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Endocrinology Vol. 141, No. 9 3296-3303
Copyright © 2000 by The Endocrine Society

ARTICLES

Androstenedione Treatment of Pregnant Baboons at 0.7–0.8 of Gestation Promotes a Premature Forward Shift in the Nocturnal Maternal Plasma Estradiol Surge Relative to Progesterone and Increases Myometrial Contraction Activity1

Dino A. Giussani, Susan L. Jenkins, James A. Winter, Jennifer D. Tame and Peter W. Nathanielsz

Laboratory for Pregnancy & Newborn Research (S.L.J., J.A.W., J.D.T., P.W.N.), College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401; and The Physiological Laboratory (D.A.G.), University of Cambridge, Downing Street, Cambridge CB2 3EG, United Kingdom

Address all correspondence and requests for reprints to: Peter W. Nathanielsz, Laboratory for Pregnancy & Newborn Research, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853-6401. E-mail: pwn1{at}cornell.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Androstenedione treatment of pregnant monkeys at 0.8 of gestation reproduces endocrine, biophysical, and biochemical changes similar to those measured during spontaneous, term labor in the pregnant monkey. In the pregnant baboon, the spontaneous onset of labor at term has been attributed to a forward shift in the nocturnal estradiol surge relative to that of progesterone in maternal plasma. This study investigated whether androstenedione treatment of the pregnant baboon at 0.7–0.8 of gestation promotes a premature forward shift in the nocturnal surge of maternal plasma estradiol relative to progesterone and whether this shift is associated with premature increases in nocturnal myometrial activity. Eight pregnant baboons were prepared surgically under general anesthesia with vascular catheters and myometrial electromyogram electrodes between 121 and 139 days of gestation (term is ca. 185 days). Catheters were maintained patent by continuous infusion of heparinized saline from the time of surgery until one of two treatments began following at least 9 days of postoperative recovery. In four baboons (Group I), the saline administration was replaced by a continuous infusion of 10% intralipid vehicle during Day 1 of the experimental protocol. During Day 2 and Day 3, the intralipid infusion was switched for a continuous infusion of androstenedione dissolved in intralipid set at a low (0.8 mg·kg-1·h-1) and at a high (1.6 mg·kg-1·h-1) dose, each delivered for 24 h. The other four pregnant baboons (Group II) received 10% intralipid vehicle for Days 1, 2, and 3 of the experimental protocol. One baboon from Group I received an additional dose of 0.4 mg·kg-1·h-1 for 24 h before the low and the high dose of androstenedione. In each baboon, during each experimental day, maternal arterial blood samples (1 ml) were taken at 1 h intervals for 12 h, starting 3 h before the onset of darkness in the animal’s environment, for measurement of maternal plasma estradiol and progesterone concentrations via RIA. Myometrial contractions were counted during each night-time period of the experimental protocol. All pregnant baboons demonstrated increases in maternal plasma estradiol and progesterone concentrations at night-time. Androstenedione had a dose-dependent effect in elevating day-time maternal plasma estradiol concentrations and in promoting a forward shift in the nocturnal surge of maternal plasma estradiol without affecting the nocturnal progesterone profile in maternal plasma. Maternal treatment with androstenedione also led to an increase in nocturnal myometrial contraction activity. We conclude that androstenedione treatment of the pregnant baboon at 0.7–0.8 of gestation promotes a premature forward shift in the nocturnal estradiol surge relative to that of progesterone in maternal plasma and that this shift is associated with an increase in nocturnal myometrial contraction activity, in a similar way to that measured during spontaneous onset of labor at term in this species.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
IT IS WELL ACCEPTED that many of the processes that promote labor and delivery in a number of species such as the sheep (1, 2), monkey (3, 4), baboon (5, 6), and woman (7, 8, 9) are triggered by an increase in the expressed bioactivity of placental estrogens. For example, estrogens stimulate the synthesis of oxytocin by the maternal hypothalamus (10) and the intrauterine tissues (11), they increase placental prostaglandin synthesis (12), uterine estrogen (13), and oxytocin receptor message and protein (14, 15), and elevate gap junction (16) and gap junction connexin proteins in the myometrium (17, 18). The estrogenic drive in late gestation is achieved via different strategies in different species. In nonprimate species such as the sheep, cow, goat, and rat, parturition is preceded by a precipitate fall in progesterone and a rise in estradiol in maternal blood (19). However, in primates species such as the human (9, 20, 21), chimpanzee (22), rhesus monkey (3, 4), and baboon (5, 6), a fall in maternal plasma progesterone does not occur before birth. Thus, at first sight it appears that the maternal plasma estrogen:progesterone ratio remains relatively constant during late gestation through to delivery.

