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Hypothalamic functions in patients with pituitary insufficiency
Borgers, A.J.F.
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Borgers, A. J. F. (2013). Hypothalamic functions in patients with pituitary insufficiency
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Download date: 16 Jun 2017
Chapter 9
Summary and General Discussion
Summary and General Discussion
The main objective of this thesis was to increase our understanding of hypothalamic
(dys)function in patients with pituitary insufficiency. This goal was driven by the clinical
experience of persisting symptoms in patients adequately treated for pituitary insufficiency.
We focused primarily on patients who had a history of compression of the optic chiasm
(CC), cranial radiotherapy (CRT) and/or pituitary surgery to optimize the chance of the
presence of functional damage to the hypothalamus.
At present, there are hardly any studies on hypothalamic post-mortem specimens from
these patients. A major methodological dilemma studying hypothalamic function in vivo is
the limited specificity of clinical and biochemical tests reflecting hypothalamic functions.
As a consequence, disentangling hypothalamic function in patients with pituitary
insufficiency is very challenging. To assess hypothalamic functions we made use of a
variety of techniques focusing on 1) hypothalamic output parameters (chapters 2, 3, 4
and 5), 2) human post-mortem hypothalamic tissue specimens (chapters 6 and 7) and 3)
nuclear imaging of the brain (chapter 8). This chapter provides a summary of the findings
presented in this thesis, followed by a general discussion.
SUMMARY
Chapter 1 provides an introduction to the anatomy of the pituitary gland and to the
treatment of pituitary insufficiency. Furthermore, the hypothalamus and its main functions
are briefly reviewed. We discuss the impairments perceived by patients with pituitary
insufficiency and present our general hypothesis.
The effect of cranial radiotherapy on hypothalamic output parameters
Experimental studies suggest that neurons in the ventromedial hypothalamus regulate
visceral fat content independently of food intake by modulating the sympathetic tone (1).
The anatomical basis for his phenomenon is that distinct subsets of pre-autonomic neurons
within the hypothalamus project to the visceral and subcutaneous fat compartments via
the autonomic nervous system, representing a neuroanatomical network by which the
hypothalamus may control body fat distribution (2-4). Therefore, we investigated abdominal
fat distribution in chapter 2 as hypothalamic output parameter, and demonstrated that
a history of CRT is associated with a higher visceral to subcutaneous fat ratio in men
with pituitary insufficiency. An additional hypothalamic output parameter that we studied
in the present thesis is baroreflex sensitivity (BRS). This parameter reflects the capability
of the autonomic nervous system to detect and respond effectively to acute changes in
blood pressure by changing heart rate (5). In chapter 3 we compared BRS in hypopituitary
patients with a history of CRT to hypopituitary patients without a history of CRT. Our
data indicates that a history of CRT is associated with a decreased BRS, which suggests
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Chapter 9
that CRT in patients with pituitary insufficiency causes reduced capability to increase
parasympathetic activity and/or to antagonize sympathetic activity (5).
The effect of compression of the optic chiasm on hypothalamic output
parameters
Suprasellar tumours frequently cause pituitary insufficiency as well as visual impairments
due to CC. In close proximity to the optic chiasm is the hypothalamic suprachiasmatic
nucleus (SCN). This hypothalamic nucleus has been identified as the main regulatory centre
of sleep, and of circadian organization in general (6,7). Hypothetically, expanding tumours
not only compress the optic chiasm, but also the SCN, which harbours the biological
clock. Therefore, we hypothesized that sleep patterns are altered in hypopituitary patients
with a history of CC. Indeed, in chapter 4 we demonstrated that CC is associated with
permanent shorter sleep duration in hypopituitary patients, which could not be attributed
to differences in hormonal replacement therapy. Another hypothalamic output parameter
that we studied is skin temperature (chapter 5). The preoptic area, a hypothalamic region
situated in close vicinity of the SCN, is critically involved in temperature regulation (8).
Of note, several studies reported an association between sleep and fluctuations in skin
temperature (9-14). For instance, skin temperature modulates the effect of early morning
light on sleep (15), and mild skin warming enhances sleep propensity (16-19). Based on the
observation that hypopituitary patients with a history of CC have shorter sleep duration
(chapter 4), we hypothesized that thermoregulation and its association with sleep would
be disturbed in this group as well. Our main finding was a lower proximal skin temperature
during the day in hypopituitary patients with a history of CC. In addition, the typical
correlation between sleep onset latency (i.e. the required time between lights out and
the onset of sleep) and pre-bedtime distal-to-proximal skin temperature gradient (9,20)
was absent in these patients, whereas it was clearly present in those without CC as well as
in healthy subjects. Thus, patients with CC show impaired skin temperature regulation in
association with disturbed sleep.
