Serum gonadotropin and ovarian steroid levels in women during administration of a norethindrone-ethinylestradiol triphasic oral contraceptive

CONTRACEPTION

SERUM GONADOTROPIN AND OVARIAN STEROID LEVELS IN WOMEN DURING ADMINISTRATION OF A NORETHINDRONE-ETHINYLESTRADIOL TRIPHASIC ORAL CONTRACEPTIVE

W.Y. Lingl,

D.W. Johnstonl, R.H. Leal, A.E. Bentl, J.Z. Scott*, and M.R. Toews3

IDepartment

of Obstetrics and Gynaecology, Halifax, Nova Scotia

Dalhousie

University

*Department

of Obstetrics and Gynaecology, Edmonton, Alberta

University

of Alberta

30rtho

Pharmaceutical (Canada) Ltd., Mills, Ontario, Canada

Don

ABSTRACT We studied the inhibitory effect of a triphasic oral contraceptive (OC) regimen on the pituitary and ovarian function in 29 normal, healthy women. ORTHO* 7/7/7 Tablets contain a constant low dose of ethinylestradiol (EE) and a step-wise increasing level of norethindrone (NE). The pills for the first, middle and last weeks of the *l-day regimen contained, respectively, 0.5, 0.75, and 1.00 mg NE, and all contained 0.035 mg EE. The subjects were divided into 3 groups on the basis of their histories of OC use. Ten had not taken an OC in the previous 2 months, 10 were switched to this study from a fixed-dosa e combination OC containing 0.050 mg estrogen, and 9 had been taking ORTHO 7/”7/7 Tablets for 5 or more cycles. Serum levels of FSH, LH, estradiol and progesterone were measured and statistically compared with those from 5 normal, untreated women. The results from all study cycles showed that the four hormone profiles were significantly suppressed as compared to the normal patterns. Thus, one mode of action of this new triphasic OC is to inhibit ovulation by suppression of pituitaryovarian function. This OC treatment appeared to be equally effective among women with varying prior histories of OC therapy.

Reprint

request:

D. W. Johnston, M.D. Dartmouth Professional Centre 277 Pleasant St., Suite 503 Dartmouth, N.S. Canada B2Y 407

*Trademark Submitted Accepted

for publication for publication

June 17. 1985 October 9. I S85

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INTRODUCTION The progestin-estrogen combination oral contraceptive (OC) is used extensively as an effective fertility control agent. Since its introduction in 1960, continuing attempts at reduction of hormone dosage and refinements in formulation have been made in order to develop an OC that would provide a high degree of efficacy with minimal side effects. Thus, from the conventional fixeddose formulation, two-stage or biphasic OC regimens were developed (I-3). More recently, triphasic OCs have been introduced (4-6). Each variable-dose regimen is formulated to deliver its steroid content(s) in a stepwise pattern that would roughly correspond to the phasic hormonal fluctuations of the menstrual cycle. ORTHO 7/7/7 Tablets is a 21-day triphasic OC formulation containing a constant level of ethinylestradiol (EE) and sequentially increasing levels of norethindrone (NE) at 7-day intervals. The present study was undertaken to investigate the effects of this regimen on the serum levels of pituitary gonadotropins and ovarian steroids in normal women, with or without previous exposure to 00.

MATERIALS AND METHODS SUBJECTS Twenty-nine women volunteers (age 19-33) completed this study after giving informed consent. Each had a complete physical examination within 90 days of entering the study and was judged to be in good health. Each had a normal menstrual history with no gynecologic complications, and none was taking medication other than that specified in the study. TREATMENTPROTOCOL ORTHO 7/7/7 Tablets, the triphasic OC study drug, contained 21 tablets in a cycle; the pills for the first, middle and last weeks of the regimen contained, respectively, 0.5, 0.75 and 1.00 mg NE, and all contained 0.035 mg EE. In order to study the contraceptive effect of ORTHO 7/7/7 Tablets in women having varied previous exposures to OC, the subjects were separated into three groups. Group A: To study the ovulation inhibition effect on women not recently using an OC, Group A was composed of 10 subjects (age 19-30) who had not Two received steroid therapy for at least two months prior to study entry. For the first cycle, the subjects consecutive cycles were studied in each subject. were to take the first tablet on cycle day 5 or 7 as prescribed by her physician (cycle day 1 being the first day of menses) and complete the tablet course twentyone days later. All subjects were told to start the second 21-day therapy after seven pill-free days from the previous cycle. Group B: To study the effect of ORTHO 71717 Tablets on women who were 10 subjects (age 21-28) who were previously taking fixed-dose contraceptives, taking combination OC containing the equivalent of 0.05 mg EE t 1.0 mg NE for at For this group, one cycle on the least three consecutive cycles were studied. fixed-dose OC followed by one cycle of study drug therapy was examined. Seven subjects began treatment of ORTHO 7/7/7 Tablets after 7 days, and 3 subjects after 8 pill-free days following the previous cycle.

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Group C: We studied I cycle in each of 9 women taking ORTHO 71717 Tablets for 5 to 13 cycles.

