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REVIEW ARTICLE
Year : 2022 | Volume
: 33
| Issue : 3 | Page : 114-118
The roles of aromatase inhibitors in treating hypogonadism and male infertility
William J Huang
Department of Urology, Taipei Veterans General Hospital, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Correspondence Address:
William J Huang
Department of Urology, Taipei Veterans General Hospital, College of Medicine, National Yang Ming Chiao Tung University, Taipei
Taiwan
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/UROS.UROS_28_22
Testis is an organ with both endocrine and exocrine functions. The former stands for testosterone release, and the latter represents sperm production. Spermatogenesis is a process highly depending on adequate supply of testosterone by the Leydig cells of the testis. In men at the reproductive age, more than 90% of testosterone produced is used for spermatogenesis. In men with diminished testosterone secretion in testis, or hypogonadism, the spermatogenesis process is impaired. Testosterone can be converted into estradiol through the catalyzation of aromatase, a cytochrome P450 enzyme presented in the peripheral tissue. Blocking the activity of aromatase causes an elevation of serum testosterone and a decrease of serum estradiol levels. These effects result in an increase of testosterone-to-estradiol ratio. Infertile males with dysfunction of spermatogenesis may demonstrate a low testosterone-to-estradiol ratio. Studies have shown that aromatase inhibitors (AIs) are beneficial to treat patients with impaired spermatogenesis, by demonstrating improvement of the semen parameters in men with oligoasthenoteratozoospermia. Besides, AIs can also be applied in other health issues, such as hypogonadism-related erectile dysfunction, short statue, depression, or male breast cancer. There are two different types of AIs: steroidal and nonsteroidal. Steroidal AI (e.g., testolactone) is an irreversible, but weaker inhibitors, while nonsteroidal AIs (e.g., letrozole and anastozole) are potent reversible inhibitors. Both types of AIs demonstrate plausible effects to improve semen parameters. In this review, the physiological action of aromatase and the indications of AIs treatment are discussed in detail, especially focusing on the function of spermatogenesis in infertile men.
Keywords: Anastrozole, aromatase inhibitors, aromatase, hypogonadism, letrozole, male infertility, spermatogenesis, testosterone
The endocrine and exocrine functions of the testis
The testis is an organ with both endocrine and exocrine functions. The endocrine function is represented by testosterone (T) release by the Leydig cells within the testicular interstitial space. The exocrine function is the sperm production that is conducted by the seminiferous tubules organized by the Sertoli cells. Both functions are sophisticatedly regulated by the interplay of hormones from the hypothalamus–pituitary–gonad axis, wherein negative feedback of gonadal steroids (majorly estrogens) plays a key role in gonadotropin secretion moderation. These estrogens are converted from T in the peripheral tissues via the action of a cytochrome P450 enzyme, aromatase, in males.
Testosterone in the testis
The T concentration in the testicular interstitium is estimated to be >100-folds of that in the serum.[1],[2],[3] In males of reproductive age, >90% of the T that is released from the testis is used to stimulate spermatogenesis in the seminiferous tubules. A minor portion of T that is produced in the testis is drained into the systemic circulation to cultivate a peripheral hormone milieu to develop male reproductive tissues (e.g., the prostate, seminal vesicles, penis, and scrotum) and functions (e.g., erection and ejaculation) and the completeness of the secondary sexual characteristics. Maintaining a high intratesticular T concentration is crucial for fostering competent spermatogenesis, which can only be provided by robust Leydig cells under the precise luteinizing hormone (LH) regulation.
Hypogonadism and treatment
Male hypogonadism is defined as a status with low serum T associated with clinical symptoms,[4] which can be managed by elevating the serum testosterone. Hence, patients can be treated by either exogenous or endogenous methods to resume the serum T. Exogenous T, including topical or injectable formula, is effective to build up T levels; however, it may also result in increased estrogens through the peripheral conversion by aromatase. The estrogens may then play the function of negative feedback to suppress the activities of the hypothalamus and pituitary glands. Thus, long-term use of exogenous T may halt spermatogenesis and result in testicular atrophy.
