Transdermal Testosterone Improves Verbal Learning and Memory in Postmenopausal Women Not on Estrogen therapy. (2014)

Transdermal Testosterone Improves Verbal Learning and Memory in Postmenopausal Women Not on Estrogen therapy. (click to view abstract)

Objective

The aim of this study was to examine the effects of testosterone on verbal learning and memory in postmenopausal women.

Design

Randomised placebo-controlled trial in which participants were randomized (1:1) to transdermal testosterone gel 300mcg/ day, or identical placebo, for 26 weeks.

Patients

92 post-menopausal women aged 55-65 years, on no systemic sex hormone therapy.

Measurements

The primary outcome was the score for the International Shopping List Task (ISLT) of CogState. Secondary outcomes included other CogState domains, the Psychological General Well-Being Index (PGWB) and safety variables.

Results

89 women, median age 60 years, were included in the primary analysis. Testosterone treatment resulted in statistically significantly better performance for the ISLT (improved verbal learning and memory) compared with placebo, adjusted for age and baseline score (mean difference 1·57; 95%CI 0·13, 3·01) p=0.03). There were no significant differences for other CogState domains or the PGWB scores. At 26 weeks, the median total testosterone was 1·7 nmol/L (interquartile range (IQR) 1·1, 2·4) in the testosterone group and 0·4nmol/L (IQR 0·3, 0·5) in the placebo group.

Conclusions

The small but statistically significant effect of testosterone treatment on verbal learning and memory in postmenopausal women provides the basis for further clinical trials.

Reduced incidence of breast cancer with testosterone therapy (2013)

(Full PDF) - Article in Press - Maturitas 2013

Objectives: There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estro- gen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design: This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anas- trozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results: Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women’s Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion: T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by main- taining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer. 

Testosterone therapy in women: Myths and misconceptions (2013)

(FULL PDF) Maturitas Volume 74, Issue 3 , Pages 230-234, March 2013

Abstract 

Although testosterone therapy is being increasingly prescribed for men, there remain many questions and concerns about testosterone (T) and in particular, T therapy in women. A literature search was performed to elucidate the origin of, and scientific basis behind many of the concerns and assumptions about T and T therapy in women.

This paper refutes 10 common myths and misconceptions, and provides evidence to support what is physiologically plausible and scientifically evident: T is the most abundant biologically active female hormone, T is essential for physical and mental health in women, T is not masculinizing, T does not cause hoarseness, T increases scalp hair growth, T is cardiac protective, parenteral T does not adversely affect the liver or increase clotting factors, T is mood stabilizing and does not increase aggression, T is breast protective, and the safety of T therapy in women is under research and being established.

Abandoning myths, misconceptions and unfounded concerns about T and T therapy in women will enable physicians to provide evidenced based recommendations and appropriate therapy.

Improvement in scalp hair growth in androgen-deficient women treated with testosterone: a questionnaire study (2012)

(FULL PDF) British Journal of Dermatology  Volume 166, Issue 2, pages 274–278, February 2012

Background  Androgens are thought to have an adverse effect on female scalp hair growth. However, our clinical experience of androgen replacement therapy in women with androgen deficiency, in which hair loss was seldom reported, led us to question this concept.

Objectives  To evaluate the effect of subcutaneous testosterone therapy on scalp hair growth in female patients.

Methods  A total of 285 women, treated for a minimum of 1 year with subcutaneous testosterone implants for symptoms of androgen deficiency, were asked to complete a survey that included questions on scalp and facial hair. Age, body mass index (BMI) and serum testosterone levels were examined.

Results  Out of the 285 patients, 76 (27%) reported hair thinning prior to treatment; 48 of these patients (63%) reported hair regrowth on testosterone therapy (responders). Nonresponders (i.e. no reported hair regrowth on therapy) had significantly higher BMIs than responders (P = 0·05). Baseline serum testosterone levels were significantly lower in women reporting hair loss prior to therapy than in those who did not (P = 0·0001). There was no significant difference in serum testosterone levels, measured 4 weeks after testosterone implantation, between responders and nonresponders. No patient in this cohort reported scalp hair loss on testosterone therapy. A total of 262 women (92%) reported some increase in facial hair growth.

Conclusions  Subcutaneous testosterone therapy was found to have a beneficial effect on scalp hair growth in female patients treated for symptoms of androgen deficiency. We propose this is due to an anabolic effect of testosterone on hair growth. The fact that no subject complained of hair loss as a result of treatment casts doubt on the presumed role of testosterone in driving female scalp hair loss. These results need to be confirmed by formal measurements of hair growth.

