TTW levothyroxine showed high rates of adherence to levothyroxine therapy during Ramdan and high rates of post-Ramadan euthyroidism that were similar to SDT levothyroxine with better convenience and more involvement in the family gatherings that usually take place at Ramadan. The present study confirms the safety and efficacy of TTW L-T4 demonstrated in the previously published pilot study one year ago [7].

Several studies reporting the impact of fasting Ramadan on thyroid function in hypothyroid patients have included exclusively patients rendered euthyroid on stable L-T4 therapy. Post-Ramadan dysthyroidism was found to occur at variable rates. Oudghiri et al. reported 19%, Elsherbiny reported 20%, Alkaf et al. reported 25.4%, Elsherbiny reported 25.7%, and El-Kaissi et al. reported 32% of their patients being dysthyroid in post-Ramadan visit [6, 8, 10,11,12].

In the previously published pilot study, post-Ramadan dysthyroidism was 18.2% in the twice or thrice weekly L-T4 group versus 17.7% in the daily L-T4 group, without statistical difference [7]. In the present study, post-Ramadan dysthyroidism was only 8.8% in the twice or thrice weekly L-T4 group versus 5.5% in the daily L-T4 group, also without statistical difference.

Pre-Ramadan TSH, age, gender, and L-T4 regimen were among the determinants of post-Ramadan thyroid status, however, adherence was the most consistently reported determinant [6, 8, 10,11,12].

Nonadherence to L-T4 may be due to pure forgetfulness, confusion about its permanency, drug intolerance or merely fear of adverse effects, or an absence of symptoms [13, 14]. However, the need to take on a daily basis, on an empty stomach an hour before food is definitely burdensome [15]. This is specifically true in Ramadan fasting when patients need either to extend their fasting hours by one more hour if they take L-T4 before Iftar or break their fast and then have a second shorter fast for 3–4 h to empty their stomach to take L-T4 before Suhor [8]. This is further complicated by the frequent family gatherings at Iftar meal when patients are socially obliged to share the meal with the family, limiting their ability to take L-T4 at Iftar.

This has been reflected in research with high rates of reported nonadherence to L-T4 during Ramadan. El-Kaissi et al. reported 30%, Oudghiri et al. reported 36%, Dabbous et al. reported 64%, and Karoli et al. reported 75% of their patients being nonadherent to LT4 instructions during Ramadan [10, 16,17,18]. In the present study, 96% of the patients in the twice or thrice weekly L-T4 group were adherent to L-T4 instructions compared to 89% in the standard daily L-T4 group, although without statistical significance. In the previously published pilot study, adherence to L-T4 instructions also exceeded 90% at 91% in the twice or thrice weekly L-T4 group versus 88.5% in the daily L-T4 group, also without statistical difference [7].

The use of once weekly levothyroxine is supported by the fact that it has a long elimination half-life of 7 days, and an autoregulatory mechanism exists carried out by deiodinases to prevent hyper- and hypofunction at the beginning and the end of the dosing interval, respectively [19]. The efficacy and safety of once weekly L-T4 have been confirmed in 3 randomized crossover studies [15, 19, 20]. Although once weekly L-T4 is not used routinely in hypothyroid patients, it has shown higher efficacy in achieving better control in patients with treatment refractory hypothyroidism [3, 14].

Based on the same principles, twice weekly and every other day L-T4 are alternatives to standard daily L-T4 that proved to be as safe and effective as SDT [4, 5]. The need for a slightly higher L-T4 dose when switching a patient from daily to once weekly L-T4 dosing was suggested by Grebe et al. to achieve complete euthyroid state, however this was never tested in a subsequent research. [19] Rajput et al. and Bornschein et al. didn’t make a similar suggestion and considered the same daily L-T4 dose given as a once weekly dose an equal alternative. [15, 20] Taylor et al. and Dayal et al. also didn’t recommend a higher L-T4 dose when using twice weekly and alternate day L-T4 dosing. [21] This unsettled question about the need to increase the L-T4 dose when switching to weekly L-T4 dosing may also explain the significantly increased TSH in TTW versus SDT groups in the present study.

In the present study, twice or thrice weekly L-T4 aimed to decrease the burden of altered routine for hypothyroid patients fasting during Ramadan from a daily routine to only 2 or 3 days, thus allowing 4–5 days a week of usual routine for any Muslim fasting Ramadan. Instead of once weekly mega L-T4 dose, the weekly dose was divided into 2 or 3 weekly successive doses to be more acceptable and less worrisome for patients. The choice of dosing days to be Saturdays and Sundays ± Mondays were specifically chosen to avoid usual days of family gatherings; these are Thursdays and Fridays.

The main limitation of the present study is the long list of exclusions – cardiac diseases, pregnancy, and history of thyroid cancer – making TTW L-T4 not applicable for many hypothyroid patients. Another limitation of the present study includes significantly higher pre-Ramadan TSH in the TTW group which may have resulted in lower (yet non-significant) rates of post Ramadan euthyroidism. A third limitation is the significantly younger age in the TTW group, unlike a previous study linking younger age to decreased adherence to L-T4 [6], in the present study the TTW group showed higher adherence rates during Ramadan (yet non-significant), however, pre-Ramadan adherence was not assessed. The strengths of the present study include the novel utility of twice or thrice weekly L-T4 dosing during Ramadan resulting in a high rate of adherence (96.5%), a high rate of post-Ramadan euthyroidism (91.2%), and better convenience and potentially better quality of life. A final point of strength is the larger number of participants relative to the previous pilot study.