Impact of Isotretinoin Therapy on Thyroid Hormone Levels in Patients with Acne Vulgaris: A Systematic Review and Meta-Analysis

Abstract

Introduction

Systemic isotretinoin is extensively used to treat moderate-to-severe acne vulgaris and may have systemic endocrine effects through the hypothalamic-pituitary-thyroid axis.

Objectives

To investigate the changes in thyroid hormone levels after commencement of systemic isotretinoin among patients with acne vulgaris.

Methods

A PubMed, ScienceDirect, Scopus, and Cochrane Library search was performed. Pooled analysis was conducted utilizing Review Manager (RevMan 5.4.1).

Results

A total of 447 patients from eight observational studies were included. After three and four months, no increase in TSH levels was observed following isotretinoin treatment with a standardized mean difference (SMD) of 0.09 (95% CI: −0.27–0.46; P=0.62) and (SMD=0.72; 95% CI: −0.01–1.45; P>0.05), respectively. However, a significant increase in TSH levels was observed at six months (SMD=0.54; 95% CI: 0.05–1.03; P=0.03). T4 levels showed no alteration at three months (SMD= −0.24; 95% CI: −0.56–0.08; P=0.14) but were reduced at four months (SMD= −0.79; 95% CI: −1.20–−0.38; P=0.0001) and six months (SMD= −0.87; 95% CI: −1.57–−0.17; P=0.01). T3 levels were reduced at three months (SMD= −0.42; 95% CI: −0.80–−0.04; P=0.03), four months (SMD=−0.63; 95% CI: −1.03–−0.23; P=0.002), and 6 months (SMD= −1.13; 95% CI: −1.77–−0.55; P=0.0001).

Conclusion

Long-term isotretinoin treatment may cause time-dependent changes in thyroid hormone levels.

Introduction

Acne vulgaris, a chronic inflammatory disease of the pilosebaceous follicles, predominantly impacts the face, neck, chest, and back [1]. It is the most prevalent dermatological disease in youth and early adulthood [2]. It impacts 9% of the global population, with cases reaching 85% among 12–24-year-olds and 50% among 20–29-year-olds [3].

Isotretinoin, a synthetic analog of vitamin A, remains the preferred treatment for severe or resistant acne vulgaris because of its potent ability to reduce sebaceous gland secretion and follicular hyperkeratinization [4]. The Food and Drug Administration (FDA) of the United States authorized it in 1982 as a remedy for severe acne, and in 1983, it was approved in Europe. However, it is commonly associated with adverse effects, including elevated lipid and hepatic enzyme levels, skin and mucous membrane xerosis, and teratogenicity [5–6]. With the widespread and increasing use of isotretinoin, especially for acne vulgaris, there has been growing interest in understanding its potential effects on endocrine function and metabolic processes [6].

Retinoid receptors in the target cells are bound and activated by retinoids such as isotretinoin [7]. Retinoid X receptors (RXRs) and retinoic acid receptors (RARs) are the two primary subgroups of the retinoid receptors involved [7]. The steroid thyroid superfamily of receptors includes both of these receptors [8]. The highly selective retinoids for the RXRs also influence thyroid and vitamin D-responsive genes [9]. This was observed previously in the use of bexarotene, an RXR ligand, which leads to hypothyroidism through the central pathway and the alteration of the peripheral metabolism of thyroid hormones [10].

A few studies have investigated the changes in endocrine hormones after systemic isotretinoin treatment [1,6,11]. The studies have indicated that isotretinoin treatment results in some observed changes in the levels of thyroid hormones [4,12,13].

Objectives

This review aimed to comprehensively analyze these studies and integrate the data about alterations to thyroid hormone levels in individuals with acne vulgaris after systemic isotretinoin treatment.

Methods

Registration and Protocol

This review followed PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) [14]. The study has been registered with PROSPERO under CRD420251242304.

Literature Search

Through October 2025, two independent authors conducted a comprehensive literature search for papers of significance. The first strategy employed a specified search criterion for four databases: PubMed, ScienceDirect, Scopus, and Cochrane Library. The search strategy involved using specific keywords combined with Boolean operators. The search string for ScienceDirect was as follows: ((“Acne” OR “Acne vulgaris”) AND (Isotretinoin) AND (“Thyroid hormones” OR “Thyroid stimulating hormone” OR “Thyroxine”). The search strategy for each database is provided in the appendix (Supplementary Table S1). Additionally, the reviewers carefully reviewed the included studies’ references for relevant studies.

