Physiologic thyroid activation in normal early pregnancy is induced by circulating hCG

In normal early pregnancy, serum free thyroxine (T4) increases and serum TSH decreases, indicating that the thyroid gland is activated physiologically. To identify the factor responsible for this thyroid activation, we measured the serum thyroid-stimulating activity in comparison with the serum level of hCG in 39 normal women in early pregnancy. Serum thyroid-stimulating activity was measured by a sensitive cyclic adenosine 3',5'-monophosphate (cAMP) accumulation assay using a rat thyroid cell line (FRTL-5). Thyroid-stimulating activity was detected in 37 women (95%), and the activities of individuals correlated positively with their serum free T4 levels (r = 0.474; P less than .01) and negatively with their serum TSH levels (r = -0.376; P less than .02). Moreover, serum thyroid-stimulating activity correlated closely with the serum hCG level (r = 0.741; P less than .001), but was completely abolished by pre-treatment of the sera with hCG antibodies. These data indicate that in normal early pregnancy, the thyroid gland is physiologically activated by serum hCG, which has intrinsic thyroid-stimulating activity.     

The human chorionic gonadotropin molecule from patients with trophoblastic diseases has a high thyrotropic activity but is less active in the ovary

To examine the pathogenesis of hyperthyroidism in women with trophoblastic diseases, the biological activity of human chorionic gonadotropin (hCG) molecules in women with normal pregnancy (n?=?85) and in women with trophoblastic diseases (vesicular mole, n?=?30; and choriocarcinoma, n?=?12) was compared. Hyperthyroidism (thyroid stimulating hormone (TSH) <?0.3 mIU/l) was observed more frequently in women with trophoblastic diseases. All the sera were then subjected to Chinese hamster ovary cells transfected with the human TSH receptor (CHO-hTSHr cells) and cAMP production was compared. Sera from the women with choriocarcinoma showed the highest cAMP production. Interestingly, significant correlation between serum hCG level and cAMP production in CHO-hTSHr cells was observed only in women with trophoblastic disease. All the sera were then applied to CHO cells transfected with hCG/luteinizing hormone (LH) receptor (CHO-hCG/LHr cells). In contrast to the findings with the TSH receptor, sera from the women with normal pregnancy showed the highest cAMP production in these cells. Correlation between serum hCG level and cAMP production in CHO-hCG/LHr cells was significant only in normal pregnancy. These results indicate that the hCG molecule from women with trophoblastic diseases displays enhanced thyrotropic activity.     

HCT and thyroid function in molar pregnancy.

HCT, TSH, T3, T4, PBI, T3-RSU, TBG binding capacity, BMR and thyroid uptake of radioiodine were measured simultaneously on the volunteers with hydatidiform mole and normal pregnancy. TRH stimulation tests were performed on the two groups. The serum HCT levels were higher in association with molar pregnancy than in normal pregnancy. TSH levels were within the nonpregnant range in the two groups. T3, T4, PBI, ETR, BMR and thyroid uptake of radioiodine suggested thyroid hyperfunction in molar pregnancy with a greater degree than that in normal pregnancy. TBG binding capacity and T3-RSU were similar in two groups. The peak TSH levels of TRH stimulation tests ranged widely in patients with molar pregnancies but were within the nonpregnant range in the subjects with normal pregnancies. These findings suggest thyroid hyperfunction in the molar pregnancy is due to a larger amount of HCT than in normal pregnancy.     

Placento-thyroidal relationship in normal pregnancy.

