Metformin reduces oxandrolone- induced depression-like behavior in rats via modulating the expression of IL-1ß, IL-6, IL-10 and TNF-α.

Oxandrolone (OXA) is an androgen and anabolic steroid (AAS) that is used to reverse weight loss associated with some medical conditions. One of the side effects of OXA is its potential to induce depressive symptoms. Growing evidence suggested that neuroinflammation and cytokines play crucial roles in sickness behavioral and associated mood disturbances. Previous studies showed that metformin attenuated neuroinflammation. This study investigated the potential protective role of metformin against OXA-induced depression-like behavior and neuroinflammation. Twenty- four Wistar male rats were randomly grouped into four groups: the control group (Control) received only vehicle; the oxandrolone group (OXA) received oxandrolone (0.28 mg/kg, i.p); the metformin group (MET) received metformin (100 mg/kg, i.p); and the oxandrolone / metformin group (OXA + MET) received both oxandrolone (0.28 mg/kg, i.p) and metformin (100 mg/kg, i.p). These treatments were administered for fourteen consecutive days. Behavioral tests to measure depression-like behavior were conducted before and after treatments. qRT-PCR was used to measure the relative expression of proinflammatory and anti-inflammatory cytokines in the hippocampus and hypothalamus. The results showed that oxandrolone induced depression-like behavior and dysregulated pro-/anti-inflammatory cytokines, while metformin attenuated these effects. These findings suggest that metformin is a potential treatment to reverse the depressive effects induced by oxandrolone that involve neuroinflammatory effects.

Oxandrolone treatment in juvenile rats induced anxiety-like behavior in young adult animals.

AIMS: Oxandrolone (OXA) is a synthetic steroid used for the treatment of clinical conditions associated with catabolic states in humans, including children. However, its behavioral effects are not well known. Our goal was to evaluate the anxiety-like behavior induced in young adult rats after the treatment of juvenile animals with OXA. METHODS: Four-week-old male rats were separated into three groups: Control (CON), therapeutic-like OXA dose (TD), and excessive OXA dose (ED), in which 2.5 and 37.5 mg/kg/day of OXA were administered via gavage for four weeks for TD and ED, respectively. Behavior was evaluated through the elevated plus maze (EPM) and open field (OF) tests. Protein expression of catalase (CAT), superoxide dismutase (SOD), Tumor necrosis factor-α (TNF-α), and dopamine receptor 2 (DrD2) were analyzed in tissue samples of the hippocampus, amygdala, and prefrontal cortex by Western Blot. RESULTS: OXA induced anxiety-like behaviors in both TD and ED animals; it decreased the time spent in the open arms of the EPM in both groups and reduced the time spent in the central zone of the OF in the TD group. In the hippocampus, CAT expression was higher in TD compared with both control and ED animals. No differences were found in the amygdala and prefrontal cortex. TNF-α, SOD, and DrD2 levels were not altered in any of the assessed areas. CONCLUSIONS: Treatment of juvenile rats with OXA led to anxiety-like behavior in young adult animals regardless of the dose used, with minor changes in the antioxidant machinery located in the hippocampus.

Potential risk for developing severe COVID-19 disease among anabolic steroid users.

A severe case of COVID-19 was observed in an otherwise healthy 28-year-old man who had taken oxandrolone 40 mg/day as an anabolic steroid. The patient had been taking oxandrolone for enhanced bodybuilding 30 days prior to presenting to an outpatient clinic with COVID-19 symptoms. The patient reported that his symptoms have rapidly worsened over the course of 4 days prior to presenting at the clinic. As part of an experimental antiandrogen treatment for hyperandrogenic men suffering from COVID-19, he was administered a single 600 mg dose of the novel antiandrogen proxalutamide. Twenty-four hours after administration of this dose, marked improvement of symptoms and markers of disease severity were observed. To our knowledge, this is the first case that potentially links anabolic steroid use to COVID-19 disease severity.

Effect of oxandrolone and timing of pubertal induction on final height in Turner syndrome: final analysis of the UK randomised placebo-controlled trial.

