Using 17-OHP as Serum Biomarker to Monitor Therapy in Patients With Hypogonadotropic Hypogonadism

Case Review Using 17-OHP as Serum Biomarker to Monitor Therapy in Patients With Hypogonadotropic Hypogonadism A. Mouzannar, MD,1 M. Narasimman,2 P. Patel, MD,1 R. Ramasamy, MD1 1Department of Urology, University of Miami Miller School of Medicine, Miami, FL; 2Northwestern University, Evanston, IL Exogenous testosterone administration decreases intratesticular testosterone (ITT) significantly, an essential hormone for spermatogenesis. Therefore, treatment of patients with hypogonadotropic hypogonadism (HH) who desire infertility can be challenging. These patients are treated with recombinant follicle-stimulating hormone (FSH), clomiphene citrate, and human chorionic gonadotropin (hCG) to increase their ITT. However, there is no approved serum biomarker for ITT and it can only be measured via invasive testicular biopsy or aspiration. Previous authors have speculated that serum 17-hydroxyprogestrone (17-OHP) can be used as serum biomarker for ITT. In our case report, we demonstrate increase in 17-OHP associated with spermatogenesis after commencing treatment for infertility in patient with HH. [Rev Urol. 2019;21(4):180–182] © 2020 MedReviews®, LLC KEY WORDS 17-Hydroxyprogesterone (17-OHP) • Intratesticular testosterone (ITT) • Biomarker • Infertility • Hypogonadotropic hypogonadism I ntratesticular steroids are comprised of testosterone (~70%), 17-hydroxyprogesterone (17OHP; ~20%), and other hormones (~10%).1 Intratesticular testosterone (ITT) is essential for initiation and maintenance of spermatogenesis.2 However, ITT cannot be reliably measured 180 • Vol. 21 No. 4 • 2019 • Reviews in Urology without invasive testicular sampling.3 Further, serum testosterone does not accurately reflect ITT.4 A serum marker would be clinically valuable. Studies have demonstrated that 17-OHP can potentially be used as serum biomarker for ITT.1 We hypothesized that we can utilize serum Using 17-OHP as Serum Biomarker 17-OHP to understand spermatogenesis recovery for patients with hypogonadotropic hypogonadism (HH) who are simultaneously receiving testosterone replacement therapy (TRT). Herein, we report the case of a man with HH who was started on human chorionic gonadotropin (hCG) and recombinant folliclestimulating hormone (FSH), while simultaneously continuing TRT for symptom relief. Traditionally, in men who are interested in fertility, exogenous TRT is stopped prior to starting medications to stimulate spermatogenesis such as clomiphene citrate and/or hCG. Given patients with HH do not release luteinizing hormone and FSH, we hypothesize that continuing TRT will unlikely cause any negative effects on return of spermatogenesis when initiating hCG and rFSH given TRT will be able to further suppress an already suppressed pituitary gland. We also speculate that serum 17-OHP will serve as a useful serum surrogate for ITT and reflect return of spermatogenesis in men with HH. Case Report A 28-year-old man presented with primary infertility. His fiancée is also age 28 years with no significant past medical history. They had been having unprotected intercourse to conceive for the past 2 years. The patient has history of congenital HH. He was treated for growth hormone deficiency as a child. In addition, he has been on TRT (125 mg IM weekly) for 10 years. The rest of the medical history included Hashimoto thyroiditis (treated with levothyroxine 88 mcg/day), and ganglion cyst removal from the wrist. He denied smoking or illicit drug abuse, and his family history is non-contributory. Evaluation at University of Miami The patient had masculine hair distribution. His body mass index was 33. No gynecomastia was present. Testicular size was 2 cc on the right and nubbin on the left. He had no varicocele, and both vas deferens and epididymis were palpable bilaterally. Semen