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Biomedical subjects

J Sandow

Publications and source records attributed to J Sandow.

At least 73 records · Page 4Linked to original sources
PubMed1983

Clinical applications of LHRH and its analogues.

The physiological requirement for activation of pituitary gonadotrophin secretion by pulsatile LHRH stimulation is discussed, and compared with the effect of pituitary stimulation by LHRH agonists. Initial stimulation is followed by a phase of progressive pituitary and gonadal inhibition. This inhibition is fully reversible at the end of agonist treatment. Clinical applications of high dose suppression are the treatment of precocious puberty and hormone-dependent tumours (mammary and prostatic carcinoma). In women, agonist administration by nasal spray is a reversible method of inhibiting ovulation, and may also be useful in the treatment of endometriosis. Clinical advantages of agonist therapy are favourable biological tolerance, lack of side effects and rapid reversibility.

Adolescent↗
PubMed1983

Antibody production against an agonist analogue of luteinizing hormone-releasing hormone: evaluation of immunochemical and physiological consequences.

Because of the widespread long-term clinical use of luteinizing hormone-releasing hormone (LRH) agonists, the possibility of antibody development to one of these, (D-Ser-(Butt)6) LRH (1-9) nonapeptide-ethylamide (buserelin), has been studied by examining sera from experimental animals and humans receiving long-term agonist-treatment for ability to bind 125I-labelled buserelin. None of the sera from monkeys, rabbits, dogs or rats receiving buserelin by sc injection or via minipump or from 81 patients receiving the agonist by sc injection or nasal spray had detectable antibodies. The immunochemistry of buserelin was investigated by actively immunizing male rabbits against the agonist. This also enabled us to determine the possibility of this stimulus to the immune response resulting in the generation of antibodies which could cross-react with endogenous LRH and neutralize its biological effect. All 41 rabbits immunized against unconjugated buserelin and all 23 immunized against buserelin conjugated to a protein carrier developed antibodies, those in the latter group producing highest titres. Serum from one of the animals immunized against unconjugated buserelin and from 9 of the animals immunized against conjugated buserelin had the capacity to bind 125I-labelled LRH. These LRH antibody titres were very low and were insufficient to cause suppression of serum testosterone concentrations or affect testicular weight except in one rabbit immunized against unconjugated agonist. The LRH antibody titre in this rabbit was always less than 1:100 which our other studies have indicated to be too low to produce a biological effect. It may be that the association of low LRH antibody titre with decreased testes weight in this animal was fortuitous. We conclude that the possibility of circulating antibodies being produced to buserelin or their interfering with the action of endogenous LRH is extremely low.

Animals↗
PubMed1982

[Experimental animal studies on the topical and systemic activity of prednisolone-17-ethylcarbonate-21-propionate].

Prednisolone-17-ethylcarbonate-21-propionate (PrEP, Hoe 777) was tested for antiinflammatory activity in various animal models by topical and systemic administration. In those models being indicative of topical efficacy, the potency of PrEP was the same as that of desoximetasone. However, systemic effects after topical administration of PrEP in shaved skin of the dorsum of rats were relatively weak compared with the reference compound. Moreover, there were less systemic glucocorticoid effects after s.c. administration of PrEP than after desoximetasone. Thus, PrEP is obviously a compound with a considerable split of topical and systemic activity, suggesting its testing in man for systemic effects after topical administration.

Administration, Topical↗
PubMed1980

Ovulation inhibition by daily i.m. administration of a highly active LH-RH analog (d-ser(TBU)6-LH-RH-(1-9)-nonapeptide-ethylamide).

A highly active LH-RH-analog (D-Ser(TBU)6-LH-RH-(1-9)-nonapeptide-ethylamide = HOE 766) was administered to normally cyclic and ovulatory women in a double-blind study. Each woman received from day 1 through day 14 of the cycle according to a randomization plan either 10 microgram HOE 766 i.m. or a placebo. Ovulation was inhibited for at least two weeks in all subjects receiving HOE 766. The initially very marked release of LH measured 4 hourse after the injection decreased within 3 days by approximately 50%, and remained at this level for the remainder of the experiment while the initially high FSH response was abolished during further treatment. In 3 out of 5 women receiving the analog, serum estradiol was severely suppressed, in the remaining 2 slightly. Within 5 days after the discontinuation of treatment, the pituitary had regained the capacity to respond normally to LH-RH. It is postulated that follicular maturation is disturbed by the unphysiologic pattern of gonadotropin secretion during administration of HOE 766.

Adult↗
PubMed1980

Competition of various LH--RH analogs and fragments with 135I-LH--RH for specific binding sites on isolated pituitary plasma membranes.