The UK Turner syndrome (TS) study examined the effect on final height of oxandrolone 0.05 mg/kg/day (maximum dose 2.5 mg) versus placebo from 9 years of age; and delaying ethinylestradiol induction of puberty by 2 years from 12 (E12) to 14 (E14) years in growth hormone-treated girls with TS. The study ran from 1999 to 2013. By 2011, eighty-two of 92 participants had reached final height and an interim analysis using the Super-Imposition by Translation And Rotation model showed significant increases in final height with both oxandrolone and E14. The analysis has been repeated now that all 92 patients have reached final height. Oxandrolone still significantly increased final height by 4.1 cm (95% CI 1.6 to 6.6, n=92) compared with 4.6 cm previously. However, the E14 effect was no longer significant at 2.7 cm (95% CI -0.8 to 6.1, n=56) compared with 3.8 cm previously.

[The medical aspect of using anabolic androgenic steroids in males attending gyms of Saint-Petersburg].

BACKGROUND: Anabolic androgenic steroids (AASs) are often used by individuals engaged in physical recreational activity. AASs inhibit the hypothalamus-pituitary-gonad axis and can cause erectile dysfunction and reduced fertility. There is no data on the use of AASs in this category of people in the Russian Federation; therefore, a study exploring the rate and patterns of using steroids for non-medical purposes is topical. Aim - of this study was to investigate the rate and patterns of using AASs in males attending gyms in Saint Petersburg. MATERIAL AND METHODS: We used individual anonymous postal survey of males attending gyms. We analyzed demographic and anthropometric data, information on the use of AASs, awareness of their side effects, used agents, patterns and duration of their use, and rehabilitation therapy. RESULTS: Out of 1,815 sent questionnaires, we received back 762 ones. The criteria were met by 550 questionnaires. The mean age was 29.3±7.4 years. The use of AASs was reported by 30.4% of respondents. The main AAS (74.3%) consumers were males aged 22 to 35 years. The most popular drug was Testosterone Propionate (51.5%); the drug was often combined with Oxandrolone (19.7%). In 70.6% of cases, drugs were administered by injection or injection combined with tablet intake. The injectable testosterone dose ranged from 500 to 2,000 mg/week and above. The most common dose was 1,000 mg/week (23.9%). AAS administration for more than 1 year was reported in 16.1% of males. Anastrozole (55%), hCG (51.3%), Clomiphene (41.3%), and Tamoxifen (30.5%) were used during the recovery period. The main source of information on AASs, doses, and dosage patterns was the Internet (48.7%). A negative attitude towards AASs was found in 17.3% of respondents. The desire to receive qualified information about AASs and their impact on health was reported by 54.8% of the surveyed respondents. CONCLUSION: Almost every fourth gym visitor has experience in using AASs. These are males of an optimal reproductive age. The common pattern of using AASs is an aggressive steroid course followed by a recovery period. The list of used drugs and their doses indicate a significant pharmacological intervention and a high risk to health.

Investigation into Possible Association of Oxandrolone and Heterotopic Ossification Following Burn Injury.

Oxandrolone, a testosterone analog, is used to counteract the catabolic effects of burn injury. Recent animal studies suggest a possible hormonal association with heterotopic ossification (HO) development postburn. This work examines oxandrolone administration and HO development by exploring historical clinical data bridging the introduction of oxandrolone into clinical practice. Additionally, we examine associations between oxandrolone administration and HO in a standardized mouse model of burn/trauma-related HO. Acutely burned adults admitted between 2000 and 2014, survived through discharge, and had a HO risk factor of 7 or higher were selected for analysis from a single burn center. Oxandrolone administration, clinical and demographic data, and elbow HO were recorded and were analyzed with logistic regression. Associations of oxandrolone with HO were examined in a mouse model. Mice were administered oxandrolone or vehicle control following burn/tenotomy to examine any potential effect of oxandrolone on HO and were analyzed by Student's t test. Subjects who received oxandrolone had a higher incidence of elbow HO than those that did not receive oxandrolone. However, when controlling for oxandrolone administration, oxandrolone duration, postburn day oxandrolone initiation, HO risk score category, age, sex, race, burn size, and year of injury, there was no significant difference between rates of elbow HO between the two populations. In agreement with the review, in the mouse model, while there was a trend toward the oxandrolone group developing a greater volume of HO, this did not reach statistical significance.

Topical Oxandrolone Reduces Ear Hypertrophic Scar Formation in Rabbits.

