The Endocrine Society 2014

[Michael Scally MD]

ICE/ENDO 2014 [The Endocrine Society 2014]

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https://endo.confex.com/endo/2014endo/webprogram/start.html

 

[Michael Scally MD]

Utilization Patterns of Parenteral Testosterone Preparations in Hypogonadal Men
https://endo.confex.com/endo/2014endo/webprogram/Paper11535.html

Introduction: Testosterone replacement therapy (TRT) is prescribed to treat hypogonadism (HG). However, most patients only use TRT for a short time, with nearly half discontinuing after 3 months. The aim of this study was to assess whether the use of parenteral TRT (defined as short-acting injectable, P-TRT) in men with HG has similar utilization patterns.

Materials and Methods: 517 men ≥18 years-old from the Truven MarketScan® Database with HG and P-TRT initiated in 2009 were followed for 12 - 30 months. Treatment discontinuation was defined as a medication gap of >30 days. A restart was defined as a refill of the P-TRT after a medication gap. Patients with one medication gap only were classified as continuous users. Patients with more than one medication gap were classified as intermittent users.

Results: For continuous users, only 58 patients (31.2%) continued P-TRT 3 months after initiation. With time, the number of treated patients reduced: 23 (12.4%) at 6 months and 9 (4.8%) at 12 months. By the end of 2.5 years, none remained on therapy.

Duration of P-TRT was longer for many of the intermittent users. 3 months after initiation of therapy, 131 patients (39.6%) received P-TRT. With time, the number of treated patients declined: 95 (28.7%) at 6 months and 84 (25.4%) at 12 months. By the end of 2.5 years, 48 (14.5%) patients received P-TRT.

Some intermittent users had multiple medication gaps followed by a restart. The mean duration of P-TRT was 2-3 months (median 1 month) followed by a mean gap in P-TRT of about 2-5 months (median 2-3 months). At each of the pre-specified time points, some intermittent patients were off P-TRT, but restarted P-TRT at a later date. When considering these patients as being in active therapy, 330 (99.7%), 301 (90.9%) and 257 (77.6%) patients received P-TRT at 3, 6 and 12 months, respectively.

After the first discontinuation, 59 patients (11.4%) switched to using topical testosterone and were removed from this study.

Conclusions: The results suggest that high discontinuation rates may be due to the disease state rather than cost, dosing, daily use, or application method. Looking beyond adherence, many men who discontinued P-TRT displayed episodic use. We hypothesize that patients use P-TRT when they are symptomatic and discontinue therapy when symptoms abate. After discontinuation, it’s our assumption that patients who remain asymptomatic stay off P-TRT whereas those whose symptoms recur reinitiate P-TRT.

 

[Michael Scally MD]

Reductions of Weight and Waist Size in 362 Hypogonadal Men with Obesity Grades I to III Under Long-Term Treatment with Testosterone Undecanoate (TU): Observational Data from Two Registry Studies
https://endo.confex.com/endo/2014endo/webprogram/Paper13211.html

Introduction: Inverse associations between testosterone and obesity are well established. Obesity has a greater impact on the decline of testosterone with advancing age than age itself.

Methods: From two prospective, cumulative registry studies of 561 hypogonadal men, 362 men with obesity grade I (BMI 30-34.9), grade II (BMI 35-39.9) and grade III (BMI ≥ 40 kg/m2) were selected. All men received TU injections for up to 6 years. Measures were taken at each three-monthly visit.

Results:

Grade I (n=185, mean age: 58.4±8.0 years): Weight (kg) decreased from 101.88±6.2 to 89.34±6.7. Changes were statistically significant for all six years vs. previous year. Change from baseline was -12.55±0.44 kg, percent change from baseline -12.28±0.44%. Waist circumference (WC; cm) decreased from 107.07±7.57 to 97.09±6.95. Changes were statistically significant for five years vs. previous year and approached significance at the end of six vs. five years. Mean change from baseline was -9.24±0.3 cm. BMI (kg/m2) decreased from 32.51±1.39 to 28.63±1.92, mean change from baseline -3.99±0.14 kg/m2.

Grade II (n=131, mean age: 60.6±5.6 years): Weight (kg) decreased from 117.02±6.99 to 96.78±7.47. Changes were statistically significant for all six years vs. previous year. Change from baseline was -20.67±0.51 kg, percent change from baseline -17.66±0.43%. WC (cm) decreased from 114.23±7.51 to 102.52±6.5. Changes were statistically significant for all six years vs. previous year. Mean change from baseline was -12.29±0.33 cm. BMI (kg/m2) decreased from 37.39±1.46 to 31.05±2.02, mean change from baseline -6.58±0.16 kg/m2.

Grade III (n=46, mean age: 60.3±5.4 years): Weight (kg) decreased from 129.02±5.67 to 103.33±4.17. Changes were statistically significant for all six years vs. previous year. Change from baseline -27.15±0.74 kg, percent change from baseline -20.83±0.54%. WC (cm) decreased from 118.41±5.69 to 106.48±4.91. Changes were statistically significant for all six years vs. previous year. Mean change from baseline was -12.44±0.36 cm. BMI (kg/m2) decreased from 41.93±1.5 to 33.62±1.58, mean change from baseline -8.79±0.23 kg/m2.

Conclusions: All changes were more pronounced with increasing obesity grade. All changes were in a clinically meaningful magnitude and sustainable for the full observation period. TRT seems to be an effective approach to achieve sustained weight loss in obese hypogonadal men, thereby potentially reducing cardiometabolic risk.

 

[Michael Scally MD]

The Pharmacokinetics of Different Doses and Dosing Regimens of Testosterone Undecanoate Injection for the Treatment of Male Hypogonadism
https://endo.confex.com/endo/2014endo/webprogram/Paper14875.html

Background/Objective: Testosterone (T) treatment for male patients with hypogonadism can improve signs and symptoms. Guidelines from The Endocrine Society recommend raising T concentrations into the midnormal range for adult men, without reaching excessively high T concentrations.

A US phase 3 study was conducted to evaluate the pharmacokinetics (PK) of intramuscular (IM) testosterone undecanoate (TU) in hypogonadal men using varying doses and dosing regimens to achieve (1) average T concentrations (Cavg) within the adult eugonadal range (300–1000 ng/dL) and (2) ≤5% of men with maximum T concentration (Cmax) ≥1800 ng/dL.

Methods: Dosing regimens –
Part A (n=237): 750 mg (A-750) or 1000 mg (A-1000) TU IM every 12 weeks (max, 13 total injections).
Part B (n=134): 1000-mg TU loading dose, then either 750 mg (B-750) or 1000 mg (B-1000) 8 weeks later, followed by the same dose every 10 weeks (750 mg) or 12 weeks (1000 mg) thereafter (max, 10 [B-750] or 8 [B-1000] injections).
Part C (cohort 1 [n=130; published in (1)]; cohort 2 [n=23]): 750 mg (C-750) TU IM initial dose, 4 weeks later, and then every 10 weeks (max, 9 injections).

