Testosterone Administration and Polycythemia, Definition of Androgen Deficiency and the Role of SHBG, Injecting hCG - Intramuscularly or Subcutaneously?
 

Dr. Scally early on recognized the lack of research and treatment for individuals using anabolic-androgenic steroids (AAS). He has remained as the sole physician by reputation and publication to actively pursue and advocate the proper use of AAS to optimize health. Dr. Scally has personally cared for thousands of individuals using AAS. His protocol for Anabolic Steroid Induced Hypogonadism has been presented before the Endocrine Society, American Association of Clinical Endocrinologists, American College of Sports Medicine, & International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV.

Testosterone Replacement and Polycythemia

Q: Is there any way to avoid Polycythemia when doing TRT? I know that injections are more prone to causing this. I recently switched from shots and am currently doing 25mg T cream and 100iu HCG every day, but I am still getting elevated hematocrit and RBC. It looks like I might need to do a therapeutic phlebotomy twice in the next month for my numbers to come back within the normal range. Is there anything to be concerned about with doing frequent phlebotomies?

A: This is something that is sure to come up with TRT. This is an additional reason why I suggest individuals who are on TRT for low normal testosterone come off once every 12-18 months. This not only ensures the functionality of the HPTA but if polycythemia is a problem this will ameliorate or fix it. I was referred a patient who had polycythemia and the referring doctor was unable to stop TRT due to symptoms.

Comparison of transdermal nonscrotal testosterone patch with intramuscular injections of testosterone enanthate observed that 15.4 percent and 43.8 percent of patients, respectively, had at least one documented elevated hematocrit value (defined as over 52 percent) during the course of ~1 year. Erythrocytosis was associated with supraphysiologic levels of bioavailable testosterone and estradiol, and it occurred more frequently in the group that received intramuscular injections of testosterone.

There has been demonstrated a direct relation between testosterone dosage and the incidence of erythrocytosis. Erythrocytosis occurred in 2.8 percent of men receiving 5 mg per day by nonscrotal patches and in 11.3 percent and 17.9 percent of men treated with gel preparations of 50 mg per day (delivering 5 mg per day) and 100 mg per day (delivering 10 mg per day), respectively.

Phlebotomy is on the whole a safe procedure, the frequency of side effects being low and their severity weak. Although untoward events are unlikely with mild erythrocytosis of relatively short duration, the hematocrit or hemoglobin level should be monitored in men receiving testosterone-replacement therapy so that appropriate measures, such as dosage reduction, the withholding of testosterone, therapeutic phlebotomy, or blood donation, may be instituted if erythrocytosis develops. It is reassuring that as far as we can determine, no testosterone-associated thromboembolic events have been reported to date.

Definition of Androgen Deficiency and the Role of SHBG

Q: Why do we need SHBG? What would happen if we lowered SHBG too much? Can lowering SHBG be used as a form of Testosterone Replacement Therapy?

A: Total Testosterone (TT), BT and DHEA-S decreased with age; 0.2, 0.7 and 1.2%/year respectively. SHBG showed an increase with age of 1.1%/year. Clinically if an individual is symptomatic, a TT test is sufficient if the level is low normal oe abnormal. However, if the TT is normal one would measure SHBG and FT (or calculate FT using SHGB level) to see if the individual is T deficient using FT or BT as a reference. I know of no method naturally to manipulate SHBG levels without also affecting sex hormones.

Androgen action is the sum effect of bioactive androgens and the intrinsic responsiveness of the androgen receptor (AR) in target cells. The major circulating androgen in males is testosterone and ~98% of testosterone molecules are bound to proteins in the blood, principally to sex hormone-binding globulin (SHBG) and also to albumin and cortisol-binding globulin. It is assumed that bound hormones cannot exit blood capillaries and are therefore not bioavailable, and so SHBG concentrations are commonly measured as a supplement to total testosterone determinations. The measurement of unbound free testosterone has been proposed as a better measure of bioactive testosterone.

