Aromatase inhibition for the treatment of idiopathic hypogonadotropic hypogonadism in men with premature ejaculation. (Original Article).

Background: Idiopathic hypogonadotropic hypogonadism (IHH) has been observed to occur in men with premature ejaculation (PE). Common IHH therapies include testosterone replacement, which increases testosterone levels but suppresses gonadotropin release; and gonadotropin-releasing hormone supplementation, which restores gonadotropin levels but is impractical for chronic use. Hormonal imbalances associated with IHHIPE are thought to be related to hyperactivity of the cytochrome P-450 enzyme aromatase.

Methods: Ten male patients with a diagnosis of IHH/PE were treated with the aromatase inhibitor anastrazole (1 mg/d orally). Levels of free and total testosterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and estradiol were determined at baseline and after 2 weeks of therapy.

Results: After 2 weeks of therapy with anastrazole, levels of testosterone, luteinizing hormone, and estradiol had returned to normal. No effect was noted on premature ejaculation.

Conclusion: These results suggest that aromatase inhibition with anastrazole may provide a practical and efficacious alternative, for the treatment of IHH but is not effective in preventing premature ejaculation.

Key Words: anastrazole, aromatase, hypogonadism, idiopathic hypogonadotropic hypogonadism, premature ejaculation

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Hypogonadism now occurs with greater frequency in sexually mature men without obvious evidence of either hypothalamic or pituitary disease. In a study of men with sexual dysfunction, premature ejaculation (PE) was found to be associated with idiopathic hypogonadotropic hypogonad ism (IHH). (1) Extrapolation of the studies of Laumann et al, (2) who reported a 21% prevalence of premature ejaculation in men along with the frequent occurrence of hypogonadotropic hypogonadism, leads to the possibility that there is a large number of men suffering from the effects of hormonal inadequacy. These findings suggest that premature ejaculation, a common problem in younger men, could become a marker for IHH in a fashion analogous to the occurrence of anosmia in Kallmann's syndrome. (3)

Hypogonadal function occurs as a result of testicular failure either primary or secondary to altered hypothalamic-pituitary-gonadal function. Primary testicular failure is associated with diminished testosterone levels and elevated gonadotropin levels, which result in a hypergonadotropic hypogonadal pattern. (4) IHH, however, is associated with diminished levels of both testosterone and gonadotropins. (5)

Still another pituitary-gonadal dysfunction pattern has been observed in morbidly obese men. This pattern is characterized by diminished levels of testosterone and gonadotropins and elevated estradiol levels. The result of this hormonal imbalance is a hypogonadal obesity cycle (6) that seems to be related to the increase in the activity of aromatase, a cytochrome P-450 enzyme that converts C19 to C18 steroids. (7) Increased aromatase activity, secondary to the accumulation of adipose tissue, results in both a decrease in testosterone levels and a relative increase in estradiol levels. (8)

Recent literature related to male hypogonadism suggests that testosterone replacement is the most common treatment for hypogonadal disorders, (9-11) with its most appropriate use being for those situations associated with primary testicular. failure. In men with adult-onset IHH, the decrease in hypothalamic-pituitary-gonadal function usually results from gonadotropin-releasing hormone (GnRH) deficiency, (12) which appears to be a permanent and irreversible defect. (13)

Because GnRH therapy is costly, complex, and impractical for routine therapy for a large patient population and because of the disadvantages associated with exogenous testosterone administration, another therapeutic modality was sought for the treatment of men with IHH. During the treatment of morbidly obese men with IHH, testolactone, an aromatase inhibitor, was observed to increase both testosterone and luteinizing hormone (LH) levels to the normal range, (6) suggesting that aromatase inhibition could restore normal pituitary-gonadal function in patients with IHH. To this end, the nonsteroidal aromatase inhibitor anastrazole was selected for use in this study because of its relative safety (14) and once-daily dosing schedule. (15)

