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Department of Poultry Science, University of Arkansas (J.D.K. Y.K.K., M.L.R.), Fayetteville, Arkansas 72701; the Departments of Veterinary Biosciences (N.A., G.I., G.L.J., P.S.C.) and Animal Science (H.N.), University of Illinois, Urbana, Illinois 61801; and the Department of Neurobiology and Physiology, Northwestern University (T.P.-H., F.W.T.), Evanston, Illinois 60208; and the Department of Biological Sciences, Middle Tennessee State University (A.E.J.), Murfreesboro, Tennessee 37132
Address all correspondence and requests for reprints to: Dr. John D. Kirby, Department of Poultry Science, John Tyson Building, Room O114, University of Arkansas, Fayetteville, Arkansas 72701. E-mail: jkirby{at}comp.uark.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The increased testis size and sperm production observed in treated rats are due to large increases in the number of Sertoli, Leydig, and germ cells (6, 7, 8, 9, 10). The trophic factors traditionally associated with the growth and maturation of the testis and its constituent cell types are the gonadotropins, FSH and LH (11). Treated animals are severely hypothyroid during the period of PTU administration (0–25 days postnatally), which results in decreased serum gonadotropin levels (6, 12). However, although TSH, T3, and T4 levels recover quickly in treated rats after the cessation of PTU treatment, reaching normal levels by about day 45, serum gonadotropin levels remain depressed by 40–60% (12). Therefore, unlike any previously described model for increasing testis size and sperm production, neonatal hypothyroidism permanently reduces serum gonadotropin levels both during PTU treatment and throughout the treated animal’s life (12, 13). Despite the chronically depressed serum gonadotropin levels, circulating levels of testosterone are normal in adult PTU-treated rats (2, 12). These results suggest that neonatal goitrogen treatment must produce one or more permanent alterations in the hypothalamo-hypophysial-testicular axis that result in decreased gonadotropin secretion. These changes may be associated with the increased size of the endocrine testis as Leydig and Sertoli cell numbers are increased (7, 8), leading to a decreased requirement for the gonadotropins to maintain normal testis function, an alteration in hypothalamic GnRH synthesis and secretion, or a change in pituitary cellular composition or in the functional capacity of the gonadotropes in PTU-treated males.
To better understand the permanent reduction in serum gonadotropin
levels after transient neonatal hypothyroidism, we conducted a series
of experiments to evaluate pituitary and hypothalamic function in the
adult male PTU-treated rat. First, we evaluated the effect of a single
GnRH injection on circulating LH levels in intact males. Second, we
measured the effects of castration on circulating LH and FSH levels,
hypothalamic GnRH content, and pituitary contents of FSH and LH. Third,
we characterized the distribution of LH- and FSH-immunoreactive cells
in the adenohypophysis of intact as well as castrated, control and
neonatally PTU-treated rats. Finally, we quantified relative changes in
messenger RNA (mRNA) levels of the common 
- and the unique
ß-subunits of LH and FSH in the pituitaries of control and treated
males after castration. Our results suggest that neonatal PTU treatment
leads to a permanent reduction in gonadotrope function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Treatment
For litters designated controls, mothers and litters remained
untreated and received food and water (see above) ad
libitum. Treated litters were made hypothyroid by the addition of
either 0.006% (Exp 1) or 0.1% (Exp 2–4; wt/vol) PTU (Sigma Chemical
Co., St. Louis, MO) to the mother’s water from immediately after birth
until 25 days of age. The palatability of treated water was improved by
adding cherry Kool-Aid and sugar (1%, wt/vol). PTU ingested by the
mother is transferred to the pups through the milk and results in
severe hypothyroidism (12, 14). The 0.006% PTU dose used in Exp 1
produces a similar suppression of thyroid hormone concentrations as the
0.1% PTU dose during the treatment period, and testis size is
equivalent in rats given these two doses at 90 days of age (14). At 25
days of age, pups were weaned and housed three or four to a cage, with
all animals receiving tap water and food ad libitum for the
remainder of the experiment.
