madman
Super Moderator
Nelson's house!
Mix of therapeutic T doses and does of T used/abused for the sole purpose of muscle enhancement!
* We stratified the entire cohort into two groups: those not on concurrent testosterone therapy during hCG/FSH reboot (No testosterone therapy) vs. those who were (Concurrent testosterone therapy). Although testosterone dosing was not standardized within this latter cohort, all patients were undergoing 100 mg-400 mg of injectable testosterone therapy per week.
----
* Three-quarters of infertile men with prior testosterone therapy demonstrated sperm concentration improvements after hCG/FSH reboot. Concurrent use of testosterone therapy did not dampen hCG/FSH-mediated spermatogenic recovery. Patients with larger testicular volumes, higher starting sperm concentrations, and lower serum FSH levels were more likely to respond to hCG/FSH reboot. Patient age and prior testosterone therapy duration did not predict therapy success contrary to previous studies (19).
--------
* Using GoodRx as a benchmark, examples of purified hCG include Pregnyl and Novarel which cost ~$300 per 10,000IU ($0.03/IU). Now discontinued Bravelle (urofollitropin) was a form of purified FSH and cost ~$750 for 750 IU ($1/IU). A 250-microgram (~6000 IU) Ovidrel vial (recombinant choriogonadotropin alfa) costs ~$250 ($0.04/IU). A 900 IU cartridge of Follistim (recombinant follitropin beta) averages $3000 ($3.33/IU). A single month’s supply of brand hCG and FSH dosed at 3000 IU and 75 IU three times a week would cost ~$4000. Currently, 81 503b compounding pharmacies across the US are approved to compound hCG and FSH (20). Only 4 supply both hCG and FSH and are limited to Nevada, Texas, Pennsylvania, and Massachusetts. Reported costs are $50-$80 per 10,000 IU of purified hCG and $165 per 1500 IU of purified FSH.
-------
* Interestingly, work by Roth demonstrates that far lower doses of hCG than those used clinically (just 125 IU of hCG every other day for 5 days) can adequately restore intratesticular testosterone levels required for spermatogenesis (21). Perhaps current hCG treatment regimens are supratherapeutic. Fortunately, reported side effects of hCG are minimal (22,23). Conversely, dosing oligospermic men with the 75 IU of FSH three times a week employed in this study may be subtherapeutic. A meta-analysis by Canarella assessed the efficacy of FSH dosing in men with idiopathic oligospermia and grouped dosing regimens into low (175-262.5 IU/week), intermediate (350-525 IU/week), and high (700-1050 IU/week) (24). Those on the low-dosing regimen demonstrated improvements only in sperm motility. Those on the high-dosing regimen demonstrated increases in sperm concentration, total sperm count, and motility.
----------
* In our patient cohort of severely oligospermic men undergoing hCG/FSH, we found that 58% of these patients returned to normospermia. Our findings may support that hCG/FSH is a superior treatment regimen for the recovery of spermatogenesis in infertile men with a history of testosterone use.
------
* Optimal dosing of hCG and FSH for male factor fertility remains to be determined
---------8
Introduction
Three percent of US males under 40 utilize testosterone therapy, which unbeknownst to many, can result in testicular atrophy, decreased sperm count, and reduced fertility(1–3). Current guidelines from the American Urological Association and the American Society for Reproductive Medicine recommend against testosterone monotherapy for individuals trying to conceive(4). Despite this recommendation, 25% of men are not aware of the negative impact of testosterone on fertility(5), and more worrisome, 25% of urologists incorrectly believe that testosterone can improve male fertility(6). Due to the limited number of high-quality studies, there currently exists no standardized treatment regimen for restoring sperm parameters in infertile men with prior testosterone use.
--------
Clinicians have designed and utilized various regimens of off-label spermatogenic restoration therapies. The simplest therapy is discontinuing testosterone with the hope of a return to normospermia. Liu published an analysis of over 30 studies from 1990-2005 emphasizing the utility of testosterone as a form of reversible hormonal male contraceptive given for 16-78 weeks(7). Men included in this study were eugonadal, normal on physical exam, and had two semen analyses with sperm concentrations of at least 20 million [M] per mL before initiating testosterone. Two-thirds of men returned to normospermia within 6 months, and all men at 2 years following testosterone cessation. However, this study carries important caveats. Many infertile males have used testosterone for longer than the few months to one year time frame described in this study. A significant number may also harbor undiagnosed forms of male factor infertility before testosterone use.
