\
Biomed Res 1998; 9 (2): 165-170
Minireview:
Insulin deficiency and reproductive dysfunction in females: Experimental verification
Amar Chatterjee, Zalina Ismail and Rabimab Zakaria
Department of Physiology, School ofMedic:::l Sciences Universiti Sains Malaysia, 16150 Kubang Keria9-, Kelantan, Malaysia
Key words: Insulin deficiency, reptoductive dysfunction, diabetic, hypothalamus, steroid
Background
Deficient production, storage, secretion or targettissue ineffectiveness of insulin leads to inappropriate and chronic hyperglycemia, the diabetes. It is now acknowledged that when beta-cell destruction is the primary cause of hyperglycemia, insulin resistance develops secondarily [ 1]. Recent-onset IDDM patients studied after a few days of insulin therapy are markedly insulin resistant [2.3]. In well defmed streptozotocin-diabetic rats, insulin resistance has also been detected 48h or more after the streptozotocin injection, affecting both glucose production and giucose utilization [4,5].
Reproductive dysfunction is a common problem in experimentally-induced [6,7], spontaneous/genetic [8,9] and clinically diabetic females [ 10,11]. Diabetes-associated delayed menarche, menstrual irregularities and an increased incidence of infertility are now well accepted. Uncontrolled diabetic state dur-
ing pregnancy moreover, results in serious medical complications to the fetus including congenital malformation due to early growth retardation [ 12, 13,14] and spontaneous abortion [ 15, 16]. Diabetes also causes a significant neonatal morbidity and mortality [17].
Hypothalamic-pituitary axis
Based on their fmdings scientists pu,t forward several speculative views on the mechanism of action of insulin at different levels of the reproductive endocrine axis. Irregular or anovulatory cycle in diabetic rats has been attributed to impaired GnRH release [ 18] with a corresponding lack of LH surge [ 19]. Such an incidence is thought to be the consequence of reduced positive feed-back action of gonadal steroid on the hypothalamus [20]. Estradiol replacement, however, failed to normalise the hypothalamic-pituitary
166
axis [21] possibly as a result of reduced number of hypothalamic estrogen receptors as found in diabetic rats [22]. Kirchick eta! [23] conversely, showed an attenuated pituitary response to exogenous GnRH in diabetes. The pituitary refractoriness to GnRH has also been confirmed in diabetic human [24] and in the gonadectomized diabetic male and female rats [20, 25] . However, the negative effect of diabetes on circulating gonadotropins has never been detected in spontaneously diabetic male rats [26], male mice [27], PMSG-treated gilts [28] and even in diabetic men [29]. The reduced LH pulse frequency as evident in rats [30] and humans [31] could possibly be the appropriate consequence of diabetes. Since the secretion of FSH requires minimal GnRH stimulation [32], diabetes possibly fails to affect the serum levels ofFSH [33].
Ovarian steroidogenesis
Although cholesterol metabolism is profoundly altered in diabetes [34], the unaltered ovarian P450 sec or 3[-HSD enzyme activity in diabetes [35] could possibly manage to maintain the ovarian progesterone output with much lower concentration of insulin [36]. In diabetic pseudopregnant rats, insulin however, fails to restore normal luteal functions [37]. Insulin treatment similarly fails to improve progesterone concentration in the follicular fluid of diabetic gilts [38]. Serum estradiol level has not been found to be depressed in short-term diabetic rats [39]. Since the absence of insulin is associated with decreased ability of follicles to grow [ 40], insulin treatment is found to result in an increased follicular diameter with higher levels of estradiol in cows [ 41] gilts [ 42] and in rats [43]. Insulin deficiency in rats is also associated with low serum estradiol levels [44].
In vitro studies have moreover shown the stimulatory action of insulin · on granulosa cell aromatase activity [45], on theca androgen [46], and estradiol production [47]. It is, therefore, theorised that diabetes either inhibits the conversion of progesterone to testosterone or the aromatization of testosterone to estradiol [28]. Muerer et al [28], on the other hand, have observed a lower estradiol: progesterone ratio in diabetic than in normal.
Endometrial decidualization and implantation
Decidualization of uterine stromal cells during the establishment of pregnancy is initiated by the coordinate actions of progesterone and estrogen [48]. Such an endometrial differentiation is however, found to be depressed in diabetic females [ 49]. Because, an inadequate progesterone stimulation of stromal cells generally promotes programmed cell death [50]. Since estrogen upregulates both estrogen and proges-
Chatterjee et al
terone receptors gene expression in uteri [51, 52], its significance in the establishment of pregnancy is very much logical [53]. Delayed implantation is however, not evident in the spontaneous diabetic Chinese hamster [54]. While the uterine decidual cells are eventually transformed into the defmitive chorioallantoic placenta or decidua unit [55], impaired placental development in diabetic animals [56] might be possible.