Estimations of serum HCT, HTSH, T4, T3, PBI, ETR, Triosorb, TBG-binding capacity, BMR and urinary total estrogen were made simultaneously in 160 women in normal pregnancy. TRH stimulation tests were made in 20 cases in each trimester of pregnancy. HCT was detectable even in early pregnancy, tending to increase gradually toward the terminal stage of pregnancy as serum thyrotrophin bioactivity showed. On the other hand, serum TSH level measured by radio-immunoassay remained essentially the same throughout the course of pregnancy as in the nonpregnant state, moreover, it was suggested by the TRH stimulation test that pituitary TSH secreting function of pregnant women was similar to that of the non-pregnant. These findings suggest that thyroid hyperfunction during pregnancy which is shown by progressively increased T3, T4, and PBI may not be due to high estrogen-high TBG binding capacity-low free thyroxinenegative feed back-high TSH secretion but to HCT originating from placenta. In spite of thyroid hormone increase, it is true that the clinical picture of hyperthyroidism is not manifest among normal pregnant women, and ETR remained within the non-pregnant range throughout the course of pregnancy. We have also demonstrated that Triosorb decreased progressively. This may be interpreted to be due to the increase of TBG binding capacity which is increased progressively and binds more of free thyroxine during pregnancy. Such a change in TBG binding capacity is well known to be caused by the effect of estrogen which is progressively increased during pregnancy. In a word, it is possible to say that there is a placento-thyroidal system in pregnancy; HCT elevates thyroid function and TBG increased by estrogen carries thyroid hormone to target organ.     

Human chorionic gonadotropin exhibits normal biological activity in patients with recurrent pregnancy loss.

To test the hypothesis that the structural abnormality of human chorionic gonadotropin (hCG) may induce recurrent pregnancy loss, we examined the biological activity of hCG in pregnant women with a history of repeated miscarriages (n = 44). Pregnant women without a history of miscarriage (n = 85) were included as controls. Serum hCG, estradiol (E2) and progesterone levels were found to be significantly lower in the pregnancy loss group. There was no difference in serum thyroid hormone levels. Sera from both groups of women were then incubated with Chinese hamster ovary (CHO) cells transfected with hCG/luteinizing hormone receptor (CHO-hCG/LHr) or human thyroid stimulating hormone receptor (CHO-hTSHr). Biological response to hCG in women with recurrent pregnancy loss was identical to that of women in the control group in both CHO-hCG/LHr and CHO-hTSHr cells. When sera were subjected to high performance liquid chromatography, no difference in hydrophobicity was observed between control and patients groups. The structure of the hCG molecule and its biological activity in women with a history of recurrent pregnancy loss are apparently not different from those in women with normal pregnancy. Lower serum progesterone and E2 levels in the patient group can be explained by lower serum hCG levels in these women. Intrinsic gonadotropic and thyrotropic activities of the hCG molecule appear to play no major role in recurrent pregnancy loss.     

First-trimester maternal serum human thyroid-stimulating hormone in chromosomally normal and Down syndrome pregnancies

Maternal serum human thyroid-stimulating hormone (TSH) levels were investigated in chromosomally normal and Down syndrome pregnancies to determine whether TSH can be used as a marker for Down syndrome in the first trimester. Measurements were conducted on stored serum samples collected from 23 Down syndrome pregnancies and 115 unaffected pregnancies before chorionic villus sampling (CVS), between 9 and 11 completed weeks of pregnancy. The samples were matched for gestational age, maternal age, maternal weight and duration of storage of the serum sample. Maternal TSH concentration was slightly decreased in Down syndrome pregnancies, with a median of 0.84 multiples of the median (MoM). Maternal serum human chorionic gonadotropin (hCG) concentration was slightly elevated in Down syndrome pregnancies, with a median of 1.03 MoM. Both differences were not significant applying matched rank analysis (p=0.50 for TSH and p=0.43 for hCG). The association between TSH and hCG in unaffected pregnancies was also measured. The Spearman correlation coefficient between TSH and hCG was -0.21 which was statistically significant (p=0.02, 95% confidence interval -0.38 to -0.03). However, it was concluded that TSH is not a useful marker for distinguishing Down syndrome-affected pregnancies from normal pregnancies in the first trimester.     

