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Objective To examine the utility of the GnRH (gonadotrophin-releasing hormone) test in the management of patients with pituitary and parapituitary lesions. Patients and Methods A 5-year retrospective study of LH (luteinizing hormone) and FSH (follicle stimulating hormone) responses to GnRH test in patients with HP (hypothalamic-pituitary) disease in a regional endocrine centre. Serum LH and FSH concentrations were measured at baseline and at 20 and 60 min after an intravenous bolus of 100 mcg (micrograms) of GnRH. The GnRH responses were categorised by tumour size, tumour type, and gonadal status. Results Of the 104 patients studied, 46 were male and 58 were female. There were 50 normal, 38 subnormal and 16 exaggerated LH responses compared with 34 normal 67 subnormal and three exaggerated responses for FSH. Seventy-four patients (71.2%) were hypogonadal. Normal LH responses were achieved in half of the hypogonadal subjects and normal FSH responses in more than a third. Furthermore, the LH responses were exaggerated in nine hypogonadal patients compared with three for FSH. The GnRH test could not differentiate between pituitary or parapituitary lesions either by size or type of lesion. An exception was the male non-functioning adenoma (NFA) sub-group (10 patients, all were hypopituitary, seven were hypogonadal), which demonstrated significant subnormal LH and FSH responses compared with other male and female tumour type sub-groups. Conclusions The data from this study indicate that the GnRH test is unhelpful in the clinical assessment of the HP axis in patients with HP disease. [PUBLICATION ABSTRACT]
Pituitary (2008) 11:271278 DOI 10.1007/s11102-008-0124-4
The GnRH test in the assessment of patients with pituitary and parapituitary lesions: results of a 5-year retrospective study
N. K. Chammas S. M. Chambers P. E. Harris
Published online: 19 April 2008 Springer Science+Business Media, LLC 2008
Abstract Objective To examine the utility of the GnRH (gonadotrophin-releasing hormone) test in the management of patients with pituitary and parapituitary lesions. Patients and Methods A 5-year retrospective study of LH (luteinizing hormone) and FSH (follicle stimulating hormone) responses to GnRH test in patients with HP (hypothalamic-pituitary) disease in a regional endocrine centre. Serum LH and FSH concentrations were measured at baseline and at 20 and 60 min after an intravenous bolus of 100 mcg (micrograms) of GnRH. The GnRH responses were categorised by tumour size, tumour type, and gonadal status. Results Of the 104 patients studied, 46 were male and 58 were female. There were 50 normal, 38 subnormal and 16 exaggerated LH responses compared with 34 normal 67 subnormal and three exaggerated responses for FSH. Seventy-four patients(71.2%) were hypogonadal. Normal LH responses were achieved in half of the hypogonadal subjects and normal FSH responses in more than a third. Furthermore, the LH responses were exaggerated in nine hypogonadal patients compared with three for FSH. The GnRH test could not differentiate between pituitary or parapituitary lesions either by size or type of lesion. An exception was the male non-functioning adenoma (NFA) sub-group (10 patients, all were hypopituitary, seven were hypogonadal), which
demonstrated signicant subnormal LH and FSH responses compared with other male and female tumour type subgroups. Conclusions The data from this study indicate that the GnRH test is unhelpful in the clinical assessment of the HP axis in patients with HP disease.
Keywords GnRH Pituitary
Introduction
Pituitary and parapituitary tumours are frequently associated with reproductive dysfunction and evidence of hypogonadotrophic hypogonadism is common in these subjects [1]. Biochemical assessment of the functional integrity of the hypothalamo-pituitary-gonadal axis is fundamental to the investigation of pituitary tumours. In patients with large macroadenomas, pituitary hormone deciencies are almost invariable with growth hormone (GH) and FSH/LH being the most commonly affected. In patients with microadenomas, pituitary hormone deciencies are uncommon, although it may be benecial in these patients to determine basal gonadotrophin levels, serum testosterone or oestradiol levels, to provide a baseline for future care [2].
