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.
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 Glaser, Constantine Dimitrakakis, Nancy Trimble, Vincent 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.
TSH is Not the Answer: Rationale for a New Paradigm to Evaluate and Treat Hypothyroidism, Particularly Associated with Weight Loss
C. Rowsemitt, Thomas Najarian
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Abstract
While many endocrinologists continue to debate the appropriate levels of TSH to use as boundaries for normal limits, we believe using TSH to assess thyroid function is counterproductive, particularly in those patients attempting to lose weight. From the published literature and our own clinical experience, we have come to understand that the set point for metabolism is adjusted downward in the hypocaloric state. The decrease in metabolism is often referred to as part of the “famine response.” This metabolic response has been docu- mented in several major vertebrate classes demonstrating its widespread importance in nature. In our current environment, the famine response limits the patient’s ability to lose weight while consuming a hypocaloric diet and performing modest levels of exercise. Our own experience with the famine response is consistent with that found in the literature. Treating to normalize thyroid hormone levels and eliminate hypothyroid symptoms results in the suppression of TSH. This is understood as a normal part of treatment once we accept that the thyroid set point has been lowered. This is not an argument to use thyroid hormones to increase metabolism above normal to achieve weight loss. Our goal is to correct the hypothyroid response in a weight loss patient and return him/her to normal metabolism so that the patient feels normal and is better able to lose weight and maintain that loss.
Female androgen insufficiency: the Princeton consensus statement on definition, classification, and assessment
Gloria Bachmann, John Bancroft, Glenn Braunstein, Henry Burger, Susan Davis, Lorraine Dennerstein, Irwin Goldstein, Andre Guay, Sandra Leiblum, Rogerio Lobo, Morris Notelovitz, Raymond Rosen, Philip Sarrel, Barbara Sherwin, James Simon, Evan Simpson, Jan Shifren, Richard Spark, Abdul Traish, Princeton
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Abstract
Objective: To evaluate the evidence for and against androgen insufficiency as a cause of sexual and other health-related problems in women and to make recommendations regarding definition, diagnosis, and assessment of androgen deficiency states in women.
Design: Evaluation of peer-review literature and consensus conference of international experts.
Setting: Multinational conference in the United States.
Patient(s): Premenopausal and postmenopausal women with androgen deficiency.
Intervention(s): Evaluation of peer-review literature and development of consensus panel guidelines.
Result(s): The term “female androgen insufficiency” was defined as consisting of a pattern of clinical symptoms in the presence of decreased bioavailable T and normal estrogen status. Currently available assays were found to be lacking in sensitivity and reliability at the lower ranges, and the need for an equilibrium dialysis measure was strongly emphasized. Causes of androgen insufficiency in women were classified as ovarian, adrenal, hypothalamic-pituitary, drug-related, and idiopathic. A simplified management algorithm and clinical guidelines were proposed to assist clinicians in diagnosis and assessment. Androgen replacement is currently available in several forms, although none has been approved for treatment of sexual dysfunction or other common symptoms of female androgen insufficiency. Potential risks associated with treatment were identified, and the need for informed consent and careful monitoring was noted. Finally, the panel identified key goals and priorities for future research.
Conclusion(s): A new definition of androgen insufficiency in women has been proposed along with consensus-based guidelines for clinical assessment and diagnosis. A simplified management algorithm for women with low androgen in the presence of clinical symptoms and normal estrogen status has also been proposed.
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.
Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study
Agnès Fournier, Franco Berrino, and Françoise Clavel-Chapelon
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Abstract
Large numbers of hormone replacement therapies (HRTs) are available for the treatment of menopausal symptoms. It is still unclear whether some are more deleterious than others regarding breast cancer risk. The goal of this study was to assess and compare the association between different HRTs and breast cancer risk, using data from the French E3N cohort study. Invasive breast cancer cases were identified through biennial self-administered questionnaires completed from 1990 to 2002. During follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women. Compared with HRT never-use, use of estrogen alone was associated with a significant 1.29-fold increased risk (95% confidence interval 1.02–1.65). The association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: the relative risk was 1.00 (0.83–1.22) for estrogen–progesterone, 1.16 (0.94–1.43) for estrogen–dydrogesterone, and 1.69 (1.50–1.91) for estrogen combined with other progestagens. This latter category involves progestins with different physiologic activities (androgenic, nonandrogenic, antiandrogenic), but their associations with breast cancer risk did not differ significantly from one another. This study found no evidence of an association with risk according to the route of estrogen administration (oral or transdermal/percutaneous). These findings suggest that the choice of the progestagen component in combined HRT is of importance regarding breast cancer risk; it could be preferable to use progesterone or dydrogesterone.
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.
Recent Advances in Hormone Replacement Therapy
Roger NJ Smith and John WW Studd
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Abstract
In view of the benefits of hormone replacement therapy (HRT) and the experience that only 10% of women maintain therapy, it is vital that all doctors are familiar with the pros and cons of HRT, so that women may be correctly advised. Here we discuss new issues and developments in HRT and current views on indications, complications and regimens of treatment.
Safety of maternal testosterone therapy during breast feeding
Rebecca Glaser, David Zava, Melanie Parsons, Mark Newman
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Abstract
Testosterone, delivered by pellet implant, has been successfully used to treat depression and fatigue in women. ‘Breast feeding’ has been listed as a contraindication to testosterone therapy, despite a paucity of data to support this recommendation.
This study examined 3 methods of delivery of testosterone therapy in a breast-feeding mother who presented with low testosterone and symptoms of testosterone deficiency. Sublingual drops containing 1 mg of testosterone were dosed twice daily. Vaginal cream containing 0.5 mg of testosterone was applied daily in the morning. Lastly, a 100 mg testosterone pellet was implanted into the subcutaneous tissue with re-implantation at 3 months.
Serial testosterone levels were measured in breast milk, capillary blood in the mother (finger-stick) and capillary blood in the infant (heel-stick). Capillary bloodspot* testosterone ranges are variable and are approximately three times higher than serum ranges (baseline, females).
Testosterone was measurable in the mother’s blood and absent from both breast milk and the infant’s blood by all three methods of delivery; sublingual drops, vaginal cream and pellet implant.
After 5 months of maternal testosterone therapy by pellet implant, there were no adverse affects noted in the infant. Testosterone levels in infant blood remained unaffected. The mother’s symptoms of depression, irritability, anxiety, decreased libido, aches, pains, physical and mental exhaustion, resolved with testosterone therapy delivered by pellet implant.
Testosterone therapy by sublingual drops, vaginal cream and subcutaneous pellet implant in breast feeding mothers does not increase the level of testosterone in breast milk or infant’s blood and does not have adverse clinical effects in the infant. Further studies are recommended. Unsubstantiated ‘contraindications’ should be questioned.
