Inhibins as Biomarkers for Reproductive Cancers

Inhibin is a dimeric (α and either βA or βB subunit) protein involved in the regulation of fertility. Inhibin A and B or its free α subunit monomer are elevated in various gonadal and prostate cancers and thus serve as useful diagnostic tools for certain ovarian tumors either as a serum marker or as an immunocytochemical marker for tissue sections. Serum inhibin levels are of value in the initial diagnosis and subsequent follow-up of sex cord stromal tumors, in particular granulosa cell tumors, and mucinous epithelial adenocarcinomas primarily after menopause. Immunocytochemistry using inhibin α subunit antisera can aid in the classification of sex cord stromal tumors and their differentiation from other cancers. Although serum inhibins are elevated in prostatic and testicular cancers, this is of little diagnostic value at the present time.

KEYWORDS

Ovarian cancer - granulosa cell tumors - mucinous carcinomas - inhibin α subunit - prostate cancer

REFERENCES

• 1 de Kretser D M, Hedger M P, Loveland K L, Phillips D J. Inhibins, activins and follistatin in reproduction.  Hum Reprod Update. 2002;  8 529-541
• 2 Knight P G, Glister C. Local role of TGF-beta superfamily members in the control of ovarian follicle development.  Anim Reprod Sci. 2003;  78 165-183
• 3 Lappohn R E, Burger H G, Bouma J, Bangah M, Krans M, de Bruijn H WA. Inhibin as a marker for granulosa cell tumours.  N Engl J Med. 1989;  321 790-793
• 4 Matzuk M M, Finegold M J, Su J G, Hseuh A J, Bradley A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice.  Nature. 1992;  360 313-319
• 5 Robertson D, Cahir N, Findlay J K, Burger H G, Groome N. The biological and immunological characterisation of inhibin A and B forms in human follicular fluid and plasma.  J Clin Endocrinol Metab. 1997;  82 889-896
• 6 Lambert-Messerlian G M, Steinhoff M, Zheng W et al.. Multiple immunoreactive inhibin proteins in serum from postmenopausal women with epithelial ovarian cancer.  Gynecol Oncol. 1997;  65 512-516
• 7 Petraglia F, Luisi S, Pautier P et al.. Inhibin B is the major form of inhibin/activin family secreted by granulosa cell tumours.  J Clin Endocrinol Metab. 1998;  83 1029-1032
• 8 Robertson D M, Stephenson T, Pruysers E et al.. Characterisation of inhibin forms and their measurement by an inhibin α subunit ELISA in serum from postmenopausal women with ovarian cancer.  J Clin Endocrinol Metab. 2002;  87 816-824
• 9 Robertson D M, Cahir N, Burger H G, Mamers P, Groome N. Inhibin forms in serum from postmenopausal women with ovarian cancers.  Clin Endocrinol (Oxf). 1999;  50 381-386
• 10 Boggess J F, Soules M R, Goff B A, Greer B E, Cain J M, Tamimi H K. Serum inhibin and disease status in women with ovarian granulosa cell tumors.  Gynecol Oncol. 1997;  64 64-69
• 11 Schumer S T, Cannistra S A. Granulosa cell tumor of the ovary.  J Clin Oncol. 2003;  21 1180-1189
• 12 Sluijmer A V, Heineman M J, Evers J LH, de Jong F H. Peripheral vein, ovarian vein and ovarian tissue levels of inhibin in a postmenopausal patient with a granulosa cell tumour.  Acta Endocrinol (Copenh). 1993;  129 311-314
• 13 Jobling T, Mamers P, MacLachlan V et al.. A prospective study of inhibin in granulosa cell tumours of the ovary.  Gynecol Oncol. 1994;  55 285-289
• 14 Cooke I, O'Brien M, Charnock F M, Groome N, Ganesan T S. Inhibin as a marker for ovarian cancer.  Br J Cancer. 1995;  71 1046-1050
• 15 McCluggage W G. Recent advances in immunochemistry in gynaecological pathology.  Histopathology. 2002;  40 309-326
