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Endocrinology Vol. 140, No. 5 2405-2414
Copyright © 1999 by The Endocrine Society

ARTICLES

Long-Term Growth after Hypophyseal Stalk Transection and Hypophysectomy of Beef Calves1

Lloyd L. Anderson, Douglas L. Hard, Allen H. Trenkle and Sang-Joon Cho

Neuroscience Program (L.L.A., S.-J.C.), Department of Animal Science (L.L.A., A.H.T., S.-J.C.), Iowa State University, Ames, Iowa 50011; and The Dairy Business (D.L.H.), a unit of Monsanto Company, St. Louis, Missouri 63167

Address all correspondence and requests for reprints to: Dr. L. L. Anderson, Department of Animal Science, Iowa State University, 2356 Kildee Hall, Ames, Iowa 50011-3150. E-mail: llanders{at}iastate.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Hypothalamic hormones regulate episodic and basal secretion of hormones from the anterior pituitary gland that affect metabolism and growth in cattle. This study focused on long-term growth in young calves subjected to hypophysectomy (HYPOX), hypophyseal stalk transection (HST), and sham operation control (SOC). Cross-bred (Hereford x Aberdeen Angus) and Hereford, and Aberdeen Angus calves were HYPOX (n = 5), HST (n = 5), or SOC (n = 8) at 146 ± 2 days of age, whereas another group was HST (n = 5) or SOC (n = 7) at 273 ± 5 days of age. Body weight was determined every 21 days from birth to 1008 days of age. Anterior vena cava blood was withdrawn at 4-day intervals from day 64–360 for RIA of GH, TSH, T4, T3, and LH, and at 20-min intervals for 480 min to determine episodic hormone secretion. Daily feed intake was determined in HST and SOC calves during an 80-day period. Birth weight averaged 35 ± 1 kg (± SE) and was 142 ± 4 kg at 126 days and 208 ± 8 kg at 252 days before surgery. From day 146-1008, growth was arrested (P < 0.001) in HYPOX (0.06 ± 0.01 kg/day) compared with SOC (0.50 ± 0.04 kg/day) calves. Growth continued but at a significantly lower rate (P < 0.05) in calves HST at 146 days (0.32 ± 0.07 kg/day) and 273 days (0.32 ± 0.06 kg/day) compared with SOC (0.50 ± 0.09 kg/day). Growth continued to be impaired to 1008 days, but more so in those HST at 146 days (432 ± 43 kg BW) than 273 days (472 ± 5 kg BW) and less (P < 0.05) than SOC (586 ± 37 kg BW). Daily feed intake was consistently less (P < 0.05) in HST compared with SOC calves. Although episodic GH secretion was abolished and peripheral serum GH concentration remained consistently lower in HST (2.4 ng/ml) than SOC (5.5 ng/ml; P < 0.01), the calves continued to grow throughout 1008 days. Peripheral serum TSH concentration was less (P < 0.05) HST compared with SOC calves. There was an abrupt decrease (P < 0.001) in serum T4 (4-fold) and T3 (3-fold) concentration after surgery that remained to 360 days in HST compared with SOC calves. At the time calves were killed, pituitary gland weight was markedly reduced (P < 0.001) in HST (0.18 ± 0.01 g/100 kg BW) compared with SOC (0.54 ± 0.03 g/100 kg BW). Histological examination of pituitary glands from HST calves indicated the persistence of secretory GH and TSH cells in the same areas of the adenohypophysis as SOC calves. Coronal sections of the gland stained with performic acid-Alcian blue-periodic acid-Schiff-orange G, revealed GH and TSH secreting cells in HST calves similar to controls. These results indicate that long-term growth continues, but at a slower rate, after hypophyseal stalk transection of immature calves in spite of complete abolition of episodic GH secretion and consistently decreased basal secretion of GH, TSH, T4, and T3 compared with sham-operated animals. Growth was abolished after hypophysectomy of immature calves in which circulating GH and TSH was undetectable.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
SOMATIC growth in vertebrates is thought to be dependent on pituitary GH; without pituitary GH production or peripheral GH action, postnatal growth is severely stunted (1, 2, 3). For example, a deficiency in GH production or GH receptor (GHR) gene has been demonstrated to stunt growth (4). A notable exception is the guinea pig, in which hypophysectomy does not alter the growth rate, and treatment with bovine GH (bGH) does not affect growth or increase insulin-like growth factor (IGF)-I levels (5, 6, 7). Hormones are generally released episodically, but evidence for the requirement of endogenous pulsatile GH secretion for growth in mammals is unknown. GH secretion in the guinea pig is pulsatile and controlled by endogenous GH-releasing hormone (GHRH), somatostatin (SRIH), and possibly a GH-releasing peptide receptor (8). GHR is expressed in various tissues and binds guinea pig GH; recent evidence focuses on an unusual binding specificity of guinea pig GH-binding protein (GHBR), being highly heterogeneous in molecular weight and binding affinities but more generalized binding affinity for ovine- and bovine-GH but not human GH (9). Although IGF-I and IGF-II are present in high concentration in guinea pig serum, hypophysectomy does not decrease nor does bGH or oGH treatment in such animals increase their production. Ymer et al. (7) demonstrated complex GH binding patterns not only in guinea pig but also in rat sera.

