CLINICAL EXPERIMENTS WITH ANDROGENS (1939)

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madman

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From experimental observations, it is well known that androgenic substances are chemically changed and excreted after entering the circulation. The effectiveness of any androgenic preparation depends on many factors. One of the most important, besides the frequency of administration and the dosage, is the method of administration. The use of various solvents, the addition of fatty acids to the androgenic solutions, esterification of the substances, and many other variations have been studied in an attempt to increase the efficiency of administration of androgenic substances. The fact that pure crystalline testosterone is readily absorbed by the body fluids undoubtedly leads to waste when excess material is given. In order to overcome this difficulty and to decrease the rate of absorption, testosterone has usually been injected in an oily solution as the propionate. Injection of testosterone propionate has proved far more effective than the equivalent amounts of free testosterone. The intensity and duration of the action of testosterone have been thus enhanced, and treatment of hypogonadism in human beings have been satisfactorily carried out with injections at intervals of from three to four days.1 From the results of animal experiments it would appear that when large amounts of testosterone propionate are injected at such intervals an appreciable proportion of the substance is wasted. Testosterone has also been used clinically in the form of inunctions and by oral administration. It is not entirely satisfactory in the form of inunctions and when given by mouth enormous amounts are necessary to elicit a clinical response. A method of administration that would tend to stimulate the secretion of this hormone by the testis has been sought. If the androgenic substance can be administered so that the amount absorbed daily is not in excess of the physiologic requirements, waste will be eliminated and expenses can be kept to a minimum. Before the prevalent intramuscular injection of the testosterone propionate in an oily solution is supplanted, a new method must prove to be more convenient, more efficient, less expensive and devoid of harmful consequences.

The first use of pure androgens and estrogens by subcutaneous implantation of crystals or pellets was reported by Deanesly and Parkes 2 in 1937 and 1938. Their, work indicated that tablets of compressed crystals implanted subcutaneously produced stronger and longer effects of stimulation than similar doses given by injection. Schoeller and Gehrke 3 later showed the superior effect of implanted testosterone and testosterone propionate tablets in fowls. Having knowledge at the time of the work that Deanesly was carrying out in experimental animals, we first implanted pellets of crystalline testosterone subcutaneously into a patient with hypogonadism in the fall of 1937, but these pellets were too small to produce any significant clinical results. Three recent reports4 have referred to the implantation of small pellets of testosterone in human beings with questionable results. In the fall of 1938, soon after Thorn 5 began his work with the implantation of moderate-sized pellets of desoxycorticosterone acetate, we began to make and implant pure testosterone in large pellets weighing up to 800 mg. We have now implanted these pellets into a series of thirteen patients with hypogonadism.0 We have implanted pellets subcutaneously or intramuscularly in the leg, arm, back, and scrotum. The pellets have been removed later and reweighed in order to calculate the average amount that has been absorbed daily. The actual curve of absorption probably shows a gradual decrease as the size of the pellet becomes smaller. Tissues surrounding the pel¬ lets, which are foreign bodies, have been removed and studied pathologically. Assays of the urinary androgens and estrogens have been made before and after implantation. A systematic study of various aspects of pellet implantation with both crystalline testosterone and some of its esters is now being completed and an evaluation of the clinical results will be discussed in a forthcoming report.7 A study of the effects of testosterone and its esters in the monkey, comparing the method of injection with the implantation of pellets, is also in progress."

Our purpose in this report is to present a new technic for the subcutaneous implantation of solids such as pellets of pure crystalline androgenic substance by the use of an "injector" instrument."








*The clinical results, though just beginning in these patients are indicative of the activity of crystalline testosterone when implanted subcutaneously in the form of pellets. The method may prove to have important clinical applications, but more extensive work is necessary to establish this with certainty.
 
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Fig. 1.—The instruments used to make pellets of various sizes. A the press; B, the die with three sizes of pellets; C, the punches ; D, the assembled press with a punch in place; E, the heavy metal mallet.
Screenshot (3026).png
Screenshot (3027).png
 
Fig. 2.—A. the "injector" instrument with fenestra closed; A'. the mechanism to open and close fenestra at will; B, three sizes of pellets; C, instrument with fenestra opened by rotating handle (note the bladelike point); D, end of injector showing obdurator extruding a pellet; E, same as D but with two pellets being extruded.
Screenshot (3028).png

Screenshot (3029).png
 
Fig. 3.—Method of depositing pellet by means of a new "injector" instrument. A instrument entering skin of leg through a wheal of local anesthetic; B, end of instrument below fascia lata with obturator being pushed forward to extrude and deposit pellet (the fenestra has been opened by rotating window); C, skin clip to close puncture wound.
Screenshot (3030).png

Screenshot (3031).png

Screenshot (3032).png
 
Fig. 4 (case 1).—Appearance of patient, aged 21, with hypogonadism before and after implantation of pellets of crystalline testosterone in muscle of back. A full view and genitalia before implantation; B, same ninety days later.
Screenshot (3033).png

Screenshot (3034).png
 
Fig. 5 (case 2).—-Appearance of patient, aged 34, with hypogonadism before and after implantation of large pellet of testosterone weighing 750 mg. into scrotum. In some respects this could be termed a "synthetic testicle." A full view and genitalia before implantation; B, same two and one-half months later. Slower absorption of large pellet in scrotum was taking place as compared to case 1
Screenshot (3035).png

Screenshot (3036).png
 
fig. 6.—Sections of tissue showing reaction around cavities where pellets had been placed for three months in the subcutaneous tissue of arms of two patients. A, many giant cells with some round cells and leukocytes; B, fibrous tissue, some of which is hyaline, and a dense collection of round cells.
Screenshot (3037).png

