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Open research questions in Hormonal and reproductive studies

34 unresolved questions extracted from the limitations and future-work sections of 533 Hormonal and reproductive studies papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in these conditions, but their effects on male reproductive endocrinology remain incompletely defined.

    Metabolic Reversal of Functional Hypogonadism? GLP-1 Receptor Agonists and Male Reproductive Endocrinology—A Systematic Review · 2026 · DOI

  • Unresolved Issues Key Clinical Messages (Post-TRAVERSE) TRT does not increase the risk of major adverse car- diovascular events (MACE) when prescribed to men with rigorously confirmed hypogonadism and titrated to physiological testosterone levels, including those at high baseline cardiovascular risk. Non-MACE safety signals (atrial fibrillation, venous thromboembolism, acute kidney injury) were numerically higher in the TRT arm in TRAVERSE, with low absolute event rates. These findings warrant vigilance rather than contraindication, particularly in men with pre-existing risk factors. Erythrocytosis represents the most consistent adverse event of TRT. Hematocrit should be monitored regularly, and TRT should be reduced or temporarily withheld if hematocrit ≥ 54%. No excess risk of prostate cancer has been observed in RCTs and meta-analyses up to mid-term follow-up; long- term oncologic safety remains under investigation. TRT should be initiated only in men with biochemically confirmed hypogonadism (total testosterone < 300 ng/dL on two separate morning samples using reliable assays) and clinically relevant symptoms. Functional hypogonadism related to obesity or meta- bolic syndrome should prompt lifestyle and comorbidity management as first-line therapy. TRT may be considered in persistently symptomatic men after careful risk–benefit evaluation. Before initiating TRT: assess hematocrit, PSA (age- and risk-appropriate), blood pressure, glycemic and lipid profile, obstructive sleep apnea risk, and personal history of venous thromboembolism or arrhythmias. Reassess testosterone levels, hematocrit, symptoms, and adverse events at 3–6 months and periodically thereafter. Blood pressure and cardiovascular status should be moni- tored during treatment. Individualized ECG monitoring may be considered in men with prior atrial fibrillation, conduction abnormalities, or significant arrhythmic risk. In 2025, the FDA removed the boxed cardiovascular warn- ing previously applied to testosterone use for age-related decline, while maintaining restrictions to approved indica- tions and emphasizing appropriate monitoring. Key uncertainties include long-term oncologic safety, optimal duration of TRT in very old men (> 80 years), and integration of TRT into multimorbidity and frailty manage- ment pathways.

    Testosterone replacement therapy and cardiovascular safety in older men: lessons from TRAVERSE and beyond · 2026 · DOI

  • We acknowledge that this study has some limitations that may affect the interpretation of the results. Samples were collected remotely, resulting in a 24–72 h lag between col- lection and assay, however serum stability of a least 3 days has been previously verified [50, 51]. The sample is a self- selected convenience sample of test purchasers, which likely results in a dual bias: overrepresenting individuals of higher socioeconomic status and those who are symp- tomatic or experiencing fertility difficulties. Given the strict exclusion criteria applied, this cohort likely represents a well-screened population actively engaged in reproductive health monitoring. Consequently, the findings may not be generalisable to the broader population. The current exclu- sion criteria focused on self-reported hirsutism and PCOS diagnosis. However, acne and female pattern hair loss are also key clinical features of hyperandrogenism. The poten- tial inclusion of individuals with T-related acne or hair loss, but without hirsutism or a PCOS diagnosis, represents a limitation, as this may slightly inflate the upper quantiles. We acknowledge that insulin resistance is a common meta- bolic factor that can influence T [52]. Whilst we did not have direct biochemical measurements of insulin sensitivity for this cohort, we excluded participants with a history of Type 1 or 2 diabetes. The number of individuals reporting this condition was negligible, and as the final reference cohort was restricted to those with a normal BMI and regular men- strual cycles, the impact of undiagnosed insulin resistance is likely minimal. Further, self-reported data may lead to erroneous report- ing of medical history. The reference cohort was predomi- nantly white (white = 83.7%, Asian = 5.5%, Black = 1.8% Mixed = 4.8%, Other = 4.2%). Future studies should expand this model into more diverse populations.

    Redefining testosterone reference ranges for adult females · 2026 · DOI

  • The effectiveness of the existing therapies for sexual dysfunction treatment and the restoration of reproductive hormones in hypogonadal men with type II diabetes remain unexplored.

    Various interventions for infertility in men with type II diabetes and hypogonadism · 2023 · DOI

  • Of the limited studies available, many link a ‘hegemonic masculinity’ with men’s AAS use; adopting a singular identity perspective and generalizing ‘steroid use.

    A Triad of Physical Masculinities: Examining Multiple ‘Hegemonic’ Bodybuilding Identities in Anabolic-Androgenic Steroid (AAS) Online Discussion Groups · 2023 · DOI

  • Whether the sensitization of the adrenals to ACTH varies according to COC contents and whether it relates to experienced side effects needs to be investigated.

