Correspondence

Hypercalcemia in Pregnancy and Lactation Associated with Parathyroid Hormone-Related Protein

N Engl J Med 1993; 328:666-667March 4, 1993

Article

To the Editor:

Parathyroid hormone-related protein is produced by tumors associated with hypercalcemia and by a variety of normal tissues including lactating breast tissue1. We describe a woman who had hypercalcemia associated with elevated serum concentrations of parathyroid hormone-related protein during pregnancy and lactation.

Lethargy, thirst, polyuria, and nocturia developed in a 34-year-old woman who was 35 weeks pregnant. Physical examination was normal. Her serum calcium concentration was 11.9 mg per deciliter (normal, 9.0 to 10.4) initially and 14.0 mg per deciliter at delivery at 38 weeks of gestation. The serum parathyroid hormone concentration was low. No evidence of tumor or other recognized cause of hypercalcemia was found. The hypercalcemia persisted despite treatment with 30 mg of prednisone per day, but it resolved six months post partum. The patient was asked to return early in any future pregnancy to have serum calcium measured.

Two years later the patient presented in the ninth week of gestation; she was asymptomatic, the serum calcium concentration was 11.4 mg per deciliter, and serum parathyroid hormone was low (and remained low until 13 months post partum). Late in this pregnancy, when the serum calcium concentration was greater than 12.0 mg per deciliter, the same symptoms developed as in the earlier pregnancy (Figure 1Figure 1Serum Calcium and Parathyroid Hormone-Related Protein Concentrations in a Woman with Hypercalcemia Related to Pregnancy and Lactation.). A healthy infant was delivered at 38 weeks of gestation. The infant's serum calcium concentration was 11.6 mg per deciliter at birth but became normal within 24 hours. During the third trimester the mother had elevated serum parathyroid hormone-related protein concentrations (6 to 8 pmol per liter [normal, <2]), as measured by an N-terminal radioimmunoassay (sensitivity, 2 pmol per liter) that detects circulating parathyroid hormone-related protein in 100 percent of patients with humoral hypercalcemia of cancer but not in any normal subjects2. Her serum parathyroid hormone-related protein and calcium concentrations remained elevated for several months during lactation. The protein was undetectable in the infant's serum at birth.

As well as in various tumors, parathyroid hormone-related protein can be found in the skin, placenta, pregnant uterus, and lactating mammary gland. Milk from a variety of mammalian species3 contains high concentrations of the protein; this woman's milk contained 4 to 19 nmol per liter (normal, 2 to 20), suggesting breast tissue as the source of the protein during pregnancy. A previous report described a woman who had mammary hypertrophy and hypercalcemia during pregnancy that resolved with bilateral mastectomy4.

Parathyroid hormone-related protein may have a paracrine role in the lactating breast, but occasionally, as in the present case, it may reach the circulation from the activated breast in sufficient amounts to exert humoral effects.

F. Lepre, F.R.A.C.P.
Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia

V. Grill, F.R.A.C.P.
P.W.M. Ho, B.Sc.
T.J. Martin, M.D., D.Sc., F.R.A.C.P.
St. Vincent's Institute of Medical Research, Melbourne, Victoria 3065, Australia

4 References

1. 1

   Martin TJ. Properties of parathyroid hormone-related protein and its role in malignant hypercalcaemia. Q J Med 1990;76:771-786
   Web of Science | Medline

2. 2

   Grill V, Ho P, Body JJ, et al. Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer. J Clin Endocrinol Metab 1991;73:1309-1315
   CrossRef | Web of Science | Medline

3. 3

   Budayr AA, Halloran BP, King JC, Diep D, Nissenson RA, Strewler GJ. High levels of a parathyroid hormone-like protein in milk. Proc Natl Acad Sci U S A 1989;86:7183-7185
   CrossRef | Web of Science | Medline

4. 4

   Khosla S, van Heerden JA, Gharib H, et al. Parathyroid hormone-related protein and hypercalcemia secondary to massive mammary hyperplasia. N Engl J Med 1990;322:1157-1157
   Web of Science | Medline

Citing Articles (13)

Citing Articles

1. 1

   Carey Winkler, Fred Coleman. 2010. Endocrine Emergencies. , 425-437.
   CrossRef

2. 2

   Martin N. Montoro, T. Murphy Goodwin. 2010. Calcium Metabolism and Diseases of the Parathyroid Glands during Pregnancy. , 352-370.
   CrossRef

3. 3

   H. A. Tran, N. Petrovsky. (2002) Pregnancy-associated osteoporosis with hypercalcaemia. Internal Medicine Journal 32:9-10, 481-485
   CrossRef

4. 4

   A. Morton. (2002) Milk-alkali syndrome in pregnancy, associated with elevated levels of parathyroid hormone-related protein. Internal Medicine Journal 32:9-10, 492-493
   CrossRef

5. 5

   Gordon J. Strewler. (2000) THE PARATHYROID HORMONE–RELATED PROTEIN. Endocrinology & Metabolism Clinics of North America 29:3, 629-645
   CrossRef

6. 6

   Epstein, Franklin H., , Strewler, Gordon J., . (2000) The Physiology of Parathyroid Hormone–Related Protein. New England Journal of Medicine 342:3, 177-185
   Full Text

7. 7

   F. Harsoulis, B. Karayiannis, D. Karvo. (2000) Primary hyperparathyroidism in pregnancy. Journal of Obstetrics & Gynaecology 20:2, 188-189
   CrossRef

8. 8

   Jorge H. Mestman. (1998) Parathyroid Disorders of Pregnancy. Seminars in Perinatology 22:6, 485-496
   CrossRef

9. 9

   John Eisman. (1998) Relevance of pregnancy and lactation to osteoporosis?. The Lancet 352:9127, 504-505
   CrossRef

10. 10

    Yoshiko Hirota, Takanobu Anai, Isao Miyakawa. (1997) Parathyroid hormone–related protein levels in maternal and cord blood. American Journal of Obstetrics and Gynecology 177:3, 702-706
    CrossRef

11. 11

    AC Koeger, F Oberlin. (1997) Métabolisme phosphocalcique pathologique pendant la grossesse et l'allaitement. La Revue de Médecine Interne 18:7, 546-552
    CrossRef

12. 12

    W. Khovidhunkit, S. Epstein. (1996) Osteoporosis in pregnancy. Osteoporosis International 6:5, 345-354
    CrossRef

13. 13

    Janet L. Funk, Dolores M. Shoback, Harry K. Genant. (1995) Transient osteoporosis of the hip in pregnancy: natural history of changes in bone mineral density. Clinical Endocrinology 43:3, 373-382
    CrossRef