The effect of expanding sellar tumours on human post-mortem
hypothalamic tissue
To further confirm our hypothesis that expanding suprasellar tumours impair the function
of the SCN (chapter 4), we investigated the expression of two key neuropeptides in
that area, i.e. arginine vasopressin (AVP) and vasoactive intestinal peptide, as assessed
by quantitative immunocytochemistry in post-mortem hypothalamic tissue specimens of
patients with a suprasellar tumour inducing permanent visual field defects. We showed in
chapter 6 that AVP-immunoreactivity in the SCN was lower in patients with a suprasellar
tumour than in controls. This raises the intriguing possibility that selective impairment of
SCN neurons contributes to sleep-wake disturbances in these patients, although this is
highly speculative.
132
Summary and General Discussion
Serotonin transporters in the hypothalamus
Serotonergic signalling has been implicated in various hypothalamic functions including
circadian rhythmicity, feeding behaviour and neuroendocrine regulation (21-24). These
functions show remarkable similarities with functional impairments in hypopituitary
patients, which rises the intriguing question whether the hypothalamic serotonergic system
is affected in these patients. As a first step to address this research question, we studied
the functional neuroanatomy of serotonergic signalling in post-mortem hypothalamic
tissue specimens in chapter 7. Serotonin transporters (SERT) were ubiquitously expressed
in fibers throughout the hypothalamus, with a very dense track of fibers in the perifornical
area, as a plexus along the ependyma and in close proximity to the anterior commissure.
Moreover, the SCN and the infundibular nucleus showed strong SERT-immunoreactivity,
suggesting a local modulatory role for serotonin in these hypothalamic nuclei. We then
went on to study in chapter 8 hypothalamic specific-to-nonspecific [123I]FP-CIT binding
ratios in vivo using single photon emission computed tomography, in hypopituitary patients
with a history of surgery, CRT and CC. We compared the results with similar data obtained
in hypopituitary patients without hypothalamic damage and in healthy control subjects.
We hypothesized that SERT expression was altered in response to CC and treatment of a
sellar tumour. However, we could not detect a difference between the groups. This may
be due, at least in part, to technical limitations.
GENERAL DISCUSSION
Cranial radiotherapy and hypothalamic impairment
We showed that CRT is associated with alterations in BRS and body fat distribution
(chapters 2 and 3). An important question is whether these findings are related to
hypothalamic impairment. It is well-known that CRT delivered to the pituitary may induce
adverse effects. The development and severity of such side-effects depend on the
combination of the vicinity of healthy tissue to the radiation target, the type of tissue,
the dose and fractioning of CRT. Damage can induce immediate lethal effects on cells, or
induce accumulating sublethal damage that limits the potential for cell replication (25).
Cell death after radiation which occurs in the mitotic phase of the cell cycle (late G2-early
S), may be the reason for a delayed onset of chronic complications of radiation in slowlyreplicating cells, such as those present in the hypothalamic-pituitary unit (26,27). Ionising
radiation is known to be able to induce degenerative changes in glial cells, leading to a
lack of tropic neural support and demyelinisation, which in turn may cause subacute and
chronic neural damage in the hypothalamus.
By far the most common side effect of pituitary radiation is hypopituitarism, with a
five-year incidence of approximately 20% (28). Furthermore, visual complications due
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Chapter 9
to optic neuropathy (29), neurological symptoms, vascular problems resulting in stroke
(30) and secondary tumours (31) are seen, although the incidence of these complications
is probably less than 1% (32). Evidence for hypothalamic injury after irradiation has
been provided by studies on the effects of CRT on the lactotropic axis. Lactotrophs are
prolactin producing pituitary cells that receive predominantly inhibitory signals from
the hypothalamus. It has been noted that prolactin levels increase after CRT, but that
hyperprolactinemia does not occur when lactotrophs were directly damaged, suggesting
hypothalamic injury or hypohalamus-pituitary disconnection after irradiation (33). Another
clue came from studies on the differential effects of pituitary brachytherapy compared
with CRT. Follow-up studies of patients treated with brachytherapy (instillation of Yttrium90 in the sella turcica, total dose 50-150Gy) for pituitary adenomas revealed a reduced risk
of hypopituitarism when compared with external CRT with a total dose of 37.5 – 45Gy
(34,35). Moreover, serum prolactin levels did not show an increase after brachytherapy
(36). The lower incidence of hypopituitarism after sellar brachytherapy despite higher total
radiation doses when compared with CRT and the preservation of normal prolactin levels
suggest a lower threshold for radiation induced damage in hypothalamic tissue.
