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Biomedical subjects

J M Hutson

Publications and source records attributed to J M Hutson.

At least 127 records · Page 7Linked to original sources
PubMed1994

Prenatal androgen blockade with flutamide inhibits masculinization of the genitofemoral nerve and testicular descent.

Prenatal androgen blockade with the antiandrogen flutamide inhibits the inguinoscrotal phase of testicular descent. The evidence suggests that androgens may act indirectly via the sexually dimorphic genitofemoral nerve (GFN) to control this phase. Rats were exposed to flutamide on gestational days 16 through 19. Seven-day-old rats were subjected to retrograde fluorescent labelling of the GFN combined with immunohistochemistry for calcitonin gene-related peptide (CGRP), a neurotransmitter found in the GFN. Fluorescent-labelled and CGRP-immunoreactive neurons in the GFN spinal nucleus were quantified. Sexual dimorphism of the GFN nucleus was absent in the flutamide-treated rats but obviously present in control rats. Furthermore, control male nuclei had 24% more CGRP-immunoreactive neurons and 12% more fluorescent-labelled neurons than did flutamide-treated male nuclei. This study shows that prenatal androgen blockade with flutamide inhibits masculinization of the GFN, with significant reduction of its CGRP content. This supports the proposal that androgens act via the GFN, with CGRP as the second messenger, to control inguinoscrotal testicular descent.

Animals↗
PubMed1994

The effect of flutamide on testicular descent in rats examined by scanning electron microscopy.

The effect of prenatal flutamide exposure on testicular descent was investigated by using scanning electron microscopy (SEM) in prenatal and postnatal rats. In 20-day-old fetal rats, SEM showed no significant difference in the degree of gubernacular development or testicular descent relative to the kidney between flutamide-treated (74.5 +/- 2.2 U) and control rats (73.3 +/- 1.5 U); however, there was significant inhibition in oestrogen-treated rats (44.3 +/- 2.2 U) (P < .001). (The distance between the kidney and the bladder neck was standardized to 100 U.) In 5-day-old rats, SEM showed inhibited downward growth of the processus vaginalis in flutamide-treated rats. The length of processus vaginalis below the inguinal ligament was 32.8 +/- 2.4 U in flutamide-treated rats and 51.7 +/- 1.8 U in controls (P < .001). In 30- to 35-day-old mature rats, the frequency of cryptorchidism was 41.3% for flutamide-treated rats and 0% for controls (P < .001). Some cryptorchid testes were located in the lower abdominal cavity (10.9%); others were in the suprainguinal position (26.1%) or on the line of descent in the inguinal region (4.3%). In the flutamide-treated group, no testes were located in the posterior abdominal cavity, near the kidney. These results suggest that transabdominal descent of the testis is independent of androgen action, but that androgens control inguinoscrotal descent of the testis by regulating gubernacular migration and the growth of the processus vaginalis.

Animals↗
PubMed1994

Ontogeny of gubernacular contraction and effect of calcitonin gene-related peptide in the mouse.

The mouse gubernaculum undergoes inguinoscrotal migration in the first postnatal week and also shows rhythmic contractions in organ culture in response to calcitonin gene-related peptide (CGRP). This study aimed to investigate the ontogeny of gubernacular contractile activity and effect of CGRP in organ culture in relation to the normal time of migration. Two hundred eighty gubernacula from male mice of 17 and 19 days' gestation, and of postnatal days 0,2,4,7, 10, and 14 were studied. Half were cultured with CGRP 714 nmol/L, and the other half were cultured without CGRP as controls. All were examined daily (for 7 days) for contractions. In the control group, the cumulative percentages of contractile gubernacula increased from 5% to 100% with age; in the CGRP group, these values ranged from 65% to 100%. There were significant differences between the two groups from prenatal day 17 to postnatal day 4 (P values ranged from less than .001 to less than 0.05, respectively). With increasing age in the CGRP group, the highest contractile rates were observed at the fewest number of days in culture. From prenatal day 17 to postnatal day 4, the gubernaculum had increasing endogenous contractility, but there was low endogenous contractility without exogenous CGRP. Contractility of gubernacula was enhanced strongly by exogenous CGRP, and the culture days of the peak contractile rates lined up in the reverse order. These results suggest that the days of optimal gubernacular contraction with CGRP in vitro are in keeping with the days of natural migration in vivo. This is consistent with the hypothesis that CGRP (released from the genitofemoral nerve) is important for gubernacular migration.

Animals↗
PubMed1994

Calcitonin gene-related peptide receptors in the gubernaculum of normal rat and 2 models of cryptorchidism.

