Objectives: The objective of the study was to evaluate the prevalence and impact of impaired thyroid-stimulating hormone (TSH) levels on the reproductive outcomes of in vitro fertilization patients diagnosed with endometriosis and compared to controls without endometriosis. Design: This is a retrospective cohort study on prospectively collected data. Setting: The study was conducted at tertiary care university hospital. Participants: Participants were infertile women with histopathological diagnosis of endometriosis. Methods: For 12 months (January 2018 to January 2019), women were deemed suitable and subsequently divided according to serum TSH levels above or below 2.5 mIU/L and compared to patients without endometriosis. Needed sample size was at least 41 patients for each cohort of women. Co-primary outcomes were the live birth rate (LBR), clinical pregnancy rate (CPR), and pregnancy loss rate (PLR). Results: Overall, 226 women (45 with endometriosis and 181 controls without endometriosis) were included. Diagnoses of Hashimoto thyroiditis were significantly more frequent in women with rather than without endometriosis (14/45 [31.1%] vs. 27/181 [14.9%]; p = 0.012). Similarly, in women with endometriosis, Hashimoto diagnosis rates were higher with TSH ≥2.5 mIU/L compared to TSH <2.5 mIU/L (9/15 [60%] vs.5/30 [16.6%]; p = 0.001) so were the Hashimoto diagnosis rates in control group (women without endometriosis) with TSH ≥2.5 mIU/L compared to TSH <2.5 mIU/L (17/48 [35.4%] vs. 10/133 [7.5%], respectively; p = 0.001). Effect size analysis confirmed an increased risk of Hashimoto thyroiditis in women with endometriosis and TSH ≥2.5 mIU/L compared to women with endometriosis and TSH <2.5 mIU/L (risk ratio [RR] 3.60 [95% CI 1.46–8.86]) and in women with endometriosis and TSH ≥2.5 mIU/L compared to non-endometriotic euthyroid patients (RR 7.98 [95% CI 3.86–16.48]). Dysmenorrhea risk was higher in endometriotic euthyroid women compared to euthyroid patients with no endometriosis (RR 1.87 [95% CI 1.21–2.87]). The risk was still increased in euthyroid women with endometriosis relative to dysthyroid women with no endometriosis (RR 1.97 [95% CI 1.11–3.50]). There were no significant differences between the four groups for CPR, LBR, PLR and retrieved oocytes, immature oocytes, degenerated and unfertilized oocytes, cultured blastocysts, embryos and transferred embryos. Limitations: Limitations of the study were retrospective design, limited sample size, and use of different ovarian stimulation protocol. Conclusions: Thyroid autoimmunity seems more common in women with endometriosis and TSH over 2.5 mIU/L. However, there was no significant impact on in vitro fertilization and reproductive outcomes related to the coexistence of endometriosis, Hashimoto disease, and higher TSH levels. Due to limitations of the study, additional evidence is required to validate the abovementioned findings.

Endometriosis is a persistent inflammatory disorder characterized by the occurrence of tissue that resembles endometrium outside the uterus [1]. According to estimates, it affects more than 10–20% of reproductive-age women and causes lesions in the peritoneum and ovaries, leading to dysmenorrhea, persistent pelvic discomfort, dyspareunia, and infertility [2]. Estrogen has a significant part in the pathophysiology of endometriosis, making it an estrogen-dependent condition [3]. Estrogen also generates systemic and localized inflammation and allows the transplantation of endometrial tissue into the peritoneum, which affects proliferation and immortalization of ectopic endometrial cells [4]. Using self-reported data from mail-in surveys, the Endometriosis Association conducted a large cross-sectional survey in the USA and found that women with endometriosis had substantially greater incidences of autoimmune disorders, including hypothyroidism (9.6% against 1.5% in the overall population) [5].

It has been reported that thyroid autoimmunity and endometriosis could be related and that among the inflammatory variables, autoimmunity may act as a significant part in the development of endometriosis [6, 7]. The prevalence of positive anti-thyroid antibodies has also been associated with endometriosis [8].

Therefore, immunological or endocrine system problems, or both, may be linked to infertility and reproductive impairment since menstrual abnormalities, infertility, and higher pregnancy morbidity are common in women with thyroid disease. A higher incidence of pregnancy losses has also been linked to isolated thyroid autoimmunity, especially in the first trimester [9, 10]. Endometriosis has been repeatedly linked to several immunological alterations, including complement deposits, autoantibodies to endometrial antigens, a decline in natural killer lymphocytes, and cytotoxic consequences on autologous endometrium [11]. In women with thyroid autoimmunity, endometriosis was more prevalent − 25% versus 14% and 44% versus 9% respectively – than in controls, according to studies by Abalovich et al. [12] and Gerhard et al. [13].

Although current evidence seems to stand for a pivotal contribution for autoimmunity in the pathogenesis of endometriosis and a higher incidence of thyroid pathology in women dealing with such disease, data still appear contradictory and conflicting, depicting the necessity for additional evidence to draw firm conclusions [6]. Moreover, even if a relationship between thyroid autoimmunity and endometriosis could be ascertained, it is still debated whether the coexistence of endometriosis and thyroid pathology has a synergistic effect in harming patient’s reproductive health by lowering fertility outcomes. Therefore, the aim of this report was to estimate the prevalence and impact of impaired thyroid-stimulating hormone (TSH) levels and thyroid autoimmunity on the reproductive outcomes of women diagnosed with endometriosis, in comparison with women without endometriosis.

Study Design

The current investigation was conceived as a retrospective cohort study using data that were acquired prospectively on infertile women who underwent their first cycle of assisted reproductive techniques (ARTs) at the University Medical Centre of Ljubljana, Department of Human Reproduction, from January 2018 to January 2019. The study procedure complied with the Committee on Publication Ethics’ (COPE) standards and the Helsinki Declaration. The protocol’s design, data collection, analysis, and interpretation procedures, as well as its first draft and any future updates, all adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement’s reporting requirements for observational studies [14].

Inclusion and Exclusion Criteria

Women in their reproductive years (between the ages of 22 and 41) who had experienced early pregnancy loss, primary or secondary infertility, or both, and who were undergoing diagnostic laparoscopy and ART were included. As defined by the World Health Organization, a woman was deemed infertile if, following a year of consistent, unprotected sexual activity, she was unable to conceive naturally. Based on the Bologna criteria for diminished ovarian reserve, women had to have an adequate ovarian reserve, defined as serum anti-mullerian hormone levels of 0.8 ng/mL or higher [15].

