Specialities

Specialities

Bone Disorders
Cardiovascular Risk
COVID-19
Diabetes
Endocrine Oncology
General Endocrinology
Obesity
Paediatric Endocrinology
Pituitary Disorders
Reproductive Endocrinology
Thyroid Disorders
Chronic Kidney Disease
Liver Disorders
Adrenal Disorders
Search

Trending Topic

Stastical analysis indication diabetes mellitus .generative ai
5 mins

Trending Topic
Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Forty-four Years of the UK Prospective Diabetes Study: Legacy Effect and Beyond

Saptarshi Bhattacharya, Sanjay Kalra, Lakshmi Nagendra

Very few trials in the history of medical science have altered the treatment landscape as profoundly as the UK Prospective Diabetes Study (UKPDS). Even 44 years after its inception, the trial and post-study follow-up findings continue to fascinate and enlighten the medical community. The study was conceived at a time when there was uncertainty about […]

touchREVIEWS in Endocrinology. 2024;21(1):1–2:Online ahead of journal publication

Connect With Us:

Facebook
X (Twitter)
Instagram
Youtube
Linkedin
Reproductive Endocrinology
11 mins

Gonadotrophic Hormones – An Overview of their Involvement in Gonadal and Extragonadal Tumours

Maria Alevizaki, Ilpo Huhtaniemi
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Jul 5th 2011 European Endocrinology, 2011;7(1):8-13 DOI: http://doi.org/10.17925/EE.2011.07.01.8
Select a Section…
1

Abstract

Overview

Abstract
The concept of the direct involvement of gonadotrophins in tumorigenesis has been around for a long time. First, because the gonads are direct targets of gonadotrophin action, their tumours have been proposed to be gonadotrophin-dependent. Second, the recent findings of gonadotrophin receptors in extragonadal tissues has prompted the hypothesis that some extragonadal tumours (e.g. breast, uterus, prostate, pituitary and adrenal) could also be under the direct regulatory action of gonadotrophins. However, although supported by numerous in vitro experiments and experimental animal models, the clinical evidence for a direct tumorigenic role of gonadotrophins remains weak. The purpose of this brief review is to present a critical evaluation of current information, both clinical and experimental, about the involvement of gonadotrophins in the induction and growth of gonadal and extragonadal tumours.

Keywords
Follicle-stimulating hormone (FSH), luteinising hormone (LH), human chorionic gonadotrophin (hCG), gonadotrophin receptors, ovarian cancer, breast cancer, prolactinoma, adrenal tumour

Disclosure: The authors have no conflicts of interest to declare.
Received: 21 October 2010 Accepted: 3 February 2011 Citation: European Endocrinology, 2011;7(1):8–13
Correspondence: Ilpo Huhtaniemi, Institute of Reproductive and Developmental Building, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. E: ilpo.huhtaniemi@imperial.ac.uk

Keywords

Follicle-stimulating hormone (FSH), luteinising hormone (LH), human chorionic gonadotrophin (hCG), gonadotrophin receptors, ovarian cancer, breast cancer, prolactinoma, adrenal tumour

2

Article

There are three gonadotrophic hormones: follicle-stimulating hormone (FSH) and luteinising hormone (LH), produced by the anterior pituitary gland, and human chorionic gonadotrophin (hCG), produced by placental trophoblasts. Besides stimulating gonadal steroidogenesis and gametogenesis, these hormones have stimulatory effects on the proliferation of their target cells. Therefore, it is feasible that gonadotrophins could participate in the initiation or subsequent growth of tumours arising in their target organs.

There are three gonadotrophic hormones: follicle-stimulating hormone (FSH) and luteinising hormone (LH), produced by the anterior pituitary gland, and human chorionic gonadotrophin (hCG), produced by placental trophoblasts. Besides stimulating gonadal steroidogenesis and gametogenesis, these hormones have stimulatory effects on the proliferation of their target cells. Therefore, it is feasible that gonadotrophins could participate in the initiation or subsequent growth of tumours arising in their target organs. Ovarian granulosa and testicular Sertoli cells are the classic target cells for FSH action, and ovarian theca, granulosa and luteal cells and testicular Leydig cells those for LH. Hence, gonadotrophin action in the ovary and testes could be either directly or through paracrine links responsive to gonadotrophin stimulation. Recent findings of gonadotrophin receptors in normal and tumorous extragonadal tissues have widened the tumorigenic potential of these hormones outside their classic sites of action within gonads.1,2 The purpose of this review is to briefly summarise current information about the role of gonadotrophins in gonadal and extragonadal tumorigenesis. Ovarian Tumours
Ovarian cancer is the most common cause of death from gynaecological cancers worldwide.3 Its aetiology remains unclear, but it is likely multifactorial. Because the ovaries are the best characterised, and physiologically the only undisputed, target of gonadotrophin action in the female, it is natural that tumorigenesis of this organ has been related to their actions. The currently available data are based, on the one hand, on epidemiological association studies of gonadotrophin levels with occurrence of ovarian cancer and, on the other hand, on laboratory studies demonstrating gonadotrophin receptor expression and actions in tumour tissues and cells.

Epidemiological Data on Gonadotrophin Levels and Ovarian Cancer
The ‘gonadotrophin theory’ of the origin of ovarian cancer has been around for a long time, but because of the variability of evidence it remains hypothetical and controversial.4,5 Both elevated endogenous levels of gonadotrophins in conditions such as post-menopause, incessant ovulations and polycystic ovarian syndrome and exposure to exogenous gonadotrophins during infertility treatment have been associated with increased ovarian cancer risk. A major caveat in reaching valid conclusions is that it has been difficult to differentiate effects of the gonadotrophins from those of the basal phenotype of the patients; infertility itself is an independent risk factor for ovarian cancer.

