Pozwolilem sobie wsadzic czesc o wiele dluzszego artykulu o antykoncepcji dla mezczyzn, niestety po angielsku jesli ktos nie zrozumie to potem w skrocie wytlumacze po polsku.
Jest to odnosnie deci i blokowania wydzielania wlasnego testosteronu, natomiast jesli chodzi o "deca dick" to wyglada to troszke inaczej niz Gochan przedstwail, pozniej to wytlumacze bo teraz mi sie chce spac
P.S wiem ze art przydlugi ale nauki nigdy za wiele koksy
3. HORMONAL METHODS
3.1 Physiological Basis for Hormonal Contraception
The concept underlying hormonal contraception in men and women is the use of agents to inhibit the hormonal regulation of the gonadal functions, gametogenesis and steroidogenesis. Hormonal regimens utilise the evolutionarily conserved mechanisms that initiate sexual maturation, as well as seasonality and the hypothalamic reaction to transient adverse environmental circumstances 83. In women, the anovulatory state during pregnancy was the physiological clue that allowed the development of ovarian sex steroids to inhibit contraception in women. Similar transient and reversible disruption of the menstrual cycle in stressful situation is now also well known, indicating the potential for reversible inhibition of gonadal function by suspension of its hormonal regulation. The immature testis and ovary remain quiescent for decades before puberty heralds the hormonal induction of full gametogenic and steroidogenic activity. Hence, manipulation of the hormonal mechanism, which evolved to switch gonadal activity on and off, is likely to be a safe and effective way to regulate fertility.
Hormonal male contraceptive regimes aim to suppress sperm production to the point where the man is rendered temporarily infertile by the reversible induction of azoospermia. This exploits the fact that spermatogenesis is dependent upon pituitary gonadotropin secretion and that sperm production can be abolished by administration of hormonally active agents. Hormonal agents that activate the negative steroidal feedback mechanism inhibit the hypothalamic secretion of GnRH into the pituitary portal system and, thereby, pituitary gonadotrope secretion of LH and FSH into the bloodstream. Using this mechanism, administration of hormonally active drugs aims to abolish pituitary gonadotropin support of testicular endocrine and exocrine function. Gonadotropin withdrawal leads to loss of LH-dependent Leydig cell testosterone production and FSH-dependent Sertoli cell function. This removes the hormonal support of spermatogenesis, maintained via the Sertoli cells. These somatic cells of the germinal epithelium uniquely express FSH receptors and are also the target of androgen action, as they express the androgen receptor whereas germinal cells do not 84, 85. Hence, effective gonadotropin withdrawal leads to Sertoli cells deprived of FSH action and removes the high levels of intratesticular testosterone, maintained at an ambient concentrations ~100 times higher than in the bloodstream 86, 87, which is essential to maintain spermatogenesis. As a result, the dose and pharmacokinetics of testosterone preparations may be important for effective suppression of spermatogenesis since, theoretically, delivery of excess testosterone could prevent maximal depletion of intratesticular testosterone, thereby ensuring suboptimal suppression of spermatogenesis 88-90.
3.1.1 Proof of principle
A key strategic issue in developing a hormonal male contraceptive is defining the degree of suppression of sperm output required. Landmark WHO studies established that hormonally induced azoospermia provides highly reliable, reversible contraception 2, 3. Overall, the contraceptive failure rate was 1.4% per annum for men whose sperm concentrations were consistently lower than 3 million per mL with no pregnancies produced by men with azoospermia. All contraceptive failures were in the minority (~25%) of men who remained severely oligozoospermic (0.1-3 million sperm/ml) with pregnancy rates directly proportional to sperm output. Hence azoospermia can be considered a sufficient, but not absolutely necessary, condition for effective male contraception, rather like anovulation is for female contraception whereby women using progestin-only contraceptives obtain secure contraception despite ovulation 10, 91. Nevertheless, in order to ensure contraception as reliable as modern female methods 92, uniform azoospermia remains the desirable target for male contraceptive regimens. No regimen yet achieves this consistently in all men, although androgen-progestin combinations are closest to achieving this goal. Hormonal methods based on such combinations provide the most likely opportunity in the near future to develop a practical contraceptive method for men 93.
