How stress affects female reproduction: An overview
Faculty of Medicine, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia
- *Corresponding Author:
- Amar Chatterjee
Professor of Physiology
Faculty of Medicine Universiti Teknologi MARA
40450 Shah Alam, Selangor, Malaysia
Accepted March 03 2009
Chronic anxiety, depression and physical exertion-related stress consistently activate the hypothalamic-pituitary-adrenal axis. Almost each component of this activated axis, such as CRH, ACTH, β-endorphin and glucocorticoids exerts profound inhibitory effects on the hypothalamic-pituitary-ovarian axis and subsequently leads to reproductive failure in females. The pulsatile secretion of GnRH and the response of gonadotrophs to GnRH stimulation are severely impaired. Increased levels of glucocorticoids moreover inhibit gonadal axis at the hypothalamic, pituitary and ovarian levels and concurrently result in deficient ovarian steroidogenesis, amenorrhea, anovulation, defective endometrial decidualization and implantation, abnormal fetal outcome and delayed parturition. Stress-associated growth hormone deficiency with a corresponding deficiency of insulin-like growth factor-1 at the level of the pituitary, ovary and uterine endometrium also leads to defective reproductive outcome in females. Moreover, stress-related imbalance between prooxidant and antioxidant forces may cause damage to the released ovum, embryo fragmentation, implantation failure or abortion.
Stress, Female Reproduction
Individuals frequently encounter stressful conditions. In vertebrates, a major universal response of stress is hyperactivation of the hypothalamic-pituitary-adrenal (HPA) axis. Since female hypothalamus contains higher concentration of corticotrophin-releasing hormone (CRH) than the male , the reactivity of the HPA axis to stress could reasonably be higher in females than the males . Sustained/prolonged activation of the HPA axis in psychological stress at work place in the women , prisoner awaiting execution , malnutrition in anorexia nervosa prolonged intense exercise in humans ,crowded and long distance transportation of the non-rodent mammals , stress of chair restraint in monkeys , and restraint stress in laboratory animals  all have been shown to inhibit the hypothalamic-pituitary-ovarian (HPO) axis Hypothalamic-pituitary-adrenal responses increase after chronic or repeated stress despite robust levels of circulating glucocorticoids . Chronic hyperactivation of any of the components of the HPA axis such as, corticotrophin-releasing hormone , corticotropin , β-endorphin , glucocorticoids , other associated substances, such as pro-inflammatory cytokines , or deficiency of GH-induced insulin-like growth factor-1 [IGF-1]  results in reproductive failure in females.
CRH and female reproduction
Stress is a potent activator of CRH release from the hypothalamus and extrahypothalamic sites . CRH type- I receptor knockout mice have however, been shown to have a deficient ability to mount an effective stress response . A direct neural connection between CRH and GnRH has been documented . CRH, the major regulator of the HPA axis and the CRH-induced proopiomelanocortin peptide, such as β-endorphin reduce the hypothalamic GnRH pulse generator activity  and concurrently inhibit GnRH secretion . The resulting decrease in pulsatile release of LH  subsequently leads to anovulation , interruption of endometrial decidualisation  and pregnancy wastage . Receptors for CRH are identified in most of the female reproductive tissues including the ovary, uterus and placental trophoblast . CRH in the ovarian theca and granulosa cells  is found to reduce ovarian steroidogenesis in a dose-dependent manner  which suggests that the ovarian CRH may lead to ovarian failure in women exposed to high psychological stress . At the uterine level, an excess of CRH may induce infertility  and at the placental level it may induce premature labor, because stress-induced premature labor due to an excess placental CRH is reversed by CRH antagonist . However, locally produced normal concentration of CRH is proposed to be essential in promoting endometrial decidualisation and implantation .
Proopiomelanocortin-derived ACTH, β-endorphin and female reproduction
Stress-induced elevated levels of ACTH inhibit pulsatile release of LH  by decreasing responsiveness of the pituitary gonadotrophs to GnRH . Suppressive effect of ACTH on gonadotropin secretion has been recorded in Cushing’s disease . CRH activated β-endorphin moreover suppresses GnRH pulses  and pulsatile release of LH . All these changes result in depression of the pituitary-ovarian axis.
