In the control theories, aging is under genetic and environmental control. Endocrine function plays an important role in this control system by mediating between the environmental influence and the presumptive “aging gene”. Therefore, the intrinsic aging of the hypothalamus, such as the changes in sensitivity to feedback suppression or stimulation, may lead to homeostatic failure and then age-related pathology.
As the subject of study we have selected the senile changes in the hypothalamicpituitary-ovarian axis in the rat of the Wistar strain. The cessation of estrous cycle and the onset of persistent estrus or repetitive pseudopregnancy usually take place as early as at the end of the first half of life in rats.
In this paper the results of the following experiments are briefly dealt with : (i) reciprocal transplantation of ovaries between young and old rats (the term “old” designates here “incapable of reproduction”), (ii) comparison of LH and FSH binding abilities in the ovarian preparations, (iii) comparison of serum and pituitary concentrations of LH, FSH and prolactin and the modifications after ovariectomy or by the administration of pharmacological drugs, and (iv) the difference between young and old rats in intensity of dopamine fluorescence in the hypothalamus.
The results of these experiments seem to point to the hypothalamic-pituitary part rather than more peripheral organs (ovaries) as being primarily responsible for the outcome of the senile changes in the female rat.

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The changes of hormone secretion and its control mechanism in the pituitary-gonadal axis in the aging male were studied, and the following results were obtained.
1. The mean levels of serum total testosterone and free testosterone index declined progressively from the 5th decade with, however, a wide range of individual values, and the increments of serum testosterone after LH-RH or hCG administration were significantly reduced in the aged men studied. On the other hand, basal serum LH and FSH levels increased slowly after the 5th decade, indicating a more pronounced increase after the age of 70. The responses of these gonadotropins and LH subunits to LH-RH increased significantly in the aged group.
2. Three days after daily administration of testosterone propionate, serum testosterone levels in the aged group were elevated more definitely than those in the young group, and basal LH and FSH levels in both groups were suppressed to nearly the same extent, but the responses of LH and FSH to LH-RH did not decrease except for a young group given a higher dose of testosterone propionate.
3. Cytosol testosterone and 5a-dihydrotestosterone receptors in the hypothalamus and pituitary of aged male rats decreased to about 50% of those in the control young male rats, whereas estradiol receptors remained unchanged.
These results indicate that the changes in pituitary-gonadal function in aging men may occur primarily in the testis and suggest the possibilities that (1) the feedback action of testosterone on gonadotropin secretion could be exerted at the hypothalamic level rather than at the pituitary level, and that (2) the set point of testosterone in its negative feedback control of gonadotropin secretion in the aged males might be reset at a higher level, probably due to the decrease in gonadal steroid hormone receptors in the hypothalamus and pituitary.

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Observing the hormonal secretion of the anterior lobe of pituitary in women, gonadotropin increases significantly in the climacteric and senile period, particularly in FSH, as compared to the reproductive period. While TSH, ACTH, GH remain unchanged and PRL decreases slightly. In general it would seem that the elevated gonadotropin level is well sustained throughout the remainder of life even past the age of 80.
Concerning the ability of the secretion of steroid hormone in the ovary, estradiol is gradually reduced through the premenopausal period, and testosterone is inversely increased. This pattern becomes more apparent after the menopause. It seems to have the same tendency of cyclic-AMP and steroid dehydrogenase in the ovary. However, estradiol in peripheral blood decreases slightly during the senile period, also testosterone decreases gradually with aging. It means testosterone secreted by the ovary seem to have converted into estradiol in other organs.
TeBG has no definite evidence of any relation to the process of aging. Furthermore DHA and DHA-S have a tendency to decrease. However, there is no significant change in cortisol with aging.
During the past 20 years, there has been a tendency of menarche occuring at an earlier age, and particularly menopause beginning at a later age.
Estradiol receptor in the uterus has sustained well in qualitative reactivity even in old age.
The loss of balance between sexual desire and sexual intercourse is gradually aggravated with aging. It seems that psychotropics rather than estradiol has a greater meaning in regard to the sexual activity of the aged rat. Therefore this provides us a clue that women seem to have a necessity of an emotional adjustment in their sexual life on the process of aging.

