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Obstetrics and Gynecology Dec 1991Lichen sclerosus typically affects the vulva of postmenopausal women. Because serum levels of dihydrotestosterone are low in women with vulvar lichen sclerosus and... (Clinical Trial)
Clinical Trial
Lichen sclerosus typically affects the vulva of postmenopausal women. Because serum levels of dihydrotestosterone are low in women with vulvar lichen sclerosus and because dihydrotestosterone is an effector androgen in vulvar skin, this double-blind cross-over study assessed five women with vulvar lichen sclerosus to determine the response to treatment with dihydrotestosterone. Objective gross and microscopic improvement in lichen sclerosus accompanied sustained treatment with topical dihydrotestosterone, but not with vehicle alone. However, there was no change in symptoms (itching and dyspareunia) in these women, although dihydrotestosterone did improve some of the features of vulvar lichen sclerosus and may represent a new treatment for this disease.
Topics: Administration, Cutaneous; Adult; Aged; Aged, 80 and over; Dihydrotestosterone; Double-Blind Method; Female; Humans; Keratosis; Middle Aged; Vulva
PubMed: 1945205
DOI: No ID Found -
International Journal of Molecular... May 2019Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol...
Regioselective synthesis of novel ring A-fused arylpyrazoles of dihydrotestosterone (DHT) was carried out in two steps under facile reaction conditions. Aldol condensation of DHT with acetaldehyde afforded a 2-ethylidene derivative regio- and stereo-selectively, which was reacted with different arylhydrazines in the presence of iodine via microwave-assisted oxidative cyclization reactions. The 17-keto analogs of steroidal pyrazoles were also synthesized by simple oxidation in order to enlarge the compound library available for pharmacological studies and to obtain structure-activity relationship. The antiproliferative activities of the structurally related heteroaromatic compounds were tested in vitro on human cervical and breast adenocarcinoma cell lines (HeLa, MCF-7 and MDA-MB-231) and on two androgen-independent malignant prostate carcinoma cell lines (PC-3 and DU 145). Based on primary cytotoxicity screens and IC assessment, a structure-function relationship was identified, as derivatives carrying a hydroxyl group on C-17 exhibit stronger activity compared to the 17-one counterparts. Cancer cell selectivity of the derivatives was also determined using non-cancerous MRC-5 cells. Furthermore, the proapoptotic effects of some selected derivatives were verified on androgen therapy refractive p53-deficient PC-3 cells. The present study concludes that novel DHT-derived arylpyrazoles exert cancer cell specific antiproliferative activity and activate apoptosis in PC-3 cells.
Topics: Androgens; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dihydrotestosterone; Humans; Male; Models, Molecular; Prostatic Neoplasms; Pyrazoles
PubMed: 31052484
DOI: 10.3390/ijms20092170 -
European Journal of Medicinal Chemistry Mar 2023The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step...
Investigating a new C2-symmetric testosterone dimer and its dihydrotestosterone analog: Synthesis, antiproliferative activity on prostate cancer cell lines and interaction with CYP3A4.
The synthesis of a 17α-linked C2-symmetric testosterone dimer and its dihydrotestosterone analog is reported. The dimers were synthesized using a short five-step reaction sequence with 28% and 38% overall yield for the testosterone and dihydrotestosterone dimer, respectively. The dimerization reaction was achieved by an olefin metathesis reaction with 2nd generation Hoveyda-Grubbs catalyst. The dimers and their corresponding 17α-allyl precursors were tested for the antiproliferative activity on androgen-dependent (LNCaP) and androgen-independent (PC3) prostate cancer cell lines. The effects on cells were compared with that of the antiandrogen cyproterone acetate (CPA). The results showed that the dimers were active on both cell lines, with an increased activity towards androgen-dependent LNCaP cells. However, the testosterone dimer (11) was fivefold more active than the dihydrotestosterone dimer (15), with an IC of 11.7 μM vs. 60.9 μM against LNCaP cells, respectively, and more than threefold more active than the reference drug CPA (IC of 40.7 μM). Likewise, studies on the interaction of new compounds with drug-metabolizing cytochrome P450 3A4 (CYP3A4) showed that 11 was a fourfold stronger inhibitor than 15 (IC of 3 μM and 12 μM, respectively). This suggests that changes in the chemical structure of sterol moieties and the manner of their linkage could largely affect both the antiproliferative activity of androgen dimers and their crossreactivity with CYP3A4.