SHBG, corticosteroid binding globulin, and albumin are important steroid hormone binding proteins in human plasma. SHBG is best known for its role as a binding protein of sex hormones in human plasma. In normal men and women, between 40 and 65% of circulating testosterone (T) and between 20 and 40% of circulating estradiol (E2) is bound to SHBG. Binding of T to SHBG decreases its metabolic clearance rate and its conversion rate to androstenedione. Binding to SHBG also prevents bound hormone from diffusing out of the bloodstream, thereby preventing hormone binding to the intracellular androgen or estrogen receptors. The non-SHBG-bound fraction of hormone is considered to be bioactive (free hormone hypothesis).

The free hormone hypothesis states that the biological activity of a given hormone is affected by its unbound (free) rather than protein- bound concentration in the plasma. This hypothesis is likely to be valid for any given hormone will depend largely on which step in the tissue uptake process (plasma flow, dissociation from plasma binding proteins, influx, or intracellular elimination) is rate-limiting to the net tissue uptake of that hormone. The free hormone hypothesis could hold even if tissue uptake of hormone occurred by a mechanism that acted directly on one or more circulating protein- bound pools of hormone. The free hormone hypothesis is not likely to be valid for all hormones with respect to all tissues. It is likely to be valid with respect to all tissues for the thyroid hormones, for cortisol, and for the hydroxylated metabolites of vitamin D. Many of the other steroid hormones it is likely to be valid with respect to some tissues, but not with respect to others (in particular, the liver) and for some of the steroid hormones (in particular, progesterone) it may not hold at all.

The definition of androgen deficiency (AD) is still a matter of controversy. AD can be defined purely biochemically, using T levels with percentile cutoff values (e.g. 2.5 standard deviations below the range for normal young males), or using only signs and symptoms. This has attempted to be remedied by using FT as a measurement. The growing interest in measuring blood free testosterone (FT) is constrained by the unsuitability of the laborious reference methods for wider adoption in routine diagnostic laboratories. Various alternative derived testosterone measures have been proposed to estimate FT from either additional assay steps or calculations using total testosterone (TT) and sex hormone-binding globulin (SHBG) measured in the same sample. Currently, there is no standardized reference for FT.

The place of SHBG in the androgen system is controversial. On one hand, it is generally accepted that androgens, unlike estrogens, reduce SHBG concentrations. Thus, SHBG concentrations are lower in males administered AAS. Administration of testosterone results in a 2-fold lowering of SHBG in normal and hypogonadal men. On the other hand, concentrations of testosterone and SHBG in males appear to be positively correlated.

In vitro experiments show that with increasing levels of SHBG and stable levels of T and E2 the ratio of unbound E2 to unbound T increases. T and E2 bind to the same binding site on SHBG, but the binding affinity for T is higher than that for E2. On the basis of the relatively greater decrease in the bioavailability of T compared with that of E2, SHBG has been regarded as an estrogen amplifier.

Clinical findings show with increasing SHBG levels the non-SHBG-bound fraction of T decreased from 80 to 36% and that of E2 from 89 to 53%. Higher levels of SHBG were associated with higher levels of both total T and total E2. Higher SHBG levels are associated with lower levels of non-SHBG-E2 but slightly higher levels of non-SHBG-T (SHBG levels were negatively related with levels of non-SHBG-E2 whereas there was a positive association between levels of SHBG and non-SHBG-T.) There is a negative relationship between SHBG levels and the E2/T ratio of either total or non-SHBG-bound hormone. High concentration of SHBG is associated with a lower (non-SHBG-bound) estrogen/androgen ratio and vice versa.

In eugonadal men the HPTA will respond to a decreasing level of non-SHBG-T with an increase in LH and T, assuming that non-SHBG-T is driving the feedback inhibition of the HPTA. In cross-sectional studies, the plasma concentrations of T and SHBG are positively correlated. This correlation not only reflects the high binding affinity of SHBG for T, resulting in increased storage of the steroid, but may also be explained by the effect of SHBG levels on the bioavailability of T. Higher SHBG levels would then lead to lower levels of bioactive T, a decreased feedback signal on GnRH and thereby on LH secretion by the pituitary and a subsequent increase of T levels until a new set point is reached. Endogenous E2 can also have an effect on LH release by the pituitary. When bioavailable E2 levels decrease, this might lead to increased LH release by the pituitary with a resulting increase in testicular T production. The decreased feedback inhibition of non-SHBG-E2 on the release of LH by the pituitary probably explains the slightly positive relationship between levels of non-SHBG-T and SHBG.

