ASPECTS OF MEDICAL THERAPY OF
`
`NEUROENDOCRINE DISORDERS
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`1
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`TEVA1075
`Teva Pharmaceuticals USA, Inc. v. Corcept Therapeutics, Inc.
`PGR2019-00048
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`If we pay attention to the common opinion of men, we
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`shall see that they are conscious of the eternity of their
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`mind; but they confuse eternity with duration, and
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`attribute it to imagination or memory, which they believe
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`will remain after death
`- Spinoza; Ethica V, 34 -
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`ASPECTS OF MEDICAL THERAPY OF
`NEUROENDOCRINE DISORDERS
`
`ASPECTEN VAN DE MEDICAMENTEUZE BEHANDELING
`
`VAN NEUROENDOCRIENE ZIEKTEN
`
`PROEFSCHRIFT
`
`TER VERKRIJGING VAN DE GRAAD VAN DOCTOR
`
`AAN DE ERASMUS UNIVERSITEIT ROTTERDAM
`
`OP GEZAG VAN DE RECTOR MAGNIFICUS
`
`PROF. DR. C.J. RIJNVOS
`
`EN VOLGENS BESLUIT VAN HET COLLEGE VAN DEKANEN.
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`DE OPENBARE VERDEDIGING ZAL PLAATSVINDEN OP
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`WOENSDAG 27 MEl 1992 OM 13.45 UUR
`
`DOOR
`
`AART JOHANNES VAN DER LELIJ
`
`GEBOREN TE 'S GRAVENHAGE
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`5
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`PROMOTIE-COMMISSIE
`
`Promotor:
`
`Prof. Dr. S.W J. Lamberts
`
`Overige !eden:
`
`Prof. Dr. J.C. Birkenhiiger
`Prof. J.H.P. Wilson
`Prof. Dr. G.H. Zeilmaker
`
`In de drukkosten van dit proefschrift werd bijgedragen door Sandoz B.V. te Uden.
`
`Het proefschrift werd gedrukt door Haveka B.V. te Alblasserdam.
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`6
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`ABBREVIATIONS
`
`ACIH
`
`CRH
`cr
`DA
`
`FSH
`
`GHRH
`
`GnRH
`GH
`IGF-I
`mMA
`LH
`m-RNA
`MRI
`PRL
`RIA
`Sm-C
`
`TRH
`
`TSH
`
`adrenocorticotropic hormone (corticotropin)
`
`corticotropin releasing hormone
`
`computer tomogram
`
`dopamine
`follicle stimulating hormone
`growth hormone releasing hormone
`gonadotropin releasing hormone
`growth hormone
`insulin-like growth factor-I
`immunoradiometric assay
`luteinizing hormone
`messenger ribonucleic acid
`magnetic resonance imaging
`prolactin
`radioimmuno assay
`somatomedin-C
`
`thyrotropin releasing hormone
`thyrotropin
`
`7
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`8
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`CONTENTS:
`
`1.
`
`SURVEY OF LITERATURE ...............................
`
`11
`
`1.1
`
`1.2
`
`1.3
`
`1.4
`
`1.5
`
`Introduction ................................... 12
`
`Prolactinomas ..................................
`Introduction
`1.2.1
`1.22 Radiodiagnostics
`1.2.3 Treatment
`1.2.4 Bromocriptine
`1.2.5 Side Effects
`1.2.6 Cabergoline
`1.2.7 Pergolide
`1.2.8 CV 205-502
`1.2.9 Complications of treatment with dopaminergic drugs
`
`14
`14
`15
`15
`16
`16
`17
`18
`18
`19
`
`Acromegaly .................................... 20
`Introduction
`20
`1.3.1
`1.3.2 Relation between tumor-size, GH- and IGF-I levels
`22
`22
`1.3.3 Treatment
`1.3.4 Surgery
`23
`1.3.5 Radiotherapy
`23
`1.3.6 Bromocriptine
`23
`24
`1.3.7 Octreotide
`
`Cushing's Syndrome ............................. 25
`1.4.1 Diagnostic tests
`25
`1.4.2 Radiodiagnostic techniques
`26
`1.4.3 Localizing by sampling of the inferior petrosal sinus
`26
`1.4.5 Treatment
`26
`1.4.6 Surgery
`26
`1.4.7 Radiotherapy
`27
`1.4.8 Medical therapy
`27
`27
`1.4.9 Ketoconazole
`1.4.10 Aminoglutethimide
`27
`28
`1.4.11 Metyrapone
`1.4.12 Suramin
`28
`1.4.13 Mifepristone (RU 486)
`28
`Thyrotropin (TSH)-secreting adenomas ............... 29
`Introduction
`29
`1.5.1
`1.5.2 Therapy
`30
`1.5.3 Surgery and radiotherapy
`30
`1.5.4 Dopaminergic Drugs
`30
`1.5.5 Octreotide
`30
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`9
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`9
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`1.6
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`1.7
`
`Nonfunctioning tumors
`Introduction
`Therapy
`
`1.6.1
`1.6.2
`
`References
`
`Aims and scope of the thesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`The sensitivity of growth hormone (GH) secretion to medical
`treatment in acromegalic patients
`. . . . . . . . . . . . . . . . . . . . . . . .