Topics: Male; Humans; Testosterone; Dihydrotestosterone; Androgens; Cytochrome P-450 CYP3A; Prostatic Neoplasms; Cell Line; Cell Line, Tumor
PubMed: 36848848
DOI: 10.1016/j.ejmech.2023.115222 -
International Immunopharmacology Jul 2022Traumatic Brain Injury (TBI) has long-term devastating effects for which there is no accurate and effective treatment for inflammation and chronic oxidative stress. As a...
Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology.
BACKGROUND
Traumatic Brain Injury (TBI) has long-term devastating effects for which there is no accurate and effective treatment for inflammation and chronic oxidative stress. As a disease that affects multiple signalling pathways, the search for a drug with a broader spectrum of pharmacological action is of clinical interest. The fact that endocrine disruption (e.g hypogonadism) has been observed in TBI patients suggests that endogenous therapy with testosterone, or its more androgenic derivative, dihydrotestosterone (DHT), may attenuate, at least in part, the TBI-induced inflammation, but the underlying molecular mechanisms by which this occurs are still not completely clear.
AIMS AND METHODS
In this study, the main aim was to investigate proteins that may be related to the pathophysiological mechanism of TBI and also be pharmacological targets of DHT in order to explore a possible therapy with this androgen using network pharmacology.
RESULTS AND CONCLUSIONS
We identified 2.700 proteins related to TBI and 1.567 that are potentially molecular targets of DHT. Functional enrichment analysis showed that steroid (p-value: 2.1-22), lipid metabolism (p-value: 2.8-21) and apoptotic processes (p-value: 5.2-21) are mainly altered in TBI. Furthermore, being mitochondrion an organelle involved on these molecular processes we next identified that out of 32 mitochondrial-related proteins 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), peroxisome proliferator activated receptor gamma (PPGARG) and prohibitin are those found highly regulated in the network and potential targets of DHT in TBI. In conclusion, the identification of these cellular nodes may prove to be essential as targets of DHT for therapy against post-TBI inflammation.
Topics: Androgens; Brain Injuries, Traumatic; Dihydrotestosterone; Humans; Hydroxymethylglutaryl CoA Reductases; Inflammation; Mitochondrial Proteins; PPAR gamma; Prohibitins
PubMed: 35344815
DOI: 10.1016/j.intimp.2022.108721 -
Annals of Nuclear Medicine Jan 20177α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized...
OBJECTIVE
7α-Substituted androgen derivatives may have the potential to visualize androgen receptors with positron emission tomography. In the present study, we synthesized fluoropropyl derivatives of 7α-(3-[F]fluoropropyl)-testosterone ([F]7) and 7α-(3-[F]fluoropropyl)-dihydrotestosterone ([F]15), and characterized their in vitro binding, in vivo biodistribution, and performed blocking studies in mature androgen deprived male rats.
METHODS
We synthesized [F]7 and [F]15. In vitro binding to recombinant rat AR ligand binding domain protein was determined using a competitive radiometric ligand-binding assay with the high-affinity synthetic androgen [17α-methyl-H]-methyltrienolone ([H]R1881). In vivo biodistribution was performed in mature male rats treated with diethylstilbestrol (chemical castration). A blocking study was performed by co-administration of dihydrotestosterone (36 µg/animal).
RESULTS
7α-(3-Fluoropropyl)-testosterone (7) and 7α-(3-fluoropropyl)-dihydrotestosterone (15) showed competitive binding to recombinant rat AR ligand binding domain protein. The IC value of 15 (13.0 ± 3.3 nM) was higher than 7 (47.8 ± 10.0 nM). In contrast to the AR binding affinity, the ventral prostate uptake of [F]7 and [F]15 at 2 h post-injection was similar (0.07 % injected dose/g of tissue). A blocking study indicated that specific binding of [F]15 is observed in the ventral prostate. [F]7 and [F]15 showed moderate levels of bone uptake, which indicates moderate metabolic de-fluorination in rodents.
