Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 480–482

480

Blackwell Science, Ltd Letter to the Editor

Letters to the EditorLetters to the EditorLetter to the Editor Re: Oestrogens, triglycerides and pancreatitis

I read with interest the article by Nanda et al. on the differenteffects of oral and topical oestrogens on plasma lipids, withtheir conclusion that the topical route should be used inwomen with high triglycerides.1 A study by Goldenberget al. recently assessed 56 women referred to their centre withhypertriglyceridaemia (serum triglycerides >4.5 mmol/L).2

Twenty-four of these women were taking exogenousoestrogen including two women using transdermal oestro-gen, and one woman using tamoxifen. Nine of these 24women taking exogenous oestogens had a history of acutepancreatitis. Of importance to obstetricians and gynaecolo-gists, pancreatitis with severe hypertriglyceridaemia has beenreported with clomiphene, intramuscular oestradiol valerateduring endometrial preparation for cryopreserved embryo,and endogenous oestrogen with pregnancy.3,4 The latterhas been successfully treated with various modalities includingplasma exchange, lipid pheresis, heparin and insulin infu-sions, total parenteral nutrition and restriction of dietary fat.Recurrence in subsequent pregnancies has been avoidedby the use of low fat, low carbohydrate diets supplementedwith medium chain triglycerides.5 While fibrates and fishoils have been used safely in pregnancy, they are usuallynot effective in the setting of hypertriglyceridaemia related toexogenous oestrogens or pregnancy. Thus while topicaloestrogens might be associated with a lowering of triglyceridesin the general population, their use in women with baselinetriglycerides greater than 5 mmol/L is contraindicated untilfurther studies in this group at high risk of pancreatitis areperformed.

Adam MORTONPhysician, Mater Hospital, South Brisbane,

Queensland 4101, Australia

References

1 Nanda S, Gupta N, Mehta HC, Sangwan K. Effect of oestrogenreplacement therapy on serum lipid profile. Aust NZ J ObstetGynaecol. 2003; 43: 213–217.

2 Goldenberg NM, Wang P, Glueck CJ. An observational studyof severe hypertriglyceridemia, hypertriglyceridemic acutepancreatitis, and failure of triglyceride-lowering therapy whenestrogens are given to women with and without familial hyper-triglyceridemia. Clin Chim Acta. 2003; 332: 11–19.

3 Castro MR, Nguyen TT, O’Brien T. Clomiphene-induced severehypertriglyceridemia and pancreatitis. Mayo Clin Proc. 1999;74: 1125–1128.

4 Ruman J, Brenner S, Sauer MV. Severe hypertriglyceridemiaand pancreatitis following hormone replacement prior to cryo-thaw transfer. J Assist Reprod Genet. 2002; 19: 94–97.

5 Mizushima T, Ochi K, Matsumura N et al. Prevention of hyperli-pidemic acute pancreatitis during pregnancy with medium-chaintriglyceride nutritional support. Int J Pancreatol. 1998; 23: 187–192.

December 2003436Letter to the EditorLetters to the EditorLetters to the EditorLetter to the Editor

Author’s reply

Thank you for the opportunity to respond to the letter fromDr Morton.

Acute pancreatitis (AP) is one of the complicationsassociated with severe primary and secondary hypertriglyc-eridaemia. The elevation in serum triglycerides probablyinduces the release of free fatty acids, responsible for thepancreatic damage.1 Hypertriglyceridaemia over 1000 mg/dLcan provoke acute pancreatitis. Any factor that causes an abruptincrease in serum triglycerides to levels greater than 1000 mg/dL(11 m mol/L) can precipitate a bout of pancreatitis.2

Oral oestrogens increase triglyceride levels.3 Improper useof oestrogens can convert a mild primary lipid abnormalityinto a clinically life-threatening situation.4 In patients withbaseline hypertriglyceridaemia, the addition of oestrogencan lead to the chylomicronaemia syndrome (triglycerideslevel greater than 1000 mg/dL) with AP as a sequelae.3 In mostof the reported cases of pancreatitis occurring as a result ofoestrogen induced hypertriglyceridemia, triglyceride levelswere above 1000 mg/dL.1,5,6

Glueck et al. have reported hypertriglyceridaemia andpancreatitis in seven patients who were on oestrogen replace-ment therapy, their initial visit fasting plasma triglyceridelevels were >1500 mg/dL.5 Davidoff et al. have reported two casesof hypertriglyceridaemia and pancreatitis following the useof oral contraceptive pills. Their fasting plasma triglyceride levelswere 7100 and 3560 mg/dL, respectively.6

