Clomiphene citrate: A potential alternative for testosterone therapy in hypogonadal males

Abstract Background Hypogonadism is a worldwide problem among men causing sexual, physical and mental problems. Testosterone therapy is the first‐choice treatment for male hypogonadism, with several side effects, that is, subfertility. Clomiphene citrate (CC) is an alternative off‐label therapy for a certain group of hypogonadal males, especially for those with an active or future child wish. There is scarce literature in usage of CC for men with hypogonadism. The aim of this retrospective study was to evaluate the effectiveness and safety of CC for hypogonadal males. Methods In this single‐centre study, men treated with CC for hypogonadism were evaluated retrospectively. Primary outcome was hormonal evaluation including total testosterone (TT), free testosterone (FT), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Secondary outcomes were hypogonadal symptoms, metabolic and lipid parameters, haemoglobin (Hb), haematocrit (Ht), prostate specific antigen (PSA), side effects, the effect of a trial without medication and potential predictors for biochemical and clinical response. Results In total, 153 hypogonadal men were treated with CC. Mean TT, FT, LH and FSH increased during treatment. TT increased from 9 to 16 nmol/L, with a biochemical increase in 89% of the patients. In patients who continued CC treatment, an increased level of TT persisted after 8 years of treatment. With CC treatment, 74% of the patients experienced hypogonadal symptom improvement. LH at the lower normal range before CC treatment was predictive for better TT response. During CC therapy, few side effects were reported and no clinical important changes in PSA, Hb and Ht were found. Conclusion Clomiphene citrate is an effective therapy on short and long term, improving both clinical symptoms and biochemical markers of male hypogonadism with few side effects and good safety aspects.


| INTRODUC TI ON
Male hypogonadism is a biochemical and clinical testosterone deficiency syndrome with a prevalence of symptomatic hypogonadism ranging between 2.1% and 5.7% in males aged above 30 years of age. [1][2][3][4] Prevalence increases with age and certain comorbidities, such as cardiovascular disease, diabetes mellitus (DM), obesity and malignancies. 2,5 Decreased libido, lack of energy, mood changes, decreased muscle mass, and erectile dysfunction are common hypogonadal symptoms. 6,7 Testosterone therapy (TTh) is the treatment of first choice for male hypogonadism. 8 However, exogenous testosterone leads to negative feedback on the hypothalamic-pituitary-gonadal (HPG) axis, causing suppression of endogenous testosterone production and spermatogenesis. 9 Other side effects are, changed lipid serum, polycythaemia and gynecomastia. [9][10][11] Clomiphene citrate (CC) is an alternative off-label pharmacological treatment for a certain group of males with hypogonadism. CC is a selective oestrogen receptor modulator, occupying oestrogen receptors in the hypothalamus and pituitary gland, leading to increased secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and so, stimulating testicular endogenous testosterone production and preserving spermatogenesis. 12,13 Since the 1960s, CC has been often used for ovulation induction in females. For males, the United States Food and Drug Administration (FDA) did not approve the medicine with reason of unclear clinical effect because of the lack of well-controlled and well-powered controlled trials. [14][15][16][17] However, CC is described over more than 30 years off-label to hypogonadal men, especially those with an active or future child wish, or hypogonadal males who do not want to use TTh. 18 Compared to TTh, CC is easy in usage and comes with little costs. For example, in our country, costs of CC are about 12 times lower than regular TTh. 19 To support the outcomes in the scarce literature on the efficacy of CC therapy, the purpose of this retrospective study was to evaluate the effectiveness and safety of CC therapy for male hypogonadism.

| Study design
A retrospective, single-centre study was conducted in the University Medical Center (UMC) Utrecht. Hypogonadal men, who wanted to preserve their endogenous testicular function or men who had other reasons for not willing to use TTh and therefore treated with CC within the time frame from January 2012 to January 2021 were included. Ethical approval for this retrospective study was obtained from the local Research Ethics Committee, UMC Utrecht, the Netherlands (WAG/mb/20/500309). All patients were informed that CC is used as an off-label therapy.