For the past 25 years the integrity of the HP-gonadal axis in pituitary dysfunction has largely been assessed using the GnRH test [37]. The validity of this approach has been called into question over the last decade with regards to its diagnostic utility [8]. There have been reports that the GnRH test is of some value in distinguishing between hypothalamic and pituitary causes of hypogonadism [9, 10], is marginally useful in diagnosing delayed puberty [11] but more so in hypogonadotrophic hypogonadism and true precocious puberty [12]. There are few available data on the aetiological diagnostic ability of the
N. K. Chammas P. E. HarrisEndocrine Unit, Kings College Hospital, London SE5 9PJ, UK
N. K. Chammas (&)
Reproductive Medicine Unit, Imperial College Healthcare NHS Trust, St. Marys Hospital, Praed Street, London W2 1NY, UK e-mail: [email protected]
S. M. ChambersClinical Biochemistry, Kings College Hospital, London SE5 9PJ, UK
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GnRH test for pituitary tumours [2, 12, 13]. This study describes one centres experience of using the GnRH test in pituitary and parapituitary tumours. The aim was to identify possible aetiological responses that might facilitate patient management.
Subjects and methods
Subjects
Subjects included were male and female patients with pituitary tumours on whom the GnRH test had been performed over the period of January 1995 to December 1999 at the programmed investigation unit (PIU) in Kings College Hospital, London. The medical case-notes were requested through the clinical audit and effectiveness department and the Clinical Biochemistry department provided a list of all the GnRH tests in question. Patients who underwent the test but whose medical notes were not located or those whose results were not documented were excluded from the study. Patients were seen at Kings College Hospital endocrine clinics or referred from district general hospitals in the South East region.
Methods
Study design
A 5-year retrospective audit of the information derived from the measurement of LH and FSH responses to intravenous GnRH in male and female patients with pituitary and parapituitary tumours in a tertiary endocrine centre. The information obtained from each case-note included the patients sex, age-group, clinical symptoms and signs, clinical/histological diagnosis, radiological ndings, baseline endocrine biochemistry and dynamic pituitary function tests (insulin stress test or glucagon test and GnRH test) as well as treatment given. The GnRH and other clinical and biochemical tests were performed during the course of investigations of these patients ahead of surgical or radio-therapy treatment. In a small proportion of patients referred from district general hospitals medical treatment had already been initiated.
A combination of clinical symptoms and signs together with biochemical values, were used to describe the pituitary status of every patient. The patients were grouped according to clinical, histological and radiological diagnoses.
GnRH response
The basal value refers to the 0 min value for serum LH and FSH just before GnRH test was administered; the maximum
value documented after the GnRH test is given (either at 20 min or at 60 min) is referred to as the peak value.
Since the normal responses of LH and FSH to GnRH test do not appear to have been established by modern assays, previous authors describe a wide spectrum of normal responses. LH responses after administration of GnRH in normal pubertal children are usually above 10 U/l. In adults, LH values may increase 3- to 10-fold above baseline after GnRH administration while FSH values should at least double [69, 14]. For the purpose of this study, GnRH test responses were dened as follows:
A normal response (N) was dened as one in which the administration of GnRH produced an increase of Cthree times the basal LH value or Ctwice the basal FSH value. In addition, peak LH should exceed 10 U/l and peak FSH should exceed 2 U/l.
When the peak value, whether at 20 or 60 min, was less than three times the basal value for LH and less than twice the basal value for FSH, the response was termed subnormal (S).
An exaggerated response (E) was dened as one in which the GnRH test produced a factorial increase of C12 9 the basal LH and FSH.
The GnRH responses were analysed by tumour size, tumour type and gonadal status. Comparisons between individual sub-groups were performed through comparing values obtained from logarithmic transformation of responses. We used the mean of the values obtained for each sub-group to assess signicant statistical differences in responses between sub-groups. The following equation was applied to obtain the logarithmic values:
Square root of Log LH peak value or FSH peak value
LH basal value or FSH basal value Clinical categories
The study population was separated by clinical/histological category into: Prolactinomas, non-functioning adenomas, gonadotrophadenomas, somatotrophadenomas, corticotrophadenomas and other category. The other category included pituitary apoplexy, idiopathic hypopituitarism, craniopharyngiomas, empty sella, optic nerve gliomas, arachnoid cysts and Rathkes pouch and other brain tumours such as meningiomas and astrocytomas.
Radiological categories
Dened as follows:
Microadenoma: A focal hypointensity on CT (computerized tomography) or MR (magnetic resonance) scan \10 mm in diameter.
