Hormone Implants Technology
Related wiki pages
I've done my best, but I'm not very confident in what I've written here. I've collected this information from the experiences of trans people, doctors who use implants, compounding pharmacies, academic papers, and patents. Implants are a very old technology and unfortunately I'm not aware of anyone doing any research on improving them.
It appears that the estrogen implants we use today are little changed from when they were invented around 1940 as compressed or fused estradiol crystals shaped into small cylinders. The technology of implants in general has continued to advance and is now quite sophisticated (and difficult to understand), but none of that appears to be applied to what we use. I suspect its either because there's no money to be made in this area, or because the existing implants are difficult to improve on, or perhaps both.
The lab preparation of implants is described in many papers.
2018 - Patient-derived xenograft model for uterine leiomyoma by sub-renal capsule grafting by Vanida Ann Serna and Takeshi Kurita - contains detailed instructions on how to make pellets for mice.
2017 - Subcutaneous testosterone-letrozole therapy before and concurrent with neoadjuvant breast chemotherapy: clinical response and therapeutic implications by Rebecca L. Glaser, Anne E. York and Constantine Dimitrakakis - "The combination testosterone-letrozole (T + L) implants were compounded at Millennium Wellness Center. Non-micronized T, letrozole, and stearic acid powders were mixed by mechanical means in a geometric ratio of 15:1:1. A manual pellet press was used to compress the triturate into 3.1 mm diameter cylindrical pellets containing 60 mg of T and 4 mg of letrozole (60 mg T þ4 mg L). The pellets were then placed in sealed glass vials and terminally sterilized via autoclave for 40 minutes at 121°C."
2013 - Renal Capsule Xenografting and Subcutaneous Pellet Implantation for the Evaluation of Prostate Carcinogenesis and Benign Prostatic Hyperplasia by Tristan M. Nicholson, Kristen S. Uchtmann, Conrad D. Valdez, Ashleigh B. Theberge, Tihomir Miralem, William A. Ricke, DOI - describes preparation of estradiol/cholesterol pellet for mice, see also YouTube video Prostate Cancer and Benign Hyperplasia: Evaluation | Protocol Preview by JoVE (Journal of Visualized Experiments) in 2022
2010 - Pellet Information - this appears to be a fax from one pharmacist to another on how to make pellets.
1990 - Dose-dependent effects of chronic treatment with estradiol or progesterone on LH secretion in ovariectomized rats by Anna Ratka, James W. Simpkins - cholesterol and estradiol pellets with varying proportions used to control blood levels.
To obtain E₂ pellet, the hormone and CHOL were thoroughly mixed in desired ratio and melted in an oil-bath (temp. 200°C). Using heated pasteur pipette, aliquots of the mixture were transferred to small molds made of aluminum foil. Cooled and solidified pellets were unwrapped from the foil and their weights were adjusted to 100 mg. Physicochemical properties of P4 (liquid crystal) did not allow us to make melted pellets. Therefore, the mixture of P₄ with CHOL at appropriate ratio was prepared for each pellet and then pressed using a F.J. Stokes model A3 tablet maker (F.J. Stokes Corporation, Philadelphia, PA).
1964 - (Note) An Improved Method of Producing Hormone-Cholesterol Pellets by Ronald Wieder, Michael B. Shimkin - the entire two page paper shows methods to lab prepare hormone-cholesterol pellets by sucking molten mixture into a glass tube and plastic (Tygon) tubes.
1951 - Absorption of hormone implants in man by P.M.F.Bishop, S.J.Folley, DOI
The pellets used, specially made for us by Organon Laboratories Ltd., consisted of pure crystals of the hormone without diluent or excipient. They were of two types : cylindrical cast or fused pellets, and compressed pellets in the shape of cylinders with convex ends. The fused pellets were made by heating the crystals to a temperature at which they fused and allowing the melt to solidify in the mould (a glass tube). The compressed pellets were prepared by compressing the crystals under a sufficiently high pressure to render them coherent. Nine hormones or their esters were studied, and wherever possible a comparison was made between fused and compressed pellets. In the case of stilboestrol and hexoestrol only compressed pellets were used, because in our experience fused pellets of these substances tend to disintegrate immediately after implantation.
