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Insulinoma associated with pregnancy
CASE REPORT Insulinoma associated with pregnancy Adriana G. Diaz, M.D.,a Javier Herrera, M.D.,a Mariana L opez, M.D.,a F elix M. Puchulu, M.D.,b c a Pedro Ferraina, M.D., and Oscar D. Bruno, M.D. Divisions of a Endocrinology and b Diabetes and c Department of Surgery, Hospital de Clınicas, University of Buenos Aires, Buenos Aires, Argentina
Objective: To report three cases of insulinoma associated with pregnancy. Design: Case report. Setting: Divisions of Endocrinology and Gastroenterologic Surgery, Hospital de Clınicas, University of Buenos Aires, Argentina. Patient(s): Three patients with hypoglycemic signs due to insulinoma appearing during pregnancy or shortly after delivery. Intervention(s): Laparoscopic excision of insulinoma in two and laparotomy in one of the patients were performed after the end of their pregnancies. Main Outcome Measure(s): Disappearance of hypoglycemic crises and histologic proof of insulinomas. Result(s): In two of the three patients, hypoglycemia occurred within 2–12 weeks after delivery, suggesting that signs could have been masked because of metabolic changes during gestation; in the third patient, hypoglycemia appeared in the first trimester but was misinterpreted. Conclusion(s): Insulinoma is often not suspected during the first trimester of pregnancy because signs resemble episodes of hypotension or emesis. Later, with the increase in insulin resistance, symptoms subside. (Fertil Steril 2008;90:199.e1–e4. 2008 by American Society for Reproductive Medicine.) Key Words: Insulinoma, hypoglycemia, pregnancy
Insulinomas are rare insulin-secreting tumors that occur with an incidence of 1 per 250,000 people per year. Characteristically, patients with insulinoma present profound and symptomatic hypoglycemia. Hypoglycemic episodes are diagnosed in the presence of the Whipple’s triad, consisting of neuroglycopenic or autonomic manifestations, simultaneous low plasma glucose, and the relief of all symptoms through correction of hypoglycemia (1). Confirmation of diagnosis is usually obtained by showing the association of hypoglycemia with nonsuppressed insulin secretion, during normal or prolonged fasting (2). Typically, insulinomas are small benign tumors; malignancy or association with multiple endocrine neoplasia (MEN 1) is seen in less than 10%–15% of all cases (1). Insulinoma associated with pregnancy is a very rare event. Until recently, approximately 20 cases had been reported. Most of the reported cases appeared during the first trimester with hypoglycemic episodes (3). We report here three new clinical cases of insulinoma associated with pregnancy and/ or the postpartum period. Received April 22, 2007; revised June 21, 2007; accepted June 25, 2007. Request reprints: Oscar D. Bruno, M.D., Division of Endocrinology, Hospi rdoba 2351, 1120 tal de Clınicas, University of Buenos Aires, Avenida Co Buenos Aires, Argentina (FAX: 54-11-48050631; E-mail: bodomingo@ intramed.net).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.06.092
CASE REPORTS Case 1 A 35-year-old obese (BMI 43 kg/m2) woman presented 3 months after the delivery of twins with episodes of confusion, dizziness, and loss of consciousness that progressed in frequency and duration. The babies, a girl and a boy, were born at 36 weeks’ gestation and weighed 1800 g and 1900 g, respectively. Seizure disorder was diagnosed and treated with phenytoin, showing no clinical response. Episodes improved with frequent carbohydrate ingestion. During the next 4 years, the patient gained 45 kg. At this stage she was admitted to our institution for further evaluation. Prolonged fasting test results were positive after 8 hours; biochemical findings were consistent with endogenous hyperinsulinism (Table 1). Results from abdominal computed tomographic (CT) scan and mesenteric arteriography were negative. A 15-mm mass in the junction of the head and body of the pancreas was removed through exploratory laparotomy. Immediately after surgery the patient showed hyperglycemia that resolved spontaneously. Pathology and immunostaining confirmed the diagnosis of insulinoma. Case 2 A 35-year-old woman was admitted to our institution on the 26th postpartum day with confusion, dysarthria, and
Fertility and Sterility Vol. 90, No. 1, July 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
199.e1
TABLE 1 Laboratory test results in three patients with insulinoma associated with pregnancy. Test Glycemia (mg/dL) Serum insulin (mU/mL) (MEIA) Serum C-peptide (nmol/L) Positive PFT results at: (h)
Normal values
Case 1
Case 2
Case 3
70–110 5–25 0.2–1.2
27 25.7 0.90 8
34 6.8 0.29 17
42 68.7 nd 3
Note: MEIA ¼ microparticle enzyme immunoassay; nd ¼ not done; PFT ¼ prolonged fasting test. Diaz. Insulinoma and pregnancy. Fertil Steril 2008.