Safety of Maternal Testosterone Therapy During Breastfeeding
Rebecca L. Glaser, MD, FACS, Mark Newman, MS, Melanie Parsons, MASc, David Zava, PhD, Daniel Glaser-Garbrick
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Abstract
This article is an adaptation of an abstract/poster presentation made at the 13th International Congress on Steroidal Hormones and Hormones & Cancer, Quebec City, Canada (September 2008), concerning the topic of breast feeding as a contraindication to testosterone therapy. The purpose of the presentation and this article is to provide a summary of the findings of a study that was conducted to evaluate maternal absorption of testosterone and its excretion into breast milk by using three methods of delivery: sublingual drops, vaginal cream, and pellet implant. Testosterone was measurable in maternal blood by all three methods of delivery. No significant increase of testosterone was seen in breast milk when testosterone was delivered by vaginal cream, sublingual drops, or subcutaneous pellet implant. Testosterone was very low in infant blood at baseline and during testosterone therapy by pellet implant. There were no adverse clinical affects in the infant after seven months of continuous testosterone therapy to the mother by subcutaneous pellet implant. Testosterone delivered by sublingual drops, vaginal cream, and pellet implant was absorbed but not measurably excreted into breast milk. Testosterone, delivered by a 100-mg subcutaneous pellet implant, was effective in relieving symptoms of testosterone deficiency and was not measurably increased in breast milk or measurable in infant serum. Maternal testosterone therapy is safe for the breast-fed infant. Testosterone by pellet implant may be a safer and more physiologic alternative to psychotropic medications.
ACOG committee opinion no. 556: Postmenopausal estrogen therapy: route of administration and risk of venous thromboembolism
American College of Obstetricians and Gynecologists
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Abstract
The development of menopausal symptoms and related disorders, which lead women to seek prescriptions for postmenopausal estrogen therapy and hormone therapy, is a common reason for a patient to visit her gynecologist, but these therapies are associated with an increased risk of venous thromboembolism. The relative risk seems to be even greater if the treated population has preexisting risk factors for venous thromboembolism, such as obesity, immobilization, and fracture. Recent studies suggest that orally administered estrogen may exert a prothrombotic effect, whereas transdermally administered estrogen has little or no effect in elevating prothrombotic substances and may have beneficial effects on proinflammatory markers. When prescribing estrogen therapy, the gynecologist should take into consideration the possible thrombosis-sparing properties of transdermal forms of estrogen therapy. As part of the shared decision-making process, the gynecologist should weigh the risks against the benefits when prescribing combination estrogen plus progestin hormone therapy or estrogen therapy and counsel the patient accordingly.
Vulvodynia: Strategies for Treatment
ANDREW T. GOLDSTEIN, MD, STANLEY C. MARINOFF, MD, MPH, and HOPE K. HAEFNER, MD
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Introduction
In 2003, the International Society for the Study of Vulvovaginal Disease (ISSVD) revised its definition of the frequently used and well-accepted term ‘‘vulvodynia.’’ The new classification acknowledges that vulvar pain can be attributed to diagnosable disorders such as infections, dermatologic disorders, neoplastic processes, and neurologic disorders. The other category is vulvodynia, pain not related to a specific, identifiable disorder. Vulvodynia is often described as a vulvar discomfort with sensations of burning, irritation, or rawness. In addition, the ISSVD further expanded its classification of vulvodynia into generalized and localized pain. These categories are further subdivided to provoked pain or unprovoked pain. Additionally, there is a category for pain that is both provoked and unprovoked (mixed). Vestibulodynia (previously termed vestibulitis) is a pain localized to the vestibule. The suffix ‘‘-itis’’ has been excluded from the recent ISSVD terminology because studies found a lack of association between excised tissue and inflammation. Other terminologies have classified vestibulodynia as primary or secondary; in the primary subset, the pain has been present since the first tampon use or intercourse, and with secondary vestibular pain, women have had painless tampon insertion or intercourse, then the vestibular pain develops at a later time.
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.
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.
3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer
Yufei Li, Nathaniel W. Mahloch, Nicholas J.E. Starkey, Mónica Peña-Luna, George E. Rottinghaus, Kevin L. Fritsche, Cynthia Besch-Williford, Dennis B. Lubahn
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Abstract
3,3’-Diindolylmethane (DIM) is an acid-derived dimer of indole-3-carbinol, found in many cruciferous vegetables, such as broccoli, and has been shown to inhibit prostate cancer (PCa) in several in vitro and in vivo models. We demonstrated that DIM stimulated both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) transcriptional activities and propose that ERβ plays a role in mediating DIM’s inhibition on cancer cell growth. To further study the effects of DIM on inhibiting advanced PCa development, we tested DIM in TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. The control group of mice were fed a high fat diet. Three additional groups of mice were fed the same high fat diet supplemented with 0.04%, 0.2% and 1% DIM. Incidence of advanced PCa, poorly differentiated carcinoma (PDC), in the control group was 60%. 1% DIM dramatically reduced PDC incidence to 24% (p=0.0012), while 0.2% and 0.04% DIM reduced PDC incidence to 38% (p=0.047) and 45% (p=0.14) respectively. Though DIM did affect mice weights, statistical analysis showed a clear negative association between DIM concentration and PDC incidence with p=0.004, while the association between body weight and PDC incidence was not significant (p=0.953). In conclusion, our results show that dietary DIM can inhibit the most aggressive stage of prostate cancer at concentration lower than previously demonstrated, possibly working through an estrogen receptor mediated mechanism.
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: testosterone, androgens, human, male, cardiovascular, stroke, cerebrovascular accident, myocardial infarction, heart attack, death, 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.
Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina
A M Smith, K M English , C J Malkin, R D Jones, T H Jones, and K S Channer
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Abstract
Objective: In women, sex hormones cause increased morbidity and mortality in patients with coronary heart disease (CHD) and adversely affect the coagulation profile. We have studied the effect of physiological testosterone replacement therapy in men on coagulation factor expression, to determine if there is an increased risk of thrombosis.
Methods: Double-blind, randomized, placebo-controlled trial of testosterone in 46 men with chronic stable angina. Measurements of free, total and bioavailable testosterone, luteinising hormone (LH) and follicle-stimulating hormone (FSH), estradiol, plasminogen activator inhibitor-1 (PAI-1), fibrinogen, tissue plasminogen activator (tPA) and full blood count were made at 0, 6 and 14 weeks.
Results: Bioavailable testosterone levels were: 2.58^0.58 nmol/l at baseline, compared with 3.35^0.31 nmol/l at week 14 (P , 0.001) after treatment compared with 2.6^0.18 nmol/l and 2.44^0.18 nmol/l in the placebo group (P was not significant). There was no change in fibrinogen (3.03^0.18 g/l at baseline and 3.02^0.18 g/l at week 14, P ¼ 0.24), tPA activity (26.77^4.9 Iu/ml and 25.67^4.4 Iu/ml, P ¼ 0.88) or PAI-1 activity (0.49^0.85 Iu/ml and 0.36^0.06 Iu/ml, P ¼ 0.16) with active treatment and no differences between the groups (at week 14, P value 0.98, 0.59 and 0.8 for fibrinogen, PAI-1 and tPA respectively). Haemoglobin concentration did not change over time, in the testosterone group (1.44^0.02 g/l and 1.45^0.02 g/l, P ¼ 0.22).
Conclusion: Physiological testosterone replacement does not adversely affect blood coagulation status.
Type 2 Diabetes and Testosterone Therapy
Geoffrey Hackett
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Abstract
A third of men with type 2 diabetes (T2DM) have hypogonadotrophic hypogonadism (HH) and associated increased risk of cardiovascular and all-cause mortality. Men with HH are at increased risk of developing incident T2DM. We conducted MEDLINE, EMBASE, and COCHRANE reviews on T2DM, HH, testosterone deficiency, cardiovascular and all-cause mortality from May 2005 to October 2017, yielding 1,714 articles, 52 clinical trials and 32 randomized controlled trials (RCT). Studies with testosterone therapy suggest significant benefits in sexual function, quality of life, glycaemic control, anaemia, bone density, fat, and lean muscle mass. Meta-analyses of RCT, rather than providing clarification, have further confused the issue by including under-powered studies of inadequate duration, multiple regimes, some discontinued, and inbuilt bias in terms of studies included or excluded from analysis.