Beneficial effects of testosterone therapy in women measured by the validated Menopause Rating Scale (MRS) (2011)

(FULL PDF) - Maturitas Volume 68, Issue 4, April 2011, Pages 355–361 

Objectives

This study was designed to measure the beneficial effects of continuous testosterone therapy, delivered by subcutaneous implant, in the relief of somatic, psychological and urogenital symptoms in both pre- and post-menopausal patients, utilizing the validated Health Related Quality of Life (HRQOL), Menopause Rating Scale (MRS).

Study design

300 pre- and post-menopausal women with symptoms of relative androgen deficiency, were asked to self-administer the 11-item MRS, at baseline and 3 months after their first insertion of the subcutaneous testosterone implant. Baseline hormone measurements, menopausal status and BMI, were assessed to determine correlation with symptoms and clinical outcome.

Main outcome measurements

Changes related to therapy were determined. Total MRS scores as well as psychological, somatic and urogenital subscale scores were compared prior to therapy and following testosterone implant therapy.

Results

Pre-menopausal and post-menopausal females reported similar hormone deficiency symptoms. Both groups demonstrated similar improvement in total score, as well as psychological, somatic and urogenital subscale scores with testosterone therapy. Better effect was noted in women with more severe complaints. Higher doses of testosterone correlated with greater improvement in symptoms.

Conclusion

Continuous testosterone alone, delivered by subcutaneous implant, was effective for the relief of hormone deficiency symptoms in both pre- and post-menopausal patients. The validated, HRQOL questionnaire, Menopause Rating Scale (MRS), proved a valuable tool in the measurement of the beneficial effects of testosterone therapy in both cohorts.

Low salivary testosterone levels in patients with breast cancer (2010)

(FULL PDF) BMC Cancer 2010, 10:547 

Background

Correlation between circulating sex steroid levels and breast cancer has been controversial, with measurement of free, or bioavailable hormone rarely available. Salivary hormone levels represent the bioavailable fraction. To further elucidate the role of endogenous hormones in breast cancer, we aimed to assess correlation between salivary sex steroid levels and breast cancer prevalence.

Methods

Salivary hormone levels of testosterone (T), Estradiol (E2), Progesterone (P), Estriol (E3), Estrone (E1), DHEAS and Cortisol (C) were measured by Enzyme Immunoassay (EIA) in 357 women with histologically verified breast cancer and 184 age-matched control women.

Results

Salivary T and DHEAS levels were significantly lower in breast cancer cases vs. controls (27.2+13.9 vs. 32.2+17.5 pg/ml, p < 0.001 for T and 5.3+4.3 vs. 6.4+4.5 ng/ml, p = 0.007 for DHEAS). E2 and E1 levels were elevated and E3 levels were lowered in cases vs. controls.

Conclusions

Salivary T levels, representing the bioavailable hormone, are significantly lower in women with breast cancer compared to age-matched control women. These findings support the protective role of biovailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue.       

High Serum Testosterone (>550ng/dL) Is Associated With Reduced Risk of Cardiovascular Events (30% reduction) and Stroke (24% reductions) and in Elderly Men (2011)

(Full PDF) J Am Coll Cardiol. 2011;58(16):1674-1681.

OBJECTIVES:

We tested the hypothesis that serum total testosterone and sex hormone-binding globulin (SHBG) levels predict cardiovascular (CV) events in community-dwelling elderly men.

BACKGROUND:

Low serum testosterone is associated with increased adiposity, an adverse metabolic risk profile, and atherosclerosis. However, few prospective studies have demonstrated a protective link between endogenous testosterone and CV events. Polymorphisms in the SHBG gene are associated with risk of type 2 diabetes, but few studies have addressed SHBG as a predictor of CV events.

METHODS:

We used gas chromatography/mass spectrometry to analyze baseline levels of testosterone in the prospective population-based MrOS (Osteoporotic Fractures in Men) Sweden study (2,416 men, age 69 to 81 years). SHBG was measured by immunoradiometric assay. CV clinical outcomes were obtained from central Swedish registers.

RESULTS:

During a median 5-year follow-up, 485 CV events occurred. Both total testosterone and SHBG levels were inversely associated with the risk of CV events (trend over quartiles: p = 0.009 and p = 0.012, respectively). Men in the highest quartile of testosterone (≥550 ng/dl) had a lower risk of CV events compared with men in the 3 lower quartiles (hazard ratio: 0.70, 95% confidence interval: 0.56 to 0.88). This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline (hazard ratio: 0.71, 95% confidence interval: 0.53 to 0.95). In models that included both testosterone and SHBG, testosterone but not SHBG predicted CV risk.

CONCLUSIONS:

High serum testosterone predicted a reduced 5-year risk of CV events in elderly men.

Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. (2013)

(full PDF) Obesity (Silver Spring). 2013 Oct;21(10):1975-81

DESIGN AND METHODS:

Open-label, single-center, cumulative, prospective registry study of 255 men (aged 33-69 years, mean 58.02 ± 6.30 years), with T levels below 12.13 nmol/L (mean: 9.93±1.38). 215 men for at least 2 years, 182 for 3 years, 148 for 4, and 116 for at least 5 years were studied. They received parenteral T undecanoate 1,000 mg/12 weeks after an initial interval of 6 weeks.

RESULTS:

Body weight (BW) decreased from 106.22 ± 16.93 kg to 90.07 ± 9.51 kg. Waist circumference (WC) reduced from 107.24 ± 9.14 cm to 98.46 ± 7.39 cm. BMI (m/kg(2) ) declined from 33.9 ± 5.51 m/kg(2) to 29.13 ± 3.09 m/kg(2) . All parameters examined were statistically significant with P < 0.0001 versus baseline and versus the previous year over 5 years indicating a continuous weight loss over the full observation period. The mean per cent weight loss after 1 year was 4.16 ± 0.31%, after 2 years 7.54 ± 0.32%, after 3 years 9.23 ± 0.33%, after 4 years 11.42 ± 0.35% and after 5 years 13.57 ± 0.37%.

Onset of effects of testosterone treatment and time span until maximum effects are achieved (2011)

(full PDF) European Journal of Endocrinology (2011)165675–685

Effects on sexual interest appear after 3 weeks plateauing at 6 weeks, with no further increments expected beyond. Changes in erections/ejaculations may require up to 6 months. Effects on quality of life manifest within 3–4 weeks, but maximum benefits take longer. Effects on depressive mood become detectable after 3–6 weeks with a maximum after 18–30 weeks. Effects on erythropoiesis are evident at 3 months, peaking at 9–12 months. Prostate-specific antigen and volume rise, marginally, plateauing at 12 months; further increase should be related to aging rather than therapy. Effects on lipids appear after 4 weeks, maximal after 6–12 months. Insulin sensitivity may improve within few days, but effects on glycemic control become evident only after 3–12 months. Changes in fat mass, lean body mass, and muscle strength occur within 12–16 weeks, stabilize at 6–12 months, but can marginally continue over years. Effects on inflammation occur within 3–12 weeks. Effects on bone are detectable already after 6 months while continuing at least for 3 years.

Testosterone and the aging male: To treat or not to treat? (2010)

Maturitas, Volume 66, Issue 1, May 2010, Pages 16–22

It is well-established that total testosterone (TT) in men decreases with age and that bioavailable testosterone (bio-T) falls to an even greater extent. The clinical relevance of declining androgens in the aging male and use of testosterone replacement therapy (TRT) in this situation is controversial. Most studies have been short term and there are no large randomized placebo-controlled trials. Testosterone has many physiological actions in: muscles, bones, hematopoietic system, brain, reproductive and sexual organs, adipose tissue. Within these areas it stimulates: muscle growth and maintenance, bone development while inhibiting bone resorption, the production of red blood cells to increase hemoglobin, libido, enhanced mood and cognition, erectile function and lipolysis. Anabolic deficits in aging men can induce: frailty, sarcopenia, poor muscle quality, muscle weakness, hypertrophy of adipose tissue and impaired neurotransmission. The aging male with reduced testosterone availability may present with a wide variety of symptoms which in addition to frailty and weakness include: fatigue, decreased energy, decreased motivation, cognitive impairment, decreased self-confidence, depression, irritability, osteoporotic pain and the lethargy of anemia. In addition, testosterone deficiency is also associated with type-2 diabetes, the metabolic syndrome, coronary artery disease, stroke and transient ischemic attacks, and cardiovascular disease in general. Furthermore, there are early studies to suggest that TRT in men with low testosterone levels may improve metabolic status by: lowering blood sugar and HbA1C in men with type-2 diabetes, reducing abdominal girth, ameliorating features of the metabolic syndrome, all of which may be protective of the cardiovascular system. The major safety issue is prostate cancer but there is no evidence that supports the idea that testosterone causes the development of a de novo cancer. So on balance in a man with symptoms of hygonadism and low or lowish levels of testosterone with no evidence of prostate cancer such as a normal PSA a therapeutic (4–6 months) trial of TRT is justified. Treatment and monitoring of this duration will determine whether the patient is responsive.

External Handout from hormonebalance.org - Medications that increase Aromatase Activity

http://hormonebalance.org/userfiles/file/Medications%20that%20increase%20aromatase.pdf

Acute Anti-Ischemic Effect of Testosterone in Men With Coronary Artery Disease (1999)

(Full PDF) Circulation. 1999; 99: 1666-1670 

Background—The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men.

Methods and Results—After withdrawal of antianginal therapy, 14 men (mean age, 58±4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579±204 versus 471±210 seconds; P<0.01) and total exercise time (631±180 versus 541±204 seconds; P<0.01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135±12 versus 123±14 bpm; P<0.01) and at peak exercise (140±12 versus 132±12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213±3750 versus 21 619±3542 mm Hg×bpm; P<0.05) and at peak exercise (26 746±3109 versus 22 527±5443 mm Hg×bpm; P<0.05).

