Prevalence and Pathogenesis of Macro-Thyrotropin in Neonates: Analysis of Umbilical Cord Blood from 939 Neonates and Their Mothers.

Background: Macro-thyrotropin (macro-TSH) is a large molecular weight TSH that causes elevated serum TSH concentrations due to its slow clearance. It is primarily a complex of TSH and anti-TSH autoantibodies. The aims of this study were to examine the prevalence and nature of macro-TSH in neonates and to determine how to cope with macro-TSH in neonates suspected to have congenital hypothyroidism through neonatal mass screening. Methods: The presence of macro-TSH was examined using polyethylene glycol (PEG), gel filtration chromatography (GFC), and 125I-TSH binding studies in 939 umbilical cord blood samples from neonates and their mothers. Results: Among 138 serum samples with a PEG precipitation ratio of TSH >68.9% (mean + standard deviation), human anti-mouse antibodies were found in nine samples. The presence of macro-TSH was examined in the remaining 129 serum samples using a 125I-TSH binding study and GFC. The 125I-TSH binding study revealed that four babies (0.43%) had significantly high ratios of 125I-TSH binding to their sera. Two of the babies were siblings, and their mother and the other two mothers also showed significantly high binding ratios. The 125I-TSH binding was displaced by a large amount (1 µg) of unlabeled human TSH in a similar way between babies and their mothers in all cases, suggesting the presence of anti-TSH autoantibodies in their sera. Further characterization of the autoantibodies in one baby and its mother showed a low affinity and high specificity to human TSH, and the nature was very similar between them. These findings may indicate that the anti-TSH autoantibodies that developed in the mother were transferred to the baby through the placenta and formed macro-TSH by binding to neonatal TSH. GFC revealed macro-TSH in only one baby and its mother, probably because of the dissociation of TSH from autoantibodies during the analytical procedure. Conclusions: Macro-TSH was found in 0.43% of neonates, and their mothers all had macro-TSH as well. We recommend that if a baby's serum TSH concentration is high enough to consider levothyroxine treatment suspecting congenital hypothyroidism but the free thyroxine level is normal, their mother's macro-TSH should be checked.

Neonatal oral fluid as a transmission route for bifidobacteria to the infant gut immediately after birth.

Bifidobacteria are one of the most abundant bacterial groups in the infant gut microbiota and are closely associated with infant health and can potentially affect health in later life. However, the details regarding the source of bifidobacteria have yet to be completely elucidated. This study aimed to assess neonatal oral fluid (OF) as a transmission route for bifidobacteria to the infant gut during delivery. Neonatal OF and infant feces (IF) were collected immediately and one month after birth from 15 healthy vaginally delivered newborns. Bifidobacterium strains were isolated from OF and IF samples, and the similarity of strains between the OF-IF pairs was evaluated based on the average nucleotide identity (ANI) value. The 16S rRNA gene sequencing results revealed the presence of Bifidobacteriaceae at >1% relative abundance in all OF samples. Bifidobacterium strains were isolated from OF (9/15) and IF (11/15) samples, and those sharing high genomic homology (ANI values >99.5%) between the neonatal OF and IF samples were present in one-third of the OF-IF pairs. The results of this study indicate that viable bifidobacteria are present in neonatal OF and that OF at birth is a possible transmission route of bifidobacteria to the infant gut.

Effectiveness on high-grade cervical abnormalities and long-term safety of the quadrivalent human papillomavirus vaccine in Japanese women.

This study for the first time assessed quadrivalent human papillomavirus (qHPV) vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease in Japanese women (16-26 years old), as previously demonstrated in overseas trials, and vaccine safety in a longer term (48-month) open-label study (NCT01544478). Participants received three doses of qHPV vaccine (Day 1, Month 2, Month 6). Effectiveness endpoints, assessed in the per-protocol population, included incidence of HPV6/11/16/18-related cervical intraepithelial neoplasia (CIN) Grade 2 or worse (CIN Grade 2 and 3, adenocarcinoma in situ, and/or cervical cancer) as primary endpoint and incidence of external genital lesions (EGLs). Disease related to other high-risk HPV types was also assessed. Adverse events (AEs) and serious AEs (SAEs) were collected from Days 1-15 after any vaccination; vaccine-related SAEs, deaths, and new medical conditions were collected throughout the study. A total of 1030 women received at least one vaccination. No cases of CIN2 or worse or EGLs were reported in the per-protocol population. Injection site-related AEs were reported in 14.5% of participants; most were mild and resolved within 15 days. Vaccine-related systemic AEs occurred in 8.6% of participants, most commonly headache (2.3%), malaise (1.7%), and pyrexia (1.3%). There were no vaccine-related SAEs; one participant discontinued due to a vaccine-related AE of mild uticaria. Overall, qHPV vaccine effectiveness against HPV6/11/16/18-related high-grade cervical disease and EGLs was indicated in Japanese women. The vaccine was well-tolerated, without new safety signals throughout the 48-month study period. Findings are consistent with overseas qHPV vaccine pivotal trials. CLINICAL TRIAL REGISTRY: clinicaltrials.gov; NCT01544478.