Glucocorticoids and female reproduction
Persistent increase in serum concentration of glucocorticoids in humans , rhesus monkeys , cattle , pigs , sheep , and laboratory rodents  evidently suppresses the hypothalamic-pituitary-ovarian (HPO) axis. Glucocorticoids receptors are found in the hypothalamic GnRH neurons  and in the pituitary gonadotrophs . Stress-like glucocorticoid concentration blocks pituitary tissue concentration of GnRH  and the responsiveness of the gonadotrophs to GnRH  with a resulting attenuation of LH pulse frequency . An impaired generation of LH surge subsequently results in anovulation  as well as menstrual disorders . Glucocorticoids receptors have been demonstrated in the ovaries  and ovarian granulosa cell cytosol . A direct effect of glucocorticoids could possibly result in follicular atresia  by suppressing the action of LH at the receptor level . Glucocorticoids also induce estrogen deficiency by suppressing granulosa cell aromatase activity . As a result, estrogen deficiency is found in anxiety and depression-related stress .Glucocorticoids reduce the number of estrogen receptor , tissue uptake of estrogen  and estrogen-stimulated DNA synthesis in the uterus .Glucocorticoids also reduce blood flow protein synthesis , IGF-1 m-RNA expression  and prostaglandins synthesis  in the uterus. Most of these estrogen-induced uterine profiles are essentially important for blastocyst implantation , endometrial decidualization , pregnancy maintenance  and parturition . Estrogen deficiency not only impairs luteal steroidogenesis , it also jeopardizes receptor expression of estrogen and progesterone in the uterus  which may subsequently result in pregnancy wastage  or delayed parturition  Parental stress-associated shorter gestation, smaller birth weight in humans  could possibly be linked to the free access of excess glucocorticoids through placental barrier
GH-IGF-1 axis suppression and female reproduction
Attenuated release of growth hormone (GH) in panic disorder patients (64) has also been recorded in stressed primates  and laboratory animals . In humans, elevated levels of glucocorticoids concurrently suppress GH secretion and the effects of IGF-1 on its target tissues Laron dwarfism, sexual maturity is always found to be delayed . GH insensitivity similarly impairs formation of functional corpus luteum of pregnancy . It is therefore proposed that full reproductive potential requires adequate levels of GH-induced IGF-1 in peripheral circulation . IGF-1 receptors have been located in the hypothalamus, pituitary, ovaries and reproductive tract . IGF-1 is found to influence the release of GnRH , gonadotropins secretion , follicular growth, steroidogenesis and ovulation . Therefore, induction of ovulation in Laron dwarfism by IGF-1 treatment is often successful .
Interleukins and female reproduction
Pro-inflammatory cytokine, such as IL-18  acts as a regulator of the HPA axis during stress. Serum levels of IL-18 are found to be elevated in depression and panic disorders . Stressors are found to induce hypothalamic IL expression  and elevate pituitary IL-18 synthesis  and TNFα in particular suppresses the secretion  and surge  of LH. Prolonged cytokine exposure directly activates corticotropin and glucocorticoids release . Cytokines, therefore suppress female reproduction directly or indirectly by activating hypothalamic secretion of CRH, pituitary secretion of ACTH and β-endorphin as well as by peripheral elevation of glucocorticoids and inhibition of ovarian steroidogenesis .
Oxidative stress and female reproduction
In a healthy body, reactive oxygen species (ROS) and antioxidant remain in balance. When this balance is disturbed, oxidative stress (OS) develops .Stressful conditions depress the cellular antioxidant mechanism and subsequently develop OS . Elevated levels of glucocorticoids in stress cause free radical formation  and subsequently decrease sex steroids synthesis . Estrogens have antioxidant effects, therefore its deficiency during stress may lead to an overproduction of ROS  which subsequently interferes with oocyte maturation induces embryo fragmentation, implantation failure or abortion .
Stress-related hyperactivation of the HPA axis with a corresponding inhibition of the HPO axis may possibly act as the major cause of impaired fecundity in women. The National Survey for Family Growth of USA indicates that the number of women with impaired fecundity has increased to about 35% from 1982 to 1995.
Encouraging cooperation of Professor Dr Dato’ Khalid Yusoff (Dean) and Professor Dr Hamim Rajikin (Deputy Dean, Students and Alumni), Faculty of Medicine, UiTM, is very much appreciated.
- Fredericksen SO, Ekman R, Gottfries C-G et al. Reduced concentration of galanin, arginine vasopressin, neuropeptide Y and peptide YY in the temporal cortex but not the hypothalamus of brains from schizophrenics. Acta Psychiatrica Scand 1991; 83: 273-277.