Conclusions—Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.                      

Does Testosterone therapy increase the risk of prostate cancer? A meta-analysis of 44 studies. (2009)

Abstract - Int J Impot Res. 2009 Jan-Feb;21(1):9-23.

This paper provides a systematic review of the literature about prostate cancer risk associated with testosterone therapy for hypogonadism. A comprehensive search of MEDLINE, EMBASE and other resources was conducted to identify articles that highlight occurrences of prostate cancer in men receiving testosterone therapy for hypogonadism treatment. Articles that met study inclusion criteria were assessed for causality between testosterone treatment and prostate cancer, increased prostate-specific antigen or abnormal digital rectal examination findings. Of 197 articles relating to testosterone therapy, 44 met inclusion criteria: 11 placebo-controlled, randomized studies; 29 non-placebo-controlled studies of men with no prostate cancer history; and 4 studies of hypogonadal men with history of prostate cancer. Of studies that met inclusion criteria, none demonstrated that testosterone therapy for hypogonadism increased prostate cancer risk or increased Gleason grade of cancer detected in treated vs untreated men. Testosterone therapy did not have a consistent effect on prostate-specific antigen levels.

Lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism (2013)

Abstract - World Journal of Urology, October 2013

Methods

Two hundred and sixty-one hypogonadal patients (mean age 59.5 years) presenting with erectile dysfunction, having also been evaluated for LUTS, received a single testosterone undecanoate injection at day 1, at week 6 and quarterly thereafter. Parameters, including International Prostate Symptom Score (IPSS), post-voiding residual urine volume, transrectal ultrasound, prostate volume and prostate-specific antigen were measured at each treatment visit. Two hundred and fifty-nine patients were included in the full analysis set. These were subsequently divided into weight losers (L ≥ 5 % weight loss at last visit from baseline) and non-losers (NL). t test analyses were used to compare the IPSS means of these subgroups. The potentially confounding effect on IPSS of using the phosphodiesterase-5 inhibitor (PDE5i) vardenafil was also accounted for.

Results

Mean IPSS showed a significant decrease with time following initiation of testosterone treatment (p < 0.05). No significant differences were observed in either IPSS between L and NL groups or in mean IPSS between vardenafil users and non-users.

Conclusion

Testosterone replacement is associated with improvements in LUTS which are not confounded by weight loss or PDE5i. The mechanisms of this association require further investigation.

Testosterone Replacement Alone for Testosterone Deficiency Syndrome Improves Moderate Lower Urinary Tract Symptoms: (2013)

(full PDF) World J Mens Health. 2013 April; 31(1): 47–52.

Results

After TRT, PSA remained unchanged after a year of treatment (p=0.078). Compared with their counterparts (n=229), the patients without BPH medication had similar baseline prostate characteristics in all variables, including prostate volume, IPSS, maximal flow rate, voiding volume, and PSA, except the median amount of residual urine, which was higher in the patients without BPH medication (21 ml vs. 10 ml). In the no-BPH medication group, the total IPSS score was decreased significantly (p=0.028), both in storage symptoms (questionnaire 2, 4, 7) and voiding symptoms (questionnaire 1, 3, 5, 6), while the maximal flow rate and residual urine amount remained unchanged after a year of TRT. During the median follow up of 15.1 months, no patients experienced urinary retention, BPH-related surgery, or admission for urinary tract infection.

Conclusions

Over a year of TRT for the no-BPH medication patients with moderate LUTS and maintained a relatively high maximal flow rate and improved both storage and voiding symptoms, without the clinical progression of BPH or rising PSA.

Men with a free testosterone levels below 17.3 pg/ml had an adjusted 3.3-fold risk of developing premature coronary artery disease compared to age matched controls (2007)

The association between androgen levels and premature coronary artery disease in men.   Coron Artery Dis. 2007 May;18(3):159-62. (Abstract)

OBJECTIVE:  The relationship between androgens and the risk of development of coronary artery disease has not been clarified well. This study was planned to determine the relationship between serum androgen levels and premature development of coronary artery disease in men.

METHODS:  Sixty-nine men below 45 years of age with documented coronary artery disease (mean age 41.0+/-4.7) constituted the study group. Control group consisted of 56 men with similar age and normal coronary angiograms (mean age 41.3+/-3.8). Total and free testosterone, estradiol, and fasting plasma total, low-density lipoprotein, and high-density lipoprotein cholesterol, and triglyceride levels were measured, and compared between the two groups.

