Biomedical subjects
Publications and source records attributed to S Bhasin.
Hemodynamic data are presented which not only depict typical tamponade physiology, but demonstrate that hypotension may not necessarily be present with slow accumulation of pericardial fluid in myxedema patients. This case is unique in that severe hypertension, as part of the presentation of hypothyroid tamponade, has never been reported.
FSH is a major regulator of inhibin production in the testis. FSH effects on Sertoli cell inhibin production are believed to be mediated, at least in part, via the cAMP second messenger system. Previously, it has been shown that 8-bromo-cAMP (8-Br-cAMP) stimulates inhibin-alpha mRNA levels. This study examines whether the cAMP-induced increase in inhibin-alpha mRNA levels results from increased alpha mRNA synthesis, decreased degradation of mRNA, or both. The effects of cAMP on inhibin-alpha gene transcription were examined using nuclear run-on assays. Furthermore, the ability of 8-Br-cAMP to drive the transcription of chimeric constructs containing a 2.2-kilobase (kb) segment of the 5'-regulatory region of the alpha gene placed upstream of the coding region of the luciferase reporter gene was also examined. Data from nuclear run-on assays demonstrated rapid induction of alpha gene transcription by cAMP within 2 h and maximal 4- to 5-fold increase within 4-8 h in primary Sertoli cells. Transfection of TM.4 and JEG.3 cells with an alpha (2.2 kb):luciferase chimeric construct (containing 2.2 kb of the alpha gene 5'-flanking DNA) revealed rapid time-dependent induction of luciferase activity by 8-Br-cAMP in these cell types. To examine the effects of 8-Br-cAMP on alpha mRNA stability, cells were pretreated with medium or 50 micrograms/ml 8-Br-cAMP for 24 h before addition of 5 microM actinomycin D to arrest new RNA synthesis, and the decay of alpha mRNA transcripts was assessed over 24 h by Northern analysis and nonlinear regression.(ABSTRACT TRUNCATED AT 250 WORDS)
FSH, a major regulator of inhibin production in the testis, is believed to exert its effects via cAMP second messenger system. Inhibin alpha-subunit gene appears to be regulated by cAMP and has a palindromic cAMP response element sequence TGACGTCA. However, the regulation of the inhibin beta B-subunit gene by cAMP has been less clear. It has been assumed that beta B may not be regulated by cAMP, based mainly on observations that FSH stimulates only alpha, not beta B, mRNA levels, and that the 5'-up-stream regulatory region of the beta B gene does not contain the classical cAMP response element. However, we have observed that 8-bromo-cAMP stimulates beta B mRNA levels in both primary Sertoli (approximately 2-fold) and TM.4 cells (approximately 5-fold). We examined whether this cAMP-induced increase in beta B mRNA levels is the result of increased transcription or altered mRNA stability. Data from nuclear run-on assays demonstrate about a 2-fold increase in relative mRNA synthesis rates in primary Sertoli-cells and about a 4- to 5-fold increase in TM.4 cells. Transfection studies in TM.4 and JEG.3 cell lines with beta B:luciferase chimeric reporter gene constructs containing 1.5 kilobases of the beta B 5'-up-stream regulatory region revealed marked cAMP induction of reporter gene activity in both cell types.(ABSTRACT TRUNCATED AT 250 WORDS)
Anomalous origin of the right coronary artery from the left sinus of Valsalva is a rare but clinically significant congenital abnormality, difficult to diagnose angiographically. We describe a patient in whom magnetic resonance imaging was used to delineate the anomalous course of the right coronary artery following angiographic demonstration limited by technical considerations.
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PURPOSE: Gonadal functions were evaluated in 26 male patients with Hodgkin's disease (HD), who were in continuous unmaintained remission following combination chemotherapy consisting of COPP/MOPP. MATERIALS AND METHODS: These patients had received chemotherapy during the prepubertal phase. The median duration after termination of chemotherapy was 72 months. RESULTS: Semen analysis of 18 patients showed azoospermia. Hormonal analysis showed elevated mean levels follicle-stimulating hormone (FSH) and inhibin as compared to age-matched controls, whereas luteinizing hormone levels were only marginally elevated. CONCLUSIONS: These results suggest that COPP/MOPP causes severe damage to germinal epithelium even when given during prepubertal age. Sertoli cells, which are responsible for secretion of inhibin, are resistant to these cytotoxic agents. Our data emphasize the lack of gross dysfunction of Leydig cells. It is possible that an alternative chemotherapy protocol (ABVD) may be used in young patients to minimize the gonadal damage.
