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PubMed2004

Prospective, multicenter, randomized phase II trial of the herbal supplement, PC-SPES, and diethylstilbestrol in patients with androgen-independent prostate cancer.

PURPOSE: To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC). PATIENTS AND METHODS: A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES. RESULTS: Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots. CONCLUSION: PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.

Administration, Oral↗
PubMed2002

Induction of reproductive tract developmental abnormalities in the male rat by lowering androgen production or action in combination with a low dose of diethylstilbestrol: evidence for importance of the androgen-estrogen balance.

This study tested the hypothesis that testis/reproductive tract abnormalities induced in the rat by neonatal treatment with diethylstilbestrol (DES) result from disturbance of the androgen-estrogen balance. Male rats were treated neonatally with a dose of DES (0.1 micro g) that induced either no or small effects on its own or with a dose (10 micro g) that induced major reproductive tract abnormalities. To allow quantification, the abnormalities chosen for study were distension of the rete testis and efferent ducts and reduction in epithelial cell height in the efferent ducts and vas deferens. To alter the androgen-estrogen balance, other rats were treated with DES (0.1 micro g) in combination with a treatment to suppress either androgen production [GnRH antagonist (GnRHa)] or androgen action (flutamide); other rats were treated with GnRHa or flutamide alone. Testosterone levels were measured to verify the effects of treatment. Combined administration of DES (0.1 micro g) plus GnRHa or flutamide induced significantly greater distension/overgrowth of the rete testis and efferent ducts (ED) and a reduction in epithelial cell height of the ED than did DES (0.1 micro g) administered alone. Neither GnRHa nor flutamide affected rete or ED distension when administered alone, but both significantly reduced ED epithelial cell height. Neonatal treatment with bisphenol-A (100 micro g) with or without GnRHa had no significant effect on any of these parameters. In contrast to the ED, a reduction in cell height of the vas deferens was induced to an equal extent by DES (10 micro g), DES (0.1 micro g) with GnRHa, and GnRHa alone, suggesting greater sensitivity of this tissue to both androgen and estrogen action. The induction of major abnormalities in rats treated with DES (10 micro g) was coincident with loss of androgen receptor immunoexpression in affected tissues. Reduced androgen receptor immunoexpression was also induced by combined treatment with DES (0.1 micro g) plus GnRHa or flutamide, whereas treatment with any of these compounds alone had no or only minor effects. These findings suggest that reduced androgen action sensitizes the reproductive tract to estrogens, demonstrating that the balance in action between androgens and estrogens, rather than their absolute levels, may be of fundamental importance in determining normal or abnormal development of some regions of the male reproductive tract.

Androgen Antagonists↗
PubMed2006

Adverse effects of the model environmental estrogen diethylstilbestrol are transmitted to subsequent generations.

The synthetic estrogen diethylstilbestrol (DES) is a potent perinatal endocrine disruptor. In humans and experimental animals, exposure to DES during critical periods of reproductive tract differentiation permanently alters estrogen target tissues and results in long-term abnormalities such as uterine neoplasia that are not manifested until later in life. Using the developmentally exposed DES mouse, multiple mechanisms have been identified that play a role in its carcinogenic and toxic effects. Analysis of the DES murine uterus reveals altered gene expression pathways that include an estrogen-regulated component. Thus, perinatal DES exposure, especially at low doses, offers the opportunity to study effects caused by weaker environmental estrogens and provides an example of the emerging scientific field termed the developmental origin of adult disease. As a model endocrine disruptor, it is of particular interest that even low doses of DES increase uterine tumor incidence. Additional studies have verified that DES is not unique; when other environmental estrogens are tested at equal estrogenic doses, developmental exposure results in increased incidence of uterine neoplasia similar to that caused by DES. Interestingly, our data suggest that this increased susceptibility for tumors is passed on from the maternal lineage to subsequent generations of male and female descendants; the mechanisms involved in these transgenerational events include genetic and epigenetic events. Together, our data point out the unique sensitivity of the developing organism to endocrine-disrupting chemicals, the occurrence of long-term effects after developmental exposure, and the possibility for adverse effects to be transmitted to subsequent generations.

Animals↗
PubMed1979

Diethylstilbestrol and estradiol binding to serum albumin and pregnancy plasma of rat and human.

