Nama : Yosua Herling Kumambong

Pembimbing : Dr. dr. Fabiola M.S. Adam, Sp.PD, K-EMD

Tanggal Baca: 6 Juni 2023
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4, e1402–e1412
https://doi.org/10.1210/clinem/dgab868
Clinical Research Article

Clinical Research Article

Oral Contraceptive and Menopausal Hormone

Therapy Use and Risk of Pituitary Adenoma:
Cohort and Case-Control Analyses

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David J. Cote,1,2,3 John L. Kilgallon,3 Noah L. A. Nawabi,3 Hassan Y. Dawood,3
Timothy R. Smith,2,3 Ursula B. Kaiser,2,4 Edward R. Laws Jr,2
JoAnn E. Manson,5,6 and Meir J. Stampfer1,6,7
1
Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital
and Harvard Medical School, Boston, Massachusetts 02115, USA; 2Pituitary/Neuroendocrine Center,
Department of Neurosurgery, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA;
3
Computational Neuroscience Outcomes Center, Department of Neurosurgery, Brigham and Women’s
Hospital, Boston, Massachusetts 02115, USA; 4Division of Endocrinology, Diabetes, and Hypertension,
Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA;
5
Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston,
Massachusetts 02115, USA; 6Department of Epidemiology, Harvard T. H. Chan School of Public Health,
Boston, Massachusetts 02115, USA; and 7Department of Nutrition, Harvard T. H. Chan School of Public
Health, Boston, Massachusetts 02115, USA
ORCiD numbers: 0000-0001-5419-1517 (D. J. Cote); 0000-0002-9426-7595 (J. E. Manson).

Abbreviations: BMI, body mass index; OC, oral contraceptive; ICD, International Classification of Diseases; MHT, menopausal
hormone therapy; MVHR, multivariable-adjusted hazard ratio; MVOR, multivariable-adjusted odds ratio; NHS, Nurses’ Health
Study; NHSII, Nurses’ Health Study II; OR, odds ratio; RPDR, Mass General Brigham Research Patient Data Registry.
Received: 17 July 2021; Editorial Decision: 23 November 2021; First Published Online: 3 December 2021; Corrected and
Typeset: 9 December 2021.

Abstract
Context: No prospective epidemiologic studies have examined associations between
use of oral contraceptives (OCs) or menopausal hormone therapy (MHT) and risk of
pituitary adenoma in women.
Objective: Our aim was to determine the association between use of OC and MHT and
risk of pituitary adenoma in two separate datasets.
Methods: We evaluated the association of OC/MHT with risk of pituitary adenoma in the
Nurses’ Health Study and Nurses’ Health Study II by computing multivariable-adjusted
hazard ratios (MVHR) of pituitary adenoma by OC/MHT use using Cox proportional
hazards models. Simultaneously, we carried out a matched case-control study using an
institutional data repository to compute multivariable-adjusted odds ratios (MVOR) of
pituitary adenoma by OC/MHT use.

ISSN Print 0021-972X ISSN Online 1945-7197

e1402   https://academic.oup.com/jcem Printed in USA
© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.
For permissions, please e-mail: journals.permissions@oup.com
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4 e1403

Results: In the cohort analysis, during 6 668 019 person-years, 331 participants reported a
diagnosis of pituitary adenoma. Compared to never-users, neither past (MVHR = 1.05; 95%
CI, 0.80-1.36) nor current OC use (MVHR = 0.72; 95% CI, 0.40-1.32) was associated with risk.
For MHT, compared to never-users, both past (MVHR = 2.00; 95% CI, 1.50-2.68) and current
use (MVHR = 1.80; 95% CI, 1.27-2.55) were associated with pituitary adenoma risk, as was
longer duration (MVHR = 2.06; 95% CI, 1.42-2.99 comparing more than 5 years of use to
never, P trend = .002). Results were similar in lagged analyses, when stratified by body
mass index, and among those with recent health care use. In the case-control analysis,
we included 5469 cases. Risk of pituitary adenoma was increased with ever use of MHT
(MVOR = 1.57; 95% CI, 1.35-1.83) and OC (MVOR = 1.27; 95% CI, 1.14-1.42) compared to never.
Conclusion: Compared to never use, current and past MHT use and longer duration
of MHT use were positively associated with higher risk of pituitary adenoma in 2

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independent data sets. OC use was not associated with risk in the prospective cohort
analysis and was associated with only mildly increased risk in the case-control analysis.
Key Words: cohort, case control, epidemiology, menopausal hormone therapy, oral contraceptives, pituitary adenoma

