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Winston-Salem (Nc) | United States
Wife of Arthur Charles, mother of Anne. Wife of Patrick dec UK Mother of Clarrie and Joy Chapman. Husband of Frances, father of Noel and Margarette.
DIX , Gregory Mark. Husband of Ruth, father of Leonie and Shayne. Father of Tim dec , Debbie, Kerry and Jenny. Father of Marlene and John. Mother of Marlene and John. Born Mt Barker 1 December died 19 November Born 23 February Died 9 October Mother of Tim dec , Debbie, Kerry and Jenny.
Husband of Joan, father of Ross. Wife of Harold, mother of Patricia and Marion. Husband of Edith, father of Patricia and Marion. Son of Robert and Phyllis. Born Mt Barker 6 June died 2 November Husband of Alice, father of Philip. Wife of Roy, mother of Phillip. Born Albany 20 July Died 9 February Husband of Winifred, father of Robert, Kenneth and Gordon. Born Forrest Hill 27 February died 18 November Wife of Harold Edward. Buried 29 September Mother of Leo and Herbert.
Father of Leo and Herbert. Husband of Mary, father of Joan and Betty. Wife of Peter, mother of Julie, Fiona and David. Son of Sidy Ella and family. Mother of Joan, Peter and Patricia.
Father of Joan, Peter and Patricia. Buried 23 March Husband of Jean, father of Elaine and Penny. Born Adelaide 19 July died 23 March Wife of George, mother of Elaine and Penny.
Buried 25 May Born Carmarthen 28 August Died 19 May Daughter of J H Colley. Wife of Jack, mother of Robyn and Ken. Born Walkaway 23 December died 27 November Wife of Robin, mother of Gilbert, John and Kerry. Born Subiaco 24 November died 7 September Husband of Connie, father of Gilbert, John and Kerry.
Buried 10 February Born Narrikup 30 April died 3 October Wife of Arnold, mother of Gwen and Caroline. Husband of Mabel, father of Ian, Evan and Ray. Husband of Anne, father of Lesley and Allan. Mother of Jean, Margaret, Eileen and Peter. Born Boulder 28 May died 10 May Husband of Elsie, father of Shirley, Ken, Norman.
Mother of John, David, Heather and Ruth. Born Geraldton 14 May died 14 July Father of John, Barbara and Colin. Mother of John, Barbara and Colin. Buried 29 July Buried 11 February Born Mt Barker 28 February died 1 July Mother of Kath, Meg, Joan and Ray. Father of Kath, Meg , Joan and Ray. Buried 27 December Husband of Victoria Mary.
Wife of James, mother of Estelle. Wife of Norman, mother of Graeme. Son of Gwen and Jack. Husband of Eva, father of Estelle. Father of Derek and Eric. Wife of Monty, mother of Alex, Eric and Keith. Husband of Margaret, father of Alex, Eric dec and Keith dec. Wife of Edward John. Born and died 28 October - 15 hours. Born Gnowangerup 28 April died 20 October Husband of Joan, father of Walter.
Wife of Robert S. Father of Hildabeth and Maureen. Wife of Frank Nalder. Mother of Hildabeth and Maureen. Born Brentford 1 April died 3 March Husband of Kathleen, father of Kerry. Born Mt Barker 20 June died 4 September Born E Wagin 15 November died 1 May Born Mt Barker 8 September died 9 June Husband of Ida, father of Betty. Born Albany 21 June Died 1 November Daughter of Brian and Gwenda.
Buried 8 November Buried 7 September aged Husband of Irene, father of Patricia, Gregory and Karen. Husband of Doris, father of David, Joan and Joyce. Wife of Dave, mother of David, Joan and Joyce. Son of Flo and Robert. Husband of Dimp, father of Jenny and Douglas. Husband of Bernice, father of Geoffrey. Buried 19 August Sister of Amy Bowden. Buried 30 December Wife of Thomas P.
Father of Milton and June. Mother of Milton and June. Born Moora 16 Nov died 4 August Buried 10 November aged 78 years. Buried 19 April Father of Maureen, Ursula, Jennifer and Donna. Mother of Maureen, Ursula, Jennifer and Donna. Wife of Stanley, mother of John, Trevor and Mabel. Husband of Melba, father of John, Trevor, Mabel. Born Rotherham, England 17 November died 26 January Husband of Mabel Rhoda.