3.2 Steroidal Methods
3.2.1 Androgen Alone - Testosterone
Testosterone provides both gonadotropin suppression and androgen replacement making it an obvious first choice as a single agent for a reversible hormonal male contraceptive. Although androgen-induced, reversible suppression of human spermatogenesis has long been known 94-97, systematic studies of androgens for male contraception began in the 1970's 98, 99. Feasibility and dose-finding studies 100 mostly using testosterone enanthate (TE) in an oil vehicle as a prototype showed that weekly im injections of 100-200 mg TE induce azoospermia in most Caucasian men 101 but less frequent or lower doses fail to sustain suppression 102-105.
The largest systematic experience with an androgen alone regimen arises from the two WHO studies in which over 670 men from 16 centres in 10 countries received weekly injections of 200 mg TE. In these studies ~60% of non-Chinese and over 90% of Chinese men became azoospermic with the remainder achieving severe oligozoospermia 2, 3. Azoospermia occurs in 3-4 months and is then maintained consistently during ongoing treatment. This effect is reversible after stopping injections with sperm reappearing at 3 months and normal output by 6 months. Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia or behavioural effects and these effects were reversible. Increases in body weight, lean body mass and hemoglobin and decreases in testis size and plasma urea were all reversed after cessation of treatment and there was no evidence of liver, prostate or cardiovascular disorders 2, 3, 106.
The WHO studies have revealed striking within and between population differences in susceptibility to hormonally induced azoospermia 107, which remain unexplained 108. Possibly related are population differences between Asian and European men in testicular structure or hormonal regulation whereby Asian men have lower testis weight and germinal cell populations as well as higher Leydig, Sertoli and apoptotic cell numbers 109, 110. Functional differences have also been reported with lower testosterone production rates in Chinese men residing in China compared with Chinese or American men residing in the USA 111. Similarly, Asian men had greater susceptibility to suppression of pulsatile LH secretion as well as higher and more irregular baseline pulsatile FSH secretion compared with American men despite similar testosterone concentrations 112. Whether these variations explain the higher susceptibility to hormonally-induced azoospermia in Chinese men remains unclear. While often considered to have a genetic basis, such ethno-pharmacological variations may also be due to environmental factors including nutrition 113 as illustrated by the influence of migration on androgen-dependent prostate size in Chinese men 114. Currently, such population differences have less practical significance for hormonal male contraception since the goal of achieving uniform azoospermia now appears achievable with combination hormonal regimens. These population differences may however have interesting implications for geographical variation in susceptibility to hormone-dependent disease.
The pharmacology of testosterone formulations is crucial for suppression of sperm output. Oral androgens have major first-pass hepatic effects leading to prominent route-dependent effects on hepatic protein secretion (eg SHBG, HDL cholesterol). Such route-dependent adverse effects may be similar to the venous thromboembolism and hepatic adenomas, which are associated with oral ingestion of synthetic contraceptive estrogens. Short-acting testosterone preparations requiring daily or more frequent administration (oral, transdermal patches or gels), which may be acceptable for androgen replacement therapy, are not suitable for hormonal male contraception. In addition, dermal androgen gels have been reported to be topically transferred leading to virilization of the female partner 115, 116. Parenteral forms of testosterone (injectable, implants) delivery are consistently more effective than non-parenteral (oral, transdermal) forms of testosterone delivery in male contraceptive regimens. Weekly TE injections required for maximal suppression of spermatogenesis 100 are far from ideal in causing injection site pain 117 and supraphysiological blood testosterone concentrations, the latter risking both excessive androgenic side effects and suboptimal efficacy if it prevents maximal depletion of intratesticular testosterone. Currently marketed oil-based testosterone esters have essentially similar (cypionate, cyclohexane-carboxylate) or shorter (propionate) duration of action compared with the enanthate ester 118 rendering them unsuitable for a practical hormonal male contraceptive. Some pharmacological features of testosterone enanthate, notably its supraphysiological peaks in blood testosterone which may be counterproductive in depleting intratesticular testosterone, will require re-evaluation with more steady-state testosterone formulations for hormonal male contraceptive regimens. These shorter acting esters are now considered obsolete in favour of longer-acting depot testosterone preparations which aim to maintain physiological testosterone levels for much longer periods are needed for better acceptability.
