Prevalence and clinical associations with primary hypogonadism in male systemic sclerosis

Abstract

Background:

Systemic sclerosis may affect male and female fertility. Premature ovarian failure has been reported in female systemic sclerosis patients, but the effects on male fertility in systemic sclerosis have not been studied.

Objectives:

We aimed to determine the prevalence and clinical associations with primary hypogonadism among male systemic sclerosis patients.

Methods:

This was a cross-sectional pilot study, including 30 adult male systemic sclerosis patients attending the Scleroderma Clinic, Khon Kaen University. Testosterone deficiency symptoms were assessed using the Aging Males’ Symptoms Rating Scale, urological examination, and blood testing (for total testosterone, free testosterone, follicle-stimulating hormone, and luteinizing hormone). We excluded patients with congenital hypogonadism and any acquired disorders of the testes and genitalia. The definition of primary hypogonadism was based on the International Society for the Study of the Aging Male 2015 diagnostic criteria for hypogonadism.

Results:

Seven patients met the definition of primary hypogonadism—a prevalence of 23.3% (95% confidence interval: 9.9–42.3). The respective mean age and mean systemic sclerosis duration was 59.4 ± 11.9 and 5.5 ± 4.7 years. Older age at onset, high triglyceride level, and older age starting corticosteroid treatment were significantly associated with primary hypogonadism (p = 0.02, 0.02, and 0.03, respectively). Systemic sclerosis subset, disease severity, and immunosuppressant use were not associated with primary hypogonadism among Thai male systemic sclerosis patients.

Conclusion:

Around one-quarter of male systemic sclerosis patients had primary hypogonadism. Elderly onset of systemic sclerosis, hypertriglyceridemia, and late corticosteroid treatment were risk factors for developing primary hypogonadism.

Introduction

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and/or internal organs and vascular dysfunction, together with humoral responses, including the presence of SSc-related antibodies. ¹ Major internal organ (kidneys, lungs, and heart) involvement is related to a poor clinical outcome.^1,2 Patients express concern regarding other aspects of the disease (i.e. limitations to mobility, sleep disturbance, pain, depression, and sexual dysfunction), which affect their quality of life. ³ SSc is usually found in females (i.e. 3–14 females for every 1 male, depending on the study).^4–7 SSc might cause impairment of gonadal function in both males and females.^8–12 Premature ovarian failure, exemplifying female gonadal function, has been reported in female SSc patients, particularly in those receiving a high cumulative dose of cyclophosphamide. Other significant concerns include early menopause and low ovarian reserve. ¹⁰ There are no similar reports on male gonadal function in SSc.

Primary hypogonadism is defined by a lack of testicular testosterone accompanied by symptoms suggestive of testosterone deficiency.^13–15 A 2017 study showed that male SSc patients had a significantly lower testosterone and bioactive testosterone level than matched controls, but clinical symptoms of testosterone deficiency were not exhibited. ¹² No previous study has evaluated the association between primary hypogonadism and SSc in males. The combination may result in male infertility and require further treatment (i.e. testosterone supplements) to improve symptoms and quality of life.

The current study aimed to identify the prevalence of primary hypogonadism and the clinical associations in male SSc. This assessment will benefit male SSc patients in their family planning.

Method

Thai male SSc patients above 18 who attended the Scleroderma Clinic, Khon Kaen University, between July and December 2020, were enrolled in the cross-sectional pilot study. The subjects were randomly sampled by the clinic’s administrator, who was not involved in the study. We excluded patients with congenital hypogonadism, any acquired disorders of the testis and genitalia, drug abuse, alcohol dependence, and dependent status. Thirty-two eligible patients were enrolled, but two were excluded due to acquired disorders of the genitalia and dependent status. Thirty volunteers were then assessed for testosterone deficiency symptoms using the Aging Males’ Symptoms Rating Scale, and all underwent urological examination, and blood testing (for total testosterone, free testosterone level, follicle-stimulating hormone (FSH), and luteinizing hormone (LH)) around the same time on the same date. The physician who did the urological examination was blinded to the hormone level. The blood testing was performed in the early morning (before 10 a.m.), and all laboratory tests were done only once.