RESULTS:  Mean age, body mass index, and the frequency of hypertension were similar between the two groups; however, diabetes mellitus, smoking, hyperlipidemia, and family history of coronary artery disease were more frequent in the coronary artery disease group. Total and free testosterone levels of the patients with coronary artery disease were significantly lower than those of controls, whereas estradiol levels did not differ. Multivariate logistic regression analysis revealed that free testosterone levels (P=0.014; odds ratio=0.90; 95% confidence interval=0.87-0.99), hyperlipidemia (P<0.001; odds ratio=8.2; 95% confidence interval=3.17-21.0), and smoking (P=0.026; odds ratio=3.12; 95% confidence interval=1.15-8.48) were independent predictors of premature coronary artery disease. Moreover, using receiver operating characteristic analysis, patients with free testosterone levels below the cut-off value of 17.3 pg/ml had an adjusted 3.3-fold risk of developing premature coronary artery disease compared to those with free testosterone levels above the cut-off level (odds ratio=3.3; 95% confidence interval=1.57-6.87).

CONCLUSION:  A low level of free testosterone may be related to the development of premature coronary artery disease.

Are biochemical tests of thyroid function of any value in monitoring patients receiving thyroxine replacement? (1986)

(Full PDF Available) Br Med J (Clin Res Ed). 1986 September 27; 293(6550): 808–810.

Most physicians feel that a suppressed TSH is an indication that the dose of thyroid should be reduced (except with thyroid cancer). While a suppressed TSH may be an indication the patient is hyperthyroid, this study found that was the case only 20% of the time. In other words, doctors who make the assumption that a suppressed TSH means over-replacement and decrease the dose based on the suppressed TSH will be wrong 80% of the time because 80% of the time a suppressed TSH was shown not to be an indication that the patient was hyperthyroid or receiving too much thyroid replacement.​​​​

Effect of combination therapy with thyroxine (T4) and 3,5,30-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study (2009)

(Full PDF)  European Journal of Endocrinology (2009) 161 895–902

Background: Treatment of hypothyroidism with 3,5,30-triiodothyronine (T3) is controversial. A recent meta-analysis concludes that no evidence is present in favour of using T3. However, the analysis included a mixture of different patient groups and dose-regimens.
Objective: To compare the effect of combination therapy with thyroxine (T4) and T3 versus T4 monotherapy in patients with hypothyroidism on stable T4 substitution.

Study design: Double-blind, randomised cross-over. Fifty micrograms of the usual T4 dose was replaced with either 20 mg T3 or 50 mg T4 for 12 weeks, followed by cross-over for another 12 weeks. The T4 dose was regulated if needed, intending unaltered serum TSH levels.
Evaluation: Tests for quality of life (QOL) and depression (SF-36, Beck Depression Inventory, and SCL- 90-R) at baseline and after both treatment periods.

Inclusion criteria: Serum TSH between 0.1 and 5.0 mU/l on unaltered T4 substitution for 6 months. Results: A total of 59 patients (55 women); median age 46 years. When comparing scores of QOL and depression on T4 monotherapy versus T4/T3 combination therapy, significant differences were seen in 7 out of 11 scores, indicating a positive effect related to the combination therapy. Forty-nine percent preferred the combination and 15% monotherapy (PZ0.002). Serum TSH remained unaltered between the groups as intended.

Conclusion: In a study design, where morning TSH levels were unaltered between groups combination therapy, (treated with T3 20 mg once daily) was superior to monotherapy by evaluating several QOL, depression and anxiety rating scales as well as patients own preference. 

Do we need still more trials on T4 and T3 combination therapy in hypothyroidism? (2009)

(Full PDF)   European Journal of Endocrinology (2009) 161 955–959 

Approximately 10% of hypothyroid patients are dissatisfied with the outcome of levothyroxine replacement. It is unlikely that slight over- or under-treatment with thyroxine (T4) explains remaining complaints. Meta-analysis of randomized clinical trials shows no advantage of T4/tri-iodothyronine (T3) combination therapy over T4 monotherapy. However, each of these trials can be criticized, and none is perfect: most of them failed to mimic the physiological ratio of serum free T4 (FT4) to free T3 (FT3) concentrations. Development of a sustained-release T3 preparation given as a single nighttime dose (together with levothyroxine once daily) might maintain physiological serum FT4–FT3 ratio’s throughout 24 h. Genetic polymorphisms in deiodinase 2 and thyroid hormone transporters have been associated with well-being, fatigue, depression, and greater improvement on combination therapy. Future trials should target carriers of these polymorphisms to see whether they do better on T4/T3 combination therapy than on T4 monotherapy. 

