Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042755 (masculinization)
 2,562 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Male ferrets born in the laboratory received subcutaneous Silastic capsules containing either the aromatase inhibitor, androst-1,4,6-triene-3, 17-dione (ATD), the 5 alpha-reductase inhibitor, testosterone-17 beta-carboxylic acid (17 beta C), or no hormone, for 15 days beginning on the day of birth; an additional group of females received empty Silastic capsules. All ferrets were gonadectomized when 11 weeks of age and were subsequently tested for masculine sexual behavior after a latin-square sequence of treatments with subcutaneous Silastic capsules containing testosterone (T), estradiol (E), or dihydrotestosterone (DHT). After T, control males displayed significantly more neck gripping, mounting and pelvic thrusting than control females, and males treated neonatally with ATD or 17 beta C were no less responsive than control males. After DHT, little masculine sexual behavior was shown by any group. After E, the duration of mounting was significantly longer in control and ATD males than in control females or 17 beta C males. Subsequently, however, there were no differences between control and 17 beta C males on any parameter of masculine sexual performance, when they were retested sequentially after subcutaneous implantation of E followed by E + DHT. Additional groups of newborn male and female ferrets received subcutaneous capsules containing either ATD, 17 beta C, or no hormone and were killed on postnatal day 7. Administration of ATD, but not 17 beta C, strongly inhibited aromatase activity in the hypothalamus + preoptic area. In all groups, the formation of significantly inhibited cortical 5 alpha-reductase activity. Plasma concentrations of T were equivalent on postnatal day 7 in males given each of the neonatal treatments. These results suggest that behavioral masculinization in the male ferret results primarily from the neonatal action in brain of T itself, and not from its estrogenic or 5 alpha-reduced androgenic metabolites.
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PMID:Normal differentiation of masculine sexual behavior in male ferrets despite neonatal inhibition of brain aromatase or 5-alpha-reductase activity. 686 14

We assessed the activity of the aromatase enzyme complex in slices of brain from rats by measuring the release of 3H2O from [1 beta-3H]testosterone. In hypothalami from 12-day-old rats, the rate of aromatase activity was linear with time and amount of tissue. The reaction was saturated at a substrate concentration of 0.1 microM, and the apparent Km of the reaction was 27 nM. The production of 3H2O was inhibited by 4-hydroxyandrostenedione, with an apparent Ki of 20 nM. Aromatase activity was first detected in the diencephalon of 16-day-old fetuses and reached maximum rates in hypothalamic tissue between days 18 and 20 of gestation. The highest rate of activity per mg protein (approximately 4.8 pmol h-1 mg protein-1) was observed in the preoptic area (POA) on the 20th day of embryonic development. However, when expressed as a rate per tissue fragment, aromatase activity was as high in the medial basal hypothalamus as in the POA. After day 20 of gestation aromatase activity rapidly decreased in the POA and medial basal hypothalamus of both males and females. The lowest levels were observed between postnatal days 16 and 20. Aromatase activity was not detectable in cerebral cortex and cerebellum at any age studied. Since serum testosterone was higher in males than females during the first 4 days of postnatal life, and since aromatase activity is elevated in the hypothalamus at this time, our results support the current concept that local formation of estrogen mediates testosterone-induced masculinization of the brain during the neonatal period. However, our results also indicate that failure of the rat brain to undergo complete sexual differentiation before birth cannot be due to an inability of the fetal hypothalamus to aromatize androgens, since aromatase activity was higher in the hypothalamus than in any other fetal tissue.
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PMID:Changes in aromatase activity in the rat brain during embryonic, neonatal, and infantile development. 709 85

The clinical course, histology, and steroid secretion observed in two patients with hilus cell tumors are presented. One patient had signs of virilism and the other had estrogenic signs only. Steroid secretion was examined by measuring peripheral and ovarian venous gradients and pre- and postoperative levels of hormones to explain the profound differences in the biological effects exerted by the neoplasms. In the patient with virilism, the tumor's major secretory product was testosterone (T), and the dominant biosynthetic pathway was pregnenolone (Pe) leads to 17-hydroxypregnenolone leads to 17-hydroxyprogesterone leads to androstenedione (delta) leads to T. In the patient with estrogenic signs, the major secretory product was delta, derived from a similar pathway of pregnenolone leads to 17-hydroxypregnenolone leads to 17-hydroxyprogesterone leads to delta. Circulating estrone and estradiol levels were elevated, but the tumor showed limited aromatase activity, as reflected by 60- to 1500-fold larger peripheral-ovarian venous gradients of delta and T than estrone and estradiol. The high circulating estrogen levels mainly arose from the peripheral aromatization of the increased secretion of delta by the tumor. It was concluded that a similar steroidogenic pathway was employed by both tumors. The predominant secretion by the neoplasm of either T of delta was determined by the presence and the oxidation reduction equilibrium of the 17 beta-dehydrogenase enzyme. The action of this enzyme resulted in profound differences in the biological effects exerted by these tumors.
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PMID:Steroid secretion by masculinizing and "feminizing" Hilus cell tumors. 720 43