Serum T intensive PK (IPK) was assessed after the second (part C, cohort 2), third (part B), or fourth (part A) injections. Adverse events (AEs) and tolerability were assessed.

Results: At screening, Cavg was 187.3, 189.1, and 197.6 ng/dL in parts A, B, and C (cohort 2), respectively.

All dosing regimens produced mean Cmax within the eugonadal range and had similar IPK profiles. Mean Cmax was highest with the 1000-mg TU dose, regardless of dosing regimen.

With all dosing regimens, most men had Cmax ≤1500 ng/dL (A-750: 115/119 [96.6%]; A-1000: 101/114 [86.3%]; B-750: 21/22 [95.5%]; B-1000: 95/112 [84.8%]; C-750: 22/23 [95.7%]). Cmax ≥1800 ng/dL occurred only in the A-1000 (7/114 [6.1%]) and B-1000 (9/112 [8.0%]) arms; none of the men receiving 750 mg TU in parts A or C had Cmax ≥1800 ng/dL.

TU was well tolerated in all dosing regimens. The most common AEs in part C after injection 2 (cohort 2) were influenza-like illness and sinusitis (2 patients each); none were considered treatment related; no shortness of breath was reported. AEs for Part C (750 mg) injections 3 and 4 (cohort 1) were previously published and 1 patient experienced a pulmonary reaction event (mild coughing) after a single injection (received 6 additional injections), which resolved in 10 minutes (1).

Conclusions: TU 750 mg at baseline, 4 weeks, and then every 10 weeks (C-750) resulted in most men achieving eugonadal Cmax within the injection 2 interval and no men with Cmax ≥1800 ng/dL (unlike the other dosing regimens).

Additional injections using the C-750-mg dosing regimen maintained Cavg (494.0 ng/dL) within the eugonadal range, indicating that this regimen provided the most physiologic T levels (1). All injections were tolerated without notable AEs.


(1) Wang et al. J Androl. 2010;31:457-465.

 

[Michael Scally MD]

Effects of One Year Testosterone Versus Anastrazole Treatment on Physiological Functions in Hypogonadal Older Men
https://endo.confex.com/endo/2014endo/webprogram/Paper16245.html

Testosterone (T) and Estrogen (E) levels decline with age in men. It is not clear if restoring T levels with long-term T replacement is beneficial or detrimental. In addition, the role lack of E plays in age-related changes in older men is not well studied.

In a 12 month randomized, double-blind, placebo-controlled study, we restored T levels in older men (age ≥ 65 years) using T gel (5gm) or anastrazole (1mg), an aromatase inhibitor (AI) that decreases T to E conversion, in order to study the physiological consequences of T vs T+E replacement.

Non-diabetic men were randomized into 3 groups:
Placebo (P)-group (n=11, age = 71±1 years, T levels (ng/dl)=301.5±13.9, E levels(ng/dl)= 1.7±0.1);
T-group (n=10, age=71±1years, T levels =331.5±22 and E levels =2.0±0.2) and
AI-group (n=10, age=70±1 years, T levels =318.0±29, E levels = 1.6±0.2).

Glucose and insulin levels during 2-hr OGTT, leptin (ng/ml), IGF-1(ng/ml) and fasting lipid levels cholesterol, triglyceride , HDL, LDL were measured at baseline and at 3, 6 and 12 months during treatment. Oral glucose insulin sensitivity (OGIS) index was derived from the OGTT.

By 6 months, values of T and E levels in the 3 groups were as follows,
P-group: T=400.5±49.1, E=1.8±0.2;
T-group: T=653.6±96.2, E=2.5±0.5;
AI-group: T=536.0±31.7, E=0.9±0.1.

Using intent to treat analysis, no significant change in OGIS was noted between any of the groups.

Baseline leptin and IGF-1 levels were:
P-group (leptin 7.4 ± 1.1, IGF-1 = 113.0±9.4);
T-group (leptin = 7.7 ± 1.5, IGF-1 = 112.1±10.5);
AI-group (leptin = 7.0±1.9, IGF-1=109.2±9.8).

By 3 months, there was a significant difference between the two treatment groups (P<0.05) with an increase in leptin levels in the T-group (Δleptin = 1.6±1.4) and a decrease in the AI-group (Δleptin = -1.7±1.1), and the levels remained similar through subsequent months. IGF-1 levels significantly increased in the T group (but not AI group) and peaked at 6 months (ΔIGF-1 = 15.3±10.3).

For lipid levels, a significant decrease in HDL levels in the T-group was noted when compared to the placebo group with the largest decrease at 6 months (baseline HDL (mg/dl): P-group=51.7±3.8, T-group= 44.1±2.4, AI-group=47.5±2.5; ΔHDL at 6 months: P-group =0.9±2.2, T-group=-5.9±1.2, AI-group= 1.7±2.2). No significant changes in lipid levels were noted over time in P-group or the AI-group.

Restoring T levels to physiological range does not change insulin sensitivity in elderly men with borderline T levels. However, restoring T impacted IGF-1, HDL and leptin levels; increases in IGF-1 and decreases in HDL are due to combined T and E effects while decreases in leptin are mediated by E effects.

 

[Michael Scally MD]

Single Doses of the SERM Lasofoxifene Increases Testosterone Levels for over 28 Days in Healthy Men
https://endo.confex.com/endo/2014endo/webprogram/Paper13945.html

Lasofoxifene (laso) is a next-generation selective estrogen receptor modulator (SERM) that at a daily dose of 0.5 mg has been shown to reduce the risk of nonvertebral and vertebral fractures, ER-positive breast cancer, coronary heart disease, and stroke in postmenopausal women, but with an increased risk of venous thromboembolic events(1).

The effects of laso in males are unknown.

Certain SERMs have been shown to stimulate endogenous testosterone (T) production in men via perturbation of the gonadal axis(2).

Here we report the potent and prolonged effect of a single dose of laso to increase circulating T levels in young healthy men.

The study was an investigator-blind, randomized, placebo-controlled, parallel group, single ascending dose study of laso or placebo in 36 healthy male volunteers age 18-41, consisting of 5 fasted dose groups (1, 3, 10, 30 and 100 mg) and 1 fed dose group (100 mg) where each group has 4 subjects receiving laso and 2 receiving placebo. Pharmacokinetic parameters, luteinizing hormone (LH), and total T in plasma samples were measured out to 28 days postdose.

Following oral administration of single doses of laso, Cmax and AUC(0-∞) increased in a dose proportional fashion with overall mean T1/2 of 116 ± 44 hours (group mean Tmax of 6.0-9.5 hours). At the 100 mg dose, food appeared to have little effect on the absorption of laso and only delayed Tmax 2.5 hours to the parallel group.

Changes in LH were detected with the higher doses of laso (10, 30, and 100 mg) with a transient and relative small early decrease in LH (19-39% drop from baseline) within 24 hours, followed by a large rebound increase of 200-500% from baseline during days 3-7. LH levels remained elevated relative to baseline to day 28, the last data point collected, except for the 10 mg group in which LH levels gradually returned to the placebo level. The pooled placebo group also had a 25 ± 28% drop in LH at 12 hours.

