Management of Male Fertility in Hypogonadal Patients on TRT

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Abstract

Testosterone is crucial in regulating several body functions in men, including metabolic, sexual, and cardiovascular functions, bone and muscle mass, and mental health. Therefore, optimizing testosterone levels in men is an important step to maintaining a healthy body and mind, especially as we age. However, traditional testosterone replacement therapy has been shown to lead to male infertility, caused by negative feedback in the hypothalamic–pituitary–gonadal (HPG) axis. Recent advances in research have led to the discovery of many new methods of administration, which can have more or less suppressive effects on the HPG axis. Also, the usage of ancillary medications instead of or after testosterone administration might help maintain fertility in hypogonadal patients. The goal of this narrative review is to summarize the newest methods for optimizing fertility parameters in patients undergoing treatment for hypogonadism and to provide the necessary information for healthcare providers to make the right treatment choices.


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1. Introduction

Testosterone replacement therapy (TRT) is gaining more and more popularity since the increase in clinical data supporting the benefits for hypogonadal patients. Cardiovascular, metabolic, and sexual functions, bone and muscle mass, and mental health can be impaired if testosterone levels are low, while testosterone replacement therapy has been shown to improve these parameters [1–4]. One large-scale study (The Massachusetts Male Aging Study) approximated the occurrence of low testosterone to be 25.3% in middle-aged/elderly men (40–70 years), whereas hypogonadism, including specific symptoms along with low testosterone levels, was observed in 6–12% of this population [5]. It is important to differentiate between primary and secondary hypogonadism, and organic (caused by the malfunctioning of the testes, hypothalamus, or pituitary gland), and functional hypogonadism (due to aging) [6]. Male hypogonadism is impairment in one or both of the two major functions of the testes: sperm production and testosterone production. These impairments are caused by diseases of the testes (primary hypogonadism) or diseases of the pituitary gland or hypothalamus (secondary hypogonadism). In general, patients with primary hypogonadism display impaired levels of testosterone and elevated levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), while patients with secondary hypogonadism usually have reduced levels of testosterone and levels of LH and FSH on the lower end. However, chronic administration of exogenous testosterone is linked to the inhibition of the hypothalamic–pituitary–gonadal (HPG) axis, leading to impaired endogenous testosterone and sperm production, ultimately triggering the onset of male infertility [7]. Indeed, testosterone activates hypothalamic neurons, which affect gonadotropin-releasing hormone (GnRH)-secreting neurons, inhibiting GnRH secretion the key regulator of the reproductive axis. The pulsatile secretion regulates the secretion of the gonadotropins FSH and LH, which regulate sperm and testosterone production. Due to this negative feedback in the HPG axis, exogenous testosterone has even been investigated as a potential male contraceptive therapy [8]. The severity of the shutdown also depends on the duration and dosage of testosterone, with longer treatments and higher dosages leading to more severe shutdowns of the HPG axis. Also, the administration method can influence the grade of impairment, with medium--–long-acting injectable drugs being more suppressive compared with short-acting drugs [7]. Also, concomitant administration of ancillary drugs such as human chorionic gonadotropin (HCG), aromatase inhibitors (AIs), or selective estrogen receptor modulators (SERMs) can prevent or diminish the downregulated HPG axis functions in response to exogenous testosterone [9]. However, there is no consensus about the exact protocol for restoring or maintaining fertility in hypogonadal patients on TRT, and many healthcare professionals are not aware of the tools available to prevent impaired sperm production in their patients. This review will highlight novel methods to minimize fertility-related side effects due to TRT and provide directions for healthcare professionals in this field.




