High-Fat, High-Sugar Diet Disrupts the Preovulatory Hormone Surge and Induces Cystic Ovaries in Cycling Female Rats

Katrina M Volk, Veronika V Pogrebna, Jackson A Roberts, Jennifer E Zachry, Sarah N Blythe, Natalia Toporikova, Katrina M Volk, Veronika V Pogrebna, Jackson A Roberts, Jennifer E Zachry, Sarah N Blythe, Natalia Toporikova

Abstract

Diet-induced obesity has been associated with various metabolic and reproductive disorders, including polycystic ovary syndrome. However, the mechanisms by which obesity influences the reproductive system are still not fully known. Studies have suggested that impairments in hormone signaling are associated with the development of symptoms such as acyclicity and ovarian cysts. However, these studies have often failed to address how these hormonal changes arise and how they might contribute to the progression of reproductive diseases. In the present study, we used a high-fat, high-sugar (HFHS) diet to induce obesity in a female rodent model to determine the changes in critical reproductive hormones that might contribute to the development of irregular estrous cycling and reproductive cycle termination. The HFHS animals exhibited impaired estradiol, progesterone (P4), and luteinizing hormone (LH) surges before ovulation. The HFHS diet also resulted in altered basal levels of testosterone (T) and LH. Furthermore, alterations in the basal P4/T ratio correlated strongly with ovarian cyst formation in HFHS rats. Thus, this model provides a method to assess the underlying etiology of obesity-related reproductive dysfunction and to examine an acyclic reproductive phenotype as it develops.

Keywords: decreased luteinizing hormone; hormone surge; increased estradiol; obesity; ovarian cysts; testosterone.

Figures

Figure 1.
Figure 1.
HFHS diet increases body weight and abdominal fat. (a) Mean HFHS and control animal body weights by weeks of diet exposure. (b) Average percentage of abdominal fat weight relative to total body weight. Error bars indicate standard error of the mean; gray circles, HFHS diet group; and open circles, controls.
Figure 2.
Figure 2.
HFHS diet increases irregular cycling. Graph showing fraction of time spent in each stage of the estrous cycle.
Figure 3.
Figure 3.
HFHS diet increases fasting insulin, but not glucose, levels. (a) Mean insulin levels over time after a glucose tolerance test in HFHS and control rats. (b) Mean insulin area under the curve (AUC) between control and HFHS rats after a glucose tolerance test. (c) Mean fasting insulin levels between control and HFHS groups. (d) Mean fasting glucose levels in HFHS and control rats.
Figure 4.
Figure 4.
HFHS diet is associated with altered ovarian morphology. (a) Representative photomicrograph of a control ovary. CL are evident throughout the section. (b) Representative photomicrograph of an ovary from a HFHS rat showing numerous fluid-filled cysts (cy) and fewer CL compared with the control ovary. (c) Mean number of cysts per ovary section. (d) Mean number of CL per ovary section. (e) Mean number of GFs per section. Error bars indicate standard error of the mean.
Figure 5.
Figure 5.
HFHS diet alters LH, but not FSH, levels on diestrus. (a) Mean concentration of LH on diestrus. (b) Mean FSH levels on diestrus. Error bars indicate standard error of the mean.
Figure 6.
Figure 6.
HFHS diet is associated with altered steroidogenesis. (a) Mean progesterone levels of HFHS and control rats on diestrus. (b) Mean T levels of HFHS and control rats on diestrus. (c) Mean E2 levels of HFHS and control rats on diestrus. (d) Mean ratio of P4/T of HFHS and control rats on diestrus. (e) Mean ratio of T/E2 of HFHS and control groups on diestrus. (f) Mean ratio of P4/E2 of HFHS and control groups on diestrus. Error bars indicate standard error of the mean.
Figure 7.
Figure 7.
