Testosterone replacement therapy (TTh) is becoming increasingly common among men of reproductive age in the United States. An estimated 3 million men are on TTh; however exogenous testosterone use can disrupt the hypothalamus-pituitary-gonadal (HPG) axis, leading to reduced spermatogenesis and possible infertility. In normal physiology, the hypothalamus releases Gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to release Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH). FSH then stimulates the Sertoli cells in the testis to support spermatogonial differentiation and maturation. LH stimulates the Leydig cells in the testes to produce endogenous testosterone. Regulation of this HPG axis occurs via negative feedback where testosterone directly inhibits the release of GnRH and LH from the hypothalamus and pituitary, respectively. The use of exogenous testosterone thus leads to reduced Sertoli function causing diminished spermatogenesis.~The spontaneous recovery of spermatogenesis after cessation of TTh is possible but may take months to years and cause the patient to experience new onset of severe hypothalamic hypogonadal symptoms. Human chorionic gonadotropin (HCG) is a naturally occurring protein that mimics LH and may be used as a therapy to support the return of spermatogenesis quickly with minimal side effects and resolve hypogonadal symptoms. Studies have shown that testosterone-induced infertile patients can recover sperm in the ejaculate in 4.6 months when treated with HCG supplemented with clomiphene citrate, tamoxifen, anastrozole, or recombinant FSH. With the cessation of TTh, despite the use of LH stimulatory protocols, these patients still experience hypogonadal symptoms. Recent preliminary results show the potential to offset hypogonadism symptoms that accompany exogenous testosterone cessation through administration of 4.5% intranasal testosterone gel. Natesto is a nasally administered exogenous 4.5% testosterone gel, administered from a non-pressurized, manual pump dispenser equipped with a specialized nasal applicator which administers 125uL (5.5mg of testosterone). Previous studies have shown that a single nasal dose has a rapid absorption with a Tmax at 60 mins and a half-life that ranged between 10-100 minutes. Three to four daily doses achieve eugonadal levels of circulating testosterone comparable to normal pulsatile-regulated release of testosterone. It has also been shown that men on Natesto maintain FSH and LH levels as well as total motile sperm count within the normal range. In this prospective study, the investigators seek to confirm the role of Natesto to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional TTh.
In this prospective study, the investigators plan is to confirm the role of Natesto (intranasal testosterone) to combat hypogonadal symptoms in men trying to recover spermatogenesis following the withdrawal of conventional Testosterone replacement therapy.