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Biology of Reproduction 62, 1445-1451 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Articles

Opposing Effects of Androgen and Estrogen on Pituitary-Adrenal Function in Nonpregnant Primates1

Dino A. Giussania, Daniel M. Farbera, Susan L. Jenkinsa, Andrew Yena, James A. Wintera, Jennifer D. Tamea, and Peter W. Nathanielsz2,a

a Laboratory for Pregnancy & Newborn Research, Department of Physiology, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401 c The Physiological Laboratory, University of Cambridge, Cambridge CB2 3EG, United Kingdom


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Maternal administration of androstenedione produces a sustained fall in maternal plasma adrenocorticotropic hormone (ACTH) concentrations in the pregnant nonhuman primate. We hypothesize a negative feedback influence on the maternal hypothalamo-pituitary-adrenal (HPA) axis by androgens in primates. This may reflect an important maternal adaptation during pregnancy in primates preventing premature induction of labor by maternal stress. However, androstenedione is precursor for placental estradiol-17ß synthesis, and infusion of androstenedione into pregnant primates elevates maternal plasma estradiol-17ß to term concentrations. Thus, it could be argued that 1) the effects attributed to androstenedione on the maternal HPA axis are mediated by estrogen rather than by androgen and 2) the negative influence of androgens may be on placental ACTH rather than, or in addition to, pituitary ACTH. To discriminate between androgenic and estrogenic effects of androstenedione on pituitary and/or placental ACTH function in primates we measured plasma ACTH, cortisol, and dehydroepiandrosterone sulfate (DHEAS) concentrations in nonpregnant baboons after treatment with either androstenedione or estradiol-17ß.

Nine female baboons were studied between 14 and 22 days postpartum prior to estrous cycling. After 2 days of baseline, a continuous i.v. infusion of androstenedione (1.5 mg/kg per h in 10% intralipid, IL) was started at 0900 h and maintained for 9 days in 3 baboons. A similar protocol was carried out in another 3 baboons that received a continuous i.v. infusion of estradiol-17ß (10 µg/kg per h in 10% IL) instead of androstenedione. Three additional baboons received continuous i.v. IL vehicle alone and served as controls. Arterial blood samples (0.5 ml) for measurement of plasma hormones were taken during baseline and after 1, 3, 5, 7, and 9 days of infusion.

Baseline plasma ACTH, DHEAS, and cortisol concentrations were similar among all groups. Plasma ACTH did not change during IL, increased following estradiol-17ß, and fell during androstenedione treatment. Accordingly, plasma cortisol and DHEAS concentrations were also unaltered by IL, and both steroids increased during estradiol-17ß treatment. In contrast, plasma cortisol and DHEAS remained unaltered from baseline during androstenedione treatment, despite the fall in plasma ACTH measured at this time.

These data in the nonpregnant baboon 1) are consistent with negative feedback on pituitary ACTH by androgens and 2) demonstrate a positive influence on pituitary-adrenal function by estrogen in primates.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The localization of androgen receptor in the hypothalamus from adult [1] and fetal [2] baboons and in the hypothalamus and pituitary from the adult rat [3] suggest a feedback control system by androgens that may regulate hypothalamo-pituitary-adrenal function in a similar manner to the well-established negative feedback regulation of glucocorticoids on the axis. Indirect evidence that this feedback system on the hypothalamo-pituitary-adrenal (HPA) axis by androgen is operational in adult animals has been suggested since 1) gonadectomy of the male hamster leads to enhanced levels of glucocorticoid [4] and 2) following stress induced by foot shock or by exposure to a novel environment, plasma adrenocorticotropic hormone (ACTH) and glucocorticoid levels are higher in gonadectomized male rats when compared to intact rats [5].

We have reported that a physiological increase in maternal plasma androstenedione concentration, following exogenous androgen administration into the pregnant rhesus monkey, produces a sustained fall in maternal plasma ACTH concentrations [6]. This provides support for a negative feedback influence of androgens on the HPA axis in the pregnant nonhuman primate. However, androstenedione is a precursor for estrogen biosynthesis within the placenta [7], and i.v. infusion of androstenedione to pregnant monkeys elevates maternal plasma estradiol concentration to values similar to those obtained at normal term in the rhesus monkey [8–10]. Therefore, it could be argued that in studies in pregnant animals [6], the effects on the HPA axis attributed to increased androgens are mediated by increased placental estrogens instead of, or in addition to, androgenic effects. Furthermore, since it has been suggested that the primate placenta is capable of producing and secreting ACTH [11], androstenedione-induced androgen negative feedback may be on placental ACTH instead of, or in addition to, pituitary ACTH.