We investigated calcitonin gene-related peptide binding in the gubernaculum from a normal rat, a TS rat (congenitally cryptorchid from unknown causes) and a flutamide rat (cryptorchid secondary to prenatal antiandrogen treatment). Gubernacular sections from 2-day-old male pups were incubated with 125iodine-calcitonin gene-related peptide with various concentrations of unlabeled calcitonin gene-related peptide. After exposure to x-ray film, developed film was quantified by computerized densitometry. The binding analysis showed that concentrations of calcitonin gene-related peptide receptors were 22.9 +/- 2.12, 13.5 +/- 1.70 and 30.3 +/- 2.63 (mean plus or minus standard error of mean, fmol./mg. polymer) for each rat, respectively, and there were significant differences between the normal and TS rats (p < 0.01), and the normal and flutamide rats (p < 0.05). However, there was no significant difference in the dissociation constant among the 3 models. This result shows that deficiency and excess of calcitonin gene-related peptide binding in the gubernaculum are associated with cryptorchidism. Calcitonin gene-related peptide released from the genitofemoral nerve may regulate its own receptor concentration to control gubernacular motility in vivo.

Animals↗
PubMed1994

Capsaicin increases the frequency of cryptorchidism in flutamide-treated rats.

Capsaicin, a specific neurotoxin that irreversibly results in degeneration of sensory C fibers of the peripheral nerves, was investigated for its ability to affect testicular descent. In particular, we investigated the ability of prenatal flutamide, postnatal capsaicin or combined prenatal flutamide with postnatal capsaicin to induce undescended testes in rats. Within these treatment groups the frequency of maldescent was 42% in the animals treated prenatally with flutamide, 32% with postnatal capsaicin, and 100% with prenatal flutamide and postnatal capsaicin. Of interest, it was found that all animals that received capsaicin had maldevelopment of the scrotum. Our data suggest that capsaicin increased the frequency of cryptorchidism in rats prenatally treated with flutamide, perhaps by inhibition of scrotal development. These findings indicate that sensory nerves to the scrotum may affect scrotal development and testicular descent.

Animals↗
PubMed1994

Transabdominal testicular descent is really ovarian ascent.

Some investigators have suggested that testicular descent relative to the ovary is actually caused by the relative upward growth of the structures adjacent to the testis and that in the early phase of descent the testis is anchored to the inguinal region as the embryo enlarges. This concept was founded on results from the dissection of human fetuses. In this study the development of the urogenital system in fetal mice is examined using scanning electron microscopy to determine the distance between the bladder neck and the lower pole of the gonad. The results of this study confirm that transabdominal descent of the testis relative to the ovary is in one sense really ascent of the ovary in the fetal mouse, while the testis is anchored to the inguinal region by the developed gubernaculum. The testis shows real movement at the beginning of the inguinoscrotal phase of testicular descent at birth.

Animals↗
PubMed1994

Hormonal control of testicular descent and the cause of cryptorchidism.

This paper briefly reviews the literature on testicular descent and presents new observations from the authors' laboratory which suggest new ways of looking at old problems. There is now good evidence that testicular descent occurs in two morphologically and hormonally distinct phases. Relative 'transabdominal migration' of the testis compared with the ovary occurs at 10-15 weeks of gestation in the human and 'inguinoscrotal' migration occurs at 26-35 weeks of gestation. We have proposed previously that the first phase is controlled by Müllerian inhibiting substance although this remains controversial. The second phase is androgen dependent and is possibly mediated indirectly through the release from the genitofemoral nerve (GFN) of the neuropeptide calcitonin gene-related peptide (CGRP). Recently we have used three different rodent models of undescended testis to determine the involvement of the GNF and/or CGRP. The testicular feminization mouse with complete androgen resistance and the rat exposed prenatally to the antiandrogen flutamide have a deficiency of CGRP in the GFN. In contrast, the mutant trans-scrotal rat which has normal androgen levels has an excess of CGRP in the GFN. All cryptorchidism models, despite their different primary cause, have in common an abnormality of the GNF and/or CGRP which is consistent with the hypothesis that normal testicular descent in the rodent may be mediated by the GFN.

Abdomen↗
PubMed1994

Absence of normal sexual dimorphism of the genitofemoral nerve spinal nucleus in the mutant cryptorchid (TS) rat.