BACKGROUND: Wound healing is a complex process. Despite extensive studies, hypertrophic and keloid scars still occur, and can be functionally and cosmetically problematic. In an attempt to prevent hypertrophic scar formation, the effects of topical oxandrolone, using hyaluronic acid as a biomaterial, were studied on ear wounds in rabbits. METHODS: Deep second-degree burns were inflicted on each ear in 10 New Zealand rabbits. On the left ears, considered the control side, hyaluronic acid gel was applied, whereas on the right ears, the study side, a combination of oxandrolone and hyaluronic acid was applied. Dressings were changed every 2 days for 2 weeks. At week 10, biopsy specimens from the postburn scars were harvested for histologic and immunohistochemical examinations. RESULTS: Fourteen wounds were studied, half on the control side and half on the study side. Six hypertrophic scars were encountered on the control side and only one scar was encountered on the study side. In addition, an increased degree of inflammation, an increased amount of collagen and fibroblast cellularity, increased vascularization, and increased myofibroblast activity were observed on the control side. CONCLUSION: Topical administration of oxandrolone using hyaluronic acid as a biomaterial led to better healing and prevented hypertrophic scar formation.

Reduced Postburn Hypertrophic Scarring and Improved Physical Recovery With Yearlong Administration of Oxandrolone and Propranolol.

BACKGROUND: Massive burns induce a hypermetabolic response that leads to total body wasting and impaired physical and psychosocial recovery. The administration of propranolol or oxandrolone positively affects postburn metabolism and growth. The combined administration of oxandrolone and propranolol (OxProp) for 1 year restores growth in children with large burns. Here, we investigated whether the combined administration of OxProp for 1 year would reduce scarring and improve quality of life compared with control. STUDY DESIGN: Children with large burns (n = 480) were enrolled into this institutional review board-approved study; patients were randomized to control (n = 226) or administration of OxProp (n = 126) for 1 year postburn. Assessments were conducted at discharge and 6, 12, and 24 months postburn. Scar biopsies were obtained for histology. Physical scar assessments and patient reported outcome measures of physical and psychosocial function were obtained. RESULTS: Reductions in cellularity, vascular structures, inflammation, and abnormal collagen (P < 0.05) occurred in OxProp-treated scars. With OxProp, scar severity was attenuated and pliability increased (both P < 0.05). Analyses of patient-reported outcomes showed improved general and emotional health within the OxProp-treated group (P < 0.05). CONCLUSIONS: Here, we have shown improvements in objective and subjective measures of scarring and an increase in overall patient-reported physical function. The combined administration of OxProp for up to a year after burn injury should be considered for the reduction of postburn scarring and improvement of long-term psychosocial outcomes in children with massive burns.

Oxandrolone Treatment Results in an Increased Risk of Gonadarche in Prepubertal Boys With Klinefelter Syndrome.

Context: Klinefelter syndrome (KS) is a common genetic condition in which males have an extra X chromosome. KS is associated with testosterone deficiency, neurodevelopmental delays, and cardiometabolic disorders. There has been recent interest in prepubertal androgen treatment; however, the effects on puberty and gonadal function are unknown. Objective: To compare onset of puberty and testicular function in prepubertal boys treated with 2 years of oxandrolone (Ox) vs placebo (Pl). Design: Double-blind, randomized, controlled trial. Setting: Single tertiary care referral center. Participants: Eighty prepubertal boys with KS; mean age: 8.0 ± 2.2 years (range: 4 to 12). Interventions: Ox 0.05 mg/kg vs identical-appearing Pl capsule given for 2 years. Outcome Measures: Onset of gonadarche (testicular volume ≥4 mL) and onset of pubarche (Tanner 2 pubic hair); change in testicular hormone concentrations. Results: Ox-treated group had 20.5 times higher odds of reaching gonadarche (OR 95% CI: 6.5, 77.8) and 28.1 times higher odds of reaching pubarche (OR 95% CI: 8.8, 110.4) during the 2-year study period after adjusting for baseline age. Gonadarche and pubarche both occurred at a younger age in the Ox group (gonadarche: 9.8 ± 1.5 vs 12.1 ± 1.0 years, P < 0.001; pubarche: 10.2 ± 1.1 vs 11.6 ± 1.3 years, P = 0.02). Serum concentrations of testicular hormones and gonadotropins were not different between groups. Conclusions: Two years of Ox treatment in prepubertal boys with KS results in an increased risk of early gonadarche, on average 2 years earlier than in Pl-treated boys. Ox did not affect serum concentrations of testicular hormones.

