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Laboratory of Neuroendocrinology, Department of Neurobiology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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estradiol, gonadotropin-releasing hormone, luteinizing hormone, ovulatory cycle
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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30 wk). Although the majority of ovary-intact animals were able to generate P cycles of normal appearance in the first breeding season, no such cycle was produced at the time of the second season [6]. Clarke et al. [7] also noted that ovulatory failure increased with age in their in utero testosterone-treated ewes. This decline in ovarian function could be explained if the androgenized ewes progressively lost the ability to generate an LH surge in response to elevated E concentrations. Thus, the second aim of the present study was to determine if the positive-feedback mechanism no longer operates in the in utero testosterone-treated animals as they age. The approach taken was to administer exogenous E to the in utero-androgenized and control ewes at a range of ages, from 19 wk before the expected age of puberty to just before the time of the second breeding season, to determine if and when this steroid is able to trigger an LH surge.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Studies were performed on 9 control and 11 androgenized Polled Dorset ewes that were born between 25 March and 14 April 2000 (mean date of birth, 30 March ± 1.4 days). The androgenized animals had been exposed to testosterone during fetal life by injecting their mothers twice weekly with testosterone propionate (100 mg/injection in 1 ml of vegetable oil; Sigma-Aldrich, Poole, U.K.) as described previously [4, 6]. The testosterone propionate treatment was begun 30 days after conception and continued until Day 90 of the 147-day pregnancy. This period of treatment encompasses the "critical period" for the sexual differentiation of neuroendocrine function in the developing lamb [2, 9, 10]. Control animals received no in utero steroid treatment. Lambs remained with their mothers until weaned at 10 wk of age. All animals were maintained outdoors at the Babraham Institute (52°12'N) except for the 2-day experimental periods, when they were housed indoors, in small groups with free access to food and water. Procedures were approved by the local Welfare and Ethics committee and performed under Home Office Project Licenses PPL 80/ 1037 and PPL 80/1506.
Reproductive Cycles and Ovarian Biopsy
Blood samples were collected twice per week from all ewes beginning at approximately 15 wk of age (mid-July 2000), and sampling continued until the end of October 2001, when the animals were approximately 19 mo of age. Plasma was stored at –20°C until the time of assay. Changes in P concentrations in these samples were used to indicate reproductive cycles. A cycle was determined to have occurred if P concentrations were raised to greater than 1 ng/ml for two or three but no more than four samples (therefore, spanning at least 10 but no more than 14 days; normal length of the ovine luteal phase) before decreasing to values less than 1 ng/ml for at least one sample (normal length of the follicular phase) before the onset of the following cycle [6]. Puberty was defined as the time when P concentrations were first elevated to greater than 1 ng/ml in the first reproductive cycle [11]. In late October 2000, when the ewes were approximately 30 wk of age, biopsy specimens of the ovarian cortex (approximately the size and shape of a grain of cooked rice) were collected from seven control and eight androgenized animals via midventral laparotomy under general anesthesia (sodium pentobarbitone, 20 mg/kg i.v.; Sagatal; RMB Animal Health Ltd.) to determine the number and proportion of different-sized follicles in the ovarian cortex [12].
Experimental Design
Development of the E-stimulated LH surge before puberty
Whether the ewes could respond to follicular-phase concentrations of E with an LH surge was determined on five occasions, at 4-wk intervals, before the predicted time of puberty (age, 30 wk) [6]. Specifically, these experiments were carried out on five occasions in 2000, 13 June, 12 July, 9 August, 6 September, and 4 October, when the ewes were approximately 11, 15, 19, 23 and 27 wk of age, respectively (Fig. 1). On each occasion, E was administered as four 3-cm Silastic capsules containing crystalline estradiol benzoate (Sigma-Aldrich) placed under the skin of the front axilla to raise E concentrations to late-follicular-phase levels (7–12 pg/ml) [13]. All implants were soaked in water for 24 h before implantation to prevent an acute peak in E concentration [14]. Blood samples were collected by jugular venipuncture at 3-h intervals from 5 to 26 h after E administration and then at 4-h intervals until 34 h, and the plasma samples were stored at –20°C before being assayed for LH. Immediately following the final sample, the E implants were removed from the animals.