Three or more prior in vitro fertilization (IVF) cycles, hydrosalpinx, untreated endometrial polyps, adhesions or other intrauterine or cervical anomaly, untreated mullerian anomaly, untreated abnormal PRL or TSH, history of malignancy within 5 years since enrollment, non-endometriosis laparoscopic surgery, reproductive hormonal treatment within 6 months from surgery were considered as exclusion criteria. Women were also asked to report the presence of dysmenorrhea, defined as pelvic discomfort or cramps during the menstrual flow (menstrual dysmenorrhea).

Patients were subsequently divided in two groups according to the intraoperative presence or absence of superficial, deep, or ovarian endometriosis. The diagnosis of endometriosis was therefore laparoscopically staged (according to the revised American Society for Reproductive Medicine [rASRM] criteria) and confirmed by histopathological analysis after excision. Only women with histopathological confirmation were included in the study.

According to the Endocrine Society Clinical Practice Guideline, prior to becoming pregnant, a TSH level of less than 2.5 mIU/L is advised [16]. Women receiving levothyroxine treatment had a basal TSH value greater than or equal to 2.5 mlU/L. Consequently, we divided the two groups into two smaller groups: those with TSH levels greater than or equal to 2.5 mIU/L (whether they were taking levothyroxine or not) and those with TSH values lower than 2.5 mIU/L who were on levothyroxine were classified as thyroid dysfunction patients. Patients with TSH levels ≥2.5 mIU/L at enrollment who started levothyroxine and subsequently had modified TSH levels were also classified as thyroid dysfunction patients. Therefore, thyroid-healthy women were defined as those who did not take levothyroxine and had TSH levels less than 2.5 mIU/L.

TSH levels were measured using Roche Elecsys TSH agent for the Roche Cobas e601 module automated analyzer using electrochemiluminescence for immunoassay analysis for the Roche Cobas 6000 analyzer (Roche Molecular Diagnostics Slovensko, s.r.o., Bratislava, Slovakia). Diagnosis of Hashimoto thyroiditis was made throughout evaluation of thyroid hypofunction, with thyroid autoantibodies (thyroid peroxidase antibodies and thyroglobulin antibodies) and thyroid ultrasound. Thyroid peroxidase antibody levels equal or above 35 IU/mL and/or thyroglobulin antibody levels equal or above 40 IU/mL were used as diagnostic thresholds. Ultrasonographic diagnostic features were decreased echogenicity, heterogeneity hypervascularity, small intraglandular cysts, and presence of hypoechoic micronodules with echogenic rim [17].

ART Protocol

Ovarian stimulation was carried out by means of short or long gonadotropin-releasing hormone agonist or antagonist protocol. The protocol choice was tailored to patient’s characteristics to maximize the fertility outcomes.

Patients in the short, standardized protocol, from the second day of their menstrual cycle, were daily stimulated using 225 IU of recombinant follicle-stimulating hormone (Puregon; Schering-Plough, Kenilworth, NJ, USA). When the dominant follicle measured 13 mm in diameter, 0.25 mg of the gonadotropin-releasing hormone antagonist cetrorelix acetate (Cetrotide; Merck Serono, Darmstadt, Germany) was injected.

Women in the long protocol were treated with buserelin acetate daily in doses of 0.6 mg (Suprefact; Hoechst AG, Frankfurt/Main, Germany) subcutaneously beginning on day 22 of the menstrual cycle and continuing for 14 days. Controlled ovarian stimulation with recombinant follicle-stimulating hormone (Puregon; Schering-Plough, Kenilworth, NJ, USA) was initiated when the pituitary desensitization requirements were satisfied (estradiol concentration less than 0.07 nmol/L, endometrial thickness less than 4 mm, lack of follicles more than 5 mm).

A minimum number of three leading follicles of minimum 17 mm in diameter to start the final oocyte maturation process were needed. Depending on the overall number of follicles present on the trigger day, oocyte maturation was stimulated. If there were fewer than 20 follicles that were at least 11 mm in diameter, 6,500 IU of recombinant hCG (Pregnyl, Organon, Jersey City, NJ, USA, or Ovitrelle, Merck Serono, Darmstadt, Germany) was used. We administered 0.6 mg of buserelin acetate in a single bolus when there were equal to or more than 20 follicles that were less than 11 mm in diameter. Transvaginal ultrasound-piloted oocyte retrieval was accomplished 34–36 h following triggering.

A single bolus of 1,500 IU hCG was administered subcutaneously for luteal phase support 60 min following the oocyte pick-up to patients with a regular or moderate-high ovarian response (less than 20 oocytes) and a decreased hazard of causing ovarian hyperstimulation syndrome. Beginning 24 h following ovarian puncture and continuing during 12 weeks of gestation, the patients were administered 2 mg of oral estradiol (Estrofem, Novo Nordisk, Bagsvaerd, Denmark) and 200 mg of micronized vaginal progesterone (Utrogestan, Cyndea Pharma SL, Olvega, Spain) every 8 h. When there was a high risk of ovarian hyperstimulation syndrome or an abnormal ovarian responsiveness (over 20 oocytes), all good-grade embryos were frozen on days 5 or 6. Luteal assistance was not administered in these situations.

Oocytes were fertilized using intracytoplasmic sperm injection (ICSI) or traditional IVF. In case of severe male factor infertility, ICSI was employed.

On days 3 or 5 following retrieval, no more than two embryos were transferred in accordance with Slovenian national standards for a single embryo transfer. Patients who previously had blastocyst growth breakdown or who only had one or two developed embryos received transfers of day three cleavage stage embryos. Oocytes and embryo quality were graded according to the standardized criteria of Gardner and Schoolcraft [18].

Study Variables

The co-primary outcomes of this study were the live birth rate (LBR), clinical pregnancy rate (CPR), and pregnancy loss rate (PLR), which were defined as follows: LBR was the birth of a live fetus after 24 weeks of gestational age; CPR was ultrasound visualization of one or more intrauterine gestational sacs and fetal heartbeat; and PLR was the spontaneous termination of pregnancy before 12 weeks of gestation. Co-secondary outcomes were the following IVF outcomes: oocytes retrieved (defined as number of retrieved oocytes after one procedure), immature oocytes (defined as those having a germinal vesicle or germinal vesicle break down without a polar body [MI stage]), degenerated oocytes (defined as an empty zona pellucida or damaged oocyte [fragments of oocytes] inside the zona pellucida) and unfertilized oocytes (defined as the number of non-fertilized eggs after IVF/ICSI), number of cultured blastocysts (defined as the number of formed blastocysts after 5 days of culture), embryos (defined as the number of embryos that could be possibly transferred to the patient) and transferred embryos (defined as the number of embryos that were transferred to the patient during the embryo transfer procedure).

