Figure - available from: Therapeutic Advances in Endocrinology and Metabolism
This content is subject to copyright.
Schematic representation of circulating levels of testosterone adult male patients with hypogonadism receiving testosterone enanthate or testosterone undecanoate IM. Time 0 represents before treatment; serum concentrations are indicated following IM injections of 250 mg of enanthate or 1000 mg of undecanoate. The grey area represents normal serum levels of testosterone for an adult male. Data obtained from references.46,49–51 Modified with permission from Rey and Grinspon. 52 © 2020 The Authors.
Source publication
Clinical manifestations and the need for treatment varies according to age in males with hypogonadism. Early foetal-onset hypogonadism results in disorders of sex development (DSD) presenting with undervirilised genitalia whereas hypogonadism established later in foetal life presents with micropenis, cryptorchidism and/or micro-orchidism. After the...
Citations
... Gonadotropin treatment should be discussed as an option for patients with MPHD and HH, along with FSH priming before hCG therapy to enhance testicular growth. Long-term studies are needed to assess their impact on adult fertility [31]. In patients with congenitally acquired MPHD and HH, detecting low serum fertility markers may represent a diagnostic pitfall and cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts. ...
Objective
During the process of transition from paediatric to adult health care, counselling concerning fertility is an important issue and is based mainly on serum markers of gonadal function. Here, we analysed these markers in adolescents with various underlying endocrine diseases at the time of transition.
Methods
After reaching near adult height and late puberty (girls: bone age [BA] ≥14 years, and boys: BA ≥16 years), we assessed stages of puberty according to Tanner and measured testes or ovarian volumes and serum markers of gonadal function (anti‐Mullerian hormone [AMH], inhibin B, 17β‐estradiol, testosterone).
Results
One hundred and ten patients (56 females and 54 males) were included from May 2010 to March 2016 with multiple pituitary hormone deficiency (MPHD; n = 17), growth hormone deficiency (GHD; n = 35), Turner syndrome (TS; n = 27), short stature after being born small for gestational age (SGA; n = 20) and Klinefelter syndrome (KS; n = 11). Female and male adolescents exhibited mature secondary sexual characteristics. The levels of serum inhibin B and AMH were lower in TS and female MPHD than in GHD and SGA, each independently (p < 0.05). The levels of serum AMH were higher whereas serum inhibin B were lower in male MPHD and KS (p < 0.05). Ovary volumes were significantly smaller in patients with TS, and testicular volumes were smaller in patients with KS.
Conclusions
After current established treatments with sex steroids, the development of secondary sexual characteristics was mature. However, impaired markers of fertility have been identified in patients with TS, KS and MPHD, reflecting gonadal dysgenesis in TS and KS, but gonadal immaturity in MPHD as gonadal gonadotropin stimulation is lacking throughout development. Consequently, in patients with MPHD, these markers cannot reliably predict individual fertility, which warrants consideration and incorporation in future treatment concepts.
... In 46,XY DSD patients with impaired gonadal steroidogenesis, such as deficiencies in StAR, P450scc, 17α-hydroxylase, 17,20-Lyase or POR and in 46,XX patients with POR deficiency, sex hormone replacement is needed at the age of puberty to induce secondary sex characteristics, optimize the growth spurt, and guarantee bone mass accrual. In patients raised as boys, testosterone replacement schemes are similar to those used in any form of hypogonadism, starting at the age of normal pubertal onset, i.e. approximately 12 years [37,38]. In patients raised as girls also, treatment is the same used to other forms of hypogonadism, with initial estrogen administration to promote breast and uterus development, followed by the addition of progestins to induce menstrual cycles [38]. ...
Introduction:
Disorders of Sex Development (DSD) associated with adrenal dysfunction occur due to different defects in the proteins involved in gonadal and adrenal steroidogenesis.
Areas covered:
The deficiencies in 21-hydroxylase and 11β-hydroxylase lead to DSD in 46,XX patients, defects in StAR, P450scc, 17α-hydroxylase and 17,20-lyase lead to 46,XY DSD, and 3β-HSD2 and POR deficiencies cause both 46,XX and 46,XY DSD. Challenges in diagnosis arise from the low prevalence and the variability in serum steroid profiles. Replacement therapy with hydrocortisone and fludrocortisone helps to minimize life-threatening adrenal crises; however, availability is still an unresolved problem in many countries. Adverse health outcomes, due to the disease or its treatment, are common and include adult short stature, hypertension, osteoporosis, obesity, cardiometabolic risk, and reproductive health issues. Potential biomarkers to improve monitoring and novel treatment options that have been developed with the primary aim to decrease adrenal androgen production are promising tools to help improve the health and quality of life of these patients.
