|Year : 2020 | Volume
| Issue : 2 | Page : 56-61
Subclinical hypothyroidism and erectile dysfunction: The potential nexus
Marwa H Abdul-Hadi, Nawar R Hussian, Huda A Rasheed, Hayder M Al-Kuraishy, Ali I Al-Gareeb
Department of Pharmacology, Toxicology and Medicine, College of Medicine, Almustansiriya University, Baghdad, Iraq
|Date of Submission||16-Oct-2019|
|Date of Decision||11-Nov-2019|
|Date of Acceptance||26-Nov-2019|
|Date of Web Publication||25-Apr-2020|
Hayder M Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriya University, P. O. Box 14132, Baghdad
Source of Support: None, Conflict of Interest: None
Purpose: The aim of the study was to evaluate the link between subclinical hypothyroidism (SCH) and erectile dysfunction (ED). Materials and Methods: Seventy-two male patients aged 23–41 years with SCH compared with 25 healthy matched subjects were recruited, and they were divided into Group A: healthy controls (n = 25), Group B: patients with SCH with ED (n = 43), and Group C: patients with SCH without ED (n = 29). Thyroid function test and hormonal assay included total testosterone (TT), sex hormone-binding globulin, free androgen index, and prolactin (PRL) were measured; erectile function was assessed by the 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire. Results: Free triiodothyronine serum level and thyroid uptake were lower in patients with SCH with ED (240.31 ± 23.85 pg/dL) as compared with patients with SCH without ED or the controls (P = 0.008 and P = 0.004, respectively). Thyroid-stimulating hormone (TSH) serum levels differed significantly; they were normal in the control group (2.86 ± 1.86 mIU/L), higher in patients with SCH with ED (12.41 ± 4.73 mIU/L), and relatively low in patients with SCH without ED (7.32 ± 4.81 mIU/L) (P = 0.001). TT serum level was low in patients with SCH with ED as compared with the controls, but this level was high in patients with SCH without ED as compared with those with SCH with ED (P = 0.001). PRL serum level was high in patients with SCH with or without ED as compared with the controls (P = 0.001). IIEF-5 score was low in patients with SCH with ED (11.73 ± 5.79) as compared with the controls (P = 0.001, 95% confidence interval [CI] = 14.3985–7.8215) or patients with SCH without ED (P = 0.001, 95% CI = 13.1152–6.7448). Conclusion: SCH-induced ED is related to the elevated PRL and reduced TT and TSH serum levels more than 10 mIU/L. Furthermore, the high TSH serum level was linked with the low IIEF-5 scores; therefore, the severity of SCH is correlated with the severity of ED.
Keywords: Erectile dysfunction, prolactin, subclinical hypothyroidism, testosterone
|How to cite this article:|
Abdul-Hadi MH, Hussian NR, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Subclinical hypothyroidism and erectile dysfunction: The potential nexus. Urol Sci 2020;31:56-61
|How to cite this URL:|
Abdul-Hadi MH, Hussian NR, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Subclinical hypothyroidism and erectile dysfunction: The potential nexus. Urol Sci [serial online] 2020 [cited 2021 Jan 24];31:56-61. Available from: https://www.e-urol-sci.com/text.asp?2020/31/2/56/283254
| Introduction|| |
Subclinical hypothyroidism (SCH) is a mild form of hypothyroidism, in which thyroid-stimulating hormone (TSH) is slightly elevated to compensate the reduction of thyroid function. Thyroid hormones, which are thyroxine (T4) and triiodothyronine (T3), are within the normal range in SCH; therefore, clinical features of hypothyroidism are commonly not seen. It has been noted that 26.8% of patients with SCH developed overt hypothyroidism within 6 years from the early diagnosis. The causes of SCH are Hashimoto's disease, radioactive iodine, thyroid surgery, and medications, such as lithium, amiodarone, tetracycline, aminoglutethimide, ethionamide, and thalidomide. The risk factor for the development of SCH is female gender that has 2–5 times more risk than male due to hormonal changes, young age, and history of iodine intake.