Wife of Harry Stace. Died 26 January Born Perth 20 March died 6 February Husband of Lorna, father of Errol, Maurice and Marilyn. E on headstone - 28 June Buried 8 January Husband of Rose, father of Audrey and Jack. Born Hepburn 12 September died 3 December Born Marinup 21 February died 16 June Born Kojonup died 20 June Wife of Walter, mother of Raymond and Gwenda.
Wife of Jack, mother of Glyn, Lorraine and Geoff. Husband of Kathleen Gertrude, father of Raymond and Gwenda. Husband of May, father of Les and Beth. Born Mt Barker 6 April died 4 January Born Mt Barker 17 June died 27 February Wife of John, mother of Edward, Fred and Malcolm. Husband of Jean, father of Edward, Fred and Malcolm.
Son of Eric and Phoebe. Born Albany 14 November died 31 January Wife of Frank, and Robert Knapp dec. Born 9 July died 20 March Husband of Cecilia May. Eldest son of James And Mary. Buried 31 August Wife pf Pat, mother of Peter and Brian. Born - died Ashes interred 16 August Grave No. Born Lithuania 28 August died 27 Dec Wife of Milenko, mother of Roy, Victor dec and Regina.
Son of Ona and Milenko, brother of Radojko and Pegina. Buried 10 July Buried 10 December Wife of Glen, mother of Fayemarie and Sharne. Husband of Betty, father of Peter, Glenda and Nathan. Husband of Elsie Hope, father of Mike and Margaret. Born Queensland 18 May died 5 October Born Echula, Victoria 3 March died 11 April Husband and father of Maida, Anne, John and Susan.
Mother of Campbell John. Father of Campbell John. Only son of Aenid and John. Wife of Malcolm, mother of Judith and John. Buried 23 June Born Fitzroy, Vic 22 March died 30 May Husband of Hedwig, father of Vera and Maria.
Wife of George, mother of Vera and Maria. Buried 3 April Only daughter of Prudence Arber. Son of Andrew and Sophie. Born Denmark 24 December died 17 August Mother of Dale, Karen and Frances.
Father of Dale, Karen and Frances. Brother of Henry Leonard. Buried 21 April Buried 15 November Only son of Jean and John. Buried 26 October Daughter of J and A. Brother of Beatrice, Mary, Nancy and Evelyn. Oct - 10 October. Husband of Laura, father of Florence and Marguerite.
Aug - 11 July Wife of Harry, mother of Florence and Marguerite. Husband of Lily, father of Shirley, Vaughan and Christine. Buried 15 February Buried 24 May Aged abt 55 years. Husband of Claire, father of Steven, Phillip and Sherrene.
Mother of Terry Max. Father of Lorraine, Ray and Colin. Father of Jean, Osborne, John and Harry. Mother of Jean, Osborne, John and Harry. Son of John and Ruth, brother of Kaye. Such Western market failure may only be overcome if the growing needs for voluntary family planning in rapidly industrialising countries like China, India and Brazil where the national priority to curb population growth may encourage emerging home markets re-establish priority for local pharmaceutical industry development Although theoretically effective, neither celibacy nor castration is an acceptable or practical contraceptive method.
Periodic abstinence, the limiting of sexual intercourse to "safe" days 17 , has high contraceptive efficacy if the rules are followed perfectly but the failure rates rise steeply with rule breaking While inherently safe, it has limited acceptability due to low reliability, inflexibility and interference in the spontaneity of love-making. Withdrawal is a traditional male method of contraception whereby intercourse culminates in extra-vaginal ejaculation Often overlooked as a contraceptive method, together with abortion, it was the major pre-industrial method of family planning largely responsible for the demographic transition from high to low birth rates in industrial nation states and continues to be used by 40 million couples 2.
This cost- and device-free method has limited reliability in its demanding requirement for skill and self-control. While safe and reasonably effective for experienced users, interfering with the pleasurability of coitus leads to a correspondingly high failure rate in practice.
Other sexual practices that avoid intravaginal ejaculation have also been used traditionally to avoid conception. These include masturbation, oral and anal intercourse, deliberate anejaculation and retrograde ejaculation After centuries of use in preventing sexually transmitted infections, now over 50 million couples rely on condoms for contraception 2.
Condoms provide safe, cheap, widely available, user-controlled and reversible contraception with few side-effects. In case of latex allergy, non-rubber polyurethane, natural membrane condoms can be substituted. Differences in contraceptive use behaviours may explain lower reported 1st year failure rates for condoms in France The major limitations of condoms for contraception are relatively high failure rates and interference with sexuality.
