Shaun McGrath

Patterns of Plasma Corticotropin-Releasing Hormone, Progesterone, Estradiol, and Estriol Change and the Onset of Human Labor

CONTEXT Clinical prediction of preterm delivery is largely ineffective, and the mechanism mediating progesterone (P) withdrawal and estrogen activation at the onset of human labor is unclear. OBJECTIVES Our objectives were to determine associations of rates of change of circulating maternal CRH in midpregnancy with preterm delivery, CRH with estriol (E3) concentrations in late pregnancy, and predelivery changes in the ratios of E3, estradiol (E2), and P. DESIGN AND SETTING A cohort of 500 pregnant women was followed from first antenatal visits to delivery during the period 2000-2004 at John Hunter Hospital, New South Wales, Australia, a tertiary care obstetric hospital. PATIENTS Unselected subjects were recruited (including women with multiple gestations) and serial blood samples obtained. MAIN OUTCOME MEASURES CRH daily percentage change in term and preterm singletons at 26 wk, ratios E3/E2, P/E3, and P/E2 and the association between E3 and CRH concentrations in the last month of pregnancy (with spontaneous labor onset) were assessed. RESULTS CRH percentage daily change was significantly higher in preterm than term singletons at 26 wk (medians 3.09 and 2.73; P = 0.003). In late pregnancy, CRH and E3 concentrations were significantly positively associated (P = 0.003). E3/E2 increased, P/E3 decreased, and P/E2 was unchanged in the month before delivery (medians: E3/E2, 7.04 and 10.59, P < 0.001; P/E3, 1.55 and 0.98, P < 0.001; P/E2, 11.78 and 10.79, P = 0.07). CONCLUSIONS The very rapid rise of CRH in late pregnancy is associated with an E3 surge and critically altered P/E3 and E3/E2 ratios that create an estrogenic environment at the onset of labor. Our evidence provides a rationale for the use of CRH in predicting preterm birth and informs approaches to delaying labor using P supplementation.

Hormone trajectories leading to human birth.

The mechanisms regulating human parturition and labor remain unknown. This ignorance is expensive as preterm birth is responsible for 70% of neonatal mortality and 50% of cerebral palsy. Methods for the prediction of preterm birth and treatments for women in preterm labor have poor efficacy reflecting our limited knowledge of the mechanisms involved. Recent research has supported the view that parturition is a cascade of events that commences early in pregnancy and involves the mother, fetus, placenta, membranes, cervix and myometrium. Although a number of the key hormones and proteins involved have been identified, the relationships between these factors in time and tissues remain unclear. Placental production of Corticotropin-releasing hormone (CRH) is proposed as an early event regulating the cascade of events. Central to the onset of parturition will be a mechanism for progesterone withdrawal and estrogen activation in human. Two forms of progesterone receptor with opposing actions exist in the human myometrium. Progesterone receptor A (PR-A) is a dominant negative repressor of progesterone receptor B (PR-B). Preliminary studies strongly support the hypothesis that the onset of human parturition is initiated by rising concentrations of PR-A in the myometrium.

Clinical and biochemical improvement in acromegaly during pregnancy.

Numerous case reports of pregnancy in acromegaly exist, however detailed descriptions of changes in placental and pituitary GH and IGF-I throughout gestation are rare. A 19-yr-old female presented to this institution with signs and symptoms of a GH-secreting pituitary adenoma. Following transphenoidal hypophysectomy, she had 3 unplanned pregnancies, despite ongoing active disease. No pregnancy was complicated by glucose intolerance or hypertension and 3 healthy newborns were delivered near or at term. Clinical improvement was observed during each pregnancy, accompanied by IGF-I levels lower than in the non-pregnant state, the majority lying within the normal range. This was despite increasing placental GH levels, and was not consistent with previous reports in the literature. Further surgical and medical therapies for acromegaly failed to normalize non-pregnant GH or IGF-I levels in this woman. Estrogen is known to alter GH signaling via its interaction with Janus kinase/signal transducers and activators of transcription (JAK-STAT) pathways. We hypothesize that increasing concentrations of estrogen or other pregnancy-related hormones resulted in her clinical and biochemical improvement during pregnancy. This may be used for future therapeutic benefit.

