a b s t r a c t
The purpose of this prospective pilot study was to determine the therapeutic effect of continuous
testosterone, delivered as a subcutaneous implant, on the severity of migraine headaches in pre- and
post-menopausal patients. Twenty-seven women with a history of documented migraine headache were
asked to rate their headache severity using a five-point scale at baseline (prior to therapy); and again,
3 months following treatment with testosterone implants. Improvement in headache severity was noted
by 92% of patients and the mean level of improvement was statistically significant (3.3 on a 5 point scale).
In addition, there was no difference in the level of improvement between pre- and post-menopausal
cohorts. Seventy-four percent of patients reported a headache severity score of ‘0’ (none) on testosterone
implant therapy for the 3-month treatment period. Continuous testosterone was effective therapy in
reducing the severity of migraine headaches in both pre- and post-menopausal women.
© 2012 Published by Elsevier Ireland Ltd.
1. Introduction
Migraine headaches are associated with hormonal changes in
females. This pilot study was designed to determine the effect of
continuous testosterone, delivered by subcutaneous implant, on
migraine headache severity in pre- and post-menopausal women.
Testosterone replacement is usually equated to males with
gonadal disorders resulting in low testosterone. However,
testosterone has wide ranging biological effects in pre- and postmenopausal
women, in part because of widespread androgen
receptors found in brain, spinal cord, nerves, breast, bone, muscles,
cardio-vascular system, lungs, GI tract, bladder, vaginal tissue,
uterus, skin, hair follicles and adipose tissue. Testosterone can also
exert its effect indirectly via aromatization to estrogen in these
organs, ovary and adrenal gland.
Androgen production in women declines gradually through-
out the reproductive years [1]. A woman of 40 has approximately
half the testosterone of a 21 year old [2]. Recent studies have
focused on testosterone therapy in both pre- and post-menopausal
women with symptoms of relative androgen deficiency including;
diminished sense of well-being, dysphoric mood (sadness, depres-
sion, anxiety, irritability), fatigue, decreased libido, insomnia, hot
flashes, bone loss, decreased muscle strength, changes in cognition
and memory, pain, vaginal dryness and incontinence [3,4]. Con-
tinuous testosterone delivered by subcutaneous implant has been
safely used in women since 1938 and until recently, was the only
licensed form of testosterone for women in England.
Migraine headaches occur in 18% of the female population
with their peak prevalence occurring during 35–45 years of age
[5]. Forty to seventy percent of women have menstrual migraine,
which are migraines that occur during perimenstrual time-period
(2 days before to 3 days after the onset of menstruation). It has
been demonstrated that declining serum levels of estrogen trig-
ger attacks of menstrual migraine. Therefore, there is ample data
to suggest that fluctuations in ovarian hormones are responsible for
the provocation of migraine headache in susceptible women [6].
There is sparse data suggesting that androgens are effective
in the prevention of migraine and other headache disorders.
Lichten and colleagues reported that administration of danazol
to premenopausal women was associated with a decrease in the
frequency of migraine headache [7]. Another study reported that
migraine headaches improved with constant, adequate dosages of
estrogen-androgen combinations as well as testosterone alone in
post-menopausal women; also, that hormone delivery by pellet
implantation gave superior results compared to oral or other parenteral
routes of administration [8]. A recent study reports that
testosterone replacement in patients with cluster headaches and
low testosterone levels resulted in complete relief of headaches
[9].
We aimed to study the effects of subcutaneous testosterone
implants on the severity of migraine headaches in pre- and postmenopausal
patients self-referred or referred by their physician for
symptoms of androgen deficiency including: hot flashes, sleep disturbances,
depressive mood, anxiety, irritability, physical fatigue,
impaired memory, chronic pain, urinary problems and vaginal dry
ness.
2. Materials and methods
2.1. Study group
In an ongoing 10-year IRB approved trial on breast cancer occurrence
and subcutaneous testosterone implant therapy,1 it was
observed that patients often reported relief of their headaches
with therapy. Patients also reported that their headache would
recur prior to (re)-insertion of subsequent testosterone implant,
often as the first or foremost symptom associated with declining
testosterone levels. Because of this observation, it was decided to
perform a pilot study that prospectively evaluated the effect of
testosterone implants on headaches in pre- and post-menopausal
women treated for symptoms of androgen deficiency.
Criteria for inclusion in the prospective study included a documented
history of migraine headache with previous workup with
CT, MRI or other testing for headaches, diagnosis of migraine
headache by primary care physician, visit to a neurologist for
headache, and/or prior use of medication prescribed for migraine
headache. In addition, all patients included in the study had experienced
a migraine headache within 4 weeks of their initial visit to
the clinic. All patients signed a consent form.
