Graves' disease remains the most frequent cause of hyperthyroidism but poorly described in men. The objective was to study the specificities of Graves' disease in this population at Abass Ndao University Hospital Center in Dakar (Senegal).
Patients and methods
It was a descriptive and analytical retrospective study conducted over 20 years. The parameters taken into account were epidemiological, clinical, and progressive.
624 cases were reported with a prevalence of 28.79% among 2167 cases of Graves' disease. The mean age was 32.1±13 years, family history and irritating factors were respectively found in (15.4%) and (42.46%). The delay of consultation was 11.79±25 months and there were goiter in 89.90% and Graves' orbitopathy in 72.92%. The goiter was statistically correlated with free T4 > 70 pmol/l [OR=2.85(1.53-5.30), p=0.0002] and Graves' orbitopathy with volume of goiter [OR=2.08(1.42-3.07), p=0.0001]. The average starting treatment dose with of Antithyroid Drug (ATD) was 38.3±1 mg/day of Carbimazol. Only a dose of ATD > 30 pmol/l was significantly correlated with early maintenance therapy (≤ 3 months) [OR=0.078(0.04-0.14), p=0.0000].
Complications were thyrotoxic heart diseases (06.89%), moderate-to-severe or sight-threatening orbitopathy (01.12%). After 30 months, 250 subjects (40.06%) were regularly followed. The remission affected 96 patients (38.4%) of whom 26 subjects relapsed at the end of the follow-up. Among the 154 patients (61.60%) who failed treatment, 48 (31.17%) had a thyroidectomy. Failure to medical treatment was significantly correlated with age <30 years [OR=1.96(1.11-3.47), p=0.009], size of goiter [OR=2.50(1.34-4.64), p=0.002] and initial values of free T4 > 70 pmol/l [OR=1.89(1.04-4.42), p=0.017].
Graves' disease in male subject is characterized by delayed diagnosis, a larger goiter, a high rate of lost sight and relapse. The follow-up needs to take into account the risk factors of failure to improve the choices and therapeutic recourses. Radioiodine treatment remains a necessity.
Keywords: Dakar; Graves' disease; Male; Senegal
Hyperthyroidism is the most common endocrinopathy whose major etiology is Graves' disease. Graves' disease is characterized by a thyrotoxicosis syndrome associated with a vascular diffuse goiter, a Graves' orbitopathy and presence of anti-TSH receptor antibodies. It is more common in women with a peak frequency between 40 and 60 years [1,2]. Graves' disease is an autoimmune thyroid disorder with a genetic component and environmental factors predisposing to its occurrence. Associated environmental factors include stress, infection and peripartum [3,4]. The pathophysiology of Graves' disease is based on an auto-stimulatory by TSH-Receptor Antibodies (TRAb) on the thyroid gland (vascular goiter), retro-orbital smooth muscle and retro-bulbar fibroblasts (Graves' orbitopathy), and subcutaneous tissue (dermopathy) . The diagnosis associates a thyrotoxicosis and specific signs such as Graves' orbitopathy, vascular goiter and pretibial myxoedema in rare cases. The medical treatment is mainly based on Antithyroid Drug (ATD) treatment over a period of 18 to 24 months. Ablative treatments (i.e., radioiodine therapy and surgery) are the cornerstones of healing. Although the particularities in women are sufficiently well documented , specific data in male subjects remain rare, most often embedded in an overall description of Graves' disease. A moroccan series reports on 6 years of follow-up, a mean age of 45 years, a more severe Graves' orbitopathy and a higher relapse rate compared to the female sex . The objective of this work was to study the epidemiological, clinical and evolutionary characteristics of Graves' disease in male subjects at the Medical Clinic II of Abass Ndao University Hospital Center in Dakar (Senegal).
