甲状腺疾病对女性生殖功能的影响

甲状腺激素（TH）一方面直接作用于卵巢,另一方面通过影响性激素结合球蛋白（SHBG）的合成,调节泌乳素（PRL）、促性腺激素释放激素（GnRH）的分泌和凝血因子的功能而对月经周期进行调控。不孕女性的自身免疫性甲状腺疾病（AITD）患病率明显高于年龄匹配的经产妇,尤其是继发于子宫内膜异位或多囊卵巢综合征（PCOS）的不孕女性。伴或不伴AITD的妇女行辅助生殖技术（ART）的成功率并无显著差异。但患AITD的孕妇在妊娠前3个月发生流产的风险明显高于正常孕妇。此外,行ART之前的控制性超排卵（COH）过程对甲状腺功能有着不可忽略的影响,特别是对于合并AITD的妇女。故不孕妇女应于行ART之前筛查甲状腺功能,及时发现AITD,并在COH之后和妊娠期随访AITD妇女的甲状腺功能。妊娠早期阶段出现甲状腺功能异常的孕妇应接受L-Td治疗以避免妊娠并发症的发生。但关于是否应在孕前或孕期使用L—T。治疗甲状腺功能正常的AITD妇女仍缺乏足够的临床研究。     

The role of thyroid autoimmunity in fertility and pregnancy

The thyroid gland and gonadal axes interact continuously before and during pregnancy. Hypothyroidism influences ovarian function by decreasing levels of sex-hormone-binding globulin and increasing the secretion of prolactin. In women of reproductive age, hypothyroidism can be reversed by thyroxine therapy to improve fertility and avoid the need for use of assisted reproduction technologies. For infertile women, preparation for medically assisted pregnancy comprises controlled ovarian hyperstimulation that substantially increase circulating estrogen concentrations, which in turn can severely impair thyroid function. In women without thyroid autoimmunity these changes are transient, but in those with thyroid autoimmunity estrogen stimulation might lead to abnormal thyroid function throughout the remaining pregnancy period. Prevalence of thyroid autoimmunity is significantly higher among infertile women than among fertile women, especially among those whose infertility is caused by endometriosis or ovarian dysfunction. Presence of thyroid autoimmunity does not interfere with normal embryo implantation, but the risk of early miscarriage is substantially raised. Subclinical and overt forms of hypothyroidism are associated with increased risk of pregnancy-related morbidity, for which thyroxine therapy can be beneficial. Systematic screening for thyroid disorders in pregnant women remains controversial but might be advantageous in women at high risk, particularly infertile women.     

Relationship between sex hormone-binding globulin and pregnancy outcome in women undergoing controlled ovarian hyperstimulation for assisted reproduction

The purpose of this study was to determine whether the changes of sex hormone-binding globulin (SHBG) affect the pregnancy outcome in women undergoing controlled ovarian hyperstimulation (COH) for assisted reproduction. Forty-five infertile women who were undergoing pituitary desensitization and COH for in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI) and 19 women with normal menstrual cycles participated in the study. Fasting blood samples of the follicular and luteal phases, including follicular fluid during oocyte retrieval, were obtained for determination of estradiol (E(2)), progesterone (P(4)), testosterone (T), and SHBG concentrations. The SHBG levels increased progressively during the course of COH, but remained constant throughout normal menstrual cycles. A positive correlation existed between E(2) and SHBG levels in both the follicular and luteal phases. The mean plasma SHBG concentration and E(2)/T ratio were significantly higher, while the level of T and the free androgen index were significantly lower, in the luteal phase of women who conceived than in those who did not conceive following COH. The changes of follicular fluid SHBG level and E(2)/T ratio were similar to those in plasma. We concluded, therefore, that increases in SHBG in the follicular and luteal phases may be a reflection of the functional state of ovarian stimulation, and further that such elevations may influence the pregnancy outcome through the modulation of circulating estrogen and androgen balance during down-regulated COH cycles for IVF/ICSI.     

Thyroid disorders in infertile women.

