Dihydrotestosterone Gel Research Articles

A Novel KISS1R Loss-of-function Variant in a Chinese Child with Congenital Hypogonadotropic Hypogonadism

Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disorder, resulting from impaired production, secretion, or action of gonadotropin-releasing hormone (GnRH). Variants of the KISS1R gene can result in CHH. Herein we describe a Chinese boy with CHH, caused by a novel, compound heterozygous variant in KISS1R. A male infant presented to the pediatric urological surgeon at three months of age for micropenis. Laboratory investigations done at this time revealed low levels of serum gonadotropins and testosterone, suggesting a lack of minipuberty. Topical application of dihydrotestosterone gel was recommended, but the parents refused treatment. The child was brought to our hospital at 3.3 years of age for the same complaint. A diagnosis of CHH was considered, and next generation sequencing revealed a compound heterozygous variant including a novel c.182C>A (p.S61*) and a c.418C>T (p.R140C) in KISS1R. We describe a novel compound heterozygous variant in the KISS1R in a boy with CHH, born to non-consanguineous Chinese parents. This report adds to the spectrum of variants in KISS1R seen in children with CHH.

Long-term stability study and evaluation of intact steroid conjugate ratios after the administration of endogenous steroids.

The most frequently detected substances prohibited by the World Anti-Doping Agency (WADA) belong to the anabolic steroids class. The most challenging compounds among this class are the endogenous anabolic steroids, which are detected by quantitative measurement of testosterone (T) and its metabolites with a so-called "steroid profiling" method. The current steroid profile is based on the concentrations and ratios of the sum of free and glucuronidated steroids. Recently, our group developed a steroid profiling method for the detection of three free steroids and 14 intact steroid conjugates, including both the glucuronic acid conjugated and sulfated fraction. The study aimed at evaluating the long-term stability of steroid conjugate concentrations and ratios, and the influence of different endogenous steroids on this extended steroid profile. A single dose of oral T undecanoate (TU), topical T gel, topical dihydrotestosterone (DHT) gel, and oral dehydroepiandrosterone (DHEA) was administered to six healthy male volunteers. One additional volunteer with a homozygote deletion of the UGT2B17 gene (del/del genotype) received a single topical dose of T gel. An intramuscular dose of TU was administered to another volunteer. To avoid fluctuation of steroid concentrations caused by variations in urinary flow rates, steroid ratios were calculated and evaluated as possible biomarkers for the detection of endogenous steroid abuse with low doses. Overall, sulfates do not have substantial additional value in prolonging detection times for the investigated endogenous steroids and administration doses. The already monitored glucuronides were overall the best markers and were sufficient to detect the administered steroids.

Iris Sommer—unravelling biological mechanisms of psychiatric disorders

When Iris Sommer retires, she wants to leave behind a new treatment for psychiatric illness that really makes a difference. “I realise this is easier said than done,” she tells The Lancet Psychiatry. “In neurology, we understand underlying mechanisms so much better than before. But in psychiatry, we are still trying to understand even the basic mechanisms behind many conditions.” Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutationWe report a 46, XY infant with an M807T mutation in his androgen receptor that abrogated cellular responses to testosterone, but not to dihydrotestosterone (DHT), resulting in ambiguous genitalia. Treatment with a topical DHT gel restored male genital development allowing the infant to be reared in accordance with his chromosomal sex. Full-Text PDF Amisulpride and olanzapine followed by open-label treatment with clozapine in first-episode schizophrenia and schizophreniform disorder (OPTiMiSE): a three-phase switching studyFor most patients in the early stages of schizophrenia, symptomatic remission can be achieved using a simple treatment algorithm comprising the sequential administration of amisulpride and clozapine. Since switching to olanzapine did not improve outcome, clozapine should be used after patients fail a single antipsychotic trial—not until two antipsychotics have been tried, as is the current recommendation. Full-Text PDF Prosopometamorphopsia and facial hallucinationsIn July, 2011, a 52-year-old woman presented to our psychiatric outpatient clinic in The Hague with a life-long history of seeing people's faces change into dragon-like faces and hallucinating similar faces many times a day. She could perceive and recognise actual faces, but after several minutes they turned black, grew long, pointy ears and a protruding snout, and displayed a reptiloid skin and huge eyes in bright yellow, green, blue, or red. She saw similar dragon-like faces drifting towards her many times a day from the walls, electrical sockets, or the computer screen, in both the presence and absence of face-like patterns, and at night she saw many dragon-like faces in the dark. Full-Text PDF