CONCLUSION
[F]15 is better than [F]7 in terms of radiochemical yield, in vitro binding affinity, prostate specific binding and stability against in vivo metabolic de-fluorination. However, the net uptake level of [F]15 in prostate might be insufficient for in vivo visualization. Although [F]7 and [F]15 improved in vivo stability against de-fluorination, other basic characterization data in rodents were not superior to the current standard tracer 16β-[F]fluoro-5α-dihydrotestosterone. It is also revealed that the shorter side chain length of 7α-[F]fluoromethyl-dihydrotestosterone is superior to the longer three carbon chain in [F]15, in terms of net prostate uptake and in vivo metabolic stability.
Topics: Androgens; Animals; Chemistry Techniques, Synthetic; Dihydrotestosterone; Male; Radiochemistry; Rats; Receptors, Androgen; Testosterone; Tissue Distribution
PubMed: 27680022
DOI: 10.1007/s12149-016-1130-7 -
The Veterinary Clinics of North... Mar 2010Over the last 10 years, trilostane, a competitive inhibitor of steroid synthesis, is being widely used for the treatment of canine hyperadrenocorticism. Trilostane...
Over the last 10 years, trilostane, a competitive inhibitor of steroid synthesis, is being widely used for the treatment of canine hyperadrenocorticism. Trilostane causes a significant but reversible decrease in cortisol production and a concomitant improvement in clinical signs in most dogs with this common condition. Side effects, though infrequent, can be serious: dogs treated with this drug require regular monitoring. This review summarizes current knowledge of the use of this drug with particular emphasis on its efficacy, safety, adverse reactions, and effects on endocrine parameters. Brief mention is made of its other uses in dogs and other species.
Topics: Acute-Phase Proteins; Adrenal Cortex Hormones; Adrenocortical Hyperfunction; Animals; Creatinine; Dihydrotestosterone; Dog Diseases; Dogs; Enzyme Inhibitors; Haptoglobins; Thyroid Hormones
PubMed: 20219488
DOI: 10.1016/j.cvsm.2009.10.008 -
Applied Radiation and Isotopes :... Sep 2015Noninvasive in vivo imaging of androgen receptor (AR) levels with positron emission tomography (PET) is becoming the primary tool in prostate cancer detection and...
Noninvasive in vivo imaging of androgen receptor (AR) levels with positron emission tomography (PET) is becoming the primary tool in prostate cancer detection and staging. Of the potential (18)F-labeled PET tracers, (18)F-FDHT has clinically shown to be of highest diagnostic value. We demonstrate the first automated synthesis of (18)F-FDHT by adapting the conventional manual synthesis onto the fully-automated ELIXYS radiosynthesizer. Clinically-relevant amounts of (18)F-FDHT were synthesized on ELIXYS in 90 min with decay-corrected radiochemical yield of 29±5% (n=7). The specific activity was 4.6 Ci/µmol (170 GBq/µmol) at end of formulation with a starting activity of 1.0 Ci (37 GBq). The formulated (18)F-FDHT yielded sufficient activity for multiple patient doses and passed all quality control tests required for routine clinical use.
Topics: Dihydrotestosterone; Drug Design; Equipment Design; Equipment Failure Analysis; Fluorine Radioisotopes; Isotope Labeling; Radionuclide Generators; Radiopharmaceuticals; Rheology; Robotics; Specimen Handling
PubMed: 26046518
DOI: 10.1016/j.apradiso.2015.05.010 -
The Journal of Clinical Investigation Sep 1970Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and...
Dihydrotestosterone in prostatic hypertrophy. II. The formation and content of dihydrotestosterone in the hypertrophic canine prostate and the effect of dihydrotestosterone on prostate growth in the dog.
Three types of studies have been performed in immature, mature, and hypertrophic prostate glands of the dog. First, the concentrations of testosterone and dihydrotestosterone have been measured in the three types of gland. Dihydrotestosterone was the predominant hormone recovered in all prostates studied and was present in approximately five times higher concentration in the hypertrophic as compared to the other types of dog prostate. Second, pharmacological doses of dihydrotestosterone were administered to castrated dogs for 9 months and resulted in a distinct acceleration of prostatic growth as compared to testosterone treatment. Third, the rates of formation and degradation of dihydrotestosterone were measured in normal and hypertrophic tissue and were found to be essentially the same. These observations suggest that dihydrotestosterone accumulation may be causally linked to the development of canine prostatic hypertrophy. However, the mechanism by which dihydrotestosterone accumulates in the prostate remains to be determined.