Current Thyrotropin Immunoassays Recognize Macro-Thyrotropin Leading to Hyperthyrotropinemia in Females of Reproductive Age.

BACKGROUND: Macro-thyrotropin (macro-TSH) is a high molecular weight form of TSH that leads to hyperthyrotropinemia. This study was undertaken to examine the prevalence and nature of macro-TSH in females of reproductive age. METHODS: Blood samples were taken from 1794 female patients who visited the Hamada Obstetrics and Gynecology Hospital in Tokyo, Japan, complaining of infertility. The serum of 305 patients with TSH concentrations >2.5 mIU/L was screened for macro-TSH by the polyethylene glycol method. Samples with TSH precipitation ratios by polyethylene glycol >70% were further analyzed using gel filtration chromatography (GFC), protein G columns, and 125I-TSH binding experiments. RESULTS: Screening of the 305 patients revealed that 63 had serum TSH precipitation ratios >70%. GFC revealed that immunoreactive TSH, with a molecular weight of approximately 150 kDa, eluted at higher ratios (79.6 ± 24.4%) in 27 of the 63 patients compared to 0.4 ± 2.0% in the control group. Serum TSH concentrations in 24 of the 27 patients were spuriously elevated due to human anti-mouse antibodies. Macro-TSH was found in the other three patients, and one of them had detectable anti-TSH autoantibodies. Eight of the remaining 36 patients who did not have high-molecular-weight TSH assessed by GFC had immunoglobulin G-associated TSH. Three commercially available TSH immunoassays (Elecsys®, Centaur®, and Architect®) all recognized macro-TSH leading to the elevated serum TSH concentrations. CONCLUSIONS: Macro-TSH was present in 0.17% of infertile women. Commercial TSH immunoassays recognized macro-TSH, resulting in the diagnosis of hyperthyrotropinemia.

Impact of macroprolactin on galactorrhea and the rate of patients possibly affected by macroprolactin.

The clinical influence of macroprolactin (MPRL) is not clearly understood and the rate of patients potentially affected by MPRL is unknown. We investigated the influence of MPRL on the onset of galactorrhea and estimated the rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea. Data of patients with obstetric or gynecological symptoms who had undergone PRL fractionation testing were retrospectively analyzed. To evaluate factors influencing galactorrhea, a multivariate logistic regression analysis was performed and the adjusted odds ratios of MPRL for galactorrhea were calculated. Cutoff values for the total PRL level and the proportion of MPRL fractions for galactorrhea were determined by ROC analysis using a multivariate logistic model. The prevalence of patients with a proportion of MPRL fraction greater than or equal to the cutoff value for galactorrhea was estimated. The median proportion of MPRL fraction was 30.1% and increased as PRL level increased. Total PRL and MPRL had a significant influence on the onset of galactorrhea and the adjusted odds ratio was 1.09 in total PRL and 0.94 in MPRL. The rate of patients with a proportion of MPRL fraction that may possibly affect galactorrhea was estimated to be 33.5% of the study population, and thus found to be twelve times or more the number of macroprolactinemia patients. Future prospects for hyperprolactinemia may require diagnostic criteria using free prolactin levels and so MPRL fraction measurement is important for the diagnosis and treatment of patients with obstetric and gynecological symptoms.

Phase III trial comparing the efficacy and safety of recombinant- or urine-derived human chorionic gonadotropin for ovulation triggering in Japanese women diagnosed with anovulation or oligo-ovulation and undergoing ovulation induction with follitropin-alfa.

Aim: Outside of Japan, recombinant-human chorionic gonadotropin (r-hCG) is widely used for the induction of final follicular maturation and early luteinization in women undergoing ovulation induction; whereas in Japan, urine-derived hCG (u-hCG) is predominantly used. The primary objective of this study was to demonstrate the non-inferiority of r-hCG to u-hCG for ovulation induction, as assessed by the ovulation rate. Methods: This was an open-label, parallel-group, randomized, multicenter, phase III trial in Japanese women with anovulation or oligo-ovulation secondary to hypothalamic-pituitary dysfunction or polycystic ovary syndrome, undergoing ovulation induction with recombinant-human follicle-stimulating hormone. The women were randomized (2:1) to receive either a single 250 µg s.c. dose of r-hCG or a single 5000 IU i.m. dose of u-hCG for ovulation triggering. Results: Eighty-one women were randomized to either r-hCG (n=54) or u-hCG (n=27). Ovulation occurred in 100% of the participants and treatment with r-hCG was observed to be non-inferior to u-hCG for ovulation induction. Overall, the type and severity of adverse events were as expected for women receiving fertility treatment. Conclusion: This study demonstrated that r-hCG was non-inferior to u-hCG for inducing ovulation. Furthermore, r-hCG demonstrated an expected safety profile, with no new safety concerns identified.