The hypothalamus regulates episodic GH secretion from the pituitary in part by its endogenous release of GHRH, SRIH, and possibly, a yet-unidentified GH secretagogue for which the receptor has been described (10, 11, 12, 13, 14, 15). The neurophophyseal link between the hypothalamus and the pituitary is essential for connecting these releasing and inhibiting hormones (16). In the young animal, episodic GH secretion occurs during stages of rapid growth and wanes during maturity and senescence. Although aging animals and humans lack robust episodic GH secretion, the pituitary is fully capable of responding to GHRH or GH-secretagogue challenge with supraphysiological GH release.

Less clear is the role of episodic GH release in long-term growth. To our knowledge, no long-term studies have been carried out in the mouse, rat, hamster, rabbit or other species to determine the GH requirement for long-term growth after interruption of either episodic GH release or reduced basal GH secretion. This study focuses on long-term growth in calves subjected to either hypophyseal stalk transection or hypophysectomy. The hypotheses to be tested were that cattle require endogenous GH secretion for growth, but the episodic pattern for this hormone secretion is not essential for long-term growth. The results clearly show that although cattle depend on the pituitary for GH to sustain growth, episodic secretion of GH is not essential for long-term growth. Indeed, growth can continue during a prolonged period in the complete absence of pulsatile GH release in this species. These findings reveal important implications for sustaining or augmenting long-term growth, as well as maintaining immune function and well-being in the older animal.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Fifteen male and 15 female cross-bred (Hereford x Aberdeen Angus), and Hereford and Aberdeen Angus calves born at the Animal Reproduction Laboratory, Iowa State University, suckled their dam to 4 months of age. Calves were weighed at birth and 21-day intervals throughout the study. They were fed a diet consisting of 49% cracked corn, 39% dehydrated alfalfa, 5.6% solvent-extracted soybean meal, 5.6% cane molasses, 0.5% dicalcium phosphate, 0.2% iodized salt, 0.02% trace mineral, and 0.1% vitamin A (5.2 million IU/kg). In addition, animals received free choice legume-grass hay mix during winter and access to hay and legume-grass-pasture during spring, summer, and autumn.

Each animal was fitted with an indwelling catheter (Tygon microbore tubing, 1.27 mm id, Fisher Scientific, Pittsburgh, PA) in a jugular vein before surgery and maintained for sequential bleeding. The catheters were filled with sterile saline with 40 U heparin/ml. Blood (8 ml) was collected by venipuncture at 4-day intervals, centrifuged at 1,500 x g and the serum stored at -20 C until RIA for GH, TSH, T4, T3, and LH. Animal care and procedures used were in accordance with the guidelines and approval of the Iowa State University Committee on Animal Care.

Surgical procedures for hypophyseal stalk transection and hypophysectomy
Hypophyseal stalk transection (HST), hypophysectomy (HYPOX), and sham operation control (SOC) were performed as previously described (17). Briefly, anesthesia was induced with an iv injection of thiamylal sodium (1–2 g, Surital, Parke-Davis, Morris Plaines, NJ) for endotracheal intubation and maintained on a closed-circuit system of halothane (1–4%; Fluothane, Fort Dodge Laboratories, Inc., Fort Dodge, IA) and O2 (600–1100 cc/min). HST, HYPOX, and SOC were performed by a supraorbital approach with the calf suspended in ventral recumbency by canvas belts. An animal head restrainer (18), attached to the front of a cattle squeeze chute, permitted the head to be raised, lowered, tilted, and turned to the desired position for neurosurgical intervention. A sterile mannitol solution (20%, 150–225 ml) was iv-infused for 20 min, immediately preceding lifting the brain, to prevent cerebral swelling. After the brain was exposed and the dura mater severed, a de Martel brain retractor (Victoria Medical S.A., Paris, France) was mounted on the frontal bone, and the ventral surface of the left cerebral hemisphere lifted to expose the hypothalamic area. The left internal carotid artery was clamped with two silver hemostatic clips and severed to allow an unobstructed view of the hypophyseal stalk.

