Prolactin secretion from the anterior pituitary gland is regulated by multiple factors including prolactin-release inhibiting factors (PIFs) and prolactin releasing factors. PIFs, however, usually dominate to exert a tonic inhibition in the biological system, and the physiological PIF is believed to be dopamine. However, there is accumulating evidence that dopamine can not only inhibit but also stimulate prolactin release. Many investigators believe that this is achieved by activating inhibitory and stimulatory subtypes of dopamine receptors. We tried to demonstrate that one subtype of dopamine receptors is capable of both inhibiting or stimulating prolactin release using GH(4)ZR(7) cells. GH(4)ZR(7) cells express only a short form of dopamine D(2) receptors (D(2s)). Low concentrations of three well-established D(2) receptor agonists (dopamine, apomorphine and bromocriptine) stimulated prolactin release from GH(4)ZR(7) cells while high concentrations inhibited the release. Haloperidol, a D(2) receptor antagonist, blocked the inhibitory action, but was unable to block the dopamine-induced stimulatory action. Pretreatment of cells with phenoxybenzamine, a receptor alkylating agent, abolished both the dopamine-induced stimulatory and inhibitory actions. Our results support the thesis that the stimulation of prolactin release induced by dopamine is mediated through dopamine D(2s) receptors since the GH(4)ZR(7) cells have only D(2s) receptors among dopamine receptors. We have concluded that the D(2s) receptor is capable of both stimulating and inhibiting prolactin release, probably via the activation of a G(s) protein by low concentrations and a G(i) protein by high concentrations of dopaminergic agents.
A Chang and SH Shin
G. Benagiano, M. Ermini, C. C. Chang, K. Sundaram and Fred A. Kind
Determination of radioactivity in urine and faeces was used to monitor absorption of labelled 6-methyl-17α-acetoxypregna-4,6-diene-3,20-dione from polydimethylsiloxane implants. Based on previously determined in vitro diffusion rates, mean absorption was 60% in hamsters, 80% in rabbits, and 85% in rats during the first month after implantation. Thereafter, excretion of radioactive material has slowly decreased. After six months, the rate declined to 40% of the original value.
Fred A. Kincl, K. Sundaram, C. C. Chang and Harry W. Rudel
Dissolution of progesterone, 19-nor-4-pregnene-3,20-dione and 6-methyl-17α-acetoxy-4,6-pregnadiene-3,20-dione was measured from lipid pellets of various composition. Values obtained in in vitro studies indicated that, after an initial period, the dissolution was constant. Studies in hamsters demonstrated that in vivo absorption declined with time at a rate similar to that observed with polydimethylsiloxane implants.
Fred A. Kincl, I. Angee, C. C. Chang and Harry W. Rudel
Determination of radioactivity in urine, faeces and various organs in rats was used to monitor the absorption of labelled 6-methyl-17α-acetoxy-4,6-pregnadiene-3,20-dione from polydimethylsiloxane implants or after oral administration. Given orally, peak plasma levels were obtained 4 h after administration. It took about 4 days to reach steady plasma levels when PDS implants were used. For a hypothetical biologically effective dose, megestrol acetate plasma levels were about 15 times higher than when an implant was used. Increased plasma levels seen after oral administration were reflected in increased uptake by various tissues. Compared to levels seen in animals having a PDS implant the increase was 40 times higher in liver, 60 times in kidneys, 8 times in adrenals, 6 times in testes and 12 times higher in the brain.
Y Furuhata, R Kagaya, K Hirabayashi, A Ikeda, KT Chang, M Nishihara and M Takahashi
BACKGROUND: Human growth hormone (hGH) transgenic (TG) rats have been produced in our laboratory. These TG rats are characterized by low circulating hGH levels, virtually no endogenous rGH secretion, and massive obesity. OBJECTIVE: To elucidate how energy balance and leptin sensitivity contributed to the establishment of this obesity. DESIGN AND METHODS: Food intake, locomotor activity and leptin concentrations in serum and cerebrospinal fluid were measured in TG rats and their non-transgenic littermates (control). The effect of intraperitoneal and intracerebroventricular injection of leptin on food intake and body weight gain was also examined. RESULTS: An increase in food intake and a decrease in locomotor activity were observed from 4 and 7 weeks of age, respectively, in the transgenic rats compared with control. Serum leptin concentrations of the transgenic rats were more than twice as high as those of control rats and were associated with an increased white adipose tissue mass and ob gene expression. Intraperitoneal injection of leptin significantly decreased food intake and body weight gain in control rats, but not in transgenic rats. Leptin concentration in the cerebrospinal fluid of transgenic rats was not different from that of control rats, and intracerebroventricular injection of leptin was similarly effective in reducing food intake and body weight gain as it was in control rats. CONCLUSIONS: These results suggest that the transgenic rats, whose GH secretion is suppressed, develop obesity due to early onset of an increase in food intake and a decrease in locomotor activity with leptin resistance resulting from deteriorating leptin transport from peripheral blood to cerebrospinal fluid.