| Patient population
Men aged above 18 years with low (<12.1 nmol/L, defined by the EAU guidelines) 3 or relatively low TT in combination with clear hypogonadal symptoms, wherefore treatment with CC, were included.
Relatively low testosterone was defined as testosterone <15 nmol/L in combination with, (1) low free testosterone <243 pmol/L or (2) young adult males with a history of orchiectomy and clear com-

| Primary outcomes
Study primary outcome was hormonal assessment at baseline and at 1, 3, 6 and 12 months during CC therapy and annually thereafter measured with immunoassay (Atellica®, Siemens, Erlangen, Germany) the immunoassay was replaced in 2014, however, hormonal values were comparable using both immunoassay tools:  A reversed effect was defined as a significant decrease in TT and/ or FT.

| Hormonal evaluation
Data of hormonal levels are provided in Table 2  hypergonadotropic hypogonadism (n = 11) only the two biochemical responders described symptom improvement. Appendix S1-S2.

| Correlations
A correlation was found between symptom improvement during treatment and a higher increase in TT at first measurement during treatment (p = .000, r = .34). A second correlation was found TA B L E 3 Biochemical and clinical response of CC therapy and hypogonadal symptom improvement.

| DISCUSS ION
This study is supporting evidence for the long-term efficacy of CC in hypogonadal males with increases in total testosterone, free testosterone and gonadotrophins and a total biochemical increase in TT in 89% of the patients. Therewithal, in 74% of patients, a clinical effect was observed as described as an improvement of hypogonadal symptoms with CC therapy. In total 81% of the patients had both a biochemical and clinical response. This study is, to our knowledge, the first large retrospective cohort study on both clinical and biochemical effect of CC in hypogonadal males with long follow-up and identification of potential predictors for success.
Levels of TT, FT, LH, FSH and SHBG increased after start treatment. Increased testosterone levels lasted with ongoing treatment until 8 years of FU. This improvement of hormone levels has been described in previous studies, showing TT at baseline ranging between 7 and 11 nmol/L and at first measurement during treatment ranging between 16 and 24 nmol/L (n = 34-400). [21][22][23][24] The results of testosterone and gonadotrophins show that CC is effective in increasing endogenous testosterone secretion by stimulating the HPG axis in hypogonadal men. Only 10% of our study population was biochemical non-responder, all these patients stopped CC therapy during the first 6 months. In the study, mean LH before treatment was 4.7 IU/L in the responder group and 13.7 IU/L in the non-responder group.
Of the 16 patients with hypergonadotropic patients, six were biochemical responders. Of which, the patient with Klinefelter who showed a biochemical and symptomatic improvement.
For further research and practice it is important to be critical who to include or to prescribe CC therapy. However with these results, it could be considered to try CC therapy also in hypergonadotropic patients. Although, it could be recommended then to do an early testosterone measurement, to evaluate the biochemical response and for early detection of a potential reversed effect. Furthermore, it is debatable if patients with TT levels >12 nmol/L and < 15 nmol/L should be included. However, in all these eight patients there was a biochemical improvement and in six of them (75%) there was clinical improvement (increased libido). Considering of inclusion of these patients is supported by the study of Zitzmann (2006), showing that testosterone deficiency symptoms may also be seen with TT levels as high as 15 nmol/L. 25 It is unknown whether CC is effective on the long term.

| CON CLUS ION
Clomiphene citrate therapy for hypogonadal males shows promising effect on both clinical symptoms and the biochemical testosterone insufficiency with few reported side effects and good safety aspects compared with TTh. Therefore, it is worth to be considered especially in males presenting with symptoms of hypogonadism and low testosterone who wish to preserve their testicular function and are not eligible for TTh. Low to normal LH at baseline seems to predict

FU N D I N G S TATEM ENT
The authors did not receive funding for this study.

CO N FLI C T O F I NTE R E S T S TATE M E NT
There is no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data on data collection and analysis are available on request.