The most recent study on this topic was carried out in Sweden5 on 2,768 women treated between 1961 and 1975 with gonadotrophins or clomiphene citrate, the latter inducing an increase in endogenous gonadotrophin secretion. No overall increase in the frequency of invasive ovarian cancers was found, but in women treated because of non-ovulatory disorders, the risk was elevated (odds ratio [OR] 5.89, 95% confidence interval [CI] 1.91–13.75), and the risk was higher with clomiphene than with gonadotrophins. Although the authors emphasise caution in interpreting the results, they considered that further research on the long-term safety of modern hormonal infertility treatments was warranted. This is especially important in light of the current gonadotrophin treatments of in vitro fertilisation (IFV), where the hormone doses used are much higher than in the Swedish study, which was based on historical data.

Besides treatment with exogenous gonadotrophins, other potential modes of gonadotrophin involvement in ovarian tumorigenesis include the possible role of normal or post-menopausally elevated endogenous gonadotrophin levels,6 and the possibility that the suppression of endogenous gonadotrophin secretion could offer a treatment option. Epidemiological data, including the role of oral contraceptive use, pregnancy and, possibly, lactation, all suppressing the exposure of a woman to LH and FSH, support an association between gonadotrophin levels and ovarian cancer.7 However, case-control studies on the prognostic value of pre-diagnostic FSH concentrations on ovarian cancer risk provided negative evidence, showing in both in preand post-menopausal women, that high FSH levels could in fact be protective.8-10 These data are consistent with the finding of an association between hormone replacement therapy (HRT) and increased ovarian cancer risk, because gonadotrophin levels are also suppressed in this condition.11 Hence, gonadotrophins may be involved in the pathogenesis of ovarian cancer, but in the opposite fashion to that originally proposed. How FSH could be protective is not known, but it could be a sign of lower endocrine activity in ovaries at lower risk. On the other hand, the increased risk of gonadotrophin suppression in HRT could also suggest an active protective role of FSH.

Overall, the link between infertility treatments with gonadotrophins and ovarian cancer remains contentious and weak,12 and the same is true of the associative data on the role of endogenous gonadotrophin levels.9,10,13

In Vitro Data on Gonadotrophin Effects on Ovarian Cancer
Can we derive useful information about the role of gonadotrophins from in vitro data on normal ovarian surface epithelial (OSE) cells and their malignant forms? OSE is the site of origin of the majority of ovarian malignancies, and it is not considered a classic target for gonadotrophins (rather, the classic targets are granulosa cells for FSH and theca and luteal cells for LH). Nevertheless, normal and malignant OSE cells do express both forms of gonadotrophin receptor,14–17 but the findings on the effects of these hormones on OSE growth have been variable and contradictory. About half of primary OSE tumours express one or both of the gonadotrophin receptors (see Table 1).18 FSH and LH have been shown to stimulate thymidine incorporation of OSE cells, to activate the classic cyclic adenosine monophosphate (cAMP) signalling pathway of gonadotrophins and to inhibit apoptosis.16,19,20 In OSE cells, both gonadotrophins also upregulate the expression of epidermal and vascular endothelial growth factor receptors, important mediators of the stimulation of cell proliferation and tumour angiogenesis.21–23 Furthermore, hCG has been shown to be antiapoptotic, possibly through upregulation of insulin-like growth factor 1 expression.24Overexpression of FSH receptors in OSE cells has been found to increase their growth and to activate potentially oncogenic signalling cascades.25,26 Further evidence for direct FSH effects on OSE was found in gene expression profiling, but whether the altered gene expression is indicative of suppression or stimulation of cell growth remained unclear.27 Collectively, the numerous in vitro findings demonstrate growth-stimulatory, antiapoptotic and angiogenic effects of gonadotrophins on normal and malignant OSE cells. However, the link between these in vitro findings and clinical observations on human ovarian cancer still remains weak.

Therapeutic Effect of Gonadotrophin Ablation in Ovarian Cancer
A recent review summarised the results of gonadotrophin suppression with GnRH agonists in refractory or recurrent epithelial ovarian cancer.28 In these 11 small trials (total n=369), response rates ranged between 0 and 22%. It was concluded that gonadotrophin-releasing hormone (GnRH) agonists may provide modest efficacy as salvage therapy in patients with relapsed disease, and in some cases may provide long-term disease stabilisation. The novel GnRH antagonists may offer more effective treatment because of their more effective suppression of FSH,29 but no data exist yet on such treatment.

Sex cord stromal cell tumours, including granulosa cell tumours (GCT), are a small subgroup of ovarian tumours of which GCT are the most common form (approximately 5% of ovarian cancers). Because normal granulosa cells are targets of gonadotrophin action, it is feasible that GCT could also respond directly to gonadotrophins. Indeed, gene expression profiling of granulosa cells demonstrates gonadotrophin-induced upregulation of genes with oncogenic potential.30 However, the few small treatment trials with GnRH agonists for the suppression of gonadotrophin secretion have yielded modest results.31–34 Curiously, this logical treatment modality for GCTs has not been extensively studied.

The best evidence for the gonadotrophin theory of pathogenesis of ovarian cancer would be a positive therapeutic response to gonadotrophin ablation therapy. Unfortunately, the results of the clinical treatment trials with GnRH analogues either alone or in various treatment combinations have been at best promising.35–38 If the gonadotrophin theory holds true, the role of gonadotrophins is most likely in the initial induction and early growth of the tumours. However, when they have reached the stage at which they can be diagnosed, the gonadotrophin dependence may already have been lost and gonadotrophin ablation may no longer be effective.

Another strategy to exploit gonadotrophin receptor expression in ovarian tumours has been to use it as a decoy to target gonadotrophin molecules tethered with therapeutic compounds to tumour cells. Successful attempts have been made in animal experiments with hCG– doxorubicin39 and hCG–hecate40 conjugates. These promising findings await verification in clinical conditions.

