Clinical Notes
Clomiphene Citrate for Treatment Refractory Chronic
Cluster Headache
Todd Rozen, MD
A treatment refractory chronic cluster headache patient is presented who became cluster-free on clomiphene citrate. The
author has previously reported a SUNCT patient responding to clomiphene citrate. Hypothalamic hormonal modulation
therapy with clomiphene citrate may become a new preventive choice for trigeminal autonomic cephalalgias. The possible
mechanism of action of clomiphene citrate for cluster headache prevention will be discussed.
Key words: cluster headache, trigeminal autonomic cephalalgias, clomiphene citrate, testosterone, suprachiasmatic nucleus,
headache
(Headache 2007;••:••-••)
INTRODUCTION
Treatment refractory cluster headache is associated
with significant patient disability and even has
led to patient suicide. As such, there is an ongoing
search by headache specialists for new and effective
cluster headache preventive and abortive treatments.
Cluster headache is one of the trigeminal autonomic
cephalalgias (TACs), which along with SUNCT and
paroxysmal hemicrania are a group of headache disorders
considered to be hypothalamic influenced. On
positron emission tomography scanning and functional
magnetic resonance imaging (MRI), each of
these headache syndromes has shown hypothalamic
activation during headache attacks.1-3 Based on these
neuroimaging findings, there has been a recent focus
on hypothalamic modulation for cluster headache
treatment.Agents that directly or indirectly affect the
hypothalamus such as melatonin have shown efficacy
in cluster headache prevention, while direct hypothalamic
modulation with deep brain stimulation has
been effective in some of the most treatment refractory
cluster headache cases.4,5 Hormonal manipulation
of the hypothalamus may also be a possible
treatment strategy for cluster headache. Clomiphene
citrate is an ovulatory stimulant, which actively alters
hypothalamic estrogen receptors. The author has
already shown the partial effect of clomiphene citrate
in SUNCT syndrome.6Atreatment refractory chronic
cluster headache patient is presented who had a dramatic
and sustained response to clomiphene citrate
treatment. The possible mechanism of action of clomiphene
citrate for cluster headache prevention will
be discussed.
CASE REPORT
The patient is a 40-year-old gentleman who began
to develop cluster headaches at the age of 21 years.
The headaches started daily from onset and with no
remission periods. The patient would experience
between 4 and 8 cluster headaches per day.
From the Michigan Head Pain and Neurological Institute, Ann
Arbor, MI, USA.
Address all correspondence to Dr. Todd Rozen, Neurology,
Michigan Head Pain & Neurological Institute, 3120 Professional
Drive, Ann Arbor, MI 48104, USA.
Accepted for publication September 3, 2007. Conflict of Interest: None
ISSN 0017-8748
doi: 10.1111/j.1526-4610.2007.00995.x
Published by Blackwell Publishing
Headache
© 2007 the Author
Journal compilation © •••• American Headache Society
1
The headaches were 100% right-sided in a retroorbital/
periorbital distribution. On the side of the
headache, the patient would develop eyelid ptosis,
conjunctival injection, lacrimation, and nasal rhinorrhea.
He would also become very agitated, pacing the
floors or screaming out in pain. Each cluster attack
would last 60 minutes on average. He would experience
multiple headaches each evening after falling
asleep, being awoken 2 to 3 times per night. He was a
long-standing cigarette smoker since his teens. Neuroimaging
to exclude secondary etiologies included a
brain MRI with pituitary cuts and magnetic resonance
angiography (MRA) of the extracranial and intracranial
circulation. These were normal studies. Multiple
medications were tried for the patient’s headaches as
he had been seen at a dedicated headache center for
12 years.Abortive therapies were sometimes effective
including high flow oxygen (15 L/minute), sumatriptan
injection, and intramuscular dihydroergotamine
(DHE). Past preventive agents (all at top dosing
schedules) included: valproic acid, methysergide,
methylergonovine, verapamil, topiramate, lithium,
gabapentin, baclofen, lamotrigine, mycophenolate
mofetil, levetiracetam, oxcarbazepine, olanzapine,
clonidine, melatonin, nimodipine, tizanidine,
indomethacin, daily frovatriptan and naratriptan,
daily DHE injections, mirtazapine, pregabalin,
memantine, modafanil, ramelteon, as well as daily
opiates.As short courses of corticosteroids would suppress
his headaches, he also, prior to coming to the
headache center, had been placed on a year-long trial
of daily prednisone up to 100 mg per day which caused
a number of adverse events and eventually the cluster
headaches broke through back to a daily occurrence.
The patient also tried a number of anesthesiologic
procedures including: greater occipital nerve blockade,
cervical facet blocks, selective C2 nerve blocks,C3
medial branch nerve blocks, sphenopalatine ganglion
rhizotomy, and trigeminal nerve blocks, all without
benefit. He did not have a greater occipital nerve
stimulator trial or deep brain hypothalamic stimulation.
As most treatment options had been exhausted
the patient ended up on daily DHE injections, with
some improvement but still experiencing 1 to 2 attacks
per day. During this time period, the author was treating
a SUNCT patient with clomiphene citrate and
because this agent appeared to be helping another
hypothalamic influenced TAC, it was decided to try
this hormonal agent on the case patient. Prior to starting
the clomiphene citrate,hormone laboratory testing
was completed and showed normal total testosterone
levels (464 ng/mL; normal range 241-827 ng/mL), low
normal free testosterone levels (9.2 pg/mL;normal for
ages 30-39 years; 8.7-25.1 pg/mL), low normal luteinizing
hormone (LH) levels (1.8 mIU/mL; normal 1.4-
18.1 mIU/mL), normal prolactin, and follicle
stimulating hormone (FSH) levels.Clomiphene citrate
was started at 50 mg/day and the patient’s headaches
decreased from daily to one headache 3-5 days per
week. The dose was increased to 75 mg then 100 mg
and his headaches became 80% improved with rare
headaches 1 to 3 times per week. In addition to an
improvement in pain, he stated his sleeping pattern
was greatly improved, actually feeling rested after a
night sleep for the first time since his headaches began
in his twenties. After being on clomiphene citrate
for 40 days, his hormone levels were retested. Total
testosterone increased from 464 ng/mL to 1221
ng/mL, free testosterone increased from 9.2 pg/mL
to 22.7 pg/mL, and LH increased from 1.8 mIU/mL to
12.5 mIU/mL. Unfortunately, his insurance company
would not cover the cost of the clomiphene citrate,
so he had to stop the medication after 3 months of
treatment. His headaches returned to daily, multiple
headaches per day and he was placed back on
daily injectable DHE, which he remained on for
18 months. His endogenous hormones returned to
pre-clomiphene citrate levels. During his time on daily
DHE,he was given testosterone supplementation with
a testosterone cream but showed no improvement
after 3 months of therapy. Eight months ago, the
patient was placed back on clomiphene citrate 50 mg
per day and after 2 weeks of treatment, he became
pain-free and remains pain-free to this date. Not only
have his headaches completely alleviated with no
breakthrough attacks, but his sleep pattern has also
become “normal again” with the patient feeling completely
rested after a night sleep.



