The effects of pre‐ and postnatal exposure to the nonsteroidal antiandrogen flutamide on testis descent and morphology in the Albino Swiss rat

Kassim, Normadiah M.; McDonald, Stuart W.; Reid, O.; Bennett, N.K.; Gilmore, D. P.; Payne, A. P.

doi:10.1046/j.1469-7580.1997.19040577.x

Cited by 62 publications

(50 citation statements)

References 39 publications

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“…Undescended testes were smaller in weight than descended testes, and the histological degeneration in the testis was attributed to abdominal cryptorchidism. In a study of flutamide-induced cryptorchidism, Kassim et al (1997) found differences in degree of abnormalities of spermatogenesis, depending on the intra-abdominal position of the testes, which support our findings of testicular degeneration being a secondary change due to abdominal cryptorchidism. Association of the testicular hypospermatogenesis and lower number of sperm in the lumen of the epididymal ductules was evidenced by histological findings at the final necropsy .…”

Section: Discussionsupporting

confidence: 80%

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

et al. 2004

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-Flutamide, when administered subcutaneously to female rats at doses of 3, 10, or 30 mg/ kg/day during late pregnancy (gestational days 16-21), significantly and dose-dependently decreased anogenital distance (AGD) of the male offspring in each dose group compared to controls. Significant delays in preputial separation were found in males at a dose of 30 mg/kg, but body weight gain was not inhibited. Cryptorchidism and absence of the prostate gland and seminal vesicles were found in males at doses ≥ 10 mg/kg, and testicular hypoplasia at a dose of 30 mg/kg. Hypospadias was noted in all dose groups and vaginal pouches at doses of ≥ 10 mg/kg. The effects on the accessory reproductive organs were severe, although the effects on the testes themselves were mild. However, those effects appeared to become more pronounced with growth, as evaluated on Days 30 and 42 and Weeks 16 to 18. Most of these affected animals displayed cryptorchidism. Male offspring exposed to flutamide in utero showed impairments of sexual behavior as adults in a dose-related manner. Number and frequency of mounts with intromissions was markedly decreased in all treated groups as compared to controls. At 10 mg/kg, no mounting with ejaculation was observed, and at a dose of 30 mg/kg, no mounting with intromission or ejaculation was observed. These changes in sexual behavior were closely associated with abnormalities of the external genitalia. Animals with hypospadias did not display mounts with ejaculation. However, F1 males that copulated at a dose of 3 mg/kg had a normal reproductive function. Histological examination of the reproductive organs revealed degeneration of the seminiferous tubules, hypospermatogenesis, and hypoplasia and inflammation of the seminal vesicles and prostate. Serum levels of FSH, LH, and testosterone in these animals were comparable between control and all dose groups. Therefore, the male reproductive dysfunction seen in the present study could not be attributed to abnormal sex hormone levels during maturation, but to possible demasculinization of the brain and progressively delayed dysmorphorogy of the male genitalia caused by fetal exposure to flutamide.

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Section: Discussionsupporting

confidence: 80%

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

et al. 2004

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“…Flutamide's reduction of testes size in the present study ( Figure 1A) is consistent with its effects in developing rats [5,17]. This reduction in testes size can be explained either by flutamide's direct antiandrogenic effect on the testes or by flutamide's up-regulation of aromatase activity and consequent increased E 2 production [16].…”