Both BRS and abdominal fat distribution are influenced by the hypothalamus. As the
hypothalamus is situated in close vicinity to the sella turcica and is susceptible to radiation
induced toxicity (37), it is conceivable that CRT for sellar tumours also inflicts some degree
of damage to the hypothalamus. Consequently, this may lead to changes in hypothalamic
function, resulting in altered BRS and abdominal fat distribution as shown in chapters 2
and 3. In conclusion, based on our results in chapters 2 and 3 and on the observations
by others we propose that hypothalamic impairment may result from CRT tumours in the
sellar region.
Expanding sellar tumours and hypothalamic impairment
The reported alterations in sleep and skin temperature in patients with a history of CC
(chapters 4, 5 and 6) contribute to our understanding of the functional impairments in
patients with pituitary insufficiency. On the basis of our results, we postulate that changes
in sleep and skin temperature were in essence caused by the expanding sellar tumour.
Thus, growing tumours induce mechanical pressure to adjacent structures including the
SCN, preoptic area and retinohypothalamic tract. This then causes impaired function
of these hypothalamic nuclei, leading to alterations in circadian rhythmicity and skin
temperature. In line with this assumption, we found lower AVP-immunoreactivity in the
SCN in patients treated for a suprasellar tumour (chapter 6). Injury to surrounding tissue
is highly conceivable, as tumour growth within the sella results in increased tissue pressure
that can reach levels as high as 60mmHg (38), whereas normal intrasellar pressure is
believed to be similar or less than the normal intracranial pressure of 7-15mm Hg (39,40).
Additional studies have highlighted several consequences of mechanical pressure due to
growing tumours. Visual field defects due to CC (41,42), mild hyperprolactinemia and
134
Summary and General Discussion
loss of pituitary hormone secretion have been demonstrated in patients with pituitary
stalk compression (43,44). Also, increased intrasellar pressure is supposed to be a major
mechanism involved in the pathogenesis of headaches (38). Furthermore, patients treated
for a non-functioning macroadenoma, who had visual field defects preoperatively, display
impaired quality of life with increased fatigue, daytime somnolence, disturbed distribution
of sleep stages and disturbed circadian movement rhythm, possibly due to impaired SCN
function (45-48). Together, these studies support the concept that hypothalamic function
may be altered by expanding pituitary tumours giving rise to CC.
Serotonergic neurotransmission and hypothalamic impairment
The rationale to study the hypothalamic serotonergic neurotransmission (chapters 7
and 8) was based on the striking similarity between the functions of the hypothalamus
considered to be influenced by the serotonergic system and the functions affected
in patients with pituitary insufficiency, including the regulation of circadian rhythms,
appetite, obesity, and neuroendocrine responses (21-24). However, very few data are
available on the functional neuroanatomy underlying serotonergic signalling in the human
hypothalamus. Therefore, we took a first step to explore SERT expression in post-mortem
hypothalamic tissue (chapter 7). We demonstrated that SERT was abundantly expressed
in fibers throughout the hypothalamus. As a next step, we confirmed this finding in the
human hypothalamus in vivo, showing SERT binding selectively in the hypothalamus of
healthy subjects by fusing SPECT-scan with conventional MRI (chapter 8). Once we had
demonstrated SERT in the human hypothalamus, we studied SERT binding in patients
treated with cranial surgery and CRT for an expanding sellar tumour inducing visual field
defects. We hypothesized that subjects suffering from hypothalamic impairment may have
impaired serotonergic neurotransmission. Contrary to our expectations, hypothalamic
binding ratio of SERT was not altered in those patients. The obvious conclusion is that
serotonergic signalling is not involved in the pathophysiology of hypothalamic impairment.
However, we cannot exclude that the effect was more subtle than the current design was
able to detect. Therefore, a larger study would be needed to confirm our result. Another
limitation is that only one molecular component of this system, i.e. the SERT, has been
studied. Although the concentration of transporters is believed to reflect the homeostatic
tone of neurotransmitter systems (49), it will be interesting to study serotonin release by
fenfluramine-challenge (e.g. as in (50)) as well as synaptic serotonin levels using depletion
with tryptophan or para-chlorophenylalanine to get a more complete picture (51).
Alternative hypotheses
The results presented in this thesis provide important clues that help to disentangle the
question whether the function of the hypothalamus is impaired as a consequence of an
expanding sellar tumour, CRT treatment and/or CC. It should be noted, though, that our
studies were all cross-sectional, which hampers the possibility to study causal relations.