CONCLUSION
In conclusion, clomiphene citrate has now been
shown to be effective in the treatment of both
SUNCT and chronic cluster headache, both hypothalamic
influenced headache syndromes. Hormonal
manipulation may become a standard of therapy for
treatment resistant TAC cases. Clomiphene citrate’s
ability to directly modulate the hypothalamus and
possibly the SCN makes it a very attractive treatment
option when standard TAC therapy does not work.
The suggested starting dose of clomiphene citrate is
50 mg per day. If there is no improvement in headaches
after 1-2 weeks of therapy, raising the dose to
100 mg per day is suggested. Treatment response
appears to occur within 1-2 weeks of starting an effective
dose as demonstrated by our cluster and SUNCT
patients. Higher dosing schedules have not been
readily studied in the gynecologic literature so are not
suggested. The long-term risk of clomiphene citrate
treatment in males is unknown. In short course
therapy, adverse events appear to be minor but there
are reports of gynecomastia, testicular tumors, and
pulmonary embolism in men receiving clomiphene
citrate. Serial prostate-specific antigen levels are recommended
during treatment as well as prostate and
testicular examinations. The role of clomiphene
citrate in female TAC patients is unknown at present.
REFERENCES
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Goadsby PJ. Hypothalamic activation in cluster
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2. Matharu M, Cohen AS, McGonigle DJ, et al. Posterior
hypothalamic and brainstem acivation in hemicrania
continua. Headache. 2004;44:747-761.
3. May A, Bahra A, Buchel C, Turner R, Goadsby PJ.
Functional magnetic resonance imaging in spontaneous
attacks of SUNCT. Short-lasting neuralgiform
4
headache with conjunctival injection and tearing.
Ann Neurol. 1999;46:791-794.
4. Peres MFP, Rozen TD. Melatonin in the preventive
treatment of chronic cluster headache. Cephalalgia.
2001;21:993-995.
5. Leone M, Franzini A, Broggi G, Bussone G. Hypothalamic
stimulation for intractable cluster headache:
Long-term experience. Neurology. 2006;
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6. Rozen TD, Saper JR, Sheftell FD, Dodick DW. Clomiphene
citrate as a new treatment for SUNCT
(hormonal manipulation for hypothalamic influenced
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7. Leone M,Bussone G.Areview of hormonal findings
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involvement. Cephalalgia. 1993;13:309-317.
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9. Stillman MJ. Testosterone replacement therapy for
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13. Neulen J, Zahradnik HP, Flecken U, Breckwoldt M.
The effect of clomiphene on the synthesis of prostaglandins
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prostaglandin-like substances in cluster headache
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PJ. Regulation of calcitonin gene-related peptide
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Congrats Alley.  Very informative and very interesting.