`
`Dynamics of the acute effects of octreotide, bromocriptine and both
`drugs in combination on growth hormone secretion in
`acromegaly .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .
`
`Long-term in vitro treatment of human growth hormone (GH)-
`secreting pituitary adenoma cells with octreotide causes
`. . . . . . .
`accumulation of intracellular GH and GH-mRNA levels
`
`Preoperative treatment of acromegaly with the Sandostatin analog
`octreotide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`
`31
`31
`31
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`32
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`49
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`53
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`65
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`79
`
`99
`
`(a nonergot
`tolerability of CV 205-502
`The efficacy and
`dopaminergic drug) in macroprolactinoma patients and in
`. . . . . . . . . . . . 107
`prolactinoma patients intolerant to bromocriptine
`
`Primary pharyngeal pituitary tumors. Differential diagnosis and
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
`treatment
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`Rapid reversal of acute psychosis in patients with severe Cushing's
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
`syndrome
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`2.
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`3.
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`4.
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`5.
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`6.
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`7.
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`8.
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`9.
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`10.
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`Current thoughts about optimal medical therapy of functioning
`. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
`pituitary adenomas
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`11.
`
`Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
`
`12.
`
`13.
`
`14.
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`Samenvatting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
`
`Curriculum vitae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
`
`Dankwoord . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
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`10
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`CHAPTER 1.
`CHAPTER ‘E .
`
`SURVEY OF LITERATURE:
`SURVEY 0F LETERATURE:
`
`ll
`11
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`11
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`11
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`1.1
`
`Introduction:
`
`The pituitary gland is silllated within the sella turcica, which is located as a recess
`of the anterior cranial fossa in the sphenoid. The pituitary gland itself is made up of an
`anterior lobe (adenohypophysis) and a posterior lobe (neurohypophysis).Acromegalywas
`the first pituitary disease to become recognized as a clinical entity, although initially it
`was not clear, whether the eosinophilic adenomas, causing pituitary enlargement were
`causative or just a manifestation of the syndrome itself. Fallowing the documented
`clinical improvement of acromegalic patients after partial hypophysectomy, it was proven
`
`that the pituitary adenomas were etiologic 1• Nowadays, the anterior pituitary can be
`divided in at least seven distinct hormone-secreting cell types 2•
`Pituitary tumors can be classified according to their clinical presentation 3,to the
`innnunocytochemical staining properties of the tumor or to the type of hormone(s) they
`hypersecrete in vivo 4
`• Using immunocytochemical technics, the prevalence of different
`types of pituitary adenomas could be estimated in large series of surgical removed
`pituitary tumors s 6
`• (See Table 1)
`
`Table 1:
`
`TYPE OF PITUITARY TUMOR
`
`PREVALENCE IN%
`
`PROlACTINOMAS
`
`GH SECRETING TUMORS
`
`FSH/LH SECRETING
`TUMORS
`
`ACTH SECRETING TUMORS
`
`TSH SECRETING TUMORS
`
`NON FUNCTIONING
`TUMORS (no or few hormone
`positive cells could be detected)
`
`25-30
`
`15-35
`
`4
`
`15
`
`< 1
`
`20-30
`
`As mentioned above, pituitary adenomas originate in and are composed of
`adenohypophyseal cells. They are frequently occurring neoplasms. In unselected
`pituitaries of adults obtained post-mortem a prevalence from 6 up to 23 per cent is
`recorded 7 8 9
`
`. They also represent some 15 % of the intracranial neoplasms 10. While
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`most pituitary adenomas are histologically benign, slow growing tumors, some adenomas
`show a more rapid growth, with extension into the surrounding tissues, eventually causing
`damage to the optic nerve(s) and/or other cranial nerves 11
`•
`Apart from their presence within the sella turcica, adenohypophyseal cells have
`been also demonstrated within the nasopharyngeal region. Erdheim first described the
`pharyngeal pituitary in 1904 12
`• Like the pituitary adenohypophysis, the pharyngeal
`
`types 12• Though
`hypophysis contains at least seven hormone-producing cell
`transsphenoidal vascular connections exist, it is unclear whether the pharyngeal pituitary
`has secretory properties 14
`• Its function is unknown.
