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Timing of Prenatal Androgen Excess Determines Differential Impairment in Insulin Secretion and Action in Adult Female Rhesus Monkeys¹

Wisconsin Regional Primate Research Center (J.R.E., D.A.D., J.W.K., D.H.A.), Department of Obstetrics and Gynecology (J.R.E., D.H.A.), Endocrinology-Reproductive Physiology Program (J.R.E., D.H.A.), and Department of Physiology (J.W.K.), University of Wisconsin, Madison, Wisconsin 53715-1299; and Department of Obstetrics and Gynecology, Mayo Clinic (D.A.D.), Rochester, Minnesota 55905

Address all correspondence and requests for reprints to: Prof. David H. Abbott, Department of Obstetrics and Gynecology, Wisconsin Regional Primate Research Center, University of Wisconsin, 1220 Capitol Court, Madison, Wisconsin 53715. E-mail: abbott{at}primate.wisc.edu

	Abstract

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This study determined whether timing of prenatal androgen excess resulted in differential impairment of insulin-glucose homeostasis in adult female rhesus monkeys. Ten female rhesus monkeys exposed to testosterone propionate starting on gestational day 40 (early treated), 9 females exposed to testosterone propionate starting between gestational days 100–115 (late treated), and 15 control females were studied. The modified minimal model was used to examine various measures derived from an iv glucose tolerance test, with regression analysis performed between these variables and body mass index. In addition, the disposition index (DI) and the hyperbolic relationship between insulin sensitivity (S_I) and acute insulin response to glucose were examined. Early treated females demonstrated impaired pancreatic ß-cell function, as shown by diminished DI and decreased percentile ranking for the hyperbolic relationship between S_I and acute insulin response to glucose. In contrast, late treated females exhibited both an increase in DI and a negative relationship between body mass index and S_I. These results suggest that prenatal androgen excess in female rhesus monkeys, regardless of gestational timing, perturbs insulin-glucose homeodynamics, with androgen excess in early and late gestation impairing pancreatic ß-cell function and altering insulin sensitivity, respectively.

	Introduction

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EXPOSURE OF female rhesus monkeys to prenatal androgens induces a predictable sequence of irreversible physiological changes. Prenatally androgenized females exhibit an increase in menarchal body mass that is associated with disordered ovarian function during adolescence (1). By adulthood, prenatally androgenized female rhesus monkeys also demonstrate diminished estrogen negative feedback on hypothalamo-pituitary function (2) accompanied by LH hypersecretion (3), hyperandrogenism, and anovulation (4).

In addition to androgen-induced changes in the hypothalamo-pituitary-gonadal axis, anovulatory prenatally androgenized monkeys show insulin resistance from obesity (4), suggesting the functional integration of insulin-glucose homeostasis and ovarian function in primates. This hypothesis is further supported by the finding that women with polycystic ovarian syndrome (PCOS) exhibit a constellation of disorders characterized by LH hypersecretion (5), hyperandrogenic anovulation (6), and reduced peripheral insulin sensitivity (S_I), leading to glucose intolerance in 20–30% of such individuals (7).

To date, however, the degree to which prenatal androgen exposure in adult female rhesus monkeys permanently alters insulin-glucose homeostasis remains unknown. Therefore, the present study examined S_I and pancreatic ß-cell function in prenatally androgenized and normal adult female rhesus monkeys undergoing iv glucose tolerance test (FSIGT). The study demonstrated that prenatal androgen excess perturbed insulin-glucose homeodynamics regardless of gestational age. Early gestational androgen excess may impair insulin secretion by pancreatic ß-cells, whereas late gestational androgen alters insulin sensitivity.

	Materials and Methods

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Animals

The 34 adult female rhesus monkeys (Macaca mulatta) used in this study were maintained at the Wisconsin Regional Primate Research Center (WRPRC) according to standard protocol (1, 8). Animals were fed Purina monkey chow (Ralston Purina Co., St. Louis, MO; product no. 5038) with occasional supplementation of fresh fruits and bread. This formulation of monkey chow provides 70% of calories as carbohydrate, 13% as fat, and 17% as protein. The Graduate School animal care and use committee of the University of Wisconsin–Madison approved all experiments and animal protocols. Animal maintenance was conducted in accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals and the Animal Welfare Act with its subsequent amendments. Prenatally androgenized females were developed as previously reported (1). Briefly, 19 prenatally androgenized females were produced by injecting pregnant rhesus monkeys carrying female fetuses with 10 mg testosterone propionate (TP), sc, for 15–35 consecutive days. The TP injections were initiated either on gestational day 40 (early treated; n = 10) or between days 100–115 (late treated; n = 9; total gestation, 165 days). The early treated, prenatally androgenized females had external genital masculinization and obliteration of the external vaginal orifice, whereas the late treated, prenatally androgenized females showed no genital virilization except for clitoromegally. All prenatally androgenized females displayed masculinized behavior independent of genital masculinization (9). The control group for the study consisted of 15 females that were not exposed to prenatal androgen treatment. The early treated and late treated, prenatally androgenized females as well as the control females were of similar midreproductive ages (15.5 ± 0.8, 15.4 ± 0.9, and 16.9 ± 0.9 yr), body weights (8.4 ± 0.7, 8.2 ± 0.2, and 8.5 ± 0.5 kg), and body mass indexes [BMIs; body weight (kilograms)/crown-rump length (meters squared); 37.4 ± 2.6, 35.9 ± 1.8, and 37.5 ± 1.7 kg/m², respectively].

