The Efficacy of Anastrozole in Subfertile Men With and Without Abnormal Testosterone to Estradiol Ratios

Yang Yang; Shuyun Chen; Hong Chen; Yi Guo; Xiaoming Teng

Transl Androl Urol. 2022;11(9):1262-1270.

Abstract and Introduction

Abstract

Background: Aromatase inhibitors (AIs), such as anastrozole, have shown effectiveness in treating oligoasthenozoospermia due to abnormal testosterone to estradiol (T/E₂) ratio (T/E₂ <10). However, its efficacy in subfertile men without abnormal T/E₂ ratio (T/E₂ >10) remained unevaluated. This retrospective study aimed to investigate whether patients with T/E₂ ratio >10 could also benefit from anastrozole treatment.

Methods: One hundred and five subfertile patients treated with 1 mg anastrozole daily were included, in which 62 patients had a T/E₂ ratio of <10, and 43 patients had this ratio >10. Semen parameters and sex hormone levels (including FSH, LH, PRL, E₂ and total T) were measured before and after a three-month treatment. T/E₂ ratio and total progressive motility sperm count were calculated from these results.

Results: Patients in both groups (T/E₂ ratio <10 and >10) showed significant increase in sex hormone levels (FSH, LH and total T), T/E₂ ratio and semen parameters (semen volume, sperm concentration, total sperm count, progressive motility and total progressive motility count). The changes of these parameters between two groups were comparable. A subgroup analysis comparing the effect of anastrozole on overweight and normal patients also showed no significant difference. Improvements in semen parameters were seen in some azoospermic and cryptozoospermic patients.

Conclusions: The majority of subfertile men with and without abnormal T/E₂ ratios responded to anastrozole treatment with significantly improved semen parameters and sex hormone levels. Anastrozole showed potential effectiveness in male subfertile patients with T/E₂ >10, to be confirmed by future prospective, randomized, controlled studies.

Introduction

Although not thoroughly understood, the role of estradiol in spermatogenesis has been highlighted in recent years.^[1] Estradiol negatively feeds back on the hypothalamus and pituitary to reduce secretion of gonadotropins, decrease serum testosterone level and eventually affect spermatogenesis.^[2] Excessive estradiol and/or low testosterone level have been shown by studies to be associated with oligoasthenozoospermia. This specific type of male infertility has also been described as a treatable endocrinopathy,^[3] as they show the same manifestation of low testosterone to estradiol (T/E₂) ratios.

To correct the high estradiol and/or low testosterone level, endocrinological management has been applied in the treatment of male infertility as an off-label option,^[4] which could be categorized into two types: selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). SERMs competitively bind estradiol receptors to reduce the negative feedback on hypothalamus and pituitary. On the other hand, aromatase, a cytochrome p450 enzyme, which is expressed in the testes, brain, and adipose tissue in men, is responsible for converting testosterone into estradiol.^[5] By inhibiting this enzyme, AIs could directly lower serum estradiol level and therefore attenuate the negative feedback.^[6,7]

Studies have shown that both SERMs and AIs were generally effective in treating oligoasthenozoospermia due to high estradiol and/or low testosterone.^[8,9] However, both drugs also failed to produce favorable prognosis in some patients.^[10,11] A drug selection dilemma was therefore raised. To address this issue, based on the cohort study conducted by Pavlovich et al.,^[3] it seems that a consensus has gradually been reached, that patients with T/E₂ ratios (T in ng/dL and E₂ in pg/mL) less than 10 are advised to be treated with AIs (such as anastrozole and letrozole),^[12] as most studies have shown improvement in sperm concentration and sperm motility after AIs treatment.

Still, two studies have showed that semen parameters from patients who failed the SERMs treatment could be restored after switching to AIs administration.^[13,14] Therefore, it raised the concern that whether AIs could be effective in patients with T/E₂ ratios >10. Moreover, there has been another study with much larger sample size to compare T/E₂ ratios between idiopathic infertile men and fertile controls, finding the normal T/E₂ ratio in fertile men to be more than 10.^[15]

Therefore, our study intended to assess the efficacy of anastrozole administration in subfertile men with and without abnormal T/E₂ ratios, and to investigate whether patients with T/E₂ ratio >10 could also benefit from anastrozole treatment. We present the following article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-22-95/rc).

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Next Section

Abstract and Introduction
Methods
Results
Discussion
Conclusions
References

Table 1. Basic characteristics of the study population
Demographic	Total (n=105)	Group T (n=43)	Group E (n=62)	P value
Age (years), mean (SD)	32.67 (5.03)	33.28 (5.16)	32.24 (4.94)	0.301
BMI (kg/m²), n (%)
<24	29 (27.6)	13 (30.2)	16 (25.8)	0.618
≥24	76 (72.4)	30 (69.8)	46 (74.2)
Height (cm), mean (SD)	174.89 (5.70)	176.44 (5.62)	175.81 (5.55)	0.109
Weight (kg), mean (SD)	79.73 (12.66)	77.70 (12.40)	81.15 (12.74)	0.171
Smoking (number/day), n (%)
0	85 (81.0)	35 (81.4)	50 (80.6)	1
1–9	8 (7.6)	3 (7.0)	5 (8.1)
≥10	12 (11.4)	5 (11.6)	7 (11.3)
Alcohol consumption (%), n (%)
No	101 (96.2)	41 (95.3)	60 (96.8)	1
Yes	4 (3.8)	2 (4.7)	2 (3.2)
Left testicle size (mL), mean (SD)	13.24 (2.22)	12.95 (2.25)	13.43 (2.20)	0.278
Right testicle size (mL), mean (SD)	13.47 (2.89)	13.16 (2.35)	13.68 (3.21)	0.364
Varicocele, n (%)
No	99 (94.3)	41 (95.3)	58 (93.5)	1
Yes	6 (5.7)	2 (4.7)	4 (6.5)

SD, standard deviation; BMI, body mass index; T/E₂, testosterone/estradiol. Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10.