`In the following pages, some aspects of the treatment and problems which can
`occur dnring treatment of each of the pituitary adenomas, as mentioned in Table 1, will
`be described.
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`13
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`13
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`1.2
`
`P:rolactinomas:
`
`1.2.1
`
`Introduction:
`
`Prolactin is a 21,500 Dalton single-chain polypeptide which cao be found in the
`circulation in 50 kDa and 150 kDa molecular valiants. The information is encoded on
`chromosome 6 and transcription cao be enhanced or suppressed by a vatiety of hormonal
`factors. Secretion occurs in a pulsatile manner. Hypothalamic regulation of PRL mainly
`involves tonic inhibition by dopantine which is transported via the ponal vessels. The
`physiological importance of vatious hypothalamic stimulating factors is still largely
`unknown 15• Prolactin secreting tumors are the most common hormone secreting
`pituitary tumors 16
`• Not only prolactinomas cause high serum PRL levels, but also
`pregnancy, hypothyroidism, liver cirrhosis, renal failure and the use of several drugs
`shonld be considered in its differential diagnosis. Iatrogenic hyperprolactinemia occurs
`during the use of:
`
`•
`Antidepressant drugs (eg amitriptyline, imiprantine)
`•
`Antihypertensive drugs ( eg methyldopa)
`•
`Opiates
`•
`Estrogens
`•
`Neuroleptics ( eg perphenazine, haloperidol)
`Dopantine receptor blocking agents ( eg domperidone,
`•
`metoclopramide ).
`
`Because serum PRL levels do correlate well with the size of the sellar mass, only
`large tumors (with extra sellar extension) with considerably elevated serum PRL levels
`
`cao be consistent with the diagnosis of a prolactinoma 17. If this is not the case, also
`"non-functioning" pituitary tumors, as well as mixed pituitary tumors and other sellar
`disorders with a large tumor mass cao account for a mild hyperprolactinemia (less than
`150 p.g/L) 18•
`
`14
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`14
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`1.2.2 Radiodiagnostics:
`
`Presently high resolution CT scan is the most accurate method to obtain indirect
`information about pituitary anatomy. Contiguous images in the coronal and sagittal
`planes with 2-3 mm collimation are recommended. Magnetic resonance imaging is still
`a relatively new imaging procedure, which has the potential for improving the
`visualization of the sellar region. Because it is still relatively new, it is yet not possible
`to detertuine whether it is superior to the high resolution CT scan. Baker 19 reported
`in a comparative investigation of MRI and CT scans that 10% of studies were judged
`superior by MRI, 10% superior by CT and 80 % were of equal value. In visualization of
`optic nerves and cavernous sinus, MRI is superior to CT, while it is the other way around
`in the visualization of calcified tissue.
`
`1.2.3 Treatment:
`
`A number of reports indicate that PRL levels, as well as tumor size remain
`unaltered for several years in the majority of untreated women with microprolactinomas 20
`21 22• Because of other problems or complaints, treatment may be necessary.
`Galactorrhea, for instance (especially in women) is one reason 23 24
`• Also sexual
`dysfunction (in men) 25 26, infertility v and/ or menstrual disturbances can necessitate
`treatment. In women osteoporosis can develop, due to the hypogonadal state caused by
`abnormalities in the pulsatile secretion of GnRH 23 29
`• Although headaches often
`occur in patients with macroadenomas of the pituitary, there also appears to be an
`increased incidence of headaches in hyperprolactinemic women with normal radiologic
`evaluation of the sellar region, although no correlation between PRL levels and the
`severity of the headaches was found 30•
`Disturbances of the visual system may occur in patients with a macroprolactinoma.