--------
Another treatment utilized is hCG injection monotherapy. hCG works as an LH analog stimulating Leydig cells to produce testosterone in the testicles, a requirement for spermatogenesis(8). Previous studies have demonstrated that hCG taken every other day preserved spermatogenesis in men on testosterone therapy(9). Treatment regimens range from 1000-3000IU one to three times a week. A second regimen utilized is the combination of hCG and a Selective Estrogen Receptor Modulator (SERM) or an Aromatase Inhibitor (AI). SERMs (clomiphene or tamoxifen) and AIs (anastrozole) block the negative feedback of endogenous estradiol,which increases production of LH and FSH, the latter of which stimulates Sertoli cells which are critical for sperm maturation(10–12). Wenker illustrated the utility of testosterone cessation and combination therapy with hCG (dosed 3000 IU every other day) and a SERM or AI for the treatment of azoospermic or severely oligospermic men with a history of testosterone use. Forty-seven of the 49 patients (95.9%) demonstrated improved semen parameters(13).
-----------
More recently, two authors have explored hCG and FSH therapy in restoring sperm parameters in infertile men with prior testosterone use. Campbell compared the efficacy of hCG/clomiphene vs. hCG/FSH therapy in azoospermic men with prior testosterone use and found hCG/FSH therapy resulted in faster return of sperm in theejaculate, averaging 5.5 months vs. 14.8 months in the hCG/clomiphene group (14). In a small series of 10 patients, Hakky explored hCG/FSH stimulation in men undergoing concurrent testosterone therapy and found improvements in sperm concentrations increasing from 2.99 M total motile sperm to 98.4 M after treatment (15). Complementing these data, Tatem described a practice pattern in which if no improvements in semen parameters are observed after 3 months of hCG/clomiphene therapy, providers may switch patients to hCG/FSH therapy thereafter (16).
-------------
We hypothesized that direct gonadotropic stimulation with purified hCG and FSH (in lieu of indirect SERM/AI-mediated FSH release) would result in improved recovery of spermatogenesis in azoospermic, severely oligospermic (<5M/mL sperm), and oligospermic (>5M/mL but <15M/mL sperm) men with a history of testosterone use. Secondarily, we investigated whether concurrent use of testosterone therapy during combination hCG/FSH therapy would dampen spermatogenic recovery as compared to discontinuation of testosterone therapy entirely. As withdrawal of testosterone often leads to the recurrence of hypogonadal symptoms, most patients receiving testosterone are reluctant to stop even for fertility purposes (17). Furthermore, a recently published clinical trial found no difference in spermatogenic recovery in patients with congenital hypogonadotropic hypogonadism continuing testosterone vs. those who did not during hCG/FSH therapy (18). We hypothesized that our patients would respond similarly. We present the largest cohort to date undergoing dual hCG/FSH gonadotropic therapy for the treatment of infertility secondary to prior testosterone use.
------------4
Materials and Methods
We conducted a retrospective cohort analysis of men prescribed 3000 International Units (IU) of hCG and 75IU of FSH three times a week (self-administered by subcutaneous injection) who sought infertility treatment at a single andrology clinic at Baylor College of Medicine from January 2020-March 2024. We termed this therapy “hCG/FSH reboot”. All patients received these medications from a single local compounding pharmacy with approved access to purified (i.e. non-recombinant) preparations of hCG and FSH. To promote patient compliance and not deviate from the standard three times a week dosing of hCG monotherapy, all patients were instructed to draw up both the hCG and FSH into the same syringe and inject both agents via one injection on Mondays, Wednesdays, and Fridays.
----------
Electronic charts were reviewed to record patient age, race, body mass index (BMI), co-morbidities, female partner age, duration of current conception attempt, and testicular size (exam and/or ultrasound) before hCG/FSH reboot. Prior duration of testosterone use, administration route, and indication for testosterone therapy before and during hCG/FSH reboot were noted. Semen analyses (sperm concentrations) and serum hormone values (FSH, LH, and testosterone) collected at 3-month intervals before and during hCG/FSH reboot were recorded. Sperm concentrations were classified as azoospermic (no sperm), severely oligospermic (<5 M/mL), oligospermic (>5M/mL but <15M/mL), or normospermic (>15M/mL). Duration of hCG/FSH reboot was defined as the interval from the semen analysis analyzed at the initiation of hCG/FSH reboot to the highest documented sperm concentration recorded during therapy. This endpoint was chosen to represent the ceiling for treatment response, or i.e. the “best case scenario” for a patient undergoing treatment, as not all patients had a similar number of semen analyses, nor do we know whether hCG/FSH therapy promotes spermatogenesis linearly with time. Patient data were de-identified, securely stored, and analyzed.
-----------
The primary aim of this study was to evaluate the efficacy of hCG/FSH reboot in improving sperm concentrations in infertile men with a history of testosterone therapy. The secondary aim of this study was to determine the impact of concurrent testosterone therapy use on spermatogenic recovery during hCG/FSH reboot. We stratified the entire cohort into two groups: those not on concurrent testosterone therapy during hCG/FSH reboot (No testosterone therapy) vs. those who were (Concurrent testosterone therapy). Although testosterone dosing was not standardized within this latter cohort, all patients were undergoing 100 mg-400 mg of injectable testosterone therapy per week. Finally, we determined whether specific patient variables predicted a positive response to hCG/FSH reboot (i.e. moving from a lower sperm concentration group to a higher group).