quadriplegia. She related a history of frequent episodes of dizziness starting within the first trimester of pregnancy that mitigated with frequent meals. Subsequently she did not have any other hypoglycemic signs. Pregnancy developed without complications, ending in normal delivery at 40 weeks’ gestation of a normal baby girl weighing 3170 g. At admission, laboratory study results were normal except for a capillary blood glucose value of 43 mg/dL. Symptoms subsided after administration of an intravenous glucose infusion. Additional studies were performed. Prolonged fasting test results were positive after 17 hours (Table 1). Results on abdominal CT and endoscopic ultrasound were unrewarding. An intra-arterial calcium stimulation test (4) induced selective insulin rise in the splenic artery region. Laparoscopy with intraoperative ultrasound showed a mass in the tail of the pancreas. Enucleation of an 8-mm tumor was performed. Pathological analysis was consistent with insulinoma. Postoperatively the patient had hyperglycemia (180 mg/dL) and developed pancreatic cysts and hyperamylasemia that resolved spontaneously with no complications. She remains asymptomatic and normoglycemic after a 2.5-year follow-up.
Case 3 A 22-year-old primigravid woman developed headache, tremor, tachycardia, confusion, and loss of consciousness during the second month of pregnancy. Hypoglycemia (<40 mg/dL) was diagnosed. Frequent meals were indicated, but she developed hyperemesis gravidarum requiring enteral feeding (4200 kcal/day, 455 g carbohydrate per day) until delivery; she gained 30 kg during her pregnancy. With that regimen hypoglycemia was controlled, and she did not experience any further hypoglycemic episodes. Pregnancy developed without other complications. At 39 weeks’ gestation she delivered a baby boy weighing 2600 g. While lactating, 4 weeks after delivery, she developed a recurrence of symptomatic hypoglycemia that was mitigated by frequent meals and snacks. Over the next 2 years she gained another 10 kg. Later she was admitted to our hospital because of a severe hypoglycemic event. Results from a 72-hour fasting test were positive after 3 hours (Table 1). Magnetic resonance imaging showed a 25-mm cystic image in the tail of the pancreas. Endoscopic ultrasound revealed two adjacent lesions: a 199.e2
Diaz et al.
Insulinoma and pregnancy
12 20-mm cystic mass and a 17 15-mm solid hypoechoic lesion. Intraoperative ultrasound confirmed both lesions. Laparoscopic distal pancreatectomy was performed. Immediately after surgery, blood glucose levels rose to 120 mg/ dL, returning to normal values without treatment during the following days. Pathological analysis revealed an insulinoma in the solid nodule and a glucagonoma in the cystic nodule. MEN 1 genetic analysis was negative. After a 15-month follow-up she remains asymptomatic.