T levels followed the pattern of change in LH.
At 12 hours, T levels were reduced relative to baseline by -31 ± 8% (placebo), -60 ± 0% (30 mg), -48 ± 20% (100 mg), and -48 ± 15% (100 mg fed).
At day 7, T levels were increased +22 ± 23% (placebo), +36 ± 0% (30 mg), +82 ± 20% (100 mg), and +90 ± 50% (100 mg fed).
T changes appeared to be more sensitive than LH whereas the 1 mg group had 46 ± 34% increase from baseline at day 3 versus 5 ± 14% for placebo.
The changes in T were long lasting and at day 28 the increases were 15 ± 28% (placebo), 24 ± 81% (1 mg), 57 ± 38% (3 mg), 28 ± 18% (10 mg), 81 ± 49% (30 mg), 109 ± 42% (100 mg), and 92 ± 38% (100 mg fed).

Group mean T levels appeared to plateau at 30-40 nmol/L 7-14 days postdose regardless of laso dose or LH level. For example, at day 21 T levels were 25.5 (3 mg), 35.2 (10 mg), 32.7 (30 mg), 39.3 (100 mg), and 33.2 (100 mg fed) nmol/L.

The pharmacodynamic effects of laso on the gonadal axis are quite different from other SERMs and warrant further study for potential clinical benefits of laso treatment in men.

(1) Cummings et al., N Engl J Med. 2010 Feb 25; 362(8):686-96.
(2) Grefhorst et al., J Clin Endocrinol Metab. 2010 Dec;95(12):5443-8.

Disclosure: KM: Employee, Ligand Pharmaceuticals Incorporated. RAM: Employee, Pfizer, Inc.. EGV: Employee, Ligand Pharmaceuticals Incorporated. LZ: Employee, Ligand Pharmaceuticals Incorporated. Nothing to Disclose: GCW

 

[Michael Scally MD]

Persistence with Testosterone Replacement Therapy (TRT) in a US Health Plan
https://endo.confex.com/endo/2014endo/webprogram/Paper13090.html

Purpose: To determine whether persistence to testosterone replacement therapy (TRT) was affected by TRT formulation and symptom response.

Methods: Men ≥18 years with hypogonadism (HG) were identified from the 2008-2010 Reliant electronic medical records database.

Non-persistence was defined as a gap between prescription refills greater than twice the days supplied in the previous prescription. Surveys using validated instruments for measuring symptoms of HG were collected, and symptom reporting was evaluated based on persistence.

Results: A total of 488 men were diagnosed with HG in the period, and 408 of these initiated TRT at some point. Average patient age was 53.1 years (SD=13 years).

Care was sought by 35% of patients at internal medicine practices (n=169), 28% at endocrinologists (n=134), 10% at urologists (n=49), and 8% at primary care practices (n=39).

Overall 22% (n=89) of patients were persistent with TRT during the follow-up period; another 26% switched therapies (n=106).

Patients using testosterone gels (n=64 [32%]) were more likely to be persistent than those using testosterone injections (n=16 [10%]; p<0.001). In addition, 28% (n=56) of men taking gels switched to another therapy, compared to 13% (n=21) of men using injections and 56% (n=28) of men using a patch (gel v. injection, p=0.0007; gel v. patch, p=0.0004).

Surveys were mailed to 133 men with HG identified in the database in 2012; 95 were included in the final analysis. Of those, 24 respondents were persistent on TRT and 63 were not. The most commonly reported symptoms for seeking treatment and the most bothersome at the time of survey were erectile dysfunction (ED), loss of energy or feeling tired, and decreased sex drive.

At the time of the survey, men who had been persistent were slightly less likely to report loss of energy or decreased sex drive compared to men who were not persistent (NS); however, persistence appeared to have no effect on ED symptomology.

Conclusions: In this health plan, persistence to TRT was low among men with HG, with slight differences found by therapy type. Factors that might influence persistence, such as treatment expectations, symptom improvement, and financial considerations, require further study.

Disclosure: EFS: Employee, Eli Lilly & Company. PKP: Clinical Researcher, Eli Lilly & Company. PD: Researcher, Eli Lilly & Company. RLW: Researcher, Lilly USA, LLC. Nothing to Disclose: MM

 

[Michael Scally MD]

The Influence of Testosterone Gel Treatment on Spermatogenesis: A Pilot Study
https://endo.confex.com/endo/2014endo/webprogram/Paper15723.html

The number of reproductive–age patients with hypogonadism is increasing. Prescription of intramuscular testosterone injections may be the cause of decreased sperm production, because of supraphysiological peak concentrations of testosterone. Testosterone formulation that is not suppressing pituitary LH and FSH production and thus not leading to spermatogenesis impairment may be used.

The aim was to study the influence of testosterone gel treatment (Androgel), taken 50 mg daily, on the parameters of spermatogenesis.

Materials and methods: We studied 18 men with confirmed eugonadotropic hypogonadism, who received treatment with Androgel 50 mg daily for 3 months. All men had history of previous fatherhood. Serum testosterone, SHBG levels were assessed before and after 3 months of testosterone treatment.

Spermatogenesis parameters, such as sperm volume, sperm count, motility (a+b), percent of normal forms and vitality, were assessed before and after 3 months of Androgel treatment. Data is presented as a median and quartile range. Statistical analysis was made using Wilcoxon test.

Results: Median age of the patients was 35 [30;44] years. Normalization of testosterone levels was achieved in all patients: from 8.4 [7.6;11.2] to 16.3 [15.3;18.0] nmol/l, p<0.001.

There was a significant increase in sperm volume from 2.05 [1.6;4.0] to 2.6 [1.8;4.4] ml, p<0.001. No significant difference was found in sperm count (from 19.0 [15.0;37.0] to 23.0 [15.0;47.0] million in 1 ml, p=0.24.) sperm motility (a+b) (from 42.6 [18.0;47.0] to 42.0 [25.0;51.0] %, p=0.69), percent of normal forms (from 24.0[14.0;32.0] to 15.0 [13.0;22.0] %, p=0.06) and vitality of spermatozoa (from 76.0[65.0;86.0] to 77.0 [58.0;81.0] %, p=0.5).

Conclusion: Androgel treatment during 3 months doesn’t lead to decrease in sperm count and volume without any change in sperm vitality, motility (a+b) or percent of normal forms. More studies are needed to evaluate the long-term effect of Androgel treatment on spermatogenesis.

 

[Michael Scally MD]

Association Between Endogenous Testosterone and Cardiovascular Clinical Outcomes
https://endo.confex.com/endo/2014endo/webprogram/Paper16125.html

Cardiovascular disease (CVD) is considered a leading cause of death in men more than women, with testosterone (T) potentially contributing to vascular risk. Cross-sectional studies in men have shown an association between low serum T and cardiovascular disease (CVD), carotid atherosclerosis, metabolic syndrome, and mortality, with others suggesting a J-shaped association. Testosterone levels decline in men with aging and chronic disease. We hypothesize that low T is independently associated with clinical atherosclerosis, as defined by incidence of cardiovascular outcomes.

