The Endocrine Society 2014

[Michael Scally MD]

Male Sexual Function Can be Maintained without Aromatization: Randomized Placebo-Controlled Trial of Dihydrotestosterone (DHT) in Healthy, Older Men
https://endo.confex.com/endo/2014endo/webprogram/Paper12225.html

Introduction: Male sexual function is highly androgen dependent but whether aromatisation of testosterone is required remains contentious. Recent evidence from administration of an aromatase inhibitor to younger men (Finkelstein et al NEJM 369:1011-1022, 2013) suggested partial dependence on aromatisation.

Aim: To investigate the effects selective estrogen deficiency induced by a non-aromatizable androgen, DHT, on sexual function of healthy middle-aged and older men.

Methods, Outcome Measures and Analysis: Randomized clinical trial of daily transdermal DHT (70 mg) or placebo gel treatment for 24 months in 114 healthy middle-aged and older (>50 yr) men without known prostate disease (Idan et al Ann Intern Med 153:621-632, 2010).

The endpoints were responses to a validated psychosexual and mood questionnaire completed before, at 3 months, then at 6 monthly intervals during and 3 months after study. Data were analyzed by mixed model analysis of variance for repeated measures using age and body mass index (BMI) as covariates and including interactions of treatment with age and time-on-study.

Results: Serum DHT was increased with complete suppression of serum LH, FSH and estradiol throughout the 24 month study resulting in reduced spinal bone density and hormonal recovery post-study. There were no spontaneous complaints or discontinuations for adverse changes in sexual function during the study.

DHT administration had no effects on any measure of sexual function, apart from a mild decrease in overall sexual desire, more prominent in younger men and reversible after cessation of treatment. Increasing age and, less often increasing BMI, were associated with significant decreases in most aspects of sexual function.

Conclusions: We conclude that aromatization may not be required to maintain male sexual function in healthy eugonadal middle-aged or older men but age and obesity are significantly associated with decreases in most aspects of self-reported sexual function and satisfaction.

The apparent dependence of young male sexual function on aromatisation may be conditional on age and obesity and can be overcome by a non-aromatizable androgen.

(1) Finkelstein, J.S. et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med369, 1011-22 (2013).
(2) Idan, A. et al. Long-term effects of dihydrotestosterone treatment on prostate growth in healthy, middle-aged men without prostate disease: a randomized, placebo-controlled trial. Ann Intern Med 153, 621-32 (2010).

 

[Michael Scally MD]

Steroidal Extracts from Nutritional Sports Supplements Sold in Australia Test Positive for Androgenic Activity
https://endo.confex.com/endo/2014endo/webprogram/Paper15386.html

Nutritional sports supplements are often marketed to athletes claiming to help build lean muscle tissue, reduce body fat, and enhance endurance. The world-wide dietary supplement market is estimated to be worth $142.1 billion USD and is expected to reach $204.8 billion USD by 2017.

The lack of good manufacturing practice and regulation in the production and sale of nutritional supplements has led to the covert fortifying of these supplements with anabolic steroids to better achieve the claimed benefits. It has been discovered that in some instances these additions are not declared on the product label. Therefore, the aim of the study was to screen a range of nutritional sports supplements from the Australian market for the presence of androgens using an in vitro yeast cell-based bioassay.

Seventy four nutritional supplements were randomly purchased from Sydney-based stores that included protein powders, amino acids, creatines, fat metabolisers, ‘testosterone-boosters’, carbohydrates, and stimulant/nitric oxide ‘pre-workout’-based supplements.

Steroid extracts were obtained using solid-phase extraction with a C18 column. The steroid extracts were then tested for androgenic activity using a yeast-based bioassay whereby Saccharomyces cerevisiae cells were co-transformed with a human androgen receptor (AR) expression vector and a β-galactosidase reporter vector under the control of tandem androgen response elements.