Total testosterone, FSH, and LH levels were measured with the electrochemiluminescence immunoassay (ELISA), using a Cobas e immunoassay analyzer, as per the manufacturer’s instructions (Cobas). In addition, free testosterone was calculated from the albumin, sex hormone-binding globulin, and total testosterone level using the validation method by Vermeulen et al. ¹⁶ Albumin was measured using a colorimetric assay, while the sex hormone-binding globulin was measured with chemiluminescent microparticle immunoassay (CMIA), as per the manufacturer’s instructions (Abbott, USA).

Patients’ method

Patient diagnosis of SSc was based on the classification criteria for SSc as per the ACR/EULAR 2013. ¹ The patients were classified as limited cutaneous SSc (lcSSc) or diffuse cutaneous SSc (dcSSc), according to LeRoy et al. ¹⁷ The onset of SSc was defined as the time of the first non-Raynaud’s phenomenon SSc symptoms. SSc duration was calculated as the interval between disease onset and the last data collection time.

Pulmonary involvement was defined by findings of pulmonary fibrosis, ground-glass opacity, or traction bronchiectasis performed by high-resolution and computed tomography (HRCT) of the chest. Pulmonary arterial hypertension (PAH) was diagnosed when the mean pulmonary arterial pressure (mPAP) is >20 mmHg at rest with a pulmonary artery wedge pressure of ⩽15 mmHg and a pulmonary vascular resistance of ⩾3 Wood units, as confirmed by right heart catheterization. ¹⁸ Scleroderma renal crisis (SRC) included (a) the recent onset of severe hypertension (systolic blood pressure (SBP) ⩾ 140 mmHg; diastolic blood pressure (DBP) ⩾ 90 mmHg; a rise in SBP ⩾ 30 mmHg and/or a rise in DBP ⩾ 20 mmHg); (b) a rapid increase in serum creatinine (⩾50% over baseline or serum creatinine > 120% of the upper limit of normal for local laboratory); and (c) microangiopathic hemolytic anemia. ¹⁹ Stomach involvement included dyspepsia, early satiety, and bloating. ²⁰ Intestinal involvement was characterized by diarrhea, bloating, malabsorption, constipation, and ileus or pseudo-intestinal obstruction. Dependent status was defined by the inability to do basic daily living activities by themselves.

Primary hypogonadism was defined in the International Society for the Study of the Aging Male 2015 (ISSAM) diagnostic criteria for hypogonadism. ¹³ The criteria included all of the following:

1. The presence of characteristic symptoms and signs of testosterone deficiency combined with a decreased serum concentration of testosterone; ¹³

2. The presence of characteristics of testosterone deficiency was based on the Aging Males’ Symptoms Scale (AMS) that identifies clinical characteristics of androgen deficiency. The Thai version of the AMS was used to ensure cultural and linguistic accuracy and sensitivity.^15,21 A score ⩾ 27 suggests symptoms of androgen deficiency. A score of 27–36 indicates “mild” symptoms, 37–49 “moderate,” and > 50 “severe”; ¹⁵

3. A decreased serum concentration of testosterone (total testosterone < 350 ng/dL or free testosterone <65 pg/mL) ¹³ and increased serum FSH and LH (based on our center’s laboratory reference range of >8 mIU/mL and >6 mIL/mL, respectively).^14,22

The Human Research Ethics Committee of Khon Kaen University reviewed and approved the study; according to the Helsinki Declaration and the Good Clinical Practice Guidelines (HE631045). All eligible patients signed informed consent before enrollment.