Human Uterine Wall Tension Trajectories and the Onset of Parturition

Uterine wall tension is thought to be an important determinant of the onset of labor in pregnant women. We characterize human uterine wall tension using ultrasound from the second trimester of pregnancy until parturition and compare preterm, term and twin pregnancies. A total of 320 pregnant women were followed from first antenatal visit to delivery during the period 2000–2004 at the John Hunter Hospital, NSW, Australia. The uterine wall thickness, length, anterior-posterior diameter and transverse diameter were determined by serial ultrasounds. Subjects were divided into three groups: women with singleton pregnancies and spontaneous labor onset, either preterm or term and women with twin pregnancies. Intrauterine pressure results from the literature were combined with our data to form trajectories for uterine wall thickness, volume and tension for each woman using the prolate ellipsoid method and the groups were compared at 20, 25 and 30 weeks gestation. Uterine wall tension followed an exponential curve, with results increasing throughout pregnancy with the site of maximum tension on the anterior wall. For those delivering preterm, uterine wall thickness was increased compared with term. For twin pregnancies intrauterine volume was increased compared to singletons (), but wall thickness was not. There was no evidence for increased tension in those delivering preterm or those with twin gestations. These data are not consistent with a role for high uterine wall tension as a causal factor in preterm spontaneous labor in singleton or twin gestations. It seems likely that hormonal differences in multiple gestations are responsible for increased rates of preterm birth in this group rather than increased tension.

Prediction of preterm delivery using plasma corticotrophin-releasing hormone and other biochemical variables.

Preterm delivery is responsible for the vast majority of neonatal mortality in developed countries and is also associated with substantial long-term morbidity. The incidence of preterm birth remains between 6-10% despite many advances in our understanding of the physiology of human parturition. Biochemical markers have been used in an attempt to identify more accurately those women, amongst high and low-risk groups who will deliver preterm, from their counterparts who will go on to deliver at term. Only by accurately identifying those women early, who will eventually deliver preterm, will specific interventions be able to be used in order to try and treat the cause or delay delivery until a safer time for the fetus. The clinical utility of these markers when used alone in an unselected population remains limited. As our understanding of the pathophysiology of preterm delivery improves, the challenge lies for researchers to combine these markers in the most effective way to unravel the complex biological system of parturition and improve the predictive capability of a biochemical test for prematurity.

Corticotrophin-releasing hormone and parturition.

Substantial data now indicate that placental production of corticotrophin-releasing hormone is linked to the duration of human pregnancy and probably plays a key role in the onset of parturition. Corticotrophin-releasing hormone (CRH) was first identified by Wiley Vale and coworkers in the hypothalamus. Soon after the peptide hormone was found also in the human placenta and in large concentrations in the blood of pregnant women. Initial studies indicated that concentrations of placentally derived maternal plasma corticotrophinreleasing hormone increased as gestation advanced. Several groups then reported that concentrations were higher in the blood of women presenting in premature labour. A large prospective study by McLean et al. (1995) reported that maternal plasma concentrations of corticotrophin-releasing hormone at 16±20 weeks of gestation were predictive of final length of gestation. Women who would deliver prematurely had an exponential rise in corticotrophin-releasing hormone which was more rapid than that of subjects who would later deliver at term, who in turn had a more rapid rate of rise than subjects who would delivery post-term (see Fig. 1). These data suggested that the duration of gestation in the human is predetermined by events early in pregnancy in many subjects. Essentially it identified that a type of biological clock existed which governed the length of human pregnancy. This controversial finding has largely been confirmed by subsequent publications (Wadhwa et al., 1998; Hobel et al., 1999; Leung et al., 1999; Prickett et al., 2000). One contradictory study published not long after McLeans original work (Berkowitz et al., 1996) lacked power to detect a difference between the groups early in pregnancy due to the lack of sensitivity in the assay method. Unfortunately, from a clinical viewpoint the positive predictive value of an individual maternal plasma corticotrophinreleasing hormone estimation for preterm labour is low (Leung et al., 1999; McLean et al., 1999; Prickett et al., 2000). Typical values reported in the literature range from 3 ́6% to 45%. Several papers have reported that subjects entering preterm labour related to intrauterine infections did not have elevated concentrations of corticotrophin-releasing hormone, and this may be at least one reason for the relatively poor predictive value of the test. Several cohorts where multiple risk factors for preterm labour have been reported indicate that combinations of analytes may improve the positive predictive value. In addition, recent studies suggest that the rate of rise of corticotrophin-releasing hormone may be a more powerful predictor than the absolute level. Placental production of corticotrophin-releasing hormone is under different control mechanisms to hypothalamic production. In particular, while glucocorticoids inhibit hypothalamic production of CRH, they stimulate placental production. This stimulatory effect occurs via the cyclic AMP response element in the CRH promoter (Cheng et al., 2000). The exponential rise observed in corticotrophin-releasing hormone during pregnancy may well be driven by a positive feed forward circuit involving glucocorticoid production (Karalis et al., 1996). Although the placental production of CRH has been linked to the length of gestation, the mechanisms by which it could exert biological actions remain uncertain. Several potential sites of action have been identified through the localization of CRH receptors in different tissues. CRH receptors are present in the human myometrium and several different isoforms and receptor subtypes have been identified by Hillhouse and his group in Warwick (Grammatopoulos & Hillhouse, 1999). In the myometrium it seems likely that CRH would exert a relaxational effect through the stimulation of cyclic AMP production for the majority of gestation. Potentially, changes in Gs proteins at the end of gestation and alterations in CRH receptor subtypes might lead to the onset of a CRH-mediated parturition. CRH receptors have also been demonstrated in the membranes and Jones & Challis (1990) have reported the ability of CRH to stimulate prostaglandin release from these membranes. Prostaglandins play a key role in the final pathways of human parturition causing both myometrial contractions and participating in the cascade which leads to softening of the cervix. Although placental CRH is predominantly released into the maternal circulation release also occurs into the fetus. Within the fetus several potential sites of action have been identified, notably the fetal pituitary where CRH might stimulate ACTH and drive increased production of cortisol and DHEA-S, which might participate in the onset of parturition. CRH receptors have also been identified in the fetal adrenal where CRH stimulation in vitro has been shown to increase production of DHEA-S (Smith et al., 1998), the obligate precursor to oestriol during human pregnancy. It therefore remains unclear how, or if, CRH from the human