Methods

The study participants were 10 consecutive male patients who presented to a men's health program with a diagnosis of primary PE. Premature ejaculation was defined as persistent or recurrent ejaculation with minimal sexual stimulation or shortly after penetration and before the person wishes it, without other sexual dysfunction. The study design was the same as previously reported on the effects of fenfluramine on ejaculatory function. (16)

Before initiation of therapy, a complete medical history was taken, a physical examination was performed, and a computed tomography brain scan was obtained. None of the participants had a history of thyroid disease or had used any medications known to affect the hypothalamic-pituitary-go-nadal axis for at least 3 months before being entered into the study. No specific psychological testing was performed and all participants were determined to be in general good health. Throughout the study, participants were instructed to maintain their usual lifestyle and to refrain from using any other medications.

Blood samples were obtained by venipuncture before initiation of therapy and again after 2 weeks of therapy for hormone level analyses. All blood samples were obtained in the morning before 11 AM. Participants were asked to note the effect of the therapy on premature ejaculation after 2 weeks of treatment and at monthly intervals thereafter.

Assays for LH, follicle-stimulating hormone, thyroid-stimulating hormone, total testosterone, and prolactin were performed by a commercial laboratory using the IMMULITE (Diagnostic Products Corp., Los Angeles, CA) solid-phase, two-site, chemiluminescent, immunometric assay. Free testosterone and estradiol concentrations were determined by the Coat-A-Count solid phase [I.sup.125] radioimmunoassay (Diagnostic Products). The normal range and mean for all laboratory values were supplied by the commercial laboratory.

Results

The results of the medical history and physical examination indicated that all of the participants had normal male secondary sexual characteristics, and the onset of the PE was first noted at the beginning of sexual activity. Seven of the men reported previous paternity. There was no family history of anosmia and all had a normal sense of smell. The mean age of the participants was 42 [+ or -] 2.8 years. The average body mass index (wt[kg]/ht[[m.sup.2]]) for the group was 27.8 [+ or -] 2.7, with a range of 23.2 to 33.9. Only two of the men had body mass index values greater than 30. Although testicular volumes were not determined, testicular size appeared slightly smaller but grossly within normal limits.

The results of the hormone level assays before and after treatment with anastrazole are listed in Table 1. Mean baseline hormone concentrations were as follows: total testosterone, 4.0 [+ or -] 1 ng/ml (normal limits [NL], 8.9 [+ or -] 3 ng/ml); free testosterone, 13 [+ or -] 2.2 pg/ml (NL 26 [+ or -] 6.7 pg/ml); LH, 3.0 [+ or -] 3.6 mIU/ml (NL, 4.5 [+ or -] 1.6 mIU/ml); and estradiol, 45.1 [+ or -] 8.3 pg/ml (NL, 25 [+ or -] 12.5 pg/ml). Levels of prolactin and follicle-stimulating hormone were within the normal range.

After 2 weeks of anastrazole treatment, mean total testosterone levels had increased to 7.8 [+ or -] 0.9 ng/dl, mean free testosterone levels had increased to 25.4 [+ or -] 2.1 pg/ml, mean LH levels had increased to 5.2 [+ or -] 1 mIU/ml, and estradiol levels had decreased to 25.2 [+ or -] 5.7 pg/ml. All changes in pre-and posttreatment hormone levels were statistically significant at the P < 0.05 level. The posttreatment hormone levels did not differ significantly from normal limits. These results clearly indicate that the initial pattern of hypogonadotropic hypogonadism was reversed after anastrazole administration. The mean total and free testosterone concentrations had a remarkable return to almost normal levels, with only one individual below the mean [+ or -] 1 SD. The mean LH concentration increased at least to the normal range in all patients, with elevations in two individuals above 1 SD. The mean LH concentration increased at least to the normal range in all patients, with elevations in two individ uals above 1 SD and estradiol levels decreased to within the normal range in all patients.

