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SAMUEL A. GUNN, THELMA CLARK GOULD and W. A. D. ANDERSON

Summary.

Between 24 and 40 hr after cadmium treatment in the rat, whilst the testis and caput epididymidis are undergoing haemorrhagic necrosis, the cauda epididymidis and contained spermatozoa remain morphologically normal. Sexual activity is diminished but fertile matings occur. By 7 days, reduced androgen output results in atrophic changes in the accessory glands, cauda epididymidis and vas deferens, in which spermatozoa are now degenerate. Few males mate and these are infertile. The changes in the cauda can be prevented by testosterone treatment and fertility remains normal up to 9 days after the dose of cadmium.

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SAMUEL A. GUNN, THELMA CLARK GOULD and W. A. D. ANDERSON

The observations of Pařízek & Zahor (1956) and Pařízek (1957a, b) on the selective destructive effect of cadmium on the testis of the rat and mouse have since been confirmed by Meek (1959), Kar & Das (1960), Gunn, Gould & Anderson (1961), Allanson & Deanesly (1962), Chiquoine (1964), Mason, Brown, Young & Nesbit (1964) and others. During studies on the induction of interstitial cell tumours of the testis by cadmium (Gunn, Gould & Anderson, 1963), we noted that cadmium failed to cause any degree of damage to the testis of the BALB/c mouse. A study was, therefore, undertaken to determine if this resistance to cadmium-induced testicular injury was unique to the BALB/c strain of mice and whether strain differences in testicular response to cadmium might also be observed in rats. A single subcutaneous (interscapular) injection of 0·03 m-mole/kg of CdCl2 was chosen for the preliminary testing since overwhelming testicular

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M L Gould, P R Hurst and H D Nicholson

Oestrogen plays an important role in testicular function. This study used mice null for oestrogen receptor α (ERα) or β (ERβ) to investigate which receptor mediates the effects of oestrogen within the testis. Groups of ERα knockout mice (αERKO) and ERβ knockout mice (βERKO) and wild-type littermates (n=5–8) were killed at 11 weeks post partum. One testis was fixed in Bouin’s fluid for stereology and the other frozen for testosterone measurement. Trunk blood was collected for testosterone RIA. The optical disector combined with the fractionator methodology was used to estimate Leydig, Sertoli and germ cell numbers. At all times, the knockout animals were compared with their wild-type littermates. The physical disector quantified cells stained immunohistochemically for the apoptotic marker active caspase-3 and Hoechst staining was used to identify nuclear fragmentation. The mean Leydig cell volume was measured using the point sampled intercept method. The Leydig cell number per testis was significantly increased in βERKO mice but not in αERKO mice. Plasma and testicular testosterone concentrations were increased in αERKO mice but no changes were observed in βERKO mice. Hypertrophic Leydig cell changes were observed in αERKO mice, and a decreased mean cell volume was seen in βERKO mice. No difference in Sertoli cell number per testis was observed in any of the groups. The spermatogonial cell number per testis was increased in βERKO mice. Immunohistochemistry identified increased numbers of active caspase-3-labelled germ cells per testis in αERKO mice but not βERKO mice. Hoechst staining supported these findings. There was significant germ cell loss in αERKO mice. This study suggests that ERβ may be involved in regulation of Leydig cell proliferation and testosterone production in the adult mouse testis.

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K. G. Gould, C. E. Graham and D. C. Collins

It has repeatedly been demonstrated that administration of prostaglandin (PG) F-2α to nonprimates is luteolytic and inhibits progesterone synthesis, while administration of PGE-2 stimulates progesterone synthesis. The luteolytic effect of PGF-2α has not been conclusively demonstrated in vivo in the primate, variable effects on the circulating progesterone levels having been reported (Shaikh, 1972; Auletta, Speroff & Caldwell, 1973; Shaikh & Klaiber, 1974; Korda, Shutt, Smith, Shearman & Lyneham, 1975; Lyneham, Korda, Shutt, Smith & Shearman, 1975). PGE-2 has been reported to increase progesterone synthesis by the primate corpus luteum (Channing, 1971). It is becoming apparent that route of administration, dosage and other unknown factors can alter the effect of PGF-2α on progesterone synthesis (Channing, 1972; Auletta et al., 1973; Puri & Laumas, 1975; Henderson & McNatty, 1975). Attempts to isolate the factors whereby PGs affect granulosa cells by the use of in-vitro systems have met with limited success, because PGs in vitro frequently exhibit effects which differ from those seen in vivo (Lindner et al., 1974). We therefore examined the effect of the developmental state of the follicle on its response to PG and dibutyryl cyclic AMP in vitro. Dibutyryl cyclic AMP (dbcAMP) is considered to mimic the action of gonadotrophins, because synthesis of its analogue, cAMP, is believed to be a step in the intracellular action of gonadotrophins (Marsh, 1976).