The aims of the present study were to discriminate between the possible androgenic and estrogenic influences of androstenedione on the HPA axis, and between the possible effects of androstenedione on pituitary and placental ACTH. Thus, the effects of either androstenedione treatment alone or estrogen treatment alone on pituitary-adrenocortical function in nonpregnant primates, thereby eliminating androgen-stimulated estrogen biosynthesis within the placenta, were investigated. Arterial blood gases and pH were measured throughout the protocol in order to discount the possibility of any endocrine changes resulting from alterations in arterial blood gas status.

Some of these results have been published in abstract form [12].


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Use of Animals

Nine female baboons (18.6 ± 0.5 kg; mean ± SEM) carrying patent femoral artery catheters from previous experimentation were used in this study between 14 and 22 days postpartum. All baboons were not rearing their young, were not lactating, and were studied prior to resumption of estrous cycling. Previous studies in these animals, when pregnant, involved intravascular administration of saline (0.9% NaCl) only. The animals were initially obtained from the Southwest Foundation for Biomedical Research (San Antonio, TX) and acclimated to the laboratory conditions as previously described in detail [13, 14]. All procedures were approved by the Cornell University Institutional Animal Care and Use Committee and were performed in facilities approved by the American Association for the Accreditation of Laboratory Animal Care. In brief, all animals were housed in individual cages in sight of at least one other baboon, in rooms with controlled light:dark cycles (14L:10D), and placed in quarantine. During quarantine, the animals were jacketed, and the tether through which vascular catheters were to be connected after surgical instrumentation was suspended from the top of the cage. One week later, the tether was fixed to the back of the jacket. The animals were fed daily (Purina 5045 High Protein Monkey Chow; Purina, Richmond, IN), and fresh fruits and water were continuously available.

Treatment Groups

Catheters were maintained patent by continuous infusion of heparinized saline (25 IU heparin/ml at 0.5 ml/h) from the time of surgery until the commencement of one of three treatments. After 2 days of baseline, androstenedione (4-androstenedione-3,17-dione; Sigma, St. Louis, MO) dissolved in 10% intralipid (IL; Kabi Vitrum, Alameda, CA) was infused i.v. continuously for 9 days at 1.8 mg/kg per h at a rate of 4.0 ml/h in 3 baboons (group I). Another 3 baboons received a continuous i.v. infusion of estradiol-17ß (Sigma) in 10% IL for 9 days at 10 µg/kg per h delivered at the same rate, instead of androstenedione (group II). A further 3 baboons received a continuous i.v. infusion of 10% IL alone at 4.0 ml/h for 9 days and served as the controls (group III). Arterial blood samples (0.8 ml) were taken from all animals for RIA measurement of plasma ACTH, dehydroepiandrosterone sulfate (DHEAS), and cortisol and blood gases and pH (ABL 500; Radiometer, Copenhagen, Denmark; measurements corrected to 38°C) at 0, 2, and 4 h after lights-off during the 2 days of baseline and after 1, 3, 5, 7, and 9 days of infusion. All arterial blood samples for hormone analyses were collected using aseptic techniques and transferred immediately into chilled polypropylene collection tubes. Tubes were centrifuged at 4°C at 1200 x g for 5 min. Plasma was removed, aliquoted, immediately flash frozen in liquid nitrogen, and stored at -20°C until assayed. Remaining red blood cells from the centrifuged tubes were resuspended in heparinized saline (25 IU heparin/ml) and returned into the animal's arterial circulation. All hormone assays were performed within 2 mo of blood collection.