Transdermal Oxandrolone: Ex Vivo Percutaneous Absorption Study.

BACKGROUND: Oxandrolone is a potent synthetic testosterone analogue that possesses strong anabolic property and weak androgenic activity. Apart of their clinical implicances, oral oxandrolone can potentially promote several adverse effects. It is known that the transdermal delivery of drugs may represent a means to avoid or minimize oral adverse effects Thus, the objective of this study was to evaluate the permeability of oxandrolone in human skin on a preliminary basis for possible future determination of the transdermal route as an alternative to oral treatments. METHODS: We used a percutaneous absorption assay in Franz diffusion cells coupled with freshly excised human skin. The drug release kinetics were determined to predict the efficiency of this alternative route for the drug. RESULTS: Nearly 236 µg (86.7%, in terms of applied dose) of the product was prevented to permeate due to the barrier function of the stratum corneum (SC); 21.6% reached the receptor medium (RM), and the remaining 4.3% were quantified within viable layers of the skin (in vivo, dermis is vascularized). The total amount of drug able to exert effect is the sum of the drug quantified within remained skin (RS) and RM: then, a total of 247.6 µg of oxandrolone (25.9% of the applied dose) would be able to permeate through a non damaged skin. The accuracy of the data is demonstrated by the calculated mass balance (average recovery = 112.6%). CONCLUSION: Transdermal oxandrolone could be a viable alternative for traditional oral form, once clinical studies are conducted to prove this hypothesis.

Reversal of Growth Arrest With the Combined Administration of Oxandrolone and Propranolol in Severely Burned Children.

BACKGROUND: The hypercatabolic response in severely burned pediatric patients is associated with increased production of catecholamines and corticosteroids, decreased formation of testosterone, and reduced strength alongside growth arrest for up to 2 years after injury. We have previously shown that, in the pediatric burned population, the administration of the testosterone analog oxandrolone improves lean body mass accretion and bone mineral content and that the administration of the ß1-, ß2-adrenoceptor antagonist propranolol decreases cardiac work and resting energy expenditure while increasing peripheral lean mass. Here, we determined whether the combined administration of oxandrolone and propranolol has added benefit. METHODS: In this prospective, randomized study of 612 burned children [52% ±â€Š1% of total body surface area burned, ages 0.5-14 years (boys); ages 0.5-12 years (girls)], we compared controls to the individual administration of these drugs, and the combined administration of oxandrolone and propranolol at the same doses, for 1 year after burn. Data were recorded at discharge, 6 months, and 1 and 2 years after injury. RESULTS: Combined use of oxandrolone and propranolol shortened the period of growth arrest by 84 days (P = 0.0125 vs control) and increased growth rate by 1.7 cm/yr (P = 0.0024 vs control). CONCLUSIONS: Combined administration of oxandrolone and propranolol attenuates burn-induced growth arrest in pediatric burn patients. The present study is registered at clinicaltrials.gov: NCT00675714 and NCT00239668.

Anabolic and anticatabolic agents in critical care.

PURPOSE OF REVIEW: A complex network of hormones and other effectors characterize the hypermetabolic response in critical illness; these mediators work together to induce numerous pathophysiologic alterations. Increased incidence of infection, multiorgan failure, long-term debilitation, delays in rehabilitation, and death result from an inability to meet the prohibitively elevated protein and energy requirements, which occur during illness and can persist for several years. Pharmacologic interventions have been successfully utilized to attenuate particular aspects of the hypermetabolic response; these modalities are a component of managing critically ill patients - including those patients with severe burns. Here, we review recent advances in pharmacologically attenuating the hypermetabolic and catabolic responses. RECENT FINDINGS: Propranolol, a nonspecific ß-adrenergic receptor antagonist, is one of the most widely used anticatabolic therapies. Oxandrolone, testosterone, and intensive insulin therapy represent anabolic pharmacological strategies. Promising therapies, such as metformin, glucagon-like peptide 1, peroxisome proliferator-activated receptor agonists, are currently being investigated. SUMMARY: Profound metabolic derangements occur in critically ill patients; this hypermetabolic response is a major contributor to adverse outcomes. Despite the pharmacological therapies currently available to counteract this devastating cascade, future studies are warranted to explore new multimodality agents that will counteract these effects while maintaining glycemic control and preventing unfavorable complications.