Thyroid hormones have profound effects on reproduction and pregnancy. There is a known association of hyper- and hypothyroidism with menstrual disturbances and decreased fecundity. Women with reproductive failure also have an increased prevalence of organ specific autoimmunity compared to fertile women. The present study aims to answer the following questions: 1) is there an increased prevalence of thyroid antibodies in infertile women? 2) are thyroid antibodies associated with a particular cause of infertility? and 3) do these antibodies influence outcome of the in vitro fertilization procedure? The answers to the two first questions were evaluated with a case-control study looking at the occurrence of thyroid autoimmunity and thyroid function tests among women of infertile couples (n=438), presenting for the first time at the department of reproductive medicine. For comparison, a control population of parous women (n=100), matched for age, was included. In 45% of the infertile couples a female cause of infertility was identified: endometriosis (11%), tubal disease (30%) and ovarian dysfunction (59%). Male infertility was diagnosed in 38% and idiopathic infertility in 17% of the couples. Mean serum TSH levels were significantly higher in patients with infertility compared with control patients: 1.6 +/- 2.6 versus 1.2 +/- 0.7 mIU/L. The proportion of positive TPO-Abs was higher in all women of infertile couples, compared with controls (14% versus 8%), but the difference was not significant. Considering only the female causes of infertility a significant higher proportion of women had positive TPO-Abs compared with controls (18% versus 8%), and in particular a high prevalence of thyroid autoimmunity was found in women suffering from endometriosis (29%). Both hypo- and hyperthyroidism were more frequent when TPO-Abs were positive, compared to women without thyroid autoimmunity. The results of the present study indicate that endometriosis, increases the relative risk for associated thyroid autoimmunity to 2.3, and therefore screening for thyroid auto-antibodies could be systematically proposed in these women.     

Thyroid pathology and female fertility: Myth or reality?

The relationship between thyroid state and female fertility is an area of particular interest for both clinicians and researchers worldwide. This is partially due to the increasing prevalence of infertility and to the understanding of its complex and multifactorial aetiology. Studies conducted in variable forms of female infertility (e.g., recurrent miscarriages or polycystic ovarian syndrome) together with the worldwide rising use of assisted reproduction technologies (ART) contributed the uncovering of the potential role of thyroid conditions in relation to ovarian function and fertility. However, as the title of this short review suggests, several aspects are yet to be elucidated and several questions are still awaiting an answer. This short review is mainly focusing on the distinct roles of thyroid dysfunction and thyroid autoimmunity in infertile women undergoing ART procedures.     

Thyroid dysfunction and autoimmunity in infertile women.

A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy parous controls with the aim of assessing the prevalence of autoimmune thyroid disease (AITD) and hitherto undisclosed alterations of thyroid function. Female origin of the infertility was diagnosed in 45% of the couples, with specific causes including endometriosis (11%), tubal disease (30%), and ovarian dysfunction (59%). Male infertility represented 38% and idiopathic infertility 17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L. Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were not more prevalent in the infertile women than in controls. The prevalence of positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated women of infertile couples, compared to controls (14% vs. 8%), but the difference was not significant. However, in infertility of female origin, a significant higher prevalence of positive TPO-Ab was present, compared to controls: 18% versus 8%. Furthermore, among the female causes, the highest prevalence of positive antibodies was observed in women with endometriosis (29%). When thyroid antibodies were positive, both hypothyroidism and hyperthyroidism were more frequent in all women of infertile couples and in the women with a female infertility cause, compared to women in the same groups but without positive TPO-Ab. The present study shows that in infertile women, thyroid autoimmunity features are significantly more frequent than in healthy fertile controls and this was especially the case for the endometriosis subgroup.     

Euthyroid women with autoimmune disease undergoing assisted reproduction technologies: the role of autoimmunity and thyroid function

Thyroid dysfunction and the presence of thyroid antibodies increase the risk of infertility and miscarriage. The aim of the present study was to assess if patients with autoimmune thyroid disease undergoing assisted reproduction technologies (ART) are afflicted by poor pregnancy and/or delivery rate and if the outcome is conditioned by pre-ART thyroid status. The study was retrospective (from January 2000 to January 2005) and was carried out at the Division of Physiopathology of Human Reproduction. Women who underwent ART were tested for TSH, free T4 (FT4), thyroid peroxidase antibodies (TPOAb) before and during pregnancy. A total of 416 euthyroid women were selected; 42 (10.1%) were TPOAb (+). Women >35 yr were excluded. The endpoints were pregnancy and delivery rates. RESULTS: no differences in pregnancy and delivery rates were observed between women with and without antibodies. In TPOAb (+), women who failed to become pregnant or miscarried displayed higher TSH values before ART (2.8 mIU/l) compared to the ones who delivered (1.6 mIU/l; p=0.032) and compared to TPOAb (-) (1.1 mIU/l; p=0.018). CONCLUSIONS: in euthyroid women undergoing ART the pregnancy and delivery rates are not affected by the presence of TPOAb. In TPOAb (+) high-normal TSH values are associated with increased risk of unsuccessful pregnancy or subsequent miscarriage. Further studies are required to ascertain possible benefits of levo-T4 (L-T4) in such patients.     

