Introduction Rationale

The clinical absence of first signs of pubertal developmental milestones is defined as delayed puberty (DP) in boys and girls.1 Functional delay in the production of gonadotropin-releasing hormone (GnRH) from the hypothalamus considered responsible for DH.2 CDGP due to individual genetic variations, malnutrition, chronic illness and other functional defects can be the underlying case for DP.3 DP can present with socio physiological burden for patients and their families.

Diagnosis for DP among boys are based on the assessment of clinical signs and symptoms and a low testosterone (TE) concentrations in serum in the morning on at least two occasions (< 10.4 nmol/L).4,5 In conditions like hypogonadism, where enough hormones for masculine growth and development during puberty (TE) or enough sperm or both6 are not produced due to congenital or acquired conditions external hormonal treatments are required.7 Based on causes of DP like CDGP or hypogonadism for young boys, chemically synthesized TE has been used since 1935 as a common clinical intervention, targeting genital maturation, adequate secondary sexual characteristics developments, attainting the optimal muscular and bone growth.8,9

The typical clinical approach for adolescent males with CDGP or hypogonadism is the prescription for Testosterone Replacement Therapy (TRT). Currently various choices of interventions for TE replacement and management for adults are available, including intramuscular (IM), subcutaneous, oral and transdermal preparations,10–15 but the right tittered choice and mode of administration of TE for young adults are not available.16–18 Pitfalls in the use of TE usages for adolescents have disclosed multitudes of risks, associated behavioral deviations in the pre pubertal group and below target height line achievement with non-advancement of one’s age which has generated a warning for its usage.19–21 Earlier short acting esters of TE like Sustanon®, were used as IM preparations that have been used for many years for the treatment of pubertal TE deficiency.22 Studies report the safety and efficacy of short-term use of  TE Enanthateor oral  TE undecanoate in inducing puberty and increasing growth in young males with CDGP.23,24

Though the long-term safety and efficacy of Transdermal testosterone therapy (TRT) for puberty completion and maintenance have not been established, reliable evidence on the use of Transdermal testosterone (TT) for adolescent boys to induce and maintain puberty are emerging.25–27 It is optimal that  all kinds of TE therapies for young males are administered and monitored to better mimic the physiologic pubertal development. A critical lack of scientific evidence based guidelines for prescribing transdermal TE for adolescent boys hinders achieving this and the current  TRT regimens are based on consensus and expert opinion.

The US Food and Drug Administration has currently approved only IM TE esters (TE enanthate) and subcutaneous TE for DP, while no preparation is approved for long-term use in the adolescent age.17,28–32 In adult males with hypogonadism several TE formulations like transdermal nasal, subcutaneous, and oral formulation have been are recently developed with improved pharmacokinetic profile and to ease the administration route increasing patient compliance.33–36 These formulations are not approved for pediatric age, although some of them are used as off-label regimens.37–40 Pediatric uses of exogenous TE has been reported for the treatment of microphallus in infants and the management of diminished or absent mini puberty.41–43.

Critically limited evidences are available in support of the use of TT in the long term use boys with DP. Current practices lacks evidence based guidelines and the recommendations in selecting the route of administration and in the ideal preference of monitoring of the TE dose are based on expert opinions and consensus. It is of paramount importance clinically to identify and utilize an effective, safe, convenient to use and cost effective regimen of TE treatment which optimally mimics the physiological situation, as the majority of boys diagnosed with DP require longer periods of treatment.

TT for young males has not yet been a topic of any meta-analysis or a systematic review to this date and thus this review has a highlighted an importance in providing guidelines and evidence to the current TT treatment requirements to treat DP. Hence this study aims to compare the TT intervention to other types of TE interventions recommended to treat the symptoms of DP among young males.

In this study, a PRISMA guided systematic review is undertaken including randomized-controlled trials (RCTs) and non-randomized studies with an objective to evaluate the TT treatment options involving young male population diagnosed with DP. The review question formulated for this review is as follows. Participants (P): Boys younger than 19 years, Intervention (I): TT preparations for DP for young boys. Comparisons(C): Injectable TEs and oral TE. Outcomes (O): Serum TE levels, bone mineral density, height velocity and pubertal growth, adverse effect and quality of life.

