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Departments of Pediatrics,3
Obstetrics and Gynecology,4
Ecology and Evolutionary Biology,5
Molecular and Integrative Physiology,6
the Reproductive Sciences Program,7 University of Michigan, Ann Arbor, Michigan 48109
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2.5 yr of age. Reproductive cycles of control and prenatally T-treated females were synchronized with PGF2
, and peripheral blood samples were collected every 2 h for 120 h to characterize cyclic changes in E2, LH, and FSH and then daily for 14 days to monitor changes in luteal progesterone. To assess LH pulse patterns, blood samples were also collected frequently (each 5 min for 6 h) during the follicular and luteal phases of the cycle. The results revealed that, in prenatally T-treated females, 1) the preovulatory increase in E2 was normal; 2) the latencies between the preovulatory increase in E2 and the peaks of the primary LH and FSH surges were longer, but the magnitudes similar; 3) follicular-phase LH pulse frequency was increased; 4) the interval between the primary and secondary FSH surges was reduced but there was a tendency for an increase in duration of the secondary FSH surge; but 5) luteal progesterone patterns were in general unaltered. Thus, exposure of the female to excess T before birth produces perturbances and maltiming in periovulatory gonadotropin secretory dynamics, but these do not produce apparent defects in cycle regularity or luteal function. To reveal the pathologies that lead to the eventual subfertility arising from excess T exposure during midgestation, studies at older ages must be conducted to assess if there is progressive disruption of neuroendocrine and ovarian function.
aging, follicle-stimulating hormone, gonadotropins, infertility, luteinizing hormone, neuroendocrine, neuroendocrinology, ovulatory cycle, polycystic ovarian syndrome, seasonal reproduction
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Earlier studies with ovariectomized E2-clamped model have determined that prenatal T treatment disrupts the positive-feedback actions of E2 [13–16]. Similarly, our more recent studies in ovary-intact animals found that administration of follicular phase levels of E2 delayed the onset of LH surges in females treated from Day 60 to Day 90 (T60– 90) or 30–90 (T30–90) of gestation (term is 147 days) [5]. Differences were noted that, related to the duration of prenatal T exposure, the disruption of the positive-feedback mechanism being more severe when treatment was longer [5]. In the T30–90 females, the latency to the surge from the inception of E2 signal was longer and the amplitude of the LH surge was attenuated. To avoid the confounding effects of the reproductive cycle, these studies had been conducted during the anestrous season, when sheep are naturally not cycling. Observations of the patterns of reproductive cycles in the two groups of prenatally T-treated (T60–90) females were revealing. Females with the most defective surge system (T30–90 females) became anovulatory prematurely and had no progestogenic cycles by the time of the second breeding season [9]. By contrast, the majority of the T-60–90 females had repetitive progestogenic cycles both during the first and second breeding seasons [9]. The presence of continued progestogenic cycles in these T60–90 animals, despite their documented defective surge mechanism during the nonbreeding season, raises the possibility that the prenatally programmed disruptions in positive-feedback actions of E2 may not be manifest during the breeding season when the ovary is active. Alternatively, such defects in E2-positive feedback may persist during the breeding season to impact the development of primary/secondary FSH surges and compromise luteal function to an extent that was not detected by biweekly progesterone (P4) measurements. Thus, in the present study, we hypothesized that prenatal T will 1) not affect the timing and amplitude of the preovulatory E2 increase after luteolysis but will increase the latency from preovulatory E2 rise to the LH/FSH surge, 2) disrupt the dynamics of pulsatile LH secretion, 3) disrupt the time course and magnitude of the primary/secondary FSH surges, and 4) produce luteal defects as a consequence of the inappropriate programming of the positive feedback. These hypotheses were tested by studying T60–90 females between 2 and 3 yr of age (third breeding season) as these females continued to cycle, unlike the T30–90 females, in which reproductive cycles had already ceased.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All procedures were approved by the Institutional Animal Care and Use Committee of the University of Michigan and were consistent with the National Institutes of Health Guide for Use and Care of Animals. This study was conducted during the third breeding season with 2.5-yr-old control (C) and T60–90 Suffolk females that were maintained at the University of Michigan Sheep Research Facility (Ann Arbor, MI; 42°18'N). Details of prenatal T treatment have been described previously [5]. Briefly, pregnant sheep from Days 60 through 90 of gestation were injected (i.m.) twice weekly with 100 mg T propionate (Sigma, St. Louis, MO) suspended in cottonseed oil. The lambs were born in March/April 1998. Sheep used in this study were part of a larger group for which the timing of puberty and positive-feedback responses to E2 during the first anestrous season have been described [5]. Those studies found that the T60–90 females achieved reproductive competence at the same time as C females, had repetitive cycles during the first and second breeding seasons, and manifested compromised E2 feedback, when tested during the first anestrous season. After the completion of that larger study [5], a subset of C females (n = 5) and T60–90 females (n = 8) were maintained for this study in the third breeding season. Much of the year, they grazed freely on pasture grasses and were supplemented with daily rations of alfalfa pellets. During the winter months, they were fed hay and alfalfa pellets in covered areas. The females were provided with water and minerals ad libitum and were treated regularly with antihelmintics to minimize parasitic infections.