The requirement for regular and correct application during sexual foreplay disturbs the spontaneity of lovemaking and dulls erotic sensation. These aesthetic drawbacks limit the popularity of condoms especially among stable couples Latex condoms are perishable through tears or snagging on nails, clothing or jewellery as well as deterioration from exposure to light, heat, humidity or organic oils.
Although the theoretical requirements for condom use to protect against sexually transmitted infections differ from those to prevent pregnancy, in practice the protections are similar Laboratory testing of condoms standardizes integrity and durability for strength and leakage and, although viral penetration is not routinely tested, synthetic latex or polyurethane but not natural membrane condoms are effective albeit imperfect at preventing passage of prototype human pathogenic viruses Novel spermicides with virucidal properties being developed to provide antimicrobial together with contraceptive protection 33 may not enhance condom efficacy for either as non-compliance is the major cause of failure for both Vasectomy, used by over 40 million couples for family planning 2 , varies widely in prevalence between countries depending upon cultural factors, public education and availability of male-oriented facilities For men having completed their family and fit for minor surgery, vasectomy is a very safe and highly effective office procedure 36, Relative contraindications include risks from office-type surgery bleeding disorders, allergy to local anaesthetic or scrotal pathology post-inguinal surgery scarring, keloid-proneness, active genitourinary or groin infections.
Vasectomy is usually performed under local anaesthesia via scrotal incisions and involves excising a segment of vas deferens. Interposing a fascial barrier between the occluded cut ends significantly reduces the risk of failure due to recanalization 38, The Chinese-developed "no-scalpel" technique 40 minimizes skin incision and reduces immediate side-effects bleeding, infection fold to 0.
Among those with severe, persistent post-vasectomy pain not improved by medical treatment, both vasectomy reversal and epididymectomy are reported to relieve pain but controlled prospective comparisons of these surgical procedures are lacking It may be reported as groin or testicular pain precipitated or aggravated by intercourse, ejaculation or exertion and accompanied by tender, distended epididymes 43, Fascial interposition significantly reduces failure rate 39, 49 so that, in the hands of an experienced practitioner, no-scalpel vasectomy with fascial interposition is now the method of choice 42, Additional studies suggest that cautery may further enhance reliability 51, 52 and that leaving an open testicular end reduces retrograde pressure-related complications pain, sperm granuloma, epididymal and testicular damage thereby better preserving reversibility Vasectomy is highly effective once sperm are cleared from the distal vas deferens.
However, flushing with saline or water or spermicides nitrofurazone 61 , euflavine 62, 63 or chlorhexidine 64 during surgery does not accelerate sperm clearance but the evidence remains weak Non-irritant spermicides that inhibit sperm function without chemical sclerosis of the vas that would impair potential reversibility, may have promise Although azoospermia may occur sooner 71 , reliable evidence is lacking to support the reliability of earlier time points as recanalization, where motile sperm persist in the ejaculate, may occur within the first few weeks after vasectomy 72 and persistence of motile sperm in the ejaculate indicates technical failure.
Although detailed information on the rate of sperm clearance from the ejaculate after vasectomy remains sparse, time since vasectomy rather than number of ejaculations is more predictive of sperm clearance Vasectomy causes no consistent changes in circulating hormones 76 , sexual function or risk of cardiovascular or other diseases 36, 77, 78 including testis cancer A small increase in risk of prostate cancer after vasectomy in case-control studies , but unaffected by vasectomy reversal 85 , appears attributable to surveillance and detection bias, rather than a biological effect Vasectomy is a quick, simple, highly effective and convenient method of permanent sterilization; its major drawback as a male contraceptive is its limited reversibility.
Elective sperm cryostorage is occasionally useful but may reflect ambivalence about the irreversible intent of vasectomy. Cumulative rate of requests for reversal, mostly prompted by remarriage, are 2. This discrepancy is most probably attributable to technical limitations of microsurgery as even the lowest reported rates of azoospermia bilateral non-patency after microsurgical vaso-vasostomy indicate that nearly half such men have at least one non-patent vas deferens 93 so that re-operation should be a prominent consideration if pregnancy does not ensue.