More detailed studies of Wilson and colleagues in the baboon have clearly revealed that maternal plasma estradiol and progesterone concentrations have pronounced 24 h rhythms; the concentration of both steroids increasing dramatically during the night-time period (5). In addition, they have elegantly demonstrated that 10 to 12 days before spontaneous delivery of the baboon fetus at term, the nocturnal surge in maternal plasma estradiol relative to that of progesterone occurs earlier (5). Wilson and colleagues have hypothesized that this forward shift in the maternal estradiol surge creates a window of time during which the estrogen:progesterone ratio is increased, providing increased estrogenic expressed bioactivity for recruitment of parturitional events in the baboon.

We (23) and others (24, 25, 26) have hypothesized that androgens provide the predominant precursor for placental estrogen biosynthesis during late gestation in primate pregnancy. Accordingly, we have previously demonstrated that sustained administration of androstenedione to pregnant rhesus monkeys at 0.8 of gestation reproduces many of the changes that occur during spontaneous term labor in the monkey. For example, continuous infusion of androstenedione to preparturient monkeys elevated maternal plasma estradiol to concentrations measured at term, resulted in persistent switching in myometrial activity patterns from contractures to contractions, induced progressive cervical effacement and dilatation and led to premature live delivery of the monkey fetus (23, 27, 28, 29). However, the effects of androstenedione on parturitional events in other primate species are unknown. Using serial blood sampling techniques, this study investigated whether androstenedione treatment of pregnant baboons at 0.7–0.8 of gestation, at rates that produce mean maternal plasma estradiol concentrations similar to those measured at term in this species, leads to a premature forward shift in the nocturnal estrogen surge relative to that of progesterone in maternal plasma. In addition, we also determined whether this induced shift is associated with a premature increase in nocturnal myometrial contraction activity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Use of animals
Eight multiparous pregnant baboons (16.9 ± 1.9 kg; mean ± SD) carrying fetuses of known gestational ages were obtained from the University of Chicago (Chicago, IL), or the Southwestern Foundation for Biomedical Research Instruments, Inc. (San Antonio, TX) and acclimated to the laboratory conditions as previously described in detail (30). All procedures were approved by the Cornell University IACUC and were performed in facilities approved by the American Association for the Accreditation of Laboratory Animal Care. In brief, all animals underwent a full physical examination, were housed in individual cages, in rooms with controlled 15-h light, 9-h dark, 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, St. Louis, and fresh fruits) and water was continuously available.

Surgical instrumentation and postsurgical management
Following food deprivation for 24 h, surgery was performed between 121–139 days gestational age (dGA; term is ca. 180 days, see Table 1Go) under general anesthesia (15 mg·kg-1 ketamine for induction; 1–2% halothane in O2 for maintenance) (31). Polyvinyl catheters (id = 0.04 in; od = 0.07 in, Tygon, Baxter, NJ) were placed in the dorsal aorta and inferior vena cava via the left femoral artery and vein, respectively. In addition, multistranded electrodes (AS 632, Cooner Wire, Chatsworth, CA) were sewn on different sites of the anterior surface of the uterine body to monitor myometrial electromyographic (EMG) activity. Catheters were filled with heparinized saline (25 iu heparin·ml-1) and tunneled sc with the electrode leads to exit between the shoulder blades.


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  		Table 1. Details of animals studied

 
After surgery the pregnant baboon was returned to her cage and connected to the tether restraint system (31). At least 9 days were allowed before commencement of any experiment during which time antibiotics (Oxacillin, iv infusion of 100 mg·kg-1·day-1) and analgesia (Buprenorphine, ia infusion of 15 µg·kg-1·day-1 for 2 days) were administered to the mother.

