Refining the Endocrine Stratification of Non-Obstructive Azoospermia: Commentary on the Global Andrology Forum Guidelines

I read with great interest this important comprehensive literature review [1], all the recommendations provided are acceptable in my opinion.

However, there is an important clinical differentiation within patients with non-obstructive azoospermia that must be considered when evaluating hormonal therapy options.

In clinical practice we observe patients with hypergonadotropic non-obstructive azoospermia (NOAH), and patients with normogonadotropic non-obstructive azoospermia (NOAN).

It is clear that NOAH patients have a greater degree of testicular endocrine impairment than NOAN patients, as confirmed by significantly reduced serum inhibin B concentrations and bitesticular volume. NOAN patients differ histologically from NOAH patients in the post-meiotic phase (significant increase in elongated spermatids and round spermatids), a phase that is not hormonally controlled by follicle-stimulating hormone (FSH) [2].

There are also at least four aspects that deserve further investigation due to potential clinical implications, according this differentiation:

• (1) In NOAN patients, it is desirable to differentiate between patients with normal and low intratesticular testosterone (ITT) concentrations, a hormonal aspect of fundamental importance in regulating the post-meiotic phase of spermatogenesis. My group recently identified a value of 17-alpha-hydroxyprogesterone (17αOH-P)≤1.18 ng/mL as most predictive of response to hormonal treatment with FSH, representing a possible marker of a partial defect in testicular steroidogenesis associated with reduced ITT levels. Indeed, in testicular steroidogenesis, progesterone is converted to 17αOH-P by the hydroxylase activity of the CYP17 enzyme. Then, 17αOH-P undergoes 17–20 lyase activity by the same enzyme and is converted to androstenedione. The latter is used as a substrate for Testosterone biosynthesis [3].

• (2) The pharmacological treatament to be proposed for NOAN patients should be chorionic gonadotropin [4]. Are there specific doses for this category of patients? Certainly we cannot consider them with patients with hypogonadotropic hypogonadism in whom 2,000 IU of chorionic gonadotropin are usually combined with FSH twice a week [5]. Could the 17αOH-P value represent a valid aid in establishing a therapeutic algorithm [3]?

• (3) Boys who complete puberty without reaching a target normal testicular volume (≥12 mL), in the presence of normal signs of sexual maturation and androgenization (an expression of normal Leydigian function) who are found to have severe oligozoospermia or azoospermia at the first spermiogram, evidently performed after reaching an adequate chronological and bone age, should be supported immediately with chorionic gonadotropin? How do we define this category of patients? They do not present a condition of delayed puberty, but rather a condition of incomplete puberty in my opinion [6,7].

• (4) Seminal α-glucosidase concentrations in NOAH and NOAN patients are significantly lower than in normozoospermic patients [1]. We know thatα-glucosidase represents a marker of epididymal secretory function. We know that androgens control epididymal secretory function. In particular, it has been known for over 25 years that testosterone and dihydrotestosterone stimulate α-glucosidase secretion, while cyproterone acetate (antagonist) inhibits it [8]. Is it possible to suppose that the epididymal secretory deficiency of α-glucosidase could further contribute to differentiating NOAN and NOAH patients?