In many species of vertebrates, major sex differences affect reproductive behavior and endocrinology. Most of these differences do not result from a direct genomic action but develop following early exposure to a sexually differentiated endocrine milieu. In rodents, the female reproductive phenotype mostly develops in the absence of early steroid influence and male differentiation is imposed by the early action of testosterone, acting at least in part through its central conversion into estrogens or aromatization. This pattern of differentiation does not seem to be applicable to avian species. In Japanese quail (Coturnix japonica), injection of estrogens into male embryos causes a permanent loss of the capacity to display male-type copulatory behavior when exposed to testosterone in adulthood. Based on this experimental result, it was proposed that the male reproductive phenotype is "neutral" in birds (i.e. develops in the absence of endocrine influence) and that endogenous estradiol secreted by the ovary of the female embryo is responsible for the physiological demasculinization of females. This model could be recently confirmed. Females indeed display a higher level of circulating estrogens that males during the second part of their embyronic life. In addition, treatment of female embryos with the potent aromatase inhibitor, R76713 or racemic vorozole which suppresses the endogenous secretion of estrogens maintains in females the capacity to display the full range of male copulatory behaviors. The brain mechanisms that control this sexually differentiated behavior have not been identified so far but recent data suggest that they should primarily concern a sub-population of aromatase-immunoreactive neurons located in the lateral parts of the sexually dimorphic preoptic nucleus. The zebra finch (Taeniopygia guttata) exhibits a more complex, still partly unexplained, differentiation pattern. In this species, early treatment with exogenous estrogens produces a masculinization of singing behavior in females and a demasculinization of copulatory behavior in males.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sexual differentiation of brain and behavior in quail and zebra finches: studies with a new aromatase inhibitor, R76713. 762 66

Placental aromatase deficiency, which was characterized by maternal and fetal virilization and by a low level of estrogen excretion into urine during pregnancy, was studied by biochemical and molecular genetical techniques. Among enzymes participating in the electron transport system of the patient's placental microsomes, only aromatase activity was observed to be reduced (< 3% of normal levels). Northern and Western blotting analyses showed that the transcription of the aromatase gene and the translation of its mRNA seemed to proceed normally in the patient's tissue. However, the aromatase cDNA isolated from the patient was found to contain an extra DNA fragment of 87 base pairs (bp) which encoded 29 amino acids in frame but no termination codon. The insertion was located at the splicing point between exon 6 and intron 6 of the normal aromatase gene. The extra DNA fragment represented the first part of intron 6 except that its initial GT was altered to GC. These findings indicated that, in the patient's aromatase gene, the splicing between exon 6 and intron 6 did not occur at the normal position. This reflected the presence of one point mutation in its consensus sequence which caused the next cryptic consensus sequence 87 bp downstream, to be used according to the canonical GT/AG rule. The protein molecule thus translated contained an extra 29 amino acids. Furthermore, the patient's aromatase cDNA was observed to produce a protein molecule with a trace of activity in the transient expression system of COS-7 cells and in the high level expression system of baculovirus-insect cells. Direct DNA sequencing of aromatase genes from the patient and parents confirmed that this deficiency is a hereditary disease with an autosomal recessive inheritance pattern. The patient and parents are homozygote and heterozygotes, respectively, for this mutation.
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PMID:Genetic analysis of human placental aromatase deficiency. 768 36

The present study investigated 1) the importance of the aromatization process during the perinatal period for the development of the sexually dimorphic nucleus in the preoptic area of the hypothalamus (SDN-POA) of male rats, and 2) the relationship between SDN-POA volume and parameters of masculinization in male rats that were treated perinatally with the aromatase-inhibitor ATD. Males were treated with ATD either prenatally or pre- and neonatally, or with the vehicle. Masculine sexual behavior and partner preference were investigated in adulthood. Thereafter, animals were sacrificed and SDN-POA volume was measured. The SDN-POA volume was reduced in both the prenatally and the pre- and neonatally treated group, with a larger reduction in the latter than in the former group. Combined pre- and neonatal ATD treatment resulted in reduced frequency of mounts, intromissions, and ejaculations, as well as a reduced preference for a female over a male. The SDN-POA size was significantly and positively correlated with frequency of masculine sexual behavior, as well as preference for a female over a male.
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PMID:SDN-POA volume, sexual behavior, and partner preference of male rats affected by perinatal treatment with ATD. 797 5