analysis revealed azoospermia with normal volume and pH. He was started on FSH 75 IU tiw and HCG 3000 IU tiw for 6 months. Semen analysis showed 1.7 M/mL sperm concentration with 56% motility. Thus, he underwent sperm cryopreservation. Hormonal levels before and 6 months after treatment are shown in Table 1. Discussion There is no reliable serum biomarker for measurement of ITT. Therefore, assessment of ITT requires invasive testicular biopsy or aspiration that can be associated with testicular injury.3 This makes monitoring patients with HH on treatment for infertility challenging, as serum testosterone does not reflect ITT and spermatogenesis. Amory and colleagues1 showed that serum 17-OHP is strongly associated with ITT concentrations in normal men receiving gonadotropin suppression and hCG. They reported that serum 17-OHP decreased by 60% of patients on placebo, compared with 70% increase in men administered a high dose of hCG. This study strongly suggested that 17-OHP can be used as a serum biomarker for ITT. Unfortunately, serum testosterone does not reflect ITT levels. Actually, it was shown that ITT can be 100 times higher than serum testosterone levels in normal men.4 On the other hand, patients with HH, on replacement therapy, may have normal serum testosterone, yet low ITT.5 Therefore, we believe that 17-OHP can be useful in certain clinical scenarios, such as patients with HH or anabolic TABLE 1 Hormone Pre-treatment Post-treatment (6 mo) Reference Range Total testosterone 77 ng/dL 204 ng/dL 250–827 ng/dL Estradiol 18 pg/mL ,15 pg/mL ,39 pg/mL 17-Hydroxyprogesterone 19 ng/dL 63 ng/dL 32–307 ng/dL Luteinizing hormone 0.9 mIU/mL 0.8 mIU/mL 1.5–9.3 mIU/mL Follicle-stimulating hormone 3.5 mIU/mL 1.5 mIU/mL 1.6–8.0 mIU/mL Vol. 21 No. 4 • 2019 • Reviews in Urology • 181 Using 17-OHP as Serum Biomarker continued steroid abuse desiring fertility;17OHP levels may represent adequate ITT levels to achieve spermatogenesis. Additionally, 17-OHP levels can be used to guide clomiphene citrate and hCG therapy (dosage and duration) for patients undergoing medical treatment for oligo or azoospermia.6 order to increase their ITT and induce spermatogenesis. Serum 17-OHP was previously studied as serum biomarker to represent ITT, and in turn, spermatogenesis. We had similar outcomes, when we measured serum 17-OHP on our patient. 3. 4. 5. References Conclusions Treatment of HH in men who desire fertility can be challenging. Patients with HH are treated with recombinant FSH and HCG in 1. 2. Amory JK, Coviello AD, Page ST, et al. Serum 17-hydroxyprogesterone strongly correlates with intratesticular testosterone in gonadotropin-suppressed normal men receiving various dosages of human chorionic gonadotropin. Fertil Steril. 2008;89:380-386. Bremner WJ, Matsumoto AM, Sussman AM, Paulsen CA. Follicle-stimulating hormone and human spermatogenesis. J Clin Invest. 1981;68:1044-1052. 182 • Vol. 21 No. 4 • 2019 • Reviews in Urology 6. Hsieh TC, Pastuszak AW, Hwang K, Lipshultz LI. Concomitant intramuscular human chorionic gonadotropin preserves spermatogenesis in men undergoing testosterone replacement therapy. J Urol. 2013;189:647-650. Roth MY, Page ST, Lin K, et al. Dose-dependent increase in intratesticular testosterone by very low-dose human chorionic gonadotropin in normal men with experimental gonadotropin deficiency. J Clin Endocrinol Metab. 2010;:3806-3813. Roth MY, Lin K, Bay K, et al. Serum insulin-like factor 3 is highly correlated with intratesticular testosterone in normal men with acute, experimental gonadotropin deficiency stimulated with low-dose human chorionic gonadotropin: a randomized, controlled trial. Fertil Steril. 2013;99:132-139. Patel A, Patel P, Bitran J, Ramasamy R. Can serum 17-hydroxyprogesterone and insulin-like factor 3 be used as a marker for evaluation of intratesticular testosterone? Transl Androl Urol. 2019;8(suppl 1): S58-S63.