Autoimmune Hashimoto's Disease and Feminization Level—Testing the Immunocompetence Hypothesis

Abstract

Morphological femininity depends mainly on estrogen levels at puberty and is perceived as a cue of a woman's biological condition. Due to the immunostimulant properties of estradiol, estradiol-dependent feminine traits are expected to be positively related to immunity. However, heightened immunity in women may increase the risk of autoimmune disease, thus the relationship between femininity and immune quality may be complex. This study aimed to assess the relationship between morphological femininity and both the occurrence and severity of Hashimoto thyroiditis (HT) in women of reproductive age. Moreover, 95 women with HT and 84 without HT (all between 20 and 37 years) participated in the study. Morphological femininity was assessed based on somatic measurements of sexually dimorphic traits (2D:4D ratio, WHR, breast size, facial sexual dimorphism). The occurrence and severity of HT were assessed by serum TPOAb levels. The results showed that only the 2D:4D ratio of the right hand was higher in the HT group, indicating higher femininity in these women. However, there was also a positive relationship between facial femininity and TPOAb level in women with HT, indicating a higher severity of the disease. The results suggest that prenatal and pubertal exposure to estrogens may increase the probability or severity of autoimmune diseases in adulthood, but the relationship is tentative.

Keywords

autoimmune disease immunocompetence estradiol sexual dimorphism biological cue

Introduction

Femininity in women or masculinity in men are sex-typical characteristics dependent on sex hormone levels (Fink et al., 2003). In women, higher estradiol (E2) and lower testosterone (T) levels are related to a greater expression of body and facial feminine traits, such as a narrow waist and greater gluteo-femoral and breast adiposity, oval face shape, narrower jaw, less prominent brow ridge, rounded eyes, and bigger and fuller lips (Jasieńska et al., 2004; Küchler et al., 2021; Mondragón-Ceballos et al., 2015; Puts et al., 2012). These traits develop as early as in intrauterine life (Fink et al., 2005; Zheng & Cohn, 2011), and then through puberty (Tanner, 1990) and adult age (Jasieńska et al., 2004) reflecting estradiol level across ontogeny.

Feminine traits are cross-culturally perceived as attractive and it has been suggested that physical attractiveness may be a cue of a woman's biological condition, including fertility, and general health (Jasieńska et al., 2004; Kayar & Çilengiroglu, 2015; Klimek et al., 2016; Law Smith et al., 2006; Nedungadi & Clegg, 2009). One of the key components of the biological condition is immunity and some research on the adaptive role of sexually dimorphic traits suggests that femininity may be a cue of a woman's immunocompetence (Jones, 2018), which would explain why more feminine women are perceived as more attractive (Gray & Boothroyd, 2012). Yet, there is little direct evidence that female appearance signals immunity. For example, research finds that women's facial attractiveness does not correlate with the strength of antibody response to vaccination (Rantala et al., 2013) or salivary immunoglobulin level (Cai et al., 2019). Also, Foo et al. (2017a, 2017b) showed no link between facial femininity and immune functioning in women. On the other hand, some studies have suggested that women's facial attractiveness reflects a stronger antibacterial immune response (Mengelkoch et al., 2022), and that femininity is positively related to resistance to respiratory pathogens (Thornhill & Gangestad, 2006), and negatively to the prevalence of infection (Gray & Boothroyd, 2012). Furthermore, Foo et al. (2020) showed that immune function during puberty that is, when sexually dimorphic traits develop under the influence of sex steroids, predicts facial femininity in adulthood.

One may expect a positive relationship between estradiol-dependent traits and immunity due to the immunostimulant properties of E2 that enhance both cell-mediated and humoral immune responses (Walker, 2011). E2 receptors alpha and beta (ER α/β) are expressed on most immune cells and E2 can modulate lymphocyte cytokine production, cytokine receptor expression, and activation of effector cells (Dong et al., 2015; Karpuzoglu & Zouali, 2011; Pernis, 2007; Salem, 2004). Estradiol can also strengthen immune response by activating a plethora of cells such as phagocytes, dendritic cells, natural killers, and CD8 + T cells Furthermore, estradiol also increases local immune response and mucus production in the nasal cavity and upper respiratory traits (Di Stadio et al., 2020). Also, lower testosterone levels may contribute to higher immunity in women, as, in contrast to estradiol, T has an immunosuppressant effect (Foo et al., 2017a, 2017b; Posma et al., 2004). As a result, women, in general, are characterized by stronger innate and adaptive immunity (Klein & Flanagan, 2016; Walker, 2011) and are less susceptible to a variety of infectious agents compared to men (Foo et al., 2017a, 2017b).