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K. G. Gould, J. R. Faulkner and D. Pernikoff

Summary. Administration of 200 μg mestranol/day (oestrogen) to ovariectomized chimpanzees caused a rapid decrease of circulating gonadotrophin concentrations to values similar to those in intact females. Administration of 2 mg chlormadinone acetate (progestagen) resulted in a prompt and significant rise in LH and FSH. This rise was accompanied by alteration in the physical characteristics and electrolyte composition of the cervical mucus which were the same as those observed around the time of ovulation. These results suggest a role of preovulatory progesterone secretion in relation to changes associated with ovulation in the chimpanzee.

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SAMUEL A. GUNN, THELMA CLARK GOULD and W. A. D. ANDERSON

Summary.

It is known that the selective injurious effect of cadmium on the testis can be prevented by zinc, cysteine or selenium. Studies, conducted in CD-1 mice, were initiated to determine whether any of these treatments offered protection by preventing cadmium from reaching the testis in doses sufficient to cause injury. Using cadmium chloride, labelled with 109Cd, it was shown that none of these protective agents decreased the amount of cadmium reaching the testis. Zinc acetate evoked no significant changes, cysteine brought about a slight enhancement of cadmium level but selenium dioxide produced a marked and prolonged elevation of cadmium uptake by the testis. Comparable studies in which selenium, rather than cadmium, was labelled (75Se) demonstrated that, in the presence of cadmium, selenium levels were augmented. Possible mechanisms are discussed to explain the diverse means of protection offered by zinc, cysteine and selenium. Since the site of cadmium-induced testicular injury has been pin-pointed at its vasculature, it is suggested that these protective agents exert their action at the vascular level.

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SAMUEL A. GUNN, THELMA CLARK GOULD and W. A. D. ANDERSON

Wetterdal (1958) showed that zinc, an element essential for spermatogenesis, is incorporated into developing spermatogenic elements within the testis. Cadmium, physico-chemically similar to zinc, causes selective destruction of the testis; administration of zinc prevents cadmium damage (Parizek, 1957; Kar, Das & Mukerji, 1960; Gunn, Gould & Anderson, 1961). Parizek (1960) suggested that cadmium exerts testicular injury by displacing zinc from its natural sites in seminiferous tubules and that the haemorrhagic reactions, so characteristic of cadmium injury, are a secondary effect. More recent evidence indicates that the vascular endothelium of the testis is the primary site of damage and that necrosis of parenchyma follows secondarily (Gunn, Gould & Anderson, 1963a; Chiquoine, 1964; Mason, Brown, Young & Nesbit, 1964; Niemi & Kormano, 1965; Waites & Setchell, 1966). The following experiments were initiated using radio-isotopes to determine

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D. R. Mann, D. C. Collins, M. M. Smith and K. G. Gould

Summary. Treatment of 4 adult male rhesus monkeys for 8–12 months with 100–400 μg of a GnRH antagonist/day by means of using osmotic minipumps led to suppressed serum concentrations of LH and testosterone followed by various degrees of recovery toward pretreatment values. The serum LH response to a challenge of native GnRH was reduced by 30–75% during antagonist treatment. The serum testosterone response to GnRH was exaggerated above the response in the pretreatment period, suggesting hypersensitivity of the testis to gonadotrophin. Antagonist administration under these conditions did not alter body weight or abolish ejaculatory response. Antagonist infusion caused a 96% decrease in sperm counts. Spermatozoa recovered during the final month of antagonist treatment showed a reduced ability to penetrate denuded hamster ova. Testicular biopsies performed at the end of antagonist treatment revealed persistent spermatogenesis. However, the cellularity of the seminiferous tubules was decreased below that of pretreatment biopsies. The results of this study suggest that the amount of testosterone needed to maintain normal spermatogenesis is greater than that needed to maintain electroejaculatory response in monkeys.