The equilibrium binding of diethylstilbestrol (DES) and 17 beta-estradiol (E2) to plasma proteins has been characterized. DES exhibits a 10- to 20-fold greater binding affinity index for bovine serum albumin and rat plasma than E2. As expected, E2 gave high values for binding to plasma from pregnant mice or rats, reflecting the presence of alpha-fetoprotein. DES bound to these samples as it did to bovine albumin and rat plasma. These results suggested that DES ineracts weakly with alpha-fetoprotein. This was verified by Scatchard plots of DES and E2 binding to rat and human pregnancy plasma. High affinity, low capacity binding was demonstrated with E2 but not with DES. The significantly lower binding of DES suggests that increased delivery of DES to the fetus may be at least partially responsible for the transplacental toxicity and carcinogenicity of DES.

Animals↗
PubMed1983

The ontogeny of estrogen responsiveness reexamined: the differential effectiveness of diethylstilbestrol and estradiol on uterine deoxyribonucleic acid synthesis in neonatal rats.

Previous reports have indicated that 17 beta-estradiol is unable to stimulate DNA synthesis in the neonatal rat uterus. Possible causes for this unresponsiveness that have been suggested include the ontogenic acquisition of late responses to estrogen and the sequestering of injected estradiol by the higher concentration of serum alpha-fetoprotein. To test these hypotheses we have examined the mitogenic potency of diethylstilbestrol (DES), a nonsteroidal estrogen which has a lower affinity for alpha-fetoprotein. Our results reveal that 1.0 microgram DES administered in a single injection can stimulate DNA synthesis 24 h later in 5-day-old rats, the youngest tested. By comparison, a single injection of 1.0 microgram estradiol did not stimulate DNA synthesis until rats reached an age of 10-15 days. Higher doses of estradiol administered in a single injection stimulated DNA synthesis in neonates but to a lesser extent than DES. The potency of estradiol relative to DES increased with age up to 28 days, at which time they were equipotent. The magnitude of the stimulation of DNA synthesis increased with age even with DES because control levels of DNA synthesis are high in young rats and decreased as the rats matured. These results indicate that uterine cells of neonatal rats have no inherent inability to synthesize DNA in response to estrogen and are consistent with the hypothesis that serum alpha-fetoprotein is responsible for the decreased potency of estradiol.

Aging↗
PubMed1983

Diethylstilbestrol metabolism by the fetal genital tract.

Oxidative metabolism of diethylstilbestrol (DES) was measured in both the male and female genital tracts of the fetal mouse in organ culture. The major oxidative metabolite formed was Z,Z-dienestrol, whose formation appeared to be time dependent in the isolated fetal genital tract of both sexes. This peroxidative metabolite, which has been previously linked to bioactivation of DES in adult target tissues, was not detected in the fetal liver cultures. In addition, fetal genital tracts were capable of O-methylation of DES. In fact, a new metabolite, 4'-O-methyl-DES, was formed in fetal genital tissues but not in liver cultures. On the other hand, conjugation of DES occurred extensively in the fetal liver and placenta but not in the fetal genital tissues; conjugated DES was found primarily in the media. Thus, the fetal genital tract, which is the primary target for the transplacental carcinogenicity of DES, has the capacity to metabolize this compound.

Animals↗
PubMed1984

Liposome-entrapped diethylstilbestrol effect on prostate gland and plasma testosterone levels in rats.

The effects of liposome-encapsulated diethylstilbestrol (DES) on the size of the ventral prostate gland and total testosterone levels in rats were studied. DES was encapsulated in phosphatidycholine-cholesterol-stearylamine-alpha-tocopherol containing multilamellar liposomes in a molar ratio of 4:5:1:0.01. The liposome suspension or free DES plus blank liposomes were administered sc on days 1, 3, and 5 at a dose of 400, 87, or 12 micrograms/kg. Plasma testosterone values showed a decrease with dose for animals treated with either entrapped DES or free DES. Prostate gland weight per g animal and prostatic protein mg per g animal on day 7 were significantly decreased in the treated animals compared to those in controls dosed with DES plus buffer containing liposomes. In addition, there was a body weight loss for the high dose DES-encapsulated animals and for high and medium dose DES plus blank liposome-treated and blank liposome-treated animals over the treatment period, although only the DES-encapsulated group value was statistically significant (P less than 0.05). Animals at the other doses did not lose weight, but exhibited weight gains which were less than those observed for sham-injected animals. Rats that received 7 micrograms/kg liposome-entrapped DES for 4 weeks had significantly lower prostate gland weights, prostatic protein levels, and testosterone levels than control animals receiving the same regimen of free DES plus blank liposomes. Results from the studies indicate that liposome-entrapped DES was more effective in decreasing the size of the prostate gland and that the desired therapeutic end point (prostate ablation) may be attained with a lower dose of DES, which would decrease the risk of weight loss in the experimental animals.