Correlation of androgen receptor and SRD5A2 gene mutations with pediatric hypospadias in 46, XY DSD children.

We performed an exploratory study by analyzing the correlation of 46, XY disorders of sex development (46, XY DSD) with androgen receptor (AR) and steroid 5α-reductase-2 (SRD5A2) gene mutations and a safety analysis of dihydrotestosterone (DHT) gel treatment for pediatric micropenis. We collected samples from 76 pediatric patients with 46, XY DSD and 50 healthy adult men with normal fertility as the control group. The pediatric patients were treated with DHT gel (0.1-0.3 mg/kg/day) for three to six months. The extended penis length, testicular volume, and multiple blood parameters were collected before treatment and one, three, and six months after treatment. Of the 76 cases with 46, XY DSD, 31.58% had hypospadias with micropenis and 6.58% had male pseudohermaphroditism. Through AR gene screening, it was found that 14 patients had AR point mutations and 22 patients had SRD5A2 mutations. After treatment with DHT, the penis length of the patients significantly improved after one, three, and six months of treatment, with longer treatment times resulting in greater improvement. Before treatment with DHT, the average serum DHT value of patients with 46, XY DSD was 24.29 pg/mL. After one, three, and six months of treatment, this value increased to 430.71, 328.9, and 323.6 pg/mL, respectively. We conclude that for pediatric patients who have male hermaphroditism or hypospadias with micropenis, AR and SRD5A2 gene mutation detection should be performed. Local application of DHT gel can promote penis growth effectively without systemic adverse reactions.

Male sexual function can be maintained without aromatization: randomized placebo-controlled trial of dihydrotestosterone (DHT) in healthy, older men for 24 months.

Male sexual function is highly androgen dependent but whether aromatization of testosterone (T) to estradiol is required remains contentious. This study aims to investigate the effects of selective estrogen deficiency induced by a nonaromatizable androgen, dihydrotestosterone (DHT), on sexual function of healthy middle-aged and older men. Randomized clinical trial of daily transdermal DHT (70 mg) or placebo gel treatment in 114 healthy middle-aged and older (>50 years, mean 60.5 years) men without known prostate disease maintaining selective estrogen deficiency for 24 months. The end points were responses to a psychosexual and mood questionnaire completed before, at 3 months, then at 6 monthly intervals during and 3 months after study. Data were analyzed by mixed model analysis of variance for repeated measures using age and body mass index (BMI) as covariates and including interactions of treatment with age and time-on-study. DHT treatment increased serum DHT with complete suppression of serum T, luteinizing hormone, follicle stimulating hormone, and estradiol throughout the 24-month study resulting in reduced spinal bone density. There were no spontaneous complaints, or discontinuations for, adverse effects on sexual function during the study. DHT administration had no effects on any of 33 measures of sexual function and mood, apart from a mild, but significant decrease in overall sexual desire, which was reversible after cessation of treatment. Increasing age and less often increasing BMI were associated with significant decreases in most aspects of sexual function. We conclude that aromatization plays only a minimal role in maintenance of sexual function in healthy eugonadal middle-aged or older men, but age and obesity are significantly associated with decreases in most aspects of self-reported sexual function and satisfaction. The dependence of male sexual function on aromatization may be conditional on age and obesity and can be overcome by a nonaromatizable androgen.

