Bleeding patterns with low-dose, monophasic oral contraceptives

CONTRACEPTION

BLEEDING PATTERNS WITH LOW-DOSE, MONOPHASIC ORAL CONTRACEPTIVES

Ph.D.,l Richard A. Edgren, James Gordon, M.D.,3 Walter S. Keifer, Jr, M.D.4

lDirector, Scientific California 94303

H.

Affairs, Syntex Laboratories,

21725 Soledad Way, San Diego, California

Nelson,

M.D.,2

Robert

T.

Inc., Palo Alto,

92109

3Scripps Clinic, 1066 North Torrey Pines Road, La Jolla, California 92037 4215 Calle Leandro, Cathedral

City, California

92234

ABSTRACT Cycle control over 12 months with low-dose oral contraceptives (OCs) was 21 analyzed using calendars of bleeding on pill-taking days 1 through (intermenstrual bleeding; IMB). One preparation contained 0.5 mg norethindrone and 0.035 mg ethinyl estradiol (NET+EE), the other 0.3 mg norgestrel and 0.03 mg ethinyl estradiol (Ng+EE). Half the subjects had previously used OCs containing 20.05 mg estrogen (switch-over); the others had not previously used OCs for 2 months or more (fresh). Fresh subjects reported more IMB than switch-over subjects, especially during the first three cycles; IMB decreased over time for both groups. Ng+EE subjects had fewer IMB episodes during the early cycles than NET+EE subjects. Daily incidence of IMB formed a characteristic W-shaped curve in the NET+EE subjects that was most apparent in early cycles.

Address reprint

requests

to Richard A. Edgren, Ph.D.

Submitted for publication February 17, 1989 Accepted for publication May 31, 1989

SEPTEMBER 1989 VOL. 40 NO. 3

CONTRACEPTION

INTRODUCTION Cycle control with low-dose oral contraceptives (OCs) has been poorly documented. Although reduction of the steroidal components of OCs has apparently not been accompanied by a measurable decrease in efficacy, it is generally conceded that these reductions, carried out in the interest of safety, have been accompanied by an increase in cyclic irregularity, including Although not affecting contraception, IMB intermenstrual bleeding (IMB). l-4 has lon been recognized as the side effect most likely to lead to cessation of use of ocsfi-6 Unfortunately, valid data documenting this putative increased rate of IMB with the low-dose OCs do not exist. Over the past 30 years, IMB data have been collected, analyzed and presented in a variety of ways. Use of different data collection techniques, OC preparations, and definitions of IMB have prevented direct comparisons of data from different studies. Originally, during the later bleeding” (BTB) and “spotting” were 1950s and early 196Os, “breakthrough considered separately in reports of IMB. BTB was usually defined as IMB that required use of sanitary protection, while spotting was a lesser amount of bleeding that did not require protection. The distinction has recently been compromised by the introduction of minipads, the impact of which remains to be assessed. Definitions of severity of bleeding may also vary among women and cultures. To obtain a valid picture of menstrual irregularities of OC users, al1 days of bleeding during each cycle of use, irrespective of interpretations of severity, must be collected, and all days of bleeding must be considered when cycle control with OC use is discussed. Another problem with many OC studies is that two distinct types of OC users are often combined in the data analysis. Women taking another OC prior to enrollment who are switched to the study OC and women who had not been taking OCs prior to enrollment must be considered as two separate populations. Although this information is generally collected, it is frequently employed only in demographic comparisons, and groups are not stratified for this characteristic in the analysis of cyclic control or complaints of bleeding. As documented by this study, cyclic control during the first few months on a low-dose OC differs significantly between these two groups. Different proportions of fresh and switch-over subjects could easily bias single-figure estimates of IMB and preclude study-to-study comparisons. Finally, the potencies of the components of OCs have an impact on IMB that has not yet been accurately evaluated. After 30 years, there is still little agreement on the relative impact of ethinyl estradiol versus mestranol.798 On the other hand, the totally synthetic newer progestogens that are homologated at carbon 18 (norgestrel, Ievonorgestrel, gestodene, desogestrel) clearly control IMB at lower doses than the natural 13-methyl steroids (norethindrone and its acetate, ethynodiol diacetate, lynestrenol). This greater “potency” may also extend to such other indices of activity as androgenicity and metabolic impact, so judgements based solely on milligram amounts are invalid. Furthermore, the implications of the interactions between estrogen and progestogen are presently unclear.9-I2

