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Estrogen is primarily and directly responsible for inducing the ductal component of breast development, as well as for causing fat deposition and connective tissue growth. Conversely, androgens are responsible for pubic and body hair growth, as well as acne and axillary odor. The metabolic effects of estrogen in postmenopausal women have been linked to the genetic polymorphism of the ER. The actions of estrogen are mediated by the estrogen receptor (ER), a dimeric nuclear protein that binds to DNA and controls gene expression. Some estrogen metabolites, such as the catechol estrogens 2-hydroxyestradiol, 2-hydroxyestrone, 4-hydroxyestradiol, and 4-hydroxyestrone, as well as 16α-hydroxyestrone, are also estrogens with varying degrees of activity. All of the different forms of estrogen are synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.citation needed
Once bound to the AR, testosterone is irreversibly converted to dihydrotestosterone (DHT) through the enzymatic action of 5-α reductase (Wilborn et al., 2010). In contrast, there are no differences observed between men and women in relation to intramuscular testosterone concentrations and steroidogenic enzymes (Vingren et al., 2008). The mitigation of age and disease-related muscle wasting and dysfunction remains a major research effort.
However, the mechanisms of lactate action on testosterone production by Leydig cells are not clear yet. High affinity binding of LHRH in the anterior pituitary activates LH secretion by a calcium-dependent mechanism, resulting in LH secretion (Dufau and Catt, 1979; Fry and Kraemer, 1997). Secretion of LH is principally regulated by LH releasing hormone (LHRH) via portal circulation from the hypothalamus. This activation is dependent on the frequency and amplitude of LH secretion, with pulses occurring in the human at the rate of ~8–14 pulses.day−1 in men. SC, satellite cell; AR, androgen receptor; IRS, insulin receptor substrate; ARE, androgen response element.
While GH replacement therapy has been proposed to treat depression as a result of GH deficiency, the long-term effects of such therapy are unknown. In adults, somatomedin alteration contributes to increased osteoclast activity, resulting in weaker bones that are more prone to pathologic fracture and osteoporosis. Other drugs like octreotide (somatostatin agonist) and bromocriptine (dopamine agonist) can be used to block GH secretion because both somatostatin and dopamine negatively inhibit GHRH-mediated GH release from the anterior pituitary. Accompanying problems can include sweating, pressure on nerves (e.g., carpal tunnel syndrome), muscle weakness, excess sex hormone-binding globulin (SHBG), insulin resistance or even a rare form of type 2 diabetes, and reduced sexual function.citation needed
That makes TRT one of the few hormone therapies with a directly demonstrated hematologic benefit in a defined subgroup (Pencina et al., JAMA Network Open, 2023). In practice, however, the most reliable clinical data are not simply "more muscle." They are broader and more measured. That does not mean testosterone is a universal answer for erectile dysfunction. In men with so-called functional hypogonadism, improving weight, sleep, metabolic health, and medication burden may be part of the treatment plan whether or not TRT is eventually used (Corona et al., Andrology, 2020). This is especially important because obesity, sleep apnea, alcohol use, medications, depression, and chronic illness can imitate or contribute to low-testosterone symptoms. The diagnosis requires a compatible symptom picture plus repeated biochemical confirmation, usually with morning testosterone testing under appropriate conditions (Mulhall et al., Journal of Urology, 2018; Corona et al., Andrology, 2020). The American Urological Association, the Endocrine Society, and the European Academy of Andrology all emphasize that men should not be labeled testosterone deficient from symptoms alone.
Lall et al. conducted a 9-week study with female GH-deficient and GH-intact mice to assess ipamorelin’s effects on adiposity and weight gain (61). Beck et al. evaluated ipamorelin’s effects on POI in bowel resection patients via a multicenter, double-blinded, placebo-controlled trial (59). Greenwood-Van Meerveld et al. assessed ipamorelin’s effects in rodent models with induced postoperative ileus (POI) (58). The group that started ibutamoren during the second year saw the same changes while the group that switched to placebo in the second year saw a reversal of the changes induced by ibutamoren treatment in the first year. The original ibutamoren treatment group was separated into either a placebo or continued ibutamoren treatment group. This change in weight was attributed to mild fluid retention that was noted with the ibutamoren treatment arm that resolved with treatment cessation.
Prolonged GH excess thickens the bones of the jaw, fingers and toes, resulting in heaviness of the jaw and increased size of digits, referred to as acromegaly. Eventually, the adenoma may become large enough to cause headaches, impair vision by pressure on the optic nerves, or cause deficiency of other pituitary hormones by displacement.citation needed Like most other peptide hormones, GH acts by interacting with a specific receptor on the surface of cells.citation needed