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METHODS
An observational study was done on the medical records of 5 adult male patients presenting to a clinic with induced hypogonadotropic hypogonadism. Patients were monitored and treatment recorded for the purposes of this observational study.
SUBJECTS
The medical records of five males age 27-49, mean 35.2, weighing 77-100 kg, mean 89.8 kg, with serum total testosterone levels below 240 ng/dL and serum luteinizing hormone (LH) levels below 1.5 mIU/mL were examined. Average presenting testosterone level was 98.2 ng/dL (normal= 240-827 ng/dL) while average LH level was undetectable at <1.0 mIU/mL (normal= 1.5-9.3 mIU/mL). The 5 patients had a history of AAS usage ranging from 9-60 months prior to presentation. All patients had ceased any testosterone therapy or AAS usage prior to initiation of treatment. Initial laboratory values confirmed that all patients had discontinued AAS long enough for endogenous lab values to fall below normal reference ranges. All patients were muscular in nature with an average BMI less than 27 at presentation. Table 1 presents the patient characteristics, anabolic history, and side effects upon presentation of the 5 patients.
LABORATORY STUDIES
Initial blood screening consisted of:
AST, ALT, GGT, TOTAL CHOLESTEROL, LH, FSH, TESTOSTERONE, GLUCOSE, PROLACTIN, PSA TOTAL, TSH, T3 UPTAKE, T4 TOTAL, T4 FREE, HEMOGLOBIN, HEMATOCRIT
Table 2 shows all baseline serum blood levels at presentation. Baseline blood screening excluded any form of hyperprolactinemia or hypothyroidism as causes of hypogonadism in most patients. After physician examination and history and physical evaluation, it was determined that a history of AAS usage was present and most likely the cause of the patients’ hypogonadotropic hypogonadal lab values; not hyperprolactinemia or hypothyroidism.
Laboratory testing was performed by Quest Diagnostics Inc., (Houston, TX) and SmithKline Beecham Clinical Laboratories, (Houston, TX). Repeat serum LH & testosterone samples were measured by immunoassay using chiron reagant kits on an ACS-180 instrument.
METHODS
A review of patients’ medical records showed a treatment intervention of (a) human chorionic gonadotropin (HCG) (Ferring Pharmaceuticals), (b) clomiphene citrate (Teva Pharmaceuticals), and (c) tamoxifen (AstraZeneca). Typical dosage of HCG consisted of 2500 units every other day for 16 days.
All HCG injections were self-administered intramuscularly. Starting dosages of clomiphene citrate and tamoxifen were 50mg and 20 mg daily, respectively. Patients started all three medications simultaneously and reported for the first follow-up blood work after completion of HCG, 16 days later. The post HCG blood analysis assessed testosterone-total response only. If testicular stimulation, i.e. testosterone production, was inadequate, additional HCG was administered at this stage of therapy rather than waiting an additional 30-45 days before the protocol completion. If the testicular response to the HCG demonstrated sufficient testicular stimulation (typically a blood serum level of >300 ng/dL), clomiphene citrate and tamoxifen were continued for 15 and 30 days, respectively. The arbitrary cut-off level of 300 ng/dL was used as a general assessment where sufficient Leydig cell stimulation was taking place even in light of artificial stimulation from HCG. A repeat blood sample was then taken at day 45 to assess hypothalamic-pituitary-gonadal axis status via luteinizing hormone and total testosterone levels. Because of the varying cessation times of the medications, the concluding blood sample was taken after a 30 and 15-day washout period of HCG and clomiphene citrate, respectively. For HPGA function to be considered normal, both LH and testosterone values had to fall within the normal reference ranges. For the purposes of patient treatment, if LH and testosterone values were still below normal limits at the conclusion of 45 days of treatment, a repeat protocol administration of HCG, clomiphene citrate, and tamoxifen was given. This protocol was repeated with every patient until LH and testosterone values reached normal ranges.