Testosterone pellets implanted subdermally by trochar provide physiological testosterone levels sustained for 4-6 months 119 and represent a prototype for newer injectable formulations in development. Testosterone-loaded biodegradable microspheres 120, 121, testosterone undecanoate 122 and testosterone buciclate 123 having 2-3 months duration of action appear promising although all require large (4mL) injection volumes. The most promising appears to be injectable testosterone undecanoate, which has demonstrated adequate androgen replacement at a dose of 1000 mg each 6 weeks in Chinese 122 and European 124 men. This longer acting ester in an oil depot formulation has been utilised in highly effective contraceptive regimens either as 1000 mg monthly in Chinese men 125 or together with a progestin at 1000 mg per 6 weeks in European men 126. Depot androgens suppress spermatogenesis faster, at lower doses and with fewer metabolic side effects than TE injections. Azoospermia is still not achieved uniformly 127 although the addition of a depot progestin almost achieves this goal 128. These findings of high rates of azoospermia have also been reported for combinations of an oral progestin with testosterone enanthate injections 129, 130. By demonstrating the achievability of the benchmark of universal but reversible azoospermia, these studies show the feasibility of a depot androgen/progestin combination for hormonal male contraception. Hence the future role of androgens in hormonal male contraceptive regimens appears to be as part of an androgen/progestin combination probably in a depot formulation. Alternatively a synthetic androgen with sufficient progestin cross-reactivity might create this combination functionality in a single steroid or non-steroid molecule.
3.2.2 Androgen Alone - Other androgens and anti-androgens
Oral synthetic 17-a alkylated androgens such as methyltestosterone 131, fluoxymesterone 132, methandienone 133 and danazol 134, 135 suppress spermatogenesis but azoospermia is rarely achieved. More importantly, the class-specific hepatotoxicity inherent in the 17-a alkyl substituent 136 renders them unsuitable for long-term clinical use, including for androgen replacement therapy or contraception. This obsolete class of synthetic androgen is disappearing from the market. Athletes self-administering supra-therapeutic doses of androgens also exhibit suppression of spermatogenesis 133, 137.
Synthetic androgens lacking the 17-a alkyl substituent have been little studied although injectable nandrolone esters produce azoospermia in 88% of European men 89, 138 whereas oral mesterolone is ineffective 139. A more potent nandrolone derivative, 7a-methyl nandrolone (MENT) has also been developed for applications including hormonal male contraceptive regimens 140. Among nandrolone derivatives like MENT and norethisterone, the 7a-methyl substitutent enhances androgen receptor potency, while producing steric inhibition of 5a reduction 141. Like nandrolone 142, MENT is a selective androgen with its 5a derivative having reduced androgenic activity 143, unlike testosterone which is activated to the more potent androgen DHT by 5a reduction, particularly the type II enzyme expressed in the prostate. As a result, nandrolone and its derivatives may be considered relatively prostate-sparing androgens 144, a potential non-contraceptive benefit of a male contraceptive. This hypothetical advantage might have stronger cogency if inhibition of 5a reductase proves an effective chemopreventive approach for prostate cancer 145. Like testosterone, MENT is aromatised to a potent estrogen (7a-methyl estradiol) although it differs from nandrolone which is minimally aromatisable. These metabolic fates may be important for androgen effects on certain tissues, notably bone, where aromatisation is required for at least part of androgen action. More potent, synthetic steroidal 146 and non-steroidal 147, 148 androgens lacking 17-a alkyl groups remain to be evaluated. The ability of tissue co-regulators, intranuclear proteins that modulate the activity of the ligand-activated androgen receptor 149, to influence tissue specificity of androgen action, remains to be fully explored.
Antiandrogens have been tested on the basis that some dose might selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects 150. Cyproterone acetate (CPA), an orally active steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to unacceptable, symptomatic androgen deficiency when used alone 151. More recently CPA has been re-investigated in combination with injectable testosterone enanthate to produce high efficacy in suppression of sperm output in small studies using CPA doses ranging from 100 mg down to 12.5 mg daily 130, 152, although CPA was ineffective when combined with oral testosterone undecanoate 153. In all studies CPA produced a lowering of hemoglobin, presumably reflecting anti-androgenic effects manifest selectively on marrow and epididymis but not other androgen-dependent tissues. Although CPA is an unlikely candidate for further clinical development 154, its tissue-selective antiandrogenic activity illustrates the potential for designer androgens 155, 156.
In contrast, pure non-steroidal antiandrogens lacking androgenic or progestin effects, such as flutamide, nilutamide and casodex, fail to suppress spermatogenesis when used alone 157, 158. The latter findings would be expected from their reflex hypergonadotropic effects on gonadotropin negative feedback in an intact closed-loop, hypothalamo-pituitary system.