Two supplements had relative potencies (RP) (defined as ‘extract receptor activity/receptor activity of testosterone (T)’) greater than T, 2.64 ± 0.33 (p-value 0.0197) and 7.20 ± 0.24 (p-value 0.0008), respectively. A third supplement had a RP less than, but not significantly different than, T (0.79 ± 0.067, p-value 0.0504). Four supplements activated AR, however with lower RP values than T (supp. 4 RP = 0.21 ± 0.03, p-value 0.0066; supp. 5 RP = 0.43 ± 0.09, p-value 0.0162; supp. 6 RP = 0.27 ± 0.02, p-value 0.0053; and supp. 7 RP = 0.36 ± 0.04, p-value 0.0025).

In summary, steroid extracts from 7 sports nutritional supplements from the Australian market had AR bioactivity, however, only 1 of these supplements declared the addition of an androgen.

 

[Michael Scally MD]

Pharmacokinetic-Pharmacodynamic Study of Subcutaneous Injection of Nandrolone Decanoate in an Oil Vehicle Using Dried Blood Spots (DBS) Blood Sampling Coupled with Ultra High Pressure Liquid Chromatography, Tandem Mass Spectrometry (LC-MS) Assays
https://endo.confex.com/endo/2014endo/webprogram/Paper12227.html

Introduction: Testosterone (T) and nandrolone (N) esters in an oil vehicle usually require deep intramuscular injections by skilled medical personnel. As intramuscular injections often deposit injectate into subdermal fat, more convenient self-administered subcutaneous injections of androgen esters may be feasible.

Aim: To investigate the (a) pharmacokinetics and pharmacodynamics of subcutaneous injection of N decanoate (ND) in healthy volunteer men using DBS for time intensive blood sampling without frequent clinic visits and (b) feasibility of subcutaneous injections of androgen ester in an oil vehicle.

Methods: Healthy eugonadal men (n=8, age 31 ± 10 (SD) year, height 175 ± 7 cm, weight 80.7 ± 0.8 kg, BMI 26.3 ± 3.0 kg/m2) were administered 100 mg ND in 2 mL arachis oil vehicle (MSD, Australia) by subcutaneous injection into a single abdominal site.

Capillary blood obtained by finger prick was dried onto filter paper, recording the exact sampling time, before and daily for 21 days. Venous blood was sampled before and at weekly intervals to also store serum and spot onto filter paper.

After storage at room temperature, DBS were eluted and extracted for assay of N and T by LC-MS/MS (tandem triple quadrupole API5000) in a single batch run. Serum N and T concentrations were estimated with adjustment for capillary blood sample volume and hematocrit to define peak (N) or nadir (T) time and concentration from the individual daily measurements.

Results: From the daily measurements, serum N rose to a peak concentration of 2.50 ± 0.25 (SEM) ng/mL at a median (range) of 6 (4-13) days causing a reduction in serum T from 3.50 ± 0.57 ng/mL at baseline to a nadir of 0.38 ± 0.13 (SEM) ng/mL representing 89 ± 3% maximal suppression at a median (range) of 8 (5-16 hr).

In simultaneously sampled capillary and venous blood, there was a high correlation with serum N (Passing-Bablok r=0.956 & 0.964, respectively) as well as for serum T (r=0.948 & 0.992) respectively. There were no complaints of discomfort following the injections.

Conclusions: This study demonstrates that
(a) DBS sampling coupled with LC-MS steroid assays can achieve intensive time sampling for PK/PD studies in the community without requiring clinic visits, venesection or frozen serum storage and
(b) androgen esters in an oil vehicle can be delivered effectively by subcutaneous injection avoiding the need for medically supervised deep intramuscular injections.

 

[Michael Scally MD]

Prostate Cancer Aggressiveness Is Strongly Dependent of Overweight and Obesity and Related to Androgen Deficiency
https://endo.confex.com/endo/2014endo/webprogram/Paper14879.html

INTRODUCTION AND OBJECTIVES: In prostate cancer (PCa) patients, obesity has been associated with worse outcome, especially more frequent biochemical recurrence after radical prostatectomy and low testosterone (<3ng/mL) with tumor aggressiveness, assessed by the predominant Gleason pattern (prdGP).