The pellets were dried to constant weight in a desiccator over calcium chloride. After they had been weighed and measured they were returned for sterilisation in the factory and finally dispatched to one of us (P. M. F. B.) for implantation.
1950 - Absorption of steriods from subcutaneously implanted tablets of the pure hormine and the hormone mixed with cholesterol by Florencio Fuenzalida, DOI
When preparing the mixture, cholesterol and the steroid hormone were dissolved in ether which was evaporated at 60° C. The residue was triturated, compressed to tablets, dried and weighed.
1944 - Absorption of subcutaneously implanted hormone pellets by Michael B. Shimkin, Egon Lorenz, Rose Wyman, Sue Gray Norton, DOI,
Diethylstilbestrol melting point 169-171 degrees C. (corrected), was melted over an oil bath, and drawn up into thick-walled glass tubes equipped with well-fitting metal plungers. Upon solidification, the material was extruded and the resultant solid strings were cut with a razor blade into segments of desired length (Shimkin and White, 1941). No lubricant was used in the glass tubes, and after cutting, the pellets were washed lightly with absolute alcohol. The walls of the cylinders were very smooth, but the cut ends were somewhat irregular in comparison. Pellets measuring 1.1x1.1 mm. 2.4x2.4 mm., and 3.1x3.1 mm. and weighing approximately 1.2, 12.5, and 27.5 mg., respectively, were thus prepared.
The preparation of hormone pellets by fusion rather than by compression has several advantages, the chief one for clinical use being the preparation under sterilizing conditions. By maintaining the heat of melted diethylstilbestrol at 175-180 degrees C. for 20 minutes after the addition of 10 million spores of B. tetanus per 100 mg. of the chemical, the pellets- were noninfective to guinea pigs into which they were implanted.3 In these experiments, fused pellets were advantageous because their surfaces tend to become less eroded than the usual compressed pellets, and little or no protein material-deposition occurs within the pellets (Deanesly and Parkes, 1943).
1941 - Absorption Rate of Hormone-Cholesterol Pellets by Michael B. Shimkin, Julius White
The hormone-cholesterol pellets were prepared as follows: Pyrex glass tubing, about 8 mm. in diameter and with a 2 mm. bore, was cut into 8 to icon, segments. A well-fitting steel wire was inserted into the tube as a plunger, the rubber cap over the proximal end of the tube being penetrated by the wire in order to obtain better suction. The inner surface of the tube was oiled lightly with liquid petrolatum. The desired quantities of the hormone and of cholesterol were mixed and melted in an oil bath. The resultant solution was drawn up into the lubricated glass tube by means of the wire plunger. As soon as the material solidified in the tube it was extruded by the plunger. The solid rod of the hormone and cholesterol mixture thus formed was divided into pellets of desired size by means of a razor blade. The pellets were then washed rapidly in ether and more thoroughly in alcohol to remove the oil on the surface and to smooth the rough edges. Solid hormone pellets were prepared in the same manner.
Care was exercised not to draw up the molten hormone'cholesterol into the tube too rapidly, or to use too much lubricant, as the pellets would be hollow and fragile or somewhat soft.
The pellets were not as hard as those formed by compression and could be crushed easily. However, they withstood reasonably rough handling without fragmenting, unless they were hollow. One of the advantages of the method was that the pellets could be prepared under sterile conditions, thus making unnecessary subsequent sterilization of the pellets.
1940 - Subcutaneous implantation of compressed crystalline theelin pellets in the treatment of menopausal cases by Henry G. Bennett Jr., Gerson Biskind, Jerome Mark
Pellets of pure crystalline estrogens have been made by direct compression of the crystals in drilled, machine ground, steel plates. The pellets used have been 1.83 mm. in diameter, 2.0 to 3.0 mm. in length, and 5.0 to 6.0 mg. in average weight. The estrogen pellets have been sterilized in a dry steam autoclave at 250 F under 15 pounds of pressure for 30 minutes
The life of an implant in the body is related to its surface area, with a larger surface area having a shorter life and higher peak blood levels. Larger diameter implants are mechanically more robust and less likely to break in shipping. However large implants also require a larger trocar/hole, and logically speaking would be more likely to result in a larger scar.
