Estrogens and male reproduction

n males, estrogens exert pleiotropic effects by acting on several tissue and organs, including the male reproductive system. The action of estrogens is manifest from prenatal life during which the exposure to estrogen excess might influence the development of some structures of the male reproductive tract. Male fertility is under the control of estrogens, especially in rodents. The loss of function of estrogen receptor alpha and/or of the aromatase enzyme leads to infertility in mice. In men, estrogens are able to exert their actions at several levels through the reproductive tract and on several different reproductive cells. However, the regulation of human male reproduction is more complex and the role of estrogens is less clear compared to mice. During fetal and perinatal life, estrogen acts on the central nervous system by modulating the development of some areas within the brain that are committed to controlling male sexual behavior in terms of setting gender identity, sexual orientation development and the evolution of normal adult male sexual behavior. This organizational, central effect of estrogens is of particular significance in other species (especially rodents and rams), being probably less important in men where psychosocial factors become more determining. Other relevant, non-reproductive physiological events depend on estrogen in men and they involve bone maturation and mineralization as well as metabolic functions. In this chapter we provide an update of estrogen\u2019s role in male reproductive function by reviewing the physiological actions of estrogen on male reproduction and the pathophysiology related to estrogen deficiency and estrogen excess. Phenotypes associated with estrogen deficiency and excess in rodents and in man have shed new light on the mechanisms involved in male reproduction, challenging the perception of the predominant importance of androgens in men. It is now clear that the imbalance between estrogen and androgen in men might affect male reproductive function even in presence of normal circulating androgens. Some uncertainties still remain, especially regarding the impact of abnormal serum estrogen levels on male health, particularly due to the fact that estrogen is not routinely measured in men in clinical practice. Advancements in methods to precisely measure estrogens in men, together with a reduction of their costs, should provide better evidence on this issue and inform clinical practice. New basic and clinical research is required to improve our knowledge on the role of estrogen in male reproductive function and men\u2019s health in general. For complete coverage of all related areas of Endocrinology, please see our online FREE web-book, www.endotext.org

Estrogens, Male Reproduction and Beyond

In males, estrogens exert pleiotropic effects by acting on several tissue and organs, including the male reproductive system. The action of estrogens is manifest from prenatal life during which the exposure to estrogen excess might influence the development of some structures of the male reproductive tract. Male fertility is under the control of estrogens, especially in rodents. The loss of function of estrogen receptor alpha and/or of the aromatase enzyme leads to infertility in mice. In men, estrogens are able to exert their actions at several levels through the reproductive tract and on several different reproductive cells. However, the regulation of human male reproduction is complex, and the role of estrogens is less clear compared to mice. During fetal and perinatal life, estrogen acts on the central nervous system by modulating the development of some areas within the brain that are committed to controlling male sexual behavior in terms of setting gender identity, sexual orientation development and the evolution of normal adult male sexual behavior. This organizational, central effect of estrogens is of particular significance in other species (especially rodents and rams), but probably less important in men where psychosocial factors become more determining. Other relevant, non-reproductive physiological events, such as bone maturation and mineralization and glucose metabolism, depend on estrogen in men and an increasing body of evidence is disclosing new non-reproductive estrogen function. In this chapter we provide an update of estrogen’s role by reviewing the physiological actions of estrogen on male reproduction and the pathophysiology related to estrogen deficiency and estrogen excess. Phenotypes associated with estrogen deficiency and excess in rodents and in man have shed new light on the mechanisms involved in male reproduction, challenging the perception of the predominant importance of androgens in men. It is now clear that the imbalance between estrogen and androgen in men might affect male reproductive function even in presence of normal circulating androgens. Some uncertainties still remain, especially regarding the impact of abnormal serum estrogen levels on male health, particularly due to the fact that estrogen is not routinely measured in men in clinical practice. Advancements in methods to precisely measure estrogens in men, together with a reduction of their costs, should provide better evidence on this issue and inform clinical practice. In parallel, new basic, genetic, and clinical research is required to improve our knowledge on the role of estrogen in male reproductive function and men’s health in general

Investigating the basis of sexual dysfunction during late-onset hypogonadism

Late-onset hypogonadism (LOH) is the term used to describe the decline in serum testosterone levels associated with increasing age in men above 40 years. A number of symptoms are attributed to LOH, but the most common association is that of sexual dysfunction. LOH has recently come under greater scrutiny with the widespread use of testosterone therapy, and concerns regarding the efficacy and safety of testosterone replacement therapy have been raised. In particular, the cardiovascular safety and the beneficial effects of testosterone replacement therapy on general health have been questioned. This review will give an overview of the current evidence for the relationship of LOH and male sexual dysfunction

Male hypogonadism: recommendations from the Fifth International Consultation on Sexual Medicine (ICSM 2024)

