Clinical application of aromatase inhibitors to treat male infertility

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madman

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BACKGROUND: Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia or various degrees of asthenospermia and oligozoospermia. Spermatogenesis is a complex and coordinated process, which is under precise modulation by the hypothalamic-pituitary–gonadal (HPG) axis. An aberrant hormone profile, especially an imbalance between testosterone (T) and estradiol (E2), plays an essential role in male infertility. In the male, E2 is produced mainly from the conversion of T by the aromatase enzyme. Theoretically, reducing an abnormally elevated T: E2 ratio using aromatase inhibitors (AIs) could restore the balance between T and E2 and optimize the HPG axis to support spermatogenesis. For decades, AIs have been used to treat male infertility empirically. However, owing to the lack of large-scale randomized controlled studies and basic research, the treatment efficacy and safety of AIs in male infertility remain controversial. Therefore, there is a need to summarize the clinical trials and relevant basic research on the application of AIs in the treatment of male infertility.

OBJECTIVE AND RATIONALE: In this narrative review, we summarized the application of AIs in the treatment of male infertility, including the pharmacological mechanisms involved, clinical trials focused on patients with different types of infertility, factors affecting treatment efficacy, and the side effects. SEARCH METHODS: A literature search was performed using MEDLINE/PubMed and EMBASE, focusing on publications in the past four decades concerning the use of AIs for treating male infertility. The search terms included AI, male infertility, letrozole, anastrozole, testolactone, azoospermia, oligozoospermia, aromatase polymorphisms, obesity, and antiestrogens, in various combinations.

OUTCOMES: Clinical studies demonstrate that AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men. Large-scale surveys suggest that obesity may result in symptoms of hypogonadism in both fertile and infertile males, such as decreased semen quality and attenuated sexual function, which can be improved by AIs treatment. Polymorphisms of the aromatase gene CYP19A1, including single nucleotide polymorphisms and tetranucleotide TTTA repeats polymorphism (TTTAn), also influence hormone profiles, semen quality, and treatment efficacy of AIs in male hypogonadotropic hypogonadism and infertility. The side-effects of AIs in treating male infertility are various, but most are mild and well-tolerated.

WIDER IMPLICATIONS: The application of AIs in treating male infertility has been off-label and empirical for decades. This narrative review has summarized the target patients, dose, treatment duration, and side-effects of AIs. Polymorphisms of CYP19A1 that may affect AIs treatment efficacy were also summarized, but a full understanding of the mechanisms involved in AIs action requires further study.




Introduction

Infertility affects 15% of men and contributes to nearly half of all cases of infertility (Barratt et al., 2017). Various factors and clinical entities contribute to male infertility, including but not limited to varicocele, inflammation, genetic disorders such as Klinefelter syndrome and Y chromosome microdeletion, and congenital abnormalities, e.g. cryptorchidism, as well as environmental factors such as radiation and hyperthermia (Docampo and Hadziselimovic 2015; Jensen et al., 2017; Agarwal et al., 2018; Choy and Eisenberg, 2018; Krausz and RieraEscamilla, 2018; De Felice et al., 2019). These pathogenic factors usually lead to impaired spermatogenesis, presenting as azoospermia or varying degrees of oligozoospermia, teratozoospermia, and asthenozoospermia. Among them, non-obstructive azoospermia (NOA) is the severest type of impairment (Esteves, 2015). Notably, 43–45% of patients with oligozoospermia and NOA have been found to be hypogonadal, presenting as impaired testicular function and testosterone (T) synthesis (Nieschlag and Nieschlag, 2010). Although IVF and microsurgical testicular sperm retrieval (micro-TESE) combined with ICSI have enabled fertility for many couples, these techniques are still expensive and come with their own challenges and limitations (Flannigan et al., 2017; Niederberger et al., 2018; Schlegel et al., 2021). Also, many patients with NOA or severe oligozoospermia would barely benefit from these techniques. As such, medical therapies that improve spermatogenesis to sustain natural conception or decrease the level of ART necessary to achieve a pregnancy are required, and these are still limited (Tournaye, 2012; Pan et al., 2018).

It is known that spermatogenesis is a complex, coordinated process leading to the continuous production of spermatozoa, and it depends on an intact and well balanced hypothalamic–pituitary–gonadal (HPG) axis (Jarow and Zirkin, 2005; Neto et al., 2016; Wang et al., 2018). GnRH is secreted from the hypothalamus to stimulate the pituitary to produce LH and FSH (Yen, 1975; Skorupskaite et al., 2014). In men, LH stimulates Leydig cells in the testis to produce testosterone (T), which is necessary for spermatogenesis (Mendis-Handagama, 1997; Ramaswamy and Weinbauer, 2014). A fraction of T is converted to estradiol (E2) under the catalytic action of the enzyme aromatase (Carreau et al., 2003). FSH is crucial to maintain normal functions of Sertoli cells, a core component of the testis microenvironment or niche that supports spermatogenesis (Griswold, 1998; Walker and Cheng, 2005).