Clomiphene Citrate
aka Clomid

An overseas name is 'Serpafar'

It appears to be quite easy to acquire.
Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or
Multimedia File Viewing and Clickable Links are available for Registered Members only!!  You need to or
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UnderTheRadar wrote on Jan 28^th, 2009 at 6:53pm:



UTR, you ask good questions, but unfortunately I am unable to answer them.  You might want to ask your doc, or do the research yourself.

alley

shelticon2 wrote on Dec 2^nd, 2008 at 3:55pm:

Anyone else using diet to increase Testosterone levels??  I am over 1/2 way through my cycle and am getting pounded, so I am going to covert my regular low carb, no sugar diet into a more carb friendly one including a zinc supplement (creatine is another one I'm going to check into), for now.  I have yet to read more on testosterone friendly diets and if anyone has any good links, please share them!

thanks,
~mel

MITYRARE wrote on Jan 29^th, 2009 at 4:33pm:

Anyone else using diet to increase Testosterone levels??  I am over 1/2 way through my cycle and am getting pounded, so I am going to covert my regular low carb, no sugar diet into a more carb friendly one including a zinc supplement (creatine is another one I'm going to check into), for now.  I have yet to read more on testosterone friendly diets and if anyone has any good links, please share them!

thanks,
~mel
[/quote]


Melissa, I have been looking at this very question myself and from what i have found Testosterone is linked to zinc and fat.  

There are tons of places on the net to find out about Test. friendly diets...all the weight lifting and body building sites have information...not sure how accurate all the info is though.

I also have found that zinc found in food along with protein and fat is most likely to help testosterone production. Fat and zinc are both required so adding steak, oysters(yuck), beans and nuts to your diet may result in higher test. numbers compared with just a zinc supplement. Zinc and fat are required.

I have been living  low-carb low-fat for a couple of years since i lost 85 pounds, and i have been successful in keeping it all off, but adding nuts and beans and such is definately not going to happen with me...just too risky and addictive....that being said, I do eat alot of lean steak as an important protein component of my low cal diet.

Paul [/quote]

[quote
Did you know that one thing body builders do to increase their testosterone is eat 18-20x their bodyweight in calories?? [/quote]

I think i will have to increase my physical activity before i try it! 

Imagining a 750 pound Paul!!!!! jokes

Week #8 HRT Report

Still CH free.

I can still force (trigger) a light shadow, but not a CH.

Livin' it up!!!

Paul

That is awesome news, Paul.  My wish for you is that your PF time lasts forever.


Carol

Bump for testosterone treatment.

Steambug, I think you need an endrocrinologist to sort it out, but i believe the Clomid to be directly responsible for your headache remission. Most neuros know squat.

Clomiphene is used by male anabolic steroid users to bind the estrogen receptors in their bodies, which blocks the effects of estrogen ( enlarged breasts which is a side effect of anabolic steroid use and testosterone injections)

It also restores the body's natural production of testosterone.  Testosterone and general hormone imbalances are linked to many suffering from CH because the hypothalamus is involved in regulation of hormone activity.

My fingers are crossed that by getting a blood endocrine workup and finding a hormone imbalance and sorting thru that you may have a shot at long term remission...check into it.

Paul

southwalessunshine wrote on Mar 25^th, 2009 at 12:15pm:


Please report back to us.  Fingers crossed for you.

I am painfree now into week 15!!!!!!!


paul

WOOHOO!!....week 20 and loving it.


Paul

This was a pleasure to read.
Thrilled for you Paul.
Absolutely thrilled for you Bob (alley)

Feel good

E