Hypogonadotropic hypogonadism in men with hereditary hemochromatosis

Abstract

Hereditary hemochromatosis is a genetic disease that progresses silently. This disease is often diagnosed late when complications appear. Hypogonadotropic hypogonadism (HH) is one of the classical complications of hemochromatosis. Its frequency is declining probably because of earlier diagnosis and better informed physicians. Certain symptoms linked to HH can have an impact on a patient's sexuality, such as decreased libido, erectile dysfunction, and impairment of ejaculation, as well as on his reproductive capacities. This review is based on an online search in English, French and German language publications found in PubMed/Medline, up to 23 September 2016 using the following key word: Male infertility, Hypogonadotropic Hypogonadism, Hereditary Hemochromatosis. Thirty-four papers met these inclusion criteria. This review describes the impact of iron overload on male fertility, resulting in hypogonadotropic hypogonadism and proposes treatment modalities.

Keywords: Hereditary Hemochromatosis; Hypogonadotropic Hypogonadism; Male infertility.

Fig. 1

Testis Histopathology. Perl’s staining highlights iron in the interstitium and in the basal membrane of seminiferous tubules in case of iron overload (From [17])

Fig. 2

Model for compartmentalized iron transport in the testis. The seminiferous tubule (SFT) is partially protected from systemic iron overload. Here is a model of testis showing the anatomy of interstitial tissue and SFT, where male germ cell development proceeds from the SFT basal membrane (BM) to the SFT lumen (Lu). SC, Sertoli cell; SG, spermatogonia; PLS, preleptotene spermatocyte; PCS, pachytene spermatocyte; RS, round spermatid; ES, elongated spermatid. Three SC and their immediate surroundings are shown. Iron transport across the SFT basal membrane is very limited. Within the SFT some SG and mainly primary spermatocytes acquire iron-loaded ferritin from SC, and upon maturation elongating spermatids return iron to the SC, which traffic it back to a new generation of spermatocytes. Obligatory iron losses through spermatozoa that leave the testis are replenished by the peripheral circulation through the transferrin-TfR-1 system. Ferroportin likely plays its main role in iron trafficking across the interstitial space, where selective barriers at the smooth muscle cells of blood vessels and the peritubular myoid cells provide the male germ cells with additional protection from the periphery. RB, residual body. (From [17])

Fig. 3

Management optimisation of male patients with hereditary hemochromatosis. In patients presenting increased Ferritin ≥300 μg/L, with or without clinical manifestations, investigations should be provided including a hormonal check-up. In case of abnormal sex hormone concentrations, phlebotomy weekly should be proposed alone if patients are younger than 40, systematically associated with gonadotrophin treatment if 40 or older. According to cases reported in the literature, we also recommend a systematic replacement therapy with gonadotropin associated with phlebotomy in infertile hereditary hemochromatosis patients until they obtained the desired child. Finally, before stopping the replacement therapy and returning to a less intense rhythm of phlebotomy, cryopreservation of spermatozoa is offered to them