5 α-Reductase Type 2 Deficiency — Response to Dihydrotestosterone Gel: Authors’ Reply

To the Editor: We read with great interest the letter by Ammini et al. on our article “5 α-reductase type 2 deficiency—Response to dihydrotestosterone gel” [1]. While Ammini et al. observed increased penile length in response to dihydrotestosterone gel in a 13-y-old child who was clearly in pubertal development, we observed almost similar magnitude of response in our patient at the age of one year. We opine that if treatment is initiated at a young age, it may help in lessening parental anxiety. There is a preferance towards male genitoplasty in these patients as reported by Ammini et al. in their cohort [2]. Similar gender reversal at puberty has been described in 56–63 % of patients with 5-α reductase deficiency from Dominican Republic, New Guinea, south Lebanon and Turkey who had been raised as females [3]. Early detection and management will make adjustment to gender reversal smoother with less psychological stress to the patient. While hCG treatment is successful in some of the patients with isolated cryptorchidism, surgical correction may be required for co-existing chordee after suitable increase in penile length with dihydrotestosterone gel.

5 α-Reductase Type 2 Deficiency — Response to Dihydrotestosterone Gel: Correspondence

To The Editor: In the article by Madhavarao et al., recently published in Indian Journal of Pediatrics, the authors have described response to Dihydrotestosterone (DHT) gel in a case with 5 α-reductase 2 deficiency (5αRD). The child was put on three monthly intramuscular testosterone injections (25 mg), which increased the stretched penile length (SPL) to 2.1 cm from initial SPL of 1.3 cm and both the testes descended to labioscrotal folds with increase in rugosity. The authors also reported that the application of DHT gel increased SPL to 3 cm within 1 mo and later to 3.4 cm after 5 mo [1]. We also observed increase in SPL after application of DHT cream in one of our patients with 5αRD. Our patient, born of a consanguineous marriage, was reared as female until 13 y when diagnosis of 46, XY DSD was made. He had small phallus (SPL 2.5 cm) with chordee, bifid scrotum and penoscrotal hypospadias. USG revealed left testis was in labioscrotal fold and right testis in inguinal canal. His basal hormonal levels were LH 5.96 mIU/mL, FSH 15.83 mIU/mL, Testosterone (T) 4.35 ng/mL, DHT 210 pg/mL, T/DHT 20.7, Androstenedione (A) 0.92 ng/mL, T/A 4.7. DHT and Awere estimated by radio immuno assay (RIA) after Celitechromatography. He was advised to apply DHT cream over the phallus. On next follow up at 7 mo, the SPL had increased to 5 cm. Psychological evaluation revealed male gender identity. Most of our peri-pubertal children with 5αRD had opted for male genitoplasty [2]. Molecular genetic studies revealed homozygous missense mutation of R246Q on exon 5 of SRD5A2 gene. This mutation has been reported by some centers from India [3, 4]. To correct cryptorchidism, alternative treatment with hCG is recommended [5].

5 α-Reductase Type 2 Deficiency: Response to Dihydrotestosterone Gel

5α-reductase (5α-R) deficiency is an important cause of ambiguious genitalia in genetic males; however therapeutic experience in literature is limited. In this report authors describe a child with 46 XY Disorder of Sexual Differentiation (DSD), due to 5α-reductase deficiency, who was managed with Dihydrotestosterone (DHT) gel.

Detection of dihydrotestosterone gel, oral dehydroepiandrosterone, and testosterone gel misuse through the quantification of testosterone metabolites released after alkaline treatment

