Regulatory Actions of LH and Follicle-Stimulating Hormone on Breast Cancer Cells and Mammary Tumors in Rats.

Gonadotrophins are mainly known to influence the body through the formation of gonadal steroids. However, receptors for luteinizing hormone (LH) and follicular-stimulating hormone (FSH) are present in a set of extra-gonadal tissues in humans and animals, but their functional relevance is uncertain. In this article, we present experimental evidence that, in T-47D breast cancer (BC) cells, FSH, and LH alter the expression of genes involved in adhesion, motility, and invasion through the activation of their receptors. Using miniarray technology we also found that LH influences the expression of a broad set of genes involved in cancer biology in T-47D cells. Interestingly, the regulatory actions of FSH and LH depend on the modality of exposure, with significant differences between pre-pubertal-like vs. post-menopausal-like amounts of gonadotrophins, but not after intermittent administration, representative of fertile life. We also studied the modulation of the circulating levels of gonadotrophins in an in vivo rat model of BC progression and observed a direct correlation with the extent of cancer growth. These results support the hypothesis that gonadotrophins may have direct effects on extra-gonadal tissues. They also highlight that gonadotrophins could potentially contribute to BC progression, particularly in post-menopausal women who typically have higher gonadotrophin levels. This research may ultimately lead to testing the use of gonadotrophin-modulating drugs in BC patients.

The role of progesterone therapy in early pregnancy: from physiological role to therapeutic utility.

Progesterone is a steroid hormone of essential role in reproduction. In early pregnancy, it is responsible for preparation of endometrium for implantation process and maintenance of gestational sac in uterus, also by modulation of maternal immune system. Even though, several indices has been proposed as markers of endogenous progesterone synthesis (progesterone or luteinizing hormone measurements, endometrial biopsy), none has been proved to be reliable in detecting luteal phase defect. Currently, several pharmaceutical formulations are available, but in clinical setting the non-oral formulations seems to be effective in therapy. Progesterone is effective in the treatment of patients undergoing assisted reproductive technology procedure, as a luteal phase support. Some studies showed also its efficacy in the treatment of threatening or recurrent miscarriage, but newer trials neglected this beneficial effect. Due to controversies regarding utility of progesterone supplementation in these conditions, further studies are needed to address this issue.

LH and FSH promote migration and invasion properties of a breast cancer cell line through regulatory actions on the actin cytoskeleton.

Reproductive hormones influence breast cancer development and progression. While the actions of sex steroids in this setting are established, tentative evidence suggests that follicle-stimulating hormone (FSH) and luteinizing hormone (LH) may also play a role, yet this remains elusive. We here identify that T-47D breast cancer cells express functional receptors for FSH and LH, and that these hormones regulate breast cancer cell motility and invasion through the control of the actin cytoskeleton and the formation of cortical actin aggregates and focal adhesion complexes. Such actions are mediated by the cytoskeletal controllers Moesin and focal adhesion kinase (FAK). Moesin is recruited rapidly by FSH and LH through a signaling cascade requiring the G protein Gα13 and the Rho-associated kinase, ROCK-2. FSH and LH activate FAK via a Gαi/ß and c-Src-dependent signaling cascade. Both cascades involve signaling to phosphatidylinositol-3 kinase and Akt. FSH and LH receptors and the related signaling intermediates are necessary for the actions of gonadotrophins on breast cancer cell cytoskeletal rearrangement, migration and invasion. These findings provide original information on the actions of gonadotrophins on breast cancer cells and may have clinical implications for the use of drugs that modulate gonadotrophins in breast cancer patients.

Recurrent endometrial hyperplasia as a presentation of estrogen-secreting thecoma - case report and minireview of the literature.

Thecoma is a rare ovarian tumor, presenting usually in postmenopausal women as unilateral, benign, solid lesion. About 15% of affected patients develop endometrial hyperplasia (EH) and 20% are diagnosed with endometrial cancer. In this case report, we present 60-year-old women admitted because of recurrent spotting of 5 years duration, which started 1 year after menopause. In history, the patient underwent three times curettage procedures and once (1 year before admission) had estradiol levels typical for reproductive-age women. At admission, we found elevated serum levels of estradiol (222.5 pg/ml) and a small mass in the right ovary. The markers of germ cell tumors were negative. After the initial diagnosis, the patient was qualified for total abdominal hysterectomy with bilateral salpingo-oophorectomy. The histopathological examination and immunohistochemical staining confirmed the thecoma diagnosis. In follow-up examination after 8 weeks, we found decreased serum estradiol levels and relief of the symptoms. In conclusion, we want to underline that in cases of EH, especially in patients with a history of recurrences, the special attention should be paid for differential diagnosis. In such cases, the estrogen-secreting tumors should be excluded.