For HST, the hypophyseal stalk was severed, and a nylon disc (8.0 mm diameter and 0.45 mm thickness) was inserted between the severed ends of the tubular stalk to prevent vascular regeneration. For HYPOX, the internal carotid and hypophyseal stalk were separated as described previously, the diaphragma sellae cut, and the pituitary gland removed with Hardy bayonet curettes (no. 80–1330, no. 80–1332, and no. 80–1347; Codman & Shurtleff, Inc., Randolph, MA) and Hardy pituitary spoon (no. 80–1336). After complete removal of pituitary remnants, the basal region of the sella turcica was cauterized and swabbed with cotton gauze soaked in Bouin’s fluid. The sella turcica was filled with thrombin-soaked Gel-foam (Pharmacia & Upjohn Co., Kalamazoo, MI). For SOC, surgical procedures consisted of lifting the left cerebral hemisphere for an equivalent period as required for HST or HYPOX. Water and food intake returned to normal 6–24 h after surgery. The calves were monitored throughout the postoperative recovery period for changes in body temperature, respiration rate, and feed consumption. Cortisone acetate (50 mg, im, Cortone, Merck & Co., Inc., West Point, PA) was given to reduce stress during the first 24 h of the recovery period. The duration of anesthesia for these neurosurgical interventions required 3–4 h.

Hormone RIA
Serum GH was measured in 100 µl aliquots in duplicate by using highly purified bGH (USDA-bGH-I-1, 3.2 IU/mg) for labeling with 125I (IMS 30, Amersham Corp., Arlington Heights, IL) by the chloramine-T method, highly purified bGH (Dr. C. H. Li) for standards (0.125–2 ng), and incubations at 4 C for 72 h by procedures similar to those described previously (19). PBS-1% BSA (pH 7.4, 600 µl) and antibodies to bGH produced in rabbit (1:200,000, 400 µl) were added to the assay tube and incubated 48 h; then 100 µl 125I-bGH was added and incubated 24 h followed by addition of antirabbit {gamma}-globulin (1:45; #130330, Cappel, Organon Teknika, Westchester, PA), and incubated 72 h. To each assay tube 2 ml PBS (pH 7) was added, centrifuged, the supernatant decanted, and the precipitate counted in an {gamma} scintillation counter. Assay sensitivity was 0.125 ng/tube. Intraassay and interassay coefficients of variance were 3.5% and 11.2%.

Serum TSH was measured in 200-µl aliquots in duplicate by using highly purified bovine TSH (bTSH, 30–40 IU/mg, Dr. J. G. Pierce) for labeling with 125I (IMS 30, Amersham Corp.) by the chloramine-T method, purified bTSH (21 IU/mg, NIH) for standards (0.1–50 ng), and incubations at 4 C by procedures similar to those described previously (20, 21). Ovine TSH antiserum (anti-oTSH, Dr. S. L. Davis) was diluted with 1:400 normal rabbit serum (NRS) and then preabsorbed with FSH (NIH-FSH-B1) and LH (NIH-LH-B8) to remove nonspecific antibodies that react with these gonadotropins. PBS-1% BSA (pH 7, to 500 µl) and anti-oTSH (1:80,000, 200 µl) were added and the assay tube was incubated 24 h. Then 100 µl of 125I-bTSH was added, incubated 24 h, and followed by addition of antirabbit {gamma}-globulin produced in goat (no. 130330, Cappel, Organon Teknika), and incubated 72 h. To each assay tube, 2.5 ml PBS (pH 7) was added and centrifuged, the supernatant was decanted, and the precipitate was counted 2 min in a {gamma} scintillation counter (Packard Cobra Auto {gamma} 5003). Assay sensitivity ranged from 0.3–10 ng/tube. Intraassay and interassay coefficients of variance were 6.4% and 9.8%.

Thyroxine serum concentration was measured by using T4-125I immunoassay procedures described by Chopra et al. (22). Serum samples of 20 µl in duplicate were assayed with T4 standards ranging from 2–32 µg/dl. Assay sensitivity was 2.5 ng/ml. Intraassay and interassay variances were 3.6% and 8.2%.

Triiodothyronine serum concentration was measured by using T3-125I immunoassay procedures described by Chopra et al. (23). Serum samples of 100 or 150 µl in duplicate were assayed with T3 standards ranging from 25 to 800 ng/dl. Assay sensitivity was 4.5 ng/dl. Intraassay and interassay coefficients of variance were 2.5% and 6.0%.

Serum LH was measured in 200-µl aliquots in duplicate by using highly purified bovine LH (bLH, NIH) for labeling with 125I (Amersham Corp.) by the chloramine-T method and for standards (0.036–20 ng) similar to those procedures described previously (24). After dilution with ovine LH antiserum (GDN no. 15, 1:40,000) and 1:400 NRS, 200 µl were added to each assay tube containing serum unknown and PBS and incubated 24 h at 4 C, and 100 µl 125I-bLH were added and incubated 72 h at 4 C; centrifuged, the supernatant decanted, and radioactivity of the precipitate counted. Assay sensitivity was 0.2 ng/ml. Intraassay and interassay coefficients of variance were 8.3% and 9.1%.

