A progestin isn't a progestin: dienogest for endometriosis as a blueprint for future research - Review as a contribution for discussion.

The different etiopathogenetic mechanisms and the diversity of clinical features of endometriosis has not yet allowed to identify a causal pharmacological monotherapy satisfying the unresolved medical needs in this important female disease. Therefore, despite the search for new therapeutic principles for the indication, the strategy of gradual optimization of established therapeutic principles should not be disregarded.In the case of progestins, the fact that each compound has its own, specific profile may allow to study the therapeutic relevance of the various signal cascades influenced by their receptors.Using the example of the progestin dienogest, the different genomic and non-genomic mechanisms of action are discussed. It is pharmacodynamic profile is unique compared to other progestins.In light of the emerging multitude of pathomechanisms in endometriosis, a monotherapy may not be possible, and then the search for broad spectrum compounds or combination therapies with dual or multiple mode of action in a clinically relevant dose range might be considered. The progestogenic action may greatly benefit from, by way of example, additional anti-inflammatory and/or anti-fibrotic and/or pro-apoptotic activities. Such a strategy could lead to new drug classes.

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.

Transient analysis of drug delivery from a toroidal membrane: Applications for medicated vaginal rings.

A mathematical construct is proposed to analyze drug released from matrix-type vaginal rings. This work is intended to support experimental studies and promote the fabrication of these devices. The transport of a dissolved drug through a toroidal membrane was predicted using diffusion equations and their solutions. This dynamic framework led to the estimation of the time elapsed before releasing 98% of the ethynodiol diacetate from the polymer. Closed-form expressions, easily adaptable to spreadsheet implementation, were developed to simulate the controlled delivery of levonorgestrel initially dispersed in a silicone vaginal ring. As the loading increased, a greater amount of medication was delivered. However, the fractional release decreased from 32.6% to 23.1% when the dosage changed from 4.137 g/cm3 to 8.274 mg/cm3. The expressions were further simplified for thin rings.

Bone health in estrogen-free contraception.

Estrogens and progestogens influence the bone. The major physiological effect of estrogen is the inhibition of bone resorption whereas progestogens exert activity through binding to specific progesterone receptors. New estrogen-free contraceptive and its possible implication on bone turnover are discussed in this review. Insufficient bone acquisition during development and/or accelerated bone loss after attainment of peak bone mass (PBM) are 2 processes that may predispose to fragility fractures in later life. The relative importance of bone acquisition during growth versus bone loss during adulthood for fracture risk has been explored by examining the variability of areal bone mineral density (BMD) (aBMD) values in relation to age. Bone mass acquired at the end of the growth period appears to be more important than bone loss occurring during adult life. The major physiological effect of estrogen is the inhibition of bone resorption. When estrogen transcription possesses binds to the receptors, various genes are activated, and a variety modified. Interleukin 6 (IL-6) stimulates bone resorption, and estrogen blocks osteoblast synthesis of IL-6. Estrogen may also antagonize the IL-6 receptors. Additionally, estrogen inhibits bone resorption by inducing small but cumulative changes in multiple estrogen-dependent regulatory factors including TNF-α and the OPG/RANKL/RANK system. Review on existing data including information about new estrogen-free contraceptives. All progestins exert activity through binding to specific progesterone receptors; hereby, three different groups of progestins exist: pregnanes, gonanes, and estranges. Progestins also comprise specific glucocorticoid, androgen, or mineralocorticoid receptor interactions. Anabolic action of a progestogen may be affected via androgenic, anti-androgenic, or synadrogenic activity. The C 19 nortestosterone class of progestogens is known to bind with more affinity to androgen receptors than the C21 progestins. This article reviews the effect of estrogens and progestogens on bone and presents new data of the currently approved drospirenone-only pill. The use of progestin-only contraceptives leading to an estradiol level between 30 and 50 pg/ml does not seem to lead to an accelerate bone loss.

Hormonal contraceptives: pharmacology tailored to women's health.

