Simultaneous effects of IGF1 and Fadrozole on parthenogenesis and pluripotency markers in chicken embryo.

So far, a synergistic effect was detected between insulin-like growth factor-I (IGF1) and anti-aromatase for sex reversal and pre-/post-natal growth of fertilized chicken embryo. Here, we hypothesized whether the growth and sexual female-to-male reversal effects of IGF1 and an anti-aromatase, Fadrozole, could improve the development of unfertilized, parthenogenetic chicken embryos. Simultaneous administration of IGF1 and Fadrozole increased the percentage of grade A embryos from 1.7% (no injection group) to 70.6%. The expression profile of parthenotes and newly laid fertilized embryos showed that IGF1 and Fadrozole increased SOX2 and NANOG expression, while decreased the TBX3 expression in the parthenogenetic embryos. However, a considerably higher expression of PRDM16, IGF2, NODAL and HDAC2 was observed in the fertilized group compared to the parthenogenetic embryos. In conclusion, chicken sexual determination is initiated at the earliest stage of embryonic development before gonadal differentiation. Combined administration of IGF1 and Fadrozole increased the developmental rate of parthenogenetic embryos. Also, simultaneous supplementation of IGF1 and Fadrozole induced the expression of pluripotency genes with no effect on the expression of growth and differentiation factors.

ZENK induction in the zebra finch brain by song: Relationship to hemisphere, rhythm, oestradiol and sex.

Oestradiol is abundant in the zebra finch auditory forebrain and has the capacity to modulate neural responses to auditory stimuli with specificity as a result of both hemisphere and sex. Arrhythmic song induces greater ZENK expression than rhythmic song in the caudomedial nidopallium (NCM), caudomedial mesopallium (CMM) and nucleus taeniae (Tn) of adult zebra finches. The increases in the auditory regions (i.e. NCM and CMM) may result from detection of errors in the arrhythmic song relative to the learned template. In the present study, zebra finches were treated with oestradiol, the aromatase inhibitor fadrozole or a control and then exposed to rhythmic or arrhythmic song to assess the effect of oestradiol availability on neural responses to auditory rhythms. ZENK mRNA was significantly greater in the left hemisphere within the NCM, CMM and Tn. Main effects of sex were detected in both auditory regions, with increased ZENK in males in the NCM and in females in the CMM. In the CMM, an effect of hormone treatment also existed. Although no pairwise comparison was statistically significant, the pattern suggested greater ZENK expression in control compared to both fadrozole- and oestradiol-treated birds. In the NCM, an interaction between sex and hormone treatment suggested that the sex effect was restricted to control animals. An additional interaction in the NCM among sex, stimulus rhythmicity and hemisphere indicated that the strongest effect of laterality was present in males exposed to arrhythmic song. The hormone effects suggest that an optimal level of oestradiol may exist for processing rhythmicity of auditory stimuli. The overall pattern for left lateralisation parallels the left lateralisation of language processing in humans and may suggest that this hemisphere is specialised for processing conspecific vocalisations. The reversed sex differences in the NCM and CMM suggest that males and females differentially rely on components of the auditory forebrain for processing conspecific song.

Testosterone Differentially Affects T Cells and Neurons in Murine and Human Models of Neuroinflammation and Neurodegeneration.

The high female-to-male sex ratio of multiple sclerosis (MS) prevalence has continuously confounded researchers, especially in light of male patients' accelerated disease course at later stages of MS. Although multiple studies have concentrated on estrogenic mechanisms of disease modulation, fairly little attention has been paid to androgenic effects in a female system, and even fewer studies have attempted to dissociate hormonal effects on the neurodegenerative and neuroinflammatory processes of MS. Herein, we demonstrate the differential effects of hormone treatment on the acute inflammatory and chronic neurodegenerative phases of murine experimental autoimmune encephalomyelitis. Although s.c. treatment with testosterone and aromatase inhibitor applied beginning on the day of immunization ameliorated initial course of disease, similar treatment administered therapeutically exacerbated chronic disease course. Spinal cord analyses of axonal densities reflected the clinical scores of the chronic phase. In vitro, testosterone treatment not only decreased Th1 and Th17 differentiation in an aromatase-independent fashion, but also exacerbated cell death in induced pluripotent stem cell-derived primary human neurons under oxidative stress conditions in an aromatase inhibitor-dependent manner. Thus, through the alleviation of inflammatory processes and the exacerbation of neurodegenerative processes, androgens may contribute to the epidemiologic sex differentials observed in MS prevalence and course.

