Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate

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1 Select patients with hypogonadotropic hypogonadism may respond to treatment with clomiphene citrate Scott J. Whitten, M.D., a Ajay K. Nangia, M.D., c and Peter N. Kolettis, M.D. b a Division of Reproductive Endocrinology and Infertility and b Division of Urology, University of Alabama, Birmingham, Alabama; and c Division of Urology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Objective: To review the management of male hypogonadotropic hypogonadism (HH) and evaluate the efficacy of clomiphene citrate (CC). Design: Retrospective review. Setting: Two university-based urology clinics. Patient(s): Ten patients referred for male infertility evaluation. Intervention(s): Patients were treated with either clomiphene citrate or injectable gonadotropins. Main Outcome Measure(s): Changes in seminal parameters, gonadotropin levels, serum testosterone, and gnancy. Result(s): Ten men who were evaluated for infertility were diagnosed with HH. Four had Kallmann s syndrome, four idiopathic HH, and two panhypopituitarism. Eight patients were azoospermic, and two were oligospermic on sentation. Three of the four men with adult-onset idiopathic HH responded to CC alone with increases in testosterone, FSH, and LH. Semen parameters in this group also improved, and two of the three men achieved gnancies with CC alone. Out of the ten men actively attempting conception, four gnancies were achieved. Three gnancies (two with CC and one with gonadotropins) were in men diagnosed with adult-onset idiopathic forms of HH. Conclusion(s): Select patients with adult-onset idiopathic forms of HH may benefit from a trial of clomiphene citrate. (Fertil Steril 2006;86: by American Society for Reproductive Medicine.) Key Words: Hypogonadotropic hypogonadism, male infertility, clomiphene citrate Infertility affects approximately 15% of couples who are attempting to conceive (1). Of those couples diagnosed as being subfertile, 20% are due solely to male factors, and another 27% are attributable to both the male and the female partners (2). An uncommon cause of male infertility is hypogonadotropic hypogonadism (HH), accounting for only 1% 2% of all cases. Hypogonadotropic hypogonadism is diagnosed when low serum gonadotropin measurements are accompanied by low serum testosterone and/or oligo/azoospermia. Congenital and acquired forms of HH may have variable clinical sentations and often require different treatment strategies based on the age at sentation, the degree of prior pubertal development, and the treatment objective, whether to induce pubertal maturation, to improve libido, or to achieve fertility. Congenital forms of HH, such as Kallmann s syndrome, where there is defective migration of GnRH-secreting neurons, have been successfully treated with therapy targeted to the level of the pituitary (GnRH pump) or gonad (hcg/ hmg) to induce these changes (3 9). In contrast, some acquired forms of idiopathic HH that have a functional, not Received October 7, 2005; revised and accepted May 9, Reprint requests: Scott J. Whitten, M.D., Instructor/Fellow, Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, University of Alabama at Birmingham, th Street South, OHB339, Birmingham, AL (FAX: ; sjwmd@yahoo.com). anatomic, defect that sent pubertally, resent a select population that may benefit from pharmacologic manipulation of the hypothalamic-pituitary-gonadal axis. Improvements in semen parameters have been accomplished in this group with GnRH pumps and gonadotropins (10, 11), but other, less expensive, therapy, such as clomiphene citrate (CC), may prove to be beneficial as well. This study was performed to review the management and treatment outcomes of a rare cause of male infertility, i.e., HH. We identified a subset of male infertility patients with an adult-onset idiopathic form of HH that responded to clomiphene citrate (CC). METHODS The Institutional Review Boards of the University of Alabama at Birmingham and Dartmouth-Hitchcock Medical Center approved this study. Ten men with HH were identified from two university-based urology practices between 2000 and Patients underwent an evaluation consisting of a history and physical, semen analysis, and endocrine testing. We stratified patients into