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Hormone Withdrawal Symptoms in Oral

Contraceptive Users
PATRICIA J. SULAK, MD, ROGER D. SCOW, MD, CHERYL PREECE, MS,
MARK W. RIGGS, PhD, AND THOMAS J. KUEHL, PhD

Objective: To measure the timing, frequency, and severity of Oral contraceptives (OCs), the most common method of
hormone-related symptoms in oral contraceptive (OC) users, reversible birth control, are used by approximately 80%
specifically to compare active-pill with hormone-free inter- of women in the United States at some time during their
vals. reproductive years.1 Despite the continuous reduction
Methods: Using daily diaries, women recorded pelvic in hormone content since OC introduction almost 40
pain, bleeding, headaches, analgesic use, nausea or vomit- years ago, side effects continue to affect compliance.2 4
ing, bloating or swelling, and breast tenderness during
The most commonly reported side effects are nausea
active-pill intervals and hormone-free intervals. Participants
and vomiting, breakthrough bleeding and spotting,
either had no prior OC use, had taken OCs and were
headaches, bloating or swelling, and breast tender-
restarting, or had been taking OCs continuously for 12
ness.57
months or longer.
Although women are prescribed OCs as treatment for
Results: Two hundred sixty-two women, 26 with no pre-
vious OC use, 43 prior users, and 193 current users, provided
menorrhagia or dysmenorrhea, the long-term success
daily records of hormone-related symptoms. Subjects with rates of current low-dose OCs in managing those com-
no prior OC use and prior users restarting were similar in no mon menstrual disorders is not known. There is also a
recent OC use, and because of the small sample, they were lack of information comparing symptoms in new-start
pooled for analysis as new-start OC users. Current users had OC users with long-term users during the 21 days of
patterns of symptoms that were more frequent during hor- hormone-containing pills and the 7-day hormone-free
mone-free intervals than during the three active-pill weeks. interval. If problems are a result of the 7-day hormone
These included pelvic pain (70% versus 21%, P < .001), withdrawal, knowledge of the types and severity of
headaches (70% versus 53%, P < .001), use of pain medica- complaints could lead to specific interventions.
tion (69% versus 43%, P < .001), bloating or swelling (58% In this study, we examined prospectively hormonal
versus 19%, P < .001), and breast tenderness (38% versus symptomatology in women currently using or newly
16%, P < .001). Similar patterns were seen in new-start OC initiating OCs to assess frequency, timing, and severity
users after the first cycle. Among new-start OC users, men- of complaints during each of the 21 days of active pills
strual flow patterns, headache, bloating or swelling, and compared with the 7 days of hormone-free pills.
breast-tenderness symptoms decreased during the three cy-
cles to approach those levels of current users.
Conclusion: Almost all symptoms assessed were signifi- Materials and Methods
cantly worse during the 7-day hormone-free interval than
during the 21 days of hormone-containing pills. (Obstet Women who requested OCs were recruited from the
Gynecol 2000;95:261 6. 2000 by The American College of obstetrics and gynecology practice of Scott and White
Obstetricians and Gynecologists.) Clinic from November 1996 to August 1997 and were
eligible for participation if they had no prior OC use,
had used OCs previously but not in the prior 3 months,
or were current users of OCs for 12 months or more.
From the Departments of Obstetrics and Gynecology, Biostatistics, Women not currently using OCs were considered new
Pathology, and Medical Biochemistry and Genetics, Scott and White starts because they were never users or were not taking
Clinic and Memorial Hospital, Texas A&M University Health Science OCs for a minimum of 3 months before enrollment. All
Center College of Medicine, Temple, Texas.
Supported by a grant from Scott, Sherwood, and Brindley Foundation, patients used a combination low-dose OC of 21 active
Temple, Texas. pills containing 35 g or less of ethinyl estradiol (E2)

