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BACKGROUND AND PURPOSE: There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. MATERIALS AND METHODS: Radiosensitivity was assessed using a micronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G(0) phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predispostion? Br. J. Cancer 1998;77;614-620) and an assay of G(2) phase chromatid radiosensitivity ('G(2) assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G(2) assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G(2) assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possiblity of individualising radiotherapy dose presciptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998;79:606-613)). RESULTS: The HR patients could be identified in some of the assays. For example, for acute skin reactions, 9/123 patients were judged as HR; they had significantly higher G(2) scores than normal reactors (P=0.004). For the late reactions, the mean HDR MN scores were higher for the 4/47 patients who had severe telangiectasia (P=0.042) and the 8/47 patients had severe fibrosis (P=0.055). However, there were no trends towards increased chromosomal radiosensitivity with the micronucleus scores at HDR or LDR, or with G(2) chromosomal radiosensitivity. CONCLUSIONS: While these results support the concept of using lymphocytes to detect elevated sensitivity to radiotherapy (as an alternative to fibroblasts), these assays are unlikely to be of assistance for the prediction of normal tissue effects in the clinic in their present form.

Chromosome 9 is highly structurally polymorphic. It contains the largest autosomal block of heterochromatin, which is heteromorphic in 6–8% of humans, whereas pericentric inversions occur in more than 1% of the population. The finished euchromatic sequence of chromosome 9 comprises 109,044,351 base pairs and represents >99.6% of the region. Analysis of the sequence reveals many intra- and interchromosomal duplications, including segmental duplications adjacent to both the centromere and the large heterochromatic block. We have annotated 1,149 genes, including genes implicated in male-to-female sex reversal, cancer and neurodegenerative disease, and 426 pseudogenes. The chromosome contains the largest interferon gene cluster in the human genome. There is also a region of exceptionally high gene and G + C content including genes paralogous to those in the major histocompatibility complex. We have also detected recently duplicated genes that exhibit different rates of sequence divergence, presumably reflecting natural selection.

The finished sequence of human chromosome 10 comprises a total of 131,666,441 base pairs. It represents 99.4% of the euchromatic DNA and includes one megabase of heterochromatic sequence within the pericentromeric region of the short and long arm of the chromosome. Sequence annotation revealed 1,357 genes, of which 816 are protein coding, and 430 are pseudogenes. We observed widespread occurrence of overlapping coding genes (either strand) and identified 67 antisense transcripts. Our analysis suggests that both inter- and intrachromosomal segmental duplications have impacted on the gene count on chromosome 10. Multispecies comparative analysis indicated that we can readily annotate the protein-coding genes with current resources. We estimate that over 95% of all coding exons were identified in this study. Assessment of single base changes between the human chromosome 10 and chimpanzee sequence revealed nonsense mutations in only 21 coding genes with respect to the human sequence.

Chromosome 13 is the largest acrocentric human chromosome. It carries genes involved in cancer including the breast cancer type 2 (BRCA2) and retinoblastoma (RB1) genes, is frequently rearranged in B-cell chronic lymphocytic leukaemia, and contains the DAOA locus associated with bipolar disorder and schizophrenia. We describe completion and analysis of 95.5 megabases (Mb) of sequence from chromosome 13, which contains 633 genes and 296 pseudogenes. We estimate that more than 95.4% of the protein-coding genes of this chromosome have been identified, on the basis of comparison with other vertebrate genome sequences. Additionally, 105 putative non-coding RNA genes were found. Chromosome 13 has one of the lowest gene densities (6.5 genes per Mb) among human chromosomes, and contains a central region of 38 Mb where the gene density drops to only 3.1 genes per Mb.

Purpose : The feasibility of using cryopreserved lymphocytes to detect inter-individual differences in chromosomal radiosensitivity was investigated. Typically, such studies are conducted with fresh blood samples but, in a clinical setting, when availability of samples is unpredictable, this is not always convenient. The sensitivity of 23 normal healthy donors, 11 breast cancer patients who had shown severe acute skin reactions to radiotherapy and seven ataxia telangiectasia (A-T) heterozygotes was determined. Materials and methods : Thawed lymphocytes were exposed to high (HDR) or low dose rate (LDR) gamma irradiation (3.5 Gy) in G 0, stimulated with PHA, treated with cytochalasin-B 24h later and then harvested at 90h for the determination of micronucleus (MN) yields in binucleate cells. Results : Each normal donor was tested one to three times. Mean MN yields were 76.1 +/- 9.3/100 cells at HDR and 44.5 +/- 5.3 at LDR, giving an LDR sparing effect of 39.6 +/- 9.3%. A relatively high proportion of tests f...