The fact that an intact HPTA appears to prevent the non-SHBG-T concentration to fall with increasing SHBG levels makes the in vivo situation in eugonadal men totally different from the in vitro situation where changes in hormone binding to SHBG do not evoke adaptations in the HPTA. This means that SHBG cannot be regarded as an estrogen amplifier in eugonadal men.

This has important implications for androgen action since <40% of testosterone is physiologically bound to SHBG, and is therefore not biologically active. The positive correlation of SHBG with testosterone will tend to minimize and moderate the androgenic effects of changing total testosterone in men.

Low serum SHBG, low total testosterone, and clinical AD are associated with increased risk of developing Metabolic Syndrome over time, particularly in nonoverweight, middle-aged men (BMI, <25). Low SHBG and/or AD may provide early warning signs for cardiovascular risk and an opportunity for early intervention in nonobese men.

Total E2 levels will be increased only if T is subsequently aromatized, the extent of which is influenced by parameters such as age and BMI. However, in contrast to T, E2 levels are not directly regulated by HPTA activity. The regulation of peripheral E2 levels by the HPTA is indirect and therefore probably not as tight compared with T levels.

Conditions associated with high SHBG levels in men such as advanced age, liver disease, hyperthyroidism, and estrogen administration. These conditions are associated with increased estrogen/androgen ratios and gynecomastia, and they seem to confirm the concept of SHBG as an estrogen amplifier.

In the pathogenesis of gynecomastia, a high estrogen/androgen balance seems to be of importance. Men with low levels of SHBG and a resulting high estrogen/androgen ratio would have a higher risk of developing gynecomastia, although this association has not been reported in the literature. Probably the changes in the estrogen/androgen ratio brought about by SHBG in eugonadal men are too subtle to cause gynecomastia.

However, besides the altered SHBG levels, these conditions are also associated with altered gonadal function. Hypogonadism is frequently observed in liver cirrhosis patients. In hyperthyroid men, lower levels of non-SHBG-T are frequently but not always reported, which suggests that the HPTA in these men is not always able to fully compensate for the rise in SHBG concentration. Moreover, the increased estrogen/androgen ratio in hyperthyroid subjects might be caused by increased androgen aromatization. The age-associated increase in SHBG is not associated with an increase in T levels, which suggests that the HPTA of older men is not capable of responding to a fall in T levels. Therefore, it is likely that the relative hypogonadism and not the increased SHBG per se may explain the high estrogen/androgen ratio in these men.

Injecting HCG - Intramuscularly or Subcutaneously?

Q: I have heard some people say to inject HCG intramuscularly and some say subcutaneously. Which one is it?

A: One should always inject hCG subcutaneously. The simplest reason is the comfort of the injection; less trauma to tissues; and decreased risk of infection. SC v IM are equally effective. As far as the kinetics of the injections one would expect them to be fairly similar. the reason why testosterone preparations last a longer time is due to the depot (oil) in which they are injected. hCG is soluble in water and will therefore be absorbed quickly. Other considerations are the weight of the individual. There are clinical indicators to monitor while taking hCG. If the hCG is being used for HPTA normalization a serum testosterone ashould be obtained while taking hCG and not after. this is critical and important for successful HPTA normalization.

Weissman, A., S. Lurie, et al. (1996). "Human chorionic gonadotropin: pharmacokinetics of subcutaneous administration." Gynecol Endocrinol 10(4): 273-6.