Pituitary adenomas are common lesions of the pituitary use of OC or MHT, and longer duration use of these medi-
gland, with an estimated prevalence as high as 20% based cations, would be associated with higher risk of pituitary
on autopsy and radiological studies, but often remain adenoma. We further hypothesized that, owing to reverse
undiagnosed for years before discovery (1, 2). They can causation, these associations would be attenuated in lagged
cause debilitating symptoms including visual field deficits, analyses, particularly for OC use.
headache, hypopituitarism, and symptoms attributable to
hyperfunction for hormone-secreting adenomas (1-5).
Identification of individuals at risk of pituitary adenoma
Materials and Methods
may allow for early and effective treatment (5). Currently, Nurses’ Health Study Analysis
a large proportion of lesions are incidentally discovered (3). Study participants
In addition, diagnosis is often made among young women The methods of the NHS and NHSII have been previ-
during evaluation of amenorrhea or infertility, as pituitary ously described (14). NHS was started in 1976 with an
adenomas can cause these disorders (5). enrollment of 121 701 female nurses aged 30 to 55 years;
A potential link between oral contraceptive (OC) or NHSII began in 1989 with an enrollment of 116 686 fe-
menopausal hormone therapy (MHT) use and pituitary ad- male nurses aged 25 to 42 years. Participants completed a
enoma incidence is plausible, given that estrogen stimulates baseline questionnaire and subsequent biennial follow-up
lactotroph cells in the pituitary gland (6). Previous case- questionnaires. Questionnaires were expanded across the
control studies have examined the association between OC course of the study to include detailed information on
use and incidence of pituitary adenoma with mixed results, dietary factors, physical activity, and health behaviors, in
but that design is subject to bias (7-12). It is possible, for addition to assessment of health outcomes. Follow-up rates
example, that women experiencing menstrual irregularity in the cohorts have been higher than 90% (15). The study
or other symptoms as the result of an as-yet undiagnosed protocol was approved by the institutional review boards
pituitary adenoma are then treated with OC or MHT, of the Harvard T. H. Chan School of Public Health and
leading to an observed association in case-control studies Brigham and Women’s Hospital, and those of participating
despite the lack of a causal relationship. To our knowledge, registries, as required.
no prospective studies have examined associations between
OC or MHT and incidence of pituitary adenoma. Assessment of oral contraceptive use
In this study, we conducted 2 complementary analyses At baseline, participants reported their use of OC. Use was
in parallel. In the Nurses’ Health Study (NHS) and Nurses’ categorized as never, past, or current, and was updated
Health Study II (NHSII) cohorts, we prospectively assessed every 2 years from baseline until 1982 in the NHS (at
the association between OC and MHT use and risk of pi- which point fewer than 500 participants reported current
tuitary adenoma (13). In addition, we performed a case- use) or until the end of follow-up in the NHSII. Participants
control analysis using data from the Mass General Brigham also reported overall duration of OC use, which was cat-
Research Patient Data Registry (RPDR) to examine the egorized as never, 0 to 1 years or less, more than 1 to
same associations. We hypothesized that past or current 2 years or less, more than 2 to 3 years or less, more than 3
e1404  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4

to 4 years or less, more than 4 to 5 years or less, or more 2017 for NHSII), whichever came first. We included 118 993
than 5 years. Self-report of OC use was validated among participants in the NHS and 115 044 in the NHSII. We
215 participants in the NHSII, with 99% agreement be- constructed Cox proportional hazards models to calculate
tween self-report and a telephone interview using a struc- multivariable-adjusted hazard ratios (MVHRs) and 95% CIs
tured life events calendar for ever use, and a correlation of to evaluate risk of pituitary adenoma by OC and MHT use,
0.94 between mean durations of use (42.7 mo by telephone using months as the time metameter and age and calendar
interview vs 44.6 mo by self-report) (16). year as stratification variables. For missing values for these
variables, we carried forward prior responses up to 4 years. If
Assessment of menopausal hormone therapy use data were still missing, those participants no longer contrib-
At baseline, participants reported their use of MHT. Use uted person-time to the analysis. We adjusted for smoking in
was categorized as never, past, or current, and was updated multivariable-adjusted Cox models because it may be related
every 2 years from baseline until the end of follow-up in to likelihood of diagnosis. To assess the independent effects

