Research Articles

Female Research Articles

Effect of different hormonal therapies on thyroid function in surgical menopause: short-term results

C Tamer Erel, Altay Gezer, Levent M Sentürk, Asli Sommunkiran, Semih Kaleli, Hakan Seyisoglu

Abstract

Objective: To determine the effects of different hormone replacement therapy (HRT) regimens on thyroid function in surgical menopause.

Study design: In a randomized, controlled study, 59 euthyroid women with surgical menopause were randomized to an estrogen-only (n=20), tibolone (n=20) or calcium-only (n=19) group. On the 5th postoperative day and 4th and 12th weeks, serum E2, TSH, free T3 and free T4 levels were determined.

Results: Although the initial and week 4 serum E2, TSH, free T3 and free T4 levels were comparable, the week 12 serum E2 and TSH levels were different between the subjects on estrogen therapy and those receiving tibolone or calcium only (p=0.008 and 0.000, respectively). Serum E2 levels were higher and TSH levels lower in subjects receiving estrogen. Moreover, serum TSH levels correlated negatively with serum E2 levels in the 12th week of estrogen use (r=-0.354, p=0.006). TSH increased in the tibolone group as compared to the estrogen group but was still lower than in the calcium-only group; however, the differences were not statistically significant.

Conclusion: Irrespective of different regimens, HRT does not have an important short-term effect on thyroid function in women with surgical menopause.

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Increased need for thyroxine in women with hypothyroidism during estrogen therapy

Baha M. Arafah, M.D.

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Abstract

Background: Women with hypothyroidism that is being treated with thyroxine often need higher doses when they are pregnant. Whether this need can be attributed solely to estrogen-induced increases in serum thyroxine-binding globulin or whether other factors are involved is not known.

Methods: In 11 postmenopausal women with normal thyroid function and 25 postmenopausal women with hypothyroidism treated with thyroxine, I assessed thyroid function before they started estrogen therapy and every 6 weeks for 48 weeks thereafter. The women with hypothyroidism included 18 women receiving thyroxine-replacement therapy and 7 women receiving thyrotropin-suppressive thyroxine therapy. On each occasion, serum thyroxine, free thyroxine, thyrotropin, and thyroxine-binding globulin were measured.

Results: In the women with normal thyroid function, the serum free thyroxine and thyrotropin concentrations did not change, whereas at 12 weeks the mean (+/-SD) serum thyroxine concentration had increased from 8.0+/-0.9 microg per deciliter (103+/-12 nmol per liter) to 10.4+/-1.5 microg per deciliter (134+/-19 nmol per liter, P<0.001) and the serum thyroxine-binding globulin concentration had increased from 20.3+/-3.5 mg per liter to 31.3+/-3.2 mg per liter, P<0.001). The women with hypothyroidism had similar increases in serum thyroxine and thyroxine-binding globulin concentrations during estrogen therapy, but their serum free thyroxine concentration decreased from 1.7+/-0.4 ng per deciliter (22+/-5 pmol per liter) to 1.4+/-0.3 ng per deciliter (18+/-4 pmol per liter, P<0.001) and their serum thyrotropin concentration increased from 0.9+/-1.1 to 3.2+/-3.1 microU per milliliter (P<0.001). The serum thyrotropin concentrations increased to more than 7 microU per milliliter in 7 of the 18 women in the thyroxine-replacement group and to more than 1 microU per milliliter in 3 of the 7 women in the thyrotropin-suppression group.

Conclusions: In women with hypothyroidism treated with thyroxine, estrogen therapy may increase the need for thyroxine.

The bioidentical hormone debate: are bioidentical hormones (estradiol, estriol, and progesterone) safer or more efficacious than commonly used synthetic versions in hormone replacement therapy?

Kent Holtorf

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Abstract

Background: The use of bioidentical hormones, including progesterone, estradiol, and estriol, in hormone replacement therapy (HRT) has sparked intense debate. Of special concern is their relative safety compared with traditional synthetic and animal-derived versions, such as conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), and other synthetic progestins. Proponents for bioidentical hormones claim that they are safer than comparable synthetic and nonhuman versions of HRT. Yet according to the US Food and Drug Administration and The Endocrine Society, there is little or no evidence to support claims that bioidentical hormones are safer or more effective.

Objective: This paper aimed to evaluate the evidence comparing bioidentical hormones, including progesterone, estradiol, and estriol, with the commonly used nonbioidentical versions of HRT for clinical efficacy, physiologic actions on breast tissue, and risks for breast cancer and cardiovascular disease.

Methods: Published papers were identified from PubMed/MEDLINE, Google Scholar, and Cochrane databases, which included keywords associated with bioidentical hormones, synthetic hormones, and HRT. Papers that compared the effects of bioidentical and synthetic hormones, including clinical outcomes and in vitro results, were selected.

Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bioidentical hormones have some distinctly different, potentially opposite, physiological effects compared with their synthetic counterparts, which have different chemical structures. Both physiological and clinical data have indicated that progesterone is associated with a diminished risk for breast cancer, compared with the increased risk associated with synthetic progestins. Estriol has some unique physiological effects, which differentiate it from estradiol, estrone, and CEE. Estriol would be expected to carry less risk for breast cancer, although no randomized controlled trials have been documented. Synthetic progestins have a variety of negative cardiovascular effects, which may be avoided with progesterone.

