headache - therapeutics - testosterone - clomiphene - hypothalamus
cefaleia - terapêutica - testosterona - clomifeno - hipotálamo
Patients who were treated for difficult-to-control episodic and chronic cluster headaches
and results are described. Hypothalamic modulation by means of hormone treatment seems
to be the new solution for preventive treatment.
Cluster headache is certainly the most painful and incapacitating of primary headaches,
particularly for patients who suffer from long bouts or for those who present with
the chronic form. Cluster headaches are characterized by a periorbital unilateral
pain associated with ipsilateral autonomic signs (ptosis, miosis, conjunctival hyperemia,
tearing, rhinorrhea, nasal congestion). Its episodic form is characterized by weeks
or months (cluster periods) of pain, separated by pain-free intervals of months or
years[1]. Chronic cluster headaches affect nearly 10% of patients and episodes persist for
at least one year with no remission or with remissions that last for at least one
month. These patients usually need one or two preventive drugs such as corticosteroids,
verapamil, and lithium carbonate, among others. The need for high doses is common,
often making tolerability difficult. In addition, about 1% of patients become refractory
to treatment[1].
The hallmark of the cluster headache is its circadian and seasonal rhythmicity. Several
studies have shown a hypothalamic involvement, initially suggested because of hormonal
variation detected in patients and treatment results with lithium. The significant
drop in plasma testosterone levels in cluster headache patients was the first evidence
of hypothalamic involvement[2]. Romiti et al.[3] showed a reduction in plasma testosterone only during bouts in episodic cluster
headaches.
Hypothalamic activation during the attacks was proven by means of positron emission
tomography and this was a milestone in the therapeutic approach[4]. In addition to positron emission tomography findings, studies using magnetic resonance
spectroscopy demonstrated the presence of asymmetry in this area. It seems that the
posterior inferior hypothalamus is larger in patients with cluster headaches, during
and outside cluster periods. The areas found in studies with different examinations
were identical[5].
Therefore, findings in relation to cluster headaches drive forward new clinical and
surgical treatment with stereotactic stimulation of the posterior inferior hypothalamus,
particularly for patients with chronic cluster headaches with no response to clinical
treatment. The stimulation that directly or indirectly affects the hypothalamus has
proven efficacy in the prevention of cluster headaches[6],[7].
Clomiphene is a nonsteroidal agent with estrogenic and anti-estrogenic properties,
which may induce ovulation in women who do not ovulate. It competes with endogenous
estrogen at hypothalamic estrogen receptors, preventing the hypothalamus from recognizing
sufficient levels and decreasing the secretion of gonadotropin-releasing hormone (GnRH),
with no negative feedback. Without being interrupted, the hypothalamus continues stimulating
the pituitary gland by increasing GnRH secretion. The pituitary increases the levels
of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and these act on
the gonads, stimulating the ovaries and testicles to produce estrogens and androgens[8],[9],[10].
In women, FSH and LH stimulate ovaries to produce progesterone and estrogens. Estrogens
are responsible for female sexual development and for monthly hormonal alterations.
Estrogens are, in reality, a group of hormones called estradiol, estriol and estrone,
with the most active being estradiol E2. Their roles are practically identical[11]. Estrogens have extended action in the female body and are responsible for the estro
(female side) of the cellular universe, female anatomy and female behavior, and have
only a subtle manifestation in males. With maximized activity during the menacme,
it acts on the ovary (maturing the follicle and ovum), uterus, vagina, cervix, fertilization
and fetus maintenance. Progesterone is a hormone directly linked to reproduction and
is released during the second phase of the cycle in order to prepare the woman’s body
for pregnancy. Pregnant or not, the woman’s behavior changes and differs from the
estrogenic phase, which occurred before. The main androgenic products produced by
the ovaries are dehydroepiandrosterone, testosterone and androstenedione. Testosterone
is considered the most potent of the androgens[12].
In men, the FSH stimulates spermatogenesis by the cells of the seminiferous tubules
by producing estrogens, while LH stimulates the production of testosterone by the
interstitial cells of the testicles. Testicular secretion of testosterone is regulated
primarily by the secretion of LH by the pituitary gland, which stimulates steroidogenesis
in Leydig cells, increasing the substrate for its production and regulating testicular
blood flow. The hypothalamic GnRH is secreted occasionally and controls the secretion
of LH. Testosterone, in turn, provides negative feedback, inhibiting the secretion
of GnRH[12].