Exp 1: pituitary responsiveness to exogenous GnRH
To assess the ability of the pituitaries of control and
PTU-treated rats to produce LH in response to an exogenous GnRH
challenge, 140- to 160-day-old male rats, weighing 300–600 g, were
anesthetized with thiamylal sodium by ip injection (25 mg/kg; Bio-tal,
Boehringer Ingelheim, St. Joseph, MO). The hair in the neck region was
clipped, and an incision was made to expose the right external jugular
vein. Polyethylene (PE-10) cannulas were implanted via the external
jugular vein so that the catheter tip was located at the entrance to
the right atrium. The distal end of the catheter was tunneled sc to the
nape of the neck, exteriorized through a skin incision, and sutured in
place. The end of the catheter was then attached to an adapter and a
23-gauge needle, and used to take intermittent blood samples. The
overall volume of the cannula was 190 µl. The cannula was filled with
heparinized saline (250 IU/ml) and capped to prevent leakage when not
in use. Two animals were implanted at a time (one control and one
PTU-treated), and the procedure was replicated for six pairs of males.
About 18–24 h after cannulation, two samples (500 µl) were drawn at
10-min intervals, and then various doses of GnRH (Sigma) dissolved in
saline (10, 50, and 250 ng/kg) were given iv, and blood samples were
drawn 5, 10, 15, 20, 30, and 40 min after the GnRH injection. Samples
were transferred to sterile tubes and centrifuged, and the plasma was
removed and stored at -20 C until assayed for LH. After removal of
plasma, the rat’s red blood cells were resuspended in sterile
Ringer’s saline and reinfused to the animal. To reduce the number of
animals used, all three GnRH doses were given to some animals, with a
2-day interval between doses; the doses were administered from lowest
to highest in sequence. At the conclusion of the final blood sampling,
the animals were killed, and their testes were removed and weighed.
LH levels in plasma samples were determined by RIA using materials provided by the NIDDK (Rockville, MD). The assay used LH S-10 as the primary antibody, and the standard was LH RP-3. All samples were run in duplicate in a single assay. The intraassay coefficient of variation (CV) was less than 8%.
Exp 2: changes in LH, FSH, and GnRH after castration
At 150 days of age, treated and control rats (24/group) were
anesthetized with methoxyflurane (Pittman Bowe, Mundelein, IL) and bled
by cardiac puncture. Twelve animals in each group were castrated, and
testes and epididymides were removed and weighed. All of the animals
were then bled by cardiac puncture under methoxyflurane anesthesia on
days 1, 3, 7, and 14 postcastration. After clotting at room
temperature, serum from each animal was separated, aliquoted, and
stored at -70 C for determination of hormone concentrations by RIA.
After the final bleeding, animals were decapitated, and hypothalami and
pituitaries were removed, weighed, snap-frozen in liquid nitrogen, then
stored at -20 C for subsequent hormone determinations. Testes of
intact males were also removed and weighed.
Anterior pituitaries were extracted for gonadotropin measurements as previously described (15). Briefly, individual pituitaries were homogenized in ice-cold PBS (pH 7.0) containing 1% Triton X-100 (vol/vol) and 1% egg white albumin (wt/vol). After homogenization, extracts were diluted to 2.5 ml with extraction buffer, vortexed, centrifuged to clarity, and aliquoted. Aliquots were stored at -20 C until assayed.
Hypothalami were extracted for the GnRH assay as previously described (16). Briefly, each dissected hypothalamus, including the preoptic area and median eminence, was placed in a Dounce homogenizer (Kontes Co., Vineland, NJ) and homogenized in 800 µl 0.1 M HCl. The homogenate was then centrifuged at 3500 x g for 30 min at 4 C. The supernatant was extracted with 3 ml 100% ethanol and centrifuged at 3500 x g for 30 min at 4 C. The resulting extract was air-dried in a vacuum centrifuge, and the residue was resuspended in 1.0 ml PBS-gelatin buffer (0.1% gelatin, wt/vol) and assayed for GnRH immunoreactivity.
LH and FSH were measured by standard RIA procedures, using materials provided by the NIDDK. The LH assay used antirat LH S-10 as the primary antibody, and the standard was LH RP-2. All serum and pituitary extract samples were assayed in duplicate in a single assay, with an intraassay CV of 9%. For the FSH assay the primary antibody was antirat FSH S-11, and the standard was FSH RP-2. As with the LH assay, all samples were assayed in duplicate in a single assay (intraassay CV, 8%).
Hypothalamic GnRH contents were measured using the assay described by Levine and co-workers (17). Samples were measured in a single assay with an intraassay CV of 7.2%.
