Intratesticular steroids are comprised of testosterone (~70%), 17-hydroxyprogesterone (17-OHP; ~20%), and other hormones (~10%).1 Intratesticular testosterone (ITT) is essential for initiation and maintenance of spermatogenesis.2 However, ITT cannot be reliably measured 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 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.
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.
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.
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 steroid abuse desiring fertility;17- OHP 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
Treatment of HH in men who desire fertility can be challenging. Patients with HH are treated with recombinant FSH and HCG in 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.