Statistical analysis

The prevalence and 95% CI of primary hypogonadism in male SSc were investigated. Percentages and proportions were calculated for the categorical data, while means with SDs or medians with interquartile ranges (IQR) were calculated for the continuous data, as appropriate. Odds ratios with 95% CIs were used to confirm any clinical association with primary hypogonadism. p -values < 0.05 were considered statistically significant. All statistical analyses were performed using STATA16.0 (StataCorp., College Station, TX, USA).

Results

Patient characteristics

A total of 32 potentially eligible male SSc patients were enrolled in the study; however, 2 were excluded because of dependent status (1 case) and history of varicocele surgical treatment (1 case). As such, a total of 30 patients were included in the study. The mean age was 59.4 ± 2.2 years. The majority (76.7%) had the dcSSc subset. The mean age at disease onset was 60.0 ± 2.3 years, while the mean disease duration was 5.5 ± 0.9 years. At the initial presentation, 22 of 30 (73.3%) had Raynaud’s phenomenon, and 16 had mRSS > 10 points with a median mRSS of 11 (8–17). Half of the patients (50%) had pulmonary fibrosis, and 46.7% had esophageal involvement. None of the patients had a renal crisis. Almost all patients (96.7%) received low-dose glucocorticoid, and 36.7% received cyclophosphamide. The overall demographic data are presented in Table 1.

Table 1.

Demographics.

Data	N = 30
Demographic aspect
1. Age at visit (years); mean ± SD	59.4 ± 11.9
2. Age at onset (years); mean ± SD	54.0 ± 12.7
3. Duration of disease (years); mean ± SD	5.5 ± 4.7
4. BMI (kg/m2); mean ± SD	21.0 ± 3.4
Comorbid disease
5. Diabetes mellitus (%)	4 (13.3)
6. Hypertension (%)	3 (10.0)
7. Hyperlipidemia (%)	5 (16.7)
8. Current smoking (%)	6 (20.0)
9. Current alcoholic drinking (%)	19 (63.3)
SSc clinical characteristic
10. dcSSc subset (%)	23 (76.7)
11. mRSS on the study date; median (IQR)	5 (2–8)
12. Raynaud’s phenomenon (%)	10 (33.3)
13. Telangiectasia (%)	13 (43.3)
14. Arthritis (%)	1 (3.3)
15. Esophageal involvement (%)	14 (46.7)
16. Stomach involvement (%)	3 (10.0)
17. Intestinal involvement (%)	3 (10.0)
18. Pulmonary fibrosis (%)	15 (50.0)
19. Pulmonary hypertension (%)	5 (16.7)
20. Renal crisis (%)	0
Laboratory test
21. HbA1 C (%); mean ± SD	5.7 ± 0.8
22. Cholesterol level (mg/dL); mean ± SD	198.1 ± 105.3
23. Triglyceride level (mg/dL); mean ± SD	159.6 ± 57.8
24. LDL level (mg/dL); mean ± SD	115.6 ± 47.8
25. HDL level (mg/dL); mean ± SD	44.2 ± 18.3
26. Triglyceride / HDL ratio; median (IQR)	4.0 (2.2–5.5)
Characteristics of testosterone deficiency based on the Aging Males’ Symptoms Scale
27. Aging Males’ Symptoms Scale (scoring points); mean ± SD	36.8 ± 6.8
28. No/little complaints; total score < 26 (%)	1 (3.3)
29. Mild complaints; total score 24–36 (%)	13 (43.3)
30. Moderate complaints; total score 37–49 (%)	15 (50.0)
31. Severe complaints; total score ⩾ 50 (%)	1 (3.3)
Medication
Cyclophosphamide
32. Using (%)	11 (36.7)
33. Cumulative dose (g); median (IQR)	10.5 (9–19.2)
34. Duration of used (days); median (IQR)	408 (287–692)
35. Starting age (years); mean ± SD	55.1 ± 13.4
Prednisolone
36. Using (%)	29 (96.7)
37. Cumulative dose (g); median (IQR)	3.9 (1.5–8.4)
38. Duration of used (days); median (IQR)	586 (214–1342)
39. Starting age (years); mean ± SD	54.1 ± 12.6

dcSSc: diffuse cutaneous systemic sclerosis; FSH: follicle-stimulating hormone; HDL: high-density lipoprotein; IQR: interquartile range; LDL: low density lipoprotein; LH: luteinizing hormone; mRSS: modified Rodnan skin score; SSc: systemic sclerosis.