Hormone Analyses

ACTH Plasma concentrations of ACTH were measured by RIA in 50 µl unextracted plasma with kits purchased from INCStar (Stillwater, MN) as previously described [6]. Samples or standards (50 µl) were incubated with antiserum (INCStar; 50 µl) for 24 h at 4°C. Radioiodinated ACTH (INCStar; 50 µl) was then added and incubated for a further 24 h at 4°C. Goat anti-rabbit precipitating complex (200 µl) was added and incubated for 20 min at room temperature. Cold PBS (0.01 M NaPO4, 0.9% NaCl, pH 7.2; 1 ml) was added to each tube and centrifuged at 1000 x g for 30 min at 15°C. Intraassay coefficient of variation (CV) for the control pool (containing 19.4 pg/ml) was 5.9%; interassay CV for the control pool was 12.8%. The lower limit of detection of this assay (90% B/B0) was 0.25 pg/tube, which represents 5 pg/ml. Cross-reactivity of the antibody at 1200 pg/ml was porcine ACTH1–39 100%, human ACTH1–24 100%, AVP < 0.01%, oxytocin < 0.01%, ß-endorphin < 0.01%, {alpha}-melanocyte-stimulating hormone < 0.01%, human growth hormone < 0.01%. Serial dilutions of pregnant baboon plasma gave parallel responses in the assay. Accuracy was evaluated by adding known amounts of human ACTH1–39 to plasma samples and measuring the final concentrations by RIA.

DHEAS A commercial assay kit (Diagnostic Products, Los Angeles, CA; #TKDS-1) for human plasma dehydroepiandrosterone was validated for analysis of baboon plasma. Dehydroepiandrosterone recovery was determined by mixing baboon plasma pool 1:1 with dehydroepiandrosterone of known concentration in human plasma (100, 200, 2500, and 5000 ng/ml). All dehydroepiandrosterone-spiked samples were diluted 1:1 with kit zero calibrator to ensure measurements from the linear region of the standard curve. Recovery was 98.7 ± 3.7%. Parallelism was demonstrated by serial dilution of baboon plasma in kit zero calibrator. Intraassay CV was 8.3% and interassay CV was 13.8% for a baboon quality-control sample of 91.6 ng/ml (n = 8). Assay lower limit of detection (90% B/B0) was 0.75 ng/tube (n = 5), which represents 15 ng/ml. Cortisol and estradiol are not detectable in the DHEAS assay. Androstenedione has 1.2% cross-reactivity in the DHEAS assay.

Cortisol A commercial assay kit (Diagnostic Products; #KCOD2) for human plasma cortisol was validated for analysis of baboon plasma. Cortisol recovery was determined by mixing baboon plasma pool 1:1 with cortisol solution of known concentration in human plasma (11, 51, 100, 195, 460 ng/ml). All cortisol-spiked samples were diluted 1:1 with kit zero calibrator to ensure measurements from the linear region of the standard curve. Recovery was 101.2 ± 1.1%. Parallelism was demonstrated by serial dilution of rhesus plasma in kit zero calibrator. Intraassay CV was 6.7%, and interassay CV was 8.8% for a baboon control sample of 374.1 ng/ml (n = 11). Assay lower limit of detection (90% B/B0) was 4.5 ng/ml (n = 11). Androstenedione, DHEAS, and estradiol are not detectable in the cortisol assay at its lower limit of detection.

Estradiol The assay for measurement of estradiol has been previously validated for use in nonhuman primates, and the assay procedures have been described in detail. Maternal plasma estradiol was measured on duplicate 200-µl plasma aliquots [15]. The lower limit of detection of the assay (90% B/B0) was 15 pg/ml. Intra- and interassay CVs were 3.2% and 8.7%, respectively. Androstenedione, cortisol, and DHEAS are not detectable in the estradiol assay at the assay's lower limit of detection of 15 pg/ml.

Androstenedione A commercial assay kit (Diagnostic Products; #TKAS2) for human plasma androstenedione was used for analysis of baboon plasma. Androstenedione recovery was determined by mixing baboon plasma pool 1:1 with androstenedione of known concentration in human plasma (0.4, 1.5, 4.0, and 10.0 ng/ml). All androstenedione-spiked samples were diluted 1:1 with kit zero calibrator to ensure measurements from the linear region of the standard curve. Recovery was 99.9 ± 10.4%. Parallelism was demonstrated by serial dilution of rhesus plasma in kit zero calibrator. Intraassay and interassay CVs were 5.9% and 8.3%, respectively, for a baboon quality control sample of 5.1 ng/ml (n = 6). All samples of any particular animal were run within the same assay. Assay lower limit of detection (90% B/B0) was 0.11 ng/ml. Cortisol has 0.002% cross-reactivity, DHEAS has 0.003% cross-reactivity, and estradiol is not detectable in the androstenedione assay.