OBJECTIVE: To examine the relationship between serum T levels and sexual function when T levels are varied in the normal male range by pharmacological means. Two groups of healthy men were treated with a depot form of GnRH agonist leuprolide acetate (Lupron depot; TAP Pharmaceuticals, Chicago, IL) on days 1 and 31 to suppress endogenous T production and either 4 (n = 6) or 8 (n = 5) mg/d T replacement by a sustained release, long-acting T microcapsule formulation on day 1. OUTCOME MEASURES: Sexual function was evaluated by daily logs of sexual activity and electroencephalogram-coupled nocturnal penile tumescence recording before and after 9 weeks of treatment. RESULTS: Serum T levels in 4 and 8 mg/d groups were at low and high ends of the normal male range, respectively (10.5 +/- 1.7 versus 26.5 +/- 3.4 nmol/L). The number and duration of rapid eye movement (REM) periods, latency to REM sleep, erections/REM period, magnitude, and duration of tumescence were not significantly different between the 4 and 8 mg groups. Sexual logs also did not show significant differences in overall scores or in subcategories of intensity of sexual feelings (libido) and sexual activity between the two doses. CONCLUSIONS: These data indicate that erectile function and sexual activity and feelings are restored by relatively low T levels. These data may help explain why some partially hypogonadal men continue to have normal sexual function and the absence of good correlation between serum T levels in the normal range and sexual function.
Clinicians and clinical investigators have developed improved means for controlling testicular function in men. New and refined approaches for stimulation and inhibition of the hypothalamic-pituitary-testicular axis are now available. This chapter reviewed the most successful ways to inhibit the reproductive axis in men and its current application to the treatment of precocious puberty, metastatic prostate cancer, benign prostate hyperplasia and as prospective male contraceptives. Safe, effective and reversible medical approaches to male contraception are now approaching reality. Azoospermia and severe oligozoo/azoospermia can now be accomplished in the majority of men with combined GnRH antagonists and replacement doses of testosterone. Androgens and androgen-progestogen concentrations will induce azoospermia in over 90% of Asian men and azoospermia or severe oligospermia in Caucasian ethnic groups. Field trials are ongoing to determine whether testosterone administration will be more effective than condoms as contraceptives. True precocious puberty can now be managed more effectively than in the past by suppression of gonadotropin secretion with GnRH analogues. Precocious puberty due to other causes can be treated more effectively with inhibitors of steroidogenesis and blockers of androgen action. Metastatic prostate cancer, previously treatable with either castration or oestrogens, is now amenable to suppression of androgen secretion. GnRH analogues are given either alone or combined with blockers of androgen action. While significant palliative effects are observed with endocrine ablative therapy in most men with Stage C or D prostate cancer, modest increases in duration of survival may be seen. Benign prostate hyperplasia was previously approachable only with surgical intervention. Recent data have suggested that medical treatment with 5 alpha-reductase inhibitors and/or selective alpha-adrenergic blockers may offer non-surgical alternatives in some patients. More data are needed to determine the role of medical management of this common disorder.
Limitations of presently available testosterone esters (enanthate and cypionate) include the fluctuating serum testosterone levels and the need for relatively frequent injections (every 10-21 days). These limitations of testosterone esters have prompted the development of more physiological and longer acting systems for androgen delivery. This paper reports pharmacokinetic and pharmacodynamic data with a second generation long-acting testosterone microcapsule formulation in hypogonadal men. This was a single dose, open label, nonrandomized study. Ten hypogonadal men with primary (n = 6) or secondary (n = 4) hypogonadism, otherwise in good health, received 630 mg microencapsulated testosterone in dextran solution (IM) on day 1. Serum total and free testosterone; LH; FSH; dihydrotesterone; estradiol; sex hormone-binding globulin; total cholesterol; high, low, and very low density lipoprotein cholesterol; triglycerides; and apoprotein-AII and -B were measured on multiple occasions during the 2-week control period and the 16-week treatment period. In addition, on days 0, 1, 28, 56, and 84, subjects were hospitalized for detailed hormone analyses over the 24-h period. Serum total and free testosterone levels rose quickly into the midnormal range and stayed uniformly in the eugonadal range for about 70-77 days, after which serum testosterone levels declined gradually into the hypogonadal range. Testosterone release from the microcapsule formulation over the first 10 weeks approximated zero order kinetics. Serum dihydrotestosterone levels rose into the normal range, and testosterone to dihydrotestosterone ratios remained in the physiological range. Serum estradiol levels rose and stayed in the midnormal male range. Serum sex hormone-binding globulin levels decreased significantly during treatment. Serum LH and FSH levels also significantly decreased in the six hypergonadotropic men. Total cholesterol low and very low density lipoprotein cholesterol and triglyceride levels did not change, but plasma high density lipoprotein cholesterol levels decreased significantly during treatment. These data indicate that testosterone microcapsule formulation provides uniform eugonadal levels of testosterone for about 10 weeks. The long duration and zero order kinetics make it an attractive alternative to existing methods of androgen replacement.