Data Collection

Two databases were used for retrieving study data. The Computerized Database of Reproductive Surgery at the Department of Human Reproduction, containing patients’ hospital charts, was used to obtain anonymized information on the clinical and demographic characteristics of women, as well as the type and indication of surgery for endometriosis. Patient’s age (median and 95% confidence interval [CI]), body mass index (median and 95% CI), TSH, follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL) levels (median and 95% CI), Hashimoto disease and dysmenorrhea rate (absolute number and percentage), menstrual cycle length (median and 95% CI) were all extracted from the Computerized Database of Reproductive Surgery (n = 898).

The National Register of Assisted Reproductive Technology (NRART) was used to extract IVF and reproductive outcomes (median number of retrieved, immature, degenerated, and unfertilized oocytes [median and 95% CI], number of cultured blastocysts, embryos and transferred embryos [median and 95% CI], LBR, CPR, and PLR [absolute number and percentage]). The Republic of Slovenia’s Ministry of Health first used NRART in 1983, and since 1999, data have also been routinely provided to the IVF Monitoring (EIM) Consortium of the European Society of Human Reproduction and Embryology (ESHRE).

Only women with complete reporting of all the study variables were included in the analysis; those with missing data from at least one of the two study databases were therefore excluded.

Sample Size Calculation

The comparison of the co-primary outcome CPR between groups of women with and without endometriosis undergoing IVF/ICSI was used to calculate sample size. The alpha error level was fixed at 0.05, the power was set at 80%, and the group ratio was set at 1 to 4. Pregnancy rates were observed to be 28% in women with concomitant endometriosis and 33% in the group without endometriosis, as previously published [19]. As a result, there should be a minimum of 40 participants in each arm of the study.

Statistical Analysis

STATA 14.1 (StataCorp L.L.C., College Station, TX, USA) was employed for all the analysis. The data were displayed as an absolute number (percentage) or, for continuous variables, as the median with 95% CI, after evaluation of data distribution with the Shapiro-Wilk test. Furthermore, we used Mann-Whitney U or Kruskal-Wallis tests, where appropriate, for comparisons involving continuous variables; for categorical variables, we used χ2 or Fisher’s test for multiple comparisons. For continuous variables, the effect size was expressed as mean difference with 95% CI and for categorical variables as risk ratio (RR) with 95% CI. Logistic regression analysis reporting adjusted odds ratio for age, body mass index and years of infertility was used to evaluate factors (e.g., ovarian stimulation protocol) that might interfere with primary and secondary outcomes. Statistical significance was set at p value (p) ≤ 0.05.

Among the 898 women undergoing IVF/ICSI in our institution during the study period, 515 matched the inclusion criteria; of those, 286 were excluded due to missing TSH information. Therefore, 229 women were initially included. Subsequently, 3 women were removed from the analysis due to missing outcome data. Overall, 226 women were included in the final analysis. Of those, 45 (19.9%) were diagnosed with endometriosis and 181 (80.1%) without. TSH levels were ≥2.5 mIU/L in 63 women (27.9%), of which 15 were included in the endometriosis group and 48 in the non-endometriosis group (Fig. 1).

Fig. 1.

Flowchart of women included in the study according to STROBE guidelines.

Fig. 1.

Flowchart of women included in the study according to STROBE guidelines.

Close modal

Among the 63 patients with thyroid dysfunction, 32 (51%) were treated with levothyroxine. Of those, 7 out of 15 (48%) were diagnosed with endometriosis while 25 out of 48 (52%) were non-endometriotic. Considering all patients, a multiple blastocyst transfer was carried out in 32 out of 226 (14.2%) women, while the other patients were subjected to a single transfer (85.8%).

There was no significant dissimilarity on baseline features of the two main groups (Table 1). However, there were significantly more cases of Hashimoto thyroiditis in the endometriosis group relative to the non-endometriosis group (14/45 [31.1%] vs. 27/181 [14.9%]; p = 0.012). When divided by fertilization techniques (IVF or ICSI), there were no differences regarding oocyte and embryo characteristics between endometriotic and non-endometriotic patients (Table 2).

Table 1.

Baseline characteristics of infertile patients included in the analysis

Endometriosis (n = 45)Non-endometriosis (n = 181)p value
Age, median (95% CI) 33 (31–35) 33 (32–35) 0.920 
BMI, median (95% CI), kg/m2 22 (21–23) 23 (22–24) 0.109 
TSH under 2.5 mIU/L, n (%) 30/45 (66.7) 133/181 (73.4) 0.335 
TSH over 2.5 mIU/L, n (%) 15/45 (33.3) 48/181 (26.6) 0.335 
FSH, median (95% CI), IU/L 7.6 (6.4–8.4) 6.8 (6.4–7.3) 0.610 
LH, median (95% CI), IU/L 4.9 (3.8–5.8) 5.1 (4.6–5.5) 0.968 
PRL, median (95% CI), ng/mL 9.8 (7.5–10.8) 10.1 (9.2–11) 0.749 
Hashimoto disease rate, n (%) 14/45 (31.1) 27/181 (14.9) 0.012 
Dysmenorrhea rate, n (%) 19/45 (42.2) 51/181 (28.1) 0.071 
Menstrual cycle length, median days (95% CI) 29 (28–31) 28 (27–30) 0.187 
Stimulation protocol   0.267 
 Long 43 (95.55) 161 (88.95)  
 Short 2 (4.45) 20 (11.05)  
Endometriosis (n = 45)Non-endometriosis (n = 181)p value
Age, median (95% CI) 33 (31–35) 33 (32–35) 0.920 
BMI, median (95% CI), kg/m2 22 (21–23) 23 (22–24) 0.109 
TSH under 2.5 mIU/L, n (%) 30/45 (66.7) 133/181 (73.4) 0.335 
TSH over 2.5 mIU/L, n (%) 15/45 (33.3) 48/181 (26.6) 0.335 
FSH, median (95% CI), IU/L 7.6 (6.4–8.4) 6.8 (6.4–7.3) 0.610 
LH, median (95% CI), IU/L 4.9 (3.8–5.8) 5.1 (4.6–5.5) 0.968 
PRL, median (95% CI), ng/mL 9.8 (7.5–10.8) 10.1 (9.2–11) 0.749 
Hashimoto disease rate, n (%) 14/45 (31.1) 27/181 (14.9) 0.012 
Dysmenorrhea rate, n (%) 19/45 (42.2) 51/181 (28.1) 0.071 
Menstrual cycle length, median days (95% CI) 29 (28–31) 28 (27–30) 0.187 
Stimulation protocol   0.267 
 Long 43 (95.55) 161 (88.95)  
 Short 2 (4.45) 20 (11.05)  

CI, confidence interval; BMI, body mass index.