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Macroadenoma: A focal hypointensity [10 mm in diameter, with or without suprasellar extension.
Invasive macroadenoma: As for macroadenoma but with extension into surrounding structures such as cavernous or sphenoidal sinus.
Other structural abnormalities on CT or MRI scan.
Age groups
Age groups were classied as follows:
Age group 1 (Agp1): \13 years. There are insufcient data to divide the patients into pre-pubertal or pubertal groups by Tanner puberty score.
Age group 2 (Agp2): 1349 years. Puberty was dened as[13 years of age, at which age the basal gonadotrophins were consistently measurable. One female patient in this group was post-menopausal.
Age group 3 (Agp3): [50 years. Females in this group were post-menopausal.
Pituitary status
Adrenocorticotrophic hormone (ACTH) and growth hormone reserve were assessed by measuring serum cortisol and growth hormone after insulin-induced hypoglycaemia using the insulin tolerance test (or glucagon test in patients in whom the insulin tolerance test is contraindicated). Normal responses were dened as a peak cortisol level [550 nmol/l with a rise of [170 nmol/l from baseline and a peak GH level of [20 mU/l. Basal concentrations of prolactin, free thyroxine, gonadal steroids, sex hormone binding globulin (SHBG) and IGF-1 were also measured. All hormonal data were reviewed and analysed on the basis of reference values for the Clinical Biochemistry department at Kings College Hospital.
Gonadal status
Hypogonadism in female patients was diagnosed clinically on the basis of primary amenorrhoea or secondary amenorrhoea of at least 3 months duration and in male patients with impaired libido and erectile dysfunction, in combination with clinical signs on physical examination in both sexes.
This was supported biochemically by an oestradiol level of \70 pmol/l in females and a testosterone of \9 nmol/l in males. LH and FSH deciency is diagnosed in the male by the presence of a low serum testosterone (\9 nmol/l) without appropriate elevation of serum LH, in the premenopausal female by amenorrhoea with low serum oestradiol (\70 pmol/l) and without elevation of serum LH and
FSH, and in the post-menopausal female by lack of the normal elevation of basal LH and FSH levels [14].
GnRH test protocol
GnRH was supplied in vials containing 100 mcg of synthetic GnRH with a diluent. A forearm venous cannula was inserted and a 100 mcg of synthetic GnRH was given intravenously as a bolus and ushed with normal saline, and blood samples were collected for analysis at time 0 min (immediately prior to administration time) 20 and 60 min after the injection for measurement of LH and FSH.
Gonadotrophin assay
LH and FSH were measured on the Bayer Immuno-1 random access analyser, using a heterogeneous dual-monoclonal enzyme-linked (alkaline phosphatase) method, with magnetic separation.
The LH method was calibrated against WHO International Reference Preparation (IRP) 68/40. The lower limit of detection is 0.5 U/l and the upper reporting limit is 200 U/l. Coefcient of variation (CV) is up to 5.2% within calibration and 6.0% between calibration.
The FSH method was calibrated against the WHO IRP 78/549. Our lower reporting limit is 0.5 U/l and upper reporting limit is 150 U/l. CV is up to 3.9%, within calibration and 4.2% between calibration. Cross-reactivity has been checked against LH (IRP 80/552) and was 3.6%, TSH (IRP 80/558) and was 1.3% and FSH (rDNA-FSH, National Institute for Biological Standards and Control (NIBSC)) and was 1.9%.
Imaging
MR scans were performed using either a Siemens 1.0 T or an IGE 1.5 T scanner. After an initial sagittal localiser, the pituitary was imaged in both the sagittal and coronal planes by means of 3 mm contiguous slices using a T1 weighted spin-echo sequence. Patients were scanned both before and after enhancement with intravenous gadolinium.
Statistical methods
All statistical analyses were performed using Microsoft Excel 2000. Comparisons between groups were made by applying a two-tailed, t-test assuming equal variance to the values obtained from the logarithmic transformation of individual responses.
For the purpose of statistical analysis, all hormone concentrations below the limit of detection of the assay
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were assigned values equal to the limit of detectability of the assay.
