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Laboratory of Neuroendocrinology, The Babraham Institute, Babraham Hall, Cambridge CB2 4AT, United Kingdom
Address all correspondence and requests for reprints to: Jane Robinson, Laboratory of Neuroendocrinology, The Babraham Institute, Cambridge CB2 4AT, United Kingdom. E-mail: jane.robinson{at}bbsrc.ac.uk
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Introduction |
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Materials and Methods |
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Three separate experiments were performed to determine whether the inhibitory action of P on episodic LH release is dependent on the sex or prenatal steroid treatment of the animals. Two of the studies were carried out during the anestrous season, the first in the presence and the second in the absence of a low physiological concentration of circulating E. The final study was performed during the breeding season in the absence of exogenous E.
Exp 1 (Anestrus, in presence of exogenous E)
One week before the study began, the 3-cm E implants, which had
been present since early post natal life, were replaced with a 1-cm
implant, to maintain follicular phase concentrations of steroid (1–2
pg/ml, 9). The characteristics of episodic LH release were determined
in mid-April, in the male, female and T60 animals. Samples of jugular
blood were obtained by venipuncture at 15-min intervals for 6 h on
two occasions, once immediately before the implantation of P (1 CIDR
sc), and on a second occasion 7 days after implantation.
Exp 2 (Anestrus, no E)
The 1 cm E implants were removed 14 days before this study began
in mid-May. To determine the effects of P (1 CIDR) on LH secretion
blood samples were collected from all four groups (male, female, T60,
T30) at 10-min intervals for 6 h, immediately before P
administration and at the same frequency 2 days later. Progesterone
concentrations were measured in two samples from each animal, chosen at
random from these frequent samples. Specifically, one sample was
selected from those collected before P implantation and one from those
collected after 2 days of exogenous P.
Exp 3 (Breeding Season, no E)
Following Exp 2, all of the animals were given a sc 3-cm
estradiol implant and concentrations of LH monitored in samples
collected twice per week for 6 weeks, from 16 July until 27 August.
This was to confirm that all the animals had the reduced responsiveness
to E negative feedback and the elevated gonadotropin concentrations
that are characteristic of the breeding season (10). The implant was
removed 1 week before the study began in mid-September. The design was
identical to study 2, with samples collected on two occasions at 10-min
intervals for 6 h, once before and a second time 2 days after P (1
CIDR) administration. One of the T30 animals died between Exp 2 and 3
of unknown causes, leaving four animals in this group.
Determination of LH and P concentrations
Circulating concentrations of LH were determined in the plasma
by RIA (11). The antiserum was NIDDK rabbit antisheep LH and the
standard was NIDDK-S11. Intra and interassay CVs were 13.7 and 10.4%,
respectively, and the limit of detection of the assays was 0.2 ng/ml.
Concentrations of circulating P resulting from implantation of two
CIDRs were measured in a single assay using a commercially
available RIA kit (Coat-A-Count, Diagnostic Products
Corp., Los Angeles, CA). Concentrations of P in animals during Exp 2
were measured in a separate assay. The sensitivity of the assay was
0.12 ng/ml.
P administration
Concentrations of P were raised to early luteal phase levels
using a single CIDR device (InerAG, NZ) placed just beneath the skin on
the inner surface of the upper front leg. As CIDRs are normally
Y-shaped for intravaginal delivery, they were modified for sc
implantation. Specifically, the CIDR was streamlined by tying the two
arms together with surgical silk and the tail was completely removed.
To ensure that these implants produced the same circulating
concentrations of P in the male, female, and T60 and T30 animals, a
preliminary study was performed. Four animals from each group were
given two CIDRs and blood samples collected immediately before, and on
days 2, 4, 6, 8, and 10 after P administration (see Fig. 1
). Within 2 days, concentrations of P
were raised to about 4.5 ng/ml, and these levels did not change
significantly over the next 8 days. There was no significant difference
in P concentrations among the four groups on any day of sampling.
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Results |
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Exp 1 (Anestrus, in presence of exogenous E)
The effect of exogenous P on the characteristics of episodic LH
secretion in two representative female, male and T60 female sheep are
shown in Fig. 2. P had an action on
episodic LH release only in the control females (see Fig. 3). Specifically, P depressed mean LH
pulse frequency in this group (P < 0.05; No P;
4.6 ± 0.8: +P; 3.4 ± 0.8 pulses/6 h), whereas there was no
effect in the control males or in the T60 ewes. P did not alter either
mean LH release or the mean amplitude of the LH pulses in any group. It
is, however, clear that mean LH concentrations before P administration
(No P; middle panel, Fig. 3) were significantly lower
(P < 0.05; ANOVA with Tukey’s posthoc test) in the
females than the males and T60 females. Although there was also a trend
for both pulse frequency and amplitude to be lower, this did not
achieve statistical significance. The depressed LH concentrations in
the females may be because they are more responsive to the inhibitory
actions of the 1 cm E implant than are the males and androgenized
females. Therefore, study 2 was performed 14 days after the removal of
the E-implant.