Correlations between cyst and CL counts vs P4/T ratio on diestrus in HFHS and control rats. (a) Plot of individual numbers of cysts vs P4/T ratio on diestrus. (b) Plot of individual numbers of CL vs P4/T ratio on diestrus. Open circles represent individual control rats; exponential black dotted line fitted to controls. Gray circles represent HFHS rats; exponential gray dotted line fitted to HFHS. Vertical black dotted lines denote the separation between cycling (n = 21) and noncycling (n = 4) rats.
Figure 8.
Figure 8.
HFHS diet disrupts hormonal levels on proestrus. (a) Mean estradiol levels throughout the preovulatory surge on proestrus. (b) Mean progesterone levels throughout the preovulatory surge on proestrus. (c) Mean LH levels throughout the preovulatory surge on proestrus. (d) Mean FSH levels throughout the preovulatory surge on proestrus. (n = 12 control; n = 13 HFHS).

References

    1. Siega-Riz AM, King JC; American Dietetic Association, American Society of Nutrition . Position of the American Dietetic Association and American Society for Nutrition: obesity, reproduction, and pregnancy outcomes. J Am Diet Assoc. 2009;109(5):918–927.
    1. Hartz AJ, Barboriak PN, Wong A, Katayama KP, Rimm AA. The association of obesity with infertility and related menstrual abnormalities in women. Int J Obes. 1979;3(1):57–73.
    1. Dağ ZÖ, Dilbaz B. Impact of obesity on infertility in women. J Turk Ger Gynecol Assoc. 2015;16(2):111–117.
    1. Nelson SM, Fleming RF. The preconceptual contraception paradigm: obesity and infertility. Hum Reprod. 2007;22(4):912–915.
    1. Giviziez CR, Sanchez EGM, Approbato MS, Maia MCS, Fleury EAB, Sasaki RSA. Obesity and anovulatory infertility: a review. JBRA Assist Reprod. 2016;20(4):240–245.
    1. Wei S, Schmidt MD, Dwyer T, Norman RJ, Venn AJ. Obesity and menstrual irregularity: associations with SHBG, testosterone, and insulin. Obesity (Silver Spring). 2009;17(5):1070–1076.
    1. Bellver J, Melo MAB, Bosch E, Serra V, Remohí J, Pellicer A. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil Steril. 2007;88(2):446–451.
    1. Bellver J, Busso C, Pellicer A, Remohí J, Simón C. Obesity and assisted reproductive technology outcomes. Reprod Biomed Online. 2006;12(5):562–568.
    1. Jungheim ES, Schoeller EL, Marquard KL, Louden ED, Schaffer JE, Moley KH. Diet-induced obesity model: abnormal oocytes and persistent growth abnormalities in the offspring. Endocrinology. 2010;151(8):4039–4046.
    1. Carmina E, Bucchieri S, Esposito A, Del Puente A, Mansueto P, Orio F, Di Fede G, Rini G. Abdominal fat quantity and distribution in women with polycystic ovary syndrome and extent of its relation to insulin resistance. J Clin Endocrinol Metab. 2007;92(7):2500–2505.
    1. Cosar E, Uçok K, Akgün L, Köken G, Sahin FK, Arioz DT, Baş O. Body fat composition and distribution in women with polycystic ovary syndrome. Gynecol Endocrinol. 2008;24(8):428–432.
    1. Gambineri A, Pelusi C, Vicennati V, Pagotto U, Pasquali R. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26(7):883–896.
    1. Sam S. Obesity and polycystic ovary syndrome. Obes Manag. 2007;3(2):69–73.
    1. Nestler JE. Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol. 1997;15(2):111–122.
    1. 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(2):191–196.
    1. Pasquali R, Gambineri A, Pagotto U. The impact of obesity on reproduction in women with polycystic ovary syndrome. BJOG. 2006;113(10):1148–1159.
    1. Ovalle F, Azziz R. Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril. 2002;77(6):1095–1105.
    1. Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38(9):1165–1174.
    1. Toprak S, Yönem A, Cakir B, Güler S, Azal O, Ozata M, Corakçi A. Insulin resistance in nonobese patients with polycystic ovary syndrome. Horm Res. 2001;55(2):65–70.
