication-related reasons project were in 312 attests to the of Weight records obtained subjects. high acceptability lynestrenol-mes¬ of 2 or more at time ther¬ tranol. Causes of are summarized in Changes kg. any during discontinuing were considered One hundred and Table I. While these data refer to the 20-tablet apy significant. the regimen is three gained weight and 79 lost weight. In many regimen, 22-day equally acceptable. instances the weight gained was subsequently lost. In 130 women there was no change. TABLE I..Reasons for Withdrawal from Study of Lynestrenol-Mestranol Control Related to medication Fertility Side effects.patient's decision. 3 There were no pregnancies among the women Nausea and vomiting. 1 as Nervousness. 1 taking lynestrenol-mestranol faithfully, pre¬ Slight menstrual flow. 1 scribed. Side effects.physician's advice. 2 Undue fatigue. 1 Not specified. 1 Post-Medication Fertility 1 Fear of injury. Pregnancies did occur in 12 women who dis¬ 6 continued contraception or who omitted two or Not related to medication more tablets in the same cycle. Moved away. 11 Contraception not needed (separation from husband). 12 Removed from program (uncooperative). 17 TABLE III..Outcome of Post-Treatment Inconvenience of visit to clinic. 5 Pregnancies, Died*. 1 Lynestrenol-Mestranol Study Opposition of husband or relatives. 3 Full-term deliveries. 7 Accidental pregnancy (tablet omissions). 13 Spontaneous abortion. 1 Could not be located. 39 Awaiting delivery. 2 Pregnancy desired. 5 10 106 stated that she died of other *Neighbours pneumonia.no TABLE IV..Babies Resulting from Post-Treatment information could be obtained. Pregnancies.Sex Distribution Males. 2 Unpleasant Side Effects Females.... 4 Table II compares the types, numbers and per¬ Sex unknown. 1 centages of complaints voiced with the 5-mg. tab- 7 Canad. Med. Ass. J. and others: Oral Contraceptive Agent 1027 Nov. 12, 1966, vol. 95 Rice-Wray

No.of There was nothing unusual in the outcome of Womtn these pregnancies (Table III) or in the children born to these mothers, except for one stillborn (meningoencephalocele) (Tables IV and V).

TABLE V..Condition of Babies Normal. 6 VL Meningoencephalocele* (stillborn). 1 22 21 26 26 30 32 34 36 39 iO 42 ii 46 49 50 52 Si 56 50 60 145 CYCLE LENGTH IN DAYS Fig. 2..Length of first cycle after suspension of medica¬ 5 0.150 mg. (28 women). *In a larger group of post-treatment pregnancies following tion with lynestrenol mg.-mestranol the use of a variety of progestin- compounds, in our clinic population, the incidence of meningoencephalocele in the babies was 0.67 per 1000 live births compared to an incidence an inhibition of and arteriolar of 0.53 in a large maternity hospital in Mexico City. causing glandular growth which begins early in the cycle. The ap¬ pearance is similar to that observed with nore¬ Pregnanediol Excretion Studies thynodrel, and norethisterone ace¬ During medication with lynestrenol-mestranol, tate. The glands resemble those seen with of 257 determinations were of norethynodrel. Early in the cycle they are small 4.6% pregnanediol with little secretion. ovulatory level (Table VI). In our laboratory, a and inactive, very figure higher than 1.0 mg./24 hr. is considered The stromal changes are more like those noted indicative of ovulation. with norethisterone and norethisterone .

TABLE VI..Pregnanediol Determinations During Lynestrenol-Mestranol Therapy (Cycle Day 22) Cycle 3 Cycle 6 Cycle 12 Cycle 18 Cycle 24 Total cycles No. tests % No. tests % No. tests % No. tests % No. tests % No. tests % Anovulatory. 65 91.7 64 95.5 56 96.6 55 98.2 100 245 95.3 Ovulatory. 6 8.3 3 4.5 2 3.4 1.8 1 12 4.6 Table VII shows the ovulatory pregnanediol levels obtained in 22 long-term users of lynestrenol- mestranol in the first three cycles after suspension of medication. All of these women ovulated within this span.