Strong immune response in women may, however, lead to immunopathology (Klein & Flanagan, 2016). The high female-to-male incidence rate for autoimmune diseases suggests that higher estradiol levels may be linked with autoimmune diseases (Hayter & Cook, 2012). E2 suppresses T and B cells’ lymphopoiesis and enhances the humoral B cell immune response in humans which is important for adaptive immunity but also enhances the immune response in autoimmunity (Moulton, 2018; Straub, 2007). E2 also reduces the expression of a protein called an autoimmune regulator (AIRE), important for the expression of tissue-specific antigens and a key factor in central tolerance, preventing autoimmune disorders (Dragin et al., 2016). Murine studies have revealed further immunoregulatory effects of estradiol including increased production of autoantibodies in autoimmune thyroiditis (Qin et al., 2018). Furthermore, E2 regulates several cytokines that may have pro-inflammatory results, skewing TH1-type to TH2-type response may contribute to autoimmune disorders (Moulton, 2018). For instance, it has been shown that E2 activates synovial cell proliferation, including macrophages and fibroblast concentrations (Schmidt et al., 2009), and exacerbates the inflammation in patients with rheumatoid arthritis (RA) (Cutolo et al., 2004). Additionally, lower T levels in women may also contribute to a higher rate of autoimmune diseases compared to men (Gubbels Bupp & Jorgensen, 2018; Moulton, 2018; Shepherd et al., 2021). For instance, T level is inversely associated with the risk of systemic lupus erythematosus (SLE) (Pakpoor et al., 2017), the severity of RA and multiple sclerosis (MS), possibly due to its anti-inflammatory properties (Bove et al., 2015; Lashkari et al., 2018). In turn, treatment with testosterone alleviates the symptoms of these autoimmune diseases (Cheng & Wang, 2023; Ocon et al., 2017).

Reports show that the effect of E2 on autoimmune diseases depends on its concentration, which fluctuates within the menstrual cycle and changes at different life stages (Moulton, 2018; Ngo et al., 2014). For example, exacerbation of SLE is more common during the pubertal period and pregnancy when E2 levels increase (Pierdominici & Ortona, 2013), whereas after menopause when the concentration of E2 falls, clinical signs can be low or completely suppressed (Urowitz et al., 2006). E2-mediated triggering and pathogenic mechanisms may however vary among autoimmune diseases. For instance, MS or RA improves during gestation and exacerbates postpartum and after menopause (Christianson et al., 2015; Mollard et al., 2018; Østensen et al., 2011; Piccinni et al., 2016; Vukusic et al., 2004). Despite that, higher E2 levels generally are linked with an increased risk of autoimmunity (Moulton, 2018). Thus, higher estradiol levels, potentially related to higher morphological femininity, may exert a cost on the immune system and increase female susceptibility to autoimmune diseases (Chailurkit et al., 2014; Hughes & Choubey, 2014).

One of the most common autoimmune diseases is Hashimoto thyroiditis (HT), which frequency has increased considerably in recent years (Ralli et al., 2020). HT affects as many as 5%–20% of young women (Artini et al., 2013; Bortun et al., 2021; Nielsen et al., 2020), which is up to 10 times more often than men (Ralli et al., 2020), suggesting the role of sex hormones in its pathogenesis (Santin & Furlanetto, 2011). Some reports have associated HT with hyperestrogenism (Chailurkit et al., 2014; Chen et al., 2017; Skrzynska et al., 2021). E2 may not only contribute to HT onset but to severity as well (Yang et al., 2023), via stimulating B cells to produce autoantibody, including thyroid peroxidase (TPOAb) (Cheng et al., 2021; Zhang et al., 2022) that is, a serological marker for the diagnosis of HT (Brčić et al., 2016; Siriwardhane et al., 2019). A positive correlation between E2 level and TPOAb titers has been observed, in both men and women (Arduc et al., 2015; Chen et al., 2017; Skrzynska et al., 2021). Additionally, female sex hormone profiles with low testosterone levels may also contribute to autoimmune thyroid disease (Chen et al., 2017).

