On the dimorphism and the pressure-temperature state diagram of gestodene, a steroidal progestogen contraceptive.

The pressure-temperature phase diagram of the dimorphism of the contraceptive drug gestodene is constructed using the temperature and enthalpy of fusion of form I (469.5K, 107Jg-1), and those of the endothermic transition from form II to form I (311K, 8.52Jg-1). At ordinary pressure, the sign of the enthalpy of this transition indicates that these polymorphs are enantiotropically related and that form II, whose melting temperature is calculated to be about 452K, is the stable form at room temperature. Considering the inequality in the specific volumes of the two polymorphs, it is shown that the two forms remain enantiotropically related on increasing pressure, because the I-II equilibrium and the melting equilibria I-L and II-L diverge as a consequence of the negative slope dP/dT of the solid-solid equilibrium. In addition, it is demonstrated that the heats of dissolution, inferred from solubility measurements, lead to virtually the same value of the heat of transition from II to I as for the differential scanning calorimetry measurements.

Fluorine-18 Labeled Fluorofuranylnorprogesterone ([18F]FFNP) and Dihydrotestosterone ([18F]FDHT) Prepared by "Fluorination on Sep-Pak" Method.

To further explore the scope of our recently developed "fluorination on Sep-Pak" method, we prepared two well-known positron emission tomography (PET) tracers 21-[18F]fluoro-16α,17α-[(R)-(1'-α-furylmethylidene)dioxy]-19-norpregn-4-ene-3,20-dione furanyl norprogesterone ([18F]FFNP) and 16ß-[18F]fluoro-5α-dihydrotestosterone ([18F]FDHT). Following the "fluorination on Sep-Pak" method, over 70% elution efficiency was observed with 3 mg of triflate precursor of [18F]FFNP. The overall yield of [18F]FFNP was 64-72% (decay corrected) in 40 min synthesis time with a molar activity of 37-81 GBq/µmol (1000-2200 Ci/mmol). Slightly lower elution efficiency (~55%) was observed with the triflate precursor of [18F]FDHT. Fluorine-18 labeling, reduction, and deprotection to prepare [18F]FDHT were performed on Sep-Pak cartridges (PS-HCO3 and Sep-Pak plus C-18). The overall yield of [18F]FDHT was 25-32% (decay corrected) in 70 min. The molar activity determined by using mass spectrometry was 63-148 GBq/µmol (1700-4000 Ci/mmol). Applying this quantitative measure of molar activity to in vitro assays [18F]FDHT exhibited high-affinity binding to androgen receptors (Kd~2.5 nM) providing biological validation of this method.

Removal of synthetic sex hormones by hydrothermal carbonization.

One of the most prominent fields of environmental chemistry is the study and the removal of micro-pollutants from aqueous matrices. Analytical techniques for their identification and quantification are becoming more sensitive and comprehensive and, as a result, an increasing number of drugs have been detected in environmental samples. However, the literature shows that conventional treatments for drinking water and wastewater are not sufficient for remove these compounds. This study aims to check whether the process of hydrothermal carbonization (CHT) is effective in removing the synthetic sex hormones: ethinyl estradiol, gestodene and cyproterone acetate from aqueous samples. The system used in CHT basically consists of a pressurized reactor made of stainless steel and solutions of compounds of interest, both individual and mixed, with a concentration of 1.0 µg.L-1 and a pH range of 2.0 to 3.0. The maximum surface temperature in the reactor was about 180 °C, the internal pressure was 20 bar with 90 minutes for the reaction. Four experiments were conducted, one for each hormone and one with the three hormones together. In individual tests removal of the compounds was found to be 99.8% for ethinyl estradiol, 99.3% for gestodene and 100% for cyproterone acetate. For a mixture of the hormones treated under the same conditions, the mean values of CHT-removal of Ethinylestradiol, Gestodene and Cyproterone Acetate were 99.60%, 96.80% and 68.90%, respectively. The impact of the matrix effect may have affected the efficiency of the hormone removal process by CHT.

Comparison of [17(20)E]-21-Norpregnene oxazolinyl and benzoxazolyl derivatives as inhibitors of CYP17A1 activity and prostate carcinoma cells growth.