RESULTS
All five patients were considered eugonadal by normal laboratory reference ranges by the conclusion of treatment. Average serum total testosterone rose from 98.2 to 692.8 ng/dL. Average serum LH rose from <1.0 to 7.92 mIU/mL. An average of 48,974 U of HCG (five 10,000 Unit boxes), 3412.5 mg of clomiphene citrate (68.25 50mg tablets), and 968.71 mg of tamoxifen (48.44 20mg tablets) were used to treat all patients to eugonadal. Total treatment time ranged from 43-120 days. Mean elapsed time from initiation of treatment to eugonadal was 68.6 days. Statistical analysis was performed using repeated measures ANOVA. Pre and post treatment testosterone values were significantly (p<.001) different as were the LH values (p<.0008). Table 3 demonstrates the hormone changes during the treatment period and the duration to eugonadal.
ADVERSE EVENTS
None of the study subjects had any serious or treatment-terminating effects as a result of the multi-drug protocol. No problems were noted with regards to parameters of normal urologic function or treatment causing gynecomastia. Any side effects documented at presentation were reversed by the conclusion of treatment.
DISCUSSION
This observational study demonstrates the possible efficacy of HCG, clomiphene citrate, and tamoxifen citrate in returning the HPGA to normal physiological function in adult males suffering from androgen induced hypogonadotropic hypogonadism. In the case of decreased testicular function manifested by low testosterone levels, it is of primary importance to first return the normal function of the testicular cells. The initial lack of response to HCG should not immediately be a cause for the initiation of testosterone replacement therapy, as with the current accepted therapy modality by many physicians. Blood analysis confirmed that no exogenous testosterone was administered during the treatment period, as exogenous androgens would have had a suppressive effect on endogenous gonadotropin production. Therefore, because of the corresponding normal gonadotropin and testosterone values, it is accepted that gonadotropin and testicular function were normal by the conclusion of treatment. The standard treatment of HIV-related muscle wasting, AAS therapy, may involve decades of treatment and the attendant problems with any therapy of a prolonged nature. Polycythemia vera, elevated hepatic enzymes, and prolonged negative alterations in lipid profile are a few of the dangers experienced by HIV patients administered AAS for extended periods. Of greatest concern is the increasing numbers of individuals who are currently being treated with AAS to increase muscle mass either for medicinal or recreational means without attention being given to periodically returning the HPGA to normal. With roughly 4 million men in the U.S. being considered hypogonadal (Lacayo R., 2000; Sheffield-Moore et al, 1999; Shelton DL, 2000), an estimated 200,000 men are currently receiving testosterone treatment for the condition (Shelton DL, 2000). As stated earlier, AAS are being prescribed to HIV & AIDS sufferers to combat progressive muscle loss. The Centers for Disease Control and Prevention (CDC) reported an estimated 635,000+ men diagnosed with AIDS through December 2000 while an estimated 97,700 have been reported with HIV (Centers for Disease Control, vol.12, No. 2, table 5; Centers for Disease Control, vol. 12, No. 2, table 6). In 2000 alone over 31,000 men were diagnosed with the AIDS virus (Centers for Disease Control, vol. 12, No. 2, figure 3). Between hypogonadal, AIDS, & HIV males, potentially over 900,000 men are being administered AAS therapy.
