THE CLASSICAL CONCEPT of neuroendocrine control of the pituitary as proposed by Harris stipulates that the endocrine functions of the anterior pituitary are controlled by hypothalamic releasing factors or release-inhibiting factors. It was postulated that these factors are present in hypothalamic neurons which project into the median eminence (ME) of the basal hypothalamus and end in contact with the hypothalamic-hypophyseal portal vessels (1). It has subsequently been shown that growth hormone (GH) secretion is regulated by both stimulatory and inhibitory factors of hypothalamic origin. Like other anterior pituitary hormones, GH is secreted episodically. In all mammalian species so far studied spontaneous episodes of GH secretion occur several times over a 24-h period (2–8). Particularly in the adult male rat there is a striking regularity in the GH pulses which occur at 3- to 4-h intervals and reach levels of several hundred ng/ml.

Sexual dimorphism in the control of growth hormone secretion.

The long-term skeletal effects of ovariectomy and aging were studied in female Sprague-Dawley rats sacrificed at 270, 370, and 540 days after bilateral ovariectomy (OVX) or sham surgery at 90 days of age. The proximal tibia was processed undecalcified for quantitative bone histomorphometry. For continuity, data from these late time points were combined with previously published data from earlier time points (0-180 days). A biphasic pattern of cancellous bone loss was detected in the proximal tibial metaphysis of OVX rats. An initial, rapid phase of bone loss out to 100 days was followed by an intermediate period of relative stabilization of cancellous bone volume at the markedly osteopenic level of 5-7%. After 270 days, a slow phase of bone loss occurred during which cancellous bone volume declined to 1-2%. Both the initial, rapid phase and the late, slow phase of bone loss in OVX rats were associated with increased bone turnover. In control rats, cancellous bone volume remained constant at 25-30% out to 270 days (12 months of age), then decreased to approximately 10% by 540 days (21 months of age). This age-related bone loss was also associated with increased bone turnover. It is interesting to note that the proximal tibial growth plates were closed in approximately a quarter of the control rats by 15-21 months of age. Our data indicate that a slow rate of bone loss and increased bone turnover persist in OVX rats during the later stages of estrogen deficiency. Therefore, the development of osteopenia is coincident with increased bone turnover in OVX rats as well as in aged, control rats.

Long-term effects of ovariectomy and aging on the rat skeleton

Female Sprague Dawley rats were subjected to either bilateral ovariectomy or sham surgery. Tetracycline derivatives were administered to each rat on two separate occasions to label sites of bone formation. All rats were sacrificed at 5 weeks postovariectomy and their proximal tibiae were processed undecalcified for quantitative bone histomorphometry. A twofold decrease in trabecular bone volume was noted in the proximal tibial metaphysis of ovariectomized rats. This bone loss was associated with elevated histomorphometric indices of bone resorption and formation. Ovariectomy increased osteoclast surface and numbers as well as osteoblast surface and numbers. Elevations in calcification rate and fractional trabecular bone surface with double tetracycline labels also suggest that bone formation was stimulated in ovariectomized rats. In addition, ovariectomized rats exhibited a greater rate of longitudinal bone growth relative to sham-operated control rats. These histomorphometric data indicate that ovariectomy induces marked bone loss and accelerated skeletal metabolism in rats.

Skeletal alterations in ovariectomized rats

Gonadal hormones and behavioral regulation of body weight

Publisher Summary Sex and reproductive condition often have very dramatic effects on the behaviors, affecting body weight and composition in a wide variety of species, although most of the experimental work has been performed with rats. Gonadal steroids also affect behavioral and physiological regulation of body weight. A great deal of descriptive research and simple endocrinological approaches have given a good idea of how regulatory behaviors and body weight fluctuate with variations in reproductive status and which hormones are responsible for these fluctuations. A variety of factors, including diet palatability, environmental temperature, relative levels of various metabolic hormones, and the opportunity to exercise in running wheels, affect body weight level in rats. Several kinds of neurological damage may also raise or lower body weight set-point. Animals expend calories in a wide variety of ways, but the two principal sources of energy loss (and the two most affected by behavior) are exercise and heat loss to the environment. In female rats, estradiol is the principal ovarian steroid influencing behavioral regulation of energy balance, as well as progesterone also affects weight regulation in female rats. An estrogen-like compound could be used to lower body weight and combat obesity in human being. An ideal weight-control drug would be one that acts on neural weight-regulating systems to lower body weight set-point without being estrogenic or anti-estrogenic in other hormone-sensitive systems. Food intake is linked to sex hormone secretion to ensure that eating and energy stores will increase during pregnancy, and the fluctuations during estrous cycles are simply a by-product of this association.

Sex Hormones, Regulatory Behaviors, and Body Weight

Effect of medroxyprogesterone acetate upon stimulated release of growth hormone in men.

In 3 mildly osteoporotic male patients, human growth hormone administration produced increased urinary calcium and hydroxyproline excretion without reduction of fecal calcium, effects considered compatible with increased bone resorption. During growth hormone therapy, the serum phosphorus rose without definite reduction of urinary phosphorus excretion, suggesting a possible nonrenal origin of the hyperphosphatemic action of growth hormone. The expected anabolic effects of growth hormone were also observed, including reduction of blood urea nitrogen and of urinary nitrogen excretion. Superimposed estrogen therapy reduced the elevations of urinary calcium, urinary hydroxyproline, and of serum phosphorus, and antagonized the nitrogen-retaining effects of growth hormone. While there was no significant reduction in urinary phosphorus excretion during growth hormone therapy, concomitant estrogen administration appeared to produce detectable phosphaturia in 2 patients. The favorable effect of estrogen u...

Estrogenic Antagonism of Metabolic Effects of Administered Growth Hormone

In four acromegalic patients, estrogen therapy did not significantly alter the mean values of basal radioimmunoassayable plasma growth hormone. In two patients, estrogen therapy did not qualitatively alter the lack of reduction of plasma growth hormone levels after oral administration of glucose, nor did it reduce in these patients the response of plasma growth hormone to insulin-induced hypoglycemia. In one of the patients, insulin sensitivity with respect to glucose and the hypoglycemia-induced growth hormone rise seemed greater during estrogen therapy. Despite the absence of demonstrable reductions inplasma growth hormone level under varying experimental circumstances, the administration of estrogen resulted in reduction of urinary calcium and hydroxyproline excretion, in reduction of radiocalcium bone accretion rates and exchangeable pools, in reduction of serum phosphorus, and in more negative nitrogen balances. The experimental data therefore suggest that estrogen may be a peripheral antagonist of the effects of excessive growth hormone secretion in acromegaly.

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Martin Schiffer

Papers

Effect of medroxyprogesterone acetate upon stimulated release of growth hormone in men.

Estrogenic Antagonism of Metabolic Effects of Administered Growth Hormone

Mechanism of estrogenic action in acromegaly