Histology
Postmortem examination of each animal confirmed the completeness of stalk transection. The nylon disc was in the proper location and had prevented vascular regeneration of the stalk in each calf. Furthermore, there was no development of a network of arterioles and venules for any revascularization between the hypothalamus and the pituitary gland in the HST calves. The pituitary gland from HST and SOC calves was cut transversely and fixed in Susa’s solution for histological evaluation. Coronal sections of the glands were cut at 6 µm and stained with performic acid-Alcian blue-periodic acid-Schiff-orange G by the method Heath describes (25), whereas other sections were stained with hematoxylin and eosin. At the time when HYPOX calves were killed, the sella turcica was examined for remnants of pituitary tissue. The thyroid gland was transected from the middle of the left lobe and fixed 4 h in Bouin’s fluid (35 C); picric acid was removed by several changes of 70% ethanol containing saturated lithium carbonate. The tissues were stored in 70% ethanol, dehydrated, embedded, and cut at 7 µm. One set of sections was stained with hematoxylin and eosin, and another with Mallory triple stain.

Statistical analyses
The experimental units in this study were the individual calves. Growth and hormone data were analyzed by a split-plot analysis using a one-way ANOVA, and Student’s t tests for continuous variables was used for comparisons between groups (26, 27).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Growth and food consumption
Birth weight of beef calves averaged 35 ± 1 kg (± SE) and was 142 ± 4 kg at 126 days and 208 ± 8 kg at 252 days of age before surgery (Figs. 1Go and 2Go). From days 146-1008, growth was arrested (P < 0.001) in HYPOX (0.06 ± 0.01 kg/day) compared with SOC (0.50 ± 0.04 kg/day) calves (Fig. 1Go). Growth continued but at a significantly lower rate (P < 0.05) in calves HST at 146 days (0.32 ± 0.07 kg/day) and 273 days (0.32 ± 0.06 kg/day) compared with SOC (0.50 ± 0.04 kg/day; Figs. 1Go and 2Go). Long-term growth in HST calves to 1008 days of age was less in those HST at 146 days (432 ± 43 kg body wt) than at 273 days (472 ± 5 kg body wt) compared with SOC (586 ± 37 kg body wt; P < 0.05).



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  		Figure 1. Growth in beef calves subjected to hypophysectomy (•), hypophyseal stalk transection ({blacksquare}) or sham operation ({diamondsuit}) at 146 ± 2 days of age. Birth weight averaged 35 ± 1 kg with subsequent body weights at 21-day intervals. Number of calves is indicated in parentheses. Values are mean ± SE.

 


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  		Figure 2. Growth in beef calves subjected to hypophyseal stalk transection ({blacktriangleup}) or sham operation (•) at 273 ± 5 days of age. Birth weight averaged 35 ± 1 kg with subsequent body weights at 21-day intervals. Number of calves is indicated in parentheses. Values are mean ± SE.

 
There were no significant differences in birth weight of male and female calves and growth before cranial surgery; however, at 400 days of age growth in the HST male calves was significantly greater than in the HST female calves (Table 1Go). After HYPOX or HST, daily feed intake was less than SOC calves. Daily feed intake throughout an 80-day period was consistently lower (P < 0.05) in HST compared with SOC calves, but there was no within group significant difference as related to sex (Fig. 3Go). This result may relate to decreased appetite or reduced feed-to-gain in HYPOX and HST calves compared with SOC.


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  		Table 1. Effect of sex on growth in HST and SOC beef calves

 


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  		Figure 3. Daily feed intake of HST ({blacktriangleup}) and SOC (•) beef calves during an 80-day period beginning 30 days after surgery. Number of calves is indicated in parentheses. Values are mean ± SE.

 
GH peripheral serum concentration
From 72–146 days of age, GH serum concentration at 4-day intervals before surgery averaged 3–6 ng/ml (Fig. 4Go). After HST at day 146, GH decreased abruptly to 1.9 ng/ml and remained at this basal level to day 372, and consistently lower (P < 0.01) than SOC calves, but within group there was no significant sex-related difference in serum GH concentration. Episodic GH secretion was abolished (P < 0.001) in HST compared with SOC calves as indicated by sequential blood sampling at 20-min intervals throughout 8 h (Fig. 5Go). Average GH serum concentrations remained consistently at basal level of 2.4 ng/ml in HST compared with 5.5 ng/ml in SOC calves (P < 0.01).