Exp 3: changes in gonadotropes after castration
At 150 days of age, treated and control males (12/group) were
anesthetized with methoxyfluorane, and blood was collected by cardiac
puncture. Three control and three treated males were decapitated, and
their pituitaries were removed and immersed in Bouin’s fixative at 4
C. The remaining animals were then castrated as described in Exp 2. The
castrated animals (three per time point) were decapitated, and their
pituitaries were fixed for immunocytochemical analyses on days 14 and
28 postcastration.
After fixation, pituitaries were embedded in Paraplast (Brunswick Company, St. Louis, MO) after conventional dehydration with ethanol. Four-micron thick transverse sections were cut from the ventral region of the pituitary and placed on precleaned glass slides. Deparaffinized sections were incubated with normal rabbit serum (1:500) as a control or specific antisera (1:500) after treatment with 10% normal goat serum in PBS. Antiserum against porcine LH (USDA-306–684p) was used to localize LH, and an antiserum against the ß-subunit of porcine FSH (USDA-398–04p) was used for localization of FSH. Sections were processed with a Rabbit ExtrAvidin Staining Kit (Sigma), using the avidin-biotin-peroxidase method. Peroxidase was visualized with a hydrogen peroxidase 3,3'-diaminobenzidine (Sigma) solution. All sections were then counterstained with hematoxylin.
Images of five representative sections of each pituitary were captured using a x40 objective on a Zeiss photomicroscope (Carl Zeiss, Inc., New York, NY) interfaced to a Macintosh 8100/80 computer (Apple Computers, Inc., Cupertino, CA). The images were printed with a laser printer. Morphometric data were collected from the printed images using the Zeiss photomicroscope fitted with a light tube through which a light emitting diode cursor was viewed and a digitizing pad (Jandel Scientific, Corte Madera, CA) interfaced with a computer. The data were stored and analyzed using the Sigma-Scan software package (Jandel Scientific, Corte Madera, CA).
Exp 4: effect of castration on gonadotropin subunit mRNA levels
At 150 days of age, PTU-treated and control rats (20/group) were
anesthetized with methoxyfluorane and castrated. Additionally, 5
males/group were decapitated, and their pituitaries were removed. Total
pituitary RNA was isolated using the single step guanidinium
thiocyanate method described by Chomczynski and Sacchi (18). Total RNA
was also isolated from 5 control and 5 treated males on days 1, 3, 7,
and 14 after castration.
As the RNA samples were isolated, 8–10 µl total RNA solution from
each male were denatured and electrophoretically separated on a 1%
agarose gel using Tris-formalin buffer and visualized after ethidium
bromide staining (19). After inspecting each sample for 18S and 28S
ribosomal bands, the samples were quantitated at 260 and 280 nm and
stored at -85 C. After all 50 samples had been isolated and
quantitated, the remaining 12–22 µl (
8–30 µg) total RNA were
transferred to a nylon membrane (Sigma) in a 10 x 5 grid using a
dot blot apparatus (Stratagene, La Jolla, CA) and cross-linked to the
membrane with a UV cross-linking apparatus (Stratagene). The filter was
subsequently prehybridized in Quickhyb (Stratagene) at 60 C for 2
h and then hybridized for 2 h at 60 C with an
[-32P]deoxy-CTP-labeled probe after random priming
(Promega, Madison, WI) and removal of unincorporated radiolabel using a
spin column (19). After hybridization, the filter was washed three
times to a final stringency of 0.1 x SSC (standard saline
citrate) and 0.1% SDS at 60 C and placed on autoradiography film for
24 h. After the film was developed, the complementary DNA (cDNA)
probe was removed by boiling in 50% formamide (19), and the filter was
placed on film for 48–72 h to ensure complete probe removal. This
process was completed, in sequence, for rat cDNAs corresponding to
FSHß, LHß, and the common -subunit and for a human 28S ribosomal
RNA. After autoradiography, individual samples were quantitated using a
GS670 imaging densitometer and Molecular Analyst software (Bio-Rad,
Hercules, CA). The RNA levels are expressed as a ratio of the target
mRNA to 28S RNA.
Statistical analyses
All results are presented as the mean ± SEM.
Differences in serum levels of LH and FSH after castration were
analyzed using the repeated measures option within the SAS general
linear models procedure; potential interactions tested included
treatment x castration x time (SAS Institute, Cary, NC).