The effect of hormone manipulations on sex ratios varies with environmental conditions in a turtle with temperature-dependent sex determination.

Exogenous application of steroids and related substances to eggs affects offspring sex ratios in species with temperature-dependent sex determination (TSD). Laboratory studies demonstrate that this effect is most pronounced near the constant temperature that produces 1:1 sex ratios (i.e., pivotal temperature). However, the impact of such chemicals on sex determination under natural nest temperatures (which fluctuate daily) is unknown, but could provide insight into the relative contributions of these two factors under natural conditions. We applied estradiol (E2) and an aromatase inhibitor (fadrozole) to eggs of the painted turtle (Chrysemys picta), a species with TSD, and allowed eggs to incubate under natural conditions during two field seasons (in 2012 and 2013). Exogenous E2, fadrozole, and nest temperature contributed to variation in offspring sex ratio, but the relative contributions of these factors differed between years. In 2012, a much hotter than average season, sex ratios were heavily female biased regardless of nest temperature and chemical treatment. However, in 2013, a milder season, both nest temperature and chemical treatment were important. Moreover, a significant interaction between nest temperature and treatment demonstrated that exogenous estradiol induces female development regardless of nest temperature, but aromatase inhibition widens the range of temperatures that produces both sexes.

Computational model of the fathead minnow hypothalamic-pituitary-gonadal axis: Incorporating protein synthesis in improving predictability of responses to endocrine active chemicals.

There is international concern about chemicals that alter endocrine system function in humans and/or wildlife and subsequently cause adverse effects. We previously developed a mechanistic computational model of the hypothalamic-pituitary-gonadal (HPG) axis in female fathead minnows exposed to a model aromatase inhibitor, fadrozole (FAD), to predict dose-response and time-course behaviors for apical reproductive endpoints. Initial efforts to develop a computational model describing adaptive responses to endocrine stress providing good fits to empirical plasma 17ß-estradiol (E2) data in exposed fish were only partially successful, which suggests that additional regulatory biology processes need to be considered. In this study, we addressed short-comings of the previous model by incorporating additional details concerning CYP19A (aromatase) protein synthesis. Predictions based on the revised model were evaluated using plasma E2 concentrations and ovarian cytochrome P450 (CYP) 19A aromatase mRNA data from two fathead minnow time-course experiments with FAD, as well as from a third 4-day study. The extended model provides better fits to measured E2 time-course concentrations, and the model accurately predicts CYP19A mRNA fold changes and plasma E2 dose-response from the 4-d concentration-response study. This study suggests that aromatase protein synthesis is an important process in the biological system to model the effects of FAD exposure.

Role of brain aldosterone and mineralocorticoid receptors in aldosterone-salt hypertension in rats.

Central blockade of mineralocorticoid receptors (MRs) or angiotensin II type 1 receptors (AT1Rs) attenuates aldosterone (aldo)-salt induced hypertension. We examined the role of the subfornical organ (SFO), aldo synthesized locally in the brain, and MR and AT1R specifically in the paraventricular nucleus (PVN) in aldo-salt hypertension. Wistar rats were treated with subcutaneous aldo (1 µg/h) plus saline as drinking fluid, and gene expression was assessed by real-time qPCR. Other sets of rats received chronic intra-cerebroventricular (icv) infusion of aldo synthase (AS) inhibitor FAD286, MR blocker eplerenone or vehicle, electrolytic or sham lesions of the SFO, or intra-PVN infusion of AAV-MR-siRNA or AAV-AT1aR-siRNA. Infusion of aldo had no effect on 11ßHSD2, MR and AT1R mRNA in different nuclei but increased CYP11B2 mRNA in the SFO, and serum and glucocorticoid-kinase 1 (Sgk1) and epithelial sodium channel (ENaC) γ subunit mRNA in the SFO and supraoptic nucleus (SON). MR-siRNA decreased both MR and AT1R mRNA in the PVN by ∼ 60%, but AT1aR-siRNA only decreased AT1R mRNA. SFO lesion, blockade of brain AS or MR, or knockdown of MR or AT1R in the PVN similarly attenuated aldosterone-induced saline intake by ∼ 50% and hypertension by ∼ 70%. These results suggest that an increase in circulating aldosterone may via MR and AT1R in the SFO increase local aldosterone production in hypothalamic nuclei such as the SON and PVN, and via MR enhance AT1R signaling in the PVN. This central aldosterone-MR-AT1R neuro-modulatory pathway appears to play a major role in the progressive hypertension.