Objectives

Using a broad set of eligibility criteria and an inclusive search strategy this systematic review sought to evaluate the existing evidence and systematically review the interventional effects of TT to other modes of TE administration for the treatment of DP among young and adolescent males.

Methods Protocol and Registration

Detailed eligibility criteria and methods of analysis were specified in advance and documented in a published review protocol.44 This review conforms to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines45 and is registered with the International Prospective Register of Systematic Reviews (PROSPERO) (registration number CRD 42022369699). The institutional review board ruled out the need for an ethical approval for a systematic review.

Inclusion and Exclusion Criteria

The full text articles retrieved were assimilated that were relevant after review of the titles and abstracts. Final eligibility assessment was done independently for full text articles and all studies were individually appraised.

Inclusion criteria for the studies were (1) Methodologies of clinical trials without limitation on intervention design features, systematic reviews, meta-analysis, case reports and series, cross sectional studies on young and adolescent boys with DP (below 18 years) from 2015 until 2022, comparing TT to other modes of TE treatment. (2) Studies which included at least 3 of the following post-interventional outcomes helpful to assess the DP related clinical presentations: Serum TE levels, body mass index, bone mineral density, LSH, FSH and adverse effects. Studies on adults, studies on women, trans genders, animal studies, narrative reviews letters to editor, editorials, commentaries, and abstracts only available were excluded. Table 1 summarizes the inclusion and exclusions criteria designed for this study.

Table 1 The Inclusion and Exclusion Criterias for the Study Selection

Table 1 describes these criteria.The Figure 1 illustrates the PRISMA flow diagram for the studies selected in the search process and eligibility appraisal.

Figure 1 PRISMA Flowchart elaborating on study retrieval and inclusion in this study.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.45

Information Sources and Search Strategy

Based on the study eligibility criteria, a search strategy was designed consisting of a systematic, computer-assisted, literature search of existing evidence from several online databases like MEDLINE, Embase, Cochrane Reviews, Web of Science, the Allied and Contemporary Medicine (AMED) for articles published between 2015 to 2022. Boolean logics with keywords “types of TE”, “modes of TE administration”, “DP”, “TT”, “CDGP”, “adolescent boys” and “hypogonadism”, “androgens”, hypogonadal boys, IM TE injections, to which relevant subheadings like “administration & dosage”, modes of administration (buccal, cream, gel, implant, injections, oral, patch, transdermal) were applied in combination to optimize the search results.

Study Selection

The selected studies were independently identified, selected, and appraised. To avoid possible selection bias, grey literatures including published and unpublished thesis, was obtained by searching Web of Science, ProQuest Dissertations and clinicaltrials.gov. The reference sections of retrieved original articles and reviews were scanned for studies that might have been missed in the primary searches. Studies were filtered with regard to study design and methodological features, main and secondary reported outcomes evaluated under this study. Eligibility was tracked and arranged with EndNote (Version 5.0 Thompson Reuters, 2011).

Data Collection Process

Data extraction for all variables was independently completed and assessed using a customized data extraction spreadsheet. Search results were combined and duplicates were deleted. The selected titles and abstracts were reviewed, and full‐text reports were retrieved of those that were potentially relevant, and later classified as included or excluded. Data from the included studies were extracted into the predesigned spreadsheet.

Data Items

Full-data extraction was done for study design details including the publication details, methodological attributes, and post interventional outcomes featured in the study, TE duration and preparation used, remarks of the included study, participant demographics. Table 2 and Table 3 and are illustrative of this data extraction and synthesis.

Table 2 Main Outcome Comparison and Descriptions

Table 3 Adverse Events and Patient Satisfaction on Transdermal Testosterone Treatment for Young and Adolescent Boys with Delayed Puberty

A meta-analysis was ruled out due to the heterogeneous nature of the limited amount of studies which are available. This there was no further statistical analysis involved and the review was summarized narratively after the explicit quality assessment process. This directs to a key research gap of the lack of evidence in this topic and contributes to the medical decisions based on weaker scientific support.