Conclusion: Physiological data and clinical outcomes demonstrate that bioidentical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animal-derived counterparts. Until evidence is found to the contrary, bioidentical hormones remain the preferred method of HRT. Further randomized controlled trials are needed to delineate these differences more clearly.

A critique of the Women’s Health Initiative hormone therapy study

Edward L. Klaiber, M.D., William Vogel, Ph.D., and Susan Rako, M.D.

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Abstract

This review critiques The Women’s Health Initiative (WHI) study, focusing on aspects of the study design contributing to the adverse events resulting in the study’s discontinuation.  Conclusion(s:Two aspects of the design contributed to the adverse events: [1] The decision to administer continuous combined conjugated equine estrogen (CEE)/medroxyprogesterone acetate (MPA) or E alone as a standard regimen to a population with little previous hormonal treatment, ranging in age from 50–79 years, who, because of their age, were predisposed to coronary and cerebral atherosclerosis. [2] Selection of an untested regimen of continuous combined CEE plus MPA, which we hypothesize, negated the protective effect of E on the cardiovascular and cerebrovascular systems. Multiple observational studies that preceded the WHI study concluded that the use of E alone and E plus cyclic (not daily) progestin combination treatments initiated in early menopause had beneficial effects. The therapeutic regimens resulted in prevention of atherosclerosis and reductions in coronary artery disease mortality. It is our conclusion that the WHI hormonal replacement study had major design flaws that led to adverse conclusions about the positive effects of hormone therapy. An alternative hormonal regimen is proposed that, on the basis of data supporting its beneficial cardiovascular effects, when initiated appropriately in a population of younger, more recently menopausal women, has promise to yield a more favorable risk/benefit outcome.

Testosterone pellets implants and migraine headaches: A pilot study

Rebecca GlaserConstantine DimitrakakisNancy TrimbleVincent Martin

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Abstract

The purpose of this prospective pilot study was to determine the therapeutic effect of continuous testosterone, delivered as a subcutaneous implant, on the severity of migraine headaches in pre- and post-menopausal patients. Twenty-seven women with a history of documented migraine headache were asked to rate their headache severity using a five-point scale at baseline (prior to therapy); and again, 3 months following treatment with testosterone implants. Improvement in headache severity was noted by 92% of patients and the mean level of improvement was statistically significant (3.3 on a 5 point scale). In addition, there was no difference in the level of improvement between pre- and post-menopausal cohorts. Seventy-four percent of patients reported a headache severity score of ‘0’ (none) on testosterone implant therapy for the 3-month treatment period. Continuous testosterone was effective therapy in reducing the severity of migraine headaches in both pre- and post-menopausal women.

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

 Rebecca Glaser , Anne E. York , Constantine Dimitrakakis

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Abstract

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.

No increase in the incidence of breast carcinoma with subcutaneous administration of estradiol

E M Davelaar, G Gerretsen, J Relyveld

Abstract

Between 1972 and mid-1990 the frequency of breast cancer was studied in a group of 261 mostly premenopausal women of the gynaecological department of the Municipal Hospital in The Hague, the Netherlands. All the patients had had a total hystero-adnexectomy after which they were substituted with estradiol implants. On the basis of a stratified lifetable giving the cumulative incidence of breast cancer in the Netherlands, an expected incidence of 2 per 1000 person-years was estimated for the observed group (mean observation period: 8.25 years). There were three cases of breast cancer in the observed group. This means an incidence density of 1.4 per 1000 person-years. It is concluded that this form of oestrogen substitution does not increase the risk of breast cancer.

Testosterone and Breast Cancer Prevention

R. Glasera, C. Dimitrakakis

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Abstract

Testosterone (T) is the most abundant biologically active hormone in women. Androgen receptors (AR) are located throughout the body including the breast where T decreases tissue proliferation. However, T can be aromatized to estradiol (E2), which increases proliferation and hence, breast cancer (BCA) risk. Increased aromatase expression and an imbalance in the ratio of stimulatory estrogens to protective androgens impacts breast homeostasis.

Recent clinical data supports a role for T in BCA prevention. Women with symptoms of hormone deficiency treated with pharmacological doses of T alone or in combination with anastrozole (A), delivered by subcutaneous implants, had a reduced incidence of BCA. In addition, T combined with A effectively treated symptoms of hormone deficiency in BCA survivors and was not associated with recurrent disease. Most notably, T + A implants placed in breast tissue surrounding malignant tumors significantly reduced BCA tumor size, further supporting T direct antiproliferative, protective and therapeutic effect.

Incidence of invasive breast cancer in women treated with testosterone implants: a prospective 10-year cohort study

Rebecca L. Glaser, Anne E.York, and Constantine Dimitrakakis

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Abstract

Background: Testosterone implants have been used for over eighty years to treat symptoms of hormone deficiency in pre and postmenopausal women. Evidence supports that androgens are breast protective. However, there is a lack of data on the long-term effect of testosterone therapy on the incidence of invasive breast cancer (IBC). This study was specifically designed to investigate the incidence of IBC in pre and postmenopausal women (presenting with symptoms of androgen deficiency) treated with subcutaneous testosterone implants or testosterone implants combined with anastrozole.