Animals↗
PubMed1984

Müllerian duct maintenance in heterotypic organ culture after in vivo exposure to diethylstilbestrol.

Prenatal exposure to diethylstilbestrol (DES) results in the persistence of Müllerian ducts in male offspring. The influence of DES on Müllerian duct regression was studied using an organ culture system in which DES-treated or control indifferent ducts (embryonic reproductive tracts) were cocultured along with treated or control embryonic testes. Prenatal DES exposure was by sc injection of the mother (100 micrograms/kg BW) on days 9 through 12 of gestation. Embryonic tissues were removed on day 13 of gestation and cultured for 72 h. In organ culture, Müllerian duct regression, comparable to that seen in vivo, occurred when control reproductive tracts were associated with control testes. However, maintenance of the Müllerian duct was observed in 100% of the tissues when DES-treated testes and DES-treated reproductive tracts were cultured together. When recombinations were formed by the association of control reproductive tracts and DES-treated testes, there was regression of the Müllerian duct (87%). However, in the combinations of DES-treated reproductive tracts and control testes, 41% of the cultured tissue demonstrated partial regression of the Müllerian duct, and 59% showed no regression. These data support previous in vivo results that prenatal exposure to DES has an inhibitory effect on Müllerian duct regression and further suggest that this inhibitory effect is mainly due to a decrease in responsiveness of the treated embryonic Müllerian duct.

Animals↗
PubMed1985

Time course of induction of prolactin-secreting pituitary tumors with diethylstilbestrol in male rats: response of tuberoinfundibular dopaminergic neurons.

3,4-Dihydroxyphenylalanine (Dopa) accumulation and dopamine (DA) and noradrenaline levels were measured in the median eminence (ME) of Fisher 344-derived inbred male rats. These animals had been treated with Silastic capsules containing 8-9 mg diethylstilbestrol (DES) or with empty capsules for 3, 7, 14, or 30 days and had the pellets removed 22 days before killing. In an additional group of rats, the DES pellets were continuously present until killing. Blood was collected before treatment was started, at pellet removal, 2 days before killing, and at killing. All rats received 50 mg/kg hydroxybenzylhydrazine (NSD-1015), an L-aromatic amino acid decarboxylase inhibitor, iv 30 min before killing, and the subsequent accumulation of Dopa provided an indirect measure of DA synthesis. Treatment with DES for 7, 14, or 30 days produced an elevation of circulating PRL. Although this elevation of PRL levels was substantially reduced after pellet removal, this parameter was still elevated in the 30-day DES-treated rats at the time of killing. Pituitary levels of PRL and PRL secretion in vitro were elevated in both the 14- and the 30-day DES-treated rats. Rats treated continuously with DES had markedly elevated circulating PRL levels, and the pituitary content and in vitro release of this hormone were also enhanced. DA synthesis, as evidenced by the accumulation of Dopa after NSD-1015 treatment, was significantly elevated in the ME of rats treated with DES for 14 or 30 days while the concentration of DA was reduced in the 30-day treated rats. DA synthesis in the ME was not different from controls in rats treated continuously with DES, although DA levels were markedly suppressed. Pituitary weights were elevated, and BWs were reduced in rats continuously treated with DES. Pituitary weights were also elevated in rats treated with DES for 30 days although not as much as in rats treated continuously with DES. A progressive reduction in seminal vesicles and testes weights was observed with longer periods of DES treatment. Testosterone levels were suppressed in rats treated continuously with DES. In a second study in which rats received DES pellets for 2 months and then the pellets were removed for 4 months, 1 mg bromocriptine sc markedly suppressed the elevated levels of circulating PRL. Collectively, these results show that 14 to 30 days of DES treatment are sufficient to induce PRL-secreting adenohypophysial tumors in adult male rats, although considerable involution of the tumor appears to occur after pellet removal.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1985

Prenatal diethylstilbestrol exposure alters murine uterine responses to prepubertal estrogen stimulation.