Female poor responders

Female poor responders are represented by normovulatory women showing a 'gonadal failure' in term of inadequate number of recruited follicles under conventional controlled ovarian hyperstimulation (COH) for assisted reproductive technologies (ART). ARTs offers today a high chance of pregnancy to infertile couples when a normal ovarian response provides a large choice of embryos for transfer. On the contrary, failure of the ovary to produce enough oocyte for treatment, reduces significantly the likelihood of conceiving in ART, not only in the treatment cycle, but also predicting a poor prognosis in subsequent cycles. Up to date, poor response remains one of the most frequent problems in the field of assisted reproduction. First described in 1981, poor response has been investigated by several authors, but many aspects are still controversial. In this paper definition, pathophysiology and management of poor response are revised and discussed.     

The Systematic Screening and Management of Hypothyroidism and Hyperthyroidism During Pregnancy

Altogether, thyroid function abnormalities during pregnancy can affect up to 10% of all women. The high prevalence of both hypo- and hyperthyroidism, the obstetrical repercussions associated with thyroid dysfunction in the mothers, as well as the potential role of maternal thyroid dysfunction as an influence on fetal development constitute solid arguments for a further increase of our knowledge of the pathophysiological processes underlying the alterations of thyroid function related to the pregnant state. In this review, the focus will be on the most clinically relevant aspects associated with hypothyroidism [autoimmune thyroid disorders (AITDs), subfertility, risk of miscarriage, risk of hypothyroidism in women with AITD and treatment of hypothyroid women] and with hyperthyroidism (clinical presentations during pregnancy, Graves' disease and its management, fetal hyperthyroidism in women with antithyroid-stimulating hormone receptor antibodies and gestational transient thyrotoxicosis associated with human chorionic gonadotropin stimulation of the maternal thyroid gland). I also propose a global strategy for the systematic screening of hypo- and hyperthyroidism in the pregnant state.     

Management of thyrotoxicosis and pregnancy: Review of the current literature and an update of the care pathway

Pregnancy can be complicated by hyperthyroidism or thyrotoxicosis. Diagnosis is founded on an increase in free thyroid hormones and low TSH. The most frequent etiologies are Graves’ disease, an autoimmune disease linked to stimulatory anti-TSH receptor antibodies, and non-autoimmune gestational hyperthyroidism linked to the TSH-like activity of the chorionic growth hormone (hCG). During pregnancy, thyrotoxicosis can entail maternal, obstetrical and fetal or neonatal complications. Graves’ hyperthyroidism may be responsible for fetal and neonatal hyperthyroidism due to placental transfer of stimulatory anti-TSH receptor antibodies. During pregnancy, treatment of thyrotoxicosis must restore normal thyroid function in the mother without affecting fetal thyroid function. The recent reassessment of the prevalence of teratogenic effects in children of women treated with antithyroid drugs in the first weeks of gestation should orient the care pathway before and during pregnancy for women of child-bearing age with hyperthyroidism linked to Graves’ disease.     

Periovulatory increases in tissue homing potential of circulating CD56(bright) cells are associated with fertile menstrual cycles

CD56(bright) lymphocytes appear in the uterus 3-5 d after ovulation coincident with the onset of stromal cell decidualization. Although the source of these uterine immune cells is not defined, a subset of blood CD56(bright) cells exhibits enhanced capacity to adhere to decidual vascular endothelium during the periovulatory period of menstrual cycles. In this study, the effects of early pregnancy on the adhesive capacity of CD56(bright) cells to bind uterine substrates were examined in a time-course study of 18 infertile women undergoing natural cycles before transfer of frozen/thawed embryos and 18 infertile women undergoing controlled ovarian stimulation. There were three pregnancies in the natural cycle group and seven in the hormone-stimulated cohort. Hormone levels, and number and quality of transferred embryos were similar between pregnant and nonpregnant cycles. However, the adhesive function of CD56(bright) cells increased before ovulation in hormone-treated women who became pregnant and before embryo transfer in naturally cycling women who became pregnant. This pattern of incremental adhesion, which was less frequently observed in unsuccessful cycles, suggests a role for NK cells in implantation. These results support the idea that temporal control of NK cell homing to the uterine microenvironment is a prerequisite to pregnancy.     