- Lund TD, Munson DJ, Haldy ME, et al. Androgen inhibits, while estrogen enhances, restraint-induced activation of neuropeptide neurones in the paraventricular nucleus of the hypothalamus. J Neuroendocrinol 2004; 16: 272- 278.
- Walter FL, Chen K, Hubbard J, et al. Psychological stress in the workplace and menstrual function. Am J Epidem 1999; 49: 127-134.
- George P Chrousos MD, David J, et al. Interaction between the hypothalamic- pituitary-adrenal axis and the female reproductive system: clinical implications. NIH Conference 1998; 129: 229-240.
- Vermeulen A. Environment, human reproduction, menopause and andropause. Environ Health Perspect 1993; 101: 91-100.
- Rivest S, Rivier C. The role of corticotrophin-releasing factor and interleukin-1 in the regulation of neurons controlling reproductive functions. Endocr Rev 1995; 16: 177-199.
- Moberg GP. Influence of the adrenal axis upon the gonads. Oxford Rev Reprod Biol 1987; 9: 456-496.
- Chen M-D, O’Byme KT, Chiappini SE, et al. Hypoglycemic ‘stress’ and gonadotropin-releasing hormone pulse generator activity in the rhesus monkey: role of the ovary. Neuroendocrinology 1992; 56: 666- 673.
- Imaki T, Naruse M, Harada S, et al. Corticotropinreleasing factor up-regulates its own receptor m-RNA in the paraventricular nucleus of the hypothalamus.Brain Res Mol Brain Res 1996; 38: 166-170.
- Kalantaridou SN, Makrigiannakis A, Zoumakis E et al. Stress and the female reproductive system. J Reprod Immuno 2004; 62: 61-68.
- Makino S, Smith MA, Gold PW. Regulatory role of glucocorticocoids and glucocorticoid receptor mRNA levels on tyrosine hydroxylase gene expression in the locus coeruleus during repeated immobilization stress. Brain Res 2002; 943: 216-223.
- Marti O, Harbuz MS, Andres R, et al. Activation of the hypothalamic-pituitary axis in adrenalectomized rats: potentiation by chronic stress. Brain Res 1999; 821: 1-7.
- Mann DR, Evans D, Edoimiyoya F, et al. A detailed examination of the in vivo and in vitro effects of ACTH on gonadotropin secretion in the adult rat. Neuroendocrinology 1985; 40: 297-302.
- Rabin DS, Johnson EO, Brandon DD, et al. Glucocorticoids inhibit estradiol- mediated uterine growth: possible role of the uterine estradiol receptor. Biol Reprod 1990; 42: 74-80.
- Rivier C, Rivest S. Effect of stress on the activity of the hypothalamic-pituitary- gonadal axis: peripheral and central mechanisms. Biol Reprod 1991; 45: 523-532.
- Sahlin L. Dexamethasone attenuates the estradiol-induced increase of IGF-1 mRNA in the rat uterus. J Steroid Biochem Mol Biol 1995; 55: 9-15.
- Horrocks PM, Jones AF, Ratcliffe WA, et al. Pattern of ACTH and cortisol pulsatility over twenty-four hours in normal males and females. Clin Endocrinol 1990; 32: 127-134.
- Smith GW, Aubry JM, Dellu F, et al. Corticotropinreleasing factor receptor-1 deficient mice display decreased anxiety, impaired stress response and aberrant neuroendocrine development. Neuron 1998; 20: 1093-1102.
- Petraglia F, Sutton S, Vale W, et al. Corticotropinreleasing factor decreases plasma luteinizing hormone levels in female rats by inhibiting gonadotropinreleasing hormone release into hypophysial-portal circulation. Endocrinology 1987; 120: 1083-1088.
- Li XF, Bowe JE, Lightman SL, et al. Role of corticotrophin-releasing factor receptor-2 in stress-induced suppression of pulsatile luteinizing hormone secretion in the rat. Endocrinology 2005; 146: 318-322.
- Chatterjee A, Chatterjee R, Singh R, et al. Acute physical activity and its impact on ovulation in rats. Biomed Res 1994; 5: 57-60.
- Chatterjee A, Chatterjee R, Singh R, et al. Treadmill running modulates endometrial decidualization in rats. Biomed Res 1995; 6: 109-113.
