n Review Article

Corticosteroid Injections: A Review of

Sex-Related Side Effects
Emily M. Brook, BA; Caroline H. Hu, BA; Kiera A. Kingston, BS; Elizabeth G. Matzkin, MD

Although there are several types of cor-

abstract ticosteroids, most are a variation of corti-
sone, a derivative of cortisol. Cortisol has
Corticosteroid injections are used as a nonoperative modality to combat anti-inflammatory properties as a steroid
acute inflammation when conservative treatments fail. As female patients are naturally produced in the body.5 By re-
regularly seen by orthopedic physicians, it is essential to identify and under- ducing vascular permeability, suppressing
stand potential sex-related side effects. The aim of this article is to examine the production of inflammatory mediators
available literature for sex-related side effects of orthopedic-related cortico- such as prostaglandins and leukotrienes,
steroid injections. Although the incidence is low, sex-related side effects, and inhibiting the excitation of C fibers,
such as abnormal menstruation, lactation disturbances, facial flushing, and corticosteroids are clinically effective in
hirsutism, are associated with corticosteroid injections. Physicians should be increasing joint mobility, reducing joint
aware of these female-specific side effects and relay this information as part inflammation, and decreasing erythema,
of the informed consent process. [Orthopedics. 2017; 40(2):e211-e215.] swelling, and acute pain.6 Corticosteroids
commonly used today include triamcino-
lone acetonide (TA), methylprednisolone
acetate, betamethasone acetate and disodi-

C
orticosteroid injections are a non-
surgical treatment modality fre-
quently used in orthopedic clinics
when other conservative treatments are
ineffective. Corticosteroids are often used
to treat knee and shoulder osteoarthritis,
rotator cuff tendinopathy, adhesive capsu-
litis, and acute inflammation. The use of
corticosteroid injections in orthopedics
began in the 1950s to treat the rheumatoid
joint. Throughout the 1950s, clinicians
used intra-articular corticosteroid injec-
tions to combat inflammation locally and
to prevent systemic side effects.1 How-
ever, the initial orthopedic use of cortico-
steroid injections was not without contro-
versy, as several case studies in the early
1960s suspected that corticosteroid injec-
tions caused tendon rupture.2,3
As a result of Title IX legislation
passed in 1972, female participation in
athletics has increased at all age levels.
Correspondingly, female sports-related
injuries requiring orthopedic intervention
have also escalated.4 As medical technol-
ogy continued to develop, corticosteroid
injections became a common treatment
for joint inflammation in a broad spectrum
of orthopedic injuries for both male and
female patients. Today, orthopedists com-
monly inject intra-articular or epidural
corticosteroids to reduce joint and spine
inflammation and acute pain and to in-
crease joint mobility.
um phosphate, and dexamethasone. They
are often injected with a local anesthetic
such as lidocaine or bupivacaine.7
The authors are from the Department of Or-
thopaedic Surgery (EMB, CHH, EGM), Brigham
and Women’s Hospital, and the Boston University
School of Medicine (KAK), Boston, Massachu-
setts; and the University of Minnesota Medical
School (CHH), Minneapolis, Minnesota.
The authors have no relevant financial rela-
tionships to disclose.
Correspondence should be addressed to:
Elizabeth G. Matzkin, MD, Department of Ortho-
paedic Surgery, Brigham and Women’s Hospital,
75 Francis St, Boston, MA 02115 (ematzkin@
partners.org).
Received: November 6, 2015; Accepted:
March 28, 2016.
doi: 10.3928/01477447-20161116-07

