Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Reproductive Biology and Endocrinology
Published in: Reproductive Biology and Endocrinology 1/2014

Open Access 01-12-2014 | Review

The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis

Authors: Megan M Emori, Ronny Drapkin

Published in: Reproductive Biology and Endocrinology | Issue 1/2014

Login to get access

Abstract

Ovulation has long been associated with an increased risk in ovarian cancer, yet the underlying molecular mechanisms remain obscure. Two aspects of ovulation have been linked to ovarian cancer pathogenesis. The first is the impact of repetitive tissue injury and repair that occurs with each ovulatory event. The second is the release of follicular fluid that accompanies the follicular rupture and its effect on the ovarian and fallopian tube epithelial cells. Hormones are an important component of follicular fluid, which transiently bathes the ovarian surface and fallopian tube epithelium during ovulation. Much work has been done exploring the role of hormones in fertility, but some, such as estrogen, have also been implicated in the pathogenesis of ovarian and other cancers. Understanding the role of hormones within follicular fluid, as well as how they are altered in disorders which increase ovarian cancer risk, will enhance our ability to assess risk and develop preventative strategies. This review provides an in depth discussion of the logistics of using and studying follicular fluid in ovarian cancer research, and discusses the fluctuations in follicular fluid hormone levels during normal physiological processes versus conditions that increase ovarian cancer risk.
Appendix
Available only for authorised users
Literature
1.
Vaughan S, Coward JI, Bast RC, Berchuck A, Berek JS, Brenton JD, Coukos G, Crum CC, Drapkin R, Etemadmoghadam D, Friedlander M, Gabra H, Kaye SB, Lord CJ, Lengyel E, Levine DA, McNeish IA, Menon U, Mills GB, Nephew KP, Oza AM, Sood AK, Stronach EA, Walczak H, Bowtell DD, Balkwill FR: Rethinking ovarian cancer: recommendations for improving outcomes. Nat Rev Cancer. 2011, 11: 719-725.PubMedCentralCrossRefPubMed
2.
3.
4.
5.
Cramer DW, Welch WR: Determinants of ovarian cancer risk. II. Inferences regarding pathogenesis. J Natl Cancer Inst. 1983, 71: 717-721.PubMed
6.
7.
Mandai M, Yamaguchi K, Matsumura N, Baba T, Konishi I: Ovarian cancer in endometriosis: molecular biology, pathology, and clinical management. Int J Clin Oncol. 2009, 14: 383-391.CrossRefPubMed
8.
Vercellini P, Crosignani P, Somigliana E, Vigano P, Buggio L, Bolis G, Fedele L: The ‘incessant menstruation’ hypothesis: a mechanistic ovarian cancer model with implications for prevention. Hum Reprod. 2011, 26: 2262-2273.CrossRefPubMed
9.
Backman S, Kollara A, Haw R, Stein L, Brown T: Glucocorticoid-induced reversal of interleukin-1β-stimulated inflammatory gene expression in human oviductal cells. PLoS One. 2014, 9: e97997-PubMedCentralCrossRefPubMed
10.
Lau A, Kollara A, St John E, Tone AA, Virtanen C, Greenblatt E, King W, Brown T: Altered expression of inflammation-associated genes in oviductal cells following follicular fluid exposure: implications for ovarian carcinogenesis. Exp Biol Med. 2014, 239: 24-32.CrossRef
11.
McCartney CR, Eagleson CA, Marshall JC: Regulation of gonadotropin secretion: implications for polycystic ovary syndrome. Semin Reprod Med. 2002, 20: 317-326.CrossRefPubMed
12.
Yancik R, Ries LG, Yates JW: Ovarian cancer in the elderly: an analysis of surveillance, epidemiology, and end results program data. Am J Obstet Gynecol. 1986, 154: 639-647.CrossRefPubMed