The natural occurrence of endogenous anabolic steroids together with their availability in different administration forms makes the detection of their misuse a great challenge for doping control laboratories. Nowadays, the detection of endogenous steroids abuse is performed by the analysis of the steroid profile. Recently, androst-1,4-dien-3,17-dione (1,4-AD), androst-4,6-dien-3,17-dione (4,6-AD), 17β-hydroxy-androst-4,6-dien-3-one (6-T), and androst-15-en-3,17-dione (15-AD) have been described as testosterone (T) metabolites released after basic treatment of the urine. In the present work, the usefulness of these metabolites has been evaluated detecting the use of three different forms of endogenous steroids in a single dose: dihydrotestosterone gel (DHT), oral dehydroepiandrosterone (DHEA), and T gel. After the independent administration of these endogenous steroids, a rise in the value of several of the ratios calculated between the tested metabolites was noticed. For DHT, a small increase was observed for the ratios 1,4-AD/15-AD, 6-T/15-AD and 4,6-AD/15-AD although only for one volunteer. Better results were obtained for oral DHEA and T gel where an increase was observed in all volunteers for several of the tested ratios. The detection time in which the misuse can be detected (DT) has been evaluated using two different approaches: (1) comparison with population based reference limits, and (2) comparison with individual threshold levels. The obtained DTs were compared with the results of previously published markers for the misuse of such substances. When using basic released metabolites, shorter DTs were obtained for DHT, similar DTs for DHEA, and the detectability was substantially improved for T gel.

A role for dihydrotestosterone treatment in older men?

A role for dihydrotestosterone treatment in older men?

Dihydrotestosterone Administration Does Not Increase Intraprostatic Androgen Concentrations or Alter Prostate Androgen Action in Healthy Men: A Randomized-Controlled Trial

Concern exists that androgen treatment might adversely impact prostate health in older men. Dihydrotestosterone (DHT), derived from local conversion of testosterone to DHT by 5α-reductase enzymes, is the principal androgen within the prostate. Exogenous androgens raise serum DHT concentrations, but their effects on the prostate are not clear. To determine the impact of large increases in serum DHT concentrations on intraprostatic androgen concentrations and androgen action within the prostate. Double-blind, randomized, placebo-controlled. Single academic medical center. 31 healthy men ages 35-55. Daily transdermal DHT or placebo gel. Serum and prostate tissue androgen concentrations and prostate epithelial cell gene expression after 4 wk of treatment. Twenty-seven men completed all study procedures. Serum DHT levels increased nearly sevenfold, while testosterone levels decreased in men treated with daily transdermal DHT gel but were unchanged in the placebo-treated group (P < 0.01 between groups). In contrast, intraprostatic DHT and testosterone concentrations on d 28 were not different between groups (DHT: placebo = 2.8 ± 0.2 vs. DHT gel = 3.1 ± 0.5 ng/g; T: placebo = 0.6 ± 0.2 vs. DHT gel = 0.4 ± 0.1, mean ± se). Similarly, prostate volume, prostate-specific antigen, epithelial cell proliferation, and androgen-regulated gene expression were not different between groups. Robust supraphysiologic increases in serum DHT, associated with decreased serum T, do not significantly alter intraprostatic levels of DHT, testosterone, or prostate epithelial cell androgen-regulated gene expression in healthy men. Changes in circulating androgen concentrations are not necessarily mimicked within the prostate microenvironment, a finding with implications for understanding the impact of androgen therapies in men.

Daily Application of Dihydrotestosterone Gel Does Not Prevent Age-Related Growth of the Prostate Gland

Daily Application of Dihydrotestosterone Gel Does Not Prevent Age-Related Growth of the Prostate Gland

Population based evaluation of a multi-parametric steroid profiling on administered endogenous steroids in single low dose

Steroid profiling provides valuable information to detect doping with endogenous steroids. Apart from the traditionally monitored steroids, minor metabolites can play an important role to increase the specificity and efficiency of current detection methods. The applicability of several minor steroid metabolites was tested on administration studies with low doses of oral testosterone (T), T gel, dihydrotestosterone (DHT) gel and oral dehydroepiandrosterone (DHEA). The collected data for all monitored parameters were evaluated with the respective population based reference ranges. Besides the traditional markers T/E, T and DHT, minor metabolites 4-OH-Adion and 6α-OH-Adion were found as most sensitive metabolites to detect oral T administration. The most sensitive metabolites for the detection of DHEA were identified as 16α-OH-DHEA and 7β-OH-DHEA but longest detection up to three days (after oral administration of 50 mg) was obtained with non-specific 5β-steroids and its ratios. Steroids applied as a gel had longer effects on the metabolism but were generally not detectable with universal decision criteria. It can be concluded that population based reference ranges show limited overall performance in detecting misuse of small doses of natural androgens. Although some minor metabolites provide additional information for the oral testosterone and DHEA formulations, the topical administered steroids could not be detected for all volunteers using universal reference limits. Application of other population based threshold limits did not lead to longer detection times.