- Chatterjee A, Harper MJK. Interruption of implantation and gestation in rats by reserpine, chlorpromazine and ACTH: possible mode of action. Endocrinology 1970; 87: 966-969.
- Chrousos GP. The hypothalamic-pituitary-adrenal axis and immune-mediated inflammation. N Eng J Med 1995; 332: 1351-1362.
- Mastorakos G, Scopa CD, Vryonidou A, et al. Presence of immunoreactive corticotropin-releasing hormone in normal and polycystic human ovaries. J Clin Endocr Metab 1994; 79: 934-939.
- Ghizzoni L, Mastorakos G, Vottero A, et al. Corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulosa-lutein cells in a CRH and interleukin-1 receptor-mediated fashion. Endocrinology 1997; 138: 4806-4811. Chatterjee/Chatterjee
- Bromberger JT, Matthews KA, Kuller LH, et al. Prospective study of the determinants of age at menopause. Am J Epidemiol 1997; 145: 124-133.
- Makrigiannakis A, Zoumakis E, Margioris AN, et al. Regulation of the promoter of the corticotrophinreleasing hormone gene in transfected human endometrial cells. Neuroendocrinology 1996; 64: 85-92.
- Webster EL, Lewis DB, Torpy DJ, et al. In vivo and in vitro characterization of antalarmin, a nonpeptide corticotrophin-releasing hormone (CRH) receptor antagonist: suppression of pituitary ACTH release and peripheral inflammation. Endocrinology 1996; 137: 5747-5750.
- Zoumakis E,Chatzaki E, Charalampopoulos I, et al. Cycle and age-related changes in corticotrophinreleasing hormone level in human endometrium and ovaries. Gynecol Endocrinol 2001; 15: 98-102.
- Li XF, Edward J, Mitchell JC, et al. Differential effects of repeated restraint stress on pulsatile luteinizing hormone secretion in female Fischer, Lewis and Wister rats. J Neuroendocrinology 2004; 16: 220-227.
- Luton J-P, Thieblot P, Valcke C-J et al. Reversible gonadotropin deficiency in male Cushing’s disease. J Clin Endocr Metab 1977; 45: 488-495.
- Petraglia F, Vale W, Rivier C. Opioids act centrally to modulate stress-induced decrease in luteinizing hormone in the rat. Endocrinology 1986; 119: 2445-2450.
- Saketos M, Sharma N, Santoro NF. Suppression of the hypothalamic-pituitary- ovarian axis in normal women by glucocorticoids. Biol Reprod 1993; 49: 1270- 1276.
- Dubey AK, Plant TM. A suppression of gonadotropin secretion by cortisol in castrated male Rhesus monkeys (Macaca mulatta) mediated by the interruption of hypothalamic gonadotropin-releasing hormone release. Biol Reprod 1985; 33: 423-431.
- Thibier M, Roland O. The effect of dexamethasone (DXM) on circulating testosterone (T) and luteinizing hormone (LH) in young postpubertal bulls. Theriogenology 1976; 5: 53-60.
- Turner AI, Hemsworth PH, Tilbrook AJ. Inhibition of the secretion of LH by sustained but not repeated acute elevation of cortisol in the absence but not the presence of oestradiol. J Endocrinol 1999; 163: 477-486.
- Juniewicz PE, Johnson BH, Bolt DJ. Effect of adrenal steroids on testosterone and luteinizing hormone secretion in the ram. J Androl 1987; 8: 190-196.
- Brann DW, Putnam CD, Mahesh VB. Corticosteroid regulation of gonadotropin and prolactin secretion in the rat. Endocrinology 1990; 126: 159-166.
- Chandran UR, Attardi B, Friedman R, et al. Glucocorticoid receptor-mediated repression of gonadotropinreleasing hormone promoter activity in GT1 hypothalamic cell lines. Endocrinology 1994; 134: 1467-1474.
- Breen KM, Stackpole CA, Clarke IJ, et al. Does the type II glucocorticoid receptor mediate cortisol-induced suppression in pituitary responsiveness to gonadotropin-releasing hormone? Endocrinology 2004; 145: 2739-2746.
- Breen KM, Oakley AV, Pytiak AV, et al. Does cortisol acting via the type II glucocorticoid receptor mediate suppression of pulsatile LH secretion in response to psychosocial stress? Endocrinology 2007; 148:1882-1890.
- Melis GB, Mais V, Gambaccini M. Dexamethasone reduces the post castration gonadotropin rise in women. J Clin Endocr Metab 1987; 65: 237-241.