three diagnostic categories: Kallmann s syndrome (HH with anosmia), idiopathic/ acquired HH (HH without anosmia), and panhypopituitarism (HH along with other pituitary deficiencies requiring hormone replacement). Baseline gonadotropins, T, semen analyses, and testicular volumes (volume of an ellipsoid calculated by l w h 0.71 were compared for each group Fertility and Sterility Vol. 86, No. 6, December /06/$32.00 Copyright 2006 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 Patients who had spontaneous normal puberty, normal testicular volumes, and evidence of gonadotropin secretion (albeit low) yet no other etiology identified to explain their HH were selected to receive a trial of CC. We review the treatments selected and the responses observed in each patient. RESULTS The results are summarized in Table 1. Kallmann s Syndrome Four patients (#1 4) with HH associated with anosmia were diagnosed with Kallmann s syndrome. The gonadotropin levels in this group were all less than 1 miu/ml. Two of the four patients (#3 and 4) were siblings, and three (patients #2 4) of the four had received peripubertal testosterone/ hcg therapy for pubertal maturation. One of the siblings (patient #4) had an undescended testis at puberty. Two of the unrelated subjects (patients #1 and 2) were obese and had gynecomastia without galactorrhea. All four men (patients #1 4) were azoospermic at sentation. Three subjects (patients #2 4) were on testosterone replacement, and the one patient (#1) that was not on replacement had a T level of 22 ng/dl. Mean testicular volume for this group was cc (range cc). All four men (patients #1 4) were started on hcg injections (patient #1 1,000 IU; patients #2 4 2,500 IU) three times per week. This was followed by the addition of FSH (75 IU) or FSH/LH ( IU) three times per week. Serial testosterone levels were obtained and the dose of hcg was increased as indicated. Periodic semen analyses were performed to assess the spermatogenic response. After 5 to 6 months of therapy three patients (#1, 3, and 4) remained azoospermic. One patient (#2) responded after 1 year of therapy with an improvement in sperm concentration to 2 million/ml. This patient achieved gnancy 1 month later. Idiopathic/Acquired Hypogonadotropic Hypogonadism Four men (patients #5 8) were diagnosed with idiopathic hypogonadotropic hypogonadism, sumably acquired. On sentation, they were either azoospermic or oligozoospermic and had very low T levels and normosmia. One of the patients admitted to brief ( 1 month) anabolic steroid use several years earlier. Pituitary gonadotropin levels in this group were low, with baseline mean FSH and LH levels of 1.6 ( ) miu/ml and 1.5 ( ) miu/ml, respectively. Patient #8 was already taking CC yet was still azoospermic despite achieving normal gonadotropin levels (FSH 4.0 miu/ml, LH 3.2 miu/ml). His gonadotropin levels before receiving CC were unavailable. The other three patients (#5 7) all had gonadotropin levels of 1.0 miu/ml at baseline. Mean testicular volume was cc (range cc). All four (patients #5 8) had normal magnetic resonance imaging of the brain and normal PRL levels, and three (patients #5 7) had karyotypes performed, which were 46,XY. Patient #8, who had viously taken CC and remained azoospermic, was started on hcg and recombinant FSH three times per week and his sperm concentration increased to 31 million/ml and his T to 260 ng/dl. He achieved two gnancies with intrauterine inseminations. The three other men (patients #5 7) were started on 50 mg CC three times per week. Pretreatment FSH and T levels in TABLE 1 Testosterone, FSH, and spermatogenic response after () 3 6 months of treatment. # Age Diagnosis T T FSH FSH Sperm Sperm Testicular volume Treatment Pregnancy 1 33 Kallmann s hcg 1000 IU 3 /wk No 2 27 Kallmann s hcg/fsh 3 /wk Yes 3 20 Kallmann s NA NA NA NA hcg/fsh 3 /wk No 4 21 Kallmann s NA NA NA NA hcg/fsh 3 /wk No 5 31 I/A-HH CC 50 mg 3 /wk Yes 6 30 I/A-HH CC 50 mg 3 /wk Yes 7 28 I/A-HH NA CC 50 mg 3 /wk No 8 40 I/A-HH NA hcg/fsh Yes 9 33 panhypopit CC 50 mg 3 /wk No panhypopit NA NA NA NA 4 NA 5.11 hcg planned No Note: Age in years, baseline; T in ng/dl, FSH in miu/ml, sperm in million/ml, testicular volume in cc. Kallmann s Kallmann s syndrome; I/A-HH idiopathic or acquired hypogonadotropic hypogonadism; panhypopit panhypopituitarism; CC clomiphene citrate; NA not available. Whitten. Hypo/hypotreatment with clomiphene citrate. Fertil Steril Fertility and Sterility 1665