The Atherosclerosis Risk in Communities (ARIC) study is a large prospective multicenter cohort of people aged 45-64 years followed since 1987 to evaluate risk factors associated with incident CVD.

We measured plasma total T by liquid chromatography mass spectrometry at visit 4(1996-1998) using samples obtained prior to 10:30 AM, in males without prevalent CVD including stroke or prior T therapy. Cochran-Armitage test for trend and general linear models regression was used to assess the cross-sectional association of quartile of T with cardiovascular risk factors and 10 year coronary heart disease (CHD) risk. Proportional hazard regression analysis was performed to assess the association of T quartiles with incident CHD and congestive heart failure (CHF) events.

Multivariable regression analysis was adjusted for age, race, center, body mass index (BMI), waist circumference, smoking status, diabetes, hypertension, LDL and HDL. In 1558 males (mean (SD) age= 63.1 (5.6) years, BMI=28.2 (4.27) kg/m2) mean plasma T was 402.2 (165.1) ng/dL with results divided into quartiles (288.4, 377.6, 480.1 ng/dL).

Lower T was significantly associated with higher BMI, greater waist circumference, presence of diabetes, hypertension, lower HDL, never smoking, and greater 10 year CHD risk(p=0.01). Median follow-up was 12.8 yrs for incident CHD (287 events) and 13.1 yrs for incident CHF (140 events).

Following multivariable adjustment, there was no association of quartile (Q) of T with incident CHD [hazard ratio (HR)=0.87 (95%CI=0.60-1.26) for Q1; 0.97 (95%CI=0.69-1.38) for Q2; 0.97 (95%CI=0.69-1.36) for Q3 compared to reference of Q4] or for incident CHF [HR=0.77 (95%CI=0.46-1.29) for Q1; 0.72 (95%CI=0.43-1.21) for Q2; 0.87 (95%CI=0.53-1.42) for Q3 compared to reference of Q4].

Low plasma T in men is cross-sectionally significantly associated with CVD factors including BMI, waist circumference, low HDL, diabetes, and hypertension, which is reflected in a significant increased 10 year CHD risk.

However, after controlling for key CVD risk factors, there was no association between T and future clinical cardiac events. Our results are reassuring that neither high nor low T levels increased clinical CVD events.

 

[Michael Scally MD]

Large Sample Evaluation of the Performance of Free Testosterone Calculations: Impact of Correct SHBG Binding Stoichiometry and Albumin Adjustment
https://endo.confex.com/endo/2014endo/webprogram/Paper12234.html

Introduction:It has been suggested that evaluation of “free” (protein unbound) testosterone may be useful in clinical practice. However, laborious direct laboratory measurement is rarely available so various formulae to calculate “free” testosterone (cFT) have been proposed. Widely used equilibrium binding equations involve multiple assumptions and plug-in constants (including incorrect stoichiometry for testosterone binding to SHBG) and were validated in only small samples whereas the assumption-free empirical formulae have been developed and validated in two studies involving over 6000 samples.

Aim: To investigate the comparative performance of alternative cFT formulae in a large sample from a major commercial pathology laboratory.

Methods: Coded data from the results of 123,572 consecutive blood samples requesting serum testosterone in the clinical practice of a large commercial pathology laboratory over 7 years (2007-13) were provided for analysis of blood testosterone and SHBG (Roche E170) and albumin (Roche BCG) together with patient gender and age. cFT was calculated in 106,941 samples (86%) with complete data according to published equilibrium binding (Sodergard (FTS), Vermeulen (FTV)) and empirical (Nanjee-Wheeler(FTN), FTA, FTZ) equations together with modified FTS and FTV formulae using the correct SHBG binding stoichiometry (FTS2, FTV2, respectively), FTV adjusted for individual albumin concentrations (FTV+a) and free androgen index (FAI). All calculation were compared with the best validated (FTZ) by Lin’s concordance correlation coefficient (CCC, NCSS v9 software) with estimates of slope and intercept.

Results: There were more (50.5%) samples from female (n=62,441, mean age 36.3 (SD 13.2, range 0-97 years) than male (n=61,131, 53.3 (17), 0-99 years) patients. Compared with FTZ (CCC, slope, intercept), conventional equilibrium binding formulae [FTS (0.767, 1.73, -30.0), FTV (0.846, 1.51, -21.8)] and another empirical formula [FTN (0.9801, 1.64, -4.9) displayed non-linear deviation which were progressively greater at higher concentrations. These deviations were improved by correcting stoichiometry [FTS2 (0.893, 1.13, -28.2), FTV2 (0.919, 1.02, -21.9)] but not by including correction for albumin [FTV+a (0.863, 1.49, -22.9)]. FAI was very poorly correlated with FTZ (0.323, 0.27, -7.41).

Conclusions: Using this large sample of clinical data, we conclude that
(a) all cFT formulae consistently and progressively (with concentration) overestimate cFT relative to the assumption-free, laboratory-validated FTZ formula,
(b) deviations are greater for equilibrium binding than the best empirical formulae and
(c) correcting erroneous stoichiometry of equilibrium binding formulae improves their performance to closer approximate the best empirical formula,
(d) albumin adjustment makes little difference and
(e) FAI is unrelated to cFT.

 

[Michael Scally MD]

Pharmacokinetic Profile of 50 Mg and 100 Mg Doses of Subcutaneous Testosterone Enanthate Administered with the Novel Jet-InjectorTM
https://endo.confex.com/endo/2014endo/webprogram/Paper14028.html

Topical treatments for males with hypogonadism (HGM) result in physiologic testosterone (T) concentrations but require daily administration, dose titration, and carry risk of transfer to women and children, leading to abnormal development of male sexual characteristics.

T for IM injection (IMT) does not carry this risk, but may be painful, inconvenient, and typically cannot be self-administered. IMT may also be associated with T level peaks and troughs leading to mood swings.

The pharmacokinetic (PK) profile of subcutaneous T enanthate (TE) administered with the Jet-Injector™ (JT), a novel, pre-filled, self-administration system for T, were studied.

Twenty adults (age 31-69) with HGM (T <300 mg/dL at two screening visits with documented clinical symptoms received 50 mg (n=10) or 100 mg (n=10) JT weekly for 6 weeks in clinic administered by a healthcare professional.

Mean baseline T was 301 ng/dL for patients in the 50 mg group and 214 ng/dL in the 100 mg group.
At week 1, both doses produced normal mean total T concentrations 24 h post-dose (433 ng/dL in the 50 mg group [range 197-821 ng/dL] and 545 ng/dL in the 100 mg group [range 388-833 ng/dL]).
Pre- and post-dose T levels rose with successive doses and plateaued at week 5.
At week 6, 24 h post-dose mean T was 421 ng/dL in the 50 mg group (range 263-640) and 1042 ng/dL in the 100 mg group (range 526-1420).
In the 50 mg group, T Cmin was generally unchanged. In the 100 mg group, T Cminincreased through week 5.