Bio-available testosterone levels fall acutely following myocardial infarction in men: association with fibrinolytic factors
Peter J Pugh, Kevin S Channer, Helen Parry, Tom Downes, T Hugh Jone
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Abstract
The effect of acute myocardial infarction on plasma levels of testosterone in men is unclear. No previous studies have evaluated the bio-available fraction of testosterone. Low plasma testosterone levels have been associated with several risk factors for myocardial infarction, including an unfavorable fibrinolytic profile. In a prospective, case control study, we examined changes in plasma levels of sex hormones, including bio-available testosterone, in patients with acute myocardial infarction and in control subjects. In addition, changes in hormone levels in patients were compared with alterations in the fibrinolytic profile. Thirty male patients admitted with chest pain were studied. Twenty two had acute myocardial infarction and eight had non-specific chest pain. Plasma levels of total and bio-available testosterone, 17beta-estradiol, sex hormone binding globulin and insulin were measured at baseline and throughout admission. In addition, fibrinolytic factors (plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA) and fibrinogen) were measured in patients who received fibrinolysis. Height and weight, and the subsequent development of heart failure or myocardial dysfunction were also recorded. Patients had lower levels of bio-available testosterone (2.07 +/- 0.75 nmol/L vs. 5.3 +/- 1.7 nmol/L, p < 0.05) and higher levels of 17beta-estradiol (87.9 +/- 39.5 pmol/L vs. 48.1 +/- 18.4 pmol/L, p < 0.001) than controls. Total and bio-available testosterone levels fell acutely following myocardial infarction (11.9 +/- 3.8 nmol/L to 9.7 +/- 3.3 nmol/L, p < 0.05; 1.95 +/- 0.76 nmol/L to 1.55 +/- 0.67 nmol/L, p < 0.05). This reduction was associated with elevation of PAI-I activity and reduction of tPA activity, independent of changes in plasma insulin levels. Patients with lower baseline levels of testosterone and higher levels of 17beta-estradiol had a relatively pro-thrombotic fibrinolytic profile and increased risk of complications. In conclusion, total and bio-available levels of testosterone fall following acute myocardial infarction in men, in association with adverse changes in fibrinolytic profile. It is not clear whether this association represents a direct effect of testosterone on thrombotic tendency but warrants further investigation.
The Testosterone Controversy
With references adapted from an article posted by William Faloon of Life Extensions
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Abstract
Testosterone levels are high in young men, but plummet during aging. Despite compelling findings of efficacy, conventional doctors still question the value of testosterone replacement in maturing men. This oversight is causing needless heart attacks and strokes. Low testosterone is associated with excess abdominal fat,1-4 loss of insulin sensitivity,5,6 andatherosclerosis.7,8 A critically important role of testosterone is to enable HDL to remove excess cholesterol from the arterial wall and transport it to the liver for disposal. This effect of enhancing HDL is termed “reverse cholesterol transport” and is vital to preventing arterial occlusion.9,10 Cardiologists routinely prescribe statin drugs to lower LDL, a lipoprotein that transports cholesterol from the liver to the arteries. These same doctors, however, fail to maintain sufficient testosterone levels in their patients to enable HDL to remove cholesterol buildup in the arteries. This is one reason why statin drugs have not always been shown to work in older men, who require functional HDL to keep arterial linings free of excess cholesterol. 11,12 Numerous studies document the vital role that testosterone plays in maintaining youthful metabolic processes throughout the body.6,7,13-21 A large new study confirms the deadly impact of low testosterone in older men.22 What’s scary are clinical trials designed by doctors who have no idea how to achieve youthful hormone levels. Men who enroll in these studies are subjected to lethal dangers because testosterone and estrogen blood levels are not properly balanced. Cells throughout a man’s body are laden with receptor sites that are activated by the hormone testosterone. When testosterone is available to bind to these receptor sites, good things happen such as elevated mood and improved cognition in response to plentiful testosterone being available to the brain.23-25 Be it muscle, bone, vascular, or nerve tissue, testosterone provides critical command signals for your cells to behave in a youthful manner.8,26-33 As testosterone levels diminish, degenerative processes set in.
Testosterone treatment to prevent or revert type 2 diabetes in men enrolled in a lifestyle programme (T4DM): a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial
Prof Gary Wittert, MD, Karen Bracken, PhD , Kristy P Robledo, PhD , Prof Mathis Grossmann, PhD , Prof Bu B Yeap, PhD , Prof David J Handelsman, MD , et al.
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Background
Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme.
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.
A Harvard expert shares his thoughts on testosterone-replacement therapy
An interview with Abraham Morgentaler, M.D.
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It could be said that testosterone is what makes men, men. It gives them their characteristic deep voices, large muscles, and facial and body hair, distinguishing them from women. It stimulates the growth of the genitals at puberty, plays a role in sperm production, fuels libido, and contributes to normal erections. It also fosters the production of red blood cells, boosts mood, and aids cognition.
Over time, the testicular “machinery” that makes testosterone gradually becomes less effective, and testosterone levels start to fall, by about 1% a year, beginning in the 40s. As men get into their 50s, 60s, and beyond, they may start to have signs and symptoms of low testosterone such as lower sex drive and sense of vitality, erectile dysfunction, decreased energy, reduced muscle mass and bone density, and anemia. Taken together, these signs and symptoms are often called hypogonadism (“hypo” meaning low functioning and “gonadism” referring to the testicles). Researchers estimate that the condition affects anywhere from two to six million men in the United States. Yet it is an underdiagnosed problem, with only about 5% of those affected receiving treatment.
Studies have shown that testosterone-replacement therapy may offer a wide range of benefits for men with hypogonadism, including improved libido, mood, cognition, muscle mass, bone density, and red blood cell production. But little consensus exists on what constitutes low testosterone, when testosterone supplementation makes sense, or what risks patients face. Much of the current debate focuses on the long-held belief that testosterone may stimulate prostate cancer.
Dr. Abraham Morgentaler, an associate professor of surgery at Harvard Medical School, the director of Men’s Health Boston, and a member of Perspectives’ editorial board, specializes in treating prostate diseases and male sexual and reproductive difficulties. He has developed particular expertise in treating low testosterone levels. In this interview, Dr. Morgentaler shares his views on current controversies, the treatment strategies he uses with his own patients, and why he thinks experts should reconsider the possible link between testosterone-replacement therapy and prostate cancer.