2. Exogenous Testosterone and the HPG Axis

Exogenous testosterone administration can lead to dramatic increases in serum testosterone levels. When serum testosterone levels rise, a signal to suppress the production of GnRH from the hypothalamus is sent, leading to an inhibited release of LH and FSH by the pituitary gland. As stated above, the HPG axis regulates testosterone and sperm production via the release of GnRH, consisting of LH, responsible for testosterone production in the testes via Leydig cell stimulation, and FSH, responsible for sperm production in the testes via Sertoli cell stimulation. Depending on the serum testosterone level, the HPG axis will release adequate amounts of GnRH to maintain serum testosterone levels and sperm production in balance in a self-regulating manner. Indirectly, testosterone is converted into estrogen via the aromatase enzyme. Estrogen also triggers the negative feedback in the HPG axis. As exogenous testosterone administration increases serum testosterone levels, the amount of estrogen also increases since a part of the exogenous testosterone is converted into estrogen via the aromatase enzyme. Therefore, if testosterone is administered exogenously, the hypothalamus will sense this and downregulate GnRH release, leading to impaired endogenous testosterone and sperm production in the testes. Especially if the dosage and duration of exogenous testosterone administration are significant, the downregulation of GnRH, sperm, and endogenous testosterone release will be severe. On a side note, not only testosterone but also androgenic anabolic steroids (AASs) trigger similar effects on the HPG axis. Therefore, not only TRT patients but also AAS users might face similar side effects related to male infertility. AAS users tend to use higher dosages and are, therefore, prone to harsh and long periods of HPG axis shutdown and impaired sperm production.




3. Different Testosterone Products (Table 1)

(1) Long-acting drugs(a) Injectable testosterone undecanoate


These results suggest that male infertility occurs about 3 months into treatment with injectable testosterone undecanoate. Recovery of healthy spermatogenesis seems to occur about 5–6 months on average after the cessation of testosterone undecanoate injections. However, if the testosterone treatment duration is longer than 3 years, recovery might take several years and the use of ancillary drugs to stimulate gonadotropins.


(2) Medium-acting drugs

(a) Injectable testosterone enanthate


With testosterone enanthate, depending on the dosage and duration of TRT, sperm recovery should occur within 6–12 months after cessation, but the use of ancillary drugs and a longer treatment duration might be needed depending on each individual.


(b) Injectable testosterone cypionate

Testosterone cypionate is very similar to enanthate and is often used interchangeably with enanthate.

Testosterone cypionate can be treated similarly to enanthate, with the same sperm recovery expectations.





(3) Short-acting drugs

(a) Oral testosterone undecanoate


Long-term studies on the fertility outcomes of oral testosterone undecanoate need to be undertaken, but based on the limited information available, it seems to be on the milder side and comparable to topical testosterone gel.


(b) Nasal testosterone gel

Nasal testosterone gel seems to be one of the best options for hypogonadal men wanting to preserve fertility, especially in those suffering from primary hypogonadism.


(c) Topical testosterone gel

Topical testosterone gel is also on the milder side with regard to fertility issues. However, the side effects might be dose-dependent.




4. Alternatives to TRT to Raise Testosterone While Maintaining Fertility

Depending on the type of hypogonadism, there are several indirect options to restore healthy testosterone levels. These methods focus on triggering endogenous testosterone production in the testes, rather than directly administering exogenous testosterone.


(1) Human Chorionic Gonadotropin (HCG)

HCG can be very effective, with no side effects on fertility, and safe for patients with secondary hypogonadism. However, HCG can be expensive or not easily available depending on the country


(2) Human Menopausal Gonadotropin (HMG)

Even though it has some LH activity, HMG is not able to preserve the Leydig cell function and sufficient spermatogenesis. Therefore, it is often used in combination with HCG to trigger spermatogenesis in patients with hypogonadotropic hypogonadism [36].

These results support the theory that testosterone stimulation via LH is crucial for spermatogenesis, which probably cannot be achieved with FSH alone.

hMG or rFSH are useful in the treatment of patients who do not respond enough to HCG treatment alone.





(3) Aromatase Inhibitors (AIs)

AI monotherapy in hypogonadal oligo-azoospermic patients is still not completely understood to this day, but the results look promising.




(4) Selective Estrogen Receptor Modulators (SERMs)

Tamoxifen has been shown to improve testosterone, gonadotropin, and sperm release, making it an alternative treatment option for testosterone deficiency in men.

However, the side effects from tamoxifen seem to be harsher than those from clomiphene, including gastrointestinal distress, venous thromboembolic events, and other cardiovascular events, making tamoxifen a suboptimal choice for the treatment of testosterone deficiency [48].

SERMs, especially clomiphene might be a good alternative to testosterone in hypogonadal men seeking fertility.