DISCUSSION Insulinoma is a rare tumor of the pancreatic islet b cells. Hypoglycemia and neuroglycopenic symptoms that subside after the administration of carbohydrates are the hallmarks of the diagnosis of insulinoma. Fasting is the most effective diagnostic procedure and has a twofold purpose: to document hypoglycemia and its relationship to the patient’s symptoms, and to demonstrate inappropriate insulin secretion in the face of hypoglycemia. Although some investigators recommend the 48-hour fast (5), the diagnosis of insulinoma has centered on a 72-hour fast. Patients are fasted for up to 72 hours under close medical supervision. Blood glucose level is controlled by a reflectance meter every 6 hours. When glucose is <60 mg/dL, blood glucose is collected hourly. The test is continued until the patient develops hypoglycemia, defined as plasma glucose <45 mg/dL accompanied or not by neuroglycopenic symptoms, or until attaining a maximum of a 72hour fast. The coexistence of plasma glucose <45 mg/dL, plasma insulin R6 mU/mL (RIA) or R3 mU/mL (ultrasensitive method), C peptide R0.2 nmol/L, negative sulfonylurea, and negative insulin antibodies is consistent with the diagnosis of insulinoma (2). Insulinoma can occur coincidentally with pregnancy or in the postpartum period. The real incidence of this tumor is probably underestimated owing to difficulties in reaching diagnosis in such periods. Only approximately 20 cases of insulinoma occurring during pregnancy have been reported in the literature (3). Most of them showed suggestive hypoglycemic signs by 16 weeks’ gestation; only one patient became symptomatic at week 35 (malignant insulinoma). In four cases symptoms developed after delivery. Frequent meals and intravenous glucose infusions were adequate for Vol. 90, No. 1, July 2008
hypoglycemia control. Five patients were operated at 12–17 weeks’ gestation. The diagnosis of insulinoma is often not suspected during the first trimester because weakness, nausea, hypotension, and even mild episodes of hypoglycemia are common at the beginning of normal pregnancy. At this stage many pregnant patients with insulinoma have symptoms similar to those of normal pregnant women. Late in pregnancy, with the rise in insulin resistance, clinical hypoglycemia can be absent or attenuated, so the tumors may be masked. Hypoglycemic episodes may be absent during the second half of pregnancy even in the presence of a confirmed insulinoma, but in the postpartum period they often recur after a rebound in insulin sensitivity. This particular adaptation in insulin sensitivity during pregnancy could explain why most of the previous reported cases showed suggestive hypoglycemic signs by week 16 of gestation, before insulin resistance appeared. Only one of the reported patients (with malignant insulinoma) became symptomatic by week 35, whereas symptoms developed when insulin sensitivity rebounded after delivery in the remaining cases. Frequent meals and intravenous glucose infusions were adequate for hypoglycemia control in most of the cases, and only a small number of patients were operated on at weeks 12–17 of gestation (3). Physiologically, glucose values tend to be lower in the first trimester of normal pregnancy, which is usually attributed to a significant rise in insulin production and insulin sensitivity, probably due to an increase in estrogens (6). Late in pregnancy, placental hormones are implicated in the alteration of maternal glucose metabolism, inducing peripheral insulin resistance and contributing to altered b cell function. Estrogen, progesterone, and cortisol rise in late pregnancy, but they seem to have only a minor role in the development of insulin resistance. Human placental lactogen seems to act directly, inducing growth of pancreatic islets b cells and stimulating insulin secretion. Recently human placental growth hormone has been suggested as one of the hormones primarily responsible for insulin resistance during pregnancy. Human placental growth hormone increases the expression of p85a subunit affecting the binding to IRS-1 and reducing PI 3-kinase insulin signaling and translocation of GLUT-4 to the plasma membrane (7). Other factors that have been implicated in the decrease of insulin sensitivity during pregnancy are the increase in tumor necrosis factor (TNF)-a and leptin. Circulating plasma TNF-a is produced by the placenta and highly correlated with in vivo insulin resistance (8). Circulating leptin concentrations in humans closely correlate with fasting insulin concentration and body fat percentage. Leptin rises significantly during late pregnancy, but its role in insulin signaling needs further investigation. During the first weeks after delivery, placental hormones disappear and insulin sensitivity returns to normal. In obese patients, however, insulin resistance can persist until postpartum week 16 (9). Pregnancy does not alter the ability of hypoglycemia to suppress insulin secretion; therefore, the diagnosis of endogenous hyperinsulinism can be made by prolonged fasting as Fertility and Sterility