Treatment groups
Catheters were maintained patent by continuous infusion of heparinized saline (25 iu heparin·ml-1 at 0.5 ml·h-1) from the time of surgery until the commencement of one of two treatments (Table 1Go). In 4 baboons (Group I, androstenedione-treated) the saline administration was replaced by a continuous infusion of vehicle alone (intralipid 10%, Kabi Vitrum, Inc., Alameda, CA) set at 0.5 ml·h-1 for Day 1 of the experimental protocol. During Day 2 and Day 3 of the experimental protocol the intralipid infusion was switched for a continuous infusion of androstenedione dissolved in intralipid set at a low (0.8 mg·kg-1·h-1) and at a high (1.6 mg·kg-1·h-1) dose, each delivered for 24 h at 0.5 ml·h-1. One pregnant baboon from Group I was infused with an additional dose of 0.4 mg·kg-1·h-1 androstenedione for 24 h before the low and the high androstenedione treatment. The other 4 pregnant baboons (Group II, controls) received 10% intralipid vehicle for Days 1, 2, and 3 of the experimental protocol. In each baboon, during each experimental day, maternal arterial blood samples (1ml) were taken at 1 h intervals for 12 h starting 3 h before the onset of darkness in the animal’s environment. The myometrial electromyogram record was assessed for night-time switches in myometrial activity patterns from contractures to contractions as previously described in detail (32), and the number of myometrial contractions was counted during the night-time period, also starting 3 h before the onset of darkness in the animal’s environment.

All arterial blood samples for hormone analyses were collected under strict aseptic techniques, transferred into chilled polypropylene tubes and centrifuged at 4 C at 1200 g for 5 min. Plasma was removed, aliquoted, flash frozen, and stored at -20 C until assayed. Remaining red blood cells from the centrifuged tubes were re-suspended in heparinized saline solution (25 IU heparin·ml-1) and returned into the animal’s arterial circulation. All hormone assays were performed within 2 months of plasma collection.

Hormone analyses
Measurement of plasma estradiol and progesterone concentrations in baboon plasma was determined by RIA. Both assays have been previously described in detail (23, 31, 33). Maternal plasma estradiol and progesterone were measured on duplicate 200 µl and 100 µl plasma aliquots, respectively, using kits from Diagnostic Products Corp. (Los Angeles, CA). The lower limit of detection of the assays, defined as 90% B/BO was 25 pg·ml-1 for estrogen and 0.2 ng·ml-1 for progesterone. Intra and interassay coefficients of variation were 3.2 and 8.7% for estradiol and 7.5 and 19.7% for progesterone, respectively.

Data and statistical analyses
The additional treatment of one pregnant baboon in Group I with 0.4 mg·kg-1·h-1 androstenedione was not incorporated into the statistical analysis of the data. For each group of animals, mean maternal plasma estradiol and progesterone concentrations measured at 1 h intervals were plotted for the 12 h sampling regimen during the 3 days of the experimental protocol (see Fig. 2Go). To determine if a forward shift in the nocturnal increase in maternal plasma estradiol had occurred during androstenedione infusion, the mean concentration of estradiol during each night-time hour (0–9 h) was compared with the mean day-time estradiol concentration (-3 to 0 h) during each day of the protocol (see Fig. 2Go). Mean baseline concentrations of progesterone and estradiol were calculated for each day of the experimental protocol (see Fig. 3Go, A and B). In addition, the change from mean day-time baseline in the ratio of estrogen:progesterone in maternal plasma, and in the number of myometrial contractions were plotted for each group of animals for the 12 h sampling regimen (see Fig. 4Go). Differences between treatment groups in any variable measured from day to day of the protocol were assessed for statistical significance using a two-way ANOVA for repeated measurements and the Student Newman Keuls test, Dunnett’s multiple comparison test or the Student’s t test for unpaired data, as appropriate. Significance for all statistical analyses was accepted when P < 0.05.