In summary, despite the undisputed expression of gonadotrophin receptors in a large proportion of ovarian cancer cells, of both surface epithelial and sex cord stromal origin, as well as the documented effects of gonadotrophins in vitro on various oncogenic and antiapoptotic signalling pathways, the results of gonadotrophin ablation therapies have been modest. If gonadotrophins are important in the pathogenesis of ovarian tumours, it would seem that they are more important in the initial steps of the process. Later on, when the tumours are diagnosed and treated, gonadotrophin dependence may have been lost. Although ovarian cancer is an endocrine-related malignancy, and gonadotrophins may play some role in its pathogenesis, the most critical hormonal mehanisms in its pathogenesis still remain unclear. Curiously, no data are available on gonadotrophin receptor expression in human testicular tumours. Extragonadal Tumours
Several normal and tumorous extragonadal tissues express gonadotrophin receptors, especially those for LH/hCG.1,18 It is therefore natural that direct gonadotrophin actions on these tumours have been proposed, as well as gonadotrophin ablation for their therapy. However, these findings are often confounded by the fact that what appears to be a direct gonadotrophin effect actually occurs through gonadotrophin-stimulated gonadal steroidogenesis.

Uterine Tumours
Several studies have demonstrated the expression of LH/hCG receptors (LHCGR) in normal endometrium, myometrium, uterine vessels and the fallopian tubes.1 Endometrial cancer expresses LHCGR both at messenger RNA (mRNA) and protein level (see Table 2), and one study even demonstrated LH-dependent tumour cell invasion in vitro.41 Because these tumours also express the hCG subunits,42 it is possible that there exists at least in a subgroup of them an autocrine hCG/LHCGR circuit that stimulates cell growth. Arcangeli et al.43 recently reviewed the existing seven studies on therapy of endometrial cancer with GnRH agonists, and concluded that the results are conflicting. Owing to the large variability in the level of LHCGR expression, the authors hypothesised that only patients with high receptor levels could benefit from gonadotrophin suppression therapy. On the other hand, because of the possibility of autocrine LHRGR stimulation through tumour-tissue-expressed hCG, the suppression of endogenous gonadotrophins might be ineffective, requiring action of an antagonistic gonadotrophin molecule.

Breast Tumours
LHCGR has been shown to be expressed in normal and neoplastic breast tissue44,45 and in breast cancer cell lines.44,46–48 Because of the protective effect of parity on breast cancer, pregnanacy hormones, including hCG, have been hypothesised to provide a protective effect. In contrast to the tumorigenic effects of gonadotrophins on several other organs, the majority of observations show that hCG has growthinhibitory and apoptotic effects in human breast cancer cells.49 The clinical significance of these findings is uncertain, because a recent systematic study on 1,551 breast cancer tissue samples and 42 breast cancer cell lines by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) showed that their LHCGR expression levels were either undetectable or very low.50 Therefore, on the basis of this study, the direct action of LH or hCG on human breast tissue, whether normal or malignant, seems unlikely, and the role of gonadotrophins, including the effect of hCG during pregnancy, in the biology of normal or malignant breast tissue is more likely indirect through effects on ovarian function. The role of hCG in tumorigenesis is discussed in more detail below.

Prostate Tumours
Human benign prostatic hyperplasia and prostate cancer tissues express LHCGR and FSHR (see Table 2). The expression of FSHR in particular is of interest, because the current standard endocrine therapy of prostate cancer by GnRH agonists only suppresses LH, whereas a rebound of FSH levels occurs following an initial decline.51 If these receptors are functionally important, which is currently not known, GnRH antagonist treatment may prove more effective, because it provides constant suppression of both gonadotrophins.29Adrenal Tumours
Normal adrenocortical tissue expresses LHCGR, and the adrenal gland is the extragonadal tissue with the strongest evidence for functionally meaningful direct gonadotrophin actions.52 LHCGR expression has been detected in various types of adrenal tumour including adrenocorticotrophic hormone (ACTH)-independent macronodular hyperplasia, aldosterone-producing adrenal adenoma and pregnancyassociated Cushing’s syndrome with adrenal adenoma or carcinoma (see Table 2). GnRH therapy has been shown to have a positive therapeutic effect in some of the tumours,53 proving the functional significance of this ectopic receptor expression. It may even be possible that the peak in appearance of adrenal tumours in peri-/postmenopausal women is related to the concomitant increase in gonadotrophin secretion.54

Human Chorionic Gonadotrophin and Tumorigenesis
The placental gonadotrophin hCG holds a different position with respect to tumorigenesis. Besides normal trophoblast, intact hCG, its α- and β-subunits and degraded/post-translationally modified forms (nicked hCG, β-core fragment and hyperglycosylated hCG) are synthesised by a number of extratrophoblastic malignancies, and their determination as tumour markers provides an important diagnostic tool.55–57 Despite the high production rate of hCG in pregnancy, hardly anything is known about its functions. One possible function is to provide a growth stimulus to the placenta and/or foetus, and hCG may provide the same effect in autocrine fashion when produced ectopically by tumours. Similarly to LH (see above), hCG has been shown to both stimulate and inhibit the proliferation of various tumour cells in vitro. Similar cell-type-dependent effects have been shown with its free β- subunit.58–60 Besides gestational trophoblastic disease, in particular hCGβ is produced by some testicular germ cell tumours, cervical and ovarian cancers, bladder, renal, prostate, various gastrointestinal, neuroendocrine, breast, head and neck and haematological cancers.57,61 The paradox, in particular with breast cancer, is that hCG has been demonstrated to be both protective and promoting for tumour growth. Only some of these malignancies express LHCGR,50 so the mechanism of their action in the autocrine regulation of tumour growth remains unclear. Because of its structural similarity to molecules of the cystine knot growth factor/TGFβ superfamily, it is possible that the function of the tumour-produced hCG or hCGβ is mediated by mechanisms other than binding to the classical LHCGR.