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To test the hypothesis that diabetes is a form of accelerated aging, the following observations were made. 1) The incidence rate of diabetes mellitus had its peak at around 50 years of age with a gradually decreasing rate thereafter. This was clearly different from the manner of incidence of such disease as arteriosclerosis which increased with advancing age. 2) 100g of the oral glucose tolerance test performed on elderly subjects aged 60 to 89 years revealed high incidence of abnormal tolerance, 21% diabetic and 53% borderline types. 3) The insulin secretory capacity to glucose load of the subjects was not different from that of young and middle-aged subjects from 20 to 49 years old. Therefore, decreased tolerance to glucose load could not be ascribed to deficient insulin secretion. 4) No abnormality of glucagon response to glucose load was found in the old. 5) Serum β-N-acetylhexosaminidase activity was not increased in elderly subjects, again contrasting with the increased activity found in diabetics. 6) Both glycolytic and gluconeogenic enzyme activities were decreased in the liver of aged rats. 7) No specific abnormality in insulin secretory response was observed in Werner's syndrome which might be considered to be a model for aging.
All the above observations do not support the aforementioned hypothesis. Abnormality of glucose tolerance frequently observed in elderly subjects appears to be caused by other pathogenesis than diabetes mellitus.

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Measurements of bone mineral content (BMC), intestinal ⁴⁷Ca absorption, calcium regulating hormones, sex hormones and other hormones were performed on 32 healthy aged subjects (60y.o-85y.o) and 26 controls (15y.o-42y.o).
In BMC, there was a progressive fall after age 40 in both sexes, with the rate of decrease being greater in women than in men, so that at age 70-80, BMC was only 70% of that seen at age 40 in males and 50% in females.
There was a significant correlation between BMC and plasma testosterone levels in the men and between plasma estrogens and BMC in the women, suggesting that testosterone might play an important role in maintaining bone remodeling at the normal rate in males, whereas estrogens were important in females.
Plasma PTH showed no change with age and sex. However, response of the parathyroid to EDTA infusion was significantly lower in the aged females than that seen in the aged males and the controls, indicating that the aged females were in an occult hypoparathyroid state. Basal plasma calcitonin levels were lower in the aged of both sexes than those in the controls. Response of C-cell to Ca infusion was also low, indicating that the C-cells function was reduced in the aged subjects.
Plasma 1,25(OH)₂D was reduced in the aged subjects, while plasma 25(OH)D levels were slightly high. It was speculated that the decrease in the conversion of 25-OH-D₃ to 1,25(OH)₂D₃ might be an important factor in causing a decrease in the rate of mineral turnover in bone with age.
In conclusion : aging and calcium metabolism is characterized by a chronic negative imbalance. This negative balance could be a reflection of a hormonal imbalance occurring with aging, and it would become more important to define these changes in order to devise both therapeutic and preventive measures.

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Insulin is secreted from pancreatic B-cells, acts on liver cells, and is distributed throughout the target cells of the body. When it acts on the target cells, it must bind to the specific receptor on the surface of the cell membrane.
In this paper I reported on the binding characteristics of insulin on adipocytes of rats and pigs, the changes in insulin action in various pathological conditions, and finally some properties of anti-insulin receptor antibodies on adipocyte metabolism. The changes in the number of insulin receptor sites are closely associated with the circulating insulin concentration. When rats were fasted for 24 hr., the binding of insulin to the adipocytes increased mainly due to the increase in receptor number and not to the change in affinity, and these changes were restored by refeeding. These changes of the binding were reversely correlated with the change in plasma IRI concentrations. 2-deoxyglucose uptake and the glucose oxidation by the adipocytes were also decreased by fasting; however the latter was more pronouncedly disordered. When expressed as a percent change above basal, adipocytes obtained from fasted and control rats revealed similar insulin effects on glucose transport per unit insulin bound to the cells, suggesting that the coupling mechanism between receptor and effector was not significantly disturbed. However when the values were expressed in absolute terms, basal and insulin-stimulated glucose transport was significantly lower with fasting. Similar increase in number and not in affinity, of insulin receptors of adipocytes was demonstrated in streptozotocin treated diabetic rats. Plasma IRI levels were significantly lower in diabetic than in control rats.
In a clinical study, we investigated the insulin binding to the peripheral circulating mononuclear cells obtained from several pathological conditions. The specific binding of insulin to the cells was lower in lipoatrophic diabetes, Werner syndrome, and in extreme obese states; however, the binding was not significantly different between hyperglycemic diabetics (FBS>140) and normal controls.
There are several factors which are known to compete with insulin on binding with insulin receptors : they are NSILAs, somatomedin A and anti-insulin receptor antibodies. Plasma gamma globulin fraction obtained from a Sjögren syndrome with extreme insulin resistance revealed insulin-like activities on rat as well as on human adipocytes. They were the promotion of glucose transport, glucose oxidation and protein synthesis, and the inhibition of lipolysis. When the antibody was present in the incubation medium, the binding of insulin to the adipocytes was suppressed by the reduction in affinity. The discrepancy between the insulin action in vivo and in vitro are not disclosed on this pathological condition. The possibilities of the specific changes in the receptor of the patient's own cells were discussed.