Estetrol Modulates Endothelial Nitric Oxide Synthesis in Human Endothelial Cells.

Estetrol (E4) is a natural human estrogen that is present at high concentrations during pregnancy. E4 has been reported to act as an endogenous estrogen receptor modulator, exerting estrogenic actions on the endometrium or the central nervous system but presenting antagonistic effects on the breast. Due to these characteristics, E4 is currently being developed for a number of clinical applications, including contraception and menopausal hormone therapy. Endothelial nitric oxide (NO) is a key player for vascular function and disease during pregnancy and throughout aging in women. Endothelial NO is an established target of estrogens that enhance its formation in human endothelial cells. We here addressed the effects of E4 on the activity and expression of the endothelial nitric oxide synthase (eNOS) in cultured human umbilical vein endothelial cells (HUVEC). E4 stimulated the activation of eNOS and NO secretion in HUVEC. E4 was significantly less effective compared to E2, and a peculiar concentration-dependent effect was found, with higher amounts of E4 being less effective than lower concentrations. When E2 was combined with E4, an interesting pattern was noted. E4 antagonized NO synthesis induced by pregnancy-like E2 concentrations. However, E4 did not impede the modest induction of NO synthesis associated with postmenopausal-like E2 levels. These results support the hypothesis that E4 may be a regulator of NO synthesis in endothelial cells and raise questions on its peculiar signaling in this context. Our results may be useful to interpret the role of E4 during human pregnancy and possibly to help develop this interesting steroid for clinical use.

Diurnal Variation of Plasma Brain-Derived Neurotrophic Factor Levels in Women with Functional Hypothalamic Amenorrhea.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is strongly related to hormonal networks and is modulated by hypothalamic activity. OBJECTIVE: To evaluate plasma BDNF concentration in patients with functional hypothalamic amenorrhea (FHA), with reference to the BDNF circadian rhythm and its relation with the cortisol (F) rhythm, and to assess whether the duration of amenorrhea might influence the BDNF:F ratio in FHA. DESIGN: This was an observational study evaluating 36 amenorrheic and 30 eumenorrheic women. SETTING: Basal values of BDNF and hormones were examined in blood samples collected from 7:00 to 9:00 h in all the women. Basal BDNF and F levels were determined in blood samples collected in 12 subjects from each group at 8:00, 12:00, 16:00, 20:00, and 24:00 h. RESULTS: BDNF plasma levels are significantly lower in amenorrheic women (p < 0.001) than in the follicular phase of eumenorrheic women. There are no correlations between BDNF values (p > 0.05), sex steroids, and F in FHA. Low plasma BDNF levels in FHA are not significantly correlated with duration of amenorrhea. The 24-hour variation of BDNF in amenorrheic women is significantly lower when compared to the control group, and normal daily variations of BDNF disappeared in FHA patients. F preserved its circadian rhythm in both groups. CONCLUSIONS: Interactions between BDNF, the hypothalamus-pituitary-adrenal axis, and sex steroids might be critical in clinical conditions of modified homeostasis/adaptation, such as FHA.

Endometritis in Infertile Couples: The Role of Hysteroscopy and Bacterial Endotoxin.

OBJECTIVE: The role of endometritis on infertility is still controversial. The aim of our prospective controlled study was to select infertile couples and to analyze: hysteroscopic findings of endometritis, bacterial endotoxin level in the menstrual blood, histological pattern of endometrial biopsy and to determine the effect of antibiotic therapy on endometritis resolution. METHODS: 100 infertile couples of University Hospital waiting for in vitro fertilization program. We evaluated the incidence of endometritis in infertile population by hysteroscopy, endometrial biopsy and bacterial endotoxin levels in the menstrual samples. Moreover, we verified the effectiveness of antimicrobial treatment on the endometritis resolution by hysteroscopic control. RESULTS: Out of 100 women enrolled, 15 showed hysteroscopic evidence of endometritis and 12 of these patients presented higher bacterial endotoxin in the menstrual samples. The histological results were positive for endometritis in 9 cases, 1 woman had no adequate samples and 5 patients had negative result. After antibiotic therapy, 9 patients had a complete hysteroscopic endometritis resolution, 4 patients had an improvement and in 2 cases there was no endometrial change. Concerning histological findings after therapy, we had negative results in 12 patients and persistent inflammatory findings in 2 patients. CONCLUSION: Our study demonstrated a high incidence of endometritis in infertile couples (15%). The endometrial biopsy was in agreement with the hysteroscopic findings in 60% of the cases, and the bacterial endotoxin level in the menstrual samples was higher in 12 patients with suspected endometritis, then its measurement can be helpful to confirm an endometrial infection but its influence must be confirmed with further researches. The antibiotic therapy can improve the hysteroscopic endometrial inflammatory aspect in over 80% of cases.

