Male Fertility and Testosterone Therapy

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34.1 Hypogonadism, Male Fertility, and Testosterone Therapy


34.2 Defining Hypogonadism

34.2.1 Workup of Hypogonadism


34.3 Epidemiology of Hypogonadism
34.3.1 Hypogonadism in Reproductive-Age Men
34.3.2 Aging Fathers



34.4 Testosterone Physiology and Pathophysiology
34.4.1 Testosterone Physiology
34.4.2 The Role of Intratesticular Testosterone
34.4.3 Testosterone as a Contraceptive



34.5 Trends in Prescribing Patterns
34.5.1 Testosterone Therapy Prescribing Patterns
34.5.2 Anabolic Steroid Prescribing Patterns





34.6 Management of Hypogonadal Men Who Already on Testosterone and Now Want to
Restore Fertility


We now provide an overview of management strategies that can be used to help men using exogenous testosterone who desire restoration of fertility. Understanding these different management strategies will allow providers to engage in shared decision-making and advise men based on how soon they are hoping to conceive children.


34.6.1 Testosterone Withdrawal

The most conservative approach for a man on testosterone therapy who is interested in restoring fertility is to stop testosterone and monitor for improvements in spermatogenesis. In the WHO study, healthy men who developed azoospermia on testosterone enanthate had a median time to recovery of 3.7 months to reach sperm concentration of at least 20 million/mL after stopping testosterone therapy. In a pooled analysis of 30 studies examining testosterone therapy as a short-term contraceptive, the probability of sperm concentration recovering to 20 million/mL was 67% within 6 months, 90% within 12 months, and 100% within 24 months [20]. Additional work has demonstrated that both advanced age and increased duration of exogenous testosterone prolong the time to recovery of spermatogenesis [21]. Similar studies in men who have used AAS have shown a spontaneous return of sperm concentration to normal levels between 5 and 18 months after AAS cessation[22]. It is important to highlight that most of these time estimates are based on studies in healthy, fertile men who were taking testosterone for contraception. It is possible that men with hypogonadism may not recover spermatogenesis as quickly or to the same degree without additional interventions. In some cases, recovery could take up to two years or more, and sperm production may not return to pretreatment levels[20,23].

The major limitations to testosterone withdrawal include recurrence of bothersome hypogonadal symptoms and prolonged time before recovery of spermatogenesis.
Furthermore, men who were started on testosterone therapy without a urologic or endocrinologic evaluation may have underlying endocrinologic disorders, such as hypogonadal hypogonadism, that impact both hypogonadal symptoms and spermatogenesis.




34.6.2 Testosterone Withdrawal and Lifestyle Modification

All hypogonadal men should be counseled on the importance of healthy weight loss, physical activity, and improving sleep hygiene to reduce signs and symptoms of testosterone deficiency [1].
An inverse relationship between testosterone and excess body weight has been reported in men of all ages, with lower testosterone levels found in subjects with higher body mass index (BMI) [24]. It is thought that at least 10% of weight loss is required to achieve increases in testosterone levels [25].In a study of middle-aged, obese men with median testosterone levels of 199 ng/dL (6.9 nmol/L) randomized to testosterone or placebo in combination with an intensive diet program, the placebo group lost 11% of their body weight, and this was associated with a modest increase in total testosterone by 84 ng/dL (2.9 nmol/L) [26]. However, at follow-up more than one year after completion of the study, many of these men had regained 66% of their weight. Testosterone levels fell back to their pre-study baseline. For morbidly obese patients who are considering bariatric surgery, there are small, nonrandomized studies that also support improvements in testosterone correlating with decreases in BMI [27]. Finally, while studies show conflicting results regarding the relationship between sleep and testosterone levels, most studies suggest a correlation between decreased sleep quality and worse symptoms of testosterone deficiency [28].

While the improvements in testosterone levels with weight loss appear modest, this approach helps optimize the overall health of men and could improve hypogonadal symptoms beyond the measured changes in testosterone levels.
The limitations of this approach include prolonged time before the recovery of spermatogenesis, likely similar to testosterone withdrawal alone, as well as the challenges associated with achieving and maintaining weight loss.