SEPTEMBER 1989 VOL. 40 NO. 3

CONTRACEPTION

The present study compared bleeding patterns of women taking either of two monophasic, low-dose OCs. Half of the women enrolled were currently using an OC containing at least 0.05 mg of estrogen and were switched to one of the study OCs; the rest were nonusers or had not used OCs for at least 2 months. While both of the preparations contained ethinyl estradiol at approximately equal doses, they contained different progestogens, differing in amount as well as in progestational potency. METHODS This randomized, multicenter study evaluated bleeding patterns in healthy, female volunteers taking one of two OC products for 12 months. Women 15 to 39 years of age who requested oral contraception and were menstruating regularly were considered for admission to this study. One-half of the enrollees were to be “fresh” subjects, i.e., women who had not taken OCs for at least 2 months preceding the study; the other half were to be “switch-over” subjects, i.e., women who had been taking an OC containing at least 0.05 mg estrogen per tablet for at least 2 months preceding the study. Women with any conditions contraindicating OC use and women weighing 20% more than that recommended by life insurance Approval of the protocol was obtained tables were not eligible for recruitment. for each site and subjects provided written informed consent. Prior to enrollment, demographic information and medical history were obtained Cervical cytology was performed and a physical examination was conducted. unless a normal report within the previous 6 months was available. A urine specimen and a fasting blood sample were obtained for analysis at a designated laboratory. Upon enrollment, women were randomly assigned to one of two combination OCs. One study preparation contained Commercial 28-day packages were used. 0.5 mg norethindrone and 0.035 mg ethinyl estradiol (Brevicon@*) per tablet and is referred to as NET+EE. The other study OC contained 0.3 mg norgestrel and 0.03 mg ethinyl estradiol (Lo/Ovral@**) per tablet and is referred to as Ng+EE. For cycle 1, fresh subjects began study OCs on the fifth day after beginning menstrual bleeding; switch-over subjects began study OCs on the eighth day after taking the last active tablet of their earlier series. Subjects kept daily calendars during each cycle, in which they recorded whether study medication was taken, whether any bleeding occurred, and type and degree of complaints, if any. For analysis, IMB was defined as any spotting or bleeding that occurred during the 21 days when active tablets were taken; days 1 through 3 were included only if bleeding was separated from the withdrawal bleeding period by at least 1 day. Subjects mailed their calendars to the investigators after each cycle, and visited

*Syntex (F.P.) Inc., Humacao, Puerto Rico **Wyeth Laboratories, Philadelphia, PA

SEPTEMBER 1989 VOL. 40 NO. 3

287

CONTRACEPTION

their investigator at the end of cycles 1, 3, 6, and 12. At each visit, investigators reviewed the daily calendar with the subjects, elicited information about any additional complaints, and recorded use of other medications; subjects received breast and pelvic examinations and blood pressure was measured. At visits following cycles 6 and 12, laboratory evaluations were repeated. A Papanicolaou smear was performed after cycle 12. Demographic characteristics were assessed for baseline comparability using Three factors: investigator, parametric analysis of variance procedures. treatment (NET+EE or Ng+EE), and prior OC use (fresh or switch-over subjects), were included in the model. Incidences of IMB were computed from the calendars and analyzed for each cycle using an analysis of variance procedure on the arc sine The severity of complaints was analyzed using the transformed counts. Wilcoxon/Mann-Whitney procedure to compare fresh versus switch-over and NET+EE versus Ng+EE subjects. RESULTS Demographic

Characteristics

Most of the demographic characteristics of the subjects taking either study OC were similar. Minor between-investigator differences in the study population probably resulted from sampling differences or differing techniques among investigators. Randomization of subjects appeared to have created comparable treatment groups. Mean age was 23 years for those taking NET+EE and 24 years for those taking Ng+EE. Not surprisingly, prestudy menstrual characteristics differed between fresh and switch-over subjects. Compared with fresh subjects, switch-over subjects reported significantly shorter durations of menses (p<.OOl), a lower incidence of dysmenorrhea (p<.OOl), and shorter cycle lengths (~~05). These confirm the well-known effects of OCs. Laboratory variables measured at baseline and at 6 and 12 months remained within normal limits, as did the Papanicolaou smears. Eight physicians enrolled a total of 322 subjects; 268 were valid for analysis. The two most common reasons for exclusion of the 54 invalid subjects were: body weight exceeded that specified in the protocol (15 women) and loss to follow-up (10 women). Otherwise, subjects either failed to meet other study requirements or to follow the protocol. Numbers of subjects analyzed are listed in Table I. No pregnancies were reported during the study. Terminations Of the valid subjects, 38% (103) completed 12 cycles. Of those valid subjects not completing 12 cycles (165), 109 discontinued primarily for personal, nonmedical reasons. Thirty-two of the valid patients cited bleeding irregularities and 23 cited other medical complaints as reasons for discontinuing the study. Discontinuation rates for the two OC regimens were similar throughout the study. The discontinuation rate, however, was greater for fresh subjects: by the end of cycle 4, 29% of fresh subjects had discontinued the study compared with 20% of