Table 2.

Comparison of oocyte and embryo outcomes among IVF and ICSI procedures in women with and without endometriosis

EndometriosisNon-endometriosisp value
IVFICSIIVFICSI
Oocytes retrieved, median (95% CI) 7.0 (5.0–9.5) 7.5 (4.9–10.5) 9 (7.2–10.1) 8.0 (6.2–10.5) 0.499a 
Immature oocytes, median (95% CI) 1.0 (0.0–2.0) 1.0 (0–2) 1.5 (1.0–2.0) 1.0 (0–2) 0.215a 
Degenerated oocytes, median (95% CI) 0.6 (0–1.0) 0.7 (0–1.0) 0.8 (0.5–1.0) 0.6 (0–1.0) 0.144a 
Unfertilized oocytes, median (95% CI) 0.9 (0.5–1.0) 0.8 (0.4–0.9) 1.0 (0.5–1.5) 0.9 (0.5–1.5) 0.638a 
Blastocysts developed, median (95% CI) 1.9 (1.2–2.7) 2.0 (1.1–3.1) 1.8 (0.9–2.5) 1.9 (1.3–3.0) 0.955a 
Embryos obtained, median (95% CI) 1.7 (0.5–3.0) 2.0 (1.3–2.8) 1.8 (0.9–2.7) 1.8 (1.3–2.5) 0.801a 
Embryos transferred, median (95% CI) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.911a 
EndometriosisNon-endometriosisp value
IVFICSIIVFICSI
Oocytes retrieved, median (95% CI) 7.0 (5.0–9.5) 7.5 (4.9–10.5) 9 (7.2–10.1) 8.0 (6.2–10.5) 0.499a 
Immature oocytes, median (95% CI) 1.0 (0.0–2.0) 1.0 (0–2) 1.5 (1.0–2.0) 1.0 (0–2) 0.215a 
Degenerated oocytes, median (95% CI) 0.6 (0–1.0) 0.7 (0–1.0) 0.8 (0.5–1.0) 0.6 (0–1.0) 0.144a 
Unfertilized oocytes, median (95% CI) 0.9 (0.5–1.0) 0.8 (0.4–0.9) 1.0 (0.5–1.5) 0.9 (0.5–1.5) 0.638a 
Blastocysts developed, median (95% CI) 1.9 (1.2–2.7) 2.0 (1.1–3.1) 1.8 (0.9–2.5) 1.9 (1.3–3.0) 0.955a 
Embryos obtained, median (95% CI) 1.7 (0.5–3.0) 2.0 (1.3–2.8) 1.8 (0.9–2.7) 1.8 (1.3–2.5) 0.801a 
Embryos transferred, median (95% CI) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.911a 

CI, confidence interval.

aKruskal-Wallis test.

When women were stratified according to the occurrence or lack of endometriosis and serum TSH levels over or under 2.5 mIU/L, there were comparable rates of ICSI or IVF among subgroups (Table 3). In addition, similar serum FSH, LH, and PRL levels were found between groups (Table 2). In women with endometriosis, Hashimoto diagnosis rates were more frequent with TSH ≥2.5 mIU/L relative to TSH under 2.5 mIU/L (9/15 [60%] vs. 5/30 [16.6%]; p = 0.001). Similarly, the Hashimoto diagnosis rates in the non-endometriosis group were higher with TSH ≥2.5 mIU/L relative to TSH under 2.5 mIU/L (17/48 [35.4%] vs. 10/133 [7.5%]; p = 0.001).

Table 3.

Primary and secondary outcomes of included patients according to serum TSH levels