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Can exogenous E stimulate an LH surge during anestrus? On May 2, 2001, during the first anestrous period, the LH response to exogenous E was assessed by the same method as described above. On this occasion, plasma was harvested from jugular blood samples that were collected at 3-h intervals between 8 and 32 h after E administration.
We were unable to elicit LH surges in the androgenized ewes in response to exogenous E on any occasion before puberty or during the first anestrous period. Because of this unexpected finding, three additional experiments were designed to look for an explanation of this result. First, we tested the possibility that the circulating concentrations of E generated by the four 3-cm implants were insufficient to stimulate the LH surge system of the in utero-androgenized ewe. Second, we determined if LH surges in the androgenized ewes were delayed such that they began after the 34-h sampling period. Third, we looked at the possiblity that an E-stimulated surge of GnRH was not translated into an LH surge in the androgenized ewe because of the inability of the pituitary gland of the androgenized animal to respond to GnRH.
Is the concentration of E insufficient to generate an LH surge in androgenized ewes? During the first anestrous period (Fig. 1), when the ewes were approximately 13 mo of age, the surge mode of LH secretion was tested again (May 30, 2001), with an increased concentration of E. The control ewes and five of the androgenized ewes received four 3-cm E implants as described previously. A further group of androgenized ewes (n = 5) received eight 3-cm implants (four implants placed beneath the skin of both front axillae, which will double the circulating concentration of estradiol) [15]. Samples of jugular blood were collected at 3-h intervals between 8 and 32 h after E administration.
Is the LH surge delayed in the androgenized ewe On the fifth occasion on which the response to E positive feedback was tested (age, 27 wk; 4 October) the blood-sampling period was extended by 20 h (4-h intervals) such that the last sample was collected at 54 h after E implantation.
Is the pituitary gland of the androgenized ewe insensitive to GnRH stimulation? Before the start of the second breeding season (June 7, 2001) (Fig. 1), at an approximate age of 14 mo, "pituitary responsiveness" was tested in all 20 ewes. Each animal was given a 250-ng i.v. bolus of synthetic GnRH (LHRH; jugular vein; Sigma-Aldrich) in 0.9% saline. This dosage and route of administration has been used previously in sheep to produce a burst of LH release similar to that of a normal endogenous pulse (1–8 ng/ml) [16]. Blood samples were collected at 15-min intervals via jugular venipuncture starting 15 min before treatment and continuing for 90 min afterward.
Determination of Circulating LH and P Concentrations
The LH assays were carried out in the week immediately following each of the five trials before puberty to assess the responsiveness of the animals to the E treatment before the next trial. In addition, all these samples were included in a single assay to determine if the amplitude of the response to the E challenge changed as the animals matured. The LH was measured in duplicate aliquots of plasma (100 µl) using a double-antibody RIA method initially described by Niswender et al. [17] and modified at Babraham as described by Robinson et al. [18]. The primary antibody was NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) anti-ovine LH-1 (A.F. Parlow, National Institutes of Health, Bethesda, MD), and the standard was NIH-LH-S12. Inter- and intra-assay coefficients of variation were 8.2% and 12.3%, respectively. The mean assay sensitivity was 0.78 ng/ml. An LH surge was determined to have occurred if hormone values exceeded twice the average baseline concentration for a minimum of 6 h [19]. The time of onset of the LH surges, the peak LH concentrations, and time of the LH peak were compared among the groups using a one-way ANOVA.