Differences in testis, pituitary, and hypothalamic weights were
analyzed using the general linear models procedure, as were differences
in pituitary and hypothalamic hormone concentrations. When indicated,
differences between group means were determined using Tukey’s honest
significant difference test, and differences between paired means were
analyzed using Tukey’s protected t test. For each analysis,
homoscedascity of error variances was ensured by visual inspection of
the calculated residual errors after plotting them against their
respective predicted values. Differences were considered significant
when P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1: pituitary responsiveness to exogenous GnRH
Injection of a 10 ng/kg GnRH dose did not affect plasma LH in
either control or PTU-treated adult rats (data not shown). In control
rats, injection of a single dose of 50 ng/kg GnRH (Fig. 1a
) induced a significant increase in LH concentration
from 0–5 min, and peak plasma LH concentrations were obtained between
10–15 min postinjection, but the response in PTU-treated rats was not
significant.
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Exp 2: changes in LH, FSH, and GnRH after castration
Serum FSH levels were 48% higher in intact control males than in
intact PTU-treated males (9.2 ± 0.9 vs. 6.2 ±
1.0 ng/ml, respectively). After castration, serum FSH levels in control
rats increased rapidly (Fig. 2), peaking at 35.1 ±
1.1 ng/ml on the 14th day postcastration. As observed in control males,
serum FSH levels rose rapidly in treated males after castration.
However, peak FSH concentrations were only 26.1 ± 1.2 ng/ml by
the 14th day postcastration (Fig. 2). Serum FSH levels were
significantly elevated in control compared with treated males at all
times except the first day after castration. The proportional increase
in serum FSH levels was similar in both treated and control males 7–14
days after castration (4.1- and 3.9-fold, respectively), indicating no
significant treatment by castration by time interactions.
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). LH levels rose 8.5-fold in control
males, from 0.61 ± 0.06 ng/ml in intact males to 5.23 ±
0.65 ng/ml by the 14th day postcastration. Serum LH levels rose from
0.35 ± 0.05 ng/ml in intact treated males to 2.96 ± 0.33
ng/ml 14 days after castration, an 8.6-fold increase. Serum LH levels
were significantly elevated in control males compared to those in
treated males at all times except the first day after castration, with
no significant treatment by castration by time interaction.
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) was
significantly elevated in intact treated rats compared to intact
control males (5.25 ± 0.28 vs. 3.97 ± 0.22 µg
hypothalamus, respectively). At 14 days after castration, GnRH contents
were significantly reduced in both groups, with no significant
differences observed between the control and PTU-treated animals at
this time (Fig. 4).
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). In pituitaries from control males, the mean FSH
content increased 2.4-fold 14 days after castration. However, the mean
pituitary FSH content of treated males was not significantly elevated
14 days after castration (Fig. 5).
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). Castration
induced a 7.1-fold increase in LH content (micrograms per
adenohypophysis) of pituitaries from control males. In treated males,
castration induced a smaller, but significant, increase in pituitary LH
content within 14 days (1.36 ± 0.39 µg/adenohypophysis in
intact PTU-treated males and 1.94 ± 0.22 µg/adenohypophysis in
PTU-treated castrates).
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, a and b). However,
PTU-treated males had approximately 20% more LH-immunoreactive cells
per unit area than were observed in the controls. Although more
abundant, the LH-immunoreactive cells present were smaller than those
in controls (Table 1). Castration induced a dramatic
increase in the size and proportion of LH-immunoreactive cells present
within the adenohypophysis of control rats. This effect was pronounced
14 days after castration (Fig. 7c and Table 1). The number of cells
that immunostained for LH in adult PTU-treated rats after castration
showed an increase similar to that seen in controls 14 days after
castration (Fig. 7d and Table 1). In all cases, there was no specific
staining of any cells in the intermediate lobe of the pituitary or in
the neurohypophysis. Specific staining for LH was not detected in any
sections from pituitaries of control or PTU-treated rats (either before
or after castration) that had been stained with normal rabbit serum as
a control (Fig. 7, e and f).