The diagnosis of SCH is done by the biochemical test of thyroid function, in which T3 and T4 are within the normal range, but TSH serum levels are elevated more than the normal range. Patients with TSH serum levels of 4.0–10 mIU/L are considered to have mild SCH which does not need treatment, but TSH serum levels more than 10 mIU/L are considered severe SCH, which needs treatment. Moreover, 75% of patients with SCH have TSH <10 mIU/L since TSH and T4 serum levels show considerable variability among healthy controls due to unique hypothalamic–pituitary–thyroid axis for each person which probably explains that high TSH serum level is associated with normal and subnormal free T4 (FT4). A previous study illustrated that 46% of patients with SCH that had TSH <7 mIU/L will normalize within 2 years. In addition, transient high TSH serum level may be detected during recovery from thyroiditis and nonthyroid diseases, while persistence and high TSH serum level are seen in different clinical conditions including obesity, adrenal insufficiency, TSH resistance, and aging.,
Patients with SCH are usually asymptomatic, but Jorde et al. showed that cognitive dysfunctions, depressive symptoms, and memory disorders are more not uncommon in patients with SCH compared to healthy euthyroid controls. Besides, Biondi and Cooper reported some clinical signs and symptoms of SCH such as weight gain, muscle weakness, and fatigue, which were more common in the elderly compared to younger patients. It has been noted by different studies that the long-term consequences of SCH are linked with the development of heart failure, ischemic heart disease, dyslipidemias, and stroke, which are correlated with the levels of TSH.,
Furthermore, SCH is associated with low testosterone and high prolactin (PRL), which collectively lead to erectile dysfunction (ED). In spite of this suggestion, there is a controversy regarding the role of SCH in the pathogenesis of ED. Sarma et al. showed that SCH in male patients is associated with the reduction of sperm motility and androgen serum levels causing ED. On the other hand, Corona et al. illustrated that insignificant association between SCH and ED.
Therefore, the aim of the present study was to demonstrate the link between SCH and ED.
| Materials and Methods|| |
In this single-institution cross-sectional study, 72 male patients aged 23–41 years with SCH compared with 25 healthy matched subjects were recruited from the National Endocrinology Center from January to April 2018 and were selected according to the diagnostic criteria of the European Thyroid Association.
The present study was approved by the explicit-controlled ethical committee under the Principled Clearance Number RNTW 231/4/2018 in accordance with the Declaration of Helsinki. All patients and enrolled participants gave informed verbal consent for their participation in this study after their interview, physical examination, and routine investigations. Inclusion criteria included newly diagnosed patients with SCH with or without ED. Exclusion criteria included psychological diseases, neurological diseases, diabetes mellitus, end-stage kidney disease, hepatic dysfunction, connective tissue disorders, history of intake of drugs that affect erectile function (dopamine receptor agonist and antagonist agents, thiazide diuretics, β-blockers, antipsychotics, and antidepressants), malignant disorders, and organic or psychological causes of sexual dysfunction. The exclusions in this study depend on the detailed history, physical examination, and routine biochemical and radiological investigations according to the presented cases.
The recruited patients and enrolled male participants were divided into three groups according to the assessment of thyroid function test and evaluation of erectile functions as follows:
- Group A: Healthy controls (n = 25)
- Group B: Patients with SCH plus ED (n = 43)
- Group C: Patients with SCH without ED (n = 29).
Body mass index (BMI) was estimated by specific equation as follows: BMI = weight (kg)/height (cm). Blood pressure measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were determined by a digital sphygmomanometer at the supine position through the mean of three readings 5 min apart.
After an overnight fast, 5 mL of venous blood was obtained from the recruited patients and enrolled healthy participants; the blood samples were centrifuged at 3000/rpm and were stored at −20°C for later analysis.
Thyroid function test and hormonal assay
Thyroid function test and hormonal assay included TSH (Human enzyme-linked immunosorbent assay [ELISA Kit; ab100660, Abcam, USA]), total T4 (total and free thyroxine, Human ELISA Kit, ab178664, Abcam, USA), FT4, total T3 (Human T3 ELISA Kit, ab108664, Abcam, USA), free T3 (FT3), thyroid hormone uptake (Tuptake or T3uptake) measured by radiometric assay, free thyroxine index (FT4I) = total T4 × T3uptake, and free triiodothyronine index (FT3I) = total T3 × T3uptake.
Total testosterone (TT) was measured by the ELISA Kit method (ADI-901-065, ENZO immunoassay); sex hormone-binding globulin (SHBG) was measured by the ELISA Kit method (Human ELISA Kit, MIC126834); free androgenic index (FAI) = PRL serum level was measured by ELISA (Human ELISA Kit, ab108655, Abcam, USA).