-------------
Statistical analyses were performed using GraphPad Prism (Version 10) and R (Version 4.4.1). Normality of data was assessed via the Shapiro-Wilk test (alpha 0.05). For normally distributed data unpaired student’s t test was performed. For non-normally distributed data unpaired Mann-Whitney test was performed. A completecase sensitivity analysis was performed to account for potential bias due to missing data. To assess an individual’s change in sperm concentration during hCG/FSH reboot, a paired Wilcoxon Signed Rank test was performed for these non-normally distributed data. Simple logistic regression analysis was performed to determine the impact of patient variables on the improvement in sperm concentration after hCG/FSH reboot. P<0.05 deemed significance. The study was reviewed and approved by the Baylor College of Medicine Institutional Review Board (IRB H-23509: Recovery of Spermatogenesis after Testosterone Administration)
--------------4
Discussion
Three-quarters of infertile men with prior testosterone therapy demonstrated sperm concentration improvements after hCG/FSH reboot. Concurrent use of testosterone therapy did not dampen hCG/FSH-mediated spermatogenic recovery. Patients with larger testicular volumes, higher starting sperm concentrations, and lower serum FSH levels were more likely to respond to hCG/FSH reboot. Patient age and prior testosterone therapy duration did not predict therapy success contrary to previous studies (19). Overall, we present a novel and efficacious treatment strategy for restoring spermatogenesis in men with prior testosterone use.
-------------
A major limitation to hCG/FSH therapy is cost and availability. These medications are either purified from the urine of pregnant (hCG) or post-menopausal (FSH) donors or made recombinantly. Using GoodRx as a benchmark, examples of purified hCG include Pregnyl and Novarel which cost ~$300 per 10,000IU ($0.03/IU). Now discontinued Bravelle (urofollitropin) was a form of purified FSH and cost ~$750 for 750 IU ($1/IU). A 250-microgram (~6000 IU) Ovidrel vial (recombinant choriogonadotropin alfa) costs ~$250 ($0.04/IU). A 900 IU cartridge of Follistim (recombinant follitropin beta) averages $3000 ($3.33/IU). A single month’s supply of brand hCG and FSH dosed at 3000 IU and 75 IU three times a week would cost ~$4000. Currently, 81 503b compounding pharmacies across the US are approved to compound hCG and FSH (20). Only 4 supply both hCG and FSH and are limited to Nevada, Texas, Pennsylvania, and Massachusetts. Reported costs are $50-$80 per 10,000 IU of purified hCG and $165 per 1500 IU of purified FSH.
---------------
Optimal dosing of hCG and FSH for male factor fertility remains to be determined. As hCG administration does not augment serum LH levels, clinicians will often monitor changes in serum testosterone and semen analyses to assess efficacy and adjust dosing accordingly. Interestingly, work by Roth demonstrates that far lower doses of hCG than those used clinically (just 125 IU of hCG every other day for 5 days) can adequately restore intratesticular testosterone levels required for spermatogenesis (21). Perhaps current hCG treatment regimens are supratherapeutic. Fortunately, reported side effects of hCG are minimal (22,23). Conversely, dosing oligospermic men with the 75 IU of FSH three times a week employed in this study may be subtherapeutic. A meta-analysis by Canarella assessed the efficacy of FSH dosing in men with idiopathic oligospermia and grouped dosing regimens into low (175-262.5 IU/week), intermediate (350-525 IU/week), and high (700-1050 IU/week) (24). Those on the low-dosing regimen demonstrated improvements only in sperm motility. Those on the high-dosing regimen demonstrated increases in sperm concentration, total sperm count, and motility.
--------------
Complementing clinical indications to continue testosterone therapy during hCG/FSH reboot, we hypothesized that any negative pituitary feedback signaled by exogenous testosterone (thereby dampening endogenous LH and FSH release) is overcome by adequate if not superior gonadotropic stimulation with exogenous hCG and FSH. Men with azoospermia and oligospermia have been shown to harbor anti-FSH antibodies(25). Thus, one could speculate that the therapeutic introduction of antigenically foreign hCG/FSH, to which an individual’s immune system has yet to develop neutralizing antibodies, could temporarily restore adequate gonadotropic signaling. Looking toward the future, recombinant technology has led to hCG and FSH molecules with enhanced biologic activity and longer serum half-lives secondary to N-glycosylation and sialylation modifications and often escape immunogenicity(26–28). For the infertile male requiring prolonged gonadotropic treatment, recombinant formulations may escape immunologic surveillance and permit longer-term spermatogenic signaling. Future clinical studies may benefit from measuring serum anti-Mullerian hormone and inhibin-B for Sertoli cell response (18) and 17-hydroxyprogesterone (a promising biomarker for intratesticular testosterone levels) for Leydig cell response (29).