The main androgens produced in the adrenal gland are androstenedione and dehydroepiandrosterone.
Despite having low activity, these are converted into testosterone (more active) in
the peripheral tissues. The adrenal gland produces residual quantities of testosterone.
In women, the adrenal gland is responsible for the production of between 50% and 60%
of androgenic requirements, but in men, the biological significance of this secretion
is minimal[11],[12].
The steroid hormones produced by the gonads have a fundamental role in the metabolism
of lipids and proteins. From among the androgens, testosterone has an important effect
on the circulating levels of cholesterol, increasing low-density lipoproteins and
reducing high-density lipoproteins[11].
It seems that the direct replacement of testosterone does not affect cluster headache
attacks, possibly because synthetic testosterone does not reach hypothalamic receptors.
Moreover, clomiphene is the only form of testosterone replacement that does not interfere
in men’s spermatogenesis or in women’s fertility[9]. Clomiphene, which showed a partial effect in a case of short-lasting unilateral
neuralgiform headache with conjunctival injection and tearing (SUNCT), and absolute
effect in another two cases: one case of SUNCT and a described case of refractory
chronic cluster headaches. The medication effect seemed to be similar to that which
occurs in direct surgical stimulation. Therefore, clomiphene is a putative candidate
for cluster headache prevention[8],[9],[10].
Suffering from intractable cluster headaches is an atrocious condition that affects
all aspects of the patients’ lives and may even lead to suicide as a desperate solution
to stop the pain. We must remember that patients with difficult-to-manage cluster
headaches, including patients whose episodic cluster period is longer, frequently
need more efficient treatment in order to control attacks[8].
The absolute control of attacks as early as possible might shorten the cluster periods,
or increase the remission period, or even prevent episodic pain from becoming chronic.
As this process is still unknown, we should aim at decreasing the suffering of patients
with difficult-to-manage cluster headaches, reduce the medication dosage or even change
the pattern of attacks[8],[9].
METHODS
We report on the experience of a tertiary headache center with clomiphene treatment
in 15 patients suffering from episodic and chronic headaches fulfilling the ICHD (International
Classification of Headache Disorder) III edition – beta criteria. These patients’
chronic and episodic headaches were refractory to current prophylactic medication.
The episodic headache patients presented with longer cluster periods, exceeding the
average time of previous cluster cycles.
These patients accepted hormone therapy despite having been made aware of the limited
number of studies published on the subject.
The following tests were performed: complete blood count, glucose, urea, creatinine,
sodium, potassium, aspartate aminotransferase (AST), alanine aminotransferase (ALT),
gamma glutamyltransferase (GGT), total cholesterol and fractions, triglycerides, dehydroepiandrosterone, total
and free testosterone, sex hormone-binding globulin, free testosterone index, androstenedione,
FSH, LH, progesterone, estradiol E2 and prostate-specific antigen in males. Female
patients had a transvaginal ultrasound in addition to the biochemical tests. Patients
with risk factors for ischemic disease were excluded from the study. Tests were repeated
every month until the absolute control of attacks.
Previous medications were maintained so that withdrawal did not interfere in the interpretation
of results. Clomiphene was prescribed in morning doses of 300 mg for two days, 100
mg for nine days, followed by 50 mg.
Demographic and clinical data were ascertained: sex, age, pattern of pain, disease
history, smoking habits, total testosterone before the use of clomiphene, total testosterone
after the use of clomiphene, number of days using clomiphene, number of previous bouts,
number of consecutive months of pain in the current cluster in episodic and chronic
cases, number of months since chronicity, number of days until the complete absence
of pain but still in the cluster period and the number of days up until the complete
remission characterizing the end of the cluster.
The latter two events were characterized as endpoints in clomiphene treatment. Survival
analysis techniques were used considering the elapsed time between:
-
the start of the treatment with clomiphene and complete absence of pain, but still
in the cluster period (defined by patients as any sensation besides pain that made
them consider that they were still in the attack period);
-
the start of the treatment with clomiphene and complete remission characterizing the
end of the cluster period;
-
total absence of pain and complete remission.