`This does not happen so often as in non.functioning adenomas because due to the other
`complaints mentioned above (especially in women), patients do seek medical help in an
`earlier stage 31
`•
`H one decides to treat a patient, one can choose between surgical treatment,
`medical treatment, radiotherapeutic treatment or any combination of these modalities.
`Drug therapy is nowadays the treatment of choice, not ouly for microprolactinomas but
`also for macroprolactinomas. The main reason is that surgical cure is uulikely in these
`patients, while risk of tumor recurrence is high 32
`• Prior to the advent of medical
`treatment, therapy usually consisted of surgical resection and/ or radiotherapy. It
`
`15
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`15
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`appeared that pituitary radiation does not cause a rapid reduction in serum PRL levels.
`It does prevent a progression of the disease over the long-term, however 33 34 35•
`
`1.2.4 Bromocriptine:
`
`Prolactin secretion is inhibited by dopamine and stimulated by estradiol. The
`dopamine necessary for inhibition is released from nerve terminals in the median
`eminence and posterior pituitary. Estradiol may act directly on the anterior pituitary or
`by modulation of the two dopaminergic systems 36• 1n 1971, the first clinical study on
`the effect of the dopaminergic drug 2-Br-alpha-ergocryptine mesylate (bromocriptine)
`was performed 37
`• Bromocriptine (maluly acting at D2 receptors) directly stimulates
`neuronal and pituitary cell membrane dopamine receptors 38 39
`• After ingestion, peak
`levels are reached after 2 hours. Absorption after oral administration is about 28 %.
`First -pass metabolism is approximately 94 %. Excretion in the feces is 98 %; urine
`excretion is 2 % of the dose. PRL levels remain suppressed for 9-14 hours after a single
`dose 40 41
`•
`Long-term treatment with 2.5 mg bromocriptine three times daily results in a
`
`further decrease of PRL levels 42• After short-term parenteral (7 days) and long-term
`peroral (4-6 weeks) treatment, electron microscopic morphometric evaluation of the
`adenomas showed that a reduction in size of prolactinoma cells occurs within a few days
`(half-time to maximum shrinkage, 22 days). The total volume of cellular Iysosomes
`decreased significantly to about one-half of the pretreatment value, while the number of
`stored secretory granules did not change significantly 43
`• Bromocriptine is capable of
`improving visual disturbances and reducing tumor size objectively in patients with large
`tumors within several days or weeks 44
`• It reduces tumor size by a mean of 50% or
`more in about 50% of the patients with a macroprolactinoma and decreases PRL levels
`to normal in about 70% of the patients 42
`• Discontinuation of therapy may be associated
`with a rapid expansion of tumor size and increase in PRL levels, so most patients require
`dopaminergic therapy indefinitely 45
`
`•
`
`1.2.5 Side Effects:
`
`Side effects, which are roughly the same for all of the dopaminergic drugs, are (in
`order of importance): nausea, orthostatic hypotension, headaches, fatigue, nasal
`congestion, abdominal cramps and constipation 46
`• One can try to minimize these
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`l6
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`side-effects by beginning therapy with a low dose, given at bedtime with a snack and by
`increasing this dose over weeks until it achieves a therapeutic response.
`
`The occurrence of side-effects, as well as the need for two or three daily doses of
`bromocriptine remain important problems in the long-term treatment of prolactinoma
`patients. Also bromocriptine appears unable to normalize plasma PRL levels in about
`30% and to reduce tumor size in one-third of cases 46
`• Therefore recently other
`doparninergic drugs have been developed, including metergoline, lisuride, pergolide,
`mesulergine, terguride, dihydroergocristine, dihydroergocriptine, cabergoline and CV
`205-502. Metergoline, dihydroergocristine and terguride were less effective than
`bromocriptine 47 48 49
`, while lisuride and mesulergine were more poorly tolerated
`than bromocriptine 50 51
`• In the next chapters cabergoline, pergolide and CV 205-502
`will be discussed in more detail.