Expert opinion:
Steroid profiling by mass spectrometry and next-generation sequencing technologies represent useful tools for establishing an etiologic diagnosis and drive personalized management. Nonetheless, access to health care still remains an issue requiring urgent solutions in many resource-limited settings.
... An overview of the literature in recent years shows that research on congenital hypogonadotropic hypogonadism is mostly focused on genetic mechanisms, particularly genetic mutations. In addition, there is a lack of long-term results to assess the effect of hormone therapy for this type of disease on adult fertility, and more high-quality studies are required in this respect [57]. ...
Background
Cryptorchidism is defined as failure of unilateral or bilateral testicular descent, which increases the risk of infertility and testicular carcinoma. Although there is much research on cryptorchidism, few studies have used the bibliometric analysis method. The purpose of this study was to conduct a comprehensive analysis of cryptorchidism from muti-dimensional perspectives to summarize the research hotspots and trends in cryptorchidism research.
Methods
Relevant studies on cryptorchidism were retrieved from the Web of Science Core Collection (WoSCC) database from 2000 to 2022. A comprehensive bibliometric analysis of cryptorchidism was performed by using the CiteSpace, Tableau Public, and VOSviewer software, including the annual distributions of publications, countries, authors, institutions, journals, references, and keywords.
Results
From January 1st, 2000 to May 17th, 2022, a total of 5023 papers concerning cryptorchidism were identified for analysis. The USA contributed the most publications (n = 1193) in this field, and the annual number of publications rose rapidly in China. The University of Melbourne published the largest number of papers (n = 131). “Hutson, John M.” was the most core author ranked by publications (n = 51), and “Skakkebaek, Niels E.” enjoyed the largest number of citations (4441). The JOURNAL OF UROLOGY published the largest number of papers (n = 225), while the average citations per publication of the 75 papers in HUMAN REPRODUCTION reached 62.38. Additionally, burstness analysis of references and keywords showed that cryptorchidism research was mainly focused on the exploration of the optimal mode of treatment for cryptorchidism, including hypogonadism such as Kallmann syndrome and Klinefelter syndrome.
Conclusion
Cryptorchidism has attracted continuous attention from the scientific community concerned. International collaboration in the field has witnessed significant growth in recent years and remains essential to further enhance collaborative efforts between scholars from different countries. In addition, the exploration of the optimal treatment modality for cryptorchidism, especially in the prevention of adult infertility, remains a major focus of future research. High-quality follow-up studies are also needed in the future. The pathogenesis (especially at the genetic level) and treatment of hypogonadism such as Kallmann syndrome and Klinefelter syndrome have attracted increasing attention recently, which may usher in some breakthroughs in coming years.
... The therapeutic approach for gonadotropic hormone deficiencies involves replacing the corresponding sex-steroid, rather than the gonadotropins (testosterone injection, dihydrotestosterone gel application or recombinant human gonadotropin subcutaneous infusion) [4,6,7,60,61]. ...
Congenital growth hormone deficiency (GHD) is a rare disease caused by disorders affecting the morphogenesis and function of the pituitary gland. It is sometimes found in isolation but is more frequently associated with multiple pituitary hormone deficiency. In some cases, GHD may have a genetic basis. The many clinical signs and symptoms include hypoglycaemia, neonatal cholestasis and micropenis. Diagnosis should be made by laboratory analyses of the growth hormone and other pituitary hormones, rather than by cranial imaging with magnetic resonance imaging. When diagnosis is confirmed, hormone replacement should be initiated. Early GH replacement therapy leads to more positive outcomes, including reduced hypoglycaemia, growth recovery, metabolic asset, and neurodevelopmental improvements.
... T is a primary male sex hormone that plays an important role in the body by regulating sex drive (libido), sperm production, bone mass, muscle mass, and strength (6,7). As men age, there is a slow and continuous decrease in T levels, leading to a condition called hypogonadism (gonadal failure and hypothalamic-pituitary axis failure) (8). The decline level of T is responsible for age-related impairment in spermatogenesis leading to infertility (9,10). ...
Background:
The male reproductive system undergoes several adverse age-related changes like decreased hormone synthesis, sperm count, and testicular alteration that can impact on fertility.