After 2 weeks and again after 4 weeks of treatment with anastrazole, no improvement in premature ejaculation symptoms was reported by the participants. After the fourth week of anastrazole therapy, they were all started on sertraline, and varying degrees of retardation of the premature ejaculation were noted.

Discussion

The results of this study involving 10 men diagnosed with IHH associated with PB indicate that treatment with the aromatase inhibitor anastrazole returned LH and testosterone levels to the normal range and also lowered estradiol levels. The reduction in estradiol levels occurred because of inhibition of the biotransformation of C17 (testosterone) to C18 steroids (eg, estradiol). (8) These results indicate that aromatase inhibition appears to correct the pituitary-gonadal dysfunction in these patients but has no effect on premature ejaculation.

These results are in sharp contrast to those observed after the administration of exogenous testosterone (17) and dihydrotestosterone gel to patients with IHH. (11) The administration of testosterone resulted not only in decreased LH levels but also in increased estradiol concentrations, whereas the use of dihydrotestosterone gel resulted in decreased levels of LH, testosterone, and estradiol.

A common characteristic in men with IHH is decreased levels of both LH and testosterone. The results of this study showed that, after therapy with anastrazole, there were simultaneous increases in both testosterone and LH. Similar findings have also been reported with the selective inhibition of aromatization by anastrazole with significant increases in both testosterone and gonadotropin levels. (18)

There are several possible explanations for the parallel increases in both LH and testosterone levels after anastrazole administration. The diminished testosterone concentrations may be the result of two contributing components--one central and one peripheral. The reduced LH level would account for the decrease in testicular testosterone synthesis. Wang and Swerdloff (11) reported that the administration of testosterone with the aromatase inhibitor testolactone prevented gonadotropin inhibition by testosterone, which suggests that a component of this inhibitory feedback mechanism is related to the conversion of testosterone to estrogen by aromatase. In addition, when testolactone was administered alone, an increase in gonadotropin levels occurred, further suggesting that the inhibitory effects of testosterone on gonadotropin release were, at least in part, aromatase dependent. Recently, Hayes et al (19) reported that anastrazole administration reversed this peripheral aromatase effect, resulting in decreased estradiol and increased testosterone levels.

All of the patients in this study had PE and normal male secondary sex characteristics. PE is usually classified as primary or secondary. (1) In the primary form, its onset occurs with the beginning of sexual activity, which suggests that adequate hypothalamic-pituitary-gonadal function was present for normal male development at that time. Because PE has been viewed as an anxiety-related form of male sexual dysfunction, (18) the problem appears to be more complex and to contain other significant biologic components.

The normalization of testosterone levels after treatment with anastrazole did not appear to influence the PE response after 4 weeks of treatment, suggesting that PE is a complex and heterogenous disorder with disparate manifestations, regardless of the causal factors. Therefore, the hypogonadal state appears to be only one facet of a clinical disorder that symptomatically responds to serotonergic agents. (20)

The corrective effect of anastrazole administration on LH and testosterone levels was evident in this brief study. One limitation to the general application of these findings is that only single-point gonadotropin, testosterone, and estradiol levels were available for the evaluations. In addition, although there was no control group, the uniform responses noted in all patients suggest that a placebo effect was unlikely. Of special interest is the observation that anastrazole administration resulted in restored testosterone levels to the midnormal range. Although these results could be an artifact related to the relatively small sample size or single-point levels, they may also be the result of the reestablishment of normal function and resetting of the hypothalamic-pituitary-gonadal axis. Further investigation is needed to determine whether the responses are physiologic and whether the normal rhythms of secretion will return as is seen with GnRH therapy.

During this short study, no anastrazole-related side effects were reported and direct benefits related to the corrected testosterone levels were not observed. Nevertheless, the normalization of androgen levels appears to be necessary to both prevent and reverse the consequences of the chronic hypogonadal state. (21) Aromatase inhibition provides a convenient and safe alternative to testosterone or GnRH replacement therapy.