Long-Term Administration of Oxandrolone Improves Lung Function in Pediatric Burned Patients.

Pulmonary dysfunction is a significant contributor to morbidity and mortality in the pediatric burned population. We have previously reported that the administration of a synthetic testosterone derivative, oxandrolone, significantly reduced hypermetabolism, and significantly increased height percentile, bone mineral content, lean body mass, and strength in pediatric burned patients. We hypothesize that the administration of oxandrolone will improve pulmonary function in burned pediatric subjects. A subset of severely burned pediatric subjects from a prospective clinical trial (n = 222) were included in our study (n = 54, 7-18 years, ≥30% TBSA burn). The subjects were previously randomized to either the control arm (n = 35) or the oxandrolone arm (0.1 mg/kg twice/day for 12 months, n = 19). Maximum voluntary ventilation, the ratio between forced expiratory volume and forced vital capacity, and diffusion capacity were measured 6 months following burn injury, and results were compared between burned subjects with and without oxandrolone administration. Maximum expired ventilation (VEmax) was also measured in a subset of burned subjects. Subjects treated with oxandrolone had a significantly higher maximum voluntary ventilation (98 ± 53 L/min vs 115 ± 56 with treatment, P = .03). During maximal exercise, subjects treated with oxandrolone had a significantly higher VEmax compared with untreated subjects (32.0 ± 8.7 L/min vs 43.7 ± 13.6 with treatment, P = .02). The administration of oxandrolone was associated with improved lung function in pediatric burned patients.

FIVE-YEAR OUTCOMES AFTER LONG-TERM OXANDROLONE ADMINISTRATION IN SEVERELY BURNED CHILDREN: A RANDOMIZED CLINICAL TRIAL.

Administration of oxandrolone, a nonaromatizable testosterone analog, to children for 12 months following severe burn injury has been shown to improve height, increase bone mineral content (BMC), reduce cardiac work, and augment muscle strength. Surprisingly, the increase in BMC persists well beyond the period of oxandrolone administration. This study was undertaken to determine if administration of oxandrolone for 2 years yields greater effects on long-term BMC and bone mineral density (BMD). Patients between 0 and 18 years of age with ≥30% of total body surface area burned were consented to an IRB-approved protocol and randomized to receive either placebo (n = 84) or 0.1 mg/kg oxandrolone orally twice daily for 24 months (n = 35). Patients were followed prospectively from the time of admission until 5 years postburn in a single-center, intent-to-treat setting. Height, weight, BMC, and BMD were recorded annually through 5 years postinjury. The long-term administration of oxandrolone for 16 ± 1 months postburn (range, 12.1-25.2 months) significantly increased whole-body (WB) BMC (p < 0.02) and lumbar spine (LS) BMC (p < 0.05); these effects were significantly pronounced for a longer time in patients who were in growth spurt years (7-18 years). When adjusted for height, sex, and age, LS BMD was found to significantly increase with long-term oxandrolone administration (p < 0.0009). Fewer patients receiving oxandrolone exhibited LS BMD z scores below -2.0 as compared with controls, indicating a significantly reduced risk for future fracture with oxandrolone administration. Long-term oxandrolone patients had significantly greater height velocity than controls throughout the first 2-year postburn (p < 0.05). No adverse side effects were attributed to the long-term administration of oxandrolone. A comparison of the current patients receiving long-term oxandrolone to previously described patients receiving 12 months of oxandrolone revealed that long-term oxandrolone administration imparted significantly greater increases in WB-BMC, WB-BMD, and LS-BMD (p < 0.05). In conclusion, the administration of oxandrolone for up to 24 months to severely burned pediatric patients significantly improves WB BMC, LS BMC, LS BMD, and height velocity. The administration of long-term oxandrolone was more efficacious than administration for 12 months. Additionally, fewer patients in the oxandrolone cohort met the diagnostic criteria for pediatric osteoporosis, pointing to a reduced risk for future bone fracture. This study demonstrates that administering oxandrolone for up to 2 years following severe burn injury results in greater improvements in BMC, BMD, and height velocity.

Oxandrolone Augmentation of Resistance Training in Older Women: A Randomized Trial.