Because of the ectopic production of hCG by tumour cells, hCG vaccinations have potential as antitumour therapy.62,63 Some animal experiments on the efficacy of such antitumour vaccines have provided promising results. One clinical study with hCG vaccination has demonstrated increased survival time of patients with advanced colorectal cancer.63 Another strategy to exploit hCG in cancer therapy is to attach to hCG cytotoxic agents and direct them in this way to LHCGR-epressing tumours.48,64

Animal Models of Gonadotrophin-dependent Tumorigenesis Ovarian and Testicular Tumours
The gonadotrophin theory of ovarian tumorigenesis was originally introduced in the 1940s based on an animal model using ovarian autotransplantations into a rat spleen. The transplants developed into tumours in gonadectomised animals exposed to high gonadotrophin levels, but failed to transform when one ovary was left intact or the animal was hypophysectomised, i.e. in the presence of low or normal gonadotrophin levels.65 Since then, several reports on the development of gonadotrophin-dependent gonadal and extragonadal tumours have been described in genetically susceptible spontaneous66 or transgenic mouse models.67–69 Of note, the gonadotrophindependent ovarian tumours in these models originated mainly from granulosa cells, thus providing models only for a minority (5%) of human ovarian malignancies. Gonadotrophin-dependent testicular tumours developing in the same mouse models usually originate from Sertoli cells70 or foetal Leydig71 cells, but, curiously, adult Leydig cells in the mouse seem to be resistant to gonadotrophin-induced tumorigenesis. These mouse models are useful for studies on the mechanisms of gonadotrophin-dependent normal and neoplastic growth of gonadal sex cord stromal (endocrine) cells, but not for the most common type of malignant gonadal tumours, i.e. ovarian cancers originating from OSE cells and testicular germ cell tumours. Several rodent models also exist for tumours with OSE origin, and in some of them it has been shown that gonadotrophins do influence tumour growth,72–75 thus providing further experimental evidence for the in vitro findings on gonadotrophin-dependent growth of cultured normal and malignant OSE cells (see above). However, with respect to direct tumorigenic effects of gonadotrophins, these studies have to be interpreted with caution because they do not discriminate between direct effects on OSE and indirect effects through stimulation of ovarian steroidogenesis and other potential paracrine factors.

Extragonadal Tumours
The potential role of gonadotrophins in the regulation of extragonadal tumours is prompted by the presence of FSHR and especially LHCGR in a number of extragonadal normal and tumorous tissues (see above). Indeed, various extragonadal tumours have been found in transgenic mice where FSH or LH actions are amplified in the same tissues that have been shown to express receptors for these hormones, i.e. the adrenal,76,77 mammary78,79 and pituitary80 glands. LH- and/or hCG-overexpressing mice develop a multitude of extragonadal tumours in the adrenal cortex, mammary gland and pituitary gland (see Figure 1).69,81 However, despite the possibility of direct gonadotrophin action due to LHCGR expression in all these tumours, this is apparently not the case, because gonadectomy of the transgenic mice abolishes all extragonadal phenotypes. Therefore, although high gonadotrophin levels are able to induce tumours in extragonadal tissues in rodent models, the effects are invariably secondary to gonadal stimulation and speak against direct tumorigenic effects of these hormones.

Conclusions
A wealth of information exists on gonadotrophin receptor expression in ovarian and extraovarian tumours both in humans and in experimental animal models. There is also in vivo evidence that high gonadotrophin levels may promote both gonadal and extragonadal tumorigenesis.

However, most of the evidence on direct gonadotrophin effects on human tumours is from in vitro studies, and the results on therapeutic effects of gonadotrophin ablation are at best modest. Animal models with chronically elevated gonadotrophin levels clearly document the formation and/or growth acceleration of gonadal and extragonadal tumours, but effects on the latter appear indirect through stimulation of gonadal sex hormone production. The discrepancy between convincing direct gonadotrophin effects in vitro and their absence in vivo is striking. One explanation is that gonadotrophin dependence is apparent only in the early stages of tumorigenesis, after which tumour growth becomes autonomous or dependent on other regulators. If this is the case, only limited therapeutic effects can be expected from gonadotrophin ablation. The clinical benefit from this information may be the knowledge that individuals exposed to high gonadotrophin levels may carry an increased risk of tumorigenesis. Conclusions concerning breast cancer are particularly problematic, because both protective and promoting effects of LH/hCG on this tumour have been demonstrated. A very recent intriguing finding may revive the field of gonadotrophindependent tumorigenesis. Radu et al.2 studied FSHR expression in the tumours of 1,336 patients and found a high level of FSHR expression in the vascular endothelium in a narrow region surrounding a wide variety of tumours including prostate, breast, colon, pancreas, urinary bladder, kidney, lung, liver, stomach, ovary and testis. This exciting finding may open up multiple possibilities for exploiting FSHR expression, such as tumour imaging, targeting cytotoxic molecules to tumours and inhibition of tumour angiogenesis by inhibiting FSH secretion and/or action.

In conclusion, it is well documented both clinically and experimentally that gonadotrophin-stimulated gonadal sex hormone production can promote hormone-dependent tumours both in gonads and in other tissues. By contrast, the evidence for direct tumorigenic effects of gonadotrophins relies mainly on in vitro studies, and the clinical and experimental evidence in vivo is still far from being convincing and conclusive.

