Overall cohort
Fifty-two males with Cushing’s disease were included. The mean age at diagnosis was 36.5 ± 13.7 years. HH was observed in thirty-nine patients (75%) at diagnosis. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months, while seven were persistently hypogonadal during the follow-up (> 1 year). 14, 14, 3 and 1 patient(s) achieved eugonadism in 1,3,6,12 month(s) after the surgery, respectively.
Comparison of patients with eugonadism vs. hypogonadism at diagnosis
As shown in Table 1, age and maximal tumor diameter at diagnosis were not significantly different between patients of the two groups. Patients with eugonadism had lower midnight serum cortisol [17.4(13.6, 30.4) vs 23.8(15.2, 34.9) µg/dL, p = 0.036] as well as lower ACTH levels at baseline than those who were diagnosed with hypogonadism. No significant differences were found between the two groups in PRL, FSH, LH, TSH, FT4, TT3 and IGF-1 index (Table 1).
Table 1
Comparison of characteristics between patients with eugonadism vs. hypogonadism at diagnosis
Variable
|
Patients with eugonadism
|
Patients with hypogonadism
|
P value
|
Number
|
13
|
39
|
/
|
Height(cm)
|
166.2 ± 10.0
|
171.8 ± 5.4
|
0.014
|
Weight(kg)
|
68.7 ± 11.8
|
79.7 ± 12.0
|
0.009
|
BMI(kg/m^2)
|
24.8 ± 2.8
|
27.0 ± 3.5
|
0.032
|
HbA1c(%)
|
5.9 ± 0.6
|
6.5 ± 1.3
|
0.067
|
Age(years)
|
30(19.5, 39.0)
|
32(28, 47.5)
|
0.164
|
Maximum tumor diameter(mm)
|
4(2.5, 6.0)
|
5(3, 6.75)
|
0.147
|
8a.m. serum cortisol(µg/dL)
|
28.1 ± 9.0
|
30.7 ± 13.8
|
0.409
|
16p.m. serum cortisol(µg/dL)
|
26.5 ± 11.3
|
28.3 ± 13.2
|
0.637
|
24p.m. serum cortisol(µg/dL)
|
17.4(13.6, 30.4)
|
23.8(15.2, 34.9)
|
0.036
|
24-hour UFC(µg/24-hour)
|
537.9(360.0, 760.0)
|
789.4(432.5, 1726.4)
|
0.095
|
8a.m. ACTH(pg/mL)
|
65.6(26.0, 110.2)
|
114.0(67.7, 159.0)
|
0.014
|
16p.m. ACTH(pg/mL)
|
70.5(52.4, 100.9)
|
92.3(79.3, 150.3)
|
0.024
|
24p.m. ACTH(pg/mL)
|
53.2(27.4, 78.4)
|
99.4(64.5, 145.1)
|
0.001
|
TSH(mIU/L)
|
0.91(0.57, 1.74)
|
0.76(0.33, 1.42)
|
0.328
|
FT3(pmol/L)
|
4.77 ± 1.31
|
3.66 ± 0.80
|
0.010
|
FT4(pmol/L)
|
15.05 ± 3.18
|
14.53 ± 2.51
|
0.631
|
TT3(nmol/L)
|
1.59 ± 0.72
|
1.20 ± 0.34
|
0.071
|
TT4(nmol/L)
|
87.77 ± 18.21
|
74.85 ± 19.38
|
0.041
|
IGF-1 index
|
0.69 ± 0.35
|
0.64 ± 0.23
|
0.687
|
FSH(IU/L)
|
5.81(4.67, 6.86)
|
5.47(2.88, 7.91)
|
0.643
|
LH(IU/L)
|
4.53(3.24, 5.58)
|
4.44(2.09, 5.48)
|
0.317
|
TT(nmol/L)
|
10.7(7.7, 14.8)
|
5.06(3.89, 5.60)
|
< 0.001
|
PRL(ng/mL)
|
15.5 ± 4.1
|
18.5 ± 11.8
|
0.352
|
Total testosterone was negatively correlated with ACTH and 24-hour UFC
To further explore the correlation between TT and the cortisol level, Pearson’s correlation analyses was performed. As shown in Fig. 1, Total testosterone was negatively correlated with midnight serum ACTH level (r=-0.427, p = 0.0025) and 24-hour UFC (r=-0.334, p = 0.022).
ACTH was independently associated with hypogonadism at diagnosis
To go deep into the association between the prevalence of hypogonadism and serum ACTH levels, we divided the 52 patients into three groups according to tertiles of ACTH levels. Compared to individuals with low levels of 8a.m. ACTH (Fig. 2), 16p.m. ACTH (Fig. 3), and 24p.m. ACTH (Fig. 4), the prevalence of hypogonadism in those with high levels of ACTH was significantly higher. The multiple logistic regression model shown in Table 2 demonstrated that plasma levels of midnight ACTH at diagnosis was significantly associated with hypogonadism, even after adjusting for age, body mass index (BMI), maximal tumor diameter, LH, FSH, TT4, PRL and midnight serum cortisol at diagnosis (Table 2).