Four new 4,5-dihydro-1,3-oxazole, and four new benzo-[d]-oxazole derivatives of [17(20)E]-21-norpregnene, differing in the structure of steroid moiety, were synthesized and evaluated for their potency to inhibit 17α-hydroxylase/17,20-lyase (CYP17A1) activity. Among new compounds, the only oxazolinyl derivative comprising 5-oxo-4,5-seco-3-yn- moiety potently inhibited CYP17A1. Binding modes of the oxazolinyl derivatives of [17(20)E]-21-norpregnene were analyzed by molecular dynamics simulations, and model of alternate, water-bridged type II interaction was proposed for these compounds. Eight new compounds, together with two CYP17A1-inhibiting oxazolinyl derivatives synthesized earlier, abiraterone and galeterone were evaluated for their potency to inhibit prostate carcinoma PC-3 and LNCaP cells growth. Oxazolinyl and benzoxazolyl derivatives comprising 3ß-hydroxy-5-ene moieties potently inhibited prostate carcinoma cell growth; inhibitory potencies of 3-oxo-4-en- and 5-oxo-4,5-seco-3-yn- derivatives were significantly lower.

The synthetic progestin, gestodene, affects functional biomarkers in neonatal rat osteoblasts through an estrogen receptor-related mechanism of action.

BACKGROUND: Clinical studies have shown that gestodene (GDN), a potent third-generation synthetic progestin, affects bone resorption. However, its mode of action in bone cells is not fully understood. The aim of this study was to establish whether GDN affects bone directly or through its bioconversion to other metabolites with different biological activities. METHODS: In this study, we investigated the effects of GDN and its A-ring reduced metabolites on proliferation, differentiation, and mineralization of calvarial osteoblasts isolated from neonatal rat and their capacity to displace [3H]-E2 at ER binding sites. RESULTS: In contrast to progesterone, gestodene did exert significant effects on osteoblast activities. The most striking finding was the observation that the A-ring reduced derivatives 3ß,5α-tetrahydro-GDN and 3α,5α-tetrahydro-GDN, though to a lesser extent, had greater stimulatory effects on the osteoblast activity than those observed with GDN. The effects on osteoblast proliferation and differentiation induced by GDN-reduced derivatives were abolished by the antiestrogen ICI 182780, consistent with their binding affinities for the estrogen receptor. In addition, the presence of a 5α-reductase inhibitor or inhibitors of aldo-keto hydroxysteroid dehydrogenases abolished the GDN-induced enhancement of osteoblast differentiation. These results indicated that GDN is metabolized to the A-ring reduced metabolites with estrogen-like activities and through this mechanism, GDN may affect the osteoblast activity. CONCLUSION: Together, the data suggest that synthetic progestins derived from 19-nortestosterone such as GDN, have beneficial effects on bone due to their biotransformation into metabolites with intrinsic estrogenic activity.

Effects of Tibolone on the Central Nervous System: Clinical and Experimental Approaches.

Hormone replacement therapy (HRT) increases the risk of endometrial and breast cancer. A strategy to reduce this incidence is the use of tibolone (TIB). The aim of this paper was to address the effects of TIB on the central nervous system (CNS). For the present review, MEDLINE (via PubMed), LILACS (via BIREME), Ovid Global Health, SCOPUS, Scielo, and PsycINFO (ProQuest Research Library) electronic databases were searched for the results of controlled clinical trials on peri- and postmenopausal women published from 1990 to September 2016. Also, this paper reviews experimental studies performed to analyze neuroprotective effects, cognitive deficits, neuroplasticity, oxidative stress, and stroke using TIB. Although there are few studies on the effect of this hormone in the CNS, it has been reported that TIB decreases lipid peroxidation levels and improves memory and learning. TIB has important neuroprotective effects that could prevent the risk of neurodegenerative diseases in postmenopausal women as well as the benefits of HRT in counteracting hot flashes, improving mood, and libido. Some reports have found that TIB delays cognitive impairment in various models of neuronal damage. It also modifies brain plasticity since it acts as an endocrine modulator regulating neurotransmitters, Tau phosphorylation, and decreasing neuronal death. Finally, its antioxidant effects have also been reported in different animal models.

Degradation of gestodene (GES)-17α-ethinylestradiol (EE2) mixture by electrochemical oxidation.