MARCH/APRIL 2017 | Volume 40 • Number 2 e211

n Review Article
Corticosteroid injections are an effi-
cient treatment for inflammation; how-
ever, there is still potential for adverse
side effects. Although the incidence of
side effects is low, orthopedic surgeons
should still be aware of the possibil-
ity and convey that information to the
patient during informed consent. Fur-
thermore, the female orthopedic patient
may face unique sex-related adverse side
effects. This article discusses potential
non–sex-specific and sex-specific side
effects to increase orthopedic surgeons’
awareness of them.
Methods
All available literature was searched.
Literature searches were conducted in
academic databases such as PubMed
and Google Scholar. The search period
spanned from 1961 to 2014. Combina-
tions of search terms included steroid,
corticosteroid, triamcinolone, TA, injec-
tion, subacromial, glenohumeral, intra-
articular, adverse events, adverse side
effects, female side effects, and adverse
reactions. A manual search of the refer-
ence lists of the initially reviewed articles
was subsequently performed.
Non–Sex-Related Side Effects
Although corticosteroid injections are
simple to perform and the risk-benefit ra-
tio is highly favorable, some adverse side
effects do occur. High-incidence side ef-
fects include infection, tendon rupture,
postinjection flare, skin or fat atrophy, hy-
popigmentation, and transient increase in
blood glucose.
Infection
Infection can be a severe adverse side
effect for procedures that involve a break
in the skin. It is estimated that infection
will occur in 4.6 of every 100,000 intra-
articular corticosteroid injections, which is
a low incidence.8 Outbreaks may occur be-
cause of contaminated multiple-dose vials
of lidocaine or the corticosteroid. An out-
break of Staphylococcus aureus occurred
e212
in 2001 when a contaminated vial of lido-
caine was used for intra-articular cortico-
steroid injections and caused 5 patients to
be hospitalized because of joint or soft tis-
sue infection.9 Although the incidence of
a contaminated multiple-dose vial is low,
the serious consequences of contamina-
tion highlight the need for proper storage
conditions and the importance of the ad-
ministration of the injection under sterile
techniques.
Holland et al10 reported on infections
occurring after intra-articular cortico-
steroid injection from 2005 to 2009 and
found 73 incidents of infection due to
treatment errors during or after the proce-
dure. The most common treatment error
was a lack of aseptic technique, leading
to 18 infections. In 24 cases, the infection
was not identified early and patients sub-
sequently developed complicated infec-
tions or septic arthritis.
Tendon Rupture
The most widely known potential side
effect of intra-articular corticosteroid in-
jections is tendon rupture. A 1979 study
identified 13 patients who had ruptured
tendons after an intra-articular injection
of triamcinolone hexacetonide mixed
with procaine or lidocaine.11 Currently,
it is known that excessive corticosteroid
injections into the same joint or a higher
dose of corticosteroid can cause weaken-
ing of tendons and cartilage, leading to
potential rupture.12 Orthopedic surgeons
can avoid tendon rupture by limiting in-
jections into a joint within a time period
and using less concentrated corticosteroid
doses.
Postinjection Flare
Postinjection flare, or pain around the
site of the injection, is common, with stud-
ies reporting frequencies ranging from
3.4% to 81% after soft tissue injection.13
Postinjection flare typically occurs later
in the same day as the injection and is
thought to be caused by chemical synovitis
in response to the injected crystals.14
Skin or Fat Atrophy
Localized skin or fat atrophy is com-
mon following corticosteroid injections
of less soluble agents, such as triamcino-
lone, into subcutaneous fat. Kumar and
Newman15 reported that 0.6% of patients
receiving corticosteroid injections experi-
enced fat atrophy. In addition, Park et al16
reported on a patient who presented with
hypopigmentation and muscle atrophy 1
month after a 20-mg TA injection into the
transverse carpal ligament.
Sex-Related Side Effects
Although pain, infection, and tendon
weakness or rupture are some of the most
common and widely known side effects
affecting both sexes, it is important to dis-
cuss and understand potential sex-specific
complications of corticosteroid injections
in females. Currently, no side effects spe-
cific to males after intra-articular cortico-
steroid injections have been documented
in the orthopedic literature.
Abnormal Menstruation
Several review articles and case reports
identify abnormal menstruation as a side
effect of intra-articular and epidural cor-
ticosteroid injections. Previous literature
indicates that intramuscular TA injec-
tions cause a disturbance in female sex
hormones such as luteinizing hormone
and progesterone.17 In one study, 51% of
women who had received either an intra-
articular, epidural, or soft tissue TA injec-
tion with a mean dose of 24 mg reported a
disturbance in menstruation. Disturbances
ranged from timing of menses, occurring
earlier or later than expected, to increased
loss of blood and longer duration of men-
struation. Triamcinolone acetonide may
interfere with female sex hormones, caus-
ing disturbances in levels that manifest as
irregular menstruation.18
Epidural corticosteroid injections have
also resulted in abnormal vaginal bleed-
ing. A comprehensive study reported that,
of 6926 women, 197 (2.8%) presented
with abnormal vaginal bleeding after an
Copyright © SLACK Incorporated

