Increased Incidence of Thyroid Disease among Men with

Hypergonadotropic Hypogonadism

JACOB0 WORTSMAN, M.D. An association between hypothyroidism and hypogonadism has been
H. WESTON MOSES, M.D. described in the syndrome of autoimmune polyglandular failure and in
Springfield, Illinois Klinefelter’s syndrome. The incidence of thyroid disease among males
with hypogonadism was evaluated. Patients were divided into those
MARIA L. DUFAU, M.D., Ph.D. with hypergonadotropic hypogonadttm (Group I; n = 19) and those
Bethesda, Maryland with isolated hypogonadotropic hypogonadiim (Group II; n = 17),
according to their serum concentrations of follicle-stimulating hor-
mone, luteinizing hormone, and testosterone. Nine cases of thyroid
diseases were encountered in Group I; these included benign and
malignant thyroid tumors, hypothyroidism due to Hashimoto’s thyroid-
itis, and hypothyroidism due to amiodarone therapy. Only one case of
thyroid disease (hypothyroidism due to Hashimoto’s thyroiditis) was
found in Group II (p <O.Ol). Patients of Group I were also significantly
older than patients of Group II (51 f 4 versus 37 f 4 years; p <O.Ol);
and patients with thyroid diseases were also older than those without
thyroid disorders (60 f 6 versus 43 f 6 years, p <O.l). lt is concluded
that older subjects with hypogonadlsm and long-term elevation of
levels of serum gonadotropins should undergo careful evaluation of
thyroid gland morphology and function.

Hypogonadism and hypothyroidism have been noted to occur together in

the syndrome of autoimmune polyglandular failure [l] and in Klinefelter’s
syndrome [2,3]. The hypogonadism of the polyglandular failure syndrome
affects mostly females and is usually associated with adrenal failure; the
thyroidal involvement is expressed as autoimmune thyroiditis [I]. Alter-
ations of thyroid function have also been described in isolated hypogo-
nadism due to chromosomal abnormalities (Klinefelter’s syndrome) [2,3].
However, a connection between Klinefelter’s syndrome and thyroid
dysfunction has not been definitively confirmed [4]. Recently, we noted a
high prevalence of thyroid disease in males with the hypergonadotropic
variety of hypogonadism. To substantiate a possible relationship, we
undertook a retrospective review of the records from patients with
hypogonadism.

PATlENTS AND METHODS

From the Department of Medicine, Southern Illi- The clinical population included 49 male patients with the diagnosis of
nois University, Springfield, Illinois, and the Mo- hypogonadism, seen at an endocrine clinic between 1978 and 1984. The
lecular Endocrinology Section, Endocrinology
and Reproduction Research Branch, National In-
referring complaints included impotency, infertility, and decreased size of
stitutes of Health and Human Development, Be- the gonads. Determination of luteinizing hormone, follicle-stimulating hor-
thesda, Maryland. Requests for reprints should mone, and testosterone levels was performed by standard radioimmunoas-
be addressed to Dr. Jacob0 Workman, P.O. Box say techniques.
3926, Springfield, Illinois 62708. Manuscript ac- For statistical analysis, patients were divided into those with hypergo-
cepted April 24, 1985. nadotropic hypogonadism (Group I) and those with isolated hypogonadotro-