Experimental procedures

Determination of ovulatory status. To determine ovulatory status, each female underwent daily perineal inspection for the presence of menses and twice weekly blood sampling (between 0800–1000 h) for serum progesterone determinations. Each animal was studied for 90 days (approximately three menstrual cycles). A menstrual cycle was considered ovulatory if two serum progesterone values greater than 1 ng/mL were obtained 15 days before menses (1, 3). Experimental procedures were performed within 5 days of menses in ovulatory females (e.g. early follicular phase) or at random in anovulatory females. All procedures were performed between the months of September and May to avoid possible seasonal quiescence in menstrual activity (10).

FSIGT. Each animal underwent a single FSIGT as previously described (12). Briefly, after an overnight fast, each animal was anesthetized with ketamine hydrochloride (15 mg/kg, im) and diazepam (1.25 mg/kg, im). Supplemental ketamine was administered as appropriate to maintain anesthesia (5–10 mg/kg, im). A catheter was placed into the vena cava through the saphenous vein for blood sampling (e.g. 32 samples over 195 min) and for administration of glucose (300 mg/kg at 0 min) and tolbutamide (5 mg/kg at 20 min).

Assay procedures. All assays were performed at the WRPRC Assay Services Laboratory as previously described (11, 12). Glucose was measured by the glucose oxidase method [intra- and interassay coefficients of variation (CVs), respectively, 2.9% and 4.0%]. Insulin was determined by RIA (CVs, 2.8% and 6.9%). Progesterone was measured by enzyme immunoassay (CVs, 4.6% and 12.9%).

Data analysis and statistical methods

Summary measures derived from FSIGT. Insulin sensitivity (the measure of the fraction of glucose cleared from the circulation per unit increase in insulin) and glucose effectiveness (Sg; the measure of the ability of glucose to increase its own uptake and to suppress hepatic glucose production at basal insulin levels) were determined using the modified minimal model method (13). Further measures derived from the FSIGT were basal insulin (I_b; mean of the four prechallenge plasma insulin values, -15, 10, -5, and -2 min), basal glucose (G_b; average of the four prechallenge plasma glucose values), acute insulin responses to glucose (AIRg; average elevation of posthepatic plasma insulin concentration above the baseline for the 2, 3, and 4 min samples), acute insulin response to tolbutamide (AIRtol; average elevation of posthepatic plasma insulin concentration above the baseline for the 22, 23, and 24 min samples), glucose disappearance rate (K_G; slope of the log linear regression of plasma glucose concentration between 10 and 19 min), and disposition index (DI or ß-cell compensation index; product of S_I and AIRg) (12).

Percentile ranking for the hyperbolic relationship between S_I and AIRg. The hyperbolic relationship between S_I, as the independent variable and AIRg as the dependent variable was determined using data obtained from 30 normal adult female rhesus monkeys fed a special, purified diet, undergoing FSIGT (age, 11.3 ± 0.4 yr; BW, 7.2 ± 0.3 kg; BMI, 31.1 ± 1.1 kg/m²) (14, 15) by previously described human methodology (16). Log transformation of S_I and AIRg (r² = 0.45; P 0.0001; Fig. 1) created the best-fit hyperbolic line compared to a linear fit line (r² = 0.21; P 0.01). Standard least squares regression, which only accounts for error in the dependent variable, was used because the range of error for S_I was relatively small compared to the range of values for the dependent variable (17). The hyperbolic relationship between S_I and AIRg (Z = ([ln (AIRg) - 6.17 + 0.67 x ln(S_I)])/0.594) was derived from the equation for the hyperbolic curve. The Z score for each study animal was calculated using their S_I and AIRg values, with the corresponding percentile ranking determined from a standard table of normal distribution.