The objective of the present study was to evaluate the pharmacokinetics of human chorionic gonadotropin (hCG) following different regimens of subcutaneous and intramuscular single-dose administration. Two hypogonadotropic hypogonadal volunteers received hCG injections without prior ovarian stimulation. The regimens included a single dose of 10,000 IU hCG either subcutaneously or intramuscularly, or 5000 IU hCG intramuscularly. Serum beta-hCG concentrations were measured periodically up to 13 days after hCG administration. Each of the three regimens exhibit a similar pharmacokinetic profile and the highest serum beta-hCG concentrations were achieved with a dose of 10,000 IU administered subcutaneously. Seven days after hCG administration beta-hCG was detectable only after subcutaneous or intramuscular administration of 10,000 IU, but not after a single intramuscular injection of 5000 IU. From the preliminary results of the study it is suggested that a single intramuscular dose of 5000 IU hCG might be sufficient to trigger ovulation, but for luteal-phase support a higher dose may be needed. Subcutaneous administration of hCG for the induction of ovulation or luteal-phase support in gonadotropin-induced cycles is feasible and might offer a better tolerance and cost-effectiveness of infertility treatments, leading to their further simplification.

Trinchard-Lugan, I., A. Khan, et al. (2002). "Pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin in healthy male and female volunteers." Reprod Biomed Online 4(2): 106-15.

The pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin (rHCG) were investigated in three studies of healthy volunteers. After single intravenous doses of 25, 250 and 1000 microg, rHCG and urinary HCG (uHCG) showed linear pharmacokinetics described by a bi-exponential model, although the area under the curve (AUC) for uHCG was ~29% lower than for rHCG. After intramuscular or subcutaneous administration (absolute bioavailability, 40-50% for both), rHCG pharmacokinetics could be described by a first-order absorption, one-compartment model. During multiple subcutaneous dosing, the amount of HCG increased by approximately1.7-fold. A comparison of liquid and freeze-dried rHCG and freeze-dried uHCG showed pharmacokinetic bioequivalence. In down-regulated male subjects, single doses of 125 microg rHCG, given intravenously, intramuscularly or subcutaneously, produced comparable increases in serum testosterone, inhibin and 17beta-oestradiol, with little further increase during repeated subcutaneous administration (in female subjects, this produced a sustained comparable increase in serum androstenedione and testosterone concentrations). In conclusion, the pharmacokinetics and pharmacodynamics of rHCG are similar to those of uHCG and are not affected by the use of different formulations. In healthy subjects, rHCG produces pharmacodynamic responses consistent with HCG physiology and is suitable for use in the same clinical indications as uHCG. The secured source and high purity of rHCG may offer important advantages.

Burgues, S. and M. D. Calderon (1997). "Subcutaneous self-administration of highly purified follicle stimulating hormone and human chorionic gonadotrophin for the treatment of male hypogonadotrophic hypogonadism. Spanish Collaborative Group on Male Hypogonadotropic Hypogonadism." Hum Reprod 12(5): 980-6.

The efficacy and safety of highly purified follicle stimulating hormone (FSH) associated with human chorionic gonadotrophin (HCG) was studied in 60 men with hypogonadotrophic hypogonadism. Of these men, 16 suffered from Kallmann's syndrome, 19 from idiopathic hypogonadotrophic hypogonadism and 25 from hypopituitarism. Basal testosterone concentrations were found to be far below the normal range. At baseline, 26 patients were able to ejaculate and all of them showed azoospermia, while the remaining patients were aspermic. All patients self-administered s.c. injections of FSH (150 IU x three/week) and HCG (2500 IU x two/week) for at least 6 months and underwent periodic assessments of testicular function. Testosterone concentrations increased rapidly during treatment and all but one patient reached normal values. Testicular volume showed a sustained increase reaching almost 3-fold its baseline value. At the end of treatment, 48 patients (80.0%) had achieved a positive sperm count. The maximum sperm concentration during treatment was 24.5 +/- 8.1 x 10(6)/ml (mean +/- SEM). The median time to induce spermatogenesis was 5 months. Eleven patients reported adverse events, generally not related to treatment. Three patients experienced gynaecomastia. No local reactions at injection site were observed. In conclusion, the s.c. self-administration of highly purified FSH + HCG was well tolerated and effective in stimulating spermatogenesis and steroidogenesis in these patients.

Jones, T. H., J. F. Darne, et al. (1994). "Diurnal rhythm of testosterone induced by human chorionic gonadotrophin (hCG) therapy in isolated hypogonadotrophic hypogonadism: a comparison between subcutaneous and intramuscular hCG administration." Eur J Endocrinol 131(2): 173-8.