13.
Bächler M, Menshykau D, De Geyter C, Iber D: Species-specific differences in follicular antral sizes result from diffusion-based limitations on the thickness of the granulosa cell layer. Mol Hum Reprod. 2014, 20: 208-221.CrossRefPubMed
14.
Auersperg N: Ovarian surface epithelium as a source of ovarian cancers: unwarranted speculation or evidence-based hypothesis?. Gynecol Oncol. 2013, 130: 246-251.CrossRefPubMed
15.
Bahar-Shany K, Brand H, Sapoznik S, Jacob-Hirsch J, Yung Y, Korach J, Perri T, Cohen Y, Hourvitz A, Levanon K: Exposure of fallopian tube epithelium to follicular fluid mimics carcinogenic changes in precursor lesions of serous papillary carcinoma. Gynecol Oncol. 2014, 132: 322-327.CrossRefPubMed
16.
Jiang JY, Macchiarelli G, Miyabayashi K, Sato E: Follicular microvasculature in the porcine ovary. Cell Tissue Res. 2002, 310: 93-101.CrossRefPubMed
17.
Carson R, Findlay J, Mattner P, Brown B: Relative levels of thecal blood flow in atretic and non-atretic ovarian follicles of the conscious sheep. Aust J Exp Biol Med Sci. 1986, 64: 381-387.CrossRefPubMed
18.
Rodgers RJ, Irving-Rodgers HF: Formation of the ovarian follicular antrum and follicular fluid. Biol Reprod. 2010, 82: 1021-1029.CrossRefPubMed
19.
Shalgi R, Kracier P, Rimon A, Pinto M, Soferman N: Proteins of human follicular fluid: the blood-follicle barrier. Fertil Steril. 1973, 48: 109-118.
20.
Garzo VG, Dorrington JH: Aromatase activity in human granulosa cells during follicular development and the modulation by follicle-stimulating hormone and insulin. Am J Obstet Gynecol. 1984, 148: 657-662.CrossRefPubMed
21.
De los Santos MJ, Garcia-Laez V, Beltran D, Labarta E, Zuzuarregui JL, Alama P, Gamiz P, Crespo J, Bosch E, Pellicer A: The follicular hormonal profile in low-responder patients undergoing unstimulated cycles: is it hypoandrogenic?. Hum Reprod. 2013, 28: 224-229.CrossRefPubMed
22.
Jana SK, Babu KN, Chattopadhyay R, Chakravarty B, Chaudhury K: Upper control limit of reactive oxygen species in follicular fluid beyond which viable embryo formation is not favorable. Reprod Toxicol. 2010, 29: 447-451.CrossRefPubMed
23.
Agarwal A, Saleh RA, Bedaiwy MA: Role of reactive oxygen species in the pathophysiology of human reproduction. Fertil and Steril. 2003, 79: 829-843.CrossRef
24.
King SM, Hilliard TS, Wu LY, Jaffe RC, Fazleabas AT, Burdette JE: The impact of ovulation on fallopian tube epithelial cells: evaluating three hypotheses connecting ovulation and serous ovarian cancer. Endocr Relat Cancer. 2011, 18: 627-642.PubMedCentralCrossRefPubMed
25.
Ghoneim IM, Waheed MM, El-Bahr SM, Alhaider AK, Al-Eknah MM: Comparison of some biochemical and hormonal constituents of oversized follicles and preovulatory follicles in camels (Camelus dromedarius). Theriogenology. 2013, 79: 647-652.CrossRefPubMed
26.
Walsh SW, Matthews D, Browne JA, Forde N, Crowe MA, Mihm M, Diskin M, Evans AC: Acute dietary restriction in heifers alters expression of genes regulating exposure and response to gonadotropins and IGF in dominant follicles. Anim Reprod Sci. 2012, 133: 43-51.CrossRefPubMed
27.
Johnson PA, Giles JR: The hen as a model of ovarian cancer. Nat Rev Canc. 2013, 13: 432-436.CrossRef
28.
29.
Gougeon A: Human ovarian follicular development: from activation of resting follicles to preovulatory maturation. Ann Endocrinol (Paris). 2010, 71: 132-143.CrossRef
30.
31.