The genitalia examination revealed that the respective right and left testis size was 11.5 ± 2.9 and 11.2 ± 2.6 g. The overall male SSc mean total testosterone level was 457.5 ± 200.6 ng/dL (range 161.0–1054.0), and the median total testosterone level was 407 ng/dL (IQR 327–582). The mean free testosterone level was 90.9 ± 33.5 pg/mL (range 25.7–165.0). The respective mean FSH and LH level was 16.6 ± 11.9 mIU/mL and 12.2 ± 6.1 mIU/mL.

Prevalence and clinical associations with primary hypogonadism in male SSc

Primary hypogonadism was found in 7 cases according to the ISSAM diagnostic criteria of hypogonadism for a prevalence of 23.3% (95% CI: 9.9–42.3). The patients with primary hypogonadism (a) had an older age at onset, (b) late corticosteroid treatment, and (c) had a higher triglyceride level than the patients with normal gonadal function (63.2 ± 8.6 years vs 51.1 ± 12.5 years; OR 1.14 (95% CI: 1.01–1.29), 63.3 ± 8.5 years vs 51.1 ± 12.3; OR 1.15 (95% CI: 1.01–1.31), and 220.5 ± 16.5 vs 142.2 ± 10.9; OR 1.03 (95% CI: 1.01–1.06), respectively). There was no significant between-group difference in clinical characteristics, testis size, and treatment (Table 2). We did not perform a logistic regression analysis to precisely define associated factors with primary hypogonadism among male SSc because of the statistical limitation imposed by having a small population for a pilot study.

Table 2.

Clinical associations with primary hypogonadism.