Methods: The 10-year prospective cohort study was approved in March 2008 at which time recruitment was initiated. Recruitment was closed March 2013. Pre and postmenopausal women receiving at least two pellet insertions were eligible for analysis (N = 1267). Breast cancer incidence rates were reported as an unadjusted, un-weighted value of newly diagnosed cases divided by the sum of ‘person-time of observation’ for the at-risk population. Incidence rates on testosterone therapy were compared to age-specific Surveillance Epidemiology and End Results (SEER) incidence rates and historical controls. Bootstrap sampling distributions were constructed to verify comparisons and tests of significance that existed between our results and SEER data.

Results: As of March 2018, a total of 11 (versus 18 expected) cases of IBC were diagnosed in patients within 240-days following their last testosterone insertion equating to an incidence rate of 165/100000 p-y, which is significantly less than the age-matched SEER expected incidence rate of 271/100000 p-y (p < 0.001) and historical controls.

Conclusion: Long term therapy with subcutaneous testosterone, or testosterone combined with anastrozole, did not increase the incidence of IBC. Testosterone should be further investigated for hormone therapy and breast cancer prevention.

Testosterone inhibits estrogen/progestogen-induced breast cell proliferation in postmenopausal women

Marie Hofling, Angelica Lindén Hirschberg, Lambert Skoog, Edneia Tani, Torsten Hägerström, Bo von Schoultz

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Abstract

Objective: During the past few years serious concern has been raised about the safety of combined estrogen/progestogen hormone therapy, in particular about its effects on the breast. Several observations suggest that androgens may counteract the proliferative effects of estrogen and progestogen in the mammary gland. Thus, we aimed to study the effects of testosterone addition on breast cell proliferation during postmenopausal estrogen/progestogen therapy.

Design: We conducted a 6-month prospective, randomized, double-blind, placebo-controlled study. A total of 99 postmenopausal women were given continuous combined estradiol 2 mg/norethisterone acetate 1 mg and were equally randomly assigned to receive additional treatment with either a testosterone patch releasing 300 microg/24 hours or a placebo patch. Breast cells were collected by fine needle aspiration biopsy at baseline and after 6 months, and the main outcome measure was the percentage of proliferating breast cells positively stained by the Ki-67/MIB-1 antibody.

Results: A total of 88 women, 47 receiving active treatment and 41 in the placebo group, completed the study. In the placebo group there was a more than fivefold increase (P<0.001) in total breast cell proliferation from baseline (median 1.1%) to 6 months (median 6.2%). During testosterone addition, no significant increase was recorded (1.6% vs 2.0%). The different effects of the two treatments were apparent in both epithelial and stromal cells.

Conclusions: Addition of testosterone may counteract breast cell proliferation as induced by estrogen/progestogen therapy in postmenopausal women.

Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications

Rebecca L. Glaser, MD, Anne E. York, MS, and Constantine Dimitrakakis, MD, PhD

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Abstract

Objective: Hormone receptor-positive breast cancers respond favorably to subcutaneous testosterone combined with an aromatase inhibitor. However, the effect of testosterone combined with an aromatase inhibitor on tumor response to chemotherapy was unknown. This study investigated the effect of testosterone-letrozole implants on breast cancer tumor response before and during neoadjuvant chemotherapy.

Methods: A 51-year-old woman on testosterone replacement therapy was diagnosed with hormone receptor- positive invasive breast cancer. Six weeks before starting neoadjuvant chemotherapy, the patient was treated with subcutaneous testosterone-letrozole implants and instructed to follow a low-glycemic diet. Clinical status was followed. Tumor response to ‘‘testosterone-letrozole’’ and subsequently, ‘‘testosterone-letrozole with chemo- therapy’’ was monitored using serial ultrasounds and calculating tumor volume. Response to therapy was determined by change in tumor volume. Cost of therapy was evaluated.

Results: There was a 43% reduction in tumor volume 41 days after the insertion of testosterone-letrozole implants, before starting chemotherapy. After the initiation of concurrent chemotherapy, the tumor responded at an increased rate, resulting in a complete pathologic response. Chemotherapy was tolerated. Blood counts and weight remained stable. There were no neurologic or cardiac complications from the chemotherapy. Cost of therapy is reported.

Conclusions: Subcutaneous testosterone-letrozole was an effective treatment for this patient’s breast cancer and did not interfere with chemotherapy. This novel combination implant has the potential to prevent side effects from chemotherapy, improve quality of life, and warrants further investigation.

Low salivary testosterone levels in patients with breast cancer

Constantine Dimitrakakis, David Zava, Spyros Marinopoulos, Alexandra Tsigginou, Aris Antsaklis, Rebecca Glaser

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Abstract

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 bioavailable testosterone in counteracting the proliferative effects of estrogens on mammary tissue.

Male Research Articles

Adding a vacuum erection device to regular use of Tadalafil improves penile rehabilitation after posterior urethroplasty

Dong-Liang Zhang, Zhong Chen, Fei-Xiang Wang, Jiong Zhang, Hong Xie, Ze-Yu Wang, Yu-Bo Gu, Qiang Fu, and  Lu-Jie Song