Developmental toxicity of endocrine disruptors in early life stages of zebrafish, a genetic and embryogenesis study.

Endocrine disrupting compounds (EDCs) are capable of interfering with the endocrine system and are increasingly widespread in the aquatic environments. In the present study, zebrafish (Danio rerio) embryos and larvae were used to assess how EDCs may interfere with embryogenesis. Therefore, zebrafish embryos were exposed to 17α-ethinylestradiol (EE2: 0.4, 2, 4 and 20 ng/L), genistein (Gen: 2, 20, 200 and 2000 ng/L) and fadrozole (Fad: 2, 10, 50 and 250 µg/L), between 2 and 144 h post-fertilization (hpf). Somite development, heartbeat, malformations, mortality and hatching rates were evaluated. In parallel, the expression patterns of hormone receptors (esr1, esr2a, esr2b and ar) and apoptotic pathways related genes (p53 and c-jun) were determined using quantitative real-time PCR. Results showed that EE2, Gen and Fad caused a higher mortality and also malformations in larvae compared with control. A significant toxic effect was observed in the heartbeat rate, at 144 hpf, in larvae exposed to EE2 and Fad. QPCR revealed alterations in the expression levels of all the evaluated genes, at different time points. esr1 and c-jun genes were upregulated by EE2 and Gen exposure while the expression of esr2a, esr2b and ar genes was downregulated. Fad exposure decreased esr1, p53 and c-jun expression levels. This study shows a toxic effect of EE2, Gen and Fad to vertebrate embryogenesis and a relation between hormones action and apoptosis pathways.

Changing neuroestrogens within the auditory forebrain rapidly transform stimulus selectivity in a downstream sensorimotor nucleus.

The activity of sensory circuits is shaped by neuromodulators, which can have downstream consequences for both sensorimotor integration and behavioral output. Recent evidence indicates that brain-derived estrogens ("neuroestrogens") can act as local circuit modulators in the songbird auditory forebrain. Specifically, neuroestrogens fluctuate in the auditory caudomedial nidopallium (NCM) during social interactions and in response to song stimuli. Within minutes of elevation, neuroestrogens also enhance auditory response properties of NCM neurons, and acute blockade of estrogen production in NCM disrupts behavioral song preferences. Here, we test the hypothesis that fluctuating neuroestrogens within NCM influence stimulus selectivity in a downstream sensorimotor nucleus (HVC, used as a proper name) that receives indirect auditory input from NCM. Dual extracellular recordings coupled with retrodialysis delivery show that song selectivity in HVC is rapidly enhanced by increasing neuroestrogens in NCM in adult males. Conversely, inhibiting neuroestrogen production in NCM causes a rapid decline in song selectivity in HVC, demonstrating the endogenous nature of this modulatory network. In contrast, HVC selectivity is unaffected by neuroestrogen delivery to either nearby caudomedial mesopallium or into HVC itself, indicating that neuroestrogen actions are restricted to NCM. In juvenile males, identical neuroestrogen treatment in NCM also does not alter HVC selectivity, consistent with a developmental maturation of the auditory network. Lastly, the rapid actions of estrogens leading to enhanced HVC selectivity appear to be mediated by membrane-bound receptors in NCM. These findings indicate that steroid-dependent modulation of sensory processing is not locally restricted and can be transmitted transynaptically to influence downstream sensorimotor and premotor targets.

Fadrozole and finasteride exposures modulate sex steroid- and thyroid hormone-related gene expression in Silurana (Xenopus) tropicalis early larval development.

Steroidogenic enzymes and their steroid products play critical roles during gonadal differentiation in amphibians; however their roles during embryogenesis remain unclear. The objective of this study was to investigate the expression and activity of aromatase (cyp19; estrogen synthase) and 5 beta-reductase (srd5 beta; 5 beta-dihydrotestosterone synthase) during amphibian embryogenesis. Expression and activity profiles of cyp19 and srd5 beta were first established during Silurana (Xenopus) tropicalis embryogenesis from Nieuwkoop-Faber (NF) stage 2 (2-cell stage; 1h post-fertilization) to NF stage 46 (beginning of feeding; 72 h post-fertilization). Exposures to fadrozole (an aromatase inhibitor; 0.5, 1.0 and 2.0 microM) and finasteride (a putative 5-reductase inhibitor; 25, 50 and 100 microM) were designed to assess the consequences of inhibiting these enzymes on gene expression in early amphibian larval development. Exposed embryos showed changes in both enzyme activities and sex steroid- and thyroid hormone-related gene expression. Fadrozole treatment inhibited cyp19 activity and increased androgen receptor and thyroid hormone receptor (alpha and beta) mRNAs. Finasteride treatment inhibited srd5 beta (activity and mRNA), decreased cyp19 mRNA and activity levels and increased estrogen receptor alpha mRNA. Both treatments altered the expression of deiodinases (thyroid hormone metabolizing enzymes). We conclude that cyp19 and srd5 beta are active in early embryogenesis and larval development in Silurana tropicalis and their inhibition affected transcription of genes associated with the thyroid and reproductive axes.