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both cohorts. Participants also reported duration of MHT of OC and MHT use, we further conducted an analysis that
use, which was categorized as never, 1 year or less, more cross-classified both by OC and MHT use. In this analysis,
than 1 to 5 years or less, or more than 5 years. Beginning in users were categorized as never OC/MHT users (reference),
1978 in the NHS and at baseline in the NHSII, participants ever MHT/never OC users, never MHT/ever OC users, and
also reported the type of MHT, categorized as estrogen ever OC/ever MHT users.
only or estrogen plus progestin. To evaluate duration relationships, we assigned the
median of each duration category to all members of that
Identification of pituitary adenoma cases category, and tested for the trend across categories in a
Each biennial questionnaire included a list of diagnoses and multivariable-adjusted Cox model.
a space to write in any other important diagnosis. All cases To address reverse causation—the possibility that OC
of pituitary adenoma were identified by participants who or MHT use among pituitary adenoma cases may be af-
reported their diagnosis in the write-in space on the bien- fected by prediagnostic disease—we applied the main ana-
nial questionnaires. The date of diagnosis was taken to be lysis variables in 4- and 8-year lagged analyses, resulting in
12 months before the return of the questionnaire where the the exclusion of the first 4 and 8 years of follow-up in each
diagnosis was identified. We did not seek medical records case. In a secondary analysis, we stratified by BMI (< 25 vs
to confirm cases of pituitary adenoma. ≥ 25) to assess whether the association between OC and
MHT and pituitary adenoma differs by BMI.
Covariate assessment In a secondary analysis, we aimed to account for the
Smoking status was reported by participants on each bi- possibility that women taking MHT or OC may be more
ennial questionnaire and was categorized as never, past, or regular health care users, and therefore be more likely to
current. Body mass index (BMI) was calculated for each experience an incidental diagnosis of a pituitary adenoma.
time period by using the reported height at baseline and In this analysis, we limited to women who reported recent
the updated weight, and was categorized according to the health care use within the 2 most recent questionnaire cycles.
World Health Organization categorization as less than 25, Analyses were performed separately in each cohort and
25 to 30, or more than 30. Age at menarche was reported then combined by fixed-effect meta-analysis. All statis-
at baseline and was categorized as younger than 11, 11 to tical analyses were performed using the SAS 9.4 statistical
14, or older than 14 years. package (SAS Institute), and all P values were derived from
To account for potential diagnostic or surveillance bias, 2-sided tests; the statistical significance threshold was set
we used biennial data to create a variable representing re- to .05.
cent health care use. On each questionnaire, all participants
reported whether they had undergone a recent physical
exam, sigmoidoscopy/colonoscopy, or breast exam within Mass General Brigham Research Patient Data
the most recent questionnaire cycles. Registry Case-Control Analysis
Data source
Statistical analyses The Mass General Brigham health care system established
We began follow-up time at the date of return of the base- the RPDR in 2002 to provide centralized data storage for
line questionnaire and continued to the date of pituitary ad- demographic, administrative, and clinical data from elec-
enoma diagnosis, death from another cause, date of return tronic medical record systems. This data source has been
of last questionnaire, or the end of follow-up (June 2018 used for studying a variety of other health exposures and
for NHS and Health Professionals Follow-Up Study; June outcomes (17-20). In 2012, a validation study of RPDR
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4 e1405

compared the registry to a surgeon-collected case log and never use. We also constructed a single model that mutu-
demonstrated that after accounting for mismatches, RPDR ally adjusted MHT use for OCs, and vice versa. We fur-
captured 96% of primary joint arthroplasties from 2000 ther conducted a sensitivity analysis using a 1-year lag, in
to 2009 (17). which both the index date for controls and diagnosis date
for cases were taken to be 365 days before their original
Study participants diagnosis or index date, to take into account the possibility
Using RPDR’s web-based query interface, we identified that cases were diagnosed earlier at another site and later
cases of pituitary adenoma diagnosed within our hos- appeared in the medical record on presentation for a spe-
pital system among women from 2010 to 2020. We used cialty referral. All statistical analyses for this portion of the
a comprehensive search including both International analysis were performed using R version 3.6.1, and all P
Classification of Diseases, Revision 9 (ICD-9; 227.3) and values were derived from 2-sided tests. All supplementary
Revision 10 (ICD-10) codes (D35.2). In the overall ana- tables are available in a data repository (21), and all data

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lysis, the date of diagnosis was taken to be the date when are available from the investigators on reasonable request.
a code for pituitary adenoma first appeared in the medical
record. These cases were frequency matched to controls
Results
from the same institutional data repository, selected at
random from the larger cohort of all women with a med- Nurses’ Health Studies Analysis
ical record during these years. Matching factors were age During 6 668 019 person-years of follow-up, 331 partici-
(within 10 y), race, sex, and overall health care use (a com- pants (132 in NHS, 199 in NHSII) reported a new diag-
posite metric based on the number of encounters, diag- nosis of pituitary adenoma (Table 1). Participants in the
noses, and visits in the medical record). The index date for NHSII were younger on average than those in the NHS
controls was the date of a randomly selected encounter in (34.8 vs 42.9 y) and reported a longer duration of OC use
the medical record. In additional analyses, we restricted to but a shorter duration of MHT use. In addition, partici-
cases that had co-occurring hyperprolactinemia (ICD-10: pants in NHSII were substantially younger at the time of
E22.1) diagnosed at the same encounter as the pituitary diagnosis than those in NHS (42.4 vs 60.3 y).
adenoma, in an effort to attempt to identify patients with We observed no strong associations between OC use
prolactinoma from the overall pool of pituitary adenomas. and pituitary adenoma (Table 2). Compared to never
use, neither past (MVHR = 1.05; 95% CI, 0.80-1.36)
Assessment of oral contraceptive and menopausal nor current OC use (MVHR = 0.72; 95% CI, 0.40-1.32)
hormone therapy use was associated with risk of pituitary adenoma. Similarly,
The data repository provided a list of all medications that longer duration of OC use was not associated with risk
appeared in each participant’s medical record, with associ- (MVHR = 0.95; 95% CI, 0.68-1.31 comparing > 5 y to
ated dates of administration. From this list of medications, never use, P trend = .43).
we identified OC and MHT, and further identified whether In contrast, strong positive associations were observed
participants did or did not receive these medications be- between MHT use and higher risk of pituitary adenoma.
fore their diagnosis of pituitary adenoma (for cases) or In the pooled analysis, compared to never use, both past
their index date (for controls). We followed medication use (MVHR = 2.00; 95% CI, 1.50-2.68) and current use
from the time of first entry into the data repository until (MVHR = 1.80; 95% CI, 1.27-2.55) were associated
the index date of control selection or date of diagnosis for with higher risk. Similarly, longer duration of MHT use
cases. was associated with a higher risk of pituitary adenoma
(MVHR = 2.06; 95% CI, 1.42-2.99 comparing > 5 y to
Covariate assessment never use, P trend = .002). When cross-classified by both
Covariates were drawn from the medical record and in- OC and MHT use, strong positive associations were ob-
cluded age (y, continuous) and race (White vs non-White). served for participants ever using MHT but never using OC
These matching factors were adjusted for in the final ana- (MVHR = 2.18; 95% CI, 1.43-3.33) and ever using MHT
lysis to improve precision and limit possible biases in con- and ever using OCs (MVHR = 1.93, 95% CI, 1.34-2.80),
trol selection. compared to never MHT/OC use. No such association
was identified for ever OC use in the absence of MHT use
Statistical analyses (MVHR = 1.00; 95% CI, 0.70-1.42).
We constructed logistic regression models, adjusted for age When examined by type, positive associations were ob-
and race, to estimate multivariable-adjusted odds ratios served for both estrogen only and estrogen and progestin
(MVORs) and 95% CIs for ever use of MHT and OCs vs MHT (Table 3). For estrogen only, use for 1 to 5 years was
e1406  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4