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  		Figure 4. GH concentration in peripheral serum at 4-day intervals before surgery ({circ}), and after HST ({blacktriangleup}) and SOC (•) of beef calves to day 372 of age. Number of calves is indicated in parentheses. Values are mean ± SE.

 


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  		Figure 5. GH concentration in peripheral serum from sequential blood samples at 20-min intervals during 8 h in hypophyseal stalk transection ({blacktriangleup}) and sham-operated control (•) beef calves. The number denotes the individual calf ear tag identification.

 
TSH, T4, and T3 peripheral serum concentration
From 68–146 days of age before surgery, TSH peripheral serum concentration ranged from 5–7 ng/ml (Fig. 6Go). After HST, TSH concentration from days 146–360 was less (P < 0.05) than SOC calves. Thyroxine serum concentration ranged from 60–80 ng/ml before surgery in these young growing calves. Immediately following HST, T4 decreased (P < 0.001) less than 20 ng/ml and remained consistently at this basal level to day 360; T4 ranged from 70–100 ng/ml throughout this period in the SOC calves. Triiodothyronine serum concentration ranged from 300–400 ng/dl before surgery. T3 concentration abruptly decreased (P < 0.001) 3-fold to <100 ng/dl after HST and remained at this basal level to day 360; T3 ranged from 250–300 ng/dl during this period in SOC calves (Fig. 6Go). There were no sex-dependent differences within groups of HST and SOC calves as related to TSH, T4, and T3 serum concentration.



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  		Figure 6. Thyroid stimulating hormone, thyroxine, and triiodothyronine concentration in peripheral serum at 4-day intervals before surgery ({circ}), and after HST ({diamondsuit}) or SOC ({blacksquare}) of beef calves at 146 ± 2 days to 360 days of age. Number of calves is indicated in parentheses. Values are mean ± SE.

 
Seasonal environmental temperature and photoperiod significantly altered (P < 0.05) GH peripheral serum concentration in SOC compared with HST calves (Fig. 7Go). Although there were marked differences in T3 serum concentration in HST and SOC calves, there was no significant correlation with environmental temperature and photoperiod. T4 and LH serum concentration in HST and SOC calves also was unrelated to environmental changes (data not shown). In contrast, PRL peripheral serum concentration in both HST and SOC calves was markedly affected by environmental temperature and photoperiod with peak hormone concentrations in summer and basal in winter (data not shown).



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  		Figure 7. Seasonal changes in GH and T3 concentration in peripheral serum of HST ({blacktriangleup}) and SOC (•) beef calves as related to photoperiod and mean maximal ({blacksquare}) and minimal ({square}) environmental temperatures. Number of calves is indicated in parentheses. Values are mean ± SE.

 
LH peripheral serum concentration
Overall LH serum concentration as indicated by sequential blood sampling at 20-min intervals throughout 8 h was significantly decreased in HST compared with SOC calves (Table 2Go). Although baseline LH concentration remained similar in both groups, episodic LH secretion was abolished in HST compared with SOC calves, and nondetectable in HYPOX calves.


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  		Table 2. Serum LH concentration in SOC, HST, and HYPOX beef calves

 
Pituitary and thyroid histology
At the time calves were killed, pituitary gland weight of HST calves was 33% (P < 0.01) that of SOC animals (Table 3Go). In three HYPOX calves, no pituitary remnants were found at the time they were killed, whereas in the other two HYPOX animals the sella turcica contained approximately 10% scar tissue but no viable adenohypophyseal cells on histological examination.


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  		Table 3. Bovine pituitary, adrenal, and thyroid gland development after hypophyseal stalk transection, hypophysectomy, or sham operation

 
Pituitary glands from HST calves indicated persistence of secretory cells in the same areas of the adenohypophysis as SOC (Fig. 8Go). In coronal sections from HST and SOC calves stained with performic acid-Alcian blue-periodic acid (PAS)-Schiff-orange G, acidophils, basophils, and chromophobes were present. The severed ends of the hypophyseal stalk remained separated by the nylon disc in all HST animals. Adenohypophyseal regression varied among HST calves but was pronounced in ventromedial and least in dorsolateral regions of the gland. Infarcted regions of the gland contained necrotic parenchymal cells and fibroblasts. Areas of seemingly viable parenchyma contained a dense population of acidophils as indicated by dark orange color with Alcian blue-PAS-orange G. In pars distalis, basophilic {delta} cells were numerous and granulated in SOC animals, but they were sparse and degranulated in HST calves. Adenohypophyseal secretory cells of HST animals seemed viable with less-abundant cytoplasm indicating hormone production but little storage compared with SOC calves.