Recent studies suggest that morphological femininity may be a cue of the risk of HT development. For instance, in comparison to healthy women, those with HT had a higher 2D:4D ratio (Pruszkowska-Przybylska et al., 2021; Święchowicz et al., 2022), a marker of high fetal E2/T ratio (Manning et al., 2014; Zheng & Cohn, 2011), suggesting that the risk of HT may be predicted not only by sex steroids in adulthood but also by prenatal exposure to these hormones. However, both studies (Pruszkowska-Przybylska et al., 2021; Święchowicz et al., 2022) suffered from a lack of HT diagnosis, and the participants self-declared the presence of HT. Furthermore, the rapid increase in E2 levels at puberty may be also related to the risk of autoimmune disease development in girls (Yang et al., 2023). Thus, feminine traits that develop during puberty (e.g., facial femininity, waist-to-hip ratio, breast size) might be also cues of the HT risk in adulthood. Surprisingly, waist-to-hip ratio (WHR), which is inversely related to estradiol level, is higher in patients with HT compared to the control group both in euthyroid (i.e., with TSH level within the reference range), pubertal girls (İşgüven et al., 2016), and adult women (Ruggeri et al., 2016). This may be caused by the positive association between thyroid autoimmunity and the development of abdominal obesity, metabolic syndrome, and cardiovascular diseases (Kim et al., 2021; Sarfo-Kantanka et al., 2017; Yang et al., 2022). Furthermore, TPOAb positivity is associated with higher waist circumference (WC) (Chen et al., 2018) and worse lipid profile in women (Kang et al., 2015), even in the euthyroid state. This suggests that higher WHR levels in women with Hashimoto's disease may be a result of the disease.

Regarding the immune-modulating effect of E2 that may also result in a higher risk of autoimmune disease the role of estradiol-dependent morphological femininity as a cue of immunity may be complex. Thus, this study aimed to assess the relationship between morphological femininity and the occurrence and severity of HT in women of reproductive age. However, an alternative hypothesis is also possible, that morphological femininity is a cue of a woman's biological condition and more feminine women will also have a lower risk of developing HT despite their higher levels of E2.

The occurrence and severity of HT were assessed based on TPOAb levels, which is suggested to be a more sensitive indicator of the autoimmune process in the thyroid gland than autoantibodies against thyroglobulin (Tg) or thyroid ultrasound (Guan et al., 2019; Ragusa et al., 2019). Femininity was assessed based on traits developing at various stages of ontogeny allowing to assess the long-term exposure to E2, which may be a better predictor of autoimmune dysfunction than adult levels of E2, determined based on single sampling. As body adiposity (Han et al., 2016) and sex steroid levels (DeBruine, 2014; Kirchengast & Gartner, 2002; Jasieńska et al., 2004; Law Smith et al., 2006; Mondragón-Ceballos et al., 2015) have been shown to contribute to the level of a woman's morphological femininity we controlled for these variables in the analyses. Finally, as some authors point out that a better predictor of the risk of developing various diseases, including HT, may be the E2/T (Chen et al., 2017; Morselli et al., 2016), thus we also controlled for testosterone level.

Material and Methods

Participants and Study Procedure

The study was carried out in the Department of Human Biology at the University of Wroclaw (Poland) during the years 2018–2022. Participants were 95 women with (HT group) and 84 women without (non-HT group) Hashimoto thyroiditis, recruited via social networks and information in the local media. Women were selected for participation if they met the following criteria: age between 20 and 37 years, no menstrual cycle disorders and no diagnosed fertility problems, no hormonal medication or contraception use, nor pregnancy/lactation within 6 months before recruitment. Furthermore, women could not have any current infection or chronic disease and could not take any constant treatment other than thyroid hormones in the HT group (used up to 12 months before the recruitment). Participants were invited to an examination between the second and the fourth day of their menstrual cycle.

The study protocol was approved by the local Ethic Committee of Wroclaw Medical University (Nr KB-618/2018). All participants gave their written informed consent to participate in the study and to use their data for scientific purposes.

Data were collected from 95 women with HT group and 84 women (non-HT group) without Hashimoto thyroiditis. Both groups consisted of women of European origins, between 20 and 37 years. Women with TPOAb > 5 IU/ml level were included in the HT group, and women with a concentration of TPOAb ≤ 5 IU/ml were allocated to the non-HT group. Euthyroidism was defined as TSH, fT3, and fT4 within normal ranges (0.5–4.0 mlU/l, 80–180 ng/dl ng/dl, and 0.8–1.8 ng/dl respectively). Hypothyroidism was defined as a TSH level > 4.0 mlU/l with fT3 and fT4 within the normal range or exceeded according to the American Thyroid Association criteria (Alexander et al., 2017). According to the endocrine function of the thyroid gland, 95% of the HT group were women in the euthyroid stage (EuHT), whose TSH, fT3, and fT4 hormone levels remained within the normal laboratory range. Only 5% of women already developed hypothyroidism.