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The effects of a combined GnRH antagonist and testosterone (T) replacement regimen on gonadotropins and spermatogenesis were examined to assess its potential as a male contraceptive regimen. The potent Nal-Glu GnRH antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5, D4-p-methoxybenzoyl-2-amino butyric acid6,D-Ala10]GnRH) was administered daily (7.5 mg, sc) to eight normal men for 16 weeks. T enanthate was given im starting at week 2 and every 2 weeks thereafter through week 14 of the treatment phase. Serum LH, FSH, T, and estradiol concentrations were measured frequently during the 5-week control period, the 16-week treatment phase, and the 14-week recovery phase. Semen analyses were performed every week during the control phase and every 2 weeks during the treatment and recovery phases. Seven of eight subjects became azoospermic by 6-10 weeks of treatment; the eighth subject, who failed to achieve azoospermia, suppressed his sperm count to 7 million/mL by week 14 (from a mean baseline of 42 million/mL) before treatment was prematurely terminated because of localized swelling at each of his injection sites. Sperm counts returned to baseline 10-14 weeks after the end of Nal-Glu administration. Seven of the eight subjects showed suppression of LH to the limit of assay detection (less than 0.2 U/L), whereas the eighth subject showed incomplete suppression. Serum bioactive and immunoreactive LH concentrations showed concordant responses. Mean serum FSH concentrations were also markedly suppressed. Serum T and estradiol concentrations declined dramatically during the first 2 weeks of Nal-Glu GnRH treatment, but returned to the normal physiological range after T enanthate replacement was initiated. Libido and sexual potency were maintained. No systemic side-effects, other than erythema and induration at injection sites, were observed. These data demonstrate that combined GnRH antagonist plus T treatment can predictably and reversibly induce azoospermia in most men and has potential as a male contraceptive regimen.
When serum levels of a hormone are at or below the detection limit of the measurement system, accurate characterization and quantitation of pulsatile hormone secretion may be difficult. This point is well illustrated in this study, which used two immunoassays with markedly different assay sensitivities to quantitate pulsatile LH secretion in men in whom serum LH levels had been suppressed by the administration of a GnRH antagonist. Five normal men received 5 mg Nal-Glu, sc, daily for 21 days. Blood was drawn at 10-min intervals over 8 h on days 0 and 21. Samples were assayed in triplicate in both a conventional LH RIA with a sensitivity of 0.6-1.0 IU/L and a two-site-directed ultrasensitive immunofluorometric assay (IFMA) with assay sensitivity ranging from 0.05-0.125 IU/L. LH pulses were analyzed by Cluster analysis (C) and were corroborated by the Detect algorithm (D). Nal-Glu suppressed LH (C) pulse amplitude from 4.0 +/- 0.7 to 0.40 +/- 0.03 IU/L by LH RIA and from 7.8 +/- 2.1 to 0.21 +/- 0.04 IU/L by LH IFMA. An apparent reduction in LH pulse number was observed in the RIA data on day 21 by both pulse detection methods [4.2 +/- 0.4 vs 2.4 +/- 0.2/8 h on days 0 and 21 by C (P < 0.005); 5.8 +/- 0.8 vs. 2.8 +/- 0.7 by D (P < 0.05)]. However, the IFMA measurements in the same samples using the more sensitive LH IFMA showed no difference in pulse number between days 0 and 21. The RIA data correlated well with the IFMA data, with a concordance coefficient ranging from 0.66-0.9. In summary, the Nal-Glu GnRH antagonist markedly decreases LH pulse amplitude, but not pulse frequency. These observations are consistent with competitive inhibition of GnRH action at the pituitary site by the Nal-Glu antagonist; they indicate that assay characteristics can significantly affect quantitation of hormone pulse pattern and underscore the need for ultrasensitive LH assays for accurate assessment of LH pulse characteristics when LH levels are low or suppressed.
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Knowledge about nutritive value of food, diet during diseases and antenatal and postnatal period was assessed amongst 152 adolescent school girls. A total of 23.69 and 55.93% students had incorrect knowledge that pulses and non-vegetarian foods should be avoided during later half of the pregnancy. A total of 63.82, 66.45 and 71.72% of subjects had incorrect knowledge that almonds have more nutritive value than groundnuts, fruits are rich sources of calories and desi ghee has more nutritive value than vanaspathi, respectively. Majority (90.78%) had correct knowledge that obesity is caused due to excess intake of calories than required by an individual and low iron content and poor availability of iron from food is a major cause of anemia in mothers and children.
Knowledge and skills amongst 34 multipurpose workers working in an ICDS project about growth monitoring was assessed using interview technique. All workers had correct knowledge about rationale of growth monitoring. A total of 73.5% and 94.1% had knowledge that flattened growth curve indicates no weight gain and descending growth indicates decrease in weight, respectively.