Prepubertal estrogen stimulation was used to investigate the effects of prenatal diethylstilbestrol (DES) exposure on subsequent growth, secretory activity, and cellular differentiation of the mouse uterus in vivo. Secretory activity was examined using sensitive silver staining of two-dimensional gel electrophoresis of uterine luminal fluid (ULF). Decreased uterine growth response, decreases in ULF quantity and protein concentration, alterations in specific ULF proteins, and altered cellular differentiation were found. This system provides a method for evaluation of the effects of prenatal exposure to DES or other compounds on the estrogen-induced secretory activity of the uterus. The alterations found in this study may be partially responsible for the decreased fertility in this mouse model and may have implication for DES-exposed women.

Animals↗
PubMed1986

Neonatal diethylstilbestrol treatment: response of prolactin to dopamine or estradiol in adult mice.

The effects of neonatal diethylstilbestrol (DES) treatment on pituitary PRL response to dopamine (DA) inhibition or estrogen stimulation were studied in C3H/MTV+ mice at 10 weeks, 5 months and 8 months of age using synthesis and release of [3H]PRL by the pituitary as endpoints. In the DA study, anterior pituitaries from ovariectomized or intact, neonatally hormone-treated mice were incubated for 6 h in the presence or absence of DA. In the estrogen study, serum and anterior pituitaries were obtained from ovariectomized neonatally hormone-treated mice injected with oil or 17 beta-estradiol for 7 days before death. Neonatal treatment of mice with 2.5 micrograms/day DES altered basal [3H]PRL synthesis and release as well as circulating PRL concentrations. The results of analysis of variance indicated a significant interaction between the effects of neonatal hormone treatment and DA treatment on [3H]PRL release. Neonatal DES treatment did not alter the response of pituitary PRL to estrogen treatment at the ages examined.

Animals↗
PubMed1989

Female gene expression in the seminal vesicle of mice after prenatal exposure to diethylstilbestrol.

Previous studies from our laboratory on the feminization of the male mouse reproductive tract after prenatal exposure to diethylstilbestrol (DES) showed that the mRNA for the major estrogen-inducible uterine secretory protein, lactoferrin (LF), was constitutively expressed in the seminal vesicle of male mice exposed prenatally to DES, but not in the seminal vesicle of control mice. After castration, treatment with 17 beta-estradiol (20 micrograms/kg.day) for 3 days induced the LF mRNA in the seminal vesicle of both control and prenatally DES-exposed mice; however, the levels in DES-treated tissues were approximately 6-fold higher than those in control tissue. This report describes the presence of LF in seminal vesicle tissues and secretions of prenatally DES-exposed mice, as determined by immunohistochemistry and Western blot analysis. Further, these data are correlated with immunolocalization of the estrogen receptor in the seminal vesicle tissue. We conclude that the seminal vesicle of prenatally DES-exposed male mice has acquired two key characteristics of female tissues, namely LF production/regulation and estrogen receptor localization/distribution similar to that in uterine tissues.

Animals↗
PubMed1991

Diethylstilbestrol metabolites and analogs: differential ligand effects on estrogen receptor interactions with nuclear matrix sites.

