Increased longevity and population aging will increase the number of men with late onset hypogonadism. It is a common condition, but often underdiagnosed and undertreated. The indication of testosterone-replacement therapy (TRT) treatment requires the presence of low testosterone level, and symptoms and signs of hypogonadism. Although controversy remains regarding indications for testosterone supplementation in aging men due to lack of large-scale, long-term studies assessing the benefits and risks of testosterone-replacement therapy in men, reports indicate that TRT may produce a wide range of benefits for men with hypogonadism that include improvement in libido and sexual function, bone density, muscle mass, body composition, mood, erythropoiesis, cognition, quality of life and cardiovascular disease. Perhaps the most controversial area is the issue of risk, especially possible stimulation of prostate cancer by testosterone, even though no evidence to support this risk exists. Other possible risks include worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, worsening untreated sleep apnea or severe heart failure. Despite this controversy, testosterone supplementation in the United States has increased substantially over the past several years. The physician should discuss with the patient the potential benefits and risks of TRT. The purpose of this review is to discuss what is known and not known regarding the benefits and risks of TRT.

/pdf/the-benefits-and-risks-of-testosterone-replacement-therapy-a-4ayhit97q0.pdf

The benefits and risks of testosterone replacement therapy: a review

Alzheimer’s disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3–7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer’s disease. Blocking FSH action in these mice abrogates the Alzheimer’s disease-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer’s disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer’s disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent. Follicle-stimulating hormone acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer’s disease. 

FSH blockade improves cognition in mice with Alzheimer’s disease

Low free testosterone is an independent risk factor for Alzheimer's disease.

Leuprolide acetate is a synthetic nonapeptide that is a potent gonadotropin-releasing hormone receptor (GnRHR) agonist used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. As its basic mechanism of action, leuprolide acetate suppresses gonadotrope secretion of luteinizing hormone and follicle-stimulating hormone that subsequently suppresses gonadal sex steroid production. In addition, leuprolide acetate is presently being tested for the treatment of Alzheimer's disease, polycystic ovary syndrome, functional bowel disease, short stature, premenstrual syndrome and even as an alternative for contraception. Mounting evidence suggests that GnRH agonist suppression of serum gonadotropins may also be important in many of the clinical applications described above. Moreover, the presence of GnRHR in a multitude of non-reproductive tissues including the recent discovery of GnRHR expression in the hippocampi and cortex of the human brain indicates that GnRH analogs such as leuprolide acetate may also act directly via tissue GnRHRs to modulate (brain) function. Thus, the molecular mechanisms underlying the therapeutic effect of GnRH analogs in the treatment of these diseases may be more complex than originally thought. These observations also suggest that the potential uses of GnRH analogs in the modulation of GnRH signaling and treatment of disease has yet to be fully realized.

Leuprolide acetate: a drug of diverse clinical applications.

A mechanistic understanding of aging has yet to be described; this paper puts forth a new theory that has the potential to explain aging in all sexually reproductive life forms The theory also puts forth a new definition of aging – any change in an organism over time This definition includes not only the changes associated with the loss of function (ie senescence, the commonly accepted definition of aging), but also the changes associated with the gain of function (growth and development) Using this definition, the rate of aging would be synonymous with the rate of change The rate of change/aging is most rapid during the fetal period when organisms develop from a single cell at conception to a multicellular organism at birth Therefore, ‘fetal aging’ would be determined by factors regulating the rate of mitogenesis, differentiation, and cell death We suggest that these factors also are responsible for regulating aging throughout life Thus, whatever controls mitogenesis, differentiation and cell death must also control aging Since life-extending modalities consistently affect reproduction, and reproductive hormones are known to regulate mitogenesis and differentiation, we propose that aging is primarily regulated by the hormones that control reproduction (hence, the Reproductive-Cell Cycle Theory of Aging) In mammals, reproduction is controlled by the hypothalamic-pituitary-gonadal (HPG) axis hormones Longevity inducing interventions, including caloric restriction, decrease fertility by suppressing HPG axis hormones and HPG hormones are known to affect signaling through the well-documented longevity regulating GH/IGF-1/PI3K/Akt/Forkhead pathway This is exemplified by genetic alterations in Caenorhabditis elegans where homologues of the HPG axis pathways, as well as the daf-2 and daf-9 pathways, all converge on daf-16, the homologue of human Forkhead that functions in the regulation of cell cycle events In summary, we propose that the hormones that regulate reproduction act in an antagonistic pleiotrophic manner to control aging via cell cycle signaling; promoting growth and development early in life in order to achieve reproduction, but later in life, in a futile attempt to maintain reproduction, become dysregulated and drive senescence

Living and dying for sex: A theory of aging based on the modulation of cell cycle signaling by reproductive hormones

Alzheimer disease affects almost 4 million Americans and costs $65 billion annually. The disease is more common in women than in men, and studies suggest that oestrogen may have a protective effect. Oestrogen replacement lowers circulating concentrations of gonadotropins. When gonadotropins are added to rat granulosa cells in culture, the number of low density lipoprotein (LDL) receptors and the rate of uptake of low density lipoprotein increases. Many proteins found in Alzheimer disease plaques are ligands for low density lipoprotein receptors (LDLR) on central nervous system (CNS) neurones. This study evaluated whether gonadotropins may be associated with Alzheimer disease. Circulating concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) levels in 40 male residents of long-term care facilities with the primary diagnosis of dementia were compared to 29 age-matched controls. Serum concentrations of FSH and LH were significantly higher in dementia patients. We speculate they may play an aetiologic role in the deposition of abnormal proteins, particularly those associated with low density lipoprotein receptors, in CNS neurones.

An association of elevated serum gonadotropin concentrations and Alzheimer disease

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An association of elevated serum gonadotropin concentrations and Alzheimer disease