2.2. Data collection and statistical analysis
Female patients presenting to the clinic (RG) with symptoms of
androgen deficiency and a chief complaint of migraine headache,
were asked to rate their headaches on a 5-point scale developed
for this pilot trial. The 5-point rating scale permitted the patient
to describe the perceived severity of their headache: none 0, mild
1, moderate 2, severe 3, or extremely severe 4. The initial (baseline)
survey was completed at the patient’s first office visit, prior
to testosterone implant therapy. Approximately 3 months later, at
their next appointment for testosterone (re)-implantation, patients
were asked to rate the severity of their migraines while on therapy.
The mean scores were calculated at baseline (prior to therapy)
and 3 months later (on average), following testosterone therapy,
in the entire cohort as well as pre- and post-menopausal groups
individually. A paired Student’s t-test was used to determine if
the perceived severity of migraines changed significantly after
treatment. Student’s t-tests were also used to determine if the
severity was different for pre- vs. post-menopausal patients.
2.3. Therapy
Patients were treated with 130 ± 19.7 mg (range 100–160 mg) of
testosterone, delivered subcutaneously in a sustained release pel-
let implant. Subcutaneous testosterone dosing is weight-based and
effect is dose dependent [4]. Published data confirms efficacy as
well as safety in doses of 75–225 mg in up to 3 decades of therapy
[4,8,10–16]. Under local anesthesia, the 3.1 mm (diameter) pellets
were advanced into the subcutaneous tissue in the upper gluteal
area using a small trocar placed through a 5 mm incision, which
was then closed with a steri-strip. There were no complications
related to the procedure.
3. Results
3.1. Patient demographics
Twenty-seven patients, previously diagnosed with ‘migraine
headache’, were enrolled in the study and received their first testos-
terone pellet insert between June 2009 and March 2010. Sixteen
(59%) were pre-menopausal and 11 (41%) were post-menopausal,
either spontaneous or surgical. The mean age of the combined
cohort was 47.4 ± 9.6 years (range 31–79); 41.8 ± 5.5 years (range
31–52) for pre-menopausal patients, 55.5 ± 8.7 years (range 45–79)
for post-menopausal patients.
3.2. Severity scoring and response to therapy 138
Mean severity scores for intensity of headaches at baseline (pre-
treatment) and at follow-up (on testosterone therapy) are listed
in Table 1. Significant improvement in migraine headache sever-
ity was demonstrated in the entire group as well as in pre- and
post-menopausal cohorts treated with testosterone implant ther-
apy. The perceived severity score after treatment was significantly
less than before treatment (t = 14.3, df = 26, P < 0.0001). There was
no difference in pre-treatment severity (t = 1.0, df = 25, P = 0.32) or
post-treatment severity (t = 1.5, df = 25, P = 0.14) by menopausal sta-
tus. In addition, there was no difference in the absolute change
in pre- and post-treatment severity by menopausal status (t = 0.8,
df = 25, P = 0.39).
Self reported medication use prior to testosterone therapy,
frequency of headaches, pre-therapy severity scoring, and post-
therapy severity scoring for each patient is listed in Table 2. The
majority of patients reported no headaches and no use of medications
(for headaches) during testosterone implant therapy (Table 2).
Twenty-five of the 27 patients returned for a second pellet
implant, on average, 3 months later. Of the 2 patients that did not
return, one reported no improvement, and one reported improvement
in headache, but did not return for therapy (both patients
were contacted by phone). All 25 patients that returned for therapy
completed the follow-up questionnaire.
Of the 25 women who returned for a second pellet (re)-insertion,
20 (74%) reported a score of ‘0’ (no migraine headache) with
testosterone therapy alone for ten or more weeks following implantation.
Two (7%) patients improved for 2–3 weeks only. Of the three
remaining patients; one had less migraine occurrence (frequency),
but same severity (Score 3 to 3), one had complete relief of migraine
(0) but with continued daily, prescription ‘preventative’ medication
(i.e. Triptan) and one went from extremely severe (4) requiring
hospitalization to severe (3) and no longer required hospitalization
(Table 2). No adverse reactions to testosterone pellet therapy were
reported.
3.3. Additional/prior hormone therapy
Two pre-menopausal patients on oral contraception for
migraine headache control, discontinued them after their first
testosterone pellet implant. A third patient remained on oral contraception
for birth control. A fourth pre-menopausal patient was
able to discontinue her 0.0375 mg transdermal estradiol patch that
had been prescribed for hot flashes, insomnia, fatigue, vaginal dryness
and urinary symptoms. A fifth patient discontinued her topical
progesterone cream, which had also been prescribed for hot flashes.