The persistence of residual spermatogenesis in a minority of men during hormonal suppression regimens remains unexplained. One potential explanation was based on the observation that during hormonal suppression, indirect human 159 as well as direct experimental 160 evidence raised the possibility that testicular 5a reductase may have supported the persistence of spermatogenesis despite marked reduction in intratesticular testosterone. Clinical trials have not supported this hypothesis as a type 2 5a reductase inhibitor, finasteride, failed to enhance the achievement of hormonally-induced azoospermia 161, 162. .Whether residual type 1 5a reductase activity in the testis 160 or persistence of very low levels of plasma gonadotropins 163 explain the residual low levels of ongoing sperm production, remains to be evaluated.
3.2.3. Androgen combination regimens
The WHO male contraceptive efficacy studies indicated that universal azoospermia was the desirable target for an effective hormonal male contraceptive regimen. Yet those studies together with small dose-ranging studies showing that neither higher dosage 164 nor more steady-state delivery 127 of testosterone could achieve this goal, suggested that a regimen based on testosterone alone was unlikely to be sufficiently effective for development of a practical male contraceptive. The need for regimens with enhanced efficacy sufficient to achieve universal azoospermia has led to androgen combination regimens including a second, gonadotropin-suppressing agent, such as GnRH analogs or non-androgenic sex steroids (estrogen, progestin, mixed). Such combination regimens can enhance gonadotropin suppression while reducing testosterone dosage. This might enhance efficacy of spermatogenic suppression by avoiding excessive testosterone doses that may be counterproductive in achieving the goal of maximal depletion of intratesticular testosterone, which is necessary for complete inhibition of spermatogenesis 87, 165, 166. Whether the enhanced efficacy of combination regimens also achieves any improved safety profile depends on the balance between the risks and benefits of adding a second drug compared with the modest degree of androgen dose-sparing, which might reduce androgenic side-effects.
3.2.3.1 Androgen/Estrogen Combination Regimens
Estradiol augments testosterone-induced suppression of primate spermatogenesis 167 and fertility 168 raising the possibility that estrogens might be a useful class of second gonadotropin suppressing agents in combination male contraceptive regimens. While estradiol augments testosterone-induced suppression of spermatogenesis in humans 169, the estrogenic side effects (gynecomastia, mastalgia) and modest efficacy at tolerable doses, makes estradiol-based combinations impractical for male contraception. Nevertheless, these observations highlight the advantages of aromatisable gonadal steroids in male contraceptive regimens. For example, progestins such as cyproterone acetate 170 and norethisterone 171 form potent estrogenic metabolites that may contribute to their suppression of pituitary gonadotropin and spermatogenesis 126, 172. Further, non-aromatisable androgens like nandrolone 173 may be less effective at maintaining spermatogenic suppression. The efficacy and tolerability of newer estrogen partial agonistic analogs ("SERM's") in combination with testosterone remain to be evaluated.
3.2.3.2 Androgen/Progestin Combination Regimens
The most effective combination steroid regimens have involved combinations of progestins with testosterone for androgen replacement. These have shown significant improvement in the rate and extent of spermatogenic suppression compared with androgen alone regimens 128-130. Progestins are potent inhibitors of pituitary gonadotropin secretion with negligible direct effect on spermatogenesis and long-acting depot formulations are used for female contraception. Nevertheless, synthetic progestins and their metabolites often display cross-reactivity with androgen and estrogen receptors that influences their net biological activity. The conventional categorization of progestins into high and low androgenicity, arising from contraceptive steroid marketing, has little biological meaning when these agents are used in men with their high circulating androgen background and requirements. Given the hepatotoxicity of 17-a alkylated androgens, the potential hepatotoxicity of 17-a alkylated progestins when co-administered with androgens will require evaluation.
Used alone, progestins suppress spermatogenesis but cause androgen deficiency symptoms including impotence 174, 175, so concomitant androgen replacement is necessary. Extensive feasibility studies concluded that progestin-androgen combination regimens during the 1970's had promise as hormonal male contraceptives if more potent and durable agents were developed 100, 176. The most detailed information from these early studies on androgen/progestin regimens derives from studies with medroxyprogesterone acetate (MPA) combined with testosterone. Monthly injections of both agents or daily oral progestin with dermal androgen gels produce azoospermia in ~60% of fertile men of European background with the remainder having severe oligozoospermia and impaired sperm function 100, 176, 177. More recent studies show nearly uniform azoospermia achieved in men treated with depot MPA and either of two injectable androgens in Indonesian men 178, 179 or testosterone depot implants in Caucasian men 128. Nevertheless, injectable depot MPA has suboptimal properties for a progestin in a male contraceptive regimen and depot with more steady-state and user-controllable properties (eg implants) would be preferable.