epidural corticosteroid injection. Of the
197 patients, 137 premenopausal and 60
postmenopausal women experienced ab-
normal vaginal bleeding.19 The authors of
the study recommended that medical pro-
fessionals inform female patients that ab-
normal vaginal bleeding is a potential side
effect of the procedure.19
Çok et al6 described abnormal compli-
cations after a 48-year-old premenopausal
woman was treated with an 80-mg meth-
ylprednisolone epidural injection for L4-
L5 lumbar stenosis. The patient reported
uterine bleeding lasting for 2 days on the
second day postinjection. Similarly, a
42-year-old premenopausal woman who
was treated with an 80-mg methylprednis-
olone injection for L5-S1 stenosis returned
to the clinic presenting with abnormal
uterine bleeding 5 days postinjection that
lasted for 3 days. The authors surmised
that an epidural corticosteroid injection
triggers neuroaxial corticosteroids, which
normally initiate a negative feedback loop
on the hypothalamic-pituitary-ovarian
axis, causing progesterone levels to drop,
resulting in uterine bleeding.6
Another case study found a similar side
effect of abnormal uterine bleeding in a
71-year-old postmenopausal woman who
was evaluated for knee pain. She was giv-
en 1 mL of intra-articular triamcinolone
and returned to the clinic 2 weeks later
reporting vaginal spotting that resolved
spontaneously after 5 days. Other causes
of postmenopausal bleeding were ruled
out with transvaginal ultrasound and en-
dometrial biopsy. Estrogen, progesterone,
luteinizing hormone, and follicle stimulat-
ing hormone levels were not measured, so
it is difficult to surmise a definitive cause
of the patient’s postmenopausal bleeding;
however, the hypothalamic-pituitary-ovar-
ian axis is also suspected.20
Proposed Causes of Abnormal Men-
struation. Several case reports have in-
dicated that abnormal menstruation and
vaginal bleeding may occur after cortico-
steroid injection but it is difficult to under-
stand the exact mechanism, as hormone
MARCH/APRIL 2017 | Volume 40 • Number 2
levels are rarely measured in the patients.
Weitoft et al21 measured levels of metal-
loproteinases, testosterone, oestradiol, fol-
licle stimulating hormone, and luteinizing
hormone before and 24 hours, 48 hours, 1
week, and 2 weeks after an intra-articular
injection of 20 mg of triamcinolone hex-
acetonide in 18 women treated for knee
synovitis. A significant decrease in metal-
loproteinases, testosterone, and oestradiol
was shown, indicating that intra-articular
corticosteroid treatment causes a tempo-
rary, but significant, suppression of sex
hormones.21 At the cellular level, patients
who were injected with glucosteroids for
persistent knee arthritis showed a signifi-
cant decrease of steroid receptor cells in
synovial tissue.22
A 1978 study measured hormone levels
after an injection of TA was given during
day 1 or 2 of the menstrual cycle.23 Mea-
surements of follicle stimulating hormone,
luteinizing hormone, estradiol, and pro-
gestins were performed daily. Levels of
estradiol and progestins decreased postin-
jection but follicle stimulating hormone
and luteinizing hormone levels remained
constant. The authors concluded that in-
jected TA could potentially suppress the
hypothalamic-pituitary-ovarian axis and
may also have a direct affect on the ovary.
The literature has long suggested that
intra-articular and epidural corticosteroid
injections could diffuse into the plasma
and suppress the hypothalamic-pituitary-
adrenal axis, resulting in a mild and tran-
sient reduction in serum cortisol. A pau-
city of literature exists on the mechanism
of corticosteroid diffusion into the plasma.
However, some literature indicates that
corticosteroids may diffuse from intrasy-
novial spaces to extrasynovial interstitial
spaces and subsequently the capillary bed
or, alternatively, through lymphatic drain-
age.24,25 The amount of corticosteroid that
becomes intravascular is unknown. In
2010, Gitkind et al26 described a 47-year-
old premenopausal woman who was treat-
ed for a broad-based disk herniation with
multiple epidural corticosteroid injections,
n Review Article
each resulting in significant postinjection
menorrhagia. The patient was injected with
2 mL of betamethasone sodium phosphate
and reported excessive uterine bleeding 5
days later that lasted for 12 days. It was