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  		Figure 2. Maternal plasma estradiol and progesterone profiles from the serial samples taken during the experimental protocol. Values represent the mean ± SEM of the hourly plasma samples taken from the pregnant baboons. Group I baboons (A4A, n = 4) received 10% intralipid iv during Day 1, a low dose of androstenedione iv (0.8 mg·kg-1·h-1) during Day 2, and a high dose of androstenedione iv (1.6 mg·kg-1·h-1) during Day 3. Group II baboons (Controls, n = 4) received 10% intralipid iv during Days 1, 2, and 3 of the experimental protocol.

 


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  		Figure 3. Bars represent the mean ± SEM of four pregnant baboons treated with androstenedione (Group I, black bars) and four pregnant baboons that were infused with 10% intralipid vehicle (Group II, white bars). Baseline plasma concentrations of progesterone (P4, A) and estradiol (E2, B) represent the mean of all samples taken before the onset of darkness in the animal’s environment during each of the days of the experimental protocol. aP < 0.05 represents differences by post hoc analysis, indicating a significant main effect of time; bP < 0.05 represents differences by post hoc analysis indicating a significant main effect of treatment (two-way repeated measures ANOVA with Student’s-Newman Keuls or Dunnett’s tests).

 


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  		Figure 4. Hourly change from mean baseline (-3 to 0 h) in the estrogen:progesterone ratio (E:P) and in the number of myometrial contractions (mean ± SEM) during low- and high-dose androstendione treatment (•) or during intralipid infusion ({circ}). aP < 0.05 represents differences by post hoc analysis indicating a significant main effect of time; bP < 0.05 represents differences by post hoc analysis indicating a significant main effect of treatment (two-way repeated measures ANOVA with Student’s t test for unpaired data).

 

   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Day-time concentrations of estradiol and progesterone were similar in Group I (androstenedione-treated: estradiol 2187.2 ± 868.2 pg·ml-1; progesterone 15.7 ± 1.8 ng·ml-1) and Group II (intralipid vehicle-infused: estradiol 2116.9 ± 789.7 pg·ml-1; progesterone 20.1 ± 3.6 ng·ml-1) animals on Day 1 of the experimental protocol.

During Day 1 of the experimental protocol, while on infusion of intralipid, an increase in nocturnal (0–9 h) maternal plasma estradiol and progesterone concentrations relative to day-time concentrations occurred in both groups of pregnant baboons studied (P < 0.05, Figs. 1Go and 2Go). Although the nocturnal increases in the concentrations of both steroids appeared greater in Group I (androstenedione-treated) than in Group II (intralipid vehicle-infused controls) baboons during intralipid infusion, this apparent difference was not significant.



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  		Figure 1. Maternal plasma estradiol profiles from the serial samples taken during the 4-day experimental protocol in baboon no. 1 from Group l. This baboon received 10% intralipid iv during Day 1, 0.4 mg·kg-1·h-1 androstenedione iv for 24 h, 0.8 mg·kg-1·h-1 androstenedione iv for 24 h, and 1.6 mg·kg-1·h-1 androstenedione iv for 24 h. Note the dose-dependent increase in baseline plasma estradiol, in the forward shift in the estradiol surge in maternal plasma after lights off (0), and in the number of nocturnal myometrial contractions (numbers in brackets). Myometrial counts after the 0.8 mg·kg-1·h-1 androstenedione infusion day were not available (na) since EMG activity showed electrical error on this day.

 
Neither intralipid vehicle infusion nor androstenedione treatment of the pregnant baboon affected baseline plasma concentrations of progesterone or the nocturnal increases in maternal plasma progesterone during Days 2 and 3 of the infusion protocol (Figs. 2Go and 3AGo). In contrast, while intralipid vehicle infusion did not affect baseline maternal plasma estradiol or the nocturnal surge in maternal plasma estradiol, androstenedione had a dose-dependent effect in elevating baseline plasma concentrations of estradiol to concentrations similar to those measured at term in this species, and in promoting a forward shift in the nocturnal surge of maternal plasma estradiol relative to that of progesterone (Figs. 1Go, 2Go, and 3BGo). Accordingly, in Group I animals, while the mean maternal plasma estradiol concentration measured at 6 h and 7 h after lights off (0) was significantly elevated from baseline during Day 1, the mean maternal plasma estradiol concentration was significantly elevated from baseline at 5 h, in addition to 6 h and 7 h after lights off during Day 2 (Fig. 2Go). Elevations in maternal plasma estradiol in the night-time hours during Day 3 were not significantly different from baseline, since by this day, baseline plasma estradiol concentrations had become significantly elevated in Group I animals (Figs. 2Go and 3BGo). In contrast, the profiles of maternal plasma progesterone in Group I animals, and of maternal plasma estradiol and progesterone in Group II animals, during Days 2 and 3 of the experimental protocol were not different from Day 1 (Fig. 2Go).