Whether robotic microsurgery can improve the technical success of vaso-vasostomy to become a cost-effective and widely available alternative to human microsurgery remains to be established 95, Experimentally in a variety of mammalian species, open ended vasectomy is preferable to complete vas occlusion in preventing the back pressure-induced damage to spermatogenesis and seminiferous tubular integrity which are important contributors to failure of vasectomy reversal , However, optimal management depends on local clinical expertise as well as access to microsurgery and reproductive technologies.
The feasibility of successful vasectomy reversal has led to the proposal that, although vasectomy is intended as permanent, select individuals may consider it a reversible contraceptive method US national economic indicators strikingly influence rates of vasectomy and of vasectomy reversal, which are increased and decreased, respectively, according to the unemployment rate and personal income ; whether same correspondence applies in countries with national health schemes that reduce financial limitations on access to elective health care remains unknown.
Pooled summary of contraceptive efficacy from two WHO male contraceptive efficacy studies 10, 11 where contraceptive failure rate pregnancy rate is plotted against the current sperm concentration in the ejaculate. This illustrates a summation of all data pooled from both studies. Data comprise monthly observations of the mean sperm concentration averaging monthly sperm counts and whether a pregnancy occurred in that month or not.
Pregnancy rate per person-years, Pearl index on the y-axis is plotted against the cumulative sperm density in million sperm per ml indicating that contraceptive failure rates are proportional to sperm output. The inset is the same data re-plotted in discrete sperm concentration bands rather than cumulatively.
For comparison, the average contraceptive failure rates in the first year of use 23, of modern reliable contraceptive methods are indicated by diamond symbols. The efficacy, safety, simplicity and acceptability of vasectomy suggest that a reversible mechanical method of vas occlusion would be an attractive male contraceptive option. Since vasectomy reversal is neither cheap nor widely available, more reversible vas occlusion methods are needed A nonsurgical, potentially reversible technique involving percutaneous injections of polymers that harden in-situ to form occluding plugs which may be later removed to restore fertility was reported but, despite preliminary positive findings , formal evaluation showed vas occlusion had lower efficacy inducing azoospermia than vasectomy In a phase II randomized clinical trial a urethane-coated nylon thread intra-vas device was more acceptable with fewer complications but was less effective in producing azoospermia, compared with no-scalpel vasectomy A hydrophilic gel, composed of styrene maleic anhydride in dimethyl sulfoxide, forms a charged spermicidal biopolymer when injected into the vas deferens which is stable but potentially removable.
Preliminary non-comparative clinical evaluation showed azoospermia in 12 men with no pregnancies in their wives for 12 months following intravasal injection suggesting vasal occlusion ; however, some morphologically damaged and non-functional sperm persist in the ejaculate but the mechanisms of the deleterious effects on sperm structure and function remain unexplained One randomized controlled clinical trial has shown that a prototype implantable non-occlusive intra-vasal device, comprising a nylon thread encased in barium-impregnated polyurethane, is as effective for sterilization as standard no-scalpel sterilization with no more adverse effects ; however the reversibility of this device remains to be demonstrated.
Other technical developments including percutaneous injection of sclerosants and transcutaneous delivery of physical agents ultrasound, lasers continue to be developed slowly It has long been known that even brief elevations of testicular temperature can profoundly suppress spermatogenesis while sustained elevation may contribute to testicular pathology in cryptorchidism, varicocele and occupational male infertility Clinical studies evaluating the potential for tight scrotal supports as a practical male contraceptive method , showed a reversible decrease in sperm output but of inadequate magnitude for reliable contraception.
Given the dubious acceptability and safety of heat-induced suppression of sperm output, the feasibility of a male contraceptive method based on testicular heating remains to be established. Data is plotted as a Kaplan-Meier survival plot of the increasing proportion of men recovering to various thresholds over time since last treatment. The data of last treatment is defined as the time elapsed from the end of the last treatment cycle, that is the latest date of the first missed treatment dose.
The thresholds are a sperm concentration of 3, 10 or 20 million sperm per mL in the ejaculate or a return to their own pre-treatment baseline sperm concentration. Sperm vaccines to interrupt fertility have long been of interest with a patent issued for vaccination with semen Sperm express unique epitopes within the immunologically protected adluminal compartment of the seminiferous tubules at puberty, long after the definition of immune self-tolerance hence explaining their potential autoimmunogenicity.
Experimental models for an effective sperm vaccine targeting surface-expressed antigens involved in fertilization have been reported. Yet practical application requires resolving problems of the large antigenic load requiring virtually complete functional blockade, variability of individual immune responses, restricted access of antibodies into the seminiferous tubules and epididymis and the risks of autoimmune orchitis or immune-complex disease.
