The possible role of human placental lactogen in worse outcomes of differentiated thyroid cancer in pregnancy
Lactogens comprise three closely related peptide hormones: human growth hormone (hGH), human placental lactogen (hPL), and human prolactin (hPRL). hPRL and hGH originate from the pituitary and hPL is secreted by syncytiotrophoblasts of the placenta. Levels of hPL vary during pregnancy; it can be detected from the sixth week of gestation, increases steadily in the first and second trimesters, and peaks at a constant level in the third. hPL expression has been reported in testicular, ovarian, and breast cancers. Of the endocrine tumors, differentiated thyroid cancer (DTC) is the most frequently seen and commonly occurs in younger women and pregnancy has the potential to exacerbate thyroid cancer progression or recurrence. Although hGH binds well to GH receptors (GHR) and PRL receptors (PRLR), hPRL only binds to PRLR. hPL per se has no specific receptor yet it is able to bind to PRLRs with a high affinity regardless of its low (23%) structural homology to PRL. Paradoxically, hPL binds weakly to GHR even though they have significant (85%) amino acid sequence homology. We hypothesized that high levels of hPL could explain the worse outcomes of DTC in pregnancy. A possible mechanism could be that hPL binds GHR–PRLR in thyroid tissue and promotes tumor growth. Alternatively, the high affinity of hPL for PRLRs expressed in thyroid cancer may account for these results. Conversely, hPL binding to GHR, albeit weakly, might also play a role in worsened outcomes. Additional studies must be performed in order for the pathophysiologic mechanisms to be elucidated.
The most frequently seen endocrine tumor is differentiated thyroid cancer (DTC) and it is common in younger women(1). Numerous factors are known to induce thyroid cell growth in the course of normal pregnancy(2). Human chorionic gonadotropin, which is especially increased in the first trimester of pregnancy, directly but temporarily stimulates the thyroid gland. This stimulatory effect may partially account for pregnancy-related thyroid enlargement(3).
Increased concentrations of estrogen may have a negative impact in thyroid cancer growth, but this remains controversial(4,5). Magri et al. proposed that estrogen receptor-β negativity, estrogen receptor-α positivity, and high expression of androgen receptor in thyroid cancer were associated with a more aggressive phenotype(6). Relative iodine deficiency during gestation can also have an effect on stimulation of thyroid tissue growth(3). It is reasonable to propose that pregnancy may increase the risk of thyroid cancer progression or recurrence because normal thyroid growth and thyroglobulin production are induced by pregnancy(7). In a recent study, Mesutti et al. indicated that pregnant women have higher rates of DTC persistence/recurrence, which lends support to the argument that pregnancy has a negative impact on patients with DTC; however, no differences were found between the groups regarding estrogen receptor pattern, sodium/iodide symporter (NIS) expression, and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations. Consequently, the authors concluded that additional future studies were required because the underlying causes were yet to be revealed(8).
We hypothesize that high levels of hPL could explain the worse outcomes of DTC in pregnancy.
a. Human placental lactogen and pregnancy
Lactogens comprise three closely related peptide hormones: human growth hormone (hGH), human placental lactogen (hPL), and human prolactin (hPRL)(9). The tertiary structures of these hormones are comparable and their functions overlap(10). hPRL and hGH principally originate from the pituitary and hPL, known as chorionic somatomammotropin hormone (CSH), is secreted by syncytiotrophoblasts of the placenta. Levels of hPL vary during pregnancy; it can be detected from the sixth week of gestation, increases steadily in the first and second trimesters, and peaks at a constant level in the third. Serum levels of hPL display slight changes throughout the day. Induced hyperglycemia or hypoglycemia do not affect serum hPL. Its half-life is approximately 30 min and it immediately disappears from the blood after labor(11,12). hPL stimulates mammary gland development and lactogenesis and directly affects fetal growth and metabolism(13). At term, no other protein hormone has greater levels than maternal serum hPL(14).