in the nonpregnant state. Although some investigators recommend that procedure when insulinoma is suspected in a pregnant woman (3), this test could be harmful for both mother and baby; so if strictly necessary, it has to be done under very close supervision. In our first case, obesity could have maintained insulin resistance until the appearance of hypoglycemic episodes that occurred 12 weeks after delivery of twins. The possibility of new growth of an insulinoma during the period between delivery and the time of symptoms is very unlikely. Further difficulties in making the diagnosis were probably related to the lack of experience in this pathology in the rural medical center where the patient lives. In the second case, we admitted the patient to our institution (a third-level university hospital), and the diagnosis was made immediately. Probably these two patients could have had symptoms or signs of hypoglycemia that were not duly appreciated during pregnancy. In case 3, a symptomatic episode of hypoglycemia was confirmed at the beginning of pregnancy. Nevertheless, diagnosis of insulinoma was not suspected. The occurrence of severe hyperemesis gravidarum complicated the course of pregnancy. Hypoglycemia and acidosis could have acted synergistically, maintaining the tendency to vomiting. As in the first case, obesity and a hypercaloric diet gave the patient relative protection against hypoglycemia. Theoretically the coexistence of a glucagonoma might have also exerted a protective action for hypoglycemia, but we cannot ascertain this hypothesis because glucagonoma syndrome (10) was absent and plasma glucagon levels were not measured. The coexistence of multiple endocrine tumors led us to consider MEN 1 syndrome. This patient did not present any other familial or personal history suggesting MEN 1 syndrome, such as hyperparathyroidism or pituitary disease, which can be related to approximately 7.6% of insulinomas (1); although MEN 1 genetic analysis was negative, the patient remains under close supervision to disclose any early manifestation of associated diseases. In summary, insulinoma associated with pregnancy could be difficult to diagnose. Such a possibility has to be taken into account in the differential diagnosis of symptomatic hypoglycemia during the first trimester or in the postpartum period. If diagnosis is confirmed during gestation, surgery can be performed in the second trimester. In some cases, however, a conservative approach could be advised until delivery, to proceed to definitive surgical treatment preceded by tumor localization, after the end of pregnancy. REFERENCES 1. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinomas—incidence. Recurrent and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66:711–9. 2. Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332:1144–52. 3. Takacs CA, Krivak TC, Napolitano PG. Insulinoma in pregnancy: a case report and review of the literature. Obstet Gynecol Surv 2002;57:229–35. 4. Jackson JE. Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 2005;19:229–39.
199.e3
5. Hirshberg B, Livi A, Bartlett DL, Libutti SK, Alexander HR, Doppman JL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endocrinol Metab 2000;85:3222–6. 6. Whitemann VE, Homko CJ, Reece EA. Management of hypoglycemia and diabetic ketoacidosis in pregnancy. Obst Gynecol Clin North Am 1996;23:87–107. 7. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, et al. Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 2004;145:1144–50.
199.e4
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Insulinoma and pregnancy
8. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, HustonPresley L, Friedman JE, et al. TNF-a is a predictor of insulin resistance in human pregnancy. Diabetes 2002;51:2207–13. 9. Kirwan JP, Varastehpour A, Jing M, Presley L, Shao J, Friedman JE, et al. Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. J Clin Endocrinol Metab 2004;89: 4678–84. 10. van Beek AP, de Hass ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol 2004;151:531–7.