A 3mm implant has a larger surface area than a 4.5mm implant, and in practice it appears that the the life of a 3mm implant is indeed shorter than a 4.5mm implant. Further, the 3mm implants are more fragile than the 4.5mm implant and break in shipping at a much higher rate, and as far as I know the rate of breakage of 100mg 4.5mm implants is negligible. A broken implant can still be used, but as its surface area is increased it will last even less time and with higher levels. In Australia 200mg 4.5mm implants have been used in the past, but were again fragile and susceptible to breakage in shipping and discontinued (perhaps its feasible to improve the packaging of the implant, or to coat it in something to protect it?).
The choice of implant size may simply depend on the trocar the doctor has available. Its not possible to insert a 4.5mm implant with a 3mm trocar, and while its possible to use a 4.5mm trocar for a 3mm implant its not ideal as its going to require a larger hole than necessary.
In Australia there are two common diameters of estrogen implants, 3mm and 4.5mm, and they are mostly 100mg. The lifetime of these implants in the body is commonly 6-12 months, depending on the individual, the dosage, and the blood level at which new implants are inserted. I have heard of far longer life than 12 months.
When I've had 4.5 mm implants in the past they required a suture (which was removed a week later), while the 3mm implants have not. Over time you can either have less larger holes, or more smaller ones, but I don't know which is best in terms of scarring.
In the USA smaller implants seem to be more common, and multiple implants are used to get higher doses. The lifetime of these implants appears to be substantially shorter than the Australian ones.
Repeated implants cause a build up in estrogen levels/extended life. What causes it?
Organon's Irish license (pdf) for their 25mg estradiol implant states that it contains 25mg of estradiol (as hemihydrate), no excipients, and a 5 year shelf-life.
There's two ways of making implants
Some companies call say their compressed pellets are "compressed/fused", or simply fused. I'm not sure if this is correct terminology as I am understood that fused means heat fused only.
There's a paper that says that past a certain point compression does not affect the rate of absorption (reference it).
There's papers that say the rate of absorption does not differ between compressed and fused implants (reference them).
I've heard (from personal discussion) that Organon pellets were heat fused, and that its likely that all other pellets now available are compressed powder. Apparently the Organon implants have a very hard surface compared to compressed pellets and much better stability in levels (e.g the day to day fluctuations in levels). Cavender 2009 describes and has photos of Organon and Testopel testosterone implants, and although not explicitly stated it appears that Organon implant is heat fused.
There's a paper on rats that measures levels daily after implantation (reference it, does it look at heat vs compressed?).
Ballard 1962 review prior papers (page 920-921) and it appears that
Bishop 1945 discusses the how the absorption of cast and fused pellets differ, saying that the area based absorption equation only applies to cast pellets. I assume the are referring to the long term absorption rather than that of the first hours/days as the paper on that is much later.
The above findings apply to cast pellets; with compressed pellets other factors must be taken into account. Thus large compressed pellets of pure hexoestrol show at the outset an abnormally high absorption rate due to the loss of an easily soluble component but thereafter the absorption rate is approximately linear for a considerable period and there is evidence that the absorption rate during the linear phase is proportional to surface area (Folley 1944). How far absorption during the linear phase is affected by the deposition of insoluble protein material in the pores of the tablet (ghost formation; Folley, 1942) it is impossible to say, but it does not affect the situation as regards cast pellets, since as Deanesly & Parkes (1943) have shown, ghost formation does not occur in cast pellets.
Thom 1981 shows a graph of implant estradiol levels over 8 months, with levels peaking after 1-3 months. Although the paper is supported by Organon its not clear if the implant is compressed or fused. In an much earlier paper the supplied both types. Its also not clear to me what the change in levels represents in terms of absorption.
Innovation Compounding say they make "fused" pellets.