Evidence of the negative effects of several pharmaceutical molecules, such as hormones and steroids, on the environment can be observed throughout the world. This paper presents the results of the anodic oxidation of the mixture of gestodene steroid hormones and 17 α-ethinylestradiol present in aqueous medium. The tests were conducted in an undivided cell containing a working volume of 50 mL, using a Na2SO4 solution as support electrolyte and boron-doped diamond electrodes. The experiments were adjusted to the structure of a 33 factorial design. The evaluated factors were: support electrolyte concentration (0.02, 0.05, and 0.10 M), pH of the reaction media (2, 3, and 4), and current density (16, 32, and 48 mA cm-2). Under the optimum conditions (0.02 M Na2SO4, pH 4, and current density of 32 mA cm-2), the degradation of at least 93% of the initial concentration of gestodene and 17α-ethinylestradiol was reached in a reaction time of 5 and 10 min, respectively. The complete degradation of both molecules required 15 min of reaction. Under these conditions, the degradation profile of the pharmaceutical mixture as each one of the active ingredients, followed a pseudo-first order kinetic behavior (kmix = 0.0321, kGES = 0.4206, and kEE2 = 0.3209 min-1).

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring.

Preparation and in vitro/in vivo evaluation of gestodene (GEST) intravaginal ring (IVR) formulations which can release a constant dose of GEST during 3 weeks were investigated. In present study a reservoir gestodene intravaginal ring, including a gestodene silicone elastomer core and the non-active silicone layer, was reported, which was manufactured by reaction injection moulding at 80°C for 20 min. The raw materials compatibility experiments showed that the silicone elastomer core carrier wouldn't interact with drugs. In vitro release samples were determined by HPLC and the experiment was performed under sink conditions. The equation of cumulative release verse time was Y=64.76χ+5.44 (r=0.9998), performing zero-order release at about the target dose of 60 µg/day over 21 days. Drug release increased with temperature elevating from 45 to 55°C, which could be attributed to optimizing the prescription. In addition, the pharmacokinetic and safety studies of gestodene intravaginal ring were evaluated in female New Zealand White rabbits. The GEST in plasma was analyzed by LC-MS/MS and the results proved that the correlation between in vitro and in vivo was relatively well.

The impact of testosterone, tibolone and black cohosh on purified mammary and placental 17ß-hydroxysteroid dehydrogenase type 1.

CONTEXT: Mammary and placental 17ß-hydroxysteroid dehydrogenase type 1 (17ßHSD1). OBJECTIVE: To assess the impact of testosterone, tibolone, and black cohosh on purified mammary and placental 17ßHSD1. MATERIALS AND METHODS: 17ßHSD1 was purified from human mammary gland and placenta by column chromatography, its activity was monitored by a radioactive activity assay, and the degree of purification was determined by gel electrophoresis. Photometric cofactor transformation analysis was performed to assess 17ßHSD1 activity without or in presence of testosterone, tibolone and black cohosh. RESULTS: 17ßHSD1 from both sources displayed a comparable basal activity. Testosterone and tibolone metabolites inhibited purified mammary and placental 17ßHSD1 activity to a different extent, whereas black cohosh had no impact. DISCUSSION: Studies on purified enzymes reveal the individual action of drugs on local regulatory mechanisms thus helping to develop more targeted therapeutic intervention. CONCLUSION: Testosterone, tibolone and black cohosh display a beneficial effect on local mammary estrogen metabolism by not affecting or decreasing local estradiol exposure.

[Preparation and release mechanism of gestodene reservoir-type intravaginal rings].

This study taking gestodene (GEST) as a model, investigated the factors affecting reservoir-type intravaginal ring (IVR)'s drug release. This paper reported a gestodene intravaginal ring of reservoir design, comprising a gestodene silicone elastomer core encased in a non-medicated silicone sheath, separately manufactured by reaction injection moulding at 80 degrees C and heating vulcanization at 130 degrees C is reported. The test investigated the factors affecting drug release through a single variable method, taking the drug release rates of 21 days as standards. When changing the thickness of the controlling sheath outside, the ratio of the first day of drug release and mean daily release (MDR), named the relatively burst effect, is closing to 1 with the thickness of controlling sheath increasing, while the 1.25 mm sheath corresponding to 1.04 controlled the burst release effectively; a positive correlation (r = 0.992 2) existed between the average drug release (Q/t) and drug loading (A) within a certain range. The C6-165 controlling sheath with high solubility of GEST is easier to achieve controlled release of the drug; GEST crystalline power is more effective to implement controlled release of drugs among difficent states of the drug. A 1/4 fractional segment core gives a relatively burst effect of 1.76, while the 1/1 and 1/2 are 1.93 and 1.87 separately, at the same drug loading, concluding that use of a fractional segment core would allow development of a suitable GEST reservoir IVR. In summary, GEST reservoir-type IVR could be adjusted by the thickness of controlling sheath, the loading of drug, the material properties of controlling sheath, the dispersion state of drug, the additive composition and structure of intravaginal ring, to control the drug release behavior and achieve the desired drug release rate.