Vol. 90, No. 1, July 2008
Objective: To report three cases of insulinoma associated with pregnancy. Design: Case report. Setting: Divisions of Endocrinology and Gastroenterologic Surgery, Hospital de Clınicas, University of Buenos Aires, Argentina. Patient(s): Three patients with hypoglycemic signs due to insulinoma appearing during pregnancy or shortly after delivery. Intervention(s): Laparoscopic excision of insulinoma in two and laparotomy in one of the patients were performed after the end of their pregnancies. Main Outcome Measure(s): Disappearance of hypoglycemic crises and histologic proof of insulinomas. Result(s): In two of the three patients, hypoglycemia occurred within 2–12 weeks after delivery, suggesting that signs could have been masked because of metabolic changes during gestation; in the third patient, hypoglycemia appeared in the first trimester but was misinterpreted. Conclusion(s): Insulinoma is often not suspected during the first trimester of pregnancy because signs resemble episodes of hypotension or emesis. Later, with the increase in insulin resistance, symptoms subside. (Fertil Steril 2008;90:199.e1–e4. 2008 by American Society for Reproductive Medicine.) Key Words: Insulinoma, hypoglycemia, pregnancy
Insulinomas are rare insulin-secreting tumors that occur with an incidence of 1 per 250,000 people per year. Characteristically, patients with insulinoma present profound and symptomatic hypoglycemia. Hypoglycemic episodes are diagnosed in the presence of the Whipple’s triad, consisting of neuroglycopenic or autonomic manifestations, simultaneous low plasma glucose, and the relief of all symptoms through correction of hypoglycemia (1). Confirmation of diagnosis is usually obtained by showing the association of hypoglycemia with nonsuppressed insulin secretion, during normal or prolonged fasting (2). Typically, insulinomas are small benign tumors; malignancy or association with multiple endocrine neoplasia (MEN 1) is seen in less than 10%–15% of all cases (1). Insulinoma associated with pregnancy is a very rare event. Until recently, approximately 20 cases had been reported. Most of the reported cases appeared during the first trimester with hypoglycemic episodes (3). We report here three new clinical cases of insulinoma associated with pregnancy and/ or the postpartum period. Received April 22, 2007; revised June 21, 2007; accepted June 25, 2007. Request reprints: Oscar D. Bruno, M.D., Division of Endocrinology, Hospi rdoba 2351, 1120 tal de Clınicas, University of Buenos Aires, Avenida Co Buenos Aires, Argentina (FAX: 54-11-48050631; E-mail: bodomingo@ intramed.net).
0015-0282/08/$34.00 doi:10.1016/j.fertnstert.2007.06.092
CASE REPORTS Case 1 A 35-year-old obese (BMI 43 kg/m2) woman presented 3 months after the delivery of twins with episodes of confusion, dizziness, and loss of consciousness that progressed in frequency and duration. The babies, a girl and a boy, were born at 36 weeks’ gestation and weighed 1800 g and 1900 g, respectively. Seizure disorder was diagnosed and treated with phenytoin, showing no clinical response. Episodes improved with frequent carbohydrate ingestion. During the next 4 years, the patient gained 45 kg. At this stage she was admitted to our institution for further evaluation. Prolonged fasting test results were positive after 8 hours; biochemical findings were consistent with endogenous hyperinsulinism (Table 1). Results from abdominal computed tomographic (CT) scan and mesenteric arteriography were negative. A 15-mm mass in the junction of the head and body of the pancreas was removed through exploratory laparotomy. Immediately after surgery the patient showed hyperglycemia that resolved spontaneously. Pathology and immunostaining confirmed the diagnosis of insulinoma. Case 2 A 35-year-old woman was admitted to our institution on the 26th postpartum day with confusion, dysarthria, and
Fertility and Sterility Vol. 90, No. 1, July 2008 Copyright ª2008 American Society for Reproductive Medicine, Published by Elsevier Inc.