Steady state Cavg[0-168h] T levels at week 6 were higher in the 100 mg group vs. the 50 mg group (927 vs. 420 ng/dL; 2.21-fold higher).
In the 50 mg group at week 6, Cmax was 624 ng/dL (range 388-825 ng/dL) and Tmax was 46.2 h; Cmin was 286 ng/dL (range 211-372 ng/dL).
In the 100 mg dose at week 6, Cmax was 1427 ng/dL (range 662-2120 ng/dL) and Tmax was 33.9 h; Cmin was 584 ng/dL (range 236-860 ng/dL).
Mean AUC(0-168h) at week 6 was 704.96 and 1556.94 ng*h/ml for the 50 and 100 mg doses, respectively.

Serum estradiol and dihydrotesterone rose proportionately with T levels. JT injection took 3-4 seconds per patient and consistently provided the precise dose.

JT rapidly restored and maintained steady, physiologic Cavg[0-168h] levels of T with attenuated peak to trough fluctuations relative to that seen with higher doses of TE administered on a 1-2 times per month schedule. This may be clinically important in avoiding treatment-related mood swings observed with IM TE.

These PK data suggest that JT may represent an alternative to daily topical T that decreases risks associated with secondary exposure while delivering T replacement weekly via a self-administration option.

Disclosure: RSS: Ad Hoc Consultant, Antares Pharma Inc.. JSJ: Employee, Antares Pharma Inc..

 

[Michael Scally MD]

Ausrm-057 - a Novel Selective Androgen Receptor Modulator (SARM) for Transdermal Administration
https://endo.confex.com/endo/2014endo/webprogram/Paper14626.html

Drug discovery efforts have identified selective androgen receptor modulators (SARMs) that, similar to steroidal androgens, exert strong anabolic effects on skeletal muscle and bone, but with minimal androgenic effects in tissues such as prostate.

To date, only oral SARMs have been developed whose efficacies in the clinic are critically limited by adverse events including induction of liver enzymes such as alanine aminotransferase (ALT) and lowering of high density lipoprotein (HDL).

To overcome these drawbacks we developed SARMs for transdermal administration as mostly used in testosterone (T) therapy. A 3-alkoxy-pyrrolo[1,2-b]pyrazoline compound termed AUSRM-057 was identified that bound to human androgen receptor (AR) with a Ki of 0.45 nM with great selectivity over other nuclear receptors such as progesterone, glucocorticoid and estrogen receptor alpha.

AUSRM-057 potently activated AR in a C2C12 muscle cell reporter gene assay with an EC50 of 0.5 nM and induced hypertrophy in human myotubes with a comparable EC50 of 0.2 nM. AUSRM-057 showed good aqueous solubility of 1.3 g/L at pH7.4 and in silico predictions as well as a skin parallel artificial membrane permeability assay (PAMPA) indicated good skin penetration.

Indeed, when measuring human skin permeation in vitro an excellent flux of 2.8 µg/cm2/h was determined without any permeation enhancers. In a short single subcutaneous (s.c.) injection 24h biomarker in vivo assay in castrated rats, it reduced more potently the atrophy marker gene MAFbx and induced more potently the hypertrophy marker gene IGF1 in levator ani (LA) muscle than T. Furthermore, it only partially induced the prostate marker gene probasin compared to T.

In a two week Hershberger assay using castrated rats AUSRM-057 showed dose-dependent effects fully restoring LA weight at 0.3 mg/kg/day s.c. with high selectivity over prostate stimulation. Next, AUSRM-057 was assessed in young growing pubertal rats where two week treatment selectively stimulated LA over prostate at 1 mg/kg/day. Finally, AUSRM-057 restored LA muscle weight and significantly increased triceps brachii and quadriceps muscle weights compared to vehicle treated animals without significant stimulation of prostate weight in voluntary running adult castrated mice following 2 week s.c. administration of 1 mg/kg/day.

In conclusion, we have identified a novel highly potent SARM AUSRM-057 that exerts selective anabolic action on skeletal muscle tissues over androgenic prostate tissues and easily penetrates human skin. Thus, AUSRM-057 holds promise as a novel transdermal SARM for the treatment of various muscle wasting disorders avoiding important limitations of oral SARMs.


Disclosure: TU: Employee, Novartis Pharmaceuticals. SS: Employee, Aurigene. CP: Employee, Aurigene. SW: Employee, Novartis Pharmaceuticals. SR: Employee, Aurigene. DS: Employee, Aurigene. SC: Employee, Aurigene. CI: Employee, Novartis Pharmaceuticals. PGS: Employee, Novartis Pharmaceuticals. BL: Employee, Novartis Pharmaceuticals. MP: Employee, Novartis Pharmaceuticals. MB: Employee, Novartis Pharmaceuticals. HK: Employee, Novartis Pharmaceuticals.

 

[Michael Scally MD]

Natural History of the Progression of Compensated Hypogonadism to Primary Hypogonadism in Ageing Men: Hormonal and Phenotypic Characteristics – Longitudinal Data from the European Male Ageing Study (EMAS)
https://endo.confex.com/endo/2014endo/webprogram/Paper14694.html

A state of compensated hypogonadism (CHG) has recently been defined in ageing men as elevated serum concentration of LH (> 9.5 IU/L) in the face of normal testosterone (T > 10.5 nmol/L).

CHG can be regarded as a transitional state during the progression from eugonadism (EUG) (T > 10.5 nmol/L, LH < 9.4 IU/L) to primary hypogonadism (PHG) (T < 10.5 nmol/L, LH > 9.4 IU/L).

We sought to identify the hormonal and phenotypic characteristics associated with the progression of CHG during a follow-up of 4.3 yr. Community-dwelling men (n = 3,369) aged 40-79 yr in 8 European countries participated in EMAS, a prospective observational cohort survey.

Of 279 men with CHG at baseline, 47 (16.8%) were lost to follow-up. Of the remaining men 36 (15.5%) died, 132 (56.9%) remained in CHG and 15 (6.5%) progressed to PHG. Differences in characteristics amongst the defined gonadal status were investigated using descriptive statistics and linear and logistic regression models.

At baseline, men with CHG had a 10-fold increased risk of developing PHG as compared with EUG men, after adjusting for age, BMI, smoking status and comorbidity. When compared with persistent CHG at baseline, men progressing to (i.e. incident) PHG had similar age and BMI, but their total T (13.3 + 2.6 [SD] vs 19.1 + 5.6 nmol/L), free T (188 + 58 vs 268 + 74 pmol/L), and FSH (39.0 + 24.3 vs 22.5 + 15.1 IU/L), but not LH, differed significantly (p< 0.01). Moreover, they demonstrated significantly lower (p< 0.03 or less) physical function, higher prevalence of low moods and prostate disease.