正常孕妇垂体-甲状腺轴功能变化的研究

目的了解正常孕妇妊娠各期及产后垂体-甲状腺轴功能的变化;探讨妊娠期人绒毛膜促性腺激素(hCG)对垂体-甲状腺轴的调节作用.方法采用放射免疫法,测定正常孕妇妊娠早、中、晚期及产后甲状腺功能参数[血清总三碘甲状腺原氨酸(TT3)、总甲状腺素(TT4)、血清游离三碘甲状腺原氨酸(FT3)、游离甲状腺素(FT4)、促甲状腺素(TSH)]、hCG及甲状腺结合球蛋白(TBG)的水平.结果(1)血清TT3、TT4水平在妊娠各期均较产后显著升高,其中TT4在妊娠早期最高为(170.00±40.28)nmol/L,TT3在妊娠中期最高为(2.64±0.53)mmol/L.(2)血清FT3水平在妊娠早期[(4.37±0.78)pmol/L]和中期[(4.75±0.90)pmol/L]显著升高,晚期[(3.94±0.75)pmol/L]下降,产后最低(2.96±0.84)pmol/L];血清FT4妊娠早期最高[(14.07±1.44)pmol/L],中期[(12.86±0.84)pmol/L]和晚期(11.29±1.00)pmol/L]逐渐下降,产后[(10.45±1.45)pmol/L]最低.(3)血清TSH水平在妊娠早期最低为(0.88±0.83)mU/L,妊娠中期[(1.86±1.04)mU/L]和晚期[(1.48±0.90)mU/L]上升,产后(2.82±1.42)mU/L]达最高峰.(4)血清hCG水平在妊娠早期最高为(309.05±320.02)μg/L,中期(69.11±19.18)μg/L]和晚期[(86.25±44.60)μg/L]下降,产后[(29.95±20.91)μg/L]最低.(5)hCG与TSH呈负相关,而与FT4、TT4呈正相关.结论(1)hCG可能在整个妊娠期及产后一定时间内,对垂体-甲状腺轴功能有一定的调节作用.(2)产后部分孕妇处于一过性甲状腺功能低减状态.     

Thyroxine requirement during pregnancy for replacement therapy of hypothyroidism

We examined the dose requirements of thyroxine (T4) and desiccated thyroid during eight pregnancies of six women who had undergone total thyroidectomy for thyroid carcinoma. In five pregnancies from four patients treated with T4, serum free T4, which was measured by a newly developed radioimmunoassay, decreased during pregnancy but increased above the normal range after delivery. Consistent with these changes in free T4, serum TSH (measured by a highly sensitive immunoradiometric assay) increased during pregnancy but returned to an undetectable level after delivery, with one exception. The serum triiodothyronine (T3)-to-T4 ratio, which is related to peripheral conversion of T4 to T3, was lower in patients treated with T4 than in normal controls, regardless of pregnancy. The ratio decreased further during pregnancy, and so relative deficiency of T3 during pregnancy was suspected, especially in T4-treated patients. On the other hand, in two pregnancies from two other patients treated with desiccated thyroid at a dose most equivalent to that of T4, serum free T4 decreased to a low-normal value during gestation but returned to the normal range after delivery, whereas serum TSH scarcely changed during pregnancy. These findings indicate that replacement therapy for pregnant patients with hypothyroidism after total thyroidectomy should include an increased dose of T4; in contrast, the dose of desiccated thyroid need not be changed.     

The use of plasmapheresis for rapid hormonal control in severe hyperthyroidism caused by a partial molar pregnancy

Introduction  The hormone human chorionic gonadotropin (hCG), secreted by molar tissue, is structurally similar to thyroid-stimulating hormone (TSH). Hyperthyroidism in trophoblastic disease is thought to be the result of TSH receptor activation by extremely elevated levels of hCG. Significant elevations in hCG levels are less common in cases of partial moles. Materials and methods   We describe a patient with partial molar pregnancy in which the levels of hCG and thyroid hormones were significantly high. It was not possible to decrease the elevated thyroid hormone concentrations to safer levels using medical treatment strategies only. Since the patient’s vaginal bleeding increased gradually, plasmapheresis was used to rapidly control the thyroid hormones during the preoperative preparation of the patient for anesthesia and surgery. After the evacuation of the molar tissue, the levels of the thyroid hormones detected after the plasmapheresis started to decrease even further. Conclusion  Plasmapheresis may be used as an alternative to antithyroid medication for the rapid control of thyroid hormones in cases of severe hyperthyroidism caused by molar pregnancy.     

Pituitary response to LHRH in midtrimester pregnancy.