INTRODUCTION: Sarcopenia is disproportionately present in older women with disability, and optimum treatment is not clear. We conducted a double-blind, randomized, placebo-controlled trial to determine whether oxandrolone administration in elderly women improves body composition or physical function beyond that which occurs in response to progressive resistance training (PRT). METHODS: Twenty-nine sedentary women (age 74.9 ± 6.8 yr; 5.9 ± 2.8 medications per day) were randomized to receive high-intensity PRT (three times a week for 12 wk) combined with either oxandrolone (10 mg·d(-1)) or an identical placebo. Peak strength was assessed for leg press, chest press, triceps, knee extension, and knee flexion. Power was assessed for leg press and chest press. Physical function measures included static and dynamic balance, chair rise, stair climb, gait speed, and 6-min walk test. Body composition was assessed using dual energy x-ray absorptiometry. RESULTS: Oxandrolone treatment augmented increases in lean tissue for the whole body (2.6 kg; 95% confidence interval (CI), 1.0-4.2 kg; P = 0.003), arms (0.3 kg; 95% CI, 0.1-0.5 kg; P = 0.001), legs (0.8 kg; 95% CI, 0.1-1.4 kg; P = 0.018), and trunk (1.4 kg; 95% CI, 0.4-2.3 kg; P = 0.004). Oxandrolone also augmented loss of fat tissue of the whole body (-1 kg; 95% CI, -1.6 to -0.4; P = 0.002), arms (-0.2 kg; 95% CI, -0.5 to -0.02 kg; P = 0.032), legs (-0.4 kg; 95% CI, -0.6 to -0.1; P = 0.009), and tended to reduce trunk fat (-0.4 kg; 95% CI, -0.9 to 0.04; P = 0.07). Improvements in muscle strength and power, chair stand, and dynamic balance were all significant over time (P < 0.05) but not different between groups (P > 0.05). CONCLUSIONS: Oxandrolone improves body composition adaptations to PRT in older women over 12 wk without augmenting muscle function or functional performance beyond that of PRT alone.

Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Karyotype-specific ear and hearing problems in young adults with Turner syndrome and the effect of oxandrolone treatment.

OBJECTIVE: To evaluate karyotype-specific ear and hearing problems in young-adult patients with Turner syndrome (TS) and assess the effects of previous treatment with oxandrolone (Ox). STUDY DESIGN: Double-blind follow-up study. SETTING: University hospital. PATIENTS: Sixty-five TS patients (mean age, 24.3 yr) previously treated with growth hormone combined with placebo, Ox 0.03 mg/kg per day, or Ox 0.06 mg/kg per day from the age of 8 years and estrogen from the age of 12 years. INTERVENTION: Ear examination was performed according to standard clinical practice. Air- and bone conduction thresholds were measured in decibel hearing level. MAIN OUTCOME MEASURES: We compared patients with total monosomy of the short arm of the X chromosome (Xp), monosomy 45,X and isochromosome 46,X,i(Xq), with patients with a partial monosomy Xp, mosaicism or other structural X chromosomal anomalies. We assessed the effect of previous Ox treatment. RESULTS: Sixty-six percent of the patients had a history of recurrent otitis media. We found hearing loss in 66% of the ears, including pure sensorineural hearing loss in 32%. Hearing thresholds in patients with a complete monosomy Xp were about 10 dB worse compared with those in patients with a partial monosomy Xp. Air- and bone conduction thresholds were not different between the placebo and Ox treatment groups. CONCLUSION: Young-adult TS individuals frequently have structural ear pathology, and many suffer from hearing loss. This indicates that careful follow-up to detect ear and hearing problems is necessary, especially for those with a monosomy 45,X or isochromosome 46,X,i(Xq). Ox does not seem to have an effect on hearing.

Effect of oxandrolone and timing of oral ethinylestradiol initiation on pubertal progression, height velocity and bone maturation in the UK Turner study.

