- Email: [email protected]
Estrogen Ratio in Male Hypogonadism
Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 2005 200525716721Original ArticleClomiphene Citrate Effects in Male HypogonadismShabsigh et al.
716
Clomiphene Citrate Effects on Testosterone/Estrogen Ratio in Male Hypogonadism Ahmad Shabsigh, MD, Young Kang, MD, Ridwan Shabsign, MD, Mark Gonzalez, MD, Gary Liberson, MD, Harry Fisch, MD, and Erik Goluboff, MD Department of Urology, NY Presbyterian Medical Center, New York, NY, USA DOI: 10.1111/j.1743-6109.2005.00075.x
ABSTRACT
Aim. Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol. These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testostosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts. In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio. Methods. Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed. Results. The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 ± 39.8 ng/dL and 32.3 ± 10.9, respectively. By the first follow-up visit (4–6 weeks), the mean testosterone level rose to 610.0 ± 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients. Conclusions. Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estadiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway. Shabsigh A, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, and Goluboff E. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716–721. Key Words. Endocrinologic Studies of Sexual Function; Testosterone; Male Hypogonadism
Introduction
H
ypogonadism in aging males results in a steady decline in testosterone levels at a rate of 1% per year after age 40 years [1]. Testosterone deficiency has been implicated with decline in sexual function, loss of libido, osteoporosis, weight gain, muscle weakness, decreased lean body mass, diabetes mellitus, and cognitive changes [2]. The etiology of hypogonadism in the aging male is a combination of hypothalamus–pituitary axis dysfunction and primary testicular failure with decreased production of testosterone by Leydig cells [3]. The most common treatment of symptomatic late-onset hypogonadism is testosterone therapy
J Sex Med 2005;2:716–721
with various transcutaneous, buccal, oral, and intramuscular delivery methods [2]. These delivery methods all share a common shortcoming. Because exogenous testosterone formulations cannot mimic the natural endogenous pathway of hypothalamus–pituitary hormonal axis, suppression of the hypothalamic–pituitary–gonadal axis is inevitable via a negative feedback mechanism [2]. Low levels of gonadotropin releasing hormone (GnRH), in turn, further decrease production of luteinizing hormone (LH) and follicular stimulating hormone (FSH) by the pituitary gland. The low LH levels translate to low testosterone production by the Ledydig cells in the testes. The reduction in FSH results in suppression of spermatogenesis.
717
Clomiphene Citrate Effects in Male Hypogonadism These endocrinologic changes are clinically manifested in reduction of both testicular size and sperm count. Moreover, excess testosterone from an external source can be metabolized to estradiol, which can result in gynecomastia. Other reported side effects include inadvertent contact contamination of spouse and children for gels and transdermal patches as well as hepatotoxities for oral formulations. Hypogonadism in aging is also associated with increased body weight, adipose tissue, and estrogens, resulting from peripheral conversion of testosterone to estradiol. The negative feedback mechanism from excess estradiol results in a paradoxically low LH secretion from the pituitary despite a physiologically low testosterone level. The term secondary hypogonadism most accurately describes the predominant physiological process that occurs with aging [4]. Clomiphene citrate is a weak estrogen receptor antagonist and thus may be considered a selective estrogen receptor modulator (SERM). It competes with estradiol for the estrogen receptors at the level of the hypothalamus and blocks the normal negative feedback mechanism of circulating estradiol on the hypothalamus, preventing estrogen from limiting the production of GnRH [5]. The increase in GnRH level then stimulates the pituitary gland to release more FSH and LH, resulting in an increase in sperm and testosterone production by the testes [6]. The aim of this preliminary study was to determine whether clomiphene citrate is effective in stimulating this endogenous testosterone production pathway and in improving the testosterone/ estrogen ratio. In addition, we will address the applicability of this medication as a therapeutic option for hypogonadism. Materials and Methods
This is an open-label, flexible-dose, proof of concept study. The definition of hypogonadism used was a testosterone level less than 300 ng/dL, as per Wang and Swerdloff [7]. In our study we evaluated 36 Caucasian males seen in the Male Reproductive Center of Columbia Presbyterian Medical Center. Majority of these patients were otherwise healthy individuals seeking treatment for subfertility. As part of their work-up, they were found to have testosterone levels < 300 ng/dL. The average age of these patients was 39 years, ranging between 27 and 60 years. Twelve patients were older than 40 years.
All patients were examined and interviewed by one urologist. Any abnormal physical findings were reported. Special attention was given to testicular size (measured by visual inspection). Before the initiation of clomiphene citrate treatment, blood samples were obtained to determine baseline measurements of serum testosterone, estradiol, LH, and FSH. All patients were started on clomiphene citrate 25 mg once a day. All patients were on the medication for at least 3 months. Patients were followed prospectively and seen at 4–6 weeks after treatment began for evaluation of treatment response. The entire cohort was followed for at least 1 year. Testosterone and estradiol levels were repeated at the first follow-up visit and compared with pretreatment levels. Patients were asked if they experienced any side effects related to the use of clomiphene citrate. Simple statistical analysis (ttest) was utilized to analyze responses to therapy.
Main Outcome Measures
The main outcome measures in this paper are the changes in testosterone and estradiol levels after administration of clomiphene citrate to hypogonadal men. Testosterone/estradiol ratio was calculated to evaluate the potential benefit of clomiphene citrate in stimulating testosterone while causing minimal changes in estradiol levels. This may diminish estrogen-related side effects such as gynecomastia and nipple tenderness.