New aromatase inhibitors as second-line endocrine therapy in postmenopausal patients with metastatic breast carcinoma: a pooled analysis of the randomized trials.

BACKGROUND: New aromatase inhibitors (AI) (second-generation: formestane and fadrozole; third-generation: letrozole, anastrozole, vorozole, and exemestane) have been tested in several controlled clinical trials after tamoxifen failure in metastatic breast carcinoma (MBC). They have resulted in better survival compared with megestrol acetate (MEG) in a number of studies. The authors performed a pooled analysis including all the Phase III trials published between 1996 and 2004 evaluating the AIs approved or not by the Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medical Products (EMEA) as second-line endocrine therapy (ET) for patients with MBC. METHODS: The overall response rate (ORR) and time to disease progression (TTP) were considered the primary end points, whereas toxicity was regarded as a secondary objective. Relative risk, 95% confidence interval, and heterogeneity were derived using 2 methods. RESULTS: No significant differences in ORR and TTP were noted in the entire group of 9 trials comparing AI with MEG (3908 patients) and in the 6 trials comparing nonsteroidal AI and MEG (2415 patients). AI yielded significantly more hot flashes than MEG (P = 0.004) but caused significantly less toxicity than MEG in weight gain (P = 0.001), dyspnea (P = 0.008), and peripheral edema (P = 0.03). Significant heterogeneity for nausea, weight gain, dyspnea, and peripheral edema was registered. When steroidal AIs were excluded from the toxicity analysis, nausea maintained its strongly significant heterogeneity (P = 0.0002), whereas weight gain, dyspnea, and peripheral edema lost their significance. CONCLUSIONS: This pooled analysis suggested that AIs in second-line ET for patients with MBC do not seem to add any significant benefit to MEG in terms of ORR and TTP. With regard to toxicity, the findings in the current study showed that weight gain, dyspnea, and peripheral edema are more frequent with the use of MEG, whereas hot flashes were more represented using AI.

Modulation by steroid hormones of a "sexy" acoustic signal in an Oscine species, the Common Canary Serinus canaria.

The respective influence of testosterone and estradiol on the structure of the Common Canary Serinus canaria song was studied by experimentally controlling blood levels of steroid hormones in males and analyzing the consequent effects on acoustic parameters. A detailed acoustic analysis of the songs produced before and after hormonal manipulation revealed that testosterone and estradiol seem to control distinct song parameters independently. The presence of receptors for testosterone and estradiol in the brain neural pathway controlling song production strongly suggests that the observed effects are mediated by a steroid action at the neuronal level.

Differential expression pattern and steroid hormone sensitivity of SNAP-25 and synaptoporin mRNA in the telencephalic song control nucleus HVC of the zebra finch.

Gonadal steroid hormones play an important role in the process of sexual differentiation of brain areas and behavior such as singing and song learning in songbirds. These hormones affect behavior controlling circuits on both the gross morphological and ultrastructural levels. Here we study whether the expression of genes coding for synaptic proteins is sensitive to gonadal steroid hormones and whether such altered expression coincides with changes in brain area size. We treated adult male zebra finches with the aromatase inhibitor fadrozole, to reduce estrogen synthesis and analyzed the mRNA expression of the synaptic proteins synaptoporin (SPO) and synaptosomal-associated protein 25 kDa (SNAP-25) in song control areas and surrounding tissues of adult male zebra finches. SPO and SNAP-25 are differently expressed throughout the song system. Generally, the telencephalic song nuclei expressed SNAP-25 at high intensity whereas SPO expression was area-specific. Elevated levels of SNAP-25 mRNA were present in the nucleus hyperstriatalis ventrale pars caudale (HVC) and in the robust nucleus of the archistriatum (RA). SPO mRNA was found in moderate levels in the HVC, in low levels in the lateral nucleus magnocellularis (lMAN) and Area X, and was absent in the RA. The treatment significantly increased the mRNA level of SPO in the HVC, whereas SNAP-25 expression level was not affected. These expression patterns are not explained by the decrease of HVC volume after treatment. The decreased HVC size is not area-specific but correlates with an overall reduction in size and an overall increase in cell density of the forebrain.