The change from mean baseline in the estrogen: progesterone concentration ratio in maternal plasma was similar during intralipid infusion in Group I animals during Day 1, and in Group II animals during Days 1, 2, and 3 of the experimental protocol. Consequently, these data were pooled and compared with the change from mean baseline in the estrogen:progesterone concentration ratio in Group I animals during low dose (Day 2) and high-dose (Day 3) androstenedione treatment (Fig. 4Go). Low dose androstenedione treatment elevated the estrogen:progesterone ratio soon after the onset of darkness in the animal’s environment and reversed the ratio by 9 h of darkness (Fig. 4Go). While the increase in the estrogen:progesterone ratio after the onset of darkness did not reach significance, a greater reversal in the ratio occurred by 9 h of darkness during high dose androstenedione treatment (Fig. 4Go).

The mean number of myometrial contractions counted during the night-time period on Day 1 (baseline) of the experimental protocol was not different for baboons in Group I (11 ± 6, mean ± SEM, androstenedione-treated) and in Group II (26 ± 14, intralipid vehicle-infused controls). While the number of myometrial contractions counted during night-time fell below, or remained the same as, baseline in Group II (intralipid vehicle-infused controls) baboons during Days 2 (12 ± 4) and 3 (20 ± 12) of the experimental protocol, androstenedione treatment in Group I baboons resulted in an increase in the number of nocturnal myometrial contractions above baseline over the same experimental periods (Day 2 = 18 ± 11, Day 3 = 34 ± 15, P < 0.05). When the change from mean baseline in the number of myometrial contractions was compared between intralipid infusion and androstenedione treatment, low dose androstenedione treatment elevated the number of myometrial contractions 1 h after the onset of darkness, and high dose androstenedione treatment elevated the number of contractions 1–3 h after the onset of darkness (Fig. 4Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The mechanisms mediating the forward shift in the nocturnal surge in maternal plasma estradiol during spontaneous term labor in the baboon are unknown. However, there is good evidence to suggest that the predominant precursor for increased placental estrogen production in late gestation in the pregnant primate is likely to be fetal adrenal androgen and that the nocturnal surge in maternal plasma estrogen may represent a change in the drive to the fetal adrenal. For example, it is known that fetal adrenal secretion of the estrogen precursor dehydroepiandrosterone sulfate also increases at night-time and with advancing gestation (26, 33, 34), that there is an increase in aromatase enzyme activity in the primate placenta with gestation (35, 36), that the primate fetal adrenal is under trophic control by factors such as ACTH, PRL, placental CRH, and vasopressin (34, 37, 38, 39, 40), and that maternal cortisol may inhibit the activity of the fetal pituitary-adrenal axis because the 24 h rhythm in maternal cortisol in primates is antiphase to the nocturnal increase in fetal plasma androgen (33, 36, 39) and treatment of pregnant women and pregnant nonhuman primates with glucocorticoids crosses the placenta and lowers placental estrogen biosynthesis by inhibiting fetal pituitary function (37, 38, 39). The forward shift in the maternal plasma estradiol surge relative to that of progesterone at term in the primate may thus result from a number of factors, at least, including increased activation of the fetal adrenal by PRL, ACTH, placental CRH, and vasopressin (34, 37, 38, 39, 40) and/or desensitization of the fetal HPA to the negative feedback effects of maternal cortisol (41, 42), and/or increased aromatase enzyme activity (35, 36).