BACKGROUND: In recent years, several new oral contraceptives have become available. In some ways, they represent an evolution in terms of individualization and compliance on the part of women. The new formulations make it increasingly possible to prescribe a specific hormonal contraceptive on an individual basis. METHODS: A systematic literature search of PubMed was performed using the following combination of terms: 'oral contraceptives', 'estroprogestins' and 'combined oral contraceptive'. Only English-language papers published between January 2000 and July 2014 were included in our analysis. The present review analyzes all aspects of the choice of oral contraceptives in the different phases of a woman's life in detail. RESULTS: Regarding the estrogen component, lowering the dose of ethinylestradiol (EE) helped reduce associated side effects. Natural estradiol is now available and represents a valid alternative to EE. And regarding progestins, the dose has changed over time, as well as the endocrine and metabolic characteristics. These are the fruit of much research into improvement of old products (19-nor-progesterone-derived progestins) with androgenic effects and testing of new molecules with improved metabolic neutrality in terms of insulin sensitivity and lipid parameters. New progestins were a genuine turning point because they greatly reduced major side effects, such as water retention, and their anti-androgenic properties made them indicated for all forms of hyperandrogenism associated with acne and mild hirsutism. The associations of estradiol/dienogest and estradiol/nomegestrol acetate are the most suitable contraceptives for women with abundant menstrual bleeding and can increase the number of potential users of hormonal contraception. CONCLUSION: Progress in the provision of new oral contraceptives has improved the risk/benefit ratio, by increasing benefits and reducing risks. The present challenge is to tailor contraceptives to individual needs in terms of efficacy and protection of reproductive health.

Does the contraceptive pill influence peak nasal inspiratory flow values?

BACKGROUND: Early oral contraceptive pills (OCP) had higher estrogen levels and have been thought to cause nasal obstruction in about 40% of women users. A recent small study conducted on women taking OCP showed no significant effects on nasal patency. The aim of the present study was to analyse in a large number of volunteers if Peak Nasal Inspiratory Flow (PNIF) values could be influenced by modern OCP. METHODOLOGY: PNIF was measured in 257 women (from 14 to 51 years old), divided into two groups: the study group composed of 109 healthy women taking modern OCP; the control group composed of 148 healthy women who did not take OCP. 9 women in the study group were excluded because of allergic disease, 248 females were finally considered. Data were statistically analysed and figures/tables were produced to see the effect of OCP on PNIF. RESULTS: The present study could not show any effect of OCP on nasal function. Moreover, while height influenced PNIF in both groups, age was not statistically significant. CONCLUSION: From the present study, it seems that OCP could have no effects on nasal airflow, confirming that modern OCP with lower estrogen doses should not affect nasal mucosa or nasal patency.

[Oral contraceptive pill and thrombotic risk: epidemiological studies]. / Pillola e rischio trombotico: gli studi wpidemiogici.

The venous thromboembolism (VTE) is a rare event during childbearing age and during the assumption of combined oral contraceptive. The absolute risk of VTE in users of combined oral contraceptives is 20-30 per 100000 women years. A number of case-control studies published in recent years have shown an apparent increase in the risk of VTE among users of oral contraceptives (OCs) containing desogestrel, gestodene, drospirenone and cyproterone, relative to the use of levonorgestrel. The data derived from these recent studies is of borderline statistical significance because any important factors are not considered to evaluate the real correlation between the assumption of OCs and risk of venous thromboembolism. Among the factors that should be considered, there are: EE dose, duration of use, coexistance of other risk factors of venous thromboembolism (age, BMI, familiarity, surgical interventions) and other prescription bias. The lack of these factors is likely to contribute to the increased risk of venous thromboembolism observed in users of third-generation OCs when compared to that in users of second-generation OCs. To date, because of the inadequacy of epidemiological studies, the data about the correlation between OCs and TVE, are not conclusive and it will be necessary to carry out other studies to clarify this debating point, definitively.

Catalytic oxidative degradation of 17α-ethinylestradiol by FeIII-TAML/H2O2: estrogenicities of the products of partial, and extensive oxidation.

The oxidative degradation of the oral contraceptive 17α-ethinylestradiol (EE(2)) in water by a new advanced catalytic oxidation process was investigated. The oxidant employed was hydrogen peroxide in aqueous solution and the catalyst was the iron tetra-amido macrocyclic ligand (Fe(III)-TAML) complex that has been designated Na[Fe(H(2)O)(B*)] (Fe(III)-B*). EE(2) (10 µM) was oxidised rapidly by the Fe(III)-B*/H(2)O(2) (5 nM/4 mM) catalytic oxidation system at 25 °C, and for reactions at pH 8.40-11.00, no unchanged EE2 was detected in the reaction mixtures after 60 min. No oxidation of EE(2) was detected in blank reactions using either H(2)O(2) or Fe(III)-B* alone. The maximum rate of EE(2) loss occurred at pH 10.21. At this pH the half-life of EE(2) was 2.1 min and the oxidised products showed around 30% estrogenicity removal, as determined by the yeast estrogen screen (YES) bioassay. At pH 11.00, partial oxidation of EE(2) by Fe(III)-B*/H(2)O(2) (5 nM/4 mM) was studied (half-life of EE(2) was 14.5 min) and in this case the initial intermediates formed were a mixture of the epimers 17α-ethynyl-1,4-estradiene-10α,17ß-diol-3-one (1a) and 17α-ethynyl-1,4-estradiene-10ß,17ß-diol-3-one (1b) (identified by LC-ToF-MS and (1)H NMR spectroscopy). Significantly, this product mixture displayed a slightly higher estrogenicity than EE(2) itself, as determined by the YES bioassay. Upon the addition of further aliquots of Fe(III)-B* (to give a Fe(III)-B* concentration of 500 nM) and H(2)O(2) (to bring the concentration up to 4 mM assuming the final concentration had dropped to zero) to this reaction mixture the amounts of 1a and 1b slowly decreased to zero over a 60 min period as they were oxidised to unidentified products that showed no estrogenicity. Thus, partial oxidation of EE(2) gave products that have slightly increased estrogenicity, whereas more extensive oxidation by the advanced catalytic oxidation system completely removed all estrogenicity. These results underscore the importance of controlling the level of oxidation during the removal of EE(2) from water by oxidative processes.