Objective:
The study aims to investigate the effects of testosterone propionate (TP), and ayurvedic formulation Swarna Bhasma (SB) on D-galactose (D-gal) induced reproductive aging in male Wistar rats.
Materials and methods:
60 male Wistar rats were divided into 10 groups of 6 animals. Reproductive aging was induced by D-gal (150 mg/kg Bwt) exposure for 60 days. The rats were then treated by post and combination treatment with TP (2 mg/kg Bwt) and SB (6.75 mg/kg Bwt). Then sperm parameters, reproductive hormones, inflammatory markers, testicular antioxidant enzymes, steroidogenic enzymes, and histological manifestation of testis were evaluated.
Results:
Exposure of D-gal caused significant (p < 0.001) decrease in serum testosterone (T), testicular steroidogenic, and antioxidant enzymes. Administration of TP increased the serum T level, testicular antioxidant enzymes, and spermatogenic profile at a significant level of (p < 0.001) compared to D-gal. Further, the SB treatment significantly (p < 0.001) elevated the serum T level, sperm count, testicular antioxidant enzymes, steroidogenic enzymes, when compared to D-gal.
Conclusion:
Both the treatment of TP and SB treatments recovered the reproductive impairments caused by D-gal. However, exogenous T supplementation via TP administration is associated with various side effects during long-term use. SB is an Ayurvedic formulation having a long history of usage in India. The current findings suggest that the SB may be used as a good alternative for potentiating reproductive function in aging males.
... Додаткові дослідження також показали більш низькі значення АМГ (та інгібіну В) згідно з нормативними даними у 2-річних дітей чоловічої статі з крипторхізмом, що свідчить про функціональний дефект клітин Сертолі в такому стані [60,61]. В об'єднаних даних досліджень [62,63] нормальний рівень АМГ був 100% прогностичним показником наявності яєчка, тоді як низьке значення було прогностичним у 86 % випадків, а невизначений АМГ був прогностичним для відсутності тестикулярної тканини (анорхії) у 94 % випадків. За результатами [64], у хопчиків із нульовими показниками гонадотропінів та тестостерону і низькою концентрацією АМГ та інгібіну B діагностовано гіпогонадотропний гіпогонадизм, підтверджений результатами молекулярно-генетичного дослідження. ...
Background. Anti-Mullerian hormone (AMH) has now gained popularity as a marker of ovarian reserve. It is important to determine the place and role of AMH in children. The purpose of this work was to analyze the data of the scientific literature on the role of AMH in pediatric practice. Materials and methods. A review of the literature in PubMed was conducted, limiting itself to articles in English and updating the search in February 2022. The search term was “anti-Mullerian hormone”. A total of 437 manuscripts were found, including 37 review articles. The search was gradually narrowed with filters of clinical trials and systematic reviews to 75 articles. The references of the original and review articles were then checked to ensure a complete review. AMH is responsible for the differentiation of the gonads, provokes the regression of Mullerian ducts in the male fetus, correlates with karyotype, sexual development, levels of luteinizing hormone, follicle-stimulating hormone, and its serum levels reflect the ovarian reserve in women, even in childhood. Serum AMH is high from prenatal life to puberty. In postnatal period, the secretion of AMH by the testes is stimulated by follicle-stimulating hormone and strongly inhibited by androgens. AMH is of clinical value as a marker of testicular tissue in men with differences in sexual development and cryptorchidism, as well as in the assessment of persistent Mullerian duct syndrome. Determination of AMH is useful for assessing the function of the gonads without the need for stimulation tests and guides the etiological diagnosis of childhood male hypogonadism. In women, AMH is used as a prognostic marker of ovarian reserve and fertility. The use of criteria developed for adult women is problematic for adolescent girls, as clinical signs associated with polycystic ovary syndrome are normal phenomena of puberty. AMH can be used as an additional criterion in the diagnosis of polycystic ovary syndrome in adolescents. However, the lack of an international standard for AMH limits comparisons between AMH analyzes. Conclusions. AMH has broad clinical diagnostic utility in pediatrics, but interpretation is often complex and should be made in the context of not only the age and sex, but also the stage of development and puberty of the child. Recognition of the role of AMH beyond the development and maturation of the gonads may lead to new diagnostic and therapeutic applications that will further expand its use in pediatric practice.