Incidence rates were calculated, and the distribution of time elapsed until each successful
event, was described by means of respective quartiles. The accumulated probabilities
until each successful event was estimated based on the Kaplan-Meier method[13].
The research project was approved by the Ethics in Research Committee (nº 2.149.356).
All individuals were informed about the purpose of the research and signed the informed
consent document.
RESULTS
Ten men and five women were studied. Seven patients were chronic and eight episodic
headache. Ages varied between 25 and 64 years and the average age was 40.4 years.
Disease onset ranged from 2–27 years, with an average of 10.6 years. The number of
bouts varied from three to 16 and the average was 6.6 bouts four patients presented
with one bout, as they were considered chronic right from the beginning.
The average time of pain before clomiphene varied from one to 350 months and the average
was 41.7 months.
Total testosterone was below the gender-related lower limit in three patients and
at the lower limit in all others. After the use of clomiphene, there was an increase
in testosterone to normal limits. Only three patients were above the normal upper
limit.
Clomiphene was used for a minimum of 45 days and a maximum of 180 days. Average treatment
time was 104 days. There were no significant side effects. One patient presented with
mild acne and another presented with an ovarian cyst. Both conditions regressed when
the medication was discontinued. There was no weight gain or significant biochemical
changes of the blood.
The start of the treatment with clomiphene and the total absence of pain, but still
in the cluster period ([Table 1] and [Figure 1]).
Table 1
Number of days up until the total absence of pain.
|
Variable
|
Time at risk
|
Incidence rate
|
No. of subjects
|
Survival time
|
|
|
25%
|
50%
|
75%
|
|
Chronic
|
285
|
0.0245614
|
7
|
25
|
30
|
60
|
|
Episodic
|
98
|
0.0816327
|
8
|
8
|
10
|
15
|
|
Total
|
383
|
0.0391645
|
15
|
10
|
15
|
30
|
Figure 1 Graph showing the number of days up until the total absence of pain.
The average time since the start of the treatment with clomiphene until the disappearance
of pain was 15 days.
The reading with regards to the 1st (p25) and 3rd quartile (p75) is similar; 25% of
patients reported the disappearance of pain within 10 days after the start of treatment
and 75% within 30 days.
The start of treatment with clomiphene and the complete remission, characterizes the
end of the cluster ([Table 2] and [Figure 2]).
Table 2
Number of days until complete remission .
|
Variable
|
Time at risk
|
Incidence rate
|
No. of subjects
|
Survival time
|
|
|
25%
|
50%
|
75%
|
|
Chronic
|
486
|
0. 0144033
|
7
|
60
|
60
|
90
|
|
Episodic
|
380
|
0.0210526
|
8
|
22
|
30
|
43
|
|
Total
|
866
|
0.017321
|
15
|
30
|
60
|
90
|
Figure 2 Graph showing the number of days until complete remission
The average time from the start of the treatment with clomiphene until cluster remission
was 60 days.
In the evaluation of complete remission, 25% of patients reported complete remission
within 30 days after the start of the treatment (60 days in chronic patients and 22
in episodic patients) and 75% within 90 days.
Total absence of pain and complete remission are in [Table 3] and [Figure 3].
Table 3
Number of days between the end of pain and complete remission.
|
Variable
|
Time at risk
|
Incidence rate
|
No. of subjects
|
Survival time
|
|
|
25%
|
50%
|
75%
|
|
Chronic
|
201
|
0.0348259
|
7
|
20
|
30
|
35
|
|
Episodic
|
282
|
0.0248227
|
7
|
15
|
20
|
82
|
|
Total
|
483
|
0.0289855
|
14
|
18
|
26
|
35
|
Figure 3 Graph showing the number of days between the end of pain and complete remission.
After the disappearance of pain, the average time until cluster remission was 26 days.
In the evaluation between the length of pain-free time and complete remission, 25%
of patients had an interval of 18 days and 75% of patients had an interval of 35 days.
The end of the actual cluster cycle occurred in all patients, including the chronic
individuals.
Half the patients reported the disappearance of pain and the remission of clusters
within 15 and 60 days, respectively. Once the pain had disappeared, half the patients
reported the remission of clusters in up to 26 days.