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Abstract

This study aimed to evaluate whether adding a vacuum erection device (VED) to regular use of Tadalafil could achieve better penile rehabilitation following posterior urethroplasty for pelvic fracture-related urethral injury (PFUI). Altogether, 78 PFUI patients with erectile dysfunction (ED) after primary posterior urethroplasty were enrolled and divided into two treatment groups: VED combined with Tadalafil (Group 1, n = 36) and Tadalafil only (Group 2, n = 42). Changes in penile length, testosterone level, International Index of Erectile Function-5 (IIEF-5) questionnaire, Quality of Erection Questionnaire (QEQ), and nocturnal penile tumescence (NPT) testing were used to assess erectile function before and after 6 months of ED treatment. Results showed that the addition of VED to regular use of Tadalafil preserved more penile length statistically (0.4 ± 0.9 vs −0.8 ± 0.7 cm, P < 0.01). IIEF-5 score and QEQ score in Group 1 were higher than Group 2 (both P < 0.05). After treatment, 21/36 (58.3%) Group 1 patients and 19/42 (45.2%) Group 2 patients could complete vaginal penetration. Group 1 patients also had markedly improved testosterone levels (P = 0.01). Unexpectedly, there was no significant difference in NPT testing between two therapies. For PFUI patients with ED after posterior urethroplasty, the addition of VED to regular use of Tadalafil could significantly improve their conditions – improving erection and increasing penile length – thus increasing patient satisfaction and confidence in penile rehabilitation.

The role of vacuum pump therapy to mechanically straighten the penis in Peyronie’s disease

Amr Abdel Raheem, Giulio Garaffa, Tarek Abdel Raheem, Michelle Dixon, Amanda Kayes, Nim Christopher, David Ralph

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Abstract

Objective: To assess the efficacy of vacuum therapy in mechanically straightening the penile curvature of Peyronie’s disease (PD).

Patients and methods: Modelling of the tunica albuginea has been shown to be possible during penile implant surgery and this principle has been applied as an alternative conservative therapy. In all, 31 patients with PD (mean duration 9.9 months; mean age 51 years, range 24-71) completed the study. Over a 12-week period, the patients used a vacuum device (Osbon ErecAid, MediPlus, High Wycombe, UK) for 10 min twice daily. The assessment at study entry and at completion after 12 weeks included the International Index of Erectile Function questionnaire, a perceived pain intensity score, stretched penile length measurement and the angle of penile deformity after an intracavernous injection with prostaglandin E1.

Results: there was a clinically and statistically significant improvement in penile length, angle of curvature and pain after 12 weeks of using the vacuum pump. Of the 31 patients, 21 had a reduction in the angle of curvature by 5-25 degrees, three had worsening of the curvature and there was no change in the remaining seven. The curvature was corrected surgically in 15 patients while the remaining 16 (51%) were satisfied with the outcome.

Conclusion: vacuum therapy can improve or stabilize the curvature of PD, is safe to use in all stages of the disease, and might reduce the number of patients going on to surgery.

Vacuum therapy in penile rehabilitation after radical prostatectomy: review of hemodynamic and antihypoxic evidence

Sheng-Qiang Qian, Liang Gao, Qiang Wei, Jiuhong Yuan

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Abstract

Generally, hypoxia is a normal physiological condition in the flaccid penis, which is interrupted by regular nocturnal erections in men with normal erectile function. [1] Lack of spontaneous and nocturnal erections after radical prostatectomy due to neuropraxia results in persistent hypoxia of cavernosal tissue, which leads to apoptosis and degeneration of cavernosal smooth muscle fibers. Therefore, overcoming hypoxia is believed to play a crucial role during neuropraxia. The use of a vacuum erectile device (VED) in penile rehabilitation is reportedly effective and may prevent loss of penile length. The corporal blood after VED use is increased and consists of both arterial and venous blood, as revealed by color Doppler sonography and blood gas analysis. A similar phenomenon was observed in negative pressure wound therapy (NPWT). However, NPWT employs a lower negative pressure than VED, and a hypoperfused zone, which increases in response to negative pressure adjacent to the wound edge, was observed. Nonetheless, questions regarding ideal subatmospheric pressure levels, modes of action, and therapeutic duration of VED remain unanswered. Moreover, it remains unclear whether a hypoperfused zone or PO 2 gradient appears in the penis during VED therapy. To optimize a clinical VED protocol in penile rehabilitation, further research on the mechanism of VED, especially real-time PO 2 measurements in different parts of the penis, should be performed.

Vacuum therapy in erectile dysfunction–science and clinical evidence

J Yuan, A N Hoang, C A Romero, H Lin, Y Dai, R Wang

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Abstract

Vacuum therapy (VT) utilizes negative pressure to distend the corporal sinusoids and to increase the blood inflow to the penis. Depending on its purpose, VT could be used as vacuum constriction device (VCD), with the aid of an external constricting ring which is placed at the base of penis to prevent blood outflow, maintaining the erection for sexual intercourse. Also, as a vacuum erectile device (VED), without the application of a constriction ring, just increases blood oxygenation to the corpora cavernosa and for other purposes. The emerging of phosphodiesterase 5 inhibitors (PDE(5)I) for the treatment of erectile dysfunction (ED) eclipsed VCD as therapeutic choice for ED; however, widespread usage of VED as part of penile rehabilitation after radical prostatectomy and other purposes rekindle the interest for VT. The underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections, and potentially increases the likelihood of preserving erectile function. Due to its ability to draw blood into the penis regardless of nerve disturbance, VED has become the centerpiece of penile rehabilitation protocols. Herein, we reviewed the history, mechanism, application, side effects and future direction of VT in ED.