Data and Statistical Analyses

There was no difference in arterial plasma concentrations of ACTH, DHEAS, and cortisol or in arterial blood gases and pH during the 2 days of baseline for all treatment groups. Thus, baseline plasma hormone concentrations, blood gases, and pH were pooled and are expressed as mean ± SEM. In addition, there were no differences in daily arterial plasma concentrations of ACTH, DHEAS, and cortisol or in arterial blood gases and pH at lights-off and 2 and 4 h after lights-off for all treatment groups. Thus, daily plasma hormone concentrations and arterial blood gases and pH were pooled and are expressed as mean ± SEM. For any one group of animals, arterial plasma concentrations of ACTH, DHEAS, and cortisol, as well as arterial blood gases and pH, measured postinfusion were compared to respective baseline measurements using repeated measures ANOVA, and any differences were assessed using Dunnett's post hoc test. Statistical significance was accepted at P < 0.05.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Circulating plasma estradiol concentrations were unaltered from baseline in androstenedione-treated (group I, 400.9 ± 60.8 pg/ml, mean ± SEM) and IL-infused (group III, 568.2 ± 85.3 pg/ml) animals. In contrast, i.v. infusion of estradiol-17ß resulted in sustained elevations of circulating plasma estradiol concentrations in group II animals (Fig. 1A). These circulating concentrations of estradiol are similar to those measured in pregnant baboons in late gestation [16]. Similarly, circulating basal plasma concentrations of androstenedione were unaltered from baseline in the estradiol-treated (group II, 5.7 ± 1.2 ng/ml) and IL-infused (group III, 8.9 ± 3.2 ng/ml) animals. In contrast, androstenedione treatment of group I baboons produced a sustained increase in circulating plasma androstenedione concentrations (Fig. 1B). These resulting circulating plasma androstenedione concentrations measured in the nonpregnant baboons were approximately 10-fold higher than those measured in pregnant women [17] and pregnant rhesus monkeys [6] in late gestation.



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  		FIG. 1. Circulating arterial plasma concentrations of estradiol (A) and androstenedione (B) during baseline and during 9 days of infusion. Values are mean ± SEM (n = 3). Gray bars represent postinfusion concentrations, *P < 0.05, baseline vs. postinfusion, ANOVA + Dunnett's test

Baseline measurements of arterial blood gases and pH were similar between all experimental groups (group I: pH 7.44 ± 0.01, PaCO2 31.2 ± 2.1 mmHg, PaO2 100 ± 6 mmHg; group II: pH 7.42 ± 0.01, PaCO2 34.2 ± 1.9 mmHg, PaO2 112 ± 3 mmHg; group III: pH 7.49 ± 0.02, PaCO2 36.9 ± 1.6 mmHg, PaO2 96 ± 4 mmHg) and remained unaltered by 9 days of i.v. infusion of either IL vehicle or androstenedione or estradiol.

Baseline plasma concentrations of ACTH, DHEAS, and cortisol were also similar among all treatment groups. However, plasma ACTH concentrations were unchanged during IL infusion, increased following estradiol treatment, and decreased during androstenedione treatment (Fig. 2). Accordingly, plasma cortisol and DHEAS concentrations were also unaltered by IL infusion, and both hormones increased during estradiol treatment (Fig. 3). In contrast, plasma cortisol and DHEAS concentrations remained unaltered from baseline concentrations during androstenedione treatment (Fig. 3), despite a decrease in plasma ACTH concentrations measured at this time (Fig. 2).



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  		FIG. 2. Effect of IL vehicle infusion or androstenedione or estradiol treatment on circulating arterial plasma concentrations of ACTH in the baboon. Values are mean ± SEM of n = 3 for each group. White bar represents baseline concentration. Gray bars represent postinfusion concentrations. *P < 0.05, baseline vs. postinfusion, ANOVA + Dunnett's test



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  		FIG. 3. Effect of IL vehicle infusion or androstenedione or estradiol treatment on circulating arterial plasma concentrations of cortisol and DHEAS in the baboon. Values are mean ± SEM of n = 3 for each group. White bar represents baseline concentration. Gray bars represent postinfusion concentrations. *P < 0.05, baseline vs. postinfusion, ANOVA + Dunnett's test


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although feedback inhibition of the HPA axis by glucocorticoids has been well established at both the hypothalamic and pituitary level by a number of in vivo (e.g., [18, 19]) and in vitro (e.g., [20, 21]) studies, the acute regulation of placental corticotropin-releasing hormone (CRH) by glucocorticoids appears to oppose regulation of hypothalamic CRH. For example, the dramatic rise in placental CRH peptide [22–24] and mRNA [25] in human late gestation occurs at a time when fetal adrenal glucocorticoids are markedly elevated [26]. Furthermore, maternal administration of the synthetic glucocorticoid betamethasone is not associated with a decrease in placental CRH peptide in maternal plasma [27], and glucocorticoids stimulate in vitro CRH output from placenta and fetal membranes in a dose-dependent manner [28] and induce an increase in CRH gene expression in the human placenta [29].