----------
Our article is timely and complements recent work by Ledesma (30). Ledesma demonstrated that 28% of azoospermic men with a history of testosterone use remained azoospermic despite treatment with hCG/clomiphene. We demonstrate that a comparable 35% of azoospermic men with prior testosterone use remained azoospermic despite hCG/FSH. Potential etiologies in our cohort included delayed puberty, orchidopexy, left testicular cancer and chemotherapy, pituitary adenoma, empty sella syndrome, LH beta chain mutation, Crohn’s Disease on high-dose corticosteroids, severe obesity, and Klinefelter syndrome. Whereas their study found that only 6% of azoospermic men returned to normospermia after hCG/clomiphene(30), we found that 14% of azoospermic patients returned to normospermia after hCG/FSH. We hypothesize that hCG/clomiphene therapy requires more than just 6 months treatment, as supported by Campbell, who demonstrated faster resolution of azoospermia in men undergoing hCG/FSH vs. hCG/clomiphene (14). When grouping both azoospermic and severely oligospermic patients, Ledesma found that 17% returned to normospermia after hCG/clomiphene. In our patient cohort of severely oligospermic men undergoing hCG/FSH, we found that 58% of these patients returned to normospermia. Our findings may support that hCG/FSH is a superior treatment regimen for the recovery of spermatogenesis in infertile men with a history of testosterone use.
------------
The inherent limitation of our study is its retrospective nature without strict inclusion criteria, randomization, or patient monitoring (i.e., some data, such as hormone levels, are not completely captured). Specific limitations and selection biases also include the following: 1) exclusion of patients not undergoing a subsequent semen analysis after initial prescription of hCG/FSH therapy (n=102, potentially missing those patients unable to afford the high cost of hCG/FSH), 2) exclusion of patients without a documented history of testosterone use (n=39, raising the question of whether hCG/FSH therapy would benefit testosterone naïve infertile patients), and 3) exclusion of patients documented to be normospermic (>15 M/mL) despite being treated for infertility (n=8, highlighting whether gonadotropic therapy could improve not only sperm quantity but quality). Accordingly, one should not generalize our findings and propose that hCG/FSH therapy would benefit all infertile male patients.
-----------
Our study is also limited by its relatively short follow-up. Although the median time on hCG/FSH reboot to achieve the highest documented sperm concentration was 4.7 months, the upper quartile of therapy duration ranged from 8.7 to 29.4 months. Within this upper quartile, however, 73% of patients still demonstrated an improvement in their sperm concentrations vs. 74% of patients in the lower three quartiles. This raises the possibility that some patients may take longer to respond to hCG/FSH reboot therapy. Longer follow-up will be required to better understand this regimen’s safety and efficacy profile. Finally, we did not assess fertility outcomes in patients undergoing hCG/FSH reboot therapy as our IRB did not include calling patients for follow up. However, men with isolated hypogonadotropic hypogonadism treated with human Menopausal Gonadotropin ,a combination of urinary purified LH and FSH, can reliably achieve pregnancy despite having severe oligospermia or oligospermia(31). Thus, we posit that any improvement in sperm concentration secondary to hCG/FSH therapy represents a means to restore fertility in men with prior testosterone use.
--- --------
Key to implementing standardized, guideline-based treatment protocols for the treatment of infertility secondary to testosterone use are prospective trials. To confirm these data, the authors are currently designing a multi-center, randomized, and controlled trial to assess hCG/FSH therapy in infertile men with prior testosterone use. Studies of importance should also include prospective trials comparing the efficacy of hCG monotherapy or hCG/Clomiphene to hCG/FSH, as well as the efficacy of hCG/FSH therapy in testosterone naïve patients(18).
-----------
Ultimately, the strength of this study is its size, representing the largest study to date investigating the utility of gonadotropic hCG/FSH therapy in restoring spermatogenesis in men with a history of testosterone use. Subjects followed a consistent medication regimen throughout the study, allowing appropriate analyses with semen analyses and hormonal testing at 3-month intervals. With hope of increased availability and reduced cost, hCG/FSH gonadotropic therapy may represent the optimal regimen for spermatogenic recovery in infertile men with a history of testosterone use
--------4
Conclusions
We report optimal recovery of spermatogenesis with hCG/FSH reboot therapy in infertile men with a history of testosterone use. Moreover, we demonstrate that concurrent testosterone therapy does not impede hCG/FSH-mediated spermatogenic recovery. Although further prospective trials are needed, we present an efficacious treatment strategy to optimally restore semen parameters in infertile men with a history of testosterone use.