Testosterone and E2 generate negative feedback to the pituitary and hypothalamus, resulting in decreased production of FSH and LH (Allan et al., 2010). Additional HPG feedback mechanisms exist for inhibin and activin, two molecules produced by the Sertoli cell to negatively and positively regulate the HPG axis, respectively (Fig. 1) (Toulis et al., 2010; Hedger and Winnall, 2012).
Strikingly, E2 has been demonstrated to provide a more powerful negative feedback on the HPG axis than T, reflecting its indispensable role in regulating spermatogenesis (Raven et al., 2006). However, increased E2 levels resulting from excess aromatase activity have been observed in a proportion of infertile men, especially patients with NOA or oligozoospermia, presenting as reduced T: E2 ratio (Pavlovich et al., 2001). Reducing abnormally elevated E2 levels via inhibiting aromatase conversion of T to E2 or blocking E2 effects on central receptors could repress the excessive negative feedback on the HPG axis, leading to improvement of spermatogenesis and relief of hypogonadism symptoms. Theoretically, this can be attained by the administration of aromatase inhibitors (AIs) or selective estrogen receptor modulators (SERMs), which have been used to treat male infertility or hypogonadism empirically for decades (Schlegel, 2012; Cannarella et al., 2019; Schlegel et al., 2021). In this narrative review, we mainly discuss the application of AIs in the treatment of male infertility and hypogonadism, including the pharmacological mechanisms, clinical trials aimed at patients with different types of infertility, factors affecting treatment efficacy, and side effects.





*Roles of aromatase and estrogen in the male reproductive system
-The expression and function of aromatase
-The pathogenic effects of aberrant aromatase function in male
-Requirement for estrogen in the male reproductive system
-Detrimental effects of excess estrogen on spermatogenesis



*Clinical trials of aromatase inhibitors in treating male infertility


*Aromatase inhibitors for obesity-related male infertility and hypogonadism

-Impact of obesity on male fertility and potential mechanisms
-Clinical trials of aromatase inhibitors in treating obesity-related male infertility and hypogonadism



*Relations between aromatase polymorphisms and male fertility
-Side-effects of aromatase inhibitors

In general, treating male infertility with AIs is well tolerated and safe for most patients. Among the side effects, loss of libido was most common, especially for letrozole. Regular sexual intercourse is an indispensable part of male infertility treatment, therefore much attention should be paid to this side-effect. For patients who could not overcome declined sexual desire or sexual arousal, anastrozole may serve as a better alternative. In addition, about 10% of subjects presented increased liver enzymes during letrozole and anastrozole treatment, so it is necessary to monitor the patient’s liver function carefully. In most trials, the investigators conducted a liver function test once a month for the subjects. The incidence of other side-effects was relatively low, such as rash, dry mouth, ocular symptoms, and digestive system symptoms, but these side-effects affected the daily life of a few subjects and were more likely to reduce their compliance to the treatment, therefore the patients still need to be fully informed.





Conclusions and future perspectives

AIs have been shown to effectively improve the sex hormone profile and semen quality in infertile men with or without a low serum T: E2 ratio and pregnancies may be achieved naturally after the treatment. Obesity is closely associated with hypogonadotropic hypogonadism and decreased male fertility, which could also be ameliorated by AIs. Polymorphisms of the aromatase CYP19A1 gene may be related to aberrant aromatase activity and affect the treatment efficacy of AIs, findings which still need to be validated by further basic and clinical research. However, most evidence comes from non-randomized cohort studies and case studies, and RCTs are required to evaluate the efficacy and risks of using AIs in treating male infertility before a medication guideline can be made for clinical practice
 

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madman

Super Moderator
Figure 1. The hypothalamic-pituitary-gonadal axis in the male. GnRH is secreted from the hypothalamus, which stimulates the anterior portion of the pituitary gland to produce LH and FSH. LH stimulates Leydig cell production of testosterone, and a fraction of testosterone is converted into estradiol by aromatase. FSH stimulates the Sertoli cell to produce androgen-binding protein and various growth factors, which are essential to sustain spermatogenesis. Testosterone, estradiol, and inhibin secreted by the Sertoli cell all generate negative feedbacks on the hypothalamus and pituitary.
Screenshot (9600).png
 

madman

Super Moderator
Figure 2. Proposed pathways for male infertility associated with obesity. Aromatase excess activity in adipose tissues of obese men causes aberrantly high estradiol (E2) level, which generates powerful negative feedback on the hypothalamic-pituitary-gonadal axis and ultimately impairs spermatogenesis. Obesity-related obstructive sleep apnea, insulin resistance, and cardiovascular diseases are also risk factors for male infertility by inducing decreased androgen levels or erectile dysfunction (ED).
Screenshot (9601).png
 

madman

Super Moderator
*Polymorphisms of the aromatase CYP19A1 gene may be related to aberrant aromatase activity and affect the treatment efficacy of AIs, findings which still need to be validated by further basic and clinical research
 
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