Thyroid Insufficiency - Is Thyroxine (T4) the Only Valuable Drug? (2001)

W. V. Baisier, J. Hertoghe and W. Eeckhaut, Journal of Nutritional and Environmental Medicine, 2001, Vol. 11, No. 3 , Pages 159-166 

Purpose: To evaluate the efficacy of a drug containing both liothyronine and thyroxine (T3 + T4) in hypothyroid patients who were treated, but not cured, with thyroxine (T4 alone). Design: Practice-based retrospective study of patients' records. Materials and Methods: The records of 89 hypothyroid patients, treated elsewhere with thyroxine but still with hypothyroidism, seen in a private practice in Antwerp, Belgium, were compared with those of 832 untreated hypothyroid patients, over the same period of time (May 1984-July 1997). Results: The same criteria were applied to both groups: a score of eight main symptoms of hypothyroidism and the 24 h urine free T3 dosage. The group of 89 patients, treated elsewhere with T4, but still complaining of symptoms of hypothyroidism, did not really differ from the group of untreated hypothyroid patients as far as symptoms and 24 h urine free T3 were concerned. A number of these patients were followed up during treatment with natural desiccated thyroid (NDT): 40 T4 treated patients and 278 untreated patients. Both groups responded equally favourably to NDT. Conclusions: Combined T3 + T4 treatment seems to be more effective than treatment with T4 alone in hypothyroid patients.
 

Study showing the relative potency of T3 to T4, in terms of its ability to inhibit TSH, was 100:12 (

(Pubmed) http://www.ncbi.nlm.nih.gov/pubmed/105890

The relative potency of T3:T4:rT3 appeared to be approximately 100:12:1 when estimated from the lowest doses that caused significant inhibition of TRH-induced release of TSH,

Combined Therapy with Levothyroxine and Liothyronine in Two Ratios, Compared with Levothyroxine Monotherapy in Primary Hypothyroidism: a Double-Blind, Randomized, Controlled Clinical Trial (2005)

The Journal of Clinical Endocrinology & Metabolism May 1, 2005 vol. 90 no. 5 2666-2674                                     

Abstract

Controversy remains about the value of combined treatment with levothyroxine (LT₄) and liothyronine (LT₃), compared with LT₄ alone in primary hypothyroidism. We compared combined treatment with LT₄ and LT₃ in a ratio of 5:1 or 10:1 with LT₄ monotherapy. We conducted a double-blind, randomized, controlled trial in 141 patients (18–70 yr old) with primary autoimmune hypothyroidism, recruited via general practitioners. Inclusion criteria included: LT₄ treatment for 6 months or more, a stable dose for 6 wk or more, and serum TSH levels between 0.11 and 4.0 μU/ml (mU/liter). Randomization groups were: 1) continuation of LT₄ (n = 48); 2) LT₄/LT₃, ratio 10:1 (n = 46); and 3) LT₄/LT₃, ratio 5:1 (n = 47). Subjective preference of study medication after 15 wk, compared with usual LT₄, was the primary outcome measure. Secondary outcomes included scores on questionnaires on mood, fatigue, psychological symptoms, and a substantial set of neurocognitive tests. Study medication was preferred to usual treatment by 29.2, 41.3, and 52.2% in the LT₄, 10:1 ratio, and 5:1 ratio groups, respectively (χ² test for trend, P = 0.024). This linear trend was not substantiated by results on any of the secondary outcome measures: scores on questionnaires and neurocognitive tests consistently ameliorated, but the amelioration was not different among the treatment groups. Median end point serum TSH was 0.64 μU/ml (mU/liter), 0.35 μU/ml (mU/liter), and 0.07 μU/ml (mU/liter), respectively [ANOVA on ln(TSH) for linear trend, P < 0.01]. Mean body weight change was +0.1, −0.5, and −1.7 kg, respectively (ANOVA for trend, P = 0.01). Decrease in weight, but not decrease in serum TSH was correlated with increased satisfaction with study medication. Of the patients who preferred combined LT₄/LT₃ therapy, 44% had serum TSH less than 0.11 μU/ml (mU/liter). Patients preferred combined LT₄/LT₃ therapy to usual LT₄ therapy, but changes in mood, fatigue, well-being, and neurocognitive functions could not satisfactorily explain why the primary outcome was in favor of LT₄/LT₃ combination therapy. Decrease in body weight was associated with satisfaction with study medication.                   