Plasma P concentrations were determined using a commercially available RIA kit (Coat-A-Count; Diagnostic Products Corp.) that has been previously validated for use in sheep [20]. The mean detection limit of the assays was 0.1 ng/ml, and the inter- and intraassay coefficients of variation were 7.2% and 3.7%, respectively.
Statistical Analyses
All analyses were performed using the InStat for MacIntosh statistical computer package. In all analyses, one-way ANOVA with the Tukey post-hoc test was used except when stated otherwise. Significance was set at P < 0.05. All group data are presented as the mean ± SEM.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The ewes that were pretreated with androgens exhibited the marked virilization of the external genitalia that has been reported previously [1, 4]. Specifically, the testosterone-treated ewes had a penis and a scrotum that did not, however, contain any testicular tissue. Internally, the animals have ovaries and a blind-ending uterus but no vagina.
Reproductive Cycles in the First Breeding Season
The percentage of ewes undergoing reproductive cycles during the course of the study is shown in Figure 1, and representative patterns of P secretion in control and androgenized animals in the first season are shown in Figure 2. During the first breeding season, all the control ewes (9/ 9) exhibited several regular cycles in P secretion. The mean date of onset of these cycles was 2 November ± 5.2 days, when the ewes were 30.6 ± 0.5 wk of age. In contrast, only 7 of the 11 androgenized animals had any cycles in P secretion during this period. This number is significantly lower than that in controls (P < 0.05, Fisher exact test). The mean date of onset of cycles in these seven animals was 19 November ± 10.3 days, when the animals were 31.1 ± 1.0 wk of age, neither of which is significantly different from controls (Fig. 3). Despite the fact that the time of puberty onset was similar in the cyclic control and androgenized ewes, fewer P cycles were observed in the androgenized animals than in the controls. Specifically, the seven androgenized animals had an average of 2.6 ± 0.2 cycles (n = 7), compared with 4.8 ± 0.5 cycles in the controls (n = 9; P < 0.01). This resulted in a shorter breeding season in the former group (androgenized, 48.7 ± 7.8 days; control, 74.1 ± 7.9 days; P < 0.05) (Fig. 3). It also was noted that cycles were less regular in the androgenized animals (see animal 1441, Fig. 2), with longer periods of low P concentrations (<1 ng/ml) being observed between peak values compared with controls.
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Ovarian Biopsy
The time of collection of the ovarian biopsy specimens, relative to the time of onset of reproductive cycles, is shown in Figure 1. The biopsy procedure did not appear to disrupt the P cycles in the four animals that had begun reproductive cycles. Figure 2 shows the time of biopsy relative to changes in P secretion in two cyclic control animals (1384 and 1395).
Reproductive Cycles in the Second Breeding Season
After a period of anestrus, all control animals began a second breeding season, with a mean date of onset of 23 July ± 8.0 days (Fig. 1). All continued to have regular, repeated cycles in P until the last blood sample was collected at the end of October 2001. In contrast, significantly fewer (7/11; P < 0.05, Fisher exact test) of the androgenized animals had any cycles in P, and only one was still cycling at the end of October (P < 0.0001 vs. controls, Fisher exact test) (Fig. 1). Of these seven animals, five also had exhibited cycles in the first breeding season. However, two had cycles only in the second breeding season, and two that had cycles in the first breeding season had none in the second. The mean time of onset of the second breeding season in these seven animals was 5 August ± 11.7 days, which was not significantly different from controls (P = 0.41) (Fig. 3). A substantial difference, however, was observed in the patterns of P secretion among these seven testosterone-treated animals (Fig. 4). Specifically, only three androgenized ewes had consecutive P cycles, similar to those observed in controls that were of a normal duration (16 days). The remaining four animals had cycles that were either highly irregular or separated by abnormally long periods of low P concentrations. For example, ewe 1421 (Fig. 4) had three cycles in the second season, with the interval between the peak P of the first and second cycle and of the second and third cycle being 23 and 28 days, respectively, as opposed to 16 or 17 days, as in controls. As in the first breeding season, the number of cycles in the second season (up to the end of October) was less in androgenized animals (androgenized, 3.43 ± 0.48; controls, 5.66 ± 0.64; P < 0.01) (Fig. 3). Because most of the androgenized animals had stopped cycling by the end of October, the length of the season to this date also was significantly reduced (androgenized, 62.4 ± 8.6 days; control, 92.8 ± 8.4 days; P < 0.05) (Fig. 3).