Screenshot (3038).png
 
From experimental observations, it is well known that androgenic substances are chemically changed and excreted after entering the circulation. The effectiveness of any androgenic preparation depends on many factors. One of the most important, besides the frequency of administration and the dosage, is the method of administration. The use of various solvents, the addition of fatty acids to the androgenic solutions, esterification of the substances, and many other variations have been studied in an attempt to increase the efficiency of administration of androgenic substances. The fact that pure crystalline testosterone is readily absorbed by the body fluids undoubtedly leads to waste when excess material is given. In order to overcome this difficulty and to decrease the rate of absorption, testosterone has usually been injected in an oily solution as the propionate. Injection of testosterone propionate has proved far more effective than the equivalent amounts of free testosterone. The intensity and duration of the action of testosterone have been thus enhanced, and treatment of hypogonadism in human beings have been satisfactorily carried out with injections at intervals of from three to four days.1 From the results of animal experiments it would appear that when large amounts of testosterone propionate are injected at such intervals an appreciable proportion of the substance is wasted. Testosterone has also been used clinically in the form of inunctions and by oral administration. It is not entirely satisfactory in the form of inunctions and when given by mouth enormous amounts are necessary to elicit a clinical response. A method of administration that would tend to stimulate the secretion of this hormone by the testis has been sought. If the androgenic substance can be administered so that the amount absorbed daily is not in excess of the physiologic requirements, waste will be eliminated and expenses can be kept to a minimum. Before the prevalent intramuscular injection of the testosterone propionate in an oily solution is supplanted, a new method must prove to be more convenient, more efficient, less expensive and devoid of harmful consequences.

The first use of pure androgens and estrogens by subcutaneous implantation of crystals or pellets was reported by Deanesly and Parkes 2 in 1937 and 1938. Their, work indicated that tablets of compressed crystals implanted subcutaneously produced stronger and longer effects of stimulation than similar doses given by injection. Schoeller and Gehrke 3 later showed the superior effect of implanted testosterone and testosterone propionate tablets in fowls. Having knowledge at the time of the work that Deanesly was carrying out in experimental animals, we first implanted pellets of crystalline testosterone subcutaneously into a patient with hypogonadism in the fall of 1937, but these pellets were too small to produce any significant clinical results. Three recent reports4 have referred to the implantation of small pellets of testosterone in human beings with questionable results. In the fall of 1938, soon after Thorn 5 began his work with the implantation of moderate-sized pellets of desoxycorticosterone acetate, we began to make and implant pure testosterone in large pellets weighing up to 800 mg. We have now implanted these pellets into a series of thirteen patients with hypogonadism.0 We have implanted pellets subcutaneously or intramuscularly in the leg, arm, back, and scrotum. The pellets have been removed later and reweighed in order to calculate the average amount that has been absorbed daily. The actual curve of absorption probably shows a gradual decrease as the size of the pellet becomes smaller. Tissues surrounding the pel¬ lets, which are foreign bodies, have been removed and studied pathologically. Assays of the urinary androgens and estrogens have been made before and after implantation. A study of the effects of testosterone and its esters in the monkey, comparing the method of injection with the implantation of pellets, is also in progress."

Our purpose in this report is to present a new technic for the subcutaneous implantation of solids such as pellets of pure crystalline androgenic substance by the use of an "injector" instrument."








*The clinical results, though just beginning in these patients are indicative of the activity of crystalline testosterone when implanted subcutaneously in the form of pellets. The method may prove to have important clinical applications, but more extensive work is necessary to establish this with certainty.
A method of administration that would tend to stimulate the secretion of this hormone by the testis has been sought


Is there or is someone already trying a minimum daily dose of injected testosterone that could not suppress HPG? I heard some reports of people using little Testosterone Gel, but I find it difficult.
 
A method of administration that would tend to stimulate the secretion of this hormone by the testis has been sought


Is there or is someone already trying a minimum daily dose of injected testosterone that could not suppress HPG? I heard some reports of people using little Testosterone Gel, but I find it difficult.

Use of exogenous esterified injectable T, let alone T-pellets, patch, transdermal application (gels/creams), buccal, where one achieves steady-state let alone T levels high enough to achieve the therapeutic benefits will result in a shutdown of the HPTA.

As you should very well know mid-normal let alone in many cases higher-end T levels are needed in order to achieve relief/improvement of low-T symptoms and overall well-being.





TESTOSTERONE PHARMACOKINETICS

The various testosterone formulations have a wide range of dosing intervals including long-acting preparations: subcutaneous pellets (3 to 6 months), injectable IM testosterone undecanoate (10 weeks); intermediate-acting preparations: IM testosterone cypionate/enanthate (1 to 3 weeks); daily preparations: topical/transdermal formulations; and short-acting preparations: oral testosterone undecanoate (twice daily) and nasal testosterone (two to three times daily). All formulations, with the exception of the short-acting ones, have a target of long-term maintenance of sustained steady-state testosterone levels in the mid-normal range, which leads to suppression of the endogenous activity of the HPG axis.




post #78/79/80
 
Beyond Testosterone Book by Nelson Vergel
*Endocrine systems are regulated dynamically in response to positive or negative stimuli within a homeostatic environment. Modalities of T therapy evolved to extend the dosing interval and maintain sustained “steady-state” T levels. Long-acting TTh can inhibit the HPG axis, which in turn suppresses pituitary LH and FSH secretion, reducing circulating levels of LH and FSH and endogenous T production
 
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