Collected data included somatic measurements, standardized facial photographs, blood test results, and personal questionnaires.

Assessment of Morphological Femininity

Morphological femininity was determined by breast size, waist-to-hip ratio (WHR), and 2D:4D ratio. Breast size was calculated as chest circumference at nipple level to chest circumference under the breasts ratio, following Jasieńska et al. (2004). WHR was calculated as waist circumference divided by hip circumference ratio. Breast size is positively and WHR inversely related to femininity. All circumferences were measured with a non-stretchable measuring tape. The 2D:4D ratio was calculated for both hands. Digit lengths were measured as the distance between points pseudophalangion (pph) and dactylion (da). Each measurement was taken twice in both hands, using a digital caliper, and the average value was taken. The 2D:4D value above one is considered to be more feminine. The percentage of body fat mass was obtained by bioelectrical impedance analysis using the mBCA 515 analyzer (SECA®). The researcher taking the measurements was aware of a participant's status as either HT or non-HT.

Facial femininity was assessed based on the facial width-to-height ratio (fWHR) and composite face femininity index (CFFI) measured in the photos. Due to the lack of photographs of one subject, 94 instead of 95 women with HT were included in the statistical analyses involving these variables. Face images were taken under standardized photographic conditions with a digital still camera (Nikon D7100 with Tamron SP AF 17–50 mm F/2.8 XR Di II LD IF camera lens). Camera-to-head distance and camera settings were held constant. Participants had no make-up, glasses, or earrings, and were asked to keep neutral facial expressions. fWHR was measured as the distance between the left and right boundary of the face (width) divided by the distance between the upper lip and the highest point of the eyelid (height), following Stirrat and Perrett (2010), using WebMorph (DeBruine, 2018). Lower fWHR values indicate a more feminine face.

CFFI was measured from each photograph, using a vector analysis method following methodology from Cai et al. (2019), using code for R scripts [https://osf.io/98qf4/; R script for analyzing sexual dimorphism stores, following Scott et al. (2010) and Komori et al. (2011)] by Holzleitner et al. (2014). A lower score indicates a more feminine face shape. Additionally, adult 50 male (M_age = 27.67 years, SD = 3.14 years) and 50 female (M_age = 25.92 years, SD = 1.85 years) faces (recruited from the Polish population from Wroclaw and the surrounding area) were used to build sexual dimorphism scores.

Furthermore, as an aggregate measure incorporating femininity markers may more accurately reflect the levels of morphological femininity than a single marker, aggregate composite body femininity index (CBFI) was calculated by Z scoring breast size, WHR, right and left 2D:4D, and averaging for each individual the four Z scores.

Blood Samples and Hormones Levels Analyses

All blood samples (both for HT and non-HT groups) were collected between 7:30 and 9:00 a.m. into EDTA Vacutainers (BD®) after an overnight fast. Blood samples were collected on the same day as morphological measurements. The blood samples from the HT group and non-HT group were drawn at the same time. Serum E2, TPOAb, TSH, fT3, and fT4 levels were measured in a certified analytical laboratory. Estradiol level (E2) was measured on the Roche Cobas analyzer, using Roche's technology (ElectroChemiLuminescence methods). The serum E2 concentration was expressed in pg/ml. The concentrations of TPOAbs were measured with radioimmunoassay kits (ThermoFisher Scientific, Germany) (sensitivity 5.5 IU/ml; intra-assay CV—3.9%; inter-assay CV—4.1%). Serum TSH concentration was measured with the immunoradiometric method (sensitivity 0.025 mlU/l; intra-assay coefficient of variation (CV) —0.6%; inter-assay CV—2.1%), and serum-free T3 (fT3) (sensitivity 0.3 pmol/l; intra-assay CV—6.4%; inter-assay CV—5.5%) and the serum-free T4 (fT4) (sensitivity 0.03 pmol/l; intra-assay CV—10.3%, inter-assay CV—7.6%) concentrations were detected with radioimmunoassay kits (all DIAsource ImmunoAssays S.A., Belgium).