BACKGROUND: A UK study showed final height in Turner syndrome (TS) girls receiving growth hormone is affected by age at pubertal induction and oxandrolone (Ox). Using data from that study, we analysed the effect of timing of oral ethinylestradiol (EE2) and Ox on height velocity (HV), bone maturation and pubertal progression, and compared growth response in EE2-treated versus spontaneous puberty. METHODS: Analysis of HV, bone age and pubertal stage in 92 TS girls (7-13 years) randomised to Ox (0.05 mg/kg/day; max: 2.5 mg/day) or placebo from 9 years, and EE2 (year 1: 2 µg/day; year 2: 4 µg/day; year 3: 6/8/10 µg/day×4 months) or placebo at 12 years with EE2 at 14 years. Girls enrolled at >12.25 years received EE2 at 14 years ('late group'). RESULTS: Fifty-six girls were randomised to EE2 at 12 years (n=28, 11 Ox) or 14 years (n=28, 13 Ox); there were 19 girls in the late group (9 Ox) and 17 girls with spontaneous puberty (10 Ox). Girls receiving EE2 at 12 versus 14 years had faster bone maturation, but neither group showed acceleration. Ox increased HV without altering bone maturation or pubertal progression. Girls with spontaneous puberty had greater pubertal growth (mean PHV 8.5 cm/year; p<0.001) and height gain (p<0.001) than EE2-treated girls despite similar mean enrolment height SD and dysmorphology scores. CONCLUSION: Pubertal induction with EE2 does not replicate the acceleration observed in unaffected girls or TS girls with spontaneous puberty.

Oxandrolone for the treatment of bone marrow failure in Fanconi anemia.

BACKGROUND: A majority of Fanconi anemia (FA) patients will experience bone marrow failure (BMF) and androgen therapy (most often oxymetholone) may be utilized as a treatment to improve BMF-related cytopenias. However, oxymetholone is associated with toxicities making identification of other agents of interest. In this study we aimed to evaluate the toxicity profile and hematologic response in patients with FA who are treated with low-dose oxandrolone, a synthetic non-fluorinated anabolic steroid, similar to oxymetholone, with known dosing thresholds for virilization. PROCEDURE: A single arm, Phase I/II study was designed to treat patients on low-dose oxandrolone. If no toxicity or hematologic response was noted at 16 weeks, a single dose escalation was offered. Subjects were regularly assessed for toxicity, including determinations of virilization, behavioral changes, and liver and kidney function. At 32 weeks, those who demonstrated hematologic response were allowed to continue study treatment, and those without improvement were deemed non-responsive. RESULTS: Nine subjects completed the study and were followed for a median of 99 weeks (46-136 weeks). Three (33.3%) subjects developed mild sub-clinical virilization and continued treatment with a dose reduction. None (0%) had adverse behavioral changes. Two (22.2%) developed elevated liver function tests at 42 and 105 weeks. Seven (77.8%) subjects had a hematologic response. CONCLUSION: Oxandrolone appears to be well-tolerated, has limited toxicities at the administered doses in FA with patients, and may be an alternative androgen for the treatment of BMF in FA.

Long-term effects of previous oxandrolone treatment in adult women with Turner syndrome.

OBJECTIVE: Short stature is a prominent feature of Turner syndrome (TS), which is partially overcome by GH treatment. We have previously reported the results of a trial on the effect of oxandrolone (Ox) in girls with TS. Ox in a dose of 0.03 mg/kg per day (Ox 0.03) significantly increased adult height gain, whereas Ox mg/kg per day (0.06) did not, at the cost of deceleration of breast development and mild virilization. The aim of this follow-up study in adult participants of the pediatric trial was to investigate the long-term effects of previous Ox treatment. DESIGN AND METHODS: During the previous randomized controlled trial, 133 girls were treated with GH combined with placebo (Pl), Ox 0.03, or Ox 0.06 from 8 years of age and estrogen from 12 years. Sixty-eight women (Pl, n=23; Ox 0.03, n=27; and Ox 0.06, n=18) participated in the double-blind follow-up study (mean age, 24.0 years; mean time since stopping GH, 8.7 years; and mean time of Ox/Pl use, 4.9 years). We assessed height, body proportions, breast size, virilization, and body composition. RESULTS: Height gain (final minus predicted adult height) was maintained at follow-up (Ox 0.03 10.2±4.9 cm, Ox 0.06 9.7±4.4 cm vs Pl 8.0±4.6 cm). Breast size, Tanner breast stage, and body composition were not different between groups. Ox-treated women reported more subjective virilization and had a lower voice frequency. CONCLUSION: Ox 0.03 mg/kg per day has a beneficial effect on adult height gain in TS patients. Despite previously reported deceleration of breast development during Ox 0.03 treatment, adult breast size is not affected. Mild virilization persists in only a small minority of patients. The long-term evaluation indicates that Ox 0.03 treatment is effective and safe.