Clinical characteristic	Primary hypogonadism (N = 7)	Normal gonadal function (N = 23)	OR (95% CI)	p value
Demographic aspect
Age at visit (years); mean ± SD	65.3 ± 3.0	57.6 ± 2.6	1.09 (0.97–1.22)	0.14
Age at onset (years); mean ± SD	63.2 ± 8.6	51.1 ± 12.5	1.14 (1.01–1.29)	0.02*
SSc duration (years); mean ± SD	2.0 ± 1.4	6.5 ± 4.9	0.63 (0.40–1.01)	0.06
BMI (kg/m2); mean ± SD	20 ± 2.2	21.2 ± 3.7	0.93 (7.16–1.21)	0.59
Comorbid disease
Diabetes mellitus (%)	0	4 (17.4)	NA	–
Hypertension (%)	1 (14.3)	2 (8.7)	1.75 (0.03–38.62)	0.67
Hyperlipidemia (%)	2 (28.6)	3 (13.0)	2.67 (0.17–29.79)	0.33
Current smoking (%)	1 (14.3)	6 (21.7)	0.60 (0.01–7.33)	0.67
Current alcoholic drinking (%)	4 (57.1)	15 (65.2)	0.71 (0.09–6.16)	0.70
SSc clinical characteristic
dcSSc subset (%)	5 (71.4)	18 (78.3)	0.69 (0.08–9.50)	0.71
mRSS; mean ± SD	14.3 ± 9.8	13.0 ± 9.8	1.01 (0.93–1.11)	0.76
Raynaud’s phenomenon (%)	6 (85.7)	16 (69.6)	2.65 (0.23–137.71)	0.40
Salt and pepper appearance (%)	7 (100)	16 (69.6)	NA	–
Arthritis (%)	0 (0)	1 (4.4)	NA	–
Esophageal involvement (%)	5 (57.1)	9 (39.1)	2.07 (0.27–17.27)	0.40
Stomach involvement (%)	1 (14.3)	2 (8.7)	1.75 (0.03–38.62)	0.67
Intestinal involvement (%)	3 (13.0)	0	NA	–
Pulmonary fibrosis (%)	5 (71.3)	10 (43.5)	3.25 (0.40–39.37)	0.20
Pulmonary hypertension (%)	1 (14.3)	4 (17.4)	0.79 (0.14–10.48)	0.85
Renal crisis (%)	0 (0)	0 (0)	–	–
Genital examination and hormonal test
Size of right testis (g); mean ± SD	11.0 ± 1.0	11.6 ± 0.6	–	0.64
Size of left testis (g); mean ± SD	10.7 ± 0.9	11.3 ± 0.5	–	0.60
Total testosterone level (ng/dL); mean ± SD	241.1 ± 64.5	523.0 ± 180.8	–	<0.001*
Free testosterone level (pg/mL); mean ± SD	52.7 ± 15.4	102.5 ± 28.4	–	<0.001*
FSH level (mIU/mL); mean ± SD	27.8 ± 7.8	13.2 ± 10.8	–	0.003*
LH level (mIU/mL); mean ± SD	16.2 ± 3.6	11.0 ± 6.3	–	0.047*
Characteristics of testosterone deficiency based on the Aging Males’ Symptoms Scale
Aging Males’ Symptoms Scale (scoring points); mean ± SD	38.9 ± 5.0	37.5 ± 7.3	1.03 (0.91–1.17)	0.64
No/ little complaints; total score < 26 (%)	0	1 (4.8)	–	0.87
Mild complaints; total score 24–36 (%)	3 (42.9)	10 (43.5)	–	–
Moderate complaints; total score 37–49 (%)	4 (57.1)	11 (47.8)	–	–
Severe complaints; total score ⩾ 50 (%)	0	1 (4.4)	–	–
Laboratory test
HbA1C (%); mean ± SD	5.7 ± 0.2	5.8 ± 0.2	0.92 (0.21–3.97)	0.91
Cholesterol level (mg/dL); mean ± SD	202.5 ± 26.9	196.8 ± 24.5	1.00 (0.99–1.00)	0.91
Triglyceride level (mg/dL); mean ± SD	220.5 ± 16.5	142.2 ± 10.9	1.03 (1.01–1.06)	0.02*
LDL level (mg/dL); mean ± SD	136.5 ± 22.9	109.6 ± 9.8	1.01 (0.99–1.03)	0.23
HDL level (mg/dL); mean ± SD	46 ± 17.5	43.7 ± 18.9	1.01 (0.96–1.06)	0.78
Triglyceride/HDL ratio; median (IQR)	5.0 (4.5–6.7)	3.7 (1.9–5.3)	–	0.12
Medication
Cyclophosphamide
Using (%)	4 (57.1)	7 (30.4)	3.05 (0.38–25.74)	0.20
Cumulative dose (g); median (IQR)	8.0 (5.9–14.1)	13.8 (10.4–20.2)	–	0.33
Duration of used (days); median (IQR)	485.5 (357.5–668)	408 (141–692)	–	0.46
Starting age (years); median (IQR)	58.5 (52.5–67)	57 (54–61)	–	0.42
Prednisolone
Using (%)	7 (100)	22 (95.7)	NA	–
Cumulative dose (g); median (IQR)	3.9 (1.0–7.7)	4.2 (1.8–8.8)	–	0.41
Duration of used (days); median (IQR)	586 (98–1059)	633 (214–1601)	–	0.30
Starting age (years); median (IQR)	63.3 ± 8.5	51.1 ± 12.3	1.15 (1.01–1.31)	0.03*

dcSSc: diffuse cutaneous systemic sclerosis; FSH: follicle-stimulating hormone; HDL: high-density lipoprotein; IQR: interquartile range; LDL: low density lipoprotein; LH: luteinizing hormone; mRSS: modified Rodnan skin score; NA no data available due to zero in one cell; SSc: systemic sclerosis.