Table 1. Baseline characteristics of the Nurses’ Health Study (1976) and Nurses’ Health Study II (1989) participants

NHS NHSII

Full cohort(N = 118 993) Cases(n = 132) Full cohort(N = 115 044) Cases(n = 199)

Age, y 42.9 (7.2) 41.1 (4.1) 34.8 (4.7) 34.4 (4.5)

BMI (median, SD)a 23.8 (4.2) 24.6 (2.7) 24.1 (5.1) 25.0 (4.0)
Smoking status (%)
Never 51 731 (43) 53 (40) 73 656 (64) 143 (72)
Past 27 717 (23) 32 (24) 28 781 (25) 48 (24)
Current 39 212 (33) 44 (33) 10 963 (10) 8 (4)
Missing 333 (1) 3 (2) 1644 (1) 0
Raceb
White 78 945 (66) 88 (67) 103 639 (90) 174 (87)

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Non-White 22 144 (19) 29 (22) 9638 (8) 22 (11)
Missing 17 904 (15) 15 (11) 1767 (2) 3 (2)
OC usec
Never 62 777 (53) 58 (44) 18 993(17) 38 (19)
Past 49 188 (41) 65 (49) 82 621 (72) 140 (70)
Current 7028 (6) 9 (7) 13 204 (11) 19 (10)
OC use duration (mo, median, SD) 46.8 (42.2) 44.0 (20.9) 54.6 (43.7) 48.4 (27.6)
MHT usec
Never 101 455 (85) 109 (83) 101 379 (88) 158 (79)
Past 6840 (6) 13 (10) 8497 (7) 19 (10)
Current 9505 (8) 10 (8) 4352 (4) 20 (10)
MHT use duration (mo, median, SD) 49.5 (48.3) 63.1 (39.5) 19.5 (25.5) 26.3 (24.6)
Time to diagnosis from baseline (y, median, SD) 19.0 (11.0) 8.0 (7.1)
Age at diagnosis (y, median, SD) 60.3 (12.5) 42.4 (8.6)

Abbreviations: BMI, body mass index; MHT, menopausal hormone therapy; NHS, Nurses’ Health Study; NHSII, Nurses’ Health Study II; OC, Oral contraceptive.
a
Age-adjusted.
b
Available from baseline in the NHSII and from 1992 in the NHS. All NHS participants who did not survive to complete 1992 questionnaire are listed as missing.
c
May not sum to total because of missing baseline values.