The role of vacuum erection devices in penile rehabilitation after radical prostatectomy

T Lehrfeld, D I Lee

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Abstract

Even nerve-sparing radical prostatectomy damages the cavernous nerves and leads to temporary erectile dysfunction (ED) in men recovering from prostate cancer surgery. Historically, patients recovering from prostate cancer surgery have been advised that the return of erectile function (EF) can take from 6 to 18 months, or even longer. Unfortunately, the return of sexual function in these patients remains variable, but is generally thought to be dependent on the individual patient’s pre-surgery EF, as well as the degree of cavernous nerve disruption during prostate removal. Recently, there has been a growing movement to proactively treat patients postoperatively for presumed nerve damage to stimulate nerve recovery and possibly reduce the degree of irreversible damage. This would reduce the on-demand therapy these patients would require, and hopefully remove the requirement for an implantable prosthesis. The underlying hypothesis is that the artificial induction of erections shortly after surgery facilitates tissue oxygenation, reducing cavernosal fibrosis in the absence of nocturnal erections, potentially increasing the likelihood of preserving EF. Vacuum erection devices (VED), because of their ability to draw blood into the penis regardless of nerve disturbance, have become the centerpiece of penile rehabilitation protocols. This review will discuss the pathophysiology of radical prostatectomy induced ED and the rationale for rehabilitation. It will then discuss current protocols, including those involving the VED.

High levels of circulating testosterone are not associated with increased prostate cancer risk: A pooled prospective study

 Pär Stattin, Sonja Lumme, Leena Tenkanen, Henrik Alfthan, Egil Jellum, Göran Hallmans, Steinar Thoresen, Timo Hakulinen, Tapio Luostarinen, Matti Lehtinen, Joakim Dillner, Ulf-Håkan Stenman, Matti Hakama

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Abstract

Androgens stimulate prostate cancer in vitro and in vivo. However, evidence from epidemiologic studies of an association between circulating levels of androgens and prostate cancer risk has been inconsistent. We investigated the association of serum levels of testosterone, the principal androgen in circulation, and sex hormone‐binding globulin (SHBG) with risk in a case‐control study nested in cohorts in Finland, Norway and Sweden of 708 men who were diagnosed with prostate cancer after blood collection and among 2,242 men who were not. In conditional logistic regression analyses, modest but significant decreases in risk were seen for increasing levels of total testosterone down to odds ratio for top vs. bottom quintile of 0.80 (95% CI = 0.59–1.06; ptrend = 0.05); for SHBG, the corresponding odds ratio was 0.76 (95% CI = 0.57–1.01; ptrend = 0.07). For free testosterone, calculated from total testosterone and SHBG, a bell‐shaped risk pattern was seen with a decrease in odds ratio for top vs. bottom quintile of 0.82 (95% CI = 0.60–1.14; ptrend = 0.44). No support was found for the hypothesis that high levels of circulating androgens within a physiologic range stimulate development and growth of prostate cancer.

Testosterone Replacement Therapy in Hypogonadal Men at High Risk for Prostate Cancer: Results of 1 Year of Treatment in Men With Prostatic Intraepithelial Neoplasia

Ernani Luis Rhoden, Abraham Morgentaler

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Abstract

Purpose:

One of the greatest concerns among clinicians regarding testosterone replacement therapy (TRT) is the fear of causing or promoting prostate cancer. We evaluated prostatic changes in hypogonadal men with and without high grade prostatic intraepithelial neoplasia (PIN), which is considered a prostatic precancerous lesion, after 1 year of TRT.

Materials and Methods:

A total of 75 hypogonadal who completed 12 months of TRT were studied. All underwent prostate biopsy prior to initiating treatment. Of the men 55 had benign prostate biopsies (PIN−) and 20 had PIN without frank cancer (PIN+). All men with PIN underwent repeat biopsy to exclude cancer prior to the initiation of testosterone treatment. Prostate specific antigen (PSA), and total and free testosterone were determined prior to treatment and at 1 year. Repeat biopsy was performed for a change noted on digital rectal examination or for a PSA increase of 1 ng/l or greater.

Results:

PSA was similar at baseline in men with and without PIN (1.49 ± 1.1 and 1.53 ± 1.6 ng/dl, p >0.05) and after 12 months of TRT (1.82 ± 1.1 and 1.78 ± 1.6 ng/dl, respectively, p >0.05). A slight, similar increase in mean PSA was noted in the PIN− and PIN+ groups (0.25 ± 0.6 and 0.33 ± 0.6 ng/dl, p >0.05). One man in the PIN+ group had cancer after biopsy was performed due to abnormal digital rectal examination. Four additional men in the PIN− group and 2 in the PIN+ group underwent re-biopsy for elevated PSA and none had cancer. No differences were noted between the PIN− and PIN+ groups with regard to total and free testosterone at baseline and at 1 year (p = 0.267).

Conclusions:

After 1 year of TRT men with PIN do not have a greater increase in PSA or a significantly increased risk of cancer than men without PIN. These results indicate that TRT is not contraindicated in men with a history of PIN.