To monitor reproductive status, blood samples were obtained twice weekly from all sheep for measurement of P4 until initiation of this study in the middle of the third breeding season. At that time, PGF2 was administered twice, 11 days apart, to induce luteolysis and synchronize cycles by a method described in detail previously [17]. During the next reproductive cycle, patterns of gonadotropin, E2, and P4 were characterized. To assess broad follicular-phase changes in gonadotropin and E2 patterns, infrequent samples were obtained at 2-h intervals for 120 h starting at the second PGF2 injection. To monitor temporal changes in LH secretion, blood samples were collected frequently (5-min intervals for 6 h) twice during the follicular phase (10–16 and 28–34 h postadministration of PGF2) and once during the midluteal phase. To assess changes in luteal P4 secretion, daily samples were collected for 14 days after cessation of 2-hourly samples.
Radioimmunoassays
Plasma LH and FSH levels were measured using validated assays in all 2-h samples [18, 19]. The results are reported in terms of NIH-LH-S12 and NIDDK-ovine FSH-1. The sensitivity of the LH assay was 0.90 ± 0.11 ng/ml (mean ± SEM, n = 13 assays). The intraassay coefficient of variation (CV) based on three quality-control pools, measuring 0.8, 12.8, and 21.4 ng/ml, averaged 17.4 ± 2.6%, 5.5 ± 0.6%, and 5.1 ± 1.0%, respectively. The sensitivity of the FSH assay averaged 0.72 ng/ml (n = 2 assays). The CV, based on two quality-control pools, measuring 4.5 and 28.8 ng/ml, were 13.0% and 2.1%, respectively. The median variance ratio for the LH and FSH assays averaged 0.023 and 0.031, respectively. After characterization of the LH surge, to determine the timing of preovulatory E2 peak, circulating E2 concentrations were measured in samples beginning 36 h before onset of LH surge and ending at the end of LH surge. Circulating E2 concentrations were measured in duplicate in 200 µl of serum after extraction with 2 ml diethyl ether by a commercially available RIA assay kit (Estradiol MAIA; BioChem ImmunoSystems, New York, NY). This assay has been validated for use in sheep [20]. E2 assay sensitivity averaged 0.3 pg/ml (n = 4 assays). Intraassay coefficient of variation at 80% and 20% displacement points averaged 10.6% ± 1.1% and 5.3% ± 0.6%, respectively. Interassay coefficient of variation based on three quality-control pools averaging 1.6, 6.3, and 35.3 pg/ml were 10.4%, 10.6%, and 8.1%, respectively. Recovery averaged 91.5% ± 2.5%. Plasma concentrations of P4 were measured by a commercial RIA kit (Coat-A-Count P4; Diagnostic Products Corporation, Los Angeles, CA) in daily samples. This assay has been validated for use in sheep [21]. Sensitivity of P4 assay averaged 17.2 pg/ml (n = 2 assays). The intraassay CV, based on four quality-control pools averaging 0.8, 1.6, 2.2, and 14.4 ng/ml, averaged 11.8%, 8.8%, 6.1%, and 7.95%, respectively. The interassay coefficient of variation for the same quality control pools were 2.1%, 5.2%, 3.9%, and 2.4%, respectively.