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Chapter 9
Moreover, despite a large body of evidence showing a relation between (treatment of)
sellar tumours and hypothalamic (dys)function, conclusive evidence of hypothalamic
impairment in patients with pituitary insufficiency has not been given to date. Therefore,
the hypothesized direct relations between hypothalamic dysfunction and (treatment of)
expanding sellar tumours can be questioned.
If hypothalamic dysfunction is not directly related to the results found in this thesis, which
other factors could be involved as underlying mechanism? Traditionally, anterior pituitary
deficiencies and their hormonal treatment have been considered as likely candidates to
explain increased visceral to subcutaneous fat ratio (52-55), alteration of sympathovagal
balance (56-58) and sleep disturbances (59-62) in hypopituitary patients. To control for the
potential confounding effect of various hormonal deficiencies, we included only patients
with pituitary insufficiency in chapters 2, 3, 4, 5 and added a control group with pituitary
insufficiency in chapter 8. By doing so, groups were comparable concerning biochemical
parameters, hormonal treatment regimens and endocrine deficiencies. This method
minimizes the possibility that differences in hormonal substitution strategy account for the
results obtained.
Alternatively, rather than injury to hypothalamic structures per se, other structures that are
involved in sleep, temperature regulation, BRS or abdominal body fat distribution could
be impaired. For instance, the baroreceptor signal is relayed via the glossopharyngeal and
vagal nerves to the nucleus tractus solitarius. Neurons of this nucleus subsequently convey
this signal via the ventrolateral medulla and rostral ventrolateral medulla in the lower
brainstem to the spinal cord (5). It is conceivable that CRT injures non-hypothalamic parts
or branches of the baroreflex loop, resulting in altered excitatory/inhibitory input to several
pre-autonomic neurons of the hypothalamus. In addition, CRT may harm forebrain regions
or fibers of passage originating from these forebrain regions, as those are also able to
modulate the key medullary nuclei subserving the baroreflex (63,64). Another player may
be the retinohypothalamic tract, which transmits photic information from the retina to the
SCN in the hypothalamus and is involved in synchronization of the SCN to the light-dark
cycle (65,66). Injury to this tract by the tumour or the treatment may inhibit entrainment
of the circadian clock, resulting in altered sleep characteristics.
A final possibility is melatonin secretion, which plays a role in the regulation of human
sleep (67-70). The pathway involved in melatonin secretion starts in the SCN, and travels
via the paraventricular nucleus and the intermediolateral nucleus of the upper thoracic
spinal cord to the superior cervical ganglion and finally to the pineal gland (71,72). Injury
to part of the extrahypothalamic pathway involved in melatonin excretion is a possible
mechanism explaining the effects on sleep (73).
Implications for clinical practice
Patients as well as doctors involved in the treatment of expanding sellar tumours are
frequently unprepared for the development of several long-term side effects. Often, limited
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Summary and General Discussion
education or support is provided to patients, as physicians focus primarily on adequate
hormonal replacement therapy and may be oblivious to subtle functional and poorly
understood impairments that are associated with pituitary insufficiency. Consequently,
subtle derangements of the sleep/wake cycle, transient hyperprolactinemia, slowly
progressive obesity or autonomic dysregulation in patients with pituitary insufficiency
may be easily overlooked. We recommend that physicians be aware of the impairments,
even after long-term remission of the initial disease, e.g., by postgraduate training and
continuous medical education programs. Physicians should inform the patients about
potential long-term consequences of expanding pituitary tumours, thereby contributing
to the process of disease acceptance. In addition, some of the strategies discussed below
may aid to ameliorate the impairments.
In the studies presented in chapter 2 and chapter 3, patients were treated with
conventional external beam radiotherapy, which is the most frequently used method of CRT
to treat large remnants of pituitary adenomas with evidence of progression after surgery
or if surgery is not able to normalize excess of hormones (74). Relatively novel treatment
modalities for pituitary tumours are stereotactic radiosurgery techniques and intensitymodulated radiation therapy that focuses high dose radiation at precise intracranial targets
(75). These modalities have the clear advantage to offer a more precise radiation delivery
in one dose in combination with a reduced amount of normal tissue exposed to high
radiation doses compared with conventional methods. Potentially this can reduce the
risk of long-term treatment-related morbidity like pituitary insufficiency, BRS and body
fat distribution. However, long-term follow-up studies are needed to demonstrate their
presumed superiority and efficacy (76).