Sexual dimorphism of the genitofemoral nerve spinal nucleus has been demonstrated in normal rodents. Calcitonin gene-related peptide is a neurotransmitter, present in the genitofemoral nerve, that has been implicated in the regulation of gubernacular migration and inguinoscrotal testicular descent. A combination of retrograde fluorescent labelling of the genitofemoral nerve and immunohistochemistry for calcitonin gene-related peptide was used in 1-3-day-old mutant TS rats with 85% incidence of congenital cryptorchidism and an absence of the normal sexual dimorphism of the genitofemoral nerve spinal nucleus was demonstrated. There was no significant difference between male and female nuclei with respect to fluorescent-labelled neurones as well as those immunoreactive for calcitonin gene-related peptide, in contrast to an obvious sexual dimorphism present in normal control animals. This lack of normal sexual dimorphism of the genitofemoral nerve nucleus is likely to be important in the pathogenesis of cryptorchidism in this animal model.

Animals↗
PubMed1993

Hydrometrocolpos following prenatal dexamethasone treatment for congenital adrenal hyperplasia (21-hydroxylase deficiency).

A female with congenital adrenal hyperplasia (21-hydroxylase deficiency) received prenatal dexamethasone treatment. Suppression of the fetal adrenal was initially inadequate but adequate in later pregnancy. The baby showed masculinisation without clitoral enlargement and a narrow urogenital sinus with resulting hydrometrocolpos. It is possible that dexamethasone treatment which is initially inadequate increases the risk of this latter complication.

Adrenal Hyperplasia, Congenital↗
PubMed1993

Exogenous calcitonin gene-related peptide causes gubernacular development in neonatal (Tfm) mice with complete androgen resistance.

It has been proposed that testicular descent is controlled indirectly by androgens acting on the central nervous system to mediate migration of the gubernaculum to the scrotum. Accumulating evidence suggests that the genitofemoral nerve may release a newly described neurotransmitter, calcitonin gene-related peptide (CGRP) to stimulate gubernacular motility during migration. This study aimed to determine whether exogenous CGRP could stimulate gubernacular migration in mice with complete androgen resistance (testicular feminization mouse [Tfm]). CGRP was injected into the right groin of neonatal Tfm mice at 2-day intervals until 2 weeks of age, when the length of the processus vaginalis was measured under a dissecting microscope. The processus vaginalis length in normal male littermates was 5.9 +/- 1.8 mm (mean +/- SD) while in the female it was 1.2 +/- 0.9 mm. Exogenous CGRP had no effect on either of these. In Tfm males CGRP caused a significant increase in the length of the processus vaginalis on the injected side (2.3 +/- 0.8 mm) compared with the uninjected side (1.4 +/- 1.0 mm). These results are consistent with the hypothesis that CGRP can replace, at least partially, the effect of androgens on gubernacular migration.

Androgen-Insensitivity Syndrome↗
PubMed1993

Calcitonin gene-related peptide stimulates motility of the gubernaculum via cyclic adenosine monophosphate.

Calcitonin gene-related peptide (CGRP), N-truncated CGRP fragments CGRP 8-37 and [Tyr0]-CGRP 28-37, and dibutyryl cyclic adenosine monophosphate (DBcAMP) were studied for their effects on the neonatal male mouse gubernaculum in organ culture. Rhythmic contractions were shown in 18% of control gubernacula, which were enhanced with CGRP, inhibited by CGRP 8-37 and not affected by [Tyr0]-CGRP 28-37. A total of 60 gubernacula was exposed to increasing concentrations of DBcAMP and the percentage of gubernacula showing rhythmic contractions increased from 18 to 60%. These studies demonstrate that the neonatal mouse gubernaculum exhibits endogenous contractility that can be enhanced with CGRP or DBcAMP. These results suggest that cyclic adenosine monophosphate may act as the intracellular second messenger for receptor bound CGRP in the gubernaculum. This finding is consistent with the hypothesis that CGRP from the genitofemoral nerve provides directional, chemotactic guidance for inguinoscrotal gubernacular migration during testicular descent.

Animals↗
PubMed1993

The relationship among calcitonin gene-related peptide, androgens and gubernacular development in 3 animal models of cryptorchidism.

The relationship among calcitonin gene-related peptide (CGRP), a neurotransmitter in the genitofemoral nerve, androgens and gubernacular development was studied using rats treated prenatally with the antiandrogen flutamide and the mutant cryptorchid TS rat. We compared these 2 groups with the testicular feminization mouse with androgen insensitivity. Gubernacula from male TS rats and flutamide-treated rats were maintained in organ culture and examined for contractile response to CGRP. Controls were gubernacula from normal rats and vehicle-treated rats, respectively. TS rat gubernacula have an inhibited contractile response to CGRP, whereas flutamide-treated rat gubernacula have an exaggerated response. A similar exaggerated response to CGRP has previously been demonstrated in testicular feminization mouse gubernacula. These results revealed abnormalities in gubernacular contractile response to CGRP in these cryptorchid animal models, implying that CGRP and gubernacular contractility may have key roles in mediating normal inguinoscrotal testicular descent.