Patients and Methods
This was a descriptive and analytical retrospective study conducted from January 1, 1998 to December 31, 2017 (20 years). It was performed at the Medical Clinic II of Abass Ndao Hospital Center in Dakar (Senegal). The Medical Clinic II houses a hospitalization service of internal medicine with a diabetology orientation, a unit for consultation and follow-up of pathologies of internal medicine and endocrinology (including thyroid diseases), diagnostic assistance units and the National Diabetes Center Marc Sankale. We have included the records of male patients with Graves' disease confirmed and followed in the service. Graves' disease is characterized by a thyrotoxicosis syndrome associated with a vascular diffuse goiter or a Graves' orbitopathy. The dosage of the anti-TSH receptor antibodies is not always available on the Senegal. Incomplete or misinformed files were excluded.
The parameters considered in the evaluation were:
Age divided into children (under 11 years), adolescents (from 11 to 20 years old), adults (over 20 years old), family history of thyropathy, and trigger or self-maintenance factors (family difficulties, professional, and other difficulties).
Delay of consultation, anthropometric data. The existence of a Graves' orbitopathy , a goiter (classed in grade according to the World Health Organization classification) , the values of free Tetra iodothyronine (free T4), free Triiodothyronine (T3 free) and ultrasensitive Thyroid Stimulating Hormone (TSHus) were also evaluated at baseline and at follow-up. The biochemical standards in our laboratory were 0.17 to 4.05 mIU/l for TSHus, 9 to 22 pmol/l for free T4 and 2.5 to 5.8 pmol/l for free T3. Cervical ultrasound with doppler was systematic in case with goiter. Scintigraphy and assay of anti-TSH receptor antibodies were not regularly performed because few available in Senegal.
Treatment and evolution
The modalities of medical and surgical management (no patient had benefited radioiodine therapy unavailable in Senegal) were evaluated over a period of 30 months. We studied the prescribed drugs (antithyroid drug, beta-blockers and anxiolytics), drug dosages at the beginning and during the follow-up. Carbimazol was the only one antithyroid drug used in the medical treatment of Graves' disease. The efficiency of the treatment was based on an overall assessment (clinical, changes in Carbimazol doses and biological parameters, appearance of complications). The remission was a stabilization of the disease after 12 months of discontinuation of medical treatment. Relapse was defined as a reappearance of thyrotoxicosis after a successful cessation of medical treatment. Failure of medical treatment was defined by a poor recovery of the disease occurring during treatment [9,10]. The latter also concerned the voluntary cessation of treatment for whatever reason and loss of sight. Complications sought were thyrotoxic heart diseases , acute thyrotoxic crisis, moderate-to-severe or sight-threatening orbitopathy , and agranulocytosis. The care of the complications is multidisciplinary with the cardiologists in case of thyrotoxic heart diseases and the ophthalmologists in case of moderate-to-severe or sight-threatening orbitopathy. Indications for thyroidectomy were also taken into account.For the descriptive analysis, the data were presented as a percentage for the qualitative variables and as averages with standard deviation for the quantitative variables. The statistical tests used were the Chi-2 test for qualitative variables and the student's test for quantitative variables. We also made a univariate analyze to evaluate the factors associated with relapse. A p value < 0.05 was considered statistically significant with a 95% Confidence Interval (CI). The capture and the exploitation were carried out by the software Epi info version 22.214.171.124.