Not giving up: Testosterone promotes persistence against a stronger opponent
Hana H. Kutlikova, Shawn N. Geniole, Christoph Eisenegger, Claus Lamm, Gerhard Jocham, Bettina Studer
Abstract
Recent research suggests that when we lack a sense of control, we are prone to motivational failures and early quitting in competitions. Testosterone, on the other hand, is thought to boost competitiveness. Here we investigate the interaction between these factors, testing the testosterone’s potential to enhance persistence in a competition against a stronger opponent, depending on experimentally manipulated perceived control. Healthy participants were administered a single dose of testosterone or placebo. They first underwent a task designed to either induce low or high perceived control and then entered a costly competition against a progressively stronger opponent that they could quit at any time. In the placebo group, men with low perceived control quitted twice as early as those with high perceived control. Testosterone countered this effect, making individuals with low control persist in the competition for as long as those with high perceived control, and did so also despite raising participants’ explicit awareness of the opponents’ advantage. This psychoendocrinological effect was not modulated by basal cortisol levels, CAG repeat polymorphism of the androgen receptor gene, or trait dominance. Our results provide the first causal evidence that testosterone promotes competitive persistence in humans and demonstrate that this effect depends on the psychological state elicited prior to the competition, broadening our understanding of the complex relationships between testosterone and social behaviors
Can Low-Intensity Extracorporeal Shockwave Therapy Improve Erectile Function? A 6-Month Follow-up Pilot Study in Patients with Organic Erectile Dysfunction
Yoram Vardi, Boaz Appel, Giris Jacob, Omar Massarwi, Ilan Gruenwald
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Abstract
Background: Low-intensity extracorporeal shockwave therapy (LI-ESWT) is currently under investigation regarding its ability to promote neovascularization in different organs.
Objective: To evaluate the effect of LI-ESWT on men with erectile dysfunction (ED) who have previously responded to oral phosphodiesterase type 5 inhibitors (PDE5-I). Design, setting, and participants: We screened 20 men with vasculogenic ED who had International Index of Erectile Function ED (IIEF-ED) domain scores between 5–19 (average: 13.5) and abnormal nocturnal penile tumescence (NPT) parameters. Shockwave therapy comprised two treatment sessions per week for 3 wk, which were repeated after a 3-wk no-treatment interval.
Intervention: LI-ESWT was applied to the penile shaft and crura at five different sites. Measurements: Assessment of erectile function was performed at screening and at 1 mo after the end of the two treatment sessions using validated sexual function questionnaires, NPT parameters, and penile and systemic endothelial function testing. The IIEF-ED questionnaire was answered at the 3- and 6-mo follow-up examinations.
Results and limitations: We treated 20 middle-aged men (average age: 56.1 yr) with vasculogenic ED (mean duration: 34.7 mo). Eighteen had cardiovascular risk factors. At 1 mo follow-up, significant increases in IIEF-ED domain scores were recorded in all men (20.9 5.8 vs 13.5 4.1, p < 0.001); these remained unchanged at 6 mo. Moreover, significant increases in the duration of erection and penile rigidity, and significant improvement in penile endothelial function were demonstrated. Ten men did not require any PDE5-I therapy after 6-mo follow-up. No pain was reported from the treatment and no adverse events were noted during follow-up.
Conclusions: This is the first study that assessed the efficacy of LI-ESWT for ED. This approach was tolerable and effective, suggesting a physiologic impact on cavernosal hemodynamics. Its main advantages are the potential to improve erectile function and to contribute to penile rehabilitation without pharmacotherapy. The short-term results are promising, yet demand further evaluation with larger sham-control cohorts and longer follow-up.
Low intensity extracorporeal shockwave therapy for erectile dysfunction: a study in an Indian population
Vasan Satya Srini, MD, Rahul Kumar Reddy, MD, Tamar Shultz, PhD, Bela Denes, MD
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Abstract
Erectile dysfunction (ED) has been shown to be associated with a number of physical conditions and affects not only physical but also psychosocial health. Currently oral, on-demand phosphodiesterase type 5 inhibitors (PDE5i) are preferred first line treatment. Though effective, these drugs have limitations and are associated with significant non-compliance, side effects and do not reverse the underlying pathology. Non-invasive low intensity shockwave therapy (LISWT) has been shown to significantly improve erectile function in men previously PDE5i dependent. We describe our experience and results with this therapy in an Indian population of men with ED. This study assessed the efficacy of low intensity extracorporeal shockwave therapy (LI-ESWT) on Indian men with organic ED who had previously responded to PDE5i.
Initial experience with linear focused shockwave treatment for erectile dysfunction: a 6-month follow-up pilot study
Y Reisman, A Hind, A Varaneckas and I Motil
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Abstract
Vasculogenic erectile dysfunction (ED) is defined as inability to get or keep an erection firm enough for satisfying sexual intercourse and is maybe originated by diseases, such as diabetes mellitus (DM) and atherosclerotic vascular occlusive disease. Current methods for treating vasculogenic ED aim at reducing symptoms instead of reversing the source of the dysfunction, which in the majority of the patients is due to arterial or inflow disorders.1 It has been demonstrated that shockwaves can enhance intrinsic angiogenesis and are used to treat ischemic heart disease.2 Low-intensity shockwaves (LISW) have been evaluated for treating ED in both pilot and randomized sham-controlled studies. The encouraging results that were seen in these studies were the first to show the effect of LISW on ED symptoms,3–4 but have never been evaluated elsewhere. Recently published study conducted on rats with DM-associated ED showed that low-energy shockwave therapy (LESWT) significantly restored erectile function to levels almost similar to normal levels of controls. The therapeutic efficacy of LESWT is possibly mediated by increased recruitment of mesenchymal stem cells (MSCs) that promote the regeneration of DM-damaged erectile tissues.5 The present study was aimed to assess the safety and efficacy of a new dedicated shockwave device, ‘Renova’, which was designed to achieve substantially superior organ coverage, compared with the existing devices and hence produces positive results with a shorter protocol in a multicenter study.
Tadalafil once daily and extracorporeal shock wave therapy in the management of patients with Peyronie’s disease and erectile dysfunction: results from a prospective randomized trial
A. Palmieri, C. Imbimbo, M. Creta, P. Verze, F. Fusco and V. Mirone
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Abstract
Extracorporeal shock wave therapy improves erectile function in patients with Peyronie’s disease. However, erectile dysfunction still persists in many cases. We aimed to investigate the effects of extracorporeal shock wave therapy plus tadalafil 5 mg once daily in the management of patients with Peyronie’s disease and erectile dysfunction not previously treated. One hundred patients were enrolled in a prospective, randomized, controlled study. Patients were randomly allocated to receive either extracorporeal shock wave therapy alone for 4 weeks (n = 50) or extracorporeal shock wave therapy plus tadalafil 5 mg once daily for 4 weeks (n = 50). Main outcome measures were: erectile function (evaluated through the shortened version of the International Index of Erectile Function), pain during erection (evaluated through a Visual Analog Scale), plaque size, penile curvature and quality of life (evaluated through an internal questionnaire). Follow-up evaluations were performed after 12 and 24 weeks. In both groups, at 12 weeks follow-up, mean Visual Analog Scale score, mean International Index of Erectile Function score and mean quality of life score ameliorated significantly while mean plaque size and mean curvature degree were unchanged. Intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and quality of life score in patients receiving the combination. After 24 weeks, intergroup analysis revealed a significantly higher mean International Index of Erectile Function score and mean quality of life score in patients that received extracorporeal shock wave therapy plus tadalafil. In conclusion extracorporeal shock wave therapy plus tadalafil 5 mg once daily may represent a valid conservative strategy for the management of patients with Peyronie’s disease and erectile dysfunction.