VOL. 95, NO. 2, FEBRUARY 2000 0029-7844/00/$20.00 261


PII S0029-7844(99)00524-4
plus a progestin and seven hormone-free pills. Women Table 1. Subject Characteristics
were prescribed or continued on OCs chosen by their No prior Prior Current
health-care providers. Patients were informed of the Characteristic use users users P
study by their health-care providers or by posted an- Sample 26 43 193
nouncements. Study criteria were confirmed and con- Age (y) 27 7 30 7 29 7 .26
sent forms signed. The study was reviewed and ap- Weight (kg) 71 17 69 17 67 15 .41
proved by the Scott and White institutional review Height (in) 65 2 65 3 65 3 .45
Body mass index 25.7 5.3 25.6 5.5 25.0 5.5 .73
board.
Number of gravida 0 13 (50%) 8 (19%) 90 (47%) .01
Demographic information was collected before study Race .09
initiation, including age, weight, height, body mass White 22 (85%) 37 (86%) 161 (83%)
index (BMI), education, race, and gravidity. Women Black 2 (8%) 2 (5%) 19 (10%)
were given calendars to record hormone-related symp- Asian 1 (4%) 0 (0%) 0 (0%)
Hispanic 1 (4%) 4 (9%) 13 (7%)
toms. Menstrual flow was graded on a scale of 0 to 4
Education .19
(0 no bleeding, 1 spotting that did not require 12 y 2 (8%) 0 (0%) 3 (2%)
protection, 2 light flow that soaked a tampon or pad High school/GED 5 (19%) 8 (19%) 37 (19%)
less frequently than every 8 hours, 3 moderate flow Some college 13 (50%) 18 (42%) 102 (53%)
that soaked a tampon or pad every 3 8 hours, 4 College or beyond 6 (23%) 17 (40%) 51 (26%)
Type of OC .29
heavy flow that soaked a tampon or pad more fre-
Norethindrone 7 (27%) 11 (26%) 74 (38%)
quently than every 3 hours). For this analysis, bleeding New progestins* 10 (38%) 17 (40%) 75 (39%)
grades 3 and 4 were combined as moderate to heavy Levonorgestrel 9 (35%) 15 (35%) 44 (23%)
flow. Phasic type .53
Pelvic pain or cramps were graded by women on a Monophasic 22 (85%) 33 (77%) 144 (75%)
Triphasic 4 (15%) 10 (23%) 49 (25%)
scale of 0 to 10 (0 no pain at all, and 10 the worst
Reason for using OC
pain or cramps ever experienced). Headaches also were Birth control 19 (73%) 30 (70%) 158 (82%) .16
scored subjectively daily by women on the same scale of Dysmenorrhea/ 7 (27%) 13 (30%) 37 (19%) .22
0 to 10. Types and amounts of analgesic also were pelvic pain
recorded. Women checked boxes on the calendars if PMS 0 (0%) 2 (5%) 6 (3%) .70
Menorrhagia 9 (35%) 10 (23%) 28 (15%) .03
they had nausea or vomiting, bloating or swelling, or
Irregular bleeding 10 (38%) 15 (35%) 48 (25%) .19
breast tenderness. Other 2 (8%) 4 (9%) 9 (5%) .45
Current OC users were asked to keep daily calendars
GED graduate equivalency diploma; OC oral contraceptive;
during their next two full cycles of OCs. New-start OC PMS premenstrual syndrome.
users were asked to record symptoms daily during their Data presented as mean standard deviation or n (%).
* Desogestrel and norgestimate.
first three OC cycles to assess changes over that time in
beginning OC users.
Demographic and baseline characteristics were com- height, weight, BMI, race, and education. Subjects were
pared with the use of analysis of variance for continu- predominately white (84%), and most had high school
ous variables and 2 test for categoric variables. Means educations or greater (97%). Subjects with no prior use
are reported with the standard deviation (SD). In symp- and current users had higher percentages of nulligrav-
tom results, subjects with no prior OC use and prior OC idas because prior users included many women who
users were combined as new starts. Comparisons of had delivered and were restarting OCs postpartum. As
weekly prevalence of hormone-related symptoms were indicated in Table 1, women used many OC types with
made with the use of Cochran test for comparison of various progestins. Most were using OCs for birth
matched samples.8 In the figures showing the daily control, but many had multiple reasons for use, includ-
prevalence of various symptoms, the two cycles for the ing menstrual disorders. Symptom data were not ana-
current users are aligned with the second and third lyzed by OC type or reason for initiating OCs because
cycles of the new starts. Between-group comparisons of of multiple types of OCs used, multiple reasons for
days of menstrual flow were made using the two- initiating OCs, and small sample.
sample t test. P .05 indicated statistical significance. Data on headaches were analyzed with the use of two
measures: any headache (pain score of 1 to 10), or
moderate to severe headache (pain score of 5 to 10).
Results
Figure 1 shows the percentage of women with any
Among 334 women who signed consent forms, 262 headache by cycle day and percentage with moderate to
(78%) returned detailed calendars for analysis. As dis- severe headaches for each day of the three monitored
played in Table 1, the women were similar in age, cycles in new starts and of two cycles in current users.