associated with a higher risk of pituitary adenoma com- than 5 years of MHT use had an MVHR of 2.08 (95% CI,
pared to never use (HR = 1.77; 95% CI, 1.15-2.73), but 1.40-3.08, P trend = .004).
with no trend for duration (P trend = .24). For estrogen/
progestin, use for 1 to 5 years was similarly associated with
higher risk (HR = 1.68; 95% CI, 1.05-2.68), also with no Mass General Brigham Research Patient Data
trend for duration (P trend = .64), although overall case Registry Case-Control Analysis
counts for analyses by type were limited. We identified 5469 cases of pituitary adenoma diagnosed
In 4-year (n = 235) and 8-year (n = 179) lagged analyses, in the Mass General Brigham RPDR from 2010 to 2020,
there was a mild attenuation of the estimated MVHRs for to which we frequency-matched 6262 controls on age
the association between MHT use and pituitary adenoma (10-y intervals), race (White vs non-White), female sex, and
risk, but overall findings remained similar, with positive as- health care use (Table 4).
sociations for MHT and null associations for OCs (21). In Ever use of MHT was associated with a higher risk of
the 4-year lagged analysis, OC use duration of less than pituitary adenoma (MVOR = 1.57; 95% CI, 1.35-1.83),
1 year was associated with an increased risk of pituitary as was ever use of OCs (MVOR = 1.27; 95% CI, 1.14-
adenoma (MVHR = 1.60; 95% CI, 1.08-2.36) (21). 1.42, Table 5). With the application of a 1-year lag, results
In stratified analyses, we found no substantial differ- were similar (MVOR = 1.86; 95% CI, 1.54-2.24 for ever
ences in the overall findings by BMI category for OCs or vs never use of MHT, MVOR = 1.37; 95% CI, 1.20-1.56
MHT (21). Restriction of the analysis to women with re- for ever vs never use of OCs). Mutual adjustment of MHT
cent health care use resulted in overall similar results, with for OCs and vice versa did not result in a substantial at-
null findings for OCs and positive associations between tenuation of the estimated MVORs (data not shown). In
MHT and pituitary adenoma incidence (21). Compared to the analysis restricted to patients with a co-occurring diag-
those in this group who never used MHT, those with more nosis of hyperprolactinemia, results remained statistically
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4 e1407

Table 2. Risk of pituitary adenoma in the Nurses’ Health Study and Nurses’ Health Study II by oral contraceptive and
menopausal hormone therapy use

NHS (n = 132) NHSII (n = 199) Total (N = 331)

Casesa MV 95% CI Casesa MV 95% CI Casesa MV 95% CI

HRb HRb HRb,c

OC use Never 58 Ref. 37 Ref. 94 Ref.

Past 74 1.33 0.91-1.95 144 0.84 0.58-1.21 219 1.05 0.80-1.36
Current 0 – 16 0.73 0.40-1.32 16 0.72 0.40-1.32
OC use duration, y Never 58 Ref. 37 Ref. 95 Ref.
0-1 25 1.58 0.96-2.58 38 1.07 0.68-1.69 63 1.28 0.92-1.79
1-2 7 0.87 0.39-1.96 17 0.70 0.39-1.24 24 0.75 0.47-1.20
2-3 6 0.98 0.41-2.33 19 0.87 0.50-1.51 25 0.90 0.56-1.43

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3-4 8 1.57 0.73-3.39 12 0.68 0.35-1.31 20 0.96 0.59-1.59
4-5 5 1.20 0.47-3.05 13 0.80 0.42-1.50 18 0.90 0.53-1.53
>5 23 1.33 0.80-2.21 56 0.75 0.49-1.15 79 0.95 0.68-1.31
P trend .44 .12 .43
MHT use Never 58 Ref. 122 Ref. 180 Ref.
Past 48 1.80 1.11-2.93 49 2.12 1.48-3.04 97 2.00 1.50-2.68
Current 26 1.40 0.83-2.37 25 2.19 1.38-3.49 51 1.80 1.27-2.55
MHT use dura- Never 58 Ref. 122 Ref. 180 Ref.
tion, y 0-1 9 1.25 0.60-2.60 31 1.93 1.29-2.88 40 1.74 1.23-2.48
1-5 24 1.93 1.14-3.28 21 2.13 1.29-3.53 45 2.04 1.41-2.93
>5 41 1.55 0.94-2.55 19 2.94 1.68-5.16 60 2.06 1.42-2.99
P trend .19 < .001 .002
OC and MHT cross- Never MHT/OC 28 Ref. 23 Ref. 51 Ref.
classification user
Ever MHT/Never 30 1.42 0.82-2.47 16 3.98 2.07-7.65 46 2.18 1.43-3.33
OC user
Never MHT/Ever 30 1.05 0.60-1.82 102 0.96 0.61-1.52 132 1.00 0.70-1.42
OC user
OC/MHT ever 44 2.09 1.22-3.58 58 1.81 1.09-3.00 102 1.93 1.34-2.80
user

Abbreviations: BMI, body mass index; HR, hazard ratio; MHT, menopausal hormone therapy; MV, multivariable; NHS, Nurses’ Health Study; NHSII, Nurses’
Health Study II; OC, oral contraceptive; Ref., reference.
a
Case counts may not sum to total because of missing values.
b
Adjusted for age, smoking status (never vs past vs current), BMI (< 25 vs 25-30 vs > 30), and age at menarche (< 11 y vs 11-14 y vs > 14 y).
c
Calculated by fixed-effect meta-analysis of both cohorts.