`
`1.2.6 Cabergoline:
`
`An acute oral dose of 0.3-0.6 mg cabergoline [1-(6-allylergolin-8-yl)carbonyl-1-
`dimethylantino )propyl-3-
`ethylurea] significantly lowers PRL levels in hyperprolactinemia for 7-14 days 52 53•
`Given at weekly intervals for 8-9 weeks it induces normalisation of PRL levels in about
`two thirds of hyperprolactinemic women 53 54• In a recent study by Ferrari et a!. it was
`demonstrated that serum PRL levels fell to normal and remained so in 41 of 48
`hyperprolactinemicwomen treated chronically with a weekly dose of cabergoline, ranging
`from 02-1.8 mg, usually administrated once or twice weekly; only three women needed
`treatment three times-weekly in order to achieve normal PRL concentrations 55
`• Only
`two of 48 women did not satisfactorily lower their PRL levels, although there was a 50%
`reduction of PRL levels and resumption of menses, albeit only after several months of
`high dose cabergoline treatment. Five of six women with macroprolactinomas did show
`a marked tumor shrinkage. All patients were able to tolerate effective doses of
`cabergoline without important side-effects. Similar results were later reported by
`Ciccarelli et a!. 56
`. These results indicate that cabergoline is a well-tolerated new
`doparninergic drug with long-lasting activity which represents potentially an advance in
`the chronic medical treatment of hyperprolactinemic states.
`
`17
`
`17
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`1.2. 7 Pergolide:
`
`In 1983 Kleinberg et al. reported the results of administration of pergolide
`mesylate to hyperprolactinemic patients 57
`• This drug with dopaminergic properties
`produced long-lasting reductions in PRL levels after single doses of 50 JJ.g. After 24
`hours, the values remained depressed at a mean of 29% of the base-line value. After
`three months or more of pergolide therapy, PRL levels normalized in 37 of the 41
`patients and remained slightly elevated in two. Menses resumed in 84% (16 of 19). 13
`Patients had a macroprolactinoma. After treatment ten showed a tumor shrinkage (77% ).
`The reduction in tumor size was marked in 7 of 10 patients. The majority of patients
`were found to have postural hypotension after the first dose of pergolide and also liver
`enzyme disturbances were recorded infrequently. In three patients the drug was
`discontinued after three weeks because of nausea and vomiting. Although pergolide is
`
`a potent inhibitor of PRL secretion 58 59, the drug has never found an important place
`in the treatment of hyperprolactinemic states, which is also related to the liver enzyme
`abnormalities found by Kleinberg 57
`• In a blind study involving a total of 157
`hyperprolactinemic patients the efficacy and tolerability of bromocriptine and pergolide
`were found to be the same, while also the incidence and type of side-effeCts to both
`dopamine agonists were similar 60
`
`•
`
`1.2.8 cv 205-502:
`
`is a non-ergot alkaloid
`(an octahydrobenzo-[g]-quinoline),
`CV 205-502
`dopaminergic drug, which became recently available for therapy of hyperprolactinemic
`states 61• It is a potent D-2 receptor agonist, with only a weak D-1 receptor activity. In
`studies with a single oral dose of 0.06 mg, CV 205-502 suppressed normal PRL secretion
`within two hours continuously for 36 hours 62
`• On a weight basis, in several studies, this
`drug was far more potent than bromocriptine in suppressing both normal and
`pathological PRL secretion 63 64• Vance et al. reported the results of a study in 26
`hyperprolactinemic women 65• They were treated with doses up to 0.09 mg daily. In 13
`normal menstrual cycles returned (54%) and in 12 (80%) galactorrhea decreased or
`disappeared. Thirteen (54%) achieved normalisation of PRL levels. Newman et a!.
`reported that CV 205-502 to a maximum of 0.14 mg daily was well tolerated in 10
`hyperprolactinemic patients, who were previously proven to be intolerant
`to
`bromocriptine 66• These promising results were confirmed in several studies, all showing
`the potent inhibitory effect of CV 205-502 on PRL secretion, as well as on tumor size,
`
`18
`
`18
`
`

`

`both in micro- and macroprolactinoma patients and the relative small number of
`patients, which complained of side-effects so severe that drug therapy had to be
`discontinuated 67 68 69 70•
`
`1.2.9 Complications of treatment with dopaminergic drugs:
`
`As mentioned above, side effects like nausea and other abdominal problems
`sometimes can be a reason to discontinue drug therapy. Apart from these side-effects,
`also other very . rare occurring complications of dopantinergic drug therapy of
`macroprolactinomas may occur: In patients with macroprolactinomas, which have
`infiltrated the surrounding tissues, especially in/through the sphenoidal bone, treatment
`with dopaminergic drugs which causes a reduction in tumor size, can result in leak of
`cerebrospinal fluid (liquorrhea), sometimes followed by a life-threateuing
`meuingitis 71 72 73.