SEPTEMBER 1989 VOL. 40 NO. 3

CONTRACEPTION

switch-over subjects (ps.08, likelihood chi-square test). Furthermore, the number of fresh subjects discontinuing the study following cycles 5 through 11 almost always exceeded the number of switch-over subjects who did so. Percentages of fresh and switch-over subjects completing 12 cycles were 34% and 47%, respectively.

Table I Numbers of Valid Subjects

NET+EE

Ng+EE

Totals

Fresh Subjects

73

81

154

Switch-over Subjects

60

54

114

133

135

268

Totals

Cycle Patterns Plots of daily bleeding percentages for the four subgroups (Figures 1 and 2) support the following observations: 1) For each preparation, fresh subjects showed more IMB than did the switch-over subjects; 2) The high progestational potency of norgestrel is reflected in the lower IMB rates for Ng+EE subjects during the early cycles; 3) For all fresh subjects, overall IMB was higher in early cycles and drifted downward as time progressed (early terminations may have influenced this result); and, 4) The early cycles of NET+EE showed a distinct pattern of bleeding in switch-over subjects: daily bleeding rates during the first days of tablet administration decreased progressively from the preceding menstruation or withdrawal bleed. The decreasing rates of bleeding fell to a nadir on about days 5 to 7 of tablet administration, at which point IMB rates began to increase to a peak on pill-days 10 to 13. They again fell to a second nadir on about days 15 to 18 and began to rise as the next menstruation approached. This W-shaped pattern may also be discerned in certain cycles in the two Ng+EE groups; however, as with NET+EE, as overall IMB decreased, the midcycle rise became progressively more obscure. The late rise in percentage of bleeding, immediately preceding withdrawal bleeding, is observed with both study OCs, irrespective of whether the and suggest that in some women both subjects are fresh or switch-over, preparations lose control of the endometrium before the last steroid-containing tablets of the series are taken.

SEPTEMBER 1989 VOL. 40 NO. 3

289

CONTRACEPTION

Fresh Subjects 1001

;

90

1

80

0

j

1

28

56

140

168

196

224

252

280

224

252

280

336

Study Days Switch-Over

Subjects

100

;

90

I

; I

80

I,

i

70 60 50 40 30 20 10 n 0

28

56

84

112

140

168

196

368

336

Study Days Figure 1: Percentage of NET + EE subjects with bleeding over 12 cycles. The vertical dotted lines mark the last day of active tablets in each series.

SEPTEMBER 1969 VOL. 40 NO. 3

CONTRACEPTION

Fresh Subjects 100 90 80 c” ._ $

70

2 m $

50

60 40 30 20 10 0 0

28

56

84

112

140

168

196

224

252

280

308

336

224

252

280

308

336

Study Days Switch-Over

Subjects

0

28

56

84

112

140

168

196

Study Days Figure 2: Percentage of Ng + EE subjects with bleeding over 12 cycles. The vertical dotted lines mark the last day of active tablets in each series.

SEPTEMBER 1969 VOL. 40 NO. 3

291

Within the limits of this study, data have been pooled for comparative purposes. Switch-over subjects reported significantly less IMB in the first three cycles (pc.005) than fresh subjects, slightly less in cycles 4 and 5 (p<.O7), and sporadically less thereafter (Table II). While the incidence of bleeding in fresh subjects was greatest during the early cycles, rates also differed between the two preparations (Table III). During cycle 1, IMB for fresh Ng+EE subjects approximated that of switch-over NET+EE subjects (Figures 1 and 2). During the first four cycles, subjects taking NET+EE reported significantly more IMB than subjects taking Ng+EE (Table III). For the majority of the remaining cycles, there were no statistically significant differences between NET+EE and Ng+EE in IMB.

