Testosterone Metabolism in Target Tissues: Effects of Testosterone and Dihydrotestosterone Injection and Hypothalamic Implantation on Serum LH in Ovariectomized Rats

Beyer, Carlos; Jaffe, Robert B.; GAY, VERNON L.

doi:10.1210/endo-91-5-1372

Cited by 44 publications

(12 citation statements)

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“…At the dosage used, DHTP was about as effective as TP in suppressing LH secretion; both produced significantly (P < 0-05) lower plasma concentrations of LH (Mann-Whitney U-test). These data are compatible with the evidence of Beyer, Gay & Jaffe (1972) that DHTP severely suppresses LH secretion in adult female rats.…”

supporting

confidence: 92%

SUPPRESSION OF LUTEINIZING HORMONE SECRETION IN MALE RATS BY 5α-Androstan-17β-Ol-3-One (DIHYDROTESTOSTERONE) PROPIONATE

Naftolin¹,

Feder²

1973

Journal of Endocrinology

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Dihydrotestosterone propionate (DHTP) administered to intact, 25-day-old rats over a period of 6 days causes a significant decrease in testicular weight. Concurrent administration of gonadotrophic hormone prevents this decrease in testicular weight (Feder, 1971). Similarly, Beyer, Moral\l=i'\& Cruz (1971) demonstrated that DHTP blocked ovarian compensatory hypertrophy in female rats. These findings and earlier reports (Bottomley & Folley, 1938; Dorfman & Kind, 1966) suggested that dihydrotestosterone suppressed secretion of gonadotrophic hormones. However, direct measurements of plasma concentrations of the gonadotrophins after DHTP treatment of young rats were unavailable. This report offers quantitative data on systemic plasma concentrations of luteinizing hormone (LH) in young male rats treated with DHTP. A previously described radioimmunoassay method was used for LH measurement (Niswender, Midgley, Monroe & Reichert, 1968;Naftolin & Corker, 1971).In one experiment intact Sprague\p=m-\Dawley male rats were injected daily with 125 \g=m\gDHTP, 375 \g=m\g DHTP, 125 \g=m\g testosterone propionate (TP) or 0\m=.\3ml sesame oil vehicle. The subcutaneous injections were given on days 25 to 30, inclusive, of life. Another group of males was castrated (ether anaesthesia) on day 26. All animals were killed at 31 days of age (barbiturate anaesthesia, Equithesin) and blood was drawn from the left ventricle into a heparinized syringe. The blood was immediately centrifuged under refrigeration and the plasma fraction frozen until assay. All assays were carried out under a double blind technique. Bleedings were carried out at 14.00 to 16.00 h (lights on 19.00 to 09.00 h), and testes and seminal vesicles were weighed after the rats were killed. The results are shown in Table 1. At the dosage used, DHTP was about as effective as TP in suppressing LH secretion; both produced significantly (P < 0-05) lower plasma concentrations of LH (Mann-Whitney U-test). These data are compatible with the evidence of Beyer, Gay & Jaffe (1972) that DHTP severely suppresses LH secretion in adult female rats.In a second experiment the effects of acute treatment with DHTP were studied. Intact male rats, 29 days of age, were injected at 09.00 h with 125 µg DHTP, 125 µg TP or 0-1 ml sesame oil vehicle. The rats were killed and blood was withdrawn 6 h after injection of the steroid. The results in Table 2 show that even one treatment with DHTP is highly and consistently effective in suppressing LH secretion. Acute treatment with TP also inhibited LH secretion, but the results were somewhat less

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supporting

confidence: 92%

SUPPRESSION OF LUTEINIZING HORMONE SECRETION IN MALE RATS BY 5α-Androstan-17β-Ol-3-One (DIHYDROTESTOSTERONE) PROPIONATE

Naftolin¹,

Feder²

1973

Journal of Endocrinology

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“…The other is that a metabolite is the active or more powerful form of the androgen at the intracellular level. Since administration of DHT has been found to be highly effective in suppressing gonadotrophin release in rats (Beyer, Morali & Gruz, 1971;Feder, 1971;Beyer, Jaffe & Gay, 1972;Davidson, 1972;Swerdloff, Walsh & Odell, 1972), the latter alternative, that DHT and not testosterone might be an active androgen in regulation of pituitary functions, seems most attractive.…”

Section: Discussionmentioning

confidence: 99%

Sex Differences and Hormonal Control of Testosterone Metabolism in Rat Pituitary and Brain

Denef¹,

Magnus²,

McEwen³

1973

Journal of Endocrinology

151

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The in-vitro conversion of testosterone to 17\g=b\-hydroxy-5\g=a\-androstan-3\x=req-\ one (5\g=a\-dihydrotestosterone, DHT) and 3\ g=a\ , 17\g=b\-dihydroxy-5\g=a\-androstane (3\g=a\-androstanediol, DIOL) in pituitary and slices of brain regions was compared between male and female rats. Intact pituitaries from male rats formed 2\m=.\5times more DHT and 1\m=.\5times more DIOL than those of females. A small sex difference was also detected in the hypothalamus, males again being higher than females. No sex differences could be detected in other brain regions. However, DHT formation in the brain was regionally differentiated with higher conversion rates in hypothalamus than in cortex, hippocampus, amygdala, pineal gland or cerebellum. The highest transformation, however, was found in the mid-brain. Metabolism in the pre-optic area was as low as that in the cortex. 5\g=a\-Dihydrotestosterone and DIOL formation in the pituitary increased several-fold after gonadectomy in both sexes and the sex difference disappeared. Little or no increase occurred after thyroidectomy or adrenalectomy. The increase in pituitary DHT formation after gonadectomy could be attenuated or prevented both by treatment with testosterone propionate and with oestradiol benzoate. Replacement therapy, particularly with oestradiol benzoate, gave rise to a sex difference reminiscent of that of normal animals. No significant change in pituitary DHT formation occurred in adult females which had been treated with testosterone propionate on the 4th day of life.The results suggested a close relationship between DHT formation and activity of gonadotrophin secretion, particularly at the level of the pituitary.