Treating hypogonadism with endogenous T avoids spermatogenesis suppression. A couple of methods have been advocated for this purpose, including (1) oral medication with selective estrogen receptor moderators (SERM, e.g., clomiphene citrate or tamoxifen citrate); (2) injection with human chorionic gonadotropin (hCG) or recombinant luteinizing hormone (rLH); and (3) oral medication with aromatase inhibitors (AIs).
SERMs, which serve as estrogen receptor competitors, block the estrogen negative feedback to the hypothalamus and pituitary glands. Thus, the hypothalamus and anterior pituitary will secrete more gonadotropins to enhance steroidogenesis in the testis.[5] Spermatogenesis can usually be promoted. Increased T fosters increased estradiol (E2) by the peripheral action of aromatase.
Injections of hCG or rLH are primarily indicated for males with hypogonadotropic hypogonadism, and they are effective in building up T levels and improving spermatogenesis. This treatment is typically associated with human menopausal gonadotropins or recombinant follicle-stimulating hormone injections.[6]
AIs block the T conversion to E2 and damper the negative feedback. Hence, they increase the gonadotropin secretion, elevate the T-to-E2 ratios (T/E ratios), and subsequently enhance spermatogenesis.[7]
Therefore, either injectable gonadotropins or oral medications, such as SERMs or AIs, are recommended for subfertility comorbid with hypogonadism treatment in males. All of these managements are beneficial for spermatogenesis. AIs may not be the drug of choice, but they are feasible for cases with central obesity and greater serum E2 values. Combination use of SERMs and AIs may also be applied when E2 values are too high when the patients are treated with SERMs alone.
Sometimes, SERMs are reported to be less optimal in keeping robust libido than exogenous T. However, using exogenous T agents should be carefully administered in males with comorbidities, namely, hypogonadism and subfertility. Spermatogenesis is significantly affected due to the sustained hypothalamus–pituitary axis suppression by the E2, which is converted from T by the peripheral aromatase. However, two strategies may be administered to avoid the sustained suppression from the exogenous T and maintain the spermatogenesis activity. The first is the concomitant use of injectable gonadotropins (i.e., hCG or rLH) along with exogenous T.[8] The second is the use of the short-acting intranasal T formula. The new form of the short-acting exogenous T breaks the hypothalamus–pituitary axis suppression between doses. Thus, follicle-stimulating hormone (FSH) and LH are maintained within normal ranges, thereby preserving spermatogenesis.[9]
Aromatase and T/E ratio
Aromatase, also known as CYP19A1, or estrogen synthase (or synthetase), is the sole member of family 19 of the cytochrome P450 superfamily. It conducts the key step of aromatizing androgens into estrogens.[10] More specifically, it transforms androstenedione and T into estrone and E2, respectively.[11]
Aromatase is widely distributed in the human body, ranging from the gonads (the granulosa cells of the ovary and Sertoli cells of the testis), uterus, placenta, brain, and bone to peripheral tissues, such as visceral fats, and even pathological tissues, such as endometriosis, breast cancer, and endometrial cancer.[12]
Overexpression of aromatase may accelerate the conversion of T to E2 and lowers T levels and elevates E2 concentration. Thus, the homeostasis between T and E2 is altered. Pavlovich et al. proposed a linkage of spermatogenesis and the ratio of T (in ng/dL) to E2 (in pg/mL) (the T/E ratio[13]). They showed that men with normal spermatogenesis had a higher T/E ratio (mean 14.5), while men with severe infertility had a lower ratio (mean 6.9). The cutoff value of the T/E ratio at 10 represents a status within the bottom 20th percentile of normal distribution, and a ratio of <10 is thought to be related to poor risks of normal spermatogenesis.[13]
In addition to the application in male infertility, the T/E ratio is also related to many health issues on males, such as coronary heart disease, atherosclerosis, depressive symptoms, and erectile dysfunction.[14] All indicate a beneficial effect with a higher T/E ratio.