Statistical Analysis
All values below assay sensitivity were assigned the detection limit of the assay. LH and primary FSH-surge baselines were determined by averaging the lowest point during the upslope of the primary surge and the preceding 12 points. To determine the onset of primary LH/FSH surges, the following previously published criteria were applied: 1) increase of circulating LH/FSH baseline by two times assay sensitivity lasting at least 8 h and 2) peak concentration of LH/FSH exceeding at least twice the baseline concentrations of circulating LH/FSH during pre-E2 periods [22]. The end of the surge was defined as the time when peripheral LH/FSH levels fell below the established criteria for surge onset. For secondary FSH surge, all the above criteria, excluding criteria 2, were applied. To compare the follicular LH pulse frequencies between C and T60–90 females, the series of frequent samples closest to the onset of surge was used. This was the second follicular-phase sampling (28–34 h postadministration of PGF2) in all except one C female (#939), for which the second sampling period occurred during the LH surge. For determining duration of luteal P4 increase, onset was defined as the time when daily P4 levels reached above 0.5 ng/ml. End was defined as the time when daily P4 concentrations fell below 0.5 ng/ml.
Serial LH data from a frequent sampling period were subjected to pulse analysis using the Cluster algorithm [23]. The Cluster algorithm identifies pulses using a criteria that defines a pulse such that the peak of the pulse differs significantly from both the preceding and following nadirs according to two-sample t-tests. For analysis with Cluster, the minimum number of data points in a peak and nadir were set at 2 and 2, respectively. The t-statistic values used to identify a significant increase from preceding nadir and a decrease to following nadir were both 2.6. The amplitude was calculated as the difference between the pulse peak value and preceding nadir value.
Time relationships, such as interval between PGF2 and primary LH/ FSH surge (onset and time to peak), PGF2 and secondary FSH surge (onset and time to peak), interval between time of peak E2 and LH/FSH surges, interval between primary and secondary FSH surges, gonadotropin surge characteristics (peak height, total, and duration), and pulse characteristics (mean, frequency, and amplitude) were analyzed using Student t-tests. Data were tested for homogeneity of variance and, where necessary, appropriate transformation applied (square root transformation for frequency and log transformation for all other variables). For E2, comparisons were made between peak levels of E2 achieved and the time taken for E2 levels to fall and reach steady state. All statistical analyses were carried out with the aid of the Statview for Macintosh statistical computer package, excluding ewe #911 (due to the abnormal patterns of P4 during second and third breeding season and the abnormal luteal response during the synchronized cycle). Significance was defined as P < 0.05. All results are presented as the mean ± SEM. Comparative statistics including ewe #911 are discussed, when outcomes were different.
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RESULTS |
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Figure 1 shows the progestogenic cycles of the C and T60–90 females during the second breeding season (September 2000 through March 2001) and part of the third breeding season (beginning of the breeding season to the time of PGF2 injection; September 2001 to November 2001). This provides an historic perspective on the reproductive status of these animals. All females exhibited repetitive progestogenic cycles both during the second and third breeding seasons (Fig. 1), except for one T60–90 female (#911), which had persistently elevated levels of P4 during the entire second breeding season and the beginning of the third breeding season. Excluding #911 from analyses, during the second breeding season, there were no differences between C and T60–90 females in the number of progestogenic cycles (C: 9.00 ± 0.6; T60–90: 10.00 ± 4.5 cycles) or peak P4 levels achieved (C: 5.38 ± 0.54 ng/ml; T60–90: 5.56 ± 0.56 ng/ml). The breeding season ended at the same time in C and T60–90 females. The third breeding season also began at the same time in C and T6–90 animals. Sheep #911, which had persistently elevated P4, did normalize before PGF2 injection and synchronized in response to the PGF2 injection, although subsequent luteal P4 response was abnormal (see Fig. 8).