Table 2
ACTH was independently associated with hypogonadism at diagnosis
|
B (SE)
|
P value
|
Exp(B) (95% IC)
|
Model 1
|
1.778 (0.671)
|
0.008
|
5.92 (1.59, 22.04)
|
Model 2
|
1.653 (0.688)
|
0.016
|
5.22 (1.36, 20.10)
|
Model 3
|
1.801 (0.846)
|
0.033
|
6.06 (1.15, 31.82)
|
Model 4
|
1.968 (0.996)
|
0.048
|
7.15 (1.02, 50.35)
|
Data are odds ratios (95% confidence interval). |
Model 1: unadjusted |
Model 2: adjusted for age, midnight serum cortisol and BMI at diagnosis |
Model 3: model 2 further adjusted for LH, PRL and maximum tumor diameter at diagnosis |
Model 4: model 3 further adjusted for FSH and TT4 at diagnosis |
Comparison of patients achieving eugonadism vs. persistent hypogonadism
It turned out that patients with persistent hypogonadism had a higher percentage of hypothyroidism (71.4% vs 3%, p < 0.001) as well as a higher prevalence of central diabetes insipidus (42.9% vs 0%, p < 0.001) than those who attained eugonadism after remission of Cushing’s disease, while none was diagnosed with hypothyroidism and central diabetes insipidus at baseline before the surgery. The change in LH from last visit to baseline was significantly lower among patients with persistent hypogonadism compared to the other [-2.2 (-6.1, 0.3) vs 1.3 (-0.3, 2.8), p = 0.002]. No significant differences were found between the two groups in age, follow-up time, maximum tumor diameter, change in FSH, change in weight and combined drug use (Table 3). Characteristics of seven males with persistent hypogonadism after follow-up (≥ 1 year) were shown in Table 4. No obvious lesion was detected by MRI in Case1#. And the lesion of Case 4# was flat and thin. Case 2#, 5# and 6# suffered from pituitary macroadenomas. Case 7# had experienced two times of surgery. Case 1#, 3# and 5# attained adrenal axis recovery during the follow-up.
Table 3
Comparison of characteristics between patients achieving eugonadism vs. with persistent hypogonadism
|
Patients achieving eugonadism
|
Patients with persistent hypogonadism
|
P value
|
Number
|
32
|
7
|
/
|
Age (years)
|
37.5 ± 13.7
|
41.4 ± 9.9
|
0.397
|
Follow-up time (month)
|
12.0 (3.0, 24.0)
|
12.0 (12.0, 18.0)
|
0.375
|
Maximum tumor diameter (mm)
|
5.0 (3.0, 6.0)
|
5.0 (3.0, 35.0)
|
0.419
|
Involvement of thyroid axis, n (%)
|
1 (3%)
|
5 (71.4%)
|
< 0.001
|
Prevalence of central diabetes insipidus, n (%)
|
0 (0%)
|
3 (42.9%)
|
< 0.001
|
Change in LH (from last visit to baseline, IU/L)
|
1.3 (-0.3, 2.8)
|
-2.2 (-6.1, 0.3)
|
0.002
|
Change in FSH (from last visit to baseline, IU/L)
|
-2.1 (-3.6, -0.2)
|
-2.4 (-6.0, -0.5)
|
0.382
|
Change in weight (from last visit to baseline, kg)
|
-2.0 (-6.5, 0.0)
|
-4.5 (-9.0, -0.25)
|
0.280
|
Aspirin (%)
|
1 (3.1%)
|
0 (0%)
|
0.636
|
ACEI/ARB (%)
|
4 (12.5%)
|
3 (42.9%)
|
0.058
|
Calcium-channel antagonist (%)
|
6 (18.8%)
|
2 (28.6%)
|
0.560
|
Metformin (%)
|
1 (3%)
|
1 (14.3%)
|
0.225
|
Table 4
Characteristics of 8 males with persistent hypogonadism after follow-up (≥ 1 year)
Patient
|
Age (years)
|
Maximum tumor diameter (mm)
|
Times of surgery
|
Involvement of thyroid axis
|
Present with central diabetes insipidus
|
Recovery of adrenal axis
|
Follow-up (months after surgery)
|
1
|
51
|
Unclear
|
1
|
/
|
/
|
Yes
|
24
|
2
|
48
|
36
|
1
|
Yes
|
Yes
|
/
|
18
|
3
|
36
|
4
|
1
|
Yes
|
/
|
Yes
|
15
|
4
|
53
|
5
|
1
|
/
|
/
|
/
|
12
|
5
|
43
|
15
|
1
|
Yes
|
/
|
Yes
|
12
|
6
|
31
|
35
|
1
|
Yes
|
Yes
|
/
|
12
|
7
|
28
|
3
|
2
|
Yes
|
Yes
|
/
|
12
|