Cavalieri E, Frenkel K, Liehr JG, Rogan E, Roy D: Estrogens as endogenous genotoxic agents- DNA adducts and mutations. J Natl Cancer Inst Monogr. 2000, 27: 75-94.CrossRefPubMed
32.
Liehr JG: Is estradiol a genotoxic mutagenic carcinogen?. Endocr Rev. 2000, 21: 40-54.PubMed
33.
De Resende LO, Vireque AA, Santana LF, Moreno DA, De Sa Rosa e Silva AC, Ferriani RA, Scrideli CA, Reis RM: Single-cell expression analysis of BMP15 and GDF9 in mature oocytes and BMPR2 in cumulus cells of women with polycystic ovary syndrome undergoing controlled ovarian hyperstimulation. J Assist Reprod Genet. 2012, 29: 1057-1065.PubMedCentralCrossRefPubMed
34.
Du YB, Gao MZ, Shi Y, Sun ZG, Wang J: Endocrine and inflammatory factors and endometriosis-associated infertility in assisted reproduction techniques. Arch Gynecol Obstet. 2013, 287: 123-130.CrossRefPubMed
35.
Pacella L, Zander-Fox DL, Armstrong DT, Lane M: Women with reduced ovarian reserve or advanced maternal age have an altered follicular environment. Fertil and Steril. 2012, 98: 986-994.CrossRef
36.
Sherman BM, West JH, Korenman SG: The menopausal transition: analysis of LH, FSH, estradiol, and progesterone concentrations during menstrual cycles of older women. J Clin Endocrinol Metab. 1976, 42: 629-636.CrossRefPubMed
37.
De los Santos MJ, Garcia-Laez V, Beltran-Torregrosa D, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Pellicer A, Labarta E: Hormonal and molecular characterization of follicular fluid, cumulus cells and oocytes from pre-ovulatory follicles in stimulated and unstimulated cycles. Hum Reprod. 2012, 27: 1596-1605.CrossRefPubMed
38.
Lydon JP, DeMAyo FJ, Funk CR, Mani SK, Hughes AR, Montgomery CA, Shyamala G, Conneely OM, O’Malley BW: Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev. 1995, 9: 2266-2278.CrossRefPubMed
39.
Kastner P, Krust A, Turcotte B, Stropp U, Tora L, Gronemyer H, Chambon P: Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B. EMBO J. 1990, 9: 1603-1614.PubMedCentralPubMed
40.
Kim JJ, Kurita T, Bulun SE: Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev. 2013, 34: 130-162.PubMedCentralCrossRefPubMed
41.
Faber MT, Jensen A, Frederiksen K, Glud E, Hogdall E, Hogdall C, Blaakaer J, Kjaer SK: Oral contraceptive use and impact of cumulative intake of estrogen and progestin on risk of ovarian cancer. Cancer Causes Control. 2013, 24: 2197-2206.CrossRefPubMed
42.
Hu YC, Wang PH, Yeh S, Wang RS, Xie C, Xu Q, Zhou X, Chao HT, Tsai MY, Chang C: Subfertility and defective folliculogenesis in female mice lacking androgen receptor. Proc Natl Acad Sci U S A. 2003, 101: 1209-1214.
43.
Lyon MF, Glenister PH: Reduced reproductive performance in androgen-resistant Tfm/Tfm female mice. Proc R Soc Lond B Biol Sci. 1979, 208: 1-12.CrossRef
44.
Hillier SG, Tetsuka M: Role of androgens in follicle maturation and atresia. Baillieres Clin Obstet Gynaecol. 1997, 11: 249-260.CrossRefPubMed
45.
Hillier SG: Current concepts of the roles of follicle stimulating hormone and luteinizing hormone in folliculogenesis. Hum Reprod. 1994, 9: 188-191.PubMed
46.
Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR: Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice. Endocrinology. 2000, 141: 4295-4308.PubMed
47.
48.
Slovis BH, Check JH: Younger women with diminished oocyte reserve are not more prone to meiosis errors leading to spontaneous abortion than their age peers with normal oocyte reserve. Clin Exp Obstet Gynecol. 2013, 40: 29-32.PubMed
49.
Chakrabarti J: Serum leptin level in women with polycystic ovary syndrome: correlation with adiposity, insulin, and circulating testosterone. Ann Med Health Sci Res. 2013, 3: 191-196.PubMedCentralCrossRefPubMed