Serum testosterone level was measured in a laboratory at the Department of Human Biology, University of Wrocław from the blood sample collected in a certified laboratory. Serum was separated by centrifugation then portioned into micro-tubes and stored at −80 °C until analyses. Serum total testosterone (tT) concentration was assayed using ELISA commercial kits (Demeditec Diagnostics GmbH® cat. no. DE1559). Samples preparation and assay procedure were performed in accordance with the manual supplied with the kit. Samples (included in each assay) were measured in duplicate. The absorbance was measured using a microplate reader (ASYS UVM, Biochrom®) set to 450 nm. Testosterone concentration was calculated from the standard curve and expressed in ng/ml. Inter- and intra-assay coefficient of variability (CV) was less than 10% and less than 4.2% respectively, indicating good test precision and repeatability.

Survey Data Collection

Women also completed a survey, containing questions on past and current health issues (including hormonal disorders), medications taken (levothyroxine treatment: in HT group—yes N = 13 and no N = 82, in non-HT group—no one was taking levothyroxine), and reproductive history (having biological children: in HT group—yes N = 15 and no N = 80, in non-HT group—yes N = 12 and no N = 72). The age when diagnosed with HT was obtained and the disease duration in years was calculated.

Statistical Analysis

Data distribution was tested with the Shapiro-Wilk test, kurtosis, skewness values, and plot visual inspection. The values of TSH, tT levels, and breast size were log-transformed for normalization purposes, due to their strongly skewed or leptokurtic distribution. Log-transformed values of TPOAb, fT3, E2, and E2/tT levels did not have a normal distribution, thus non-parametric tests were used in the analyses with these variables. Feminization measures such as fWHR, 2D:4D L, 2D:4D R, CFFI, and CBFI had a normal distribution, while WHR even after log-transformed did not have a normal distribution.

Differences in means of the quantitative variables between women with HT and the non-HT group were tested using Student's (age, % body fat, TSH, fT4 and tT level, fWHR, breast size, 2D:4D L, 2D:4D R, CFFI, CBFI) or Mann–Whitney's U test (TPOAb, fT3 and E2 level, E2/tT, WHR).

The relationship between TPOAb and femininity was tested using the Pearson correlation coefficient.

Subsequently, we verified if the relationship between TPOAb and femininity can be detected when controlled for the potential confounders that might impact femininity (body adiposity and adult sex hormone levels). Thus, we ran six multiple regression analyses with the measurements of femininity as the dependent variables and % body fat, E2, and testosterone as predictors.

Analyses were performed with Statistica 13.0 software. The results were interpreted as statistically significant if p < .05.

Results

Descriptive Statistics

The characteristics of HT and non-HT groups and the differences between the two groups are presented in Table 1. HT group did not differ from the non-HT group in terms of age, adiposity, estradiol, and testosterone levels. As expected, thyroid peroxidase antibodies, thyrotropin, and triiodothyronine were significantly higher in the HT group than in the non-HT group. Furthermore, the HT group did not differ from the non-HT group regarding the majority of the studied femininity measurements. Only the 2D:4D ratio of the right hand was higher in the HT group.

Table 1.

Means, Standard Deviations for the Studied Variables, and the Differences Between HT and Non-HT Groups. Bolded Results Are Significant.