In the 1990 paper Pharmacokinetics and pharmacodynamics of testosterone pellets in man by D J Handelsman, A J Conway, L M Boylan
The testosterone pellets [Organon (Sydney, Australia) PtyLtd.] are formed by fusion of crystalline testosterone at elevated temperature. The two sizes have a common cylindrical shape with a diameter of 4.5 mm and lengths of 6 mm (100 mg) and 12 mm (200 mg) with total initial surface areas of 117 mm2 (100 mg) and 202 mm2 (200 mg) per pellet.
... It should be noted that these fused pellets are quite different from the original subdermal implants made by high pressure compression into a tablet-like form of testosterone with excipient (usually cholesterol) which undergo much greater encapsulation and fibrosis than is observed with the fused pellets (16). The lesser degree of fibrosis produced by the fused pellets compared with the older compressed pellets may be responsible for the lower frequency of fibrosis but conversely may also be related to the higher rates of extrusion due to the weaker anchoring of pellets in their tracks.
In the 2004 paper/book Pharmacology of testosterone preparations by Behre, H. M., Wang, C., Handelsman, D. J., Nieschlag, E., & Nieschlag, S., page 430
The original testosterone implants were manufactured by high-pressure tableting of crystalline steroid with a cholesterol excipient. These proved brittle, hard to standardize or sterilize and exhibited surface unevenness and fragmentation during in-vivo absorption to produce an uneven late release rate. These limitations were overcome in the 1950s by switching to high-temperature moulding whereby molten testosterone was cast into cylindrical moulds to produce more robust implants. These have more uniform composition, resulting in a more steady and prolonged release and reduced tissue reaction.
At least some compounded compressed implants are made with the manually operated one ton Parr 2811 Pellet Press (its in some papers and from personal communications with compounding pharmacies). Larger volume manufacturing uses automated equipment in the USA, but not in Australia as far as I'm aware.
Parr Pellet Press 2811
YouTube
Hydraulic Press
Small hydraulic presses are readilily available for laboratory work with maximum pressures of around 5-40 tons, but these appear to be much slower to operate. They do have the advantage for experimentation of higher pressure, pressure guages, and availablilty of heated and custom die sizes. However note that the published research indicates that above a certain point higher pressure make no difference to absorption and these presses can easily exceed the maximum operating pressure for small dies, breaking them. As the pressure required for hormone pellets is relativly low the accuracy of guages on these larger presses may be quite poor.
These presses are commonly used for XRF analysis, to determine the elemental composition of materials.
Cheap lab presses are available from Chinese suppliers, but are very heavy and shipping is expensive.
YouTube
Dies - note these are not suitable for the Parr Pellet Press.
Custom dies can be made with higher maxium pressures, temperature, different sizes, etc
Cheap heated hydraulic presses are available as Rosin presses (canabis extraction). Its hard to imagine these in a professional lab, but I found it interesting.
Research
Excipients are sometimes used in implants
Serna 2018 describes using solvent to mix cholesterol and estradiol. Another applicable technique, for higher volume production, might be melt extrusion Breitenbach 2002.
Bisop 1952, page 279
We also noticed a tendency to extrusion, which is particularly noticeable for progesterone. One can almost go so far as to say that if one implants progesterone subcutaneously, it will certainly come out. Now that we have been using intramuscular implantation of progesterone with a trocar and cannula, we seldom get any extrusion at all. We also found a good deal of extrusion with testosterone propionate; for that reason we abandoned the clinical use of testosterone propionate and use testosterone itself, which does not seem to extrude nearly so much. D.C.A., estradiol and stilbmstrol have very seldom given us any trouble at all with extrusion.
Bisop 1952, page 280
FORBES: I should like to ask Dr. Bishop when extrusion occurred. Was it within a day or two of implantation? BISHOP: It was very variable. It was not local reaction or anything of that sort. Sometimes the pellet was extruded from a different site from where it had been implanted. Sometimes it occured early; sometimes the pellet had been retained for 42 days or even longer and was then extruded. Testosterone may be extruded 2-3 months after it has been implanted.
Papers
This has been used to reduce the rate of rejection/extrusion of testosterone pellets. Perhaps it might also work with progesterone pellets, or improve the sometimes variable rate of absorption of estriodiol pellets.