^*Statistical significant.

The clinical characteristics of the patients with primary hypogonadism are presented in Table 3.

Table 3.

Clinical characteristics of patients with primary hypogonadism.

Clinical characteristic	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7
Demographic aspect
Age at visit (years)	74.7	62.7	67.0	71.0	52.7	71.0	57.6
Age of onset (years)	73.4	60.5	66.7	70.1	49.0	67.1	55.7
Duration of disease (years)	1.3	2.3	0.3	0.9	3.7	3.9	1.9
BMI (kg/m2)	18.1	21.4	21.4	23.8	17.7	19.1	21.7
SSc clinical characteristic
SSc subset	dcSSc	dcSSc	lcSSc	dcSSc	dcSSc	dcSSc	lcSSc
mRSS	2	26	7	28	11	17	9
Raynaud’s phenomenon	Yes	Yes	Yes	No	Yes	Yes	Yes
Esophageal involvement	No	No	Yes	Yes	Yes	No	Yes
Stomach involvement	No	No	No	No	No	No	Yes
Pulmonary fibrosis	Yes	Yes	No	No	Yes	Yes	Yes
Pulmonary hypertension	No	No	No	No	No	Yes	No
Medication
Cyclophosphamide
Cumulative dose (g)	7	9	Never used	Never used	19.2	Never used	4.8
Duration of used (days)	385	330	Never used	Never used	750	Never used	586
Starting age (years)	73.4	61.0	Never used	Never used	49.0	Never used	56.0
Prednisolone
Cumulative dose (g)	3.9	1.5	1.0	0.4	9.0	7.7	5.6
Duration of used (days)	385	629	98	40	1059	1342	586
Starting age (years)	73.4	60.9	66.8	70.1	49.2	67.1	56.0
Evaluation of primary hypogonadism
Aging Males’ Symptoms Scale (scoring points)	32	41	44	36	45	34	40
Severity of testosterone deficiency symptoms	Mild	Moderate	Moderate	Mild	Moderate	Mild	Moderate
Size of right testis (g)	10	12	8	8	12	15	12
Size of left testis (g)	10	12	8	8	12	15	10
Total testosterone level (ng/dL)	256	181	218	161	301	344	235
Free testosterone level (pg/mL)	59	63.4	36.5	25.7	66	58.1	61
FSH level (mIU/mL)	31.5	31.5	10.5	32.1	31.5	27.6	29.9
LH level (mIU/mL)	10.85	15.83	15.04	13.32	17.3	21.49	19.43

BMI: body mass index; dcSSc: diffuse cutaneous systemic sclerosis; FSH: follicle-stimulating hormone; lcSSc: limited cutaneous systemic sclerosis; LH: luteinizing hormone; mRSS: modified Rodnan skin score; SSc: systemic sclerosis.

Discussion

Around one-quarter of male SSc patients fulfilled the definition of primary hypogonadism per the clinical hormonal deficiency and hormonal assessment. This prevalence seemed to be higher than among healthy individuals of similar age in a previous study (9%–12%); ²³ however, there was no healthy control in the study. It cannot thus be concluded whether or not the prevalence of primary hypogonadism among SSc was higher than in healthy men. Hypogonadism diagnosis requires signs and symptoms suggestive of testosterone deficiency correlated with a low serum testosterone level (including libido, erectile dysfunction, decreased muscle mass and strength, increased body fat, decreased bone mineral density, osteoporosis, decreased vitality, and depressed mood).^13,24 Although the signs and symptoms of decreased muscle mass, ²⁵ osteoporosis, ²⁶ or depressed mood ²⁷ can be found in SSc, the sex hormone level is needed to differentiate those symptoms from hypogonadism.