5. Ancillary Drugs during TRT to Maintain Fertility

TRT can rapidly trigger infertility; therefore, several ancillary drugs can be prescribed to prevent those negative side effects on fertility parameters during TRT. These ancillary drugs stimulate endogenous testosterone production and therefore help prevent a complete shutdown of the HPG axis. Note that many of these drugs can be administered on their own as alternatives to TRT, as seen in the previous section.


(1) Human Chorionic Gonadotropin (HCG)

HCG treatment in men has been investigated since the 1950s and has been demonstrated to improve endogenous testosterone levels [49].

High intratesticular testosterone (ITT) levels, usually higher than serum testosterone levels, seem to be necessary for healthy spermatogenesis in men, even though the quantitative relationship between ITT and sperm production is not understood to this day.

Sperm production can be reinitiated by HCG after chronic gonadotropin and testicular inhibition, even though FSH levels are low. Average levels of FSH are not necessary for sperm production reactivation in gonadotropin-suppressed patients [50]. Testosterone activates the androgen receptors (ARs) in Sertoli cells, triggering spermatogenesis [51]. FSH seems to act both independently and with testosterone to activate Sertoli cell proliferation, leading to spermatid maturation [52].

Concomitant HCG treatment seems to be effective in maintaining fertility in men on TRT. However, HCG alone probably triggers similar increases in serum testosterone levels. Therefore, if HCG is available, HCG alone should be used first, and the addition of testosterone should only be considered if serum testosterone does not increase to the target level. In this case, the addition of testosterone would negatively impact semen parameters.



(2) Selective Estrogen Receptor Modulators (SERMs)

SERMs can also be used in patients with secondary hypogonadism. However, SERMsi indirectly increases GnRH release via the inhibition of estrogen receptors. In male patients, even though promising results have been published, the usage of SERMs remains off-label. The main SERMs used for fertility issues are clomiphene and tamoxifen citrate. These drugs indirectly trigger the release of FSH and LH by inhibiting estrogen receptors in the hypothalamus and pituitary gland, resulting in an increase in gonadotropin-releasing hormones, ultimately stimulating the Leydig cells to release testosterone and the Sertolicells to increase spermatogenesis [7].

Clomiphene works by downregulating estrogen’s negative feedback loop in the hypothalamus. This triggers gonadotropin release and improves testicular function. Tamoxifen works similarly to clomiphene, but unlike clomiphene, tamoxifen is very active in the peripheral, leading to its usage in treating hormone-sensitive breast cancer. On the other hand, it has also been shown to be a powerful treatment for early-onset gynecomastia in men. But most interestingly, it has been shown to increase gonadotropins and improve sperm parameters in sub-fertile men [49].

When looking at different dosages and different SERMs, the subgroup analysis demonstrated that both 50 mg of clomiphene and 20–30 mg of tamoxifen daily lead to significant improvements compared with the 25 mg dosage of clomiphene [7]



(2) Aromatase inhibitors (AIs)

Aromatase inhibitors have been prescribed to treat male infertility for a long time, but there is no consensus about the efficacy and safety of AIs in the treatment of male infertility to this day. Estradiol, mainly produced through the aromatization of circulating testosterone in adipose tissue in men, affects the functions of gonadal axis regulation and spermatogenesis. Increased estradiol levels enhance the feedback in the hypothalamic-pituitary axis, triggering decreases in LH, FSH, and testosterone production. Aromatase inhibitors are traditionally used for the treatment of metastatic breast cancer, but they are also used in hypogonadal men by altering the T/E2 ratio and inhibiting increases in estradiol.

Furthermore, aromatase inhibitors can be classified as (1) nonselective, such as aminoglutethimide and testolactone, or (2) selective, such as anastrozole(Arimidex), letrozole (Femara), exemestane (Aromasin), vorozole (Rivizor), formestane (Lentaron), and fadrozole (Afema). Moreover, according to the level of selectivity, AIs can be classified into three generations, with the third generation having the highest selectivity and potency. (1) The first generation includes compounds such as aminoglutethimide (nonsteroidal). (2) The second generation includes compounds such as fadrozole (nonsteroidal) and formestane (steroidal). (3) The third generation includes compounds such as anastrozole (nonsteroidal), exemestane (steroidal), and letrozole (nonsteroidal). Compared with first-generation AIs, second-generation aromatase inhibitors are twice as efficient, whereas third-generation compounds are three to four times more efficient.