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“…These findings are in ac¬ cordance with the observation that -ring reduc¬ tion at the 5a-position of naturally occurring androgens increases their antigonadotropin acti¬ vity. In fact, the majority of data available (Beyer et al 1971(Beyer et al , 1972Pérez-Palacios et al 1975;Celotti et al 1979;Martini 1982) indicate that 5a-DHT is more effective than testosterone in suppressing LH release; thus implying that en¬ hancement of this biological activity by A-ring reduction occurs on both natural Ci9 and synthe¬ tic 19-nor-17a-ethynyl steroid compounds.…”

Section: Discussionmentioning

confidence: 99%

A-ring reduction enhances the antigonadotropic potency of norethisterone

Garza-Flores

Vilchis

Garcı́a

et al. 1986

Acta Endocrinologica

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To assess whether structural modifications on the A-ring of norethisterone (NET) could modify its antigonadotropic potency, comparative studies using NET, 5\g=a\-dihydro NET (5\g=a\-NET) and its 3\g=b\,5\g=a\ and 3\g=a\,5\g=a\tetrahydro derivatives in castrated adult rats were undertaken. The antigonadotropic effect of these compounds was evaluated by measuring the serum and pituitary immunoreactive concentrations of LH and FSH following their chronic sc administration to animals depleted of progesterone receptors. The results demonstrated that 3\g=b\,5\g=a\-NET and 5\g=a\-dihydro-NET exhibited a significantly greater gonadotropic inhibiting activity as compared with that of their parent compound. The simultaneous administration of tamoxifen with 3\g=b\,5\g=a\-NET resulted in a significant diminution of its antigonadotropic potency, particularly for LH. These data indicate that the potent antigonadotropic effect of 3\g=b\,5\g=a\-NET metabolite was mediated via oestrogen receptors. The LH inhibitory activity of 5\ g=a\ \ x=r eq-\ dihydro-NET was not suppressed by the non-steroidal antioestrogen administration, thus suggesting that 5\ g=a\ \ x=r eq-\ NET might exert its effect via androgen receptors. The overall data were interpreted as demonstrating that metabolic conversion products of NET exhibit potent antigonadotropic effect. The data are consistent with an A-ring enhancement of the antigonadotropic potency of this synthetic progestin and open an alternate approach to the development of fertility regulating agents. Norethisterone (NET), l7ct-ethynyl-l7ß-hydroxy-4-estren-3-one, has been extensively used as a progestogen in a number of hormonal contracep¬ tive formulations. It has been recognized that NET is the active compound of its ester deriva¬ tives, as well as, of other synthetic progestogens as norethinodrel, lynestrenol and ethynodiol diacetate (Murugesan et al. 1973;Kamyab et al. 1968;Howard et al. 1975). Metabolic studies have dis¬ closed that NET undergoes extensive in vivo transformations, particularly reductions on its Aring, to form dihydro and tetrahydro derivatives.Indeed, these compounds have been isolated from serum of women on contraceptive NET therapy (Braselton et al. 1979).Previous studies from this laboratory have indi¬ cated that the mode of action of NET differs from that of natural progesterone (Pérez-Palacios et al. 1981), suggesting that under certain circumstan¬ ces, the metabolic conversion of NET to its re¬ duced metabolites is necessary to express its acti¬ vity in humans. Indeed, Larrea et al. (1983, 1984), demonstrated that NET exhibits a potent estro¬ gen-like biological effect in spite of its lack of interaction with the oestrogen receptor. Further¬ more, the in vivo NET aromatization has re¬ mained a controversial and still unsolved issue (Breuer 1977; Barvieri et al. 1983). Recently, Chávez et al. (1985) demonstrated the stereospecific interaction of -ring reduced NET derivatives with intracellular putative steroid receptors other than those of progesterone.

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Testosterone Metabolism in Target Tissues: Effects of Testosterone and Dihydrotestosterone Injection and Hypothalamic Implantation on Serum LH in Ovariectomized Rats

Cited by 44 publications

References 0 publications

SUPPRESSION OF LUTEINIZING HORMONE SECRETION IN MALE RATS BY 5α-Androstan-17β-Ol-3-One (DIHYDROTESTOSTERONE) PROPIONATE

SUPPRESSION OF LUTEINIZING HORMONE SECRETION IN MALE RATS BY 5α-Androstan-17β-Ol-3-One (DIHYDROTESTOSTERONE) PROPIONATE

Sex Differences and Hormonal Control of Testosterone Metabolism in Rat Pituitary and Brain

A-ring reduction enhances the antigonadotropic potency of norethisterone

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