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depicts individual profiles of LH release, from a representative animal
from each of the four groups. As in Exp 1, exogenous P suppressed LH
release only in the females (see Fig. 5).
Specifically, during this study, mean LH concentrations
(P < 0.05; No P; 7.0 ± 1.4: +P; 3.8 ± 1.2
ng/ml), as well as LH pulse frequency (P < 0.01; No P;
6.3 ± 0.7: +P; 3.9 ± 0.9 pulses/6 h) and amplitude
(P < 0.01; No P; 9.3 ± 3.3: +P; 6.9 ± 3.1
ng/ml) were inhibited by P. It is of interest to note that the
frequency of LH pulses (Fig. 5, top panel) in the period
before the implantation of P (but not mean LH or pulse amplitude) was
significantly lower in the control females (6.3 ± 0.7 pulses/6 h)
than the control males (P < 0.01: 10.1 ± 0.4
pulses/6 h) and the T60 females (P < 0.05: 9.6 ±
0.4 pulses/6 h), although not the T30 females (7.0 ± 1.5 pulses/6
h). This was despite the fact that all the animals had been free of
exogenous E and P for 14 days.
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As was the situation in anestrus, P suppressed episodic LH release only
in the control females (individual pulse profiles, Fig. 6; mean data, Fig. 7). There was no effect on any aspect of
LH release in male sheep or the animals androgenized for 60 or 30 days
in utero. Specifically, in the females P reduced LH pulse
frequency (P < 0.01) from 9.6 ± 0.8 to 6.3
± 1.0 pulses/6 h although it did not alter mean LH release or pulse
amplitude.
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Discussion |
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Although we did not measure GnRH release directly in these experiments, but have inferred the pattern of secretion from the LH pulse profile, other studies have shown that both the long-term and acute actions of P are mediated in the brain (14, 15) by a mechanism that acts via the classical nuclear P receptor (15). A central action is supported in the current studies where P consistently inhibited the frequency of the LH pulses in all three experiments but not the amplitude or mean LH concentrations. We, conclude, therefore, that one of the actions of early in utero exposure to androgens is to alter the response of the GnRH neuron to inhibition by P. An earlier study in the androgenized ewe drew a similar conclusion relative to the mechanisms that regulate the GnRH surge (16). In this study, pregnant ewes were given a testosterone implant from day 50 until the end of pregnancy with the consequence that the female offspring were less androgenized than our T60 ewes and still able to respond to E with a LH surge. When these ovariectomized ewes were given E and P simultaneously, the LH surge was blocked in the control ewes but in only one of six androgenized animals. Taken together with our studies, these data show that fetal androgen exposure alters the response of both the tonic and surge modes of GnRH secretion to inhibition by luteal phase concentrations of P. Our data further suggest that a period of androgen exposure of as short as 30 days, from day 60–90 of pregnancy is sufficient to disrupt progesterone negative feedback on tonic GnRH release.
The first of the three studies was performed in anestrus in the presence of a low luteal phase concentration of E, as it has been shown that the inhibitory actions of P on tonic LH release are enhanced in the presence of this hormone (17). As was the case in all the studies, P depressed LH pulse frequency only in the females. However, mean LH concentrations were clearly depressed in these ewes even before P administration, when compared with the males and androgenized females. The most likely explanation for this is that the postpubertal male sheep is less responsive to E-negative feedback than the female at this time of year and that in utero exposure to androgens is responsible for this sexually dimorphic response. In support of this speculation, Wood and Foster (18) have reported that mean LH concentrations (determined in bi-weekly samples) show a transient springtime increase in postpubertal male but not female gonadectomized, E-implanted Suffolk sheep. However, in this study the sex differences did not appear to be caused by testosterone during fetal life. It is unclear why the results of our two studies differ in this regard. Perhaps they can be explained by differences in the sheep breed or the experimental methods used. Of importance may be a difference in the degree of masculization of the ewes that were given testosterone from day 30–90 in both studies. Specifically, from the appearance of the external genitalia, it might be concluded that the ewes in our study were more androgenized than those in the earlier study. If this was also true of the reproductive neuroendocrine axis, then this might explain the male-like response of the T60 ewes in our study. In summary, it has been clearly demonstrated that both male and androgenized female sheep are less responsive to E-negative feedback before puberty (1). As we have obtained very similar results before puberty in the males and androgenized females used in these studies (Forsdike and Robinson, unpublished) we would agree with Wood and Foster (18) that the prepubertal sex difference in sensitivity to E-negative feedback continues into adulthood.