Introduction Male hypogonadism is a clinical condition combining low circulating testosterone (T) and specific signs and symptoms associated with impaired hormone production. Objectives To provide the 5th International Consultation for Sexual Medicine consensus paper with recommendations concerning management strategies for hypogonadism. Outcomes A narrative review combined with expert opinions on major topics concerning diagnosis of male hypogonadism; treatment options; T impact toward cardiovascular, metabolic, sexual, and reproductive health; and prostate cancer (PCa). Methods A consensus panel was held with leading Sexual Medicine experts during the 5th ICSM. Relevant English-language peer-reviewed literature was reviewed with a focus on research from but not limited to the last 10 years. The quality of each individual study was judged with Oxford levels of evidence (LOEs) criteria, but overall LOEs were not used as a systematic review was not performed. The expert panel generated recommendations based on the quality of evidence and criteria of Grading of Recommendations Assessment, Development and Evaluation. Results This manuscript reports a narrative reappraisal combined with authoritative expert opinion on the physiological role of T throughout the male aging process, with emphasis on the critical interpretation of the hypogonadal conditions associated with sexual dysfunction and male factor infertility. Likewise, particular attention was paid to relevant everyday clinical topics including cardiovascular health, metabolism and bone safety, and PCa survivorship. Clinically effective recommendations were given for 14 categories concerning hypogonadism diagnosis and 15 categories on testosterone therapy. Strengths and limitations The combined main strength and limitation is the narrative profile of this literature review, which was intentionally devoted to addressing the critical clinical aspects of male hypogonadism, while neither provides a systematic review nor a meta-analysis of the most updated published data. Conclusions This manuscript discusses relevant clinical aspects and management recommendations of the 5th ICSM committee on male hypogonadism

Advances in the treatment of prolactinomas

Prolactinomas account for approximately 40% of all pituitary adenomas and are an important cause of hypogonadism and infertility. The ultimate goal of therapy for prolactinomas is restoration or achievement of eugonadism through the normalization of hyperprolactinemia and control of tumor mass. Medical therapy with dopamine agonists is highly effective in the majority of cases and represents the mainstay of therapy. Recent data indicating successful withdrawal of these agents in a subset of patients challenge the previously held concept that medical therapy is a lifelong requirement. Complicated situations, such as those encountered in resistance to dopamine agonists, pregnancy, and giant or malignant prolactinomas, may require multimodal therapy involving surgery, radiotherapy, or both. Progress in elucidating the mechanisms underlying the pathogenesis of prolactinomas may enable future development of novel molecular therapies for treatment-resistant cases. This review provides a critical analysis of the efficacy and safety of the various modes of therapy available for the treatment of patients with prolactinomas with an emphasis on challenging situations, a discussion of the data regarding withdrawal of medical therapy, and a foreshadowing of novel approaches to therapy that may become available in the future

Investigating the regulation of male infertility

Infertility is defined as the inability to become pregnant following one year of practicing regular and unprotected sexual intercourse and is estimated to affect 72.4 million people globally. Within the U.K., infertility has been estimated to affect 14% of couples. In 50% of cases of infertility the cause will be attributable to poor sperm quality and the main treatment is assisted reproductive technologies (ART) such as in-vitro fertilisation (IVF). However, ART is resource limited and IVF has an estimated success rate of 29%. Thus, there is an urgent need to improve our understanding of the pathophysiological mechanisms that underpin male infertility to help develop more cost-effective therapies. Recent studies have highlighted the effects of oxidative stress (including seminal reactive oxygen species (ROS) and sperm DNA fragmentation (SDF)) in sperm dysfunction. Furthermore, there is limited data showing differences in seminal microbiome in infertile compared to fertile men. However, it is unclear from the literature how oxidative stress and the seminal microbiome correlate with semen analysis. This is pertinent given that semen analysis is the gold standard investigation for diagnosing male infertility. Non obstructive azoospermia (NOA) is the absence of sperm in the ejaculate due to impaired spermatogenesis. The only method for men with NOA to conceive biological children is through sperm retrieval surgery combined with ART. However, the success rate of testicular sperm extraction in men with NOA is only 50%. In half of all cases of NOA the cause is unknown but there is emerging data showing that genetic mutations may be contributory. This knowledge is helpful in both patient counselling and clinical management. For example, men with NOA who have either Azoospermia factor A or B gene deletions have a lower likelihood of testicular tissue containing sperm and should be counselled against sperm retrieval surgery. There is emerging data showing that in some cases of idiopathic NOA, a genetic mutation may be causal. Further genetic studies are needed to help improve our understanding of the aetiology of NOA and this may help identify future therapeutic targets for men with infertility. Spermatogenesis is stimulated by gonadotropins and intratesticular testosterone. Some clinicians have trialed hormone stimulation therapy to improve sperm retrieval rates in men with NOA. However, no study has critically evaluated the literature regarding the effects of hormone stimulation therapy in improving sperm retrieval rates and also the potential adverse events. This thesis includes the first study investigating how oxidative stress markers and seminal microbiome differ in different cohorts of male infertility and fertile controls. Furthermore, I performed the first meta-analysis investigating the effects of hormone stimulation therapy on surgical sperm retrieval rates in men with NOA. I have also investigated for novel genetic mutations in a cohort of infertile men with idiopathic NOA. Collectively, the results from this thesis will improve our understanding on the aetiological factors, pathophysiological mechanisms and management of male infertility.Open Acces