Embryo development and pregnancy outcome
Early embryo development is. referred to be retarded ir1 experimental diabetes [57]. This glucose-related cleavage arrest [58] is evident in the hamster [59], in mouse [60], in cattle [61] and in humans [62]. Investigation results show that members of insulin family may act as survival factors in early embryonic development either by stimulating proliferation or by preventing apoptosis [63]. Conversely, blastocysts from diabetic rats are found to utilise glucose at a similar rate that of normal blastocysts and insulin has no effect on glucose uptake, utilization, incorporation or turnover [64]. Detrimental effect of diabetes on intrauterine growth and the development of fetoplacental unit during pregnancy have been noticed [65]. Moreover, retarded embryo growth [66] fetaldemise [67], spontaneous abortion [68], neonatal morbidity and mortality [69] are also well recorded.
Comment
The beneficial contribution of insulin starting from the follicular development until successful fetal outcome is now well accepted. However, insulin resistance as frequently develops in insulin-dependent diabetes could subsequently result in reproductive error or reproductive failure. It is now evident that by sharing insulin receptor cross reactivity [for ref. see 70] or acting as a counterpart of insulin [43] IGF-1 effectively participates in follicular development [71], in ovarian steroidogenesis [72], in embryo development [73] in uterine stromal cell proliferation [74] and possibly in implantation of blastocysts [75]. Therefore, the possible use of IGF-1 as a therapeutic alternative in insulin-resistant reproductive dysfunction seems to be a very prospective area of research.
Acknowledgements
The author [A.C] acknowledges the research grant provided byUniversiti Sains Malaysia, Penang [391/-9603/1003] that has resulted in this article. The encouraging cooperation of Dato' Professor [Dr.] Mustaffa Embong and Prof. Jamjan Rajikan and the secretarial assistance of Pn. Jusheda bt. Zakaria are highly appreciated. ·
Insulin deficiency and reproductive system dysfunction 167
References 14. Spiers PS. Does growth retardation predispose the fetus congenital malformation? Lancet
1. Olefsky JM. Insulin resistance and insulin act- 1982; 1: 312-314. ion: An in vitro and in vivo perspective. Diabe-tes 1981; 30: 148-162. 15. Kalter H. Diabetes and spontaneous abortion: A
historic review. Am J B Obstet Gynecol1987; 2. Nankervis A, Proietto J, Aitken P, Alford F. Im- 156:1243-1253.
Impaired insulin action in newly diagnosed type I [insulin dependent] diabetes mellitus. Diabet- 16. Dicker D, Feldberg D et al. Spontaneous aborti-ologia 1984; 27:497-503. on in patients with insulin-dependent diabetes
mellitus. The effect of preconceptional diabetes 3. Burcelin R, Eddouks M, Beylot M et al. Hyper- control.AmJObstetGynecol1988; 158:1161-
sensitivity to insulin during remissions in cyclo- 1164. sporin- treated IDDM patients. Diabetes Care 1993; 16:881-888. 17. Coustan DR, Berkowitz RL, Hobbins JL. Tight
metabolic control of overt diabetes in pregnan-4. Blonde! 0, Portha B. Early appearance of in cy. Am J Med 1980; 68:845-849.
vivo nsulin resistance in adult streptozotocin-in
"---' jected rats. Diabet Metab 1989; 15:382-387. 18. Katayarns S, Brownscheidle CM, W otten V et al. Absent or delayed preovulatory luteinizing
5. Koopmans S, De Boer S, Sips H, Radder J, Fro hormone surge in experimental diabetes melli-lich M, Krans M. Whole body and hepatic insu tus. Diabetes 1984; 33: 324-327. lin action in normal, starved and diabetic rats. Am J Physioll991; 260: E825-E832. 19. Vomachka MS, Johnson DC. Ovulation, ovarian
17[ -hydroxylase activity and serum concentrat-6. Chieri RA, Pivetta OH, Foglia VG. Altered ovu ion of luteinizing hormone in immature rats dia-
lation pattern in experimental diabetes. Fertil betes mellitus induced by streptozotocin. Proc Steril1969; 20: 661-666. Soc Expt Bioi Med 1982; 17: 207-213.