June 1988 The American Journal of Medicine Volume 80 1055

THYROID DISEASE IN MEN WITH HYPOGONADISM-WORTSMAN ET AL

TABLE I Hypergonadotropic Hypogonadlsm pit hypogonadism (Group II). The diagnosis qf hypergo-
(Group I) nadotropism was based on the finding of an elevated level
of either follicle-stimulating hormone or luteinizing hor-
Follicle- mone (normal range: 5 to 20 mlU/ml of the second interna-
Stimulating Luteinizing
Hormone Hormone Testosterone Thyroid tional reference preparation of human menopausal gonado-
Patient Age (mlU/ml) (mlU/ml) (WI) Dlaease tropin). The diagnosis of hypogonadotropic hypogonadism
was based on the finding of low serum testosterone level
1 66 95 34 96 Yes (normal range 300 to 1,000 ng/di) withoof elevation of
2 67 49 16 240 Yes levels of serum gonadotropins. Some of the patients includ-
3 69 119 6! 54 No ed in the present study were described in detail in previous
4 52 43 16 364 Yes
5 30 29 7 740 No pubiications [WI. Thyroid diseases were considered
6 26 61 16 293 Yes present only when documented by appropriate laboratory
7 35 24 5 72 No tests; i.e., determinations of thyroid function by thyroxine,
8 50 29 6 - No free thyroxine index, triiooothyronine, and thyrotropin; thy-
9 27 28 29 505 No roid morphology by 1311-thyroidscanning; or thyroid histolo-
10 59 50 13 47 No gy by biopsy. The data were analyzed using the chi-square
11 18 49 22 125 No test and the Student t test, where appropriate.
12 27 36 27 448 No
13 61 51 17 229 No
14 68 57 29 832 Yes RESULTS
15 38 31 18 60 Yes Of the 49 patients with hypogonadism, seven had normal
16 67 31 20 460 Yes
17 54 23 45 877 No serum testosterone concentrations without elevation of
18 76 22 16 500 Yes the levels of gonadotropins (eugonadal), and were exclud-
19 77 19 21 1,040 Yes ed from subsequent analysis. The remaining 42 patients
51 f 4’ 45 f 6” 22 f 3” 388 f 74’ 9110
were classified as having hypergonadotropic hypogo-
(yes/no) nadism (Group I), for a total of 22 patients; or hypogo-
5-207 5-207 300-100~ nadotropic hypogonadism (Group II), for a total of 20
l Mean f SEM. patients. Three of the patients from Group I were excluded
f Normal range. from the calculations because thyroid function test results
were not available, although none had thyroid-related
manifestations in the clinical history. Three of the patients
from Group II were a& excluded from the study because
TABLE II Hypogonadotroplc Hypogonadlsm
(Group II) of pm-existing pituitary disease, i.e., pituitary tumor (pro-
lactinoma) in two of the patients and severe head trauma
Follicle- with skull fracture in the remaining subject. Results of
Stimulating Luteinizing sellar tomography or computed tomographic scanning of
Hormone Hormone Testosterone Thyroid
Patient (mlU/ml) (mlU/ml) WW Disease the sella turcica were normal iy the remainder of the
Age
patients from Group II. Results of adrenal function test8
20 30 10 9 140 No were normal in Group II with the exception of Patient 26,
21 19 8 <3 22 No
22 49 3 <3 222 No who had a subnormal rise in the level of compound S
23 31 6 <3 156 No (desoxycortisol) following the overnight administration of
24 37 1 <3 180 No metyrapone.
25 47 16 20 266 No As shown in Tables I and II, the incidence of thyroid
26 52 4 9 270 No
disease was markedly higher among patients with hyper-
27 31 5 <3 92 No
28 31 7 6 120 No gonadotropic hypogonadism (Group I). Three of the pa-
29 26 <1 <3 154 No tients had large nodules with radioactive iodine uptake
30 21 9 4 260 No similar to that in the rest of the gland (Table Ill). One
31 30 1 4 32 No patient had undergone recent thyroidectomy for a cold
32 18 5 6 204 No
nodule that turned out to be malignant. Thyroid function
33 38 7 <3 <5 No
34 77 5 6 19 No test results in hypothyroid patients are shown in Table IV.
35 43 10 10 120 Yes Hashimoto’s thyroiditis causing hypothyroidism was diag-
36 57 17 18 172 No nosed in three patients by biopsy of the gland or direct
37 f 4’ 7f 1” 6f 1’ 143 f 21’ II16 examination of a surgical specimen; in one of these
(yes/no) patients, a follicular adenoma was found coincidentally.
p <o.o5t p <o.o1t p <o.oit p <o.oit p <O.Olf Amiodarone, prescribed for cardiac arrhythmias, was the
* Mean f SEM. cause of hypothyroidism in three patients, all from Group
t Significance of differences with Group I. I, in whom a preexisting state of euthyroidism had pro-