When human chorionic gonadotrophin (hCG) is used to stimulate testosterone synthesis and release in males with hypogonadotrophic hypogonadism, it is administered two or three times weekly by intramuscular injection. We have compared the pharmacokinetics of a twice weekly standard dose of hCG (5000 U) given for the first week by intramuscular injection and in the second week by self-administered subcutaneous injection. The patients studied had Kallmann's syndrome, isolated idiopathic hypogonadotrophic hypogonadism or post-traumatic isolated hypogonadotrophic hypogonadism. Salivary testosterone was collected twice daily at 08.00 h and 20.00 h, and serum testosterone was collected after 0, 24 h, 72 h, 120 h and 168 h each week. The cumulated serum and salivary testosterone levels were comparable on both intramuscular and subcutaneous hCG. In normal males there is diurnal variation in testosterone, with peak serum levels in the morning falling to a nadir in the evening. The exact nature and controlling factors of this circadian rhythm have not been established. In four of the subjects, the twice weekly hCG injections, either subcutaneous or intramuscular, produced a regular testosterone diurnal rhythm. The other four patients had fluctuations in testosterone but with no strict diurnal pattern. This study provides evidence that the luteinizing hormone-like action of hCG is necessary to prime the circadian rhythm but only a single bolus of hCG is sufficient to induce the rhythm in the absence of endogenous gonadotrophin production. In conclusion, self-administered subcutaneous hCG is safe and produces comparable levels of serum and salivary testosterone to that administered by the intramuscular route. Moreover, it was very well accepted by the patients and was preferred to conventional treatments. Human hCG in some patients with hypogonadotrophic hypogonadism produces normal physiological changes in daily testosterone levels.

Saal, W., H. J. Glowania, et al. (1991). "Pharmacodynamics and pharmacokinetics after subcutaneous and intramuscular injection of human chorionic gonadotropin." Fertil Steril 56(2): 225-9.

OBJECTIVE: The pharmacokinetics and efficiency of human chorionic gonadotropin (hCG) after subcutaneous (SC) injection was to clarify in comparison with the intramuscular (IM) mode of administration.

DESIGN: In a prospective study, the pharmacokinetics of hCG and the response of serum testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) after an IM and SC injection of 5,000 IU hCG were evaluated up to 144 hours in two randomized groups.

SETTING: The study was carried out in a clinical dermatology department providing tertiary care.

PARTICIPANTS: Twenty-four healthy male volunteers with a mean age of 22.7 +/- 4.3 years were divided into two groups.

INTERVENTIONS: Human chorionic gonadotropin (5,000 IU) was injected IM or SC.

MAIN OUTCOME MEASURE: Serum concentration of /b-hCG, T, LH, and FSH were evaluated after IM and SC administration of hCG. Differences between the two groups were determined by t-test.

RESULTS: Compared with IM administration of hCG, peak serum drug concentration was significantly delayed (P = 0.01) and serum half-life was prolonged (P = 0.01) after SC injection; however, T, LH, and FSH responses were identical.

CONCLUSIONS: Subcutaneous application of 5,000 IU hCG is as effective as IM administration in terms of steroidogenesis.

HPTA Normalization Protocol After Androgen Treatment

Q: What is the story behind the PCT protocol (HPTA Normalization Protocol After Androgen Treatment) posted on Michael Mooney's Medibolics website?

A: The protocol was worked out over a number of years with many patients. Much lower dosages were first used with no success. One has to remember that this is for an individual who is known to be normal before or at the minimum with no known pathology prior to treatment. So this would be unsuccessful in a patient with a definitive diagnosis of primary or secondary hypogonadism. However, there are a number of individuals given such a diagnosis with a prior history of AAS use that do not really fit the diagnosis given.

In my experience it has been easier to start the testicles producing T rather that the pituitary LH. But this may have more to do with the order in which they need to come online. If one is not successful in coupling the two, pituitary and testicles, but can demonstrate separately their functionality there is no worry about this occurring. In that situation lower doses are usually successful in the HPTA coming online.

Steroids with Michael Scally, M.D. #3