Chromosome 6 is a metacentric chromosome that constitutes about 6% of the human genome. The finished sequence comprises 166,880,988 base pairs, representing the largest chromosome sequenced so far. The entire sequence has been subjected to high-quality manual annotation, resulting in the evidence-supported identification of 1,557 genes and 633 pseudogenes. Here we report that at least 96% of the protein-coding genes have been identified, as assessed by multi-species comparative sequence analysis, and provide evidence for the presence of further, otherwise unsupported exons/genes. Among these are genes directly implicated in cancer, schizophrenia, autoimmunity and many other diseases. Chromosome 6 harbours the largest transfer RNA gene cluster in the genome; we show that this cluster co-localizes with a region of high transcriptional activity. Within the essential immune loci of the major histocompatibility complex, we find HLA-B to be the most polymorphic gene on chromosome 6 and in the human genome.

Introduction Urine cytology has been used in the diagnosis of urothelial cancer (UC) for high grade and in-situ lesions. Sensitivity for low grade carcinoma is problematic leading to both over and under diagnoses. To reduce this dilemma a number of biomarkers have been tried with varying results. Minichromsome Maintenance Proteins (MCMs) play a regulatory role in eukaryotic DNA replication and are expressed as normal cells progress from G0 into G1/S phase of the cell cycle. Over expression has been demonstrated in neoplasia in many sites including urothelium. The aim of the study was to evaluate use of MCM2 in urine cytology and tissue specimens to differentiate high grade from low grade UC. Methods epithelial cells retrieved from urine samples of 114 patients were stained with MCM2 using an immunocytochemical technique. MCM2 was similarly applied to 13 archived urothelial tumour specimens. MCM positive cell counts were performed on all cytology specimens and results correlated to the different grades of UC. Tumor specimens were evaluated for MCM2 staining intensity, distribution and percentage of positive cells. Results 26 of 114 patients were found to have UC. In cytology specimens the MCM mean and median cell counts increased with grade of cancer (Table 1). Non cancerous urines had mean and median MCMs of 232 and 14 respectively. In urothelial solid tissue tumour specimens, MCM2 showed strong nuclear staining characteristics where the percentage of positive cells was related to tumor grade. The lowest percentage MCM stained cells was noted in grade 1 tumours, the highest percentage in grade 3. Staining distribution was predominantly in the basal zone of the urothelium in grade 1 tumours, basal and middle epithelial zones in grade 2, and more diffusely distributed in grade 3 tumours. Table 1: MCM cell count with increasing grade of urothelial cancer. Grade Number of cases Mean Standard Deviation Median G1 3 3207 5026 600 G2 9 8177 15975 3000 G3 13 14795 14167 10000 CIS 1 40000 - 40000 Total 26 Conclusion MCM2 could be a useful biomarker in differentiating low grade from high grade UC both in cytology and biopsy tissue specimens. Disclosure All authors have declared no conflicts of interest.

The finished sequence of human chromosome 20 comprises 59,187,298 base pairs (bp) and represents 99.4% of the euchromatic DNA. A single contig of 26 megabases (Mb) spans the entire short arm, and five contigs separated by gaps totalling 320 kb span the long arm of this metacentric chromosome. An additional 234,339 bp of sequence has been determined within the pericentromeric region of the long arm. We annotated 727 genes and 168 pseudogenes in the sequence. About 64% of these genes have a 5' and a 3' untranslated region and a complete open reading frame. Comparative analysis of the sequence of chromosome 20 to whole-genome shotgun-sequence data of two other vertebrates, the mouse Mus musculus and the puffer fish Tetraodon nigroviridis, provides an independent measure of the efficiency of gene annotation, and indicates that this analysis may account for more than 95% of all coding exons and almost all genes.

Of breast cancer patients, 30% are sensitive in a lymphocyte assay of radiation-induced chromosome damage (micronucleus induction) compared with 10% of healthy controls. Twenty-two first-degree relatives of 11 sensitive patients had an average micronucleus yield significantly higher than that of 68 controls. This suggests that radiosensitivity in this assay may be an inherited characteristic associated with predisposition to breast cancer.