Table II Intermenstrual Bleeding (IMB) Rates Fresh v Switch-over

No. of Subjects

Subjects (%) with IMB

Cycle

Fresh

Switch-over

Fresh

Switch-over

p-value1

1

139

111

57

31

<.OOOl

2

122

103

47

29

.0041

3

107

95

40

21

.0027

4

98

89

39

28

.068

5

91

84

39

26

.064

6

80

78

29

32

.70

7

75

73

30

33

.92

8

69

72

33

22

.13

9

66

69

30

22

.23

10

63

65

25

20

.46

11

62

64

37

15

.0018

12

47

52

21

21

.84

1 Analysis of variance.

SEPTEMBER 1989 VOL. 40 NO. 3

CONTRACEPTION

Table III Intermenstrual Bleeding (IMB) Rates Pooled over Fresh and Switch-over Groups NET+EE v Ng+EE

No. of Subjects Cycle 1

NET+EE

Ng+EE

Subjects (%) with IMB NET+EE

Ng+EE

p-value1

33

<.OOOl

124

126

2

112

113

53

26

<.OOOl

3

100

102

43

20

.0003

4

95

92

44

24

.0029

5

88

87

37

29

.24

6

77

81

33

28

.61

7

74

74

42

22

.0095

8

70

71

32

23

.15

9

66

69

28

28

.40

10

65

63

24

31

.55

11

63

63

34

17

.0071

12

49

50

24

18

.45

58

1 Analysis of variance.

Miscellaneous

Complaints

Complaints were analyzed for the 295 subjects who returned to the clinic at least once for a scheduled, postadmission visit. Headache, reported by 23% of the subjects, was the most common complaint. Other common complaints, each reported by less than 20% of the subjects, were IMB, cramps, and nausea. No differences between fresh and switch-over subjects in severity or number of these complaints were evident. Subjects taking NET+EE reported more severe IMB (pc.005) and nausea (p<.OS) than those taking Ng+EE.

SEPTEMBER 1989 VOL. 40 NO. 3

293

CONTRACEPTION

DISCUSSION By explicitly stating our definition of intermenstrual bleeding (IMB), by collecting daily reports of bleeding and complaints, and by separating subjects based on prior use of oral contraceptives (OCs), we are able to present a precise picture of cycle control by two low-dose OCs. These techniques allow us to present a fairly complete picture of IMB over 12 cycles. Previous studies have usually reported IMB data incidental to general efficacy and safety evaluations. Limitations of other studies have included the collection of recall data sometimes a cycle or more after the event, pooling of fresh and switch-over subjects, and use of varying definitions of IMB, that is BTB versus spotting or bleeding occurring only on certain days of the pill-taking cycle. Often, study reports have failed to describe adequately the methods of data collection or definitions of cycle control, IMB, or breakthrough bleeding (BTB) employed by the authors. The need for precise terms to be applied universally by all investigators is not unique to this discussion of cycle control by low-dose OCs. A recent review paper on contraceptive failures with various birth control methods noted critical discrepancies in the definitions of terms and consequently fallacies in analyses and conclusions, thus preventing direct comparison of results from different studies.13 A uniform presentation of summaries of OC clinical studies that includes cycle control, failure rates, and adverse events might allow physicians to make better decisions for prescribing appropriate OCs. To summarize, we have presented evidence that the incidence of IMB differs between fresh and switch-over users in the early months of low-dose OC use, particularly midcycle IMB. Second, we have confirmed the work of others that IMB seems to be more common with OCs containing less potent progestogens than those containing more potent ones.12y14v15 Third, we have defined a pattern of monthly bleeding, the W-shaped graph, for a norethindrone-containing OC, with a suggestion that it also may occur to some degree with a norgestrel-containing preparation. During the first cycle of use of a low-dose OC, IMB appears to be a common occurrence in women not previously taking OCs. This was true for fresh subjects taking either study OC. The incidence of IMB during the second month decreased to only about half that of the first cycle of use and generally decreased further thereafter. Since the midcycle rise in the W-shaped pattern of IMB became progressively more obscure, cycle control can be assured for the majority of women just beginning low-dose OCs after one or more cycles of use. On the other hand, most women switching from a high-dose to a low-dose OC can expect good to excellent cycle control immediately. The increases of IMB late in the tablet sequences suggest that low-dose preparations fail to synchronize cycles as well as higher dose preparations are believed to have done. Menstrual pulses (Figures 1 and 2) were not restricted to the drug-free week; the incidence of bleeding rose just before the last active drugs of the sequence, which we refer to as “anticipatory bleeding”. Since this “anticipatory” bleeding occurs toward the end of a cycle and is usually continuous with the withdrawal bleed, we do not feel that this will prove a major problem for most women, providing the total duration of bleeding is within normal limits.