• 16 Zheng W, Senturk B Z, Parkash V. Inhibin immunohistochemical staining: a practical approach for the surgical pathologist in the diagnosis of ovarian sex cord-stromal tumors.  Adv Anat Pathol. 2003;  10 27-38
• 17 Risbridger G P, Schmitt J F, Robertson D M. Activin and inhibin in endocrine and other cancers.  Endocr Rev. 2001;  22 836-858
• 18 Ala-Fossi S L, Aine R, Punnonen R, Maenpaa J. Is potential to produce inhibins related to prognosis in ovarian granulosa cell tumours?.  Eur J Gynaecol Oncol. 2000;  21 187-189
• 19 Gebhart J B, Roche P C, Keney G L, Lesnick T G, Podratz K C. Assessment of inhibin and p53 in granulosa cell tumors of the ovary.  Gynecol Oncol. 2000;  77 232-236
• 20 Healy D L, Burger H G, Mamers P et al.. Elevated serum inhibin concentrations in postmenopausal women with ovarian tumours.  N Engl J Med. 1993;  329 1539-1542
• 21 Burger H G, Fuller P J, Chu S et al.. The inhibins and ovarian cancer.  Mol Cell Endocrinol. 2001;  180 145-148
• 22 Fuller P J, Chu S, Jobling T, Mamers P, Healy D L, Burger H G. Inhibin subunit gene expression in ovarian cancer.  Gynecol Oncol. 1999;  73 273-279
• 23 Cobellis L, Cataldi P, Reis F M et al.. Gonadal malignant germ cell tumours express immunoreactive inhibin/activin subunits.  Eur J Endocrinol. 2001;  145 779-784
• 24 Zheng W, Lu J J, Luo F et al.. Tumour stroma as the main source of inhibin production in ovarian epithelial tumours.  Am J Reprod Immunol. 2000;  44 104-113
• 25 Robertson D M, Stephenson T, Cahir N et al.. Development of an inhibin α subunit ELISA with broad specificity.  Mol Cell Endocrinol. 2001;  180 79-86
• 26 Robertson D M, Pruysers E, Burger H G, Jobling T, McNeilage J, Healy D. Inhibins and ovarian cancer.  Mol Cell Endocrinol. , in press
• 27 Skates S J, Menon U, MacDonald N et al.. Calculation of the risk of ovarian cancer from serial CA-125 values for preclinical detection in postmenopausal women.  J Clin Oncol. 2003;  21 206-210
• 28 Lambert-Messerlian G M, DePasquale S E, Maybruck W M, Steinhoff M, Gajewski W H. Secretion of activin A in recurrent epithelial ovarian carcinoma.  Gynecol Oncol. 1999;  74 93-97
• 29 Risbridger G P, Mellor S L, McPherson S J, Schmitt J F. The contribution of inhibin and activins to malignant prostate disease.  Mol Cell Endocrinol. 2001;  180 149-153
• 30 Risbridger G P, Ball E M, Wang H, Mellor S, Peehl D M. Evaluation of inhibin α subunit as a tumour suppressor in prostate cancer.  Mol Cell Endocrinol. , in press
• 31 McCluggage W G, Shanks J H, Whiteside C, Maxwell P, Banerjee S S, Biggart J D. Immunohistochemical study of testicular sex cord-stromal tumors, including staining with anti-inhibin antibody.  Am J Surg Pathol. 1998;  22 615-619
• 32 Iczkowski K A, Bostwick D G, Roche P C, Cheville J C. Inhibin A is a sensitive and specific marker for testicular sex cord-stromal tumors.  Mod Pathol. 1998;  11 774-779
• 33 Toppari J, Kaipia A, Kaleva M et al.. Inhibin gene expression in a large cell calcifying Sertoli cell tumour and serum inhibin and activin levels.  APMIS. 1998;  106 101-112
• 34 Jones R L, Salamonsen L A, Critchley H OD, Rogers P AW, Affandi B, Findlay J K. Inhibin and activin subunits are differentially expressed in endometrial cells and leukocytes during the menstrual cycle, in early pregnancy and in women using progestin-only contraception.  Mol Hum Reprod. 2000;  6 1107-1117
• 35 Fuller P J, Zumpe E T, Chu S, Mamers P, Burger H G. Inhibin-activin receptor subunit gene expression in ovarian tumours.  J Clin Endocrinol Metab. 2002;  87 1395-1401
• 36 Robertson D M, Stephenson T, Pruysers E et al.. Inhibins/activins as diagnostic markers for ovarian cancer.  Mol Cell Endocrinol. 2002;  191 97-163