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  		Figure 8. Histology of adenohypophysis from six HST and three SOC beef calves. Coronal sections (6 µm) are from the middle one-third of anteromedial adenohypophysis. Acidophils with cytoplasm were dispersed in anteromedial regions of the gland in both groups of HST and SOC calves. Acidophils are associated with somatotrophs, lactotrophs, and adrenocorticotrophs. Basophils are associated with thyrotrophs and gonadotrophs. Chromophobes were evident throughout the adenohypophysis in HST and SOC calves. These representative histological sections indicate survival of adenohypophyseal cells in HST calves (x360). The number denotes the calf ear tag identification.

 
Although thyroid gland wt remained similar in HST compared with SOC calves, histological examination revealed marked differences (P < 0.01) in epithelial cell diameter and vacuolization of colloid in follicles in the HST animals (Table 3Go). In HYPOX calves, the thyroid gland regressed (P < 0.01) compared with SOC, and epithelial cell diameter was greatly reduced with only slight vacuolization of colloid in the follicles (Table 3Go). Vacuolization of colloid in thyroid follicles was greater (P < 0.05) in SOC than HST and HYPOX calves (Table 3Go and Fig. 9Go). The colloid stained primarily basophilic in SOC calves, whereas acidophilic colloid with sparse vacuolization of greatly enlarged follicles typified HST animals (Fig. 9Go). In HYPOX calves, thyroid follicles were small with sparsely vacuolated acidophilic colloid. These cytological features suggest thyroid inactivity in HST and HYPOX calves by flattened epithelial cells and sparsely vacuolated acidophilic colloid. Although adrenal gland weight in HST calves remained similar to SOC, it was significantly decreased in HYPOX compared with SOC calves (Table 3Go).



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  		Figure 9. Histology (7 µm) of thyroid glands from SOC, HYPOX, and HST calves. In SOC, extensive vacuoles are evident at periphery of follicles, colloid stained (Mallory triple stain) predominantly basophilic, and epithelial cells are columnar with abundant cytoplasm. In HYPOX, follicles are small with vacuolization of colloid, fibroblasts in interfollicular areas of the gland, and epithelial cells are cuboidal with little cytoplasm. In HST, abundant enlarged follicles filled with acidophilic colloid, sparse vacuolization, and epithelial cells are cuboidal with little cytoplasm. Bar, 100 µm. The number denotes the calf ear tag identification.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main finding was that hypophyseal stalk-transected calves continued growth but at a significantly lower rate than sham-operated controls even with the complete absence of episodic GH secretion, as well as, a significantly lower basal blood concentration of GH and markedly decreased circulating thyroxine and triiodothyronine concentrations. In addition, the HST calves consumed significantly less daily feed than SOC that likely results from decreased appetite or feed to gain. At the time calves were killed, pituitary gland weight of HST calves was only 33% that of SOC. Pituitary histology indicated decreased cytoplasm of somatotrophs and thyrotrophs. Thyroid gland histology revealed greatly enlarged thyroid follicles bounded by cuboidal epithelium indicating lack of thyroid hormone production and secretion in HST calves in contrast to vacuolated thyroid follicles bounded by columnar epithelium indicating normal thyroid hormone production and secretion in the SOC animals. Thus, in spite of compromised pituitary function in the HST calves, they continued to grow over a long period of time to a body weight at 1000 days that was 77% that of SOC animals. The second finding was that cattle depend on pituitary GH secretion for somatic growth; hypophysectomy arrests long-term growth to 1000 days of age. GH concentration in sera from these hypophysectomized calves was below immunoassay sensitivity; long-bone growth, long winter and summer hair coat, and diminished appetite reflected both GH deficiency and hypothyroidism. It is well known that GH in the pituitary, MCR, and secretion all decrease significantly as cattle become larger (28). Release of GH from the bovine adenohypophysis is regulated by GRF, SRIH, and likely by as yet an unidentified GH-secretagogue and other neuropeptides (i.e. galanin, neuropeptide Y) to modulate GH secretion (11, 29). Blocking GRF from reaching hypophyseal somatotrophs, either by hypothalamic deafferentation (30), HST (31, 32, 33), or active immunization against GRF (34, 35, 36) blocks episodic GH release both in ruminants and swine. Short-term experiments indicated that active immunization against GRF retarded normal growth in cattle (37).

Immediately following HST in calves, normal episodic secretion of GH and LH is abolished, whereas PRL secretion is consistently elevated over a period of 14 days (31, 38, 39). Thereafter, depressed growth rates, lack of onset of pubertal estrus, and decreased PRL blood concentration result in HST calves compared with SOC animals (38, 39). Regardless, basal PRL serum concentration responds to seasonal changes, peaking in summer and exhibiting a nadir in winter, in both HST and SOC calves (40, 41). These observations in ruminants under natural environmental conditions contrast with previously reported findings of consistently elevated PRL blood concentration in the rhesus monkey under controlled environmental conditions (42). Thus, HST attenuates, but does not prevent, seasonal changes in PRL secretion, indicating that season is an important overriding regulator of PRL secretion in cattle (41).