    1. Ressler IB, Grayson BE, Ulrich-Lai YM, Seeley RJ. Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model. Am J Physiol Endocrinol Metab. 2015;308(12):E1076–E1084.
    1. Roberts JS, Perets RA, Sarfert KS, Bowman JJ, Ozark PA, Whitworth GB, Blythe SN, Toporikova N. High-fat high-sugar diet induces polycystic ovary syndrome in a rodent model. Biol Reprod. 2017;96(3):551–562.
    1. Tsutsumi R, Webster NJG. GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocr J. 2009;56(6):729–737.
    1. Helm KD, Nass RM, Evans WS. Physiologic and pathophysiologic alterations of the neuroendocrine components of the reproductive axis In: Strauss JF, Barbieri RL, eds. Yen & Jaffe’s Reproductive Endocrinology. 6th edPhiladelphia, NY: WB Saunders; 2009:441–488.
    1. Marshall JC, Eagleson CA, McCartney CR. Hypothalamic dysfunction. Mol Cell Endocrinol. 2002;186(1-2):227–230.
    1. Foecking EM, Szabo M, Schwartz NB, Levine JE. Neuroendocrine consequences of prenatal androgen exposure in the female rat: absence of luteinizing hormone surges, suppression of progesterone receptor gene expression, and acceleration of the gonadotropin-releasing hormone pulse generator. Biol Reprod. 2005;72(6):1475–1483.
    1. Wu XY, Li ZL, Wu CY, Liu YM, Lin H, Wang SH, Xiao WF. Endocrine traits of polycystic ovary syndrome in prenatally androgenized female Sprague-Dawley rats. Endocr J. 2010;57(3):201–209.
    1. Chang RJ, Laufer LR, Meldrum DR, DeFazio J, Lu JK, Vale WW, Rivier JE, Judd HL. Steroid secretion in polycystic ovarian disease after ovarian suppression by a long-acting gonadotropin-releasing hormone agonist. J Clin Endocrinol Metab. 1983;56(5):897–903.
    1. Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab. 2000;85(11):4047–4052.
    1. Tortoriello DV, McMinn J, Chua SC. Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. Endocrinology. 2004;145(3):1238–1247.
    1. Todd BJ, Ladyman SR, Grattan DR. Suppression of pulsatile luteinizing hormone secretion but not luteinizing hormone surge in leptin resistant obese Zucker rats. J Neuroendocrinol. 2003;15(1):61–68.
    1. Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda K. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev. 2007;53(2):367–378.
    1. Kauffman AS. Coming of age in the kisspeptin era: sex differences, development, and puberty. Mol Cell Endocrinol. 2010;324(1-2):51–63.
    1. Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008;28(35):8691–8697.
    1. Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab. 1998;83(2):582–590.
    1. Stephens SBZ, Tolson KP, Rouse ML Jr, Poling MC, Hashimoto-Partyka MK, Mellon PL, Kauffman AS. Absent progesterone signaling in kisspeptin neurons disrupts the LH surge and impairs fertility in female mice. Endocrinology. 2015;156(9):3091–3097.
    1. Chappell PE, Lydon JP, Conneely OM, O’Malley BW, Levine JE. Endocrine defects in mice carrying a null mutation for the progesterone receptor gene. Endocrinology. 1997;138(10):4147–4152.
    1. Chappell PE, Schneider JS, Kim P, Xu M, Lydon JP, O’Malley BW, Levine JE. Absence of gonadotropin surges and gonadotropin-releasing hormone self-priming in ovariectomized (OVX), estrogen (E2)-treated, progesterone receptor knockout (PRKO) mice. Endocrinology. 1999;140(8):3653–3658.
    1. Manikkam M, Thompson RC, Herkimer C, Welch KB, Flak J, Karsch FJ, Padmanabhan V. Developmental programming: impact of prenatal testosterone excess on pre- and postnatal gonadotropin regulation in sheep. Biol Reprod. 2008;78(4):648–660.