199.e1
TABLE 1 Laboratory test results in three patients with insulinoma associated with pregnancy. Test Glycemia (mg/dL) Serum insulin (mU/mL) (MEIA) Serum C-peptide (nmol/L) Positive PFT results at: (h)
Normal values
Case 1
Case 2
Case 3
70–110 5–25 0.2–1.2
27 25.7 0.90 8
34 6.8 0.29 17
42 68.7 nd 3
Note: MEIA ¼ microparticle enzyme immunoassay; nd ¼ not done; PFT ¼ prolonged fasting test. Diaz. Insulinoma and pregnancy. Fertil Steril 2008.
quadriplegia. She related a history of frequent episodes of dizziness starting within the first trimester of pregnancy that mitigated with frequent meals. Subsequently she did not have any other hypoglycemic signs. Pregnancy developed without complications, ending in normal delivery at 40 weeks’ gestation of a normal baby girl weighing 3170 g. At admission, laboratory study results were normal except for a capillary blood glucose value of 43 mg/dL. Symptoms subsided after administration of an intravenous glucose infusion. Additional studies were performed. Prolonged fasting test results were positive after 17 hours (Table 1). Results on abdominal CT and endoscopic ultrasound were unrewarding. An intra-arterial calcium stimulation test (4) induced selective insulin rise in the splenic artery region. Laparoscopy with intraoperative ultrasound showed a mass in the tail of the pancreas. Enucleation of an 8-mm tumor was performed. Pathological analysis was consistent with insulinoma. Postoperatively the patient had hyperglycemia (180 mg/dL) and developed pancreatic cysts and hyperamylasemia that resolved spontaneously with no complications. She remains asymptomatic and normoglycemic after a 2.5-year follow-up.
Case 3 A 22-year-old primigravid woman developed headache, tremor, tachycardia, confusion, and loss of consciousness during the second month of pregnancy. Hypoglycemia (<40 mg/dL) was diagnosed. Frequent meals were indicated, but she developed hyperemesis gravidarum requiring enteral feeding (4200 kcal/day, 455 g carbohydrate per day) until delivery; she gained 30 kg during her pregnancy. With that regimen hypoglycemia was controlled, and she did not experience any further hypoglycemic episodes. Pregnancy developed without other complications. At 39 weeks’ gestation she delivered a baby boy weighing 2600 g. While lactating, 4 weeks after delivery, she developed a recurrence of symptomatic hypoglycemia that was mitigated by frequent meals and snacks. Over the next 2 years she gained another 10 kg. Later she was admitted to our hospital because of a severe hypoglycemic event. Results from a 72-hour fasting test were positive after 3 hours (Table 1). Magnetic resonance imaging showed a 25-mm cystic image in the tail of the pancreas. Endoscopic ultrasound revealed two adjacent lesions: a 199.e2
Diaz et al.
Insulinoma and pregnancy
12 20-mm cystic mass and a 17 15-mm solid hypoechoic lesion. Intraoperative ultrasound confirmed both lesions. Laparoscopic distal pancreatectomy was performed. Immediately after surgery, blood glucose levels rose to 120 mg/ dL, returning to normal values without treatment during the following days. Pathological analysis revealed an insulinoma in the solid nodule and a glucagonoma in the cystic nodule. MEN 1 genetic analysis was negative. After a 15-month follow-up she remains asymptomatic.