Results
Population
Laboratory records revealed that 349 GnRH tests were analysed at Kings College Hospital department of Clinical Biochemistry between 1995 and 1999. The test was performed on patients aged 377 years with a variety of hypothalamic, pituitary and parapituitary lesions. We located case-notes for 282 patients who underwent GnRH dynamic testing between 1995 and 1999. Of those, 109 patients had a pituitary or a parapituitary tumour. Five patients were excluded, two having defaulted from clinic and diagnosis was not conrmed and the remaining three had no GnRH test results documented. The remaining 104 patients were studied. Patients demographics are shown in Table 1. Headaches and visual eld loss were the most frequently reported presenting symptoms occurring in 53 patients and 36 patients, respectively. Other presenting complaints included secondary amenorrhoea in 33 patients, impaired libido in 24 patients and erectile dysfunction in 11 patients.
Aetiology
The most common tumour was a prolactin-secreting adenoma (39.4%), followed by a non-functioning adenoma(20.2%) as illustrated in Fig. 1a. Radiological classication according to tumour size showed that 65.4% of tumours were macroadenomas and 11.5% were microadenomas (Fig. 1b).
Pituitary and gonadal status
This is based on clinical and biochemical assessment and is summarized in Table 2.
Prolactin measurements were documented in 55 out of 58 female and in 45 out of 46 male patients. Five out of 39 prolactinoma patients with documented prolactin levels had had their prolactin level normalised by the time the GnRH test was performed. One macroprolactinoma patient had
conrmed dopamine agonist treatment in the notes. All ve patients had a pituitary adenoma conrmed radiologically (two microprolactinoma and three macroprolactinoma patients). Further, the three macroprolactinomas were conrmed histologically.
Forty-two of 58 (72.4%) female and 32 out of 46(69.6%) male patients were hypogonadal.
Treatment
Overall, fty-eight percent of all female patients received medical treatment (dopamine agonists or somatostatin analogues). A similar proportion (56.4%) received surgical treatment and 40% received radiotherapy.
In the male group on the other hand, a lesser proportion (35%) received medical treatment, and more patients received surgical treatment (76.7%) and radiotherapy (51.2%).
Analysis of GnRH responses
Table 3 summarises the overall GnRH responses categorised by tumour type and size. In the female group, there was approximately the same proportion of normal LH and FSH responses categorised according to tumour type, but
(a)
(b)
45
41
40
No. of patients(n=104)
35
30
25
21
20
15
10
5
96 6 4 3 3 3 3 5
0
Prolactin oma
Non-functioning aden o ma
Somatotrophaden oma
Gonadotroph adenoma
Corticotrophaden oma
Empty se lla
Craniopharyng io ma
Pituitary ap opl exy
Opticnervegli oma
Suprasellarmeningi oma Oth er
80
70
No. of patients (n=104)
68
60
50
40
30
8 12 5
11
20
10
Macroaden oma
0
Not um o ur
Oth er find in gs
Invasive Macroade noma
Microaden o ma
Fig. 1 (a) Clinical/histological diagnoses in patients with pituitary and parapituitary lesions. (b) Radiological diagnoses in patients with pituitary and parapituitary lesions
Table 1 Patient demographics
Age group Male Female
Agp1 (\13 years) 2 8 Agp2 (1349 years) 26 41
Agp3 (C50 years) 18 9 Total 46 (44.2%) 58 (55.8%)
Of the female patients, 10 were post-menopausal (Agp = Age group)
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Table 2 Clinical and biochemical assessment of female and male patients
Tumour type Sex Number Hypogonadism Prolactin TSH ACTH GH
Present Absent Tested Raised Tested Decient Tested Decient Tested Decient
Prolactinoma $ 26 21 5 25 22 26 4 24 10 22 13