The feasibility of using cryopreserved lymphocytes to detect inter-individual differences in chromosomal radiosensitivity was investigated. Typically, such studies are conducted with fresh blood samples but, in a clinical setting, when availability of samples is unpredictable, this is not always convenient. The sensitivity of 23 normal healthy donors, 11 breast cancer patients who had shown severe acute skin reactions to radiotherapy and seven ataxia telangiectasia (A-T) heterozygotes was determined.Thawed lymphocytes were exposed to high (HDR) or low dose rate (LDR) gamma irradiation (3.5 Gy) in Go, stimulated with PHA, treated with cytochalasin-B 24 h later and then harvested at 90 h for the determination of micronucleus (MN) yields in binucleate cells.Each normal donor was tested one to three times. Mean MN yields were 76.1 +/- 9.3/100 cells at HDR and 44.5 +/- 5.3 at LDR, giving an LDR sparing effect of 39.6 +/- 9.3%. A relatively high proportion of tests failed to yield sufficient binucleate cells for analysis. Inter-experimental variability was also high and it was not possible to demonstrate inter-individual differences in sensitivity in spite of the use of an internal control sample from a single normal donor in each experiment. There was a small but significant increase in radiation-induced MN in the breast cancer patients compared with the normals at LDR (but not at HDR), but a complete overlap with the normal range. There was no increase in sensitivity in the A-T heterozygotes at HDR. The LDR samples failed because the LDR protocol reduced proliferation rates, and radiation-induced mitotic inhibition in this group was higher than in normals.In comparison with previous experience with fresh blood samples, the use of frozen lymphocytes is not as satisfactory because: (1) experimental failures are higher; (2) inter-experiment variability is higher: (3) dose-rate sparing is lower, suggesting poorer repair; and (4) the ability to discriminate between breast cancer cases and normals is probably lower.

Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.

It has been shown previously that sensitivity to the induction of chromosome damage by ionizing radiation is, on average, higher in G2 or G0 lymphocytes of breast cancer patients than of normal healthy controls. The authors suggested that elevated chromosomal radiosensitivity may be a marker for breast cancer predisposition. To investigate whether the G0 micronucleus assay is a true surrogate for the more demanding G2 metaphase assay, both tests have now been performed on the same blood samples from 80 patients.For the G0 micronucleus assay, cells were exposed to 3.5 Gy 137Cs gamma-rays 6 h before mitogenic stimulation, treated with cytochalasin B at 24 h post-stimulation and harvested at 90 h. For the G2 assay, at 72 h after stimulation cells were given 0.5 Gy X-rays and harvested 90 min later.Previous observations were confirmed, now with much larger numbers of donors, in that approximately 40% of breast cancer patients showed elevated sensitivity in the G2 assay (135 patients, 105 normals) and 25% in the G0 assay (130 patients, 68 normals). However, there was no correlation between G2 and G0 sensitivity for the 80 patients tested (r = -0.001, p = 0.99). Most of the sensitive patients were either G2 or G0 sensitive, with only 4% sensitive in both assays.The results suggest that different mechanisms of chromosomal radiosensitivity operate in G2 and G0 cells and that, in general, each chromosomally radiosensitive patient is defective in only one such mechanism, possibly via mutation (or polymorphism) of a single gene. Such mutations may confer cancer predisposition, of low penetrance, in a substantial proportion of patients.

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. We previously showed that 42% of an unselected series of breast cancer patients and 9% of healthy control subjects showed elevated chromosomal radiosensitivity of lymphocytes irradiated in the G2 phase of the cell cycle. We suggested that, in addition to the highly penetrant genes BRCA1 and BRCA2, which confer a very high risk of breast cancer and are carried by about 5% of all breast cancer patients, there are also low-penetrance predisposing genes carried by a much higher proportion of breast cancer patients, a view supported by recent epidemiological studies. Ideally, testing for the presence of these putative genes should involve the use of simpler methods than the G2 assay, which requires metaphase analysis of chromosome damage. Here we report on the use of a simple, rapid micronucleus assay in G0 lymphocytes exposed to high dose rate (HDR) or low dose rate gamma-irradiation, with delayed mitogenic stimulation. Good assay reproducibility was obtained, particularly with the HDR protocol, which identified 31% (12 out of 39) of breast cancer patients compared with 5% (2 out of 42) of healthy controls as having elevated radiation sensitivity. In the long term, such cytogenetic assays may have the potential for selecting women for intensive screening for breast cancer.

ψ-Endo to ψ-exo leakage during solvolysis of a ψ-endo-dienol—Fe(CO)3 dinitrobenzoate ester does not proceed via a syn, syn-cis-dienyl—Fe(CO)3 cation. The most probable leakage mechanism involves non-stereospecific ionization of the dinitrobenzoate ester. syn,syn-cis-Dienyl—Fe(CO)3 cations are formed from ψ-exo-dienol—Fe(CO)3 complex during chromatography on grade I neutral alumina.