Estradiol (E), diethylstilbestrol (DES), and three structurally similar DES derivatives and analogs, consisting of racemic mixtures of indenestrol-A (IA; rac), indenestrol-B (IB; rac), and the Z-isomer of pseudo-DES (PD) were used as probes to determine the effect of ligand on receptor-nuclear acceptor site interactions. IA (rac), IB (rac), and Z-PD have been previously shown to interact with the mouse uterine estrogen receptor with high affinity (Kd, approximately 1.5-2.2 x 10(-10) M), occupy similar levels of receptor in the nucleus in vivo, and have nuclear retention times similar to those of E and DES. However, in spite of these similarities, they differentially stimulate estrogenic responses that were previously thought to be interrelated and obligatory for full estrogenic action. In an attempt to elucidate the mechanism of differential stimulation of estrogen-regulated responses, the temporal pattern of KCl-resistant receptor sites was examined after a single injection of E, DES, IA (rac), IB (rac), Z-PD, or saline. Z-PD displayed lower levels of KCl-resistant receptor than the other compounds, whereas IA (rac) and IB (rac) had patterns similar to those of E and DES. In cell-free binding assays, all of the different receptor-ligand complexes were equally effective at competitively inhibiting the binding of receptor-[3H]E complexes to mouse uterine nuclear matrix with a Ki of 1.1 x 10(-10) M. Direct binding analysis showed no difference in the number of nuclear binding sites (range, 40.4-63.9 fmol/100 micrograms DNA) or Kd (range, 1.3-1.8 x 10(-10) M) among the different receptor-ligand complexes. Dissociation studies performed at 4 C showed no differences among the different complexes. In contrast, Z-PD-receptor complexes dissociated much faster from matrix sites at 22 C than any of the other complexes. Significant differences were noted in the proportion of complexes that were resistant to extraction with 0.6 M KCl. Forty-three percent of receptor-E complexes and 44% of receptor-DES complexes were resistant to KCl extraction, while 61% of receptor-IA and 29% of receptor-PD complexes were resistant to extraction, paralleling their activity in eliciting some estrogenic responses. In contrast, no difference was seen by gel shift assays in the ability of the ligand-receptor complexes to bind to a specific PS2 estrogen-responsive DNA sequence. These results demonstrate that the ligand may significantly affect the interaction of the estrogen receptor with nuclear acceptor sites.

Animals↗
PubMed1991

Diethylstilbestrol stimulates persistent phosphatidylinositol lipid turnover by an estrogen receptor-mediated mechanism in immature mouse uterus.

The effect of estrogen on phosphoinositide (PI) metabolism was evaluated in the immature mouse uterus, a tissue which undergoes estrogen-induced proliferation. Uteri isolated from untreated mice or from mice injected ip with diethylstilbestrol (DES) were incubated with [3H]myo-inositol and assessed for incorporation of label into PI lipids or inositol phosphate generation. DES administration elicited a rapid increase in [3H]myo-inositol incorporation, which persisted until at least 18 h post treatment. This effect could not be duplicated by incubation of uteri with DES in vitro, although [3H]myo-inositol incorporation in uteri removed from DES-treated mice remained elevated for 3 h of in vitro incubation. Stimulation of PI lipid metabolism by DES was blocked by ICI 164,384, a specific estrogen receptor antagonist. The effect of DES on PI metabolism consisted of a time-dependent increase in the specific activity of both phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate and a significant increase of inositol (1,4,5)-trisphosphate mass by 12 h post treatment. These changes occur before the onset of estrogen-induced DNA synthesis. The results indicate that estrogens rapidly modulate PI lipid turnover through an estrogen receptor-mediated mechanism. Since the metabolic products of PI lipids are important for signal transduction and cellular proliferation, altered metabolism of these lipids may play an integral role in estrogen-induced mitogenesis.

Animals↗
PubMed1975

Surface modifications evoked by estradiol and diethylstilbestrol in isolated endometrial cells: evidence from lectin probes and extracellular release of lysosomal protease.

Endometrial cells were isolated from the uteri of ovariectomized rats. The inhibitory effect of alpha-methyl-D-mannoside on fluorescein-labeled concanavalin A (Con A) binding to these cells indicates that they possess specific binding sites for Con A. The lectin also mediates adsorption of homologous erythrocytes to these cells. Both Con A binding and Con A-mediated hemadsorption to endometrial cells are depressed at 4 C compared with these functions in cells maintained at 22 C. Gross elevations in lectin-mediated hemadsorption to endometrial cells are evident following prior exposure to 1 X 10(-9)M concentrations of diethylstilbestrol (DES) or estradiol-17beta, but not to the physiologically inactive 17 alpha-epimer, at 22 C. The enhancement of hemagglutinability cannot be attributed to a corresponding increase in lectin binding at 22 C. Although estrogen treatment elicited significant increments in Con A binding as early as 5 min after addition of estrogen to cell suspensions, the increment in agglutination attributable to hormone treatment consistently ranged from 1.5-3 times greater than the increase in lectin binding. These estrogenic effects were reduced by incubation of the endometrial cells at 4 C or when cortisol, 3 X 10(-6)M, was present with estradiol-17beta. In parallel experiments, treatment with DES and estradiol-17beta, but not estradiol-17 alpha, also enhanced the release of cathepsin B 1 and acid phosphatase from uterine segments into the particle-free extracellular media in which the tissues had been incubated for 30-60 min. The marked increment in the extracellular activity of the lysosomal hydrolases induced by estrogen treatment was suppressed in cells incubated at 4 C or when cortisol was present concomitantly. These and related data suggest the hypothesis that acute increments in lysosomal hydrolase activity may contribute to cell surface alterations which have been described in both normal and aberrant processes of cell growth.