Targeting the TSH receptor in thyroid cancer

Recent advances in the arena of theranostics have necessitated a re-examining of previously established fields. The existing paradigm of therapeutic thyroid-stimulating hormone receptor (TSHR) targeting in the post-surgical management of differentiated thyroid cancer using levothyroxine and recombinant human thyroid-stimulating hormone (TSH) is well understood. However, in an era of personalized medicine, and with an increasing awareness of the risk profile of longstanding pharmacological hyperthyroidism, it is imperative clinicians understand the molecular basis and magnitude of benefit for individual patients. Furthermore, TSHR has been recently re-conceived as a selective target for residual metastatic thyroid cancer, with pilot data demonstrating effective targeting of nanoparticles to thyroid cancers using this receptor as a target. This review examines the evidence for TSHR signaling as an oncogenic pathway and assesses the evidence for ongoing TSHR expression in thyroid cancer metastases. Priorities for further research are highlighted.

Pursuing the second ipsilateral gland during minimally invasive video‐assisted parathyroidectomy

In patients with primary hyperparathyroidism (PHPT) and preoperative imaging suggesting a solitary parathyroid adenoma (SPA), focused parathyroidectomy is most often curative. Even so, large studies show up to 3% of patients experience persistent or recurrent PHPT. Unilateral neck exploration (UNE) aiming to identify the SPA and the other ipsilateral parathyroid may reduce this failure rate. We hypothesized that: (i) minimally invasive video‐assisted (MIVA) approach would facilitate UNE and (ii) this would be a clinically relevant strategy.

Prolactin correction for adequacy of petrosal sinus cannulation may diminish diagnostic accuracy in Cushing's disease

Petrosal venous prolactin concentrations have been promoted to improve the diagnostic accuracy of inferior petrosal sinus sampling (IPSS), beyond that achieved with ACTH measurement alone, in diagnosing a pituitary ACTH source and determining corticotrophinoma side (L/R). Our objective was to assess the effect of using prolactin to confirm adequacy of petrosal cannulation in a cohort of patients with ACTH‐dependent Cushings syndrome.

Charting a course through the CEAs: diagnosis and management of medullary thyroid cancer

Medullary thyroid cancer (MTC) is an uncommon thyroid cancer that requires a high index of suspicion to facilitate diagnosis of early‐stage disease amenable to surgical cure. The challenges of diagnosis, as well as management in the setting of persistent disease, are explored in the context of a case presenting with the incidental finding of elevated carcinoembryonic antigen (CEA) and an 18F‐fluorodeoxyglucose positron emission tomography (18F‐FDG‐PET)‐positive thyroid incidentaloma detected following treatment of colorectal cancer. Strategies to individualize prognosis, and emerging PET‐based imaging modalities, particularly the potential role of 18F‐DOPA‐PET in staging, are reviewed.