GDI is a rare complication during pregnancy with an estimated prevalence of 1 in 30,000 pregnancies [2, 3]. This form of DI is slightly more common in women with multiple gestations, subclinical or masked central DI, or liver dysfunction because of the impairment of the degradation of vasopressinase. It usually becomes symptomatic at the end of the 2nd or 3rd trimester of pregnancy and remits spontaneously days to a few weeks after delivery . The fact that this case clinically resolved soon after delivery is supported by the results showing immediate disappearance of vasopressinase in serum examined by western blot analysis. In most GDI cases, polyuria is resolved days to weeks after delivery . Although the reason for immediate clearance of serum vasopressinase is not elucidated, degradation of vasopressinase in the liver might be augmented in this case.
Because central DI or nephrogenic DI can also be observed during pregnancy, precise differential diagnosis and prompt treatment is important. Serum AVP level showed within the normal range, indicating that central DI could be ruled out. Although water deprivation test was clinically risky in this case, MRI imaging during pregnancy can be safely performed, and may provide us further confirmation that this was not a case of central DI. Even though clinical diagnosis of GDI was not confirmed at that time, use of DDAVP as diagnostic treatment was implemented to control her urine as well as to rule out nephrogenic DI. Final diagnosis of GDI was determined by DDAVP responsiveness and immediate resolution of polyuria after delivery. From the clinical point of view, hypotonic (191–293 < 300 mOsm/L) polyuria (3000–6000 mL) was confirmed, but serum osmolality remained low around 260–268 mOsm/L, with plasma sodium levels around 137–140 mEq/L, both of which are inconsistent with DI. As shown in Fig. 1a, her fluid intake almost always exceeded the amount of urine; thus she may not have developed dehydration and hemoconcentration.
The mechanism of GDI development is considered to comprise an increase in the amount of placental vasopressinase, which degrades AVP in circulation, which finally results in impairment of urine concentrating ability. Vasopressinase is expressed mainly in the placental syncytiotrophoblast during pregnancy and the amount is correlated with the volume of the placenta. Indeed, the placental weight was slightly higher (425 g: approximately 90th percentile at 32 w of gestation ) whereas the placental/birth weight ratio was normal in this case. Expression of vasopressinase is regulated by transcription factors such as activator protein-2 (AP-2), selective promoter factor 1 and nuclear factor-1. These relevant cis-acting elements are located in the 5′-region in the vasopressinase genomic sequence. Among these, AP-2 may be the most important transcription factor regulating vasopressinase gene expression in human placenta . Although the gene regulation of vasopressinase is not elucidated in this case, the overexpression of vasopressinase in placenta could be associated with GDI.
Vasopressinase is also known as oxytocinase, placental leucine aminopeptidase, leucyl/cystinyl aminopeptidase or insulin-regulated aminopeptidase (IRAP), and works as a zinc-dependent aminopeptidase that cleaves vasopressin as well as oxytocin, bradykinin, enkephalin, dynorphin A or other small peptide hormones. Interestingly, vasopressinase (IRAP) is localized in GLUT4 that contains GSV of insulin-sensitive tissues such as muscle and fat . GLUT4 is also reportedly expressed in the placental syncytiotrophoblast in the early stage of gestation and may mediate glucose uptake for rapid growth of the placental tissues . However, it is not known whether GLUT4 is co-expressed with vasopressinase (IRAP) in the syncytiotrophoblast in patients with GDI in the later stage of gestation. We first demonstrated the co-expression of vasopressinase (IRAP) with GLUT4 by immunohistochemical staining in the placental syncytiotrophoblast in this case. Surprisingly, both vasopressinase (IRAP) and GLUT4 are almost exclusively expressed in the membrane compartment and may play a role in enhancing the growth of the placenta.
The amount of GLUT4 is up-regulated in GDI placenta (mainly in membrane fraction) compared with that in normal control subject, indicating that vasopressinase (IRAP) may control GLUT4 not only in GSV membrane translocation but also in protein abundance. Indeed, GLUT4 levels are diminished by 40–85% in global IRAP knockout mice , exhibiting normal reproduction and maternal behavior [10, 11]. Amino terminus of IRAP overexpression causes GLUT4 membrane translocation . Our observation suggests that, in the pathophysiological situation of GDI, vasopressinase (IRAP) regulates the amount and subcellular localization of GLUT4 in the later stage of gestational placenta. This hypothesis has to be evaluated and confirmed using more GDI cases with pathophysiological examinations.
We hypothesize that the Kumamoto earthquakes may have played a part in triggering this patient’s premature contractions. Indeed, earthquake exposure has been shown to result in a significant decline in gestational age and increase in preterm delivery . As stress-induced oxytocin has uterus-contracting properties , oxytocinase can be produced from the placenta to prevent premature labor. Because oxytocinase is identical to vasopressinase, circulating vasopressin was degraded, resulting in GDI, and GDI is associate with premature birth . Because placental volume may be associated with vasopressinase overproduction in GDI and vasopressinase (IRAP) may positively regulate GLUT4 expression and membrane translocation, this IRAP/GLUT4 association could contribute to the growth of placenta, thus the symptoms of GDI may be augmented later on.
Postpartum destructive thyrotoxicosis, painless thyroiditis or silent thyroiditis is relatively common in women in the postpartum period. Despite an extensive search of the literature, no case of GDI followed by or co-existing with postpartum destructive thyrotoxicosis could be found. As a result of autoimmune mechanisms, postpartum destructive thyrotoxicosis can be observed during the clinical course of chronic thyroiditis (Hashimoto thyroiditis) . Central DI associated with lymphocytic hypophysitis may be associated with chronic thyroiditis , but was not in this case. Because there are a variety of etiologies underlying the mechanism of GDI, GDI followed by postpartum destructive thyrotoxicosis may occur. However, it is important to monitor the endocrine function and symptoms in the pregnant mother during and after the pregnancy.