Pharmacokinetics of testosterone cream applied to scrotal skin.

Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone delivered via the scrotal skin route. The study was a single-center, three-phase cross-over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate. Serum testosterone, DHT and estradiol concentrations were measured by liquid chromatograpy, mass spectrometry in extracts of serum taken before and for 16 h after administration of each of the three doses of testosterone cream to the scrotal skin. Testosterone administration onto the scrotal skin produced a swift (peak 1.9-2.8 h), dose-dependent (p < 0.0001) increase in serum testosterone with the 25 mg dose maintaining physiological levels for 16 h. Serum DHT displayed a time- (p < 0.0001), but not dose-dependent, increase in concentration reaching a peak concentration of 1.2 ng/mL (4.1 nm) at 4.9 h which was delayed by 2 h after peak serum testosterone. There were no significant changes in serum estradiol over time after testosterone administration. We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route.

Complications of injectable testosterone undecanoate in routine clinical practice.

OBJECTIVE: Injectable testosterone undecanoate (TU) was marketed within the last decade, but its complications in routine clinical practice are not well defined. DESIGN AND METHODS: Prospective observational study of consecutive TU injections in an Andrology Clinic to estimate the incidence of i) immediate cough/syncope due to pulmonary oil microembolisation (POME), ii) post-injection haematoma and iii) the prevalence of secondary polycythaemia. RESULTS: In 3022 injections given to 347 patients over 3.5 years, POME was observed after 56 injections (66% mild, 19% severe; 40% with onset before injection completed) in 43 patients. The incidence of 19 (95% CI 14-24) per 1000 injections did not differ between three experienced nurse injectors, but recurrences were more frequent than by chance. No post-injection haematoma was reported including after 269 injections to men taking antiplatelet, anticoagulant or both drugs (upper 95% confidence limit 1%) with 56 not withholding drugs prior to TU administration (upper 95% confidence limit 5.4%). Mean haematocrit was 0.44±0.04 (s.d.) with 25 (7%) >0.50, 14 (4%) >0.52 and 3 (1%) >0.54. CONCLUSION: TU injections produce a low incidence of POME with injections by experienced nurses, but recurrence is more frequent than by chance. Post-injection haematoma was not observed even among men using anticoagulant and/or antiplatelet drugs, and polycythaemia was a minor problem rarely requiring treatment other than optimising inter-injection interval.

Dispersion of a Nanoliter Bolus in Microfluidic Co-Flow.

Microfluidic systems enable reactions and assays on the scale of nanoliters. However, at this scale nonuniformities in sample delivery become significant. To determine the fundamental minimum sample volume required for a particular device, a detailed understanding of mass transport is required. Co-flowing laminar streams are widely used in many devices, but typically only in the steady-state. Because establishing the co-flow steady-state consumes excess sample volume and time, there is a benefit to operating devices in the transient state, which predominates as the volume of the co-flow reactor decreases. Analysis of the co-flow transient has been neglected thus far. In this work we describe the fabrication of a pneumatically controlled microfluidic injector constructed to inject a discrete 50nL bolus into one side of a two-stream co-flow reactor. Using dye for image analysis, injections were performed at a range of flow rates from 0.5-10µL/min, and for comparison we collected the co-flow steady-state data for this range. The results of the image analysis were also compared against theory and simulations for device validation. For evaluation, we established a metric that indicates how well the mass distribution in the bolus injection approximates steady-state co-flow. Using such analysis, transient-state injections can approximate steady-state conditions within predefined errors, allowing straight forward measurements to be performed with reduced reagent consumption.

Randomised controlled trial of whether erotic material is required for semen collection: impact of informed consent on outcome.

Semen is collected to evaluate male fertility or cryostore sperm preferentially in laboratories but such collection facilities have no standard fit-out. It is widely believed but untested whether providing erotic material (EM) is required to collect semen by masturbation in the unfamiliar environment. To test this assumption, 1520 men (1046 undergoing fertility evaluation, 474 sperm cryostorage, providing 1932 semen collection episodes) consecutively attending the semen laboratory of a major metropolitan teaching hospital for semen analysis were eligible for randomization to be provided or not with printed erotic material EM (X-rated, soft-core magazines) during semen collection. Randomization was performed by providing magazines in the collection rooms (as a variation on non-standard fit-out) on alternate weeks using a schedule concealed from participants. In the pilot study, men were randomized without seeking consent. In the second part of the study, which continued on from the first without interruption, an approved informed consent procedure was added. The primary outcome, the time to collect semen defined as the time from receiving to returning the sample receptacle, was significantly longer (by ~6%, 14.9 ± 0.3 [mean ± standard error of mean] vs. 14.0 ± 0.2 minutes, p = 0.02) among men provided with EM than those randomized to not being provided. There was no significant increase in the failure to collect semen samples (2.6% overall) nor any difference in age, semen volume or sperm concentration, output or motility according to whether EM was provided or not. The significantly longer time to collect was evident in the pilot study and the study overall, but not in the main study where the informed consent procedure was used. This study provides evidence that refutes the assumption that EM needs to be provided for semen collection in a laboratory. It also provides an example of a usually unobservable participation bias influencing study outcome of a randomized controlled trials.

Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study.

BACKGROUND: Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. OBJECTIVE: To assess the effects of testosterone and nandrolone, a non-amplifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. DESIGN: Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. SETTING: Ambulatory care research centre. PARTICIPANTS: Healthy young men randomized into three groups of 10 men. INTERVENTION: Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. MAIN OUTCOME MEASURES: Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. RESULTS: Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167 +/- 13 vs. 154 +/- 12, P = 0.03). CONCLUSION: Four weeks of treatment with testosterone or nandrolone had no beneficial or adverse effects compared with placebo on cardiac function in healthy young men.

Blood testosterone threshold for androgen deficiency symptoms.

There are few systematic studies of the relationship between blood testosterone concentrations and the symptoms of overt androgen deficiency. Because most testosterone preparations are relatively short-term, the rapid changes in blood testosterone concentrations they cause make it difficult to define any testosterone threshold. By contrast, subdermal testosterone implants provide stable blood testosterone concentrations over days to weeks, while gradually declining to baseline over 5-7 months. Hence, this provides an opportunity to define a blood testosterone threshold for androgen deficiency symptoms by observing androgen-deficient men as their familiar androgen deficiency symptoms return as testosterone pellets slowly dissolve. Among 52 androgen-deficient men who underwent 260 implantations over 5 yr, at the time of return of androgen deficiency symptoms the blood total and free testosterone concentrations were highly reproducible within individuals (F = 0.8, P = 0.49 and F = 1.4, 0.24, respectively) but varied markedly between men (F = 167 and F = 138, both P < 0.001), indicating that each person had a consistent testosterone threshold for androgen deficiency symptoms that differed markedly between individuals. The most reported symptoms of androgen deficiency were lack of energy, lack of motivation, and reduced libido. The symptomatic threshold was significantly lower in men with secondary hypogonadism compared with men with primary or mixed hypogonadism (total, 9.7 +/- 0.5 nmol/liter vs. 11.7 +/- 0.4 nmol/liter and 10.2 +/- 0.3 nmol/liter, P = 0.006; free, 146 +/- 10 pmol/liter vs. 165 +/- 6 pmol/liter and 211 +/- 18 pmol/liter, P = 0.002) but was not affected by the underlying cause of hypogonadism or by specific symptoms of any severity. Despite a wide range in individual thresholds for androgen deficiency symptoms, the mean blood testosterone threshold corresponded to the lower end of the eugonadal reference range for young men. The implications of these observations for the development of more specific quality-of-life measures, as well as for other potential androgen deficiency states such as chronic diseases and aging, remain to be determined.

Testosterone release rate and duration of action of testosterone pellet implants.

OBJECTIVE: Testosterone pellets are a highly effective subdermal depot administered at regular intervals with the timing individualized depending upon return of the patient's characteristic androgen deficiency symptoms. Yet the in vivo testosterone release rate and effective duration of action of these pellets has been little studied systematically. DESIGN: Analysis of prospectively collected data from three randomized controlled clinical trials. Collection of extruded pellets. PATIENTS: Androgen-deficient men (n = 136) undergoing long-term androgen replacement therapy with a standard dose (800 mg) of testosterone pellets implanted subdermally at intervals from 5 to 7 months. MEASUREMENTS: Testosterone release rate of pellets, consisting of pure crystalline testosterone without excipients, is estimated by measuring the dry weight lost by pellets (n = 179) over their time in situ. The effective duration of the standard regimen, and the influence of extrusion and patient or procedural characteristics on it, was estimated by timing of return for re-implantation due to recurrence of the patient's familiar androgen deficiency symptoms. RESULTS: The loss of dry weight of intact (n = 112) pellets was strongly correlated with time in situ (r2 = 0.969) providing an estimate of daily testosterone release rate per 200 mg pellet of 1.34 +/- 0.02 mg/pellet/day (95% CI 1.30-1.37 mg/day) for the first 3 months. After 756 implantations of the standard dose, men return for re-implantation at 5.8 calendar months following no or only a single pellet extrusion, but the time to return was significantly shorter after multiple extrusions. No patient or procedural features influenced the timing of return. Among men with primary hypogonadism, increases in plasma LH and FSH were more sensitive than plasma total or free testosterone to changes in testosterone delivery following an extrusion. CONCLUSION: Testosterone pellet implants release testosterone at a steady rate of 1.3 mg/200 mg implant/day (95% CI). The duration of action is about 6 months in an uncomplicated cycle with timing of return shortened by extrusions only in the 3.6% of procedures followed by multiple extrusions. No other patient or procedural features influenced duration of action. Among men with an intact hypothalamo-pituitary unit, plasma gonadotropins are more sensitive than blood total or free testosterone to reduced testosterone delivery following an extrusion.