    1. Sarma HN, Manikkam M, Herkimer C, Dell’Orco J, Welch KB, Foster DL, Padmanabhan V. Fetal programming: excess prenatal testosterone reduces postnatal luteinizing hormone, but not follicle-stimulating hormone responsiveness, to estradiol negative feedback in the female. Endocrinology. 2005;146(10):4281–4291.
    1. Blank SK, McCartney CR, Helm KD, Marshall JC. Neuroendocrine effects of androgens in adult polycystic ovary syndrome and female puberty. Semin Reprod Med. 2007;25(5):352–359.
    1. Yeung EH, Zhang C, Albert PS, Mumford SL, Ye A, Perkins NJ, Wactawski-Wende J, Schisterman EF. Adiposity and sex hormones across the menstrual cycle: the BioCycle study. Int J Obes. 2005;2013(37):237–243.
    1. Lee HS, Yoon JS, Hwang JS. Luteinizing hormone secretion during gonadotropin-releasing hormone stimulation tests in obese girls with central precocious puberty. J Clin Res Pediatr Endocrinol. 2016;8(4):392–398.
    1. Sohrabi M, Roushandeh AM, Alizadeh Z, Vahidinia A, Vahabian M, Hosseini M. Effect of a high fat diet on ovary morphology, in vitro development, in vitro fertilisation rate and oocyte quality in mice. Singapore Med J. 2015;56(10):573–579.
    1. McLean AC, Valenzuela N, Fai S, Bennett SAL. Performing vaginal lavage, crystal violet staining, and vaginal cytological evaluation for mouse estrous cycle staging identification. J Vis Exp. 2012;(67):e4389.
    1. Brawer JR, Munoz M, Farookhi R. Development of the polycystic ovarian condition (PCO) in the estradiol valerate-treated rat. Biol Reprod. 1986;35(3):647–655.
    1. Nelson JF, Felicio LS, Osterburg HH, Finch CE. Altered profiles of estradiol and progesterone associated with prolonged estrous cycles and persistent vaginal cornification in aging C57BL/6J mice. Biol Reprod. 1981;24(4):784–794.
    1. Harms PG, Ojeda SR. A rapid and simple procedure for chronic cannulation of the rat jugular vein. J Appl Physiol. 1974;36(3):391–392.
    1. Thrivikraman KV, Huot RL, Plotsky PM. Jugular vein catheterization for repeated blood sampling in the unrestrained conscious rat. Brain Res Brain Res Protoc. 2002;10(2):84–94.
    1. Douchi T, Kuwahata R, Yamamoto S, Oki T, Yamasaki H, Nagata Y. Relationship of upper body obesity to menstrual disorders. Acta Obstet Gynecol Scand. 2002;81(2):147–150.
    1. Hung C-S, Lee J-K, Yang C-Y, Hsieh H-R, Ma W-Y, Lin M-S, Liu PH, Shih SR, Liou JM, Chuang LM, Chen MF, Lin JW, Wei JN, Li HY. Measurement of visceral fat: should we include retroperitoneal fat? PLoS One. 2014;9(11):e112355.
    1. Penaforte FRO, Japur CC, Diez-Garcia RW, Chiarello PG. Upper trunk fat assessment and its relationship with metabolic and biochemical variables and body fat in polycystic ovary syndrome. J Hum Nutr Diet. 2011;24(1):39–46.
    1. Kirchengast S, Huber J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum Reprod. 2001;16(6):1255–1260.
    1. Wagenknecht LE, Langefeld CD, Scherzinger AL, Norris JM, Haffner SM, Saad MF, Bergman RN. Insulin sensitivity, insulin secretion, and abdominal fat: the insulin resistance atherosclerosis study (IRAS) family study. Diabetes. 2003;52(10):2490–2496.
    1. Kyrou I, Tsigos C. Chronic stress, visceral obesity and gonadal dysfunction. Hormones (Athens). 2008;7(4):287–293.
    1. Malafaia AB, Nassif PAN, Ribas CAPM, Ariede BL, Sue KN, Cruz MA. Obesity induction with high fat sucrose in rats. Arq Bras Cir Dig. 2013;26(Suppl 1):17–21.