50.
Siraj A, Desestret V, Antoine M, Fromont G, Huerre M, Sanson M, Camparo P, Pichon C, Planeix F, Gonin J, Radu A, Ghinea N: Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases. BMC Cancer. 2013, 13: 246-PubMedCentralCrossRefPubMed
51.
Tao X, Zhao N, Jin H, Zhang Z, Liu Y, Wu J, Bast RC, Yu Y, Feng Y: FSH enhances the proliferation of ovarian cancer cells by activating transient receptor potential channel C3. Endocr Rel Cancer. 2013, 20: 415-429.CrossRef
52.
Mak VC, Siu MK, Wong OG, Chan KK, Ngan HY, Cheung AN: Dysregulated stemness-related genes in gynecological malignancies. Histol Histopathol. 2012, 27: 1121-1130.PubMed
53.
Zhang Z, Zhu Y, Lai Y, Wu X, Feng Z, Yu Y, Bast RC, Wan X, Xi X, Feng Y: Follicle-stimulating hormone inhibits apoptosis in ovarian cancer cells by regulating the OCT4 stem cell signaling pathway. Int J Oncol. 2013, 43: 1194-1204.PubMedCentralPubMed
54.
Visser JA, De Jong FH, Laven JS, Themmen AP: Anti-mullerian hormone: a new marker for ovarian function. Reproduction. 2006, 131: 1-9.CrossRefPubMed
55.
Carlsson IB, Scott JE, Visser JA, Ritvos O, Themmen AP, Hovatta O: Anti-mullerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Hum Reprod. 2006, 21: 2223-2227.CrossRefPubMed
56.
Durlinger AL, Gruijters MJ, Kramer P, Karels B, Kumar TR, Matzuk MM, Rose UM, De Jong FH, Uilenbroek JT, Grootegoed JA: Anti-mullerian hormone attenuates the effects of FSH on follicle development in the mouse ovary. Endocrinology. 2001, 142: 4891-4899.PubMed
57.
Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH: A validated model of serum anti-mullerian hormone from conception to menopause. PLoS One. 2011, 6: e22024-PubMedCentralCrossRefPubMed
58.
Jeppesen JV, Anderson RA, Kelsey TW, Christiansen SL, Kristensen SG, Jayaprakasan K, Raine-Fenning N, Campbell BK, Yding Andersen C: Which follicles make the most anti-mullerian hormone in humans? Evidence for an abrupt decline in AMH production at the time of follicle selection. Mol Hum Reprod. 2013, 19: 519-527.CrossRefPubMed
59.
Fanchin R, Schonauer LM, Righini C, Frydman N, Frydman R, Taieb J: Serum anti-mullerian hormone dynamics during controlled ovarian hyperstimulation. Hum Reprod. 2003, 18: 328-332.CrossRefPubMed
60.
Durlinger AL, Kramer P, Karels B, De Jong FH, Uilenbroek JT, Grootegoed JA, Themmen AP: Control of primordial follicle recruitment by anti-müllerian hormone in the mouse ovary. Endocrinology. 1999, 140 (12): 5789-5796.PubMed
61.
Anckaert E, Smitz J, Schiettecatte J, Klein BM, Arce JC: The value of anti-Mullerian hormone measurement in the long GnRH agonist protocol: association with ovarian response and gonadotropin-dose adjustments. Hum Reprod. 2012, 27: 1829-1839.PubMedCentralCrossRefPubMed
62.
Geerts I, Vergote I, Neven P, Billen J: The role of inhibins B and antimullerian hormone for diagnosis and follow-up of granulosa cell tumors. Int J Gynecol Canc. 2009, 19: 847-855.CrossRef
63.
Walentowicz P, Sadlecki P, Krintus M, Sypniewska G, Mankowska-Cyl A, Grabiec M, Walentowicz-Sadlecka M: Serum anti-mullerian hormone levels in patients with epithelial ovarian cancer. Int J Endocrinol. 2013, 2013: 517239-PubMedCentralCrossRefPubMed
64.
Fevold HL, Hisaw FL, Leonard SL: The gonad stimulating and the luteinizing hormones of the anterior lobe of the hypophesis. Am J Physiol. 1931, 97: 291-301.
65.
Baird DT, Swanston IA, McNeilly AS: Relationship between LH, FSH, and prolactin concentration and the secretion of androgens and estrogens by the preovulatory follicle in the ewe. Biol Reprod. 1981, 24: 1013-1025.CrossRefPubMed