Low-intensity Extracorporeal Shock Wave Treatment Improves Erectile Function: A Systematic Review and Meta-analysis
Zhihua Lu, Guiting Lin, Amanda Reed-Maldonado, Chunxi Wang, Yung-Chin Lee, Tom F. Lue
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Abstract
Context: As a novel therapeutic method for erectile dysfunction (ED), low-intensity extracorporeal shock wave treatment (LI-ESWT) has been applied recently in the clinical setting. We feel that a summary of the current literature and a systematic review to evaluate the therapeutic efficacy of LI-ESWT for ED would be helpful for physicians who are interested in using this modality to treat patients with ED.
Objective: A systematic review of the evidence regarding LI-ESWT for patients with ED was undertaken with a meta-analysis to identify the efficacy of the treatment modality.
Evidence acquisition: A comprehensive search of the PubMed and Embase databases to November 2015 was performed. Studies reporting on patients with ED treated with LIESWT were included. The International Index of Erectile Function (IIEF) and the Erection Hardness Score (EHS) were the most commonly used tools to evaluate the therapeutic efficacy of LI-ESWT.
Evidence synthesis: There were 14 studies including 833 patients from 2005 to 2015. Seven studies were randomized controlled trials (RCTs); however, in these studies, the setup parameters of LI-ESWT and the protocols of treatment were variable. The meta-analysis revealed that LI-ESWT could significantly improve IIEF (mean difference: 2.00; 95% confidence interval [CI], 0.99–3.00; p < 0.0001) and EHS (risk difference: 0.16; 95% CI, 0.04–0.29; p = 0.01). Therapeutic efficacy could last at least 3 mo. The patients with mildmoderate ED had better therapeutic efficacy after treatment than patients with more severe ED or comorbidities. Energy flux density, number of shock waves per treatment, and duration of LI-ESWT treatment were closely related to clinical outcome, especially regarding IIEF improvement.
Conclusions: The number of studies of LI-ESWT for ED have increased dramatically in recent years. Most of these studies presented encouraging results, regardless of variation in LI-ESWT setup parameters or treatment protocols. These studies suggest that LI-ESWT could significantly improve the IIEF and EHS of ED patients. The publication of robust evidence from additional RCTs and longer-term follow-up would provide more confidence regarding use of LI-ESWT for ED patients. Patient summary: We reviewed 14 studies of men who received low-intensity extracorporeal shock wave treatment (LI-ESWT) for erectile dysfunction (ED). There was evidence that these men experienced improvements in their ED following LI-ESWT.
Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction
Shin-ichi Hisasue, Toshiyuki China, Akira Horiuchi, Masaki Kimura, Keisuke Saito, Shuji Isotani, Hisamitsu Ide, Satoru Muto, Raizo Yamaguchi and Shigeo Horie
Abstract
Objectives: To evaluate the efficacy of low-intensity shock wave therapy and to identify the predictive factors of its efficacy in Japanese patients with erectile dysfunction.
Methods: The present study included 57 patients with erectile dysfunction who satisfied all the following conditions: more than 6-months history of erectile dysfunction, sexual health inventory for men score of ≤12 without phosphodiesterase type-5 inhibitor, erection hardness score grade 1 or 2, mean penile circumferential change by erectometer assessing sleep related erection of <25 mm and non-neurological pathology. Patients were treated by a low-energy shock waves generator (ED1000; Medispec, Gaithersburg, MD, USA). A total of 12 shock wave treatments were applied. Sexual health inventory for men score, erection hardness score with or without phosphodiesterase type-5 inhibitor, and mean penile circumferential change were assessed at baseline, 1, 3 and 6 months after the termination of low-intensity shock wave therapy.
Results: Of 57 patients who were assigned for the low-intensity shock wave therapy trial, 56 patients were analyzed. Patients had a median age of 64 years. The sexual health inventory for men and erection hardness score (with and without phosphodiesterase type-5 inhibitor) were significantly increased (P < 0.001) at each timepoint. The mean penile circumferential change was also increased from 13.1 to 20.2 mm after low-intensity shock wave therapy (P < 0.001). In the multivariate analysis, age and the number of concomitant comorbidities were statistically significant predictors for the efficacy.
Conclusions: Low-intensity shock wave therapy seems to be an effective physical therapy for erectile dysfunction. Age and comorbidities are negative predictive factors of therapeutic response.
Low-Intensity Extracorporeal Shock Wave Therapy—A Novel Effective Treatment for Erectile Dysfunction in Severe ED Patients Who Respond Poorly to PDE5 Inhibitor Therapy
Ilan Gruenwald, MD, Boaz Appel, MD, and Yoram Vardi, MD
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Abstract
Introduction. Low-intensity shock wave therapy (LI-ESWT) has been reported as an effective treatment in men with mild and moderate erectile dysfunction (ED).
Aim. The aim of this study is to determine the efficacy of LI-ESWT in severe ED patients who were poor responders to phosphodiesterase type 5 inhibitor (PDE5i) therapy.
Methods. This was an open-label single-arm prospective study on ED patients with an erection hardness score (EHS) 2 at baseline. The protocol comprised two treatment sessions per week for 3 weeks, which were repeated after a 3-week no-treatment interval. Patients were followed at 1 month (FU1), and only then an active PDE5i medication was provided for an additional month until final follow-up visit (FU2). At each treatment session, LI-ESWT was applied on the penile shaft and crus at five different anatomical sites (300 shocks, 0.09 mJ/mm2 intensity at120 shocks/min). Each subject underwent a full baseline assessment of erectile function using validated questionnaires and objective penile hemodynamic testing before and after LI-ESWT.
Main Outcome Measures. Outcome measures used are changes in the International Index of Erectile Functionerectile function domain (IIEF-ED) scores, the EHS measurement, and the three parameters of penile hemodynamics and endothelial function.
Results. Twenty-nine men (mean age of 61.3) completed the study. Their mean IIEF-ED scores increased from 8.8 1 (baseline) to 12.3 1 at FU1 (P = 0.035). At FU2 (on active PDE5i treatment), their IIEF-ED further increased to 18.8 1 (P < 0.0001), and 72.4% (P < 0.0001) reached an EHS of 3 (allowing full sexual intercourse). A significant improvement (P = 0.0001) in penile hemodynamics was detected after treatment and this improvement significantly correlated with increases in the IIEF-ED (P < 0.05). No noteworthy adverse events were reported.
Conclusions. Penile LI-ESWT is a new modality that has the potential to treat a subgroup of severe ED patients. These preliminary data need to be reconfirmed by multicenter sham control studies in a larger group of ED patients.
Penile Low Intensity Shock Wave Treatment is Able to Shift PDE5i Nonresponders to Responders: A Double-Blind, Sham Controlled Study
Noam D. Kitrey, Ilan Gruenwald, Boaz Appel, Arik Shechter, Omar Massarwa and Yoram Vardi
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Abstract
Purpose: We performed sham controlled evaluation of penile low intensity shock wave treatment effect in patients unable to achieve sexual intercourse using PDE5i (phosphodiesterase type 5 inhibitor).
Materials and Methods: This prospective, randomized, double-blind, sham controlled study was done in patients with vasculogenic erectile dysfunction who stopped using PDE5i due to no efficacy. All patients had an erection hardness score of 2 or less with PDE5i. A total of 58 patients were randomized, including 37 treated with low intensity shock waves (12 sessions of 1,500 pulses of 0.09 mJ/mm2 at 120 shock waves per minute) and 18 treated with a sham probe. In the sham group 16 patients underwent low intensity shock wave treatment 1 month after sham treatment. All patients were evaluated at baseline and 1 month after the end of treatment using validated erectile dysfunction questionnaires and the flow mediated dilatation technique for penile endothelial function. Erectile function was evaluated while patients were receiving PDE5i.