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Changes in Circulating E2 Levels
Circulating patterns of E2 from all C and T60–90 females that synchronized in response to the two PGF2 injections are shown in Figures 2 and 3 (open circles). Data from one C female (#936) and one T60–90 (#912) that did not synchronize to the PGF2 injection are not shown. There was no statistical difference in the timing of preovulatory peak in E2 between C and T60–90 females (Fig. 4, top middle panel). There was wide variability in the timing of peak E2 increase in C females. Peak levels of the preovulatory increase in E2 (Fig. 4, top left panel) and subsequent fall to baseline (C: 9.0 ± 1.3 h; T60–90, 11.0 ± 1.0 h) also did not differ. In the absence of E2 measurements before PGF2 injection, the start of preovulatory E2 increase, the total amount of E2 released, and duration of preovulatory E2 increase were not determined.
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Characteristics of Gonadotropin Surges
Control and T60–90 animals differed in the dynamics of their preovulatory increases in LH (Figs. 2 and 4). There were no differences in timing of LH surge in relation to timing of PGF2 injection between treatment groups (Fig. 4, top right), possibly due to the high variability in the timing of onset of E2 peak in C females. In contrast, peak of the LH surge relative to the preovulatory E2 peak was delayed in T60–90 compared with C females (P < 0.05) (Fig. 2, histogram). The start of the LH surge relative to preovulatory E2 peak was coincident and did not differ between C and T60–90 females. The time taken for LH surge to peak after its onset was longer in T60–90 compared with C females (C: 3.50 ± 0.96 h; T60–90: 7.0 ± 1.13 h, P < 0.05). There were no effects of prenatal T on LH surge peak height (Fig. 4). Total amount of LH secreted during the LH surge was greater in the T60–90 animals (P < 0.05) and there was a tendency for an increase in duration.
The relationship between the preovulatory E2 increase and the primary FSH surge was similar to that for E2 and LH (Figs. 3 and 5). The primary FSH surge occurred simultaneously with the LH surge. Like in LH, the timing of primary FSH surge peak was delayed in relation to E2 peak (P < 0.05; Fig. 3), but the peak height, duration, and amount of FSH secreted in the primary FSH surge were unaffected by prenatal T exposure (Fig. 5, top right three panels). In contrast, the peak, duration, and the total FSH secreted in the secondary FSH surge tended to be higher in the T60–90 females (n = 6) compared with C females (n = 3; secondary FSH-surge characteristics could not be estimated in the one animal that had a late surge; Fig. 5, bottom right three panels). When ewe #911 was included, all the three variables achieved significance. Total FSH secreted during the secondary FSH surge was greater than what was secreted during the primary FSH surge in both groups. The ratio of FSH secreted between secondary and primary surges tended to be higher in the T60–90 females compared with C females (C: 172 ± 25; T60–90: 282 ± 50%; C vs. T60–90; P = 0.08). Timing of the onset of secondary FSH surge relative to the preovulatory E2 peak was similar in C and T60–90 females (Fig. 5, bottom left). The interval between primary gonadotropin surge, and the secondary FSH surge was, however, shorter in the T60–90 females compared with the C females (P < 0.05; Fig. 5, bottom, second panel from left).
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LH Pulse Characteristics
Timing of follicular-phase LH pulse frequency determination preceded the onset of LH surge by 35.0 ± 11.2 h in controls (24 ± 3.1 h without #934, which had a late surge) and 24.0 ± 2.4 h in T60–90 females and were not statistically different. Mean LH concentrations (P < 0.05) and LH pulse frequency (P < 0.05) were higher in T60–90 females compared with C females (Fig. 6). Inclusion of #911 reduced the statistical significance to a tendency. There were no differences in the LH-pulse amplitude between groups. Mean LH and LH-pulse amplitude determinations during the luteal phase (Day 9 post-PGF2) were unaffected by prenatal T treatment (Fig. 7). Mean LH frequency tended to be higher in the T60–90 females compared with C females (P = 0.08).