Expression of aromatase mRNA and effects of aromatase inhibitor during ovarian development in the medaka, Oryzias latipes.

In teleost fish, several studies have implicated estrogens in the process of ovarian development, but the exact role of endogenous estrogen is still unclear. We examined the expression of aromatase mRNA with in situ hybridization, and the effects of Fadrozole, a nonsteroidal aromatase inhibitor (AI), during ovarian development in medaka Oryzias latipes. Medaka aromatase was first detected on the ventral side of ovaries from four to 10 days after hatching (dah), after occurrence of oogenesis. AI treatment after hatching suppressed the ovarian cavity formation from 30 dah but did not affect early oogenesis and folliculogenesis during ovarian development. These results suggest that endogenous estrogen is specifically required for formation of the ovarian cavity, but is not essential for early oogenesis and folliculogenesis in medaka.

Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor.

OBJECTIVE: To assess the management of symptomatic leiomyomas using a nonsteroidal aromatase inhibitor in perimenopausal women. DESIGN: Case report. SETTING: Academic clinical practice. PATIENT(S): A 53-year-old woman suffering from recurrent urinary retention secondary to a uterine leiomyoma. INTERVENTION(S): Fadrozole, orally, 2 mg daily for 8 weeks and then 1 mg daily for 4 weeks. MAIN OUTCOME MEASURE(S): Measurements of leiomyoma volume, and levels of serum E(2), LH, and FSH. RESULT(S): Urinary retention resolved after 2 weeks of treatment and did not recur. Leiomyoma volume estimated by ultrasonography revealed a 71% reduction after 8 weeks of treatment. CONCLUSION(S): Fadrozole was useful for the management of a symptomatic leiomyoma without transient deterioration of symptoms. Clinical trials are warranted.

[Hepatic infusion of docetaxel using PEIT for a patient with stage IV breast cancer].

Hepatic infusion of docetaxel using PEIT was performed for a patient with stage IV breast cancer. Docetaxel was effective to a solitary liver metastatic lesion. A 64-year-old woman was admitted to our hospital because of a left breast mass that was bleeding. She was diagnosed with stage IV breast cancer. Surgery was performed on February 16th. The pathological diagnosis was invasive ductal carcinoma, and hormone receptors were negative. Two weeks after operation, monthly docetaxel injections were given together with doxifluidine 400 mg/day p.o., cyclophosphamide 50 mg/day p.o., and fadrozole hydrochloride hydrate 2 mg/day p.o. After two courses, hepatic infusion of docetaxel was performed using PEIT after informed consent. The patient's high serum CEA and CA15-3 level returned to the normal range. A metastatic lesion on CT changed to a cystic pattern. These results suggest that PEIT is worth trying in patients with solitary liver metastasis from breast cancer.

[An elderly woman with breast cancer and multiple liver metastasis that responded well to combination therapy of fadrozole and tamoxifen].

Few reports suggest a clinical benefit from combination treatment of fadrozole and tamoxifen for advanced breast cancer in elderly patients. We report the case of an 82-year-old breast cancer patient with multiple liver metastasis. After mastectomy, combination treatment of fadrozole and tamoxifen was added. Two months after the start of this treatment, there was a remarkable reduction in the size of metastatic lesions that continued over 6 months. CT examination revealed the largest lesion was reduced from 8.0 cm to 5.0 cm in largest diameter. The other two lesions were reduced from 3.0 cm to 2.0 cm. The reduction rate was 36%, indicating PR in the Response Evaluation Criteria in Solid Tumors (RECIST). The tumor marker CEA was remarkably reduced from 318 to 85 (ng/ml), and CA15-3 was reduced from 430 to 150 (U/ml). Tumor marker reduction continued over the 6 months corresponding to CT findings. No adverse effect was experienced. This combination therapy was useful and safe against metastatic breast cancer in a patient over 80 years of age.

[A combined effect of fadrozole and tamoxifen in postmenopausal patients with recurrent breast cancer: a preliminary report: Japanese Cooperative Study Group of Fadrozole and Tamoxifen].