DISCUSSION
The use of clomiphene in the treatment of cluster headache is recent. Two papers have
reported its use. Rozen reported on a patient who had experienced chronic cluster
headaches for 17 years before the treatment, and who had a remission of 3.5 years
before the next cluster cycle. He then restarted taking clomiphene and once again
had positive results[14]. Another two reports of SUNCT cases showed positive results[8],[9],[10].
Clomiphene is a nonsteroidal agent with estrogenic and anti-estrogenic properties.
This is because it binds to the hypothalamic estrogen receptors, preventing the hypothalamus
from recognizing sufficient levels, and decreasing the secretion of GnRH, blocking
a possible negative feedback[8]. Without being interrupted, the hypothalamus continues stimulating the pituitary
gland by increasing GnRH secretion. The pituitary increases the levels of FSH and
LH, which act on the gonads, stimulating the ovaries and the testicles to produce
estrogens and androgens[8]. The physiological and progressive increase of testosterone offers a putative explanation
for the main effect in cluster headache treatment. Another hypothesis would be an
action on orexinergic receptors, occurring at the same time as the blocking of estrogenic
hypothalamic receptors, leading to an increase of orexin-A, which could suppress trigeminal
autonomic activation. Orexin has been suggested as an important neuropeptide in the
pathogenesis of cluster headaches[8].
Clomiphene has proven to be a very safe drug but possible side effects should be closely
observed, particularly if long term use is necessary. Referral to gynecologists, urologists
and endocrinologists may help in the safety and risk/benefit evaluation[15].
There is no consensus regarding the right dosage. It varies between 25 and 400 mg/day;
however, 50 to 100 mg was used in most studies, giving the best results in testosterone
levels. It should be taken once a day in order to cross the blood-brain barrier and
quickly reach hypothalamic receptors[16].
As opposed to synthetic testosterone, clomiphene can be used by men who still wish
to have children since it does not affect spermatogenesis. It is used in cases of
male infertility to stimulate the germination epithelium by means of increasing FSH
and LH secretion. It is the testosterone replacement therapy of choice for young men
in order to preserve fertility. In the absence of any protocol, and as it is an innovative
treatment, we established a protocol based on treatments that need a quick hypothalamic
response. Cases related to the use of anabolic steroids that range from impotence
to psychiatric emergencies are examples. There is a suppression of the hypothalamic-pituitary-gonadal
axis and higher initial doses are used for a faster hypothalamic response. We opted
to use 300 mg during the first two days, 100 mg for nine days and maintained a dosage
of 50 mg afterwards[17],[18],[19].
In women, it stimulates ovulation. A barrier contraceptive method is necessary to
avoid an unwanted pregnancy, which often is multiple[12]. We suggest a levonorgestrel-releasing intrauterine system.
We observed that the use of clomiphene turned chronic headaches into episodic, and
episodic patients experienced cluster cycle interruption. These episodic patients
had presented with extended cluster periods that were not responding to effective
treatment during previous cluster cycles and some were becoming chronic. After gradually
discontinuing clomiphene, all preventive medicines were suspended.
In general, there was absolute adherence by patients to the use of clomiphene. Even
when they were aware of the hormonal changes that could occur, all were willing to
comply because there was no other solution to ease the suffering. Surgical procedures
were not performed, because they were not indicated or were denied by patients.
Further studies need to look at testosterone levels during the remission period; a
slow and progressive decrease in testosterone levels during remission could eventually
be a surrogate marker of an approach of the next bout. Maintenance of normal levels
might be a preventive treatment for the next cluster period.
Our study suggests clomiphene could be used for chronic and episodic cluster headache
patients, considerably improving their quality of life. Clomiphene could be tried
before a surgical procedure is indicated. Randomized clinical trials should be performed
to test the role of clomiphene in cluster headaches.
In conclusion, clomiphene treatment was effective and tolerable in refractory episodic
and chronic cluster headaches. It interrupted chronicity in all patients, suggesting
the drug’s positive effect.
We suggest the inclusion of a testosterone evaluation in the initial approach of all
cluster headache patients. If there are no contraindications, clomiphene should be
indicated for episodic cases of extended cluster periods and for general chronic headaches,
and not limited to refractory patients.
Additionally, patients should only be considered refractory after clomiphene treatment.