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Development of the E-Stimulated LH Surge Before Puberty
The positive-feedback responses of the control and androgenized ewes to follicular-phase concentrations of estradiol between 11 and 27 wk of age are shown in Figure 5. At 11 wk of age, all nine control ewes responded to the elevated concentrations of E with a robust surge of LH. Beginning 10.0 ± 0.9 h after E implantation, circulating gonadotropin concentrations increased from a presurge concentration of 0.3 ± 0.1 to a maximum of 23.7 ± 1.6 ng/ ml at 17.0 ± 0.7 h. Circulating LH concentrations had returned to baseline concentrations by the end of the sampling period at 34 h. This pattern of response was repeated at all four subsequent ages in the control ewes and was similar to that observed during the anestrous season (Fig. 5). Thus, LH surges were triggered by E during 45 of the 45 trials before puberty (5 occasions x 9 control animals). The amplitude of the LH surge responses to E increased significantly (P < 0.05) between 11 and 15 wk of age, after which time the response reached a plateau (Table 1). No change was observed with age in the time of onset of the surge or the time of the peak LH value following E administration. In marked contrast to controls, none of the androgenized ewes had surges in LH secretion at 11 or 15 wk of age, while only 1 of the 11 ewes exhibited a surge at each of the other time points (3/55 trials; 5 occasions x 11 androgenized animals; Weeks 19 [ewe 1392], 23 [ewe 1392], and 27 [ewe 1415]). The timing of the LH surges in these animals, however, was different from that in controls (Fig. 6). Specifically, the responses of ewe 1392 at 19 and 23 wk of age were delayed compared with those in controls (19 wk, Hour 26; 23 wk, Hour 23), whereas the LH peak was advanced markedly in ewe 1415 at 27 wk of age (Hour 11). Peak LH concentrations in ewe 1392 were similar to those in controls; however, those of ewe 1415 were markedly reduced in amplitude.
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In five of the control ewes, some of the E treatments before puberty triggered LH surges that were followed by a rise in P secretion. However, in these animals, not all induced LH surges resulted in a P elevation. In one case (see ewe 1399, Fig. 7), these P profiles appeared to be very similar in amplitude and duration to those of normal reproductive cycles, whereas those in the other four ewes were much reduced in amplitude and duration (see, e.g., ewe 1389, Fig. 7). In addition, one androgenized ewe showed small rises in circulating P concentrations that were not sufficient in amplitude to fulfil our criteria for a "cycle" (see ewe 1421, Fig. 7).
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Can Exogenous E Stimulate an LH Surge During Anestrus?
The response of the anestrous ewes to exogenous E is shown in Figure 5. At the end of this sampling period, one control and one androgenized ewe had lost one or more implants, and these animals therefore were removed from the analysis. Of the remainder, seven of eight controls had a robust LH surge, compared with 1 of 10 androgenized animals. The unresponsive control ewe had elevated P concentrations of 2.7 ng/ml in comparison to the seven responding animals (0.1 ± 0.0 ng/ml). The single androgenized animal (ewe 1415) had an advanced surge (11 h vs. 14.4 ± 0.4 h after E) that was low in amplitude (13.1 vs. 43.3 ± 2.9 ng/ml).