Passive immunization may overcome the present limited predictability of active immunization with sperm antigens so as to quickly reach and maintain, as well as allowing for volitionally controllable offset, of effective immunocontraceptive titres The smaller antigenic burden in the female reproductive tract requiring complete neutralization suggests that a sperm vaccine, using modern genetic engineering of sperm epitopes , may be better targeted for administration to women.
However, the most suitable target for contraceptive vaccines may be for feral and wild animal , Prototype hormonal contraceptive methods have been in clinical trials for nearly 4 decades 5 with proof of principle secured for contraceptive efficacy, reversibility, acceptability and short-term safety.
However, commercial product development is stalled despite unmet clinical need and popular demand for a male contraceptive as an overdue rebalancing for women who bear most family planning burden 16, Major factors in such a market failure are industry perceptions of low profitability from non-patented steroidal regimens and medico-legal fears of steroid administration to healthy men.
Opportunistic approaches include the identification through fortuitous pharmacological observation of male reproductive effects of drugs or natural products.
Among older drugs, an orally active spermicide concentrated in semen , drugs inhibiting male fertility , ejaculation or epididymal sperm function have been identified. Further, among numerous plant products and natural medicines reputed to inhibit male fertility, the most widely tested was gossypol, a polyphenolic yellow pigment identified in China as causing epidemic infertility among workers ingesting raw cottonseed oil.
Although an effective male contraceptive, the systemic toxicity of gossypol and irreversibility precluded further clinical development Subsequently, extracts of Tripterygium wilfordii, a traditional Chinese herbal medicine for rheumatoid arthritis and skin disorders, inhibit fertility and impair sperm output and function in rodents and men. Studies aiming to characterise triptolide, an active component as a potential lead for an orally effective sperm function inhibitor reveal prominent induction of germ cell apoptosis at the testicular level in addition to a post-testicular site of action Additional opportunistic approaches include recognizing that the rapidly proliferating germinal epithelium is highly susceptible to cytotoxins such as drugs, heat or ionising irradiation which damage germ cell replication, resulting in inhibition of spermatogenesis.
However, complete elimination of sperm by non-specific toxicity compromises full reversibility and the accompanying mutagenic risk from direct interference with DNA replication precludes safe use for reversible male contraception. Alternatively, planned non-hormonal approaches to developing chemical male contraception focus on sperm development maturation and function.
Such approaches may exploit the numerous biological processes required for developing functionally mature, fertile sperm which creates abundant targets for reversible inhibition of male fertility figure 3. Prominent targets include either reducing sperm output via non-hormonal mechanisms regulating spermatogenesis or post-testicular inhibition of sperm functions. One approach to reduce sperm output is by exploiting the essential requirement for retinoic acid in spermatogenesis Experimental genetic or pharmacological inhibition of vitamin A action inhibits the generation of mature sperm and male fertility , ; however, the ubiquitous roles of vitamin A in cellular replication and differentiation requires thorough safety evaluation for off-target effects in clinical trials.
Another series of orally active indazole carboxylic acid analogs, adjudin, gamendazole and indenopyridine derivatives , have been developed from the lead compound lonidamine but aiming to eliminating its non-specific muscle and liver toxicity while retaining its mechanism of action in causing reversible male infertility. The indazole carboxylic acid analogs cause reversible subfertility by disrupting highly specialized intercellular junctions between elongating spermatids and Sertoli cells leading to precocious detachment of immature, elongating spermatids which are shed prematurely from the germinal epithelium.
Clinical evaluation of such drugs remains at an early stage. The seclusion of functionally immature post-meiotic, haploid sperm during their transit through seminiferous tubules and epididymis offers targets for chemical methods to regulate male fertility as sperm are stored and mature functionally. Post-testicular targets offer the advantages of fast onset and offset of action compared with hormonal methods; however, specific target identification, selective drug targeting to the epididymis or testis and human dose optimisation remain challenging problems.
A model, rapid-onset oral spermicide was first provided by the chlorosugars that showed rapid, irreversible effect on rodent epididymal sperm but proved too toxic for clinical development. A recent promising drug lead was the recognition that an alkylated iminosugar drugs that inhibit glucosyltransferase, used therapeutically to reduce lysosomal glycosphingolipid accumulation in storage disorder type 1 Gaucher's disease , miglustat, was a potent and reversible oral inhibitor of male mouse fertility but free from apparent systemic toxicity , Miglustat treatment produced structural malformation of sperm acrosome, head and mid-piece with consequential impaired motility although sperm retain the ability to fertilize oocytes in-vitro and produce normal offspring.