# 15 10 5 14 12 13 1 14 6 14 10 NFA $ 11 6 5 11 6 11 1 10 4 10 5
# 10 7 3 10 2 10 3 8 6 9 8 Gonadotropha denoma $ 3 3 0 3 1 3 1 3 2 2 1
# 3 2 1 3 0 3 0 3 2 3 2 Somatotropha denoma $ 4 4 0 4 1 4 1 3 1 4 1
# 5 2 3 5 0 5 0 5 2 4 3 Corticotropha denoma $ 3 0 3 2 2 3 0 3 1 3 1
# 3 3 0 3 0 3 0 2 1 3 3 Other $ 11 8 3 10 2 11 4 11 5 11 6
# 10 8 2 10 2 10 1 10 7 10 6 Total $ 58 42 16 55 34 58 11 54 23 52 27
# 46 32 14 45 16 44 5 42 24 43 32 Percentage (%) $ 72.4 62 19 42.6 52
# 69.6 35.6 11.4 57 74.4
Table 3 Summary of GnRH responses in all 104 patients classied according to tumour type and tumour size
Nnormal; Ssubnormal;
Eexaggerated;Micromicroadenoma;Macromacroadenoma; InvMinvasive macroadenoma
Tumour type Sex No. Tumour size No. of Pts LH response FSH response
N S E N S E
Prolactinoma $ 26 Micro 9 7 2 5 4
Macro 13 3 4 6 7 6
Inv M 1 1 1
Other 3 1 2 3
# 15 Macro 14 7 6 1 5 9
Other 1 1 1
NFA $ 11 Macro 10 9 1 3 7
Inv M 1 1 1
# 10 Macro 7 7 1 6
Inv M 3 1 2 3
Gonadotrophadenoma $ 3 Macro 2 1 1 1 1
Inv M 1 1 1
# 3 Macro 2 2 2
Inv M 1 1 1
Somatotrophadenoma $ 4 Macro 4 2 2 2 2
# 5 Micro 1 1 1
Macro 4 4 1 3
Corticotrophadenoma $ 3 Micro 1 1 1
Macro 2 2 2
# 3 Micro 1 1 1
Macro 2 1 1 2
Other $ 11 11 3 6 2 4 7
# 10 10 5 5 3 7 Total $ 58 27 16 15 24 32 2
# 46 23 22 1 10 35 1
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more exaggerated LH responses compared to exaggerated FSH responses and more subnormal FSH responses compared to subnormal LH responses. In the male group, the LH responses remained normal more often than the FSH responses. The GnRH responses were heterogenous in all but the male NFA sub-group. Nine out of 10 patients in this sub-group demonstrated signicant subnormal LH responses, one normal FSH response and nine subnormal FSH responses. All 10 patients were hypopituitary and seven patients were also hypogonadal.
Table 4 shows the GnRH responses in hypogonadal and eugonadal female and male patients. The responses were distinctly heterogeneous. On average 40% of hypogonadal female patients demonstrated normal LH and FSH responses and over one-fth had exaggerated LH responses. Of the nine hypogonadal female patients with exaggerated LH responses seven were prolactinomas (one microprolactinoma and six macroprolactinomas) and two were somatototrophadenomas. The age range was 1855 years with only two of the nine patients being post-menopausal. The two exaggerated FSH responses were in the somatotrophadenoma subgroup, one of which was for a post-menopausal patient with high basal LH and FSH levels.
A slightly higher proportion (44%) of male hypogonadal patients demonstrated normal LH responses and 21% normal FSH responses. Only one hypogonadal male patient (56 years old) with a gonadotrophadenoma and high basal FSH levels demonstrated an exaggerated FSH response with normal basal LH level and LH response to GnRH.
Of the female eugonadal patients with subnormal responses (eight patients), one had a subnormal LH and FSH response and was perimenopausal. Of the seven patients with subnormal FSH responses one patient was oligomenorrhoeic with normal basal LH and FSH levels. In
the male eugonadal patients with subnormal responses (11 patients), four had subnormal LH and 11 had subnormal FSH responses. All 11 patients were eugonadal by clinical and biochemical criteria.
Comparisons between all female and male responses following logarithmic transformation and using the paired students t-test, showed that female LH and FSH responses were considerably higher than the male LH and FSH responses. The mean for LH responses in female patients(0.88) was signicantly higher than for male patients (0.76), P \ 0.018. Similarly female FSH responses mean value(0.55) was higher than for male patients (0.42) P \ 0.000217. Moreover, female patients had more exaggerated LH (15) and FSH (2) responses compared with male patients (one exaggerated response for LH and FSH) (Table 3).
Comparisons were then performed between all male and female groups and sub-groups and within female and male sub-groups, using the paired students t-test to check for statistically signicant differences in GnRH responses between the groups and sub-groups as explained below.