- Shreiber JR, Nakamura K, Erickson GF. Rat ovary glucocorticoid receptor: identification and characterization. Steroids 1982; 39: 569-584.
- Louvet JP, Baislic M, Bayard F, et al. Glucocorticoid receptors in rat ovarian granulosa cell cytosol. 59th An- nual Meeting of the Endocrine Society, Chicago IL, 1977; p 601 (Abstract).
- Meurer KA, Cox NM, Matamoros IA, et al. Decreased follicular steroids and insulin-like growth factor-1 and increased atresia in diabetic gilts during follicular growth stimulated with PMSG. J Reprod Fert 1991: 91: 187-196.
- Schoonmaker JN, Erickson GF. Glucocorticoid modulation of follicle-stimulating hormone-mediated granulosa cell differentiation. Endocrinology 1983; 1356- 1363.
- Hsueh AJW, Erickson GF.Glucocorticoid inhibition of FSH-mediated estrogen production of cultured rat granulosa cells. Steroids 1983; 32: 639-643.
- Andrade TG et al. Anxiolytic effect of estradiol in the median raphe nucleus mediated by 5 HT1A receptors. Behav Brain Res 2005; 163: 18-25.
- Zamorano P, Steinsapir J, Mahesh VB. Effects of 5alpha-dihydrotestosterone and dexamethasone on estrogen receptors of the anterior pituitary and uterus. Steroids 1992; 57: 18-26.
- Campbell PS. The mechanism of the inhibition of uterotropic responses by acute dexamethasone pretreatment. Endocrinology 1978; 103:716-723.
- Bigsby RM. Progesterone and dexamethasone inhibition of estrogen-induced synthesis of DNA and complement in rat uterine epithelium: effects of antiprogesterone compounds. J Steroid Biochem Mol Biol 1993; 45: 295-301.
- Monheit AG, Resnik R. Corticoid suppression of estrogen-induced uterine blood flow in nonpregnant sheep. Am J Obstet Gynecol 1981; 139: 454-458.
- Sullivan DA, Underdown BJ, Wira CR. Steroid hormone regulation of free secretory component in the rat uterus. Immunology 1983; 49: 379-386.
- Jacobs AL, Hwang D, Julian J, et al. Regulated expression of prostaglandin endoperoxide synthase-2 by uterine stroma. Endocrinology 1994; 135: 1807-1815.
- Psychoyos A. Endocrine control of egg implantation . In Greep RO, Astwood EG, Greiger SR (eds.)Hand Book of Physiology Vol. II, part 2. American Physiological Society, Washington DC 1973; 187-215.
- Chatterjee A. The possible mode of action of prostaglandins: VII. Evidence of antifertility effect prostaglandin E1 in rats. Prostaglandins 1974; 6: 413-16.
- Chatterjee A, Singh R, Chatterjee (Basu) R. Dexamethasone modulation of gestation length and parturition in rats. Pharmacol Res 1993; 27: 359-64. Stress and female reproduction
- Shetty G, Bhatnagar AS, Moudgal NR. Blockade of estrogen synthesis with an aromatase inhibitor affects luteal function of the pseudopregnant rat. J Steroid Biochem Mol Biol 1995; 55:347-353.
- Bergman MD, Schachter BS, Karelusk CEP, et al. Upregulation of uterine estrogen receptor and its messenger ribonucleic acid during the mouse oestrous cycle: The role of oestradiol. Endocrinology 1992; 130: 1923-1930.
- Sulaiman SA, Jamalullail SMS, Chatterjee A. An indigenous herbal formulation and its contraceptive profile in rats. Biomed Res 2001; 12: 65-69.
- da Costa D, Drista M, Larouche J, et al. Psychological predictors of labor/delivery and infant birth weight: a prospective multivariate study. J Psychosom Obstet Gynecol 2000; 21: 137-148.
- Gitau R, Cameron A, Fisk NM, et al. Fetal exposure to maternal cortisol. The Lancet 1998; 352: 707-708.
- Uhde TW, Vittone BJ, Siever LJ, et al. Blunted growth hormone response to clonidine in panic disorder patients. Biol Psychiatry 1986; 21: 1081-1085.
- Coplan JD, Smith EL, Trost RC, et al. Growth hormone response to clonidine in adversely reared young adult primates: relationship to serial cerebrospinal fluid corticotrophin-releasing factor concentrations. Psychiatry Res 2000; 95: 93-102.