Results
Thirty-six Caucasian men were prospectively followed in this study. The mean patient age was 39 ± 7 years. Our cohort consisted of healthy subjects without any significant comorbidities. Two patients had a history of unilateral cryptorchidism and underwent orchidopexies during their childhood. One patient had a known genetic abnormality, and three patients were obese, weighing over 225 pounds. On physical examination the average size of the right and left testicles were 27.8 ± 8 and 26.4 ± 8.4 cc, respectively. The pretreatment mean total testosterone level (n = 36) was 247.6 ± 39.8 ng/dL (ranging from 166 to 299 ng/dL), and the mean estradiol level (n = 29) was 32.3 ± 10.9 ng/dL (15– 55 ng/dL). The mean FSH (n = 36) and LH (n = 33) levels were 7.5 ± 6.8 IU/L (1.8–28 ng/dL) and 2.3 ± 2.3 IU/L (1.4–12.3 ng/dL), respectively. J Sex Med 2005;2:716–721
718 Table 1
Shabsigh et al. Testosterone and estrogen levels at baseline and after 4–6 weeks of treatment Mean ± SD
Testosterone at baseline Testosterone at follow-up visit D in testosterone level Estrogen at baseline Estrogen at follow-up visit D in estrogen level Testosterone/estrogen ratio at baseline Testoterone/estrogen ratio at follow-up visit D in testosterone/estrogen ratio
The mean testosterone/estradiol (T/E) ratio at the first visit was 8.7 (Table 1). After initiating therapy with 25 mg of oral clomiphene citrate once a day, patients were reevaluated approximately 4–6 weeks later. There was a significant increase in the mean testosterone level to 610 ± 178.6 ng/dL, an increase of 146.4% (P = 0.00001). At the same time, the mean estradiol level increased to 46.3 ± 16.6 ng/dL, a rise of 44.9% (P = 0.001). The T/E ratio increased to 14.2 ± 5.1, a rise of 60.9% (P = 0.001). This response was seen in all patients irrespective of age. In our subanalyses, the mean pretreatment testosterone levels for men aged less than 40 years (mean 35.6 years) and more than 40 years (mean 46 years) were 251.4 ± 38.9 ng/dL and 242.2 ± 41.8 ng/dL, respectively. With clomiphene citrate therapy, these values rose to 579.7 ± 152.7 ng/dL (+ 131%) and 652.4 ± 207.6 ng/dL (+169%), respectively. The estrogen levels in the two groups rose from the baseline levels of 31 ± 12.4 ng/dL and 34.5 ± 8.1 ng/dL to 52.7 ± 16.6 ng/dL (+70%) and 39 ± 13.9 ng/dL (+13%), respectively. The pretreatment T/E ratios for the below 40 group and over 40 group were 9.5 ± 4.1 and 7.4 ± 1.9, respectively. By the first follow-up visit, the younger group T/E ratio was 11.7 ± 4.4, an increase of 23.4% (4.1 ± 5.8). As for the older group, the T/E ratio was 17 ± 4.5 or an increase Table 2
P
247.6 ± 39.8 ng/dL 610 ± 178.6 ng/dL 146.4% 32.3 ± 10.9 ng/dL 46.3 ± 16.6 ng/dL 44.9% 8.7 ± 3.5 14.2 ± 5.1 60.9%
P < 0.00001
P = 0.001
P = 0.001
of 129.7 % (8.1 ± 5.9). This T/E difference between the two age groups was also statistically significant (P = 0.003) (Table 2). During the follow-up visits, the patients were asked about the major side effects such as hot flashes, headache, visual disturbances, and cardiovascular disorders. None of the patients reported any of the known side effects. Discussion
Male aging is associated with progressive decline in androgen production. This phenomenon has been described as andropause, male climacteric, or progressive androgen decline in the aging male. Because men do not experience an abrupt decrease and cessation of male hormone secretion that results in testicular failure, the term andropause is misleading [2]. As men age, alterations in the hypothalamus–pituitary–gonadal axis occur. This directly translates into decreased hypothalamic production of gonadotropins, starting a hormonal cascade resulting in decline of serum testosterone. Male hypogonadism is a dynamic process that involves multiple organs, similar to the aging process itself. The age-related decline in testosterone is due to defects at all levels of the hypothalamic– pituitary–testicular axis: pulsatile GnRH secretion is attenuated, LH response to GnRH is reduced,
Comparison of testosterone and estrogen levels between men younger and older than 40 years
Testosterone at baseline Testosterone at follow-up visit D in testosterone level Estrogen at baseline Estrogen at follow-up visit D in estrogen Testosterone/estrogen ratio at baseline Testosterone/estrogen ratio at follow-up visit D in testosterone/estrogen ratio
J Sex Med 2005;2:716–721
<40 years
≥40 years
251.4 ± 38.9 ng/dL 579.7 ± 152.7 ng/dL 131% 31 ± 12.4 ng/dL 52.7 ± 16.6 ng/dL 70% 9.5 ± 4.1 11.7 ± 4.4 23.1%
242.2 ± 41.8 ng/dL 652.4 ± 207.6 ng/dL 169% 34.5 ± 8.1 ng/dL 39 ± 13.9 ng/dL 13% 7.4 ± 1.9 17 ± 4.5 129.7%
Clomiphene Citrate Effects in Male Hypogonadism and testicular response to LH is impaired. In the testes, histopathological studies have demonstrated changes consistent with senile atrophy, resulting in a decline in testosterone production by the Leydig cells [8]. This may explain the gradual rise of LH with aging. In the liver, sex hormone-binding globulin synthesis is increased, further reducing the net bioavailable and functional testosterone [9]. Perhaps the most dramatic changes occur at the hypothalamus–pituitary axis. The normal circadian rhythm is disrupted, and LH secretion is inhibited by negative feedback mechanism via estradiol. In fact, the term secondary hypogonadism refers to these men with functioning testes and relatively low levels of LH and testosterone [10–12]. Increase in visceral fat and obesity have been implicated as key contributors to secondary male hypogonadism [13]. It is well known that diabetic men consistently have testosterone levels approximately 20% lower than the general population. This low testosterone level may be attributed to altered insulin metabolism and resistance as a consequence of decreased muscle mass and increased fat [14]. Testosterone