`
`19
`
`19
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`

`

`1.3
`
`Acromegaly:
`
`1.3.1
`
`Introduction:
`
`As described above in the introduction, acromegaly was the first recognized
`distinct clinical syndrome with the pituitary as the source of the disorder. The hormone
`produced by the somatotrophs of the anterior pituitary is growth hormone. Chromosome
`17-q contains the five gene clusters, responsible for human GH 74 75
`• The episodic
`secretion of GH is under dual hypothalamic control 76• Without altering m-RNA levels,
`somatostatin is capable of suppressing GH secretion, while growth hormone-releasing
`hormone (GHRH) stimulates the secretion as well as induces gene transcription 77 78
`79• GH secretion is predominantly regulated by the fluctuations in somatostatin
`secretion; fluctuations, which are increased during sleep and fasting 80 81
`. Not only
`GHRH and somatostatin, but also IGF-I, thyroid hormone and estrogens contribute to
`the control of GH secretion 79• Although human somatic growth is regulated almost
`primarily by GH, most of GH's growth-promoting effects are mediated by IGF-I, which
`is largely synthesized in the liver, but is also produced in the kidney, muscle, pituitary,
`tract 82 83 84
`• As a negative-feedback
`chondrocytes and
`the gastro-intestinal
`mechanism, IGF-I suppresses GH-mRNA synthesis in the pituitary 85 86• Although
`most of GH's growth promoting actions are mediated by IGF-I, animal models suggest
`that GH and IGF-I act both independently and synergistically in skeletal and organ
`growth "' 88
`•
`Because of the apparent manifestation of the disease, acromegaly is usually
`diagnosed clinically. The incidence of acromegaly is approximately 3 per million and the
`prevalence is about 40 per million 89
`• The somatotrophic cells are mainly situated in the
`lateral wings of the pituitary; their number or structure is not sex-related 90 91
`. The
`basic morphological abnormality associated with increased GH production is an increase
`in the number of GH producing adenohypophyseal cells. These adenomas are composed
`of acidophilic or chromophobic adenohypophyseal cells 92 93
`• Several disorders (Table
`2) can cause hypersecretion of GH, inducing acromegaly in adults (and gigantism before
`epiphyseal closure).
`
`20
`
`20
`
`

`

`Table 2 •
`Excess GH secretion:
`
`Pituitary:
`Densely granulated GH cell adenoma
`Sparsely granulated GH cell adenoma
`Mixed GH cell and PRL cell adenoma
`Mammosomatotroph adenoma
`Acidophil stem-cell adenoma
`Plurihormonal adenoma
`Somatotroph hyperplasia
`GH cell carcinoma
`Ectopic pituitary tumor:
`Sphenoid or parapharyngeal sinus
`Extrapituitary tumor:
`Pancreas
`Lung
`Ovary
`Breast
`
`Excess GHRH secretion:
`
`Eutopic:
`Hypothalamic hamartoma, ganglioneuroma
`Ectopic:
`Carcinoid
`Bronchus
`Gastro-intestinal tract and pancreas
`Undetermined
`Pancreatic islet cell
`Small-cell lung cancer
`Adrenal adenoma
`Pheochromocytoma
`
`Excess growth factor secretion or action:
`
`Acromegalism
`
`•
`
`: Adapted from Mehned S. Acromegaly. N Eng J Med 1990;322: 966-977 .
`
`21
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`80% of the cases of acromegaly are caused by the cotumon somatotroph adenoma,
`which can be either densely granulated, slow growing adenomas with large amounts of
`GH, or sparsely granulated, fast growing tumors 94•
`Mixed GH cell-PRL cell adenomas are histologically benign, bimorphous and
`bihormonal tumors. They are composed oflactotrophic cells and somatotrophic cells 95 %
`97
`• In the tumor, densely- or sparsely granulated GH cells may be mixed with densely(cid:173)
`or sparsely granulated PRL cells.