Variables	HT group (N = 95)		Non-HT group (N = 84)		T(177)^▪/U	p
Variables	M ± SD	Range	M ± SD	Range	T(177)^▪/U	p
Age (y)	29.55 ± 4.32	20.00–37.00	29.50 ± 4.26	20.00–37.00	395^a	.92
% Body fat	32.65 ± 7.76	18.12–48.72	32.55 ± 6.58	19.12–53.62	0.09^a	.92
TPOAb [IU/ml]	352.72 ± 338.53	9.41–1001.00	1.16 ± 0.67	0.90–4.98	0.00^b	<.001
TSH^▴ [mlU/l]	2.89 ± 1.44	1.12–10.13	1.95 ± 0.81	0.41–3.85	5.88^a	<.001
fT3 [pmol/l]	4.66 ± 0.57	2.69–6.25	4.44 ± 0.48	3.47–5.76	292.00^b	.002
fT4 [pmol/l]	12.36 ± 1.29	8.74–15.03	12.40 ± 1.10	10.31–15.54	−0.25^a	.80
E2 [pg/ml]	37.43 ± 19.08	7.00–147.00	41.87 ± 25.59	12.90–206.00	3667.50^b	.35
tT^▴ [ng/ml]	0.73 ± 0.22	0.25–1.44	0.72 ± 0.20	0.33–1.41	0.30^a	.77
E2/tT	53.97 ± 25.59	6.82–135.29	63.98 ± 48.79	13.03–381.48	3715.00^b	.43
fWHR^♦	2.13 ± 0.14	1.84–2.42	2.12 ± 0.13	1.82–2.51	0.43^a	.81
CFFI^♦	0.30 ± 0.63	−1.24 to 2.03	0.22 ± 0.56	−1.43 to 1.95	0.84^a	.40
Breast size^▴	1.17 ± 0.05	1.05–1.28	1.16 ± 0.04	1.06–1.30	1.81^a	.07
WHR	0.76 ± 0.06	0.62–0.93	0.74 ± 0.06	0.64–0.96	3347.00^b	.06
2D:4D R	0.99 ± 0.03	0.92–1.06	0.98 ± 0.04	0.90–1.08	2.00^a	.047
2D:4D L	0.99 ± 0.04	0.89–1.07	0.99 ± 0.04	0.90–1.07	1.06^a	.29
CBFI	0.07 ± 0.58	−1.29 to 1.66	−0.05 ± 0.57	−1.14 to 1.42	1.44^a	.15
Age of diagnosed HT (y)	26.75 ± 5.59	14.00–36.00	—	—	—	—
Duration of HT (y)	2.79 ± 3.25	0.01–13.00	—	—	—	—
Duration of levothyroxine treatment (m)	3.91 ± 10.25	0.00–72.00	—	—	—	—

E2 = estradiol; tT = total testosterone; fWHR = facial width-to-height ratio; CFFI = composite face femininity index; WHR = waist-to-hip ratio; 2D = second digit; 4D = fourth digit; R = right hand; L = left hand; CBFI = composite body femininity index.

▴

The analyses used logarithmic values.

♦

N = 94.

▪

df = 176.

Student's test.

Mann–Whitney U test.

The HT and the non-HT groups did not differ in terms of the number of nulliparous women and women who had at least one child (χ² = 0.08, p = .78). Furthermore, having biological children did not impact thyroid function marker levels, except for fT3 which was higher in women who had at least one child compared to nulliparous women (see supplementary materials—Table S1).

Furthermore, the duration of levothyroxine treatment was unrelated to thyroid function markers (see supplementary materials—Table S2).

The Relationship Between the Duration of HT, Age of Diagnosed HT, Thyroid Function Markers, and Femininity Level

TPOAb and TSH levels were unrelated to HT duration. Thyroid hormone levels (fT3, fT4) were negatively related to HT duration time (Table 2). There was no correlation between the age of diagnosed HT and facial or body femininity measurements. However, we observed a trend suggesting that women earlier diagnosed with HT had larger breasts (p = .09) (Table 2).

Table 2.

The Results of Pearson's Correlations Between Duration of HT and Thyroid Parameters and Pearson's Correlations Between the Age of Diagnosed HT and Femininity Measurements HT Group (N = 95). Bolded Results Are Statistically Significant.

	Duration of HT		Age of diagnosed HT
	r	p	r	p
TPOAb [IU/ml]	−.03	.81	−.12	.25
LOG TSH [mlU/l]	−.02	.88	−.07	.48
fT3 [pmol/l]	−.23	.02	.19	.06
fT4 [pmol/l]	−.19	.06	.18	.09
fWHR^♦	−.0004	1.00	−.003	.98
CFFI^♦	.15	.15	.12	.24
LOG breast size	.06	.60	−.18	.09
WHR	.09	.38	.09	.40
2D:4D R	−.03	.77	−.03	.74
2D:4D L	−.18	.07	.13	.23
CBFI	−.10	.31	−.08	.46

fWHR = facial width-to-height ratio; CFFI = composite face femininity index; WHR = waist-to-hip ratio; 2D = second digit; 4D = fourth digit; R = right hand; L = left hand; CBFI = composite body femininity index.

♦

N = 94.

The Relationship Between the Level of TPOAb and Morphological Femininity

Face sexual dimorphism was negatively related to TPOAb level. Also, the negative correlation between fWHR and positive with left 2D:4D was close to the statistical significance level (Table 3).

Table 3.

The Results of the Correlation Between TPOAb Level and Morphological Femininity Measures in the HT Group (N = 95). Bolded results are significant.

	r	p
fWHR^♦	−.19	.07
CFFI^♦	− . 30	.004
LOG breast size	.05	.63
WHR	.10	.34
2D:4D R	.04	.70
2D:4D L	.17	.10
CBFI	.07	.52
E2	−.11	.29
LOG tT	−.04	.73
E2/T	−.06	.59

♦

N = 94.