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D. R. Mann, S. R. Adams, K. G. Gould, T. E. Orr and D. C. Collins

Summary. In Exp. 1, the effect of treatment with a GnRH agonist on basal concentrations of serum testosterone and peak values of serum testosterone after administration of hCG was determined. One group of adult male monkeys was treated with a low dose (5–10 μg/day) and a second group with a high dose (25 μg/day) of a GnRH agonist for 44 weeks. Basal and peak testosterone concentrations were both significantly reduced by GnRH agonist treatment in all groups compared to untreated control animals, but the % rise in serum testosterone above basal values in response to hCG administration was unchanged by agonist treatment.

In Exp. 2, the GnRH agonist (100 or 400 ng) or a GnRH antagonist (4 μg) was infused into the testicular arteries of adult monkeys. The agonist did not alter testosterone concentrations in the testicular vein or testosterone and LH values in the femoral vein.

In Exp. 3, testicular interstitial cells from monkeys were incubated with three concentrations (10−9, 10 −7 and 10−5 m) of the GnRH agonist or a GnRH antagonist with and without hCG. After 24 h, neither basal nor hCG-stimulated testosterone production was affected by the presence of the GnRH agonist or antagonist.

The results from all 3 experiments clearly suggest that GnRH agonist treatment does not directly alter steroid production by the monkey testis.

Keywords: GnRH; testes; LH; testosterone; rhesus monkey

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D. Goulding, D. H. Williams, J. F. Roche and M. P. Boland

Superovulation in cattle normally involves the administration of gonadotrophins at specific times of the oestrous cycle, followed by the induction of luteolysis and insemination with high quality semen. The first aim of this experiment was to examine the effect of supplementary progesterone when used in conjunction with porcine FSH (pFSH) to induce superovulation in heifers. The methods compared were PGF given at mid-cycle or a progesterone-releasing intravaginal device (PRID) inserted at different phases of the cycle. The second aim was to determine whether site of insemination or use of fresh or frozen semen affected embryo production. A factorial design was used involving 185 beef heifers. The main factors were (i) synchronization methods PGF or PRID); (ii) semen type (fresh or frozen); (iii) insemination regimens (involving two inseminations and variations in the sites) and number of straws used (one or two) at the second insemination. Eight injections of pFSH were given twice a day for 4 days starting either on days 9, 10 or 11 of the oestrous cycle or on the fourth day after insertion of a PRID. Heifers were checked for oestrus, inseminated twice and embryos were recovered on day 7 of the superovulated cycle. There was no difference between heifers given either PRID or PGF in the oestrous response (93% versus 96%), number of ovulations (15.9 ± 1.11 versus 13.4 ± 1.06), large follicles (2.5 ± 0.24 versus 2.3 ± 0.23) or embryos recovered (9.1 ± 0.77 versus 9.1 ± 0.74). The number of embryos that could be frozen was lower (P = 0.05) in heifers given PRID. The stage of the cycle at which the PRID was inserted affected the number of ovulations, large follicles and embryos recovered (P < 0.04). The use of fresh or frozen semen had no effect on the number of embryos recovered, but the use of frozen semen resulted in fewer grade 1 and 2 embryos and more grade 4 and 5 embryos in PRID-treated heifers. The number of straws did not affect the number or quality of embryos recovered. In conclusion, the use of a PRID, inserted at different stages of the cycle, in conjunction with PGF and pFSH resulted in fewer freezable embryos recovered compared with the use of PGF and pFSH given at mid-cycle. The use of frozen semen did not affect the number or quality of embryos recovered following the use of PGF and pFSH at mid-cycle, but it did decrease the number of grade 1 and 2 embryos recovered following the use of PRID and pFSH; the number (two versus three) of straws used did not affect the yield or quality of embryos recovered.