The effects of lutenizing hormone releasing hormone (LHRH) on serum luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), thyroid stimulating hormone (TSH), and growth hormone (GH) were studied in 10 women in the second trimester of pregnancy. Serum LH was measured using the LHbeta-RIA, with the anti-betaLH serum being preabsorbed with purified hCG. This assay was unaffected by hCG levels up to 500 IU/ml. Basal serum levels of LH was undetectable and basal FSH levels were low in these 10 women. No release of LH or FSH was observed after administration of 100 microgram of LHRH. However, there was a statistically significant rise in PRL from mean basal levels of 139.9 ng/ml to a mean peak level of 159.0 ng/ml at 30 minutes after LHRH administration. Both TSH and GH displayed small elevations at 15 minutes after LHRH administration; however, these elevations were not significant because of the wide range in responses. The results of this study indicate that gonadotropin release is inhibited during the second trimester of pregnancy. Finally, it appears that pregnancy is a condition in which LHRH administration results in a nonspecific release of several hormones.     

妊娠晚期正常范围内血清促甲状腺激素水平升高对不良妊娠结局的影响及其相关因素分析

目的:探讨妊娠晚期正常范围内血清促甲状腺激素(TSH)升高对不良妊娠结局的影响,以及影响TSH升高的相关因素。方法:通过对2977例甲状腺功能正常孕妇进行回顾性研究,按四分位法根据血清TSH值从低到高分为4组(N1组、N2组、N3组、N4组),比较4组患者的一般情况、血压及妊娠期高血压疾病、妊娠期糖尿病、胎膜早破、早产、产后出血、巨大儿、妊娠期肝内胆汁淤积症的发生率,并分析影响TSH升高的相关因素。结果:4组孕妇年龄、孕周、体质量指数、游离甲状腺素(FT₄)、甲状腺过氧化物酶抗体(TPOAb)比较差异无统计学意义((印)P(正)>0.05)。4组孕妇收缩压、舒张压比较差异有统计学意义((印)P(正)<0.05);N1组收缩压低于N3、N4组,N2组收缩压低于N3组;N1组舒张压低于N3、N4组,N2组低于N3、N4组,差异均有统计学意义((印)P(正)<0.05)。4组妊娠期高血压疾病、妊娠期糖尿病、早产、产后出血、巨大儿的发生率差异无统计学意义((印)P(正)>0.05),4组胎膜早破、妊娠期肝内胆汁淤积症的发生率差异有统计学意义((印)...     

Hyperglycosylated hCG in gestational implantation and in choriocarcinoma and testicular germ cell malignancy tumorigenesis

OBJECTIVE: Hyperglycosylated human chorionic gonadotropin (hCG-H) is a carbohydrate variant of hCG with double-sized oligosaccharide side chains. While hCG-H is produced exclusively by stem cytotrophoblast cells in gestational choriocarcinoma, by pregnancy cytotrophoblast at implantation and by the cytotrophoblast produced in testicular malignancies, regular hCG is produced only by differentiated syncytiotrophoblast cells. STUDY DESIGN: hCG-H was measured using the Nichols Advantage hCG-H assay (Nichols Institute Diagnostics, San Clemente, California). RESULTS: hCG-H has a function separate from regular hCG. hCG-H, but not regular hCG, acts in vivo and in vitro to promote invasion, whether invasion through membranes or tumor formation. Invasion or tumorigenesis is completely blocked by administration of specific antibody to hCG-H. The same hCG-H-modulated invasion mechanisms are observed in early pregnancy, gestational choriocarcinoma and testicular cancers. CONCLUSION: hCG-H is a cytokinelike molecule, produced by cells different from those that make regular hCG and having a completely separate function. It appears to be the modulator of invasion as in implantation of pregnancy, gestational choriocarcinoma and testicular cancer malignancy.     

Serum prolactin and thyroid stimulating hormone levels following thyreotropin releasing hormone stimulation in preeclamptic patients.

Serum prolactin and thyroid stimulating hormone (TSH) levels were measured following administration of thyreotropin releasing hormone (THR) in 17 preeclamptic patients and 18 normal pregnant controls. From the 31st to the 35th pregnancy week the preeclamptic patients showed increased basal serum prolactin and TSH levels compared to controls, but later in pregnancy the differences disappeared. Following TRH stimulation, the serum prolactin and TSH responses were similar in women with and without preeclampsia. A possible role of prolactin in the development of preeclampsia is discussed.     