DISCUSSION Insulinoma is a rare tumor of the pancreatic islet b cells. Hypoglycemia and neuroglycopenic symptoms that subside after the administration of carbohydrates are the hallmarks of the diagnosis of insulinoma. Fasting is the most effective diagnostic procedure and has a twofold purpose: to document hypoglycemia and its relationship to the patient’s symptoms, and to demonstrate inappropriate insulin secretion in the face of hypoglycemia. Although some investigators recommend the 48-hour fast (5), the diagnosis of insulinoma has centered on a 72-hour fast. Patients are fasted for up to 72 hours under close medical supervision. Blood glucose level is controlled by a reflectance meter every 6 hours. When glucose is <60 mg/dL, blood glucose is collected hourly. The test is continued until the patient develops hypoglycemia, defined as plasma glucose <45 mg/dL accompanied or not by neuroglycopenic symptoms, or until attaining a maximum of a 72hour fast. The coexistence of plasma glucose <45 mg/dL, plasma insulin R6 mU/mL (RIA) or R3 mU/mL (ultrasensitive method), C peptide R0.2 nmol/L, negative sulfonylurea, and negative insulin antibodies is consistent with the diagnosis of insulinoma (2). Insulinoma can occur coincidentally with pregnancy or in the postpartum period. The real incidence of this tumor is probably underestimated owing to difficulties in reaching diagnosis in such periods. Only approximately 20 cases of insulinoma occurring during pregnancy have been reported in the literature (3). Most of them showed suggestive hypoglycemic signs by 16 weeks’ gestation; only one patient became symptomatic at week 35 (malignant insulinoma). In four cases symptoms developed after delivery. Frequent meals and intravenous glucose infusions were adequate for Vol. 90, No. 1, July 2008
hypoglycemia control. Five patients were operated at 12–17 weeks’ gestation. The diagnosis of insulinoma is often not suspected during the first trimester because weakness, nausea, hypotension, and even mild episodes of hypoglycemia are common at the beginning of normal pregnancy. At this stage many pregnant patients with insulinoma have symptoms similar to those of normal pregnant women. Late in pregnancy, with the rise in insulin resistance, clinical hypoglycemia can be absent or attenuated, so the tumors may be masked. Hypoglycemic episodes may be absent during the second half of pregnancy even in the presence of a confirmed insulinoma, but in the postpartum period they often recur after a rebound in insulin sensitivity. This particular adaptation in insulin sensitivity during pregnancy could explain why most of the previous reported cases showed suggestive hypoglycemic signs by week 16 of gestation, before insulin resistance appeared. Only one of the reported patients (with malignant insulinoma) became symptomatic by week 35, whereas symptoms developed when insulin sensitivity rebounded after delivery in the remaining cases. Frequent meals and intravenous glucose infusions were adequate for hypoglycemia control in most of the cases, and only a small number of patients were operated on at weeks 12–17 of gestation (3). Physiologically, glucose values tend to be lower in the first trimester of normal pregnancy, which is usually attributed to a significant rise in insulin production and insulin sensitivity, probably due to an increase in estrogens (6). Late in pregnancy, placental hormones are implicated in the alteration of maternal glucose metabolism, inducing peripheral insulin resistance and contributing to altered b cell function. Estrogen, progesterone, and cortisol rise in late pregnancy, but they seem to have only a minor role in the development of insulin resistance. Human placental lactogen seems to act directly, inducing growth of pancreatic islets b cells and stimulating insulin secretion. Recently human placental growth hormone has been suggested as one of the hormones primarily responsible for insulin resistance during pregnancy. Human placental growth hormone increases the expression of p85a subunit affecting the binding to IRS-1 and reducing PI 3-kinase insulin signaling and translocation of GLUT-4 to the plasma membrane (7). Other factors that have been implicated in the decrease of insulin sensitivity during pregnancy are the increase in tumor necrosis factor (TNF)-a and leptin. Circulating plasma TNF-a is produced by the placenta and highly correlated with in vivo insulin resistance (8). Circulating leptin concentrations in humans closely correlate with fasting insulin concentration and body fat percentage. Leptin rises significantly during late pregnancy, but its role in insulin signaling needs further investigation. During the first weeks after delivery, placental hormones disappear and insulin sensitivity returns to normal. In obese patients, however, insulin resistance can persist until postpartum week 16 (9). Pregnancy does not alter the ability of hypoglycemia to suppress insulin secretion; therefore, the diagnosis of endogenous hyperinsulinism can be made by prolonged fasting as Fertility and Sterility
