PubMed · 9146650
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S L Goldenberg, M E Gleave, N Bruchovsky, P Rennie. 1997. Re: Editorial comment.. https://doi.org/10.1016/s0022-5347(01)64759-1
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To determine the relative role of the androgenic and/or estrogenic components of the action of dehydroepiandrosterone (DHEA) on the histomorphology and structure of the rat mammary gland, ovariectomized (OVX) female animals received DHEA administered alone or in combination with the pure antiandrogen flutamide or the pure antiestrogen EM-800 for 12 months. We have also evaluated the effect of estradiol (E2) and dihydrotestosterone constantly released from SILASTIC brand silicon implants as well as medroxyprogesterone acetate released from poly(lactide-co-glycolide) microspheres. While 1-yr OVX resulted in a severe atrophy of the mammary gland, treatment of OVX animals with DHEA stimulated lobuloalveolar and ductal growth, as well as the secretory activity of the acinar cells, thus resulting in a lobuloalveolar type of development of the mammary gland. The addition of FLU to DHEA almost completely prevented the stimulatory effect observed with DHEA alone, whereas addition of the antiestrogen EM-800 had no significant effect on the action of DHEA on the mammary gland. At the doses used, medroxyprogesterone acetate and dihydrotestosterone also stimulated ductal and alveolar development, although to a lesser degree than that achieved with DHEA. The stimulatory effect of estradiol was mainly expressed on ductal growth with a smaller stimulatory effect on lobuloalveolar development. The above-indicated stimulatory effects on lobuloalveolar development were also reflected in significant increases of the total and parenchymal gland surface areas of the mammary gland. The present study shows that androgens induce a marked lobuloalveolar type of development of the mammary gland in the rat. Moreover, these data indicate the highly predominant or almost exclusive androgenic component in the potent stimulatory action of DHEA on the histomorphology and structure of the rat mammary gland. In fact, blockade of the potential estrogenic component of DHEA action by EM-800 did not affect the stimulatory action of DHEA on mammary gland histomorphology, whereas the antiandrogen FLU almost completely blocked the effect of DHEA.
The molecular nature of tissue-specific gene regulation by androgens has not been well defined, partly as a result of the variable expression and incomplete regulation of currently available gene models. We have therefore aimed to establish more informative models by identifying alternative genes whose expression is tightly and coordinately regulated by androgens. Female C57BL/6 mice were dosed with dihydrotestosterone- or sham-treated for 8 days, after which kidneys were removed and complementary DNA (cDNA) prepared. We then applied the subtractive hybridization techniques of random arbitrarily primed-PCR and PCR-coupled subtractive hybridization method of cDNA representational difference analysis to the isolated cDNA. In addition to well characterized androgen-regulated genes [e.g. KAP (kidney androgen-regulated protein)], we demonstrate the differential expression of six genes previously not known to be under androgen control. RNA levels of SA, Cytochrome P450 4B1, IL-6ST (interleukin-6 signal transducer), OATP (organic anion transporter), and a newly identified gene, MJAM, were up-regulated by androgen, while 16-alpha-hydroxylase was decreased. Expression of these transcripts was inhibited in dihydrotestosterone-treated females by flutamide and in males by castration, confirming their dependence on androgens. Although all the genes demonstrate tissue-specific regulation by androgen, SA showed both kidney specificity and absolute requirement for androgen for its expression. These newly identified androgen-regulated genes will constitute very useful models for studying the nature of tissue-specific gene regulation by androgens.
The concept of using endocrine therapy to shrink the prostate or its cancer preoperatively has the aim to make the cancer more amenable to complete resection by radical prostatovesiculectomy. Four large prospective, randomized phase-II-studies are published which studied the effect of neoadjuvant antiandrogenic treatment in comparison with a control without hormonal therapy. The results of these contemporary series are: 1. reduction in prostate volume, 2. significantly lower PSA-values at the time of surgery, 3. a decreased rate of positive surgical margins in patients with cT2-tumors. However, the neoadjuvant treatment does reduce neither the incidence of seminal vesical nor of lymph node involvement. Although the results of pathologic downstaging in T2-tumors are encouraging, long-term follow-up to monitor disease-free survival and overall survival is required to document the true benefit of the approach. Possible disadvantages are 1. the cost factor, 2. the side effects of treatment, 3. the delay of definitive treatment especially in case of tumor cell clones not sensitive to the hormonal approach.