Hormonal causes of recurrent pregnancy loss (RPL).

Endocrine disorders play a major role in approximately 8% to 12% of recurrent pregnancy loss (RPL). Indeed, the local hormonal milieu is crucial in both embryo attachment and early pregnancy. Endocrine abnormalities, including thyroid disorders, luteal phase defects, polycystic ovary syndrome, hyperprolactinaemia and diabetes have to be evaluated in any case of RPL. Moreover, elevated androgen levels and some endocrinological aspects of endometriosis are also factors contributing to RPL. In the present article, we review the significance of endocrine disease on RPL.

Effects of Estetrol on Migration and Invasion in T47-D Breast Cancer Cells through the Actin Cytoskeleton.

Estetrol (E4) is a natural human estrogen present at high concentrations during pregnancy. Due to its high oral bioavailability and long plasma half-life, E4 is particularly suitable for therapeutic applications. E4 acts as a selective estrogen receptor (ER) modulator, exerting estrogenic actions on the endometrium or the central nervous system, while antagonizing the actions of estradiol in the breast. We tested the effects of E4 on its own or in the presence of 17ß-estradiol (E2) on T47-D ER+ breast cancer cell migration and invasion of three-dimensional matrices. E4 administration to T47-D cells weakly stimulated migration and invasion. However, E4 decreased the extent of movement and invasion induced by E2. Breast cancer cell movement requires a remodeling of the actin cytoskeleton. During exposure to E4, a weak, concentration-dependent, re-distribution of actin fibers toward the cell membrane was observed. However, when E4 was added to E2, an inhibition of actin remodeling induced by E2 was seen. Estrogens stimulate ER+ breast cancer cell movement through the ezrin-radixin-moesin family of actin regulatory proteins, inducing actin and cell membrane remodeling. E4 was a weak inducer of moesin phosphorylation on Thr(558), which accounts for its functional activation. In co-treatment with E2, E4 blocked the activation of this actin controller in a concentration-related fashion. These effects were obtained through recruitment of estrogen receptor-α. In conclusion, E4 acted as a weak estrogen on breast cancer cell cytoskeleton remodeling and movement. However, when E2 was present, E4 counteracted the stimulatory actions of E2. This contributes to the emerging hypothesis that E4 may be a naturally occurring ER modulator in the breast.

Brain-derived neurotrophic factor plasma levels in patients with Turner syndrome.

INTRODUCTION: Brain-derived neurotrophic factor (BDNF) plays a key role in neural development and synaptic plasticity. BDNF is known to circulate in plasma and its levels are strictly linked to the sex hormones. AIM: The aim of this study was to assess the plasma BDNF concentration in patients with Turner syndrome (TS). This is a first of such study in TS women. METHODS: 31 TS patients were enrolled to the study and compared with a control group (10 healthy, ovulatory women). We collected blood for measurement of BDNF plasma concentration, estradiol (E2) and gonadotrophins serum levels. The blood was taken after overnight fasting, in menstruating women in follicular phase. RESULTS: We found that BDNF plasma concentration was significantly higher in the group of TS patients compared to the control group (mean 768.5 ± 194.9 pg/ml versus 407.2 ± 25.7 pg/ml; p < 0.0001). What is more, the BDNF levels in TS were not correlated to E2 levels, whereas in the control group, positive and strong correlation with E2 was found (r = 0.92; p < 0.0001). The testosterone concentration correlated strongly with BDNF levels in TS patients. CONCLUSIONS: In this study, we showed for the first time that TS patients has a higher BDNF levels than healthy ones and BDNF is not correlated with E2 concentration but tend to be related to testosterone. This study brings interesting insights to BDNF physiology.

Decreased plasma concentrations of brain-derived neurotrophic factor (BDNF) in patients with functional hypothalamic amenorrhea.