If X is a topological space and if K is a chain equipped with its order topology, then we denote by C(X, K) the lattice of all continuous functions from X to K. If X is the union of two disjoint open-andclosed subsets Xi and X2, then it is clear that C(X, K) is isomorphic to the direct product of the lattices C(X1, K) and C(X2, K). In Theorem 2 of [2], Kaplansky proves the following converse

THE AUTHORS HAVE REPORTED (1) that the prostate and seminal vesicle of the immature male rat show a definite weight increase 24 hours after the subcutaneous administration of testosterone propionate in oil. The rats used were 32, to 38 days old and weighed 65 to 85 gm. The mean responses of the seminal vesicles in the various groups increased consistently with the dosage. With the lowest dose used (0.00625 mg.) the increase in seminal vesicle weight above the normal control level was 10.59% and with the largest dose (0.5 mg.) the increase was 53.47%. The prostates showed a relatively smaller response than the vesicles and the response was also less consistent. While the mean seminal vesicle weights of the two highest dosage groups were significantly greater than the normal control mean, the differences between different dosage groups were not significant (in spite of the fact that there were 20–25 animals in each group).

SummaryThe administration of very large doses of estrogens to pregnant rats has caused a permanent hypospadias and lack of development of the most caudal portion of the vagina, in the female offspring. The abnormality represents an arrest of development so that conditions similar to those found in the 21-day fetus are retained.

SEVERAL WORKERS have shown that ovaries transplanted into a large series of castrate males (rats and guinea pigs) have an androgenic effect in an occasional animal (i, i, 3). Hill (4, 5) has transplanted the ovaries of mice to the ear where they are subjected to a temperature several degrees lower than are abdominal ovaries. In this position, the ovaries apparently produce an androgenic substance. This work has been confirmed by Deansely (6) n i the rat. Hill noted an extensive luteinisation of the transplanted ovaries and Deansely has suggested that there may be a relation between thecal luteinisation and the masculinising action of the graft. Desclin (7), however, disagrees with this hypothesis. Papanicolaou (8, 9) has shown that ovaries in normal guinea pigs have an androgenic action when stimulated with the APL factor of pregnancy urine. He believes that this androgenic substance i s produced by the hypertrophied interstitial tissue of the ovaries.

CERTAIN CRYSTALLINE ESTROGENS AND ANDROGENS (1–7) and t h e endogenous ovarian estrogens and testicular androgens of the rat (8–12) are inactivated by the liver. Such evidence is used to explain the fact that natural estrogens and androgens are relatively ineffective when administered by mouth. Kuizenga, Nelson and Cartland (13) found that 2, of the adrenal steroids, corticoster one and dehydrocorticosterone, as well as certain adrenal cortical extracts were just as effective orally as when given subcutaneously. This indicates that these adrenal substances, unlike the gonadal hormones, are not inactivated by the liver. Desoxycorticosterone acetate, on the contrary, was found to be much less effective orally than parenterally. By transplantation experiments in the rat, Eversole, Edelmann and Gaunt (14) have shown that the endogenous adrenal hormone or hormones necessary For maintenance of life are not inactivated by the liver.

IT IS KNOWN that many steroid hormones are less potent orally than parenterally. I Methyl testosterone is the most efficient androgen by the oral route because it -iL loses less of its parenteral effectiveness than does either testosterone or testosterone propionate. There is evidence that the endogenous testicular androgen of the rat is inactivated by the liver (1,2). If orally administered androgens are absorbed from the digestive tract into the portal blood stream, they would necessarily pass directly to the liver and, if the liver also inactivates these androgens before they pass into the general circulation, their relative ineffectiveness under these circumstances would be understandable. Testosterone propionate, when absorbed directly into the portal blood stream from pellets located in the spleen, is ineffective in the castrated rat (3,4). This finding is consistent with the idea that liver inactivation is responsible for the diminished oral effectiveness of testosterone propionate.

SummaryVentral prostates from male littermates were implanted into female rats 10 days of age. Daily treatment with chorionic gonadotropin produced no evidence of androgenic stimulation in the prostates when the females were castrated. When the ovaries were not removed the prostates of the treated animals showed evidence of stimulation at 18 to 25 days, but not after 28 days of age.