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 THYROID DISEASE IN MEN WITH HYPOGONADISM-WORTSMAN ET AL

gressed to hypothyroidism during therapy with the drug. TABLE 111 Thyroid Diseases In Hypogonadlsm
Amiodarone had not been given to any of the patients
Patient Group Diagnosis
from Group II. A history of impotency was found to pre-
cede by several years the use of amiodarone in the 1 I Functioningnodule (4 X 3 cm)
2 I Functioning nodule (4 X 3 cm)
subjects with drug-induced hypothyroidism.
4 I Functioning nodule (1.5 X 1.5 cm)
Only one case of thyroid disease was found among the 6 I Papillary carcinoma
patients from Group II: the affected subject was a 43- 14 I Hypothyroidism (amiodarone)
year-old man with small testes, low serum testosterone 15 I Hypothyroidism (Hashimoto’s thyroiditis)
level, and normal levels of gonadotropins. Special studies 16 I Hypothyroidism (Hashimoto’s thyroiditis),
performed in this case (Patient 35) showed a normal follicular adenoma
18 i Hypothyroidism (amiodarone)
response to the injection of luteinizing hormone-releasing 19 I Hypothyroidism (amiodarone)
hormone (Factrel, Ayerst; 100 1-19intravenous bolus); the 35 II Hypothyroidism (Hashimoto’s thyroiditis)
peak luteinizing hormone level was 32.1 mlU/ml (normal
response 63.8 f 40.3). However, the patient exhibited a
marked decrease in the bioactivity of circulating luteiniz-
jng hormone, determined by the rat interstitial cell testos-
terone assay [7]. His mean luteinizing hormone bioassay/ TABLE IV Thyroid Function Tests in Hypothyroid
radioimmunoassay ratio was 1.75 f 0.31 (n = 4); Hypogonadlsm
whereas the luteinizing hormone bioassay/radioimmuno
assay ratio of normal men is 3.95 f 0.97 [7]. Thyroxine Free Thyroxine Tritsdothyronine Thyrotropln
Patient Group (mgldl) Index WW Wml)
As expected, the differences between the two groups
in serum gonadotropin levels were highly significant (Ta- 14 I 1.8 0.4 77 60.0
ble II), and there was a lower mean testosterone level 15 I <l.O <0.2 57 116.0
16 I 5.1 1.5 144 11.3
among patients of Group II. As seen in Table I, a large
18 I 4.1 1.0 100 49.2
fraction of Group I patients (nine of 18) had a low testos- 19 I 9.5 2.3 69 32.5
terone concentration; nevertheless, thyroid disorders ap- 35 II 7.4 2.0 99 12.5
peared distributed equally among patients with low or 4.5-13’ 1.2-4.2” 80-200’ <lO.O”
normal testosterone levels.
The cause of the hypogonadism could be established in
only eight patients: three from Group I and five from Group
II (Table V). Two patients had a previous history of orchitis
associated with mumps; three had Kallmann’s syndrome, TABLE V Cause of Hypogonadism
documented by absence of the senses of taste and smell;
one had generalized osteopetrosis with marked involve- Patient Group Diaanosis
ment of the sella turcica; one had Cushing’s disease, and 1 I Klinefetter’s syndrome
a return to normal of serum testosterone level following (mosaic 46XX/47XXXY)
total bilateral adrenalectomy; and one had Klinefelter’s 6 I Mumps orchitis
syndrome due to mosaicism. 10 I Mumps orchitis
21 II Kallmann’s syndrome
Since patients from Group II were significantly younger
25 II Osteopetrosis sella turcica
than patients in Group I, we attempted to evaluate the 27 II Kallmann’s syndrome
possible contribution of age in determining the expression 28 II Cushing’s disease
of the thyroid disease. We compared the age of Group I 31 II Kallmann’s syndrome
patients having thyroid disease with those without a thy-
roid disorder. As seen in Table VI, patients with thyroid
diseases were significantly older, although the signifi-
cance of the difference was only marginal.
TABLE VI Relationship between Age and Presence
COMMENTS. of Thyroid Disease in Patients with
This report describes a high incidence of thyroid diseases Hypergonadotropic Hypogonadism
among patients with hypergonadotropic hypogonadism. Thyroid Disease
Although at least three of the affected patients were under (number of cases) Age (mean f SEM)
age 45 at the time of diagnosis, it is possible that age
Present (9) 60 f 6
could have played an important role in the results ob- Absent (10) 43 f 6
served. Indeed, patients with thyroid diseases were older;
p co.1
and most of the thyroid diseases exhibited by Group I