Serum thyroglobulin during the menstrual cycle, during pregnancy, and post partum

Serum thyroglobulin, TSH, thyroid hormones and thyroid volume were investigated during the menstrual cycle in 10 healthy females (day 2, 9, 16, 23 and day 2 of next cycle), during pregnancy (week 18, 24, 30 and 36) and post partum (1, 2, 3, 6 and 12 months) in 20 healthy females. During the menstrual cycle median serum thyroglobulin increased from 27 (day 2) to 32 micrograms/l (day 23, p less than 0.01). Serum TSH and thyroid volume demonstrated a similar increase with a positive correlation between serum thyroglobulin and thyroid volume (r = 0.65, p less than 0.02). Median serum thyroglobulin was significantly increased during the whole pregnancy (week 36, 73 micrograms/l) compared with post partum (1 month post partum, 22 micrograms/l, p less than 0.01), as was thyroid volume. Serum TSH was unaltered and free thyroid hormone indices decreased during pregnancy compared with post partum. No relation between changes in serum thyroglobulin and thyroid volume, TSH or thyroid hormones could be demonstrated. Serum thyroglobulin alterations thus were related to alterations in TSH and thyroid volume during the menstrual cycle. However, the increase in serum thyroglobulin and thyroid volume during pregnancy were unrelated to changes in serum TSH, indicating other mechanisms of regulation than TSH. When interpreting serum thyroglobulin levels in women, the co-existence of pregnancy and time of menstrual cycle should be taken into account in order to avoid misinterpretation of results.     

Pregnancy and autoimmune thyroid disease.

Immunological and endocrine changes related to pregnancy influence the course and development of autoimmune thyroid disease (AITD). Conversely, the presence of AITD can affect both the mother and her child-both in utero and in the neonatal period. The successful management of AITD in pregnancy requires a knowledge of the differential placental transfer of various hormones, antibodies, and drugs.     

Temporary ovarian failure in thyroid cancer patients after thyroid remnant ablation with radioactive iodine

We studied ovarian function retrospectively in 66 women who had regular menstrual cycles before undergoing complete thyroidectomy for differentiated thyroid cancer and subsequent thyroid remnant ablation with 131I. Eighteen women developed temporary amenorrhea accompanied by increased serum gonadotropin concentrations during the first year after 131I therapy. No correlation was found between the radioactive iodine dose absorbed, thyroid uptake before treatment, oral contraceptive use, or thyroid autoimmunity. Only age was a determining factor, with the older women being the most affected. We conclude that radioiodine ablation therapy is followed by transient ovarian failure, especially in older women.     

Thyroid function inside and outside of pregnancy: what do we know and what don't we know?

A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12-13, 2004. This paper reports on the session that examined the prevalence of thyroid dysfunction in reproductive-age women and the factors associated with abnormal function. For this session the following papers were presented: "Thyroidal Economy in the Pregnant State: An Overview," "The Prevalence of Thyroid Dysfunction in Reproductive-Age Women- United States," and "Risk Factors for Thyroid Disease: Autoimmunity and Other Conditions." These presentations were formally discussed by invited respondents and by others in attendance. Salient points from this session about which there was agreement include the following: physiologic changes associated with pregnancy require an increased availability of thyroid hormones by 40% to 100% in order to meet the needs of mother and fetus during pregnancy. In the first trimester of gestation the fetus is wholly dependent on thyroxine from the mother for normal neurologic development. For the maternal thyroid gland to meet the demands of pregnancy it must be present, disease-free, and capable of responding with adequate stores of iodine. Thyroid autoimmunity is common and may contribute to miscarriages, as well as to hypothyroidism. With sufficient iodine nutrition, autoimmune thyroid disease (AITD) is the most common cause of hypothyroidism. As of 1994, iodine nutrition in the United States appeared to be adequate, but its continued monitoring is essential.     

Gonadotropins as pharmacological agents in assisted reproductive technology and polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a complex endocrinopathy associated with subfertility/infertility and pregnancy complications. Most PCOS women opt for assisted reproductive technologies (ART) for successful conception; however, optimization of the relative doses of the gonadotropins [follicle-stimulating hormone (FSH), luteinizing hormone (LH)/human chorionic gonadotropin (hCG)] for appropriate steroidogenesis, without causing ovarian hyperstimulatory syndrome (OHSS), is challenging. Embryonic factors probably do not contribute to pregnancy loss in PCOS women, albeit hormonal imbalance impairs the metabolic microenvironment critical for oocyte maturation and endometrial receptivity. Certain clinical studies have confirmed the role of metabolic corrections in increasing the rate of pregnancy in PCOS women. This review focuses on the impact of untimely high LHCGR and/or LH levels on oocyte/embryo quality, pregnancy outcomes in ART, and exploring LHCGR as a potential drug target in PCOS women.     