The review was themed into main outcomes and secondary outcomes. Main outcomes of concern were the achievement of optimal serum TE levels, height velocity, bone mineral density and pubertal growth. The secondary outcomes evaluated were adverse events and quality of life.

Risk of Bias in Individual Studies

Due to the heterogeneous nature of the included studies, Mixed Methods Appraisal Tool (MMAT)

201846 was used to appraise the quality of the different study designs included in this study. The

MMAT, consists of a checklist which appraises the methodological quality of included studies in systematic reviews, qualitative, quantitative, and mixed methods studies.47 Checklists for nonrandomized and mixed method designs were used. Each study was screened with 2 questions and further a 5 assessments criteria check list to answered with Yes, No, cannot tell was used. A total score of 7 constitutes a Yes response to the screening and assessment criteria.48 Subsequently the spreadsheet was updated for the final review and summarization of the included studies.

Summary Measures and Additional Analyses

A tabular as well as narrative summary of all study design features, participant details, outcome variables of interests are presented in this review. The outcomes of interests were compared between the IM TE dose and TT dose.

Results Study Selection

This systematic review search ended only with 5 studies included from an initial hit of 126 studies Following the removal of duplicates, 110 studies were screened (titles and abstracts) to identify and 39 articles were assessed for full eligibility and only 5 studies were included in this systematic review. Full-text review led to the removal of 34 articles. The PRISMA flow diagram of study selection procedure is shown in Figure 1. A total of 842 participants were included from these included studies and Table 4 provides the summary of the attributes included studies. Out of the included studies one was a questionnaire based survey,49 two were clinical trials,50,51 and one a retrospective case reports review52 one a case report.53 This is an explicit manifestation of the dire insufficiency of clinical trials and on young males with TE requirements.

Table 4 Summary of the Attributes Included Studies

Study Characteristics

A summary of the attributes included studies included studies are comprehensively presented in Table 4.

Risk of Bias Within Studies

The methodological quality of the included articles are shown in the Table 5. Of the included reports, only 2 studies were rated as moderately strong, and the other 3 studies were moderately weak, respectively.

Table 5 Quality Assessment of the Included Studies Using Mixed Methods Appraisal Tool (MMAT)

Synthesis of Results

Due to the high heterogeneous nature of the included studies a meta-analysis was excluded and therefore progressed with a narrative synthesis.

Participant Details

In total, this review represents 842 participants, 40.02% (n = 337) were identified as having CDGP, where 20.19% (n=170) had hypogonadism and 0.83% (n=7) had hypogonadotropic hypogonadism. The mean age of the participants were 14.84 and the duration of the TE treatment were all short term with a mean of 6 months.

Main Outcomes

The main outcomes of concern were optimal serum TE level, body mass index, height velocity, testicular volume, pubertal stage (Tanner).

Serum Testosterone Level

Raising Serum TE to an optimal level is the utmost goal of TE treatment, which alleviates the symptoms of DP. The transdermal TE gel treatment is shown to be promising than IM TE for young boys with DP50,51 and suggests it to be an alternative to other modes of TE treatments. It can be seen that both gel and IM TE preparations are able to achieve desirable levels of TE within a short duration with minimal fluctuations.50–53 Studies on adult men54–57 have reported an average level of TE levels are reported by the weekly usage of short acting IM TE. Women and girls studies32,58–61 reports the favorable pharmacokinetic profile of transdermal gel compared to achieve an optimal peak of TE level.

The limited amount of evidences available in selecting TT against other modes of TE is evident in the sparse amount of studies included in this study. It is evident that there exists, a critical need for explicit clinical guidance that can be applied to monitor the safety as well as efficacy of transdermal therapy in this age group. Table 2 which is descriptive of all the main outcomes covered in this study.

Pubertal Growth

Evaluation of BMI (kg/m2) testicular volume, testicular volume, bone mineral density, pubertal stages as per tanner stages, were included to identify the growth. Table 5 is inclusive of these observed outcomes from the included study.

It can be seen that all the included studies49–53 reported the comparable efficacy of TT treatment in all the included main outcome observations.The heterogeneous nature of outcome reporting and the extremely limited availably of clinical trials makes it hard to make a definite statement.

