A Retrospective Comparison of Time to Cessation of Acute

Heavy Menstrual Bleeding in Adolescents Following Two Dose

Regimens of Combined Oral Hormonal Therapy
Lauryn P. Roth, Kristina M. Haley, Maureen K. Baldwin∗
Oregon Health & Science University, Portland, Oregon

a b s t r a c t
Study Objective: Although multiple hormonal treatment strategies are effective in decreasing heavy menstrual bleeding (HMB) in adoles-
cents, few studies have compared the relative effectiveness of hormone therapy on the basis of dose.
Design: Retrospective chart review
Setting: Urban tertiary care institution
Participants: Adolescents aged 9–19 years with acute HMB and anemia in 2008–2018
Interventions: We used billing codes to identify encounters for acute HMB with hemoglobin less than 12 mg/dl and reviewed initial treat-
ment and time until resolution of acute HMB. We excluded patients who had previously used gonadal steroids or did not complete follow-
up. We then compared patients who received combined oral ethinyl estradiol with progestin (EE/P) in standard dosing (EE ≤35 mcg/day)
vs taper dosing (EE >35mcg/day in any step-down regimen).
Main Outcome Measures: Time until patient-reported resolution of acute HMB, measured in days from initial treatment
Results: Of 207 patients with vaginal bleeding and anemia, 90 met the criteria for review of therapy type and dose. Users of combined
EE/P were hormone-naïve in 28/33 (84.8%) of those who initiated standard EE/P and 22/32 (68.8%) who initiated taper dosing. Bleeding
duration was available for 15/28 (53.6%) and 18/22 (81.8%). Resolution of HMB occurred in 0–9 days with standard dosing (mean ±SD
2.1 ± 2.3 days) versus 1–15 days for taper dosing (4.9 ± 4.7; p = 0.04). Excluding six outliers of zero or more than 10 days, HMB ceased
by 2.6 and 3 days (n = 12 and 15; p = 0.62).
Conclusion: Currently recommended higher dose combined hormonal regimens do not appear to shorten the time to resolution of acute
HMB in adolescents.
Key Words: Adolescents, Acute heavy menstrual bleeding, Anemia, Estrogen, Progestin, Hormone therapy

Introduction
The menstrual cycle is a complex event reliant on intri-
cate hormonal signaling, protein expression, inflammatory
cytokines, and effective coagulation.1 Upwards of 40% of
teens experience deviations from this highly regulated pro-
cess, causing disruptions to physical, emotional, or social
aspects of life.2 Heavy menstrual bleeding (HMB) is defined
as increased menstrual volume based on measured or per-
ceived amount, and acute HMB is the occurrence of suffi-
cient menstrual blood loss prompting medical intervention
Conflict of Interest Statement: Dr. Maureen K. Baldwin is an NIH Scholar
(K12HD085809) and receives honoraria as a consultant for Bayer and Exeltis phar-
maceutical companies. Dr. Kristina M. Haley receives grant funding from Hemosta-
sis and Thrombosis Research Society and the American Thrombosis and Hemosta-
sis Network. Both Dr. Baldwin and Dr. Haley serve in a Working Group for re-
search priorities for the National Hemophilia Foundation and as medical advisory
board members for the Foundation for Women and Girls with Bleeding Disorders.
This current work was conducted without funding as an Ob/Gyn Resident Research
project by the primary author, Lauryn Roth.
Funding: None
Prior Presentations: Oral presentation at OHSU Dept of Ob/Gyn Resident Research
Day, Portland, OR, May 2020.
∗
Address correspondence to: Maureen K. Baldwin, Oregon Health & Science Uni-
versity, 3181 SW Sam Jackson Park Road, Mailcode UHN 50, Portland, OR 97239;
Phone (503) 494-9762.
E-mail address: schaum@ohsu.edu (Maureen K. Baldwin).
1083-3188/$ – see front matter © 2021 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jpag.2021.10.003
to prevent further blood loss.3 Acute HMB may require hos-
pitalization and/or transfusion, which is often the threshold
for treatment, although intervention for HMB can be initi-
ated at any point.
Onset of normal menses occurs when progesterone lev-
els decline, followed by an influx in local endometrial in-
flammation and subsequent endothelial instability leading
to bleeding.4-6 Cessation of menses is then achieved with
effective vessel hemostasis. Initial repair of these dam-
aged vessels occurs in the absence of estrogen.7 Estrogen
then becomes essential, specifically by altering vascular en-
dothelial growth factor expression in stromal cells, allow-
ing for increased vascular support and a phase of com-
plete regeneration of the endometrium.1 Because estrogen-
dependent endometrial repair mechanisms occur through
steroid-induced gene signaling pathways, as opposed to a
direct endometrial effect, the onset of this process takes a
few days.8 Exogenous synthetic gonadol steroids could have
similar effects to endogeneous hormones, but we have lim-
ited understanding of optimal timing and dose of adminis-
tration for the purpose of bleeding management.
Current clinical recommendations for first-line treat-
ment of acute HMB in adolescents often include high-
dose regimens of oral combination therapies containing
ethinyl estradiol/progestin (EE/P), commonly marketed and