66.
Ma X, Dong Y, Matzuk MM, Kumar TR: Targeted disruption of luteinizing hormone β-subunit leads to hypogonadism, defects in gonadal steroidogenesis, and infertility. Proc Natl Acad Sci U S A. 2004, 101: 17294-17299.PubMedCentralCrossRefPubMed
67.
Chada M, Prusa R, Bronsky J, Pechova M, Kotaska K, Lisa L: Inhibin B, follicle stimulating hormone, luteinizing hormone, and estradiol and their relationship to the regulation of follicle development in girls during childhood and puberty. Physiol Res. 2003, 52: 341-346.PubMed
68.
Brodowska A, Laszczynska M, Brodowski J, Masiuk M, Starczewski A: Analysis of pituitary gonadotropin concentration in blood serum and immunolocalization and immunoexpression of follicle stimulating hormone and luteinising hormone receptors in ovaries of postmenopausal women. Histol Histopathol. 2012, 27: 241-248.PubMed
69.
Liao H, Zhou Q, Gu Y, Duan T, Feng Y: Luteinizing hormone facilitates angiogenesis in ovarian epithelial tumor cells and metformin inhibits the effect through mTOR signaling pathway. Oncol Rep. 2012, 27: 1873-1878.PubMed
70.
Zhang Z, Liao H, Chen X, Zheng Y, Liu Y, Tao X, Gu C, Dong L, Duan T, Yang Y, Liu X, Feng Y: Luteinizing hormone upregulates survivin and inhibits apoptosis in ovarian epithelial tumors. Eur J Obstet Gynecol Repod Biol. 2011, 155: 69-74.CrossRef
71.
Lee Y, Miron A, Drapkin R, Nucci MR, Medeiros F, Saleemuddin A, Garber J, Birch C, Mou H, Gordon RW, Cramer DW, McKeon FD, Crum CP: A candidate precursor to serous carcinoma that originates in the distal fallopian tube. J Pathol. 2007, 211: 26-35.CrossRefPubMed
72.
Sjoquist K, Martyn J, Edmondson R, Friedlander M: The role of hormonal therapy in gynecological cancers-current status and future directions. Int J Gynecol Cancer. 2011, 21: 1328-1333.PubMed
73.
74.
Martinez-Delgado B, Yanowsky K, Inglada-Perez L, de la Hoya M, Caldes T, Vega A, Blanco A, Martin T, Gonzalez-Sarmiento R, Blasco M, Robledo M, Urioste M, Song H, Pharoah P, Benitez J: Shorter telomere length is associated with increased ovarian cancer risk in both familial and sporatic cases. J Med Genet. 2012, 49: 341-344.CrossRefPubMed
75.
Murakami J, Nagai N, Ohama K, Tahara H, Ide T: Telomerase activity in ovarian tumors. Cancer. 1997, 80: 1085-1092.CrossRefPubMed
Metadata
Title
The hormonal composition of follicular fluid and its implications for ovarian cancer pathogenesis
Authors
Megan M Emori
Ronny Drapkin
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Reproductive Biology and Endocrinology / Issue 1/2014
Electronic ISSN: 1477-7827
DOI
https://doi.org/10.1186/1477-7827-12-60

Other articles of this Issue 1/2014

Reproductive Biology and Endocrinology 1/2014 Go to the issue

Research

Effect of inter-cycle interval on oocyte production in humans in the presence of the weak androgen DHEA and follicle stimulating hormone: a case-control study

Research

Preeclampsia induced by cadmium in rats is related to abnormal local glucocorticoid synthesis in placenta

Research

Small-scale transcriptomics reveals differences among gonadal stages in Asian seabass (Lates calcarifer)

Research

The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report

Research

The prevalence of metabolic disorders in various phenotypes of polycystic ovary syndrome: a community based study in Southwest of Iran

Review

Human steroidogenesis: implications for controlled ovarian stimulation with exogenous gonadotropins