INTRODUCTION: Functional hypothalamic amenorrhea (FHA) is a non organic, secondary amenorrhea related to gonadotropin-releasing hormone pulsatile secretion impairment. Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of survival-promoting molecules, plays an important role in the growth, development, maintenance and function of several neuronal systems. AIM OF THE STUDY: The aim of the study was the evaluation of plasma BDNF concentrations in patients with the diagnosis of FHA. MATERIAL AND METHODS: We studied 85 subjects diagnosed with FHA who were compared with 10 healthy, eumenorrheic controls with normal body mass index. Plasma BDNF and serum luteinizing hormone, follicle-stimulating hormone and estradiol (E2) concentrations were measured by immunoenzymatic method (enzyme-linked immunosorbent assay). RESULTS: Significantly lower concentration of plasma BDNF was found in FHA patients (196.31 ± 35.26 pg/ml) in comparison to healthy controls (407.20 ± 25.71 pg/ml; p < 0.0001). In the control group, there was a strong positive correlation between plasma BDNF and serum E2 concentrations (r = 0.92, p = 0.0001) but in FHA group it was not found. CONCLUSIONS: Role of BDNF in FHA is not yet fully understood. There could be found studies concerning plasma BDNF concentrations in humans and animals in the literature. However, our study is one of the first projects which describes decreased plasma BDNF concentration in patients with diagnosed FHA. Therefore, further studies on BDNF in FHA should clarify the role of this peptide.

Effects of progesterone and medroxyprogesterone on actin remodeling and neuronal spine formation.

Sex steroids are important regulators of neuronal cell morphology, and this is critical for gender differences in brain function and dysfunction. Neuronal morphology is controlled by multiprotein complexes including moesin (a member of the ezrin/radixin/moesin family), focal adhesion kinase (FAK), or the Wiskott-Aldrich syndrome protein-family verprolin homologous (WAVE1) protein, controlling dynamic remodeling of the cytoskeleton and cell membrane. We investigated the actions of natural progesterone (P) and of the synthetic progestin medroxyprogesterone acetate (MPA) on actin remodeling, focal adhesion complex formation, and actin branching in rat cortical neurons. Treatment with P and, to a lesser extent, MPA, increases the number and density of dendritic spines. P increases the phosphorylation of moesin, FAK, and WAVE1, and their redistribution toward cell membrane sites where spines are formed. Signaling to moesin is achieved by PR via a Gα/Gß-dependent signaling to the small GTPase Ras homolog gene family, member A and its related kinase, Rho-associated kinase-2. In parallel, WAVE1 recruitment is triggered by a Gαi/Gß-dependent signaling of PR to c-Src, FAK, and Rac1 GTPase. Rac1 recruits cyclin-dependent kinase-5, which phosphorylates WAVE1. Silencing of moesin, FAK, or WAVE1 abrogates the increase in dendritic spines induced by progesterone. In all applications, MPA is found to act similar to P, albeit with a lower efficacy. In conclusion, our findings indicate that the control of actin polymerization and branching and focal adhesion complex formation via moesin, FAK, and WAVE1 is a key function of progesterone receptor in neurons, which may be relevant for the regulation of dendritic spine turnover and neuronal plasticity.

Feto-placental vascular dysfunction as a prenatal determinant of adult cardiovascular disease.

Low birthweight is associated with increased rates of coronary heart disease, stroke, hypertension and non-insulin-dependent diabetes during adult life. This is thought to be the consequence of a 'programming', whereby a stimulus or insult at a critical, sensitive period of early life has permanent effects on structure, physiology and metabolism. Programming of the fetus may, hence, result from adaptations to a condition where placental nutrient supply fails to match fetal demand. Recently, compensatory feto-placental up-regulation of the nitric oxide system during fetal growth restriction (FGR) was shown. Particularly, restricted hypoxic fetuses present an elevation of nitrites and a reduction of asymmetric dimethylarginine. S-nitrosohemoglobin is consumed under hypoxic conditions. These events are followed by nitric oxide pathway down-regulation postnatally, increasing susceptibility to cardiovascular disorders later in life. The relative hyperoxia would favor any such occurrence through depletion of tetrahydrobiopterin secondary to oxygen radical formation. This concept may lead to new therapeutic strategies, based on tetrahydrobiopterin supplementation, free-radical scavenging, L-arginine administration and/or inhaled NO therapy in FGR hypoxic newborns, to improve their postnatal adaptation and to reduce the risk of metabolic pathologies in adult age.

Fertility drug use and risk of ovarian tumors: a debated clinical challenge.