in the nonpregnant state. Although some investigators recommend that procedure when insulinoma is suspected in a pregnant woman (3), this test could be harmful for both mother and baby; so if strictly necessary, it has to be done under very close supervision. In our first case, obesity could have maintained insulin resistance until the appearance of hypoglycemic episodes that occurred 12 weeks after delivery of twins. The possibility of new growth of an insulinoma during the period between delivery and the time of symptoms is very unlikely. Further difficulties in making the diagnosis were probably related to the lack of experience in this pathology in the rural medical center where the patient lives. In the second case, we admitted the patient to our institution (a third-level university hospital), and the diagnosis was made immediately. Probably these two patients could have had symptoms or signs of hypoglycemia that were not duly appreciated during pregnancy. In case 3, a symptomatic episode of hypoglycemia was confirmed at the beginning of pregnancy. Nevertheless, diagnosis of insulinoma was not suspected. The occurrence of severe hyperemesis gravidarum complicated the course of pregnancy. Hypoglycemia and acidosis could have acted synergistically, maintaining the tendency to vomiting. As in the first case, obesity and a hypercaloric diet gave the patient relative protection against hypoglycemia. Theoretically the coexistence of a glucagonoma might have also exerted a protective action for hypoglycemia, but we cannot ascertain this hypothesis because glucagonoma syndrome (10) was absent and plasma glucagon levels were not measured. The coexistence of multiple endocrine tumors led us to consider MEN 1 syndrome. This patient did not present any other familial or personal history suggesting MEN 1 syndrome, such as hyperparathyroidism or pituitary disease, which can be related to approximately 7.6% of insulinomas (1); although MEN 1 genetic analysis was negative, the patient remains under close supervision to disclose any early manifestation of associated diseases. In summary, insulinoma associated with pregnancy could be difficult to diagnose. Such a possibility has to be taken into account in the differential diagnosis of symptomatic hypoglycemia during the first trimester or in the postpartum period. If diagnosis is confirmed during gestation, surgery can be performed in the second trimester. In some cases, however, a conservative approach could be advised until delivery, to proceed to definitive surgical treatment preceded by tumor localization, after the end of pregnancy. REFERENCES 1. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning insulinomas—incidence. Recurrent and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66:711–9. 2. Service FJ. Hypoglycemic disorders. N Engl J Med 1995;332:1144–52. 3. Takacs CA, Krivak TC, Napolitano PG. Insulinoma in pregnancy: a case report and review of the literature. Obstet Gynecol Surv 2002;57:229–35. 4. Jackson JE. Angiography and arterial stimulation venous sampling in the localization of pancreatic neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 2005;19:229–39.
199.e3
5. Hirshberg B, Livi A, Bartlett DL, Libutti SK, Alexander HR, Doppman JL, et al. Forty-eight-hour fast: the diagnostic test for insulinoma. J Clin Endocrinol Metab 2000;85:3222–6. 6. Whitemann VE, Homko CJ, Reece EA. Management of hypoglycemia and diabetic ketoacidosis in pregnancy. Obst Gynecol Clin North Am 1996;23:87–107. 7. Barbour LA, Shao J, Qiao L, Pulawa LK, Jensen DR, Bartke A, et al. Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 2004;145:1144–50.
199.e4
Diaz et al.
Insulinoma and pregnancy
8. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, HustonPresley L, Friedman JE, et al. TNF-a is a predictor of insulin resistance in human pregnancy. Diabetes 2002;51:2207–13. 9. Kirwan JP, Varastehpour A, Jing M, Presley L, Shao J, Friedman JE, et al. Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. J Clin Endocrinol Metab 2004;89: 4678–84. 10. van Beek AP, de Hass ER, van Vloten WA, Lips CJ, Roijers JF, Canninga-van Dijk MR. The glucagonoma syndrome and necrolytic migratory erythema: a clinical review. Eur J Endocrinol 2004;151:531–7.
Vol. 90, No. 1, July 2008