therapy has been used as a treatment for diminished libido and erectile dysfunction in hypogonadal men. The goal of testosterone therapy should be to maintain physiological levels of testosterone. In addition, it should ideally limit the conversion of testosterone to its metabolites such as dihydrotestosterone and estradiol. This will optimize the positive effects of testosterone, while curbing the side effects of its metabolites. Moreover, any testosterone therapy should try to mimic, rather than interfere with, the circadian rhythm of testosterone production [2]. Historically, hypogonadism has been treated with testosterone supplementation. Exogenous therapy with testosterone is the mainstay of therapy, and the emphasis is placed on improving the delivery system. As a result, many different exogenous testosterone preparations are commercially available [2]. They are in oral, injectable, and transdermal formulations. Each one of these delivery systems has advantages and disadvantages. Oral agents such as fluoxymesterone, methylterstosterone, and testosterone undecanoate have the convenience of being given orally. However, they can have significant hepatotoxic and gastrointestinal side effects. Liver function tests must routinely be performed to monitor for these changes. Furthermore, absorption and bioavailability are poor, and these oral testosterone therapy agents are not
719 approved by the Food and Drug Administration (FDA) [15,16]. Intramuscular formulations of testosterone in cypionate or enanthate were the next products developed. This mode of delivery unfortunately leads to supraphysiological levels of testosterone in the first 72 hours of administration, followed by hypophysiological levels after 10–21 days. Obviously, maintenance of the normal circadian pattern of testosterone production is impossible with injectable preparations. This may, in fact, be more detrimental to the patient as he experiences more frequent swings in his testosterone levels [17,18]. There are also some data indicating an increase in hemoglobin levels and hypercoagulopathy associated with intramuscular formulations [19]. Transdermal testosterone therapy was the next generation of products made available. Its delivery system can maintain normal levels of testosterone and estradiol by applying them on the scrotal or nonscrotal skin. Normal testosterone levels can be maintained by using both types of patches. However, contact contamination to females and children is a major disadvantage with transdermal formulations [2,20,21]. Other side effects include gynecomastia, decreased sperm counts, softening, and decreased size of the testicles. Clomiphene citrate (Clomid) was recently reclassified as an SERM because of its ability to compete with estradiol for the estrogen receptors at the level of the hypothalamus [22]. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of GnRH. During clomiphene therapy, the frequency and amplitude of GnRH pulses increase, stimulating the pituitary gland to release more FSH and LH. Consequently, sperm and testicular testosterone productions are stimulated [5,23,24]. Faced with different problems associated with the currently available testosterone preparations, we sought a novel approach to manage patients with secondary male hypogonadism. We used a relatively low oral daily dose of clomiphene citrate (25 mg) in 36 men with a mean age of 39 years. All patients had low testosterone levels with an average testosterone level of 247.6 ng/dL. Patients were enrolled and followed prospectively. Serum levels of testosterone, estradiol, FSH, and LH were measured at the time of the initial visit and the first follow-up approximately 4–6 weeks later. Testosterone levels increased by a mean of 146%. Similar changes were seen in both young and old patients. Of special interest is the obserJ Sex Med 2005;2:716–721
720 vation that the T/E ratios increased in both groups, although this rise was significantly greater in the older population. This increase in the T/E ratio might be more important than total serum testosterone increase. No patients reported any side effects of clomiphene citrate including gynecomastia and nipple tenderness. In a recent article by Guay et al., 178 men with secondary hypogonadism and erectile dysfunction were treated with clomiphene citrate for 4 months. Both LH and free testosterone increased significantly in all patients. In this study 75% of patients had improvement of their erectile function [25]. The levels of testosterone have risen more in the men aged more than 40 years vs. men less than 40 years, from 251.4 ± 38.9 ng/dL to 579.7 ± 152.7 ng/dL, and from 242.2 ± 41.8 ng/dL to 652.4 ± 207.6, respectively. Tenover and Bremmer showed that, during a clomiphene challenge, testosterone rose more in younger than in older men. Of course, in their study the age differences were much greater. We cannot give a definite answer, but we can speculate that younger men have often an anxiety component to their low testosterone levels, via making adrenergic substances. This might be one explanation for the lower testosterone levels in the younger men and would be consistent with some of our anecdotal data [6]. Our study revealed promising results. Clomiphene citrate induces endogenous production of testosterone via competitive blockage of hypothalamic estrogen receptors. This effect presents a unique therapeutic opportunity for the management of hypogonadism in the aging male. Low dose, oral therapy with minimal side effects is an excellent substitute to transdermal or injectable testosterone alternatives. It enhances the endogenous androgen synthesis pathway while maintaining the natural circadian rhythm. This method of treatment is especially important in hypogonadal men with infertility, who wish to father children. Exogenous testosterone therapy suppresses spermatogenesis and the hypothalamic–pituitary– testicular axis and may cause testicular atrophy. We understand that hypogonadism in aging males affect older patients. More than 20% of patients older than 60 years have signs and symptoms of hypogonadism. This phenomenon is usually caused by a combination of primary and secondary hypogonadism. Clomiphene citrate may offer an easy and practical solution for a subset of older patients with hypogonadism. Because this is a heterogeneous group of patients, we do not expect the same response in all older patients. J Sex Med 2005;2:716–721