Tumour size
Comparisons between female and male groups and subgroups were performed using the paired students t-test to compare the mean of the values obtained for each subgroup. The only signicant result was in the male FSH responses in the macroadenoma sub-group (34 patients, mean 0.44), which were signicantly lower than the FSH responses in the microadenoma sub-group (two patients mean 0.77), P \ 0.003.
Tumour type:
Within the male tumour type sub-groups, the LH responses were signicantly subnormal in the NFA sub-group compared to other sub-groups, NFA (mean of 0.55) vs. prolactinoma (mean 0.90) P \ 0.000012 and NFA vs. somatotrophadenoma (mean 0.9), P \ 0.00015 for LH. A large proportion of these patients were hypogonadal (70%), ACTH decient (6 out of 8 tested) and GH decient (8 out of 9 tested) as shown in Table 2. Similarly, for FSH, the male NFA responses (mean 0.31) were signicantly lower than the male prolactinoma responses (mean 0.49) P \ 0.0035 and the somatotrophadenoma responses (mean0.53), P \ 0.013. Of note, the gonadotrophadenoma patients (6) demonstrated no specic response pattern.
Gonadal status
There was no signicant association between the responses of LH and FSH to GnRH stimulation and gonadal status in either male or female groups.
Table 4 GnRH responses categorised by gonadal status in male and female patients
Gonadal status No. Responses Females Males
Hypogonadal 74 LH Normal 18 14
Subnormal 15 18
Exaggerated 9 0
FSH Normal 16 7
Subnormal 24 24
Exaggerated 2 1
Eugonadal 30 LH Normal 9 9
Subnormal 1 4
Exaggerated 6 1
FSH Normal 8 3
Subnormal 8 11
Exaggerated 0 0
Total 104 58 46
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Discussion
There is a lack of consensus on what constitutes the response to GnRH stimulation of a healthy adult with normal pituitary function and which gonadotrophin response patterns are useful in differentiating health from disease. The variability in baseline gonadotrophin levels and response to GnRH during the normal female menstrual cycle makes it difcult to dene the limits of normal baseline gonadotrophins as well as normal peak response. In a normal response, LH peaks earlier than FSH and the magnitude of change is much bigger and less variable than that for FSH [6]. In addition, responses vary greatly in both adults and children. In this retrospective study, a control group was not included, normative data being based on previously published data [6, 9, 15].
The data describe the responses of 104 patients with pituitary and parapituitary lesions to GnRH. Of those patients, 74 (71.2%) were hypogonadal and in all but two patients, it was possible to produce a rise in either LH or FSH. Indeed, a normal LH response was achieved in half of the hypogonadal subjects and a normal FSH response in nearly a third. Furthermore, the LH response was exaggerated in nine hypogonadal patients (one microprolactinoma, six macro-prolactinomas and two somatotrophadenomas) compared with three for FSH (two somatotrophadenomas and one invasive gonadotrophadenoma). The eugonadal population(28.8%) also displayed subnormal LH (one female and four male patients) and FSH responses (eight female and 11 male patients) to GnRH (Table 4). In addition, the GnRH test could not differentiate between pituitary or parapituitary lesions either by size or type of lesion, with the exception of the male non-functioning adenoma sub-group (10 patients), which demonstrated signicant subnormal LH and FSH responses compared with other male tumour type sub-groups and with the female non-functioning adenoma sub-group. The latter observation is in keeping with the nding that, overall, the female LH and FSH responses were signicantly higher than the male responses (Table 3).
Earlier studies hypothesised that the use of the GnRH test in hypogonadal subjects would facilitate localization of the defect at either the hypothalamic, pituitary, or gonadal level [6]. This is not supported by the data in this study, since some patients with hypothalamic lesions failed to respond and others with primary pituitary disease responded normally.
One of the very early studies by Wentz and colleagues compared the responses of a group of 60 women with menstrual dysfunction to responses obtained from volunteers with normal ovulatory menstrual cycles. The majority of patients with secondary amenorrhoea had responses that fell into the 95% condence limits of responses for normal ovulating women. In addition, the relationship between the amplitude of the gonadotropin response and the initial baseline values
gave the most useful clinical information as most patients with low LH baseline values showed a minimal response to GnRH. They concluded that responses of patients with different forms of dysfunction may be similar, and patients with similar pathology may respond quite differently [16].