2

References

  1. Filicori M, Fazleabas AT, Huhtaniemi I, et al., Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility, Fertil Steril, 2005;84(2):275–84.
  2. Radu A, Pichon C, Campero P, et al., Expression of folliclestimulating hormone receptor in tumor blood vessels, N Engl J Med, 2010;363:1621-30.
  3. Guppy AE, Nathan PD, Rustin GJ, Epithelial ovarian cancer: a review of current management, Clin Oncol (R Coll Radiol), 2005;17(6):399–411.
  4. Mahdavi A, Pejovic T, Nezhat F, Induction of ovulation and ovarian cancer: a critical review of the literature, Fertil Steril, 2006;85(4):819–26.
  5. Sanner K, Conner P, Bergfeldt K, et al., Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden, Fertil Steril, 2009;91(4):1152–8.
  6. Cramer DW, Welch WR, Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis, J Natl Cancer Inst, 1983;71(4):717–21.
  7. Riman T, Nilsson S, Persson IR, Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies, Acta Obstet Gynecol Scand, 2004;83(9):783–95.
  8. Helzlsouer KJ, Alberg AJ, Gordon GB, et al., Serum gonadotropins and steroid hormones and the development of ovarian cancer, JAMA, 1995;274(24):1926–30.
  9. McSorley MA, Alberg AJ, Allen DS, et al., Prediagnostic circulating follicle stimulating hormone concentrations and ovarian cancer risk, Int J Cancer, 2009;125(3):674–9.
  10. Arslan AA, Zeleniuch-Jacquotte A, Lundin E, et al., Serum follicle-stimulating hormone and risk of epithelial ovarian cancer in postmenopausal women, Cancer Epidemiol Biomarkers Prev, 2003;12(12):1531–5.
  11. Zhou B, Sun Q, Cong R, et al., Hormone replacement therapy and ovarian cancer risk: a meta-analysis, Gynecol Oncol, 2008;108(3):641–51.
  12. Konishi I, Gonadotropins and ovarian carcinogenesis: a new era of basic research and its clinical implications, Int J Gynecol Cancer, 2006;16(1):16–22.
  13. Akhmedkhanov A, Toniolo P, Zeleniuch-Jacquotte A, et al., Luteinizing hormone, its beta-subunit variant, and epithelial ovarian cancer: the gonadotropin hypothesis revisited, Am J Epidemiol, 2001;154(1):43–9.
  14. Bose CK, Follicle stimulating hormone receptor in ovarian surface epithelium and epithelial ovarian cancer, Oncol Res, 2008;17(5):231–8.
  15. Syed V, Ulinski G, Mok SC, et al., Expression of gonadotropin receptor and growth responses to key reproductive hormones in normal and malignant human ovarian surface epithelial cells, Cancer Res, 2001;61(18):6768–76.
  16. Choi JH, Wong AS, Huang HF, Leung PC, Gonadotropins and ovarian cancer, Endocr Rev, 2007;28(4):440–61.
  17. Mandai M, Konishi I, Kuroda H, et al., Messenger ribonucleic acid expression of LH/hCG receptor gene in human ovarian carcinomas, Eur J Cancer, 1997;33(9):1501–7.
  18. Huhtaniemi I, Are gonadotrophins tumorigenic-A critical review of clinical and experimental data, Mol Cell Endocrinol, 2010;329(1):56–61.
  19. Gubbay O, Rae MT, McNeilly AS, et al., cAMP response element-binding (CREB) signalling and ovarian surface epithelial cell survival, J Endocrinol, 2006;191(1):275–85.
  20. Zhou H, Luo MP, Schonthal AH, et al., Effect of reproductive hormones on ovarian epithelial tumors: I. Effect on cell cycle activity, Cancer Biol Ther, 2002;1(3):300–6.
  21. Choi JH, Choi KC, Auersperg N, Leung PC, Gonadotropins upregulate the epidermal growth factor receptor through activation of mitogen-activated protein kinases and phosphatidyl-inositol-3-kinase in human ovarian surface epithelial cells, Endocr Relat Cancer, 2005;12(2):407–21.
  22. Wang J, Luo F, Lu JJ, et al., VEGF expression and enhanced production by gonadotropins in ovarian epithelial tumors, Int J Cancer, 2002;97(2):163–7.
  23. . Zygmunt M, Herr F, Keller-Schoenwetter S, et al., Characterization of human chorionic gonadotropin as a novel angiogenic factor, J Clin Endocrinol Metab, 2002;87(11):5290–6.
  24. Kuroda H, Mandai M, Konishi I, et al., Human chorionic gonadotropin (hCG) inhibits cisplatin-induced apoptosis in ovarian cancer cells: possible role of up-regulation of insulinlike growth factor-1 by hCG, Int J Cancer, 1998;76(4):571–8.
  25. Ohtani K, Sakamoto H, Kikuchi A, et al., Follicle-stimulating hormone promotes the growth of human epithelial ovarian cancer cells through the protein kinase C-mediated system, Cancer Lett, 2001;166(2):207–13.
  26. Nilsson E, Doraiswamy V, Parrott JA, Skinner MK, Expression and action of transforming growth factor beta (TGFbeta1, TGFbeta2, TGFbeta3) in normal bovine ovarian surface epithelium and implications for human ovarian cancer, Mol Cell Endocrinol, 2001;182(2):145–55.
  27. Ho SM, Lau KM, Mok SC, Syed V, Profiling follicle stimulating hormone-induced gene expression changes in normal and malignant human ovarian surface epithelial cells, Oncogene, 2003;22(27):4243–56.
  28. Zheng H, Kavanagh JJ, Hu W, et al., Hormonal therapy in ovarian cancer, Int J Gynecol Cancer, 2007;17(2):325–38.
  29. Huhtaniemi I, White R, McArdle CA, Persson BE, Will GnRH antagonists improve prostate cancer treatment?, Trends Endocrinol Metab, 2009;20(1):43–50.
  30. Rimon E, Sasson R, Dantes A, et al., Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF patients: modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases, Int J Oncol, 2004;24(5):1325–38.
  31. Maxwell GL, Soisson AP, Miles P, Failure of gonadotropin releasing hormone therapy in patients with metastatic ovarian sex cord stromal tumors, Oncology, 1994;51(4):356–9.