By analogy with the differential effects of glucocorticoids on the maternal HPA and placental CRH in the primate, we have tested the hypotheses that androgen administration to the pregnant monkey may 1) feedback negatively on the maternal HPA and 2) stimulate placental CRH. We have previously demonstrated that continuous infusion of androstenedione to pregnant monkeys at 0.8 of gestation results in persistent switching in myometrial activity patterns from contractures to contractions, cervical effacement and dilatation, and premature live delivery of the monkey fetus [8–10]. We have also reported that androstenedione treatment of pregnant monkeys leads to an inhibition of maternal plasma ACTH concentrations [6], but that it increases placental CRH mRNA and peptide to concentrations similar to those measured at spontaneous, term labor in the monkey [30]. These observations support the hypotheses that androgens, like glucocorticoids, have an inhibitory influence on the maternal HPA axis but a stimulatory one on placental CRH.

However, assessment of the effects of androgen treatment on the maternal HPA axis during pregnancy is complicated by the fact that androgens are the necessary precursor for estrogen biosynthesis within the primate placenta [7]. In addition, since the primate placenta is known to synthesize and secrete ACTH (see [11]), attenuation of circulating maternal ACTH concentrations following androstenedione treatment may reflect androgen negative feedback on placental ACTH instead of, or in addition to, pituitary ACTH.

The results presented in this paper suggest opposing effects of androgen and estrogen on circulating ACTH concentrations in the nonpregnant baboon. Therefore, these findings strongly support a negative influence of androgen on pituitary ACTH that is described for the first time in a primate species. The long-term inhibition of pituitary function with continuous treatment of the baboon with androstenedione for days in the present study also adds to previous investigations about the actions of androgens on HPA function in rats and in hamsters. For example, gonadectomy of the male hamster has been reported to lead to enhanced levels of glucocorticoid [4], and stress-induced increases in plasma ACTH and glucocorticoid levels were higher in gonadectomized male rats when compared to intact rats [5]. Secondly, testosterone replacement to castrated rats prevented gonadectomy-induced increases in ACTH [31]. Finally, male castration led to an increase in hypothalamic CRH content and CRH-immunoreactive cell numbers in the paraventricular nucleus in the rat, but replacement of the nonaromatizable androgen, dihydrotestosterone, to gonadectomized rats prevented these increases in hypothalamic CRH and CRH-immunoreactivity [32].

It is of interest whether the inhibitory actions of androstenedione on pituitary function in the primate in the present study are due to its direct binding to androgen receptors within the hypothalamus and/or pituitary [1, 2] or due to the effects of its metabolic products within the same sites. Although evidence exists for direct binding of androstenedione to androgen receptors in rat hypothalami [33], and for the localization of 17ß-hydroxysteroid dehydrogenase within the brain of the male frog [34], to our knowledge similar studies have not been performed with tissues obtained from primate species.

An increase in peripheral plasma ACTH, DHEAS, and cortisol after physiological infusions of estradiol in baboons in the present study is in keeping with an operating positive influence of estrogen on the HPA axis as evidenced by a series of independent studies in primate and nonprimate species. First, estradiol administration to adult rats leads to increased pituitary ACTH content [31]. Secondly, ACTH and corticosteroid responses to stress are greater in estradiol-treated rats compared to control rats, and the recovery of ACTH and cortisol responses to foot shock stress in rats is significantly prolonged in the presence of estradiol [35]. Thirdly, proopiomelanocortin (POMC) mRNA expression in the baboon fetal pituitary is greater in late gestation when estrogen levels are elevated than at midgestation [36]. Fourthly, POMC levels in the baboon fetal pituitary could be increased at midgestation by prematurely elevating estrogen to levels typically observed late in pregnancy [36]. This increase in POMC mRNA at term and at midgestation after treatment with estradiol is associated with an increase in the number of cells in the fetal pituitaries of these animals expressing ACTH peptide as assessed by immunocytochemistry [36].