... If testicular enlargement is observed -indicating spontaneous pubertal onset, especially during initial treatment with low doses of testosterone-, treatment is usually discontinued, and testicular volume progresses as a consequence of gonadotroph activation of LH and FSH secretion. This scheme is associated with increased growth, increased bone mineral density, development of secondary sexual characteristics and overall improved psychological well-being [38,39,42,44,51,52]. Replacement therapy is expected to mimic the normal pubertal tempo, with a progression of approximately one Tanner stage per year, so that a precocious early closure of the epiphyses is avoided. ...
... Despite the astonishing lack of published evidence, testosterone enanthate is largely the most frequently formulation to induce pubertal changes in boys, with an initial dose of ~50 mg every 4 weeks and an increase of 50 mg every 6-12 months to attain a full adult dose of 250 mg every 4 weeks after 2-3 years of treatment initiation (Table 2) [2,32,42,44,52,74,82,83]. Monitoring of the effectiveness of androgen therapy relies on the clinical assessment of the progression of genital maturation, height velocity and changes in body composition every 3-6 months. ...
... Several preparations containing FSH, LH and/or hCG exist, either obtained from urine or as recombinant products [52,89]. Formulations used in pediatric patients with hypogonadism are briefly reviewed here. ...
Introduction:
Delayed puberty, defined as the appearance of pubertal signs after the age of 14 years in males, usually affects psychosocial well-being. Patients and their parents show concern about genital development and stature. The condition is transient in most of the patients; nonetheless, the opportunity should not be missed to diagnose an underlying illness.
Areas covered:
The aetiologies of pubertal delay in males and their specific pharmacological therapies are discussed in this review.
Expert opinion:
High-quality evidence addressing the best pharmacological therapy approach for each aetiology of delayed puberty in males is scarce, and most of the current practice is based on small case series or unpublished experience. Male teenagers seeking attention for pubertal delay most probably benefit from medical treatment to avoid psychosocial distress. While watchful waiting is appropriate in 12- to 14-year-old boys when constitutional delay of growth and puberty (CGDP) is suspected, hormone replacement should not be delayed beyond the age of 14 years in order to avoid impairing height potential and peak bone mass. When primary or central hypogonadism is diagnosed, hormone replacement should be proposed by the age of 12 years provided that a functional central hypogonadism has been ruled out. Testosterone replacement regimens have been used for decades and are fairly standardised. Aromatase inhibitors have arisen as an interesting alternative for boy with CDGP and short stature. Gonadotrophin therapy seems more physiological in patients with central hypogonadism, but its relative efficacy and most adequate timing still need to be established.
... Moreover, this pharmacologic agent has also been prescribed in boys who have been diagnosed with constitutional delays of puberty, particularly because this drug prevents the conversion of androgens to estrogens and, thus, elevates the available pool of androgens in the body. 7 Likewise, Punjani et al 8 reported on the estradiol-lowering effects of anastrozole therapy in men diagnosed with testosterone deficiency who were treated with testosterone. The investigators found that anastrozole reduced estradiol but did not influence testosterone concentrations in this study population. ...
Purpose
We aimed to investigate the impact of anastrozole administration on the traditional components of the lipid profile (ie, total cholesterol [TC], LDL-C, HDL-C, and triglycerides [TGs]) by means of a systematic review and meta-analysis of randomized controlled trials.
Methods
We searched the PubMed/Medline, Scopus, Embase, and Web of Science databases for relevant randomized controlled trials published in the English language until January 18, 2022. The weighted mean difference (WMD) and 95% CIs were calculated using a random-effects model (DerSimonian and Laird methods).
Findings
Anastrozole administration significantly lowered TC concentrations when the treatment duration was ≤3 months (WMD = −2.73 mg/dL; 95% CI, −5.09 to −0.38 mg/dL; P = 0.02) and when the baseline TC concentration was ≥200 mg/dL (WMD = −3.64 mg/dL; 95% CI, −6.30 to −0.98 mg/dL; P = 0.007). HDL-C levels decreased after anastrozole administration when the treatment duration was >3 months (WMD = −1.67 mg/dL; 95% CI, −3.24 to −0.10 mg/dL; P = 0.03). Anastrozole administration had no impact on TG or LDL-C values.
Implications
Anastrozole administration in humans can decrease TC and HDL-C levels but has no effect on LDL-C or TG concentrations.