Primary hypogonadism requires diagnosing hypogonadism in conjunction with increasing follicle-stimulating hormone and luteinizing hormone.^14,22 Nowlin et al. ²⁸ conducted a small hormonal study among 10 men with SSc and reported on primary hypogonadism, albeit that was not the study’s focus. Their study found no difference in total testosterone, free testosterone, FSH, LH, and prolactin levels between male SSc and those without impotence. ²⁸ The study aimed to evaluate the etiology of impotence, not to determine the prevalence of hypogonadism—moreover, only a small number (10 cases) of male SSc patients was included. A 2017 study showed that male SSc patients had a significantly lower testosterone and bioactive testosterone level than matched controls. ¹² However, the clinical signs and symptoms suggestive of testosterone deficiency were not included, and primary hypogonadism was not of direct interest. By comparison, our study included complete data on the clinicals associated with hormonal deficiency and hormonal assessment for primary hypogonadism in men with SSc, so our results, albeit a pilot study, are valuable for further research on gonadal function in SSc.

Despite the high prevalence of erectile dysfunction in SSc,^11,29,30 primary hypogonadism occurred less frequently in our analysis. Although erectile dysfunction was not reported separately by our patients, libido and erectile dysfunction are characteristic symptoms and signs of testosterone deficiency as per the criteria for diagnosing primary hypogonadism. This was a pilot study, and the small sample size was based on a previous study investigating the association between impotence and hormonal status in men with SSc. A more extensive study should focus on the association between erectile dysfunction and sex hormone to confirm the hypothesis and provide treatment planning information for those with sexual problems.

Elderly onset of disease was a factor associated with primary hypogonadism. In general, the prevalence of primary hypogonadism is more frequent in elderly than young men.^31,32 Elderly SSc patients might simply be at greater risk of developing primary hypogonadism, but another explanation might be the greater risk of internal organ involvements (i.e. pulmonary hypertension, renal impairment, cardiac disease, and muscle weakness) among elderly onset over against younger-onset SSc patients, ³³ albeit the observed association may not indicate causation. Our results also found that the patients with primary hypogonadism seem to have more significant internal organ fibrosis (particularly pulmonary fibrosis) and gastroesophageal involvement than normal gonadal function. However, no statistical confirmation has been forthcoming on the association between internal organ fibrosis and primary hypogonadism, so it is difficult to argue for a testicular biopsy to confirm testicular fibrosis. Further study is needed to test this hypothesis.

The prevalence of gonadal problems in SSc seems to be greater in females than males. A recent study of female reproductive information revealed the respective prevalence of premature ovarian failure and early menopause at 9.7% and 35.7%. ¹⁰ A high prevalence of low ovarian reserve was found in female SSc (90.3%). ¹⁰ The majority of patients (68%) from that study had dcSSc, ¹⁰ as in our population, but that study included younger patients (less than 40 years of age, according to the definition of premature ovarian failure). The findings indicate that SSc can affect gonadal function in males and females, but more so among younger females.

Although previous data showed that cyclophosphamide was an essential factor associated with premature ovarian failure in female SSc patients, ¹⁰ our study did not find any association between the medicine and primary hypogonadism development in male SSc patients. A previous study in Sweden revealed that median testosterone levels were significantly lower in male SSc patients than in matched controls (288.4 ng/dL vs 374.6 ng/dL; p = 0.03), and cyclophosphamide use was significantly associated with lower levels of bioactive testosterone. ¹² In contrast to our study, the median total testosterone level in overall cases was higher than in a previous study (407.5 ng/dL vs 288.2 ng/dL). ¹² The findings might be explained by the lower numbers of patients using cyclophosphamide and/or fewer cumulative doses of cyclophosphamide in our patients compared with previous reports.^10,12 Our patients with primary hypogonadism underwent more frequent cyclophosphamide treatment than patients with normal gonadal function (note: not statistically confirmed due to the low numbers of patients using cyclophosphamide). A larger sample size might help evaluate the association between the amount of cyclophosphamide used and male gonadal function.