262 Sulak et al Oral Contraceptive Symptoms Obstetrics & Gynecology


starts were compared with those of current users. There
were no differences between groups in prevalence of
any pain or moderate to severe pain for either cycle
(smallest P .12).
The percentage of women who took pain medication
each cycle week was assessed. In new starts, the average
weekly percentage of women who took pain medication
during the 3 active hormone weeks of cycle 1 was 50%,
compared with 59% during the hormone-free week
(P .10). During cycle 2, the corresponding percentages
were 42% versus 70%, respectively (P .001), and
during cycle 3, 46% versus 58%, respectively (P .03).
For current users, the average weekly percentage of
women who took pain medication during the 3 active
hormone weeks of cycle 1 was 43%, compared with 69%
Figure 1. Percentage of subjects with headache on each cycle day for during the hormone-free week (P .001). During cycle
current users (A) and new starts (B). Thinner curves show percentage
of subjects with any headache, and thicker curves show percentage of
2, the corresponding percentages were 40% versus 66%,
subjects with headaches rated 5 on a scale of 0 to 10. respectively (P .001).
Menstrual flow was assessed between groups. New
starts were compared with current users by comparing
In new-start OC users, the number of headaches was the second cycles of new starts with the first reported
increased during the hormone-free interval for the cycles of current users. The number of days of with-
second monitored cycle only. In cycle 1, the average drawal flow during the hormone-free interval was
percentage of new starts with any headaches during the comparable between groups (4.3 2.2 versus 4.4 1.8;
3 active-hormone weeks was 62%, compared with 71% P .80), whereas the number of days with moderate to
during the hormone-free week (P .93). During cycle 2, heavy flow was slightly less in current users (1.2 1.5
the corresponding percentages were 49% versus 71%, versus 0.8 1.2; P .04). There was less bleeding in
respectively (P .001), and during cycle 3, 51% versus weeks 1, 2, and 3 in current users than in new starts,
60%, respectively (P .13). In current users, the number representing breakthrough flow that is higher the first
of headaches was increased during the hormone-free few months after initiation of OCs and decreases after
interval for both cycles. In cycle 1, the average percent- the third cycle.
age of current users with any headaches during the 3 Other symptoms monitored include nausea or vom-
active hormone weeks was 53%, compared with 70%
during the hormone-free week (P .001). During cycle
2, the corresponding percentages were 45% versus 62%,
respectively (P .001).
Like headaches, ratings of pelvic pain or cramps
(Figure 2) were classified as any pain (score of 1 to 10)
or moderate to severe pain (score of 5 to 10). The
hormone-free week in each cycle had significantly
higher prevalence of pain or cramps for new-start and
current users. For new starts, the average weekly prev-
alence of any pain or cramps during the 3 active
hormone weeks of cycle 1 was 38%, compared with 72%
during the hormone-free week (P .001). During cycle
2, the corresponding percentages were 19% versus 65%,
respectively (P .001), and during cycle 3, 17% versus
62%, respectively (P .001). For current users, the
average prevalence of any pain or cramps during the 3
Figure 2. Percentage of subjects with pelvic pain or cramps by cycle
active hormone weeks was 21%, compared with 70%
day for current users (A) and new starts (B). Thinner curves show
during the hormone-free week (P .001). During cycle percentage of subjects with any pelvic pain or cramps, and thicker
2, the corresponding percentages were 15% versus 72%, curves show percentage of subjects with pelvic pain or cramps rated
respectively (P .001). Pain scores from combined new 5 on a scale of 0 to 10.