This study aims to compare histological feature with patient’s gonadal status to identify an accurate predictor of high-risk disease before undergoing radical prostatectomy.

METHODS: From a prospective study of 431 PCa patients requiring radical prostatectomy, 296 preoperative sera have been stored at -70°C to assay, in a specialized laboratory in GC-MS, Testosterone (T), bioavailable T (bioT), Dihydrotestosterone (DHT), Δ4-Androstenedione (Δ4), Δ5-Androstenediol (Δ5), Dehydroepiandrosterone (DHEA) and DHEA-sulphate (S-DHEA), Androsterone (ADT), Estradiol (E2), Estrone (E1) and E1-sulphate (S-E1).

Gleason score and predominant Gleason pattern (prdGP) were determined in prostate tissue specimens, and crosschecked by two uro-pathologists.

RESULTS: The testosterone GC-MS values were stratified according to T (<3; 3-4; 4-5; 5-6; 6-7 ;>7 ng/mL) leading to 6 groups (N= 27; 39; 63; 72; 35; 60) with an increase in mean T (2.4; 3.4; 4.6; 5.4; 6.4; 8.0 ng/mL), respectively. Parallel increase was observed for bioT (0.97; 1.30; 1.44; 1.50; 1.87; 1.89 ng/mL), DHT (0.19; 0.29; 0.40; 0.53; 0.59; 0.74 ng/mL), and, to a lesser extent, for ADT (0.17; 0.21; 0.18; 0.20; 0.21; 0.24 ng/mL) and for Δ5 (0.51; 0.75; 0.93; 1.06; I.15; 1.38 ng/mL). E2 increased slightly (23; 27; 28; 28; 30; 34 pg/mL). The E2/T ratio went down from 9.8 to 4.2 at the highest T concentrations. The other steroids assessed were stable.

The body mass index (BMI) decreased (29.9; 27.2; 26.2; 26.0; 25.0; 25.2) from low to high T. When the patients were stratified according to normal BMI <25, n=121, overweight BMI 25-30, n=131 and obese BMI >30, n=44, the mean BMI was 22.7, 27.1, and 32.8, respectively. The prostate weights were similar (49; 46; 52 g).

In the tissue specimens, a slight increase in GS (6.8; 6.9; 7.0) was observed. The incidences of prdGP 4 were 25% in the normal group and 32% in the overweight group: they were statistically different (p=0002, P=0.003) with the incidence of 50% in the obese group. The corresponding hormone levels in each groups were, for T: 5.9; 5.2; 4.6 ng/mL statistically lower in the obese group (p= 0.004 and p=0.04) as well as for DHT: 0.55; 0.47; 0.40 ng/mL (p= 0.0004 and P=0.003). E1 (43 pg/mL) in the obese group was significantly higher (p=0;03) than the 39 and 37 recorded in the normal and overweight groups.

CONCLUSIONS: In diagnosed PCa patients, the pre-operative ratio T/E2 should be used to evaluate the hormonal milieu because it is strongly related to body composition and obesity. Supplementation with testosterone in obese prostate cancer might be useful to reduce the aggressiveness of their cancer.

 

[Michael Scally MD]

Aromatase Inhibition for Hypogonadotrophic Hypogonadism in Men
https://endo.confex.com/endo/2014endo/webprogram/Paper14126.html

Hypogonadotrophic hypogonadism is common in men with obesity and in men with type 2 diabetes. Treatment usually involves testosterone replacement administered either trans-dermally or intramuscularly.

Both methods predictably lead to side effects of testicular shrinkage, reduction in sperm count, and, at times gynecomastia. The gels and injections are also at times aversive to patents, and thus lead to discontinuation of treatment .

Aromatase inhibitors have been used to raise sperm counts in infertile men by raising FSH secretion. We undertook, analogously, to treat low testosterone levels by raising LH secretion by use of the aromatase inhibitor anastrozole.