A randomised controlled clinical trial of antibiotic impregnation of testosterone pellet implants to reduce extrusion rate.

OBJECTIVE: Testosterone pellet implantation is a safe, effective and convenient form of depot androgen replacement, with extrusion of pellets following about 10% of procedures the most frequent adverse effect. This study aimed to determine whether extrusion rate could be reduced by antibiotic impregnation of pellets immediately prior to implantation. DESIGN: Prospective, randomised, parallel-group, open-label study design in a single centre. One hundred and eighty-six androgen-deficient men (400 implantation procedures) were randomised into either a group who had their pellets soaked for approximately 2 min in gentamicin solution prior to implantation, or a control group who had the standard implantation procedure. METHODS: Extrusion, infection and/or bruising were evaluated prospectively by self-report from the participants, and retrospectively at subsequent implantation. Other variables (site, shaving, skin preparation, operator, pellet batch, bruising) were collected at implantation time. RESULTS: The extrusion rate was 20% lower (odds ratio=0.80, 95% confidence interval (CI) 0.40-1.62) but not statistically different between the two groups (extrusion rate 23/205 (11.2%) for the control group vs 18/195 (9.2%) for the antibiotic-soak group, P=0.42). One operator experienced more total (P=0.0002) and infection-related (P=0.0008) extrusions and marginally more bruising (P=0.06) than other operators. The operator effect did not appear to be explained by differences in experience or implantation style. There was a 4.6-fold excess (95% CI 1.6-18.6) of multiple (19 vs 4 expected) over single (22 vs 10 expected) and no (359 vs 386 expected) extrusions. Extrusion was not related to batch number (P=0.15), location (P=0.15), shaving (P=0.32), old or new site (P=0.59), or the presence of suppuration or not (P=0.42); however, povidone-iodine skin disinfectant had statistically fewer extrusions than mixed alcohol solution. CONCLUSIONS: Antibiotic impregnation prior to implantation does not significantly decrease testosterone pellet extrusion rate. An operator effect, not due to experience or procedural style, an excess of multiple extrusions and disinfectant effects were confirmed. Neither location, nor preparation of the site, nor pellet batch, influences extrusion rate.

Long-term outcomes of elective human sperm cryostorage.

BACKGROUND: Sperm cryopreservation allows men with threatened fertility to preserve their progenitive potential, but there is little data on long-term outcomes of elective sperm cryostorage programmes. METHODS AND RESULTS: Over 22 years, 930 men sought semen cryostorage in a single academic hospital, of which 833 (90%) had spermatozoa cryostored. Among 692 (74%) men surviving their illness, sperm samples were discarded for 193 (21% of all applicants, 28% of survivors) and cryostored spermatozoa were used for 64 men (7% of all applicants, 9% of survivors) in 85 treatment cycles commencing at a median of 36 months post-storage (range 12-180 months) with nearly 90% of usage started within 10 years of storage and none after 15 years. Pregnancy was most efficiently produced by intracytoplasmic sperm injection (median three cycles) compared with conventional IVF (median eight cycles) or artificial insemination (median more than six cycles; P < 0.05). A total of 141 (15%) of men had died and of these, 120 (85% of those dying) had their spermatozoa discarded; requests to prolong cryostorage were received from relatives of 21 men (2% of all applicants, 15% of deceased) of which three cases had spermatozoa transferred for use with no pregnancies reported. Sperm concentration was lower for all cryostorage groups compared with healthy sperm donor controls (P < 0.05). Following orchidectomy, men with testicular cancer had sperm density approximately half that of all other groups of men seeking cryostorage (P < 0.05), the lowering attributable to removal of one testis rather than in defects in spermatogenesis. CONCLUSION: Elective sperm cryopreservation is an effective, if sparsely used, form of fertility insurance for men whose fertility is threatened by medical treatment and is an essential part of any comprehensive cancer care programme.

