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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2004-0850
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 3 1280-1286
Copyright © 2005 by The Endocrine Society

Value of Gonadotropin-Releasing Hormone Testing in the Differential Diagnosis of Androgen Deficiency in Elderly Men

M. Christ-Crain, C. Meier, P. R. Huber, L. Zimmerli and B. Mueller

Division of Endocrinology, Diabetes, and Clinical Nutrition (M.C.-C., C.M., B.M.), Department of Central Laboratories (P.R.H.), and Medical Outpatient Clinics (L.Z.), University Hospitals, CH-4031 Basel, Switzerland

Address all correspondence and requests for reprints to: Dr. M. Christ-Crain, Division of Endocrinology, Department of Internal Medicine, University Hospitals, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: christmj{at}bluewin.ch.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Elderly men with low testosterone (T) levels are increasingly diagnosed to have partial androgen deficiency of the aging male (PADAM). Frequently, magnetic resonance imaging is performed to exclude pituitary adenoma. The value of GnRH testing to differentiate PADAM from secondary hypogonadism is unknown.

Serum levels of T as well as LH and FSH at baseline and after GnRH were evaluated in the following groups: 1) 24 elderly men with low serum T (<11.7 nmol/liter), 2) 25 elderly men with normal serum T levels (>11.7 nmol/liter), 3) 10 men with primary hypogonadism, 4) 24 men with secondary hypogonadism, and 5) 13 healthy young volunteers.

In elderly men, T levels were lower (P < 0.001) and gonadotropin levels higher (P = 0.03) compared with younger controls. LH and FSH response to GnRH was higher in elderly men with low T levels (PADAM) compared with elderly men with normal T levels (P = 0.02 and P < 0.001) in the presence of similar basal gonadotropin levels. To differentiate secondary hypogonadism from PADAM with a sensitivity of 100%, a T less than 10 nmol/liter had a specificity of 50%. This specificity was improved to 75% by using a cutoff of less than or equal to 15 mU/liter increase of LH upon GnRH stimulation.

Overall, decreased T levels and increased LH levels in elderly men suggest a primary Leydig cell dysfunction. In the subgroup of elderly men with low T levels, an increased LH response to GnRH with normal basal LH levels suggests additional, possibly hypothalamic changes. To exclude secondary hypogonadism in PADAM, diagnostic accuracy can be improved by using GnRH testing.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
ELDERLY MEN WITH low-normal testosterone (T) levels and symptoms suggestive for hypogonadism in the absence of chronic illnesses and environmental factors are increasingly diagnosed with partial androgen deficiency of the aging male (PADAM) (1). It remains unclear whether the age-related decline of T levels in elderly men is a result of diminished testicular function or because of age-associated changes in hypothalamic-pituitary feedback regulation or a combination of both (2, 3, 4, 5). A primary testicular cause is suggested by the presence of increased levels of circulating gonadotropins (6, 7). However, because a significant proportion of elderly men with low T levels are normogonadotropic (8), additional changes in hypothalamo-pituitary function are likely. A critical role of the hypothalamo-pituitary axis in the pathophysiology of PADAM is further based on the findings of a decreased and delayed LH amplitude (9, 10) and a decreased immunoreactive LH response after stimulation with estrogen antagonists (11). Together with a decreased LH pulsatility (12, 13), the maintained responsiveness of the gonadotrophs to GnRH (14) argues in favor of a decreased release of GnRH from the hypothalamus.

It is a clinical dilemma whether low T levels in elderly men in the presence of normal gonadotropin levels need further evaluation for underlying diseases of the pituitary-hypothalamic axis. It has been recommended to perform magnetic resonance imaging (MRI) in men with inadequately low T levels (<6.9 nmol/liter) (15, 16).

The present study aims to investigate whether the measurement of GnRH-stimulated gonadotropin levels may be useful to differentiate elderly men with PADAM from elderly men with secondary hypogonadism caused by pituitary disease. In addition, we evaluated whether elderly men with PADAM show distinct findings in basal and stimulated gonadotropin levels compared with elderly men with T levels within the reference range as well as compared with healthy young men.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Study subjects

Total T levels as well as LH and FSH, both basal and after GnRH stimulation, were measured in the following five groups of men. The first two groups included 49 community-living elderly men (aged 55 yr or older), recruited by newspaper advertisement or after their presentation to the medical and urological outpatient clinics for routine, non-disease-specific check-ups (17). All of these 49 men were in good general health and free of any serious acute or chronic medical conditions. In 25 of these men (first group) circulating T levels were more than 11.7 nmol/liter, whereas in 24 men (second group), serum T levels were low, defined as less than 11.7 nmol/liter, i.e. 2.5 SD below the mean total T level of the young control population. MRI was performed to exclude hypothalamo-pituitary disease. The third group included 10 men with primary hypogonadism (Klinefelter syndrome, n = 6; testicular damage, n = 4), the fourth included 24 men with secondary hypogonadism (pituitary macroadenoma before or after transsphenoidal surgery, n = 22; syndrome of empty sella, n = 2), and the fifth group included 13 young healthy controls, mainly staff members (mean age, 33.9 ± 3.0 yr).