7. Shipley EG, Danley KS. Pituitary and ovarian 20. Blades RA, Bryant KR, Whitehead SA. Feed dysfunction in experimental qiabetes. Am J back effect of steroids and gonadotropin control Physiol 1947, 150:84-94. in adult rats with streptozotocin-induced diabtes
mellitus. Diabetologia 1982, 28:348-354. 8. Johnson LM, Sidman RL. A reproductive endo-
crine profile in the diabetes [db] mutant mouse. 21. Valdes CT, Elkind-Hirsch DG, Rogers DG, Ad-Bioi Reprod 1979; 20: 552-559. Ieiman JP. The "hypothalamic-pituitary axis of
streptozotocin- induced diabetic female rats is 9. Garris DR, Smith C. Diabetes-associated endo- not normalized by estradiol replacement. Endo
metria! disruption in the ketonuric, diabetic Chi- crinology 1991; 128:433-440. nese hamster. Gynecol obstet Invest 1983; 16; 86-96. 22. Siegel LI,Wade GN. Insulin withdrawal impairs
sexual receptivity and retention of brain cell nu-10. Hall RE, Tillman AJB. Diabetes and pregnancy. clear estrogen receptors in diabetic rats. Neuro-
Am J Obstet Gynecol1951; 61 : 1107-1115. endocrinology 1979; 29:200-206.
~
11. William RH, PorteD Jr. The Pancreas. In: Text 23. Kirchick HJ, Keyes PL, Frye BE. An explanat-Book of Endocrinology. Williams RH., Ed. Phi ion for anovulation in irnmatuFe alloxan diabetic !adelphia, Saunders, 1974; 502-626. rats treated with pregnant mare's serum gonado-
tropin: reduced pituitary response to gonadotro-12. Cousins L. Congenital anomalies among infants pin-releasing hormone. Endocrinology 1979;
of diabetic mothers. Etiology, prevention, pren- 105 105: 1343-1349. atal diagnosis. Am J Obstet Gynecol1983; 147: 333-338 24. Distiller LA, Sage! J, Morley JE et al. Pituitary
responsiveness to luteinizing hormone-releasin-13. Lowy C, Beard RD, Goldsmidt J. Congenital ng hormone in insulin-dependent diabetes mell-
malformations in babies of diabetic mothers. itus. Diabetes 1975; 24; 378-380. Diabetic Med 1986; 3: 458-462.
25 . Howland BE, Zebrowski EJ. Some effects of experimentally-induced diabetes on pituitary
168
testicular relationships in rats. Horm Metab Res 1976; 8: 465-470.
26. Murray FT, Cameron DT, Orth JM et al. Gonadal dysfunction in the spontaneously diabetic B BB rat: Alterations of testes morphology, serum testosterone and LH. Hom Metab Res 1985; 17: 495-501.
27. Amador AG, BartkeA, Parkening TA et al. Hor monal regulation of testicular human chorionic gonadotropin binding· and steroidogenesis in adult mice with different forms of hereditary diabetes and obesity. Horm Res 1986; 23: 215-224.
28. Meurer KA, Cox NM, Matamoros lA, Tubbs RC. Decreased follicular steroids and I nsulinlike growth factor- I and increased atresia indiabetic gilts during follicular growth stimulated with PMSG. J Reprod Fert 1991 ; 91: 187- 196.
29. Murray FT, Wyss HU, Thomas Ret al. Gonadal dysfunction in diabetic menwith organic impotence. J Clin Endocrinol Metab 1987; 65: 127-135.
30. Dong Q, Lazurus RM, Wong LS et al. Pulsatile LH secretion in streptozotocin-induced diabetes in the rat. J Endocrinoll991; 131 : 49-55.
31. Djursing H, Anderson AN, Hagen C, Peterson K. Gonadotropin secretion before and during acute and chronic dopamine-receplor blockade in insulin-dependent diabetic patients with arne norrhea. Fertil Steril 1985; 44: 44-45.
32. Chappel SC, Ulloa-Aguirre A, Coutifaris C. Biosynthesis and secretion of follicle-stimulating hormone. Endocrine Rev 1983, 4: 179-211.
33. · Howland BE, Zebrowski EJ. Serum and pitui tary gonadotropin levels in alloxan- diabetic rats. Horm Metab Res 1974; 6:121-124.
34. O 'Meara NMG, Devery RAM, Owens D et al. Cholesterol metabolism in alloxan-induced diabetic rabbits. Diabetes 1990; 39: 626-633.
35. McLean MP, Warden KJ, SandhoffTW et al. Altered ovarian sterol carrier prote~ expression in the pregnant streptozotocin-treated diabe-. tic rat. Bioi Reprod. 1996; 55 : 38-46.