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies

Abraham Morgentaler, MD; Martin M. Miner, MD; Monica Caliber, MSc; Andre T. Guay, MD; Mohit Khera, MD; Abdulmaged M. Traish, PhD

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Abstract

Two recent studies raised new concerns regarding cardiovascular (CV) risks with testosterone (T) therapy. This article reviews those studies as well as the extensive literature on T and CV risks. A MEDLINE search was performed for the years 1940 to August 2014 using the following key words: testosteroneandrogenshumanmalecardiovascularstrokecerebrovascular accidentmyocardial infarctionheart attackdeath, and mortality. The weight and direction of evidence was evaluated and level of evidence (LOE) assigned. Only 4 articles were identified that suggested increased CV risks with T prescriptions: 2 retrospective analyses with serious methodological limitations, 1 placebo-controlled trial with few major adverse cardiac events, and 1 meta-analysis that included questionable studies and events. In contrast, several dozen studies have reported a beneficial effect of normal T levels on CV risks and mortality. Mortality and incident coronary artery disease are inversely associated with serum T concentrations (LOE IIa), as is severity of coronary artery disease (LOE IIa). Testosterone therapy is associated with reduced obesity, fat mass, and waist circumference (LOE Ib) and also improves glycemic control (LOE IIa). Mortality was reduced with T therapy in 2 retrospective studies. Several RCTs in men with coronary artery disease or heart failure reported improved function in men who received T compared with placebo. The largest meta-analysis to date revealed no increase in CV risks in men who received T and reduced CV risk among those with metabolic disease. In summary, there is no convincing evidence of increased CV risks with T therapy. On the contrary, there appears to be a strong beneficial relationship between normal T and CV health that has not yet been widely appreciated.

Regulation of Bone Metabolism by Sex Steroids

Sundeep Khosla and David G. Monroe

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Abstract

Osteoporosis is a significant public health problem, and a major cause of the disease is estrogen deficiency following menopause in women. In addition, considerable evidence now shows that estrogen is also a major regulator of bone metabolism in men. Since the original description of the effects of estrogen deficiency on bone by Fuller Albright more than 70 years ago, there has been enormous progress in understanding the mechanisms of estrogen and testosterone action on bone using human and mouse models. Although we understand more about the effects of estrogen on bone as compared with testosterone, both sex steroids do play important roles, perhaps in a somewhat compartment-specific (i.e., cancellous vs. cortical bone) manner. This review summarizes our current knowledge of sex steroid action on bone based on human and mouse studies, identifies both agreements and potential discrepancies between these studies, and suggests directions for future research in this important area.

Subcutaneous Testosterone Anastrozole Therapy in Men: Rationale

Rebecca L. Glaser, MD Anne E. York, MS

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Abstract

This analysis was designed to determine the efficacy of anastrozole, an aromatase inhibitor, combined with testosterone in a subcutaneous implant in preventing elevated estradiol levels and the subsequent side effects of excess estrogen associated with testosterone therapy. It also allowed for the establishment of normative ranges of serum testosterone levels on subcutaneous implant therapy. The study participants were 344 men who were accrued to an institutional review board-approved cohort study between April 2014 and 2017. Efficacy of the subcutaneous combination implant in maintaining low estradiol levels was evaluated. Serum levels of testosterone and estradiol were measured throughout the implant cycle, at week 4, and when symptoms returned. Correlations between patient demographics, dosing, and serum levels on therapy were evaluated. Mean testosterone dose was 1827 + 262 mg. Mean anastrozole dose was 15.3 + 3.2 mg with the majority of men receiving 16 mg of subcutaneous anastrozole. The mean interval of insertion was 4.8 months. Low estradiol levels were maintained throughout the implant cycle. Mean T level at week 4 was 1183 + 315 ng/dl and 553 + 239 ng/dl when symptoms returned. Levels of testosterone on therapy inversely correlated with body mass index. There were no adverse events attributed to testosterone or anastrozole therapy. Subcutaneous anastrozole delivered simultaneously with testosterone allowed for higher dosing of testosterone and less frequent intervals of insertion. Low- dose anastrozole released from the combination implant maintained low estradiol levels throughout the implant cycle and prevented clinical side effects attributed to excess estrogen.

Longevity Studies

Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice

Alessandro Bitto, Takashi K Ito, Victor V Pineda, Nicolas J LeTexier, Heather Z Huang, Elissa Sutlief, Herman Tung, Nicholas Vizzini, Belle Chen, Kaleb Smith, Daniel Meza, Masanao Yajima, Richard P Beyer, Kathleen F Kerr, Daniel J Davis, Catherine H Gillespie, Jessica M Snyder, Piper M Treuting, and  Matt Kaeberlein

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Abstract

The FDA approved drug rapamycin increases lifespan in rodents and delays age-related dysfunction in rodents and humans. Nevertheless, important questions remain regarding the optimal dose, duration, and mechanisms of action in the context of healthy aging. Here we show that 3 months of rapamycin treatment is sufficient to increase life expectancy by up to 60% and improve measures of healthspan in middle-aged mice. This transient treatment is also associated with a remodeling of the microbiome, including dramatically increased prevalence of segmented filamentous bacteria in the small intestine. We also define a dose in female mice that does not extend lifespan, but is associated with a striking shift in cancer prevalence toward aggressive hematopoietic cancers and away from non-hematopoietic malignancies. These data suggest that a short-term rapamycin treatment late in life has persistent effects that can robustly delay aging, influence cancer prevalence, and modulate the microbiome.

Disease or not, aging is easily treatable

Mikhail V. Blagosklonny

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Abstract

Is aging a disease? It does not matter because aging is already treated using a combination of several clinically‐ available drugs, including rapamycin. Whether aging is a disease depends on arbitrary definitions of both disease and aging. For treatment purposes, aging is a deadly disease (or more generally, pre‐disease), despite being a normal continuation of normal organismal growth. It must and, importantly, can be successfully treated, thereby delaying classic age‐related diseases such as cancer, cardiovascular and metabolic diseases, and neurodegeneration.