24 hour urine Free T3 has the highest inverse correlation with clinical symptoms of Hypothyroidism. (2000)

Journal of Nutritional & Environmental Medicine (2000) 10, 105–113

Purpose: To evaluate and compare laboratory indices of thyroid function. Design: Practice-based retrospective study of patients' records. Materials and Methods: The records of all hypothyroid patients seen in a private practice in Antwerp, Belgium, between May 1984 and July 1997 were reviewed. Only records with insufficient data were excluded; 832 patients were included in the study. Of these, 287 could also be followed during replacement therapy. Results: A score of 8 main symptoms of hypothyroidism, serum thyroxine radioimmunoassay (T4-RIA), serum T4-RIA/thyroid binding globulin (TBG), 24 h urine free triiodothyronine (T3) were considered before and after treatment. The score of these 8 main symptoms is a reliable expression of their illness in 97% of hypothyroid patients. 24 h urine free T3 correlates better with the clinical status of hypothyroid patients (R2 = 0.30) than serum T4-RIA (R2 = 0.12), and even better than T4-RIA/TBG (R2 = 0.19). Other investigators were unable to find any correlation between serum thyroid stimulating hormone (TSH) or serum free T4 and thyroid symptoms. The dosage of natural desiccated thyroid (NDT) has a correlation with 24 h urine T3 of R2 = 0.50. Conclusions: In this study symptoms of hypothyroidism correlate best with 24 h urine free T3.

Serum TSH variability in normal individuals: the influence of time of sample collection.

W V Med J. 2004 Jul-Aug;100(4):138-42.

Abstract

Difficulty in treatment decisions can arise when TSH levels measured on the same patient on the same day but at different times show considerable variability. This study was a prospective, observational evaluation of 100 consecutive adult patients who had serum TSH tests ordered by attending physicians at an outpatient clinic. Early morning fasting serum TSH levels were compared to late morning non-fasting serum TSH levels in the same patients on the same day The late morning non-fasting TSH tests declined in 97 of 100 subjects by an average of 26.39% when compared to early morning, fasting, TSH test results. 

Low salivary testosterone levels in patients with breast cancer (2010)

(FULL PDF) BMC Cancer 2010, 10:547 

Background

Correlation between circulating sex steroid levels and breast cancer has been controversial, with measurement of free, or bioavailable hormone rarely available. Salivary hormone levels represent the bioavailable fraction. To further elucidate the role of endogenous hormones in breast cancer, we aimed to assess correlation between salivary sex steroid levels and breast cancer prevalence.

Methods

Salivary hormone levels of testosterone (T), Estradiol (E2), Progesterone (P), Estriol (E3), Estrone (E1), DHEAS and Cortisol (C) were measured by Enzyme Immunoassay (EIA) in 357 women with histologically verified breast cancer and 184 age-matched control women.

Results

Salivary T and DHEAS levels were significantly lower in breast cancer cases vs. controls (27.2+13.9 vs. 32.2+17.5 pg/ml, p < 0.001 for T and 5.3+4.3 vs. 6.4+4.5 ng/ml, p = 0.007 for DHEAS). E2 and E1 levels were elevated and E3 levels were lowered in cases vs. controls.

Conclusions

Salivary T levels, representing the bioavailable hormone, are significantly lower in women with breast cancer compared to age-matched control women. These findings support the protective role of biovailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue.       

Reduced incidence of breast cancer with testosterone therapy (2013)

(Full PDF) - Article in Press - Maturitas 2013

Objectives: There is evidence that androgens are breast protective and that testosterone therapy treats many symptoms of hormone deficiency in both pre and postmenopausal patients. However, unlike estro- gen and progestins, there is a paucity of data regarding the incidence of breast cancer in women treated with testosterone therapy. This study was designed to investigate the incidence of breast cancer in women treated with subcutaneous testosterone therapy in the absence of systemic estrogen therapy.

Study design: This is a 5-year interim analysis of a 10-year, prospective, observational, IRB approved study investigating the incidence of breast cancer in women presenting with symptoms of hormone deficiency treated with subcutaneous testosterone (T) implants or, T combined with the aromatase inhibitor anas- trozole (A), i.e., T + A implants. Breast cancer incidence was compared with that of historical controls reported in the literature, age specific Surveillance Epidemiology and End Results (SEER) incidence rates, and a representative, similar age group of our patients used as a ‘control’ group. The effect of adherence to T therapy was also evaluated.

Results: Since March 2008, 1268 pre and post menopausal women have been enrolled in the study and eligible for analysis. As of March 2013, there have been 8 cases of invasive breast cancer diagnosed in 5642 person-years of follow up for an incidence of 142 cases per 100 000 person-years, substantially less than the age-specific SEER incidence rates (293/100 000), placebo arm of Women’s Health Initiative Study (300/100 000), never users of hormone therapy from the Million Women Study (325/100 000) and our control group (390/100 000). Unlike adherence to estrogen therapy, adherence to T therapy further decreased the incidence of breast cancer (73/100 000).

Conclusion: T and/or T + A, delivered subcutaneously as a pellet implant, reduced the incidence of breast cancer in pre and postmenopausal women. Evidence supports that breast cancer is preventable by main- taining a T to estrogen ratio in favor of T and, in particular, by the use of continuous T or, when indicated, T + A. This hormone therapy should be further investigated for the prevention and treatment of breast cancer. 