Ultrasound and circulating placental protein measurements in complications of early pregnancy

Maternal serum levels of human chorionic gonadotrophin (hCG), Schwangerschaftsprotein 1 (SP1) and pregnancy-associated plasma protein A (PAPP-A) were measured in an unselected group of 624 women presenting with amenorrhoea and vaginal bleeding with or without abdominal pain to an emergency gynaecological ultrasound clinic. Abdominal sector scanning was used to assess uterine contents. Pregnancy was confirmed by ultrasound in 406 pregnancies. Histological confirmation was obtained in each case of pregnancy failure. A live fetus was demonstrated in 259 women of whom six subsequently miscarried; one of these had markedly depressed serum hCG and PAPP-A, but normal SP1 levels, and two had oligohydramnios. Of the 147 women without ultrasound evidence of fetal heart action 67 had a correct ultrasound diagnosis of anembryonic pregnancy. The predictive value of a depressed serum hCG level was 70% in this group, and 31% in samples taken at less than or equal to 7 weeks. The predictive value of a normal hCG level was 96%. In 34 women missed miscarriage was diagnosed readily by ultrasound; all but five had depressed hCG and PAPP-A levels. A clinical diagnosis of a complete or incomplete miscarriage was made in 45 women and easily confirmed by ultrasound. All of them had depressed hCG, SP1 and PAPP-A levels. These results indicate that the diagnostic value of ultrasound in threatened miscarriage is often better than that of biochemical tests.     

Racial comparisons of thyroid function and autoimmunity during pregnancy and the postpartum period

OBJECTIVE: To evaluate thyroid function and the prevalence of thyroid peroxidase (TPO) antibody and autoimmunity in African-American and white women during pregnancy and the postpartum period. METHODS: Five hundred eighty-nine women were evaluated prospectively. Serum thyroid-stimulating hormone (TSH), free thyroxine (T4), and TPO, Ro, and La antibodies were obtained during pregnancy, at delivery, and postpartum. Levels of hCG were determined during pregnancy. Urinary iodine levels were evaluated in the third trimester in another group of women. All TPO antibody-positive patients were to be followed up at 3 and 6 months postpartum. RESULTS: African-American women had lower TSH values than white women at all times. Thyroid-stimulating hormone increased, and free T4 decreased from the first to third trimester of pregnancy for both groups. African Americans had higher hCG levels than whites in the first trimester but not in the third trimester. There was no difference in urine iodine excretion between African-American and white women. Finally, there was no difference in TPO antibody seropositivity between African-American and white women. Overall, 5 patients (0.8%) were diagnosed with subclinical hypothyroidism during pregnancy. CONCLUSION: Fluctuations in TSH and free T4 during pregnancy parallel reported obstetric values. African Americans demonstrated consistently lower TSH levels than whites. These differences were unexplained by racial differences in either TPO antibody seropositivity, iodine status, or chorionic gonadotropin levels.     

Serum levels of interleukin-6, interleukin-1beta and human chorionic gonadotropin in pre-eclamptic and normal pregnancy.

Studies in placentas from the first trimester and in vitro models indicate that interleukin (IL)-1beta and IL-6 induce the release of human chorionic gonadotropin (hCG). During pre-eclampsia there is an increase of pro-inflammatory cytokines; however, its relationship with hCG levels during the third trimester of pregnancy has not been determined. The aim of the present study was to evaluate the relationship between blood levels of IL-6, IL-1beta and hCG in normal pregnancy and pre-eclampsia. Blood samples during the third trimester of pregnancy from women with severe pre-eclampsia (n = 20) or normal pregnancy (n = 20) were assayed for hCG by immunoassay, IL-6 and IL-1beta by enzyme-linked immunosorbent assay. Serum level of IL-6 was significantly higher in pre-eclamptic than in normal women (16.5 +/- 2.1 vs. 4.9 +/- 1.1 pg/ml); however, IL-1beta was similar in both groups. Although hCG was higher in pre-eclampsia than normal pregnancy, the difference was not statistically significant. Furthermore, IL-1beta in normal pregnancy was correlated negatively with hCG (r = -0.69, p < 0.001). In conclusion, serum levels of IL-6 were increased in pre-eclampsia but were not correlated with hCG or IL-1beta; however, in normal pregnancy there was a negative correlation between IL-1beta and hCG. The interaction between IL-1beta and hCG at the third trimester needs to be investigated.     