    1. Myers M, Britt KL, Wreford NGM, Ebling FJP, Kerr JB. Methods for quantifying follicular numbers within the mouse ovary. Reproduction. 2004;127(5):569–580.
    1. Tilly JL. Ovarian follicle counts—not as simple as 1, 2, 3. Reprod Biol Endocrinol. 2003;1(1):11.
    1. Clark AM, Ledger W, Galletly C, Tomlinson L, Blaney F, Wang X, Norman RJ. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum Reprod. 1995;10(10):2705–2712.
    1. Wang N, Luo L-L, Xu J-J, Xu M-Y, Zhang X-M, Zhou X-L, Liu WJ, Fu YC. Obesity accelerates ovarian follicle development and follicle loss in rats. Metabolism. 2014;63(1):94–103.
    1. Balasubramanian P, Jagannathan L, Mahaley RE, Subramanian M, Gilbreath ET, Mohankumar PS, Mohankumar SM. High fat diet affects reproductive functions in female diet-induced obese and dietary resistant rats. J Neuroendocrinol. 2012;24(5):748–755.
    1. Jain A, Polotsky AJ, Rochester D, Berga SL, Loucks T, Zeitlian G, Gibbs K, Polotsky HN, Feng S, Isaac B, Santoro N. Pulsatile luteinizing hormone amplitude and progesterone metabolite excretion are reduced in obese women. J Clin Endocrinol Metab. 2007;92(7):2468–2473.
    1. De Pergola G, Maldera S, Tartagni M, Pannacciulli N, Loverro G, Giorgino R. Inhibitory effect of obesity on gonadotropin, estradiol, and inhibin B levels in fertile women. Obesity (Silver Spring). 2006;14(11):1954–1960.
    1. Sagae SC, Menezes EF, Bonfleur ML, Vanzela EC, Zacharias P, Lubaczeuski C, Franci CR, Sanvitto GL. Early onset of obesity induces reproductive deficits in female rats. Physiol Behav. 2012;105(5):1104–1111.
    1. Akamine EH, Marçal AC, Camporez JP, Hoshida MS, Caperuto LC, Bevilacqua E, Carvalho CR. Obesity induced by high-fat diet promotes insulin resistance in the ovary. J Endocrinol. 2010;206(1):65–74.
    1. van Houten ELAF, Kramer P, McLuskey A, Karels B, Themmen APN, Visser JA. Reproductive and metabolic phenotype of a mouse model of PCOS. Endocrinology. 2012;153(6):2861–2869.
    1. Poretsky L, Clemons J, Bogovich K. Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats. Metabolism. 1992;41(8):903–910.
    1. Clemens JA, Amenomori Y, Jenkins T, Meites J. Effects of hypothalamic stimulation, hormones, and drugs on ovarian function in old female rats. Proc Soc Exp Biol Med. 1969;132(2):561–563.
    1. Greer MA. The effect of progesterone on persistent vaginal estrus produced by hypothalamic lesions in the rat. Endocrinology. 1953;53(4):380–390.
    1. D’Angelo SA, Kravatz AS. Gonadotrophic hormone function in persistent estrous rats with hypothalamic lesions. Proc Soc Exp Biol Med. 1960;104(1):130–133.
    1. Wiegand SJ, Terasawa E, Bridson WE. Persistent estrus and blockade of progesterone-induced LH release follows lesions which do not damage the suprachiasmatic nucleus. Endocrinology. 1978;102(5):1645–1648.
    1. Peluso JJ, Steger RW, Huang H, Meites J. Pattern of follicular growth and steroidogenesis in the ovary of aging cycling rats. Exp Aging Res. 1979;5(4):319–333.
    1. Huang HH, Meites J. Reproductive capacity of aging female rats. Neuroendocrinology. 1975;17(4):289–295.
    1. Andersen P, Seljeflot I, Abdelnoor M, Arnesen H, Dale PO, Løvik A, Birkeland K. Increased insulin sensitivity and fibrinolytic capacity after dietary intervention in obese women with polycystic ovary syndrome. Metabolism. 1995;44(5):611–616.