The activity of aromatase can be modified by many factors. Aging, obesity, and alcohol consumption may increase the activity, while prolactin and anti-Mullerian hormone may inhibit it.[15],[16]
Males with excessive aromatase activity (seen in males with increased multirepeat nucleotides TTTA in the aromatase gene) commonly have impaired sperm production. These findings readily translated that excess aromatase function may cause infertility in males.[17] Contrarily, patients without aromatase activity (seen in patients with complete absence of CYP19A1 gene, an autosomal recessive disorder) usually presented with tall stature, osteoporotic bony density, and poor libido, while their fertility may range from normal to significant impairment. Supplementation with E2 in these patients will markedly improve their libido and sexual activity.[18] Some studies showed that AIs can treat males with prepubertal short stature by delaying the epiphyseal closure.[19],[20],[21]
Aromatase inhibitors
AIs decrease estrogen production by blocking cytochrome p450 isoenzymes 2A6 and 2C19 of the aromatase enzyme complex.[22] Inhibiting the estrogen negative feedback on the hypothalamus and pituitary offers a strong stimulation to increase GnRH and gonadotropin (including FSH and LH) release. The increased gonadotropins in turn enhance spermatogenesis in the testis. Studies have shown that AIs are beneficial to spermatogenesis in patients with nonobstructive azoospermia (NOA) and help improve semen parameters in males with oligoasthenoteratozoospermia.[23],[24] In addition, AIs can be applied in other conditions, including erectile dysfunction, short stature, depression, cognition disorder,[25] late-onset hypogonadism,[26] and male breast cancer.[27]
Peripheral androgen aromatization is particularly augmented in those with advanced body mass index. Commonly, overweighted males present with increased E2 concentration and lower T levels.[28] Losing body weight has shown effective in improving T levels.[29] Using AIs (e.g., letrozole) in males with morbid obesity has shown effective in elevating their T levels.[30]
AIs are classified by generations based on their selectivity and potency. The first-generation is the least, and the third is the most selective and potent[23][Table 1]. Pharmacologically, AIs can be divided into two different types, steroidal (type 1) and nonsteroidal (type 2). Steroidal AIs, such as testolactone (first-generation), play a role in mimicking androstenedione to cause an irreversible but weak aromatase inhibition. Whereas nonsteroidal AIs, such as letrozole and anastrozole, which are both potent third-generation reversible inhibitors, demonstrate their functions by competing with endogenous androgens to preserve the androgens, majorly T. These effects help improve spermatogenesis in males with oligozoospermia or azoospermia.[23]
The negative feedback operated in the pituitary is mainly via estrogen levels instead of T alone. Therefore, estrogen production suppression by AIs may represent a strong stimulator to enhance LH secretion. For males with low serum T levels and low T/E ratio, using AIs may significantly increase their LH and T levels and sperm production. The effects are more significant than using SERMs alone.[31],[32]
Steroid/irreversible aromatase inhibitor
First generation
Testolactone
Testolactone (brand name Teslac) had been used in several earlier trials for idiopathic infertile males; however, the results showed heterogeneous outcomes in serum T and semen analysis. Testolactone at lower doses demonstrated beneficial results,[13] but it showed no change in T or semen parameters at higher doses.[33] Pavlovich et al. treated patients with infertility with a T/E ratio of <10 with 50–100 mg of oral testolactone twice daily for 5 months and revealed a significant increase in sperm concentration and motility in 12 out of 45 males.[13] This beneficial effect is also shown in patients with Klinefelter syndrome.[34] However, testolactone at higher doses (2 g/day) ended up with no T and semen parameter changes.[33] Testolactone in a relatively higher dose has directly suppressed the T production.[35] Thus, testolactone is now no longer available in most markets worldwide due to its limited effectiveness.