We have previously shown that sustained administration of androstenedione to pregnant rhesus monkeys at 0.8 of gestation leads to persistent elevations in maternal plasma estradiol and oxytocin concentrations of similar magnitude than those measured at term, recurrent switching in myometrial activity patterns from contractures to contractions, progressive cervical dilatation and effacement, fetal membrane rupture, and live delivery of the monkey fetus (23, 27, 28, 29). We have now extended these studies to demonstrate that androstenedione administration to the pregnant baboon at 0.7–0.8 of gestation also reproduces the increase in estrogenic drive and in nocturnal myometrial contraction activity that normally occur 10 to 12 days before delivery as demonstrated by Wilson and colleagues (5). The data presented here show that the effects of androstenedione on the estrogen profile in maternal baboon plasma result both from an increase in baseline estradiol concentrations measured during the day time, before the lights going off in the animal’s environment, as well as a forward shift in the rising phase of the estrogen surge relative to that of progesterone. These findings not only strengthen the contention that androgens provide the major precursor for placental estrogen biosynthesis in the primate but also that iv infusion of androstenedione can reproduce normal, physiologic changes that occur spontaneously at term in at least two different nonhuman primate species. It should be cautioned that the model used in the present study involved increased presentation of androgen to the baboon placenta by maternal infusion of androstenedione. Clearly, there are different pathways and patterns of estrogen secretion from the primate placenta and maternal androstenedione infusion may not necessarily reflect accurately fetal adrenal C19 steroid secretion.

The promotion of a premature forward shift in the estradiol surge relative to progesterone in maternal plasma during continuous treatment with androstenedione may occur via all the routes described above including increased activation of the fetal HPA axis and/or decreased maternal cortisol feedback on the fetal HPA, in addition to the direct effects of androstenedione on placental estrogen biosynthesis where simply more precursor leads to more product. In another study, we have reported that androstenedione treatment of the pregnant monkey at 0.8 of gestation led to an increase in placental CRH messenger RNA (mRNA) and peptide concentrations, to values similar to those measured during spontaneous term labor (43). Thus, it could be argued that androstenedione-induced increases in placental estradiol may occur by premature activation of the fetal pituitary-adrenal axis, resulting from increased placental CRH, in addition to providing greater precursor to the placenta. However, another study reported that treatment of pregnant monkeys with androstenedione elevated fetal umbilical vein plasma CRH, but it did not increase fetal umbilical vein ACTH, DHEAS, and cortisol concentrations (34). A separate study reported that treatment of pregnant monkeys with androstenedione at 0.8 of gestation did not affect maternal plasma cortisol concentrations (44). These findings do not support the hypotheses that androstenedione-induced increases in maternal plasma estradiol occur due to increased activation of the fetal HPA axis, either resulting from increased stimulation by trophic factors and/or decreased inhibition by maternal cortisol, but rather, emphasize that maternal plasma estradiol increases following exogenous androstenedione administration are due to precursor- induced increases in placental estrogen biosynthesis, by-passing the fetal HPA axis. How continuous provision of androgen precursor leads to a forward shift in the daily fluctuations of maternal plasma estradiol is unknown. The conversion of C19 steroid sulfurylated precursors to estrogens in the placenta involves the action of four enzymatic systems: sulfatase, 3ß-HSD, aromatase, and 17 ß-hydroxysteroid oxidoreductase (36). It is conceivable that androstenedione may alter the diurnal activity of any of these rate-limiting enzymes by factors such as cAMP and phorbol esters (36).

It is of interest that the relationship between the fluctuations in maternal plasma estradiol and progesterone concentrations throughout the 24 h day varies between pregnant women, pregnant baboons, and pregnant rhesus monkeys (5, 20, 21, 33). While the 24 h rhythms of both circulating steroids are in phase in the baboon during late gestation before the forward shift in the estradiol surge (5), maternal nocturnal plasma concentrations of progesterone are high, and of estradiol low, in the pregnant monkey (33) and the pregnant woman (20, 21). Germain and colleagues (20) reported that the high progesterone:estrogen ratio measured in maternal plasma at night in the last trimester of pregnancy disappeared 9 days before delivery in the pregnant woman. Unfortunately, the authors did not present the data in that manuscript to be able to discriminate whether this attenuation in the progesterone:estradiol ratio 9 days before delivery in the woman is due to levels of progesterone becoming depressed at night or increasing nocturnal concentrations of estradiol, or both. However, the ‘disappearance’ of the high progesterone:estradiol ratio 9 days before birth is in agreement with a possible shift in the profile of both steroids in human maternal plasma.