The production of intersexed rats by the administration of male sex hormone to the pregnant mothers of these animals is reported. The embryonic development of genetic females is so modified that uteri, oviducts, and upper vagina; combined with epididymis, vas deferens, seminal vesicles, ejaculatory ducts, the various prostatic lobes, Cowper's glands, and a penis are found in the same adult animals. Indicative evidence that the lower part of the vagina is derived from the urogenital sinus in the rat is presented. It is suggested that an excess of androgenic substance in the human pregnant organism may be the causal factor in the production of some human intersexes.

SummaryWhen testicular tissue was implanted into the immature rat so that its venous drainage passed through the liver, there was a lack of androgenic stimulation evident in the castrate condition of the penis, prostate and seminal vesicles after a period of one to 2 months. When the testicular tissue was implanted subcutaneously, some androgenic effect on the penis and accessories was obtained. Interstitial cells in varying numbers were present in all grafts. This finding indicates probable endocrine function by the implanted tissue. It is tentatively concluded that the lack of androgenic stimulation in animals with intra-mesenteric implants of testicular tissue is due to inactivation of testicular androgens by the liver. This is in agreement with similar experiments using implanted crystals of testosterone propionate and methyl testosterone.5, 6

EXPERIMENTAL studies have shown that a diet deficient in the vitamin B complex or thiamin (vitamin Bi) will interfere with ovarian function and produce anestrous (Evans and Bishop, 1923; Parkes, 1928; Shin, 1933; and others). However it is not clear from these studies if the resulting anestrous was due to a deficiency of vitamin B complex, or due to a thiamin deficiency per se, or an effect of the concomitant inanition. In more recent studies Coward and Morgan (1941) observed that rats fed a thiamin-free diet had two or three normal cycles and then entered into anestrous. Again the effect may have been due to the thiamin deficiency per se or the resultant inanition. Others have reported that partial or acute starvation will result in ovarian atrophy or loss of estrus in rats, which they attributed to insufficient pituitary gonadotropin secretion (Mulinos et al, .1939; Mulinos and Pomerantz, 1940; Werner, 1939).

VARIOUS WORKERS (1, 2, 3) have reported that the percutaneous effectiveness of the sex hormones may be influenced by the vehicle in which they are applied. In general, alcohol, ether and benzene have been found more efficient than oils or ointments. Zondek (1) and other workers (3, 4) have compared the effectiveness of sex hormones when administered percutaneously in an ointment and when administered subcutaneously in oil. In each of these investigations a single type of ointment was used, but generalized conclusions were drawn as though applicable to ointments or creams as a class of substances. More recently Scott (5) has compared the percutaneous effectiveness of three androgens using two different ointments. In her conclusions she suggested that the androgens were more effective in her “tegin” base than in her “lanol” base. Small groups of animals were used in this study and, as in all other studies previously cited, the hormones were compared on the basis of equal milligram amounts.

In the adult male rat, castration invariably results in atrophy of the prostate within 4 or 5 days. In the immature male rat, however, castration is not accompanied by atrophy of the prostate. Pric...

As RULE, the potencies of the various physiologically active steroids have been compared on the basis of their actual weights. Either effects obtained by identical milligram amounts are graded, or those milligram or microgram doses which bring about equal effects are considered equi-effective. There is no objection to such methods as long as the substances compared have at least approximately the same molecular weights. The differences in the molecules of testosterone and andro-sterone or estradiol and estrone are so small, that they become insignificant in relation to other factors influencing the results in animal experimentation. Thus in many instances,comparisons based on equal molecular amounts will not differ essentially from those based on equalmilligram amounts. If, however, substances with weights deviating 15 per cent and more are beingcompared, it would seem worthwhile to take such differences into account, particularly when thepart of the molecule causing the increase in weight is known to be ...

THE PRESENT STUDY is concerned with the relative percutaneous effectiveness of αestradiol, α-estradiol benzoate, and α-estradiol dipropionate. The uterine weight of castrated rats after a constant period of treatment was used as the criterion for effectiveness of the estrogens, with the uterine weight of the untreated spayed rat as control. This type of test, measuring a ‘graded reaction’ was selected in preference to an ‘all or none’ response type of test, with which a ‘minimal effective dose’ is determined. Although the latter is the most commonly used method to assay estrogenic potencies (by determining the lowest dose which produces estrus in the vaginal smear of 50 per cent of the animals), we refrained from using it, because this type of test places a premium on rapid absorption. The esterified hormones are, there fore, penalized, because of their slower rate of absorption, and a true indication of their effectiveness relative to the nonesterified forms cannot be obtained.

