Twenty-three postmenopausal women with a median of 2 years past menopause (range, 1 to 12 years) and a median age of 52 years (range, 39 to 62 years) were recruited to participate in a longitudinal study designed to investigate the factors that influence the increase in bone density with subcutaneous estradiol and testosterone implants.
SAN DIEGO, CA — Two new studies muddy waters on the potential cardiovascular risks previously linked to testosterone-replacement therapy in men, with both studies suggesting the therapy might not be causing the cardiovascular harm suggested in previous analyses. Both are scheduled for the presentation later this week at the American College of Cardiology (ACC) 2015 Scientific Sessions.
Hormone replacement therapy by pellet implantation has been used with great success in the United States, Europe and Australia since 1938 and found to be superior to other methods of hormone delivery (Greenblatt 49, Mishnell 41, Cantrill 84, Stanczyk 88). It is not experimental.
LAS VEGAS --- Contrary to recent findings, a new retrospective study of data from 40 specialized clinics around the United States has found that testosterone therapy in men is not associated with an increased risk for myocardial infarction (MI) or stroke and may even be cardioprotective.
In spite of the negative press reports following the 2002 Women’s Health Initiative (WHI) publication, women can be reassured that in the correct circumstances, hormone replacement therapy (HRT) is beneficial and safe, particularly if treatment is started below the age of 60.
Testosterone (T) is the most abundant biologically active hormone in women. It has a direct effect at the androgen receptor in every major organ system. Local aromatization of T is a major source of bioavailable estradiol. Adequate amounts of bioavailable T are essential for optimal health, immune function, and disease prevention. More than 80% of bioavailable T in women is from the local intracrine production of T from the adrenal precursor steroids androstenedione and dehydroepiandrosterone (sulfate). Serum T levels reflect <20% of the total androgen pool in women, which limits its usefulness in diagnosing or treating androgen deficiency. The gradual decline of androgens associated with aging is responsible for many of the adverse signs and symptoms of aging, including mental and physical deterioration. Decades of evidence support the safety and efficacy of T therapy in women. We have found that subcutaneous T implant therapy relieves symptoms of hormone deficiency in women with and without breast cancer, improves their quality of life, and maintains overall health and well-being. T does not increase and may lower the risk of breast cancer. The combination of T with an aromatase inhibitor prevents the conversion of androgens to estrogens, limiting their stimulatory effect in estrogen-sensitive diseases, including breast cancer. Adequate doses of T therapy should provide adequate levels of bioavailable T in the target organs—determined by clinical response (benefits) versus adverse side effects (risks). Pharmacological dosing of T implants in women is safe and necessary for physiological effect.
Androgens are critical for immune function and overall health in both sexes. Androgens decline with age, adversely affecting mental and physical health. Replacing (declining) androgens with the consistent and continuous release of testosterone (T) from the subcutaneous implant significantly improves women's health, sexuality, and quality of life (QoL).1–6
Many controversies surround the use of T therapy in women. Recent pharmaceutical sponsored studies have focused on topical T formulations and recent narratives have argued against the use of T pellet implants.7 However, T implant therapy has been (safely) used in female patients since 1937 in doses of 50–400 mg without excessive androgenic effects.3–6,8,9 In addition, significantly higher doses (500–1800 mg) have been safely used to treat breast cancer patients.3,10
Understanding the physiology of androgens in women is the foundation for understanding the extent of T's clinical effects; the rationale behind ‘T dosing’ and ‘serum levels on therapy’; the significance of local aromatase production and its role in estrogen-sensitive diseases; and the therapeutic effects of T alone (no estrogen). In a series of studies, we provide decades of experience and evidence supporting the safety and efficacy of T implant therapy in women, including breast cancer patients.1,11–25 The therapeutic potential of T combined with an aromatase inhibitor (AI) is discussed and supported by clinical evidence.
T is the most abundant biologically active hormone in women. It is produced in the ovaries, adrenal gland, and locally at the cellular level in target organs from androgen precursors. The major portion of serum T is bound to albumin and sex hormone-binding globulin. T has a direct effect at the androgen receptor (AR). It is metabolized through the enzyme 5α-reductase to the more potent androgen, dihydrotestosterone. T is also aromatized to estradiol (E2) in the ovaries and locally in all peripheral tissues, thereby having a secondary effect through the estrogen receptor (ER). Many physicians are not aware that serum T levels are markedly (10- to more than 15-fold) higher than E2 levels throughout the female lifespan, barring pregnancy (Fig. 1).26
The major source of androgenic activity in both pre- and postmenopausal women is the local intracrine production of T from the adrenal precursor steroids dehydroepiandrosterone-sulfate (DHEAS), dehydroepiandrosterone (DHEA), and androstenedione (Fig. 2).
Androstenedione, the direct precursor to T, is found in more than fivefold higher concentrations than serum T in women.27,28 Circulating DHEA and DHEAS are present in 20- to 1000-fold higher concentrations than T. Interestingly, men and women produce similar amounts of adrenal androgens. The preandrogens contribute >75–80% of biologically active T to the AR in premenopausal women and near 100% in postmenopausal women—versus 50% in men.29–31
Serum levels of T are not a valid marker of tissue exposure in women, reflecting <20% of the total androgen activity. Accordingly, serum T levels would not be expected to correlate with androgen deficiency symptoms or clinical conditions caused by androgen deficiency.30 This concept is extremely important to comprehend. Serum T levels should not be relied on to diagnose T deficiency or manage T dosing in women.5–9
It is well recognized that T has a profound effect on lean muscle mass, bone density, and confidence as well as sex drive and performance in both sexes. It is beyond the scope of this article to provide a detailed review of the physiological effects of androgens. Excellent reviews have been previously published on the clinical significance of T in women.32
It is important to recognize that there are active ARs located in every major organ system throughout the body.33–38 Adequate amounts of (local) bioavailable T at the AR are critical for overall health, immune function, and preventing inflammation, as well as cardiovascular, neurological, gastrointestinal, pulmonary, endocrine, breast, and genitourinary health (Supplementary Table S1).32–42 Thus, clinical indications for T therapy include many signs and symptoms caused by T deficiency (Table 1).1,43
There are hundreds of studies correlating the development of heart disease with low testosterone levels. One, conducted by researchers from Columbia University’s College of Physicians and Surgeons, found that people with low concentrations of testosterone in the blood were more likely to have atherosclerosis documented by angiography.
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.
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