Shabsigh et al. This does not change the fact that clomiphene citrate might be an excellent option for some men, especially those where secondary hypogonadism is a major component of their problem. Our future work will focus on the older patients with hypogonadism. There are obvious limitations to this pilot study. Further investigation is needed to confirm the effectiveness of clomiphene citrate for the treatment of androgen deficiency in secondary male hypogonadism. Studies are needed to determine the optimal dose response in different age groups. Validated measurements of muscle strength, weight, sexual function, exercise tolerance, bone density, and mood changes are required before accepting clomiphene citrate as a standard of care for secondary hypogonadism. Long-term safety and efficacy data are not available, as well as clomiphene citrate effects on lipid metabolism. Lastly, other SERMs may function in a manner similar to clomiphene citrate and may also have benefits. We should mention that clomiphene citrate use for the treatment of hypogonadism is not approved by the FDA in the United States. This report clearly shows the short-term efficacy of clomiphene citrate in improving testosterone levels and the T/E ratio in the treatment of secondary male hypogonadism. Conclusions
Clomiphene citrate effectively induces endogenous testosterone production via competitive inhibition of the hypothalamic estrogen receptor. Clomiphene citrate was able to increase serum testosterone and improve the testosterone/estrogen ratio. Clomiphene citrate was well tolerated and may be an alternative in the treatment of secondary hypogonadism in the aging male. Further studies are needed to confirm these findings and to define the optimal dose, long-term benefits, safety, and side effects. Other SERMs may also be investigated for their potential role in the management of secondary male hypogonadism. Corresponding Author: Harry Fisch, MD, 944 Park Ave, New York, NY 10020, USA. Tel: 212-879-0800; Fax: 212-988-1634; E-mail: harryfi[email protected] Conflict of Interest: None. References
1 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on
Clomiphene Citrate Effects in Male Hypogonadism
2 3 4
5
6
7 8
9
10
11
12
serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–31. Morales A, Heaton JP, Carson CC 3rd. Andropause: A misnomer for a true clinical entity. J Urol 2000;163:705–12. Hermann M, Untergasser G, Rumpold H, Berger P. Aging of the male reproductive system. Exp Gerontol 2000;35:1267–79. Ersoz H, Onde ME, Terekeci H, Kurtoglu S, Tor H. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl 2002;25:312–6. Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 2000;6:212–24. Tenover JS, Bremner WJ. The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men. J Androl 1991;12:258–63. Wang C, Swerdloff RS. Androgen replacement therapy. Ann Med 1997;29:365–70. Neaves WB, Johnson L, Porter JC, Parker CR Jr, Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab 1984;59:756–63. Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 1989;10:366–71. Winters SJ, Troen P. Episodic luteinizing hormone (LH) secretion and the response of LH and folliclestimulating hormone to LH-releasing hormone in aged men: Evidence for coexistent primary testicular insufficiency and an impairment in gonadotropin secretion. J Clin Endocrinol Metab 1982;55:560–5. Mitchell R, Hollis S, Rothwell C, Robertson WR. Age related changes in the pituitary-testicular axis in normal men; lower serum testosterone results from decreased bioactive LH drive. Clin Endocrinol (Oxf) 1995;42:501–7. Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 1995;43:25–8.
721 13 Tan RS, Pu SJ. Impact of obesity on hypogonadism in the andropause. Int J Androl 2002;25:195–201. 14 Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM. Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab 2002;87:4522–7. 15 Morales A, Johnston B, Heaton JW, Clark A. Oral androgens in the treatment of hypogonadal impotent men. J Urol 1994;152:1115–8. 16 Morales A, Johnston B, Heaton JP, Lundie M. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J Urol 1997;157:849–54. 17 Sokol RZ, Palacios A, Campfield LA, Saul C, Swerdloff RS. Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men. Fertil Steril 1982;37:425–30. 18 Nankin HR. Hormone kinetics after intramuscular testosterone cypionate. Fertil Steril 1987;47:1004– 9. 19 Winkler UH. Effects of androgens on haemostasis. Maturitas 1996;24:147–55. 20 McClellan KJ, Goa KL. Transdermal testosterone. Drugs 1998;55:253–8. 21 Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 2000;6:212–24. Review. 22 Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems. Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA 1989; 5:2525–30. 23 Tan RS, Vasudevan D. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril 2003;79:203–5. 24 Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: Double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995;80:3546–52. 25 Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Clomiphene increases free testostgerone levels in men with both secondary hypogonadism and erectile dysfunction: Who does and does not benefit? Inter J Impot Res 2003;15:156–65.