However, miglustat effects were species- and mouse strain-dependent and were not effective in rabbits or men Numerous proteins identified as specifically or uniquely expressed in the epididymis provide additional opportunities for development of novel non-hormonal male contraceptive targets Post-testicular inhibition of purinergic and adrenergic receptors in the vas deferens to inhibit sperm movement through the ejaculatory ducts are feasible , ; however, interference with ejaculation is unlikely to be an acceptable form of male contraception.
The most rapidly growing area of opportunity arises from serendipitous discoveries of genes found to be necessary for normal fertility, often from gene knock-out mouse models displaying unexpected male sterility or subfertility This rapidly expanding list includes distinctive steps in spermatogenesis involving either biological processes unique to spermatogenesis, notably meiosis two-stage reductive division of diploid germinal cells into haploid gametes and spermiogenesis metamorphosis of haploid round spermatids into spermatozoa or inhibiting functions essential to sperm fertilizing ability such as flagellar motility and sperm motion including hyperactivation , excurrent ductular transport, acrosome reaction, chemoattraction to and fertilization of oocytes , and acrosomal function The most frequent mechanisms involve inhibition of ion channels in sperm , or vas deferens smooth muscle , leading to inhibition of fertilization.
One leading candidate is CatSper, the principal calcium channel activated by progesterone and essential for the sperm hyperactivation required for fertilization Experimental vaccines against catsper epitopes do inhibit mutine fertility , The genes highlighted in a previous review are in black, with new genes identified since then and others not shown previously in blue.
Communication between each cellular compartment within the testis seminiferous tubules, interstitial cells and blood vessels, as well as between individual cell types germ cells, Sertoli cells, peritubular myoid cells, Leydig cells and macrophages play essential parts in mitosis, meiosis and differentiated function.
It is noteworthy that the genes fall into specific categories of function, such as those involved in signal transduction, homologous recombination or energy production. Gene targeting in the mouse models has provided new insights into potential etiologies of male infertility. Hormonal methods are the closest to meeting the requirement for a reliable, reversible, safe and acceptable male contraceptive.
Although reliability is judged by the efficacy in preventing pregnancy in fertile female partners, as a hormonal male contraceptive aims to prevent pregnancy by reversible inhibition of sperm output, the suppression of spermatogenesis constitutes a useful surrogate marker for development and evaluation of prototype male contraceptive regimens.
This makes defining the degree of suppression of sperm output required a key strategic issue in developing a hormonal male contraceptive Two landmark WHO studies, the first ever male contraceptive efficacy studies, involving men from 16 centres in 10 countries established the proof of principle that hormonally-induced azoospermia provides highly reliable, reversible contraception 10, Hence to achieve highly effective contraception, azoospermia is analogous to anovulation as a sufficient, but not necessary, requirement.
Nevertheless, reliable contraception by modern standards 19 requires uniform azoospermia as the desirable target for male contraceptive regimens No regimen yet achieves this consistently in all men, although in some Asian countries e.
China 11 , Indonesia , an approximation to uniform azoospermia can be achieved by a variety of regimens. A study involving Chinese men in 6 centres has shown that monthly injections of testosterone undecanoate provides highly effective and reversible contraception The prototype regimen was well tolerated apart from injection site discomfort due to large oil injection volume 4 mL and reversible androgenic effects acne, weight gain, hemoglobin, lipids. Nevertheless, despite these promising findings, non-Chinese men require combination hormonal regimens involving a 2nd gonadotropin suppressing agent, notably progestins, together with testosterone to ensure adequate spermatogenic suppression.
Ultimately, the efficacy of male contraception must be established by enumerating pregnancies prevented, and not counting sperm. The present paucity of male contraceptive efficacy studies, for which placebo controls are effectively impossible , makes systematic evaluations comparing practical clinical regimens a task for the future This comprehensive review of the recovery of healthy eugonadal men, aged years, who underwent Covariables such as age, ethnicity and hormonal or sperm output kinetics had significant but minor influence on the rate, but not the extent, of recovery.