Studies recently published on patients suffering from various tissuedepleting conditions and HIV affliction (Bhasin et al, 2000; Grinspoon et al, 1998; 1999; 2000; Rabkin et al, 1999; 2000; Sattler et al, 1999; Strawford et al, 1999;1999; Van Loan et al, 1999) have not identified what should be done to restore normal endocrine status post-treatment. Considering the dosages and compounds administered in many studies, there is no question that subjects were left hypogonadal after therapy. In the cases where the periodic use of testosterone or AAS are necessary, intervention to return the HPGA to normal should be initiated as soon as possible after the cessation of the AAS. As described herein, a possible treatment modality may be the combined regimen of HCG, clomiphene citrate, and tamoxifen. Medical history has demonstrated examples of physician-induced complications resulting from treatment. Iatrogenic hyperthyroidism (Bartsch & Scheiber, 1981) and iatrogenic Cushing’s syndrome (Cihak & Beary, 1977; Kimmerle & Rolla, 1985; Smidt & Johnston, 1975; Tuel et al, 1990) are cases were administered medications or treatments provoked abnormalities in patients’ normal physiology. The administration of testosterone as a treatment for hypogonadotropic hypogonadism falls into this same category of causing endocrine related abnormalities (Bhasin et al, 1996; Marynick et al, 1979; Strawford et al, 1999; Tenover, 1992). Testosterone replacement therapy has proven to be very effective in reversing the symptoms of suppressed testosterone production, but does not treat the underlying cause of the deficiency. Positive effects of testosterone treatment; i.e. improved sex drive, improved sense of well-being, lean body mass; are all transient in light of plummeting gonadotropin levels. Upon cessation of testosterone treatment patients can expect a complete reversal of positive benefits as exogenously influenced testosterone levels metabolize and decline rapidly. Further controlled studies need to be performed showing the combined effects of HCG, clomiphene citrate, and tamoxifen in returning HPGA functioning to normal. Long-term follow-up on these patients returning to normal will be necessary to ensure permanent reversal of hypogonadotropic hypogonadal conditions. In addition, studies documenting dose-response curves for pituitary inhibition and reversal due to AAS administration are critical in determining the correct dose, duration, and form of treatment that is optimal without causing permanent damage. When the need for long-term androgen use presents, using moderately supraphysiologic doses of androgens as suggested by Strawford and colleagues (1999) coupled with post-treatment HPGA restoration as demonstrated here, may be a more effective means over high-dose protocols used to offset negative alterations in lean body mass. Unfortunately current studies have yet to adequately address a standard of patient care post-androgen therapy. Because of the negative impact of the hypogonadal state on physical and mental well- being, pharmacotherapy that restores HPGA function more rapidly than current modalities would greatly benefit men with hypogonadotropic hypogonadism.
While we believe that the treatment protocol was effective in returning normal hormonal function to these men, the lack of randomization or a control group leaves room for speculation. Although cases of spontaneous return to eugonadism with no medicinal intervention have been published, these reports documented durations anywhere from 6-18 months before normal hormone status was achieved (Gazvani et al, 1997; Wu et al, 1996). If the alternative treatment modality described herein can reverse suppressed gonadotropin production and AAS associated side effects much sooner than non-treatment, further evaluation of this therapy should continue.
METHODS
An observational study was done on the medical records of 5 adult male patients presenting to a clinic with induced hypogonadotropic hypogonadism. Patients were monitored and treatment recorded for the purposes of this observational study.
SUBJECTS
The medical records of five males age 27-49, mean 35.2, weighing 77-100 kg, mean 89.8 kg, with serum total testosterone levels below 240 ng/dL and serum luteinizing hormone (LH) levels below 1.5 mIU/mL were examined. Average presenting testosterone level was 98.2 ng/dL (normal= 240-827 ng/dL) while average LH level was undetectable at <1.0 mIU/mL (normal= 1.5-9.3 mIU/mL). The 5 patients had a history of AAS usage ranging from 9-60 months prior to presentation. All patients had ceased any testosterone therapy or AAS usage prior to initiation of treatment. Initial laboratory values confirmed that all patients had discontinued AAS long enough for endogenous lab values to fall below normal reference ranges. All patients were muscular in nature with an average BMI less than 27 at presentation. Table 1 presents the patient characteristics, anabolic history, and side effects upon presentation of the 5 patients.
LABORATORY STUDIES
Initial blood screening consisted of:
AST, ALT, GGT, TOTAL CHOLESTEROL, LH, FSH, TESTOSTERONE, GLUCOSE, PROLACTIN, PSA TOTAL, TSH, T3 UPTAKE, T4 TOTAL, T4 FREE, HEMOGLOBIN, HEMATOCRIT
Table 2 shows all baseline serum blood levels at presentation. Baseline blood screening excluded any form of hyperprolactinemia or hypothyroidism as causes of hypogonadism in most patients. After physician examination and history and physical evaluation, it was determined that a history of AAS usage was present and most likely the cause of the patients’ hypogonadotropic hypogonadal lab values; not hyperprolactinemia or hypothyroidism.
Laboratory testing was performed by Quest Diagnostics Inc., (Houston, TX) and SmithKline Beecham Clinical Laboratories, (Houston, TX). Repeat serum LH & testosterone samples were measured by immunoassay using chiron reagant kits on an ACS-180 instrument.