J Sex Med 2005;2:716–721
716
Clomiphene Citrate Effects on Testosterone/Estrogen Ratio in Male Hypogonadism Ahmad Shabsigh, MD, Young Kang, MD, Ridwan Shabsign, MD, Mark Gonzalez, MD, Gary Liberson, MD, Harry Fisch, MD, and Erik Goluboff, MD Department of Urology, NY Presbyterian Medical Center, New York, NY, USA DOI: 10.1111/j.1743-6109.2005.00075.x
ABSTRACT
Aim. Symptomatic late-onset hypogonadism is associated not only with a decline in serum testosterone, but also with a rise in serum estradiol. These endocrine changes negatively affect libido, sexual function, mood, behavior, lean body mass, and bone density. Currently, the most common treatment is exogenous testostosterone therapy. This treatment can be associated with skin irritation, gynecomastia, nipple tenderness, testicular atrophy, and decline in sperm counts. In this study we investigated the efficacy of clomiphene citrate in the treatment of hypogonadism with the objectives of raising endogenous serum testosterone (T) and improving the testosterone/estrogen (T/E) ratio. Methods. Our cohort consisted of 36 Caucasian men with hypogonadism defined as serum testosterone level less than 300 ng/dL. Each patient was treated with a daily dose of 25 mg clomiphene citrate and followed prospectively. Analysis of baseline and follow-up serum levels of testosterone and estradiol levels were performed. Results. The mean age was 39 years, and the mean pretreatment testosterone and estrogen levels were 247.6 ± 39.8 ng/dL and 32.3 ± 10.9, respectively. By the first follow-up visit (4–6 weeks), the mean testosterone level rose to 610.0 ± 178.6 ng/dL (P < 0.00001). Moreover, the T/E ratio improved from 8.7 to 14.2 (P < 0.001). There were no side effects reported by the patients. Conclusions. Low dose clomiphene citrate is effective in elevating serum testosterone levels and improving the testosterone/estadiol ratio in men with hypogonadism. This therapy represents an alternative to testosterone therapy by stimulating the endogenous androgen production pathway. Shabsigh A, Kang Y, Shabsign R, Gonzalez M, Liberson G, Fisch H, and Goluboff E. Clomiphene citrate effects on testosterone/estrogen ratio in male hypogonadism. J Sex Med 2005;2:716–721. Key Words. Endocrinologic Studies of Sexual Function; Testosterone; Male Hypogonadism
Introduction
H
ypogonadism in aging males results in a steady decline in testosterone levels at a rate of 1% per year after age 40 years [1]. Testosterone deficiency has been implicated with decline in sexual function, loss of libido, osteoporosis, weight gain, muscle weakness, decreased lean body mass, diabetes mellitus, and cognitive changes [2]. The etiology of hypogonadism in the aging male is a combination of hypothalamus–pituitary axis dysfunction and primary testicular failure with decreased production of testosterone by Leydig cells [3]. The most common treatment of symptomatic late-onset hypogonadism is testosterone therapy
J Sex Med 2005;2:716–721
with various transcutaneous, buccal, oral, and intramuscular delivery methods [2]. These delivery methods all share a common shortcoming. Because exogenous testosterone formulations cannot mimic the natural endogenous pathway of hypothalamus–pituitary hormonal axis, suppression of the hypothalamic–pituitary–gonadal axis is inevitable via a negative feedback mechanism [2]. Low levels of gonadotropin releasing hormone (GnRH), in turn, further decrease production of luteinizing hormone (LH) and follicular stimulating hormone (FSH) by the pituitary gland. The low LH levels translate to low testosterone production by the Ledydig cells in the testes. The reduction in FSH results in suppression of spermatogenesis.
717
Clomiphene Citrate Effects in Male Hypogonadism These endocrinologic changes are clinically manifested in reduction of both testicular size and sperm count. Moreover, excess testosterone from an external source can be metabolized to estradiol, which can result in gynecomastia. Other reported side effects include inadvertent contact contamination of spouse and children for gels and transdermal patches as well as hepatotoxities for oral formulations. Hypogonadism in aging is also associated with increased body weight, adipose tissue, and estrogens, resulting from peripheral conversion of testosterone to estradiol. The negative feedback mechanism from excess estradiol results in a paradoxically low LH secretion from the pituitary despite a physiologically low testosterone level. The term secondary hypogonadism most accurately describes the predominant physiological process that occurs with aging [4]. Clomiphene citrate is a weak estrogen receptor antagonist and thus may be considered a selective estrogen receptor modulator (SERM). It competes with estradiol for the estrogen receptors at the level of the hypothalamus and blocks the normal negative feedback mechanism of circulating estradiol on the hypothalamus, preventing estrogen from limiting the production of GnRH [5]. The increase in GnRH level then stimulates the pituitary gland to release more FSH and LH, resulting in an increase in sperm and testosterone production by the testes [6]. The aim of this preliminary study was to determine whether clomiphene citrate is effective in stimulating this endogenous testosterone production pathway and in improving the testosterone/ estrogen ratio. In addition, we will address the applicability of this medication as a therapeutic option for hypogonadism. Materials and Methods
This is an open-label, flexible-dose, proof of concept study. The definition of hypogonadism used was a testosterone level less than 300 ng/dL, as per Wang and Swerdloff [7]. In our study we evaluated 36 Caucasian males seen in the Male Reproductive Center of Columbia Presbyterian Medical Center. Majority of these patients were otherwise healthy individuals seeking treatment for subfertility. As part of their work-up, they were found to have testosterone levels < 300 ng/dL. The average age of these patients was 39 years, ranging between 27 and 60 years. Twelve patients were older than 40 years.
All patients were examined and interviewed by one urologist. Any abnormal physical findings were reported. Special attention was given to testicular size (measured by visual inspection). Before the initiation of clomiphene citrate treatment, blood samples were obtained to determine baseline measurements of serum testosterone, estradiol, LH, and FSH. All patients were started on clomiphene citrate 25 mg once a day. All patients were on the medication for at least 3 months. Patients were followed prospectively and seen at 4–6 weeks after treatment began for evaluation of treatment response. The entire cohort was followed for at least 1 year. Testosterone and estradiol levels were repeated at the first follow-up visit and compared with pretreatment levels. Patients were asked if they experienced any side effects related to the use of clomiphene citrate. Simple statistical analysis (ttest) was utilized to analyze responses to therapy.
Main Outcome Measures
The main outcome measures in this paper are the changes in testosterone and estradiol levels after administration of clomiphene citrate to hypogonadal men. Testosterone/estradiol ratio was calculated to evaluate the potential benefit of clomiphene citrate in stimulating testosterone while causing minimal changes in estradiol levels. This may diminish estrogen-related side effects such as gynecomastia and nipple tenderness.