Influence of implantation site and track geometry on the extrusion rate and pharmacology of testosterone implants.

BACKGROUND: Implantation of testosterone pellets under the lateral abdominal wall skin is an old but popular and effective form of androgen replacement therapy. Extrusion of one or more pellets remains the most frequent adverse event. OBJECTIVE: To determine whether an alternative implantation site (hip) and/or track geometry (two vs. four tracks) would reduce extrusion rates compared with the standard of a four-track abdominal site. Additionally, the study aimed to evaluate the effects of site and track geometry on other adverse effects (bruising, infection) and the pharmacology of testosterone release from the implants. DESIGN: A prospective, parallel-group unmasked study design in a single centre. The primary objective was to evaluate sites, with evaluation of track geometry a subordinate objective made necessary by anatomical differences. Accordingly, androgen deficient men requiring testosterone implantation with the standard dose (four 200 mg pellets) were randomized into one of three groups (ratio 1 : 1 : 2): a four-track abdomen site (standard), a two-track abdomen site or a two-track hip site. The pharmacological substudy was to evaluate the impact of site and track geometry on testosterone implant pharmacology by monthly hormone assays following implantation. PATIENTS: Two hundred and forty-six implantation procedures involving 96 androgen deficient men. MEASUREMENTS: The primary end-point, extrusion rate per procedure, and secondary end-points (bruising or infection post procedure) were evaluated prospectively by self-report from the participants, and verified when they returned next for implantation. The pharmacology substudy involved monthly blood sampling for hormone (total and free testosterone, LH, FSH) measurements. RESULTS: The extrusion rate was significantly higher [odds ratio (OR) = 2.6, 95% confidence interval (CI) 1.1-7.1] for the hip site (15/125, 12%) compared with the abdominal site (6/121, 5%). Track geometry made no significant difference (OR = 1.05, 95% CI 0.2-5.4) to the extrusion rate. No secondary end-points (bruising, infection) were significantly different according to either site or track geometry. One operator who performed the implant procedures had significantly less primary and secondary adverse events than the other operators (P = 0.006). Neither implantation site, nor track geometry influenced pharmacokinetics [peak plasma total and free testosterone concentrations and net hormone release (area-under-curve, AUC)] or pharmacodynamics [nadir plasma LH and FSH and net suppression (AUC) in men with hypergonadotrophic hypogonadism]. CONCLUSIONS: We conclude that the hip site has a higher extrusion rate than the standard abdominal wall site but that track geometry does not increase the risk of extrusion. Neither implantation site, nor track geometry influenced either other adverse effects or the pharmacokinetics or pharmacodynamics of testosterone pellet implants.

A double-blind, placebo-controlled, randomized clinical trial of transdermal dihydrotestosterone gel on muscular strength, mobility, and quality of life in older men with partial androgen deficiency.

The efficacy and safety of androgen supplementation in older men remains controversial. Despite biochemical evidence of partial androgen deficiency in older men, controlled studies using T demonstrate equivocal benefits. Furthermore, the importance of aromatization and 5alpha reduction in androgen actions among older men remains unclear. Dihydrotestosterone is the highest potency natural androgen with the additional features that it is neither aromatizable nor susceptible to potency amplification by 5alpha reduction. Therefore, the effects of dihydrotestosterone may differ from those of T in older men. This study evaluated the efficacy and safety of 3 months treatment with transdermal dihydrotestosterone gel on muscle strength, mobility, and quality of life in ambulant, community-dwelling men aged 60 yr or older. Eligible men (plasma T < or =15 nmol/liter) were randomized to undergo daily dermal application of 70 mg dihydrotestosterone gel (n = 18) or vehicle (n = 19) and were studied before, monthly during, and 1 month after treatment. Among 33 (17 dihydrotestosterone, 16 placebo) men completing the study with a high degree of compliance, dihydrotestosterone had significant effects on circulating hormones (increased dihydrotestosterone; decreased total and free testosterone, LH, and FSH; unchanged SHBG and estradiol), lipid profiles (decreased total and low-density lipoprotein cholesterols; unchanged high-density lipoprotein cholesterol and triglycerides), hematopoiesis (increased hemoglobin, hematocrit, and red cell counts), and body composition (decreased skinfold thickness and fat mass; unchanged lean mass and waist to hip ratio). Muscle strength measured by isokinetic peak torque was increased in flexion of the dominant knee but not in knee extension or shoulder contraction, nor was there any significant change in gait, balance, or mobility tests, in cognitive function, or in quality of life scales. Dihydrotestosterone treatment had no adverse effects on prostate (unchanged prostate volumes and prostate-specific antigen) and cardiovascular (no adverse change in vascular reactivity or lipids) safety markers. We conclude that 3 months treatment with transdermal dihydrotestosterone gel demonstrates expected androgenic effects, short-term safety, and limited improvement in lower limb muscle strength but no change in physical functioning or cognitive function.