Mix of therapeutic T doses and does of T used/abused for the sole purpose of muscle enhancement!
* We stratified the entire cohort into two groups: those not on concurrent testosterone therapy during hCG/FSH reboot (No testosterone therapy) vs. those who were (Concurrent testosterone therapy). Although testosterone dosing was not standardized within this latter cohort, all patients were undergoing 100 mg-400 mg of injectable testosterone therapy per week.
----
* Three-quarters of infertile men with prior testosterone therapy demonstrated sperm concentration improvements after hCG/FSH reboot. Concurrent use of testosterone therapy did not dampen hCG/FSH-mediated spermatogenic recovery. Patients with larger testicular volumes, higher starting sperm concentrations, and lower serum FSH levels were more likely to respond to hCG/FSH reboot. Patient age and prior testosterone therapy duration did not predict therapy success contrary to previous studies (19).
--------
* Using GoodRx as a benchmark, examples of purified hCG include Pregnyl and Novarel which cost ~$300 per 10,000IU ($0.03/IU). Now discontinued Bravelle (urofollitropin) was a form of purified FSH and cost ~$750 for 750 IU ($1/IU). A 250-microgram (~6000 IU) Ovidrel vial (recombinant choriogonadotropin alfa) costs ~$250 ($0.04/IU). A 900 IU cartridge of Follistim (recombinant follitropin beta) averages $3000 ($3.33/IU). A single month’s supply of brand hCG and FSH dosed at 3000 IU and 75 IU three times a week would cost ~$4000. Currently, 81 503b compounding pharmacies across the US are approved to compound hCG and FSH (20). Only 4 supply both hCG and FSH and are limited to Nevada, Texas, Pennsylvania, and Massachusetts. Reported costs are $50-$80 per 10,000 IU of purified hCG and $165 per 1500 IU of purified FSH.
-------
* Interestingly, work by Roth demonstrates that far lower doses of hCG than those used clinically (just 125 IU of hCG every other day for 5 days) can adequately restore intratesticular testosterone levels required for spermatogenesis (21). Perhaps current hCG treatment regimens are supratherapeutic. Fortunately, reported side effects of hCG are minimal (22,23). Conversely, dosing oligospermic men with the 75 IU of FSH three times a week employed in this study may be subtherapeutic. A meta-analysis by Canarella assessed the efficacy of FSH dosing in men with idiopathic oligospermia and grouped dosing regimens into low (175-262.5 IU/week), intermediate (350-525 IU/week), and high (700-1050 IU/week) (24). Those on the low-dosing regimen demonstrated improvements only in sperm motility. Those on the high-dosing regimen demonstrated increases in sperm concentration, total sperm count, and motility.
----------
* In our patient cohort of severely oligospermic men undergoing hCG/FSH, we found that 58% of these patients returned to normospermia. Our findings may support that hCG/FSH is a superior treatment regimen for the recovery of spermatogenesis in infertile men with a history of testosterone use.
------
* Optimal dosing of hCG and FSH for male factor fertility remains to be determined
---------8
Introduction
Three percent of US males under 40 utilize testosterone therapy, which unbeknownst to many, can result in testicular atrophy, decreased sperm count, and reduced fertility(1–3). Current guidelines from the American Urological Association and the American Society for Reproductive Medicine recommend against testosterone monotherapy for individuals trying to conceive(4). Despite this recommendation, 25% of men are not aware of the negative impact of testosterone on fertility(5), and more worrisome, 25% of urologists incorrectly believe that testosterone can improve male fertility(6). Due to the limited number of high-quality studies, there currently exists no standardized treatment regimen for restoring sperm parameters in infertile men with prior testosterone use.
--------
Clinicians have designed and utilized various regimens of off-label spermatogenic restoration therapies. The simplest therapy is discontinuing testosterone with the hope of a return to normospermia. Liu published an analysis of over 30 studies from 1990-2005 emphasizing the utility of testosterone as a form of reversible hormonal male contraceptive given for 16-78 weeks(7). Men included in this study were eugonadal, normal on physical exam, and had two semen analyses with sperm concentrations of at least 20 million [M] per mL before initiating testosterone. Two-thirds of men returned to normospermia within 6 months, and all men at 2 years following testosterone cessation. However, this study carries important caveats. Many infertile males have used testosterone for longer than the few months to one year time frame described in this study. A significant number may also harbor undiagnosed forms of male factor infertility before testosterone use.