All men were examined at the Research Unit of the Division of Endocrinology, Department of Medicine at the University Hospital, Basel. Study subjects received no payment for their participation. The study was approved by the local Ethics Committee for Human Studies according to the Declaration of Helsinki, and all participants provided written informed consent.

Hormone measurements

Serum total T (normal reference range, 9.9–28.0 nmol/liter) (18) as well as basal LH (reference range, 1.7–8.6 mU/liter) and FSH (1.5–12.4 mU/liter) were measured using the Elecsys-System (Roche Diagnostics, Rotkreuz, Switzerland).

GnRH testing was performed as follows. Blood samples for the measurement of serum LH and FSH levels were collected before as well as 30 and 60 min after a single iv injection of 100 µg synthetic GnRH (Ferring GmbH, Kiel, Germany).

Statistical analyses

All data are expressed as means ± SD in text and tables and means ± SEM in figures. We used the Spearman correlation method for correlation analyses between basal and stimulated LH levels. We used the differences between peak and basal LH concentration, referred to as {Delta} max, as response variable, to eliminate the additive effect of basal LH level on the peak. Two group comparisons were performed by Student’s t test and by Mann-Whitney U test in nonparametric distribution. For multiple group comparisons, one-way ANOVA or Kruskal-Wallis one-way ANOVA was applied, as appropriate.

Two-sided P values <0.05 were considered statistically significant. Data were analyzed using Statistica for Windows (version 6.0, StatSoft, Inc., Tulsa, OK). Receiver-operating characteristics (ROC) were calculated using MedCalc for Windows (version 7.2.1.0., Mariakerke, Belgium).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Characteristics

As presented in Table 1Go, young healthy controls had significantly lower body mass index (BMI) compared with all other groups. Young men and patients with primary hypogonadism were significantly younger compared with the other groups.


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  		TABLE 1. Descriptive data of the different groups

 
Men with pituitary-related secondary hypogonadism were younger compared with elderly men with low T levels (PADAM). Comparing the two groups of elderly men (i.e. with low and with normal T levels), age and BMI were similar. In the group of elderly men, MRI imaging was normal in every subject.

T, LH, and FSH levels in elderly men compared with young men

In elderly men, serum T levels were significantly lower (P < 0.001) and basal gonadotropin levels significantly higher (P = 0.03 for LH and <0.001 for FSH, respectively) compared with young healthy controls (Table 1Go and Fig. 1Go). LH and FSH levels showed a more pronounced increase after GnRH stimulation in elderly men compared with young men.



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  		FIG. 1. Comparison between T levels, basal and stimulated gonadotropin (LH and FSH) levels in young men (n = 13) and elderly men (n = 49). Small centered squares denote mean, boxes represent SEM, and whiskers 1.96 SEM.

 
Comparison of subgroups of elderly men with normal and low T levels

Serum gonadotropin levels at baseline were not significantly different between elderly men with normal T levels compared with elderly men with low serum T levels. (LH, P = 0.23; FSH, P = 0.79) (Table 1Go). In contrast, peak gonadotropin levels after GnRH stimulation were significantly higher in elderly men with low T levels. Both circulating LH and FSH increased by a mean of 621.23 and 178.42%, respectively ({Delta}LH, P < 0.001; {Delta}FSH, P = 0.008). This increase was significantly more pronounced compared with men with normal T levels (differences between groups: LH, P = 0.02; FSH, P < 0.001) (Fig. 2Go).



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  		FIG. 2. Comparison between T levels and basal and stimulated LH/FSH levels in elderly men with low compared with elderly men with normal T levels. Levels for young men are shown for comparison analysis. Small centered squares denote mean, boxes represent SEM, and whiskers 1.96 SEM.

 
Differentiation of elderly men with low T levels from men with primary and secondary hypogonadism

Compared with elderly men with low T levels (i.e. men with PADAM), men with primary hypogonadism had both significantly higher basal LH levels and a more pronounced LH increase after GnRH stimulation (Fig. 3Go). Men diagnosed with secondary hypogonadism had lower T and basal LH levels as well as a blunted LH response after GnRH stimulation compared with elderly men with PADAM.



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  		FIG. 3. Serum T levels and basal and peak LH levels in men with PADAM compared with men with primary and secondary hypogonadism. Small centered squares denote mean, boxes represent SEM, and whiskers 1.96 SEM.