Second generation
Formestane
Formestane (brand name Lentaron) is an analog of androstenedione and is also a prohormone of 4-hydroxy-T.[36] Formestane is not active by oral route due to the significant first-pass glucuronidation at the C-4 hydroxyl bond; thus, it can only be given via an intramuscular route (intramuscular depot biweekly injection form). It was not approved by the United States Food and Drug Administration but was used once in Europe. Formestane is currently withdrawn from the market due to the newer orally active and economically favorable AIs.
Third generation
Exemestane
Exemestane (brand name Aromasin) has a structure similar to 4-androstenedione and acts as a false substrate for aromatase. It inhibits serum E2 and increases T levels in males.[37] Exemestane is quickly absorbed through the oral route but encounters a significant first-pass effect in the liver.[38]
Nonsteroidal/reversible aromatase inhibitor
First generation
Aminoglutethimide
Aminoglutethimide has limited potency and may inhibit adrenal cortical functions. It is currently unavailable in the market due to its less specificity and toxicity.
Second generation
Fadrozole
Fadrozole is a second-generation nonsteroidal imidazole AI of >200 times more potent than aminoglutethimide.[39] It had been used in clinical trials, but the side effects of aldosterone suppression became apparent due to CYP11B2 suppression.[40] Contrary to aminoglutethimide, fadrozole has no suppressive effects on cortisol synthesis.
Third generation
Letrozole
Letrozole is a potent, selective, nonsteroidal AI that was the first approved AI for breast cancer treatment in 1996.[39] Letrozole belongs to the third-generation AIs and reversibly inhibits aromatase. It can avoid T conversion in visceral fat into E2.[31] Many studies have provided evidence that letrozole improves spermatogenesis for infertile males, especially those with a low T/E ratio.[2],[41],[42],[43],[44] A recent study using a mouse model demonstrated that letrozole may activate the MAPK signaling pathway and promote spermatogonia proliferation.[45] Letrozole also showed effects to improve sperm concentration in male patients with severe oligozoospermia and normal T/E ratio.[46],[47],[48]
Anastrozole
Anastrozole can significantly increase the T/E ratio and sperm concentration in infertile patients with low T/E ratios.[34],[35] The side effects of anastrozole are minimal. Approximately 7% of treated males showed transient and nonsignificant liver function alteration, and <5% reported libido changes. Subgroup of severe obesity and varicoceles were further analyzed. In these two subgroups, the T/E ratio and semen parameters both showed a statistically significant improvement. Gregoriou et al. showed that anastrozole had a more significant increment in sperm concentration and a less markedly increased LH levels than letrozole.[43] Anastrozole has also been reported to increase the intratesticular T and enhance the sperm retrieval rates for NOA patients.[49]
Vorozole
Vorozole is a potent and selective AI that is >1000-fold more active than aminoglutethimide. Vorozole shows an in vitro selectivity margin of 10,000-fold for aromatase inhibition compared to other P450- and non-P450-dependent inhibition reactions.[50] It inhibits peripheral conversion of androstenedione to estrone and demonstrates excellent oral bioavailability. Much fewer studies have been provided in the literature on its use in male infertility.
ConclusionsAIs are reasonable treatment choices for infertile males with low T levels and low T/E ratio. In addition, semen parameters are also improved after AI treatment in patients with oligozoospermia. In the commercially available AIs, the use of letrozole and anastrozole is more popular, despite the indication in the off-label use category. In addition, anastrozole has a more significant effect to increase sperm count than letrozole. The benefits of using AIs for infertile patients are promising; however, well-designed prospected randomized controlled trials remained needed to further clarify the role and potential of these agents, especially the effects of AIs on sperm retrieval rates in advanced assisted reproductive technology, such as microdissection testicular sperm extraction for patients with NOA, are of great clinical importance.
Financial support and sponsorship
Nil.
Conflicts of interest
Prof. William J. Huang, an editorial board member at Urological Science, had no role in the peer review process of or decision to publish this article.
References
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