Fourteen male patients presenting with low testosterone due to pituitary dependent hypogonadism were selected in a clinical context for treatment with anastrozole.

BMI for the diabetic group was 36.3 +/- 4.1.
BMI for the obese group was 35.6 +/- 6.2.

Average LH level for the group of six diabetic men was 6.2 +/- 2.86 ng/dl.
Average LH level for the group of eight obese non-diabetic men was 6.0 +/- 2.27 mIU/ml.

Total testosterone under treatment in the diabetic group rose from 324.8 +/- 67.21 to 506.3 +/- 106.9 ng/dl.
Total testosterone in the obese group rose from from 274.6 +/- 31.1 ng/dl to 480.0 +/- 110.2 ng/dl.

Free testosterone in the diabetic group rose from 6.3 +/- 1.6 to 10.5 +/- 1.5 ng/dl, and, in the obese group, from 7.2 +/- 1.7 to 11.7 +/- 3.9 ng/dl.

Total estrogen in the diabetic group level dropped from 121.0 +/- 20 to 72.4 +/- 29.7 pg/ml, and in the obese group from 105.4 +/- 22.3 to 79.9 +/- 29.3 pg/ml.

Testosterone/estrogen ratio in the diabetic group rose from 2.9 +/- 0.8 to 8.5 +/- 3.4, and in the obese group from 2.7 +/- 0.6 to 7.0 +/- 4.0.

Clinical improvement was noted to some degree in all patients, whether in energy, libido, or motivation. No side effects of the anastrozole were seen.

These observations demonstrate clinically significant rises in testosterone levels, both total and free, accompanaied by symptomatic improvement. The effect was equally robust for the non-diabetic obese and the diabetic men. Body mass index did not affect the result in either group, the less obese patients having proportional increases in testostosterone.

The most important effect seen, in both groups was the marked increase in the testosterone/estrogen ratio. Since this ratio may correlate with clinical improvement, it is suggested that such clinical improvement can be seen with relatively small increments of testosterone itself.

Though these findings need to be confirmed by clinical studies with larger numbers of subjects, the possiblity is here presented that aromatase inhibition may represent an alternative treatment modality to testosterone replacement in a large number of obese and diabetic men with testosterone deficiency. Such a method may be both more advantageous and acceptable to patients than testosterone administration itself.

 

[Michael Scally MD]

Clomiphene Citrate in Treatment of Obstructive Sleep Apnea Induced Hypogonadism
https://endo.confex.com/endo/2014endo/webprogram/Paper12143.html

Obstructive sleep apnea (OSA) is a disorder characterized by repetitive apneic events resulting in hypoxia and hypercapnia affecting 4 to 25% of adult males. OSA is associated with obesity, hypertension, hypogonadism and increased cardiovascular morbidity. Testosterone (T) deficiency has multiple adverse effects on health, including loss of muscle, sexual dysfunction and impaired quality of life and has been associated with increased mortality.

Continuous positive airway pressure therapy (CPAP) and weight loss increase T levels in men with OSA however, relative androgen deficiency may not be fully reversed, leading to long-standing hypothalamo-pituitary-gonadal (HPG) dysregulation. The role of T in men with OSA is controversial because concerns regarding respiratory safety. Additionally, exogenous T leads to suppression of the HPG axis with recovery lasting weeks to months following discontinuation of therapy, independent of OSA.

Clomiphene citrate (CC) is a weak estrogen receptor antagonist that competes with estradiol feedback at the pituitary and hypothalamic levels increasing LH, FSH, steroidogenesis and spermatogenesis in men, and inducing ovulation in women. CC in OSA has several potential benefits over T.

Firstly, it does’t cause suppression of HPG axis, secondly it’s not associated with erythrocytosis and thirdly, it does’t suppress spermatogenesis. Use of CC in OSA induced hypogonadism has not yet been investigated and no retrospective trials have been preformed to assess efficacy of CC in OSA induced hypogonadism.