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i) Brain receptors : Specific progesterone (P) receptors have been demonstrated in estrogen (E) -primed rat hypothalamus and anterior hypophysis, suggesting that P acts upon the brain through its receptors (R). Along with the presence of R for E, androgens (A) and corticoids in the brain, this may validate the hypothesis of the “one to one correspondence” relationship between the steroid hormone and its R.
ii) Chromatin binding : Binding of estradiol (E₂) cytosol R complexes to chromatin prepared from E sensitive (hypothalamus, hypophysis and uterus) and non-sensitive (cerebral cortex and spleen) tissues was examined to elucidate the regulative mechanism of specificity of the E sensitive cells in the brain and hypophysis. Chromatin binding depended roughly upon the amount of the cytosol Rs contained in the cells. The specificity of the target cells seemed also to be regulated at the chromatin level to some extent. In this context it is worthy that E cytosol receptors (ER) obtained from rat hypothalamus and anterior hypophysis were very similar, suggesting possible absence of organ specificity of the ERs in the hypothalamo-hypophysial-uterine system. Differential effects of E in the target tissues may be ascribable to the events after cytosol R.
iii) ER in the target system of primates and hum ans : The concentrations of ER in human uterine cytosols were the endometrium > the cervix > the myometrium >> the tube. ER was isolated by gradient centrifugation from anterior hypophysial cytosols from the Rhesus monkey. Furthermore, on sucrose density gradients of normal anterior hypophysial cytosols obtained from a patient with advanced metastatic breast cancer, there was distinct binding of P and dexamethasone, suggesting the presence of possible Rs for steroid hormones in human central targets.
iv) Applicability of newly synthetic steroids for receptorassay : R5020, R1881 and R2858 were employed for analysis of P-, A-and E Rs, respectively, in human breast cancer, human endometrial cancer, rat pituitary tumors and fetoneonatal rat brain. Decreasing concentrations of ER and PR were found in endometrial cancer with increasing grade of undifferentiation. These synthetic steroids have been found as valuable tools for the receptorassay, basically or clinically.

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Although the thyroid hormones are believed to exert their effects on intracellular sites of action, very little has been known so far of the receptors and mechanism of hormone action. Recently, however, much progress has been made in nuclear and cytosol binding proteins. In this symposium, therefore, recent advances in these fields were presented together with our newly obtained results.
Cytosol binding proteins for thyroid hormones were demonstrated in animal tissues by various methods. Above all, multiple binding proteins specific for T4 and T3 were found in the liver cytosol by Pevikon thin-layer electrophoresis. The binding sites of cytosol proteins are relatively hormone-specific and large in capacity. The cytosol proteins competitively inhibit nuclear binding and degradation of hormones. Therefore, they are thought to participate in the intracellular transport of hormones and possibly in the regulation of hormone metabolism.
Nuclear binding protein with a high-affinity, low-capacity site for T3 was found as a non-histone protein in the chromatin by Oppenheimer et al. The binding capacity is relatively large in hormone-responsive organs and small in non-responsive organs. The relative binding affinity for T4 analogues is very closely related with their hormonal activity. Furthermore, the nuclear occupancy of T3 was shown to be closely related with mitochondrial a-GPD activity. Our recently obtained results indicate that the T3-binding capacity was increased in T3-treated hyperthyroid rats. Therefore, it appears very likely that the nuclear T3-binding protein is a thyroid hormone receptor controlling hormonal action, although a molecular mechanism following T3-binding remains to be elucidated.