Aging and Immortality: Quasi-Programmed Senescence and Its Pharmacologic Inhibition

Mikhail V. Blagosklonny

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Abstract

While ruling out programmed aging, evolutionary theory predicts a quasi-program for aging, a continuation of the developmental program that is not turned off, is constantly on, becoming hyper-functional and damaging, causing diseases of aging. Could it be switched off pharmacologically? This would require identification of a molecular target involved in cell senescence, organism aging and diseases of aging. Notably, cell senescence is associated with activation of the TOR (target of rapamycin) nutrient- and mitogen-sensing pathway, which promotes cell growth, even though cell cycle is blocked. Is TOR involved in organism aging? In fact, in yeast (where the cell is the organism), caloric restriction, rapamycin and mutations that inhibit TOR all slow down aging. In animals from worms to mammals caloric restrictions, life-extending agents, and numerous mutations that increase longevity all converge on the TOR pathway. And, in humans, cell hypertrophy, hyper-function and hyperplasia, typically associated with activation of TOR, contribute to diseases of aging. Theoretical and clinical considerations suggest that rapamycin may be effective against atherosclerosis, hypertension and hyper-coagulation (thus, preventing myocardial infarction and stroke), osteoporosis, cancer, autoimmune diseases and arthritis, obesity, diabetes, macula-degeneration, Alzheimer’s and Parkinson’s diseases. Finally, I discuss that extended life span will reveal new causes for aging (e.g., ROS, ‘wear and tear’, Hayflick limit, stem cell exhaustion) that play a limited role now, when quasi-programmed senescence kills us first.

Metformin as a Tool to Target Aging

Nir Barzilai, Jill P. Crandall, Stephen B. Kritchevsky, and Mark A. Espeland

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Abstract

Aging has been targeted by genetic and dietary manipulation and by drugs in order to increase lifespan and healthspan in numerous models. Metformin, which has demonstrated protective effects against several age-related diseases in humans, will be tested in the TAME (Targeting Aging with Metformin) trial, as the initial step in the development of increasingly effective next-generation drugs.

IV Therapy

The antiviral activities of artemisinin and artesunate

Thomas Efferth, Marta R Romero, Dana G Wolf, Thomas Stamminger, Jose J G Marin, Manfred Marschall

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Abstract

Traditional Chinese medicine commands a unique position among all traditional medicines because of its 5000 years of history. Our own interest in natural products from traditional Chinese medicine was triggered in the 1990s, by artemisinin-type sesquiterpene lactones from Artemisia annua L. As demonstrated in recent years, this class of compounds has activity against malaria, cancer cells, and schistosomiasis. Interestingly, the bioactivity of artemisinin and its semisynthetic derivative artesunate is even broader and includes the inhibition of certain viruses, such as human cytomegalovirus and other members of the Herpesviridae family (e.g., herpes simplex virus type 1 and Epstein-Barr virus), hepatitis B virus, hepatitis C virus, and bovine viral diarrhea virus. Analysis of the complete profile of the pharmacological activities and molecular modes of action of artemisinin and artesunate and their performance in clinical trials will further elucidate the full antimicrobial potential of these versatile pharmacological tools from nature.

An Artemisinin-Derived Dimer Has Highly Potent AntiCytomegalovirus (CMV) and Anti-Cancer Activities

Ran He, Bryan T. Mott, Andrew S. Rosenthal, Douglas T. Genna, Gary H. Posner, Ravit Arav-Boger

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Abstract

We recently reported that two artemisinin-derived dimers (dimer primary alcohol 606 and dimer sulfone 4-carbamate 832-4) are significantly more potent in inhibiting human cytomegalovirus (CMV) replication than artemisinin-derived monomers. In our continued evaluation of the activities of artemisinins in CMV inhibition, twelve artemisinin-derived dimers and five artemisinin-derived monomers were used. Dimers as a group were found to be potent inhibitors of CMV replication. Comparison of CMV inhibition and the slope parameter of dimers and monomers suggest that dimers are distinct in their anti-CMV activities. A deoxy dimer (574), lacking the endoperoxide bridge, did not have any effect on CMV replication, suggesting a role for the endoperoxide bridge in CMV inhibition. Differences in anti-CMV activity were observed among three structural analogs of dimer sulfone 4-carbamate 832-4 indicating that the exact placement and oxidation state of the sulfur atom may contribute to its anti-CMV activity. Of all tested dimers, artemisinin-derived diphenyl phosphate dimer 838 proved to be the most potent inhibitor of CMV replication, with a selectivity index of approximately 1500, compared to our previously reported dimer sulfone 4-carbamate 832-4 with a selectivity index of about 900. Diphenyl phosphate dimer 838 was highly active against a Ganciclovir-resistant CMV strain and was also the most active dimer in inhibition of cancer cell growth. Thus, diphenyl phosphate dimer 838 may represent a lead for development of a highly potent and safe anti-CMV compound.