36. Wathes DC, Perks CM, Davis ~J. Denning" Kendall P A. Regulation of insulin-like growth factor -1 and progesterone synthesis by nsulin and growth hormone in the ovine ovary. Bioi Rep~od 1995; 53: 882-889.
Chatterjee et al
37. Garris DR, Whitehead DS, Morgan CR. Effects of alloxan-induced diabetes corpus luteurn function in the pseudopregnant rat. Diabetes 1984; 33: 611~615.
38. Matamoros lA, Cox NM, Moore AB. Effects of exogenous insulin and body condition on metabolic hormones and gonadotropin-induced follicular development in prepuberal gilts. J Anim Sci. 1991; 69: 2081-2091.
39. Kirchick HJ. Keyes PL, Frye BE. Etiology of ovulation in the immature alloxan-diabetic rat treated with pregnant mare 's serum gonadotropin: Absence of preovulatory hormone surge. Endocrinology 1978; 102:1867-1873.
40. Edwards JL, Hughey TC, Moore AB, Cox NM. Depletion of insulin in streptozotocin-induced diabetic pigs alters estradiol, insulin-like growth factor-I [IGF-1], and IGF binding proteins in cultured ovarian follicles. Bioi Reprod 1996; 55: 775-781.
41. Simpsom RB, Chase Jr CC, Spicer LJ, et al. Effect of exogenous insulin on plasma and follicular insulin-like growth factor -1 , insulin-like growth factor binding protein activity, follicular · estradiol and progesterone and follicular growth in su perovulated Angus and Brahman cows. J · Reprod. Fert 1994, 102: 483-492.
42. Matamoros lA, Cox NM, Moore AB. Exogenous insulin and additional energy affect follicullar distribution, follicular steroid concentration and granulosa cell human chorionic gonadotro pin bindingin swine. Bioi Reprod 1990; 43 : 1-7.
43. Adashi EY, Resnick CE, D'Ercole AJ et al. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. End ocrine Rev 1985; 6: 400-420.
44. Liu FTY, Lin HS, Johnson DC. Serum FSH, LH and the ovarian response to exogenous gonadotropins in alloxan-diabetic immature rats.Endocrinology 1992; 91 : 1172-1185.
45. Poresky L, Kalin MF. The gonadotropic function of insulin. Endocrine Rev 1988; 8: 132-141.
46. Morley P, Calaresu FR, Barbe GJ, Armstrong · DT. Insulin enhances luteinizing-hormone stimulated steroidogenesis by porcine theca cells. Bioi Reprod. 1989; 40:735-743.
47. Caubo B, De Vinna RS, Tonetta SA. Regulation of steroidogenesis in cultured porcine theca cells by growth factors.Endocrinology 1989; 125: 321-326.
Insulin deficiency and reproductive system dysfunction
48. Yoshimaga K. Hormonal interplay in the establ' ~) J ishment of pregnancy. In: Greep RO [ ed], Rep( roductive Physiology II. International Rev Phys
iol Vol 13. Baltimore, MD, Univ Park Pres 1977.
'\
49. Nylund L, Lunell NO, Lewander Ret al. Uteroplacental blood flow in diabetic pregnancy: measurement with indium 113 m and a computerlinked gamma c amera. Am J Obstet Gynecol 1982; 144: 298-302.
50. Moulton BC, Akcali KC, Ogle TF et al. Control of apoptosis in the uterus during decidualization In: Tilly JL [ ed. ], Cell Death in Reproductive Physiology. New York: Springer- Verlag; 1996.
r 51 . Bergman MD, Schachter BS, Karelusk CEP et
,~
al. Upregulation of the uterine estrogen receptor and its messenger ribonucleic acid during the mouse e:;trous cycle: the role of estradiol. Endocrinology 1992; 130: 923-1930 . .
52. Snijders MP, de Goeij AF, Debets-Te Baerts MJ et al. Immunocytochemical analysis of estrogen receptors and progesterone receptors in the human uterus throughout the menstrual cycle and after the menopause. J Reprod Fert 1992; 94: 363-371.
53 . Chatterjee A, Chatterjee R, Ahmad A. Dexamethasone modulation of endometrial decidualization in rats. Biomed Res 1995; 6: 153-156.
54. Furaki K, Mikamo K.Developmental-stage-dependent teratogenic effects of maternal spontaneous diabetes in the Chinese hamster. Diabetes 1983; 32: 637-643.