Results
Thirty-six Caucasian men were prospectively followed in this study. The mean patient age was 39 ± 7 years. Our cohort consisted of healthy subjects without any significant comorbidities. Two patients had a history of unilateral cryptorchidism and underwent orchidopexies during their childhood. One patient had a known genetic abnormality, and three patients were obese, weighing over 225 pounds. On physical examination the average size of the right and left testicles were 27.8 ± 8 and 26.4 ± 8.4 cc, respectively. The pretreatment mean total testosterone level (n = 36) was 247.6 ± 39.8 ng/dL (ranging from 166 to 299 ng/dL), and the mean estradiol level (n = 29) was 32.3 ± 10.9 ng/dL (15– 55 ng/dL). The mean FSH (n = 36) and LH (n = 33) levels were 7.5 ± 6.8 IU/L (1.8–28 ng/dL) and 2.3 ± 2.3 IU/L (1.4–12.3 ng/dL), respectively. J Sex Med 2005;2:716–721
718 Table 1
Shabsigh et al. Testosterone and estrogen levels at baseline and after 4–6 weeks of treatment Mean ± SD
Testosterone at baseline Testosterone at follow-up visit D in testosterone level Estrogen at baseline Estrogen at follow-up visit D in estrogen level Testosterone/estrogen ratio at baseline Testoterone/estrogen ratio at follow-up visit D in testosterone/estrogen ratio
The mean testosterone/estradiol (T/E) ratio at the first visit was 8.7 (Table 1). After initiating therapy with 25 mg of oral clomiphene citrate once a day, patients were reevaluated approximately 4–6 weeks later. There was a significant increase in the mean testosterone level to 610 ± 178.6 ng/dL, an increase of 146.4% (P = 0.00001). At the same time, the mean estradiol level increased to 46.3 ± 16.6 ng/dL, a rise of 44.9% (P = 0.001). The T/E ratio increased to 14.2 ± 5.1, a rise of 60.9% (P = 0.001). This response was seen in all patients irrespective of age. In our subanalyses, the mean pretreatment testosterone levels for men aged less than 40 years (mean 35.6 years) and more than 40 years (mean 46 years) were 251.4 ± 38.9 ng/dL and 242.2 ± 41.8 ng/dL, respectively. With clomiphene citrate therapy, these values rose to 579.7 ± 152.7 ng/dL (+ 131%) and 652.4 ± 207.6 ng/dL (+169%), respectively. The estrogen levels in the two groups rose from the baseline levels of 31 ± 12.4 ng/dL and 34.5 ± 8.1 ng/dL to 52.7 ± 16.6 ng/dL (+70%) and 39 ± 13.9 ng/dL (+13%), respectively. The pretreatment T/E ratios for the below 40 group and over 40 group were 9.5 ± 4.1 and 7.4 ± 1.9, respectively. By the first follow-up visit, the younger group T/E ratio was 11.7 ± 4.4, an increase of 23.4% (4.1 ± 5.8). As for the older group, the T/E ratio was 17 ± 4.5 or an increase Table 2
P
247.6 ± 39.8 ng/dL 610 ± 178.6 ng/dL 146.4% 32.3 ± 10.9 ng/dL 46.3 ± 16.6 ng/dL 44.9% 8.7 ± 3.5 14.2 ± 5.1 60.9%
P < 0.00001
P = 0.001
P = 0.001
of 129.7 % (8.1 ± 5.9). This T/E difference between the two age groups was also statistically significant (P = 0.003) (Table 2). During the follow-up visits, the patients were asked about the major side effects such as hot flashes, headache, visual disturbances, and cardiovascular disorders. None of the patients reported any of the known side effects. Discussion
Male aging is associated with progressive decline in androgen production. This phenomenon has been described as andropause, male climacteric, or progressive androgen decline in the aging male. Because men do not experience an abrupt decrease and cessation of male hormone secretion that results in testicular failure, the term andropause is misleading [2]. As men age, alterations in the hypothalamus–pituitary–gonadal axis occur. This directly translates into decreased hypothalamic production of gonadotropins, starting a hormonal cascade resulting in decline of serum testosterone. Male hypogonadism is a dynamic process that involves multiple organs, similar to the aging process itself. The age-related decline in testosterone is due to defects at all levels of the hypothalamic– pituitary–testicular axis: pulsatile GnRH secretion is attenuated, LH response to GnRH is reduced,
Comparison of testosterone and estrogen levels between men younger and older than 40 years
Testosterone at baseline Testosterone at follow-up visit D in testosterone level Estrogen at baseline Estrogen at follow-up visit D in estrogen Testosterone/estrogen ratio at baseline Testosterone/estrogen ratio at follow-up visit D in testosterone/estrogen ratio
J Sex Med 2005;2:716–721
<40 years
≥40 years
251.4 ± 38.9 ng/dL 579.7 ± 152.7 ng/dL 131% 31 ± 12.4 ng/dL 52.7 ± 16.6 ng/dL 70% 9.5 ± 4.1 11.7 ± 4.4 23.1%
242.2 ± 41.8 ng/dL 652.4 ± 207.6 ng/dL 169% 34.5 ± 8.1 ng/dL 39 ± 13.9 ng/dL 13% 7.4 ± 1.9 17 ± 4.5 129.7%
Clomiphene Citrate Effects in Male Hypogonadism and testicular response to LH is impaired. In the testes, histopathological studies have demonstrated changes consistent with senile atrophy, resulting in a decline in testosterone production by the Leydig cells [8]. This may explain the gradual rise of LH with aging. In the liver, sex hormone-binding globulin synthesis is increased, further reducing the net bioavailable and functional testosterone [9]. Perhaps the most dramatic changes occur at the hypothalamus–pituitary axis. The normal circadian rhythm is disrupted, and LH secretion is inhibited by negative feedback mechanism via estradiol. In fact, the term secondary hypogonadism refers to these men with functioning testes and relatively low levels of LH and testosterone [10–12]. Increase in visceral fat and obesity have been implicated as key contributors to secondary male hypogonadism [13]. It is well known that diabetic men consistently have testosterone levels approximately 20% lower than the general population. This low testosterone level may be attributed to altered insulin metabolism and resistance as a consequence of decreased muscle mass and increased fat [14]. Testosterone therapy has been used as a treatment for diminished libido and erectile dysfunction in hypogonadal men. The goal of testosterone therapy should be to maintain physiological levels of testosterone. In addition, it should ideally limit