We preformed a retrospective chart review to assess the effect of CC on HPA axis in patients with OSA induced hypogonadism. Charts at the Men’s Health Initiative in Vancouver dating from 1998 to 2013 were searched using keywords including CC, hypogonadism and OSA. Charts meeting criteria were reviewed and serum T, LH, FSH levels were analyzed at baseline and after initiating therapy to assess for efficacy of CC in restoration of HPG axis.

We hypothesized that CC is effective treatment of OSA induced hypogonadism. Our specific aims were to assess the effect of CC on HPG axis by analyzing T, LH and FSH in OSA patients with biochemically confirmed hypogonadism; assess effects on spermatogenesis and assess sustainability of restoration of HPG axis following discontinuation of CC.

Our preliminary results support this, as demonstrated by an increase in all three hormones following CC therapy. There was a 58.3%, 50.1% and 50.6% increase from baseline at 2 months in T, LH and FSH levels respectively, and this was maintained at 45.1%, 63.0% and 60.3% at 4 months (N=8).

This is the first larger retrospective case series to demonstrate benefit of CC in restoring HPG axis in OSA induced hypogonadism.

(1) Young, T., Palta, M., Dempsey, J. et al. (1993) The occurrence of sleep-disordered breathing among middle-aged adults. New England Journal of Medicine, 328, 1230–1235.

(2) Lavie P, Herer P, Peled R, Berger J, Yoffe N, Zomer J, Rubin A 1995 Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep 18:149–157.

(3) Peppard PE, Young T, Palta M, Dempsy J, Skatrud. 2000 Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 284:3015–3021.

(4) Lavie P, Herer P, Peled R, et al. Mortality in sleep apnea patients: a multivariate analysis of risk factors. Sleep. 1995; 18:149 –57.

(5) Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab. 2000;85:1151– 8.

(6) Peppard PE, Young T, Palta M, Dempsy J, Skatrud C. Longitudinal study of moderate weight change and sleepdisordered breathing. JAMA. 2000;284:3015–21.

(7) Liu, P.Y., Caterson, I.D., Grunstein, R.R. et al. (2007) Androgens, obesity, and sleep-disordered breathing in men. Endocrinology and Metabolism Clinics of North America, 36, 349–363.

(8) Barrett-Connor, E., Dam, T.T., Stone, K. et al. (2008) The association of testosterone levels with overall sleep quality, sleep architecture, and sleep disordered breathing. Journal of Clinical Endocrinology and Metabolism, 93, 2602–2609.

(9) Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM: Testosterone treatment and mortality in men with low testosterone levels, J Clin Endocrinol Metab. 2012 Jun; 97(6): 2050-8.

(10) Grunstein, R.R., Handelsman, D.J., Lawrence, S.J. et al. (1989) Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab., 68, 352–358.

(11) Strain, G.W., Zumoff, B., Miller, L.K. et al. (1988) Effect of massive weight loss on hypothalamic-pituitary-gonadal function in obese men. J Clin Endocrinol Metab., 66, 1019–1023.

(12) Bhasin, S., Cunningham, G.R., Hayes, F.J. et al. (2010) Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metabol, 95, 2536–2559.

(13)Ghanem H, Shaeer O, El-Segini A. Combination clomiphene citrate and antioxidant therapy for idiopathic male infertility: a randomized controlled trial. Fertil Steril. 2010;93(7):2232–5 [Randomized Controlled Trial].

(14) Whitten S. et al. Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate, Fertility and Sterility, Vol. 86, No. 6, December 2006.

 

[Michael Scally MD]

ELEVATED TOTAL THYROXINE AND TOTAL TESTOSTERONE, AN UNUSUAL COMBINATION
https://endo.confex.com/endo/2014endo/webprogram/Paper11802.html

Introduction: An elevated total thyroxine or total testosterone level can reflect an underlying increase of thyroid binding globulin (TBG) or sex Hormone Binding Globulin (SHBG), rather than an increased level of either active hormone. It is unusual to find both binding globulin-driven total hormone elevations in the same patient.