--------
Another treatment utilized is hCG injection monotherapy. hCG works as an LH analog stimulating Leydig cells to produce testosterone in the testicles, a requirement for spermatogenesis(8). Previous studies have demonstrated that hCG taken every other day preserved spermatogenesis in men on testosterone therapy(9). Treatment regimens range from 1000-3000IU one to three times a week. A second regimen utilized is the combination of hCG and a Selective Estrogen Receptor Modulator (SERM) or an Aromatase Inhibitor (AI). SERMs (clomiphene or tamoxifen) and AIs (anastrozole) block the negative feedback of endogenous estradiol,which increases production of LH and FSH, the latter of which stimulates Sertoli cells which are critical for sperm maturation(10–12). Wenker illustrated the utility of testosterone cessation and combination therapy with hCG (dosed 3000 IU every other day) and a SERM or AI for the treatment of azoospermic or severely oligospermic men with a history of testosterone use. Forty-seven of the 49 patients (95.9%) demonstrated improved semen parameters(13).
-----------
More recently, two authors have explored hCG and FSH therapy in restoring sperm parameters in infertile men with prior testosterone use. Campbell compared the efficacy of hCG/clomiphene vs. hCG/FSH therapy in azoospermic men with prior testosterone use and found hCG/FSH therapy resulted in faster return of sperm in theejaculate, averaging 5.5 months vs. 14.8 months in the hCG/clomiphene group (14). In a small series of 10 patients, Hakky explored hCG/FSH stimulation in men undergoing concurrent testosterone therapy and found improvements in sperm concentrations increasing from 2.99 M total motile sperm to 98.4 M after treatment (15). Complementing these data, Tatem described a practice pattern in which if no improvements in semen parameters are observed after 3 months of hCG/clomiphene therapy, providers may switch patients to hCG/FSH therapy thereafter (16).
-------------
We hypothesized that direct gonadotropic stimulation with purified hCG and FSH (in lieu of indirect SERM/AI-mediated FSH release) would result in improved recovery of spermatogenesis in azoospermic, severely oligospermic (<5M/mL sperm), and oligospermic (>5M/mL but <15M/mL sperm) men with a history of testosterone use. Secondarily, we investigated whether concurrent use of testosterone therapy during combination hCG/FSH therapy would dampen spermatogenic recovery as compared to discontinuation of testosterone therapy entirely. As withdrawal of testosterone often leads to the recurrence of hypogonadal symptoms, most patients receiving testosterone are reluctant to stop even for fertility purposes (17). Furthermore, a recently published clinical trial found no difference in spermatogenic recovery in patients with congenital hypogonadotropic hypogonadism continuing testosterone vs. those who did not during hCG/FSH therapy (18). We hypothesized that our patients would respond similarly. We present the largest cohort to date undergoing dual hCG/FSH gonadotropic therapy for the treatment of infertility secondary to prior testosterone use.
------------4
Materials and Methods
We conducted a retrospective cohort analysis of men prescribed 3000 International Units (IU) of hCG and 75IU of FSH three times a week (self-administered by subcutaneous injection) who sought infertility treatment at a single andrology clinic at Baylor College of Medicine from January 2020-March 2024. We termed this therapy “hCG/FSH reboot”. All patients received these medications from a single local compounding pharmacy with approved access to purified (i.e. non-recombinant) preparations of hCG and FSH. To promote patient compliance and not deviate from the standard three times a week dosing of hCG monotherapy, all patients were instructed to draw up both the hCG and FSH into the same syringe and inject both agents via one injection on Mondays, Wednesdays, and Fridays.
----------
Electronic charts were reviewed to record patient age, race, body mass index (BMI), co-morbidities, female partner age, duration of current conception attempt, and testicular size (exam and/or ultrasound) before hCG/FSH reboot. Prior duration of testosterone use, administration route, and indication for testosterone therapy before and during hCG/FSH reboot were noted. Semen analyses (sperm concentrations) and serum hormone values (FSH, LH, and testosterone) collected at 3-month intervals before and during hCG/FSH reboot were recorded. Sperm concentrations were classified as azoospermic (no sperm), severely oligospermic (<5 M/mL), oligospermic (>5M/mL but <15M/mL), or normospermic (>15M/mL). Duration of hCG/FSH reboot was defined as the interval from the semen analysis analyzed at the initiation of hCG/FSH reboot to the highest documented sperm concentration recorded during therapy. This endpoint was chosen to represent the ceiling for treatment response, or i.e. the “best case scenario” for a patient undergoing treatment, as not all patients had a similar number of semen analyses, nor do we know whether hCG/FSH therapy promotes spermatogenesis linearly with time. Patient data were de-identified, securely stored, and analyzed.
-----------
The primary aim of this study was to evaluate the efficacy of hCG/FSH reboot in improving sperm concentrations in infertile men with a history of testosterone therapy. The secondary aim of this study was to determine the impact of concurrent testosterone therapy use on spermatogenic recovery during hCG/FSH reboot. We stratified the entire cohort into two groups: those not on concurrent testosterone therapy during hCG/FSH reboot (No testosterone therapy) vs. those who were (Concurrent testosterone therapy). Although testosterone dosing was not standardized within this latter cohort, all patients were undergoing 100 mg-400 mg of injectable testosterone therapy per week. Finally, we determined whether specific patient variables predicted a positive response to hCG/FSH reboot (i.e. moving from a lower sperm concentration group to a higher group).