  32. Martikainen H, Penttinen J, Huhtaniemi I, Kauppila A, Gonadotropin-releasing hormone agonist analog therapy effective in ovarian granulosa cell malignancy, Gynecol Oncol, 1989;35(3):406–8.
  33. Ameryckx L, Fatemi HM, De Sutter P, Amy JJ, GnRH antagonist in the adjuvant treatment of a recurrent ovarian granulosa cell tumor: a case report, Gynecol Oncol, 2005;99(3):764–6.
  34. Fishman A, Kudelka AP, Tresukosol D, et al., Leuprolide acetate for treating refractory or persistent ovarian, J Reprod Med, 1996;41(6):393–6.
  35. Balbi G, Piano LD, Cardone A, Cirelli G, Second-line therapy of advanced ovarian cancer with GnRH analogs, Int J Gynecol Cancer, 2004;14(5):799–803.
  36. . Emons G, Ortmann O, Teichert HM, et al., Luteinizing hormone-releasing hormone agonist triptorelin in combination with cytotoxic chemotherapy in patients with advanced ovarian carcinoma. A prospective double blind randomized trial. Decapeptyl Ovarian Cancer Study Group, Cancer, 1996;78(7):1452–60.
  37. Paskeviciute L, Roed H, Engelholm S, No rules without exception: long-term complete remission observed in a study using a LH-RH agonist in platinum-refractory ovarian cancer, Gynecol Oncol, 2002;86(3):297–301.
  38. Hasan J, Ton N, Mullamitha S, et al., Phase II trial of tamoxifen and goserelin in recurrent epithelial ovarian cancer, Br J Cancer, 2005;93(6):647–51.
  39. . Gebauer G, Mueller N, Fehm T, et al., Expression and regulation of luteinizing hormone/human chorionic gonadotropin receptors in ovarian cancer and its correlation to human chorionic gonadotropin-doxorubicin sensitivity, Am J Obstet Gynecol, 2004;190(6):1621–8, discussion 8.
  40. Bodek G, Vierre S, Rivero-Muller A, et al., A novel targeted therapy of Leydig and granulosa cell tumors through the luteinizing hormone receptor using a hecate-chorionic gonadotropin beta conjugate in transgenic mice, Neoplasia, 2005;7(5):497–508.
  41. Noci I, Pillozzi S, Lastraioli E, et al., hLH/hCG-receptor expression correlates with in vitro invasiveness in human primary endometrial cancer, Gynecol Oncol, 2008;111(3):496–501.
  42. Jankowska AG, Andrusiewicz M, Fischer N, Warchol PJ, Expression of hCG and GnRHs and their receptors in endometrial carcinoma and hyperplasia, Int J Gynecol Cancer, 2010;20(1):92–101.
  43. Arcangeli A, Noci I, Fortunato A, Scarselli GF, The LH/hCG cancer: a new target in the treatment of recurrent or metastatic disease, Obstet Gynecol Int, 2010.
  44. Meduri G, Charnaux N, Loosfelt H, et al., Luteinizing hormone/human chorionic gonadotropin receptors in breast cancer, Cancer Res, 1997;57(5):857–64.
  45. Meduri G, Charnaux N, Spyratos F, et al., Luteinizing hormone receptor status and clinical, pathologic, and prognostic features in patients with breast carcinomas, Cancer, 2003;97(7):1810–6.
  46. Lojun S, Bao S, Lei ZM, Rao CV, Presence of functional luteinizing hormone/chorionic gonadotropin (hCG) receptors in human breast cell lines: implications supporting the premise that hCG protects women against breast cancer, Biol Reprod, 1997;57(5):1202–10.
  47. Jiang X, Russo IH, Russo J, Alternately spliced luteinizing hormone/human chorionic gonadotropin receptor mRNA in human breast epithelial cells, Int J Oncol, 2002;20(4):735–8.
  48. Bodek G, Rahman NA, Zaleska M, et al., A novel approach of targeted ablation of mammary carcinoma cells through luteinizing hormone receptors using Hecate-CGbeta conjugate, Breast Cancer Res Treat, 2003;79(1):1–10.
  49. Srivastava P, Russo J, Mgbonyebi OP, Russo IH, Growth inhibition and activation of apoptotic gene expression by human chorionic gonadotropin in human breast epithelial cells, Anticancer Res, 1998;18(6A):4003–10.
  50. Kuijper TM, Ruigrok-Ritstier K, Verhoef-Post M, et al., LH receptor gene expression is essentially absent in breast tumor tissue: implications for treatment, Mol Cell Endocrinol, 2009;302(1):58–64.
  51. Huhtaniemi IT, Dahl KD, Rannikko S, Hsueh AJ, Serum bioactive and immunoreactive follicle-stimulating hormone in prostatic cancer patients during gonadotropin-releasing hormone agonist treatment and after orchidectomy, J Clin Endocrinol Metab, 1988;66(2):308–13.
  52. Bernichtein S, Alevizaki M, Huhtaniemi I, Is the adrenal cortex a target for gonadotropins?, Trend Endocrinol Metab, 2008;19(7):231–8.
  53. Lacroix A, Hamet P, Boutin JM, Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome, N Engl J Med, 1999;341(21):1577–81.
  54. Alevizaki M, Saltiki K, Mantzou E, et al., The adrenal gland may be a target of LH action in postmenopausal women, Eur J Endocrinol, 2006;154(6):875–81.
  55. Stenman UH, Tiitinen A, Alfthan H, Valmu L, The classification, functions and clinical use of different isoforms of HCG, Hum Reprod Update, 2006;12(6):769–84.
  56. Cole LA, New discoveries on the biology and detection of human chorionic gonadotropin, Reprod Biol Endocrinol, 2009;7:8.
  57. Iles RK, Delves PJ, Butler SA, Does hCG or hCGbeta play a role in cancer cell biology?, Mol Cell Endocrinol, 2010 Jul 21 329(1–2):62–70.
  58. Butler SA, Staite EM, Iles RK, Reduction of bladder cancer cell growth in response to hCGbeta CTP37 vaccinated mouse serum, Oncol Res, 2003;14(2):93–100.
  59. Hamada AL, Nakabayashi K, Sato A, et al., Transfection of antisense chorionic gonadotropin beta gene into choriocarcinoma cells suppresses the cell proliferation and induces apoptosis, J Clin Endocrinol Metab, 2005;90(8):4873–9.