`Acidophil stem cell adenomas are composed of itumature cells, which are believed
`to be the precursors of both somatotrophs and lactotrophs, and they contain both
`hormones 98• The degree of hyperprolactinernia, even in large tumors, is usually mild.
`Marnmosomatotroph cell adenomas are believed to be the mature variant of the
`stem cell adenomas, also containing both hormones, as was demonstrated e.g. by reverse
`hemolytic placque assay of individual tumor cells by several authors 99 100 101• These
`patients have clinically acromegaly, while PRL levels are only slightly elevated 102
`•
`A rare tumor is the unclassified plurihormonal adenoma, which can present itself
`with acromegaly. They produce two or more hormones, can be monomorphous or
`plurimorphous and can produce unusual combinations of hormones, such as GH and
`TSH, GH, PRL and TSH, GH, PRL and ACTH, or a-subunits 103•
`Somatotroph hyperplasia is usually caused by an ectopic GHRH source and GH
`cell carcinomas are very rare (only five well-documented cases are reported 104
`
`).
`
`1.3.2 Relation between tumor-size, GH- and IGF-I levels:
`
`In most studies a positive correlation between tumor size and basal GH levels has
`106 107 103 109
`110
`been found 105
`• Up
`to
`levels of about 50-80 JJ.g/L, GH
`concentration correlates well with serum IGF-I levels, suggesting that GH levels of about
`60 JJ.g/L do stimulate IGF-I production maximally. 111 112 113 114
`•
`Whether a correlation between age and tumor volume exists, is unclear. Several
`authors have reported such a correlation 107 109, while others could not find such a
`relation 108
`•
`
`1.3.3 Treatment:
`
`As acromegaly is associated with an increase in the expected mortality rate 115,
`it has to be treated either surgically, medically or radiotherapeutically (or with any
`
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`combination of these).
`
`1.3.4 Surgecy:
`
`If a GH level < 5 JJ.g/L after transsphenoidal surgery is used as a criterium for
`cure, only 60% of the patients reach those GH levels, while only 30% of macroadenoma
`patients and very few of the patients with tumors with extrasellar extension turn out to
`
`be cured 116 117 118• Considering the fact that 50% of the patients with GH levels
`
`< 5 JJ.g/L after surgery, do still have elevated IGF-I levels 119, a real cure of
`acromegaly by surgery migbt be. rare So otber means of therapy, or combinations of
`therapy are often necessary.
`
`1.3.5 Radiotherapy:
`
`Wben increased GH production still persists after surgery, or wben tbere are
`contra-indications for surgery, external conventional ( 45 Gy), as well as proton-beam
`radiation (150 Gy) can be used as treatment. Both methods are capable of reducing GH
`levels in a majority of the patients to < 5 JJ.g/L, although these GH levels are reached
`after 10 and 5 years respectively 120 121
`• Acquired hypopimitarism as a (late)
`complication of irradiation therapy occurs in more than 50% of the patients 122•
`
`Medical therapy:
`
`1.3.6 Bromocriptine:
`
`As relatively large doses of bromocriptine are necessary to induce clinically
`beneficial effects 123 124
`, this drug is not so often used as a primary therapy of
`acromegaly, but more often as an adjuvant therapy 125
`• Barkan 119 reported that about
`70% of the patients felt some improvement in the sense of well-being, although serum
`GH and IGF-I levels remained elevated. In less than 20% of the patients, bromocriptine
`is capable of reducing GH levels to less tban 5 JJ.g/L In three reports, the administration
`of octreotide was found to be more effective in lowering GH levels than
`bromocriptine 126 127 128.