Newton and colleagues concluded that GnRH may be used to test the ability of the pituitary to release LH and FSH, but the magnitude and duration of the response is not of any additional diagnostic value [7]. More recently, Pavord et al. assessed the value of 232 combined dynamic pituitary function tests including 222 GnRH tests in patients with known or suspected pituitary disease, demonstrating that there was poor agreement between the pituitary response to GnRH and basal levels of gonadotrophins. They concluded that routine GnRH testing only assesses the readily releasable pool of gonadotrophins rather than the adequacy of the axis as a whole [14].
Westwood and colleagues evaluated the clinical usefulness of GnRH in 126 short children through a retrospective study. They demonstrated that there was no apparent relationship between either basal gonadotrophin concentrations or response to GnRH stimulation and clinical assessment of pituitary function. They concluded that an abnormal response to hormone stimulation is not diagnostic of hypothalamic-pituitary disease and that the GnRH test should not be used routinely in the investigation of children with short stature [8].
A number of factors inuence the LH and FSH responses to GnRH such as the prior GnRH secretory state, the gonadal steroid state and gonadal activity, the time course of GnRH injection and the patients gender [17]. Such factors result in a great variability of results obtained, thus limiting the diagnostic value of the test in a specic patient. While the number of subjects in the male NFA sub-group was small, reduced LH and FSH responses were demonstrated, the responses overall in this sub-group being signicantly reduced compared to other male tumour type sub-groups and to normative data [6]. Pituitary imaging demonstrated that all tumours in this sub-group were macroadenomas with a small proportion being invasive. The male NFA patients were also hypopituitary and some of these tumours immunostained for glycoprotein hormone alpha (a) sub-units. The a-sub-unit responses were documented in some instances (6 of 104 patients) but numbers were too few to comment on in the overall results and were therefore not included in Table 3.It is therefore difcult to draw any denitive conclusions regarding the value of the test as a diagnostic discriminator in the NFA sub-group. The signicantly subnormal responses in the male NFA patients may reect a more severe hypo-pituitary status appropriate to the fact that NFAs are generally detected after they had grown considerably with more frequent occurrence of hypopituitarism. Gonadotrophinomas can present with gonadal hyperstimulation [13],
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whether testicular (macro-orchidia) or ovarian, (ovarian hyperstimulation similar to that seen in ovulation induction) which may be associated with a characteristic pattern of responses. The results in this small sub-group, however, were quite heterogenous.
In the miscellaneous other category no dening responses were noted and numbers were too few to draw any conclusions regarding responses in individual subgroups. Craniopharyngiomas, which show a high incidence of hypopituitarism [18], demonstrated normal responses in two adult patients, one of whom was hypogonadal and a subnormal LH and a normal FSH in a prepubertal patient. Suprasellar arachnoid cysts may cause disorders of growth, puberty and HP function, in particular stimulation of the HP-gonadal axis [19]. The two patients examined demonstrated one normal and one subnormal GnRH response.
Exaggerated responses in male patients older than 50 years could represent primary gonadal failure. An exaggerated FSH response was demonstrated in a 74-year-old hypogonadal male with a gonadotrphinoma, who also had an elevated basal FSH level. The retrospective nature of the study meant that detailed information regarding pubertal staging and male gonadal function was not available. Similarly, it was also difcult to ascertain the stage of menstrual cycle relative to the timing of the GnRH test for the menstruating female patients. This is of relevance because previous authors have shown that there is no difference between the gonadotrophin responses to GnRH in men and in women studied during the follicular phase of their cycle but that much greater responses in both LH and FSH can be obtained in women during the luteal phase of the cycle [6]. This may explain the generally higher responses seen in the female population subgroup of patients.
The GnRH test has traditionally been performed to assess the pituitary gonadotrophin reserve although its value has been debatable for a number of years. Performing the GnRH test in post-menopausal women is unnecessary and potentially hazardous in all pituitary adenoma patients and is no longer current practice [20, 21]. The data from this study have demonstrated that the GnRH test is unhelpful in the assessment of pituitary reserve in patients with hypothalamic and pituitary disease. Detailed clinical assessment together with baseline gonadal function can provide denitive information in most cases. Occasionally, the test may be an option the clinician may choose in selected cases in particular where differentiating hypogonadism of pituitary origin and that of hypothalamic origin may prove challenging [10].