June 1988 The American Journal of Medicine Volume 80 1057

THYROID DISEASE IN MEN WITH HYPOGONADISM-WORTSMAN
patients, i.e., thyroid nodules, lymphocytic thyroiditis, and
hypothyroidism, are known to increase in incidence with
age [8-lo].
Previous studies performed in a total of seven male
patients with Klinefelter’s syndrome suggested a high
incidence of hypothyroidism [2,3]. However, in a pro-
spective study of six patients with the same type of
hypogonadism (Klinefelter’s syndrome), Burman et al [4]
were unable to duplicate those results. Also, these inves-
tigators reported that long-term replacement therapy with
testosterone does not appreciably affect thyroid function
test results. The converse situation, chronic hypothyroid-
ism, has been noted to produce a state of hypogonadotro-
pit hypogonadism in males [ 111, and multiple ovarian
cysts in females [ 121. A connection between thyroidal and
gonadal disease is also suggested by the finding of auto-
immune thyroiditis in women with gonadal dysgenesis
[131.
There was a great variability of thyroid diseases in
Group I patients. Thyroid tumors (adenomas or carcino-
mas) were the most common abnormality, documented in
five of the patients. In Patient 35, from Group II, a thyroid
tumor was also given as the indication for surgery; never-
theless, review of a microscopic slide from that case
showed only severe lymphocytic infiltration, similar to that
in Patients 15 and 16. Hypothyroidism of varying degree
was present in the subjects affected by Hashimoto’s
thyroiditis, and amiodarone therapy was also a significant
cause of hypothyroidism.
It is remarkable that the constellation of abnormalities
observed, namely, Hashimoto’s thyroiditis, hypothy-
roidism, and thyroid tumors (benign and malignant), is
similar to the range of thyroid alterations that can develop
in patients with a history of radiation to the head and neck
[9]. Thus, these disorders appear to represent the thyroi-
dal response to well-defined etiologic agents such as
external radiation or, as demonstrated in the present
study, hypergonadotropic hypogonadism. It is, therefore,
tempting to speculate that the well-accepted mediation by
thyrotropin for the experimental induction of thyroid tu-
mors [ 14,151 could represent an important pathogenic
factor in these patients. Since there is a close biochemi-
1. Trence DL, Morley JE, Handwerger ES: Polyglandular
immune syndromes. Am J Med 1984; 77: 107-l 16.
2. Davis TE, Caufield CJ, Herman RH, Goler D: Thyroid function
in patients with aspermiogenesis and testicular
sclerosis. N Engl J Med 1963; 268: 178-182.
3. Carr DH, Barr ML, Plunkett ER, Grumbach MM, Morislima
Chu EHY: An XXXY sex chromosome comptex
felter subjects with duplicated sex chromatin. J Clin Endo-
crinol Metab 1961; 21: 491-505.
1058 June 1988 The American Journal of Medicine
ET AL
cal similarity between the glycoproteins thyt’otropin, folli-
cle-stimulating hormone, and luteinizing hormone, it is
possible that follicle-stimulating hormone or luteinizing
hormone could mimic some of the effects of thyrotropin.
Thus, thyroid tumors and inflammation could result from a
direct thyroidal effect of long-term elevation of either
thyrotropin or gonadotropin levels.
The cause of the hypogonadism could be determined in
only a small fraction of the patients. This probably reflects
the insensitivity of the current diagnostic methods, e.g.,
the detection of only gross abnormalities of taste and
smell in order to make the diagnosis of Kallmann’s syn-
drome. Also, abnormalities in gonadotropin bioactivity
such as that documented in Patient 35 from Group II could
have higher prevalence and clinical significance than
previously suspected. Also of clinical interest is the find-
ing of abnormal follicle-stimulating hormone concentra-
tions in 18 of the 19 patients from Group I, whereas
luteinizing hormone levels were still normal in nine of the
subjects from the same group. Thus, involvement of
Iuteinizing hormone secretion is a late event in the course
of hypergonadotropic hypogonadism and probably heralds
the onset of the clinical symptoms.
Thyroidal abnormalities are frequently observed during
treatment with amkxlarone. In agreement with other re-
ported series [16,17], our Patients 14, 18, and 19, all of
whom were hypothyroid, had absence of a goiter, undo-
tectable titers of anti-thyroid antibodies, and were older
than 60 years. Because of the underlying cardiovascular
problem, the effect of discontinuation of amiodarone on
thyroid function could not be evaluated. It is of interest
that, in the only reported case of death from myxedema
coma during long-term amiodarone therapy, the gland
was diffusely infiltrated by deposits of amyloid [ 181.
We have demonstrated that thyroid disorders have a
high prevalence among males with hypergonadotropic
hypogonadism. The diseases that may be encountered
include benign and malignant thyroid tumors, lymphocytic
infiltration of the gland, and hypothyroidism. Therefore,
males presenting with hypogonadism and elevated levels
of serum gonadotropins should undergo careful evaluation
of thyroid gland morphology and function.
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