Clinical Research

1: Menopause hormone therapy: latest developments and clinical practice
Published online 2019 Jan 2
Author: Tomas Fait, MD, PhD

The extensive climacteric symptomatology falls into somatic (vegetative) symptoms (vasomotor disorders, psychic disorders), organic symptoms (skin changes, urogenital changes, weight changes), and metabolic symptoms (lipid spectrum changes, atherosclerosis, osteoporosis).

Pharmacotherapy can be divided into hormonal and nonhormonal therapy. Menopause hormone therapy (MHT), or hormone replacement therapy (HRT), consists of a group of preparations with sex hormones administered in cases of low level of estrogen. Estrogen-only therapy is labeled as estrogen replacement therapy (ET, ERT). For combination of estrogens and progestogens, the term is estrogen–progestogen therapy (EPT). It is advisable to distinguish between them because of significant differences in their benefit–risk ratio.

Therapeutic administration of estrogens results in removing almost all climacteric symptoms. Their administration is an effective strategy for the long-term prevention of estrogen deficiency as well as some other diseases where a direct connection is not obvious.1

The hormone therapy of choice for women in early menopausal transition is gestagen substitution, levonorgestrel intrauterine system (LNG-IUS), or low-dose monophasic contraception. In late menopausal transition, there should be an initial switch to gestagen-dominated combined sequential EPT. Start with low doses and, if not effective, increase the dose. In an effort to maintain the cycle, the patient’s wishes, the duration of administration of the replacement therapy, and the patient’s age should be considered. Sometimes, the age of 52 is said to be a threshold for administering sequential EPT. Later, in postmenopausal cases, a switch to combined continuous EPT is recommended. This is also a therapy of choice in postmenopausal women who have not used MHT so far


2: Occurrence of Acute Cardiovascular Events in Transgender Individuals Receiving Hormone Therapy
Authors: Nienke M. Nota, Chantal M. Wiepjes, Christel J.M. de Blok, Louis J.G. Gooren, Baudewijntje P.C. Kreukels, and Martin den Heijer
Originally published on 18 Feb 2019

In hypogonadal/postmenopausal individuals, hormone therapy has been associated with an increased risk for cardiovascular events (CVEs). A steeply growing population that often receives exogenous hormones is transgender individuals. Although transgender individuals hypothetically have an increased risk of CVEs, there is little known about the occurrence of CVEs in this population.1 Therefore, we determined the incidences of acute/spontaneous strokes (ischemic/hemorrhagic, transient ischemic attack, or subarachnoid hemorrhage), myocardial infarctions (MIs), and venous thromboembolic events (VTEs) in transwomen and transmen receiving transgender hormone therapy (THT). Subsequently, we compared these incidences with those reported in women and men from the general population.

This study was approved by our local ethical committee, with a waiver for informed consent.

We reviewed the medical records of all 6793 individuals who visited our gender clinic between 1972 and 2015. However, we only included individuals who received THT prescribed by our center or an affiliate, whose date of start of THT was known, and who had at least 1 follow-up visit. We excluded participants who had discontinued THT for an extended period or who had used female and male sex hormones alternately. Of the remaining 3927 participants, the records were screened by physicians and medical students for letters/notes from physicians indicating clearly that an acute CVE had occurred. We excluded subjects who had experienced a CVE before starting THT (n=52). The final population consisted of 2517 transwomen (median age 30 years) and 1358 transmen (median age 23 years). From those who experienced multiple CVEs during THT (n=3), only the first event was taken into account. THT consisted of estrogens (±antiandrogens) in transwomen and testosterone in transmen. Adolescents usually received puberty suppressors, with the addition of THT from the age of 16 years. Statistical analyses were performed using OpenEpi version 3.01

3: Hormone Replacement Therapy in Cancer Survivors 
Author: Tamas Deli, Monika Orosz, and Attila Jakab
Published by Pathology & Oncology Research on 08 January 2019

Hormone replacement therapy (HRT; also known as menopausal hormone therapy, MHT) means substituting estrogen (or compounds exerting estrogenic effects) and progesterone (or compounds exerting progestagenic effects) after the cessation of cyclic ovarian hormone production. In the context of young oncologic patients with premature ovarian insufficiency (POI) the term HRT seems to be more appropriate then MHT. Oncologic risk of MHT requires consideration from two aspects: the potential of MHT to induce tumours in patients who have no oncologic history; and the potential to cause cancer recurrence and progression in cancer survivors. The former question is frequently asked by patients and needs to be explained to those who receive MHT. To date, a lot of data from large randomised controlled trials and relevant guidelines are available in context of the most common malignancies, such as breast or colorectal cancer. Most of these are reviewed in the clinical guidelines of menopausal hormone therapy, such as that of the International Menopause Society, IMS, the National Institute for Health and Care Excellence, NICE or the American College of Obstetricians and Gynecologists, ACOG 

The situation is far more complex when it comes to cancer survivors. They can experience premature ovarian insufficiency as a consequence of cancer treatment (surgery, chemotherapy or radiotherapy), or as a result of an independent disease (see all the possible causes of POI, e.g. genetic or autoimmune diseases, or the consequence of other benign ovarian pathology), or simply may survive long enough to reach the age of physiological menopause around the age of 50. HRT may be necessary because of menopausal symptoms, but young asymptomatic patients should also receive hormone replacement if not contraindicated. It is well known that refusal of MHT decreases not only the quality of life, but also the life expectancy of young menopausal patients by several years. In a Dutch study, this was found to be 2 years lost over a 17-year follow-up period, mainly due to cardiovascular and osteoporotic morbidity. Thus, not only inadequate initiation of MHT, but also its unsubstantiated denial, ’just to be on the safe side’, harms the patient.