 
The diagnostic accuracy of various parameters (total T, direct free T, LH, and FSH basal as well as stimulated) in the differential diagnosis of primary and secondary hypogonadism was evaluated by ROC analysis and is shown in Fig. 4Go. In the differential diagnosis of primary hypogonadism and PADAM, the area under the curve for total T was 0.81 ± 0.08 (confidence interval, 0.63–0.92), for basal LH 0.995 ± 0.02 (0.88–1.0), for basal FSH 0.97 ± 0.04 (0.85–0.99), for stimulated LH 0.98 ± 0.08 (0.73–0.97), and for stimulated FSH 0.94 ± 0.06 (0.80–0.99). Targeting a 100% sensitivity to differentiate patients with primary hypogonadism from PADAM, a basal LH of more than 8 mU/liter and FSH level more than 28 mU/liter had a specificity of 95.8 and 100%, respectively. A circulating total T level of less than 8.7 nmol/liter had a specificity of 66.7%, and a maximal LH increase upon GnRH stimulation of more than 30 mU/liter had a specificity of 75%.



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  		FIG. 4. ROC curves for various parameters (T, LH, and FSH, basal as well as stimulated) for the differential diagnosis of primary hypogonadism and PADAM (A) and secondary hypogonadism and PADAM (B), respectively.

 
In the differential diagnosis of secondary hypogonadism and PADAM, the area under the ROC curve for total T was 0.84 ± 0.06 (0.70–0.93), for free T 0.608 ± 0.104 (0.427–0.770), for basal LH 0.87 ± 0.05 (0.74–0.95), for basal FSH 0.81 ± 0.06 (0.67–0.91), for stimulated LH 0.94 ± 0.04 (0.83–0.99), and for stimulated FSH 0.86 ± 0.06 (0.73–0.94). Targeting a 100% sensitivity to differentiate patients with secondary hypogonadism from elderly men with PADAM, basal LH less than 6 mU/liter and FSH levels less than 10 mU/liter had a specificity of 16.7 and 29.2%, respectively, whereas a total T level of less than 10 nmol/liter had a specificity of 50%, and a free testosterone level of less than 38.8 pmol/liter had a specificity of 20.8%. A maximal LH level after GnRH stimulation of less than 15 mU/liter had a specificity of 75%. For a total testosterone of less than 8.7 nmol/liter, the sensitivity was 79.2% with a specificity of 62.5%. For a total testosterone of less than 6.8 nmol/liter, the sensitivity was 45.8% and the specificity 79.2%. For a total testosterone of less than 5.9 nmol/liter, the respective values were 41.7 and 95.8%. Other cutoffs for the LH response to GnRH showed the following results. For an LH response after GnRH of less than 11.5, the sensitivity was 79.2% and the specificity 79.2%. For an LH response after GnRH of less than 10.6 mU/liter, the sensitivity was 70.8% with a specificity of 87.5%; for an LH response after GnRH of less than 9.3 mU/liter, the respective values were 66.7 and 95.8%.

Signs and symptoms of hypogonadism were not significantly different between men with PADAM and men with secondary hypogonadism. Lack of libido was present in 54.2% of men with PADAM and 66.7% of men with secondary hypogonadism, respectively, erectile dysfunction in 58.3 and 54.2%, fatigue in 37.5 and 58.3%, depressive mood in 25.0 and 20.8%, and a diminished osteodensity (i.e. osteopenia or osteoporosis) in 16.7 and 29.2%, respectively. Conversely, BMI was not significantly different between both groups (27.6 ± 5.4 in men with PADAM vs. 27.2 ± 3.6 in men with secondary hypogonadism).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
This study evaluates the value of GnRH testing in characterizing elderly men with PADAM and compares its diagnostic accuracy in differentiating men with PADAM from men with hypo- and hypergonadotropic hypogonadism.

It is estimated that, dependent on the method used to assess circulating T levels, approximately 20–40% of men at the age of 60 yr are found to have low serum T levels (19). The cause of partial androgen deficiency in these men is only partially understood. Some studies show increased basal gonadotropin levels compared with young men, arguing for testicular insufficiency, whereas others do not (9, 20). The gonadotropin response to GnRH administration in aged men has been reported to be increased, decreased, or similar compared with that in young men (14, 21). The sensitivity of the gonadotophs to small doses of GnRH was found to be preserved, suggesting an intact pituitary responsiveness and a decreased hypothalamic release of GnRH in aged men compared with that of young men (14). So far, no study evaluated GnRH testing in elderly men with normal circulating T levels compared with men with PADAM.