Section: Discussionsupporting

confidence: 76%

Effects of long-term flutamide treatment during development in zebra finches

Grisham

Hsia

Kim

et al. 2007

Neuroscience Letters

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The molecular mechanisms responsible for the sexual differentiation of the zebra finch song system remain mysterious. Androgen receptors are expressed in a sexually dimorphic fashion in the zebra finches song system: males have more cells expressing androgen receptors, and this sex difference appears very early in development (day 9 posthatch). Estrogen administration to hatchling females up-regulates androgen receptor expression in their song system and profoundly masculinizes their song system's morphology. Co-administering flutamide, an androgen-receptor blocker, with estrogen impedes estrogen's masculinizing effects on the song system, suggesting that androgens are required for masculine development. Accordingly, to investigate further the role of androgens in the sexual differentiation of the zebra finch song system, we sought to block androgen activity in males by administering large, sustained doses of flutamide from just before androgen receptors are expressed in the song system (day 7) through to the day of sacrifice (day 61-63).Flutamide profoundly reduced the size of the testes, demonstrating that this drug and mode of administration could have a large impact on tissues. In contrast, flutamide had only a minor impact on the song system: the number of RA neurons was slightly reduced, and the corrected HVC volume showed a trend toward demasculinization. Other brain measures (uncorrected HVC, and corrected and uncorrected volumes of Area X, lMAN, RA, and Rotundus; neuron size in lMAN, HVC, and RA; and number of HVC and LMAN neurons) were not significantly affected. The present results do not support an important role for androgen in masculinizing the song circuit after posthatch day 7.

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“…However, data were available for rats exposed to flutamide from GD 12 to PND 27 or administered flutamide by injection on PND 1-14 (listed under inguinoscrotal migration in Table 1); all testes completed transinguinal migration and were found in the scrotum at 16-20 week of age. Hence, transinguinal migration of testes occurs in rat pups, at the normal time or with slight delay, with testosterone- Barthold et al (1996); (2) Kassim et al (1997); (3) McMahon et al (1995); (4) Mylchreest et al (1999); (5) Shono et al (1994b); (6) Spencer et al (1991); (7) Spencer et al (1993).…”

Section: Role Of Testosteronementioning

confidence: 99%

Cryptorchidism in common eutherian mammals

2007

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Cryptorchidism is failure of one or both testes to descend into the scrotum. Primary fault lies in the testis. We provide a unifying cross-species interpretation of testis descent and urge the use of precise terminology. After differentiation, a testis is relocated to the scrotum in three sequential phases: abdominal translocation, holding a testis near the internal inguinal ring as the abdominal cavity expands away, along with slight downward migration; transinguinal migration, moving a cauda epididymidis and testis through the abdominal wall; and inguinoscrotal migration, moving a s.c. cauda epididymidis and testis to the bottom of the scrotum. The gubernaculum enlarges under stimulation of insulin-like peptide 3, to anchor the testis in place during gradual abdominal translocation. Concurrently, testosterone masculinizes the genitofemoral nerve. Cylindrical downward growth of the peritoneal lining into the gubernaculum forms the vaginal process, cremaster muscle(s) develop within the gubernaculum, and the cranial suspensory ligament regresses (testosterone not obligatory for latter). Transinguinal migration of a testis is rapid, apparently mediated by intra-abdominal pressure. Testosterone is not obligatory for correct inguinoscrotal migration of testes. However, normally testosterone stimulates growth of the vaginal process, secretion of calcitonin gene-related peptide by the genitofemoral nerve to provide directional guidance to the gubernaculum, and then regression of the gubernaculum and constriction of the inguinal canal. Cryptorchidism is more common in companion animals, pigs, or humans (2-12%) than in cattle or sheep (%1%). Laboratory animals rarely are cryptorchid. In respect to non-scrotal locations, abdominal testes predominate in cats, dogs, and horses. Inguinal testes predominate in rabbits, are common in horses, and occasionally are found in cats and dogs. S.c. testes are found in cattle, cats and dogs, but are most common in humans.

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The effects of pre‐ and postnatal exposure to the nonsteroidal antiandrogen flutamide on testis descent and morphology in the Albino Swiss rat

Cited by 62 publications

References 39 publications

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

Effects of Flutamide on Sex Maturation and Behavior of Offspring Born to Female Rats Treated During Late Pregnancy

Effects of long-term flutamide treatment during development in zebra finches

Cryptorchidism in common eutherian mammals

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