  60. . Srivastava P, Russo J, Russo IH, Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death, Carcinogenesis, 1997;18(9):1799–808.
  61. Stenman UH, Alfthan H, Hotakainen K, Human chorionic gonadotropin in cancer, Clin Biochem, 2004;37(7):549–61.
  62. Talwar GP, Vyas HK, Purswani S, Gupta JC, Gonadotropinreleasing hormone/human chorionic gonadotropin beta based recombinant antibodies and vaccines, J Reprod Immunol, 2009;83(1–2):158–63.
  63. Moulton HM, Yoshihara PH, Mason DH, et al., Active specific immunotherapy with a beta-human chorionic gonadotropin peptide vaccine in patients with metastatic colorectal cancer: antibody response is associated with improved survival, Clin Cancer Res, 2002;8(7):2044–51.
  64. Gebauer G, Fehm T, Beck EP, et al., Cytotoxic effect of conjugates of doxorubicin and human chorionic gonadotropin (hCG) in breast cancer cells, Breast Cancer Res Treat, 2003;77(2):125–31.
  65. Biskind M, Biskind, GR, Development of tumors in the rat ovary after transplantation into the spleen, Proc Soc Exp Biol Med, 1944;55:176–9.
  66. Dorward AM, Shultz KL, Ackert-Bicknell CL, et al., Highresolution genetic map of X-linked juvenile-type granulosa cell tumor susceptibility genes in mouse, Cancer Res, 2003;63(23):8197–202.
  67. Matzuk MM, Kumar TR, Shou W, et al., Transgenic models to study the roles of inhibins and activins in reproduction, oncogenesis, and development, Recent Progress in Hormone Research, 1996;51:123–54, discussion 55–7.
  68. Rahman NA, Kananen Rilianawati K, Paukku T, et al., Transgenic mouse models for gonadal tumorigenesis, Mol Cell Endocrinol, 1998;145(1–2):167–74.
  69. Mann RJ, Keri RA, Nilson JH, Consequences of elevated luteinizing hormone on diverse physiological systems: use of the LHbetaCTP transgenic mouse as a model of ovarian hyperstimulation-induced pathophysiology, Recent Progress in Hormone Research, 2003;58:343–75.
  70. Yan W, Burns KH, Matzuk MM, Genetic engineering to study testicular tumorigenesis, Apmis, 2003;111(1):174–81, discussion 82–3.
  71. Ahtiainen P, Rulli SB, Shariatmadari R, et al., Fetal but not adult Leydig cells are susceptible to adenoma formation in response to persistently high hCG level: a study on hCG overexpressing transgenic mice, Oncogene, 2005;24(49):7301–9.
  72. Davies BR, Finnigan DS, Smith SK, Ponder BA, Administration of gonadotropins stimulates proliferation of normal mouse ovarian surface epithelium, Gynecol Endocrinol, 1999;13(2):75–81.
  73. Osterholzer HO, Johnson JH, Nicosia SV, An autoradiographic study of rabbit ovarian surface epithelium before and after ovulation, Biol Reprod, 1985;33(3):729–38.
  74. Burdette JE, Kurley SJ, Kilen SM, et al., Gonadotropin-induced superovulation drives ovarian surface epithelia proliferation in CD1 mice, Endocrinology, 2006;147(5):2338–45.
  75. Stewart SL, Querec TD, Gruver BN, et al., Gonadotropin and steroid hormones stimulate proliferation of the rat ovarian surface epithelium, J Cell Physiol, 2004;198(1):119–24.
  76. Kero J, Poutanen M, Zhang FP, et al., Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex, J Clin Investig, 2000;105(5):633–41.
  77. Peltoketo H, Strauss L, Karjalainen R, et al., Female mice expressing constitutively active mutants of FSH receptor present with a phenotype of premature follicle depletion and estrogen excess, Endocrinology, 2010;151(4):1872–83.
  78. Tao YX, Lei ZM, Rao CV, The presence of luteinizing hormone/human chorionic gonadotropin receptors in lactating rat mammary glands, Life Sci, 1997;60(15):1297–303.
  79. Kuorelahti A, Rulli S, Huhtaniemi I, Poutanen M, Human chorionic gonadotropin (hCG) up-regulates wnt5b and wnt7b in the mammary gland, and hCGbeta transgenic female mice present with mammary Gland tumors exhibiting characteristics of the Wnt/beta-catenin pathway activation, Endocrinology, 2007 Aug;148(8):3694-703.
  80. Ahtiainen P, Sharp V, Rulli SB, et al., Enhanced LH action in transgenic female mice expressing hCGbeta-subunit induces pituitary prolactinomas; the role of high progesterone levels, Endocr Relat Cancer, 2010;17(3):611–21.
  81. Rulli SB, Kuorelahti A, Karaer O, et al., Reproductive disturbances, pituitary lactotrope adenomas, and mammary gland tumors in transgenic female mice producing high levels of human chorionic gonadotropin, Endocrinology, 2002;143(10):4084–95.
  82. Kammerman S, Demopoulos RI, Raphael C, Ross J, Gonadotropic hormone binding to human ovarian tumors, Hum Pathol, 1981;12(10):886–90.
  83. Rajaniemi H, Kauppila A, Ronnberg L, et al., LH(hCG) receptor in benign and malignant tumors of human ovary, Acta Obst Gynecol Scandinavica, 1981;101:83–6.
  84. Stouffer RL, Grodin MS, Davis JR, Surwit EA, Investigation of binding sites for follicle-stimulating hormone and chorionic gonadotropin in human ovarian cancers, J Clin Endocrinol Metab, 1984;59(3):441–6.
  85. Kobayashi F, Monma C, Nanbu K, et al., Rapid growth of an ovarian clear cell carcinoma expressing LH/hCG receptor arising from endometriosis during early pregnancy, Gynecol Oncol, 1996;62(2):309–13.
  86. Lu JJ, Zheng Y, Kang X, et al., Decreased luteinizing hormone receptor mRNA expression in human ovarian epithelial cancer, Gynecol Oncol, 2000;79(2):158–68.