Acceptability of a hormonal male contraceptive is high across a wide range of countries and cultures in potential male as well as female users 9. A majority of men in a US study were satisfied with and would recommend a transdermal gel-based hormonal contraceptive and a majority of Chinese men were satisfied with even frequent monthly injections Corroborating the acceptability of hormonal male contraception are findings from experimental studies of prototype regimens for up to 12 months usage in which most participants confirm high levels of satisfaction and willingness to try a commercial product , , , Modern safety evaluation for hormonal contraceptive methods requires long-term, large scale studies of marketed products Consequently, in the absence of any marketed male contractive, no long-term safety profile can be discerned.
Nevertheless, 4 decades of clinical trials have consistently identified mainly minor adverse effects in short- or medium term studies of prototype male hormonal contraception regimens 1, 5, This was verified in a unique, placebo-controlled study of a combined androgen-progestin regimen which again proved highly effective at reversible suppression of sperm output although the inclusion of a placebo arm rendered it ethically impossible to evaluate contraceptive efficacy but provided insight into drug-related side effects 8.
The study confirmed the benign medium-term safety profile for this prototype regimen in observing few serious adverse effects, none attributable to the steroid regimen, and, among the non-serious adverse effects reported, expected androgenic effects acne, weight gain, sweating, changes in mood or libido were more frequent than placebo but mild and rarely led to discontinuation 8.
Nevertheless, the long-term safety evaluation of novel contraceptives requires large scale observational studies of extensively used drugs to define low frequency risks but can only occur after the marketing of suitable products.
Hence, prototype hormonal methods have proven reliability and reversibility and reasonable prospects for being well accepted and safe. Although they are the most likely opportunity in the foreseeable future to develop a practical contraceptive method for men, progress depends on pharmaceutical industry development.
However, leadership in male contraceptive development has come almost exclusively from the academics working with public sector organisations 5 , notably WHO , CONRAD and the Population Council By contrast, commitment from pharmaceutical companies, including those that flourished in the post-war decades through developing female hormonal contraception, continued to languish over recent decades 16, and is effectively ceased 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 , systematic studies of androgens for male contraception began in the 's , Feasibility and dose-finding studies , mostly using testosterone enanthate TE in an oil vehicle as a prototype, showed that weekly im injections of mg TE induce azoospermia in most Caucasian men but less frequent or lower doses fail to sustain suppression The largest experience with an androgen alone regimen arises from the two WHO studies in which over men from 16 centres in 10 countries received weekly injections of mg TE.
The high efficacy among Chinese men has also been replicated using monthly TU injections 12, Effective gonadotropin suppression is a prerequisite for effective testosterone-induced spermatogenic suppression in human 14, and non-human primates , However, the reasons for within and between population differences in susceptibility to hormonally-induced azoospermia remain largely unexplained While it is postulated that the very high ambient intratesticular testosterone typically times circulating testosterone concentrations must be fully suppressed by complete inhibition of circulating LH, which maintains it , limited invasive studies measuring intratesticular testosterone and DHT suggest that the degree of depletion may not predict reliably complete suppression of sperm output Other more widely applicable, non-invasive markers of endogenous Leydig cell function such as circulating epitestosterone or hydroxyprogesterone or non-steroidal testicular products such as INSL3 may be informative as to the relative roles of gonadotropin suppression and intratesticular androgen depletion.
Following cessation of treatment, sperm reappear within 3 months to reach sperm densities of 10 and 20 million per mL at an average of Apart from intolerance of weekly injections, there were few discontinuations due to acne, weight gain, polycythemia or behavioral effects and these were reversible as were changes in hemoglobin, testis size and plasma urea.
There was no evidence of liver, prostate or cardiovascular disorders 10, 11, The pharmacokinetics of testosterone products are crucial for suppressing sperm output. Oral androgens have major first-pass hepatic effects producing prominent route-dependent effects on hepatic protein secretion eg SHBG, HDL cholesterol and inconsistent bioavailability.
Short-acting testosterone products requiring daily or more frequent administration oral, transdermal patches or gels which may be acceptable for androgen replacement therapy are not appropriate for hormonal contraception. Weekly TE injections required for maximal suppression of spermatogenesis are far from ideal and cause supraphysiological blood testosterone levels risking both excessive androgenic side effects and preventing maximal depletion of intratesticular testosterone for optimal efficacy , Other currently available oil-based testosterone esters cypionate, cyclohexane-carboxylate, propionate are no improvement over the enanthate ester , and longer-acting depot preparations are needed.
