The extragonadal biology of gonadotropin hormones: should we rename these?

New Approaches to Regulating Gonadal and Thyroid System Activity

The FSH reset hypothesis: optimizing spermatogenesis in azoospermia.

PURPOSE OF REVIEW Elevated follicle-stimulating hormone (FSH) in primary hypogonadism is usually read as maximal but failing testicular stimulation, and affected men are often considered poor candidates for hormonal therapy. This is a hypothesis-generating narrative review rather than an evidence-based treatment recommendation. It re-examines that assumption and asks whether FSH bioactivity, rather than concentration alone, might shape the testicular response. RECENT FINDINGS Circulating FSH is a mixture of glycosylation-dependent isoforms that differ in receptor-binding efficiency in experimental systems. Chronic gonadotropin excess can downregulate and desensitize the FSH receptor in animal and in vitro models. In principle, these mechanisms could combine to produce a state of functional FSH resistance, in which immunoreactive FSH is high while the effective signal in the testes is weaker. FSH suppression-associated rises in inhibin B, contemporary staged conditioning protocols, and stratification of hypergonadotropic men under the APHRODITE criteria are consistent with a strategy of temporary suppression before stimulation. SUMMARY We outline the FSH reset hypothesis, in which a finite period of pituitary suppression reduces inefficient endogenous hormone and may allow receptor recovery before controlled recombinant FSH. We then present a stepwise treatment algorithm as a model for future investigation in selected men with spermatogenic failure. The hypothesis is speculative and remains unproven in prospective trials.

Pubertal Triptorelin Exposure Alters Hypothalamic Reproductive–Metabolic Integration in a Sex-Specific Manner

Simple Summary Reproduction is primarily regulated by the hypothalamic–pituitary–gonadal axis: gonadotropin-releasing hormone (GnRH), produced by neurons in the hypothalamus, acts on the pituitary gland that produces hormones controlling gonadal (ovarian and testicular) functions. Puberty is the process of reproductive maturation that involves the activation of GnRH neurons and the pulsatile release of GnRH. GnRH agonists (GnRHa) are synthetic molecules similar to GnRH that are used as puberty blockers to treat premature puberty and as a part of treatment in some transgender adolescents. We used GnRHa to treat male and female rats at the start of puberty and examined its effects on reproductive functions and metabolism. GnRHa treatment induced the suppression of reproductive function in rats of both sexes, evidenced by changes in ovaries and testes and in pituitary markers important for the control of reproduction. The effects on metabolism were sex-specific: treated females gained more weight and had a higher food intake than controls, while treated males exhibited decreased weight gain and changes in locomotion compared to controls. Also, only females showed changes in the hypothalamic molecules regulating the energy balance. These results demonstrate that puberty blockers exert broader impact than suppressing reproductive maturation and highlight the importance of further research of their effects.

Reproduktionsmedizin und Endokrinologie

Emerging peptide and neuroendocrine strategies for TRT-induced reproductive suppression and functional male hypogonadism: a narrative review

The growing burden of male hypogonadism has raised concerns regarding the potential impact of modern lifestyles and environmental exposures on male reproductive health. Testosterone replacement therapy (TRT) is widely used for the treatment of male hypogonadism. However, prolonged TRT may suppress the hypothalamic-pituitary-testicular (HPT) axis, resulting in reduced gonadotropin production, decreased intratesticular testosterone levels, impaired spermatogenesis, testicular atrophy, and compromised fertility. Current management strategies, including human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), and selective estrogen receptor modulators (SERMs), can support recovery in some patients, but their effectiveness remains variable. This narrative review examines the emerging role of peptide and neuroendocrine strategies in TRT-induced reproductive suppression and functional male hypogonadism. A structured literature search was conducted to identify experimental, translational, and clinical studies investigating reproductive peptides and related neuroendocrine pathways. Particular attention was given to kisspeptin-based therapies, gonadotropin-releasing hormone (GnRH)-related approaches, neurokinin signaling pathways, and other developing interventions with potential relevance to male reproductive health. Current evidence suggests that peptide-based therapies may support endogenous hormonal signaling through targeted activation of the HPT axis. However, direct evidence demonstrating restoration of spermatogenesis or fertility following TRT-induced suppression remains limited, and important questions regarding long-term efficacy, safety, treatment protocols, and patient selection remain unresolved. Emerging peptide therapeutics represent a growing area of interest in reproductive endocrinology and may expand future treatment options for selected patients. Nevertheless, further well-designed clinical studies are required to establish their long-term efficacy, safety, and role in restoring reproductive function following TRT-induced suppression.

Gonadotropin-releasing hormone agonists and uterine fibroids: a look into the past or a reliable future?

The article analyzes the role of gonadotropin-releasing hormone agonists (aGn-RG) in the treatment of patients with uterine fibroids, which remain highly prevalent and have a significant impact on women’s reproductive health. Modern concepts of the pathogenesis of uterine fibroids are considered, including the role of hormonal imbalance, angiogenesis, inflammatory mediators and immunological factors. The paper provides an overview of surgical and medical treatment methods, including organ-preserving operations, uterine artery embolization, and the use of hormonal drugs. The mechanism of action of aGn-RG is considered in detail, based on induced hypoestrogenism and suppression of the function of the pituitary-ovarian axis, which leads to a decrease in the size of myoma nodes, a decrease in the severity of inflammatory processes and a decrease in symptoms. The data from meta-analyses and clinical studies confirming the effectiveness of aGn-RG in preoperative preparation, reduction of blood loss and improvement of postoperative outcomes are presented, and at the same time the limitations of the method are discussed. It is concluded that aGn-RG, including buserelin, employ an important place in the multimodal and personalized treatment of patients with uterine fibroids and endometriosis, but require balanced and differentiated use.