Table 2. Hormonal analysis of patients treated with anastrozole in both groups
Groups	Baseline	Post-treatment	P value
Group T
FSH (IU/L)	4.76 (2.51)	9.54 (5.11)	<0.001
LH (IU/L)	3.96 (1.56)	7.38 (3.61)	<0.001
PRL (ng/mL)	9.91 (3.53)	12.90 (4.53)	0.001
E2 (pg/mL)	30.26 (8.71)	21.54 (7.82)	<0.001
TT (ng/dL)	4.23 (2.00)	7.14 (2.36)	<0.001
T/E₂	14.09 (4.25)	37.57 (18.89)	<0.001
Group E
FSH (IU/L)	4.60 (2.35)	14.33 (9.66)	<0.001
LH (IU/L)	3.55 (1.39)	11.66 (8.59)	<0.001
PRL (ng/mL)	9.63 (3.61)	12.17 (5.14)	0.002
E2 (pg/mL)	41.16 (25.11)	24.18 (11.10)	<0.001
TT (ng/dL)	2.74 (1.12)	8.26 (2.58)	<0.001
T/E₂	7.16 (2.12)	40.05 (19.86)	<0.001

Data are expressed as mean (standard deviation). FSH, follicle stimulating hormone; LH, luteinizing hormone; PRL, prolactin; TT, total testosterone; T/E₂, testosterone/estradiol; Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10.

Table 3. Hormonal changes between baseline and post-treatment in both groups
Hormones	Group T	Group E	P value
FSH (IU/L)	4.78 (4.43)	9.73 (9.06)	0.001
LH (IU/L)	3.42 (3.82)	8.11 (8.67)	0.001
PRL (ng/mL)	2.99 (4.69)	2.54 (5.45)	0.664
E₂ (pg/mL)	−8.72 (10.48)	−16.97 (20.66)	0.018
TT (ng/dL)	2.91 (2.81)	5.52 (2.52)	<0.001
T/E₂	23.48 (19.11)	32.89 (19.49)	0.016

Data are expressed as mean (standard deviation). Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10; FSH, follicle stimulating hormone; LH, luteinizing hormone; PRL, prolactin; TT, total testosterone; T/E₂, testosterone/estradiol.

Table 4. Semen parameters analysis of patients treated with anastrozole in both groups
Groups	Baseline	Post-treatment	P value
Group T
Semen volume (mL)	3.37 (1.56)	3.96 (1.77)	0.002
Sperm concentration (M/mL)	6.96 (5.07)	14.75 (13.38)	0.001
Total sperm count (M)	23.18 (17.72)	50.99 (43.92)	<0.001
PR (%)	10.65 (8.45)	18.40 (12.30)	0.001
TPMC (M)	2.44 (2.77)	9.42 (9.02)	<0.001
Group E
Semen volume (mL)	3.50 (1.56)	3.95 (1.75)	0.003
Sperm concentration (M/mL)	4.59 (3.11)	12.66 (10.77)	<0.001
Total sperm count (M)	15.75 (13.19)	47.72 (46.38)	<0.001
PR (%)	10.36 (9.27)	18.08 (13.15)	<0.001
TPMC (M)	1.97 (2.20)	10.88 (16.21)	<0.001

Data are expressed as mean (standard deviation). Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10; PR, progressive motility; TPMC, total progressive motility count.

Table 5. Semen parameters changes between baseline and post-treatment in both groups
Semen parameters	Group T	Group E	P value
Semen volume (mL)	0.39 (1.00)	0.44 (1.25)	0.81
Sperm concentration (M/mL)	7.78 (12.05)	8.07 (9.71)	0.894
Total sperm count (M)	27.81 (45.79)	31.96 (43.73)	0.64
PR (%)	7.75 (9.97)	7.89 (9.31)	0.941
TPMC (M)	6.98 (8.44)	8.94 (15.76)	0.458

Data are expressed as mean (standard deviation). Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10; PR, progressive motility; TPMC, total progressive motility count.

Table 6. Semen parameters changes between baseline and post-treatment in both groups, stratified by BMI
Semen parameters	BMI (<24)			BMI (≥24)
Semen parameters	Group T (n=13)	Group E (n=16)	P value	Group T (n=30)	Group E (n=46)	P value
Semen volume (mL)	0.63 (1.14)	0.4 (1.23)	0.597	0.46 (1.27)	0.2 (0.85)	0.376
Sperm concentration (M/mL)	7.63 (14.77)	7.01 (5.64)	0.888	8.35 (10.56)	7.91 (9.71)	0.864
Total sperm count (M)	29.34 (52.98)	28.18 (27.15)	0.943	32.97 (47.34)	26.61(40.35)	0.574
PR (%)	11.83 (11.1)	9.71 (10.16)	0.580	6.85 (8.6)	6.2 (9.75)	0.775
TPMC (M)	10.07 (10.43)	8.05 (8.44)	0.551	8.64 (16.97)	6.13 (8.52)	0.497

Data are expressed as mean (standard deviation). Group E, patients with T/E₂ ratio <10; Group T, patients with T/E₂ ratio >10; PR, progressive motility; TPMC, total progressive motility count.