Molecular and structural basis of androgen receptor responses to dihydrotestosterone, medroxyprogesterone acetate and Δ(4)-tibolone.

Medroxyprogesterone acetate (MPA) has widely been used in hormone replacement therapy (HRT), and is associated with an increased risk of breast cancer, possibly due to disruption of androgen receptor (AR) signaling. In contrast, the synthetic HRT Tibolone does not increase breast density, and is rapidly metabolized to estrogenic 3α-OH-tibolone and 3ß-OH-tibolone, and a delta-4 isomer (Δ(4)-TIB) that has both androgenic and progestagenic properties. Here, we show that 5α-dihydrotestosterone (DHT) and Δ(4)-TIB, but not MPA, stabilize AR protein levels, initiate specific AR intramolecular interactions critical for AR transcriptional regulation, and increase proliferation of AR positive MDA-MB-453 breast cancer cells. Structural modeling and molecular dynamic simulation indicate that Δ(4)-TIB induces a more stable AR structure than does DHT, and MPA a less stable one. Microarray expression analyses confirms that the molecular actions of Δ(4)-TIB more closely resembles DHT in breast cancer cells than either ligand does to MPA.

Biotransformation of 17α-ethynyl substituted steroidal drugs with microbial and plant cell cultures: a review.

Structural modification of steroids through whole-cell biocatalysis is an invaluable procedure for the production of active pharmaceutical ingredients (APIs) and key intermediates. Modifications could be carried out with regio- and stereospecificity at positions hardly available for chemical agents. Much attention has been focused recently on the biotransformation of 17α-ethynyl substituted steroidal drugs using fungi, bacteria and plant cell cultures in order to obtained novel biologically active compounds with diverse structure features. Present article includes studies on biotransformation on 17α-ethynyl substituted steroidal drugs using microorganisms and plant cell cultures. Various experimental and structural elucidation methods used in biotransformational processes are also highlighted.

Development of PVP/PEG mixtures as appropriate carriers for the preparation of drug solid dispersions by melt mixing technique and optimization of dissolution using artificial neural networks.

The effect of plasticizer's (PEG) molecular weight (MW) on PVP based solid dispersions (SDs), prepared by melt mixing, was evaluated in the present study using Tibolone as a poorly water soluble model drug. PEGs with MW of 400, 600, and 2000 g/mol were tested, and the effect of drug content, time and temperature of melt mixing on the physical state of Tibolone, and the dissolution characteristics from SDs was investigated. PVP blends with PEG400 and PEG600 were completely miscible, while blends were heterogeneous. Furthermore, a single Tg recorded in all samples, indicating that Tibolone was dispersed in a molecular lever (or in the form of nanodispersions), varied with varying PEG's molecular weight, melt mixing temperature, and drug content, while FTIR analysis indicated significant interactions between Tibolone and PVP/PEG matrices. All prepared solid dispersion showed long-term physical stability (18 months in room temperature). The extent of interaction between mixture components was verified using Fox and Gordon-Taylor equations. Artificial neural networks, used to correlate the studied factors with selected dissolution characteristics, showed good prediction ability.

Alpha-glucosidase and tyrosinase inhibitors from fungal hydroxylation of tibolone and hydroxytibolones.

Sixteen new and one known metabolites 4-20 were obtained by incubation of tibolone (1) and hydroxytibolones (2 and 3) with various fungi. Their structures were elucidated by means of a homo and heteronuclear 2D NMR and by HREI-MS techniques. The relative stereochemistry was deduced by 2D NOESY experiment. Metabolites of tibolone (1) exhibited significant inhibitory activities against alpha-glucosidase and tyrosinase enzymes. Hydroxylations at C-6, C-10, C-11, C-15 positions and alpha,beta-unsaturation at C-1/C-2, C-4/C-5 showed potent inhibitory activities against these enzymes.

Dissolution rate enhancement of the poorly water-soluble drug Tibolone using PVP, SiO2, and their nanocomposites as appropriate drug carriers.