In the above paper, page 3, the graph shows a column for FarmaKeio T-200 mg Pellet. FarmaKeio is a compounding pharmacy in the USA.
https://farmakeio.com/hormone-therapy/ - "What Sets Our Pellets Apart? Triamcinolone"
https://www.evexipel.com/become-a-certified-bhrt-pellet-provider/quality/ - *"EXCLUSIVE Pellet Formulation PATENT PENDING. These pellets are Exclusive, and are supplied by FarmaKeio Outsourcing and FarmaKeio SUPERIOR Custom Compounds to EVEXIAS Health Solutions and EvexiPEL Partners. Extensive testing has been done in the development of these formulations and our whitepaper confirms the results and outcomes."
There's a 2019 lawsuit over this, BioTE Med., LLC v. Jacobsen, and in 2021 Biote Med., LLC v. Jacobsen questioning the results among other things.
Papers
In Australia 200mg estrogen implants were used for a time, but were very susceptible to breakage in shipping and discontinued in favor of 2 x 100mg implants.
In the USA College Pharmacy stopped shipping 100mg pellets for the same reason. They are now no suppliers of 100mg pellets in the USA.
Cavender 2009 says of the 200mg testosterone implant
One is marketed by Organon Laboratories Ltd., Milton Road, Cambridge, United Kingdom, and formulated as a cylindrical 5 x 15-mm pellet (diameter x length) containing 200 mg testosterone (Testosterone Implant). Each pellet is surrounded by wool or cotton for pellet protection, and stored in a sterile glass ampule.
Guarnieri 2014 discusses measuring pellet hardness and dissolution (absorption). The dissolution technique is probably not useful in for estradiol pellets as its very slow.
Drug pellets were prepared under sterile conditions in the Johns Hopkins Cell Processing Facility (Baltimore MD) with a Natoli NP RD10 tablet press (St. Charles MO). Five mg pellets were prepared using 1.25 tons of pressure. This pressure was selected because studies described in Figure 1 demonstrated that higher tableting pressures did not increase the crush resistance of the tablets. Pellets were stored at 3-8° before use. Pellet hardness was measured with a CCS Stokes Model 539 manual hardness tester (Warrington PA). Dissolution rates in saline were estimated by placing pellets on the surface of a 5 mL glass tube containing 2 mL of saline at 37° and recording the time to disintegration of the pellet.
There are also techniques to measure tablet (not pellet) crush strenth, although its not clear if hardness/crush resistance correlates with breakage in shipping.
Most of this page is about estradiol pellets.
Most implant studies look at long term absorption, however Isaksson 2011 looks at absorption (in rats) in the first 30 minutes to 42 days, finding very high peak levels within hours of implantation.
The absorption rate is proportional to the surface area of an implant at a given time (Ballard 1962, Bishop 1945). Ideally we would be able to calculate the expected life, but that appears somewhat difficult.
Compare the surface area of 1 x 100mg vs 4 x 25mg implants. I assume the diameters of implants are 3.2mm and 4.5mm as these are standard in Australia.
According to WO1984000304A1 a pure estradiol 25mg implant is 3.2mm dia x 3.5mm long. From this we can calculate the length of a single 100mg 3.5mm cylindrical implant is 14mm, a 100mg 4.5mm diameter implant is 7.1mm, and a 100mg spherical implant is 6mm diameter.
| Shape | Area (mm²) | Ratio % |
|---|---|---|
| 3.5mm x 3.5mm x 4 cylinders | 205 | 100 |
| 3.5mm x 14mm cylinder | 157 | 77 |
| 4.5mm x 7mm cylinder | 132 | 64 |
| 6mm Sphere | 113 | 55 |
Calculations
The surface area of a 3.2mm x 3.5mm cylinder (the 25mg pellet) is calculated to be 51.3 mm² and its volume 28.1 mm³ respectivly. The total surface area and volume of 4 implants is then 205mm² and 112.4mm³ respectively. Note that the linked calculator uses radius of 1.6mm rather than the 3.2mm diameter.