- Campbell GA, Kurcz M, Marshall S, et al. Effects of starvation in rats on serum levels of follicle-stimulating hormone, luteinizing hormone, thyrotropin, growth hormone and prolactin; response to LH-releasing hormone and thyrotropin- releasing hormone. Endocrinology 1977; 100: 580-587.
- Burguera B, Muruais C, Penalva A, et al. Dual and selective action of glucocorticoids upon basal and stimulated growth hormone release in man. Neuroendocrinology 1990; 51: 51-58.
- Laron Z. Growth hormone insensitivity (Laron syndrome). Rev Endocr Metab Disord 2002; 3: 347-355.
- Zaczek D, Hammond J, Suen L. et al. Impact of growth hormone resistance on female reproductive function. New insights from growth hormone receptor knockout mice. Biol Reprod 2002; 67: 1115-1124.
- Chandrashekar V, Bartke A, Coschigano KT, et al. Pituitary and testicular function in growth hormone receptor gene knockout mice. Endocrinology 1999; 140: 1082-1088.
- Codner E, Cassorla F. Growth hormone and reproductive function. Mol Cell Endocrinol 2002; 186: 133-36.
- Lackey BR, Gray SL, Henricks DM. The insulin-like growth factor (IGF) system and gonadotropin regulation: actions and interactions. Cytokine Growth Factor Rev 1999; 10: 201-217.
- Mazerbourg S, Bondy CA, Zhou J, et al. The insulinlike growth factor system: a key determinant role in the growth and selection of ovarian follicles. A comparative species study. Reprod Domest Anim 2003; 38: 247-258.
- Ibrahim ZHZ, Matson PL, Buck P, et al. The use of biosynthetic human growth hormone to augment ovulation induction with buserelin acetate human menopausal gonadotrophin treatment in women with poor ovarian response. Fertil Steril 1991; 55: 204-210.
- Sugama S, Conti B. Interleukin-18 and stress. Brain Res Rev 2007; Science Direct.
- Kokai M, Kashiwamura S, Okamura H, et al. Plasma interleukin-18 levels in patients with psychiatric disorders. J Immuno Ther 2002; 25 (Suppl 1): S68-S71.
- Nagai Y, Watanabe K, Aso H, et al. Cellular localisation of IL-18 and IL-18 receptor in pig anterior pituitary gland. Domest Anim Endocrinol 2006; 30: 144- 154.
- Matsuwaki T, Watanabe E, Suzuki M, et al. Glucocorticoid maintains pulsatile secretion of luteinizing hormone under infectious stress condition. Endocrinology 2003; 144: 3477-3482.
- Matsuwaki T, Suzuki M, Yamanouchi K, et al. Glucocorticoid counteracts the suppressive effect of tumor necrosis factor-α on the surge of luteinizing hormone secretion in rats. J Endocrinol 2004; 181: 509-513.
- Tsigos C, Chrousos GP. Physiology of the hypothalamic-pituitary-adrenal axis in health and dysregulation in psychiatric and autoimmune disorders. Endocrinol Metab Clin North Am 1994; 23: 451-466.
- Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction.Reprod Biol Endocrinol 2005; 3: 1-32.
- Inoue M. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Current Med Chem 2003; 10: 2495-2505.
- Gao HB, Tong MH, Hu YQ, et al. Mechanisms of glucocorticoid-induced Leydig cell apoptosis. Mol Cell Endocrinol 2003; 199: 153-163.
- Monder C, Miroff Y, Marandici A, et al. 11beta-hydroxysteroid dehydrogenase alleviates glucocorticoid-mediated inhibition of steroidogenesis in rat Leydig cells. Endocrinology 1994; 134: 1199-204.
- Sugino N, Karube-Harada ATaketani T, et al. Withdrawal of ovarian steroids stim lates prostaglandin F2 alpha production through nuclear factor-kappaB activation via oxygen radicals in human endometrial stromal cells: potential relevance to menstruation. J Reprod Dev 2004; 50: 215-225.
- Tarin JJ. Potential effects of age-associated oxidative stress on mammalian oocytes/embryos. Mol Hum R prod 1996; 2: 717-724.
- Agarwal A, Gupta S, Sekhon L, et al. Redox csider tions in female reproductive function and assisted reproduction: From molecular mechanisms to health im plication. Antioxidants & Redox Signaling 2008; 10: 1375-1403.