-------------
Statistical analyses were performed using GraphPad Prism (Version 10) and R (Version 4.4.1). Normality of data was assessed via the Shapiro-Wilk test (alpha 0.05). For normally distributed data unpaired student’s t test was performed. For non-normally distributed data unpaired Mann-Whitney test was performed. A completecase sensitivity analysis was performed to account for potential bias due to missing data. To assess an individual’s change in sperm concentration during hCG/FSH reboot, a paired Wilcoxon Signed Rank test was performed for these non-normally distributed data. Simple logistic regression analysis was performed to determine the impact of patient variables on the improvement in sperm concentration after hCG/FSH reboot. P<0.05 deemed significance. The study was reviewed and approved by the Baylor College of Medicine Institutional Review Board (IRB H-23509: Recovery of Spermatogenesis after Testosterone Administration)
--------------4
Discussion
Three-quarters of infertile men with prior testosterone therapy demonstrated sperm concentration improvements after hCG/FSH reboot. Concurrent use of testosterone therapy did not dampen hCG/FSH-mediated spermatogenic recovery. Patients with larger testicular volumes, higher starting sperm concentrations, and lower serum FSH levels were more likely to respond to hCG/FSH reboot. Patient age and prior testosterone therapy duration did not predict therapy success contrary to previous studies (19). Overall, we present a novel and efficacious treatment strategy for restoring spermatogenesis in men with prior testosterone use.
-------------
A major limitation to hCG/FSH therapy is cost and availability. These medications are either purified from the urine of pregnant (hCG) or post-menopausal (FSH) donors or made recombinantly. Using GoodRx as a benchmark, examples of purified hCG include Pregnyl and Novarel which cost ~$300 per 10,000IU ($0.03/IU). Now discontinued Bravelle (urofollitropin) was a form of purified FSH and cost ~$750 for 750 IU ($1/IU). A 250-microgram (~6000 IU) Ovidrel vial (recombinant choriogonadotropin alfa) costs ~$250 ($0.04/IU). A 900 IU cartridge of Follistim (recombinant follitropin beta) averages $3000 ($3.33/IU). A single month’s supply of brand hCG and FSH dosed at 3000 IU and 75 IU three times a week would cost ~$4000. Currently, 81 503b compounding pharmacies across the US are approved to compound hCG and FSH (20). Only 4 supply both hCG and FSH and are limited to Nevada, Texas, Pennsylvania, and Massachusetts. Reported costs are $50-$80 per 10,000 IU of purified hCG and $165 per 1500 IU of purified FSH.
---------------
Optimal dosing of hCG and FSH for male factor fertility remains to be determined. As hCG administration does not augment serum LH levels, clinicians will often monitor changes in serum testosterone and semen analyses to assess efficacy and adjust dosing accordingly. Interestingly, work by Roth demonstrates that far lower doses of hCG than those used clinically (just 125 IU of hCG every other day for 5 days) can adequately restore intratesticular testosterone levels required for spermatogenesis (21). Perhaps current hCG treatment regimens are supratherapeutic. Fortunately, reported side effects of hCG are minimal (22,23). Conversely, dosing oligospermic men with the 75 IU of FSH three times a week employed in this study may be subtherapeutic. A meta-analysis by Canarella assessed the efficacy of FSH dosing in men with idiopathic oligospermia and grouped dosing regimens into low (175-262.5 IU/week), intermediate (350-525 IU/week), and high (700-1050 IU/week) (24). Those on the low-dosing regimen demonstrated improvements only in sperm motility. Those on the high-dosing regimen demonstrated increases in sperm concentration, total sperm count, and motility.
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Complementing clinical indications to continue testosterone therapy during hCG/FSH reboot, we hypothesized that any negative pituitary feedback signaled by exogenous testosterone (thereby dampening endogenous LH and FSH release) is overcome by adequate if not superior gonadotropic stimulation with exogenous hCG and FSH. Men with azoospermia and oligospermia have been shown to harbor anti-FSH antibodies(25). Thus, one could speculate that the therapeutic introduction of antigenically foreign hCG/FSH, to which an individual’s immune system has yet to develop neutralizing antibodies, could temporarily restore adequate gonadotropic signaling. Looking toward the future, recombinant technology has led to hCG and FSH molecules with enhanced biologic activity and longer serum half-lives secondary to N-glycosylation and sialylation modifications and often escape immunogenicity(26–28). For the infertile male requiring prolonged gonadotropic treatment, recombinant formulations may escape immunologic surveillance and permit longer-term spermatogenic signaling. Future clinical studies may benefit from measuring serum anti-Mullerian hormone and inhibin-B for Sertoli cell response (18) and 17-hydroxyprogesterone (a promising biomarker for intratesticular testosterone levels) for Leydig cell response (29).