    1. Sakumoto T, Tokunaga Y, Tanaka H, Nohara M, Motegi E, Shinkawa T, Nakaza A, Higashi M. Insulin resistance/hyperinsulinemia and reproductive disorders in infertile women. Reprod Med Biol. 2010;9(4):185–190.
    1. Wu S, Divall S, Nwaopara A, Radovick S, Wondisford F, Ko C, Wolfe A. Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes. 2014;63(4):1270–1282.
    1. Katayama S, Brownscheidle CM, Wootten V, Lee JB, Shimaoka K. Absent or delayed preovulatory luteinizing hormone surge in experimental diabetes mellitus. Diabetes. 1984;33(4):324–327.
    1. Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology. 2005;146(9):3686–3692.
    1. Goodman RL. A quantitative analysis of the physiological role of estradiol and progesterone in the control of tonic and surge secretion of luteinizing hormone in the rat. Endocrinology. 1978;102(1):142–150.
    1. Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci. 2006;26(25):6687–6694.
    1. Kauffman AS, Park JH, McPhie-Lalmansingh AA, Gottsch ML, Bodo C, Hohmann JG, Pavlova MN, Rohde AD, Clifton DK, Steiner RA, Rissman EF. The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci. 2007;27(33):8826–8835.
    1. Clarkson J, Herbison AE. Oestrogen, kisspeptin, GPR54 and the pre-ovulatory luteinising hormone surge. J Neuroendocrinol. 2009;21(4):305–311.
    1. Radovick S, Levine JE, Wolfe A. Estrogenic regulation of the GnRH neuron. Front Endocrinol (Lausanne). 2012;3:52.
    1. Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology. 2004;145(9):4073–4077.
    1. Dungan HM, Clifton DK, Steiner RA. Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology. 2006;147(3):1154–1158.
    1. d’Anglemont de Tassigny X, Fagg LA, Carlton MBL, Colledge WH. Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology. 2008;149(8):3926–3932.
    1. Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A. Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett. 2006;401(3):225–230.
    1. Roa J, Vigo E, Castellano JM, Gaytan F, García-Galiano D, Navarro VM, Aguilar E, Dijcks FA, Ederveen AG, Pinilla L, van Noort PI, Tena-Sempere M. Follicle-stimulating hormone responses to kisspeptin in the female rat at the preovulatory period: modulation by estrogen and progesterone receptors. Endocrinology. 2008;149(11):5783–5790.
    1. Wintermantel TM, Campbell RE, Porteous R, Bock D, Gröne H-J, Todman MG, Korach KS, Greiner E, Pérez CA, Schütz G, Herbison AE. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron. 2006;52(2):271–280.
    1. Quennell JH, Howell CS, Roa J, Augustine RA, Grattan DR, Anderson GM. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology. 2011;152(4):1541–1550.
    1. Brown RE, Wilkinson DA, Imran SA, Caraty A, Wilkinson M. Hypothalamic kiss1 mRNA and kisspeptin immunoreactivity are reduced in a rat model of polycystic ovary syndrome (PCOS). Brain Res. 2012;1467:1–9.
    1. Ishii MN, Matsumoto K, Matsui H, Seki N, Matsumoto H, Ishikawa K, Chatani F, Watanabe G, Taya K. Reduced responsiveness of kisspeptin neurons to estrogenic positive feedback associated with age-related disappearance of LH surge in middle-age female rats. Gen Comp Endocrinol. 2013;193:121–129.
    1. Conneely OM, Lydon JP, De Mayo F, O’Malley BW. Reproductive functions of the progesterone receptor. J Soc Gynecol Investig. 2000;7(1, Suppl):S25–S32.
    1. Leite CM, Kalil B, Uchôa ET, Antunes-Rodrigues J, Elias LKL, Levine JE, Anselmo-Franci JA. Progesterone-induced amplification and advancement of GnRH/LH surges are associated with changes in kisspeptin system in preoptic area of estradiol-primed female rats. Brain Res. 2016;1650:21–30.