During follow-up, the annualised change were significantly greater in men with incident PHG compared with persistently EUG men in haemoglobin (-1.3 ± 3.1 vs. 0.0 ± 2.2 g/litre, p=0.05), Reuben’s Physical Performance Test scores (-0.5 ± 0.7 vs -0.1 ± 0.5, p<0.001) with higher incidence of physical symptoms: limited walking (22.2 vs. 4.1%, p=0.01), decreased physical activity (42.9 vs. 12.5%, p=0.02), fatigue (14.3 vs. 3.0%, p=0.02), > 1 comorbidity (60.0 vs. 23.3%, p=0.05) and sexual symptoms: decreased morning erections (50.0 vs. 16.3%, p=0.03), frequency of sexual thought (50.0 vs. 16.1%, p<0.001) and erectile dysfunction (66.7 vs. 16.2%, p<0.001). Similar differences (to a lesser extent) were found between men with incident PHG and persistent CHG.

At follow-up, incident PHG men also had higher SHBG levels (67.8 ± 59.5 vs. 45.3 ± 18.5 nmol/L, p<0.001) than EUG men. The proportion of men with CHG who died, 15.5%, was significantly higher than for EUG men (5.2%, p<0.05 after adjustment for age, BMI and smoking status).

In conclusion, CHG is a preferential path for the development of PHG in EUG ageing men. Baseline hormones (T, free T and FSH) but not age predict the accelerated transition from CHG to PHG in surviving men. Progression to PHG is associated with deterioration of features compatible with androgen deficiency. Men with CHG are at an increased risk of dying compared with persistent EUG.

 

[Michael Scally MD]

Natural History of the Development Compensated Hypogonadism in Eugonadal Ageing Men: Predisposing Factors, and Potential Clinical Significance - Longitudinal Data from the European Male Ageing Study (EMAS)
https://endo.confex.com/endo/2014endo/webprogram/Paper12497.html

Elevated Luteinising Hormone (LH) with normal testosterone (T) is commonly encountered in ageing men as an early indicator of dysregulation in the hypothalamic-pituitary-testicular (HPT) axis. This can be regarded as a transitional state of compensatory hypogonadism which portents the subsequent development of primary hypogonadism, when the testicular reserve eventually fails, and T falls into the hypogonadal range. Better definition of this unfolding sequence will improve understanding of the natural history and clinical significance of the ageing-related decline in T in men.

Our objective was to identify predictive factors which predispose eugonadal men (T≥10.5 nmol/l, LH≤9.4 U/l) to the development of compensated hypogonadism (T≥10.5 nmol/l, LH>9.4 U/l) and to seek evidence for deficiency in various androgen-dependent characteristics in these new ‘cases’ of compensated hypogonadism.

The European Male Aging Study (EMAS) is a multicentre prospective observational cohort survey of 3,369 community-dwelling men aged 40-79 yr at baseline followed up for 4.3 years in 8 European countries.

Participants were classified into
1) incident (eugonadal at baseline but hypogonadal at follow-up, n = 99),
2) persistent (same at baseline and follow up, n = 131) compensated hypogonadism or
3) persistent eugonadism (referent group, n =1773).

Relationships between potential risk factors for incident compensated hypogonadism and comparison of putative androgen-dependent characteristics amongst the three defined gonadal status were investigated by multiple linear and logistic regression models compared to eugondism.

Risk factors which predisposed men to the development of compensated hypogonadism included
age (OR 1.9 (CI 1.5-2.4), p<0.001), per decade),
smoking (OR 1.7 (CI 1.0-2.9), p<0.05)),
poor or fair health (OR 1.6 (CI 1.0-2.5), p<0.05)) and
chronic pain (OR 2.1 (CI 1.2-3.9), p<0.05)).

Higher LH and FSH and lower free T at baseline also predicted the development of compensated hypogonadism, which was associated with only minimal evidence of androgen deficiency after adjustments, e.g. lower haemoglobin (144.1±13.6 vs. 150.7±10.9 g/litre, p<0.001).

If compensated hypogonadism persists for several years, when free T falls further, clear evidence of impaired physical and psychological functions emerged e.g. limited walking (OR 2.1 (CI 1.2-3.8), p<0.05), decreased physical activity (OR 2.0 (CI 1.3-3.0) p<0.01) and unable to bend (OR 2.5 (CI 1.3-4.7) p<0.01).

These nascent changes in the HPT axis provide better understand of the aetiology and clinical significance of hypogonadism associated with advancing age and enable the early identification of a minority (1% per annum) of men at risk.

Elevated LH may be regarded as a highly sensitive biomarker not only of testicular dysfunction but also general health, providing evidence for a subclinical state with evolving androgen deficiency.

 

[Michael Scally MD]

Standardization of a New Protocol with Recombinant Human Chorionic Gonadotropin (rhCG) in the Assessment of Testicular Function [Cryptorchidism]
https://endo.confex.com/endo/2014endo/webprogram/Paper15395.html

Background: Cryptorchidism is the failure of one or both testes to descend into the scrotum and is the most frequent congenital birth defect in male children (2–4% in full-term male births). Cryptorchidism can occur as an isolated disorder or may be associated with other congenital anomalies such as hypogonadotropic hypogonadism, androgen insensitivity syndrome and inactivating mutations in the LH receptor gene.

Testosterone response to hCG stimulation test has been used to evaluate gonadal function in prepubertal children. Currently, hCG extracted from urine (uhCG) of pregnant women is not available in many countries, requiring standardization of a new recombinant hCG (rhCG; Ovidrel®) stimulation test.

Objectives: To determine testosterone response to rhCG stimulation test in prepubertal boys and to verify the correlation between basal AMH and rhCG-stimulated testosterone levels 7 days after injection.

Patients and Methods: We evaluated 31 prepubertal boys (age: 0.75-9.0 yr) with unilateral (n=24) or bilateral (n=7) cryptorchidism. None of the boys had previously received hormonal treatment and patients with other genital abnormalities were excluded. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), total testosterone, 17-hydroxyprogesterone (17OHP), anti-mullerian hormone (AMH), inhibin B and dihydrotestosterone (DHT) concentrations were determined at baseline and seven days after rhCG stimulation (250 mcg subcutaneously; single dose).

Results: There was no significant difference between hormone levels when unilateral was compared with bilateral cryptorchidism. All basal hormone concentrations were within the normal ranges for age.

Serum concentrations of the following hormones increased 7 days after rhCG injection: testosterone (from 10.0 ± 0.0 to 247.8 ± 135.8 ng/dL), DHT (from 4.56 ± 0.77 to 32.3 ± 17.1 ng/dL) and T/DHT ratio (from 2.19 to 7.7). rhCG-stimulated testosterone higher than 100 ng/dL indicates normal testicular function, based on the 10th percentile values for this cohort. Basal AMH was positively correlated with rhCG-stimulated testosterone levels (r=0.55; p=0.001).

Conclusions: We demonstrated that a single 7-days rhCG-stimulated testosterone levels is useful to assess testicular function and is correlated with basal AMH in this cohort. Although all patients had no impairment of testicular function, long-term follow-up of patients with mild cryptorchidism is recommended.