The pituitary gland of the calf is recessed in a deep sella turcica with the diaphragma sellae forming a thick dural roof over the gland. The caudodorsal portion of the diaphragm is tightly adhered to the gland; rostrally, it attenuates and presents a foramen for the hypophyseal stalk. The cavernous sinus and a thick rete mirabile cerebri border laterally, and often completely, around the ventral surface of the gland. The calf’s neurohypophysis consists of the median eminence of the tuber cinereum, the infundibular stem; the upper infundibular stem is encircled by pars tuberalis but is devoid in the lower part, and it continues caudad to merge with the neural lobe. The adenohypophysis (pars distalis) is large with rostral, ventral, and lateral walls of the gland, and a distinct but thin pars intermedia covers ventral and lateral surfaces of the lower infundibulum and neural lobe with a hypophyseal cleft separating it from the adenohypophysis. Notable features of rete mirabile cerebri of the bovine adenohypophysis are the abundant (i.e. approximately 20) arterial branches from the internal carotid and internal maxillary that supply the ventral aspect of the gland (43, 44). The caudal hypophyseal arteries consist of extensions of rostral and caudal retia on the dorsal and caudal surfaces of the gland. Rostral hypophyseal arteries also form aborizations, spikes, and capillary loops that penetrate the infundibulum. Two or three hypophyseal arteries arise from the arterial circle of the cerebrum (44). The hypophyseal portal vessels link vascular structures of the infundibulum with the large capillary bed and thus provide a main blood supply to the adenohypophysis and a few capillaries from the pars intermedia, the least vascular part of the pituitary gland. Vascular connections are slight between the hypophyseal stalk and the hypothalamus in the calf. After long-term HST, the pituitary gland, though much smaller, remained viable as revealed histologically and by persistence of basal GH and TSH secretion that was sufficient to sustain growth in these calves. Soon after HST, calves respond acutely to GRF challenge by GH peak release of a similar magnitude to that seen in SOC controls (31); 5 and 6 months after HST, responses to GRF remain similar to those in SOC calves. Furthermore, GH response to GRF during SRIH infusion was greatly inhibited, but the somatotropic rebound observed in intact calves after SRIH withdrawal is not observed after HST (29, 31). PRL blood concentration remains consistently elevated after HST for at least 14 days as compared with SOC calves (39). TRH administration acutely increases PRL secretion in these HST calves soon after surgery and 11 months later. Tonic hypothalamic inhibition of PRL secretion in cattle is indicated by dose-dependent increases in PRL plasma concentration immediately following iv injection of haloperidol, a neuroleptic drug that blocks dopamine receptors on lactotrophs in the adenohypophysis and by {alpha}-methyl-p-tyrosine ({alpha}MT), a drug that inhibits catecholamine synthesis in the hypothalamus by blocking the activity of tyrosine hydroxylase (40). HST calves do not respond, however, to iv administration of haloperidol or {alpha}MT 2 weeks after surgery (39).

The acute effects of HST in the rat causing an immediate increase in circulating PRL concentration are well known, but there are no long-term studies concerning the effects HST on blood concentrations of endogenous pituitary hormones affecting metabolism and statural growth in this species (45, 46, 47). Age- and sex-related differences exist in episodic GH secretion with changes in growth rate becoming evident between male and female rats at 25–30 days of age, but no correlation is evident between GH blood concentrations and rate of body weight gain after the onset of puberty (48, 49). It is known that thyroid hormone is an important regulator of GH production by rat somatotrophs by inducing transcription of the GH gene (50, 51). Hypophysectomy of immature rats arrests growth, as was seen in hypophysectomized calves in the present study, but the persistence of GH-immunoreactivity in the brains (amygdala and hypothalamus) of hypophysectomized rats and chickens suggests that GH synthesis does occur in the CNS (51, 52, 53). Brain GH concentrations increase in rats when pituitary GH concentrations decrease (54, 55), but circulating blood levels of GH in hypophysectomized rats and calves are extremely low to undetectable.

