Introduction
The symptoms of thyroid dysfunction are often associated with the change of thyroid hormones involved in all phases of reproduction and fertility (1). According to the current guidelines, the laboratory test of pituitary hormone thyrotropin (TSH) is the most sensitive and specific marker for the diagnosis and management of thyroid dysfunction (2, 3). The hypothalamus-pituitary-thyroid axis is most relevant to thyroid function. The thyrotropin-releasing hormone (TRH) is secreted from the hypothalamus and reaches the anterior pituitary within the central nervous system. Activation of TRH receptors stimulates the release of thyroid-stimulating hormone (TSH), which activates its receptors on the thyroid gland’s follicular cells. It leads to increased cellular uptake of iodine from the blood and synthesis of thyroglobulin and secretion into the blood stream of triiodothyronine (T3) and thyroxine (T4) activation of the enzyme thyroid peroxidase (TPO) (4).
Ovarian reserve function can reflect women’s endocrine function and fertility (5, 6) and is often related to age, and this function will gradually decrease (7). The diminished ovarian reserve (DOR) is defined by a reduced reproductive potential with a poor response to ovarian stimulation. Some young women still have DOR but the cause and mechanism of which are unknown. Previous studies have shown that TSH levels in infertile women were higher than those in normal fertile women (8, 9). Moreover, elevated serum TSH levels were associated with DOR in infertile patients (10). The hypothalamic-pituitary-ovarian and the hypothalamic-pituitary-thyroid axis have mutual regulation effects, such as the gonads of patients with polycystic ovary syndrome. The abnormal thyroid function may cause menstrual disorders and infertility (11, 12). It has been reported that hypoovarian reserve is related to increased TSH and thyroid autoimmune antibodies (13). On the contrary, no significant differences were observed in the prevalence of hypothyroidism between thyroid autoimmunity (TAI) and DOR (14). However, researchers have not yet determined whether the levels of TSH are associated with DOR.
Anti-Müllerian hormone (AMH) is a hormone produced by granulosa cells of early developing follicles. The serum AMH levels were closely correlated with the number of primordial follicles; therefore, AMH is a suitable biomarker for predicting ovarian function in premenopausal female patients. Therefore, it is equally important to determine whether ovarian function may be affected by impaired thyroid function in infertile patients. This study evaluated the relationship between the ovarian reserve, thyroid function, and AMH levels in infertile patients and may provide new ideas for evaluating DOR-related factors.
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Materials and Methods
Patient Enrollment
Between January 2019 to December 2020, 496 consecutive Chinese women who enrolled the Affiliated Hospital of Southwest Medical University (Luzhou, China) and Fushun Maternal and Child Health Hospital (Fushun, China), respectively, and were diagnosed as infertile according to the diagnostic criteria shown below were recruited for participation in this study. Inclusion criterianormal sex life without contraception and have not been pregnant for more than 12 months. Exclusion criteria: (a) patients with polycystic ovary syndrome; (b) the patients who had a previous history of thyroid disorders, or presence of goiter and/or nodules, or thyroid surgery; (c) a history of hypothalamic and pituitary diseases; (d) with autoimmune diseases, diabetes, and adrenal gland dysfunction; (e) patients with history of disease and chromosomal abnormalities; (f) factors that adversely impact thyroid hormone and ovarian function. We measured thyroid-related hormone and serum AMH levels.
Serum levels of luteinizing hormone, follicle stimulating hormone, estradiol, progesterone, prolactin and testosterone were analyzed at 2–5 days of the menstrual cycle to screen for infertile patients.
Using all available data on DOR, we selected all patients with a DOR defined by the following criteria: (i) woman with any of the risk factors for poor ovarian responders and/or (ii) an abnormal ovarian reserve test (i.e., antral follicular count (AFC) <5-7 follicles or AMH <0.5-1.1 ng/ml) (14, 15).
Clinical Tests
All patients were measured for height and weight. Blood samples were collected from all patients, and serum TSH, free triiodothyronine (FT3), free thyroxine (FT4), and thyroid peroxidation thyroglobulin antibody (thyroid peroxidase antibody, TPOAb), and thyroglobulin antibody (TgAb) were measured using a commercial chemiluminescence immunoassay (Snibe Co.,Ltd., Shenzhen, China; reference range: FT4, 1.00–1.70 ng/dL; TSH, 0.56–4.30 μIU/mL; prolactin, 4.91–29.32 ng/mL). Serum AMH levels were measured using the enzyme-linked immunosorbent assay kit (Guangzhou Kangrun Biotechnology Co., Ltd. Guangzhou, China; and Beckman Coulter Generation II ELISA assay, USA).