Pathophysiology of premenstrual syndrome and premenstrual dysphoric disorder.

Premenstrual syndrome (PMS) and premenstrual dysphoric disorder are triggered by hormonal events ensuing after ovulation. The symptoms can begin in the early, mid or late luteal phase and are not associated with defined concentrations of any specific gonadal or non-gonadal hormone. Although evidence for a hormonal abnormality has not been established, the symptoms of the premenstrual disorders are related to the production of progesterone by the ovary. The two best-studied and relevant neurotransmitter systems implicated in the genesis of the symptoms are the GABArgic and the serotonergic systems. Metabolites of progesterone formed by the corpus luteum of the ovary and in the brain bind to a neurosteroid-binding site on the membrane of the gamma-aminobutyric acid (GABA) receptor, changing its configuration, rendering it resistant to further activation and finally decreasing central GABA-mediated inhibition. By a similar mechanism, the progestogens in some hormonal contraceptives are also thought to adversely affect the GABAergic system. The lowering of serotonin can give rise to PMS-like symptoms and serotonergic functioning seems to be deficient by some methods of estimating serotonergic activity in the brain; agents that augment serotonin are efficacious and are as effective even if administered only in the luteal phase. However, similar to the affective disorders, PMS is ultimately not likely to be related to the dysregulation of individual neurotransmitters. Brain imaging studies have begun to shed light on the complex brain circuitry underlying affect and behaviour and may help to explicate the intricate neurophysiological foundation of the syndrome.

A hormonal contraceptive for men: how close are we?

Novel contraceptive methods for men are still not available, and the opinions about their need among experts and lay public are polarized between enthusiasm and scepticism. Of the different strategies, hormonal methods aimed at suppression of spermatogenesis have been most extensively studies, are most promising, and are the only approach with the potential of breakthrough in the near future. Their principle is to block pituitary gonadotropin secretion, which will eliminate the endocrine stimulus for testicular androgen production, thereby eliminating its support for spermatogenesis. Testosterone alone or in combination with progestin is the most promising lead. However, many obstacles still have to be overcome before a practical and acceptable method is available. The reasons for the slow progress are partly biological and partly practical and economical. It is difficult to design a method that would be effective in most men, have no side effects and be reversible, economical, and acceptable by all cultures. Unfortunately, the pharmaceutical industry is currently not participating in the development work, and the research in the field is suffering from lack of political and financial support. Ironically, with relative modest additional effort a hormonal contraceptive method for men would be available. We review in this chapter the main principles of hormonal male contraception, the results of the latest clinical trials and shed light on some future perspectives in the field.

Determination of steroid estrogens in wastewater treatment plant of a controceptives producing factory.

Steroid estrogens such as estrone (E1), 17beta-estradiol (E2), estriol (E3), and 17alpha-ethynylestradiol (EE2) have been suspected to be the main contaminants, which can affect the endocrine system of animals. Many authors have investigated these chemicals in the domestic wastewater treatment plants (WTP). However, wastewater from industries producing steroid contraceptives has not got ample attention. From the environmental point of view, the four steroids are very significant because even very low concentrations (ng/L) can cause reproductive disturbances in human, livestock and wildlife. The main purpose of the present investigation was to develop an analytical method for the determination of the four steroid estrogens present in WTP of a pharmacy factory, mainly producing contraceptive medicine in Beijing, China. Analysis was performed by solid-phase extraction (SPE) system and liquid chromatography combined with tandem mass spectrometry (LC/MS/MS). The average recoveries from effluent samples ranged from 88% to 103% and the precision of the method ranged from 9% to 4%. Based on 0.5-L wastewater samples, the limit of quantification (LOQ) was determined at 0.7 ng/L for E1, 0.8 for E2, 0.9 ng/L for E3, and 0.5 ng/L for EE2 in influent, and 1.0 ng/L for E2 and EE2, and 2.0 ng/L for E1 and E3 in effluent. In the influent samples, average concentrations of 80, 85, 73 and 155 ng/L were determined for E1, E2, E3 and EE2, respectively, showing that they were removed in this WTP to the extent of 79, 73, 85 and 67%, respectively.