34.6.3 Testosterone Withdrawal and Selective Estrogen Receptor Modulators


Selective estrogen receptor modulators (SERMs) such as clomiphene citrate and tamoxifen have been used off-label since the 1970s for the treatment of male infertility [29]. These medications inhibit the negative feedback of estrogen at the level of the hypothalamus and pituitary thereby increasing LH and FSH secretion.

While there are no studies evaluating outcomes in men previously on testosterone therapy, the mechanism of action as well as limited data in hypogonadotropic hypogonadal patients [30] supports improvements in spermatogenesis with SERMs.
This use of SERMs also reflects current practice patterns in the management of male infertility. Given its effect on the HPG axis, one can hypothesize that using clomiphene citrate would lead to quicker recovery in fertility potential over testosterone withdrawal alone in men without primary testicular failure. Using clomiphene citrate would also reduce hypogonadal symptoms compared to testosterone withdrawal. However, reassessing a hormonal profile at the time of repeat SA is important as there have been rare reported cases of azoospermia with initiation of clomiphene citrate [31].




34.6.4 Testosterone Withdrawal and Anastrozole

Anastrozole is a nonsteroidal aromatase inhibitor. It causes irreversible inhibition of the aromatase enzyme reducing peripheral conversion of testosterone to estradiol (E2).
The reduced negative feedback inhibition from estrogen on the pituitary and hypothalamus results in increased LH and FSH secretion. Anastrozole has the ability to increase testosterone levels without an associated increase in estrogen levels that can sometimes be seen with clomiphene citrate [32]. There have been no studies evaluating the use of anastrozole for hypogonadal symptoms and spermatogenesis in men who have stopped testosterone therapy. However, treatment of infertile men with low serum testosterone levels with anastrozole has been associated with increased serum testosterone from 404 to 808 ng/dL (14–28 nmol/L), decreased E2 levels, and improved sperm concentration from 5.5 to 15.6 million sperm/mL after three months of therapy [33].

Anastrozole provides another oral option for promoting gonadotropin secretion. Aromatase is present primarily in adipose tissues and thus may be particularly useful in obese men who convert a greater proportion of testosterone to estradiol. While not specifically studied in men previously on testosterone replacement, anastrozole may be helpful in men with increased estradiol levels or as an alternative agent for the rare case of azoospermia on clomiphene citrate [31,32]. Similar to SERMs, improvements in semen parameters have been seen within three months of initiating anastrozole in general infertility populations.




34.6.5 Testosterone Withdrawal and hCG

Human chorionic gonadotropin (hCG) has the biologic effect of LH and is used to stimulate Leydig cells to secrete testosterone, raising both serum and ITT [34]. By restoring ITT, hCG therapy should restore spermatogenesis for men with an intact HPG axis after cessation of testosterone.
Studies in hypogonadal men demonstrate encouraging results for the off-label use of hCG in this setting. hCG has been used to treat hypogonadism associated with anabolic steroid use resulting in the recovery of ITT production with three times per week dosing ranging from 2,000 to 3,000 units [16,22]. In a case report of anabolic steroid–induced hypogonadism and azoospermia,hCG therapy improved testosterone levels and semen parameters with a pregnancy achieved after three months [35].

hCG therapy after testosterone withdrawal should be considered for three to six months. If semen parameters have not improved and pregnancy has not been achieved, combination therapy of hCG with other agents that increase FSH activity should be considered. The major limitations of using hCG include patient comfort with injection therapy and out-of-pocket costs as insurance coverage for hCG can vary.




34.6.6 Testosterone Withdrawal and hCG-Based Combination Therapy

While hCG addresses serum and ITT levels, it has no impact on FSH activity and Sertoli cell function.
Therefore, there will be a subset of patients who will require concomitant therapies to increase FSH activity in order to optimize semen parameters. Options include SERMS, aromatase inhibitors, or FSH analogs.