    Effects of estradiol- and ethinylestradiol-based contraceptives on adrenal steroids: A randomized trial · 2022 · DOI

  • Existing evidence from available trials evaluating the effect of vitamin D supplementation on androgen levels in men is insufficient to recommend measurement of 25(OH)D levels or vitamin D supplementation in hypogonadal men.

    Vitamin D effects on androgen levels in men · 2021 · DOI

  • While earlier studies have shown that it has a protective effect in males, unfavorable effects of testosterone on glucose metabolism have been reported in females; however, whether there is a sex-specific relationship between testosterone and glucose metabolism in patients with prediabetes has not been investigated in detail hitherto.

    Increase in testosterone levels is related to a lower risk of conversion of prediabetes to manifest diabetes in prediabetic males · 2021 · DOI

  • Since conflicting results have been obtained from different studies, which examined serum levels of cytokines in patients with diabetes, and considering the fact that the origin of cytokines cannot be accurately determined from their serum changes, attempts were made in the present study to study histological changes and testicular tissue levels of TNF-α and IL-1 in rats treated with exercise.

    Effects of short- and long-term regular exercise on reproductive tissue in streptozotocin-induced diabetic male Wistar rats · 2018 · DOI

  • WHAT IS KNOWN ALREADY: In animals, some PFCs have endocrine disrupting potential, but few studies have investigated PFCs in relation to human testicular function.

    PFOS (perfluorooctanesulfonate) in serum is negatively associated with testosterone levels, but not with semen quality, in healthy men · 2012 · DOI

  • Information regarding self-administered AAS used nonmedically to enhance athletic performance or improve physical appearance is sparse and poorly documented.

    Anabolic Androgenic Steroids · 2006 · DOI

  • ABSTRACT Although the effects of hormone therapy on cardiovascular risk factors and bone metabolism have been studied, data are lacking on the gonadotropin profile after gonadectomy in the sex reassignment process (SRP).

    Evolution of Gonadal Axis After Sex Reassignment Surgery in Transsexual Patients in the Spanish Public Health System · 2006 · DOI

  • Whether this displacement of T from TeBG is the result of an in vivo effect of d-norgestrel remains to be ascertained. 6 603 CONTRACEPTION The finding of elevated values of non-TeBG bound testosterone in women on d-norgestrel-ethinyl estradiol is of interest and has not been reported previously.

    Plasma concentrations of free and non-TeBG bound testosterone in women on oral contraceptives · 1974 · DOI

  • We conclude by outlining open questions and experimental needs that would aid in establishing causal relationships between sex hormones and exercise responses in soft musculoskeletal tissues.

    Sex Hormones & Exercise in the Musculoskeletal System: From Signaling to Structure and Function · 2026 · DOI

  • Future research should focus on modelling the age-related decline of T through longitudinal testing of an individual both annually and sub-annually to provide short-term fluc- tuations in T levels, and longer-term patterns of hormonal change across the reproductive lifespan.

    Redefining testosterone reference ranges for adult females · 2026 · DOI

  • The pituitary-adrenal-gonadal axis was affected by the altitude trek (involving physical exertion and hypoxia in combination), but the origin, duration and impact of changes in various aspects of men’s health should be further investigated.

    Male sex hormones response after a month-long Himalayas trek in relation to hemoglobin oxygen saturation · 2018 · DOI

  • Facial changes associated with the administration of exogenous testosterone and bilateral oophorectomy in female-to-male (FtM) transsexual people (trans men; trans males) has not been previously documented.

    Morphological and morphometric changes in the faces of female-to-male (FtM) transsexual people · 2017 · DOI

  • Nonetheless, there are still no data on simultaneous measurements of various EDs along with steroids directly in the seminal fluid, where deleterious effects of EDs on spermatogenesis and steroidogenesis are assumed.

    Differences in Bisphenol A and Estrogen Levels in the Plasma and Seminal Plasma of Men With Different Degrees of Infertility · 2015 · DOI

  • Conflicting findings concerning the blood cortisol response have also been reported, likely due to variance in REx protocol and the level of obesity in the participants in studies.

    Acute and Chronic Effects of Resistance Exercise on the Testosterone and Cortisol Responses in Obese Males: a Systematic Review · 2014 · DOI

  • Although there are few studies on the treatment of schizophrenia with testosterone, several indirect findings have suggested testosterone as a possible treatment modality for schizophrenia.

    Short-Term Testosterone Augmentation in Male Schizophrenics · 2008 · DOI

  • Studies of exogenous testosterone administration in men have yielded mixed results, some demonstrating improvements in spatial tasks and others failing to find improvements.

    Androgens, Ageing, Behavior and Cognition: Complex Interactions and Novel Areas of Inquiry · 1999

  • Chow: Further studies on vitamin B12 deprivation and carbohydrate metabolism.

    Serum Lactate and Lactic Dehydrogenase Levels of Aging Males · 1966 · DOI

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34 open questions have been extracted from the limitations and future-work passages of 533 Hormonal and reproductive studies papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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