COVID-19 Infections in Gonads: Consequences on Fertility?

Abstract

COVID-19 may influence human fertility and sexuality in several ways. Different cell types in gonads show a constitutive expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2), which provide potential entry pathways for SARS-CoV-2. In addition to the biological effects of a COVID-19 infection on the gonads, the impact of the ongoing COVID-19 pandemic on mental health issues and sexual behavior may affect reproduction. This review summarizes the current knowledge on the influence of COVID-19 on the gonads and discusses possible consequences on human fertility. In this context, the close interaction between the hypothalamic-pituitary-adrenal axis and the hypothalamic-pituitary-gonadal axis in response to COVID-19-related stress is discussed. Some women noticed changes in their menstrual cycle during the COVID-19 pandemic, which could be due to psychological stress, for example. In addition, occasional cases of reduced oocyte quality and ovarian function are described after COVID-19 infection. In men, COVID-19 may cause a short-term decrease in fertility by damaging testicular tissue and/or impairing spermatogenesis. Moreover, decreased ratio testosterone/LH and FSH/LH in COVID-19 compared to aged-matched healthy men has been reported. Available data do not suggest any effect of the available SARS-CoV-2 vaccines on fertility. The effects of long COVID on human fertility have been reported and include cases with premature ovarian failure and oligomenorrhoea in women and erectile dysfunction in men. Despite the increasing knowledge about the effects of COVID-19 infections on human gonads and fertility, the long-term consequences of the COVID-19 pandemic cannot yet be assessed in this context.

Fig. 1

Potential factors that may affect fertility in females and males during the COVID-19 pandemic: a : SARS-CoV-2 virus entry is highly dependent on the expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine subtype 2 (TMPRSS2) and a simultaneous expression in human gonads could cause local inflammation after virus entry leading to tissue dysfunction. b : Physiological stress during the ongoing pandemic may also have an impact on the libido and the menstrual cycle. c : The interaction between the hypothalamic-pituitary-gonadal (HPG) axis and the hypothalamic-pituitary-adrenal (HPA) axis plays a crucial role in human fertility, and a possible imbalance caused by SARS-CoV-2 infection could affect fertility in the short and/or long term. ADH: Antidiuretic hormone; ACTH: Adrenocorticotropic hormone; CRH: Corticotropin-releasing hormone; FSH: Follicle-stimulating hormone; GnRH: Gonadotropin-releasing hormone; LH: Luteinizing hormone.

Fig. 2

Differential ACE2 expression in ovary and testis: a : Representative histology from the ovary of an 87-year-old patient who died from SARS-CoV-2 infection and revealed detectable SARS-CoV-2-RNA (not shown) in post-mortem ovarian tissue at autopsy. Immunostaining for ACE2 shows a prominent expression in ovarian stromal cells of hilus (left side of the image) and a weak expression in some cortical stromal cells (right side of the image). b : Representative histology from the testis of a 56-year-old patient who died from SARS-CoV-2 infection. The background shows a conventional HE-stain of the autopsy sample. Immunostaining for ACE2 demonstrates a strong expression in all cellular elements of the tubuli (Sertoli and spermatogonia, left side of the image) and a middle-strong expression in the Leydig cells in the testicular interstitium (right side of the image).