Correspondence

Normal Production of Human Chorionic Gonadotropin in Menopause

N Engl J Med 2007; 356:1184-1186March 15, 2007

Article

To the Editor:

A positive test for the presence of human chorionic gonadotropin (hCG) before menopause is an indication of pregnancy.1 A positive hCG test in menopausal women poses a diagnostic challenge, despite available guidance in the literature.1,2 Erroneous assumptions regarding the presence of cancer have led to costly diagnostic testing, delays in necessary treatment, and even the initiation of toxic cancer treatments.

Pituitary production of hCG was first demonstrated 30 years ago, and many contemporary reports indicate that the pituitary produces hCG.1-4 Low levels of hCG accompany the midcycle preovulatory surge of luteinizing hormone,1-4 and pituitary hCG is normally produced with increasing menopausal production of luteinizing hormone, owing to the decreased production of estrogen and the suppression of progesterone.1

In 2006, the USA hCG Reference Service consulted on the treatment of 120 premenopausal or menopausal women with serum hCG levels above 2 mIU per milliliter. Formal laboratory consultation was requested for 28 of these women; we present the results of the study here. Three women were prematurely menopausal due to primary amenorrhea or surgical oophorectomy at the ages of 29, 35, and 39 years; 25 were naturally perimenopausal or menopausal at the ages of 42 to 69 years. In most cases, hCG was detected during a preoperative or pretreatment evaluation (Table 1Table 1Histories of 28 Menopausal Women with Detectable Levels of hCG.). The mean (±SD) level of hCG was 9.5±6.5 mIU per milliliter (range, 2.1 to 32.0), and all 28 women had variably elevated levels of luteinizing hormone; 12 had levels of more than 200 mIU per milliliter. Although hCG levels ranged from 2.7 to 19.0% of luteinizing hormone levels, there was no correlation between measures of the two hormone levels (r²=0.78).

Pending investigation of the hCG source, scheduled surgery was postponed for eight patients, including three who were scheduled to undergo renal transplantation. Six women had a history of gestational trophoblastic disease; therefore, recurrent disease was assumed, and unnecessary chemotherapy given to three. In all cases, only pregnancy-type hCG was detected. Hyperglycosylated hCG, a marker of gestational trophoblastic neoplasm, and the hCG free β-subunit, the form of hCG produced by nontrophoblastic tumors, were absent in all patients.2,5 Results for all 28 patients support the hypothesis of normal pituitary function as the origin of the low level of hCG. Suppression of pituitary hCG production with a minimum of 2 weeks of treatment with estrogen–progesterone hormone-replacement therapy was recommended to all 28 patients. Outcome information was provided for 18 of the 28 patients (64%). In all 18 patients, hormone-replacement therapy suppressed the production of hCG to less than 2 mIU per milliliter.

Since measurement of serum or urinary hCG is increasingly performed in women as part of a preintervention assessment, positive results in menopausal women continue to create diagnostic problems that are potentially stressful. Low-level production of hCG is clearly normal in menopausal women. The finding of an hCG level of 32 mIU per milliliter or less in menopausal women may be sufficient to conclude that there is a pituitary source of hCG. However, the pituitary origin is easily confirmed by the resolution of hCG levels after the administration of hormone-replacement therapy for 2 or more weeks.

Laurence A. Cole, M.D., Ph.D.
Yasushi Sasaki, M.D., Ph.D.
Carolyn Y. Muller, M.D.
University of New Mexico, Albuquerque, NM 87131

5 References

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   Matsuura S, Ohashi M, Chen HC, et al. Physicochemical and immunological characterization of an HCG-like substance from human pituitary glands. Nature 1980;286:740-741
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   Cole LA, Khanlian SA, Muller CY, Giddings A, Kohorn EI, Berkowitz R. Gestational trophoblastic diseases. 3. Human chorionic gonadotropin-free β-subunit, a reliable marker of placental site trophoblastic tumors. Gynecol Oncol 2006;102:160-164
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Citing Articles (15)

Citing Articles

1. 1

   Donald Peter Goldstein, Ross S. Berkowitz. (2012) Current Management of Gestational Trophoblastic Neoplasia. Hematology/Oncology Clinics of North America 26:1, 111-131
   CrossRef

2. 2

   W. Norris, T. Nevers, S. Sharma, S. Kalkunte. (2011) Review: hCG, preeclampsia and regulatory T cells. Placenta 32, S182-S185
   CrossRef

3. 3

   S. White, R. Harvey, H. Mitchell, P. Schmid, M. Seckl, P. Savage. (2011) Characterisation of transient benign hCG elevations in women following chemotherapy for GTT. Journal of Obstetrics & Gynaecology 31:2, 169-172
   CrossRef

4. 4

   Taymaa May, Donald P. Goldstein, Ross S. Berkowitz. (2011) Current Chemotherapeutic Management of Patients with Gestational Trophoblastic Neoplasia. Chemotherapy Research and Practice 2011, 1-12
   CrossRef

5. 5

   LaToya R. Walker, Brian Erler. (2011) Gastric Cancer in the Setting of Persistently Elevated Human Chorionic Gonadotropin: A Case Report. Case Reports in Obstetrics and Gynecology 2011, 1-4
   CrossRef

6. 6

   Laurence A. Cole, Laura L. Laidler, Carolyn Y. Muller. (2010) USA hCG reference service, 10-year report. Clinical Biochemistry 43:12, 1013-1022
   CrossRef

7. 7

   Laurence A. Cole, Sarah A. Khanlian, Carolyn Y. Muller. (2009) Normal Production of Human Chorionic Gonadotropin in Perimenopausal and Menopausal Women and After Oophorectomy. International Journal of Gynecological Cancer 19:9, 1556-1559
   CrossRef

8. 8

   Laurence A Cole. (2009) Human chorionic gonadotropin tests. Expert Review of Molecular Diagnostics 9:7, 721-747
   CrossRef

9. 9

   2009. Female Reproductive Organ Testing. , 399-425.
   CrossRef

10. 10

    Carolyn Y. Muller, Laurence A. Cole. (2009) The quagmire of hCG and hCG testing in gynecologic oncology. Gynecologic Oncology 112:3, 663-672
    CrossRef

11. 11

    Laurence A. Cole, Donald G. Ladner. (2009) Background hCG in non-pregnant individuals: Need for more sensitive point-of-care and over-the-counter pregnancy tests. Clinical Biochemistry 42:3, 168-175
    CrossRef

12. 12

    Laurence A Cole. (2009) Human chorionic gonadotropin and associated molecules. Expert Review of Molecular Diagnostics 9:1, 51-73
    CrossRef

13. 13

    S.F. de Medeiros, R.J. Norman. (2008) Human choriogonadotrophin protein core and sugar branches heterogeneity: basic and clinical insights. Human Reproduction Update 15:1, 69-95
    CrossRef

14. 14

    Amy S. Duffield, Pamela Jarrar, Chung Shum, Nita Ahuja, Charles J. Yeo, Lori J. Sokoll. (2008) Retroperitoneal masses with associated human chorionic gonadotropin production: Report of two cases. Clinica Chimica Acta 395:1-2, 166-169
    CrossRef

15. 15

    Laurence A. Cole, Sarah A. Khanlian, Carolyn Y. Muller. (2008) Detection of perimenopause or postmenopause human chorionic gonadotropin: an unnecessary source of alarm. American Journal of Obstetrics and Gynecology 198:3, 275.e1-275.e7
    CrossRef