Androgen-Insensitivity Syndrome↗
PubMed1993

Germ cell development in neonatal mouse testes in vitro requires müllerian inhibiting substance.

To study the effect of müllerian inhibiting substance on testicular germ cell development, especially on gonocytes, whole testes (156) from newborn mice were cultured for 1 to 7 days in vitro. The synthetic medium contained either 10% fetal calf serum, which itself contains endogenous müllerian inhibiting substance, or transferrin, insulin and retinoic acid. Human recombinant müllerian inhibiting substance, rabbit antiserum against müllerian inhibiting substance and/or normal rabbit serum was added to some cultures. The cultured testes were fixed in Stieve's fixative and stained with hematoxylin and eosin, and the numbers and types of germ cells per tubule were counted under a light microscope. Preliminary studies showed that germ cell development in newborn mouse testes was similar in vitro to that observed in vivo, except for delay in vitro. Normal germ cell maturation from gonocytes to primary spermatocytes occurred in testes cultured with 10% fetal calf serum only (i), 10% fetal calf serum plus müllerian inhibiting substance plus anti-müllerian inhibiting substance antibody (ii), 10% fetal calf serum plus normal rabbit serum (iii) and transferrin, insulin and retinoic acid plus müllerian inhibiting substance (iv). Maturation from gonocytes to A-type spermatogonia was arrested in testes cultured with 10% fetal calf serum plus anti-müllerian inhibiting substance antibody (p < 0.01), transferrin, insulin and retinoic acid alone (p < 0.001) and transferrin, insulin and retinoic acid plus müllerian inhibiting substance plus anti-müllerian inhibiting substance antibody (p < 0.001). The results are consistent with the hypothesis that müllerian inhibiting substance may be involved in postnatal gonocyte development and suggest that it may be useful to treat infertility associated with undescended testes.

Animals↗
PubMed1993

The role of intra-abdominal pressure in cryptorchidism.

The effect of intra-abdominal pressure was investigated in the rat, in which the testes normally descend on or about the 21st day of age. In newborn rats less than 5 days old, the entire anterior abdominal wall musculature was excised from the level of the umbilicus to the xiphoid process. The proximal attachment of the gubernaculum also was incised bilaterally. The abdomen was re-explored on the 28th day to examine the position of the testes. Ninety-five male animals survived. The 4 testes held by adhesions and the 12 with testicular atrophy were excluded from the analysis. A combination of abdominal muscle excision and transection of the proximal gubernaculum (A) reduced the number of descended testes to 19 of 45 (42%). Transection of the gubernaculum alone (B) resulted in 30 of 43 (70%) descended testes. Where an abdominal defect was created without cutting the gubernaculum (C), 34 of 36 (96%) testes descended, which is similar to sham-operated (D) controls 50 of 50 (100%). There was a significant difference between groups A and B (p < 0.025), A and C (p < 0.005) and B and C (p < 0.025). These results show that the gubernacular attachment to the testis and the intra-abdominal pressure act synergistically to aid testicular descent in the rat.

Abdominal Muscles↗
PubMed1993

The gubernaculum in adult female, adult male and TFM male mice.

There is still controversy over whether androgens are involved in gubernacular migration during descent of the testis, prompting a review of anatomical events controlled by androgens. The gubernacular position in adult female, male, and testicular feminized male (TFM) mice (with complete androgen resistance) was observed macroscopically to determine its caudal limit and whether the adult TFM male still contained guvernacular bulk. The length of the processus vaginalis was measured, and the presence of a differentiated cremaster muscle was determined histologically. In 10 adult female mice there was neither a processus vaginalis nor a cremaster muscle, and the gubernaculum (round ligament of the ovary) attached to the external inguinal ring. In 10 adult TFM mice the gubernaculum ended at or just beyond the external ring, and was present in an amount corresponding to its size at the end of the outgrowth phase of development, with secondary infiltration by fat. The processus vaginalis was poorly developed, the cremaster muscle was undifferentiated, and there was no eversion of the cremaster sac. In 10 normal adult male mice the gubernaculum and testis had migrated to the scrotum, and the gubernaculum had regressed fully. Because gubernacular development in the androgen-resistant mouse cases after termination of transabdominal testicular migration, the anatomy of the adult confirms that, in the mouse, normal androgenic function is essential for eversion of the cremaster sac and gubernacular migration beyond the groin to the genital folds.

Animals↗