4: Fundamental Concepts Regarding Testosterone Deficiency and   Treatment: International Expert Consensus Resolutions
Published by Mayo Clinic Proceedings, Diagnosis and Treatment Guidelines, 2016.
Authors: Abraham Morgentaler, MD (Chairman); Michael Zitzmann, MD (Cochairman)

An international panel of experts met in October 2015 and made consensus statements on the benefits and safety of testosterone therapy. (1) Testosterone (T) Deficiency (TD) is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes.

5: No VTE Risk Seen With Testosterone Therapy
Published on MedPage and Mayo Clinic Proceedings, July 2015.
Authors: Jacques Baillargeon, PhD, Randall J. Urban, MD, Abraham Morgentaler, MD, Charles J. Glueck, MD, Gwen Baillargeon, MS, Gulshan Sharma, MD, MPH, Yong-Fang Kuo, PhD

The findings of this study fly directly against the recent FDA mandate changes to testosterone drug labels regarding a potential increased risk of VTE, with good retrospective data across a very large sample size. The study acknowledges its numerous limitations, and the only definitive way to truly determine the relationship between VTE and testosterone use would be to perform a prospective, controlled study. No one has directly examined the anti-inflammatory properties of testosterone, which might lower the risk of thrombosis

6: Study Finds No Convincing Evidence of Increased Cardiovascular Risk with Testosterone Therapy
Published on Wiley Online Library by AlphaMed Press, 2014.
Authors: Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS.

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.

7: Testosterone’s Impact on Cardiovascular Health
Author: Gary Huber, D.O.

The research of the past 20 years is pointing towards the conclusion that androgens are a key piece of the cardiovascular repair and recovery cycle. Low twstostywerone levles open the door for inflammation and vascular compromise. When this defixciency is corrected there is a pattern of decreased inflammation, atherosclerosis and resultant Coronary Artery Disease. Optimal testosterone levels play an integral role in the process of good cardiovascular health. “If we are not measuring testosterone levels and treating low T, we are not offering our patients every available avenue for cardiovascular health.”

8: Testosterone Therapy Does Not Hike Risk of Aggressive Prostate Cancer

Published on Renal and Urology News, September 2013.
Author: Jody Charnow
Summary: Despite the high prevalence of hypogonadism in older men and well-established health benefits of TRT, use of TRT is markedly low. The concern of increasing prostate cancer risk or cancer severity by administering TRT has been widely disproved. This population-based study adds to the growing body of evidence that TRT does not confer worse prostate cancer outcomes.


9: Estrogen Can Reduce Risk of Liver and Heart Disease in Women

Published on BioOptics World, 2013.
Author: Lee Mather
Summary: The research shows the beneficial effect that estrogen (the female hormone) has on liver metabolism by revealing a new type of estrogen receptor, which controls estrogen-responsive genes that regulate cholesterol and fatty acid production.

Professor Brian Harvey, RCSI Principal Investigator, says that estrogen tends to protect women against high cholesterol and heart disease during the child-bearing years. “Our research has allowed us to gain important insights into how estrogen may suppress some genes and prevent excessive accumulation of cholesterol and triglycerides in the blood that can progress to heart disease and liver cancers. This leaves the door open for the development of drugs that can decrease the incidence of liver and heart disease in women.”

This female-specific study showed that estrogen binds to a new type of estrogen receptor at the cell membrane and not in the nucleus of the cell. This activates a network of enzymes that slows down a regulator of genes (SREB), which usually drive the build-up of cholesterol in the liver. Estrogen was also found to suppress lipid metabolism in general, including the accumulation of fatty acids and harmful triglycerides.

10: Estrogen Is a New Weapon Against Urinary Tract Infection in Post Menopausal Woman

Published on Science Daily, 2013.
Author: Karolinska Institutet
Summary: Estrogen replacement therapy stimulates the production of the body’s own antibiotic and strengthens the cells in the urinary tract, according to a new study from Karolinska Institutet in Sweden. The results, which are published in the journal Science Translational Medicine, show that estrogen supplements may help menopausal women to ward off recurrent urinary tract infections.

In the current study, the researchers treated post-menopausal women with estrogen for 14 days, and then analyzed cells excreted in the urine. They found that estrogen acts on the epithelium in a way that the gaps between the cells lining the bladder lumen are healed, i.e. estrogen is gluing them together. This makes it more difficult for bacteria to break this protecting shield and reach the underlying cells.

11: The Bio-identical Hormone Debate: are Bio-identical Hormones (estradiol, estriol, and Progesterone) safer or More efficacious than Commonly used synthetic Versions in Hormone replacement therapy?

Published in The Journal of the North American Menopause Society, July 2003, Volume 10, Issue 4, pp 277-285.
Authors: Decker, David A. MD; Pettinga, Jane E. MD; VanderVelde, Nancy MD; Huang, Raywin R. PhD; Kestin, Larry MD; Burdakin, John H. MD
Conclusion: In these selected patients, ERT relieved estrogen deficiency symptoms and did not increase the rate or time to an ipsilateral recurrence/new primary, contralateral new primary, local-regional recurrence, or systemic metastases.

Abstract: Results: Patients report greater satisfaction with HRTs that contain progesterone compared with those that contain a synthetic progestin. Bio-identical 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 bio-identical hormones are associated with lower risks, including the risk of breast cancer and cardiovascular disease, and are more efficacious than their synthetic and animalderived counterparts. Until evidence is found to the contrary, bio-identical hormones remain the preferred method of HRT.
Estrogen Replacement Therapy in Breast Cancer Survivors: a Matched-Controlled Series

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