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Our article is timely and complements recent work by Ledesma (30). Ledesma demonstrated that 28% of azoospermic men with a history of testosterone use remained azoospermic despite treatment with hCG/clomiphene. We demonstrate that a comparable 35% of azoospermic men with prior testosterone use remained azoospermic despite hCG/FSH. Potential etiologies in our cohort included delayed puberty, orchidopexy, left testicular cancer and chemotherapy, pituitary adenoma, empty sella syndrome, LH beta chain mutation, Crohn’s Disease on high-dose corticosteroids, severe obesity, and Klinefelter syndrome. Whereas their study found that only 6% of azoospermic men returned to normospermia after hCG/clomiphene(30), we found that 14% of azoospermic patients returned to normospermia after hCG/FSH. We hypothesize that hCG/clomiphene therapy requires more than just 6 months treatment, as supported by Campbell, who demonstrated faster resolution of azoospermia in men undergoing hCG/FSH vs. hCG/clomiphene (14). When grouping both azoospermic and severely oligospermic patients, Ledesma found that 17% returned to normospermia after hCG/clomiphene. In our patient cohort of severely oligospermic men undergoing hCG/FSH, we found that 58% of these patients returned to normospermia. Our findings may support that hCG/FSH is a superior treatment regimen for the recovery of spermatogenesis in infertile men with a history of testosterone use.
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The inherent limitation of our study is its retrospective nature without strict inclusion criteria, randomization, or patient monitoring (i.e., some data, such as hormone levels, are not completely captured). Specific limitations and selection biases also include the following: 1) exclusion of patients not undergoing a subsequent semen analysis after initial prescription of hCG/FSH therapy (n=102, potentially missing those patients unable to afford the high cost of hCG/FSH), 2) exclusion of patients without a documented history of testosterone use (n=39, raising the question of whether hCG/FSH therapy would benefit testosterone naïve infertile patients), and 3) exclusion of patients documented to be normospermic (>15 M/mL) despite being treated for infertility (n=8, highlighting whether gonadotropic therapy could improve not only sperm quantity but quality). Accordingly, one should not generalize our findings and propose that hCG/FSH therapy would benefit all infertile male patients.
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Our study is also limited by its relatively short follow-up. Although the median time on hCG/FSH reboot to achieve the highest documented sperm concentration was 4.7 months, the upper quartile of therapy duration ranged from 8.7 to 29.4 months. Within this upper quartile, however, 73% of patients still demonstrated an improvement in their sperm concentrations vs. 74% of patients in the lower three quartiles. This raises the possibility that some patients may take longer to respond to hCG/FSH reboot therapy. Longer follow-up will be required to better understand this regimen’s safety and efficacy profile. Finally, we did not assess fertility outcomes in patients undergoing hCG/FSH reboot therapy as our IRB did not include calling patients for follow up. However, men with isolated hypogonadotropic hypogonadism treated with human Menopausal Gonadotropin ,a combination of urinary purified LH and FSH, can reliably achieve pregnancy despite having severe oligospermia or oligospermia(31). Thus, we posit that any improvement in sperm concentration secondary to hCG/FSH therapy represents a means to restore fertility in men with prior testosterone use.
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Key to implementing standardized, guideline-based treatment protocols for the treatment of infertility secondary to testosterone use are prospective trials. To confirm these data, the authors are currently designing a multi-center, randomized, and controlled trial to assess hCG/FSH therapy in infertile men with prior testosterone use. Studies of importance should also include prospective trials comparing the efficacy of hCG monotherapy or hCG/Clomiphene to hCG/FSH, as well as the efficacy of hCG/FSH therapy in testosterone naïve patients(18).
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Ultimately, the strength of this study is its size, representing the largest study to date investigating the utility of gonadotropic hCG/FSH therapy in restoring spermatogenesis in men with a history of testosterone use. Subjects followed a consistent medication regimen throughout the study, allowing appropriate analyses with semen analyses and hormonal testing at 3-month intervals. With hope of increased availability and reduced cost, hCG/FSH gonadotropic therapy may represent the optimal regimen for spermatogenic recovery in infertile men with a history of testosterone use
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Conclusions
We report optimal recovery of spermatogenesis with hCG/FSH reboot therapy in infertile men with a history of testosterone use. Moreover, we demonstrate that concurrent testosterone therapy does not impede hCG/FSH-mediated spermatogenic recovery. Although further prospective trials are needed, we present an efficacious treatment strategy to optimally restore semen parameters in infertile men with a history of testosterone use.