Effects of androgen deficiency and replacement on prostate zonal volumes.

BACKGROUND AND OBJECTIVES: Androgens play a key role in prostate development and disease. However the effects of androgen deficiency and replacement on the prostate during mid-life are not well understood, and there is no information on their effects on prostate zonal volumes. This study aimed to define the effects of androgen deficiency and androgen replacement therapy on prostate zonal volumes (central, peripheral & total) using planimetric prostate ultrasound with particular emphasis on the central zone of the prostate, the most hormonally sensitive and fastest growing region of the prostate and the zone where nodular benign prostate hyperplasia originates. PATIENTS AND MEASUREMENTS: Central and total prostate volume were measured directly, and peripheral prostate volume calculated, by a single observer using transrectal ultrasound in 71 hypogonadal men (aged 40 +/- 2, range 18-78 years) who were compared with individually age-matched health controls without prostate or gonadal disease. Among the men with androgen deficiency, 17 men had untreated androgen deficiency (never treated or no treatment for at least 6 months) and 54 men were receiving long-term androgen replacement therapy (median 32 months, 93% > or = 6 months) with testosterone implants (n = 27), testosterone ester injections (n = 24) or other testosterone treatment (n = 3). RESULTS: Compared with individually age-matched controls, untreated androgen deficient men (n = 17) had reduced central (4.0 +/- 0.5 vs. 6.2 +/- 0.5 ml, P < 0.001) and total (23.4 +/- 2.6 vs. 29.2 +/- 1.6 ml, P < 0.001) prostate volumes whereas the reduction in peripheral prostate volume (19.4 +/- 2.1 vs. 23.0 +/- 1.3 ml, P = 0.15) was not statistically significant. Men with treated androgen deficiency (n = 54) also still had significantly reduced central (4.8 +/- 0.4 vs. 6.8 +/- 0.4, P < 0.001), peripheral prostate volume (19.6 +/- 0.8 vs. 21.6 +/- 0.7 ml, P = 0.06) and total (24.4 +/- 1.1 vs. 28.4 +/- 1.0 ml, P = 0.008) despite prolonged restoration of physiological testosterone concentrations. Neither modality of testosterone treatment nor type of hypogonadism influenced prostate zonal volumes before or after treatment. In contrast, central, peripheral and total prostate volume increased with age among healthy controls and men with androgen deficiency regardless of androgen replacement therapy. Plasma PSA concentrations were reduced in men with untreated androgen deficiency and were similar to age-matched controls in men with treated androgen deficiency. CONCLUSIONS: We conclude that, during mid-life, chronic androgen deficiency due to hypogonadism is associated with reduced central, peripheral and total prostate volumes. Reduced prostate volumes persist even during long-term maintenance of effective androgen replacement therapy with physiological testosterone concentrations until the fourth decade of life. After that, prostate volumes increase with age regardless of androgen deficiency or replacement. These findings suggest that, during mid-life, age is a more important determinant of prostate growth than ambient testosterone concentrations maintained in the physiological range. The persistently subnormal prostate volumes despite adequate androgen replacement therapy may explain the apparent paucity of cases of overt prostate disease among testosterone-treated androgen deficient men who retain protection against prostate disease despite physiological androgen replacement therapy.

Use, misuse and abuse of androgens. The Endocrine Society of Australia consensus guidelines for androgen prescribing.

Androgen replacement therapy (ART) is usually life-long, and should only be started after androgen deficiency has been proven by hormone assays. The therapeutic goal is to maintain physiological testosterone levels. Testosterone rather than synthetic androgens should be used. Oral 17 alpha-alkylated androgens are hepatotoxic and should not be used for ART. There is no indication for androgen therapy in male infertility. Although androgen deficiency is an uncommon cause of erectile dysfunction, all men presenting with erectile dysfunction should be evaluated for androgen deficiency. If androgen deficiency is confirmed, investigation for the underlying pathological cause is required. Contraindications to androgen therapy are prostate and breast cancer. Precautions include using lower starting doses for older men and induction of puberty. Intramuscular injections should be avoided in men with bleeding disorders. Androgen-sensitive epilepsy, migraine, sleep apnoea, polycythaemia or fluid overload need to be considered. Competitive athletes should be warned about the risks of disqualification. ART should be initiated with intramuscular injections of testosterone esters, 250 mg every two weeks [corrected]. Maintenance requires tailoring treatment modality to the patient's convenience. Modalities currently available include testosterone injections, implants, or capsules. Choice depends on convenience, cost, availability and familiarity. There is no convincing evidence that, in the absence of proven androgen deficiency, androgen therapy is effective and safe for older men per se, in men with chronic non-gonadal disease, or for treatment of non-specific symptoms. Until further evidence is available, such treatment cannot be recommended.