High Serum Testosterone (>550ng/dL) Is Associated With Reduced Risk of Cardiovascular Events (30% reduction) and Stroke (24% reductions) and in Elderly Men (2011)

(Full PDF) J Am Coll Cardiol. 2011;58(16):1674-1681.

OBJECTIVES:

We tested the hypothesis that serum total testosterone and sex hormone-binding globulin (SHBG) levels predict cardiovascular (CV) events in community-dwelling elderly men.

BACKGROUND:

Low serum testosterone is associated with increased adiposity, an adverse metabolic risk profile, and atherosclerosis. However, few prospective studies have demonstrated a protective link between endogenous testosterone and CV events. Polymorphisms in the SHBG gene are associated with risk of type 2 diabetes, but few studies have addressed SHBG as a predictor of CV events.

METHODS:

We used gas chromatography/mass spectrometry to analyze baseline levels of testosterone in the prospective population-based MrOS (Osteoporotic Fractures in Men) Sweden study (2,416 men, age 69 to 81 years). SHBG was measured by immunoradiometric assay. CV clinical outcomes were obtained from central Swedish registers.

RESULTS:

During a median 5-year follow-up, 485 CV events occurred. Both total testosterone and SHBG levels were inversely associated with the risk of CV events (trend over quartiles: p = 0.009 and p = 0.012, respectively). Men in the highest quartile of testosterone (≥550 ng/dl) had a lower risk of CV events compared with men in the 3 lower quartiles (hazard ratio: 0.70, 95% confidence interval: 0.56 to 0.88). This association remained after adjustment for traditional CV risk factors and was not materially changed in analyses excluding men with known CV disease at baseline (hazard ratio: 0.71, 95% confidence interval: 0.53 to 0.95). In models that included both testosterone and SHBG, testosterone but not SHBG predicted CV risk.

CONCLUSIONS:

High serum testosterone predicted a reduced 5-year risk of CV events in elderly men.

Hormone Testing Overview

http://www.townsendletter.com/Jan2014/troubleproges0114.html

Another study recently confirmed that lycopene, the carotenoid extract from tomatoes, can help prevent prostate cancer. (2013)

Effects of lycopene on protein expression in human primary prostatic epithelial cells.  (Cancer Prev Res (Phila). 2013 May;6(5):419-27)

Clinical trials and animal studies have suggested that lycopene, the red carotenoid found in tomatoes, might be useful for the prevention of prostate cancer in the diet or as a dietary supplement through a variety of chemoprevention mechanisms. As most mechanism of action studies have used prostate cancer cells or males with existing prostate cancer, we investigated the effects of lycopene on protein expression in human primary prostatic epithelial cells. After treatment with lycopene at a physiologically relevant concentration (2 μmol/L) or placebo for 48 hours, the primary prostatic epithelial cells were lysed and fractionated using centrifugation into cytosolic/membrane and nuclear fractions. Proteins from lycopene-treated and placebo-treated cells were trypsinized and derivatized for quantitative proteomics using isobaric tags for relative and absolute quantitation (iTRAQ) reagent. Peptides were analyzed using two-dimensional microcapillary high-performance liquid chromatography-tandem mass spectrometry to identify proteins that were significantly upregulated or downregulated following lycopene exposure. Proteins that were most affected by lycopene were those involved in antioxidant responses, cytoprotection, apoptosis, growth inhibition, androgen receptor signaling, and the Akt/mTOR cascade. These data are consistent with previous studies suggesting that lycopene can prevent cancer in human prostatic epithelial cells at the stages of cancer initiation, promotion, and/or progression.

Lower urinary tract symptoms improve with testosterone replacement therapy in men with late-onset hypogonadism (2013)

Abstract - World Journal of Urology, October 2013

Methods

Two hundred and sixty-one hypogonadal patients (mean age 59.5 years) presenting with erectile dysfunction, having also been evaluated for LUTS, received a single testosterone undecanoate injection at day 1, at week 6 and quarterly thereafter. Parameters, including International Prostate Symptom Score (IPSS), post-voiding residual urine volume, transrectal ultrasound, prostate volume and prostate-specific antigen were measured at each treatment visit. Two hundred and fifty-nine patients were included in the full analysis set. These were subsequently divided into weight losers (L ≥ 5 % weight loss at last visit from baseline) and non-losers (NL). t test analyses were used to compare the IPSS means of these subgroups. The potentially confounding effect on IPSS of using the phosphodiesterase-5 inhibitor (PDE5i) vardenafil was also accounted for.

Results

Mean IPSS showed a significant decrease with time following initiation of testosterone treatment (p < 0.05). No significant differences were observed in either IPSS between L and NL groups or in mean IPSS between vardenafil users and non-users.

Conclusion

Testosterone replacement is associated with improvements in LUTS which are not confounded by weight loss or PDE5i. The mechanisms of this association require further investigation.