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The regulation of hormone receptors is exerted through genetic and environmental factors. Genetic control of hormone receptors is analyzed by studying changes in their characteristics during the ontogeny, phylogeny, and malignant transformation of the cells.
The pattern of changes in glucocorticoid receptor contents in cytosol fraction during ontogeny is quite different from tissue to tissue. In the rat's lung tissue, glucocorticoid receptor contents are high during the fetal period and decrease promptly after birth, whereas the contents in the rat's liver are low during the fetal life and start to increase after birth. Glucocorticoid receptors in thymocytes of rats during T-cell differentiation increase transiently, which gives a high sensitivity to steroid treatment in the immature thymocytes. The induction of glucocorticoid receptors in different tissues at different stages of life is strictly controlled by the genetic program. Whether the induction is mediated by humoral factor (s) remains to be clarified.
Amounts of glucocorticoid receptors in a particular tissue are subjected to species differences. In a group of steroid-sensitive animals such as the rat, mouse, rabbit and hamster, the amount of glucocorticoid receptors in liver cytosol is rich, whereas it is poor or undetectable in a group of steroid-resistant animals, such as the human, monkey, dog and guinea-pig.
Changes in hormone receptors are also observed in malignant tumors. Under certain circumstances, hormone receptors “appear” in malignant tumors originated from organs in which no detectable hormone receptor is observed. These tumors may be called hormone receptor-producing tumors.
Environmental factors are also important in regulating hormone receptors. Down regulation of hormone receptors is observed in insulin and glucocorticoids.

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Endocrine diseases due to altered hormone action in the target organ have been called “peripheral organ unresponsiveness to hormone”. With the advent of research on hormone receptors in recent years, a new term, “receptor disease', has also been used to define some disorders due to peripheral organ unresponsiveness. However, the definition of receptor diseases has not yet been established. The author tentatively defines receptor disease as disorders due to (1) an abnormality in number or affinity of hormone receptors, (2) the presence of a substance which affects interaction between hormones and receptors and (3) a change in specificity of receptors. Those diseases due to possible receptor abnormality are also tentatively included in this category.
Receptor diseases can be classified into several groups :
(1) Diseases due to congenital abnormalities in hormone receptors. Testicular feminization syndrome and Refetoffs syndrome are well-established diseases due to lack of intracellular hormone receptors.
(2) Diseases due to possible congenital abnormalities in hormone receptors. This group consists of several diseases due to peripheral organ unresponsiveness of unknown etiologies, such as pseudohypoparathyroidism, renal diabetes insipidus, congenital adrenal unresponsiveness to ACTH and Laron type dwarfism. In these diseases, congenital defect is considered to exist in either hormone receptors or subsequent biochemical reactions.
(3) Diseases with altered hormone receptors through the regulatory mechanism. Elevated plasma levels of a hormone usually reduce the number of its receptors, thus inducing lowered responsiveness to the hormone. An example from this group is obesity, in which reduced number of insulin receptors is induced by elevated plasma insulin levels.
(4) Diseases due to possible anti-receptor antibodies. Production of antibodies against receptors usually interferes with hormone-receptor interaction and impairs hormone action on target cells. Insulin-resistant diabetes caused by insulin receptor antibodies is an example from this group. Recent studies suggest a possible role of anti-TSH receptor antibodies in the pathogenesis of Graves' disease.
(5) Abnormalities in specificity of hormone receptors. Functioning tumors of endocrine organs have often multiple hormone receptors and respond to non-physiological stimuli.