M. R. Henzl, C. C. Chang, K. Sundaram and Fred A. Kind
The relationship between neonatal gonads and regulatory hypothalamopituitary centers was studied by transplanting the ovarian tissue from littermate females under the kidney capsule of male rats and hamsters. Males were castrated either neonatally or at the age of 21 and 50 days of life. Some animals were treated with 100 and 200 μg of oestradiol benzoate shortly after birth.
The ovarian tissue transplanted into males castrated on day 1 of life showed a relative abundance of luteinized follicles (average 12.6/graft). The progesterone plasma levels were the highest in this group (14.1 ng/ml). In animals castrated at a later date (21 to 50 days), the average number of luteinized follicles was markedly decreased (3.5/graft), and tertiary follicles with well-developed ova prevailed. Progesterone plasma levels were 5.0 ng/ml.
Injection of 100 μg of oestradiol benzoate (day 5 of life) into males castrated within 24 h after birth led to a decrease of luteinization regardless of when grafting was done. Neonatal injection of 200 μg oestradiol benzoate considerably impaired the graft acceptance.
It is concluded that the presence of testes in male animals impairs the formation of luteinized follicles in the ovarian graft; however, luteinization is not completely abolished and it is of interest that the luteinized tissue is capable of synthesizing progesterone.
Debraj Mukherjee, Hasan A Zaidi, Thomas Kosztowski, Kaisorn L Chaichana, Roberto Salvatori, David C Chang and Alfredo Quiñones-Hinojosa
Surgery remains a common form of treatment for sellar and parasellar tumors involving the pituitary gland and adjacent structures. Studies have suggested that pituitary surgery procedures performed at high-volume centers are associated with less adverse outcomes, yet it remains unclear which types of patients are more likely to be admitted to such centers. We set out to determine which factors most influenced admission to these high-volume centers.
A retrospective analysis of the National Inpatient Sample over an 18-year period was linked to socioeconomic and environmental data contained within the Area Resource File. Only patients undergoing transsphenoidal surgery in the United States, >18-years-old were included. The primary outcome was admission to a high-volume (>25 pituitary surgeries/year) hospital.
Overall, patients' odds of admission to a high-volume center increased over an 18-year time period. However, African–Americans (odds ratio, OR=0.46), Hispanics (OR=0.28), and Asians (OR=0.49) experienced declining odds of admission over time. Patients from high-income brackets (OR=1.53) and from areas with higher neurosurgeon density (OR=1.61) were more likely to be admitted to high-volume centers. Conversely, patients coming from counties with higher poverty (OR=0.92) were less likely to be admitted to high-volume centers.
Racial and socioeconomic factors play a significant role in the admission of patients to high-volume pituitary surgery centers. This study demonstrates potential key policy areas for meaningful intervention to help ease disparities in access to quality care for surgical pituitary disease.
Yingbo Lin, Hermine A van Duyvenvoorde, Hongyu Liu, Chen Yang, Dudi Warsito, Chang Yin, Sarina G Kant, Felix Haglund, Jan M Wit and Olle Larsson
The insulin-like growth factor1 receptor (IGF1R) is important in growth and development, and inactivating IGF1R mutations cause short stature and relatively high levels of serum IGF-I. We identified an unclassified IGF1R R1353H variant in a male with extreme tall height, very low levels of serum IGF-I and delayed and prolonged growth spurt. The index case’s mother and three sons all carried the variant, but so far only the eldest son (age 18 years) presented with tall height. We hypothesized that the variant could constitute an activating mutation.
The IGF1R R1353H variant was investigated in Igf1r−/− mouse embryonic fibroblasts (R-cells) by cell cycle, colony formation and transcriptome analyses.
The IGF1R R1353H (R-1353) exhibited significantly increased cell proliferation, G1-S progression and colony formation in soft agar. RNA sequencing identified 195 differentially expressed genes between R-WT and R-1353 (adjusted P < 1E-100). Most genes were upregulated in R-1353, including the gene encoding the androgen receptor (AR). Gene expression profiling showed the most significant enrichment in extracellular matrix organization (P = 2.76E-7), collagen biosynthesis (P = 1.21E-5) and cell adhesion (P = 7.38E-5). Retrospective biochemical analysis of the index case revealed decreased testosterone and sex hormone-binding globulin levels, whereas LH and FSH were within normal ranges. This profile suggests an increased sensitivity to androgen, which is compatible with the enhanced expression of Ar in R-1353 cells.
Our findings suggest that R1353H constitutes an activating IGF1R variant. The possible deregulation of collagen turnover and increased androgen sensitivity implicates an association to tall phenotype in male carriers.