Eligibility Criteria

Upon being retrieved from the databases, studies were analyzed and filtered based on predetermined eligibility criteria prior to their inclusion in the review. Studies were deemed suitable if they involved patients with acne vulgaris undergoing isotretinoin treatment, assessed isotretinoin as an intervention, and documented alterations in thyroid hormone levels subsequent to the commencement of isotretinoin medication. Only primary studies, including clinical trials and observational research, were considered eligible for inclusion. The exclusion criteria included publications in languages other than English, studies that did not employ isotretinoin as an intervention, and studies that did not document alterations in thyroid hormone levels following isotretinoin medication. Additionally, secondary studies such as systematic reviews, narrative reviews, and editorials were excluded.

Data Extraction

Two reviewers separately extracted data. In case of data extraction disagreements, the two reviewers reviewed them until they reached an agreement. According to PRISMA, the authors examined all references from various phases before data extraction. After abstract screening for relevancy, all irrelevant articles were removed. We next sought out and evaluated the remaining papers to determine eligibility. Studies that satisfied the eligibility criteria were incorporated, and relevant data were subsequently obtained. Author ID, setting, study design, inclusion criteria, number of participants, sex distribution, average age, isotretinoin dosage, and reported endocrine alterations were extracted from each study.

Quality Assessment

Two authors independently examined the included studies’ methodology. The Joanna Briggs Institute (JBI) critical assessment checklist for cohort studies was used to assess single-arm studies for methodological rigor. The cohort study JBI checklist has 11 questions (Supplementary Table S2). If the response is “yes,” it receives a score. If the response is “no,” “not applicable,” or “unclear,” the question receives zero. High, middle, and low quality are defined as scores of 8, 5–7, and 4, respectively.

Table 1.

Characteristics of the included studies.

Author ID	Setting	Study design	Inclusion criteria	Sample size	Male: Female	Mean Age	Isotretinoin therapy dosage (period)	Endocrine changes reported
Hareedy et al., 2021 [1].	Egypt	Prospective cohort study	Patients with severe acne	47	33:14	20.81 ± 3.5 years	0.5 mg/kg/day (6 months)	1. FT4 2. FT3 3. TSH
AlSaif et al., 2020 [11].	Saudi Arabia	Prospective cohort study	Patients with moderate-to-severe acne vulgaris with no history of any thyroid disorder or other comorbidities.	51	21:30	18 to 25 years	0.5 mg/kg/day for 8 months	1. TSH
Morey et al., 2020 [6].	India	Prospective cohort study	Patients with grade 3 and 4 acne vulgaris	30	20:10	19.3 ± 3.14	0.5 mg/kg/day (3 months)	1. T3 2. T4 3. TSH
Karadag et al., 2015 [15].	Turkey	Prospective cohort study	Patients with nodulocystic acne vulgaris	105	30:75	0.5 to 1 mg/kg/day (group 1), 0.2 to 0.4 mg/kg/day (group 2), and 0.5–1 mg/kg/day (group 3) for 6 months.	1. Pituitary hormones 2. FT3 3. TSH 4. FT4
Yildirim et al., 2017 [12].	Turkey	Prospective cohort study	Patients with acne vulgaris	51	22:29	20.47 ± 3.15	0.5 to 1 mg/kg/day (6 months)	1. TSH 2. FT3 3. FT4
Kotb et al., 2025 [4].	Saudi Arabia	Prospective cohort study	1. Patients diagnosed with acne vulgaris 2. Patients on isotretinoin therapy for four months	50	15:35	22.62 ± 3.98 years	0.5 to 1 mg/kg/day for 4 months.	1. T3 2. T4 3. TSH
Uyar et al., 2016 [13].	Turkey	Prospective cohort study	1. Patients with moderate to severe nodulocystic acne 2. Treatment with isotretinoin for at least four months	66	14:52	22.68 ± 4.51 years	0.5 to 0.8 mg/kg (4 months)	1. TSH 2. FT3 3. FT4
Karadag et al., 2011 [16].	Turkey	Prospective cohort study	Patients with acne vulgaris aged 17 to 34 years	47	16:31	20.8 ± 3.5 years	0.5–0.75 mg/kg body weight (3 months)	1. FT3 2. FT4 3. TSH

