We are grateful for the opportunity to answer to the comment by Patel et al. on our article titled ‘Sex hormone-binding globulin levels and development of hypertension in middle-aged men and women’ regarding the potential limitations of our study [1]. We appreciate the insightful critique and welcome the chance to address the raised concerns about the potential limitations of our study.

Firstly, we acknowledge the significant impact that thyroid disease, specifically hypothyroidism and hyperthyroidism, can have on sex hormone-binding globulin (SHBG) production within the liver [2]. Although our study did not explicitly account for these factors, we recognize their significance and their potential impact on SHBG levels. To address this concern, we conducted a sensitivity analysis to assess the influence of individuals with reported thyroid disorders. This information was collected at follow-up. Notably, even after excluding individuals with a history of thyroid disorders, the estimates of the association between SHBG and incidence of hypertension remained similar, in fact an increase with 1 SD of SHBG was associated with 32% decrease in the risk for hypertension at follow-up [odds ratio (OR) 0.68; 95% CI 0.52–0.88] in the final model. However, we agree that the absence of information on thyroid-stimulating hormone (TSH) levels is a limitation of our study, and this should have been acknowledged in our list of study limitations.

Patel et al. also raised a crucial point regarding the differences in sex hormone levels between middle-aged male and female individuals, particularly about testosterone, oestrogen, dihydrotestosterone, and 17-β-estradiol. We agree that these differences may influence SHBG levels and agree with the importance to consider them and potential interactions with other variables, such as family history, diabetes mellitus type 2, metabolic syndrome, smoking, and alcohol consumption in future research. Direct measurement of these hormones, however, may be methodologically difficult especially at low levels [3,4]. Moreover, this is more challenging when considering the physiological variations in hormonal levels during the menstrual cycle [5].

Furthermore, Patel et al. underscored the well founded importance of family history of hypertension. Family history is indeed a significant risk factor for hypertension and may have an association with genetic and physiological aspects of SHBG production. We acknowledge that an unequal distribution of individuals with and without a family history of hypertension in our study could impact the interpretation of the results. We, therefore, also conducted additional sensitivity analyses, including individuals without known heredity for hypertension. The information on family history of hypertension included first grade relatives and was collected at follow-up visit. We observed similar results in the final model [odds ratio (OR) 0.56; 95% confidence interval (CI) 0.35–0.91]. These findings indicate that the associations between SHBG levels and hypertension remained robust, even when considering only individuals without a family history of hypertension.

In conclusion, we appreciate the insightful comments and agree that coexisting comorbid chronic diseases, variations in sex hormones, and genetic predispositions can impact SHBG levels and consequently the reported associations with hypertension. Our sensitivity analyses to address these concerns related to thyroid disorders and family history of hypertension seem to show a remaining significant association indicating that other mechanisms are involved in this association. Furthermore, we emphasize the need to replicate these results in other cohort studies with comprehensive data on additional sex hormone concentrations, TSH levels, polycystic ovarian syndrome status, and other factors that influence SHBG levels. This could further improve our understanding of the impact of SHBG levels on blood pressure and its interaction with the metabolic syndrome.

ACKNOWLEDGEMENTS

We want to thank all the participants who made this study possible.

Conflicts of interest

There are no conflicts of interest.

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