294

SEPTEMBER 1989 VOL. 40 NO. 3

CONTRACEPTION

This study confirms two other reports of a low incidence of IMB in women switched directly from a higher dose OC to a lower dose 0~.16,17 Conclusions from both of these earlier studies were limited, however. In one study, reports of bleeding irregularities were collected only once monthly by asking the young subjects (mean age 16.1 years) to recall problems;I6 the other study collected information on a daily basis, but only for alternating cycles (i.e., first, third, etc.).17 While the second probably provided more accurate information than the first, information about the control of IMB over time was lost in both instances. The present study demonstrates the obvious - that fresh and switch-over subjects are two distinct populations and should be analyzed as such -- particularly when conclusions about cycle control and IMB for specific OCs are made. Comparisons based on pooled data would be biased by discrepancies in numbers of subjects in these two categories. It should be clear that, in light of the complex patterns of bleeding with low-dose OCs (as presented here), no single figure describing monthly rates of bleeding is particularly helpful to the physician. A single descriptive figure of IMB may be of value for internal comparative purposes, provided the populations are comparable and the methods of analysis the same, but study-to-study comparisons of such data would be almost certainly invalid. It has been suggested that the greater control of IMB by the norgestrel-containing preparation may reside in greater variability in first pass metabolism of estimate the bioavailability of norethindrone. Hiimpel and associates18 norgestrel at 87+9% while Back & a.‘9 estimate that for norethindrone at 64% with an error figure of +4% contributed by Hiimpel and Diisterberg.20 This first pass effect is based upon limited data, which hardly inspire confidence in any quantification; however, the concept corresponds to the well-known retardation of metabolism of norgestrel conferred by homologation at carbon-l 8 of norethindrone to form norgestrel. 2I This slower rate of deactivation accounts for the greater progestational and androgenic potencies of norgestrel over norethindrone in laborato animals, and presumably the greater impact of norgestrel on lipoproteins.2r2v CONCLUSION The norethindrone-containing OC examined in this study has a W-shaped curve of bleeding reminiscent of the pulses of bleeding seen with progestogen-only, “mini-pill” contraceptives23 (and RA Edgren, unpublished observations). A suggestion of this pattern was seen in some cycles of a norgestrel-containing OC. However, as reported in other OC trials, 5~~5 the incidence of IMB, particularly that occurring midcycle, progressively decreased over time for the OCs examined here. Regardless of OC type, women just beginning OCs reported significantly more IMB in the first 3 months of use than those switched from an OC containing at least 0.05 mg estrogen. In choosing an OC to prescribe, the physician must weigh the use of a more potent progestogen for possibly better short-term cycle control against the use of a less potent pro esto en with less long-term impact on lipoprotein and carbohydrate metabolism. 17 t24-37 Acknowledgements: We would like to thank Drs. R. Benson, H. Ellsworth, W. Hindle, R. Young, and K. Moghissi who contributed subject data employed in this study; M. Lange for statistical analysis, and C.J. Campos for preparation of the manuscript.

SEPTEMBER 1989 VOL. 40 NO. 3

295

CONTRACEPTION

REFERENCES 1.

Arnt IC, Ferrari contraceptives: norgestrel-ethinyl

A, Sartoretto JN, Woutersz TB: Low-dose combination oral different controlled clinical study of three a estradiol ratios. Fertil Steril 1977;28:549-53.

trial of two Bounds W, Vessey M, Wiggins P: A randomized double-blind low-dose combined oral contraceptives. Br J Obstet Gynaecol 1979;86:325-9. Greenblatt RB: 1985;8:6-27.

Oral contraceptives:

Law B: Advantages and disadvantages J Gynaecol Obstet 1979;16:556-60.

the

state

of low-dose

of the

art.

Clin

Ther

oral contraceptives.