Studies with other oral progestins such as levo-norgestrel (LNG) 180, norethisterone 116, 181 and desogestrel 182-184 combined with testosterone enanthate injections demonstrate similar efficacy to oral MPA. In addition, cyproterone acetate, an orally active progestin with additional anti-androgenic activity, has shown higher efficacy in conjunction with TE 130, 152 but not with oral testosterone undecanoate 153.
Recent dose-ranging studies with oral LNG combined with testosterone enanthate (100 mg weekly) for 6 months have shown a dose-dependent increase in proportion achieving azoospermia from 6/18 without LNG to 12/18 at the highest daily dose (500 mg/day) 129, 185. Other studies have used transdermal testosterone delivery with oral LNG doses of 250 to 500 mg daily but only 2/11 men became azoospermic 186 whereas using long-acting injectable testosterone undecanoate (1000 mg) 7/14 men were rendered azoospermic. In another study using subdermal LNG implants combined with transdermal DHT, none of 27 men achieved azoospermia despite the implants achieving similar serum LNG concentrations as other recent studies with oral LNG 187. Since injectable nandrolone, a minimally aromatisable androgen, has been used successfully in combination with progestins 90, 179, the low efficacy in the LNG/DHT study may reflect the poor compliance with a suboptimal androgen delivery rather than a specific requirement for aromatisable androgens. In concert, these studies highlight the decisive superiority of parenteral delivery of testosterone for effective suppression of spermatogenesis. Although oral LNG produced faster onset and more frequent azoospermia than testosterone alone, the goal of universal zoospermia was not achieved. In addition, weight gain and prominent (20-30%) reduction in HDL cholesterol, the latter presumably due to the first-pass hepatic effects of oral LNG, were consistent undesirable features indicating that better progestins than oral LNG are desirable for hormonal male contraception. Whether these adverse effects might be avoided by an improved depot preparation such as the biodegradable depot norethisterone implant reported 188 remains to be evaluated.
Desogestrel, a 3rd generation 17a-alkylated progestin, has demonstrated promise in preliminary dose-finding studies which suggested that doses of 300 mg daily were required for maximal spermatogenic suppression 184. Two spermatogenic suppression studies using lower doses (150 or 200 mg daily) together with testosterone enanthate injections (50 or 100 mg weekly) for 6 months produced azoospermia in 37/46 (80%) and severe oligozoospermia (<1 M/mL) in 42/48 (88%) of men 182, 183. While generally well tolerated, desogestrel also did not achieve the ideal of uniform azoospermia while producing consistent weight gain and lowering of HDL cholesterol (~20%). Further studies of higher oral desogestrel doses as well as with subdermal implants of etonogestrel, the 3-keto metabolite of desogestrel, with improved depot testosterone delivery are underway (R Anderson, personal communication).
A recent study has revived interest in an older 19-nor, 17a alkylated progestin, norethisterone 116, 181 using an injectable formulation in combination with longer-acting depot injectable, testosterone undecanoate 126. A single injection of 200mg norethisterone enanthate produced suppression of testosterone, LH, FSH, SHBG together with mild androgen deficiency symptoms, attributable to estrogenic and androgenic bioactivity of norethisterone 189. Using either 200 mg or 400 mg injectable norethisterone enanthate or 10 mg oral norethisterone acetate daily combined with 1000 mg testosterone undecanoate every 6 weeks, 36/40 (90%) achieved azoospermia within 6 months 126. These regimens maintained adequate androgen replacement and the side-effects (weight gain, sweating, mastalgia, reduction in HDL cholesterol and alkaline phosphatase, increased hemoglobin, sexual function and liver enzymes) were dose-dependent and reversible with most prominent effects observed with oral treatment. Further studies of dose optimisation, efficacy and safety of this promising depot combination regimens are needed.
Studies of other 3rd generation progestins including norgestimate, gestodene, dienogest, nomegestrol and drospirenone 190 well as existing depot progestins such as injectable levonorgestrel butanoate 191, biodegradable norethisterone 188 and non-biodegradable etonogestrel (Implanon) implants in men would be of interest. One study of norgestrel implant (Jadelle) has shown limited efficacy for gonadotropin and spermatogenic suppression despite high doses 187.
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Zmieniony przez - lifter w dniu 2003-12-03 23:26:24
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