METHODS
A review of patients’ medical records showed a treatment intervention of (a) human chorionic gonadotropin (HCG) (Ferring Pharmaceuticals), (b) clomiphene citrate (Teva Pharmaceuticals), and (c) tamoxifen (AstraZeneca). Typical dosage of HCG consisted of 2500 units every other day for 16 days.
All HCG injections were self-administered intramuscularly. Starting dosages of clomiphene citrate and tamoxifen were 50mg and 20 mg daily, respectively. Patients started all three medications simultaneously and reported for the first follow-up blood work after completion of HCG, 16 days later. The post HCG blood analysis assessed testosterone-total response only. If testicular stimulation, i.e. testosterone production, was inadequate, additional HCG was administered at this stage of therapy rather than waiting an additional 30-45 days before the protocol completion. If the testicular response to the HCG demonstrated sufficient testicular stimulation (typically a blood serum level of >300 ng/dL), clomiphene citrate and tamoxifen were continued for 15 and 30 days, respectively. The arbitrary cut-off level of 300 ng/dL was used as a general assessment where sufficient Leydig cell stimulation was taking place even in light of artificial stimulation from HCG. A repeat blood sample was then taken at day 45 to assess hypothalamic-pituitary-gonadal axis status via luteinizing hormone and total testosterone levels. Because of the varying cessation times of the medications, the concluding blood sample was taken after a 30 and 15-day washout period of HCG and clomiphene citrate, respectively. For HPGA function to be considered normal, both LH and testosterone values had to fall within the normal reference ranges. For the purposes of patient treatment, if LH and testosterone values were still below normal limits at the conclusion of 45 days of treatment, a repeat protocol administration of HCG, clomiphene citrate, and tamoxifen was given. This protocol was repeated with every patient until LH and testosterone values reached normal ranges.
RESULTS
All five patients were considered eugonadal by normal laboratory reference ranges by the conclusion of treatment. Average serum total testosterone rose from 98.2 to 692.8 ng/dL. Average serum LH rose from <1.0 to 7.92 mIU/mL. An average of 48,974 U of HCG (five 10,000 Unit boxes), 3412.5 mg of clomiphene citrate (68.25 50mg tablets), and 968.71 mg of tamoxifen (48.44 20mg tablets) were used to treat all patients to eugonadal. Total treatment time ranged from 43-120 days. Mean elapsed time from initiation of treatment to eugonadal was 68.6 days. Statistical analysis was performed using repeated measures ANOVA. Pre and post treatment testosterone values were significantly (p<.001) different as were the LH values (p<.0008). Table 3 demonstrates the hormone changes during the treatment period and the duration to eugonadal.
ADVERSE EVENTS
None of the study subjects had any serious or treatment-terminating effects as a result of the multi-drug protocol. No problems were noted with regards to parameters of normal urologic function or treatment causing gynecomastia. Any side effects documented at presentation were reversed by the conclusion of treatment.
DISCUSSION
This observational study demonstrates the possible efficacy of HCG, clomiphene citrate, and tamoxifen citrate in returning the HPGA to normal physiological function in adult males suffering from androgen induced hypogonadotropic hypogonadism. In the case of decreased testicular function manifested by low testosterone levels, it is of primary importance to first return the normal function of the testicular cells. The initial lack of response to HCG should not immediately be a cause for the initiation of testosterone replacement therapy, as with the current accepted therapy modality by many physicians. Blood analysis confirmed that no exogenous testosterone was administered during the treatment period, as exogenous androgens would have had a suppressive effect on endogenous gonadotropin production. Therefore, because of the corresponding normal gonadotropin and testosterone values, it is accepted that gonadotropin and testicular function were normal by the conclusion of treatment. The standard treatment of HIV-related muscle wasting, AAS therapy, may involve decades of treatment and the attendant problems with any therapy of a prolonged nature. Polycythemia vera, elevated hepatic enzymes, and prolonged negative alterations in lipid profile are a few of the dangers experienced by HIV patients administered AAS for extended periods. Of greatest concern is the increasing numbers of individuals who are currently being treated with AAS to increase muscle mass either for medicinal or recreational means without attention being given to periodically returning the HPGA to normal. With roughly 4 million men in the U.S. being considered hypogonadal (Lacayo R., 2000; Sheffield-Moore et al, 1999; Shelton DL, 2000), an estimated 200,000 men are currently receiving testosterone treatment for the condition (Shelton DL, 2000). As stated earlier, AAS are being prescribed to HIV & AIDS sufferers to combat progressive muscle loss. The Centers for Disease Control and Prevention (CDC) reported an estimated 635,000+ men diagnosed with AIDS through December 2000 while an estimated 97,700 have been reported with HIV (Centers for Disease Control, vol.12, No. 2, table 5; Centers for Disease Control, vol. 12, No. 2, table 6). In 2000 alone over 31,000 men were diagnosed with the AIDS virus (Centers for Disease Control, vol. 12, No. 2, figure 3). Between hypogonadal, AIDS, & HIV males, potentially over 900,000 men are being administered AAS therapy.