the conversion of testosterone to its metabolites such as dihydrotestosterone and estradiol. This will optimize the positive effects of testosterone, while curbing the side effects of its metabolites. Moreover, any testosterone therapy should try to mimic, rather than interfere with, the circadian rhythm of testosterone production [2]. Historically, hypogonadism has been treated with testosterone supplementation. Exogenous therapy with testosterone is the mainstay of therapy, and the emphasis is placed on improving the delivery system. As a result, many different exogenous testosterone preparations are commercially available [2]. They are in oral, injectable, and transdermal formulations. Each one of these delivery systems has advantages and disadvantages. Oral agents such as fluoxymesterone, methylterstosterone, and testosterone undecanoate have the convenience of being given orally. However, they can have significant hepatotoxic and gastrointestinal side effects. Liver function tests must routinely be performed to monitor for these changes. Furthermore, absorption and bioavailability are poor, and these oral testosterone therapy agents are not
719 approved by the Food and Drug Administration (FDA) [15,16]. Intramuscular formulations of testosterone in cypionate or enanthate were the next products developed. This mode of delivery unfortunately leads to supraphysiological levels of testosterone in the first 72 hours of administration, followed by hypophysiological levels after 10–21 days. Obviously, maintenance of the normal circadian pattern of testosterone production is impossible with injectable preparations. This may, in fact, be more detrimental to the patient as he experiences more frequent swings in his testosterone levels [17,18]. There are also some data indicating an increase in hemoglobin levels and hypercoagulopathy associated with intramuscular formulations [19]. Transdermal testosterone therapy was the next generation of products made available. Its delivery system can maintain normal levels of testosterone and estradiol by applying them on the scrotal or nonscrotal skin. Normal testosterone levels can be maintained by using both types of patches. However, contact contamination to females and children is a major disadvantage with transdermal formulations [2,20,21]. Other side effects include gynecomastia, decreased sperm counts, softening, and decreased size of the testicles. Clomiphene citrate (Clomid) was recently reclassified as an SERM because of its ability to compete with estradiol for the estrogen receptors at the level of the hypothalamus [22]. Clomiphene blocks the normal negative feedback of circulating estradiol on the hypothalamus, preventing estrogen from lowering the output of GnRH. During clomiphene therapy, the frequency and amplitude of GnRH pulses increase, stimulating the pituitary gland to release more FSH and LH. Consequently, sperm and testicular testosterone productions are stimulated [5,23,24]. Faced with different problems associated with the currently available testosterone preparations, we sought a novel approach to manage patients with secondary male hypogonadism. We used a relatively low oral daily dose of clomiphene citrate (25 mg) in 36 men with a mean age of 39 years. All patients had low testosterone levels with an average testosterone level of 247.6 ng/dL. Patients were enrolled and followed prospectively. Serum levels of testosterone, estradiol, FSH, and LH were measured at the time of the initial visit and the first follow-up approximately 4–6 weeks later. Testosterone levels increased by a mean of 146%. Similar changes were seen in both young and old patients. Of special interest is the obserJ Sex Med 2005;2:716–721
720 vation that the T/E ratios increased in both groups, although this rise was significantly greater in the older population. This increase in the T/E ratio might be more important than total serum testosterone increase. No patients reported any side effects of clomiphene citrate including gynecomastia and nipple tenderness. In a recent article by Guay et al., 178 men with secondary hypogonadism and erectile dysfunction were treated with clomiphene citrate for 4 months. Both LH and free testosterone increased significantly in all patients. In this study 75% of patients had improvement of their erectile function [25]. The levels of testosterone have risen more in the men aged more than 40 years vs. men less than 40 years, from 251.4 ± 38.9 ng/dL to 579.7 ± 152.7 ng/dL, and from 242.2 ± 41.8 ng/dL to 652.4 ± 207.6, respectively. Tenover and Bremmer showed that, during a clomiphene challenge, testosterone rose more in younger than in older men. Of course, in their study the age differences were much greater. We cannot give a definite answer, but we can speculate that younger men have often an anxiety component to their low testosterone levels, via making adrenergic substances. This might be one explanation for the lower testosterone levels in the younger men and would be consistent with some of our anecdotal data [6]. Our study revealed promising results. Clomiphene citrate induces endogenous production of testosterone via competitive blockage of hypothalamic estrogen receptors. This effect presents a unique therapeutic opportunity for the management of hypogonadism in the aging male. Low dose, oral therapy with minimal side effects is an excellent substitute to transdermal or injectable testosterone alternatives. It enhances the endogenous androgen synthesis pathway while maintaining the natural circadian rhythm. This method of treatment is especially important in hypogonadal men with infertility, who wish to father children. Exogenous testosterone therapy suppresses spermatogenesis and the hypothalamic–pituitary– testicular axis and may cause testicular atrophy. We understand that hypogonadism in aging males affect older patients. More than 20% of patients older than 60 years have signs and symptoms of hypogonadism. This phenomenon is usually caused by a combination of primary and secondary hypogonadism. Clomiphene citrate may offer an easy and practical solution for a subset of older patients with hypogonadism. Because this is a heterogeneous group of patients, we do not expect the same response in all older patients. J Sex Med 2005;2:716–721