IN 1934, Rowntree and his associates reported that daily treatment of rats with an extract of calves‘ thymus caused an acceleration of growth and development in the offspring of these animals. With continued treatment, the effect was found to be enhanced in each succeeding generation (1). This report met with considerable scepticism since it apparently contradicted the theory firmly established by Weismann, that acquired characters cannot be inherited. Many criticisms were directed against the work and several attempts to reproduce the phenomenon in other laboratories failed (2, 3). Nevertheless, the original group of investigators have fortified their claims by other experiments in which the same type of effect, though lesser in degree, has been obtained by weekly implantation of whole rat thymuses into rats (4, 5). Assuming the validity of these experiments, some reasonable explanation of the results should present itself.

THERE HAVE BEEN numerous reports that androgens have an inhibitory effect on II the testes of the intact rat (1—4). However, Cutuly and his coworkers have presented evidence that this effect is not obtained with all dosages (5, 6), i.e., very large doses of androgens, instead of inhibiting the testes, maintain them at a normal size. This evidence seems to have been neglected by other workers, perhaps because it happened to be incidental data included in studies on another subject. It correlated well, however, with the well known fact that androgens in similarly large doses apparently had a direct effect on the testes of hypophysectomized rats and could maintain them at a normal sise (7, 8). It seems logical to believe that the dosages used by other workers in the intact rat (which were lower than those used by Cutuly et al.) were sufficient to depress the hypophyseal gonadotropic function but insufficient to maintain the testes.

IN THE IMMATURE male rat, castration does not cause immediate atrophy of the prostate. Price (1) demonstrated that following prepuberal castration, the prosstate develops normally and maintains a functional status for a definite period. The earlier the animal is castrated, the longer the period of maintenance. Howard (a) found the same phenomenon in the mouse and also confirmed Price's findings in the rat. Howard suggested that an andromimetic activity of the immature adrenal might be responsible for the maintenance of functional prostates in the absence of the testes. Davidson and Moon (3) found that adrenocorticotropic substance administered to immature castrate male rats caused hypertrophy of the adrenal cortex. This hypertrophy was apparently associated with the production of an androgenic substance since the prostates of these rats were stimulated as indicated by gross size and histological picture. In a recent report the present authors (4) offered direct evidence of the andromimetic capacity of the...

EVIDENCE that progesterone, the corpus luteum hormone, has androgenic properties in the rat has been presented by Lamar (1) and Greene, Burrill and Ivy (2). To date, these two contributions represent the only direct evidence for the androgenicity of this substance, although indicative evidence from various other sources is not lacking (see Greene, Burrill and Ivy). Results of other attempts to demonstrate an androgenic function for progesterone have all been negative. Albrieux and his coworkers (3) found progesterone to have no influence on the seminal vesicles of the castrated rat nor on the capon comb. Hill (4), using small amounts of progestin (extract of corpora lutea) failed to find any stimulatory effect on the accessories of the castrate male rat. Dessau (5) obtained no effect on the capon comb with progesterone. Korenchevsky and Hall (6) classified progesterone as a “purely female hormone” since, on the basis of unpublished experiments, they found it to have no effect on the male sex organs.

Summary and ConclusionsTestosterone, testosterone propionate and androstenedione maintained pregnancy with resulting living fetuses in rats castrated during the latter half of pregnancy.

SummaryVentral prostates from immature male rats were implanted into female litter mates, both intact and castrated, at 10 days of age. All implants were functionally negative when recovered 10 to 25 days later. Of the 27 female ventral prostates found in intact and castrated immature females, 15 showed some degree of functional activity. The data obtained indicate (a) that in the immature rat the female prostate has a lower threshold of response to androgens than the male prostate, and (b) that there is an extra-ovarian source of androgens in the immature female rat.

THE FEMALE PROSTATE, homologue of the male ventral prostate, is present in some female rats. The incidence varies in different strains and may be increased by inbreeding (1). Price (2) demonstrated that during a limited period in the immature female rat (2,1 to 40 days of age) these prostates exhibit evidence of andrc-genie stimulation. In a previous report (3) we confirmed this finding. Included in this report were a few cases of castrate immature females which also had prostates show-ing some androgenic stimulation. This finding was indicative evidence for the hypo-thesis advanced by Price, that the female adrenal cortex might have a temporary an-dromimetic function such as has been demonstrated by us in the immature male rat (4,5). The present report concerns further investigation on this matter, specifically the respective roles of the immature ovary and adrenal in the production of the andro-genie substances responsible for stimulation of the immature female prostate.