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Exp 4: effect of castration on gonadotropin subunit mRNA levels
Relative levels of mRNA for FSHß, LHß, and their common
-subunit in intact and castrated rats are shown in Figs. 8, 9, and 10,
respectively. LHß and -subunit mRNA levels were reduced in the
pituitaries of intact treated males relative to those in controls,
whereas FSHß mRNA levels were similar. Immediately after castration,
levels of all three mRNA species were reduced in the controls, whereas
in treated males they either were reduced or did not change
significantly. Levels of FSHß and LHß mRNA were maximal by 3 days
postcastration in control males (Figs. 8 and 9). In treated males, the
increase in FSHß and LHß mRNA levels was not maximal until 7–14
days after castration and, unlike the control values, which appeared to
be decreasing by 14 days, were either stable or increasing (Figs. 8 and 9). Unlike the specific ß-subunits, changes in -subunit levels
followed a similar pattern in both the treated and control males (Fig. 10). However, as observed above, the -subunit mRNA levels were
either stable at 14 days or decreasing at a lower rate than in the
controls, which demonstrated a significant decline by day 14.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The decreased serum gonadotropin concentrations and impaired GnRH responsiveness could have resulted from reduced gonadotrope numbers. However, immunohistochemistry revealed that luteotrope and folliculotrope numbers and densities were not reduced in PTU-treated males compared to those in controls. Thus, the reduced adult levels of FSH and LH seen in the neonatally PTU-treated rat were not due to a reduction in gonadotrope number, suggesting that the critical change in these animals may be a reduction in hormone production per gonadotrope.
Changes in LH and FSH in response to castration were examined to determine whether the normal pattern of increases in gonadotropin levels and gonadotrope numbers would be seen in the PTU-treated adult rat. Removal of the negative gonadal feedback on the hypothalamic-pituitary axis by castration resulted in 4- to 8-fold increases in serum gonadotropin levels in both the treated and control males. Although the proportional increases in serum FSH and LH were similar in both groups, the absolute serum concentrations of these hormones remained significantly lower in treated males. These results further suggest that either pituitary responsiveness or secretory capacity was reduced in adult PTU-treated animals.
The normal sequelae of histological changes in the pituitaries of castrated control and PTU-treated animals corroborate our data on serum LH and FSH levels after castration in these animals. After castration, the number and size of gonadotropes increased in control rats, in agreement with previous reports (20, 21). Gonadotrope number and size were also increased in PTU-treated rats, and the magnitude of the increases were similar in both groups of animals. In the PTU-treated rats, the increase in number of FSH- and LH-immunoreactive cells further demonstrates that the reduced serum levels of gonadotropins in intact treated males are not due to an irreversible reduction in gonadotrope numbers. The large increases in gonadotrope number and size corroborate our observed increases in both serum FSH and LH after castration and further indicate that the pituitary of the PTU-treated rat is capable of producing increased levels of these hormones under specific conditions. Therefore, it is clear that the decreased serum levels of FSH and LH in treated rats are not indicative of an intrinsic inability of the pituitary to maintain gonadotropin levels within the range observed in control males. Rather, the normally decreased FSH and LH concentrations in treated males appear to reflect at least in part an alteration in the pituitary’s responsiveness to GnRH stimulation and, possibly, pituitary and/or hypothalamic sensitivity to gonadal feedback. These observations are in agreement with our data showing decreased LH production in response to an acute GnRH challenge in intact PTU-treated rats.
The effects of castration on pituitary FSH and LH content, mRNA for LHß and FSHß, and hypothalamic GnRH content provide further insight into the mechanisms involved in the decreased gonadotropin levels in PTU-treated rats. Typically, removal of the inhibitory feedback effects of the gonads results in increases in pituitary LH and FSH contents (22, 23). Conversely, pituitary FSH and LH contents fail to increase to the levels expected in treated males after castration, suggesting that gonadotropins are being synthesized and immediately secreted in these animals, perhaps as a result of a decreased ability to synthesize LH and FSH. These results, showing impaired ability to produce FSH and LH, are corroborated by data indicating that the rate of increase in the levels of mRNA for the LHß and FSHß subunits occurred more slowly in the pituitaries of treated males than in the controls.