Results: In the low intensity shock wave treatment group and the sham group 54.1% and 0% of patients, respectively, achieved erection hard enough for vaginal penetration, that is an EHS (Erection Hardness Score) of 3 (p <0.0001). According to changes in the IIEF-EF (International Index of Erectile FunctionErectile Function) score treatment was effective in 40.5% of men who received low intensity shock wave treatment but in none in the sham group (p ¼ 0.001). Of patients treated with shock waves after sham treatment 56.3% achieved erection hard enough for penetration (p <0.005).
Conclusions: Low intensity shock wave treatment is effective even in patients with severe erectile dysfunction who are PDE5i nonresponders. After treatment about half of them were able to achieve erection hard enough for penetration with PDE5i. Longer followup is needed to establish the place of low intensity shock wave treatment in these challenging cases.
Does Low Intensity Extracorporeal Shock Wave Therapy Have a Physiological Effect on Erectile Function? Short-Term Results of a Randomized, Double-Blind, Sham Controlled Study
Yoram Vardi, Boaz Appel, Amichai Kilchevsky and Ilan Gruenwald
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Abstract
Purpose: We investigated the clinical and physiological effect of low intensity extracorporeal shock wave therapy on men with organic erectile dysfunction who are phosphodiesterase type 5 inhibitor responders.
Materials and Methods: After a 1-month phosphodiesterase type 5 inhibitor washout period, 67 men were randomized in a 2:1 ratio to receive 12 sessions of low intensity extracorporeal shock wave therapy or sham therapy. Erectile function and penile hemodynamics were assessed before the first treatment (visit 1) and 1 month after the final treatment (followup 1) using validated sexual function questionnaires and venoocclusive strain gauge plethysmography.
Results: Clinically we found a significantly greater increase in the International Index of Erectile Function-Erectile Function domain score from visit 1 to followup 1 in the treated group than in the sham treated group (mean SEM 6.7 0.9 vs 3.0 1.4, p 0.0322). There were 19 men in the treated group who were initially unable to achieve erections hard enough for penetration (Erection Hardness Score 2 or less) who were able to achieve erections sufficiently firm for penetration (Erection Hardness Score 3 or greater) after low intensity extracorporeal shock wave therapy, compared to none in the sham group. Physiologically penile hemodynamics significantly improved in the treated group but not in the sham group (maximal post-ischemic penile blood flow 8.2 vs 0.1 ml per minute per dl, p 0.0001). None of the men experienced discomfort or reported any adverse effects from the treatment.
Conclusions: This is the first randomized, double-blind, sham controlled study to our knowledge that shows that low intensity extracorporeal shock wave therapy has a positive short-term clinical and physiological effect on the erectile function of men who respond to oral phosphodiesterase type 5 inhibitor therapy. The feasibility and tolerability of this treatment, coupled with its potential rehabilitative characteristics, make it an attractive new therapeutic option for men with erectile dysfunction.
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 anti–viral 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 CD4+ T 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.
Overall General Health
Inflammation and Cancer
Lisa M Coussens, Zena Werb
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Abstract
Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.
Ozone Therapy
Ozone Therapy: An Effective Solution for Acute and Chronic Pain
Bryan Rade, ND
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Abstract
Ozone is a safe, inexpensive, and effective clinical tool with a wide range of therapeutic applications. Pain management is an area where ozone excels, and many studies have been done to demonstrate its analgesic properties. Ozone was first discovered by Christain Schonbein in 1840,1 and the first US ozone generator was developed by Nikola Tesla in 1896.2 In 1902, an article on the use of ozone to treat middle ear deafness was published in The Lancet,3 and ozone therapy was used with success to treat infections during World War I. Since then, numerous clinical trials and basic research studies have been conducted to investigate the effects and mechanisms of action of ozone therapy. From the literature, ozone as a medicinal substance has been shown to be beneficial for a wide range of conditions, including pain, cardiovascular disease, mitochondrial dysfunction, infection, and non-healing skin lesions. Clinical practice has also shown benefit in neurological disorders, autoimmunity, cancer, fatigue, and others. The discussion of ozone in this article will be limited to the area of pain. For a comprehensive overview of ozone therapy, Principles and Applications of Ozone Therapy – A Practical Guide for Physicians, by Frank Shallenberger MD, HMD,4 is an excellent resource.
Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility
Noel L. Smith, Anthony L. Wilson, Jason Gandhi, Sohrab Vatsia, Sardar Ali Khan
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Abstract
The use of ozone (O3) gas as a therapy in alternative medicine has attracted skepticism due to its unstable molecular structure. How- ever, copious volumes of research have provided evidence that O3’s dynamic resonance structures facilitate physiological interactions useful in treating a myriad of pathologies. Specifically, O3 therapy induces moderate oxidative stress when interacting with lipids. This interaction increases endogenous production of antioxidants, local perfusion, and oxygen delivery, as well as enhances immune responses. We have conducted a comprehensive review of O3 therapy, investigating its contraindications, routes and concentrations of administration, mechanisms of action, disinfectant properties in various microorganisms, and its medicinal use in different pathologies. We explore the therapeutic value of O3 in pathologies of the cardiovascular system, gastrointestinal tract, genitourinary system, central nervous system, head and neck, musculoskeletal, subcutaneous tissue, and peripheral vascular disease. Despite compelling evidence, further studies are essential to mark it as a viable and quintessential treatment option in medicine.
Ozone therapy in COVID-19: A narrative review
Francesco Cattel, Susanna Giordano, Cecilia Bertiond, Tommaso Lupia, Silvia Corcione, Matilde Scaldaferri, Lorenzo Angelone, Francesco Giuseppe De Rosa
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Abstract
The main objective of this narrative review is to describe the available evidence on the possible antiviral activity of ozone in patients with COVID-19 and its therapeutic applicability through hospital protocols. Amongst different possible therapies for SARS-CoV-2 pneumonia, ozone therapy seems to have an immunological role because of the modulation of cytokines and interferons, including the induction of gamma interferon. Some data suggest the possible role of ozone therapy in SARS, either as a monotherapy or, more realistically, as an adjunct to standard treatment regimens; therefore, there is increasing interest in the role of ozone therapy in COVID-19 treatment.
The PubMed and Scopus databases and the Italian Scientific Society of Oxygen Ozone Therapy website were used to identify articles focused on ozone therapy. The search was limited to articles published from January 2011 to July 2020. Of 280 articles found on ozone therapy, 13 were selected and narratively reviewed. Ozone exerts antiviral activity through the inhibition of viral replication and direct inactivation of viruses. Ozone is an antiviral drug enhancer and is not an alternative to antiviral drugs. Combined treatment with involving ozone and antivirals demonstrated a reduction in inflammation and lung damage. The routes of ozone administration are direct intravenous, major autohaemotherapy and extravascular blood oxygenation-ozonation.
Systemic ozone therapy seems useful in controlling inflammation, stimulating immunity and as antiviral ac- tivity and providing protection from acute coronary syndromes and ischaemia reperfusion damage, thus sug- gesting a new methodology of immune therapy. Systemic ozone therapy in combination with antivirals in COVID-19-positive patients may be justified, helpful and synergic.