View larger version (18K): [in this window] [in a new window]   Figure 1. Hyperbolic relationship between SI and AIRg for 30 normal female rhesus monkeys (14 15 ). r2 reflects the correlation coefficient for the hyperbolic curve.

Glucose and insulin values were submitted to log transformation, when appropriate, to achieve homogeneity of variance and to increase linearity (18). Normality of variables was confirmed using a Lilliefors test (two-tailed). All variables were compared by nested ANOVA, using female group (control vs. prenatally androgenized female) and gestational timing of TP exposure (early vs. late treated, nested within prenatally androgenized female) as factors to determine the independent effects of these variables and possible interactions (Systat Macintosh version 5.2, Systat, Evanston, IL). When significant statistical interactions were present by ANOVA, post-hoc t tests (two-tailed) were performed on the variables. Regression analyses were performed using BMI as the dependent variable and data obtained from the minimal model as independent variables. P 0.05 was considered significant. Minimal model data were expressed as antilog of the transformed means and 95% confidence limits, whereas percentile rankings and BMI were expressed as the mean ± SEM.

	Results

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Measures of S_I and glucose regulation

The DI was decreased in the group of early treated, prenatally androgenized females compared to that in control females (P 0.05; Table 1). Conversely S_I and DI were significantly greater in the group of late treated, prenatally androgenized females than in early treated, prenatally androgenized and control females (S_I, P 0.05; DI, P 0.03). The S_G, I_b, G_b, AIRg, AIRtol, and K_G were similar in both groups of prenatally androgenized females as well as in the group of control females.

Individual percentile rankings for the hyperbolic relationship between S_I vs. AIRg for all early treated, prenatally androgenized females were below the best-fit line (e.g. the 50th percentile; Fig. 2). The individual percentile rankings for S_I vs. AIRg for late treated and control females were more evenly distributed around the 50th percentile. Consequently, the mean percentile ranking for the S_I vs. AIRg hyperbolic curve in the group of early treated prenatally androgenized females was decreased compared to those in the late treated, prenatally androgenized female and control female groups (10.3 ± 3.4 vs. 40.5 ± 9.5 and 31.3 ± 5.8; P 0.01).

View larger version (23K): [in this window] [in a new window]   Figure 2. Hyperbolic relationship between SI and AIRg for early treated (closed circles; n = 10) and late treated (open circles; n = 9), prenatally androgenized females as well as control females (open squares; n = 15). The best-fit line (50th percentile) and the 25th and 75th percentiles are based upon the hyperbolic relationship in Figure 1.

There was no statistical relationship between S_I and BMI in the groups of early treated, prenatally androgenized and control females given the range of BMI for these animals. In contrast, there was a negative relationship (r² = 0.5; P 0.03) between S_I and BMI in the group of late treated, prenatally androgenized females. There were no statistical relationships between BMI and S_g, I_b, G_b, AIRg, AIRtol, K_G, or DI in any female group.

	Discussion

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The purpose of the present study was to determine whether female rhesus monkeys exposed to androgens during prenatal life exhibited altered insulin-glucose homeodynamics and, if so, whether such alterations were related to gestational age at the time of prenatal androgen excess. Such a hypothesis was based upon previous observations that, depending upon gestational age at the time of androgen excess, prenatal androgen exposure in female rhesus monkeys caused well defined and irreversible changes in reproductive function and behavior (9). For example, prenatal exposure of female rhesus monkeys to TP starting on gestational day 40 caused male-type sexual behavior, genital masculinization, delayed menarche, and susceptibility to anovulation. The same TP dose, administered to female rhesus monkeys between gestational days 100–115, induced a similar male-type behavioral pattern and an increased risk of anovulation, but without genital masculinization or delayed menarche (4, 9). The present study complimented these observations by showing that timing of prenatal androgen excess in female rhesus monkeys permanently altered regulatory mechanisms governing insulin-glucose homeostasis.

Early gestational androgen excess in female rhesus monkeys appears to impair pancreatic ß-cell function. The DI, a relative index of the relationship between acute pancreatic insulin responsiveness (e.g. AIRg) and the ability of insulin to induce glucose uptake (e.g. S_I), was decreased in early treated, prenatally androgenized females, indicating a diminished ability of pancreatic ß-cells to respond to hyperglycemic episodes (19, 20). The mean percentile ranking for the hyperbolic relationship between S_I and AIRg in early treated, prenatally androgenized females was also significantly reduced. In humans, percentile rankings for the same relationship (e.g. S_I and AIRg) below the 50th percentile (the median percentile for a healthy, normative population) indicate diminished pancreatic ß-cell secretion of insulin and occur when reduced S_I values are combined with low or normal values of AIRg (16, 19). We found evidence of such diminished pancreatic function in early treated, prenatally androgenized females alone. All of these females had percentile rankings below the 50th percentile, ranking below age- and body size-matched controls regardless of degree of adiposity.