The results of multiple regression analyses showed a relationship between TPOAb and composite facial femininity, but not with composite body femininity, also when controlled body adiposity, sex steroids levels, levothyroxine treatment, and duration of the disease. The results showed that TPOAb was positively related to levothyroxine treatment and duration of the disease, while negatively related to composite facial femininity, nor with body adiposity and sex steroid levels (Tables 4 and 5).

Table 4.

The Results of Regression Analyses for the Relationship Between TPOAb as the Dependent Variable and the CBFI, Controlled for % Body Fat, Sex Steroids Levels, Levothyroxine Treatment, and Duration of the Disease. Bolded Results are Statistically Significant.

Variables	β	SD (β)	t(173)	p
TPOAb (dependent variable) F(5.173) = 5.09, p < .001, adj. r² = 0.10
CBFI	0.07	0.07	1.03	.31
% Body fat	−0.04	0.07	−0.49	.62
E2/tT	−0.04	0.07	−0.59	.56
Levothyroxine treatment ^♦	0.20	0.07	2.74	.007
Duration of HT	0.28	0.07	3.89	<.001

CBFI = composite body femininity index; E2 = estradiol; tT = total testosterone.

♦

Dichotomous variable (1 = levothyroxine treatment and 0 = no levothyroxine treatment).

Table 5.

The Results of Regression Analyses for the Relationship Between TPOAb as the Dependent Variable and the CFFI, Controlled for % Body Fat, Sex Steroids Levels, Levothyroxine Treatment, and Duration of the Disease. Bolded Results Are Statistically Significant.

Variables	β	SD (β)	t(172)	p
TPOAb (dependent variable) F(5.172) = 6.33, p < .001, adj. r² = 0.13
CFFI	−0.18	0.08	−2.35	.02
% Body fat	0.001	0.07	0.01	.99
E2/tT	−0.02	0.07	−0.34	.73
Levothyroxine treatment ^♦	0.21	0.07	2.96	.003
Duration of HT	0.31	0.07	4.24	<.001

CFFI = composite face femininity index; E2 = estradiol; tT = total testosterone.

♦

Dichotomous variable (1 = levothyroxine treatment and 0 = no levothyroxine treatment).

Discussion

The results of this study showed at most weak differences in composite body femininity and femininity measurements between women with HT and the non-HT group. However, the apparent trend is that women with HT tended to have higher values of WHR and breast size than the non-HT group. Additionally, the 2D:4D ratio of the right hand was more feminine in women with HT compared to the non-HT group. This might suggest that higher prenatal exposure to E2 relative to androgen in fetal life may be more important in understanding the etiology of HT than estradiol level through puberty and adult age.

More feminine value of 2D:4D in the HT women compared to the non-HT group was in line with the previous studies, showing that prenatal hormone levels may be related to HT risk later in life. Pruszkowska-Przybylska et al. (2021) revealed greater values of the digit ratio in the left hand in women with HT, whereas Święchowicz et al. (2022) showed the effect for both hands. Previous studies showed that the associations between 2D:4D and prenatal sex steroids are greater for the right hand (Manning & Fink, 2018), which may explain the lack of difference in 2D:4D of the left hand between HT and non-HT women in our study. It is noteworthy, however, that the differences in 2D:4D values of the right hand between the group with and without HT are small and insignificant after using Bonferroni correction for multiple comparisons. Moreover, some studies did not confirm that fetal and/or maternal sex hormones are associated with the 2D:4D ratio (Çetin et al., 2016; Hollier et al., 2015; Richards et al., 2020, 2021).

Although in this study women with HT and non-HT women did not differ in the mean values of facial femininity, we observed a positive relationship between facial femininity and TPOAb level within the HT group. Women with more feminine faces were characterized with the highest level of TPOAb, which is a diagnostic marker of HT and disease activity (Brčić et al., 2016; Siriwardhane et al., 2019). The results were similar when controlled for body adiposity, sex steroid levels, levothyroxine treatment, and duration of the disease. It is possible that the greatest change in estrogen levels, during puberty, reflected in facial sexual dimorphism, may also be involved in autoimmune thyroiditis development (Yang et al., 2023). The puzzling element is that although within the HT group, we observed a positive correlation between facial femininity and TPOAb levels, the non-HT group exhibited similar femininity levels as women with high and very high TPOAb levels. This may suggest that higher femininity does not predict the risk of developing HT but it does predict the severity of the disease only in women who have a predisposition for the autoimmune thyroiditis development. However, this is the first study that evaluated the link between facial femininity measurements and thyroid disorders’ severity. Thus, further studies on the influence of pubertal sex hormones on vulnerability to developing autoimmune thyroiditis are needed.