Int

Dionne P, Vickerson F: A double-blind comparison of contraceptives containing 50 PC and 30 PG ethinyl estradiol. Res 1974:16:281-S.

two oral Curr Ther

Moreno J, Rowan AJ: A comparative study of Norinyl l/35 versus Brevicon in Panama City, Panama. Contraception 1987;36:615-25. Behilovic B, Rowan AJ: A comparative study of Norinyl l/35 versus Norinyl l/50 in Belgrade, Yugoslavia. Contraception 1987;36:515-26. Goldzieher JW, Maqueo M, Chenault CB, Woutersz TB: Comparative studies of the ethinyl estrogens used in oral contraceptives. I. Endometrial response. Am J Obstet Gynecol 1975;122:615-8. 9.

Edgren RA, Sturtevant FM: Potencies Gynecol 1976;125:1029-38.

10.

Ellis J: Low-dose oral contraceptives: progestin and atherogenic potential. Clin Ther 1986;8:607-18.

11.

Stubblefield PG: Selection of steroid combinations for oral contraceptives of maximum benefit. J Reprod Med 1986;31(suppl):922-8.

12.

Swyer GIM: Potency of progestogens in oral contraceptives of menses data. Contraception 1982;26:23-7.

-

13.

Trussell J, Kost K: Contraceptive failure in the United review of the literature. Stud Fam Plann 1987;18:237-83.

States:

14.

Ravenholt RT, Kessel E, Speidel JJ, Talwar PP, Levinski MJ: A comparison of symptoms associated with the use of three oral contraceptives: a double-blind study of crossover Ovral,@ Norinyl,” and Nor1estrin.o Adv in Planned Parenthood 1978:7:222-39.

of oral contraceptives.

Am J Obstet

potency,

androgenicity,

further delay a critical

SEPTEMBER 19B9 VOL. 40 NO. 3

CONTRACEPTION

15.

Woutersz TB: A low-dose combination 1,700 women treated for 22,489 cycles.

16.

Neel EU, Litt IF, Jay MS: Side effects and compliance with low- and conventional-dose oral contraceptives among adolescents. J Adolesc Health Care 1987;8:327-9.

17.

Gerais AS, Rushwan H: A crossover pill study among Sudanese women. Gynaecol Obstet 1985;23:229-33.

18.

Hilmpel M, Wendt H, Pommerenke G, Weig Chr, Speck U: Investigations of pharmacokinetics of levonorgestrel to specific consideration of a possible first-pass effect in women. Contraception 1978;17:207-220.

19.

Back DJ, Breckenridge AM, Crawford FE, McIver M, Orme M L’E, Rowe PH, Smith E: Kinetics of norethindrone in women. II. Single-dose kinetics. Clin Pharmacol Therap 1978;24:448-453.

20.

Hiimpel M, Diisterberg B: The role of pharmacokinetics in the development In: Benagiano G, Zulli P, D czfalusy and use of long-acting progestogens. E, eds., Progestogens in Therapy. New York: Raven Press, 1983:51-72.

21.

Fotherby K, Karmjab S, Littleton P, progestational compounds in humans.

22.

Edgren RA, Jones RC, Clancy DP, Nagra CL: The biological norgestrel alone and in combination with ethinyl oestradiol. Fertil;l968;Suppl 5:13-45.

23.

Martinez-Manautou J. Chlormadinone acetate continuous in contraception -- the early days and recent experience. In: Christie GA, Moore-Robinson M, eds. Chlormadinone Acetate. A New Departure in Oral Contraception. Maidenhead: Excerpta Medica Foundation, 1969: 18-32.

24.

Burkman RT, Robinson JC, Kruszon-Moran D, Kimball AW, Kwiterovich P, Burford RG: Lipid and lipoprotein changes associated with oral contraceptive use: a randomized clinical trial. Obstet Gynecol 1988;71:33-8.

25.

Spellacy WN: Carbohydrate progestogen, and low-dose 1982;142:732-4.

26.

Spellacy WN, Buhi WC, Birk SA, Buggie J: Blood glucose and plasma insulin studies during three months’ use of a low-estrogen type oral contraceptive. Fertil Steril 1981:36:68-70.

27.

Wynn V, Niththyananthan R: The effect of progestins contraceptives on serum lipids with special reference lipoproteins. Am J Obstet Gynecol 1982;142:766-72.

SEPTEMBER 1989 VOL. 40 NO. 3

oral contraceptive: experience J Reprod Med 1981;26:615-20.

with

Int J

Klopper AI: Metabolism of synthetic J Reprod Fert;l968:Suppl 551-61.

metabolism during oral contraceptives.

effects of J Reprod

treatment with estrogen, Am J Obstet Gynecol

in combined oral to high-density

297