Based on our data, two distinct groups of elderly men can be identified by GnRH testing. First, elderly men with T levels within the normal reference range appear to have predominantly a state of decreased Leydig cell reserve (subclinical Leydig cell failure) with lower T and higher gonadotropin levels compared with young men. Second, the subgroup of elderly men with low T levels, classified as PADAM, had an increased LH and FSH response to GnRH without differences in basal gonadotropin levels compared with elderly men with normal T levels. This marked increase of LH and FSH to GnRH suggests a preserved pituitary reserve in elderly men with PADAM. Thus, the more marked decrease of circulating T levels in men with PADAM might originate from additional changes on the hypothalamic level. In agreement with this hypothesis is the finding that restoration of hypothalamic function with pulsatile GnRH administration for 36 h improved the diagnostic performance of GnRH testing in the differential diagnosis of temporary hypothalamic hypogonadism from permanent male hypogonadism caused by pituitary disease (22). As a limitation, we did not investigate GnRH pulsatility in our study to assess hypothalamic function. In addition, because of the relatively high dose of GnRH of 100 µg, our data provide mainly information on the pituitary LH reserve rather than on the sensitivity of the gonadotrophs.

It is a clinical dilemma whether low T levels in elderly men in the presence of normal LH levels should be further evaluated for the presence of underlying diseases of the pituitary-hypothalamic axis. The great majority of patients with nonfunctioning pituitary adenoma present in middle or old age when the tumor size has reached the stage of a macroadenoma and signs of hypopituitarism, particularly hypogonadism, are present (23). However, clinical manifestations of biochemical hypogonadism lack both sensitivity and specificity (17).

Basal gonadotropin levels are sufficient to differentiate a state of age-related partial androgen deficiency from primary hypogonadism. In contrast, the diagnostic value of basal T and gonadotropin levels is limited in the differential diagnosis of secondary, hypogonadotropic hypogonadism from elderly men with PADAM, as shown by ROC analyses. Namely in patients with T levels less than 6.9 nmol/liter, it has been recommended to routinely perform MRI (15). In our study, 21% (5 of 24) of the elderly men with PADAM had serum T levels below that threshold. The MRI was normal in these as well as in all of the other elderly subjects. In addition, more than 50% (13 of 24) of men with secondary pituitary-related hypogonadism had T levels greater than 6.9 nmol/liter, hence overlapping with elderly men with PADAM. Thus, sensitivity and specificity of basal circulating T levels is very limited. Similarly, basal LH and FSH levels showed a wide overlap between men with pituitary adenoma compared with elderly men with PADAM, which is in accordance with the literature (16).

In this context, the value of GnRH testing in the differential diagnosis of secondary hypogonadism from elderly men with PADAM has never been investigated. We found that LH and FSH levels upon GnRH stimulation can improve the pretest probability for a pituitary adenoma. Specifically, in elderly men with a T level less than 11.7 nmol/liter, an increase of LH more than 15 mU/liter has a 100% sensitivity to exclude pituitary-related hypogonadism. The specificity of a blunted LH increase upon GnRH stimulation of less than 15 mU/liter is 75%. This is considerably better compared with the specificity of low T levels or basal gonadotropin concentrations.

At our institution, performing MRI is three to four times more expensive compared with GnRH testing. Another drawback of MRI besides the costs is the potential of detecting nonpathogenic incidentalomas, triggering carcinophobia. Incidentalomas are present in up to 10% of the elderly population according to larger studies (24).

Thus, based on our results, we propose the following algorithm. Elderly patients with symptoms suggestive for hypogonadism should be initially screened with repeated basal measurements of T levels (18). If the T concentration is less than 11.7 nmol/liter, a GnRH stimulation should be performed. If the peak LH after GnRH stimulation is more than 15 mU/liter, costly imaging studies can be avoided. Conversely, MRI should be performed in elderly men with T levels less than 11.7 nmol/liter and a blunted LH response less than 15 IU/liter to exclude pituitary disease.

In conclusion, two groups of elderly men can be distinguished. Elderly men with normal T levels greater than 11.7 nmol/liter appear to have age-related subclinical primary Leydig cell dysfunction. Based on our data using GnRH testing, elderly men with PADAM and T levels less than 11.7 nmol/liter show additional changes at a higher, possibly hypothalamic level. Importantly, GnRH testing can help to exclude secondary hypogonadism in men with PADAM. Thereby, expensive MRI testing can be safely reduced.


   Acknowledgments
 
We thank Firma Ferring for providing LHRH ampoules and Maya Kunz for her excellent technical assistance.


   Footnotes
 
This work was supported by grants from the Freiwillige Akademische Gesellschaft Basel.

First Published Online December 14, 2004

Abbreviations: BMI, Body mass index; MRI, magnetic resonance imaging; PADAM, partial androgen deficiency of the aging male; ROC, receiver-operating characteristics; T, testosterone.

Received May 6, 2004.

Accepted December 7, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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J. M. Kaufman and A. Vermeulen
The Decline of Androgen Levels in Elderly Men and Its Clinical and Therapeutic Implications
Endocr. Rev., October 1, 2005; 26(6): 833 - 876.
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