of Excre¬ TABLE VII..Ovulatory Level Pregnanediol -% *« tion After Discontinuing Medication with Lynestrenol-Mestranol 22 Women.(two to 12 days before menses) Patients First cycle. 9 Second cycle. Third cycle. Before 76 days after first post-treatment menses. not specified as to cycle (data of subsequent Fig, 3..Cycle 10, day 21. Endometrium with markedly menses unknown). involuted inactive glands. Loose and inert stroma. Total.First three post-treatment cycles. 22 Post-Treatment Cycle Length Fig. 2 shows that the length of the first post- treatment cycle is very unpredictable. With this series, it varied from 22 to 60 days. By the third month, the cycle is normalized. Endometrial Biopsies A total of 615 endometrial biopsies were taken from 332 lynestrenol-mestranol 2.5-mg. subjects: 204 before medication; 251 in medication cycles one to 12; 124 in cycles 13 to 24; and 36 in cycles 25 to 36. 2.5 Fig. 4..Cycle 11, day 24. Irregular endometrium with The endometrial changes with lynestrenol marked predecidual transformation of the stroma and one mg.-mestranol 0.075 mg. are marked, consistently small involuted gland. and Canad. Med. Ass. J. 1028 Rice-Wray others: Oral Contracepttve Agent Nov. 12,1966, vol. 95

TABLE VIII..Laboratory Examinations.Blood Studies. Lynestrenol 2.5 mg. - Mestranol 0.075 mg. Control Cycles 2to 13 Cycles 14 to 25 Cycles 26 to 37 Test Interval Red blood cells (millions). 3.3 to 4.1 4.2 to 5.7 Hematocrit (%). 31 to 39 40 to 50 51 to 53 Hemoglobin (g./lOO ml.). 9.0 to 12.4 12.5 to 15.0 15.1 to 17.0 Sedimentation rate (mm./l hr.). 0 to 15 16 to 54 Platelets (millions). 100 to 249 250 to 500 501 to 600 Clotting time (sec.). 240 to 299 300 to 600 601 to 720 Prothrombin time (%). 46 to 79 80 to 100 Partial thromboplastin generation (sec.). 19 to 39 40 to 80 81 to 110 Clotting time of recalcified plasma (sec.). 40 to 89 90 to 120 121 to 165 Fibrinogen. 4.0to 4.9 5.0 to 10.0 Fibrinolysin (%). Negative 5to50

Edema is marked and, along with a predecidual re¬ a secretory endometrium could be expected, i.e. action, often appears in the first days of treatment. cycle day -1 to -16. Seven of these were secretory The endometrial picture with the other progestins and eight proliferative. One on cycle day -24 was mentioned is described in an earlier publication.9 secretory. Post-Treatment Endometria Papanicolaou Smears Of the 27 endometrial biopsies taken in various Of the 576 Papanicolaou smears taken during women during the first three cycles after discon¬ medication with lynestrenol-mestranol, 346 were tinuing medication, 15 were taken on days in which Neg. I, 225 Neg. II and five Suspicious III. Three

TABLE IX..Liver Profiles. Lynestrenol 2.5 mg. - Mestranol 0.075 mg. Control Cycles 2 to 13 Cycles 14 to 25 Cycles 26 to 37 Test Interval BSP (%). 1.0 to 5.0 5.1 to 6.0 6.1 to 16.3 Cephalin cholesterol. Negative + to + + + Direct bilirubin (mg. %). Negative 0.9 Indirect bilirubin (mg. %). 0.10 to 0.19 0.20 to 0.80 0.81 to 1.00 SGOT (units). 10 to 40 SGPT (units). 1 to 3 4to 50 51 to 126 Total protein (g.%). 6.4 to 6.4 6.5 to 8.2 8.3 to 9.0 Albumin (g. %). 2.8 to 3.9 4.0 to 5.5 Globulin (g.%). 1.5 to 3.4 3.5 to 5.5 A/G ratio. 0.8/1 to 1.3/1 1.4/1 to 2/1 2.1/1 to 2.3/1 Alkaline phosphatase (units). 0.4 to 0.9 1.0 to 4.0 4.1 to 6.5 Canad. Med. Ass. J. Agent 1029 Nov. 12, 1966, vol. 95 Rice-Wray and others: Oral Contraceptive