In summary, these results, based on single-point sampling of LH, testosterone, and estradiol concentrations before and after the administration of the aromatase inhibitor anastrazole, indicate alleviation of hypogonadotropic hypogonadism in these patients. Additional investigations with aromatase inhibition are clearly warranted to verify these observations and to identify the mechanisms that underlie the apparent repair of the hypothalamic-pituitary-gonadal defect.

Table 1

Clinical characteristics of patinets with hypogonadotropic hypogonadism
who were treated with the nonsteroidal aromatase inhibitor anastrazole
(a)

                                                         Testosterone
Patient                 Age               BMI           Total (ng/ml)
no.                    (yr)         (kg/[m.sup.2])         Before

 1                      42               28.6               2.4
 2                      45               27.4               4.1
 3                      48               30.5               4.2
 4                      42               33.9               3.0
 5                      37               31.4               3.4
 6                      41               25.2               4.2
 7                      44               23.2               4.4
 8                      42               25.5               4.3
 9                      42               24.5               6.6
10                      40               27.6               4.0
Mean [+ or -] SD  42 [+ or -] 2.8  27.8 [+ or -] 2.7  4.0 [+ or -] 1.0
Normal limits                                         8.9 [+ or -] 3.0

                                        Testosterone
Patient             Total (ng/ml)                  Free (pg/ml)
no.                    After             Before              After

 1                      6.8                7.9               21.4
 2                      8.2               13.7               20.5
 3                      8.8               15.9               26.6
 4                      7.0               16.1               27.2
 5                      5.6               12.2               26.0
 6                      8.9               14.6               29.1
 7                      9.0                9.2               17.8
 8                      8.6               16.5               29.2
 9                      8.0               13.1               23.9
10                      7.8               13.0               25.4
Mean [+ or -] SD  7.8 [+ or -] 0.9  13.0 [+ or -] 2.2  25.4 [+ or -] 2.1
Normal limits                        26 [+ or -] 6.7


Patient                     Estradiol (pg/ml)                LH (mIU/ml)
no.                    Before              After             Before

 1                       29                13.1               3.3
 2                       29                 21                1.9
 3                       55                 32                2.8
 4                       62                 23                2.9
 5                       52                 36                1.0
 6                       40                 20                4.6
 7                       50                 30                2.4
 8                       47                 24                3.0
 9                       49                 33                4.2
10                       45                 25                3.0
Mean [+ or -] SD  45.1 [+ or -] 8.3  25.2 [+ or -] 5.7  3.0 [+ or -] 3.6
Normal limits     25 [+ or -] 12.5                      4.5 [+ or -] 1.6


Patient             LH (mIU/ml)
no.                   After

 1                     4.1
 2                     3.8
 3                     4.8
 4                     6.8
 5                     3.9
 6                     5.7
 7                     8.0
 8                     5.2
 9                     5.4
10                     5.2
Mean [+ or -] SD  5.2 [+ or -] 1
Normal limits

(a)BMI, body mass index; LH, luteinizing harmone; SD, standard
deviation.

Accepted September 18, 2002.

References

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RELATED ARTICLE: Key Points

* Idiopathic hypogonadotropic hypogonadism (IHH) is characterized by diminished levels of testosterone and gonadotropins and may be associated with premature ejaculation.

* In morbidly obese men, IHH is characterized by diminished testosterone and gonadotropin levels, elevated estradiol levels, and accumulation of body fat. This syndrome is thought to be related to increased aromatase activity.

* Treatment with the aromatase inhibitor anastrazole was found to be effective in reversing IHH hormonal abnormalities but was not effective in reversing premature ejaculation.

From the Department of Pharmaceutical Sciences and Center for Substance Abuse Education and Research, Southern School of Pharmacy, Mercer University, Atlanta, GA.

Reprint requests to John M. Holbrook, PhD, Department of Pharmaceutical Sciences, Southern School of Pharmacy, Mercer University, 3001 Mercer University Drive, Atlanta, GA 30341. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association