Oestradiol enhances testosterone-induced suppression of human spermatogenesis.

The aim of this study was to determine for the first time in humans, the efficacy of adding a low dose oestradiol to a suboptimally suppressive testosterone dose in a depot hormonal regimen to suppress spermatogenesis in healthy eugonadal men. Twenty-six healthy men were randomized into groups that were treated by a single subdermal implantation of either 600 mg testosterone alone (T; n = 11) or together with 10 mg (TE10, n = 7) or 20 mg (TE20, n = 8) oestradiol. Administration of oestradiol produced a dose-dependent increase in peak plasma oestradiol at 1 month and prolonged suppression of plasma LH and FSH leading to significantly enhanced suppression of sperm output. Despite the augmented spermatogenic suppression, there was no significant difference in the proportions achieving azoospermia (6/26, 23%) or severe oligozoospermia (<1 or <3 x 10(6) spermatozoa per ml, 7/26, 27%) and overall these proportions were inadequate to provide reliable contraception according to the standards identified in World Health Organization male contraceptive efficacy studies. Total and free testosterone remained within the eugonadal reference range for young men throughout the study. While the lower oestradiol dosage had minimal spermatogenic suppression effects, the higher dose produced dose-limiting adverse effects of androgen deficiency and/or oestrogen excess between the fourth and sixth month of the study. This appeared to be due to the unexpectedly prolonged, low concentration of oestradiol release from the oestradiol implants. There were no significant treatment-related changes in body composition, lipids, prostate-specific antigen, haematological or biochemical variables. Thus oestradiol has a low therapeutic window and dose-limiting side-effects at dosages that fail to achieve the uniform azoospermia required of an effective male hormonal contraceptive regimen.

Extrusion of testosterone pellets: a randomized controlled clinical study.

BACKGROUND: It has previously been shown that testosterone implantation is an effective and well accepted form of androgen replacement therapy, but that pellet extrusion was the most frequent side-effect. The present study aimed to reduce the extrusion rate. OBJECTIVE: To determine whether the washing of testosterone pellets to remove potentially surface-adherent particles decreased the rate of extrusion of pellet implants. DESIGN: Prospective, randomized parallel group design in a single centre with consecutive procedures to be randomized (1 : 1) into a wash or control group. PATIENTS: The study included 251 testosterone implantation procedures in men with known androgen deficiency. MEASUREMENTS: The primary endpoint, extrusion rate per procedure, was evaluated prospectively by telephone contact at 1 week and then 3 and 6 month intervals. Secondary end-points included peri-procedure adverse events (bleeding, skin reaction, excessive discomfort) noted at the time of implant. Bruising, bleeding and infection were also evaluated as later adverse events by telephone and personal follow-up. Explanatory variables recorded as possible covariables included the number of implants used, production batch number of the implants, the operator, as well as other demographic and medical factors. RESULTS: In the wash group, the extrusion rate was 12% per procedure (19 pellets from 15 subjects) whereas in the control group, the extrusion rate was 11.1% per procedure (18 pellets from 14 subjects), indicating no evidence of any benefit of the wash procedure (OR = 1. 09 [95% CI 0.47-2.6] per procedure). There was no evidence of benefit in secondary endpoints including total adverse events (7.1%, OR 1.28 [0.44-3.9], bleeding/bruising (8.8%, 1.23 [0.47-3.3]) and infection (4.0%, 1.54 [0.35-7.6]) per procedure. Among men reporting an infection requiring antibiotic treatment according to their own general practitioners, six/ten (60%) subsequently experienced an extrusion. There were no significant differences in extrusion rate between four different operators (P = 0.24) nor among 12 different batches of pellets used during the course of the study (P = 0.77). CONCLUSIONS: The pellet washing procedure used during implantation does not reduce the subsequent extrusion rate. The higher rate of both primary and secondary adverse events in this prospective study compared with the previous retrospective survey may reflect either more rigorous follow-up or a secular trend.