Following the administration of E in anestrus, six of the androgenized ewes exhibited a prolonged period of elevated P secretion (Fig. 8). In these ewes, concentrations of P were maintained continuously at greater than 1 ng/ml for an average of 87.7 ± 19.8 days (range, 38–146 days). This phenomenon was not observed in any of the control ewes. At the time of the second breeding season in the controls, two of these androgenized ewes began to experience apparently normal P cycles (see ewes 1392 and 1406, Fig. 8).
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Is the E Concentration Insufficient to Generate an LH Surge in Androgenized Animals?
The response to E and its time course are shown in Figure 9. One androgenized ewe was excluded from the present study, because she was found to still be carrying four implants from the previous trial. All but one of the control ewes produced an LH surge in response to exogenous E. The nonresponding animal (ewe 1395) was found to have elevated concentrations of P (2.2 ng/ml) at the time of the trial, whereas this concentration averaged 0.7 ± 0.1 ng/ml in the remaining ewes. None of the androgenized animals exhibited an LH surge in response to either concentration of E. Two of these ewes (one in each E group) had P concentrations of greater than 1 ng/ml, whereas the others had mean concentrations of 0.8 ± 0.1 ng/ml.
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Is the LH Surge Delayed in the Androgenized Ewe?
During the E trial that was carried out at 27 wk of age, samples were collected for 54 h after administration of E to determine whether the surges in androgenized ewes might be delayed substantially compared with control animals. As stated earlier, one androgenized animal had an early surge during this period. However, no LH surges were observed in the other androgenized ewes during the extended period of sampling (data not shown).
Is the Pituitary Gland of the Androgenized Ewe Insensitive to GnRH Stimulation?
The mean LH profiles observed in control and androgenized ewes following an i.v. injection of 250 ng of GnRH are shown in Figure 10a. The increase in LH in the control animals following GnRH averaged 8.2 ± 2.3 ng/ml compared with 5.9 ± 1.8 in the androgenized animals (P = 0.41). Although the peak LH concentrations observed 15 min after GnRH injection were similar in both groups, the decline in LH was slower in the androgenized animals, as evidenced by significantly higher LH concentrations in these animals at all subsequent time points (P < 0.05). This may be explained by the fact that 7 of 11 androgenized animals had a second rise in LH concentrations during this period, compared with only one of nine controls (Fig. 10, b and c). This probably reflects the fact that LH pulse frequency tends to be more rapid in the androgenized ewe [4, 21].
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In the present study, androgens were given for the whole of the critical period. However, when testosterone is given only for the latter half of this important window (Days 60– 90 of gestation), both OVX+E [2] and ovary-intact [5] Suffolk ewes exhibit LH surges that are delayed by several hours following exogenous E compared with control ewes. Therefore, on 4 October, when the animals were approximately 27 wk of age, we extended the sampling period by some 40 h after the time of onset of surges in the control animals in case we might have missed delayed LH surges in the androgenized ewes. Because we did not note any signs of increased LH secretion during the extended sampling period, we are confident that E did not stimulate a late LH surge in the androgenized ewes of the present study.
Two further explanations for the lack of an E-induced LH surge in the androgenized ewes are that these animals are less responsive to E and/or GnRH. The responses to supraphysiological concentrations of E and exogenous GnRH allow us to conclude that neither the sensitivity to E nor the sensitivity to GnRH can provide an explanation for the lack of an LH surge in the E-treated, androgenized ewes of the present study. Thus, our results suggest that the ovary-intact, androgenized ewe is unable to generate a preovulatory-like surge of LH in response to the acute increase in circulating concentrations of E produced by implantation of Silastic capsules of E.
Clearly, the reason why the androgenized ewe produces patterns of P that look like normal luteal phases, in the apparent absence of a preovulatory LH surge, is puzzling. One possibility is that androgenized ewes have normal surges in LH but that these need to be triggered by a specific pattern of increased E secretion that is not mimicked by the implantation of the Silastic capsules of E that we used to test for positive feedback. The endogenous release of E during a natural follicular phase normally would increase over a 2- to 3-day period [24], and this gradual rise, as opposed to the abrupt increase generated by the implants [25], may be essential for stimulation of the GnRH surge in testosterone-treated ewes. Although this hypothesis has not been tested directly in the androgenized ewe, results from a study in ovariectomized ewes showed that an abrupt increase in estradiol concentrations was as effective as a gradual increase in generating an LH surge [15].