Clinical Case: A 56 y/o male was referred by his primary provider to the Endocrine Clinic for evaluation and management of both elevated total testosterone 1511 ng/dL (348-1197) and total thyroxine (T4) 14.8 mcg/dL (4.5-12) levels discovered during an evaluation for fatigue and erectile dysfunction. When repeated his total testosterone was again elevated at 1590 ng/dL (240-950) with normal Lutenizing Hormone (LH) 8.31 mIU/mL (1.5-9.3) and Follicle Stimulating Hormone (FSH) 3.88 mIU/mL (1.4-18.1).

His total T4 was 16.3 mcg/dL (4.5-12) with normal Thyroid Stimulating Hormone (TSH) 1.082 mcIU/mL (0.4-4.7). The corresponding free hormone levels were normal with elevated levels of the corresponding binding globulins. Free T4 was 1.19 ng/dl (0.58-1.76) with a TBG of 410 mcg/mL (12-26); free testosterone measured by equilibrium dialysis was 11 ng/dl (9-30) with SHBG of 177 nmol/L (10-57).

Elevated TBG can be associated with hepatitis, elevated estrogen levels, certain drugs, acute intermittent porphyria, or can be hereditary due to increased production of TBG. Elevated levels of SHBG have been associated with hepatitis, elevated estrogen levels, age, certain drugs, iron overload within the liver, and acute psychosocial stress.

The patient was taking none of the known causative drugs and his estradiol level was within normal limits. Despite normal liver function tests, a screen for Hepatitis C viral infection revealed an elevated antibody level. Gastroenterology referral is pending for further evaluation.

Conclusion: The mechanism by which hepatitis causes increased levels of TBG and SHBG is unclear and literature on the subject is limited. Clinicians should be aware of the association of hepatitis with elevated hormone binding globulin levels and the effects increased binding globulins may have on measurement of hormone levels. Free hormone levels should be obtained when total hormone levels do not correlate with clinical findings.

 

[Michael Scally MD]

SHBG Gene Expression in Human Liver and Hepatic Steatosis
https://endo.confex.com/endo/2014endo/webprogram/Paper12014.html

Sex hormone binding globulin (SHBG) is a circulating glycoprotein produced by hepatocytes that transports testosterone and other steroids in the blood. SHBG levels are influenced by genetic, hormonal, metabolic, and nutritional factors.

Low levels of SHBG are associated with adiposity, insulin resistance, and fatty liver, and convey an increased risk for type 2 diabetes and cardiovascular disease.

Hyperinsulinemia and intrahepatic fat content have been proposed as possible determinants of SHBG expression but so far no studies of SHBG mRNA in human liver have been published.

The nuclear receptor hepatocyte nuclear factor-4α (HNF4α) stimulates multiple genes that function in lipid metabolism, and activates SHBG gene transcription.

We examined SHBG in serum, and SHBG and HNF4α mRNAs by qRT-PCR, fasting insulin levels, insulin resistance by HOMA-IR, and hepatic triglyceride concentrations in 55 subjects with cancer, ECOG performance status 0, who were undergoing partial hepatectomy as treatment for their disease.

Patients were aged 39 to 82 yrs (61.8±11.2 yrs), and weighed 43.1 -130 kg (84.5±20.2 kg) with a BMI of 16 - 45 kg/m2 (28.9±6.5 kg/m2). Nineteen patients had T2DM and 18 were diagnosed with dyslipidemia.

There was a strong positive relationship between SHBG mRNA in liver and serum SHBG levels (R2 = 0.40, p < 0.001) with higher levels in women than men. Moreover, the level of HNF4α mRNA was a strong predictor of SHBG mRNA (overall R2 = 0.30, p < 0.001).

Hepatic triglyceride concentrations varied 30-fold from 134 to 2679 mg/dL, and increased with increasing body weight, but not all obese persons had hepatic steatosis. When subjects were divided into two groups based on low (134-412 mg/dL) or high (415-2679 mg/dL) hepatic triglyceride levels, subjects with high levels were more insulin resistant (p<0.01) based on HOMA-IR (3.31±0.51 vs 1.60 ± 0.28) and had a higher fasting blood glucose level (122±9.5 vs 99±2.8 mg/dL; p=0.02).