Because of the potential complication of these sex differences in the response to E-negative feedback, the second study was performed in anestrus, but after the E implants had been removed for 14 days. On this occasion P depressed all aspects of LH secretion in the control ewes only. However, before P administration LH pulse frequency was lower in the females than in the males or androgenized females. There are three obvious explanations for this finding, the first being that the effects of E-negative feedback had not worn off in the females by the start of the experiment. We feel that this is unlikely as Goodman and colleagues (19) have shown that LH concentrations are maximal within about a week of E removal during anestrus. The second explanation is that there is an in utero determined sex difference in the endogenous activity of the GnRH pulse generator. This conjecture is not supported by data from a study by Wood et al. (4) as they did not find any difference in steroid-independent LH secretion between young post pubertal male and female sheep 3 weeks after the removal of an estradiol implant. Rather, we favor the explanation that steroid-independent GnRH pulse frequency was lower in the females because they were sampled during the anestrous season. It is well known, in the ewe, that LH pulses are less frequent in ovariectomized ewes in anestrus than in the breeding season (19) and that this is under photoperiodic control (20). As the male sheep is generally much less seasonal than the female (21), we conclude that the rams did not exhibit such a marked seasonal suppression of LH pulse frequency. If this is correct, then it follows that in utero androgen exposure alters the mechanism by which photoperiod regulates GnRH release in the adult sheep, as has already been demonstrated in the prepubertal animal (22).
Because of this result, a third study was performed, this time in the breeding season, to confirm that there was no seasonal difference in the response to P negative feedback. Before P administration, LH pulse frequency was 50% greater in the females than during anestrus but not different from the males or either group of androgenized animals. Wood et al. (4) have also reported that LH pulse frequencies are similar in young male, female and androgenized female (30–90 days of gestation) postpubertal Suffolk sheep in the breeding season. These facts support our earlier conclusion that LH pulse frequency was inhibited during anestrus only in the females. As in the studies performed in the nonbreeding season, P inhibited episodic LH release only in the ewes but not the rams or androgenized females. In summary, we are confident that P negative feedback is sexually differentiated in the sheep because of in utero exposure of the fetus to androgens and that this response is not dependent on either the season or E status of the animal.
The mechanisms by which fetal androgens bring about these radical alterations in the steroidal control of the activity of the adult GnRH neuron are unclear. An explanation is unlikely to lie in sex differences in the number of GnRH neurons, their gross morphology or distribution in the preoptic-hypothalamic continuum as these have been shown to be similar in male and female mid-gestation ovine fetuses (23). As steroid influences on GnRH neurons are believed to be indirect (because GnRH neurons do not contain steroid receptors; 24, 25), a more fruitful approach would be to identify prenatally determined sex differences in steroid receptive inputs to GnRH neurons. It is known, both in the rat (26) and the sheep (27), that GnRH neurons in the adult male receive about half the number of synaptic inputs to the cell body as females. In the sheep, this sex difference is under the influence of prenatal androgens (27). Presumably the additional afferent neurons in the female sheep are those involved in the transduction of information about the animal’s steroidal and photoperiodic status, and it will be a challenge for the future to identify the nature of these inputs.
It is important, at this point, to consider these data in a wider context. We and others have clearly demonstrated that the prenatally androgenized female sheep is unable to respond appropriately to either E or P negative feedback on GnRH release. Further, animals androgenized from in utero days 30–90 are unable to generate a preovulatory-like GnRH surge in response to follicular phase concentrations of E. These studies were performed on animals that had been ovariectomized in early neonatal life and the steroid feedback mechanisms explored using exogenous E and P. It is interesting to speculate on the consequences of these abnormal steroid feedback mechanisms for the generation of normal reproductive cycles in the ovary intact androgenized ewe. It might be expected that estrous cycles would be absent or seriously disrupted as a consequence and there are some data to support this conjecture (28). Studies that determine the ability of the ovary-intact androgenized ewe to produce normal estrous cycles are currently underway in our laboratory.
Finally, one consequence of the reduced sensitivity of the GnRH system to E and P negative feedback in the male and androgenized females is that LH secretion is hyperstimulated. We know, from our unpublished data, that hypersecretion of LH began when these animals were less than 10 weeks of age and has continued for 2 yr, into adulthood. In addition, a further period of LH hypersecretion may have occurred prior to birth, as we know that LH secretion is sexually dimorphic in prenatal life (29). It will be important to establish whether prenatal androgens are responsible for this. Further, the consequences of LH hyperstimulation for the functioning of the adult ovary is currently unknown. Relative to this, we were intrigued to note that the ovaries of the T60 androgenized ewes were significantly enlarged and had a cystic appearance when removed at 3 weeks of age (30). The appearance of this tissue was reminiscent of the morphological appearance of ovaries from women with polycystic ovary syndrome (PCOS). Of further interest are recent publications indicating that women and adolescents with this syndrome have enhanced LH pulse frequency (31, 32, 33). Of particular importance relative to the results presented in the current manuscript was the finding that PCOS women exhibit a reduced sensitivity of the GnRH neural network to inhibition by both E and P (34). Although this common clinical fertility disorder may have several distinct etiologies none have yet been identified. Because of the similarities between our ovine data and those from women with PCOS, we and others are currently exploring the possibility that the prenatally androgenized ewe is a good animal model for PCOS (35). In relation to our current findings, it will be of interest to determine whether a proportion of women exhibiting this disorder have had abnormal prenatal/pubertal exposure to steroid hormones.
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Acknowledgments |
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Footnotes |
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Received June 15, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-amino butyric acid and catecholamines in the
preoptic/septal area prior to and during the preovulatory surge of
luteinising hormone in the ewe. J Neuroendocrinol 3:393–400
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