Infertility itself increases the incidence of ovarian carcinoma, while the potential additional risk associated with the use of fertility drugs is still debated. In 1992, the cumulative analysis of 12 US case-control studies revealed that women who received ovulation-inducing drugs had approximately three-fold higher incidence of invasive ovarian carcinoma. Other investigations reported a lower increase of the risk of invasive carcinoma or borderline tumor of the ovary in women treated with these agents. Conversely, several other case-control or cohort studies failed to detect a significant correlation between fertility drug use and ovarian tumor risk in either parous or nulliparous women compared with untreated infertile women. Moreover neither the number of treatment cycles nor the type of drug used was associated with an increased risk in most studies. Incessant ovulation and excessive gonadotropin secretion have been long considered to play a major role in the development of ovarian carcinoma, and therefore fertility drugs, which raise the serum levels of gonadotropins and increase the chances of multiple ovulations, have been retained as a risk factor for this malignancy, However, the large majority of literature data as well as the new hypotheses on ovarian carcinogenesis appear to exclude a relevant impact of fertility drug use on the risk of ovarian tumors, and especially of high-grade invasive epithelial ovarian cancers.

New insights on the pathogenesis of ovarian carcinoma: molecular basis and clinical implications.

Ovarian carcinoma can be subdivided into two categories termed type I and type II. Type I tumours, usually having an indolent clinical behaviour, are often detected in early stage, and rarely harbour p53 gene mutations. Each histological type has a distinct molecular profile with mutations of genes involved in different signalling transduction pathways, such as KRAS, BRAF, CTNNB1, PTEN, PIK3CA and ARID1A. Type II tumours, accounting for 75% of the cases, have a very aggressive biological behaviour, are usually in advanced stage at presentation, harbour p53 gene mutations in 80% of the cases, and sometimes have alterations of homologous recombination (HR). Both type I and type II tumours arise from extra-ovarian precursors. Serous carcinomas derive from tubal epithelium, endometrioid and clear cell carcinomas from endometrial tissue, and mucinous and Brenner tumours from transitional epithelial cells located near the tubo-peritoneal junction. These new concepts on the pathogenesis of ovarian carcinoma could deeply modify both the preventive approach in women with germ-line BRCA1 or BRCA2 mutations and the treatment of patients with advanced or recurrent disease. For instance, BRAF inhibitors could be used in low-grade serous carcinomas, PIK3CA inhibitors could be employed in clear cell carcinoma, and poly (ADP-ribose) polymerase inhibitors could be used not only in hereditary ovarian carcinoma but also in non-hereditary, high-grade serous ovarian carcinoma which sometimes shows defective HR.

Analysis of failures in patients with FIGO stage IIIc1-IIIc2 endometrial cancer.

AIM: To assess the pattern of failures in patients with FIGO stage IIIc(1)-IIIc(2) endometrial cancer. PATIENTS AND METHODS: Data were retrospectively analyzed for 34 patients with this malignancy who underwent extra-fascial total hysterectomy, bilateral salpingo-oophorectomy and pelvic/para-aortic node dissection. Postoperative treatment consisted of radiotherapy in 5 patients, 6 cycles of chemotherapy in 9, and 3-4 cycles of chemotherapy followed by radiotherapy in 20. The median follow-up of survivors was 33 months (range, 6 to 133 months). RESULTS: Tumour relapsed in 14 out of 34 patients (41.2%). Median time to recurrence was 17 months (range, 9.5-42 months). Vaginal recurrence developed in 2 patients (5.9%), distant recurrence in 5 (14.7%), pelvic node recurrence in 3 (8.8%) and para-aortic recurrence in 7 (20.6%). Two patients had multiple sites of recurrence. Distant failure occurred in 11.1% of the patients who received 6 cycles of chemotherapy versus 20.0% of those who had 3-4 cycles of chemotherapy followed by radiotherapy. Five-year overall survival was 60.5%, and, in particular, it was 62.5% for stage IIIc(1) and 57.0% for stage IIIc(2). CONCLUSION: FIGO stage IIIc(1)-IIIc(2) endometrial cancer relapses in approximately 40% of cases, and distant sites and para-aortic nodes represent the most common sites of failure.

Effects of red clover extracts on breast cancer cell migration and invasion.