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Luteal Progesterone
All the C and T60–90 females had luteal P4 increases (Fig. 8). Except #911, which had persistently elevated levels, P4 levels in all other animals reached baseline during the 14-day daily P4 determinations (Fig. 8). There were no differences in timing of luteal P4 increase between C and T60–90 females (Fig. 8). Duration of luteal P4 secretion tended to be longer in the T60–90 females.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Consequences of Delayed LH Surge
Considering that the E2-induced preovulatory LH surge is the most critical signal for normal ovulation [24, 25], we expected that the delayed LH surge in the T60–90 animals would disrupt luteal function. The lack of differences in biweekly P4 patterns during the second and third years and the close parallel of daily P4 patterns in the C and T60–90 animals disproved this prediction. These results indicate that the dominant follicle, once differentiated and mature, is capable of luteinizing and sustaining normal corpus luteum function even when the ovulatory trigger is delayed. These findings support remarkable resilience of the mature preovulatory follicle. The opposite condition, namely, an early LH surge that occurs before complete maturation of the preovulatory follicle, compromises luteal function, leading to inadequate and insufficient luteal phases [26].
Although the delayed LH surge had very little impact on luteal P4 secretion, it may compromise oocyte quality. Studies using prenatally T-treated Rhesus monkeys found that prenatal T treatment compromises oocyte quality [27]. Earlier studies have found that a delay in LH surge of 11.4 h in heifers [28] and 24–48 h in mice [29, 30] reduces fertilization and implantation rates and increases embryonic death and chromosome abnormalities [28–30]. In superovulation models of cattle, a delayed surge of 24–48 h was found to be associated with compromised follicular development [31], decreased ovulation rate, and lowered rate of embryo production [32]. It is unclear if a short delay of 3 h, such as that seen in this study, would have physiological impact on oocyte quality. Considering that the D60–90 animals exhibit progressive loss of cyclicity [7, 9], it is possible that the surge delay may exacerbate with advancing age.
Mechanisms That Underlie the Delayed LH Surge
The timing of LH surge, in general, is influenced by the amplitude and duration of the increase in P4 during the preceding luteal phase [33]. However, differences in dynamics of luteal P4 do not appear to be the cause of the delayed LH surge in the T60–90 animals. The peak height and duration of luteal P4 increase of the T60–90 animals were similar to that of the C females. Mechanistically, the delayed LH surge stems from a delay in the time to reach peak levels of LH in response to preovulatory E2 increase. Preovulatory increase in E2 is the peripheral signal triggering the onset of the neuroendocrine-positive-feedback mechanism. Previous studies have demonstrated that, during the follicular phase, E2 alters the pattern of pulsatile LH/GnRH release at various levels, which includes an increase in GnRH/LH pulse frequency, a decrease in GnRH/ LH pulse amplitude, and an increase in interpulse secretion of GnRH, culminating in the induction of the GnRH/LH surge [24, 34]. The delayed onset of LH surge may therefore be a function of failure of E2 to induce the required progression of changes in pulsatile GnRH secretion. While we did not characterize the progressive changes in LH/ GnRH pulse frequency throughout the follicular phase, we did find an increase in follicular phase LH/GnRH pulse frequency in the T60–90 animals compared with C females 24 h before the LH surge. Such an increase in LH pulse frequency in the T60–90 animals may be the outcome of compromised E2 negative feedback. Our studies in the T30–90 ovary-intact model (unpublished results) and the early onset of neuroendocrine puberty in the ovariectomized, E2-clamped model [16] provide support for this contention. Interestingly, the luteal phase LH pulse frequency also tended to be higher in the T60–90 animals. These findings are in line with findings of the reduced sensitivity to P4 negative feedback in the ovariectomized, E2-clamped model [35]. At the ovarian level, an increased LH drive is likely to increase follicular androgen production and compromise follicular milieu. While circulating levels of T were not measured in this study, our earlier studies using the T30–90 model provided evidence for functional hyperandrogenism, which was reflected as multifollicular ovary [7, 8], reduced activin/inhibin ßB mRNA expression [7], enhanced follicular recruitment (unpublished results), follicular persistence (unpublished), and increased follicular apoptosis (unpublished results).