EndometriosisNon-endometriosisp value
TSH <2.5 (n = 30)TSH >2.5 (n = 15)TSH <2.5 (n = 133)TSH >2.5 (n = 48)
IVF (%) 14 (46.7) 5 (33.3) 44 (33.1) 10 (20.8) 0.121 
ICSI (%) 16 (53.3) 10 (66.7) 99 (66.9) 38 (79.1) 0.121 
FSH, median (95% CI), IU/L 7.7 (6.1–8.4) 7.5 (6.2–8.9) 6.6 (6.4–7.3) 7.1 (6.5–8.4) 0.464a 
LH, median (95% CI), IU/L 4.7 (3.6–6.0) 4.9 (2.7–6.4) 5.3 (4.5–5.7) 4.9 (4.0–5.9) 0.947a 
PRL, median (95% CI), ng/mL 8.0 (6.2–11.0) 9.5 (8.0–14.1) 9.7 (8.4–10.5) 11.8 (10.0–13.4) 0.171a 
Hashimoto disease rate (%) 5 (16.6) 9 (60) 10 (7.5) 17 (35.4) 0.001b 
Dysmenorrhea rate (%) 16 (53.3) 3 (20) 38 (28.6) 13 (27.1) 0.035b 
Oocytes retrieved, median (95% CI) 7.0 (3.0–11.0) 7.0 (3.0–8.0) 8.0 (6.0–9.2) 9.0 (6.0–12.0) 0.345a 
Immature oocytes, median (95% CI) 1 (1.0–2.0) 1.0 (0–2.0) 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.079a 
Degenerated oocytes, median (95% CI) 0 (0–1.0) 0 (0–2.0) 0 (0–0.8) 1 (0–1.0) 0.501a 
Unfertilized oocytes, median (95% CI) 1.0 (0–1.0) 1.0 (0–2.0) 1.0 (0–1.0) 1.0 (0–1.0) 0.620a 
Blastocysts developed, median (95% CI) 1.5 (0–3.0) 0 (0–2.0) 1.0 (0–2.0) 1.0 (0–3.0) 0.555a 
Embryos obtained, median (95% CI) 2.0 (1.0–2.0) 2.0 (0–2.0) 1.0 (1.0–2.0) 2.0 (1.0–3.0) 0.120a 
Embryos transferred, median (95% CI) 1.0 (1.0–1.0) 0.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.329a 
CPR (%) 11 (36.7) 3 (20) 39 (29.3) 12 (25) 0.609b 
PLR (%) 6 (20) 4 (26.7) 26 (19.5) 8 (16.7) 0.863b 
LBR (%) 6 (20) 2 (13.3) 23 (17.3) 8 (16.7) 0.953b 
EndometriosisNon-endometriosisp value
TSH <2.5 (n = 30)TSH >2.5 (n = 15)TSH <2.5 (n = 133)TSH >2.5 (n = 48)
IVF (%) 14 (46.7) 5 (33.3) 44 (33.1) 10 (20.8) 0.121 
ICSI (%) 16 (53.3) 10 (66.7) 99 (66.9) 38 (79.1) 0.121 
FSH, median (95% CI), IU/L 7.7 (6.1–8.4) 7.5 (6.2–8.9) 6.6 (6.4–7.3) 7.1 (6.5–8.4) 0.464a 
LH, median (95% CI), IU/L 4.7 (3.6–6.0) 4.9 (2.7–6.4) 5.3 (4.5–5.7) 4.9 (4.0–5.9) 0.947a 
PRL, median (95% CI), ng/mL 8.0 (6.2–11.0) 9.5 (8.0–14.1) 9.7 (8.4–10.5) 11.8 (10.0–13.4) 0.171a 
Hashimoto disease rate (%) 5 (16.6) 9 (60) 10 (7.5) 17 (35.4) 0.001b 
Dysmenorrhea rate (%) 16 (53.3) 3 (20) 38 (28.6) 13 (27.1) 0.035b 
Oocytes retrieved, median (95% CI) 7.0 (3.0–11.0) 7.0 (3.0–8.0) 8.0 (6.0–9.2) 9.0 (6.0–12.0) 0.345a 
Immature oocytes, median (95% CI) 1 (1.0–2.0) 1.0 (0–2.0) 1.0 (1.0–2.0) 1.0 (1.0–2.0) 0.079a 
Degenerated oocytes, median (95% CI) 0 (0–1.0) 0 (0–2.0) 0 (0–0.8) 1 (0–1.0) 0.501a 
Unfertilized oocytes, median (95% CI) 1.0 (0–1.0) 1.0 (0–2.0) 1.0 (0–1.0) 1.0 (0–1.0) 0.620a 
Blastocysts developed, median (95% CI) 1.5 (0–3.0) 0 (0–2.0) 1.0 (0–2.0) 1.0 (0–3.0) 0.555a 
Embryos obtained, median (95% CI) 2.0 (1.0–2.0) 2.0 (0–2.0) 1.0 (1.0–2.0) 2.0 (1.0–3.0) 0.120a 
Embryos transferred, median (95% CI) 1.0 (1.0–1.0) 0.0 (1.0–1.0) 1.0 (1.0–1.0) 1.0 (1.0–1.0) 0.329a 
CPR (%) 11 (36.7) 3 (20) 39 (29.3) 12 (25) 0.609b 
PLR (%) 6 (20) 4 (26.7) 26 (19.5) 8 (16.7) 0.863b 
LBR (%) 6 (20) 2 (13.3) 23 (17.3) 8 (16.7) 0.953b 

IVF, in vitro fertilization; ICSI, intracytoplasmic sperm injection; FSH, follicle-stimulating hormone; LH, luteinizing hormone; PRL, prolactin; TSH, thyroid-stimulating hormone; CI, confidence interval. Bold indicates statistical significance; p < 0.05.

aKruskal-Wallis test.

bχ2 test for multiple comparisons.

Comparing fertility outcomes after IVF did not show a significant distinction concerning retrieved quantity of retrieved oocytes, immature or degenerated oocyte, blastocysts or embryo developed or transferred embryos (Table 3). Similarly, no significant differences concerning reproductive outcomes (CPR, LBR, and PLR) among women with or without endometriosis, and with or without TSH levels over and under 2.5 mIU/L, were found (Table 3).

Table 4 shows the size of effect related to the study’s variables among the subgroups reported as RR. There was an increased risk of Hashimoto thyroiditis in women with endometriosis and TSH ≥2.5 mIU/L compared to women with endometriosis and TSH <2.5 mIU/L (RR 3.60 [95% CI 1.46–8.86]). The risk continued to increase, reaching almost an 8-folded value, when there was a coexistence between endometriosis and TSH ≥2.5 mIU/L compared to non-endometriotic and euthyroid patients (RR 7.98 [95% CI 3.86–16.48]). Accordingly, the risk of dysmenorrhea in euthyroid women was increased when they were diagnosed with endometriosis compared to euthyroid patients with no endometriosis (RR 1.87 [95% CI 1.21–2.87]). The risk was still increased in women with endometriosis and TSH <2.5 mIU/L relative to women with no endometriosis but with TSH ≥2.5 mIU/L (RR 1.97 [95% CI 1.11–3.50]) (Fig. 2). Conversely, effect size analysis, reported as mean difference, for FSH, LH, PRL, oocytes retrieved, immature, degenerated, or unfertilized oocytes, blastocysts developed, obtained and transferred embryos did not report significant differences among subgroup comparisons (Table 4).

Table 4.

Effect sizes for categorical study variables according to comparison between groups (expressed as RRs and 95% CIs)

Endometriosis and TSH <2.5Endometriosis and TSH >2.5Non-endometriosis and TSH <2.5Non-endometriosis and TSH >2.5
Hashimoto disease  NS NS NS Endometriosis and TSH <2.5 
Dysmenorrhea NS NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease 3.60 (1.46-8.86)  NS NS Endometriosis and TSH >2.5 
Dysmenorrhea NS NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease NS 7.98 (3.86–16.48)  0.21 (0.10–0.43) Non-endometriosis and TSH <2.5 
Dysmenorrhea 1.87 (1.21–2.87NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease NS NS NS  Non-endometriosis and TSH >2.5 
Dysmenorrhea 1.97 (1.11–3.50) NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Endometriosis and TSH <2.5Endometriosis and TSH >2.5Non-endometriosis and TSH <2.5Non-endometriosis and TSH >2.5
Hashimoto disease  NS NS NS Endometriosis and TSH <2.5 
Dysmenorrhea NS NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease 3.60 (1.46-8.86)  NS NS Endometriosis and TSH >2.5 
Dysmenorrhea NS NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease NS 7.98 (3.86–16.48)  0.21 (0.10–0.43) Non-endometriosis and TSH <2.5 
Dysmenorrhea 1.87 (1.21–2.87NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 
Hashimoto disease NS NS NS  Non-endometriosis and TSH >2.5 
Dysmenorrhea 1.97 (1.11–3.50) NS NS 
Clinical pregnancy NS NS NS 
Pregnancy loss NS NS NS 
Live birth NS NS NS 

TSH, thyroid-stimulating hormone; NS, not significant. Bold indicates statistical significance; p < 0.05.