In chapters 4, 5 and 6 we demonstrated that CC is associated with altered sleep and
temperature regulation. Generally, the presence of visual field defects, severe headaches
or excessive hormone secretion is a clear indication for immediate treatment (77), while
asymptomatic patients are candidates for conservative ‘wait-and-see’ policy. The approach
for asymptomatic patients seems to be safe for microadenomas because of a low growth
propensity (78,79), but is questionable for macroadenomas as tumour enlargement
is expected with increasing follow up periods (78,80,81). One may consider treating
asymptomatic macroadenomas before they give rise to CC, as potentially this may reduce
the risk of long-term effects such as visual abnormalities, altered sleep, temperature
dysregulation and pituitary insufficiency. Moreover, early surgery may increase the
chances of complete tumour removal, whereas postponement may allow tumours to
reach dimensions or degrees of invasiveness which will make their resection more difficult.
One should keep in mind, however, that surgical interventions may be accompanied by
complications, although the incidence is low (82). Therefore, future randomized studies
comparing immediate treatment of asymptomatic macroadenomas with the ‘wait-and-see’
approach are highly relevant.
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Chapter 9
Another interesting therapeutic approach is to enforce circadian regulation, in order to
improve sleep (chapter 4). This can be achieved by a regular schedule for going to bed
and waking up, and engaging in stimulating activities in a light environment immediately
after waking up (83). Also melatonin and bright light therapy are ways to entrain the
circadian rhythm. Exogenous melatonin has been used in subjects over 55 years of age and
was shown to be effective in restoring normal sleep (84). Bright light therapy is another
method to ameliorate sleep disturbances (85). Both melatonin and light can be potential
treatments of sleep impairments in hypopituitary patients with a history of CC.
Inducing small temperature changes is also a potential mechanism to improve sleep
(chapter 5), because changes in skin temperature could modulate sleep-regulating
systems (18). Although there is currently no method to target skin temperature precisely,
applying thermosuit control of skin temperature may be a potential method to enhance
sleep quality (19).
Conclusions and directions for future research
In this thesis, we aimed to obtain insight in the (dys)function of the hypothalamus in
patients with pituitary insufficiency with a history of CC, CRT and/or pituitary surgery.
We used a variety of techniques focusing on hypothalamic output parameters (chapters
2, 3, 4 and 5), human post-mortem hypothalamic tissue specimens (chapters 6 and
7) and functional brain imaging (chapter 8). Together, our results point towards the
sensitivity of the hypothalamus to expanding sellar tumours and CRT (chapters 2, 3, 4,
5 and 6). Moreover, we demonstrated that SERT is abundantly expressed in the human
hypothalamus, both post-mortem and in vivo (chapters 7 and 8). However, SERT binding
ratio was unaltered in patients suspect for hypothalamic impairment (chapter 8), although
we do not know if this is due to methodological limitations.
Obviously, one of the main goals in future studies should be the development of test to
assess hypothalamic function directly. To date there are no tests or imaging modalities to
assess the integrity of hypothalamic function. Conventional radiologic imaging identifies
only gross anatomical abnormalities, but is not suitable to detect abnormalities at the
cellular level. In recent years, neuroimaging techniques have expanded enormously.
Advanced imaging protocols, development of new nuclear ligands, the use of 7-Tesla MRI
and pharmacological MRI generate great opportunities for detailed in vivo studies of the
human hypothalamus and pituitary. In this thesis, we reported SERT binding selectively
in the hypothalamus in vivo (chapter 8). Although hypothalamic binding ratio of SERT
was not altered in patients suspect for hypothalamic impairment (chapter 8), this type
of research may mark the beginning of the development of diagnostic tests to identify
hypothalamic impairment.
Such studies can be further supported by post-mortem hypothalamic research. The use of
biochemical and molecular techniques on brain tissue are likely to provide new insights or
to confirm new findings from clinical studies (86). To date, it is difficult to obtain specimens
138
Summary and General Discussion
of relative rare diseases such as pituitary diseases. Over a period of 25y the Netherlands
Brain Bank has been able to collect five specimens with a tumour with suprasellar
extension, which we all describe in the present thesis. Potentially, patient organizations in
the pituitary field may support brain donor programs by informing their members, who do
not always know about the existence of human brain banks and the possibility to register
as a donor. These strategies may stimulate basic research on hypothalamic impairment in
patients with pathology of the pituitary and/of hypothalamus, and provide answers to
clinical questions that need to be investigated in the coming years with the ultimate aim to
improve pituitary patient care.
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Chapter 9
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