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 L.P. Roth, K.M. Haley and M.K. Baldwin / J Pediatr Adolesc Gynecol 35 (2022) 294–298 295

Fig. 1. PRISMA flow diagram based on inclusion and exclusion criteria.

approved for use as oral contraception.3,9,10 Therapeutic rec-
ommendations are based on expert opinion and 3 small
studies, although reviews indicate a wide variety of med-
ications and regimens in use.11-14 In particular, recommen-
dations for EE/P dosing are based on one comparative study
between oral EE/P and medroxyprogesterone acetate (MPA)
that did not include a placebo arm. The randomization
arms involved 35 mcg of EE/P with 1 mg of norethindrone
dosed 3 times daily versus 20 mg of MPA 3 times daily.12
Both medications were administered in these higher doses
for 7 days and then tapered to once daily for an additional
3 weeks. This small study included 40 adult women with
chronic and acute HMB. Both study arms had high rates of
cessation of bleeding by 3 days (88% after EE/P and 76% af-
ter oral MPA).
We questioned whether higher dose regimens of com-
mercially available EE/P formulations were superior to
lower dose regimens in treating acute HMB. We aimed to
assess the time to cessation of acute HMB among adoles-
cents based on dose of oral EE/P, particularly among those
with no prior gonadal steroid use. We hypothesized that
time until resolution of acute HMB in teens is independent
of dose.
Materials and Methods
We performed a retrospective chart review over a 10-
year period (2008–2018) of adolescents receiving treatment
for acute HMB at our urban tertiary care institution. Our in-
stitutional IRB granted a waiver of consent for data under
chart review. We used ICD-9 and ICD-10 billing codes (617–
629; N93.8, N93.9 with associated descriptions: “abnormal
uterine and vaginal bleeding,” “irregular menstruation,” and
“unspecified disorders of menstruation”) to identify poten-

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296 L.P. Roth, K.M. Haley and M.K. Baldwin / J Pediatr Adolesc Gynecol 35 (2022) 294–298

Table 1
Characteristics of Adolescent Patients with Acute Heavy Menstrual Bleeding and Anemia Who Underwent Initial Management with Oral Combined Hormonal Therapy

EE/P standard dose n = 33 EE/P taper dose n = 32 P value

Age (mean ± SD, years) 15.7 ± 2.3 15.6 ± 2.7 0.85

Ethnicity 0.95
Non-Hispanic 26 (78.8) 25 (78.1)
Hispanic 7 (21.2) 7 (21.9)
Payer status 0.08
Public 20 (60.6) 12 (37.5)
Private 12 (36.4) 15 (46.9)
None 1 (3.0) 5 (15.6)
Location 0.33
Non-gyn outpatient 16 (48.5) 9 (28.1)
Gyn outpatient 1 (3.0) 2 (6.2)
ED or urgent care 3 (9.1) 6 (18.8)
Inpatient 13 (39.4) 15 (37.5)
Body mass index (kg/m2 ) 25.6 ± 8.2 29.8 ± 10.0 0.09
Anovulatory bleeding pattern 0.67
No 13 (39.4) 13 (40.6)
Yes 16 (48.5) 13 (40.6)
Unknown 3 (9.1) 6 (18.8)
Bleeding disorder 0.35
No 25 (75.8) 27 (84.4)
Yes 5 (15.2) 5 (15.6)
Unknown 3 (9.1) 0
Current malignancy 0.84
No 29 (87.9) 28 (87.5)
Yes 2 (6.1) 2 (6.2)
Unknown 2 (6.1) 2 (6.2)
Bleeding duration prior to presentation (days) 17.9 ± 22.3 24.8 ± 20.9 0.21
Bleeding description 0.11
Moderate 8 (24.2) 3 (9.4)
Heavy 25 (75.8) 29 (90.1)
Initial hemoglobin (mean ± SD, mg/dl) 8.6 ± 2.3 8.2 ± 2.5 0.48
Initial anemia severity∗ 0.52
Grade I (mild) 7 (58.3) 5 (41.7)
Grade II (moderate) 2 (66.7) 1 (33.3)
Grade III (severe) 10 (52.6) 9 (47.4)
Grade IV (life-threatening) 5 (31.3) 11 (68.8)
Recent hormonal therapy 5 (15.2) 10 (31.3) 0.12
Transfusion of packed red blood cells 10 (30.3) 13 (40.6) 0.38
Hospital admission 12 (36.4) 13 (40.6) 0.72

