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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

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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

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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:amar@kb.usm.my

Chatterjee et al