3 the three men ranged from 0.8 to 1.0 miu/ml and 41 to 164 ng/dl, respectively. At baseline, two patients (#6 and 7) were azoospermic and one (patient #5) was severely oligozoospermic. After 3 months of therapy, the mean sperm concentration of the three men (patients #5 7) increased to 69 million/ml (range ) and mean T to 816 ng/dl (range 459 1,113). For the two patients (#5 and 6) that had repeat gonadotropin levels at follow-up, the mean FSH increased to 4.8 miu/ml, and LH to 6.4 miu/ml. Two gnancies have been achieved in this subgroup on CC monotherapy at the time of the paration of this manuscript. Panhypopituitarism Two patients (#9 and 10) sented with a viously established diagnosis of panhypopituitarism (PH). Patient #10 had undergone a hypophysectomy secondary to a metastatic pituitary tumor, and patient #9 had idiopathic PH. The idiopathic PH patient (#9) was azoospermic at sentation, whereas the patient with secondary PH (#10) had an initial sperm concentration of /ml. Both men (patients #9 and 10) were receiving replacement glucocorticoids and mineralocorticoids as well as adequate T replacement. Patient #9 was also taking thyroid replacement and an angiotensinconverting enzyme inhibitor for hypertension. Both patients were advised to discontinue their T therapy. Because his gonadotropin levels were low and not absent (FSH 0.6 miu/ml, LH 0.4 miu/ml), patient #9 was given a trial of CC (50 mg three times per week) for 3 months, which resulted in a decline of his T and no improvement in his azoospermia. The CC was discontinued and 2,500 IU hcg was administered three times a week, which was the same protocol chosen as initial therapy for patient #10. However, both patients remained azoospermic. Unfortunately, patient #10 had worsening of his disease, requiring more intensive chemoradiation therapy, and therefore his fertility treatment was discontinued. DISCUSSION Male infertility due to HH is a rare diagnosis, accounting for only 1% 2% of cases. When the diagnosis of HH is made, however, careful consideration must be given to both the etiology and the onset of the HH, because this may guide further evaluation and treatment. Male HH may have a congenital etiology or it may be acquired. Congenital HH causes include Kallmann s syndrome, where GnRH-producing neurons fail to migrate from the olfactory placode to the hypothalamus, and idiopathic HH. Traditionally, patients with congenital forms of HH are diagnosed early in life because of delayed puberty, and therefore the treatment objective is to induce masculinization and secondary sexual characteristics. Several authors have documented the efficacy of using pulsatile GnRH (LHRH), T, or hcg/hmg injections in this group with success in achieving pubertal maturation (8, 9, 12). Normal serum T levels can be achieved, and these therapies may be continued for long-term hormone maintenance (13). Alternatively, these patients may be maintained on exogenous T replacement, which is available in various forms from injectable to transdermal parations (14). Once puberty has been achieved, however, some patients desire fertility. Treatment with hcg alone and in combination with FSH (or hmg) has been shown to be effective in achieving and maintaining adequate seminal parameters for conception (6). The hcg binds the LH receptor to stimulate steroidogenesis of Leydig cells to restore intratesticular levels of T to levels that allow for spermatogenesis. The FSH (or hmg) is then added to the gonadotropin regimen to enhance sperm production. Regimens combining FSH with exogenous T have not been effective in inducing spermatogenesis (15). Although rarely used, GnRH pumps have also been shown to be as effective as gonadotropins in achieving and maintaining fertility (5, 6, 16). The GnRH pumps may be used in patients that have an isolated hypothalamic defect with an intact pituitary-gonadal axis. Subcuticular or intravascular routes are used to administer small doses of GnRH in a pulsatile fashion, which may facilitate the release of endogenous pituitary gonadotropins. It may require usage for several months before a spermatogenic response is observed (6). Acquired forms of male HH may result from