Due to the immunostimulant properties of E2 and immunosuppressant effect of T and the associated risk of autoimmune diseases, we also expected that women with HT should have higher estradiol and lower testosterone levels compared to the non-HT group. However, we did not observe differences in the E2, T, or E2/T ratio between HT and non-HT women. Our only weak results on many feminization parameters and E2 levels or with HT may be interpreted concerning two aspects. Firstly, in women from affluent societies (as in our study), sex hormone levels are much higher than in traditional/hunter–gatherer societies (Kirchengast & Rühli, 2013). Perhaps women in such affluent societies (with high E2 levels) may have already reached the maximum of feminization (i.e., there is a “ceiling” effect) and therefore raising E2 levels no longer necessarily changes much in terms of feminization of the body, but only exposes to diseases for example, estrogen-dependent cancers or autoimmune diseases, including HT. Secondly, we suggest that the relationship between femininity and autoimmune disease is complex and thus morphological femininity is not a reliable cue of a woman's immunity.

The restrictive selection criteria for both women in the HT group and the non-HT group were the main strengths of the study. In all studied women thyroid function markers and sex hormone levels (E2 and T) in blood were verified, and all women in the HT group had diagnosed Hashimoto's disease by an endocrinologist. One potential limitation of the study was the relatively young age of our subjects. Some of the women of the non-HT group may develop autoimmunity in later life. Thus, it seems worth conducting a similar study among postmenopausal women. We also used only a single measurement of estradiol level, while an average of several days of the menstrual cycle would be more representative (Jasieńska et al., 2004). It is therefore worth verifying the results of this study with more measurements of estradiol levels in a given menstrual cycle. It should be emphasized, however, that in our study, the assessment of the level of morphological feminization was based mainly on body composition indicators, and not only on the level of estradiol.

Finally, despite some limitations, it was the first study that tackled the problem of the association between autoimmune thyroid disease and facial femininity which research sheds new light on. The current research seems to be novel and promising for further detailed investigation.

Conclusion

Although there is a presumption that the increase in autoimmune disease prevalence observed in recent decades may be caused by high exposure to estradiol, including increased reproductive lifespan (early menarche, late menopause), and changed reproductive patterns (longer period before first pregnancy, short lactation) associated with fewer immune challenges and (post-) industrialized, affluent lifestyles (Keestra et al., 2021), the relationship between morphological femininity, a cue of a long-term exposition to E2, and autoimmune disease was inconsistent. Women with Hashimoto thyroiditis tend to have a higher 2D:4D digit ratio for the right hand and their facial femininity may affect TPOAb antibody levels, a diagnostic marker of HT. The association between HT and femininity measurements is tentative, however prenatal and pubertal exposition to estrogens seems to increase the probability of thyroid diseases, including HT in future life. Because the literature on the relationship between morphological femininity and autoimmune thyroid diseases is very scarce, the subject requires further research.

Data are available at https://osf.io/krpwg/files/osfstorage/656b981b43d0670eadb19e09

Supplemental Material

sj-docx-1-evp-10.1177_14747049241259187 - Supplemental material for Autoimmune Hashimoto's Disease and Feminization Level—Testing the Immunocompetence Hypothesis

Supplemental material, sj-docx-1-evp-10.1177_14747049241259187 for Autoimmune Hashimoto's Disease and Feminization Level—Testing the Immunocompetence Hypothesis by Malwina Goździk, Agnieszka Żelaźniewicz, Judyta Nowak-Kornicka, Katarzyna Pawłowska-Seredyńska, Wioleta Umławska and Bogusław Pawłowski in Evolutionary Psychology

Footnotes

Acknowledgments

We are grateful to Anna Chmielińska for assistance in data collection.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the University of Wrocław (Grant numbers 0420/2577/18, 0420/2574/18) and the subvention of Department of Human Biology, University of Wrocław.

Supplemental Material

Supplemental material for this article is available online.

ORCID iDs

Agnieszka Żelaźniewicz

Judyta Nowak-Kornicka

Bogusław Pawłowski

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