    1. Krey LC, Tyrey L, Everett JW. The estrogen-induced advance in the cyclic LH surge in the rat: dependency on ovarian progesterone secretion. Endocrinology. 1973;93(2):385–390.
    1. DePaolo LV, Barraclough CA. Dose dependent effects of progesterone on the facilitation and inhibition of spontaneous gonadotropin surges in estrogen treated ovariectomized rats. Biol Reprod. 1979;21(4):1015–1023.
    1. Everett JW. Progesterone and estrogen in the experimental control of ovulation time and other features of the estrous cycle in the rat. Endocrinology. 1948;43(6):389–405.
    1. Odell WD, Swerdloff RS. Progestogen-induced luteinizing and follicle-stimulating hormone surge in postmenopausal women: a simulated ovulatory peak. Proc Natl Acad Sci USA. 1968;61(2):529–536.
    1. Wiegand SJ, Terasawa E. Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology. 1982;34(6):395–404.
    1. Everett JW. The restoration of ovulatory cycles and corpus luteum formation in persistent-estrous rats by progesterone. Endocrinology. 1940;27(4):681–686.
    1. Ronnekleiv OK, Kelly MJ. Plasma prolactin and luteinizing hormone profiles during the estrous cycle of the female rat: effects of surgically induced persistent estrus. Neuroendocrinology. 1988;47(2):133–141.
    1. Gümen A, Wiltbank MC. An alteration in the hypothalamic action of estradiol due to lack of progesterone exposure can cause follicular cysts in cattle. Biol Reprod. 2002;66(6):1689–1695.
    1. Gümen A, Sartori R, Costa FMJ, Wiltbank MCA. A GnRH/LH surge without subsequent progesterone exposure can induce development of follicular cysts. J Dairy Sci. 2002;85(1):43–50.
    1. Foecking EM, Levine JE. Effects of experimental hyperandrogenemia on the female rat reproductive axis: suppression of progesterone-receptor messenger RNA expression in the brain and blockade of luteinizing hormone surges. Gend Med. 2005;2(3):155–165.
    1. Blank SK, McCartney CR, Chhabra S, Helm KD, Eagleson CA, Chang RJ, Marshall JC. Modulation of gonadotropin-releasing hormone pulse generator sensitivity to progesterone inhibition in hyperandrogenic adolescent girls—implications for regulation of pubertal maturation. J Clin Endocrinol Metab. 2009;94(7):2360–2366.
    1. Burt Solorzano CM, Beller JP, Abshire MY, Collins JS, McCartney CR, Marshall JC. Neuroendocrine dysfunction in polycystic ovary syndrome. Steroids. 2012;77(4):332–337.
    1. Nagatani S, Guthikonda P, Thompson RC, Tsukamura H, Maeda KI, Foster DL. Evidence for GnRH regulation by leptin: leptin administration prevents reduced pulsatile LH secretion during fasting. Neuroendocrinology. 1998;67(6):370–376.
    1. Watanobe H. Leptin directly acts within the hypothalamus to stimulate gonadotropin-releasing hormone secretion in vivo in rats. J Physiol. 2002;545(Pt 1):255–268.
    1. Chhabra S, McCartney CR, Yoo RY, Eagleson CA, Chang RJ, Marshall JC. Progesterone inhibition of the hypothalamic gonadotropin-releasing hormone pulse generator: evidence for varied effects in hyperandrogenemic adolescent girls. J Clin Endocrinol Metab. 2005;90(5):2810–2815.
    1. Hughesdon PE. Morphology and morphogenesis of the Stein-Leventhal ovary and of so-called “hyperthecosis.” Obstet Gynecol Surv. 1982;37(2):59–77.
    1. Gervásio CG, Bernuci MP, Silva-de-Sá MF, Japur de Sá Rosa-e-Silva AC. The role of androgen hormones in early follicular development. ISRN Obstet Gynecol. 2014;2014: e818010.