TABLE X..Other Laboratory Examinations. Lynestrenol 2.5 mg. Mestranol 0.075 mg. Control Cycles 2to 13 Cycles 14to25 Cycles 26 to 37 No.of % No. of % No.of % No. of % Test Interval tests tests tests tests Blood urea (mg. %). 13.0 to 20.9 21.0 to 32.0 32.1 to43.0 Blood urea nitrogen (mg. %). 6.0 to 11.9 12.0 to 15.0 15.1 to20.0 Serum calcium (mg. %). 8.0 to 8.9 9.0 to 11.0 11.1 to 11.8 Serum phosphorus (mg. %). 0.5 to 2.9 3.0 to 4.5 Protein-bound iodine (gammas). 3.0 to 8.0 8.1 to 12.4 17-Ketosteroids (mg. %). 1.3 to 4.9 5.0 to 12.0 12.1 to 18.8 11-Oxysteroids (mg. %). 0.9 to 1.9 2.0 to 8.0 8.1 to 11.0 Chorionic gonadotropins. Negative + LE cells. Negative of the latter reverted to negative with continuing changes in the direct bilirubin, the serum pyruvic treatment and two were lost to follow-up. However, and oxalacetic transaminase, total protein, serum one case developed cancer of the cervix after two albumin and globulin. years of medication in spite of three previous nega¬ A single case of jaundice occurred during the tive Papanicolaou smears. The original classification study and was diagnosed as an intercurrent infec¬ of Papanicolaou was used in interpretation, i.e. tious hepatitis. The lynestrenol-mestranol was not Neg. I-normal cytology, Neg. II-inflammatory suspended. Liver function tests returned to normal changes, Neg. III-possible neoplastic changes. after the acute episode. Evaluation of glandular function: Protein-bound Eye Examinations iodine tended to increase slightly. A small study of The slit lamp examinations of the lens in treated radioiodine uptake by the erythrocytes revealed cases revealed no changes of importance from the no change with treatment. control examination. The eye studies performed A lowering of 17- and 11-oxysteroid after two to three years of medication included excretion was observed. Chorionic gonadotropins fundus, lens and visual fields. There were no patho¬ were essentially negative. logical neuro-ophthalmologic findings in any of Other tests: Blood urea and blood urea nitrogen the 25 cases examined. were low. Blood calcium tended to decrease slightly while blood phosphorus increased somewhat within Laboratory Examinations normal limits. Tables VIII, IX and X show the results of studies LE cells were consistently negative. in the control cycle and up to three years of medi¬ The 560 urinalyses taken during treatment were cation. negative. Blood counts: Low red cell counts, low hemo¬ globin and low hematocrit tended to become nor¬ Discussion mal with treatment. The leukocyte and differential Escape Ovulation counts revealed no important changes. factors: Prothrombin Escape ovulation, based on ovulatory levels of Blood clotting activity, par¬ excretion medication with tial thromboplastin generation and fibrolysin were pregnanediol during increased medication. progestin-estrogen compounds, has been reported during lynestrenol-mestranol various to occur in from 2.2 to Fibrinogen time and the platelet count were un¬ by investigators changed, while the clotting of recalcified plasma 8.0% of cycles.10 was diminished. Liver profiles: Bromsulphalein (BSP) retention Carcinogenicity gradually increased with continuing treatment The one case of cancer in this series is not indica¬ while the indirect bilirubin showed a progressive tive of a carcinogenic effect of the drug. Even in decrease. The cephalin cholesterol and the alka¬ this relatively small group, the incidence of cancer line phosphatase showed a tendency to normal is somewhat less than in the control group of levels with medication. There were no significant untreated clinic patients. In our larger series of AND OTHERS: Canad. Med. Ass. J. 1030 RICE-WRAY ORAL CONTRACEPTIVE AGENT Nov12 196, ol.95