 

[Michael Scally MD]

New Light on Therapeutic Potential of Kisspeptin
https://endo.confex.com/endo/2014endo/webprogram/Paper10724.html

Kisspeptin is a 54-amino acid peptide which is encoded by the KiSS-1 gene and activates the G protein-coupled receptor GPR54. Evidence suggests that this system is a key regulator of mammalian and human reproduction. Animal studies have shown that GPR54-deficient mice have abnormal sexual development.

Central and peripheral administration of kisspeptin stimulates the hypothalamic-pituitary-gonadal (HPG) axis whilst pre-administration of a gonadotrophin releasing hormone (GnRH) antagonist abolishes this effect.

In humans, inactivating GPR54 or KiSS-1 gene mutations cause normosmic hypogonadotrophic hypogonadism whilst activation of GPR54 signalling is associated with premature puberty.

In healthy human volunteers, the acute intravenous administration of kisspeptin potently increases plasma luteinising hormone (LH) levels and significantly increases plasma follicle stimulating hormone (FSH) and testosterone without side effects in both males and in females.

In female volunteers kisspeptin stimulates gonadotropin release most potently in the preovulatory phase of the menstrual cycle. Kisspeptin stimulates reproductive hormone release through the release of endogenous GnRH. Therefore, administration of kisspeptin to stimulate reproductive hormone release could represent a more natural way to stimulate hormone release in infertility e.g. kisspeptin might have therapeutic benefit as a more physiological trigger of oocyte maturation during IVF treatment than hCG which is currently used. Early studies in women with infertility show that kisspeptin can effectively stimulate oocyte maturation during IVF treatment.

The kisspeptin system has been shown to be important in the generation of GnRH pulses which are vital for normal fertility. Recent data shows that in healthy male volunteers acute administration of kisspeptin may be able to reset the hypothalamic GnRH clock and that an infusion of kisspeptin can stimulate pulsatile LH release.

Infusion of kisspeptin has also been shown to stimulate pulsatile LH release in normal women, patients with inactivating mutations in NKB or its receptor, patients with biochemical hypogonadism due to diabetes and in women with hypothalamic amenorrhea.

The ability of kisspeptin administration to stimulate pulsatile LH release further highlights its importance as a potential novel therapeutic target for the treatment of infertility.

 

[Michael Scally MD]

Successful Induction of Androgenesis and Spermatogenesis Using Hcg-Human Recombinant FSH to a Hypogonadotropic –Hypogonadism Male Caused By Hemochromatosis
https://endo.confex.com/endo/2014endo/webprogram/Paper16400.html

Background: Hypogonadotropic-hypogonadism male has impaired gonadal function both in spermatogenesis and androgenesis. Its cause varies wide and hemochromatosis(HC) is among them, which is very rare disease in Japan. This disease induces structual and functional disorder in pituitary by excess deposition of iron, leading to insufficient production of gonadotropin. Thus HC causes infertility, for which intensive gonadotropin treatment is required.

Clinical case: A 36-year Japanese man suffered from hereditary hemochromatosis with loss of libido as well as azoospermia. Hormonal data showed decreased gonadotropin (FSH: 4.1 IU/L, LH: 1.5 IU/L) and low testosterone (70.9 ng/dL), while serum iron level was high (286 μg/dL).

Initially hCG was administered (5,000 IU x 3 /week), which activated androgenesis, serum testosterone being 753.9 ng/dL after two weeks. This confirmed the Leydig cells were functional.

Then human recombinant FSH (150 IU x 3/week) was co-administered with hCG and production of spermatozaoa was confirmed after three months, which revealed both Sertoli cell function and potential of spermatogenesis were conserved. Though concentration of spermatozaoa was not high (0.4-0.5 x 106/ml), several specimen was cryopreserved.

Thereafter controlled ovarian stimulation of the patient’s wife was underwent and a total of 14 oocytes was retrieved. Using both fresh and cryopreserved spermatozoa intracytoplasmic sperm injection was applied and five of them were fertilized, followed by acquisition of three good morphological embryos, which were cryopreserved. Then cryo-thaw embryo transfer was attempted.

The first cycle showed marginal increase of serum hCG but clinical pregnancy was not established. In the second trial using blastocyst positive serum hCG was confirmed and course of pregnancy was uneventful. She delivered healthy baby.

Conclusion: By careful and intensive treatment with gonadotropin both androgenesis and spermatogenesis was successfully achieved in a hypogonadotropic-hypogonadism male due to HC . HC may affects testicular tissue and impairs efficacy of treatment.

In our case Leydig cell function was well conserved and both Sertoli cell function and spermatogenesis system was at least partially conserved. Like other cause of hypogonadotropic-hypogonadism male successive gonadotropin treatment with hCG and FSH to HC male is effective.

 

[Michael Scally MD]

Vitamin D Intoxication Induced By Veterinarian Vitamin Compound Usage: A Case Report
https://endo.confex.com/endo/2014endo/webprogram/Paper13477.html

Introduction: The consumption of anabolic steroids, supplements and similar products grows larger every day. Its use is mostly related to athletes and people who seek to improve their physical performance, or aesthetics. Among the many substances, the veterinary supplement ADE (similar to Synthol) has been increasingly used due to its oily vehicle that induces local edema, which simulates the increase of muscle mass.

Case report: Male, 24 y.o., previously healthy, presented fatigue, epigastric pain, nausea and vomit, which developed during 2 months, becoming worse progressively.

Admitted the use of different substances for the purpose of building muscle mass: testosterone derivatives, growth hormone, nandrolone and the veterinary vitamin compound ADE which contains 20,000,000 IU of vitamin A, 5,000,000 IU of vitamin D3 and 6,800 IU of vitamin E in each 100 mL dose. The patient admitted having used 150 mL of ADE in the past 4 months.

While hospitalized, physical examination on the patient revealed no changes and BMI was 25.1 kg/m2.
Laboratory: creatinine 3.1 mg/dL (reference range [RR] 0.8 - 1.3), urea 54 mg/dL (RR 15 - 39), albumin 3.5 mg/dL (RR 3.4 – 5.0), ALT 160 mg/dL (RR 30 – 65), AST 11 mg/dL (RR 15 – 37), alkaline phosphatase 87 U/L (RR 50 – 136), total testosterone 23 ng/dL (RR 72 – 853),

25-hydroxyvitamin D (25OHD) 150 ng/mL (toxicity > 100), 1,25 - dihydroxyvitamin D 80 pg/mL (RR 18 – 78), vitamin A 0.7 mg/dL (0.3 – 0.7), PTH < 3 pg/mL (RR 12 – 65), total calcium 13.6 mg/dL (RR 8.5 – 10.1), and urinary calcium/24 hours 635 mg/24h (RR 42 – 353).

Viral serology were negative. Urinary tract ultrasonography: signs of parenchymal nephropathy.

Diagnosis: hypercalcemia and acute kidney injury due to vitamin D intoxication caused by veterinary compound. Treated with intravenous hydration followed by corticotherapy (40 mg/day prednisone) and furosemide. On the fifth day of hospitalization, the patient was administrated with one 90 mg dose of disodium pamidronate.