Subdermal testosterone pellets sustain physiological testosterone levels for months and the newer injectable preparations testosterone undecanoate 13 , testosterone-loaded biodegradable microspheres and testosterone buciclate provide months duration of action. Depot androgens suppress spermatogenesis faster, at lower doses and with fewer metabolic side effects than TE injections but azoospermia is still not achieved uniformly although when combined with a depot progestin, this goal is achievable Oral synthetic a alkylated androgens such as methyltestosterone , fluoxymesterone , methandienone and danazol , suppress spermatogenesis but azoospermia is rarely achieved and the inherent hepatotoxicity of the a alkyl substitutent , renders them unsuitable for long-term use.
Athletes self-administering supratherapeutic doses of androgens also exhibit suppression of spermatogenesis , On the other hand, nandrolone hexyloxyphenylpropionate alone was unable to maintain spermatogenic suppression induced by a GnRH antagonist in a prototype hybrid regime where induction and maintenance treatment differ whereas testosterone appears more promising More potent, synthetic androgens lacking a alkyl groups , remain to be evaluated.
Antiandrogens have been used to selectively inhibit epididymal and testicular effects of testosterone without impeding systemic androgenic effects Cyproterone acetate, a steroidal antiandrogen with progestational activity, suppresses gonadotropin secretion without achieving azoospermia but leads to androgen deficiency when used alone In contrast, pure non-steroidal antiandrogens lacking androgenic or gestagenic effects such as flutamide, nilutamide and casodex fail to suppress spermatogenesis when used alone , Two studies evaluating the hypothesis that incomplete suppression of spermatogenesis is due to persistence of testicular DHT have reported no additional suppression from administration of finasteride, a type II 5a reductase inhibitor , ; however as testes express predominantly the type I isoforms , further studies are required to conclusively test this hypothesis using an inhibitor of type I 5-a reductase Adverse effects due to testosterone administration in prototype hormonal contraceptive regimens include asymptomatic polycythemia, weight muscle gain and acne as well as changes in mood or sexual behaviour.
These are usually minor in severity, reversible upon cessation of treatment and of minimal clinical significance 8. The safety of androgen administration concerns mainly potential effects on cardiovascular and prostatic disease As the explanation for the higher male susceptibility to cardiovascular disease is not well understood, the risks of exogenous androgens are not clear , In clinical trials, lipid changes are minimal with depot non-oral hormonal regimens 14, , , The real cardiovascular risks or benefits of hormonal male contraception will require long-term surveillance of cardiovascular outcomes The long-term effects of exogenous androgens on the prostate also require monitoring since prostatic diseases are both age and androgen-dependent.
Exposure to adult testosterone levels is required for prostate development and disease The precise relationship of androgens to prostatic disease and in particular any influence of exogenous androgens remains poorly understood. Ambient blood testosterone or DHT levels do not predict development of prostatic cancer over future decades in prospective studies of adults A genetic polymorphism, the CAG polyglutamine triplet repeat in exon 1 of the androgen receptor, is an important determinant of prostate sensitivity to circulating testosterone with short repeat lengths leading to increased androgen sensitivity , however the relationship of the CAG triplet repeat length polymorphism to late-life prostate diseases remains unclear Among androgen deficient men, prostate size and PSA concentrations are reduced and returned towards normal by testosterone replacement without exceeding age-matched eugonadal controls , In healthy middle-aged men without known prostate disease, very high doses of the potent natural androgens DHT for 2 years did not increase prostate size or age-related growth rate compared with placebo indicating that effects of even high dose exogenous androgen treatment has much less effect than age on the human prostate Similarly, self-administration of massive androgen over-dosage does not increase total prostate volume or PSA in anabolic steroid abusers although central prostate zone volumes increases In-situ prostate cancer is common in all populations of older men whereas rates of invasive prostate cancer differ many-fold between populations despite similar blood testosterone concentrations.
This suggests that early and prolonged exposure to androgens may initiate in-situ prostate cancer but later androgen-independent environmental factors promote the outbreak of invasive prostate cancer. Therefore it is prudent to maintain physiological androgen levels with exogenous testosterone, which then might be no more hazardous than exposure to endogenous testosterone.
Prolonged surveillance comparable with that for cardiovascular and breast disease in users of female hormonal contraception would be equally essential to monitor both cardiovascular and prostatic disease risk in men receiving exogenous androgens for hormonal contraception.
Extensive experience with testosterone in doses equivalent to replacement therapy in normal men indicates minimal effects on mood or behavior 10, 11, ,