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IM injections of long-acting testosterone esters (cypionate or enanthate) are cost-effective and result in physiological and predictable on-treatment serum testosterone levels, particularly when smaller doses are administered weekly (18). Major testosterone esters include testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone undecanoate. To date, limited data suggest that SC administration of testosterone enanthate and cypionate results in stable and predictable on-treatment concentrations, has good acceptability among patients, and can be self-administered more easily than IM injections.
Skin irritation and itching made testosterone patches less than desirable, but effective. The first testosterone patch, Androderm, was approved by the FDA for use in the United States in 1998. The amount of gel applied is significantly less than other brand names while still delivering the allocated strength of testosterone.
Among transgender men, patients who had previously used IM testosterone therapy with long-acting esters did not want to revert back to IM injections after they were started on SC testosterone therapy (24, 28, 51). Indeed, long-term compliance among men who are prescribed testosterone therapy with IM injections is low; approximately 69% of men on long-acting esters discontinue treatment within 3 months of therapy, and 95% discontinue it within 12 months (56). In this review, we summarize the published data on the pharmacokinetics and safety of SC administration of both long-acting (enanthate and cypionate) and ultralong-acting (undecanoate) testosterone esters in hypogonadal and transgender men. In the mid-1950s, the longer-acting testosterone esters testosterone enanthate and testosterone cypionate were introduced. Studies that have assessed patient preference regarding the route of administration of testosterone esters (enanthate and cypionate) suggest that patients generally prefer the SC route compared to the IM route (24, 28, 51). Because of the longer absorption time, it was introduced as an option to minimize peaks and troughs in serum testosterone levels after dosing, as well as to reduce the frequency of injections in men with organic androgen deficiency who require long-term testosterone therapy.
An androgen or anabolic steroid ester is an ester of an androgen/anabolic steroid (AAS) such as the natural testosterone or dihydrotestosterone (DHT) or the synthetic nandrolone (19-nortestosterone). Once injected, the ester is gradually cleaved off, allowing the active hormone to be absorbed into the bloodstream. Such blends are tailored to meet individual needs, ensuring optimal hormone levels over time.
They even upped the short ester dose by 2-3 times and were still not able to replicate the suppression and metabolic effects of the long esters. Utilizing FDA approved, shorter acting forms of T therapy to maintain homeostasis that more closely reflects normal physiology offers great promise for the treatment of men with hypogonadism—an advantage over long-acting formulations. Long-acting IM testosterone undecanoate requires an in-office visit due to its warning for serious pulmonary oil microembolism (POME) reactions and anaphylaxis (18). Prolonged exogenous T administration using injections, pellets, and topical gels result in varying degrees of these common side effects. Some, but not all, side effects from testosterone therapy (TTh) include reduced sperm production or azoospermia as described above, polycythemia, and inhibition of the HPG axis. Nasal administration of T (4.5% testosterone nasal gel, Natesto) allows for rapid absorption through the nasal mucosa such that serum T levels reach a peak concentration in ~40 min. The inhibition of HPG axis activity is evidenced by the nearly full suppression of gonadotropin levels following treatment with either IM injectable testosterone (10) or topical gel administration (9).
Once the appropriate threshold of circulating T levels is achieved, T acts as a negative feedback molecule, signaling to the hypothalamus and pituitary to inhibit secretion of GnRH and LH, respectively (2). Pulsatile release of gonadotropin-releasing hormone (GnRH) from hypothalamic neurons signals the pulsatile secretion of luteinizing hormone (LH) from the pituitary. Pulsatile secretion of a hormone refers to the intermittent secretion of the hormone in a burst-like or episodic manner rather than constantly, with the frequency varying from minutes to hours, determined in part by the half-life of the hormone.

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