FSH Surge Dynamics
As could be predicted, the delay in LH surge was reflected as a delay in the primary FSH surge. The temporal relationship between the LH and primary FSH surges were similar. This is consistent with the generation of the LH and FSH surges being similarly controlled. Studies using central depressants, GnRH antagonists, or neutralizing antibodies to GnRH in various species, including humans, have conclusively shown that the primary surges of the two gonadotropins are under the singular control of GnRH [36– 39].
The decrease in the interval between the primary gonadotropin and secondary FSH surges, but not between preovulatory E2 peak and secondary FSH surge, provide support for the premise that the secondary FSH surge is triggered in part by the fall in E2. In sheep, increasing E2 secretion from the preovulatory follicle provides the negative-feedback signal for the late follicular phase decline in FSH, which precedes the initiation of the primary gonadotropin surges [40, 41]. While not affecting the timing or magnitude of primary FSH surges, prenatal T treatment from Days 60–90 of gestation tended to increase the peak height, total FSH, and duration of the secondary FSH surge (this achieved statistical significance when ewe #911 was included in the analysis).
The tendency for an exaggerated secondary FSH surge in the T60–90 animals, in the face of a similar magnitude of preovulatory E2 increase, provides preliminary support for the involvement of other key negative regulators of FSH production/release. Inhibin and follistatin are established negative regulators and activin a positive regulator of FSH release [41]. In sheep, inhibin-A levels remain constant during the follicular phase and decline following the primary gonadotropin surges coincident with the peak of the secondary FSH surge [42]. Removal from a higher threshold of inhibin-A during the follicular phase of T60–90 animals would also be consistent with the observed increase in follicular-phase levels of LH because of the likelihood of an associated increase in androgen. Androgens are facilitators of inhibin production [43, 44]. Considering that major portion of FSH is secreted constitutively and is coupled with production [40, 45, 46], any FSH increase during the secondary FSH surge is likely to be the result of increased FSH production.
Functionally, any increase in FSH drive is likely to rescue follicles from undergoing atresia leading to multifollicular development. Multifollicular development has been found in animals that have been exposed prenatally to T from Day 30 to Day 90 of gestation [7, 8]. Similar information is not available from the ovaries of T60–90 animals during the third year. Preliminary studies characterizing follicular distribution during the second year in T60–90 animals have found no difference in follicular distribution between the C and T60–90 females, although the ovaries were considerably larger (unpublished results), suggestive of initiation of ovarian perturbations.
In summary, we found disruption of the periovulatory sequence of events involving a delay in the timing of the LH and primary FSH surge relative to preovulatory increase in E2, increased follicular LH pulse frequency supportive of developing hypergonadotropism, and a tendency for an increase in duration of secondary FSH surge. These findings are consistent with the deleterious effects of excess prenatal T on the reproductive axis. Our findings provide insight into the levels at which exposure to prenatal T excess during midgestation disrupts the reproductive axis, all of which may contribute toward cessation of reproductive activity found later in life. Furthermore, continued presence of repetitive progestogenic cycles in the face of disruptions at several levels in the preovulatory sequence attest to remarkable resiliency of the reproductive axis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Correspondence: Vasantha Padmanabhan, Reproductive Sciences Program, 300 N. Ingalls Bldg., Rm. 1109 SW, Ann Arbor, MI 48109-0404. FAX: 734 936 8620; vasantha{at}umich.edu
Received: 19 April 2004.
First decision: 17 May 2004.
Accepted: 27 August 2004.
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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ßA dimer) during the oestrous cycle, after manipulation of ovarian activity and during pregnancy in ewes. J Reprod Fertil 1998 113:159-166This article has been cited by other articles:
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  L. M. Gorton, M. M. Mahoney, J. E. Magorien, T. M. Lee, and R. I. Wood Estrogen Receptor Immunoreactivity in Late-Gestation Fetal Lambs Biol Reprod, June 1, 2009; 80(6): 1152 - 1159. [Abstract] [Full Text] [PDF]
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E. K. Roberts, J. N. Flak, W. Ye, V. Padmanabhan, and T. M. Lee Juvenile Rank Can Predict Male-Typical Adult Mating Behavior in Female Sheep Treated Prenatally with Testosterone Biol Reprod, April 1, 2009; 80(4): 737 - 742. [Abstract] [Full Text] [PDF]
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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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