To elucidate the combined effects of fadrozole (nonsteroidal aromatase inhibitor) and tamoxifen, 11 postmenopausal patients with recurrent breast cancer were examined between October 1996 and June 1998. One patient, 49 years old, was ineligible due to the short period after castration. The patients were aged 53-71 years (mean 63.5). PS was 0-1. Six patients were pre-treated with tamoxifen and 6 with oral 5-FU derivatives. One had no previous treatment. The target lesions were soft tissues in 5, bone in 4, lungs in 6 and liver in 1. The response was CR in 2, PR in 2, SD (longer than 24 weeks) in 2, NC in 1 and PD in 3. Consequently, the response rate was 60% (6 out of 10 eligible cases). Hormonal concentration was measured before and after administration of two drugs in weeks 2, 4, 6, 8 and at the end of the treatment, and significant decreases in estrogens in peripheral blood were observed. Adverse effects (4 cases of low grade headache, dizziness and elevation of GOT, GPT, gamma-GTP) did not influence the continuous administration of the drugs. We conclude that combined administration of fadrozole (2nd generation aromatase inhibitor) and tamoxifen produces a good response in postmenopausal recurrent breast cancer patients, and can be a useful treatment for patients with breast cancer.

Malignant proliferating trichilemmal tumor in the skin over the breast: a case report.

A proliferating trichilemmal tumor is relatively uncommon. It is composed of multiple cysts consisting of squamous epithelium with trichilemmal keratinization without granular layer interposition. This lesion usually occurs in the scalp of elderly women. We describe a 67-year-old woman with a malignant proliferating trichilemmal tumor in the skin over the breast. We first misdiagnosed the disease as a primary squamous cell carcinoma of the breast with a metastatic lymph node in the axilla because of the disease site and our unfamiliarity with the disease. The patient underwent radical mastectomy with axillary dissection. Eight months postoperatively, a tumor appeared in her right axilla and progressively enlarged. We subsequently excised the tumor. She is healthy as of 8 months postoperatively. To the best of our knowledge, only one case of a proliferating trichilemmal tumor occurring in the skin over the breast has been reported.

[Efficacy of combined chemoendocrine therapy with doxifluridine, cyclophosphamide, and fadrozole hydrochloride hydrate in a case of stage T4N3M1 breast cancer].

A 66-year-old female presented with a swollen lump in the left breast. She was diagnosed as having advanced breast cancer of stage T4N3 (supraclavicular lymph node) M1 (bone). The administration of CEF and TAM failed to improve her condition. After the treatment regimen was changed to combined chemoendocrine therapy with CPA, EPI, 5'-DFUR, and MPA, the areas of bone metastases were reduced. However, MPA caused side-effects (acute obstruction of the lower limb), and thus the treatment was discontinued after 4 months. Subsequently, the treatment combination was changed to CPA, EPI, 5'-DFUR, and fadrozole hydrochloride hydrate. After one year of the treatment, a complete response (CR) was obtained with the disappearance of the supraclavicular lymph node and bone metastases. After EPI reached the maximum administration amount, the remaining CPA, 5'-DFUR and fadrozole hydrochloride hydrate oral administrations were continued. As of 3 years and 10 months after the onset of the chemoendocrine therapy, CR has been maintained with suppression of the primary and metastatic lesions, without degrading the patient's quality of life.

Masculinization of genetic female nile tilapia (Oreochromis niloticus) by dietary administration of an aromatase inhibitor during sexual differentiation.

A series of experiments was carried out in which genetically female Nile tilapia (Oreochromis niloticus) fry were treated with Fadrozole, a nonsteroidal aromatase inhibitor (AI), in the diet during the period of sexual differentiation. Batches of tilapia fry treated with AI during the first 30 days following yolk-sac resorption (7-37 days post hatch, dph) showed a dose-dependent increase in the percentage of males from 0 to 200 mg. kg(-1). The percentage of males remained approximately constant (92.5-96.0%) from 200 to 500 mg. kg(-1). Any continuous 2- or 3-week treatment with 500 mg. kg(-1) AI in this 4-week period successfully masculinized the majority of the treated fish (>80%). Treatments of 1 week duration revealed that the most sensitive time to AI lies in the first week (between 7 and 14 dph). Progeny testing of males from AI-treated groups gave results indicating that these were XX males, as expected. These experiments strongly implicate aromatase activity as a key factor in sexual differentiation in the Nile tilapia.