Each of the three lactogens binds to PRLRs, which is a feature exclusive to humans. hGH binds to PRLRs and GHRs but in many species PRL binds exclusively with PRLRs. hPL per se has no specific receptor, yet it is able to bind to PRLRs with a high affinity regardless of its low (23%) structural homology to PRL. Paradoxically, hPL binds weakly to GHR even though they have significant (85%) amino acid sequence homology(15-18).
b. Human placental lactogen and cancer
hPL expression has been reported in testicular and ovarian cancers(19-21). Immunoreactive hPL has been determined in the serum of some patients with breast cancer but not in those with benign breast disease or healthy men and women(22,23). Presence of hPL in breast cancer has a negative influence on prognosis for patients(22). Contrary to these findings, one study did not find hPL in the serum of patients with breast cancer(24). The amplification of CSH genes in breast cancers was shown to be related to aneuploidy, lymph node metastases, and overexpression of the Her2/neu oncogene. Moreover, immunohistochemical labelling of hPL in carcinomas further demonstrates the relationship with gene amplification(25).
hPL is increased in histologic sections as well as serum with placental site trophoblastic tumors(26). Xiong et al. reported that the expression of placental hormones including human chorionic gonado-tropin (hCG), human placental lactogen, and pregnancy-specific 1-glycoprotein in invasive moles and choriocarcinomas were associated with the degree of tumor malignancy, biologic behaviour, and grading of trophoblastic cell differentiation(27). Remadi et al. described a case of placental site trophoblastic tumor with pulmonary metastasis that exhibited a preponderance of hPL positive cells(28). Breast carcinoma with choriocarcinomatous features that demonstrate hCG and hPL expression is a rare variant of breast carcinoma characterized by atypical malignant cells, which are morphologically similar to choriocarcinoma cells(29). hPL was detected in 19 of 97 (20%) lung tumor tissue sections in one study(30). The ectopic production of hPL may provide a specific marker for cancers in men and non-pregnant women(31). The low efficacy of cancer therapy and continuous growth of breast and prostate tumors is thought to be caused by activation of anti-apoptotic processes through long-term exposure to circulating and/or locally-produced lactogens(32). The frequency of immunoreactive hPLs in endometrial cancer is higher than in endometrial hyperplasia(33).
Wu et al. reported that hGH expression alone or combined with hPRL expression in patients with mammary or endometrial carcinoma was related to worse relapse-free survival and overall survival(34). Costa et al. reported that PRLR expression was detected in 76.1% of all thyroid cancers(35).
GH has metabolic and growth-promoting effects in various tissues of humans. Although hGH binds to hGHRs and hPRLRs, hPRL only binds to hPRLRs. GHRs and PRLRs combine and form heterodimers in breast cancer cells and this increases the likelihood of hPL binding to these receptors and promoting growth(36). Previous studies reported that ovine placental lactogen (PL) heterodimerized the extracellular domains of ruminant GHRs and PRLRs(37,38). Langenheim et al. showed that humans could form PRLR-GHR heterodimers, which provided connections for signal transduction(39).
GHR–PRLR heterodimerization in breast cancer cells augments the probability of hPL binding to such a hybrid receptor and promoting growth. We hypothesize that high levels of hPL could explain the worse outcome of DTC in pregnancy. A possible mechanism is that hPL binds GHR–PRLR in thyroid tissue and promotes tumor growth. High affinity of hPL for PRLR, which is expressed in thyroid cancer, could explain worse outcomes. Although weak, the binding of hPL to the hGH receptor may have a negative effect on outcomes. GH and PRL are potent oncogenes and hPL exerts its effects via the same receptors. hPL may have oncogenic action as a consequence of exerting its effect via the same receptors. Additional studies are required to elucidate the pathophysiologic mechanisms.H
The authors would like to thank their colleagues for their comments and suggestions on improving the article.
Conflicts of Interest
Authors declare no conflicts of interest.
About the Authors
Muhammed Kizilgul is a clinical fellow in Endocrinology and Metabolism. He is experienced in managing patients with thyroid cancer. His special interests are thyroid cancer, type 1 diabetes mellitus, islet cell alloauto-xeno transplantation.
Seyfullah Kan is a clinical fellow in Endocrinology and Metabolism. He is experienced in managing patients with thyroid cancer.
Tuncay Delibasi is a Professor of Endocrinology and Metabolism. Prof Delibasi has over 20 years’ experience in the management of thyroid cancer. He is a medical director for islet cell transplant program at the Diskapi Teaching and Research Hospital.
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