Fig. 2.

Bar graph representation of significant differences among study groups (red dots: RRs, gray lines: 95% CIs).

Fig. 2.

Bar graph representation of significant differences among study groups (red dots: RRs, gray lines: 95% CIs).

Close modal

The short protocol as reference in logistic regression analysis was used to estimate the influence of the stimulation protocol on IVF and pregnancy outcomes (Table 5). The use of a long protocol was associated with increased number of developed blastocysts in women with no endometriosis and TSH ≥2.5 mIU/L (adjusted odds ratio 2.83 [95% CI 1.02–4.31]). No other significant findings were noted. Regression analysis was not performed in endometriotic patients with TSH ≥2.5 mIU/L since all women in such subgroup underwent short protocol.

Table 5.

Logistic regression analysis for study groups according to subtype of stimulation protocol (expressed as aORs and 95% CIs)

ProtocolOocytes retrievedImmature oocytesDegenerated oocytesUnfertilized oocytesBlastocysts developedEmbryos obtainedEmbryos transferredCPRPLRLBR
Endometriosis and TSH <2.5 Long 0.85 (0.49–1.13) 1.12 (0.45–1.28) 0.82 (0.06–2.04) 0.77 (0.03–3.19) 0.86 (0.19–2.36) 1.43 (0.60–3.54) 7.78 (0.43–16.91) 2.87 (0.68–6.15) 1.02 (0.99–1.03) 1.01 (0.98–1.02) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 
Non-endometriosis and TSH <2.5 Long 0.67 (0.19–1.18) 0.52 (0.04–5.28) 5.26 (0.17–16.23) 0.53 (0.03–3.25) 0.56 (0.10–1.44) 0.84 (0.14–1.73) 1.14 (0.19–2.35) 3.22 (0.28–7.29) 1.00 (0.99–1.01) 8.00 (0.68–18.50) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 
Non-endometriosis and TSH >2.5 Long 1.00 (0.86–1.17) 0.42 (0.18–1.08) 0.70 (0.35–1.25) 0.99 (0.65–1.43) 2.83 (1.02–4.31) 0.40 (0.02–1.01) 2.40 (0.82–3.91) 8.08 (0.95–11.73) 2.44 (0.49–11.17) 0.16 (0.01–2.30) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 
ProtocolOocytes retrievedImmature oocytesDegenerated oocytesUnfertilized oocytesBlastocysts developedEmbryos obtainedEmbryos transferredCPRPLRLBR
Endometriosis and TSH <2.5 Long 0.85 (0.49–1.13) 1.12 (0.45–1.28) 0.82 (0.06–2.04) 0.77 (0.03–3.19) 0.86 (0.19–2.36) 1.43 (0.60–3.54) 7.78 (0.43–16.91) 2.87 (0.68–6.15) 1.02 (0.99–1.03) 1.01 (0.98–1.02) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 
Non-endometriosis and TSH <2.5 Long 0.67 (0.19–1.18) 0.52 (0.04–5.28) 5.26 (0.17–16.23) 0.53 (0.03–3.25) 0.56 (0.10–1.44) 0.84 (0.14–1.73) 1.14 (0.19–2.35) 3.22 (0.28–7.29) 1.00 (0.99–1.01) 8.00 (0.68–18.50) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 
Non-endometriosis and TSH >2.5 Long 1.00 (0.86–1.17) 0.42 (0.18–1.08) 0.70 (0.35–1.25) 0.99 (0.65–1.43) 2.83 (1.02–4.31) 0.40 (0.02–1.01) 2.40 (0.82–3.91) 8.08 (0.95–11.73) 2.44 (0.49–11.17) 0.16 (0.01–2.30) 
Short Reference Reference Reference Reference Reference Reference Reference Reference Reference Reference 

TSH, thyroid-stimulating hormone. Bold indicates statistical significance; p < 0.05.

This retrospective study showed that although higher rates of Hashimoto thyroiditis could be found in women with endometriosis rather than no endometriosis and in women with higher TSH levels, there might be no significant impact on fertility and reproductive outcomes related to the coexistence of endometriosis and thyroid disease. For the female reproductive system, an adequate quantity of circulating thyroid hormones is crucial [20]. The thyroid condition itself affects ovarian function: indeed, thyroid function and the hypothalamus-pituitary axis are constantly interacting [20]. Thyroid hormone receptors (TR-1 and TR-2) are expressed on the ovarian surface epithelium, follicle, and oocytes [21]. TSH receptors and RNA messenger for TR-1 and TR-2 were also discovered in samples derived from endometrial biopsies and from the ovarian epithelium [6]. While deiodinase types 2 and 3 were produced, granulosa cells did not generate type 1, indicating that the peripheral thyroid hormone thyroxin (T4) may be converted [22]. Tri-iodothyronine (T3) modulates the effects of LH and FSH; several binding sites for T3 have also been discovered in stromal and granulosa cells as well as oocytes [21, 22].

Our findings showed augmented frequencies of Hashimoto disease in women with endometriosis. Venables et al. [23] reported that thyroid autoimmunity had no impact on pregnancy outcomes in women with altered thyroid hormone profile or in euthyroid patients having IVF. However, even if our study did not find an adjuvant effect of dysthyroid pathology in women with endometriosis, the relation between thyroid immunity and the pathophysiology of endometriosis is still debated.

A new study looked into the possible pathophysiological connection between thyroid issues and endometriosis [6]. Endometriotic patients’ eutopic and ectopic endometrium exhibits dysregulated transcripts and proteins that regulate thyroid metabolism, which causes ectopic endometrium to resist T3 action and local T4 buildup [5]. On the one hand, T3 and T4 particularly operate to enhance ectopic endometrial cell proliferation and reactive oxygen species generation; on the other hand, TSH works as a proliferative and pro-oxidative hormone on endometria from both endometriosis patients and controls [6]. The results obtained in vitro were furtherly validated by experiments on mice in which it was discovered that endometriotic implants grew larger as thyroid hormone levels increased [6].