Epidemiological and clinical data
A total of 624 cases of Graves' disease were collected in male subject. The prevalence was 6.4% among 9750 cases of all thyropathies, 24.60% among 2536 cases of hyperthyroidism and 28.79% among 2167 cases of Graves' disease. The average age was 32.1±13 years. A family history of thyroid disease was found in 97 patients (15.4%) and a trigger or self-maintenance factors in 265 subjects (42.46%). The average delay of consultation was 11.79±25 months (range 1 to 36 months). The mean heart rate was 104 pulses/mn and tachycardia was found in 308 patients (50.08%). It was a goiter in 561 cases (89.90%), a Graves' orbitopathy in 455 cases (72.92%). All patients had a TSH <0.01 mIU/ml. Free T4 value was normal in 139 cases (22.27%), between 23 and 49 pmol/l in 175 cases (28.04%), between 50 and 100 pmol/l in 50 cases (8.01%) and greater than 100 pmol/l in 260 patients (41.66%). The presence of goiter was statistically correlated with the value of free T4 > 70 pmol/l [OR=2.85(1.53-5.30) p=0.0002]. Graves' orbitopathy was statistically correlated with the size of goiter [OR=2.08(1.42-3.07) p=0.0001]. We found no significant correlation with family history thyropathy, trigger or self-maintenance factors, delay of consultation, and age. Table 1 shows the epidemiological and clinical profile of subjects on admission.
All patients had initially received medical treatment with ATD (only Carbimazol). The average starting dose of treatment was 38.3±1 mg/day. This dose was less than 30 mg/day in 35.97% of cases, between 30 and 50 mg/day in 53.71%. In 10.32% of cases, it was greater than 50 mg/day. Anxiolytics and beta blocker was prescribed in 244 patients (39.10%) and 350 patients (56.09%), respectively. The simultaneous use of beta blockers and anxiolytics was found in 227 patients (36.37%). The mean duration of the attack treatment was 6.73 months. Among the patients who complied with their appointment, the maintenance treatment was effective in the first 3 months in 282 (61.84%), within 6 months in 310 patients (79.69%). Only the ATD peak dose > 30 pmol/l was significantly correlated with early initiating maintenance treatment in the first 3 months [OR=0.078(0.044-0.14) p=0.0000]. We don't found a significant correlation between early initiating maintenance treatment and respectively the initial free T4 value, the use of beta blocking or anxiolytics therapy.
Among the 624 patients initially selected, those lost to follow-up represented 229 cases (36.69%) at 6 months and 334 cases (53.52%) at 12 months of follow-up. Complications were thyrotoxic heart diseases in 43 cases (06.89%), moderate-to-severe or sight-threatening orbitopathy in 7 cases (01.12%), and agranulocytosis in 2 cases. We did not find an acute thyrotoxic crisis.After 30 months, only 250 subjects were regularly followed, with a percentage of 40.06%. Remission was observed in 96 patients (38.40%). Among them, 26 subjects (27.03%) had relapse. The 70 patients (28%) with full remission had a remission delay of 15 months in 45 cases (64.29%), 18 months for 14 cases (20%), and 21 months in 10 cases (14.29%). A failure of medical treatment was found in 154 patients (61.60%). Among the subjects with treatment failure, 48 (31.17%) had a thyroidectomy; the others (68.83%) are still under ATD treatment. Indications for thyroidectomy were failure of medical treatment in 33 cases, thyrotoxic heart diseases in 11 cases (23.40%), moderate-to-severe or sight-threatening orbitopathy in 2 cases (04.25%) and agranulocytosis in 2 cases.Failure to medical treatment was significantly correlated with age < 30 years [OR=1.96(1.11-3.47), p=0.009], presence of goiter [OR=3.43(1, 41-8.37), p=0.003], grades of goiter [OR=2.50(1.34-4.64), p=0.002] and initial values of free T4 > 70 pmol [OR=1.89(1.04-4.22), p=0.017]. Other parameters such as body mass index, family history of thyropathy, trigger or self-maintenance factors, delay of consultation, Graves' orbitopathy, and Carbimazol initial dose were not shown to be significant. Table 2 shows the factors associated with the failure of medical treatment in the 250 male subjects who completed 30 months of treatment.
Epidemiological and clinical data
Epidemiological data on Graves' disease in male subjects remain variously reported by series and authors. In the western countries, frequencies vary from 12.1% in French  to 17.2% in the United Kingdom . In Africa, values between 8.6% and 12.4% are found [13,14]. Like data in our patients, the average age stabilizes between 35 and 45 years [13,14,15-18]. The inclusion of children and adolescents partly explains the decline of this average age to 32.1 years in our study.