55. Welsh AO, Enders AC. Chorioallantoic placen- · ta formation in the rat: I. Luminal epithelial cell death and extracellular matrix modifications in the mesometrial region of implantation chambers, AmJ Anat 1991 ; 192: 215-231.
56. Levi JE, Weinberg T. Pregnancy in alloxandiabetic rats. Proc Soc Expt Bioi Med 1949; 72: 658-662.
57. Beebe LFS, Kaye PL. Maternal diabetes and retarded preimplantation development of mice. Diabetes 1991; 40: 457-461.
58. BJYWD JJG, Whittingham DG. The dynamic provision of different energy substrates improves development of one-cell random-bred mouse embryos in vitro. J Reprod. Fert. 1992; 95: 503- 511.
169
59. Schini SA, Bavister BD. Two-cell block to development of cultured hamster. embryo is caused by phosphate and glucose. Bioi Reprod. 1988; 39: 1183-1192.
60. Brown JJG, Whittingham DG. The roles of py ruvate, lactate and glucose during preimplantation development of embryos from FI hybrid mice in vitro. Development 1991 ; 112: 99-105.
61. Takahashi Y, First NL. In vitro development of bovine one-cell embryos: Influence of glucose, lactate, pyruvate, amino acids and vitamins. Theriogenology 1992; 37: 963-978.
62. Conaguhn J, Handyside AH, Wiston RML, Leese HJ. Effect of pyruvate and glucose on the development of human preimplantation embryos in vitro. J Reprod Fert 1993; 99: 87-95.
63 . Herder CA, Krusche HMB. Members of the in sulin family possibly act as survival factors on preimplantation embryos. Assessment of cell proliferation [MIBI] and apoptosis [TUNEL]. J Rep rod F ert 1996; 17: 7 [abstract 14].
64. Dufrasnes E, Vanderheyden I, Robin D, et al. Glucose and pyruvate metabolism in preimplantation blastocysts from normal and diabetic rats JReprodFert 1993; 98 : 169-177.
65. Deucher EM. Embryonic malformations in rats resulting from maternal diabetes: Preliminary observations. J Embryo! Exp Morphol1977; 41 : 93-99.
66. Kawaguchi M, Tanigawa K, Tanaka 0, Kato Y. Embryonic growtQ impaired by maternal hypoglycemia during early organogenesis in normal and diabetic rats. Acta Diabetol1994; 31 : 141- 146
67. Garris DR, Smith C. Diabetes associated endometrial disruption in the ketonuric, diabetic Chinese hamster. Gynecol Obstet Invest 1983; 16: 86-96.
68. Folgia VG, Chieri RA,Ramos MCP. Mechanisms of disturbances during pregnancy in the diabetic female rat. Horm Metab Res 1970; 2: 76-80.
69. Diamond MP, Shah DM, Hester RA et al. Complications of insulin- dependent diabetic pregnancies by pre-eclampsia and/or chronic hypertension: Analysis of outcome.Am J Perinatol 1985; 2: 263-268.
· ·"t .
170
70. Cohik WS, Clemmons DR. The insulin-like growth factors. Ann Rev Physiol1993; 55: 131-153
71. Adashi EY, Resnick CE, Herrandez ER, et al. Insulin-like growth factor-! as an amplifier of follicle-stimulating hormone action: studies on mechanism[s] and site[s] of action in cultured rat granulosa cells. Endocrinology 1988; 122: 1583-1591.
72. ParmerTG, Roberts CT Jr, LeRoith D et al. Expression, action and steroid regulation of insulin- like growth factor-! [IGF-1] and IGF-1 receptor in the rat corpus luteum: Their differential role in the two-cell populations forming the corpus luteum. Endocrinology 1991,29: 29-24-2932.
73. Kaye PL, Bell KL, Beebe LF, et al. Insulin-like growth factors [IGFs] in preimplantation development. ReprodFertDevep 1992; 4:373-386.
74. Irwin JC, Delas Fuentes L, Guidice LC. Growth factor and decidualization in vitro. Ann NY Acad Sci 1994; 734: 7-18.
75. Croze F, Kennedy TG, Scbroedter IC, et al. Expression of insplin-like growth factor-1 and insulin- like growth factor binding protein-I in the rat uterus duriog decidualization. Endocrinology 1990; 71: 1995-2000.
Correspondance to:
Professor Amar Chatterjee Department of physiology School of Medical Sciences Universiti Sains Malaysia 16150 kubang kerian, ke1antan Malaysia
Fax: +609 7653370 E-mail:[email protected]
Chatterjee et al
Top Related