Hormone Measurements
We measured basal serum levels of estradiol (E2), progesterone (P), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) for all patients on the 2nd or 3rd day of their cycle, which we always do before stimulation commencement according to classic protocols. The referral range in our laboratory for basal FSH was 3.5 to 12.5 IU/L, for LH 2.4 to 12.6 IU/L, for E2 0 to 160 pg/mL, and for P4 0 to 1.14 ng/mL. Levels of P4 were also measured on the day of OR. Blood samples were analyzed using chemiluminescent immunoassay (Snibe Co.,Ltd., Shenzhen, China). The size and number of antral follicle (AFC) were measured by Philips HD9 transvaginal ultrasound probe with a 12.0-MHz vginal transducer (Philips Healthcare, Amsterdam, the Netherlands).
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Statistical Analysis
Results were presented as a mean ± standard deviation for variables with normal distribution and as a median and interquartile range for variables for which the distribution was not normal. The normality test of the measurement data adopts the Komogorov-Sminov test. The independent sample t test is used for the comparison between the two groups of data, and the single factor is used for the comparison between the three groups Analysis of variance; count data is expressed as rate (%), using χ2 test or Fisher’s exact probability method. Correlation analysis was performed using the Pearson method. SPSS 19.0 statistical software, P<0.05 is considered statistically significant.
Results
Characteristics of Infertile Patients
Comparison of Thyroid Related Antibodies and Ovarian Reserve Function
Relationship Between Ovarian Reserve and Thyroid Hormone Levels
Discussion
Conflicting results have been reported that the different levels of AMH in women are associated with thyroid dysfunction or confirmed autoimmune thyroid disease (12, 21, 30, 31). The study of thyroid autoimmune antibodies found no significant differences in AMH and basal FSH levels and the number of antral follicles among TPOAb, TgAb, and TPOAb/TgAb groups. It is deduced from this that the ovarian reserve function of infertile women may not be affected by the level of serum thyroid autoimmune antibodies (32). Additionally, subclinical hypothyroidism (SCH), a very common thyroid disorder, is associated with female infertility. SCH is associated with decreased ovarian reserve during later reproductive age. Previous study demonstrated that TPOAb positivity was not associated with ovarian reserve (33). However, it cannot be ruled out that the duration of antibody-positive and the level of antibodies have not affected the hypothalamus-pituitary gland, which false-negative results are obtained from normal physiological activities of the ovarian. Women tend to develop autoimmune diseases more often than men throughout their lifetime. The exact etiology of autoimmune disorders remains unknown; however, it has been postulated that it may be multifactorial and associated with the autoimmune conditions with the X chromosome and X inactivation. The presence of two X chromosomes puts women at a greater risk for developing autoimmune diseases than men (34–36).
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Conclusions
This study found no significant correlation between the ovarian reserve and thyroid function-related indicators in women with infertility. However, this study has the following some limitations. 1) The sample size is small, especially the number of thyroid antibody-positive cases.The study will be further expanded in the later period to analyze the potential relevance in depth. 2) The relationship between the duration of abnormal thyroid function and ovarian reserve is required to further analysis. Future study is required to investigate the underlying molecular mechanisms regulating the diminished ovarian reserve in women with thyroid disorder.
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
Ethics Statement
The studies involving human participants were reviewed and approved by Ethics Committee of Affiliated Hospital of Southwest Medical University. The patients/participants provided their written informed consent to participate in this study.
Author Contributions
JW and Y-FL conceived and designed the study. JW, Y-JZ, MW, M-QT, and Y-FL collected patient data. Y-FL reviewed and edited the manuscript. All authors contributed to the article and approved the submitted version.
Funding
This study was supported in part by grant from the Doctoral Research Initiation Fund of the Affiliated Hospital of Southwest Medical University (NO.19084) and Sichuan Provincial Administration of Traditional Chinese Medicine (No. 2021MS488).
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher’s Note
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