Human chorionic gonadotropin follow-up in patients with molar pregnancy: a time for reevaluation

OBJECTIVE: To determine how often patients with molar pregnancy do not complete recommended follow-up and to identify factors that may predict failure to complete human chorionic gonadotropin (hCG) monitoring. This study also sought to determine how often patients with molar pregnancy who do not complete follow-up relapse after attaining at least one undetectable hCG value. METHODS: Four hundred randomly selected patients with molar pregnancy were analyzed regarding the serum hCG levels after molar evacuation. Demographic factors were determined for each patient: age, marital status, gravidity, parity, health insurance type, and distance from patient residence to trophoblastic center. RESULTS: Recommended hCG follow-up was completed in 63% of the uncomplicated 333 cases (n = 211). Three hundred twenty patients achieved at least one undetectable serum hCG level. Among the 320 patients, 33% achieved undetectable hCG values but did not complete recommended follow-up. However, none had any evidence of relapse. A distance of greater than 20 miles from the patient's residence to our center was associated with failure to complete hCG follow-up (P =.001). CONCLUSION: Because none of the 320 patients who achieved at least one undetectable hCG level has been diagnosed with gestational trophoblastic tumor relapse, it may be appropriate to reassess the duration of hCG monitoring for patients with molar pregnancy.     

A study to establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy

Objective

To establish gestation-specific reference intervals for thyroid function tests in normal singleton pregnancy.

Study design

Cross-sectional observational study performed in the Obstetric and Gynaecology department, West Middlesex University Hospital. A single blood sample from 335 pregnant women at various gestations of pregnancy was analysed for thyroid function. FT4, fT3, TSH values at each gestation of pregnancy were calculated.

Results

From the fT3, fT4 and TSH results, a 95% reference interval was calculated for each hormone for each week of pregnancy.

Conclusion

We calculated gestation-specific reference intervals for thyroid function tests throughout pregnancy to facilitate clinical management of thyroid disease in pregnancy.     

Interpretation of in-vitro thyroid function tests during pregnancy

In-vitro thyroid function tests are difficult to interpret in pregnancy because of, among other things, the effect of oestrogens on thyroid binding globulin (TBG) concentrations. In an attempt to clarify the position, serum concentrations of total thyroxine (T4), free T4, TBG, T4/TBG ratio, tri-iodothyronine (T3) and thyroid stimulating hormone (TSH) were measured. Total T4 and TBG concentrations rose to above the non-pregnant reference range by 20 weeks. The T4/TBG ratio fell to hypo-thyroid values by 20 weeks but although the free T4 level was lower in the third trimester compared with values in the first and second trimesters, only a few subjects had hypothyroid values. The TSH values remained unchanged throughout pregnancy. The significance of these changes is discussed and reference ranges for these hormones at each trimester are provided.     

Serum total and free thyroxine and thyrotropin in normal and pregnant women, neonates, and women receiving progestogens

Total serum thyroxine levels are significantly increased throughout pregnancy, returning to normal by 6 weeks post partum. Conversely, percentage-free serum thyroxine is decreased throughout pregnancy (normal at 6 weeks post partum). Thus, the absolute concentration of free thyroxine, the most important component from the physiologic standpoint, remains normal during pregnancy. Thyroid-stimulating hormone (TSH) increases significantly during the first and second trimesters of pregnancy but returns to normal levels at term. In cord serum of neonates, absolute free thyroxine level is greater than that in pregnant women at term; TSH values are greater than those in women at term and in euthyroid nonpregnant women. The use of progestogens for four or more menstrual cycles results in total, percentage-free, and absolute free thyroxine levels comparable to those found in women during pregnancy. The serum levels of TSH are normal.