hypothesized that exogenous corticoste-
roids caused a negative feedback loop on
the hypothalamic-pituitary-ovarian axis,
in addition to the hypothalamic-pituitary-
adrenal axis, leading to anovulation from
the lack of a progesterone spike and result-
ing in menorrhagia.26
Lactation Disturbance
Animal studies have shown that in-
tra-articular injections of high-dose ex-
ogenous corticosteroids diminish milk
production; however, several cases of lac-
tation disturbance in female patients fol-
lowing a corticosteroid injection have been
reported as well. McGuire27 reported on a
young mother with transient cessation of
lactation caused by a depot triamcinolone
injection into vertebral joints for severe
thoracic and cervical spine pain. How-
ever, milk production did not noticeably
decrease when a lower dose of betametha-
sone was injected into her shoulder for
bursitis, suggesting that the adverse effects
of corticosteroid can be dose dependent.
A patient who was 6 weeks postpartum
was given an intralesional 24-mg dose
of methylprednisolone for tenosynovitis
of the wrist. Lactation ceased 30 hours
postinjection but returned slowly 36 hours
after the halt of production. The injection
occurred in a highly mobile joint and it
was hypothesized that the patient could
have experienced a rapid release of corti-
costeroid into the plasma, causing a drop
in lactation levels.28
Proposed Causes of Lactation Dis-
turbance. Physiological levels of cortico-
steroids play an important role in mam-
mary development and milk production.
In mice, during lactation, glucocorticoids
act synergistically with prolactin to stimu-
late expression of milk protein genes.29
In women, lactation is activated with the
withdrawal of progesterone, in the pres-
e213
n Review Article
ence of high levels of prolactin and corti-
sol.30 In the milk ejection reflex, suckling
stimulates an increase in prolactin and
oxytocin, resulting in milk production and
milk release, respectively.30 Dexametha-
sone injections have been shown to de-
crease the oxytocin and prolactin response
to suckling in both lactating rats and
cows.31,32 The experience of the patient
reported on by McGuire27 suggested a de-
crease in both the milk ejection reflex and
the prolactin response; however, it remains
unclear whether the inhibition of milk re-
lease is secondary to decreased milk pro-
duction.
Facial Flushing
One of the most common side effects
for both men and women after a cortico-
steroid injection is facial flushing, occur-
ring in 15% of patients.33 Facial flushing
is increasingly common in female patients.
Onset typically occurs hours after injection
and it can last 3 to 4 days.14 A comprehen-
sive study of 150 patients receiving epidur-
al steroid injections of 16 mg of dexameth-
asone reported that 42 (28%) experienced
facial flushing several hours postinjection.
Female patients accounted for 67% of the
facial flushing cases and had a higher in-
cidence of flushing than their male coun-
terparts. All patients reported their facial
flushing resolved within 48 hours.13,34
Hirsutism
According to a report from a drug
safety and monitoring board in the Nether-
lands, transient hirsutism or coarse male-
pattern hair growth has occurred after
extra-articular corticosteroid injection for
carpal tunnel syndrome.13 The patient also
reported nail changes and vaginal hemor-
rhage. The potential cause was unknown.13
No other cases of hirsutism resulting from
corticosteroid injections have been docu-
mented in the literature.
Conclusion
Corticosteroid injections have been a
simple and effective treatment for joint or
e214
spine inflammation in orthopedic patients
since the 1950s. Although injecting intra-
articular corticosteroids is a minimally
invasive nonoperative treatment modal-
ity, there are still possible side effects that
physicians must be familiar with and in-
form their patients about. Orthopedists
need to be aware of sex-related side effects
in females, such as an increased incidence
of facial flushing, irregular menstrua-
tion, lactation disturbance, and hirsutism.
Although corticosteroid injections may
have adverse effects, the actual incidence
of such effects is low and these injections
remain a viable and popular treatment for
joint and spine inflammation.
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