  87. Zheng W, Lu JJ, Luo F, et al., Ovarian epithelial tumor growth promotion by follicle-stimulating hormone and inhibition of the effect by luteinizing hormone, Gynecol Oncol, 2000;76(1):80–8.
  88. Minegishi T, Kameda T, Hirakawa T, et al., Expression of gonadotropin and activin receptor messenger ribonucleic acid in human ovarian epithelial neoplasms, Clin Cancer Res, 2000;6(7):2764–70.
  89. Ji Q, Liu PI, Chen PK, Aoyama C, Follicle stimulating hormone-induced growth promotion and gene expression profiles on ovarian surface epithelial cells, Int J Cancer, 2004;112(5):803–14.
  90. Hudelist G, Wuelfing P, Czerwenka K, et al., Beta-hCG/LH receptor (b-HCG/LH-R) expression is increased in invasive versus preinvasive breast cancer: implications for breast carcinogenesis?, J Cancer Res Clin Oncol, 2009;135(2):191–5.
  91. Lin J, Lei ZM, Lojun S, et al., Increased expression of luteinizing hormone/human chorionic gonadotropin receptor gene in human endometrial carcinomas, J Clin Endocrinol Metab, 1994;79(5):1483–91.
  92. Konishi I, Koshiyama M, Mandai M, et al., Increased expression of LH/hCG receptors in endometrial hyperplasia and carcinoma in anovulatory women, Gynecol Oncol, 1997;65(2):273–80.
  93. Ji Q, Chen P, Aoyoma C, Liu P, Increased expression of human luteinizing hormone/human chorionic gonadotropin receptor mRNA in human endometrial cancer, Mol Cell Probes, 2002;16(4):269–75.
  94. Jankowska A, Gunderson SI, Andrusiewicz M, et al., Reduction of human chorionic gonadotropin beta subunit expression by modified U1 snRNA caused apoptosis in cervical cancer cells, Mol Cancer, 2008;7:26.
  95. Tao YX, Bao S, Ackermann DM, et al., Expression of luteinizing hormone/human chorionic gonadotropin receptor gene in benign prostatic hyperplasia and in prostate carcinoma in humans, Biol Reprod, 1997;56(1):67–72.
  96. Ben-Josef E, Yang SY, Ji TH, et al., Hormone-refractory prostate cancer cells express functional follicle-stimulating hormone receptor (FSHR), J Urol, 1999;161(3):970–6.
  97. Dirnhofer S, Berger C, Hermann M, et al., Coexpression of gonadotropic hormones and their corresponding FSH- and LH/CG-receptors in the human prostate, Prostate, 1998;35(3):212–20.
  98. Mariani S, Salvatori L, Basciani S, et al., Expression and cellular localization of follicle-stimulating hormone receptor in normal human prostate, benign prostatic hyperplasia and prostate cancer, J Urol, 2006;175(6):2072–7, discussion 7.
  99. Feelders RA, Lamberts SW, Hofland LJ, et al., Luteinizing hormone (LH)-responsive Cushing’s syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro, J Clin Endocrinol Metab, 2003;88(1):230–37.
  100. Bertherat J, Contesse V, Louiset E, et al., In vivo and in vitro screening for illegitimate receptors in adrenocorticotropinindependent macronodular adrenal hyperplasia causing Cushing’s syndrome: identification of two cases of gonadotropin/gastric inhibitory polypeptide-dependent hypercortisolism, J Clin Endocrinol Metab, 2005;90(3):1302–10.
  101. Saner-Amigh K, Mayhew BA, Mantero F, et al., Elevated expression of luteinizing hormone receptor in aldosteroneproducing adenomas, J Clin Endocrinol Metab, 2006;91(3):1136–42.
  102. Zwermann O, Suttmann Y, Bidlingmaier M, et al., Screening for membrane hormone receptor expression in primary aldosteronism, Eur J Endocrinol, 2009;160(3):443–51.
  103. Leinonen P, Ranta T, Siegberg R, et al., Testosteronesecreting virilizing adrenal adenoma with human chorionic gonadotrophin receptors and 21-hydroxylase deficiency, Clin Endocrinol (Oxf), 1991;34(1):31–5.
  104. Wy LA, Carlson HE, Kane P,et al., Pregnancy-associated Cushing’s syndrome secondary to a luteinizing hormone/human chorionic gonadotropin receptor-positive adrenal carcinoma, Gynecol Endocrinol, 2002;16(5):413–7.
  105. Rask E, Schvarcz E, Hellman P, et al., Adrenocorticotropinindependent Cushing’s syndrome in pregnancy related to overexpression of adrenal luteinizing hormone/human chorionic gonadotropin receptors, J Endocrinol Invest, 2009;32(4):313–6.
  106. Costa MH, Latronico AC, Martin RM, et al., Expression profiles of the glucose-dependent insulinotropic peptide receptor and LHCGR in sporadic adrenocortical tumors, J Endocrinol, 2009;200(2):167–75.
3

Article Information

Disclosure

The authors have no conflicts of interest to declare.

Correspondence

Ilpo Huhtaniemi, Institute of Reproductive and Developmental Building, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, UK. E: ilpo.huhtaniemi@imperial.ac.uk

Received

2010-10-21T00:00:00

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
7 mins

Trending Topic
Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

The International Evidence-based Guidelines for the Assessment and Management of Polycystic Ovary Syndrome: An Exemplar of Person-centred Care

Bharti Kalra, Nitin Kapoor, Atul Dhingra

Polycystic ovary syndrome (PCOS) is a multifactorial, multifaceted syndrome that affects women across all ages from adolescence to post-menopause. It is reported to be the most common endocrinopathy in women of the reproductive age group.1 The nature of this syndrome is such that it requires support and intervention from multiple medical and allied specialties. The treatment […]

touchREVIEWS in Endocrinology. 2024;20(2):2–4
Advertisement
    • 5

    Related Content in Reproductive Endocrinology

    Latest articles videos and clinical updates - straight to your inbox

    Close Popup