significantly positive for the association between MHT and outcome, limiting the possibility of reverse causation and se-
OCs and pituitary adenoma risk. lection bias. At the same time, we conducted a parallel case-
control analysis using data from RPDR, identifying more
than 5000 cases of clinician-diagnosed pituitary adenoma
Discussion and matched controls, which also allowed for a lagged ana-
Despite being relatively common lesions, few risk factors lysis to limit the possibility of reverse causation bias.
for pituitary adenoma have been identified (5, 22). Most The prospective cohort analysis demonstrates a strong
studies investigating risk factors for these tumors used a positive association between use of MHT and pituitary ad-
case-control method, which is complicated by the possi- enoma, with more than a doubling of risk for more than
bility of protopathic bias (7, 9-11). These tumors are often 5 years of use compared to never-users; this association
incidental findings and may be present for years before persisted in lagged analyses and in analyses designed to
diagnosis. The possibility of reverse causation is substantial limit potential diagnostic bias. In contrast, we did not dem-
for OC, because women with menstrual irregularities or onstrate any substantial association for OC use and pitu-
other symptoms caused by an undiagnosed adenoma may itary adenoma incidence. When mutually accounting both
be treated with OC. for OC and MHT use, strong positive associations were
In this study, we relied in part on prospective cohort identified between MHT use and pituitary adenoma risk,
data, with repeated assessment of OC and MHT use before with or without use of OCs, but no such associations were
e1408  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4

Table 3. Risk of pituitary adenoma in Nurses’ Health Study and Nurses’ Health Study II by menopausal hormone therapy use,
by hormone type

NHS (n = 124) NHSII (n = 199) Total (N = 323)

Casesa MV HRb 95% CI Casesa MV HRb 95% CI Casesa MV HRb,c 95% CI

E only duration, y Never E user 79 Ref. 186 Ref. 265 Ref.

0-1 4 0.89 0.32-2.45 1 0.71 0.10-5.08 5 0.85 0.34-2.09
1-5 18 1.76 1.04-3.00 8 1.80 0.86-3.73 26 1.77 1.15-2.73
>5 23 1.36 0.82-2.23 4 0.92 0.33-2.55 27 1.26 0.80-1.97
P trend 0.18 0.65 0.24
E + P duration, y Never E + P user 91 Ref. 187 Ref. 278 Ref.
0-1 8 1.97 0.93-4.18 2 1.02 0.25-4.19 10 1.71 0.88-3.31
1-5 15 1.58 0.88-2.86 8 1.86 0.86-3.98 23 1.68 1.05-2.68

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>5 10 1.00 0.49-2.03 2 1.34 0.32-5.63 12 1.06 0.56-2.00
P trend 0.92 0.22 0.64
Any MHT duration, y Never MHT user 61 Ref. 178 Ref. 239 Ref.
0-1 E 2 0.69 0.17-2.86 1 0.81 0.11-5.84 3 0.73 0.23-2.31
1-5 E 13 2.30 1.23-4.29 5 1.45 0.58-3.59 18 1.98 1.19-3.32
>5E 15 1.28 0.69-2.37 3 0.85 0.26-2.73 18 1.17 0.68-2.02
0-1 E + P 5 2.22 0.86-5.74 2 1.23 0.30-5.09 7 1.39 0.66-2.92
1-5 E + P 6 1.41 0.58-3.43 4 1.18 0.42-3.35 10 1.31 0.66-2.57
>5E+P 7 1.29 0.54-3.05 2 1.74 0.41-7.36 9 1.17 0.68-2.02

Abbreviations: BMI, body mass index; E, estrogen; HR, hazard ratio; MHT, menopausal hormone therapy; MV, multivariable; NHS, Nurses’ Health Study; NHSII,
Nurses’ Health Study II; P, progestin; Ref., reference.
a
Case counts may not sum to total because of missing values.
b
Adjusted for age, smoking status (never vs past vs current), BMI (< 25 vs 25-30 vs > 30), and age at menarche (< 11 y vs 11-14 y vs > 14 y).
c
Calculated by fixed-effect meta-analysis of both cohorts.

Table 4. Participant characteristics in the case-control analysisa

Cases (n = 5469) Controls (n = 6262) Total (N = 11 731)

Age (y, mean, SD) 44.8 (16.5) 46.5 (16.8) 45.7 (16.7)
With hyperprolactinemia (n, %) 882 (16.1%) 818 (13.1%) 1700 (14.5%)
Female sex (n, %) 5469 (100) 6262 (100) 11 1 (100)
White race (n, %) 4031 (73.7) 4738 (75.7) 8769 (74.8)
Ever MHT use (n, %) 408 (7.5) 313 (5.0) 721 (6.1)
Ever OC use (n, %) 768 (14.0) 679 (10.8) 1447 (12.3)

Abbreviations: MHT, menopausal hormone therapy; OC, oral contraceptive.

a
Cases and controls frequency-matched on age (in 10-y intervals), sex, and race (White vs non-White).

identified for OC use in the absence of MHT use. Although suggest a strong positive association between MHT use
this analysis included self-reported cases, estimates from and risk of pituitary adenoma, and a possible smaller in-
other epidemiologic studies of pituitary adenoma incidence creased risk with use of OCs, though the latter findings
suggest that across 6 668 019 person-years of follow-up, were inconsistent between studies. In general, these results
we should have expected approximately 172 to 493 cases do not appear to be substantially affected by recall, re-
of pituitary adenoma (23, 24), similar to our observed 331 verse causation, or diagnostic bias, although these biases
cases, suggesting that self-report may not be a major limi- cannot be absolutely excluded. In particular, surveillance
tation of this portion of the analysis. bias remains a potential issue despite our sensitivity ana-
In the case-control analysis, we again demonstrated lyses, given that OCs and, to a lesser extent, MHT, may
an increased risk for pituitary adenoma among users of cause headache, which may lead to increased rates of
MHT and also demonstrated smaller increases in risk of neuroimaging and therefore increased rates of pituitary
pituitary adenoma in individuals who had ever used OCs. adenoma diagnosis among users as compared to nonusers
Taken together, the results from these distinct data sets (25, 26).
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4 e1409