Nanoparticles of poorly water-soluble drugs prepared by supercritical fluid extraction of emulsions.

PURPOSE: The aim of the study was to develop and evaluate a new method for the production of micro- and nanoparticles of poorly soluble drugs for drug delivery applications. METHODS: Fine particles of model compounds cholesterol acetate (CA), griseofulvin (GF), and megestrol acetate (MA) were produced by extraction of the internal phase of oil-in-water emulsions using supercritical carbon dioxide. The particles were obtained both in a batch or a continuous manner in the form of aqueous nanosuspensions. Precipitation of CA nanoparticles was used for conducting a mechanistic study on particle size control and scale-up. GF and MA nanoparticles were produced in several batches to compare their dissolution behavior with that of micronized materials. The physical analysis of the particles produced was performed using dynamic light scattering (particle size), scanning electron microscopy (morphology), powder X-ray diffraction (crystallinity), gas chromatography (residual solvent), and a dissolution apparatus. RESULTS: Particles with mean volume diameter ranging between 100 and 1000 nm were consistently produced. The emulsion droplet size, drug solution concentration, and organic solvent content in the emulsion were the major parameters responsible for particle size control. Efficient and fast extraction, down to low parts-per-million levels, was achieved with supercritical CO2. The GF and MA nanoparticles produced were crystalline in nature and exhibited a 5- to 10-fold increase in the dissolution rate compared with that of micronized powders. Theoretical calculations indicated that this dissolution was governed mainly by the surface kinetic coefficient and the specific surface area of the particles produced. It was observed that the necessary condition for a reliable and scalable process was the sufficient emulsion stability during the extraction time. CONCLUSION: The method developed offers a viable alternative to both the milling and constructive nanoparticle formation processes. Although preparation of a stable emulsion can be a challenge for some drug molecules, the new technique significantly shortens the processing time and overcomes the current limitations of the conventional precipitation techniques in terms of large waste streams, product purity, and process scale-up.

Predicting fate of the contraceptive pill in wastewater treatment and discharge.

The risk of endocrine disrupters to humans and wildlife is to date poorly understood, although evidence of effects is now widespread. In understanding the risk, an important step is the determination of the partitioning, as well as chemical and biochemical transformation, of compounds in the environment, the water cycle and the food chain. This is a complex task and this paper is a first step towards estimating some of these factors from a largely theoretical approach. A chemical fate model is used to predict the fate of the contraceptive drug 17alpha-ethinylestradiol (EE2). The example of the contraceptive pill is chosen to follow the journey of the drug from human ingestion and excretion to treatment in a sewage treatment plant (STP) using fugacity-based fate models, followed by discharge into a receiving river and eventually into the estuary/sea. The model predicts how EE2 will partition into the different compartments during each stage of this journey and thereby infiltrate into the food chain. The results suggest that a person would have to ingest more than 30,000 portions of fish to consume an equivalent to a single average dose of the contraceptive pill. While this scenario is highly unlikely, the biochemical consequence of the contraceptive pill is greatly significant. Furthermore, there are many identified similarly estrogenic compounds in the environment while this study only considers one. Cumulative effects of such compounds as well as degradation into other potent compounds may be anticipated. An important message in this paper is the interrelation of wastewater effluent discharge and eventual human exposure of marginally degradable and lipophilic chemicals. While at present the main concerns regarding endocrine disrupters appear to be the fear of their occurrence in drinking water sources, it is clear that the domains of wastewater treatment and discharge, water supply and contamination of food should not be treated as separate issues. The model suggests that exposure from food (contaminated by effluent) may be much more significant than from drinking water.

Photodegradation of 17alpha-ethynylestradiol in aqueous solution exposed to a high-pressure mercury lamp (250 W).

The photodegradation of 17alpha-ethynylestradiol (EE(2)) induced by high-pressure mercury lamp (lambda> or =313, 250 W) in aqueous solution of EE(2) was investigated initially. The affecting factors on the photodegradation were studied and described in details, such as EE(2) initial concentration, Fe(3+), algae, exposure time, and so on. The concentration of EE(2) in distilled water was mainly determined using fluorescence spectrophotometer. The photodegradation of EE(2) in aqueous solution exposed to high-pressure mercury lamp was evident and could be accelerated by Fe(3+) or algae (e.g. Anabaena cylindrica) in general. With the algae concentration increasing, photodegradation rate increased. In this paper, the mechanism of photocatalytic degradation of EE(2) by Fe(3+) or algae is discussed primarily.