Assessment of erectile function
The 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire was used for the estimation of erectile function; it consists of 5 questions, with 5 scores for each question. According to this score, ED was classified into normal erectile function (>21), mild ED (17–21), moderate-to-mild ED (12–16), moderate ED (8–11), and severe ED (1–7).
The data were analyzed using SPSS (IBM SPSS Statistics for Windows version 20.0; IBM Corp, Armonk, NY, USA). and statistical software GraphPad Prism (version 6.0, GraphPad Software, 2014, Armonk, Chicago, USA). Data were expressed as mean ± standard deviation, and the differences among groups or between two different groups were assessed by one-way analysis of variance followed by Tukey post hoc test and unpaired Student's t-test, regarding the level of significance as P < 0.05.
| Results|| |
The present study illustrated that there were insignificant differences in age, BMI, blood pressure, total T4, FT4, and total T3 in patients with SCH with and without ED (P > 0.05). Besides, FT3 serum level and Tuptake were low in patients with SCH with ED (240.31 ± 23.85 pg/dL) as compared with those with SCH without ED or controls (P = 0.008 and P = 0.004, respectively). Furthermore, both FT4I and FT3I did not significantly differ in patients with SCH with or without ED as compared with the controls (P = 0.81 and P = 0.83, respectively).
On the other hand, TSH serum levels was differed significantly; they were normal in the control group (2.86 ± 1.86 mIU/L), higher in patients with SCH with ED (12.41 ± 4.73 mIU/L), and relatively low in those with SCH without ED (7.32 ± 4.81 mIU/L) (P = 0.001).
Other hormonal changes were also observed in the present study; TT serum level was low in patients with SCH with ED as compared with the controls, but this level was higher in patients with SCH without ED as compared with those with SCH with ED (P = 0.001). FAI did not significantly differ in patients with SCH with or without ED compared with the controls (P = 0.85). As well, PRL serum level was high in patients with SCH with or without ED as compared with the controls (P = 0.001), as shown in [Table 1].
|Table 1: Anthropometric and hormonal profile in patients with subclinical hypothyroidism with or without erectile dysfunction|
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The IIEF-5 questionnaire was used for the estimation of erectile function; it was normal in the male controls (22.85 ± 3.92) and reduced insignificantly in patients with SCH without ED (21.67 ± 2.74) as compared with the controls (P = 0.63, 95% confidence interval [CI] = 4.2746–1.9146). However, IIEF-5 score was low in patients with SCH with ED (11.73 ± 5.79) as compared with the controls (P = 0.001, 95% CI = 14.3985–7.8215) or patients with SCH without ED (P = 0.001, 95% CI = 13.1152–6.7448), as shown in [Figure 1].
|Figure 1: Levels of the 5-item version of the International Index of Erectile Function in patients with subclinical hypothyroidism with or without erectile dysfunction compared with the controls. *P < 0.01 versus subclinical hypothyroidism without erectile dysfunction and control and subclinical hypothyroidism without erectile dysfunction versus control not significant (P = 0.63, *P = 0.0001)|
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Regarding the association of TSH serum levels on the IIEF-5, low TSH serum level <10 mIU/L was associated with high IIEF-5 scores, whereas high TSH serum level >10 mIU/L was associated with low IIEF-5 scores. The difference between high and low TSH serum levels was significant (P = 0.0001, difference = −8.650, 95% CI = 10.7730–6.5270), as shown in [Figure 2].
|Figure 2: The relationship between thyroid-stimulating hormone serum levels and the 5-item version of the international index of erectile function. *P <0.01|
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Furthermore, TSH serum level <10 mIU/L was linked with the low PRL serum level (12.57 ± 4.79) compared with high PRL serum level (15.73 ± 4.31) in TSH serum level >10 mIU/L (P = 0.004). On the other hand, TT serum level was high in relation to TSH serum level <10 mIU/L compared to low TT serum level in relation to TSH serum level >10 mIU/L (P = 0.008). FAI did not significantly differ regarding TSH serum levels (P = 0.34), as shown in [Figure 3].