Shabsigh et al. This does not change the fact that clomiphene citrate might be an excellent option for some men, especially those where secondary hypogonadism is a major component of their problem. Our future work will focus on the older patients with hypogonadism. There are obvious limitations to this pilot study. Further investigation is needed to confirm the effectiveness of clomiphene citrate for the treatment of androgen deficiency in secondary male hypogonadism. Studies are needed to determine the optimal dose response in different age groups. Validated measurements of muscle strength, weight, sexual function, exercise tolerance, bone density, and mood changes are required before accepting clomiphene citrate as a standard of care for secondary hypogonadism. Long-term safety and efficacy data are not available, as well as clomiphene citrate effects on lipid metabolism. Lastly, other SERMs may function in a manner similar to clomiphene citrate and may also have benefits. We should mention that clomiphene citrate use for the treatment of hypogonadism is not approved by the FDA in the United States. This report clearly shows the short-term efficacy of clomiphene citrate in improving testosterone levels and the T/E ratio in the treatment of secondary male hypogonadism. Conclusions
Clomiphene citrate effectively induces endogenous testosterone production via competitive inhibition of the hypothalamic estrogen receptor. Clomiphene citrate was able to increase serum testosterone and improve the testosterone/estrogen ratio. Clomiphene citrate was well tolerated and may be an alternative in the treatment of secondary hypogonadism in the aging male. Further studies are needed to confirm these findings and to define the optimal dose, long-term benefits, safety, and side effects. Other SERMs may also be investigated for their potential role in the management of secondary male hypogonadism. Corresponding Author: Harry Fisch, MD, 944 Park Ave, New York, NY 10020, USA. Tel: 212-879-0800; Fax: 212-988-1634; E-mail: harryfi[email protected] Conflict of Interest: None. References
1 Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR. Longitudinal effects of aging on
Clomiphene Citrate Effects in Male Hypogonadism
2 3 4
5
6
7 8
9
10
11
12
serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001;86:724–31. Morales A, Heaton JP, Carson CC 3rd. Andropause: A misnomer for a true clinical entity. J Urol 2000;163:705–12. Hermann M, Untergasser G, Rumpold H, Berger P. Aging of the male reproductive system. Exp Gerontol 2000;35:1267–79. Ersoz H, Onde ME, Terekeci H, Kurtoglu S, Tor H. Causes of gynaecomastia in young adult males and factors associated with idiopathic gynaecomastia. Int J Androl 2002;25:312–6. Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 2000;6:212–24. Tenover JS, Bremner WJ. The effects of normal aging on the response of the pituitary-gonadal axis to chronic clomiphene administration in men. J Androl 1991;12:258–63. Wang C, Swerdloff RS. Androgen replacement therapy. Ann Med 1997;29:365–70. Neaves WB, Johnson L, Porter JC, Parker CR Jr, Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab 1984;59:756–63. Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 1989;10:366–71. Winters SJ, Troen P. Episodic luteinizing hormone (LH) secretion and the response of LH and folliclestimulating hormone to LH-releasing hormone in aged men: Evidence for coexistent primary testicular insufficiency and an impairment in gonadotropin secretion. J Clin Endocrinol Metab 1982;55:560–5. Mitchell R, Hollis S, Rothwell C, Robertson WR. Age related changes in the pituitary-testicular axis in normal men; lower serum testosterone results from decreased bioactive LH drive. Clin Endocrinol (Oxf) 1995;42:501–7. Vermeulen A, Kaufman JM. Ageing of the hypothalamo-pituitary-testicular axis in men. Horm Res 1995;43:25–8.
721 13 Tan RS, Pu SJ. Impact of obesity on hypogonadism in the andropause. Int J Androl 2002;25:195–201. 14 Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM. Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab 2002;87:4522–7. 15 Morales A, Johnston B, Heaton JW, Clark A. Oral androgens in the treatment of hypogonadal impotent men. J Urol 1994;152:1115–8. 16 Morales A, Johnston B, Heaton JP, Lundie M. Testosterone supplementation for hypogonadal impotence: assessment of biochemical measures and therapeutic outcomes. J Urol 1997;157:849–54. 17 Sokol RZ, Palacios A, Campfield LA, Saul C, Swerdloff RS. Comparison of the kinetics of injectable testosterone in eugonadal and hypogonadal men. Fertil Steril 1982;37:425–30. 18 Nankin HR. Hormone kinetics after intramuscular testosterone cypionate. Fertil Steril 1987;47:1004– 9. 19 Winkler UH. Effects of androgens on haemostasis. Maturitas 1996;24:147–55. 20 McClellan KJ, Goa KL. Transdermal testosterone. Drugs 1998;55:253–8. 21 Goldstein SR, Siddhanti S, Ciaccia AV, Plouffe L Jr. A pharmacological review of selective oestrogen receptor modulators. Hum Reprod Update 2000;6:212–24. Review. 22 Cunningham GR, Cordero E, Thornby JI. Testosterone replacement with transdermal therapeutic systems. Physiological serum testosterone and elevated dihydrotestosterone levels. JAMA 1989; 5:2525–30. 23 Tan RS, Vasudevan D. Use of clomiphene citrate to reverse premature andropause secondary to steroid abuse. Fertil Steril 2003;79:203–5. 24 Guay AT, Bansal S, Heatley GJ. Effect of raising endogenous testosterone levels in impotent men with secondary hypogonadism: Double blind placebo-controlled trial with clomiphene citrate. J Clin Endocrinol Metab 1995;80:3546–52. 25 Guay AT, Jacobson J, Perez JB, Hodge MB, Velasquez E. Clomiphene increases free testostgerone levels in men with both secondary hypogonadism and erectile dysfunction: Who does and does not benefit? Inter J Impot Res 2003;15:156–65.
J Sex Med 2005;2:716–721