(age 23-33) who had been

BLOOD SAMPLING Serum samples were obtained from Group A subjects on cycle days 4, 8-16, On the second cycle, samplings were carried 20, 24 and 28 during the first cycle. out on pill days I, 3, 7, 11, 15, 19 and two days after the 21st tablet. The latter sampling schedule was also applied to the first cycle of Group B subjects and for Group C. Samples from Group B subjects during the second cycle (test cycle) were collected on pill days I, 3-11, 15, 19, and 2 days after the last tablet. All serum samples were stored at -200C prior to assay. HORMONE ASSAYS As previously described (7), luteinizing hormone (LH) and follicle stimulating hormone (FSH) were separately measured with specific radioimmunoassay (RIA) kits The sensitivity for both assays was 0.3 purchased from BioRIA, Montreal, Canada. Standards. the 2nd International Reference mIU, as measured against as expressed by the interassay coefficient of Reproducibility of the assays, variation, was 7% for both FSH and LH. Steroid hormones were measured by the method previously described (8). Progesterone and estradiol (E2) were ether-extracted and measured by RIA with specific antibodies (Immunotech, Montreal, Canada). The sensitivity limits for both assays were 6.5 pg. No significant cross-reactivity was detected with NE or EE in either assay. CONTROL

SUBJECTS

Five subjects having normal ovulatory cycles were used as control. serum samples were taken from each subject over one complete menstrual and the hormonal levels measured are shown in Fig. 1. We used Student’s between each treatment

t-test to evaluate the significance group and the control cycles.

of difference

Daily cycle,

(P <0.05)

RESULTS The hormonal patterns of 3 groups of study subjects are shown in Figs. For the test cycles, there was a consistent loss of the preovulatory surges and FSH in all 29 subjects. During the follicular phase, the tonic gonadotropin levels were within the normal ran e for Group A subjects, but B and Group C subjects had significantly (P
2 to 4. of LH serum Group

The E2 profile in normal menstrual cycles shows a peak before the LH surge and a subseauentlv elevated level in the luteal ohase (Fie. 1). ORTHO 71717 Tablets suppressed E2 levels in all of the Group A subjects during the first test During the second test cycle, E2 levels were found to be in the normal cycle. range ( >I00 pg/ml) in 3 out of 10 subjects from investigation days 31 to 45 (data not shown). Using the first day of menses as a marker, these days would correspond to day 8 to 20 of the menstrual cycle. In two of these subjects, concomitant with the increase in E2 levels, the progesterone also rose but stayed

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MEAN*

301

SD

CYCLE DAYS

Figure 1. Hormone profile measured in the sera of 5 normal, untreated women (control). Samples were collected daily from each subject over one menstrual cycle. M = days of menses.

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Figure 3. Hormone pattern in 10 women who were switched from a fixed-dose OC containing 1.0 mg NE and 0.05 mg EE, or This study affords comparison of the to the ORTHO 7/7/i’ Tablets regimen (second cycle). their equivalents (first cycle) Hormone levels were uniformly suppressed in both ovulation inhibitory effect between fixed-dose and triphasic OC regimens.

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Figure 4. Hormone pattern in 9 women who had been taking ORHTO 71717 Tablets for 5 to 13 months. Only one pill cycle was studied in each subject. All hormone levels were suppressed, reflecting the long-term effect of ORTHO 7/7/7 Tablets on ovulation inhibition. M = menses.

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CONTRACEPTION far below the peak luteal phase values of the control subjects. In all other study cycles of each group, the expected estrogen rise that normally precedes the LH surge and the rise that occurs during the luteal phase was not found (Figs. 3 and 4). The luteal phase progesterone about 0.6 ng/ml, were significantly subjects, which averaged 23 ng/ml. study subjects was 6 ng/ml.

levels of all treatment groups, which averaged (P < 0.001) lower than those in the control The highest individual value found among the

DISCUSSION The present study demonstrates that ORTHO 71717 Tablets effectively inhibits ovulation by suppressing the pre-ovulatory gonadotropin surge. This effect is apparent in all subjects regardless of their prior OC histories. Our study also suggests that progressive inhibition of the tonic gonadotropin secretion may become operative during extended usage of OCs. This observation is based on the findings that during the follicular phase, the gonadotropin levels were not suppressed in subjects who had not been on OC just prior to this study (Group A), but were significantly reduced in those who had (Groups B and C). Thus, another mode of action may be a progressive suppression of the follicular maturation This possibility is corroborated by the subnormal E2 levels found in the process. late follicular phases of most study subjects. Treatment with ORTHO 71717 Tablets may also lead to an inadequate corpus luteum function as progesterone levels were markedly reduced in all subjects. It is not surprising that ORTHO 7/7/7 Tablets effectively inhibited pituitary and ovarian functions, as fixed-dose combinations of 1.0 mg of NE and 0.035 mg EE or 0.5 mg NE + 0.035 mg EE (the highest and lowest dosages in the study drug formulation) can both suppress pituitary-ovarian hormonal levels (9, 10). Based on the study design, ORTHO 71717 Tablets were found to be an effective OC regardless of whether the subject was a fresh-start on this regimen, was switched to this formulation from a higher fixed-dosage OC, or had been taking ORTHO 7/7/7 Tablets for several cycles.

ACKNOWLEDGMENTS We thank Tanya Acorn, Barb Church, Elaine Wilson and Marie Davidson their excellent clinical and technical assistance and Lois Sheppard for typing manuscript.

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Ling W Y, Wrixon W, Acorn T, Wilson E, Collins J: Mode of action of dlnorgestrel and ethinylestradiol combination in postcoital contraception. III. Effect of pre-ovulatory administration following the luteinizing hormone surge on ovarian steroidogenesis. Fertil Steril 40:631, 1983

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contraceptive:

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oral contraceptive.

with 30

concept

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