BACKGROUND: Creation of immediate release formulations for the poorly water-soluble drug Tibolone through the use of solid dispersions (SDs). AIM: SD systems of Tibolone (Tibo) with poly(vinylpyrrolidone) (PVP), fumed SiO(2) nanoparticles, and their corresponding ternary systems (PVP/SiO(2)/Tibo) were prepared and studied in order to produce formulations with enhanced drug dissolution rates. METHOD: The prepared SDs were characterized by the use of differential scanning calorimetry and wide-angle X-ray diffractometry techniques. Also dissolution experiments were performed. RESULTS: From the results it was concluded that PVP as well as SiO(2) can be used as appropriate carriers for the amorphization of Tibo, even when the drug is used at high concentrations (20-30%, w/w). This is due to the evolved interactions taking place between the drug and the used carriers, as was verified by Fourier transform infrared spectroscopy. At higher concentrations the drug was recrystallized. Similar are the observations on the ternary PVP/SiO(2)/Tibo SDs. The dissolution profiles of the drug in PVP/Tibo and SiO(2)/Tibo SDs are directly dependent on the physical state of the drug. Immediately release rates are observed in SD with low drug concentrations, in which Tibo was in amorphous state. However, these release profiles are drastically changed in the ternary PVP/SiO(2)/Tibo SDs. An immediate release profile is observed for low drug concentrations and an almost sustained release as the concentration of Tibo increases. This is due to the weak interactions that take place between PVP and SiO(2), which result in alterations of the characteristics of the carrier (PVP/SiO(2) nanocomposites). CONCLUSIONS: Immediate release formulation was created for Tibolone as well as new nanocomposite matrices of PVP/SiO((2)), which drastically change the release profile of the drug to a sustained delivery.

Novel self-assembled core-shell nanoparticles based on crystalline amorphous moieties of aliphatic copolyesters for efficient controlled drug release.

Poly(propylene succinate-co-caprolactone) copolymers [P(PSu-co-CL)] with different epsilon-caprolactone (epsilon-CL) to propylene succcinate (PSu) monomer ratios were synthesized using ring opening polymerization. These polymers consisted of crystalline poly(epsilon-caprolactone) (PCL) and amorphous poly(propylene succinate) (PPSu) moieties, as shown by WAXD. In vitro biocompatibility studies showed that these copolyesters are biocompatible. Drug-loaded nanoparticles, using tibolone as a model drug, were prepared by the solvent evaporation method. Nanoparticle size ranged between 150 and 190 nm and decreased with increasing propylene succinate (PSu) ratio in the copolymers. Nanoparticle yield, encapsulation efficiency, and drug loading increased with increasing PSu ratio. Scanning Electron Microscopy (SEM) revealed that the prepared nanoparticles had a spherical shape and Transmission Electron Microscopy (TEM) showed that they were self-assembled in core-shell structures. Amorphous PPSu and crystalline PCL comprised the core and shell, respectively. The drug is mainly located into the amorphous core in the form of nanocrystals. Drug release studies showed that complete release of the drug from the nanoparticles occurs over a period of 50 h. The release rate is greatly influenced by the copolymer composition, nanoparticle size, and encapsulation efficiency. Among the main advantages of the nanoparticles produced in this study is the absence of burst effect during drug release.

Tibolone vaginal versus per os administration in the management of post-menopausal symptoms.

UNLABELLED: Tibolone is a selective tissue estrogenic activity regulator effective in the management of climacteric symptoms, without stimulating endometrial and breast tissue proliferation. It is a well-tolerated treatment regimen with minor adverse effects. The purpose of the current trial was to investigate the efficacy of tibolone administration per os versus per vaginal, concerning the treatment of climacteric symptoms. MATERIAL AND METHOD: A total of 64 post-menopausal healthy women aged 44-55 years (mean 52,5) were enrolled in the study. The patients were divided into three groups: Group A with 24 patients receiving per os Tibolone 2.5 mg x 1 daily for 6 months, Group B with 21 patients receiving vaginally Tibolone 2.5 mg x 1 for 6 months and Group C--with 19 patients receiving only hygienodietetics advices and psychological support for 6 months. All subjects underwent a physical examination, including a transvaginal ultrasonography for the measurement of endometrial thickness and a mammography for the assessment of breast density. RESULTS: In Group A and B, climacteric symptoms were similarly reduced with non significant differences between groups: 79% (19 patients) vs 76% (16 patients) reduction for hot flushes and 83% (20 patients) vs 76% (16 patients) for sweating episodes respectively (p > 0.05). Reduction of hot flushes and sweating episodes was observed in only 2 of 19 patients (10.5%) in group C (p < 0.01). Vaginal route had better results on vaginal dryness-dyspareunia in group B (in 14 patients taken tibolone orally-58% vs 16 patients taken tibolone vaginally-76%). No statistically significant difference was found related to urine symptoms between A and B groups. Tibolone by vaginal route did not cause any severe side effects (apart of a slight discharge) and it was equally (or better) tolerated than oral route. No significant alterations in breast density and BIRADS and no increase in endometrial thickness were observed in all study groups. CONCLUSION: Tibolone is effective in relieving climacteric symptoms indifferent from applications-modus: orally or vaginally. However, further and larger studies are required to confirm results.