causes such as tumors of the central nervous system (e.g., prolactinomas) and anabolic steroid use, or it may be exercise induced or idiopathic. Many of these patients have undergone normal pubertal maturation, because the onset of the gonadotropin secretory defect often arises after puberty, although it may occur at any time. If acquired forms of HH are the result of a primary pituitary process, the inciting process should be addressed first and then the resultant state of the hypothalamicpituitary-gonadal axis can be assessed. If there are residual deficits documented at the hypothalamic or pituitary level, restoration of T levels and fertility potential are approached similarly to patients with congenital forms of HH. A subset of patients, that have normal pubertal development and subsequently develop subfertility or erectile, ejaculatory, or libido difficulties associated with low gonadotropin and T levels and/or oligo/azoospermia, are classified as an adult-onset idiopathic type of HH. In addition to a thorough history and physical, the initial evaluation should include measurements of T, gonadotropins, and PRL and semen analysis. Other tests that may be useful are dynamic testing (GnRH, hcg), karyotyping, and neuroimaging (16). Several authors suggest that this subtype of HH patients has dysfunctional secretion of GnRH, and therefore these patients may be managed similarly to congenital HH patients with gonadotropins or pulsatile GnRH (7, 10, 17). Others have used CC in attempts to improve hypogonadal symptoms in patients with idiopathic HH (18). We have identified four patients that fulfill the criteria for adult-onset idiopathic HH that were selected to receive CC 1666 Whitten et al. Hypo/hypo treatment with clomiphene citrate Vol. 86, No. 6, December 2006

4 as a first-line therapy. Clomiphene citrate is an orally ingested nonsteroidal estrogen agonist/antagonist consisting of a racemic mixture of two isoforms, en-clomiphene and zuclomiphene. The mechanism of action of clomiphene is to disrupt the negative feedback of estrogen on the hypothalamus and pituitary, which results in increased levels of gonadotropins and sex steroids. The first investigators to use clomiphene to treat subfertile males were Mellinger and Thompson in 1966 (19). Since that time, CC has been used off label in different populations of male infertility patients, with moderate elevations noted in gonadotropin levels and sperm concentration in those patients with a germinal form of hypofertility (20, 21). Other authors have demonstrated improved gnancy rates when CC is used as empiric therapy for male partners in couples with unexplained infertility (22). The optimal dosing schedule for CC in male patients has not, however, been established. Clomiphene citrate has been given as a daily dose, cyclical dosing of 25 days of medication and 5 days of rest, and alternate-day higher dose regimens (20, 22, 23). Owing to the long halflife of CC we chose an alternate-day regimen for our patients. High doses of CC in some patients may cause a decline in spermatogenesis, and therefore we elected to use a lower-dose alternate-day regimen of 50 mg three times per week (23). Our review identified patients with idiopathic HH that sented -pubertally who had an otherwise normal examination and evaluation. Because this group had testicular volumes of 10 cc and some evidence of gonadotropin secretion, although diminished, clomiphene therapy was selected for a 3-month trial at 50 mg three times per week. Three out of the four men (patients #5 7) in this subgroup demonstrated improvement in T levels and semen parameters by their 3-month follow-up visit on CC monotherapy. Two of these three men (patients #5 and 6) had documented rises in their FSH levels at follow-up. Two of the three men (patients #5 and 6) achieved gnancies, and the third patient (#7), who has only recently started therapy, was still attempting to conceive. Patient #8 s baseline gonadotropin and T levels before his initial trial of clomiphene were not available to us. He did, however, respond well to hcg/fsh and eventually achieved two gnancies with intrauterine inseminations. The four patients we classified as idiopathic adult-onset HH seem to have a more favorable prognosis compared with the other HH subtypes that we examined. Nachtigall et