In 2015, a retrospective review of 49 men highlighted the role of hCG-based combination therapy for managing infertility caused by exogenous testosterone use. All men were started on 3,000 units of hCG every other day after discontinuing exogenous testosterone. Supplemental medications were used to raise FSH levels and were based on clinician preference and clinical context. Thirty-five (71%) were prescribed clomiphene citrate, 28 (57%) were prescribed tamoxifen, 10 (20%) were prescribed anastrozole, and one (2%) was prescribed recombinant FSH. After starting hCG-combination therapy, the return of spermatogenesis or improvement in sperm concentration to>1 million/mL was documented in 48 (98.0%) of men. Average testosterone levels were within the normal range when sperm first returned to the ejaculate. The average time to first sperm recovery in the ejaculate for men with azoospermia improvement in sperm concentration above 1 million/mL from with severe oligozoospermia was 4.6 months; the mean first sperm concentration was 22.6 million/mL. There did not appear to be a difference in time to sperm recovery based on the type of testosterone supplementation previously used. Nineteen men (40%) achieved a clinically documented pregnancy during the mean 14 months of follow-up, with no significant difference by type of previous testosterone therapy or supplemental therapy used with hCG. No men discontinued therapy because of adverse effects [23].

Some experts treat with hCG alone for three to six months because many cases will demonstrate improvement in semen parameters during this time. In those without adequate spermatogenesis other agents including clomiphene, anastrozole, or recombinant FSH can be used to ensure both LH and FSH activity are present to optimize fertility potential [23,36]. The major limitations to this approach include the requirement for multiple pharmaceutical agents, the costs of medications, and the potential need for sperm extraction despite trying different medications.









34.7 Management of Hypogonadal Men Interested in Starting Testosterone Therapy and Maintaining Fertility

Both the AUA and the Endocrine Society published guidelines in 2018 that recommend against the use of exogenous testosterone in men wishing to preserve fertility [1,39]. However,there are patients who may be interested in starting testosterone therapy for hypogonadal symptoms while simultaneously maintaining fertility potential. There are emerging strategies that could allow for continued use of testosterone therapy when paternity is not a short-term goal.


34.7.1 Testosterone Therapy and hCG


In 2005, researchers demonstrated that exogenous testosterone caused ITT levels to drop by 94% in otherwise healthy,reproductive-aged men. In these men, adding hCG ranging from 250 IU to 500 IU every other day to testosterone therapy regimens maintained ITT levels [34]. However, this three-week study was too short to evaluate semen parameters or determine the short-term impact on spermatogenesis. A retrospective study in 2013 served to establish the idea of maintaining fertility while on exogenous testosterone. Twenty-six men initiating testosterone replacement therapy who desired fertility were simultaneously started on hCG. These men received 500 IU of hCG every other day while on different formulations of exogenous testosterone. Mean serum testosterone levels before initiating testosterone replacement and hCG were 207 ng/dl compared to 1,056 ng/dL on both agents. The mean pretreatment sperm concentration was 35 ± 30 million/mL. No differences in semen analysis parameters were observed during greater than one year of follow-up on testosterone and hCG. There were also no differences noted between sperm concentrations for men using different types of testosterone formulations [40]. Nine (35%) of these men achieved pregnancy at one year of follow-up. Of note, pregnancy information was incomplete as not all men were actively pursuing pregnancy during the study period.

More work is needed in this area to understand differences in outcomes across different testosterone formulations, varying duration of testosterone therapy, and impact on fertility potential based on semen parameters and pregnancy rates. The existing data suggests testosterone combined with hCG can address hypogonadal symptoms while maintaining fertility potential. The major limitations to this approach include the potential for side effects of high testosterone levels, such as erythrocytosis; requiring two pharmaceutical agents and comfort with injection therapy; as well as costs of hCG and testosterone formulations that may not be covered by insurance.