Tibolone rapidly attenuates the GABAB response in hypothalamic neurones.

Tibolone is primarily used for the treatment of climacteric symptoms. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3beta-hydroxy (OH)-tibolone, which have oestrogenic effects, and the Delta 4-isomer (Delta 4-tibolone), which has progestogenic and androgenic effects. Because tibolone is effective in treating climacteric symptoms, the effects on the brain may be explained by the oestrogenic activity of tibolone. Using whole-cell patch clamp recording, we found previously that 17beta-oestradiol (E(2)) rapidly altered gamma-aminobutyric acid (GABA) neurotransmission in hypothalamic neurones through a membrane oestrogen receptor (mER). E(2) reduced the potency of the GABA(B) receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K(+) (GIRK) channels in hypothalamic neurones. Therefore, we hypothesised that tibolone may have some rapid effects through the mER and sought to elucidate the signalling pathway of tibolone's action using selective inhibitors and whole cell recording in ovariectomised female guinea pigs and mice. A sub-population of neurones was identified post hoc as pro-opiomelanocortin (POMC) neurones by immunocytochemical staining. Similar to E(2), we have found that tibolone and its active metabolite 3 beta OH-tibolone rapidly reduced the potency of the GABA(B) receptor agonist baclofen to activate GIRK channels in POMC neurones. The effects were blocked by the ER antagonist ICI 182 780. Other metabolites of tibolone (3 alpha OH-tibolone and Delta 4-tibolone) had no effect. Furthermore, tibolone (and 3 beta OH-tibolone) was fully efficacious in ER alpha knockout (KO) and ER beta KO mice to attenuate GABA(B) responses. The effects of tibolone were blocked by phospholipase C inhibitor U73122. However, in contrast to E(2), the effects of tibolone were not blocked by protein kinase C inhibitors or protein kinase A inhibitors. It appears that tibolone (and 3 beta OH-tibolone) activates phospholipase C leading to phosphatidylinositol bisphosphate metabolism and direct alteration of GIRK channel function. Therefore, tibolone may enhance synaptic efficacy through the G(q) signalling pathways of mER in brain circuits that are critical for maintaining homeostatic functions.

Structure-activity relationships of synthetic progestins in a yeast-based in vitro androgen bioassay.

The recent identification of tetrahydrogestrinone (THG), a non-marketed designer androgen used for sports doping but previously undetectable by established mass spectrometry-based urine drug screens, and its production by a facile chemical modification of gestrinone has raised concerns about the risks of developing designer androgens from numerous marketed progestins. We therefore have used yeast-based in vitro androgen and progesterone bioassays to conduct a structure-activity study assessing the intrinsic androgenic potential of commercially available progestins and their derivatives, to identify those compounds or structures with the highest risk of forming a basis for such misapplication. Progestins had a wide range of androgenic bioactivity that was not reliably predicted for individual steroids by their progestin bioactivity. 17alpha-Hydroxyprogesterone and 19-norprogesterone derivatives with their bulky 17beta-substituents were strong progestins but generally weak androgens. 17alpha-Ethynylated derivatives of testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone such as gestrinone, ethisterone, norethisterone and norgestrel had the most significant intrinsic androgenicity of all the commercially marketed progestins. Facile chemical modification of the 17alpha-ethynyl group of each of these progestins produces 17alpha-methyl, ethyl and allyl derivatives, including THG and norbolethone, which further enhanced androgenic bioactivity. Thus by using the rapid and sensitive yeast bioassay we have screened a comprehensive set of progestins and associated structures and identified the ethynylated testosterone, 19-nortestosterone and 18-methyl-19-nortestosterone derivatives as possessing the highest risk for abuse and potential for conversion to still more potent androgens. By contrast, modern progestins such as progesterone, 17alpha-hydroxyprogesterone and 19-norprogesterone derivatives had minimal androgenic bioactivity and pose low risk.