All data are presented in n (%) with column proportions and P value for χ 2 , Fisher’s exact, or t test.
∗
Staging of Anemia Severity (World Health Organization):1 Grade I: 9.5–10.9 mg/dl; Grade II: 8.0–9.4 mg/dl; Grade III: 6.5–7.9 mg/dl; Grade IV: <6.5 mg/dl1. Badzek S,
Curic Z, Krajina Z, et al: Treatment of cancer-related anemia. Coll Antropol 2008; 32:615–622.

tial study subjects. We included female patients aged 9–19
years with an acceptable encounter for HMB, including in-
patient admission or outpatient care (ED/urgent care, pri-
mary care, Ob/Gyn clinic) and a corresponding hemoglobin
level less than 12 mg/dl. We included those with poten-
tial acute HMB if there was documentation of HMB at the
time of presentation requiring intervention. Exclusion cri-
teria included teens presenting with vaginal bleeding that
did not require intervention or in the setting of pregnancy
or structural abnormalities, including trauma. We planned
to include patients with a bleeding disorder or malignancy,
as well as current anticoagulation. If multiple eligible en-
counters were identified, we used only the first encounter
meeting study criteria.
Our primary outcome was the number of days until
acute HMB resolution compared between hormonally naïve
subjects grouped by oral standard dosing (eg, 1 pill per
day) vs taper dosing in a variety of regimens ranging up to
a total of 210 mcg/day of EE. We identified the initial med-
ical management, including combined estrogen-progestin
(EE/P), estrogen-only, or progestin-only treatments. We
then grouped patients who initiated oral EE/P with stan-
dard (EE ≤35 mcg/day) vs taper dosing (EE >35mcg/day
in any step-down regimen). We assessed for any mention
or chart evidence of prior hormonal use among those initi-
ating oral combined EE/P by reviewing the medical record
prior to the index encounter. We abstracted follow-up in-
formation from any subsequent documentation after the
initial encounter. We defined resolution of acute HMB as
cessation of heavy bleeding and return to normal menstrual
flow or amenorrhea as determined by the patient and doc-
umented in the electronic medical record(EMR). Secondary
outcomes included hospitalization and blood transfusion.
Medical records were abstracted by a single investigator
(LR) who directly entered data into RedCap software. We
performed validation for 10% of the sample for key vari-
ables and reviewed outliers. We exported data directly to
STATA version 14 (StataCorp LP, College Station, TX) to per-
form analyses including χ 2 tests of difference of propor-
tions, Fisher’s exact test where appropriate, and a t test for
continuous variables. We excluded missing variables case-
wise. An alpha value less than 0.05 was considered signifi-
cant.
Results
We identified 207 potential subjects based on ICD-9
and ICD-10 billing codes, of whom 90 met the criteria

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 L.P. Roth, K.M. Haley and M.K. Baldwin / J Pediatr Adolesc Gynecol 35 (2022) 294–298 297

Fig. 2. Duration of time in days until resolution of acute heavy menstrual bleeding compared between standard daily dosing versus step-down taper dosing of oral com-
bined ethinyl-estradiol/progestin regimens among hormonally naïve adolescents ages 9–19 with completed follow-up (mean 2.1 ± 2.3 vs 4.9 ± 4.9 days, p = 0.04). (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