Assisted reproduction and thyroid autoimmunity: an unfortunate combination?

The association between positive thyroid antibodies and an increased miscarriage rate in pregnancies after assisted reproduction technology (ART) remains controversial. We wanted to clarify this issue by performing a prospective cohort study in 234 women by systematically screening for thyroid peroxidase antibodies (TPO-Ab), serum TSH, and free T(4)(FT(4)) before the first ART cycle. Women with overt thyroid dysfunction were excluded. Fourteen percent of the cohort had positive TPO-Ab. Baseline characteristics [age, 33 +/- 5 yr; TSH, 1.6 (0.02-4.1) mU/liter; and FT(4), 12.2 (9.1-18) ng/liter] were comparable to those of the 86% of women without antibodies [age, 32 +/- 5 yr; TSH, 1.3 (0.05-3.6) mU/liter; and FT(4), 11.7 (9.5-16.5) ng/liter]. In the antibody-positive group, the pregnancy rate was 53% vs. 43% in the antibody-negative group, with an odds ratio of 0.67 [95% confidence interval (CI) (0.32-1.41); P = not significant]; however within the group that was pregnant, the miscarriage rate was 53% and 23%, respectively, with an odds ratio of 3.77 [95% CI (1.29-11.05); P = 0.016]. The age of the women was an independent risk factor for miscarriage, odds ratio 1.08 [95% CI (1.03-1.15); P = 0.005]. We conclude that women with positive TPO-Ab before the first ART cycle have a significantly increased risk for miscarriage.     

Resistance to thyroid hormone accompanied by Graves' disease

Resistance to thyroid hormone (RTH) is characterized by elevated serum levels of thyroid hormones and normal or slightly increased serum thyrotropin (TSH) levels. Recently it has been suggested that chronic TSH stimulation in RTH activates intrathyroidal lymphocytes, leading to thyroid damage and autoimmune thyroid disease (AITD). Therefore, individuals with RTH have an increased likelihood of AITD compared to unaffected relatives. We here report a 33-year-old woman in whom we diagnosed Graves' disease and treated her with thiamazole (MMI). For two years, her TSH levels were suppressed when thyroid hormones were elevated and conversely they were increased when thyroid hormones levels were decreased. These findings were common for a clinical course during treatment for Graves' disease with anti-thyroid drug. However, three years after the initiation of MMI therapy, she had a normal or gradually elevated serum TSH level even though the level of thyroid hormones never decreased, indicating inappropriate secretion of TSH. We concluded she had RTH clinically, and we demonstrated by direct sequence analysis a mutation of the TRβ gene, causing replacement of a glycine (G) with arginine (R) at codon 251. The finding of an elevated TSH level without decreased thyroid hormones should suggest the presence of RTH during therapy of Graves' disease.     

Preconception management of thyroid dysfunction

Uncorrected thyroid dysfunction in pregnancy has well‐recognized deleterious effects on foetal and maternal health. The early gestation period is one of the critical foetal vulnerability during which maternal thyroid dysfunction may have lasting repercussions. Accordingly, a pragmatic preconception strategy is key for ensuring optimal thyroid disease outcomes in pregnancy. Preconception planning in women with hypothyroidism should pre‐empt and mirror the adaptive changes in the thyroid gland by careful levothyroxine dose adjustments to ensure adequate foetal thyroid hormone delivery in pregnancy. In hyperthyroidism, the goal of preconception therapy is to control hyperthyroidism while curtailing the unwanted side effects of foetal and maternal exposure to antithyroid drugs. Thus, pregnancy should be deferred until a stable euthyroid state is achieved, and definitive therapy with radioiodine or surgery should be considered in women with Graves’ disease planning future pregnancy. Women with active disease who are imminently trying to conceive should be switched to propylthiouracil either preconception or at conception in order to minimize the risk of birth defects from carbimazole or methimazole exposure. Optimal strategies for women with borderline states of thyroid dysfunction namely subclinical hypothyroidism, isolated hypothyroxinaemia and thyroid autoimmunity remain uncertain due to the dearth of controlled interventional trials. Future trial designs should aspire to recruit and initiate therapy before conception or as early as possible in pregnancy.