Ozone Therapy: Overview of its Potential Utility in Male Reproduction
Zaher Merhi, Ali Bazzi, Rajean Moseley-LaRue, Amber Ray Moseley, André Hugo Smith, John Zhang and Marco Ruggiero
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Abstract
Ozone (O3), a highly water-soluble inorganic molecule, is a gas made of three atoms of oxygen (O) with a cyclic structure. Ozone can be produced by medical generators from pure oxygen after passing through a high voltage gradient. Ozone therapy (OT) can be given in medical practice via several routes that include transdermal, intramuscular, rectal, nasal, oral, vaginal, intravenous, intra-arterial, intraperitoneal, intra-pleural, topical, dental, intra-discal and by auto- hemotherapy. Because ozone, a highly reactive molecule, is a potent oxidant and anti-inflammatory agent, it has strong bactericidal, antiviral, anti-fungal and anti-protozoal actions as well as therapeutic effects on the immune system. With its multifaceted route of administration, OThas been used to treat several pathologies that involve the immune system such as cancers, sepsis, abscesses and chronic wounds, skin problems (such as eczema and psoriasis), HIV infection, asthma, arthritis, urologic problems, osteomyelitis and many others. The purpose of this review article is to evaluate the role of OT in the male reproductive system. We performed a review of all available basic science, experimental animal studies and clinical peer-reviewed articles published in PubMed and Google Scholar until November 2018. The literature so far retrieved shows that most studies pertaining to the effect of OT on male reproduction were performed in animals. Results to date show that OT, via improving the immune system, significantly protects testicular function in the setting of testicular torsion/ischemia, protects against the effect of gonadotoxic agents and treats bacterial infections in the semen. This article calls for a need for at least pilot studies in humans using OT in its safest route of administration, which is probably the transdermal one. This would be significant especially considering that male factor infertility constitutes up to one third of couple infertility and it is very common that poor semen parameters are irreversible with medical or surgical treatment, such as varicocele repair or vasectomy reversal.
Ozone therapy: a potential therapeutic adjunct for improving female reproductive health
Zaher Merhi, Bhavika Garg, Rajean Moseley-LaRue, Amber Ray Moseley, André Hugo Smith, John Zhang
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Abstract
Ozone is emerging as a new adjunct therapeutic agent for female infertility. We here present a review of the literature, to date, pertaining to the effect of ozone therapy on tubal, ovarian, endometrial, and vaginal factors that could potentially affect female fertility. It also presents data pertaining to the relationship of ozone therapy on pelvic adhesion formation. Most data were performed on animals and very few human studies existed in the literature. Results suggested that ozone therapy could have beneficial effect on tubal occlusion, could protect from endometritis and vaginitis, might protect ovaries from ischemia and oocyte loss and finally might lead to less formation of pelvic adhesions. There is a critical need for human studies pertaining to ozone therapy, especially using safe methods of administration, such as transdermally or intravaginally, on female fertility.
Low ozone concentrations stimulate cytoskeletal organization, mitochondrial activity and nuclear transcription
M. Costanzo, B. Cisterna, A. Vella, T. Cestari, V. Covi, G. Tabaracci, M. Malatesta
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Abstract
Ozone therapy is a modestly invasive procedure based on the regeneration capabilities of low ozone concentrations and used in medicine as an alternative/adjuvant treatment for different diseases. However, the cellular mechanisms accounting for the positive effects of mild ozonization are still largely unexplored. To this aim, in the present study the effects of low ozone concentrations (1 to 20 μg O3/mL O2) on structural and functional cell features have been investigated in vitro by using morphological, morphometrical, cytochemical and immunocytochemical techniques at bright field, fluorescence and transmission electron microscopy. Cells exposed to pure O2 or air served as controls. The results demonstrated that the effects of ozone administration are dependent on gas concentration, and the cytoskeletal organization, mitochondrial activity and nuclear transcription may be differently affected. This suggests that, to ensure effective and permanent metabolic cell activation, ozone treatments should take into account the cytological and cytokinetic features of the different tissues.
Ozone therapy in 65 patients with fibromyalgia: an effective therapy
U. TIRELLI, C. CIRRITO, M. PAVANELLO, C. PIASENTIN, A. LLESHI, R. TAIBI
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Abstract
Fibromyalgia is a chronic disorder with a very complex symptomatology. Although generalized severe pain is considered to be the cardinal symptom of the disease, many other associated symptoms, especially non-restorative sleep, chronic fatigue, anxiety, and depressive symptoms also play a relevant role in the degree of disability characteristic of the disease.
Ozone therapy, which is used to treat a wide range of diseases and seems to be particularly useful in the treatment of many chronic diseases, is thought to act by exerting a mild, transient, and controlled oxidative stress that promotes an upregulation of the antioxidant system and a modulation of the immune system. According to these mechanisms of action, it was hypothesized that ozone therapy could be useful in fibromyalgia management, where the employed therapies are very often ineffective.
Mechanisms of Action Involved in Ozone Therapy: Is healing induced via a mild oxidative stress?
Masaru Sagai and Velio Bocci
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Abstract
The potential mechanisms of action of ozone therapy are reviewed in this paper. The therapeutic efficacy of ozone therapy may be partly due the controlled and moderate oxidative stress produced by the reactions of ozone with several biological components. The line between effectiveness and toxicity of ozone may be dependent on the strength of the oxidative stress. As with exercise, it is well known that moderate exercise is good for health, whereas excessive exercise is not.
Severe oxidative stress activates nuclear transcriptional factor kappa B (NF B), resulting in an inflammatory response and tissue injury via the production of COX2, PGE2, and cytokines. However, moderate oxidative stress activates another nuclear transcriptional factor, nuclear factor-erythroid 2-related factor 2 (Nrf2). Nrf2 then induces the transcription of antioxidant response elements (ARE). Transcription of ARE results in the production of numerous antioxidant enzymes, such as SOD, GPx, glutathione-s-transferase(GSTr), catalase (CAT), heme-oxygenase-1 (HO-1), NADPH-quinone- oxidoreductase (NQO-1), phase II enzymes of drug metabolism and heat shock proteins (HSP). Both free antioxidants and anti-oxidative enzymes not only protect cells from oxidation and inflammation but they may be able to reverse the chronic oxidative stress. Based on these observations, ozone therapy may also activate Nrf2 via moderate oxidative stress, and suppress NF B and inflammatory responses. Furthermore, activation of Nrf2 results in protection against neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases. Mild immune responses are induced via other nuclear transcriptional factors, such as nuclear factor of activated T-cells (NFAT) and activated protein-1 (AP-1). Additionally, the effectiveness of ozone therapy in vascular diseases may also be explained by the activation of another nuclear transcriptional factor, hypoxia inducible factor-1a (HIF-1a), which is also induced via moderate oxidative stress. Recently these concepts have become widely accepted. The versatility of ozone in treating vascular and degenerative diseases as well as skin lesions, hernial disc and primary root carious lesions in children is emphasized. Further researches able to elucidate whether the mechanisms of action of ozone therapy involve nuclear transcription factors, such as Nrf2, NFAT, AP-1, and HIF-1a are warranted.