Steroid taking (both high-dose or long-term) can result in negative feedback to the pituitary gland and hypothalamus, leading to suppression of gonadotropin-releasing hormone (GnRH) production from the hypothalamus. GnRH is the hormone that induces testosterone production from the testis, which is the end-product of the hypothalamic–pituitary–gonadal axis. ³⁴ We found an association between late corticosteroid treatment (starting corticosteroid treatment at an older age) and primary hypogonadism. However, based on the study design, we cannot confirm that steroid use alone is directly the cause of hypogonadism, which could be due to the elderly onset of disease. So, the observed hypogonadism could have arisen in one of three ways: (a) the direct effect of steroids on gonadal function by suppression of GnRH production; (b) the indirect effect of the aging process on gonadal function in elderly onset disease; and/or (c) the combined effects of aging and steroid use on gonadal function. Notwithstanding the pathogenesis, if steroid treatment is needed in elderly SSc patients, the physician should discuss the risk of hypogonadism with the patient, and treatment should be stopped if indications cease or the dose minimized by using as short a duration as possible.

Hypertriglyceridemia was another factor significantly associated with primary hypogonadism in male SSc patients. Hypertriglyceridemia has been reported to be related to hypogonadism^35,36 and increased TG levels with low levels of high-density lipoprotein (HDL), which are features of males with hypogonadism. ³⁶ Haymana et al. ³⁶ also reported that a high TG/HDL ratio was correlated with endothelial dysfunction and inflammation. According to the pathogenesis of SSc, vasculopathy and endothelial dysfunction interact with immune-inflammatory processes and fibrosis in the pathogenic processes, ³⁷ suggesting that hypertriglyceridemia might enhance endothelial dysfunction and/or inflammation, leading to organ fibrosis. However, the role of TG on the pathogenesis of SSc remains undefined, so the role of triglycerides on endothelial function and inflammation in the pathogenesis of SSc should be further investigated. It is uncertain whether lifestyle modifications and medical treatment for lowering triglyceride levels among males with SSc with hypertriglyceridemia might reduce the prevalence of primary hypogonadism.

According to our findings, the elderly onset of SSc, late corticosteroid treatment, and hypertriglyceridemia were the risk factors for primary hypogonadism among Thai male SSc patients. Treating physicians should be aware of the reproductive outcomes for those SSc patients. Sperm banking or assisted reproductive technologies could be discussed with the patient at risk of primary hypogonadism and his partner to assist with family planning.

The strengths of our study include that (a) this is the first study to determine the prevalence of primary hypogonadism that combines the definition of clinical testosterone deficiency corroborated by hormonal tests; (b) the free testosterone was measured to preclude the gray zone of total testosterone level; (c) the symptoms of testosterone deficiency were assessed using the validated Aging Males’ Symptoms Rating Scale, so we have confidence that our results are accurate and reliable; and (d) all parameters of interest were included (namely, SSc clinical characteristics, medications, and laboratory tests of metabolic syndrome), so we can explore the initial clinical data associated with primary hypogonadism among male SSc patients. Limitations of the study were (a) this was a pilot study, and only a small population was included, which might have resulted in a low power of analysis, so a study with a larger sample size is recommended; (b) there were no data available on erectile dysfunction to clarify the relationship between primary hypogonadism and erectile dysfunction; (c) there lacked a control group, for example, healthy men with the same age; and (d) the majority of Thai SSc is dcSSc, ⁵ whereas most Caucasians and Asians have lcSSc,^6,7,38–45 so the findings might not be generalized to populations having the lcSSc subset predominantly. Notwithstanding the limitations, our findings provide preliminary information about the male reproductive problem in SSc. The study also suggests the benefit of holistic care and a multidisciplinary approach, especially for family planning and quality of life in male SSc patients.

Conclusion

Around one-quarter of males with SSc met the definition for primary hypogonadism. Those at risk of developing primary hypogonadism had (a) elderly onset SSc, (b) hypertriglyceridemia, and (c) corticosteroid use at an older age.