References
1. Coscia AM, Fleischer N, Besch PK, Brown LP, Desiderio D (1974) The effect of synthetic luteinizing hormone-releasing
factor on plasma levels in pituitary disease. J Clin Endocrinol Metab 38:83882. Lamberton RP, Jackson IM (1983) Investigation of hypothalamic-pituitary disease. Clin Endocrinol Metab 12:509534
3. White WF, Schally AV, Baba Y, Arimura A, Redding TW (1971) Evidence for peptide nature of LH and FSH-releasing hormones. Biochem Biophys Res Commun 42:5056
4. Schally AV, Nair RM, Redding TW, Arimura A (1971) Isolation of the Luteinizing hormone and follicle-stimulating hormone-releasing hormone from porcine hypothalami. J Biol Chem 246:72307260
5. Schally AV, Arimura A, Kastin AJ et al (1971) Gonadotropin-releasing hormone: one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science 173:70367038
6. Besser GM, McNeilly AS, Anderson DC et al (1972) Hormonal responses to synthetic luteinizing hormone and follicle stimulating hormone-releasing hormone in man. BMJ 3:267271
7. Newton JR, Kilpatrick MJ, Pike JM, Collins WP (1975) An evaluation of the diagnostic value of synthetic luteinizing hormone releasing hormone. Acta Endocrinol 80:417428
8. Westwood ME, Butler GE, McLellan AC, Barth JH (2000) The combined pituitary function test in children: an evaluation of the clinical usefulness of TRH and LHRH stimulation tests through a retrospective analysis of one hundred and twenty-six cases. Clin Endocrinol 52:727733
9. Mortimer CH, Besser GM, McNeilly AS et al (1973) Luteinizing hormone and follicle stimulating hormone test in patients with hypothalamic-pituitary-gonadal dysfunction. BMJ 4:7377
10. Hashimoto T, Miyai K, Uozumi T et al (1975) Effect of prolonged LH-releasing hormone administration on gonadotrophin response in patients with hypothalamic and pituitary tumours. J Clin Endocrinol Metab 41:712716
11. Vierhapper H (1985) LH-RH stimulated LH secretion in human endocrine disease. Acta Endocrinol Suppl 269:325
12. Dash RJ, Sialy R, Rao NS (1985) LH and FSH responses to GnRH in health and disease. J Steroid Biochem 23:82382613. Chanson P (2000) Gonadotroph pituitary adenomas. Ann Endocrinol 61:258268
14. Pavord SR, Girach A, Price DE et al (1992) A retrospective audit of the combined pituitary function test, using the insulin stress test, TRH and GnRH in a district laboratory. Clin Endocrinol 36:135139
15. Snyder PJ, Reitano JF, Utiger RD (1975) Serum LH and FSH responses to synthetic gonadotropin-releasing hormone in normal men. J Clin Endocrinol Metab 41:938945
16. Wentz AC, Jones GS, Rocco L, Matthews RR (1975) Gonadotropin response to luteinizing hormone releasing hormone administration in secondary amenorrhoea and galactorrhea syndromes. Obstet Gynecol 45:256262
17. Grossman A (1998) Neuroendocrine control of pituitary function. In: Grossman A (ed) Clinical endocrinology, 2nd edn. Blackwell Science Ltd
18. Paja M, Lucas T, Garcia-Uria J et al (1995) Hypothalamic-pituitary dysfunction in patients with craniopharyngioma. Clin Endocrinol 42:467473
19. Adan L, Bussieres L, Dinand V et al (2000) Growth, puberty and hypothalamic-pituitary function in children with suprasellar arachnoid cyst. Eur J Pediatr 159:348355
20. Foppiani L, Piredda S, Guido R, Spaziante R, Giusti M (2000) Gonadotropin-releasing hormone-induced partial empty sella clinically mimicking pituitary apoplexy in a woman with a suspected non-secreting macroadenoma. J Endocrinol Invest 23:118121
21. Matsuura I, Saeki N, Kubota M, Murai H, Yamaura A (2001) Infarction followed by haemorrhage in pituitary adenoma due to endocrine stimulation test. Endocr J 48(4):493498
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