Anti-malarial drug, artemisinin and its derivatives for the treatment of respiratory diseases

Cheong DHJ, Tan DWS, Wong FWS, Tran T

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Abstract

Artemisinins are sesquiterpene lactones with a peroxide moiety that are isolated from the herb Artemisia annua. It has been used for centuries for the treatment of fever and chills, and has been recently approved for the treatment of malaria due to its endoperoxidase properties. Progressively, research has found that artemisinins displayed multiple pharmacological actions against inflammation, viral infections, and cell and tumour proliferation, making it effective against diseases. Moreover, it has displayed a relatively safe toxicity profile. The use of artemisinins against different respiratory diseases has been investigated in lung cancer models and inflammatory-driven respiratory disorders. These studies revealed the ability of artemisinins in attenuating proliferation, inflammation, invasion, and metastasis, and in inducing apoptosis. Artemisinins can regulate the expression of pro-inflammatory cytokines, nuclear factor-kappa B (NF-κB), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF), promote cell cycle arrest, drive reactive oxygen species (ROS) production and induce Bak or Bax-dependent or independent apoptosis. In this review, we aim to provide a comprehensive update of the current knowledge of the effects of artemisinins in relation to respiratory diseases to identify gaps that need to be filled in the course of repurposing artemisinins for the treatment of respiratory diseases. In addition, we postulate whether artemisinins can also be repurposed for the treatment of COVID-19 given its antiviral and anti-inflammatory properties.

Novel artemisinin derivatives with potential usefulness against liver/colon cancer and viral hepatitis

Blazquez AG, Fernandez-Dolon M, Sanchez-Vicente L, Maestre AD, Gomez-San Miguel AB, Alvarez M, Serrano MA, Jansen H, Efferth T, Marin JJ, Romero MR

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Abstract

Antitumor and antiviral properties of the antimalaria drug artemisinin from Artemisia annua have been reported. Novel artemisinin derivatives (AD1-AD8) have been synthesized and evaluated using in vitro models of liver/colon cancer and viral hepatitis B and C. Cell viability assays after treating human cell lines from hepatoblastoma (HepG2), hepatocarcinoma (SK-HEP-1), and colon adenocarcinoma (LS174T) with AD1-AD8 for a short (6h) and long (72h) period revealed that AD5 combined low acute toxicity together with high antiproliferative effect (IC50=1-5μM). Since iron-mediated activation of peroxide bond is involved in artemisinin antimalarial activity, the effect of iron(II)-glycine sulfate (ferrosanol) and iron(III)-containing protoporphyrin IX (hemin) was investigated. Ferrosanol, but not hemin, enhanced antiproliferative activity of AD5 if the cells were preloaded with AD5, but not if both compouds were added together. Five derivatives (AD1>AD2>AD7>AD3>AD8) were able to inhibit the cytopathic effect of bovine viral diarrhoea virus (BVDV), a surrogate in vitro model of hepatitis C virus (HCV), used here to evaluate the anti-Flaviviridae activity. Moreover, AD1 and AD2 inhibited the release of BVDV-RNA to the culture medium. Co-treatment with hemin or ferrosanol resulted in enhanced anti-Flaviviridae activity of AD1. In HepG2 cells permanently infected with hepatitis B virus (HBV), AD1 and AD4, at non-toxic concentrations for the host cells were able to reduce the release of HBV-DNA to the medium. In conclusion, high pharmacological interest deserving further evaluation in animal models has been identified for novel artemisinin-related drugs potentially useful for the treatment of liver cancer and viral hepatitis B and C.

Peptides

Thymosin alpha 1 (T1) reduces the mortality of severe COVID-19 by restoration of lymphocytopenia and reversion of exhausted T cells

Yueping Liu, Yue Pang  Zhenhong Hu, Ming Wu, Chenhui Wang, Zeqing Feng, Congzheng Mao, Yingjun Tan,Ying Liu, Li Chen, Min Li, Gang Wang, Zilin Yuan, Bo Diao, Yuzhang Wu, and Yongwen Chen

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Abstract

Background: We previously reported that lymphocytopenia and T cell exhaustion is notable in acute COVID19 patients, especially in aged and severe cases. Thymosin alpha 1 (Tα1) had been used in the treatment of viral infections as an immune response modifier for many years. However, clinical benefits and mechanism of Tα1 supplement to COVID-19 are still unclear.

 

Methods: We retrospectively reviewed the clinical outcomes of 76 severe cases with COVID-19 admitted into two hospitals in Wuhan from December 2019 to March 2020. The thymus output in peripheral blood mononuclear cells (PBMCs) from COVID-19 patients was measured by T cell receptor excision circles (TREC). The levels of T cell exhaustion markers PD-1 and Tim-3 on CD8+ T cells were detected by flow cytometry.

Results: Compared with untreated group, Tα1 treatment significantly reduces mortality of severe COVID-19 patients (11.11% vs. 30.00%, p=0.044). Tα1 timely enhances blood T cell numbers in COVID-19 patients with severe lymphocytopenia (the counts of CD8+ T cells or CD4T cells in circulation lower than 400/μL or 650/μL, respectively). Under such conditions, Tα1 also successfully restores CD8+ and CD4+ T cell numbers in aged patients. Meanwhile, Tα1 reduces PD-1 and Tim-3 expression on CD8+ T cells from severe COVID-19 patients in comparison with untreated cases. It is of note that restoration of lymphocytopenia and acute exhaustion of T cells are roughly parallel to the rise of TRECs.

Conclusions: Tα1 supplement significantly reduce mortality of severe COVID-19 patients. COVID-19 patients with the counts of CD8+ T cells or CD4+ T cells in circulation lower than 400/μL or 650/μL, respectively, gain more benefits from Tα1. Tα1 reverses T cell exhaustion and recovers immune reconstitution through promoting thymus output during SARS-CoV-2 infection.