GH plays an important role in regulating metabolic changes necessary for growth and lactation in ruminants (56, 57) and in rats (58). Exogenous GH enhances retention of nitrogen, increases body weight gain in growing ruminants, and increases milk yield in dairy cows (57, 59, 60). A complex interaction between pituitary GH, the IGFs, their receptors, and their binding proteins in the regulation of statural growth applies in cattle and rats but remains unexplained in guinea pigs (61, 62, 63). In immature hypophysectomized rats, daily injection of recombinant human GH (rhGH) or rhIGF-I initially caused rapid and equivalent weight gains, but growth-promoting effects of IGF-I progressively decreased after 4 days (58). The rhIGF-I treated rats did continue to grow but at a slow rate compared with rhGH through a brief 18-day treatment period. Combined treatment of rhGH and rhIGF-I augmented growth greater than rhGH alone, but after day 18, the growth rates of the rats in the rGH and rGH plus rhIGF-I treated groups also declined likely as a result of the formation of rhGH antibodies by day 28 (58, 64). Additionally, the waning anabolic effect of rhIGF-I treatment could be due to changes in the IGF-binding proteins (65, 66, 67). Circulating IGFBP3 concentrations in rats are related to IGF-I concentrations, whereas acid-liable subunit concentrations appear to be under direct GH control (58).

An age-dependent decrease occurs in overall and basal GH plasma concentration and in GH amplitude and frequency of pituitary-intact cross-bred beef calves from 5 to 15 months of age (68). In pituitary-intact castrate Holstein male cattle, Moseley et al. (69) compared the effect of administering GH iv at a total dose of 48 µg/kg body wt daily either continuously, 6 iv pulses daily, a combination of continuous and pulse treatments, and vehicle controls for 10 days on nitrogen retention. Both AUC GH and nitrogen retention were significantly increased by GH administration during the 10-day period compared with vehicle-treated controls. There were no significant differences in nitrogen retention, however, as related to either continuous or pulse iv administration of GH in these cattle. A longer term study with cross-bred beef steers im injected with GH at 22.8 mg/day for 56 days resulted in a significant increase in protein gain in muscles of the carcass as well as noncarcass components of the empty body compared with vehicle injected controls (70). GRF iv injected every 4 h for 10 days significantly increased GH pulse amplitude, and a trend toward greater nitrogen retention, but this was not statistically significant compared with vehicle treated control beef calves (29). Because SRIF continuously iv infused at two dosages decreases plasma GH in a dose-dependent manner and decreases peak GH amplitude in response to a GRF challenge, pituitary liberation from the inhibitory effects of endogenous SRIF in HST calves may contribute to the stable basal GH concentration sufficient for continued long-term growth (31). Thus, it appears that raising the overall circulating basal GH concentration rather than GH pulse amplitude is required for positive nitrogen retention and growth in cattle. Moseley and colleagues findings in intact cattle support our hypothesis in that growth (positive nitrogen retention) was related to raising the overall basal GH concentration rather than an enhanced episodic pattern of hormone secretion. The results from the present study in cattle show that long-term growth is sustained by nonepisodic basal secretion of GH after HST, but absence of GH after hypophysectomy completely arrests growth. Thus, this ruminant species requires at least a modest basal level of GH secretion for statural growth unlike the guinea pig, a herbivore that is developmentally mature at birth, in which growth for a prolonged period continues unabated after hypophysectomy. In contrast, the rat, developmentally immature at birth and omnivorous after weaning, requires GH for growth; hypophysectomy arrests growth, but it is unknown whether nonepisodic endogenous basal GH secretion sustains long-term growth after HST in that species. From these results it seems that increasing circulating GH blood concentrations or argumenting endogenous basal secretion of the hormone could alter metabolism and nitrogen deposition for increased growth in cattle.


   Acknowledgments
 
We thank Drs. J. C. Van Gilder and S. E. Ziffren (Department of Surgery, College of Medicine, University of Iowa, Iowa City, IA) for counsel on surgical and postoperative procedures; Dr. S. L. Davis (Department of Animal Science, Oregon State University, Corvallis, OR) for ovine TSH antiserum; Dr. A. F. Parlow, NIDDK National Hormone and Pituitary Program for bLH; Drs. J. P. Kunesh, and P. G. Eness (Ambulatory Clinics, College of Veterinary Medicine, Iowa State University, Ames, IA) for monitoring the health status of the animals; and Messrs. M. E. Shell, C. R. Bohnker, L. P. Kertiles, and W. G. McDonald for excellent technical assistance.


   Footnotes
 
1 Presented in part at the 30th Annual Meeting of the Midwestern Section, American Society of Animal Science and American Dairy Science Association, Des Moines, Iowa, 1997 (Abstract 216). This work was supported in part by United States Department of Agriculture, Cooperative States Research Service, National Research Initative Competitive Grants Program, Grant 93–37203-8965 and 59–2191-1–2-033–0. All experiments in this report were performed following standards established by the Animal Welfare Act and NIH Guide for the Care and Use of Laboratory Animals, Publication 85–23. This is J-17986 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa (Projects 3223, 3316, and 2273, the last a contributing project to North Central Regional Project-NC-113). Back

Received September 11, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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