34.7.2 Testosterone Therapy and hCG-Based Combination Therapy

In addition to maintaining ITT levels with hCG, some men will require Sertoli cell stimulation with FSH. Clomiphene citrate has been suggested as a first-line combination therapy with hCG[41]. In three to six months, repeat semen analysis and hormonal evaluation should be performed to decide whether other oral agents or recombinant FSH should be used. Anastrozole should be employed instead of clomiphene if the testosterone-to-estradiol ratio is less than 10:1. Finally if little or no improvement in semen parameters and low FSH persists despite hCG-based combination therapy, then recombinant FSH every other day should be used for its direct gonadotropin action [16,42].

There are no studies summarizing the effect of testosterone and hCG-based combination therapy but physiologically these regimens should help promote spermatogenesis through simultaneous stimulation of Leydig and Sertoli cells. The major limitations to this approach include the potential for side effects from multiple pharmaceutical agents, comfort with injection therapy, costs of medications, a lack of data for patient selection and counseling, and the need for additional interventions despite maximal pharmaceutical therapy. Future studies should aim to evaluate the impact on the hormonal profile of these patients including testosterone, and estradiol as well as long-term effects on spermatogenesis and pregnancy rates.









34.8 Recommended Treatment Algorithms


34.8.1 Our Recommended Pathway for Restoring Fertility

First, if a patient desires pregnancy within six months and has not yet started testosterone, they should abstain from initiating testosterone therapy until a pregnancy has been achieved. Otherwise, men who are actively trying for a pregnancy should stop taking testosterone and follow the recovery regimen detailed in Figure 34.1. After stopping testosterone, men can choose any of the management options already described through shared decision-making with their physician.

Men desiring the most efficient and data-driven management option should start a regimen consisting of 2,000–3,000 IU hCG every other day [42]. Clomiphene citrate 25 mg every day or 50 mg every other day should also be incorporated to help promote FSH production and pituitary function [23]. Repeat SA and hormonal evaluation should be repeated every three months. If pregnancy is not achieved and neither FSH levels nor SA parameters show improvement, clomiphene should be discontinued and recombinant FSH 75–150 IU every other day should be added [42–44]. If this fails, testicular sperm retrieval with possible microdissection should be offered in conjunction with in vitro fertilization as a final chance for biologic paternity. Once pregnancy has been achieved, reinitiation of testosterone should be discussed with special consideration to future fertility goals [16].




34.8.2 Our Recommended Pathway for Maintaining Fertility While Initiating ExogenousTestosterone Therapy

All men wishing to preserve fertility should have a baseline SA prior to initiation of testosterone therapy. If a planned pregnancy is desired within the 6–12 month time frame, the patient can be offered exogenous testosterone supplemented with hCG 500 IU every other day (Figure 34.2) [42]. Clomiphene citrate or anastrozole should be considered as optional throughout this time.

When planning for pregnancy in more than 12 months, testosterone therapy with adjuvant 500 IU hCG can be offered. These patients should be cycled off testosterone every six months given the increased risk of impaired fertility with prolonged, uninterrupted courses of exogenous testosterone[21]. Each off-cycle can involve a four-week cycle of 3,000 IU of hCG every other day and clomiphene citrate [21]. During any of these above regimens, anastrozole may be added and titrated in dose to address elevations in estradiol (Figure 34.3).









34.9 Future Directions
34.9.1 17-hydroxyprogesterone as a Marker of Preserved Spermatogenesis
34.9.2 Short-Acting Testosterone
34.9.3 Leydig Stem Cell Injection





34.10 Conclusion

Over time, more men will need help managing hypogonadal symptoms while still wanting the option for future paternity. When these men present for evaluations, one of the most important aspects of the evaluation is the timing of the desired pregnancy. For those interested in a pregnancy within six months, testosterone therapy should be stopped, and adjuncts should be used to stimulate Sertoli and Leydig function. For patients who have a longer timeline before pregnancy is desired, testosterone can be continued with hCG to support ITT levels and spermatogenesis.

In the future, improved serum biomarkers may help urologists monitor responses to therapy and predict pregnancy outcomes. New testosterone formulations may preserve spermatogenesis or lead to quicker recoveries in sperm counts. Finally, tissue grafting has the potential to revolutionize the management of male infertility.
 

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Figure 34.1 Pathway for restoring fertility after testosterone therapy
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