7579 women using various estrogen- pressed less by the occasional case of impaired liver compounds for a total of 107,816 cycles (8293 wo- function than by the virtual absence of any con- men-years), a total of 12,590 Papanicolaou smears vincing examples of clinical detectable liver have been taken during treatment. In this large damage." series the incidence of cancer of the cervix is 0.0023 compared to 0.21 in the control group. Other inves- Thyroid Fuinctioni tigators'1413 agree that there is nio increase of posi- tive Papanicolaou smears or of cancer of the cervix Hollander et al.21 and Pincus'5 have reported an in women using oral contraceptives. Further study increase in the PBI in norethynodrel users. This is necessary to confirm a possible decrease in the is in agreement with our findings, thouigh the in- incidence of malignancy or premalignancy. crease was very slight. Blood Studies Ac!renal Ftunctioni The fact that pre-existing anemia improved in The findings in our series of a decrease in the our series during treatment is possibly the result of excretion of 17-ketosteroids and of l1-oxycorticoids an anabolic effect of the drug or due to decreased agree with the reports of Layne and Meyer.2 They menstrual blood loss. found that there is an increase in the cortisol levels in the plasma with steroid treatment. This is accom- Coagulation Factors panied by an increased binding capacity of the serum proteins, thus limiting the transport of the The studies of Donayre and Pincus", with nore- to the liver. thynodrel and ethynylestradiol 3-methyl ether (Enovid) agree with our findings of an increase in prothrombin and fibrinolytic activity and differ in SUMMARY that they report an increase in fibrinogen. It is Lynestrenol-mestranol (Lyndiol) is a safe anid effec- suggested that increases of some of the clotting tive oral contraceptive. Two satisfactory dosage regi- factors are balanced by an increased fibrinolytic mens are described, using 20 or 22 days of medication activity which could result in a homeostatic equi- per cycle. The latter method produces regular 28-day menstrual cycles and permits the patient to select a librum. convenient cycle. no Owren16 states unequivocally that there is Clinical observation as well as extensive laboratory proof of any causal relationship between throm- studies, eye examinations, Papanicolaou tests and endo- boembolic disease and the use of oral contracep- metrial biopsy studies failed to demonstrate any harm- tives. Swyer17 agrees that there is no evidence that ful effects. either estrogen or progestin are related to throm- Normnal ovarian function is rapidly restored uponl boembolism in women. discontinuing medication, and subsequent pregnancies The changes observed in the clotting factors and children are normal. apparently have no clinical significance. After an exhaustive statistical study of thromboembolic REFERENCES deaths in relation to women using norethynodrel 1. RICE-WRAY, E.: Field study with Enovid as contraceptive agent, In: Proceedings of the symposium on 19-nor and ethynylestradiol 3-methyl ether, the Wright progestational , G. D. Searle & Co., Chicago, 1957. Committee, appointed by the U.S. Food and Drug 2. RICE-WRAY, E. et al.: J. A. M. A., 180: 355, 1962. Administration, concluded that "no significant in- 3. GOLDZIEHER, J. W. et al.: Western J. Sury., 71: 187, 1963. 4. RICE-WRAY, E., GOLDZIEHER, J. W. AND ARANDA-ROSEILL, crease in the risk of thromboembolic death from A.: Fertil. Steril., 14: 402, 1963. 5. RICE-WRAY, E. et al.: , 14: 451, 1965. the use of Enovid has been demonstrated."'8 6. RICE-WArRAY, E. et al.: Amer. J. Obstet. Gynec., 93: 115, 1965. 7. FERIN, J.: Acta Endocr. (Kobenhavtr), 39: 47, 1962. Liver Toxicity 8. LAUWERYNS, J. AND FERIN, J.: Imtt. J. Fertil., 9: 35, 1964. 9. RICE-XVRAY, E. et al.: Amer. J. Obstet. Gyntec., 87: 429, 1963. The increase in BSP retention during treatment 10. GOLDZIEHER, J. W. AND RICE-WRAY, E.: Oral contracep- tion, mechanisnm and management, Charles C Thomas, probably reflects an overloading of the capacity of Springfield, Ill., p. 35, In press. the liver to handle the steroids and the dye simul- 11. TYLER, E. T.: J. A. M. A., 187: 562, 1964. 12. PINCUs, G. et al.: Science, 130: 81, 1959. taneously. In a group of our long-term cases using 13. GOLDZIEHER, J. W., MOSES, L. E. AND ELLIS, L. T.: .J. A. M. A., 180: 359, 1962. a chemically related compound, BSP retention- 14. MVALSH, F. B. et al.: Arch. Ophthal. (Chicago), 74: 628, 1965. though elevated in the first three years-became 15. DONAYRE, J. AND PINCUS, G.: Metabolism, 14: 418, 1965. normal in the fourth year and remained so. It ap- 16. OWREN, P. A.: Brit. Med. J., 1: 1283, 1963. 17. SWYER, G. 1. M.: Ibid., 2: 808, 1963. parently takes time for the liver to adapt itself. 18. Ad Hoc Advisory Committee for the Evaluation of a Possible Etiologic Relation with Thromboembolic Coni- The concern during 1965 and 1966, caused by dition: J. A. M. A., 185: 776, 1963. 19. EISELO, A., JARVINEN, P. A. AND LL'UKKAINEN, T.: Brit. reports principally from Finland19 and Sweden2" Mled. J., 1: 1416, 1965. 20. LARSSON-COHN, IT.: Ibid., 1: 1414, 1965. linking oral contraception with liver disease, has 21. HOLLANDER, C. S. et al.: Newv Eny. J. Med., 269: 501, 1963. 22. LAYNE, D. S. AND MEYER, C. J.: Metabolismii, 14: 429, 1965. largely been dissipated. An editorial in the British 23. FERIN, J.: Imt. J. Fertil., 9: 29, 1964. Medical Jo_7rnal24 nicely sums up the matter: "In 24. Editorial:r-It. Med. J., 1: 1391, 1965. 25. PINcus, G.: Suppression of ovulation with reference to view of the enormous number of women now tak- oral contraceptives, In: Modern trends in endocrin- ologyv, 2nd series, edited by H. Gardine:l Hill, Butte:- ing oral contraceptives, the clinician must be im- wvorth & Co. (Publishers) Ltd., London. 1961, l). 231.