Wilson et al. (5) reported that the high maternal plasma estradiol:progesterone ratio measured in the pregnant baboon 10 to 12 days before birth coincided with an increase in uterine activity at that time. Results presented here show that androstenedione-induced increases in the maternal plasma estrogen:progesterone ratio are also associated with increased myometrial activity. The lack of a significant increase from baseline in the estrogen:progesterone ratio in maternal plasma following the onset of darkness after high-dose androstenedione treatment may be a result of the greatly elevated baseline concentrations of maternal plasma estrogen by this time, which may approach maximal estrogen biosynthesis from continuous androgen provision. However, the greater reversal in the estrogen:progesterone ratio by 9 h of darkness after high-dose androstenedione treatment may represent dissociation between the falling phases of the estrogen and progesterone profiles, further supporting a forward shift in the estrogen surge relative to that of progesterone. It is difficult to justify if the increase in the estradiol:progesterone ratio in maternal plasma either following androstenedione (as in the present study) or that which occurs at term (5), should be correlated with the myometrial activity occurring during that night, or during the following night, or during the following 2 nights and so on, as the detailed timeline for the translation of the increased estrogenic drive and the expression of increased uterine activity is unknown. Such argument may explain the greater myometrial activity following high-dose androstenedione treatment, despite a greater change from baseline in the estrogen:progesterone ratio in maternal plasma during low-dose androstenedione treatment.

Current evidence strongly indicates that maternal oxytocin secreted in response to increased estrogen output from the placenta largely contributes to the mechanism mediating the spontaneous switch in myometrial activity from contractures to contractions in the primate at term. First, increased estrogens will increase maternal oxytocin synthesis by the hypothalamus in the monkey (10) and by the intrauterine tissues in the human (11). Second, a temporal association exists between the nocturnal transition to contraction-type myometrial activity and the nocturnal increase in maternal plasma oxytocin concentrations in the pregnant rhesus monkey (45) and the pregnant woman (46). Third, a number of studies, recently reviewed in part by Higby and colleagues (47), have reported that oxytocin antagonists will abolish in vitro and in vivo myometrial contractions in several pregnant species. Although maternal plasma oxytocin concentrations were not measured in the present study, as available plasma was exhausted, it is likely that maternal oxytocin secreted in response to increased estrogen output from the placenta also contributes to the mechanisms mediating the induced switch in myometrial activity to contractions by androstenedione because a close temporal association also exists between androstenedione-induced increases in myometrial activity and maternal plasma estrogen and oxytocin concentrations (28), and maternal treatment with the oxytocin antagonist Atosiban prevented androstenedione-induced myometrial contractions in the pregnant monkey (48).

The possibility of the existence of additional mechanisms via which the depressive effects of progesterone on parturitional events may be withdrawn during late gestation in the primate cannot be excluded. Such changes may take place in a local, paracrine fashion without the need for changes in systemic levels of progesterone in maternal plasma. For example, steroid receptors, including the estrogen and progesterone receptors, form associations with heat shock proteins. It has been reported that heat shock proteins may inhibit progesterone receptor function (49). Thus, progesterone and estrogen, interacting with their receptors and heat shock proteins, may regulate myometrial contractility throughout pregnancy and during parturition. Accordingly, we have previously reported that there is an increase in heat shock protein 90 mRNA in myometrium taken from rhesus monkeys undergoing spontaneous term labor compared with myometrium taken from monkeys not in labor (50).

In conclusion, the data presented in this study support the hypothesis that androstenedione treatment of pregnant baboons at 0.7–0.8 of gestation promotes a premature forward shift in the nocturnal estradiol surge relative to that of progesterone, and in nocturnal myometrial contraction activity, in a similar manner to that which occurs spontaneously 10–12 days before term labor in the baboon.


   Acknowledgments
 
We would like to thank Karen Moore for help with this manuscript.


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

Received March 10, 2000.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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