Note: TSH - Thyroid-stimulating hormone; FT3 - Free triiodothyronine; FT4 – Free tetraiodothyronine

Statistical Analysis

The Review Manager software (RevMan 5.4.1) was utilized to perform the statistical synthesis. Continuous outcomes were assessed utilizing the standardized mean difference (SMD). SMD was used for analysis since the levels of thyroid hormones were measured using different units. Between-study heterogeneity was evaluated using the chi-square and I² statistic, with values >75%, 50%–75%, and <50% signifying high, moderate, and low heterogeneity, respectively. Due to significant variability among studies, a random-effects model was employed for all analyses. A leave-one-out sensitivity analysis was conducted to determine which study significantly influenced the observed heterogeneity. The findings are presented using forest plots.

Results

Search Outcomes

Electronic database searches yielded 708 references. Duplication evaluation removed 391 duplicates from the review. Following elimination of duplicates, the remaining 317 records were screened for relevance based on titles and abstracts, and 278 were excluded from the review. We then sought 39 full-text articles to evaluate them according to the review’s eligibility criteria. All full texts were obtained; only eight satisfied the eligibility criteria. The remaining 31 papers were omitted due to being secondary investigations (N=5), absence of relevant outcomes (N=13), and lack of isotretinoin as a therapy (N=13). The study selection process is summarized using the PRISMA flow diagram (Figure 1).

Figure 1.

A PRISMA flow diagram summarizing the search strategy.

Characteristics of the Included Studies

Eight observational studies conducted in different settings, including Turkey, Saudi Arabia, India, and Egypt, were included [1,4,6,11–13,15,16]. All the studies included patients with acne vulgaris, with a pooled sample size of 447 patients. Furthermore, all the studies were prospective cohorts. The participants’ mean age varied between 19.3 ± 3.14 years and 22.68 ± 4.51 years. The dosage of isotretinoin ranged from 0.5 to 1 mg/kg/day, with treatment ranging from three to eight months. Alterations in thyroid-stimulating hormone (TSH), triiodothyronine (T3), and tetraiodothyronine (T4) were documented.

Changes in Thyroid-Stimulating Hormone (TSH) Levels

Studies reported changes in TSH levels from baseline up to eight months post-isotretinoin therapy initiation. A meta-analysis of the results found that no significant increase was detected in TSH levels after three and four months of isotretinoin (SMD=0.09; 95% CI: −0.27–0.46; P=0.62) and (SMD=0.72; 95% CI: −0.01–1.45; P>0.05), respectively. Both analyses had substantial heterogeneity identified (I²=77% and I²=89%, respectively). A significant increase in TSH levels was only observed after six months of isotretinoin (SMD=0.54; 95% CI: 0.05–1.03; P=0.03). The analysis had moderate heterogeneity (I²=74%) (Figure 2). A leave-one-out analysis found that Kotb et al. and AlSaif et al. contributed to the observed heterogeneity in outcomes at four and six months, respectively [4, 11]. Omitting Kotb et al. from the analysis of changes observed at four months eliminated the observed heterogeneity (I²=0%; P=0.70) [4]. Similarly, omitting AlSaif et al. from the changes observed at six months eliminated the observed heterogeneity (I²=0%; P=0.54) (Supplementary Table S3) [11].

Figure 2.

Forest plot showing changes in TSH levels after isotretinoin therapy.

Changes in Tetraiodothyronine (T4) Levels

Five of the included studies reported changes in T4 after isotretinoin therapy. A meta-analysis of the reported outcomes found that, similar to TSH, no significant change was detected in T4 levels after three months of treatment (SMD= −0.24; 95% CI: −0.56–0.08; P=0.14), with moderate between-study heterogeneity (I²=70%). A leave-one-out sensitivity analysis identified Yildirim et al. as a major contributor to the observed heterogeneity [12]. Excluding this study reduced heterogeneity to I²=59% (P=0.06) (Supplementary Table S3). However, a significant decrease in T4 levels was observed after four months (SMD= −0.79; 95% CI:−1.20–−0.38; P=0.0001) and six months (SMD= −0.87; 95% CI: −1.57–−0.17; P=0.01) (Figure 3). The latter analysis exhibited high heterogeneity across studies (I²=82%).