A second possibility is that luteinization of follicles in the androgenized ewe does not require a "surge" release of LH. Clearly, in the normal ewe, the amount of GnRH released into the portal vessels is greatly in excess of that needed to stimulate the LH surge [26]. The amount of LH needed to trigger a key reproductive event like ovulation also likely is excessive. Studies in the ewe have shown that pulsed infusion of either GnRH [16, 27] or LH [28] can lead to ovulation with normal luteal function. Thus, despite the fact that preovulatory LH secretion normally takes the form of a surge, a prolonged period of high-frequency LH pulses might be entirely sufficient to trigger ovulation in a follicle that is highly responsive to LH, because it has been adequately primed with FSH and E [29]. In this regard, it is interesting to note that LH pulse frequency in the ovariectomized, androgenized ewe is significantly greater than that in control eyes in both the absence and presence of steroids [4, 5]. A similar elevation in LH concentrations also has been noted in the ovary-intact, androgenized ewe [30]. Perhaps a period of rapid LH pulses is adequate to promote follicular luteinization in these androgenized ewes. Unfortunately, the sampling frequency used in the present study would have been inadequate to detect increases in LH pulse frequency.
Another possibility that should be considered is that the E challenges may have stimulated the release of some surge-inhibiting/attenuating factor that blocked the LH surges in the androgenized animals. Evidence for such a factor is sparse, but the limited data suggest that such a factor is an FSH-stimulated ovarian product, possibly originating from the granulosa cells but unlikely to be a steroid hormone, or inhibin A or B [31]. Clearly, ovarian function in androgenized animals is abnormal, with altered expression patterns of key mRNAs within the tissue [32].
Although we have focused this discussion on the secretion of P from corpora lutea that have been formed after an ovulation, the P may come from luteinized follicles or cysts that have not been stimulated to ovulate by an LH surge and still contain unreleased oocytes. Such bodies might release P in the irregular pattern that we observed. To our knowledge, ovarian tissue containing corpora lutea-like bodies from androgenized ewes have not been examined systematically for the presence of an oocyte either by us or by anyone working in a similar field, and research needs to be done to address this possibility.
Despite the fact that a percentage of the androgenized ewes exhibited cyclic changes in circulating P concentrations during the first and second breeding seasons, these were not always regular, and prolonged periods of low P concentrations were a common occurrence. This also was an observation made by Clarke et al. [7], who noted that the follicular phase of ewes androgenized from Day 50 to Day 100 of gestation was significantly prolonged. Severe abnormalities in the morphology and function of the ovaries of these in utero-androgenized ewes have been documented [13, 32], and these abnormalities in folliculogenesis may contribute to the irregular patterns of P secretion that we observed in the present study.
During the second breeding period, the majority of androgenized ewes had one or more elevations in P secretion that fulfilled our criteria for a cycle. These data are in marked contrast to earlier published data from our laboratory, in which no androgenized ewes had a single P cycle at the time of the second breeding season [6]. Why there should be such different responses is unclear, because the method for androgenizing the ewes, the breed of sheep, and the site of the present study were the same in both years. However, two potentially important differences between these two studies might be responsible. First, exogenous E was not administered to the animals in the earlier study to attempt to stimulate an LH surge. Perhaps, therefore, repeated stimulation of the reproductive axis with exogenous E was able to overcome the infertile condition programmed by in utero exposure to testosterone. Second, either the surgical process or the removal of an ovarian biopsy at the beginning of the first breeding season is able to prolong the period of fertility in some of the androgenized animals. In the earlier study, when all ewes became infertile in the second breeding season, no biopsies were performed. The possibility that biopsy may affect fertility may be worthy of further investigation, because we observed that six of eight biopsied animals, but only one of three nonbiopsied animals, had some P cycles in the second breeding season. It is interesting, in this regard, that the removal of ovarian tissue from certain women with subfertility or infertility caused by polycystic ovarian syndrome is one method of improving their fertility [33].