Severe hypertriglyceridaemia and pancreatitis are morelikely to occur when oestrogens are given to women with pre-existing, usually covert, primary familial hypertriglyceridaemia.5

Even for women who, before becoming pregnant,have an underlying hypertriglyceridaemia owing to a genetictriglyceride removal problem, the second or third trimesterof pregnancy can be complicated by an acute, life-threateningpancreatitis as triglycerides climb with each trimester to exceed2000 mg/dL.7

To avert the risk of triggering pancreatitis, a fasting serumtriglyceride measurement should be obtained before oestrogenreplacement is begun in postmenopausal women. Fasting levelsless than 300 mg/dL pose no risk, whereas levels greater then750 mg/dL are associated with a high probability of develop-ing pancreatitis.2 Goldenberg et al. have postulated that ifbaseline serum triglycerides exceed 500 mg/dL, oestrogenreplacement therapy should not be given.8

The important question raised here is that if chylo-micronaemia and pancreatitis may develop as a result of

Letters to the Editor

Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 480–482 481

intramuscular and endogenous oestrogen excess, would thisoccur with topical oestrogen as well? Unfortunately the studyby Goldenburg et al. that has been quoted by Dr Mortondoes not state whether the individuals who developedpancreatitis were taking oral or topical oestrogen, or theirpretreatment triglyceride levels.8 Serum triglycerides havebeen shown to decline significantly with the use of transdermaloestrogens.9–15 In our study also, significant decline in serumtriglycerides was noted in the transdermal group. Thisonly suggests that massive elevations of plasma triglycerides,leading to pancreatitis may not occur with transdermaloestrogens. However for a definitive answer, further researchis required.

Blake and Pitcher have recently reported a case ofrecurrent AP occurring in conjunction with intermittentlyused oestrogen therapy over 7 years in a patient whose plasmalipids had always been normal, suggesting that a differentmechanism must be responsible for the onset of pancreatitis.16

Dr Smiti NANDA 11/8 FM, Medical Enclave, Rohtak-124001, Haryana,

India

References

1 Chebli JM, de Souza AF, de Paulo GA et al. [Hyperlipemicpancreatitis: clinical course]. Arq Gastroenterol. 1999; 36: 4–9[in Portuguese with English abstract].

2 Greenberger NJ, Toskes PP. Acute and Chronic pancreatitis.In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL,Jameson JL (eds). Harrison’s Principles of Internal Medicine,Vol. 2, 15th edn. New York: McGraw-Hill, 2001; 1792–1804.

3 Glueck CJ, Scheel D, Fishback Steiner P. Estrogen inducedpancreatitis in patients with previously covert familial type Vhyperprolactinemia. Metabolism. 1972; 21: 657–666.

4 Stone NJ. Secondary causes of hyperlipidemia. Med Clin NorthAm. 1994; 78: 117–141.

5 Glueck CJ, Lang J, Hamer T, Tracy T. Severe hypertriglycer-idemia and pancreatitis when estrogen replacement therapy isgiven to hypertriglyceridemic women. J Lab Clin Med. 1994;123: 59–64.

6 Davidoff F, Tishler S, Rosoff C. Marked hyperlipedemiaand pancreatitis associated with oral contraceptive therapy. NEngl J Med. 1973; 289: 552–555.

7 Sanderson SL, Iverius PH, Wilson DE. Succesful hyperli-pemic pregnancy. JAMA. 1991; 265: 1858–1860.

8 Goldenberg NM, Wang P, Glueck CJ. An observationalstudy of severe hypertriglyceridemia, hypertriglyceridemic acutepancreatitis, and failure of triglyceride-lowering therapywhen estrogens are given to women with and without familialhypertriglyceridemia. Clin Chim Acta. 2003; 332: 11–19.

9 Gokmen O, Yapar Eyi EG. Hormone replacement therapy andlipid-lipoprotein concentrations. Eur J Obstet Gynecol Reprod Biol.1999; 85: 31–41.

10 Araujo DA, Farias ML, Andrade AT. Effects of transdermaland oral estrogen replacement on lipids and glucose metabolismin postmenopausal women with type 2 diabetes mellitus.Climacteric. 2002; 5: 286–292.

11 Sendag F, Karadadas N, Ozsener S, Bilgin O. Effects ofsequential combined transdermal and oral hormone replace-ment therapies on serum lipid and lipoproteins in postmeno-pausal women. Arch Gynecol Obstet. 2002; 266: 38–43.

12 Crook D, Cust MP, Gangar KF et al. Comparison oftransdermal and oral estrogen-progestin replacement therapy:effects on serum lipids and lipoproteins. Am J Obstet Gynecol.1992; 166: 950–955.