A single implant of 3.2mm diameter is 3.5 * 4 = 14mm long, and its area is 156.8 and volume is 112.6 mm³.
The surface area of a single implant is then 156.8/205 = 76.5% that of 4 individual implants. ie the initial absorption rate of the implants is 31% faster.
A single 100mg 4.5mm cylindrical implant has a calculated length of 7.1 mm and surface area of 132mm², or 132/205 = 64% the surface area of the 4 smaller implants.
A 100mg spherical implant (ie the same volume) has a calculated diameter of 6mm and surface area of 112.8 mmv, or 55% that of the 4 smaller implants. i.e. the absorption rate of the 4 smaller implants is 82% faster.
Next
3.2mm 50mg pellet
These are the largest estrogen pellets currently available in the USA.
They have double of volume of the reference 25mg pellet, ie 2x28.1 mm³ = 56.2mm³. The surface area is then 86.4mm².
5.5mm 300mg pellet
Note that no one makes 300mg estrogen pellets, and only TheraPellet make 5.5mm trocars (which I expect they won't sell unless its part of some licensing agreement).
Using the volume calculated before for a 100mg pellet having a volume of 112.4mm³, a 300mg pellet would have 3 times the volume, of 337.24mm³. A 5.5mm 300mg pellet would then have a length and surface area and area of 14.2mm and 293mm² respectivly.
Blood levels in comparison to smaller implants should be in proportion to surface area. A 100mg 3.5mm pellet has an surface area of 157², and this 5.5mm 300mg pellet has levels equivalent to 1.9 of those (ie 190mg). Similarly 2.2 (220mg) of 4.5mg 100mg pellets.
As above, a 50mg 3.2mm pellet has a surface area of 86.4mm², so 5 of them (250mg) would have a surface area of 432². The 5.5mm 300mg surface areas is only 68% of this, so levels should be that much lower. Given the total dose is 300/250 = 1.2 greater and the absorption is 1.47 slower, it should last 1.8 times longer (this is no doubt far too simple a calculatition).
Some other observations
A 200mg 4.5mm cylindrical implant is 14.2mm long.
A 200mg sphere is 7.5mm diameter.
A 4.5mm diameter sphere has a volume of 47.7mm², an area of 179mm, and weight 63.6/112.6 * 100mg = 56.5mg. Two of these spheres are 113mg and total surface area of 127.2 mm². There's 13% more estrogen, and 63% of the surface area compared to 4 individual 25mg cylinders. There's 127.2/132 = 96.4% of the surface area of a single 4.5mm cylinder - ie its 13% more estrogen and 3.6% less surface area (ie 2 spheres are about 16% better than one cylinder).
Sometimes implants are broken (in transit), so what does this do to the surface area? Should you use them or order replacements?
This is essentially the same issue as considered when using 4 x 25 mg implants vs 1 x 100mg, except in that case we considered only 4 implants (equivalent to 3 breaks).
3.2mm implants are far more fragile than 4.5mm 100mg implants, so I'll only consider those. Every break in the cylinder is equivalent to two additional faces (same as the ends of the cylinder), or twice the area of a 3.2mm diameter (1.6 mm radius) circle, i.e. 2 x 8.0 mm².
Area of 3.5mm x 14mm implant vs breaks
| Breaks | area (mm²) | ratio % |
|---|---|---|
| 0 | 157 | 100 |
| 1 | 173 | 110 |
| 2 | 189 | 121 |
| 3 | 205 | 131 |
| 4 | 221 | 141 |
From this we can see that even 2 breaks only increases the surface are by 20%, which presumably would lead to a corresponding reduction in life and increase in peak blood levels.
Encapsulation and extrusion seems to happen at a much higher rate with testosterone, so looking for information with testosterone is probably more productive.
See
To Review
Lab testing of absorption without implanting them in the body.
Papers
I see a few problems with current pellets and I hope there's some way of improving them. Radically changing implant technology doesn't appear to be a fruitful area to look at as the R&D time, cost, and medical approvals would be prohibitive. There also seems to be a lack of interest, so perhaps there's something simple that can be done.