Effect of aromatizable and unaromatizable androgen replacement in hypogonadal men on GH responsiveness

Although studies have clearly demonstrated that oestrogen replacement affects GH responsiveness by causing relative GH resistance, the effect of androgen replacement is unknown. Circumstantial evidence only suggests that androgen replacement may increase GH sensitivity and/or responsiveness. To examine the impact of androgens on GH responsiveness, hypogonadal men underwent the IGF-1 generation test in the unreplaced state, replaced with testosterone (T) and also replaced with dihydrotestosterone (DHT), its nonaromatizable metabolite. Twelve hypogonadal men with a normal GH axis were recruited. Each subject in random order had 4 weeks off T (NoRx), 4 weeks on T gel (TG) and 4 weeks on DHT gel (DHTG) applied daily, with 1 week washout between each preparation. An IGF-1 generation test using a subcutaneous injection of 7 mg of GH was performed at the end of each of these 4-week phases. Serum GHBP, total and free IGF-1, IGFBP-3 and acid-labile subunit (ALS) levels were measured at baseline and 24 h (peak) after GH administration. Despite a decrease in GHBP during the TG and DHTG phases, there were no observed differences in baseline, peak or increment (peak - baseline) total or free IGF-1 between the NoRx, TG or DHTG phases. There is no evidence of fluctuation in GH responsiveness in hypogonadal men, untreated or replaced with T or DHT alone. This implies that the increased level of oestradiol as a consequence of T replacement in hypogonadal men does not impact significantly on GH responsiveness, nor is there evidence of an androgen effect with elevated DHT levels as a consequence of either T or DHT replacement.

Does administration of transdermal dihydrotestosterone gel before hypospadias repair improve postoperative outcomes?

In an effort to improve the outcome of hypospadias repair, Kaya et al. performed a prospective, randomized study of transdermal dihydrotestosterone (DHT) gel as a preoperative adjunct to surgery. They found that patients who received DHT gel had fewer complications and better cosmesis than patients who underwent surgery alone. The authors attribute the differences between the two groups to an increased blood flow produced by the gel. The series of patients was small, and a larger sample size might have produced different results. Some of the outcomes measured were subjective, and the methods used to assess these outcomes were not clear. If a larger study confirms the results obtained by Kaya and colleagues, transdermal DHT gel might prove to be a valuable adjunct to hypospadias surgery.

Combination of subcutaneous levonorgestrel implants and transdermal dihydrotestosterone gel for male hormonal contraception