Table 5. Odds ratios of pituitary adenoma by oral contraceptive and hormone therapy use in the case-control analysis

First recorded diagnosis date 1 y before recorded date

Any pituitary adenoma

Cases MV ORa 95% CI Cases MV ORa 95% CI

MHT use Never 5061 Ref. 4710 Ref.

Ever 408 1.57 1.35-1.83 297 1.86 1.54-2.24
OC use Never 4693 Ref. 4430 Ref.
Ever 776 1.27 1.14-1.42 577 1.37 1.20-1.56

Pituitary adenoma with hyperprolactinemia

Cases MV ORa 95% CI Cases MV ORa 95% CI

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MHT use Never 805 Ref. 796 Ref.
Ever 77 1.42 0.98-2.06 57 1.82 1.16-2.94
OC use Never 651 Ref. 683 Ref.
Ever 231 1.30 1.04-1.63 170 1.40 1.08-1.83

Abbreviations: MHT, menopausal hormone therapy; MV, multivariable; OC, oral contraceptive; OR, odds ratio; Ref., reference.
a
Matched by age (in 10-y intervals), sex, and race (White vs non-White), and additionally adjusted for these factors.

Previous investigations of OC use and pituitary ad- (P trend = .6). The authors interpreted this latter finding as
enoma risk to our knowledge have been limited to case- hormone use as a consequence of a pituitary tumor, again
control studies. In a case-control study of 9 pituitary providing evidence of a protopathic bias (7). We are un-
adenoma cases and 36 controls, Coulam et al (11) reported aware of other studies of MHT and risk of pituitary ad-
a nonstatistically significant association for ever vs never enoma. The use of MHT and risk of other cancers has
use of OC (odds ratio [OR] = 0.5; 95% CI, 0.1-2.2). In been studied in detail, however, with evidence that use of
1980, Teperman et al (12) reported a nonstatistically sig- estrogen plus progestin, particularly long duration use, is
nificant relative risk of 4 for OC use (P = .25) in a case associated with an increased risk of breast cancer (27-30),
control study of 20 hyperprolactinemia cases with pituitary but no association with bladder cancer (31), lung cancer
adenoma and matched appendectomy patients. Maheux (32), or renal cell cancer (33). Importantly, estrogen plus
et al (10) reported no association for OC use comparing 70 progestin MHT has also been associated with a lower risk
patients with prolactin-secreting adenomas with 3 different of endometrial cancer (34), and estrogen-only MHT was
control groups. In 1983, the Pituitary Adenoma Study associated with lower breast cancer risk in the randomized
Group case-control analysis of 212 women with prolactin- Women’s Health Initiative (35).
secreting pituitary adenomas reported an OR of OC use of Taken together with the existing literature, the results
1.33 (95% CI, 0.81-2.22) comparing those with pituitary here are concordant with the overall finding of a possible
adenoma to matched controls, with no dose-response re- small increase in risk of pituitary adenoma with prior OC
lationship (9). A study by Shy et al (8) the same year com- use. In the prospective cohort analysis, we demonstrated
pared patients with pituitary adenoma to matched controls a positive association between less than 1 year of OC use
and accounted for the indication for OC prescription. For duration and pituitary adenoma in the 4-year lagged ana-
those who used OCs for birth control, the OR for ever vs lysis (but not the 8-y lagged analysis), which was similar
never use was 1.3 (95% CI, 0.7-2.6), but when OCs were to the finding of increased risk in the lagged case-control
prescribed for menstrual regulation, the OR was 7.7 (95% analysis. The lagged analyses and the analysis among those
CI, 3.7-17.0), providing clear evidence of a protopathic with recent health care use in the prospective cohort miti-
bias due to an undiagnosed adenoma. gate the possibility of substantial reverse causation or diag-
More recently, in 2009, a case-control study of 157 nostic bias affecting the results, unlike in prior studies of
patients with pituitary adenoma and 336 controls also these associations.
found no association between OCs and pituitary adenoma On the other hand, our results suggest, for the first time,
(OR = 0.8; 95% CI, 0.4-1.4) (7). For MHT, that same a strong positive association between MHT use and pi-
study reported an OR of 1.5 (95% CI, 0.8-2.6) for ever tuitary adenoma risk, with evidence of a duration effect.
vs never use, a statistically significant OR of 3.3 (95% CI, This finding is unlikely to be the result of reverse causation,
1.3-8.6) for less than 1 year of use but no duration trend but we cannot rule out diagnostic bias or confounding by
e1410  The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4