Efficacy and safety of recombinant human follicle stimulating hormone (Gonal-F) with urinary human chorionic gonadotrophin for induction of spermatogenesis and fertility in gonadotrophin-deficient men.

In order to evaluate the efficacy and safety of recombinant human follicle stimulating hormone (r-hFSH) in combination with urinary human chorionic gonadotrophin (HCG) to induce spermatogenesis and fertility in gonadotrophin-deficient men, we conducted a prospective, open, non-comparative multicentre study in two Australian academic medical centres. Ten men with gonadotrophin deficiency requiring induction of spermatogenesis and fertility were treated with HCG for 3-6 months followed by the s.c. self-administration of injections of r-hFSH in combination with HCG for 18 months. Among the eight men who commenced r-hFSH treatment, seven demonstrated sperm output at a median of 6 months and five achieved the target sperm output of 1. 5x10(6) per ml at a median of 9 months of FSH treatment. Mean testicular volume increased by 4.2 ml during FSH treatment. Three men produced pregnancies in their partners, two of which resulted in the birth of healthy babies and a third patient's partner had a miscarriage. We conclude that r-hFSH is well tolerated and effective in inducing testis growth, spermatogenesis and fertility in gonadotrophin-deficient men. The efficacy of r-hFSH seems comparable with urinary FSH at restoring normal fertility in gonadotrophin-deficient men.

An analysis of testosterone implants for androgen replacement therapy.

OBJECTIVE: To review 13 years of experience using fused crystalline testosterone implants for androgen replacement therapy in order to identify pattern of usage (including continuation rates) and adverse events emerging during therapy and factors associated with adverse events including implant extrusions. DESIGN: Retrospective review of prospectively collected data on characteristics of patients and implant procedures performed as well as adverse events reported during routine follow-up. PATIENTS: Over 13 years 973 implant procedures using fused crystalline testosterone implants were performed in 221 men. MEASUREMENTS: Continuation rates and adverse events such as extrusions, bleeding, infection or others were recorded and analysed in relationship to characteristics of the patient and the implant procedure performed. RESULTS: Overall rate of adverse events (108/73, 11.1%) was significantly related to increased numbers of implants (4.2 +/- 0.1 vs 4.0 +/- 0.03, P = 0.031) and higher levels of physical activity at work (P = 0.030). The most common adverse effect was extrusion (83/973, 8.5%) which was related to occupational classification (P = 0.033) and increasing work activity (P = 0.044) and occurred more frequently than by chance in multiple (16 vs 3.3 expected) rather than single (65 vs 76.1 expected) episodes. Bleeding (22/973, 2.3%) was significantly associated with an increased number of implants (4.5 +/- 0.2 vs 4.0 +/- 0.03, P = 0.020) but even in the worst cases (3/22) it was of minor clinical importance. Infection was rare (6/973, 0.6%) but occurred more among thinner men. The overall continuation rate was 92.7% increasing from 86% after the first implantation to > 99% after the tenth implant. CONCLUSIONS: This study demonstrates the very satisfactory clinical acceptability of testosterone pellet implants for androgen replacement therapy within a single unit with experienced operators. The only regular adverse effect is extrusion, which may be related to mechanical factors such as habitual work activity but also possibly procedural factors. Other adverse effects such as bleeding, infection and fibrosis were rare. An improved method of implant delivery would enhance this old but durable technology.

Pharmacokinetics and pharmacodynamics of nandrolone esters in oil vehicle: effects of ester, injection site and injection volume.

We studied healthy men who underwent blood sampling for plasma nandrolone, testosterone and inhibin measurements before and for 32 days after a single i.m. injection of 100 mg of nandrolone ester in arachis oil. Twenty-three men were randomized into groups receiving nandrolone phenylpropionate (group 1, n = 7) or nandrolone decanoate (group 2, n = 6) injected into the gluteal muscle in 4 ml of arachis oil vehicle or nandrolone decanoate in 1 ml of arachis oil vehicle injected into either the gluteal (group 3, n = 5) or deltoid (group 4, n = 5) muscles. Plasma nandrolone, testosterone and inhibin concentrations were analyzed by a mixed-effects indirect response model. Plasma nandrolone concentrations were influenced (P < .001) by different esters and injection sites, with higher and earlier peaks with the phenylpropionate ester, compared with the decanoate ester. After nandrolone decanoate injection, the highest bioavailability and peak nandrolone levels were observed with the 1-ml gluteal injection. Plasma testosterone concentrations were also influenced (P < .001) by the ester and injection site, with the most rapid, but briefest, suppression being due to the phenylpropionate ester, whereas the most sustained suppression was achieved with the 1-ml gluteal injection. Plasma inhibin concentrations were also significantly influenced by injection volume and site, with the lowest nadir occurring after the nandrolone decanoate 1-ml gluteal injection. Thus, the bioavailability and physiological effects of a nandrolone ester in an oil vehicle are greatest when the ester is injected in a small (1 ml vs. 4 ml) volume and into the gluteal vs. deltoid muscle. We conclude that the side-chain ester and the injection site and volume influence the pharmacokinetics and pharmacodynamics of nandrolone esters in an oil vehicle in men.

Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot.

Hormonally induced azoospermia induced by weekly im injections of testosterone enanthate provides effective and reversible male contraception, but more practical regimens are needed. Given our previous findings that six 200-mg pellets implanted subdermally produced more stable, physiological T levels and reduced the delivered T dose by more than 50% while maintaining equally effective suppression of sperm output with fewer metabolic side-effects than weekly 200-mg testosterone enanthate injections, we sought in this study to determine 1) whether further dose-sparing could be achieved by lower testosterone doses while maintaining efficacy and 2) the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose as a model depot progestin/androgen combination male contraceptive. Healthy volunteers were randomized into groups (n = 10) who received either of two lower T doses (two or four 200-mg T pellets) or four 200-mg T pellets plus a single im injection of 300 mg depot medroxyprogesterone acetate (DMPA). Two T pellets (400 mg, 3 mg/day) had a negligible effect on sperm output. Four T pellets (800 mg, 6 mg/day) suppressed sperm output between the second to fourth postimplant months; output returned to normal by the seventh postimplant month, although only 4 of 10 men became azoospermic or severely oligozoospermic (< 3 mol/L/mL). The addition of a depot progestin markedly increased the extent, but not the rate, of sperm output suppression, with 9 of 10 becoming azoospermic and 10 of 10 becoming severely oligozoospermic. There were no serious adverse effects during the study. Plasma total and free testosterone levels remained within the eugonadal range at all times with each treatment. Plasma epitestosterone was suppressed by all 3 regimens, consistent with a dose-dependent inhibition of endogenous Leydig cell steroidogenesis. Plasma LH and FSH measured by a two-site immunoassay were suppressed in a dose-dependent fashion by T and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either T dose. Prostate-specific antigen and lipids (total, low or high density lipoprotein cholesterol, and triglycerides) were not significantly changed in any group. Thus, a depot testosterone preparation with zero order release must be delivered at between 6-9 mg/day to provide optimal (but not uniform) efficacy at inducing azoospermia. The addition of a single depot dose of a progestin to a suboptimal testosterone dose (6 mg/day) markedly enhances the extent, but not the rate, of spermatogenic suppression, with negligible biochemical androgenic side-effects. These findings provide a basis for the use of a progestin/androgen combination depot for hormonal male contraception.

PIP: Clinical research conducted in Australia suggests that a progestin-androgen combination depot has potential for hormonal male contraception. The authors' previous research had indicated that 6 200-mg testosterone enanthate pellets implanted subdermally produced substantial reductions over injections in the delivered testosterone dose while maintaining equally effective suppression of spermatogenesis with few metabolic side effects. The present study sought to determine whether lower testosterone doses would maintain efficiency and to assess the efficacy of adding a depot progestin to a suboptimally suppressive depot testosterone dose (6 mg/day). 10 volunteers received either 2 or 4 200-mg testosterone pellets or 4 200-mg pellets plus a single intramuscular injection of 300-mg depot medroxyprogesterone acetate (DMPA). The testosterone implants alone achieved inadequate suppression of spermatogenesis for a male contraceptive; 400 mg of testosterone (3 mg/day) had a negligible effect on sperm output, while 800 mg (6 mg/day) produced azoospermia or severe oligozoospermia in only 4 of 10 men. However, the addition of DMPA markedly increased the extent, but not the rate, of sperm output suppression: azoospermia was achieved in 9 men and oligozoospermia in all 10 subjects, and sperm suppression persisted for 3 months. Epitestosterone concentrations, used as a marker of Leydig cell steroidogenesis, were decreased in a time- and dose-dependent manner, reaching castrate levels in the combined group. Plasma luteinizing hormone and follicle-stimulating hormone levels were suppressed in a dose-dependent fashion by testosterone and further suppressed by the addition of DMPA. Sex hormone-binding globulin levels were decreased by DMPA, but not by either testosterone dose. Prostate-specific antigens and lipids were not significantly altered by any regimen. There were no discontinuations or reports of side effects.