13 Adami S, Rossini M, Zamberlan N, Bertoldo F, Dorizzi R, LoCascio V. Long-term effects of transdermal and oral estrogenson serum lipids and lipoproteins in postmenopausal women.Maturitas. 1993; 17: 191–196.

14 Bhathena RK, Anklesaria BS, Ganatra AM, Pinto R. Theinfluence of transdermal oestradiol replacement therapy andmedroxyprogesterone acetate on serum lipids and lipoproteins.Br J Clin Pharmacol. 1998; 45: 170–172.

15 Taskinen MR, Puolakka J, Pyorala T et al. Hormonereplacement therapy lowers plasma Lp (a) concentrations.Comparison of cyclic transdermal and continuous estrogen-progestin regimens. Arterioscler Thromb Vasc Biol. 1996; 16:1215–1221.

16 Blake WE, Pitcher ME. Estrogen-related pancreatitis in thesetting of normal plasma lipids: case report. Menopause.2003; 10: 99–101.

December 2003436Letter to the EditorLetters to the EditorLetters to the EditorLetter to the Editor

Delivery-related perinatal death andvaginal birth after Caesarean section

Dodd and Crowther’s1 survey on vaginal birth after Caesareansection (VBAC) revealed that obstetricians are uncertainabout whether the risks of VBAC outweigh the risks ofCaesarean section (CS) for the infant. As the authors pointout in the discussion, the evidence shows that VBAC isassociated with a significantly increased risk of perinataldeath. Unfortunately, they have not expressed the results ofthese studies in a way which could be useful to the counsellingobstetrician or to the patient. What the patient needs to knowis the magnitude of the additional risk to their baby in termsthey can easily understand (i.e. one infant death in so manyVBAC attempts).

Dodd and Crowther state that ‘the meta-analysis byMozurkewich and Hutton2 suggests increased fetal andneonatal mortality (0.58 vs 0.34%; OR, 1.71; 97% CI, 1.28–2.28)’ with VBAC when compared with planned electiveCS. This can be better expressed as one additional infantdeath in 417 VBAC attempts. However, when perinataldeaths attributable to intrauterine death before the onset oflabour, lethal abnormalities and prematurity were excluded,the overall risk was 1 in 522 VBAC attempts and 1 in 1329elective CS giving an additional risk of one infant deathin 860 VBAC attempts.

Dodd and Crowther also state that in the retrospectivestudy by Smith et al.3 ‘the overall rate of delivery-relatedperinatal death was approximately 11 times greater thanthe risk for planned elective repeat Caesarean (OR, 11.6;95% CI, 1.6–86.7)’. Again this could be better expressed as

Letters to the Editor

482 Australian and New Zealand Journal of Obstetrics and Gynaecology 2003; 43: 480–482

an overall risk of infant death of one in 775 VBAC attemptsand one in 9014 CS, giving one additional infant death in 849VBAC attempts. It must be stressed that these figures referto excess risk when compared to elective CS at term forfetuses with cephalic presentation who have been assessed asbeing suitable for VBAC and who have the VBAC attempt inappropriately staffed hospitals with all the usual recommendedintensive monitoring.

The Royal Australian and New Zealand College ofObstetricians and Gynaecologists patient informationpamphlet on VBAC states that rupture of the uterine scaroccurs approximately once in every 200 VBAC attempts andof those women who do have a rupture, approximately onebirth in 10 births will result in stillbirth (implying that therisk of death is one in 2000 VBAC but ignoring the risk ofneonatal death). Interestingly, the data from Smith et al.3

indicate that the risk of delivery-related infant death of anattempted vaginal birth in women with uncomplicated termpregnancies who have not had a previous CS is one in 1003for primigravidae and one in 1811 for multiparae. Is the timeripe for us to counsel our patients on the risks involved in

aiming for a vaginal birth even when there has not been aprevious CS?

Panos MAOURIS Consultant Obstetrician

King Edward Memorial Hospital, Perth, Western Australia,

Australia

References

1 Dodd J, Crowther C. Vaginal birth after Caesarean section: Asurvey of practice in Australia and New Zealand. Aust NZ JObstet Gynaecol. 2003; 43: 226–231.

2 Mozurkewich EL, Hutton EK. Elective repeat cesarean deliveryversus trial of labor: A meta–analysis of the literature from to1989 to 1999. Am J Obstet Gynecol. 2002; 183: 1187–1197.

3 Smith GC, Pell JP, Cameron AD, Dobbie R. Risk of perinataldeath associated with labor after previous cesarean deliveryin uncomplicated term pregnancies. JAMA. 2002; 287: 2684–2690.