No hormone therapy was prescribed in addition to the testosterone
implant.
4. Discussion
Our prospective pilot study has shown that continuous testos-
terone, delivered by subcutaneous implant, was effective in
decreasing the severity of migraine headaches in pre- and
post-menopausal women. All patients in this study presented to
the clinic with symptoms of relative androgen deficiency (RAD) and
a poorer quality of life as measured by the validated, Menopause
Rating Scale, which further strengthens the relationship of hor-
mone imbalance to migraine headache. We have previously shown
that continuous testosterone, delivered by subcutaneous implant,
was equally effective in both pre- and post-menopausal patients
for relief of symptoms [4].
Interestingly, the prevalence of migraine headaches in females
(age 35–40) coincides with testosterone decline [1,2,5] and the
onset of symptoms of RAD. In this study, we have shown that sub-
cutaneous testosterone therapy had a beneficial effect on migraine
headaches, in addition to the documented beneficial effects on
symptoms of RAD. Previous studies have shown that estrogens play
an important role in migraine headaches [6]. Continuous deliv-
ery of testosterone by the implant and binding to the androgen
receptor may counteract, or balance, the affects of excess or fluc-
tuating estradiol. In clinical practice, we also see an improvement
in breast pain, anxiety, PMS, dysfunctional uterine bleeding and
other symptoms of estrogen excess with testosterone therapy. In
addition, subsequent to the collection of this data, we have found
that many pre-menopausal patients have superior headache relief
(intensity and duration) with the addition of anastrozole (an aro-
matase inhibitor that reduces estrogen) delivered in combination
with testosterone, further emphasizing the role of estrogen in
migraine headaches.
The mechanism through which testosterone modulates
migraine headaches is unknown, but might involve suppression
of cortical spreading depression (CSD), which is thought to occur
during the aura phase of migraine headache. Eikermann-Haeter
and colleagues demonstrated that the frequency of CSD was
reduced after administration of testosterone in orchiectomized
male mice that possessed the FHM1 R192Q mutation for familial
hemiplegic migraine [17]. Testosterone is a neuroactive steroid and
has been shown to increase serotontin, which may also play a role
in prevention of headaches [8,18]. The effect of testosterone as a
vasodilator [19], although controversial in the etiology of migraine
headaches, may play a role in relief of headaches by stabilizing
cerebral blood flow. Furthermore, testosterone has been shown
to be both anti-inflammatory [20] and neuro-protective [21].
Thus, there are several possible mechanisms by which continuous
testosterone may protect against migraine headaches.
Although there is significant inter-individual variation
and intra-individual circadian variation, we have previously
documented mean therapeutic total testosterone levels of
299.36 ± 107.34 ng/dl, 4 weeks following pellet implantation. In
addition, symptoms recur with serum testosterone levels two to
three times the upper limits of normal for endogenous production
(data not shown). We have found that these levels of testosterone
in serum are required to deliver adequate (i.e. biologically relevant)
amounts of testosterone to the androgen receptor for a therapeutic
effect. Unlike estradiol, there are no reports of tachyphylaxis with
subcutaneous testosterone therapy. Furthermore, in our practice
(RG) of over 12,000 testosterone insertions in over 4000 womenyears
of therapy, there has been no evidence of tachyphylaxis or
decrease in response to subcutaneous testosterone therapy.
A major weakness of this ‘proof of idea’ trial was the use of a
non-validated scale to measure severity of migraine symptoms,
along with the inability of this scale to clearly differentiate between
intensity and frequency of headaches. In addition, there was no control
group, so we were unable to quantify a ‘placebo effect’, which
can be as high as 50% for headache prevention. However, the fact
that the majority of patients reported ‘no headache’ and ‘no medication
use’ until, on average, 3 months after implantation, speaks
against placebo.
5. Conclusion
This pilot study has shown that sustained release of testosterone,
provided by the subcutaneous implant, was effective
therapy for migraine headaches in pre- and post-menopausal
patients. Further studies using a validated scale are needed to confirm
the beneficial effect of continuous testosterone therapy in
controlling difficult migraine headaches in women.
Contributors
RG and CD contributed equally to the research, design of the
study, analyzing the data, writing and editing the ms. RG recruited
participants. NT participated in writing. VM contributed to writing
and editing the ms. All authors approved the final manuscript.
Competing interest
None declared.
Funding
None.
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