Modulation of Oxidative Stress by Ozone Therapy in the Prevention and Treatment of Chemotherapy-Induced Toxicity: Review and Prospects
Bernardino Clavo, Francisco Rodríguez-Esparragón, Delvys Rodríguez-Abreu, Gregorio Martínez-Sánchez, Pedro Llontop, David Aguiar-Bujanda, Leandro Fernández-Pérez and Norberto Santana-Rodríguez
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Abstract
(1) Background: Cancer is one of the leading causes of mortality worldwide. Radiotherapy and chemotherapy attempt to kill tumor cells by different mechanisms mediated by an intracellular increase of free radicals. However, free radicals can also increase in healthy cells and lead to oxidative stress, resulting in further damage to healthy tissues. Approaches to prevent or treat many of these side effects are limited. Ozone therapy can induce a controlled oxidative stress able to stimulate an adaptive antioxidant response in healthy tissue. This review describes the studies using ozone therapy to prevent and/or treat chemotherapy-induced toxicity, and how its effect is linked to a modification of free radicals and antioxidants. (2) Methods: This review encompasses a total of 13 peer-reviewed original articles (most of them with assessment of oxidative stress parameters) and some related works. It is mainly focused on four drugs: Cisplatin, Methotrexate, Doxorubicin, and Bleomycin. (3) Results: In experimental models and the few existing clinical studies, modulation of free radicals and antioxidants by ozone therapy was associated with decreased chemotherapy-induced toxicity. (4) Conclusions: The potential role of ozone therapy in the management of chemotherapy-induced toxicity merits further research. Randomized controlled trials are ongoing.
COVID-19
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
Pierre Kory, MD, G. Umberto Meduri, MD, Jose Iglesias, DO, Joseph Varon, MD, Keith Berkowitz, MD, Howard Kornfeld, MD, Eivind Vinjevoll, MD, Scott Mitchell, MBChB , Fred Wagshul, MD, Paul E. Marik, MD
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Abstract
In March 2020, the Front Line COVID-19 Critical Care Alliance (FLCCC) was created and led by Professor Paul E. Marik to continuously review the rapidly emerging basic science, translational, and clinical data to develop a treatment protocol for COVID-19. The FLCCC then recently discovered that ivermectin, an anti-parasitic medicine, has highly potent anti-viral and anti-inflammatory properties against COVID-19. They then identified repeated, consistent, large magnitude improvements in clinical outcomes in multiple, large, randomized and observational controlled trials in both prophylaxis and treatment of COVID-19. Further, data showing impacts on population wide health outcomes have resulted from multiple, large “natural experiments” that occurred when various Efficacy of Ivermectin in COVID-19 This is a provisional file, not the final typeset article 2 city mayors and regional health ministries within South American countries initiated “ivermectin distribution” campaigns to their citizen populations in the hopes the drug would prove effective. The tight, reproducible, temporally associated decreases in case counts and case fatality rates in each of those regions compared to nearby regions without such campaigns, suggest that ivermectin may prove to be a global solution to the pandemic. This was further evidenced by the recent incorporation of ivermectin as a prophylaxis and treatment agent for COVID-19 in the national treatment guidelines of Belize, Macedonia, and the state of Uttar Pradesh in Northern India, populated by 210 million people. To our knowledge, the current review is the earliest to compile sufficient clinical data to demonstrate the strong signal of therapeutic efficacy as it is based on numerous clinical trials in multiple disease phases. One limitation is that half the controlled trials have been published in peerreviewed publications, with the remainder taken from manuscripts uploaded to medicine pre-print servers. Although it is now standard practice for trials data from pre-print servers to immediately influence therapeutic practices during the pandemic, given the controversial therapeutics adopted as a result of this practice, the FLCCC argues that it is imperative that our major national and international health care agencies devote the necessary resources to more quickly validate these studies and confirm the major, positive epidemiological impacts that have been recorded when ivermectin is widely distributed among populations with a high incidence of COVID-19 infections.
Naltrexone a potential therapeutic candidate for COVID-19
Abhinav Choubeya, Budheswar Dehuryb, Sunil Kumarc, Bikash Medhid and Prosenjit Mondala
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Abstract
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of Coronavirus Disease (COVID-19) that has resulted in a global pandemic. At the time of writing, approximately 16.06 million cases have been reported worldwide. Like other coronaviruses, SARS-CoV-2 relies on the surface Spike glycoprotein to access the host cells, mainly through the interaction of its Receptor Binding Domain (RBD) with the host receptor Angiotensin-Converting Enzyme2 (ACE2). SARS-CoV-2 infection induces a profound downstream pro-inflammatory cytokine storm. This release of the pro-inflammatory cytokines is underpinning lung tissue damage, respiratory failure, and eventually multiple organ failure in COVID-19 patients. The phosphorylation status of ERK1/2 is positively correlated with virus load and ERK1/2 inhibition suppressed viral replication and viral infectivity. Therefore, molecular entities able to interfere with binding of the SARS-CoV-2 Spike protein to ACE2, or damping hyperinflammatory cytokines storm, blocking ERK1/2 phosphorylation have a great potential to inhibit viral entry along with viral infectivity. Herein, we report that the FDA-approved non-peptide opioid antagonist drug, naltrexone suppresses high fat/LPS induced pro-inflammatory cytokine release both from macrophage cells and Adipose Tissue Macrophage. Moreover, Low Dose Naltrexone (LDN) also showed its activity as an ERK1/2 inhibitor. Notably, virtual docking and simulation data also suggest LDN may disrupt the interaction of ACE2 with RBD. LDN may be considered as a target as the treatment and (or) adjuvant therapy for coronavirus infection. Clinical toxicity measurements may not be required for LDN since naltrexone was previously tested and is an approved drug by the FDA.
Body Perfect
High Intensity Focused Electromagnetic Therapy Evaluated by Magnetic Resonance Imaging: Safety and Efficacy Study of a Dual Tissue Effect Based Non-Invasive Abdominal Body Shaping
Brian M. Kinney, MD, FACS, MSMEand Paula Lozanova, MD
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Introduction
The popularity of non-invasive body shaping procedures has been growing rapidly—the number of procedures performed in the US more than doubled between 2012 and 2016. Cryolipolysis, radiofrequency, low level laser therapy and focused ultrasound are most widely used for treating patients’ fat bulges, and their efficacy has been demonstrated in multiple previous studies. Similar to every aesthetic procedure, these technologies have also certain limitations. All current non-invasive fat removal treatments are based on thermal effects and as such, they may bring about various cold or heat related side effects. More importantly, all these modalities are designed to address only fat tissue. Subcutaneous fat is an important factor affecting patient’s body contours as it comprises approximately 25% of human body composition. However, muscle tissue comprises even a larger portion of the human body composition (42% male/36% female) and depending on individual characteristics, the condition of patient’s muscle can play either an equal or even more important role in defining the overall aesthetic appearance. Still, physical workout is currently the only generally available method for natural strengthening of one’s muscles. The use of magnetic stimulation has a proven track record when treating various medical indications, ranging from neurology, psychiatry, physiotherapy, to treating urinary incontinence in women. Furthermore, due to the non-thermal and non-ionizing nature of the technology, its application is considered relatively safe. Even though the technology is highly effective, it is not as widely used as electrical stimulation. This study brings an initial evaluation of a novel High Intensity Focused Electro-Magnetic (HIFEM) technology applied to the abdominal area, in order to assess the physiological response in treated patients. The primary goal is to quantify any effects the treatments may have on abdominal tissues, as well as to establish hypotheses for future research of this technology. The outcomes of the study are expected to suggest if HIFEM can be potentially used as a new technology for non-invasive body shaping treatments.