We report the features of a new syndrome of aromatase deficiency due to molecular defects in the CYP19 (P450arom) gene in a 46,XX female. At birth, the patient presented with a nonadrenal form of female pseudohermaphrodism. At 17 months of age, laparotomy revealed normal female internal genital structures; the histological appearance of the ovaries was normal. FSH concentrations were markedly elevated at 9.4 ng/mL LER 869, and estrone and estradiol levels were undetectable (< 37 pmol/L). By 14 yr of age, she had failed to exhibit breast development. The clitoris had enlarged to 4 x 2 cm, and pubic hair was Tanner stage IV. The plasma concentration of testosterone was elevated at 3294 pmol/L, as was androstenedione at 9951 pmol/L. Plasma estradiol levels were below 37 pmol/L. ACTH and dexamethasone tests indicated a nonadrenal source of testosterone and androstenedione. Plasma gonadotropin levels were in the castrate range. Pelvic sonography and magnetic resonance imaging showed multiple 4- to 6-cm ovarian cysts bilaterally. Despite increased circulating androgens and clitoral growth, the bone age was 10 yr at chronologic age 14 2/12 yr. Estrogen replacement therapy resulted in a growth spurt, breast development, menarche, suppression of gonadotropin levels, and resolution of the cysts. The clinical findings suggested the diagnosis of P450arom deficiency. Analyses of genomic DNA from ovarian fibroblasts demonstrated two single base changes in the coding region of the P450arom gene, one at 1303 basepairs (C-T), R435C, and the other at 1310 basepairs (G-A), C437Y, in exon 10. The molecular genetic studies indicate that the patient is a compound heterozygote for these mutations. Expression of these mutations showed that the R435C mutation had 1.1% the activity of the wild-type P450arom enzyme, whereas the C437Y mutation demonstrated no activity. The cardinal features of this syndrome are a consequence of P450arom deficiency: 1) the fetal masculinization in this syndrome can be ascribed to defective placental conversion of C19 steroids to estrogens, leading to exposure of the female fetus to excessive amounts of testosterone; 2) the pubertal failure, mild virilization, multicystic ovaries, and hyperstimulation of the ovaries by FSH and LH are the result of the inability of the ovary to aromatize testosterone and androstenedione to estrogens; and 3) the striking delay in bone age at 14 2/12 yr supports the notion that estrogens, in contrast to androgens, are the major sex steroid driving skeletal maturation during puberty. Familial P450arom deficiency, although rare, may be more common than previously suspected.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom). 820 Sep 27

Hatchling zebra finches were treated with fadrozole, an aromatase (estrogen synthesis) inhibitor, to test whether estrogen is required for normal masculine development of the song system. Injections on posthatching days 1-30 had no effect on the volumes of the robust nucleus of the archistriatum (RA) and area X or on neuron soma size in RA and high vocal center (HVC) measured on day 31. These results argue against the importance of estrogen in masculinization of the song system in males after hatching.
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PMID:Post-hatching inhibition of aromatase activity does not alter sexual differentiation of the zebra finch song system. 820 88

In rats and other mammals, sex differences in the brain and behavior result from differential secretions of gonadal steroid hormones during early critical periods of neural development. We review the experimental results that support current ideas about the mechanisms of sexual differentiation in mammals, and then apply the same experimental analysis to the study of sexual differentiation of the neural song circuit in the zebra finch (Poephila guttata), a passerine song bird. Administration of estrogen to young female zebra finches causes the female to develop a more masculine song system and to sing as an adult. This estrogenic masculinization is similar to that found for copulatory behavior in mammals. However, striking differences emerge in other aspects of the sexual differentiation process. Experiments that use endocrine agents to block the masculine development in genetic males have so far failed. Moreover, the brain of zebra finches has an unusually high expression of aromatase (estrogen synthetase) in the telencephalon, and estrogen synthesized in the brain from androgen is released into the general circulation. These results suggest that the brain is the primary source of estrogen in the body. If so, then a further understanding of sexual differentiation requires more information on the factors that regulate the cerebral synthesis of estrogen.
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PMID:Sexual differentiation of brain and behavior: the zebra finch is not just a flying rat. 825 75

Female spotted hyenas exhibit male-like genitalia and dominance over males. Hyena ovarian tissues incubated in vitro produced large quantities of the steroid hormone precursor androstenedione. The activity of aromatase, which converts androstenedione to estrogen, was one-twentieth as great in hyena versus human placental homogenates. In comparison, the activity of 17 beta-hydroxysteroid dehydrogenase, which converts androstenedione to testosterone, was equal in the two homogenates. The limited aromatase activity may allow the hyena placenta to convert high circulating concentrations of androstenedione to testosterone, which results in virilization of the fetal external genitalia and possibly destruction of fetal ovarian follicles. Androstenedione production by residual ovarian stromal cells during reproductive life accounts for the epigenetic transmission of virilization in female spotted hyenas.
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PMID:A mechanism for virilization of female spotted hyenas in utero. 839 Nov 65


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