Studies recently published on patients suffering from various tissuedepleting conditions and HIV affliction (Bhasin et al, 2000; Grinspoon et al, 1998; 1999; 2000; Rabkin et al, 1999; 2000; Sattler et al, 1999; Strawford et al, 1999;1999; Van Loan et al, 1999) have not identified what should be done to restore normal endocrine status post-treatment. Considering the dosages and compounds administered in many studies, there is no question that subjects were left hypogonadal after therapy. In the cases where the periodic use of testosterone or AAS are necessary, intervention to return the HPGA to normal should be initiated as soon as possible after the cessation of the AAS. As described herein, a possible treatment modality may be the combined regimen of HCG, clomiphene citrate, and tamoxifen. Medical history has demonstrated examples of physician-induced complications resulting from treatment. Iatrogenic hyperthyroidism (Bartsch & Scheiber, 1981) and iatrogenic Cushing’s syndrome (Cihak & Beary, 1977; Kimmerle & Rolla, 1985; Smidt & Johnston, 1975; Tuel et al, 1990) are cases were administered medications or treatments provoked abnormalities in patients’ normal physiology. The administration of testosterone as a treatment for hypogonadotropic hypogonadism falls into this same category of causing endocrine related abnormalities (Bhasin et al, 1996; Marynick et al, 1979; Strawford et al, 1999; Tenover, 1992). Testosterone replacement therapy has proven to be very effective in reversing the symptoms of suppressed testosterone production, but does not treat the underlying cause of the deficiency. Positive effects of testosterone treatment; i.e. improved sex drive, improved sense of well-being, lean body mass; are all transient in light of plummeting gonadotropin levels. Upon cessation of testosterone treatment patients can expect a complete reversal of positive benefits as exogenously influenced testosterone levels metabolize and decline rapidly. Further controlled studies need to be performed showing the combined effects of HCG, clomiphene citrate, and tamoxifen in returning HPGA functioning to normal. Long-term follow-up on these patients returning to normal will be necessary to ensure permanent reversal of hypogonadotropic hypogonadal conditions. In addition, studies documenting dose-response curves for pituitary inhibition and reversal due to AAS administration are critical in determining the correct dose, duration, and form of treatment that is optimal without causing permanent damage. When the need for long-term androgen use presents, using moderately supraphysiologic doses of androgens as suggested by Strawford and colleagues (1999) coupled with post-treatment HPGA restoration as demonstrated here, may be a more effective means over high-dose protocols used to offset negative alterations in lean body mass. Unfortunately current studies have yet to adequately address a standard of patient care post-androgen therapy. Because of the negative impact of the hypogonadal state on physical and mental well- being, pharmacotherapy that restores HPGA function more rapidly than current modalities would greatly benefit men with hypogonadotropic hypogonadism.
While we believe that the treatment protocol was effective in returning normal hormonal function to these men, the lack of randomization or a control group leaves room for speculation. Although cases of spontaneous return to eugonadism with no medicinal intervention have been published, these reports documented durations anywhere from 6-18 months before normal hormone status was achieved (Gazvani et al, 1997; Wu et al, 1996). If the alternative treatment modality described herein can reverse suppressed gonadotropin production and AAS associated side effects much sooner than non-treatment, further evaluation of this therapy should continue.