If this were is possible then the advantages might be
If there were a way to improve the pellets then to be practically useful is must be capable of being done by a compounding pharmacy. The pharmaceutical company Organon Laboratories ceased worldwide production of oestradiol implants in 2011 for commercial reasons and it seems very unlikely that any company would invest significant money in this area.
It's physically possible to insert a much higher dosage with the current surgical procedure. Cavender 2009 shows 6 to 20 of 75mg, ie 450mg to 1500mg of testosterone pellets being implanted), but it would make blood levels too high. A way of slowing down absorption would be required. Personally I'd much prefer new implants every 3 years or so.
It appears that approximately 200-300mg of estradiol is used the body per year (based roughly only 200mg per 9 months that had been common in Australia). Assuming a maximum of 1500mg were implanted this is 5 years worth of estrogen, or less if cholesterol were included to slow down absorption (as it would have to be). I'd like to know more about
Fuenzalida 1950 shows that mixing hormones (not estradiol) with cholesterol has a very large effect on absorption rates
Absorption from tablets containing 40 per cent of the steroid hormone and 60 per cent of cholesterol dropped to one fifth and even to one twentieth of that of the pure hormone tablets, although a diminution of only two and one half times would be expected according to the reduction of the surface of the steroid hormone in the mixture.
Cholesterol in some way counteracts absorption of steroid hormones.
Ballard 1962 has a couple of important points
Joseph 1977 describes the manufacture of progesterone/cholesterol implants by partially melting and extruding the mixture rather than compression.
Given that cholesterol slows down absorption, are there other suitable materials that can slow down absorption even further?
There's a discussion in the 1952 Ciba Foundation Symposium ‐ Steroid Hormone Administration (Book II of Colloquia on Endocrinology), Volume 3 page 281-282 on different shapes of implant
BISHOP: After using different sizes of pellets, we came to the conclusion that from a clinical point of view probably the 100 mg. pellet is the most convenient unit. If, for example, you wish to implant 700 mg of D.C.A., we feel it is better to implant it in 7 tablets of 100 mg. rather than in one tablet of 700 mg., because absorption depends upon the surface area of the pellets, and the larger the pellet the smaller the surface area in relation to weight, and therefore the weaker the dose you actually get. For clinical purposes pellets of 100 mg. should be made.
GADDUM: You would not want to use a smaller quantity than that?
BISHOP: There is a tendency in some quarters to use implantation methods for the relief of menopausal symptoms, particularly in women who have had hysterectomy, and in these cases probably 100mg is too high a dose and 25 mg tablets would be suitable. With regard to progesterone, the difficulty of implanting deeply a tablet as large as 1OOmg is very real, and we have had to make long thin cylindrical pellets of 25 mg.
BROWNLEE: Have you tried the effect of using small spheres?
BISHOP: We were approached in one case where a man had had both testicles removed on account of tuberculous epididymitis. He obviously required prolonged, possibly permanent, androgen treatment, because if he did not have androgen treatment he suffered very considerably from hot flushes. It was suggested that we might make an enormous spherical pellet about the size of the testicle and implant i t in the scrotum, but clearly this was not a good idea because of the very small daily dose which he would actually get.
GADDUM: The disadvantage of a sphere is that the rate of absorption will diminish. If you want a steady absorption over a long time the most effective form should be a flat disc.
FOLLEY: A flat disc would be mechanically at a disadvantage; there would be a tendency for it to crack.
Perhaps coating the pellets could help in some way, prolonging life, reducing fluctations in levels, or increasing mechanical strength.
Combine two or more hormones in one pellet. estradiol, progesterone, testosterone.
Cis women and post-op trans women sometimes have testosterone pellets in addition to estradiol. It is incompventient that testosterone pellets do not last as long as estrogen. This problem should be solved if both hormones were combined into the same pellet.
Why are pellets made of pure hormone rather than esters as used for injections where estradiol esters (valerate, cypionate, etc)? Esters are used in injections to slow down absorption, which would be benificial in our case.
Papers
It appears the manufacturers try to reduce the amount of excipients in pellets, presumably so that there's more of the hormone in a given pellet. Indeed, some manufacturers use this in their marketing materials. The pellets I have come across have from 0 to 4% excipients (ie from 96 to 100% hormone).