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The urinary 3β-hydroxy-Δ⁵-steroids excreted during the period of the first week by newborn infants were analyzed by means of gas chromatography and gas chromatography-mass spectrometry to study the changes in the amount of these steroids. The changes in the amount of each steroid after the administration of ACTH were also studied. The results are summarized as follows :
1) Seven kinds of 3β-hydroxy-Δ⁵-steroids were identified in the urine of the newborn infants. 17a, 21-dihydroxypregnenolone was newly identified.
2) The daily changes in the amount of each of these steroids differed. Generally, the amount of the C-19 steroids increased day by day and that of the C-21 steroids decreased during the period of our observation.
3) After the administration of ACTH, the amount of these urinary steroids excreted increased at nearly the same rate.

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In order to know the secretory behaviors of human growth hormone (hGH), human prolactin (hPRL), and chorionic somatomammotropin (hCS) in normal and molar pregnancy or puerperium, and after evacuation of hydatidiform mole, the following studies were undertaken.
Forty five normal pregnant women of every period of gestation, 40 women of postpartum (good or poor lactation), 20 patients with molar pregnancy between the 13th and 19th gestational week, 25 patients with good prognosis after the evacuation of hydatidiform mole, 20 patients with destructive mole, and five nonpregnant subjects volunteered for this study.
All studies were started at 0800h after an overnight fast. The subjects reported to the endocrine research facility and were placed at bed rest in a quiet room for about one hour. A#18 Medicut was placed in an antecubital vein and kept patent with a slow drip of normal saline. Two baseline blood samples were drawn 15 min. apart and the results were averaged. Immediately after the second sampling, 30g of arginine was administered intravenously over 30 min. Blood samples were collected at 30, 45, 60, 90 and 120 min. after the initiation of the infusion.
Serum was immediately separated from the blood samples by centrifugation of 3000 rpm for 10 min. and stored for assay at-20°C. HGH levels were measured by a radioimmunoassay kit (Dinabot, Tokyo, Japan). Serum hPRL was determined by a double antibody radioimmunoassay system using hPRL supplied by NIH-NIAMDD, U.S.A. HCS level was measured by the hCS-Kobe double antibody radioimmunoassay system. Immunological crossreaction was not observed between these radioimmunoassay systems within the assay ranges. Serum 17β-estradiol and progesterone were measured by a CIS(CEA-IRE-SORIN, France)'s radioimmunoassay kit for each of the steroid hormones. Statistical analysis was carried out using a Student's t test.
1. The secretions of serum hGH, hPRL and hCS during normal pregnancy were as follows :
The baseline level of hGH remained almost unchanged throughout the course of pregnancy, but that of hPRL and hCS increased with the progress of pregnancy.
The hGH response to arginine infusion decreased (p=n.s. in first trimester, P<0.01 in second trimester, P<0.001 in third trimester), but the hPRL response increased along with the progress of pregnancy (p=n.s. in first trimester, PC0.001 in second and third trimester).
During arginine infusion, the hCS concentration did not change.
2. The secretions of serum hGH and hPRL in puerperium were as follows :
The baseline level of hGH did not change as compared to that of nonpregnant or pregnant women.
The hGH response to arginine infusion was suppressed at the first postpartum week (P<0.01), then recovered to the nonpregnant level at the fifth postpartum week.
Basal and response hPRL maintained a high level from the first to third postpartum week, and decreased at the fifth postpartum week (P<0.001-0.01, respectively).
No significant difference was seen in basal and response hPRL among the subjects with good or poor lactation.
3. The secretions of serum hGH, hPRL, hCS and steroid hormones in molar pregnancy were as follows :
The baseline level of hGH did not change as compared to that of nonpregnant or pregnant women.
The hGH response to arginine infusion in molar pregnancy was greater than that in normal pregnancy (P<0.01).
Basal and response hPRL were higher than that of normal pregnant women in the same gestational week (P<0.01).
On an average, hCS concentration in molar pregnancy was 0.22/μg/ml and significantly low compared to that in normal pregnancy (P<0.001).
The mean value of 1713-estradiol was lower in molar pregnancy than in normal pregnancy (P<0.01), but no significant difference existed regarding the levels of progesterone.
4. The secretions of serum hGH,

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