Este inhibina un marker serologic util pentru femeile la postmenopauză cu cancer ovarian epitelial?

Ovarian cancer is the second most common gynecologic cancer in developed countries and the third most common gynecologic malignancy in developing countries⁽¹⁾. Of all ovarian malignancies, 95% are of epithelial type, developed from epithelial cells. It represents the fifth leading cause of death in women in Europe and the United States⁽²⁾. The disease is usually diagnosed in an advanced stage. This is due to the non­spe­cific symptomatology, which appears when cancer has already spread throughout the abdominal cavity, and the lack of some specific options for screening. Despite significant effort to develop new therapies, late diagnosis is still associated with a low treatment efficacy and a high mortality. Although during the years new diagnostic or screening methods for epithelial ovarian cancer have been introduced on a regular basis, these did not significantly improve the treatment outcome⁽³⁾.

Early diagnosis is still the best option to reduce mortality caused by epithelial ovarian cancer (EOC). More specific strategies for screening and diagnosis should have a great impact in the treatment outcome. In addition, it is considered that finding some prognostic factors should be useful for selecting the patients with poor prognosis for a more aggressive therapy^(4,5).

The combination of CA 125 and vaginal ultrasono­graphy is the most frequently used screening strategy for the patients with family history of ovarian cancer. Moreover, researchers have tried to combine other serum markers (HE4, inhibin, CEA, CA 19-9) or multimodal tests to improve the detection of malignant pathology of the ovary. Not all strategies could show a high sensitivity and specificity for the diagnosis of epithelial ovarian cancer. They are associated with a high rate of false-positive tests and the risk of more invasive testing and treatment⁽⁶⁾. Some studies reveal that combinations of biomarkers and imaging may improve ovarian cancer detection, but further studies are needed to validate these hypotheses^(6,7). 

There are some reports in the literature on inhibin level in women with epithelial ovarian carcinoma^(4,8). It is known that the serum total inhibin is a sensitive marker for diagnosis and monitoring of mucinous and granulosa-cell tumors of the ovary. Its levels decrease significantly after surgery and increase in case of recurrence. But some studies reflect that inhibin is also elevated in epithelial ovarian tumors⁽⁹⁾. 

Inhibins are members of the transforming growth factor beta (TGFb) family, a group of growth factors with similar structure but with different functions. Inhibin is synthesized as a dimeric glycoprotein consisting of an a subunit and one of two b subunits (bA, bB). The complex a/bA is called inhibin A, and the complex a/bB is known as inhibin B^(10,11).

Inhibin A is produced by the dominant ovarian fol­licle and the corpus luteum. Inhibin B, on the other hand, is released from the smaller follicles⁽¹²⁾. More exac­tly, inhibin has been isolated from follicular fluid and is produced by the granulosa cell layers of the fol­licle^(13,14). It is produced by the ovaries and secreted into the bloodstream and behave as an endocrine factor. It specifically inhibits the secretion of the follicle-sti­mu­lating hormone (FSH), a pituitary hormone which pro­motes ovarian folliculogenesis. In turn, FSH stimulates in­hibin production in the gonads, regulating fertility through a FSH-inhibin negative-feedback mechanism⁽⁹⁾. At menopause, with the depletion of ovarian follicles, serum inhibin levels decrease to nondetectable levels and serum FSH increase^(9,12).

It is established that inhibin serum level is a useful test for detecting and monitoring the recurrence of gra­nu­losa-cell tumors (GCT) and mucinous tumors of the ovary, but elevated inhibin levels were also reported in women with EOC^(9,11,16).

Blaakaer et al. suggested an inverse relationship between serum inhibin and FSH, developing a study on postmenopausal women with epithelial ovarian tumors. They showed the correlation between an elevated inhibin level and a decreased FSH level in the group of women with EOC⁽¹⁵⁾.

On the contrary, in a study on 212 postmenopausal wo­men with suspected ovarian cancer, Healy et al. de­mon­strated that inhibin concentration was negatively cor­related with serum FSH level in women with GCT, but not in women with other ovarian tumors. Also, they showed that 82% of women with mucinous carcinomas had high serum inhibin level and only some women with other types of epithelial ovarian tumors (17% of patients with EOC). The concentrations fell after tumor removal⁽¹⁶⁾.

Also, it was revealed that serous tumors secrete inhibin-related peptides, but not dimeric inhibin A⁽¹⁷⁾. Other data suggested that serum a inhibin precursor (pro-aC) levels were more often raised in women with EOC than dimeric inhibin (A and B), and pro-aC associated with CA 125 may be useful as a biomarker for EOC in postmenopausal women⁽¹¹⁾.

On the other hand, Frias et al. reported inhibin A as a possible independent prognostic factor for survival in postmenopausal women with EOC⁽⁵⁾. Menon et al. study supported the findings about the preferential secretion of precursor forms of the a subunit by EOC, rather than dimeric inhibin A. They didn’t agree on the pro-aC as biomarker for EOC due to the fact that only 11% of women had elevated levels⁽¹⁸⁾.

Other studies investigating the total inhibin as serum marker for epithelial ovarian tumors showed that the combination between CA 125 and serum inhibin may be useful for noninvasive diagnosis of EOC^(8,19).

Another study evaluated the source of elevated inhibin from ovarian epithelial tumors and the role of the gonadotropin-inhibin/activin relationship in the development of EOC. It concluded that stroma of EOC is the main source of the secretion of serum a in­hi­bin. Dimeric inhibin A production may be the re­sult of combined secretion of the a subunit by tumor stro­ma and the bA subunit by epithelium. However, the me­cha­nism of the inhibin and activin in the develop­ment of EOC remained unclear^(4,20). Tournier et al. sug­gested that inhibin genetic mutation (mutation of the INHBA gene) conducted to the genetic determinism of epi­thelial tumors⁽²¹⁾.

Despite the numerous reviews, an exact role of in­hi­bins (precursors, subunits and mature molecules of inhibin) in epithelial ovarian cancer has not been es­ta­blished yet. It has been recognized that various forms of this type of cancer produce members of the inhibin fa­mily, but the precise molecules of these products are not yet defined. The researchers admitted the importance of inhibins in epithelial ovarian tumors, but further stu­dies are needed to prove the clinical utility in the diag­nosis, management and prognosis, and also as a fac­tor in the pathogenesis of these tumors.

Due to late diagnosis and high mortality of women diagnosed with ovarian cancer, there is an imperative need for new serum markers for epithelial ovarian cancer which can improve the sensitivity and specificity of markers already used for the early diagnosis and management.

The discovery of a serum marker for epithelial ovarian cancer could represent an important step toward the screening of this disease.

Inhibin may be one of these, but additional and lar­ger stu­dies are needed to establish its accurate utility in epi­the­lial ovarian cancer. It is known that only some EOC have high serum inhibin levels. Finding the par­ti­­cu­la­ri­ties of serous type of ovarian cancer which secrete inhibin may lead to some conclusions. Also, it is essential to determine the mechanism through which inhibin le­vels are increased in women with EOC.