The displacement by various LH--RH analogs and fragments of 125I-LH--RH specifically bound to plasma membranes isolated from rat anterior pituitaries was investigated. The addition of increasing amounts of unlabelled LH--RH resulted in an increasing displacement of bound 125I-LH--RH. When some fragments of LH--RH or of an analog with little biological activities were incubated, a much weaker affinity for LH--RH binding sites could be observed. No correlation between biological effectiveness and binding affinity was, however, found when several highly active LH--RH analogs were tested. The potent analogs competed much less efficiently for specific binding sites on isolated plasma membranes than LH--RH. Binding experiments with iodine-labelled (D-Ser(But)6-LH--RH(1--9)-nonapeptide-ethylamide indicated that the small binding affinity of the superactive analog may be due to a lower association rate while the dissociation rate is comparable to that of LH--RH. Contrary to LH--RH, no binding equilibrium was reached during 2 h of incubation of the analog with plasma membranes. The physiological role of LH--RH binding sites on isolated pituitary plasma membranes remains to be elucidated.

Animals↗
PubMed1980

Antifertility effects of an LH-RH analogue in male rats and dogs.

The antifertility effects of a highly active LH-RH analogue, D-Ser(Bu)6-LH-RH(1-9)nonapeptide-ethylamide (buserelin) were studied in male rats and dogs. Pituitary-testicular function was not impaired by a "physiological" dose of 5 ng/rat; this dose gave reproducible LH release during chronic administration. At higher dose testicular LH receptors and responsiveness to HCG were diminished in intact prepubertal and adult rats. Pituitary inhibition was independent of gonadal or adrenal steroid feedback, and hypothalamic LH-RH as well as pituitary LH and FSH were reduced by 4 weeks treatment of castrate/adrenalectomized rats with 50 ng buserelin. In male dogs, a dose of 2.5 micrograms/kg sc reduced serum testosterone to 6% of controls within 8 weeks of treatment. Treatment was continued for 6 months and testicular involution was found to be reversible within 8 weeks of stopping treatment. LH-RH analogues at "supraphysiological" doses can be used as antifertility agents, but suppression of sexual activity in male dogs under treatment indicates that loss of libido will be a problem.

Adrenalectomy↗
PubMed1979

Enzyme kinetic studies and inhibition by oligopeptides of LH-RH degradation in rat hypothalamus and pituitary.

The enzyme kinetic parameters of the degradation of luteinizing hormone-releasing hormone (LH-RH) and L-cystine-bis-(4-nitroanilide) (Cys-NA) by rat hypothalamic (HYP) and pituitary (PIT) extracts and the effect of various oligopeptides on the rate of LH-RH inactivation were investigated in vitro. The 105,000 x g supernatant of 1 rat HYP inactivated 57 microgram LH-RH during a 30 min incubation (Km = 12.4 microM, V max = 2.33 microgram LH-RH/mg protein/min), and of one rat anterior PIT, 48 microgram LH-RH during 30 min of incubation (Km = 12.2 microM, V max = 8.0 microgram LH-RH/mg protein/min). The synthetic substrate Cys-NA competitively inhibited LH-RH degradation with a Ki of 8.5 microM in the HYP and 6 microM in the PIT enzyme preparation. Vice versa, LH-RH also competitively inhibited the cleavage of Cys-NA with inhibition constants of 14 microM (HYP) and 15 microM (PIT) indicating that the 2 substrates are probably cleaved by the same enzyme. The most effective inhibitors of LH-RH degradation were found to be angiotensin-related peptides, neurotensin, bradykinin, and bacitracin. A relatively weak effect was obtained with oxytocin, enkephalin and puromycin. It is concluded that endogenous oligopeptides such as angiotensins, neurotensin, bradykinin, etc., may possibly influence H-RH degradation in the PIT and the HYP. The synthetic substrate Cys-NA may be an appropriate substrate for measuring the activity of an LH-RH-degrading peptidase, which therefore could be classified as arylamidase.

Aminopeptidases↗
PubMed1979

Inhibitory control of the pituitary LH secretion by LH-RH in male rats.

Luteinizing hormone-releasing hormone (LH-RH) was administered to prepubertal male rats (intact, castrate or castrate-adrenalectomized, 60 g body weight) for 28 days (1 microgram LH-RH/day, s.c.), at a 10-fold physiological dose, as compared to the minimal FSH-releasing dose of 100 ng/rat s.c. In intact rats, serum LH and weight of androgen-dependent organs (vented prostate, seminal vesicles) were reduced after 14 days of treatment. In castrate rats, the postcastration rise in serum LH was abolished by treatment. Pituitary LH content, FSH secretion and prolactin secretion were not suppressed. Hypothalamic LH-RH was increased at 14 and 21 days. In castrate adrenalectomized male rats, LH secretion was also suppressed by 1 microgram LH-RH s.c. x 28 days. The hypothalamic LH-RH content did not increase. The pituitary LH-RH receptor level was not down-regulated after 14 days treatment either in intact or castrate male rats. Pituitary inhibition (LH release) in rats by a supraphysiological dose of LH-RH given for 28 days indicates that the optimal regime for chronic treatment has to be determined by monitoring LH release at regular intervals. Direct pituitary inhibition by LH-RH may explain some of the unexpected antifertility effects observed with high doses of LH-RH.