Both steric acid and cholesterol are used as excipients in current pellets, although stearic acid appears to be more common. As stearic acid is far more soluble in water than cholesterol I would assume it doesn't slow down pellet absorption as much. I don't know if it makes a noticable difference in the amounts used in currrent pellets.
Increasing the proportion of excipients used and improving the properties of the pellets might be a useful tradeoff. If there's less hormone in a pellet we can always increase their size or use more of them.
Can the fragility of large pellets be improved by modifying the excipients?
Progesterone and testosterone are prone to extrusion. What can be done about this?
Injection moulding could be used to make heat fused pellets at high volume.
In the manufacture of ceramics and explosives solvent can be added before pressing materials to improved the density of the resulting object. Perhaps this can be used to produce mechanically stronger and long lasting estrogen pellets. It is however an extra step and would increase the cost, but might be a more practical alternative to heat fused pellets (or hot-melt extrusion) in a small compounding pharmacy.
Papers
Patents
The 2020 publication by the National Academies of Sciences, Engineering, and Medicine 2020 is interesting and covers a range of issues regarding pellets in the USA, but appears to contain errors and bias. I'm unclear on what is going on here, but it has some appearance of an attack on compounding pharmacies and/or certain kinds of HRT.
The following is not correct as the only unusual equipment would be a relativly inexpensive pellet press, and pellets are in fact made on demmand in Australia.
To dispense a pellet in response to a patient prescription, a pharmacist would have to own and know how to operate special equipment that can mix, dry, extrude, package, and sterilize the pellets. Such equipment is simply not found in the majority of pharmacies. It also cannot be made “on demand.”
If electron bean (gamma radiation) sterilisation is used it would be outsourced to a special facility and done in batches (leading to delays), however pellets can also be heat sterilised in house.
I don't understand this point either, as how can the width of pellet comming out of a press be anything except the diameter of the die.
Also, to be sure the pellets are of uniform size, the pharmacist would have to be able to measure small differences in length and width, on the scale of ≤ 0.3 mm, among same dose pellets.
While this is strictly true, it appears misleading. Compounding pharmacies have individual recipies according to history and manufacturing processes, but they don't hide this - its published on many of their sites and its easy to call them and find out exactly how they are made. Neither would I expect a prescribing doctor to be unaware of the difference between suppliers.
There is also evidence of compounding pharmacies substituting inactive ingredients into pellet products (e.g., a cholesterol base for a steric acid base), which would completely change the release characteristics of the pellet, a formulation change that could clearly put patients at risk.
All forms of HRT have pros and cons and this paper considers pellets in isolation, ignores the benifits, ignores the downsides of of other forms of HRT, and ignores patient preference. Pellets have significant benifits in compliance (you can't forget to take them), stability of blood levels, effectiveness, patient convenience, and preference.
I've not come across any indication that variations in effectiveness between pellets causes any significant issues, especially when weighed against the benifits to the patient of pellets vs other methods of delivery. I've heard of uncommon cases where a pellet is implanted and levels remain unusually low - the doctor then inserts another one or the patient switches to another form of HRT. Its inconvenient, but not dangerous.
Pellets in Australia are typically available in 50mg and 100mg sizes, and there doesn't appear to be much concern by either doctors or patients over the relativly large difference between the various possible doses, e.g 100mg is double 50mg, yet the paper expresses concern over deviations much smaller than that. Doctors don't ask for intermediate dosages to be compounded, and difference in blood levels over time makes it kind of pointless. It doesn't appear to be a precise science, and nor is there any apparent harm in that.
Estrogen blood levels on oral (pills) and transdermal (gels/patches) HRT varies wildly depending on the indivdual, so it even more unlear to me why there's any concern over variations in pellets. You need to experiement with dosages to find what works. (I not currently aware of how estrogen blood levels vary beteen individuals using the same dose of pellets).
In Australia where trans patients have easy access to pellets there's a large preference in the use pellets by those who have tried them.
The publication may be related to this post
It's not clear how relevant these are, but there's some interesting discussions in them