Figure 3.

Forest plot showing changes in T4 levels after isotretinoin therapy.

Changes in Triiodothyronine (T3) Levels

Six studies reported changes in T3 levels. A pooled analysis of the studies found that, similar to TSH and T4, a statistically significant reduction in T3 levels was detected after three months of isotretinoin therapy (SMD= −0.42; 95% CI: −0.80–−0.04; P=0.03) in the presence of substantial heterogeneity across the studies (I²=79%) (Figure 4). A leave-one-out analysis found that Morey et al. contributed to a significant proportion of the observed heterogeneity [6]. Omitting the study reduced the heterogeneity to (I²=55%; P=0.09) (Supplementary Table S2). Similarly, T3 levels demonstrated a further significant decline after four months (SMD= −0.63; 95% CI: −1.03–−0.23; P=0.002) and six months (SMD= −1.13; 95% CI: −1.77–−0.55; P=0.0001). The latter analysis showed moderate between-study heterogeneity (I²=72%).

Figure 4.

Forest plot showing changes in T3 levels after isotretinoin therapy.

Methodological Quality of the Included Studies

The included studies did not have any low methodological quality. Only one study, by Hareedy et al., had moderate methodological quality [1]; it did not provide sufficient information regarding exposure adherence and attrition handling [1]. On the other hand, the rest of the studies provided sufficient information on enough key questions. The evidence provided in the studies was sufficient and strengthened by the prospective designs and consistent outcome measures (Supplementary Table S1).

Discussion

This review aimed to conduct an extensive overview of the effect of interventions utilizing isotretinoin on patients with acne vulgaris by synthesizing the empirical evidence on this subject. A summary estimate of a sample size of 447 patients from eight observational studies was incorporated [1,4,6, 11–13,15,16]. We synthesized data on changes observed in TSH, FT3, and FT4 at different time points after initiation of systemic isotretinoin therapy. Our pooled analysis indicated that TSH levels do not change significantly after three and four months of isotretinoin therapy. However, after six months, there is a significant increase in the TSH levels. As for the levels of T4, no significant difference was observed after three months; however, the serum levels significantly decreased after four and six months. A significant reduction was observed in serum FT3 levels throughout the three timelines.

Isotretinoin and Acne Vulgaris

The American Academy of Dermatology (AAD), in its latest guidelines, recommends using isotretinoin therapy as a first-line treatment for patients with severe acne or those who have failed to achieve remission on standard treatment with other oral or topical therapies [17]. The guidelines highlight the possible adverse systemic effects of isotretinoin and thus recommend that such patients have continuous monitoring of their lipid levels and liver function [17]. Isotretinoin also has an off-label indication, i.e., the treatment of moderate acne [18].

Isotretinoin has numerous receptors in a substantial number of cell types, which are responsible for its therapeutic effects [19]. However, this also increases the number of organ systems in which adverse events occur during its use [19]. A comprehensive meta-analysis by Kapala et al. summarized the adverse events due to isotretinoin therapy [20]. They found that the adverse events of isotretinoin range across the organ systems. The skin changes commonly reported include skin fragility, xerosis, pruritus, and erythemal changes [20]. Ophthalmic changes reported include dry and irritated eyes, which result in blurred vision, reduced night vision, and conjunctival changes [20]. In the respiratory system, isotretinoin adverse events include dry nose, nasopharyngitis, upper respiratory tract infection, epistaxis, and cough [20]. Some of the concerning side effects were in the gastrointestinal system, where isotretinoin therapy causes hypertriglyceridemia, which may result in pancreatitis. It also causes a toxic effect on the liver that could result in liver failure [20]. While comprehensive, the systematic review by Kapala et al. failed to report any of the adverse events on the endocrine system, including the effect on thyroid hormones [20].