During the anestrous season, we noted that E implantation resulted in protracted periods of P secretion in the majority of the androgenized but in none of the control animals. Such a situation would occur if the mechanisms that regulate luteolysis had become disrupted, as might be the case if uterine prostaglandin production or its delivery to the ovary was, in some way, abnormal. These patterns of elevated P concentration are reminiscent of those observed in pseudopregnancy in the goat [34, 35]. This pseudopregnant state may be induced in this species following the stimulation of ovulation during the anestrous season. A characteristic feature of pseudopregnancy is an accumulation of fluid in the uterus (hydrometra) [36] that may be related to the reduced luteolytic stimulus. A similar enlargement of the uterus that is distended with a straw-colored fluid is a common feature of the uterus of the androgenized ewe. Because recent data have shown that the androgenized ewe can respond to exogenous prostaglandin F2
(21; unpublished results), the question of whether endogenous prostaglandins gain access to the ovary needs to be resolved.
In summary, predictions made from the in utero-androgenized, OVX+E ewe model (that her ovary-intact counterpart would be unable to generate cycles in ovarian function) were not supported. This led to the hypothesis that the androgenized, ovary-intact ewe would be able to respond to exogenous follicular-phase concentrations of E with an LH surge. However, although we could demonstrate such E positive feedback in control animals, we could not produce any evidence that the androgenized ewe can exhibit steroid positive feedback. Therefore, the mechanism by which cycles in ovarian function persist in the apparent absence of the E-stimulated LH surge is an enigma and will be the focus of future studies.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Jane E. Robinson, Division of Cell Sciences, Faculty of Veterinary Medicine, University of Glasgow, Bearsden Road, Glasgow G61 1QH, Scotland. j.robinson{at}vet.gla.ac.uk
Received: 26 August 2004.
First decision: 22 September 2004.
Accepted: 18 October 2004.
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  A. Veiga-Lopez, O. I. Astapova, E. F. Aizenberg, J. S. Lee, and V. Padmanabhan Developmental Programming: Contribution of Prenatal Androgen and Estrogen to Estradiol Feedback Systems and Periovulatory Hormonal Dynamics in Sheep Biol Reprod, April 1, 2009; 80(4): 718 - 725. [Abstract] [Full Text] [PDF]
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A. Veiga-Lopez, W. Ye, D.J. Phillips, C. Herkimer, P.G. Knight, and V. Padmanabhan Developmental Programming: Deficits in Reproductive Hormone Dynamics and Ovulatory Outcomes in Prenatal, Testosterone-Treated Sheep Biol Reprod, April 1, 2008; 78(4): 636 - 647. [Abstract] [Full Text] [PDF]
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T. Steckler, M. Manikkam, E. K. Inskeep, and V. Padmanabhan Developmental Programming: Follicular Persistence in Prenatal Testosterone-Treated Sheep Is Not Programmed by Androgenic Actions of Testosterone Endocrinology, July 1, 2007; 148(7): 3532 - 3540. [Abstract] [Full Text] [PDF]
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M. Manikkam, T. L. Steckler, K. B. Welch, E. K. Inskeep, and V. Padmanabhan Fetal Programming: Prenatal Testosterone Treatment Leads to Follicular Persistence/Luteal Defects; Partial Restoration of Ovarian Function by Cyclic Progesterone Treatment Endocrinology, April 1, 2006; 147(4): 1997 - 2007. [Abstract] [Full Text] [PDF]
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