A possible cause of the variable detectability of macroprolactin by different immunoassay systems.

BACKGROUND: Macroprolactinaemia is a major cause of hyperprolactinaemia. The detectability of macroprolactin varies widely among different immunoassay systems, but the causes are not fully known. This study aimed to identify the factors influencing the detectability of macroprolactin by immunoassay systems. METHODS: The study included 1544 patients who visited an obstetric and gynaecological hospital. Macroprolactinaemia was screened using the polyethylene glycol (PEG) method and confirmed using gel filtration chromatography and the protein G method. The prolactin (PRL) values determined by enzyme immunoassay (EIA) were compared with those of a chemiluminescence immunoassay system (Centaur) that is known to cross-react the least with macroprolactin. RESULTS: Macroprolactinaemia was found in 62 of 1544 patients (4.02%) who visited an obstetric and gynaecological hospital. The ratio of EIA-determined total PRL to free PRL in the supernatant after PEG precipitation was significantly elevated in all 62 serum samples with macroprolactin compared to those in 1482 serum samples without macroprolactin. In contrast, the ratio of Centaur-determined total PRL to free PRL was significantly elevated in 32 serum samples (group 1) and was within the normal range in 30 (group 2) of 62 serum samples with macroprolactin. The prevalence of non-IgG-type macroprolactin was significantly higher in group 1 than in group 2. Centaur diagnosed hyperprolactinaemia less frequently than EIA (n=2 vs. 16) in 62 patients with macroprolactinaemia. Those two hyperprolactinaemic patients diagnosed by Centaur had non-IgG-type macroprolactin. CONCLUSIONS: Macroprolactinaemia was present in 4% of patients visiting an obstetric and gynaecological hospital. The nature of macroprolactin (IgG-type or non-IgG-type) may partly explain why macroprolactin detectability varies among different immunoassay systems.

Introduction of a new index of cervical consistency with transvaginal B-mode ultrasonography.

Changes in the length and consistency of the uterine cervix during pregnancy are known to precede pre-term labor. However, cervical consistency has not been studied in depth because its objective evaluation requires special equipment. Our aim was to define a new index to evaluate cervical consistency simply and easily using B-mode ultrasonography. The cervical length-consistency index (CLCI) is defined as the ratio of the length of the cervix stretched during compression to that before compression. CLCI increases as pregnancy progresses. The CLCI values that corresponded to digital examination results of firm, medium and soft were 112.0 ± 10.0, 124.1 ± 22.4 and 153.2 ± 35.7, respectively, thus confirming the existence of a significant relationship between the index and consistency. The CLCI may be useful in predicting pre-term labor and should therefore be investigated further in larger cohorts.

[Effectiveness of bisphosphonate administration during Gn-RH agonist therapy for endometriosis].

Gn-RH agonist therapy is widely used for treatment of endometriosis. However, it is well known that there are some side effects due to too much suppress of plasma sex steroid hormone levels. The decrease of the BMD (bone mineral density) is a serious side effect, and the BMD values are decreasing significantly even in the short period during Gn-RH agonist therapy. In this review, the author shows the effect of bisphosphonate administration on the prevention of the bone loss during Gn-RH agonist therapy for the endometriosis. By the administration of EP (estrogen-progestogen) preparations, the decreasing of the BMD can prevent (so called add-back therapy), however, there are some patients who could not be administrated these drugs because of their previous diseases. Bisphosphonate administration is much effective for the prevention of the bone loss compared with EP preparations. From these results, it is concluded that bisphosphonate administration has a beneficial effect for the prevention of the bone loss during Gn-RH agonist treatment.

Pelvic actinomycosis presenting with a large abscess and bowel stenosis with marked response to conservative treatment: a case report.

Pelvic actinomycosis is a rare disease that can result in abscess formation, bowel obstruction, and other serious complications. Moreover, the correct diagnosis can seldom be established before radical surgery because the disease often mimics pelvic neoplasms. It has been recently recognized that pelvic actinomycosis is associated with long-term use of an intrauterine contraceptive device.We report a woman with a long-standing intrauterine contraceptive device who visited our hospital complaining of symptoms mimicking large bowel ileus with a subacute course. X-ray fluorography and sigmoidoscopy showed marked stenosis in the sigmoid colon but rejected the possibility of colon cancers. Abdomino-pelvic CT and MRI revealed a huge abscess lying over the urinary bladder and anterior to the uterus. Furthermore, a cervical Papanicolaou smear disclosed Actinomyces species. We removed the intrauterine device from the patient. Subsequent high-dose ampicillin administration led to dramatic shrinkage of the abscess and improved the management of the bowel movement quickly. This is a successful case of symptomatic pelvic actinomycosis that was correctly diagnosed and treated without unnecessary surgical intervention.