... The level of testosterone secretion stimulation by hCG in X-AHC patients varies from case to case (5,9,(11)(12)(13)34). It is already known physiologically that testosterone induces maturation of Sertoli cells, which express the androgen receptor, manifested by a stop in their multiplication and a sharp decrease of their AMH secretion (35,36). Consequently, the decrease in AMH observed in our patients could suggest the presence of mature Sertoli cells which express the androgen receptor in X-AHC patients. ...
Background
NR0B1 pathogenic variants can cause congenital adrenal hypoplasia or primary adrenal insufficiency in early childhood usually associated with hypogonadotropic hypogonadism. NR0B1 is necessary for organogenesis of the adrenal cortex and to maintain normal spermatogenesis. In humans, restoration of fertility in patients carrying NR0B1 pathogenic variants is challenging.
Objective
The aim of the study was to investigate the clinical, hormonal, histological, spermiological, and molecular genetic characteristics of a cohort of patients with NR0B1 pathogenic variants, monitored for fertility preservation.
Patients
We included five patients, including four teenagers, with NR0B1 pathogenic or likely pathogenic variants. They all had primary adrenal insufficiency and were receiving replacement therapy with glucocorticoids and mineralocorticoids. Patients received recombinant follicle-stimulating hormone and recombinant human chorionic gonadotropin in order to induce spermatogenesis. Combined gonadotropin treatment was initiated between 13 years and 15 years and 6 months for the four teenagers and at 31 years and 2 months for the only adult. Physical and hormonal assessments were performed just before starting gonadotropin treatment. After 12 months of gonadotropin treatment, physical examination and hormonal assessments were repeated, and semen analyses were performed. If no sperm cells were observed in at least 2 semen collections at 3-month interval, testicular biopsy for testicular sperm extraction was proposed.
Results
Bilateral testicular volume increased from 8 ml (interquartile range, 6–9) to 12 ml (10–16) after gonadotropin treatment. Inhibin B levels were relatively stable: 110 ng/L (46–139) before and 91 ng/L (20–120) at the end of gonadotropin treatment. Azoospermia was observed in all semen analyses for all cases during gonadotropin treatment. Three patients agreed to testicular biopsy; no mature sperm cells could be retrieved in any.
Conclusion
We characterized a cohort of patients with NR0B1 pathogenic or likely pathogenic variants for fertility preservation by recombinant gonadotropin treatment, which began either at puberty or in adulthood. No sperm cells could be retrieved in semen samples or testicular biopsy even after gonadotropin treatment, indicating that gonadotropin treatment, even when started at puberty, is ineffective for restoring fertility.
Microphallus/Micropenis is a rare condition with significant physical and psychological implications for affected individuals. This article comprehensively reviews micropenis, its etiology, epidemiology, and various treatment options. We conducted a thorough literature review to collect relevant information on micropenis and microphallus, as well as related disorders. Our primary databases were PubMed, Medline, and Google Scholar. We searched for articles published in English between 2000 and 2023. Our analysis included 67 review articles, 56 research studies, 11 case reports, one guideline, and one editorial. Our search terms included "microphallus", "micropenis", "congenital hypogonadotropic hypogonadism", "androgen insensitivity syndrome", "pediatric management of micropenis", "testosterone therapy", and "psychosocial implications of micropenis". We focused on diagnosing micropenis and related conditions, including hormonal assessments, medical and surgical treatment options, psychosocial and psychological well-being, sexual development of adolescents, and sociocultural influences on men's perceptions of penile size. Additionally, we explored parenting and family dynamics in cases of micropenis and disorders of sex development, implications of hormonal treatment in neonates, and studies related to penile augmentation procedures and their effectiveness. The article highlights the importance of early diagnosis and intervention in addressing the physical and psychological well-being of individuals with micropenis. Surgical procedures, such as penile lengthening and girth enhancement, and non-surgical approaches like hormonal therapy are explored. The significance of psychological support, education, and lifestyle modifications is emphasized. Early management and comprehensive care are crucial for individuals with micropenis, from infancy to adolescence and beyond. A multidisciplinary approach involving urologists, endocrinologists, and mental health professionals is recommended. Regular assessment of treatment effectiveness and the need for updated guidelines are essential to provide the best possible care. Healthcare professionals should prioritize early diagnosis, and neonatologists should measure stretched penile length in neonates. A collaborative effort is needed among professionals, parents, and affected individuals to create a supportive environment that recognizes worth beyond physical differences. Continuous research and evidence-based updates are crucial for improving care standards.