To study the dose response characteristics of a gonadotropin-releasing hormone (GnRH) antagonist ([Ac-D2-Nal1,D4-Cl-Phe2,D3-Pal3,Arg5,dGlu6 (AA), d-Ala10] GnRH; Nal-Glu), 1.5 or 5.0 mg of Nal-Glu were administered to two groups of five normal men by daily subcutaneous injection for 21 days. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and testosterone (T) were determined on multiple occasions before, during, and after the antagonist treatment. Five milligrams Nal-Glu markedly suppressed mean serum immunoreactive LH to a mean of 1.5 +/- 0.4 IU/L (+/- SEM), immunoreactive FSH to the limit of assay detection (1 IU/L), and lowered basal mean serum T to castrate range (less than 2 nmol/L). Serum bioactive LH levels also showed a marked decrease in the 5.0-mg group similar to that seen in immunoreactive LH levels. Amplitude of immunoreactive LH pulses was markedly reduced in the 5.0-mg group on day 21. A 1.5-mg dose of Nal-Glu transiently suppressed serum immunoreactive LH levels on day 1. There was a subsequent escape on the rest of the days sampled. Serum immunoreactive FSH levels were not significantly changed over the 21-day treatment period. Serum T levels were transiently suppressed only on day 1 paralleling immunoreactive LH suppression. No adverse systemic side effects occurred. Thus, the 5.0-mg dose of this GnRH antagonist provides a pharmacological means of markedly suppressing the hypothalamic-pituitary-gonadal axis and, therefore, has potential as a male contraceptive.
In vivo and in vitro evidence indicates that FSH is a primary regulator of testicular inhibin production. However, recent reports suggest that LH may also promote inhibin secretion in vivo. To investigate whether LH regulates inhibin subunit messenger RNA (mRNA) expression as well, we examined the effects of hypophysectomy and LH replacement on the testicular content of inhibin alpha and beta-B subunit mRNAs in sexually immature and adult rats. Twenty- and 60-day-old intact and hypophysectomized rats received saline or 0.25, 2.5, 25.0, or 250 micrograms ovine LH/100 g body wt sc, twice daily for 7 days beginning on the day after hypophysectomy (n = 5/group in three separate experiments). The inhibin subunit mRNA content of each testis was measured for statistical analysis by dot-blot hybridization, and experimental results were confirmed by northern analysis of poly(A) RNA from each sample. In immature animals, the testicular content of both inhibin subunit mRNAs was decreased after hypophysectomy; inhibin alpha and beta-B mRNA levels were decreased to 6.9 +/- 0.9% and 31.7 +/- 2.7% of intact control values, respectively. In adult animals, hypophysectomy resulted in a more modest decrease in inhibin alpha subunit mRNA per testis (44.9 +/- 3.1% of controls) but had no effect on beta-B subunit mRNA. Replacement of LH to immature hypophysectomized animals did not alter levels of mRNA for either inhibin subunit. However, in adults LH restored testicular inhibin alpha subunit mRNA content in testes of hypophysectomized animals to levels seen in intact, saline-treated control animals. LH replacement also slightly but consistently decreased testicular beta-B subunit mRNA content compared to levels seen in hypophysectomized, saline-treated rats. These results indicate that although the response of inhibin subunit mRNAs to pituitary input decreases as a function of sexual maturation, LH may play an important role in regulation of inhibin subunit mRNA expression in adult but not immature testes. The mechanism(s) of LH action on testicular inhibin subunit gene expression is currently unknown, but may involve either direct actions of LH on Leydig cell inhibin subunit mRNAs or indirect actions of interstitial cell factors on Sertoli cell inhibin subunit gene expression.
Orchidectomy has been reported to decrease concentrations of thyrotrophin (TSH) in the circulation of male rats without affecting serum levels of thyroid hormones. To understand the mechanism underlying this observation, we have measured the effect of gonadal status on the in-vitro release of TSH-releasing hormone (TRH) by male rat hypothalamic fragments. Because hormone release rates can be affected by changes in the post-translational processing of the hormonal precursors, we have also studied the corresponding changes in the concentrations of TRH and TRH-Gly, a TRH precursor peptide in hypothalamus and pituitary, by radioimmunoassay. We observed a significant decline in the in-vitro release of TRH from incubated hypothalami 1 week after castration, which was quantitatively reversed by testosterone replacement. Concentrations of TRH and TRH-Gly in the posterior pituitary, on the other hand, which derive from neurones of hypothalamic origin, increased significantly with castration and were returned to the normal range by testosterone replacement. We conclude that the primary effect of testosterone is the stimulation of hypothalamic TRH release, resulting in the depletion of TRH and TRH precursors from TRH-containing neurones which project into the median eminence and posterior pituitary.