for review of hormone therapy dose and regimen. Patients
were excluded for lack of acute HMB (n = 103), pregnancy
(n = 18), or structural etiologies/trauma (n = 11; Fig. 1).
Most patients (74/90; 82%) initiated a hormonal method of
treatment. Seven (7.8%) initiated a progestin-only method,
33/65 (50.8%) initiated standard dosing of EE/P, and 32/65
(49.2%) initiated a taper of combined EE/P.
Of those who initiated either EE/P regimen, patients had
a mean age of 15.6 years, most had a BMI in the over-
weight category, and about half reported anovulatory cy-
cles (Table 1). Equal proportions of patients under review in
each group had malignancy or bleeding disorder (15%), and
none used anticoagulation. Patients were anemic at presen-
tation, with initial hemoglobin levels ranging from 4.2 to
11.8 mg/dl in the standard dose group (median 8 mg/dl),
vs 3.5–11.9 mg/dl (median 7.5 mg/dl) for the taper dos-
ing group (p = 0.48). Bleeding duration prior to presenta-
tion ranged from 1 day to 120 days and was not statisti-
cally different between groups, with a median of 12 days
in the standard dosing group and 21 days in the taper dos-
ing group (p = 0.2).
No prior hormone use was reported in 28/33 (84.8%) of
those prescribed standard EE/P and 22/32 (68.8%) for ta-
per EE/P dosing. Other nonhormonal or surgical interven-
tions including intravenous tranexamic acid, dilation and
curettage, or hysteroscopy were not utilized in the patients
evaluated. Follow-up, including complete bleeding outcome
data, was available for hormone-naïve users of EE/P for
15/28 (53.6%) and 18/22 (81.8%) and occurred by 90 days
in approximately 80%.
Time to resolution of acute bleeding was available for
57/90 (63.3%) of all subjects, with a median time to bleed-
ing resolution of 2 days (range 0–15) for all subjects and
72% experiencing cessation in 3 days. Among adolescents
initiating a standard vs taper regimen, bleeding cessation
occurred in 2.3 ± 2.3 days vs 4.3 ± 4.3 days (p = 0.07).
Among hormonally naïve teens, HMB resolution occurred
in 0–9 days with standard dose (2.1 ± 2.3 days) vs 1–15
days for taper (4.9 ± 4.7 days; p = 0.04; Fig. 2). Excluding
outliers of 0 days (n = 3, all in the standard dose group)
or more than 10 days (n = 3, all in the taper dose group),
HMB ceased by 2.6 and 3 days (n = 12 and 15; p = 0.62).
Conclusions
In this retrospective chart review of adolescent patients
presenting with acute HMB and anemia, we found that ces-
sation of heavy bleeding occurred by 3 days for 72% of pa-
tients treated with combined oral hormone therapy, regard-
less of dose. Based on these data and the lack of prospec-
tive studies comparing relative dose effectiveness or safety,
we do not see an indication for use of the step-down taper
regimens or an EE dose greater than 35 mcg.
A so-called taper regimen has been a mainstay in clin-
ical guidelines because it is the only combined dose reg-
imen that has been tested in clinical trials.3 The idea that
higher doses of estrogen result in faster resolution of bleed-
ing could be based on the single placebo-controlled trial
that demonstrated cessation of acute HMB in 8 hours in
13 of 18 adult women randomized to intravenous estro-
gen, several of whom had endometritis.13 The concept of
step-down or taper dosing for this indication was previ-
ously described in a prospective study of progestin therapy
in 24 adolescents with HMB requiring hospital admission.14
These patients were administered 60 mg of oral MPA up to
3 times daily on the first day and 20 mg daily for the next
10 days. After this loading dose, bleeding ceased in 25% by
day 1 and 29%, 21%, and 25% by up to day 4.
There is a wide variety of taper dose regimens in use,
despite no comparative dose studies and lack of FDA indi-
cation.11 These regimens may include as much as 200 mcg
of EE/day or more and are poorly tolerated. In the previ-

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298 L.P. Roth, K.M. Haley and M.K. Baldwin / J Pediatr Adolesc Gynecol 35 (2022) 294–298
ously cited Munro12 study comparing EE/P taper to MPA
taper, of 15 who completed dosing and follow-up for ta-
per dose EE/P, 4 reported missing 24 doses. There was high
dissatisfaction with the therapy related to adverse effects
among EE/P users, primarily related to nausea and cramp-
ing.
Advantages of this study include a population severely
affected by acute bleeding and anemia requiring interven-
tion. Although less severely affected teens might benefit
from gonadal steroid hormone therapy in this setting, we
are able to report outcomes for those with bleeding disor-
ders as well, which constituted approximately 15% of the
cohort. This is a particularly important population to in-
clude because presentation to emergency care with acute
HMB is a common occurrence prior to initial diagnosis
with inherited bleeding disorders, such as von Willebrand
disease.15,16 Patients and advocacy groups frequently re-
port a need for more education for emergency department
staff and primary care providers related to screening and
diagnosis of inherited bleeding disorders in menstruating
teens.17,18 Secondary analysis of individuals with bleeding
disorders was not completed due to limited data and re-
mains an area in great need of further research and atten-
tion.
Study limitations include the retrospective design and
small sample size, which could have introduced bias based
on bleeding severity or treatment effectiveness. Electronic
medical record data collection was limited by patient re-
port and incomplete provider documentation. This might
have resulted in a non-differential bias, excluding patients
who did not report their bleeding duration due to earlier
bleeding cessation or dissatisfaction with treatment. In ad-
dition, we identified all patients from a single health care
system, which could reflect treatment bias due to provider
prescribing patterns. Although we were initially concerned
about prescribing practices that might bias treatment to-
ward a specific dosing strategy for patients with varied acu-
ity, patient groups were similar with respect to bleeding
duration before presentation, as well as other characteris-
tics. Life-threatening anemia was slightly higher in patients
who received taper dosing, although it was high in both
treatment groups. We also do not know if patients in the
taper group adhered to their prescribed method. If they had
high discontinuation rates, we might not have captured the
potential benefits of higher doses.
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Higher dose combined hormonal regimens do not
shorten the time to resolution of acute HMB in teens com-
pared with standard dose. Current dosing guidelines should
be re-evaluated in comparative clinical studies to determine
the safest and most effective methods for management of
acute HMB.
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