VOL. 95, NO. 2, FEBRUARY 2000 Sulak et al Oral Contraceptive Symptoms 263
2, there were similar results (25% versus 8%, respec-
tively; P .001). During weeks 3 and 4, the prevalence
of breast tenderness was comparable (P .78 and P
.38, respectively). Breast tenderness began to increase in
the week before the hormone-free interval in current
users, with a peak during the hormone-free interval,
similar to the pattern for bloating or swelling. Current
users had more frequent breast tenderness during hor-
mone-free intervals than the active-pill weeks (38%
versus 16%, P .001).

Discussion
We documented that hormone-related symptoms some-
times varied between new starts and long-term users of
Figure 3. Percentage of subjects with bloating or swelling by cycle OCs, and between active-pill and hormone-free weeks.
day for current users (A) and new starts (B). In current OC users of more than 12 months, headaches
were more common during hormone-free intervals
compared with the active-pill weeks, probably because
iting, bloating or swelling, and breast tenderness. There of the estrogen withdrawal effect on the vasculature
was an increased prevalence of nausea or vomiting in from declining estrogen levels during hormone-free
new starts compared with current users. During the intervals. Menstrual migraines have occurred in spon-
first recorded cycle, 54% of new starts experienced taneous cycles in women not using OCs, during de-
nausea or vomiting compared with 32% of current users creased estrogen immediately before and during men-
(P .01). As seen in Figure 3, there was an increase in ses.9 12
the prevalence of bloating or swelling during the hor- The prevalence of pelvic pain and analgesic use was
mone-free interval in both groups for all cycles com- greatest during hormone-free intervals. Approximately
pared with the weeks of active-hormone pills (58% 70% of women in the two monitored cycles in current
versus 19%, P .0001 in all cycles). The bloating or users documented some degree of pelvic pain during
swelling begins in the active week before the hormone- the hormone-free interval compared with a prevalence
free interval. As seen in Figure 4, breast tenderness was of 1123% during active-pill weeks. The prevalence of
encountered more commonly in new starts compared moderate to severe pain was 2729% during the hor-
with current users. During week 1 of the first recorded mone-free week compared with 2 6% during active-pill
cycle, 22% of new starts had breast tenderness com- weeks in cycles 1 and 2 of current users.
pared with 9% of current users (P .01). During week Evaluation of menstrual flow showed expected re-
sults. Moderate to heavy menstrual flow was noted less
in current users than new starts, which is important
when counseling those who have been prescribed OCs
for menorrhagia, emphasizing the importance of ex-
plaining that significant reduction in flow might take
several months. Breast tenderness and bloating or
swelling were more likely during hormone-free inter-
vals, an increased prevalence that began in the last few
days of active pills before hormone-free intervals. Those
symptoms before hormone-free intervals might corre-
late with serum E2 levels. Combination low-dose OCs
with 35 g or less of ethinyl E2 do not produce
complete ovarian suppression.1315 Studies have docu-
mented serum FSH and 17-E2 levels suppressed at the
beginning of 7-day hormone-free intervals, but gradu-
ally increasing over the next few days. No significant
differences between FSH levels on day 7 of hormone-
Figure 4. Percentage of subjects with breast tenderness by cycle day free intervals were found compared with controls in the
for current users (A) and new starts (B). normal follicular phase of the ovarian cycle, suggesting

264 Sulak et al Oral Contraceptive Symptoms Obstetrics & Gynecology


that gonadotropin production is suppressed incom- withdrawal. A reduction in those symptoms could
pletely during hormone-free intervals.15 Estradiol levels improve acceptance and long-term use, with more
began to rise during the end of hormone-free intervals, women benefitting from contraceptive and noncontra-
peaking in the first half of the OC cycle, then declining ceptive benefits of OCs.
during the last week of active pills before the hormone-
free interval.16,17 Estrogen levels decrease during the
latter half of the interval of active hormone, which References
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VOL. 95, NO. 2, FEBRUARY 2000 Sulak et al Oral Contraceptive Symptoms 265
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Address reprint requests to:


Patricia J. Sulak, MD
Department of Obstetrics and Gynecology
Scott and White Clinic
2401 South 31st Street
Temple, TX 76508 Copyright 2000 by The American College of Obstetricians and
E-mail: psulak@swmail.sw.org Gynecologists. Published by Elsevier Science Inc.

266 Sulak et al Oral Contraceptive Symptoms Obstetrics & Gynecology