Topics: Aging; Animals; Biological Transport; Castration; Culture Techniques; DNA; Dihydrotestosterone; Dogs; Male; NADP; Organ Size; Oxidoreductases; Prostate; Prostatic Hyperplasia; RNA; Testosterone; Tritium
PubMed: 4194769
DOI: 10.1172/JCI106392 -
The Journal of Clinical Endocrinology... Mar 1987Dihydrotestosterone heptanoate (DHT-hp), a seven-carbon fatty acid ester of DHT, was synthesized, and its pharmacokinetics and effects on...
Dihydrotestosterone heptanoate (DHT-hp), a seven-carbon fatty acid ester of DHT, was synthesized, and its pharmacokinetics and effects on hypothalamic-pituitary-testicular function were determined in men and pubertal boys. Plasma DHT levels markedly increased 24 h after im injection of DHT-hp, reached their peak during the first week, and fell to baseline levels after 4-6 weeks. An estimated 43-55% of DHT-hp was converted to DHT 4-6 weeks after injection. Plasma testosterone, estradiol, LH, and FSH levels decreased by 4 days after DHT-hp injection, were lowest during the second week, and returned to baseline values after 4-6 weeks. The LH and FSH responses to GnRH were diminished by chronic administration of DHT-hp to pubertal boys at 3-week intervals for 15 weeks. The affinity of DHT-hp was 100 times less than the affinity of DHT for the human androgen receptor, and no affinity for the estrogen receptor in breast tissue could be demonstrated. Since DHT is a nonaromatizable androgen, and neither DHT nor DHT-hp binds readily to the estrogen receptor, suppression of LH and FSH secretion by this drug probably occurs via an androgen-dependent mechanism. Receptor binding and pharmacokinetic data indicate that unesterified DHT is the active principle. DHT-hp is a useful derivative of DHT, since prompt, predictable, and sustained rises in DHT occur after its administration.
Topics: Adult; Dihydrotestosterone; Estradiol; Gonadotropins, Pituitary; Humans; Hypothalamo-Hypophyseal System; Kinetics; Male; Middle Aged; Pituitary Hormone-Releasing Hormones; Testis; Testosterone
PubMed: 3546348
DOI: 10.1210/jcem-64-3-557 -
Physiology & Behavior Jul 1984The ability of androgens to stimulate masculine sexual behavior is thought to depend on the aromatization of such androgens to estrogens. In this scheme, reduced...
The ability of androgens to stimulate masculine sexual behavior is thought to depend on the aromatization of such androgens to estrogens. In this scheme, reduced androgens such as dihydrotestosterone (DHT) which cannot be aromatized, are thought to exert major peripheral but little or no central nervous system influences on the display of masculine sexual behavior. Further, an early report that DHT can induce lordosis, an estrogen (E) dependent behavior, led to a notion that DHT may effect behavior through metabolic intermediates such as 5 alpha-androstane-3 beta, 17 beta-diol (ADIOL) which then binds to estrogen receptors eliciting the E-dependent lordotic response. The present study reexamined and compared the relative effectiveness of a range of DHT dosages in stimulating a characteristic masculine (mounting) and feminine (lordosis) sexual behavior. Adult ovariectomized rats were randomly assigned to either 250 micrograms or 1 mg daily injections of DHT or DHTP. Other animals received OIL injections or crystalline DHT delivered by two different lengths (20 mm or 40 mm) of Silastic capsules. Animals were tested once weekly (for 5 weeks) for mounting behavior (20 minute test). Then animals were tested thrice (once weekly) for lordosis 4 hrs after the addition of 500 micrograms Progesterone (P). Finally, all females were tested for lordotic potential to respond to 10 micrograms EB plus P. 1 mg DHT or DHTP dosages and the 40 mm-Silastic condition significantly increased mounting behavior over that of lower dosages and OIL controls. A significant correlation existed between mounting frequency and circulating level of serum DHT. Treatment with DHTP was not different than DHT in eliciting mounting behavior.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Copulation; Dihydrotestosterone; Dose-Response Relationship, Drug; Female; Rats; Receptors, Androgen; Receptors, Estrogen; Sexual Behavior, Animal
PubMed: 6505051
DOI: 10.1016/0031-9384(84)90012-x