The patient was completely cured from hypercalcemia and had his renal function normalized, being discharged from the hospital after 14 days. Outpatient evaluation 30 days later showed normalized laboratory tests, except 25OHD that was persistently increased 9 months after treatment (107 ng/mL), since vitamin D is deposited in fat tissue and may take a longer time to normalization.

Discussion: Excessive amounts of vitamin D raise the intestinal calcium absorption, leading to hypercalcemia and related complications. Intoxication reports have been documented about adults with more than 30,000 UI daily intake. This case’s patient had used approximately 62,500 UI/day.

Bearing this in mind, this case is an important warning to overall population, raising awareness to the risks related with the use of veterinary substances for aesthetics purposes. However, reports regarding the outcomes of this practice are still lacking on scientific literature.

 

[Michael Scally MD]

Estradiol Levels in Men Are Not Correlated Cross-Sectionally with Intra-Abdominal Fat Area and Do Not Predict Change in This Fat Depot Longitudinally
https://endo.confex.com/endo/2014endo/webprogram/Paper12883.html

The relationship between estradiol levels and adiposity in men has been actively investigated, with some studies reporting a positive association between estradiol levels and fat mass and others finding no association.

A recent study found that men taking an aromatase inhibitor had increased body fat after 16 weeks, leading to the conclusion that estrogen deficiency was associated with increased adiposity (1).

We used longitudinal and cross-sectional data from the Japanese-American Community Diabetes Study to further examine this association. Subjects had baseline measurements of total testosterone and estradiol levels, fasting plasma glucose and single-slice intra-abdominal (IAF) and subcutaneous fat areas at the level of the umbilicus by computed tomography (CT). CT fat areas were re-measured 7.5 years later.

We performed univariate and multiple linear regression analyses to determine whether there was an association between Δ IAF area over 7.5 years and baseline estradiol levels. Estradiol levels were grouped into tertiles, given the distribution of the data and concerns about assay sensitivity at its lower limits.

The population included 113 Japanese-American men with the following mean characteristics: age 61.1 years, BMI 25.5 kg/m2, total testosterone level 4.8 µg/mL, and estradiol level 26.9 pg/mL.

In univariate analyses, we found no statistically significant association between estradiol tertiles and the following variables of interest:
baseline weight (p = 0.98),
Δ weight (p = 0.49),
baseline IAF (p = 0.55),
Δ IAF (p = 0.65),
baseline testosterone (p = 0.09), and
fasting plasma glucose (p = 0.32).

The multiple linear regression model to predict Δ IAF over 7.5 years included the following independent variables: baseline estradiol (tertile 2 vs 1, β = -2.91, 95% CI -17.7 to 11.8; tertile 3 vs 1, β = -0.44, 95% CI -15.4 to 14.6, overall p = 0.92), age (β = 0.44, 95% CI -0.67 to 1.54, p = 0.44), baseline IAF area (β = -0.1, 95% CI -0.23 to 0.02, p = 0.11), Δ weight (β = 5.34, 95% CI 3.63 to 7.06, p < 0.0001), and testosterone (β = -6.43, 95% CI -11.27 to -1.60, p = 0.01).

In this model, only Δ weight and total testosterone level at baseline were significantly associated with Δ IAF. A first order interaction term between estradiol and testosterone was entered into this model but was not significant (p = 0.57).

Given concerns about the sensitivity of estradiol levels at the lower range of the assay, we also examined the association between estradiol measured on a continuous scale and Δ IAF in the highest two estradiol tertiles only. There was no association in this model either (β = 0.29, 95% CI -0.67 to 1.25, p = 0.55).

In summary, our results confirm our earlier finding of a significant negative association between total testosterone level and Δ IAF area (2). However, they do not support an independent association between estradiol level and Δ IAF area over 7.5 years of follow-up in Japanese-American men.

(1) Finkelstein JS et al., N Engl J Med 2013; 369:1011-22.
(2) Tsai EC, Boyko EJ, Leonetti DL and Fujimoto WY, Int J Obesity 2000; 24:485-91.

 

[Michael Scally MD]

Clomiphene Citrate in Anabolic Steroid Users: A Retrospective Review
https://endo.confex.com/endo/2014endo/webprogram/Paper11684.html

The anabolic androgenic steroids (AAS) have been used by competitive athletes since1950s, to increase performance, gain muscle and lose body fat. Furthermore, testosterone (T) has been increasingly studied as a potential, reversible male contraceptive agent.

Regardless of the reason of exogenous steroid use the consequences are the same and lead to suppression of the hypothalamic-pituitary-gonadal (HPG) axis with all of its negative effects, including decrease in spermatogenesis and testosterone production lasting for several months to years following T exposure. Long-term adverse effects including loss of muscle and increased fat, loss of libido, energy and concentration with impaired quality of life pose a significant problem. More importantly, low testosterone states have been associated with increased mortality. Recommendations for treatment of endogenous testosterone suppression caused by AAS use are not available.

Clomiphene citrate (CC) is a weak estrogen receptor antagonist that competes with estradiol feedback at the pituitary and hypothalamic levels, leading to an increase in LH and FSH, improving steroidogenesis and spermatogenesis in men. There is only a limited amount of evidence to suggest benefit of CC in treatment of AAS induced HPG suppression. Several case reports have been reported, but to date, no larger retrospective studies have been performed.

We preformed a retrospective chart review aiming to assess the effect of CC on HPA axis in AAS users by analyzing T, LH and FSH levels prior and after CC use. Charts at the Men’s Health Initiative in Vancouver dating from 1998 to 2013 were searched using keywords including CC, hypogonadism and AAS use. Charts meeting criteria were reviewed and serum T, LH, FSH levels were analyzed at baseline as well as at different time points after initiating therapy to assess for efficacy and duration needed for restoration of HPG axis.

Our hypothesis was that Clomiphene significantly reduces the amount of time needed for HPA recovery in AAS users with specific aims to assess the effect of Clomiphene on HPA axis by analyzing information on testosterone, LH and FSH levels in AAS users prior and after Clomiphene use.

Our results support this as demonstrated by an increase in all three hormones following Clomiphene therapy. There was a 62.9%, 46.7% and 42.2% increase from baseline at 2 months in testosterone, LH and FSH levels respectively, and this was maintained at 57.8%, 46.6% and 43.9% at the 4 month mark (N=6). This reached statistical significance for testosterone levels with p<0.05 at both time points.

This is the first larger retrospective case series to demonstrate clear benefit of clomiphene in restoring HPG axis in AAS users.

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· (2)Krasnoff JB, Basaria S, Pencina MJ, Jasuja GK, Vasan RS, Ulloor J, et al. Free testosterone levels are associated with mobility limitation and physical performance in community-dwelling men: the Framingham Offspring Study. J Clin Endocrinol Metab. 2010;95(6):2790–9 [Research Support, N.I.H., Extramural].
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