The importance of the environment and genetics in the genesis of Graves' disease is well known [19-21]. These include smoking, triggers or self-maintaining factors, and a family history of thyroid disease [12,18,22]. In male subjects, Manji et al. , and Allahabadia et al. , in the United Kingdom respectively reported a family history of thyropathy in (40% and 42.5%) and active smoking in (31.4% and 44%). For Magri et al. , in Italy, the existence of family thyropathy was significantly more common in men. The profile of maintenance factors for the disease would rather depend on societal realities. Diop et al. , had already described the role and impact of stress in the onset of Graves' disease. In Senegal, Sarr et al. , found family conflict and psycho-emotional shock in 22.8% and 14.9% respectively.The frequency of the specific signs of Graves' disease was almost identical to the literature data [10,13,14,25, 26]. The presence of goiter seems less frequent compared to the female sex [12,18]. But male subjects would be characterized by a larger goiter [18,23]. As previously described in the literature, the presence of goiter in the male subject was statistically correlated with young age, Graves' orbitopathy, and free T4 value [12,18,19,23].
For medical treatment, the recommendations suggest an adaptation of the initial dose of ATD to the intensity of hyperthyroidism and profile of the patient . This is to obtain at the same time anti-thyroid and immunosuppressive actions without major adverse effects [27-29]. Our study also shows a significant correlation between the intensity of the initial dose of ATD and the early maintenance treatment. The β blockers play a major role in controlling the symptoms of thyrotoxicosis. Aside from their inhibitory action on cardiovascular symptoms, they would block the peripheral transformation of Tetraiodothyronine (T4) into the more active Triiodothyronine (T3). Their prescription should be systematic until euthyroidism. To this prescription, should be added a supportive psychotherapy and anxiolytics. As in our study, the first-line medical treatment remains the preference in Europe, Latin America and Japan; in contrast to the USA where it is rather radioiodine therapy with Iodine 131 which predominates in 59.7% .If the patient remains in persistent hyperthyroidism beyond 2 years of medical treatment, the surgical indication should be considered. However, the option of prolonged low-dose medical treatment may be used in case of patient preference [10,30]. In the absence of radioiodine therapy not available in Senegal, many of our patients preferred the long-term medical option despite its inefficiency.
In Sub-Saharan Africa, spontaneous therapeutic disruption is the main obstacle to optimizing treatment . In addition to the delay in management, this fact explains the high rate of mainly cardiovascular complications. They were reported at 9.8% and 16.6% respectively in Senegal  and Morocco . However, it is rather the female sex which would be more at risk of thyrotoxic heart diseases .The frequency of remission varies considerably by geographical area. After 30 months of follow-up, we report a complete remission in 28%. In the USA, remissions in 20 to 30% were reported after 12 to 18 months of medication . A European study of 5 to 6 years of medical treatment reports a remission in 50 to 60% . However, the remission rate in adults would not be improved by medical treatment beyond 18 months  or high doses of initial treatment by ATD . In addition, the male sex is more likely to recur, especially in smokers and those with large goiter [6,12,36,37]. In our study, failure in medical treatment was significantly correlated with young age [OR=1.96(1.11-3.47), p=0.009], goiter size [OR=2.50(1.34-4.64), p=0.002] and intensity of hyperthyroidism [OR = 1.89(1.04-4.42), p=0.017].
Graves' disease in male subjects remains an underrated reality. It is characterized by a delay in diagnosis, a larger goiter, a high rate of lost sight and more relapse. Apart from therapeutic education, patient support remains essential. The follow-up will have to take into account the risk factors of failure to improve the choices and therapeutic recourses. The fear of thyroidectomy should lead us to more advocacies to make available radioiodine therapy.
Conflict of Interest
The authors do not declare any conflict of interest.