The endocrine adverse events of isotretinoin are not common and are rarely reported in RCTs of isotretinoin therapy [19,20]. Some observational studies have shown changes, although insignificant, in different hormones, including prolactin and thyroid hormones [15,21]. The effect of isotretinoin on thyroid function was initially reported by Marsden et al. in 1984 [22]. However, later on, Oleary et al., in 1986, found that isotretinoin did not affect thyroid function [23]. This conflicting evidence was also observed in pre-clinical studies, and in the past two decades, there have been numerous studies investigating the same [1,4,11,13,15]. The process that leads to isotretinoin-associated thyroid dysfunction is still not fully understood. Suggested mechanisms include the impact on retinoic acid receptors (RARs) and retinoid X receptors (RXRs), both of which play a role in regulating thyroid hormones [24]. Isotretinoin can cause apoptosis in thyroid cells, modify the secretion of pituitary hormones, and influence the metabolism of peripheral thyroid hormones, leading to decreased FT3 and FT4 levels along with a compensatory rise in TSH [24]. Moreover, the immunomodulatory effects resulting from the activation of T and B lymphocytes could play a role in autoimmune thyroid dysfunction among individuals who are predisposed [24].

Our systematic review indicates that in almost all cases, after four months of isotretinoin therapy, the patient’s thyroid levels showed statistically significant changes. The findings indicate that isotretinoin significantly reduces the thyroid hormone levels (FT3 and FT4), which in turn, through a negative feedback mechanism, stimulates the production of more TSH, hence the observed increase in TSH levels [1]. Although the changes are statistically significant, it must be noted that across all the studies, the serum levels of these hormones were still within the normal ranges. Thus, the patients did not have any overt manifestations of hypothyroidism [1,15,16]. This indicates that isotretinoin may result in subclinical hypothyroidism or transient thyroid dysfunction [1].

While most studies indicated that the patients in their cohorts did not develop any overt sign of hypothyroidism, our results are still clinically relevant for many patients. Firstly, the development of hypothyroidism occurs in patients who are receiving long-term isotretinoin therapy. Our systematic review estimates clearly indicate that the changes in thyroid findings develop with time. These insights, therefore, suggest that it is necessary for clinicians to be mindful of the thyroid function of patients on long-term isotretinoin therapy and conduct routine thyroid function tests in such patients [4]. The findings also indicate the need for thyroid monitoring in other patients, especially those who may have subclinical hypothyroidism before treatment initiation. While no large study has reported this, case reports have indicated that some patients without a positive history of thyroid disorders develop overt hypothyroidism after long-term isotretinoin therapy for three years [25,26]. One of the case reports suggested that this hypothyroidism is reversible after treatment cessation [26].

Limitations of the Study

While this systematic review has comprehensively summarized the existing evidence on the effects of isotretinoin therapy, it is not without its limitations. Firstly, a limited number of studies (N=8) as well as a sample size that is comparatively small (N=447) were included in the study, limiting the evidence quality. Additionally, while the included studies provided evidence on thyroid hormone changes after isotretinoin therapy initiation, none of them followed the patients for long enough until treatment cessation. We therefore cannot determine whether the observed changes in thyroid hormones were transient or permanent, especially after long-term therapy. Lastly, throughout the studies, moderate-to-high heterogeneity was found in most of our analyses. The heterogeneity that was observed may be a result of the various study designs since these observational studies had differences in the sample characteristics and dosage of isotretinoin. However, this still points out the inconsistencies that are observed in the studies reporting changes in thyroid function tests after isotretinoin therapy initiation.

Recommendations

On the basis of this systematic review’s findings and limitations, the following recommendations can be made: i) Future observational studies should enroll more patients and extend their follow-up periods in order to provide higher-quality evidence; ii) Future research should stratify outcomes according to the dosage of isotretinoin to determine whether the effect of isotretinoin on thyroid hormones is dose-dependent; iii) Further studies to investigate whether routine thyroid monitoring may have significant benefits to the patients during isotretinoin treatment, before such recommendations are made for integration into clinical practice, should be conducted. It is, however, important that clinicians be cautious when administering isotretinoin to patients with existing thyroid dysfunction.

Conclusions

Our findings indicate that isotretinoin therapy affects thyroid hormone levels, namely, these levels show a significant reduction. However, the reduction may not result in overt manifestations of hypothyroidism in the short term in patients with normal thyroid function. In patients with subclinical thyroid dysfunction that results in reduced thyroid hormone levels, these reductions may result in clinical adverse events. This warrants clinicians to be mindful of the thyroid function of patients on long-term isotretinoin therapy and those beginning isotretinoin therapy with existing subclinical thyroid dysfunction.