Acid Phosphatase↗
PubMed1975

Diethylstilbestrol-elicited accumulation of cyclic AMP in incubated rat hypothalamus.

Diethylstilbestrol (DES) and 17beta-estradiol elicit significant increases in levels of endogenous and [14C]cyclic AMP in [14C]adeninelabeled hypothalami from immature female rats, but only after incubation of the hypothalami with these estrogenic agents for 40-50 min. Estriol has no effect. The 2-fold accumulation of cyclic AMP elicited by low concentrations (20 muM) of DES appears dependent on catecholamine-related mechanisms, since it is prevented by either alpha- or beta-adrenergic antagonists. Higher concentrations (100 muM) of DES elicit a 3-fold accumulation of [14C]cyclic AMP which is only partially blocked by adrenergic antagonists, haloperidol, or the adenosine antagonist, theophylline. These phenomena appear to be specific for the hypothalamus since incubation of cerebral cortical slabs with estrogens resulted in no significant increases in the levels of cyclic AMP. The slow time course in whole hypothalami and the complete lack of effects of low concentrations of estrogenic agents in chopped hypothalami suggest an indirect mechanism of action. Interaction of estrogens with receptors in cell bodies may result, after a latent period of 40-50 min, in enhanced release of catecholamines from distal synaptic terminals and in stimulation of catecholamine-sensitive adenylate cyclases at post-synaptic sites.

Adenylyl Cyclases↗
PubMed1994

Rat 17 beta-hydroxysteroid dehydrogenase type 1: primary structure and regulation of enzyme expression in rat ovary by diethylstilbestrol and gonadotropins in vivo.

17 beta-Hydroxysteroid dehydrogenase (17HSD) catalyzes the reversible conversion of estrone into estradiol. The complementary DNA (cDNA) coding for rat 17HSD type 1 was cloned from a commercial rat ovarian cDNA library, using human 17HSD type 1 cDNA as a probe. The nucleotide sequence extends for 1160 basepairs (bp), including 1035 bp of open reading frame, a stop codon, and 125 bp of 3'-untranslated sequence. The cDNA encodes a protein of 344 amino acids, with a calculated molecular mass of 36,967 daltons. The overall amino acid identity and similarity between rat and human 17HSD type 1 enzymes are 68% and 80%, respectively. Immunohistochemistry and in situ and Northern hybridizations were used to study regulation of the enzyme in rat ovary in vivo. Enzyme expression was detected in granulosa cells only, whereas no expression was observed in stromal or thecal cells. The enzyme was almost undetectable in ovaries from immature hypophysectomized rats. After 2-day treatment with recombinant FSH (recFSH), an induction of 17HSD type 1 expression was observed in granulosa cells of growing antral follicles. During 5 days of diethylstilbestrol (DES) treatment, a time-dependent increase in developing follicles was observed, showing strong expression of 17HSD type 1 in granulosa cells. Treatment with recFSH for 2 days in DES-primed animals resulted in down-regulation of ovarian enzyme expression. This reduction of enzyme expression was associated with luteinization of the follicles. hCG treatment of recFSH- or DES- plus recFSH-primed animals further induced luteinization, resulting in strong down-regulation of 17HSD type 1 expression. The enzyme was not detected in corpora lutea. The data show that 17HSD type 1 expression in rat ovary is regulated by gonadotropins and estrogens. The results suggest that expression of 17HSD type 1 and that of cytochrome P450 aromatase are regulated by distinct mechanisms, and 17HSD type 1 may be down-regulated earlier than P450 aromatase during luteinization, limiting estradiol biosynthesis in luteinizing granulosa cells in rat ovary.

17-Hydroxysteroid Dehydrogenases↗