Over the same 14-day period after castration, hypothalamic GnRH content is expected to decrease, as the loss of testosterone after castration decreases negative feedback and increases GnRH secretion, resulting in an overall reduction in GnRH content (24, 25). Although initially elevated in intact treated males, the GnRH content declined as expected in both treated and control males after castration. Currently, there are no data on either the pulsatility or total amount of GnRH secreted in PTU-treated males. Therefore, it is not possible to quantitatively compare GnRH secretion in control and PTU-treated rats, but the present data indicate that the changes in GnRH content induced by castration are similar in control and PTU-treated rats. This observation coupled with the normal postcastration increases in gonadotrope number in the pituitaries of PTU-treated males and the increases in circulating gonadotropin levels in response to both the high dose GnRH challenge and o castration suggest that the gonadotropes remain responsive to trophic stimulation, but that the synthetic capacity of individual gonadotropes is reduced in the treated male.
Previously, it was shown that the first week of postnatal life is critical for the normal functional and morphological maturation of gonadotropes in the rat (26). Furthermore, gonadotropes express the T3 receptor and may be targets of thyroid hormones (27). Therefore, the decreased levels of thyroid hormone present during this crucial neonatal period may induce permanent changes in the developing gonadotropes that reduce their maximal adult capacity for FSH and LH production. Similarly, serum FSH and LH levels are reduced by neonatal PTU treatment; this decrease may also be accompanied by decreased secretion of GnRH, although this question has not been directly addressed. As GnRH stimulates gonadotrope development (28), a decreased level of GnRH during this time could result in irreversible changes in their maximal capacity to produce LH and FSH. This potential explanation for the life-long chronic reduction in serum FSH and LH levels is noteworthy, in that the prepubertal reduction in these hormones occurs well before the hypothyroidism-induced increases in Sertoli and Leydig cells take place (6, 8, 10, 12). Further, the possibility exists that early direct effects of hypothyroidism on the development of GnRH-secreting neurons is later supplanted by the ability of the enlarged populations of Leydig and Sertoli cells in treated rats to produce normal testosterone and elevated inhibin (12) in the presence of chronically low gonadotropin levels. We originally proposed (12) that the reduction in LH required to maintain normal testosterone levels could result in a reduction in GnRH secretion, leading to a reduction in both LH and FSH; the data presented here suggest that this may be a component of the overall reduction in serum gonadotropins in adult PTU-treated rats.
Based on our studies of the effects of both acute and chronic challenges on gonadotropin levels, gonadotrope numbers, and gonadotropin subunit mRNA levels in the pituitaries of adult males after neonatal PTU treatment, the means by which gonadotropin levels remain chronically depressed become more apparent. Quantitative histochemistry of the pituitaries of treated males eliminated the possibility that the reduced LH response to an acute GnRH challenge in treated males was due to reduced numbers of luteotropes. These results suggested that the reduced levels of circulating gonadotropin observed in treated males were due to a reduced responsiveness to stimulation, an overall reduction in the synthetic capacity of the individual gonadotropes, or a combination of both.
The changes observed after castration support the conclusion that reduced circulating gonadotropin levels in treated rats were due to a reduced capacity to synthesize hormone and not solely to an inability to respond to trophic stimulation. First, castration elicited the normal increases in luteotrope and folliculotrope numbers and volume in treated males. Second, after castration, circulating gonadotropin levels increased proportionally in both treated and control males, although absolute concentrations remained significantly reduced in treated males. Third, although gonadotrope numbers increased as expected after castration in treated males, the expected increase in pituitary FSH and LH contents did not. Thus, treated males may have been secreting both LH and FSH as fast as they could be synthesized. Fourth, the castration-induced increase in the relative abundance of gonadotropin subunit mRNAs was significantly reduced and the temporal pattern was delayed in treated rats. Thus, the overall conclusion is that although the intrinsic ability of the pituitaries of treated rats to maintain normal circulating LH and FSH levels exists, gonadal feedback and an overall reduction in gonadotrope synthetic ability combine to produce the chronically reduced levels of these hormones.
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Acknowledgments |
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-subunit cDNAs;
Dr. Parlowe and the National Hormone and Pituitary Program for the rat
LH and FSH RIA materials; the USDA Animal Hormone Program for the
antisera against LH and FSH; and Dave Kuehl for technical assistance.
The authors are also grateful to Drs. Neena Schwartz, John Levine, and
David Bunick for their insight and suggestions concerning this
research. |
Footnotes |
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2 Supported by a Mellon Foundation fellowship. Permanent address:
Department of Neurobiology, 00140, University of Helsinki, Helsinki,
Finland.
3 Current address: GeneMedicine, Inc., 8301 New Trails Drive, The
Woodlands, Texas 77381.
Received January 30, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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