Despite there having been a link to endometriosis-related infertility, the molecular explanation for how thyroid dysfunction contributes to the genesis of endometriosis has not yet been established. Ascertained the inflammatory characteristics of endometriosis, it is claimed that autoimmunity could have a role in the etiopathology of the inflammatory characteristics of endometriosis. To this end, the use of progestogens (e.g., dienogest) as medical treatment acts on multiple levels: together with a moderate inhibition of gonadotropin secretion, which induces a hypoestrogenic-hypergestagenic local endocrine environment that causes ectopic endometrium atrophy, it also acts as an immunosuppressive agent capable of blocking both cytokine secretion and action on several immune system pathways [24, 25]. Similarly, discovering patients who have other autoimmune pathologies (e.g., Hashimoto thyroiditis, multiple sclerosis, or Sjögren syndrome) as comorbidities as well as finding autoantibodies to ovarian and endometrial nucleic acid antigens strengthens the idea that the disease might be included in autoimmune multiple antibody disorders [24]. However, unraveling the tangled pathogenesis of endometriosis remains an enigmatic journey.

According to our findings, in addition to the clear evidence showing that menstrual dysmenorrhea in euthyroid women is more common when they were diagnosed with endometriosis, we found that menstrual dysmenorrhea was still significantly more present in euthyroid women with a diagnosis of endometriosis compared to euthyroid patients without a diagnosis of endometriosis. Therefore, dysmenorrhea could be a symptom suggesting further examination to evaluate the presence or absence of endometriosis. However, a recent study showed that the association between premenstrual spotting and TSH levels has good predictive chances of detecting endometriosis with a diagnostic accuracy of 51.5%. On the contrary, adding dysmenorrhea to the before-mentioned features of the prediction model decreased its accuracy to 50.4% [26]. Therefore, the co-presence of increased TSH levels and premenstrual spotting may better underline a possible diagnosis of endometriosis than with the addition of menstrual dysmenorrhea [26].

Several limitations should be taken into account for a proper data interpretation. First, due to its retrospective design, the study is subject to its common biases, including selection and population biases, which reduce the overall quality of the evidence. However, we tried to reduce such limitation by collecting data prospectively. Second, the study was designed to be single centered, reducing the overall generalizability of the findings. Third, although reaching the minimum sample size, the inclusion of a relatively small number of women reduces the robustness of the results. Such limitation might be related to the exclusion of patients with missing data from the analysis, which, on the contrary, is a point of strength for the study. Additionally, even if a limited number of women underwent a long rather than a short ovarian stimulation protocol, the use of different approaches might reduce the generalizability of the findings. However, it is noteworthy that regression analysis did not show any influence of the protocol on study outcomes, except for the number of developed blastocysts in women with no endometriosis and TSH ≥2.5 mIU/L. Conversely, an additional limitation is related to the use of a short protocol in every endometriotic woman with high TSH levels, avoiding the possibility of performing a deeper analysis of the protocol choice in such subgroup of patients. Nonetheless, current evidence shows no differences in terms of ART and pregnancy outcomes in women with endometriosis according to the use of a hormone pretreatment or the use of a short protocol [27‒29]. Lastly, the number of patients excluded due to missing data regarding TSH levels is an additional limitation of study. It should be acknowledged that the inclusion of a wider number of women might interfere with the actual reporting of results. Therefore, further research is needed to validate such findings due to their inherent limitations.

Moreover, the fact that it is the first retrospective analysis of IVF and reproductive results in patients with both thyroid dysfunction and endometriosis represents an additional strength of this study. The histopathological confirmation of endometriosis in the pathology group is a further strength that increases the validity of the analysis.

According to our findings, there may not be a significant adjuvant effect on fertility and reproductive outcomes related to the coexistence of endometriosis and thyroid disease, even though women with endometriosis have higher rates of Hashimoto thyroiditis and higher TSH levels than women without endometriosis. However, due to the limitations of our study, more investigations with greater numbers of women need to be conducted to validate and expand the current knowledge on the effects of thyroid diseases on patients with endometriosis.

The Republic of Slovenia’s Medical Ethics Committee gave the approval for the study (approval ID: 0120-609/2021/7). Each participant in this study received information about the methods and provided their written informed consent to allow data to be collected and analyzed for research. Given that the study had an observational design, the data obtained were anonymized to remove any information that may be used to formally identify the patient.

The authors declare that they have no conflicts of interest to disclose regarding this publication.

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

S. Korošec, G. Riemma, and H. Ban Frangež: protocol/project development, data analysis, and manuscript writing. V. Šalamun and A. Franko Rutar: data analysis and manuscript writing. A.S. Laganà and V. Chiantera: data management and manuscript editing. P. De Franciscis: protocol/project development and manuscript editing.

Data and material are available at the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data will be made available on reasonable request. Further inquiries can be directed to the corresponding author.