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`1.3. 7 Octreotide:
`
`Since the introduction of a cyclic octapeptide analogue of somatostatin, octreotide
`(Sandostatin; SMS 201-995), therapy of acromegaly has become much more successful 129
`130 131
`• Octreotide (50 JJ.g as a single dose, subcutaneously), suppresses GH secretion
`within one hour. Maximal suppression of GH levels is reached after 3 hours. The
`response may be sustained up to 12 hours 132• The drug reduces tumor volume in 50%
`of the patients 133 and even total resolution of a tumor has been reported 134
`• The
`drug reduces the secretion of GH in 90% of the acromegalic patients and because the
`course of serum GH levels after a single-dose of octreotide correlates well with the
`serum GH levels reached during long-term treatment with SMS 201-995, octreotide has
`become the drug of first choice in the medical treatment of acromegaly 130 135 136
`137• It is usually well tolerated, although it inhibits gallbladder contractility, causing the
`development of gallstones 138
`78
`139• Some studies
`indicate
`that continuous
`subcutaneous infusion (or frequent subcutaneous injections) may be more effective than
`the usual regimen of three daily injections 140 141
`. Because serum IGF-I levels do
`correlate well with the mean 24-hour GH levels, IGF-I levels are widely used as a
`sensitive indicator of even mild hypersecretion of GH 137 142
`• Long-term therapy with
`octreotide reduced serum IGF-I levels in several groups of acromegalies by 37 to 81%
`130 143 144
`• One study suggested that pretreatment with octreotide of acromegalic
`patients results in better surgical cure rates 145
`
`.
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`1.4
`
`Cushing's Syndrome:
`
`1.4.1 Diagnostic tests:
`
`Cushing's syndrome describes the clinical symptomatology related to longstanding
`hypercortisolism. The 1 mg overnight dexamethasone suppression test is an excellent
`
`screening test with ahnost no false-negative results 146 147. Although several authors
`have reported that urine sampling of cortisol in several ways is equal or superior to
`diagnose Cushing's syndrome, these assessments are mostly too time-consuming to be of
`great value in every day practice 148 149 150 151_
`Once the diagnosis of Cushing's syndrome is made and "iatrogenic" causes of
`Cushing's syndrome have been made uulikely (medication, alcohol abuse etc.), one must
`determine whether Cushing's syndrome is caused by pituitary overproduction of AC11I
`(Cushing's disease), ectopic production of AC11I (or CRH) or overproduction of cortisol
`by an adrenal adenoma or carcinoma. To differentiate between a pituitary/ectopic or
`adrenal cause, ACTH measurements can be of great help. Although new
`innnunoradiometric assays (lRMA) for AC11I have been developed with a high
`sensitivity and specificity, these assays are often incapable of tracing "big" AC11I, which
`is secreted by most ectopic sources of AC11I, so radio innnunological determinations are
`153
`innnunoradiometric ones 152
`• To determine whether
`still preferred above
`Cusbing's syndrome has a pituitary or non-pituitary cause can be very difficult. A
`continuous dexamethasone infusion (1 mg/hr) for seven hours seems to be a superior
`diagnostic tool for this differential diagnostic problem with a decrease in serum cortisol
`levels of at least 190 nmol/1 as criterium 154
`• Ouly 2 out of 122 patients had false
`negative results and both had corticotrophin-releasing hormone (CRH) producing
`tumors. The CRH stimulation test is also a reliable test with high sensitivity and
`specificity to discriminate between pituitary and ectopic/adrenal causes 155 156
`•
`Pituitary adenomas have an exaggerated increase in ACTH and cortisol levels, while
`ectopic and adrenal Cushing's syndromes show no increase in both levels. This test is
`equally reliable as the long intravenous dexamethasone test 157 158•
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`1.4.2 Radiodiagnostic teclmiques:
`
`Several studies have shown that CT scanning is very unreliable in detecting ACTH
`producing pituitary micro-adenomas, with an overall sensitivity in localizing the adenoma
`of about 50% 159 160 161 162 163
`• This is in part due to the small size of these
`adenomas, as well as by the fact that they have the same degree of enhancement with
`contrast as normal pituitary tissue 159 163
`•
`Magnetic Resonance imaging seems to be a better way in localizing pituitary
`ACTH secreting microadenomas, with a sensitivity of about 75%, although the number
`of patients exantined is still relatively small 159 164 165 166.
`In case of an adrenal cause of Cushing's syndrome, CT scanning has a sensitivity
`of almost 100% and MR imaging offers no extra advantages over CT scanning in these
`patients 167
`•
`
`1.4.3 Localizing by sampling of the inferior petrosal sinus:
`
`By simultaneous sampling of both inferior petrosal sinuses and measuring the
`central-to-peripheral ACTH ratio, one can localize the adenoma in case of Cushing's
`disease either on the left- or right side of the pituitary gland with a sensitivity of about
`85% (AC