al. (10) also found this subset of male HH patients to be very responsive when GnRH pump therapy was used to restore fertility. These patients have greater testicular volumes at baseline compared with the other groups, which has been shown by others to be a good prognostic indicator of responsiveness to gonadotropin therapy (13). Because these patients seem to have a favorable prognosis, we chose to treat them with CC in an alternate-day regimen, which is less expensive and associated with fewer morbidities than injectable gonadotropins or GnRH pumps. We documented an improvement in gonadotropin levels and sperm concentration after only 3 4 months of therapy. Therefore, it may be justified to attempt a trial of CC in patients that fit the strict criteria for this subgroup. Obviously, this observation is based on only four patients and therefore larger multi-center controlled trials are needed to verify our results. Because this is such a rare condition, additional randomized studies comparing gonadotropins with clomiphene in this subtype of HH patients would be difficult to perform; however, larger series using strict inclusion criteria for stratifying patients may be helpful to further examine the success of clomiphene treatment in restoration of this form of male subfertility. The adult onset form of idiopathic hypogonadotropic hypogonadism is an uncommon cause of male infertility. However, when encountered, if patients meet the strict diagnostic criteria, our findings would justify a trial of CC before pursuing more expensive and invasive therapy. If patients respond to CC, improvement in semen parameters may be observed after only 3 4 months of therapy. REFERENCES 1. Guttmacher AF. Factors affecting normal expectancy of conception. J Am Med Assoc 1956;161: Collins JA, So Y, Wilson EH, et al. Clinical factors affecting gnancy rates among infertile couples. Can Med Assoc J 1984;130: Huang CC, Huang HS. Successful treatment of male infertility due to hypogonadotropic hypogonadism report of three cases. Changgeng Yi Xue Za Zhi 1994;17: Tash JA, McGovern JH, Schlegel PN. Acquired hypogonadotropic hypogonadism senting as decreased seminal volume. Urology 2000; 56: Liu L, Chaudhari N, Corle D, Sherins RJ. 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5 14. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol 2000;161: Schiason G, Young J, Pholsena M, Nahoul K, Couzinet B. Failure of combined follicle-stimulating hormone testosterone administration to initiate and/or maintain spermatogenesis in men with hypogonadotropic hypogonadism. J Clin Endocrinol Metab 1993;77: AACE Hypogonadism Task Force. American Association of Clinical Endocrinologists Medical guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients 2002 update. Endocr Pract 2002;8: Barkan AL, Reame NE, Kelch RP, Marshall JC. Idiopathic hypogonadotropic hypogonadism in men: dependence of the hormone responses to gonadotropin-releasing hormone (GnRH) on the magnitude of the endogenous GnRH secretory defect. J Clin Endocrinol Metab 1985;61: Burge MR, Lanzi RA, Skarda ST, Eaton RP. Idiopathic hypogonadotropic hypogonadism in a male runner is reversed by clomiphene citrate. Fertil Steril 1997;67: Mellinger RC, Thompson RJ. The effect of clomiphene citrate in male infertility. Fertil Steril 1966;17: Micic S, Dotlic R. Evaluation of sperm parameters in clinical trial with clomiphene citrate of oligospermic men. J Urol 1985;133: Paulson D. Clomiphene citrate in the management of male hypofertility: dictors for treatment selection. Fertil Steril 1977;28: Check JH, Chase JS, Nowroozki K, et al. Empirical therapy of the male with clomiphene in couples with unexplained infertility. Int J Fertil 1989;34: Ross L, Kandel G, Pring L, Auletta F. Clomiphene treatment of the idiopathic hypofertile male: high dose alternative-day therapy. Fertil Steril 1980;33: Whitten et al. Hypo/hypo treatment with clomiphene citrate Vol. 86, No. 6, December 2006

Index. urologic.theclinics.com. Note: Page numbers of article titles are in boldface type.

Index. urologic.theclinics.com. Note: Page numbers of article titles are in boldface type. Note: Page numbers of article titles are in boldface type. A Acquired hypogonadism, prevalence of, 165 167 primary, 165 secondary, 167 Adipose tissue, as an organ, 240 241 Adrenal hyperplasia, congenital,