New perspectives in functional hypogonadotropic hypogonadism: beyond late onset hypogonadism

Abstract

Functional hypogonadotropic hypogonadism (FHH) is an increasingly frequent condition, whose pathological mechanisms are not yet fully clarified. The concept of FHH has now completely replaced that of late onset hypogonadism, that only concerned the ageing man. FHH is the result of an impairment of the hypothalamic-pituitary gonadal axis (HPG-A) function, resulting in decreased testosterone concentrations associated with low or inappropriately normal gonadotropin levels and infertility; it can be diagnosed once organic causes of hypogonadism are excluded. The growing occurrence of FHH derives from its association with widespread conditions, such as obesity and diabetes mellitus, but also to the increasing ease and frequency of use of several drugs, such as opioids, glucocorticoids, and sex steroids. Moreover, given the tendency of many subjects to excessive physical activity and drastic reduction in caloric intake, FHH may also be secondary to low energy availability. Finally, the association with HIV infection should not be overlooked. Therefore, there is an important variability in the diseases that can lead to FHH. Despite the heterogeneity of the underlying pathologies, the mechanisms leading to FHH would seem quite similar, with the initial event represented by the impairment at the HPG-A level. Nevertheless, many different biological pathways are involved in the pathogenesis of FHH, therefore the aim of the current paper is to provide an overview of the main relevant mechanisms, through a detailed analysis of the literature, focusing specifically on pathogenesis and clinical, diagnostic and therapeutic aspects.

Functional hypogonadism in men: key causes and neuroendocrine mechanisms of its development

“…Чаще всего подобного рода нарушения происходят на фоне воздействия эндогенных или экзогенных модифицируемых факторов [6]. К основным причинам функционального снижения продукции тестостерона можно отнести ожирение и метаболический синдром в целом, наличие сопутствующих острых и хронических заболеваний, опосредованно влияющих на синтез тестостерона, прием лекарственных средств, влияющих на его продукцию, интенсивное воздействие физических факторов, таких как вибрация, излучение, шум, температура, а также нарушение сна, интенсивные физические и психоэмоциональные нагрузки и др.…”

“…Длительное ограничение в потреблении с уменьшением жировых запасов связано с гиполептинемией, которая отключает репродуктивную ось и одновременно усиливает аппетит к еде (важный компонент режима выживания). И наоборот, хронический переизбыток калорий с увеличением депо жировой ткани связан с гиперлептинемией и даже резистентностью к лептину, что весьма похожим образом с гиполептинемией подавляет ГГГ-ось и повышает аппетит [6].…”

A Literature Review and a Proposed Classification of the Relationships between Ovulatory Infertility and Lifestyle Factors Based on the Three Groups of Ovulation Disorders Classified by WHO

“…Few articles have linked WHO Group I ovulation disorders to ovulatory infertility and only one Group I disorder is connected with a lifestyle factor, i.e., hypogonadotropic hypogonadism, as hypogonadotropic amenorrhea often develops as a result of low body weight or excessive exercise. Hence, functional hypogonadotropic hypogonadism (FHH) is associated with excessive physical activity and drastically limited calorie intake, resulting in a reduced availability of energy [12], in which case there is an inverse relationship with ovulatory infertility as a reduction in exercise and weight normalization are necessary to manage FHH.…”

“…As far as WHO Group I disorders are concerned, excessive physical activity is an established cause of hypogonadotropic hypogonadism [12], so management of the disease must include lifestyle changes that would lead to an increased calorie intake and moderated exercise regimens in order to improve the patient's BMI and, thus, possibly increase the chances of pregnancy. It is worth emphasizing, though, that links between Group I disorders and ovulatory infertility are uncertain, which is why lifestyle modifications would have an impact mainly on the disorder itself.…”

“…Physical activity is also a factor present in research concerning WHO Group I ovulation disorders. It has been established that lifestyle modifications leading to weight reduction, especially exercise, have a beneficial impact on hypogonadotropic hypogonadism [3,12]. Hence, further research could be performed to replicate the earlier results and link them directly with an impact on ovulatory infertility, which is still very uncertain.…”