Adrenal Glands↗
PubMed1979

Effect of treatment with an agonist of luteinizing hormone releasing hormone on early maturational changes in pituitary and testicular function in the rat.

Male rats aged 30 days were injected once daily for between 1 and 7 days with 50 ng (D-serine t-butyl6, des-glycine-NH210) luteinizing hormone releasing hormone ethylamide (LH-RH agonist), and pituitary and testicular function were assessed. Treatment for 7 days significantly (P less than 0.02) inhibited maturational increases in the pituitary content and serum concentration of gonadotrophins, testicular luteinizing hormone (LH)-receptor concentration and the testicular capacity to secrete testosterone; the pituitary content and serum concentration of prolactin, the hypothalamic content of LH-RH and testicular weight were unaffected. In rats treated with LH-RH agonist, the initial (2 to 3 days) reduction in testicular LH-receptors and the capacity to secrete testosterone probably resulted from acutely raised levels of LH in the blood, whilst later effects may have resulted from the apparently chronic reduction in serum gonadotrophin levels. The latter may reflect a decrease in pituitary responsiveness to repeated stimulation with LH-RH agonist. Despite the extensive loss of testicular LH-receptors and diminished responsiveness, the concentration of HCG which significantly (P less than 0.05) increased testosterone secretion by the testis in vitro was the same (2 pmol/l) as that for testes from control rats.

Animals↗
PubMed1979

Studies with fragments of a highly active analogue of luteinizing hormone releasing hormone.

The minimal structural requirements for gonadotrophin releasing activity were studied with fragments of a highly active analogue of luteinizing hormone releasing hormone (LH-RH), [D-Ser(But)6]LH-RH(1-9)nonapeptide-ethylamide (Hoe 766). All fragments are related to the C-terminal structure of LH-RH and have increased enzyme stability. Ovulation in phenobarbitone-blocked rats was induced with a median effective dose/rat, of 1.9 microgram of the (3-9)-heptapeptide, Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-ethylamide and 6.8, 18.0 and 38.3 microgram for the (4-9), (5-9) and (6-9) fragments respectively. The (3-9)- heptapeptide and (4-9)-hexapeptide induced release of LH and FSH in phenobarbitone-blocked rats with a ratio similar to that of LH-RH. Degradation of LH-RH by enzyme preparations of liver, kidney and hypothalamic or anterior pituitary tissue was not modified by addition of the (3-9)-heptapeptide fragment. The organ distribution of the 125I-labelled (3-9)-heptapeptide fragments was similar to LH-RH, but not to Hoe 766. The peptide accumulated in liver and kidney, but was eliminated from the anterior pituitary gland 15 min after i.v. injection, whereas Hoe 766 showed progressive accumulation in the pituitary gland (tissue:plasma ratio = 6.6 after 60 min). In contrast to C-terminal fragments of LH-RH, the corresponding fragments of nonapeptide analogues retained significant biological activity, and the minimal structural requirements for LH release may be related to the C-terminal sequence of LH-RH.

Animals↗
PubMed1978

Treatment of cryptorchidism with pernasal gonadotropin-releasing hormone therapy.

Twenty-five boys between 1 and 10 years of age with unilateral or bilateral cryptorchidism were treated with 200 microgram of gonadotropin-releasing hormone (GnRH) pernasally six times daily until descensus was completed, or for 10 weeks at most. Complete descent of the tests occurred in 16 patients, usually after 2 to 5 weeks of treatment. No adverse side effects have been observed. Radioimmunologic measurements of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, and prolactin, carried out before treatment, at the end of treatment, and 6 months after treatment, showed a transitory increase of the LH responsiveness to GnRH in only four of the patients and in the group as a whole a slight but significant decrease of FSH responsiveness. There were no signs of precocious puberty. GnRH antibodies were not found.

Administration, Intranasal↗
PubMed1978

Pituitary gonadotropin inhibition by a highly active analog of luteinizing hormone-releasing hormone.

Chronic treatment with highly active analogs of luteinizing hormone (LH)-releasing hormone (LH-RH) induces "paradoxical" antifertility effects. Intact male rats, a reduction in testosterone production is observed after the administration of [D-Ser(But)6]-LH-RH(1-9)ethylamide (burserelin, Hoe 766), 50 ng/day subcutaneously for 4 weeks. In castrated male rats treated with the same dose of analog, plasma LH levels were reduced from days 14 to 28 and plasma follicle-stimulating hormone (FSH) levels were reduced from days 21 to 28 of treatment. Pituitary LH and FSH concentrations were also decreased. The plasma prolactin level was reduced at 14 days of treatment. The hypothalamic LH-RH content remained unchanged and the adrenal corticosterone content was lowered. These findings indicate a direct inhibitory effect of the analog on gonadotropin secretion in the absence of the gonads, and may explain some paradoxical antifertility effects observed with high doses of LH-RH analogs which exceed the physiologic dose range.

Adrenal Glands↗