Postmenopausal hormone therapy is associated with increased incidence of breast cancer. For this reason alternative therapeutic options to treat menopausal symptoms have been developed. Red clover extracts (RCE) are rich in isoflavones, particularly genistein and daidzein and they have been proved to be effective in reducing vasomotor symptoms in a number of studies. Due to their partial selectivity of action on estrogen receptors (ERs) these compounds have been claimed to be safer on the breast. In this article, we explored the action of RCE on motility and invasion of ER positive breast cancer cells and we partially characterized the signaling mechanisms. The principal isoflavones contained in RCE acted as weak estrogenic compounds when administered alone. However, when provided in association with physiological amounts of estradiol, RCE acted as estrogen antagonist on remodeling of actin cytoskeleton that are requested to enact cell movement and with related modifications of the activity of actin-binding proteins, such as moesin. These results offer novel information on the molecular actions of isoflavones contained in red clover on breast cancer cells, supporting a possible action of these molecules as natural selective estrogen receptor modulators in the presence of physiological amounts of estrogens.

Clinico-pathological and biological prognostic variables in squamous cell carcinoma of the vulva.

Several clinical-pathological parameters have been related to survival of patients with invasive squamous cell carcinoma of the vulva, whereas few studies have investigated the ability of biological variables to predict the clinical outcome of these patients. The present paper reviews the literature data on the prognostic relevance of lymph node-related parameters, primary tumor-related parameters, FIGO stage, blood variables, and tissue biological variables. Regarding these latter, the paper takes into account the analysis of DNA content, cell cycle-regulatory proteins, apoptosis-related proteins, epidermal growth factor receptor [EGFR], and proteins that are involved in tumor invasiveness, metastasis and angiogenesis. At present, the lymph node status and FIGO stage according to the new 2009 classification system are the main predictors for vulvar squamous cell carcinoma, whereas biological variables do not have yet a clinical relevance and their role is still investigational.

Patterns of failures in endometrial cancer: clinicopathological variables predictive of the risk of local, distant and retroperitoneal failure.

UNLABELLED: The aim of this study was to assess the pattern of failure and the outcome of endometrial cancer patients and to analyze the variables predictive of the risk of local, distant and retroperitoneal lymph node disease recurrence. PATIENTS AND METHODS: The authors assessed 511 patients who underwent primary surgery. The median follow-up of survivors was 74 months. Peritoneal, hematogenous and lymph node recurrences outside retroperitoneal area were considered as distant failures. RESULTS: Tumor relapsed in 83 (16.2%) patients. Median time to recurrence was 18.5 months (range, 3-129 months). The relapse was local in 13 cases, distant in 37, retroperitoneal in 22, and involved both distant and other sites in 11. Logistic regression showed that cervical involvement was the only independent predictor of local recurrence. Tumor grade, lymph-vascular space involvement (LVSI) and myometrial invasion were independent predictors of distant failure. Lymph node status and tumor grade were independent predictors of retroperitoneal recurrence. Five- and 10-year overall survival rates were 87.1% and 79.5%, respectively. Patient age, lymph node status, cervical involvement, tumor grade, LVSI and myometrial invasion were independent prognostic variables for overall survival. CONCLUSION: Cervical involvement was an independent predictor of local recurrence, LVSI and myometrial invasion were independent predictors of distant failure, lymph node status was an independent predictor of retroperitoneal relapse, and tumor grade was an independent predictor of both distant and retroperitoneal recurrence. The identification of risk factors for different patterns of failure can be useful in better tailoring adjuvant treatment.

Female infertility related to thyroid autoimmunity: the ovarian follicle hypothesis.

PROBLEM: The aim of this study was to verify whether anti-thyroid antibodies are present in the follicular milieu of euthyroid infertile women with thyroid autoimmunity undergoing in vitro fertilization (IVF) and whether IVF outcome is different in affected women with respect to negative controls. A secondary endpoint was to check whether there are changes in thyroid hormone levels during the IVF cycle. METHOD OF STUDY: Anti-thyroglobulin and anti-thyroperoxidase levels were measured in both follicular fluid and serum on the day of oocyte retrieval in women with thyroid autoimmunity. Serum TSH, FT3, and FT4 levels were measured in all patients before treatment initiation, on the day of oocyte retrieval and of pregnancy test. IVF outcome parameters were recorded in all women. RESULTS: Oocyte fertilization, grade A embryos, and pregnancy rates were lower in women with thyroid autoimmunity than in negative controls, while early miscarriage rate was higher. Anti-thyroid antibodies were measurable in follicular fluid in all affected women and were strongly correlated with serum levels. No significant changes in thyroid hormone levels were recorded in any women. CONCLUSION: The presence of anti-thyroid antibodies in ovarian follicles, as demonstrated for the first time in this study, may play a critical role in female infertility related to thyroid autoimmunity.