AIs are mainly used to control elevated estradiol (E2) levels to prevent adverse effects in men on testosterone replacement therapy.

AIs are an effective way to control E2 levels during TRT. However, the dosage needed to maintain E2 levels within the optimal range depends on each individual and requires close monitoring by a healthcare professional.





6. Ancillary Drugs after TRT to Restore Fertility

Generally, patients are not aware of the long-term repercussions of TRT with regard to spermatogenesis. Several months or years after initiation of TRT, patients might want to have kids. In this case, it is crucial to understand which drugs can restore endogenous testosterone and sperm production. Again, the majority of these drugs can also be used as an alternative to TRT or as an addition to maintain fertility while on TRT.


(1) HCG/FSH

HCG treatment is effective in restoring spermatogenesis after TRT. In some cases, the addition of HMG or rFSH might be necessary. We recommend considering the addition of HMG or rFSH if HCG treatment has not led to the desired sperm parameter improvements after 3 months.


(2) SERMs


(a) Clomiphene citrate (CC)


CC is a potent treatment option for spermatogenesis recovery after TRT. Concomitant use of HCG might improve the effects and recovery time.

Besides the above-mentioned traditional methods, there are also several other methods, such as pulsatile GnRH administration, dopamine receptor agonists, and the most commonly used male fertility treatment technique, assisted reproductive technology.

Pulsatile GnRH administration has been shown to be similarly effective in restoring LH, FSH, and testosterone levels compared with HCG treatment [63]. However, this method might not be practical nor economically feasible for many patients since similar results can be achieved with HCG treatment.

In case infertility is due to elevated prolactin levels, dopamine receptor agonists such as cabergoline can be effective in treating this condition [8].

In case all the aforementioned methods do not work, there is still the option to try assisted reproductive technology, which can lead to great results, even with impaired fertility parameters.





7. Conclusions

The preservation of fertility is one of the major concerns for men seeking testosterone replacement therapy. However, nowadays, due to the development of novel testosterone administration methods, the suppressive effects of testosterone treatment seem to be manageable, especially with short-acting testosterone preparations. However, the lack of long-term studies prevents any clear conclusions yet. As a take-home message for clinicians, for patients seeking to conceive and who are responding to HCG or clomiphene treatment, the use of these drugs might be a better option compared with testosterone. However, long-term studies on HCG or clomiphene treatment of >3 years in men are lacking. Concomitant use of HCG or clomiphene during TRT might not be optimal in men seeking fertility; therefore, monotherapy of HCG or clomiphene should be explored first. The use of ancillary drugs such as SERMs, HCG, HMG, and AIs seems to be an effective way to recover endogenous testosterone and sperm production after testosterone treatment. The duration of fertility recovery seems to be dependent on the dosage and length of the testosterone treatment. Physicians treating hypogonadism should be aware of all these options and make the right decision based on the needs and conditions of each patient. As a side note, it is not completely understood how androgens affect the physiology of the sexual accessory glands. This could also represent a link between hypogonadism and infertility [64]. Figure 1 represents a proposed flow chart for treatment options for hypogonadal men. Figure 2 represents a proposed treatment option for hypogonadal men seeking TRT and fertility.




Comments

In our opinion, hypogonadal men seeking treatment without side effects on fertility should first consider HCG or clomiphene treatment. If these options do not improve their situation, a short-acting form such as a nasal spray or oral testosterone should be considered. The addition of HCG, SERMs, or AIs to short-acting T treatment is also an option in case the sperm count declines. Long-acting injectable T treatment options, even in combination with HCG, SERMs, or AIs, involve much greater risks of developing infertility in TRT patients.
 

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madman

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Figure 1. Proposed flow chart of treatment options for hypogonadal men. TRT: testosterone replacement therapy, T: testosterone, and HCG: human chorionic gonadotropin.
1708842933540.png
 

madman

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Figure 2. Proposed treatment options for hypogonadal men seeking TRT and fertility. TRT: testosterone replacement therapy, T: testosterone, and HCG: human chorionic gonadotropin
1708842987016.png
 

madman

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