The dissociation between the effects of androstenedione on circulating ACTH concentrations and DHEAS and cortisol concentrations in the baboon in the present study is interesting. Lack of inhibition of androstenedione on adrenal cortical products may, at least in part, be due to the presence of a functional P450 aromatase within the adrenal cortex, as previously suggested by Conley et al. [37] in studies in the pig. While presence of P450 aromatase in the baboon adrenal cortex has not been reported to date, the possibility that androstenedione infusion to baboons will lead to estrogen biosynthesis within the adrenal cortex cannot be discounted. Since estrogens demonstrate potent local vasodilator actions [38], it is possible that androstenedione treatment may lead to an increased presentation of circulating ACTH to the adrenal cortex, resulting in increased secretion of ACTH-stimulated adrenal cortical products, such as DHEAS and cortisol, in the baboon. Alternatively, the maintained cortisol and DHEAS concentration may represent basal function that is relatively ACTH independent. For example, compelling and growing evidence suggests that the sympathetic innervation to the adrenal gland provides an important influence on steroidogenesis independent of an effect on plasma ACTH concentrations. Specifically, the group of Edwards has shown that in conscious hypophysectomized calves, stimulation of the splanchnic sympathetic innervation to the adrenal gland, below behavioral threshold, strongly potentiates the steroidogenic adrenal cortical response to an exogenous infusion of ACTH [39]. The output of cortisol is roughly doubled during stimulation at a relatively low frequency (4 Hz) with no change in plasma ACTH concentration. In addition, two separate studies in two different species have provided clear evidence that the normal impulse traffic in the splanchnic innervation maintains the sensitivity of the adrenal cortex to ACTH. Both in lambs [40] and in calves [41], section of the splanchnic nerves roughly halves the output of cortisol to an exogenous infusion of ACTH. Hence, it is quite plausible that the dissociation between changes in plasma ACTH and cortisol following androstenedione treatment in the nonpregnant baboon may result from neurally mediated changes in adrenocortical sensitivity alone. Another possibility is that the ratio of bioactive to immunoreactive ACTH is changed following androstenedione treatment, as has been described during situations of acute stress in humans [42] and in dogs [43]. Finally, the confounding influence of possible changes in plasma binding globulins after androstenedione treatment on circulating steroid concentrations cannot be excluded. For example, elevations in binding globulins will elevate total steroid levels in the circulation, which may be accompanied by a decline in free circulating steroid concentrations. This in turn may disinhibit the HPA axis and result in increased or maintained levels of cortisol and DHEAS. While the effect of androstenedione on circulating plasma steroid binding globulins is unknown, we do not favor this possibility, as disinhibition of the HPA axis could lead to increased levels of circulating ACTH in addition to circulating levels of cortisol and DHEAS.

In the present study, it is of interest that the circulating estradiol concentrations achieved after estradiol infusion in the nonpregnant baboon were similar to those measured in pregnant baboons in late gestation [16]. In contrast, the circulating concentrations of androstenedione achieved following androstenedione infusion in the nonpregnant baboon were approximately 10-fold greater than those measured in pregnant monkeys [6] or in pregnant women [17] in late gestation. To our knowledge there is no information on circulating maternal plasma concentrations of androstenedione in the pregnant baboon. It is possible that androstenedione levels in the pregnant primate are lower than those in the nonpregnant primate after androstenedione treatment because of conversion of androgens to estrogens within the primate placenta [36].

Finally, it must be mentioned that the baboons used in this investigation were studied prior to the resumption of estrous cycling. It may be possible that the effects of androstenedione on the HPA axis differ between cycling and noncycling animals.

In conclusion, these results suggest opposing influences of androgen and estrogen on the HPA axis in the baboon. Persistent inhibition of circulating ACTH concentrations in the nonpregnant baboon strongly supports a negative feedback influence of androgens on pituitary function, in a manner similar to that exerted by glucocorticoids, in the primate.


   ACKNOWLEDGMENTS
 
We would like to thank Karen Moore and Margaret Bardy for their help with this manuscript.


   FOOTNOTES
 
First decision: 28 September 1999.

1 This work was supported by the National Institutes of Health HD 21350. Back

2 Correspondence: Peter W. Nathanielsz, Laboratory for Pregnancy and Newborn Research, Dept. Physiology, T9 015 VRT, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853-6401. FAX: 607 253 3455; pwn1{at}cornell.edu Back

Accepted: December 21, 1999.

Received: August 18, 1999.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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