another as-yet unidentified causal risk factor for pituitary by using pituitary adenoma cases codiagnosed with
adenoma. Nonetheless, the prognostic value of an asso- hyperprolactinemia, but it remains possible that this
ciation between MHT use and incidence of pituitary ad- may include patients with nonfunctioning (or other func-
enoma in risk-stratifying patients remains. tioning) pituitary adenomas who have elevated prolactin
An association between circulating estrogens and pi- due to the stalk effect, in addition to the possibility of
tuitary adenoma incidence is plausible, given convincing undercoding or overcoding in an administrative data
evidence that estrogen stimulates lactotroph cells in the set (43). For example, physicians may not be inclined to
anterior pituitary (36-39). Among premenopausal women, code hyperprolactinemia systematically for patients with
prolactinomas arising from the lactotroph cells of the an- prolactinoma, and may elect to use only the nonspecific
terior pituitary are the most commonly occurring pituitary code for adenoma. Notably, although the pituitary ad-
adenoma subtype; incidence of this subtype decreases after enoma cases in the prospective cohorts were self-reported,
menopause, and perhaps higher levels of circulating es- all participants were nurses, and thus able to provide ac-

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trogen stimulate the growth of these lesions, increasing the curate information regarding medical conditions; the ac-
likelihood that they would come to clinical attention (40, curacy of recall has previously been confirmed in these
41). The difference in association between OCs and MHT cohorts by comparing self-report with medical records for
and pituitary adenoma is less easily explained, particularly a wide range of medical conditions (14, 44-49).
given that MHT generally contains lower levels of estrogen
than OCs. Nevertheless, the possibility of a threshold effect
remains, given that the lifetime cumulative estrogen ex- Conclusion
posure for women taking MHT is substantially higher than Compared to never use, current and past MHT use and
that of OC users, particularly since MHT users may have longer duration of MHT use were positively associated
previously used OCs. with incidence of pituitary adenoma in 2 independent data
Importantly, the effect of calendar time may also explain sets. OC use was not associated with risk in the prospective
the minor discrepancies between the 2 separate analyses. cohort analysis and was associated with only mildly in-
The case-control analysis, in general, included cases diag- creased risk in the case-control analysis. These findings
nosed more recently than the prospective cohort analysis. warrant further investigation, including corroboration in
If anything, we would expect that the active hormonal past and ongoing randomized trials of MHT, especially
content of OCs may have decreased over time (42), which those with brain imaging studies.
would not explain why the finding of increased risk of pi-
tuitary adenoma with OC use was stronger in the case-
control analysis than in the prospective cohort analysis. It Acknowledgments
is possible, however, that the case-control analysis included We would like to thank the participants and staff of the Nurses’
more long-duration users, or this difference could simply Health Study, Nurses’ Health Study II, and Health Professionals
Follow-Up Study for their valuable contributions as well as the
be due to the higher statistical power of the later analysis.
following state cancer registries for their help: Alabama, Arizona,
The 2 separate analyses include complementary Arkansas, California, Colorado, Connecticut, Delaware, Florida,
strengths and limitations. The prospective cohort ana- Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Louisiana,
lysis included repeat, prospective, highly accurate assess- Maine, Maryland, Massachusetts, Mississippi, Nevada, New
ment of OC and MHT use, allowing the calculation of Hampshire, New Jersey, New York, North Carolina, North
duration and assessment of specific types of MHT, but Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Rhode Island,
South Carolina, Tennessee, Texas, Virginia, Washington, and
was limited to self-reported pituitary adenomas. The case-
Wyoming. The authors assume full responsibility for the analyses
control analysis, on the other hand, included an extremely and interpretation of these data.
large number of clinician-diagnosed pituitary adenomas Financial Support: This work was supported by the National
(n > 5000), but had fewer granular data on OC/MHT use Institutes of Health (grant Nos. NIH PO1 CA87969, U01
and may have included some use that occurred after ini- CA167552, UM1 CA186107, U01 CA176726, UM1 CA167552,
F30 CA235791 to D.J.C., and R37 HD019938 to U.B.K.).
tial diagnosis, even in the analysis intended to account for
this. The fact that we generated overall similar results from
2 completely separate data sets with 2 different method-
Additional Information
ologies lends credence to our overall findings. Limitations
Correspondence: David J. Cote, MD, PhD, Channing Division of
include the lack of data on specific tumor types as well
Network Medicine, Harvard T.H. Chan School of Public Health,
as difficulty identifying the exact date of diagnosis, which Brigham and Women’s Hospital, 181 Longwood Ave, Boston, MA
were limitations in both data sets. In the case-control ana- 02115, USA. Email: david_cote@hms.harvard.edu.
lysis, we attempted to identify patients with prolactinoma Disclosures: The authors have nothing to disclose.
The Journal of Clinical Endocrinology & Metabolism, 2022, Vol. 107, No. 4 e1411

Data Availability: All supplementary tables are available in a quantification of errors and maximizing utility. J Arthroplasty.
data repository (21) and all data are available from the investiga- 2012;27(10):1766-1771.
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