|Figure 3: The relationship between thyroid-stimulating hormone serum levels and free androgenic index, prolactin, and total testosterone|
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Regarding the correlations of IIEF-5 with the anthropometric parameters and hormonal variables of patients with SCH with or without ED, IIEF-5 did not significantly correlate with BMI, SBP, DBP, T4, FT4, T3, and FT3 (P > 0.05), but it significantly correlated with FT3I, TSH, TT, SHBG, FAI, and PRL (P < 0.05), as shown in [Table 2].
|Table 2: Correlations of the 5-item version of the International Index of Erectile Function with the anthropometric parameters and hormonal variables of patients with subclinical hypothyroidism with or without erectile dysfunction|
Click here to view
| Discussion|| |
ED is defined as the inability to attain and maintain sufficient penile erection for satisfactory sexual performance. ED is common in men aged 40–79 years and mainly linked with metabolic and endocrine causes.
In the present study, we observed that ED is linked with SCH as revealed by the study of Krassas et al., which illustrated an association between hypothyroidism and ED. SCH with ED is mainly caused by hormonal changes since our findings showed that ED is linked to the high levels of TSH serum levels, as documented by the study of Carani et al. which reported an inverse correlation between TSH serum levels and ED.,
Regarding thyroid hormone levels in the present study, total T3 and T4 were normal in patients with SCH with or without ED, but the FT3 serum level was low in those with SCH with ED in spite of normal FT4 and T3 index, which might give a link between SCH and ED. It has been reported that thyroid hormone receptors are widely distributed in the penile corpora cavernosa and endothelial cells, which play a potential role in the regulation of the release of nitric oxide (NO) at the corpora cavernosa. In SCH, low FT3 leads to the reduction of NO and acetylcholine-dependent vasorelaxation and subsequent failure of erection.
On the other hand, SCH-induced ED in the present study might be due to the reduction of TT and elevation of PRL serum levels, which adversely affect sexual desire and performances. It has been reported that SCH is associated with low testosterone serum levels since T3 plays an important role in the regulation of testosterone synthesis. As well, high TSH serum levels inhibit testicular testosterone synthesis., Therefore, high TSH and low T3 levels in patients with SCH in the present study might explain low sex drive and ED as testosterone level is positively correlated with men erectile function. Alternatively, SCH is linked with elevated PRL serum level, as Goel et al. found that SCH is associated with ED and low sex drive.
The mechanisms of high PRL in SCH are related to elevated thyrotropin-releasing hormone (TRH) from the hypothalamus due to the reduction of the negative feedback inhibition of T3 on TRH secretion. TRH normally stimulates the release of PRL and TSH from the anterior pituitary. Besides, a reduction of PRL clearance and the inhibitory effect of dopamine on PRL secretion collectively participate in the induction of hyperprolactinemia in patients with SCH. In addition, T3 inhibits pituitary PRL mRNA; thus, low T3 induces the synthesis and release of PRL from the anterior pituitary and correlated with the elevated TSH levels in patients with SCH. Consequently, high PRL in patients with SCH may contribute to the development and the induction of ED as reported by a recent study of Krysiak and Okopień.
Therefore, our findings illustrated that SCH-induced ED was associated with elevated PRL levels and reduced TT levels, which were linked with high TSH levels and low T3 levels without significant differences in FAI regarding TSH levels. In this regard, IIEF-5 scores were positively correlated with FT3, TT, SHBG, and FAI but negatively correlated with TSH and PRL levels as noticed by different studies. For that reason, the present study demonstrated that the severity of ED was correlated with the severity of SCH, which is inconsistent with the study of Chen et al. which showed that the severity of ED is not related to the severity of SCH, whereas different studies revealed that the severity of ED is related to the degree of thyroid dysfunction since replacement therapy in patients with hypothyroidism restores normal erectile function.,
Finally, the present study had several limitations as follows: this study was a single-center cross-sectional study, which were could explain the association not causalities of ED in patients with SCH; it also has a small sample size; and TRH level was not evaluated. However, this study certainly confirmed the association between ED and SCH in spite of its small sample size.
| Conclusion|| |
SCH-induced ED is related to the elevated PRL, reduced TT and TSH serum levels more than 10 mIU/L. Furthermore, high TSH serum level was linked with low IIEF-5 scores; therefore, the severity of SCH is correlated with the severity of ED.
Informed consent has been obtained from all patients and controls.
We would like to acknowledge Dr. Salah Al-windy for his great support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]