    1. Jonard S, Dewailly D. The follicular excess in polycystic ovaries, due to intra-ovarian hyperandrogenism, may be the main culprit for the follicular arrest. Hum Reprod Update. 2004;10(2):107–117.
    1. Grynnerup AG-A, Lindhard A, Sørensen S. The role of anti-Müllerian hormone in female fertility and infertility—an overview. Acta Obstet Gynecol Scand. 2012;91(11):1252–1260.
    1. Freeman EW, Gracia CR, Sammel MD, Lin H, Lim LC-L, Strauss JF III. Association of anti-mullerian hormone levels with obesity in late reproductive-age women. Fertil Steril. 2007;87(1):101–106.
    1. Kriseman M, Mills C, Kovanci E, Sangi-Haghpeykar H, Gibbons W. Antimullerian hormone levels are inversely associated with body mass index (BMI) in women with polycystic ovary syndrome. J Assist Reprod Genet. 2015;32(9):1313–1316.
    1. Fauser BC. Observations in favor of normal early follicle development and disturbed dominant follicle selection in polycystic ovary syndrome. Gynecol Endocrinol. 1994;8(2):75–82.
    1. Kimura S, Matsumoto T, Matsuyama R, Shiina H, Sato T, Takeyama K, Kato S. Androgen receptor function in folliculogenesis and its clinical implication in premature ovarian failure. Trends Endocrinol Metab. 2007;18(5):183–189.
    1. Gelmann EP. Molecular biology of the androgen receptor. J Clin Oncol. 2002;20(13):3001–3015.
    1. Tetsuka M, Whitelaw PF, Bremner WJ, Millar MR, Smyth CD, Hillier SG. Developmental regulation of androgen receptor in rat ovary. J Endocrinol. 1995;145(3):535–543.
    1. Weil SJ, Vendola K, Zhou J, Adesanya OO, Wang J, Okafor J, Bondy CA. Androgen receptor gene expression in the primate ovary: cellular localization, regulation, and functional correlations. J Clin Endocrinol Metab. 1998;83(7):2479–2485.
    1. Gleicher N, Weghofer A, Barad DH. The role of androgens in follicle maturation and ovulation induction: friend or foe of infertility treatment? Reprod Biol Endocrinol. 2011;9(1):116.
    1. Takayama K, Fukaya T, Sasano H, Funayama Y, Suzuki T, Takaya R, Wada Y, Yajima A. Immunohistochemical study of steroidogenesis and cell proliferation in polycystic ovarian syndrome. Hum Reprod. 1996;11(7):1387–1392.
    1. Payne AH, Hales DB. Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocr Rev. 2004;25(6):947–970.
    1. Nelson VL, Qin KN, Rosenfield RL, Wood JR, Penning TM, Legro RS, Strauss JF III, McAllister JM. The biochemical basis for increased testosterone production in theca cells propagated from patients with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86(12):5925–5933.
    1. Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335(9):617–623.
    1. Nelson VL, Legro RS, Strauss JF III, McAllister JM. Augmented androgen production is a stable steroidogenic phenotype of propagated theca cells from polycystic ovaries. Mol Endocrinol. 1999;13(6):946–957.
    1. Erickson GF, Magoffin DA, Dyer CA, Hofeditz C. The ovarian androgen producing cells: a review of structure/function relationships. Endocr Rev. 1985;6(3):371–399.
    1. Li H, Chen Y, Yan LY, Qiao J. Increased expression of P450scc and CYP17 in development of endogenous hyperandrogenism in a rat model of PCOS. Endocrine. 2013;43(1):184–190.
    1. Wood JR, Nelson VL, Ho C, Jansen E, Wang CY, Urbanek M, McAllister JM, Mosselman S, Strauss JF III. The molecular phenotype of polycystic ovary syndrome (PCOS) theca cells and new candidate PCOS genes defined by microarray analysis. J Biol Chem. 2003;278(29):26380–26390.
    1. Conley AJ, Pattison JC, Bird IM. Variations in adrenal androgen production among (nonhuman) primates. Semin Reprod Med. 2004;22(4):311–326.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere