Drug products: Eltroxin, Euthyrox, Levaxin 0,1 mg u/lactose, Levaxin utan lactos, Levaxin®, Levothyroxin, Levothyroxine, Levothyroxine sodium, Levothyroxine Sodium, Levothyroxine Sodium App, Levothyroxinenatrium Teva, Levotyroxin Nycomed, L-Thyrox HEXAL, L-Thyroxin, L-Thyroxin AL, L-Thyroxin Aventis, L-Thyroxin Henning, L-Thyroxin Henning Inject, L-Thyroxine Christiaens, L-Thyroxine Serb, SYNTHROID, Tiche, Tirosint, Tirosintsol
ATC code: H03AA01
Substances: levothyroxine, levothyroxine sodium, levothyroxine sodium (hydrate)
Levothyroxine treatment is individualized, and with the goal of attaining the lowest effective dose. In pregnant women or women on oral estrogen therapy, the levothyroxine dosage requirements increase because of elevated thyroxine-binding globulin, leading to lower serum concentrations of free thyroxine.
Some studies indicate that long-term levothyroxine therapy might induce decreased bone mineral density in women, particularly postmenopausal women. No change in bone mineral density was found in men.
The main indication for levothyroxine is for the treatment of hypothyroidism. Patient’s sex is considered a predisposing factor for hypothyroidism (Graves’ disease), as women are affected 4 to 10 times more than men [1-3].
Pharmacokinetics and dosing
Levothyroxine treatment is individualized according to TSH levels.
A retrospective observational study (69 men, 88 premenopausal women, 91 postmenopausal women) showed that premenopausal women had a greater dose requirement (mg/kg bodyweight) of levothyroxine than men and postmenopausal women . All women had a greater dose requirement than men, using ideal body weight  instead of actual body weight for dose calculation, in another study . Similar results were also reported in patients with and without heart failure .
In a study (8 men, 33 women), the influence of age, weight, and patient’s sex on levothyroxine pharmacokinetics was analyzed. Patient’s sex only affected the median oral clearance rate, apparent volume of distribution, and dose-normalized peak concentration in univariate analyses. However, after adjusting for weight, patient’s sex was no longer a significant covariate. The authors concluded that physicians should consider a patient’s weight, rather than age, for estimating levothyroxine dosage requirement . The sex difference in dosing disappearing when correcting the dose for weight and body surface area is also found in boys and girls . In obese patients, no sex difference in weight-adjusted levothyroxine dosing was found .
In women on oral estrogen therapy or pregnant women, adaptation of dosage is necessary because of elevated thyroxine-binding globulin leading to decreased free thyroxine serum concentration . Levothyroxine-treated pregnant women often need to increase the daily dose by 25-30%. Following delivery, levothyroxine dose should be reduced to prepregnancy levels .
The role of patient’s sex in disease presentation and remission rate in patients with Graves’ disease treated with antithyroid drugs (ATD) was assessed in a retrospective study (64 men, 171 women). Patient’s sex was not a predictor of remission in a univariate analysis (p=0.124) .
A review (in total 3279 patients) described that most cross-sectional studies reported adverse effects at a larger number of bone sites in postmenopausal women, suggesting a negative influence on bone mineral density with (BMD) levothyroxine therapy. However, other cross-sectional studies found comparable results in pre- and postmenopausal women, but no effect of levothyroxine on BMD in men. This review reports no dose-response relationship . The original manufacturer reports that long-term levothyroxine therapy might decrease BMD in women, particularly postmenopausal women on higher doses .
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
A cross-sectional retrospective study (33238 men, 87165 women) examined the relationship between TSH and free T4. In individuals not receiving levothyroxine treatment, free T4 concentrations corresponded to higher median TSH in men than in women .
No sex differences were found in studies assessing the impact of levothyroxine treatment on depressive symptoms  or carotid atherosclerosis .
In a retrospective study in patients treated for hypothyroidism (113 men, 602 women), clinical predictors that could identify a subset of patients who might be monitored safely on a less frequent basis, were evaluated. Patient’s sex among other factors were not significantly associated with time to abnormal thyroid-stimulating hormone value (i.e. “stability over time”) .
In Taiwanese patients with or without hypothyroidism, patients with hypothyroidism who received thyroxine replacement therapy (TRT) had a lower risk of mortality than patients who did not receive TRT. In the sex-stratified analyses similar results were obtained (1559 men, 2493 women) .
Reproductive health issues
Estrogen can increase the concentration of thyroxine-binding globulin in serum. Women using contraceptives containing estrogen or hormone replacement therapy may require higher doses of levothyroxine . Regarding drug-drug interactions aspects, please consult Janusmed Interactions (in Swedish, Janusmed interaktioner).
Date of litterature search: 2021-11-01
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- Heiat A, National Institutes of Health (NIH: the NIH Consensus Conference on Health Implications of Obesity in 1985), United States Department of Agriculture (the 1990 Department of Agriculture's Dietary Guidelines for Americans), National Heart, Lung, and Blood Institute. Impact of age on definition of standards for ideal weight. Prev Cardiol. 2003;6(2):104-7. PubMed
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- Yang T, Ruegger M, Colavecchia AC, Sadhu A, Patham B, Tatara A. Comparison of Levothyroxine Dosing in Patients with and without Heart Failure. Endocr Res. 2020;45(1):50-57. PubMed
- Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med. 2001;344:1743-9. PubMed
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- Younis IR, Ahmed MA, Burman KD, Soldin OP, Jonklaas J. Stable Isotope Pharmacokinetic Studies Provide Insight into Effects of Age, Sex, and Weight on Levothyroxine Metabolism. Thyroid. 2018;28(1):41-49. PubMed
- Singh R. Determinants of levothyroxine dose required to achieve euthyroidism in pediatric population-a hospital-based prospective follow-up study. Eur J Pediatr. 2017;176(8):1027-1033. PubMed
- Mele C, Tagliaferri MA, Pagano L, Soranna D, Scacchi M, Aimaretti G et al. Levothyroxine Replacement in Obese Adults: The Role of Metabolic Variables and Aging on Thyroid Testing Abnormalities. J Clin Endocrinol Metab. 2019;104(12):6265-6274. PubMed
- Diker-Cohen T, Duskin-Bitan H, Shimon I, Hirsch D, Akirov A, Tsvetov G et al. DISEASE PRESENTATION AND REMISSION RATE IN GRAVES DISEASE TREATED WITH ANTITHYROID DRUGS: IS GENDER REALLY A FACTOR?. Endocr Pract. 2019;25(1):43-50. PubMed
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- Huang HK, Wang JH, Kao SL. Association of Hypothyroidism With All-Cause Mortality: A Cohort Study in an Older Adult Population. J Clin Endocrinol Metab. 2018;103(9):3310-3318. PubMed
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- Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T₄ in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab. 2013;98:2936-43. PubMed
- Wildisen L, Feller M, Del Giovane C, Moutzouri E, Du Puy RS, Mooijaart SP et al. Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial. JAMA Netw Open. 2021;4(2):e2036645. PubMed
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Reviewed by: Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson