[CHANGES IN THE BRAIN TESTOSTERONE METABOLISM AND SEXUAL BEHAVIOR IN MALE RATS PRENATALLY EXPOSED TO METHYLDOPA AND STRESS].

The changes of aromatase and 5α-reductase activities were studied in preoptic area (POA) and medial basal hypothalamus of 10-days-old and sexual behavior in 3-month-old male offsprings of rats exposed daily to noradrenaline antagonist methyldopa (400 mg/kg per os) 30 minutes prior to 1-hour immobilization during the last week of pregnancy (from 15th to 21st day). Prenatal stress caused aromatase activity lowering in the POA of developing brain and feminization (appearance of lordosis) and demasculinization of sexual behavior (prolongation of latent periods to the first mounting and first intromission as well as of the first ejaculation and postejaculation refractory period) in young male offspring. Oral methyldopa used prior to pregnant females stressing prevented early effect of prenatal stress on aromatase activity in the POA and normalized the male sexual behavior in young male rats by shortening both latent period to the first ejaculation and postejaculation refractory period, and an increase of numbers of ejaculation. The data obtained indicate that brain noradrenergic system plays significant role in the mechanisms of metabolic- and behavioral disturbances developing in male rats exposed to prenatal stress.

Familial hyperestrogenism in both sexes: clinical, hormonal, and molecular studies of two siblings.

Familial hyperestrogenism is a rare clinical condition of unknown etiology in which patients present excessive androgen to estrogen conversion. Excessive aromatization is primarily ascribed to abnormalities in the CYP19. Mice that lack steroid 5alpha-reductase type 1 also exhibit hyperestrogenism due to an increased availability of androgen precursors. Here we studied two adult siblings, born to unrelated parents, who presented clinical and hormonal evidence of estrogen excess. The man was treated with topical dihydrotestosterone, which promoted adequate virilization. The woman was treated with anastrazole, a potent aromatase inhibitor, with normalization of menstrual cycles. Genetic linkage to the steroid 5alpha-reductase type 1 gene (SRD5A1) was ruled out in this family. A similar analysis did not rule out linkage to CYP19, although no mutation was identified in the coding region of this gene. Aromatase mRNA was at least 10-fold more abundant in the female patient's skin fibroblasts vs. the control. Southern analysis of genomic DNA did not reveal rearrangements or amplification of the coding region of CYP19. We conclude that the phenotype of familial hyperestrogenism includes prepubertal gynecomastia, hypogonadism, and short stature in men, and precocious thelarche, macromastia, enlarged uterus, and menstrual irregularities in women. Topical dihydrotestosterone is an efficient alternative treatment in men with hyperestrogenism; in addition, second generation aromatase inhibitors are useful in both sexes.

Cytochrome P-450 17 alpha-hydroxylase protein and mRNA in the testis of the testicular feminized (Tfm) mouse.

The testicular feminized (Tfm) mouse lacks functional androgen receptors and develops with a female external phenotype and internal testes. The testes of these animals contain normal, or close to normal, numbers of Leydig cells but secrete very low amounts of androgen due to a lack of 17 alpha-hydroxylase activity. To determine whether this loss of activity is due to a lack of enzyme synthesis or a change in catalytic activity we have examined 17 alpha-hydroxylase cytochrome P-450 (P-450(17 alpha)) protein and mRNA levels in the testes of Tfm mice. Levels of P-450(17 alpha) protein were measured by immunoblotting, while mRNA was measured following reverse transcription (RT) and amplification by the polymerase chain reaction (PCR). Conditions for RT-PCR were determined which allowed semiquantification of P-450(17 alpha) mRNA relative to beta-actin mRNA. In extracts of Tfm testes P-450(17 alpha) protein was undetectable using antiserum against porcine P-450(17 alpha). In contrast, a protein of around 54 kDa was clearly detectable in extracts of control cryptorchid testes. Using RT-PCR, P-450(17 alpha) mRNA was detectable in both control and Tfm testes but, expressed in terms of beta-actin mRNA, levels of P-450(17 alpha) mRNA in control testes were 40-fold higher than those in Tfm testes. If the total amount of RNA extracted from each testis is taken into account then P-450(17 alpha) mRNA levels per testis were up to 400-fold higher in control testes. These results show that the reduced level of 17 alpha-hydroxylase activity in Tfm testes is related to reduced protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)