As androgen receptors have been identified in the primate endocrine pancreas (21), excess androgen during early prenatal life may permanently alter pancreatic development in a manner similar to that described in tissues of the central nervous system (e.g. neural centers regulating sexual behavior) and reproductive tract (22). Androgen excess in the early treated female rhesus monkeys coincides with pancreatic organogenesis (23) and therefore could have adversely affected differentiation of the pancreas, leading to diminished pancreatic ß-cell function. Moreover, if androgen excess at this early stage of development also decreases hepatic insulin clearance in monkeys, as it does in rats (24), our experimental findings may have underestimated the differences found in insulin-glucose homeodynamics between early treated, prenatally androgenized females and the other two groups of females.

Late gestation androgen excess was associated with a negative relationship between S_I and adiposity that was not found in early treated or control females. Prenatal androgen excess during late gestation may result in a unique alteration in body composition, where total body adiposity is decreased with a relative increase in the proportion of fat in the viscera. This assumption would agree with studies of perinatally androgenized female rats, which exhibited decreased total body fat in combination with increased proportion of visceral fat (25). Additionally, perinatal androgen excess in female rats is deleterious to hepatic insulin action by diminishing hepatic insulin binding and receptor function (24) which would be exacerbated by the increasing proportion of fat in the viscera. Such body composition changes are also demonstrated with long term androgen exposure in female to male human transsexuals with similar decreases in total body fat and increases in visceral fat (26). Therefore, in late treated, prenatally androgenized females, although insulin sensitivity may be increased in the lean individuals, a propensity for visceral adiposity as body mass increases may excessively promote insulin resistance and thus the negative relationship between BMI and S_I.

In the present study, the effects of estrogen on insulin-glucose homeodynamics were controlled by performing all FSIGTs during the early follicular phase of the menstrual cycle or during periods of anovulation. Estrogen levels in anovulatory prenatally androgenized females do not differ from early follicular phase values in ovulatory prenatally androgenized and control females (4). Estrogen plays an important role in modulating peripheral and hepatic insulin sensitivities. Elevated levels of circulating estrogen are associated with increased S_I in women and female rhesus monkeys alike (14, 27), and in vitro treatment of rat hepatocytes with estradiol increases insulin binding and receptor-mediated insulin clearance (24).

It is theoretically possible that prenatal androgen exposure in women can induce a PCOS-like condition without causing external genital virilization. As the human fetal ovary is capable of steroidogenesis during the second trimester of intrauterine life, abnormal ovarian androgen production could occur during a time of human development when first trimester external genital differentiation is complete (28, 29). This hypothesis is supported by the findings in diabetic pregnancies of elevated amniotic fluid androgen levels of presumed fetal ovarian origin and ovarian thecal-lutein cell hyperplasia in the subsequent female infants (30, 31). Furthermore, the fetal adrenal is steroidogenically active during midtrimester human development (32) and might additionally contribute to in utero hyperandrogenism. For example, congenital adrenal virilizing cancer has been associated with hirsutism, ovarian hyperandrogenism, and LH hypersecretion in an adolescent girl without genital ambiguity (33). Although the effect of prenatal androgen exposure in women on glucose-insulin regulation is unclear, congenital rubella syndrome recently has been linked to both PCOS and diabetes, but not genital ambiguity (34), thereby demonstrating that perturbation of normal human fetal development can induce subtle, yet permanent, abnormalities of both reproductive and metabolic function.

	Acknowledgments

 
This manuscript is dedicated to the memory of our mentor Prof. Robert W. Goy (1924–1999), a pioneer in the field of organizational effects of androgens, former director of WRPRC, and the investigator who produced the prenatally androgenized female monkeys for his studies of early development.

We thank S. G. Eisele, K. M. Boehm, and the Animal Care Staff of WRPRC for management and maintenance of the animals; C. O’Rourke for veterinary care, G. R. Scheffler, T. E. Ziegler, D. J. Wittwer, F. H. Wegner, and S. T. Baum for assistance with hormone assays and glucose; M. K. Clayton for assistance with statistical analysis; and R. J. Colman for technical assistance.

	Footnotes

 
¹ Presented in part at the 80th Annual Meeting of The Endocrine Society, New Orleans, LA, 1998. This work was supported in part by NIH Grants RR-00167 and AG-11915, and research awards from the University of Wisconsin-Madison Medical School and Graduate School research committees. This is publication 39–024 of the WRPRC.

Received April 16, 1999.

Revised November 19, 1999.

Accepted November 30, 1999.

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