TE changes the BMI and the included studies51–53 reports TT to be at par with IM TE preparations. Though from a limited amount to studies, BMI increase was apparent in all types49–53 of TE treatment. Clinical trials should be initiated to cover the anthropometric parameters, metabolic changes, changes in fat mass, lean body mass, and muscle strength comparing transdermal approach to other modes of TE treatment. It is noteworthy that in all studies with the transdermal gel approach49–53 bone age is reported to be a gradual and progressive increase during treatment more apparently.

Secondary Outcomes

Secondary outcomes included in this review were the adverse events of the interventions and the reported patient satisfaction.

Adverse Events and Patient Satisfaction

Only one study53 assessed the effect of TE therapy on patient satisfaction. Increase aggression and mood swings was reported by a study,52 whereas the other studies does not significantly draws notice to any adverse effects. The impact of TE therapy on quality of life among boys with DP is difficult to quantify due to the significant heterogeneity in study population, study duration, and the measures to identify it. One study49 reports acne or oily skin, aggressive behavior with IM TE and erythema was reported53 for a patient under IM TE treatment, while there no significant adverse events reported on TT by the other included studies. It is evident that clear conclusion cannot be derived from such limited sources on the different formulations for young boys with DP. Table 3 briefs all these observations.

Strengths and Limitations

This review has explicitly followed the PRISMA protocols and presented a transparent review, drawing on recommendations and highlighting the research gaps found. In addition, the breadth of the study inclusion criteria has ensured a comprehensive coverage of the TE intervention under review. A rigorous use of screening process, data abstraction, and quality appraisal increases the strength of conclusions has been ensured in this study. Based on these this review support the evidence of the use of TT for the clinical management of DP in boys.

A potential limitation of this review is the volume of included literature included in this study. Although short term TE preparations are being marketed on a high scale, there is a clear lack of scientific evidence and support for the consumption and prescription of these products. Due to the high volume of research con ducted with mixed samples of adults and adolescents an inability to obtain segregated data from the articles is highlighted here.

Considering the various TE preparations and modes of administration used in the literature as well as the different participant samples, this review has a great deal of clinical heterogeneity. Variation in response to the intervention was infrequently reported. Consequently, complete statistical analysis and quantitative integration of the data cannot be assimilated.

Recommendations for Future Research

Future studies recruiting sufficient sample population with longer follow up periods should be considered. These studies should report unified measurements of outcome measurements. Finally, further research exploring the potential mechanisms mediating the transdermal preparations pharmacokinetics is warranted to better understand the interventional outcomes. Such mechanisms include, but are not limited to, vascular indices of health and function as well as patient satisfaction.

Conclusion

Positive treatment effects of TE for adult men, women and transgender are well-researched and has been explored. This study exposes the critical lack of experimental researches, meta-analysis for comparing TT delivery with other TE administration routes for young males with DP. It is very imminent that there should be clinical trials undertaken in this field as there are many new combination of TE dosages and administration routes emerging in the market. These new preparations of TE should be according to the patient’s preference, cost, availability, and formulation-specific properties for the young boys with clinically evident DP.

In conclusion, though both transdermal gel andIM TRT appear to be effective preparations for the treatment of DP in young males, TT shows more promising in the mode of administration and in better outcomes of serum TE elevation and hence recommended for treating DP among young boys. However, any clinical recommendations on TT treatment needs more clinical trial and meta analyses and thus this study only provides a clinical support and not a guideline. The research gap identified needs to be filled by future clinical trials comparing TT with other modes of TE administration for young males with DP.

Patient and Public Involvement

This study being a systematic literature review, the patients selected were recruited by the researchers of the included studies. All the patient and families related aspects involved in design and implementation of the interventions were priori addressed by the authors of the selected studies.

Data Sharing Statement

This review has utilized the published data from the included studies and thus a full dataset is not openly available.

Informed Consent

For this type of study, formal consent is not required.

Funding

No fund or sponsorship in any form was obtained from any organization for carrying out this study.

Disclosure

The author has no conflict of interest to disclose.

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