There were significant inverse curvilinear relationships between the hepatic triglyceride concentration and the levels of both serum SHBG (R2=0.16, p=0.02) and SHBG mRNA (R2=0.23, p=0.003). These associations did not differ by gender, and were independent of HNF4α, age, BMI, HOMA and the diagnosis of T2DM. There was a statistically significant curvilinear association between HNF4α and hepatic triglycerides in men (R2 = 0.23, p=0.04) but not women (R2=0.09, n.s.).

Furthermore, SHBG and HNF4α expression levels were significantly inversely associated with insulin and HOMA in men (r’s > 0.05, p< 0.05) but not women. There was no relationship between HbA1c (n=28) and hepatic triglycerides (R2=0.003) or SHBG mRNA (R2=0.01).

Our findings reveal that SHBG gene expression is a major determinant of the level of SHBG in plasma, and support the notion that hepatic triglycerides are one factor that regulates circulating SHBG through a mechanism involving HNF4α and SHBG expression.

 

[Michael Scally MD]

Free Testosterone but Not Total Testosterone or Estradiol Is Associated with Sexual Function in Symptomatic Older Hypogonadal Men in the Sexual Function Trial of the Testosterone Trials
https://endo.confex.com/endo/2014endo/webprogram/Paper12367.html

Background - The relationship between sex hormone levels and sexual function in older hypogonadal men is unclear. We tested the hypothesis that total and free testosterone (TT and FT) and estradiol (E2) levels are independently associated with sexual function in symptomatic older hypogonadal men.

Methods - We evaluated 470 hypogonadal men enrolled in the Sexual Function Trial of The Testosterone Trials. At entry, men were ≥65 years, had symptoms and objective evidence of sexual dysfunction, and 2 early morning TT values on separate days with an average of <275 ng/dL. They qualified for the Sexual Function Trial if they scored ≤20 on the Sexual Desire Domain of the Derogatis Interview for Sexual Function (DISF-SDD) and had a partner willing to have sexual intercourse at least twice a month. We investigated the cross-sectional association of baseline TT (LC-MS/MS), equilibrium dialysis FT and E2 (LC-MS/MS) levels with sexual desire assessed by the DISF-SDD, erectile function evaluated by the Erectile Function Domain of the International Index of Erectile Function (IIEF-EFD), and sexual activity determined by the Psychosexual Daily Questionnaire (PDQ4) using multivariable linear regression and adjusting for confounding factors.

Results - Men in the Sexual Function Trial had a mean±SD age of 71.6±5.3 years, BMI of 31.0±3.5 and waist circumference of 110±10.7 cm. Baseline TT was 238.2±69.0 ng/dL, FT 58.3±20.2 pg/mL and E2 22.6± 9.7 pg/mL. The sexual function scores were low: DISF-SDD 11.8±6.6, IIEF-EFD 8.0±8.2 and PDQ4 1.4±1.3. In unadjusted analyses, TT and FT but not E2 were associated with sexual function. However, only FT [partial regression coefficient (ß)] remained significantly associated with DISF-SDD score (ß=0.034, p=0.04), IIEF score (ß=0.054, p=0.01) and PDQ4 score (ß=0.007, p=0.03) after adjustment for age, BMI, waist circumference, gait speed, PHQ9 (depression) score, FACIT Fatigue (vitality) score, mean arterial pressure and hemoglobin A1c. Similarly, FT (p<0.005), but not TT or E2 was associated with measures of sexual function in all men (n=788) in The Testosterone Trials.

Conclusions - FT but not TT or E2 is independently associated with measures of sexual desire, erectile function and sexual activity in older hypogonadal men with symptoms and objective evidence of sexual dysfunction. These findings suggest that FT contributes more than TT or E2 to sexual dysfunction in older hypogonadal men.