1.
Riemma
G
,
Lagana
AS
,
Schiattarella
A
,
Garzon
S
,
Cobellis
L
,
Autiero
R
, et al
.
Ion channels in the pathogenesis of endometriosis: a cutting-edge point of view
.
Int J Mol Sci
.
2020
;
21
(
3
):
1114
.
2.
Becker
CM
,
Bokor
A
,
Heikinheimo
O
,
Horne
A
,
Jansen
F
,
Kiesel
L
, et al
.
ESHRE guideline: endometriosis
.
Hum Reprod Open
.
2022
;
2022
(
2
):
hoac009
.
3.
Yela
DA
,
Vitale
SG
,
Vizotto
MP
,
Benetti-Pinto
CL
.
Risk factors for recurrence of deep infiltrating endometriosis after surgical treatment
.
J Obstet Gynaecol Res
.
2021
;
47
(
8
):
2713
9
.
4.
Amalinei
C
,
Pavaleanu
I
,
Lozneanu
L
,
Balan
R
,
Giusca
SE
,
Caruntu
ID
.
Endometriosis - insights into a multifaceted entity
.
Folia Histochem Cytobiol
.
2018
;
1
(
2
):
61
82
.
5.
Sinaii
N
,
Cleary
SD
,
Ballweg
ML
,
Nieman
LK
,
Stratton
P
.
High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis
.
Hum Reprod
.
2002
;
17
(
10
):
2715
24
.
6.
Peyneau
M
,
Kavian
N
,
Chouzenoux
S
,
Nicco
C
,
Jeljeli
M
,
Toullec
L
, et al
.
Role of thyroid dysimmunity and thyroid hormones in endometriosis
.
Proc Natl Acad Sci U S A
.
2019
;
116
(
24
):
11894
9
.
7.
Dhillon-Smith
RK
,
Coomarasamy
A
.
TPO antibody positivity and adverse pregnancy outcomes
.
Best Pract Res Clin Endocrinol Metab
.
2020
;
34
(
4
):
101433
.
8.
Adewuyi
EO
,
Mehta
D
;
International Endogene Consortium IEC
;
23andMe Research Team
;
Nyholt
DR
.
Genetic overlap analysis of endometriosis and asthma identifies shared loci implicating sex hormones and thyroid signalling pathways
.
Hum Reprod
.
2022
;
37
(
2
):
366
83
.
9.
Cunha-Filho
JS
,
Gross
JL
,
Lemos
NA
,
Brandelli
A
,
Castillos
M
,
Passos
EP
.
Hyperprolactinemia and luteal insufficiency in infertile patients with mild and minimal endometriosis
.
Horm Metab Res
.
2001
;
33
(
4
):
216
20
.
10.
Shrestha
S
,
Neupane
S
,
Gautam
N
,
Dubey
RK
,
Jha
AC
,
Doshi
NR
, et al
.
Association of thyroid profile and prolactin level in patient with secondary amenorrhea
.
Malays J Med Sci
.
2016
;
23
(
5
):
51
6
.
11.
Lagana
AS
,
Garzon
S
,
Gotte
M
,
Vigano
P
,
Franchi
M
,
Ghezzi
F
, et al
.
The pathogenesis of endometriosis: molecular and cell biology insights
.
Int J Mol Sci
.
2019
;
20
(
22
):
5615
.
12.
Abalovich
M
,
Mitelberg
L
,
Allami
C
,
Gutierrez
S
,
Alcaraz
G
,
Otero
P
, et al
.
Subclinical hypothyroidism and thyroid autoimmunity in women with infertility
.
Gynecol Endocrinol
.
2007
;
23
(
5
):
279
83
.
13.
Gerhard
I
,
Becker
T
,
Eggert-Kruse
W
,
Klinga
K
,
Runnebaum
B
.
Thyroid and ovarian function in infertile women
.
Hum Reprod
.
1991
;
6
(
3
):
338
45
.
14.
von Elm
E
,
Altman
DG
,
Egger
M
,
Pocock
SJ
,
Gøtzsche
PC
,
Vandenbroucke
JP
, et al
.
The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies
.
Int J Surg
.
2014
;
12
(
12
):
1495
9
.
15.
Younis
JS
,
Ben-Ami
M
,
Ben-Shlomo
I
.
The Bologna criteria for poor ovarian response: a contemporary critical appraisal
.
J Ovarian Res
.
2015
;
8
:
76
.
16.
De Groot
L
,
Abalovich
M
,
Alexander
EK
,
Amino
N
,
Barbour
L
,
Cobin
RH
, et al
.
Management of thyroid dysfunction during pregnancy and postpartum: an endocrine society clinical practice guideline
.
J Clin Endocrinol Metab
.
2012
;
97
(
8
):
2543
65
.
17.
Caturegli
P
,
De Remigis
A
,
Rose
NR
.
Hashimoto thyroiditis: clinical and diagnostic criteria
.
Autoimmun Rev
.
2014
;
13
(
4–5
):
391
7
.
18.
Pierson
HE
,
Invik
J
,
Meriano
J
,
Pierson
RA
.
A novel system for rapid conversion of Gardner embryo grades to linear scale numeric variables
.
Reprod Biomed Online
.
2023
;
46
(
5
):
808
18
.
19.
Casals
G
,
Carrera
M
,
Dominguez
JA
,
Abrao
MS
,
Carmona
F
.
Impact of surgery for deep infiltrative endometriosis before in vitro fertilization: a systematic review and meta-analysis
.
J Minim Invasive Gynecol
.
2021
;
28
(
7
):
1303
12.e5
.
20.
Poppe
K
,
Velkeniers
B
,
Glinoer
D
.
The role of thyroid autoimmunity in fertility and pregnancy
.
Nat Clin Pract Endocrinol Metab
.
2008
;
4
(
7
):
394
405
.
21.
Aghajanova
L
,
Lindeberg
M
,
Carlsson
IB
,
Stavreus-Evers
A
,
Zhang
P
,
Scott
JE
, et al
.
Receptors for thyroid-stimulating hormone and thyroid hormones in human ovarian tissue
.
Reprod Biomed Online
.
2009
;
18
(
3
):
337
47
.
22.
Ortiga-Carvalho
TM
,
Sidhaye
AR
,
Wondisford
FE
.
Thyroid hormone receptors and resistance to thyroid hormone disorders
.
Nat Rev Endocrinol
.
2014
;
10
(
10
):
582
91
.
23.
Venables
A
,
Wong
W
,
Way
M
,
Homer
HA
.
Thyroid autoimmunity and IVF/ICSI outcomes in euthyroid women: a systematic review and meta-analysis
.
Reprod Biol Endocrinol
.
2020
;
18
(
1
):
120
.
24.
Eisenberg
VH
,
Zolti
M
,
Soriano
D
.
Is there an association between autoimmunity and endometriosis
.
Autoimmun Rev
.
2012
;
11
(
11
):
806
14
.
25.
Schindler
AE
.
Dienogest in long-term treatment of endometriosis
.
Int J Womens Health
.
2011
;
3
:
175
84
.
26.
Birke
L
,
Baston-Bust
DM
,
Kruessel
JS
,
Fehm
TN
,
Bielfeld
AP
.
Can TSH level and premenstrual spotting constitute a non-invasive marker for the diagnosis of endometriosis
.
BMC Womens Health
.
2021
;
21
(
1
):
336
.
27.
Kaponis
A
,
Chatzopoulos
G
,
Paschopoulos
M
,
Georgiou
I
,
Paraskevaidis
V
,
Zikopoulos
K
, et al
.
Ultralong administration of gonadotropin-releasing hormone agonists before in vitro fertilization improves fertilization rate but not clinical pregnancy rate in women with mild endometriosis: a prospective, randomized, controlled trial
.
Fertil Steril
.
2020
;
113
(
4
):
828
35
.
28.
Tomassetti
C
,
Beukeleirs
T
,
Conforti
A
,
Debrock
S
,
Peeraer
K
,
Meuleman
C
, et al
.
The ultra-long study: a randomized controlled trial evaluating long-term GnRH downregulation prior to ART in women with endometriosis
.
Hum Reprod
.
2021
;
36
(
10
):
2676
86
.
29.
Guo
H
,
Du
T
,
Gao
H
,
Xi
Q
,
Wu
L
,
Lyu
Q
, et al
.
The comparison of two different protocols ultra-long versus medroxyprogesterone acetate in women with ovarian endometriosis: a prospective randomized controlled trial
.
Reprod Health
.
2022
;
19
(
1
):
198
.