The primary aim of the present study was to determine the therapeutic dose of subcutaneous levonorgestrel (LNG) to induce azoospermia or severe oligozoospermia (&lt;3 × 106/mL) in normal men requiring contraception. Transdermal 5α‐dihydrotestosterone (DHT) was combined to the treatments to maintain peripheral androgen level. Forty‐three 21–45‐year‐old healthy men were enrolled in this phase II randomised and comparative clinical performance study. The subjects were allocated to five groups to receive: (1) transdermal DHT (AndractimR, Besins Iscovesco, Paris, France) and one subdermal LNG implant (Jadelle, Leiras, Turku, Finland); (2) transdermal DHT and two subdermal LNG implants; (3) transdermal DHT and four subdermal LNG implants; (4) transdermal DHT and oral LNG (Microluton, Schering, Germany); or (5) transdermal DHT only. A total of 27 men completed the suppression phase. None of them reached azoospermia. One subject with oral LNG and transdermal DHT reached &lt;3 million/mL at 5 months of suppression, but not repeatedly. Together 2/27 (7%) subjects, one with oral LNG and DHT and the other with four subdermal LNG implants and DHT reached &lt;5 million/mL temporarily. Altogether 9/27 (33%) subjects reached &lt;20 million/mL. Serum testosterone concentrations (S‐T) decreased significantly during the first 3 months of treatment with one, two and four LNG implants and DHT and during the next 3 months S‐T remained significantly lower with two or four implants. Serum oestradiol concentrations (S‐E2) decreased significantly during the first 3 months only with four implants, but at 6 months S‐E2 was lower also in the group with two implants. Serum luteinizing hormone (LH) decreased significantly only with two LNG implants and DHT gel at 5 and 6 months. Serum FSH did not decrease in any of the groups. None of the subjects filled the criteria to continue to the efficacy phase. A total of 16 men discontinued for various reasons. Of the 27 men completing the suppression phase, all have recovered to sperm levels &gt;20 million/mL. There were no changes in blood count, lipid profile, liver function tests, prostate‐specific antigen (PSA), sex hormone binding globulin (SHBG), prolactin or cortisol. The mixed antiglobulin reaction (MAR)‐IgG, MAR‐IgA or tray agglutination test (TAT) did not change during any of the treatments. The present study shows that the LNG implants themselves are well‐tolerated by men and safe, and might be suitable for replacing part of the testosterone used as injections to reduce the androgen dose during male hormonal contraception. The DHT gel was considered as quite or very uncomfortable by 66% of the men because of feeling cold during the time it was on the skin, but uncompliance in using the gel was not reported by the men.

A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Transdermal Dihydrotestosterone Gel on Muscular Strength, Mobility, and Quality of Life in Older Men with Partial Androgen Deficiency

A Double-Blind, Placebo-Controlled, Randomized Clinical Trial of Transdermal Dihydrotestosterone Gel on Muscular Strength, Mobility, and Quality of Life in Older Men with Partial Androgen Deficiency

Kinetics and Effect of Percutaneous Administration of Dihydrotestosterone in Children

Background: Percutaneous administration of dihydrotestosterone (DHT) has been successful in promoting phallic growth in infants and children with 5α-reductase deficiency raised as males. We investigated whether percutaneous administration of DHT is similarly effective in patients with micropenis due to alternative diagnoses. Methods: Six patients (age range 1.9–8.3 years) with micropenis of variable etiology were studied prospectively. 2.5% DHT gel was applied to the phallus once daily at a dose of 0.15–0.33 mg/kg body weight. Serum DHT concentrations were measured at 0, 2, 4, 8, 12 and 24 h following application of DHT gel. Results: Peak DHT concentrations were attained within 2–8 h after application of the gel and subsequently remained within the normal adult range in all but 1 patient, who had received the lowest dose of 0.15 mg/kg. An increase in phallic growth, ranging from 0.5–2.0 cm, was achieved after 3–4 months of treatment in all patients whose DHT concentrations were maintained within adult range. Conclusion: Percutaneous administration of DHT in a dose of 0.2–0.3 mg/kg once daily for a period of 3–4 months may be useful in the management of patients with testosterone biosynthetic defects, who have sufficient masculinization to warrant male sex assignment, or in patients with micropenis prior to reconstructive surgery.

Directed pharmacological therapy of ambiguous genitalia due to an androgen receptor gene mutation

We report a 46,XY infant with an M807T mutation in his androgen receptor that abrogated cellular responses to testosterone, but not to dihydrotestosterone (DHT), resulting in ambiguous genitalia. Treatment with a topical DHT gel restored male genital development allowing the infant to be reared in accordance with his chromosomal sex.

Life-long absence of sexual drive in a woman associated with 5-dihydrotestosterone deficiency

A case of a woman who presented with lqe-long absence of sexual drive is reported. Although her history contained psychological factors that might have been etiologic in her presentation, she had not responded to sex therapy or cognitive—behavior psychotherapy undertaken at other clinics. When seen by the author, she was found to have poorly developed external genitalia. The only abnormality discovered on endocrinological evaluation was a reduced level of 5 dihydrotestoster-one. Treatment with dihydrotestosterone gel applied to her vulva generated sexual drive and her ability to become sexually aroused.