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Anabolic steroid-induced hypogonadotropic hypogonadism
... This is supported by the fact that the 'washout' period after cessation of TRT is comparable with that for AAS and has been estimated to be 4 months. 42,43 There is a paucity of data for infertility induced by AAS-mediated HH. 44 A recent study by Shankara-Narayana and colleagues 45 describes male gonadal/reproductive function in current or previous users of AAS. In this cross-sectional observational study, a total of 72 men were analysed -41 current and 31 previous users of AAS. ...
... 7 cessation are less well established and can be longer than that for TRT, with some reports documenting recovery after AAS use taking as long as 20 months. 43 This may seem paradoxical as most men taking AAS are likely to be eugonadal whereas those on TRT, by virtue of the need for TRT, are more likely to have pre-existing testicular dysfunction, which would confer a poor environment for spermatogenesis. Nevertheless, the longer recovery times following AAS may be explained by consumption of larger quantities, with doses amounting to more than 10-40 times what would be regarded physiological. ...
Use of testosterone replacement therapy (TRT) and anabolic-androgenic steroids (AAS) has increased over the last 20 years, coinciding with an increase in men presenting with infertility and hypogonadism. Both agents have a detrimental effect on spermatogenesis and pose a clinical challenge in the setting of hypogonadism and infertility. Adding to this challenge is the paucity of data describing recovery of spermatogenesis on stopping such agents. The unwanted systemic side effects of these agents have driven the development of novel agents such as selective androgen receptor modulators (SARMs). Data showing natural recovery of spermatogenesis following cessation of TRT are limited to observational studies. Largely, these have shown spontaneous recovery of spermatogenesis after cessation. Contemporary literature suggests the time frame for this recovery is highly variable and dependent on several factors including baseline testicular function, duration of drug use and age at cessation. In some men, drug cessation alone may not achieve spontaneous recovery, necessitating hormonal stimulation with selective oestrogen receptor modulators (SERMs)/gonadotropin therapy or even the need for assisted reproductive techniques. However, there are limited prospective randomized data on the role of hormonal stimulation in this clinical setting. The use of hormonal stimulation with agents such as gonadotropins, SERMs, aromatase inhibitors and assisted reproductive techniques should form part of the counselling process in this cohort of hypogonadal infertile men. Moreover, counselling men regarding the detrimental effects of TRT/AAS on fertility is very important, as is the need for robust randomized studies assessing the long-term effects of novel agents such as SARMs and the true efficacy of gonadotropins in promoting recovery of spermatogenesis.
... Anabolic steroid drugs are molecule analogs synthetically produced to mimic the chemical structure and physiological effects of steroid hormones. Synthetic T or androgen analogs are often consumed by bodybuilders, sportsmen, or simple gym enthusiasts as a mechanism to improve physical performance, promote muscle hypertrophy and hyperplasia and reduce fat mass (El Osta et al., 2016;Jarow and Lipshultz, 1990). However, anabolic steroids also exert a negative feedback over the GnRH pulsatile secretion, thus inhibiting LH and FSH release and disrupting normal HPG axis (El Osta et al., 2016;Jarow and Lipshultz, 1990). ...
... Synthetic T or androgen analogs are often consumed by bodybuilders, sportsmen, or simple gym enthusiasts as a mechanism to improve physical performance, promote muscle hypertrophy and hyperplasia and reduce fat mass (El Osta et al., 2016;Jarow and Lipshultz, 1990). However, anabolic steroids also exert a negative feedback over the GnRH pulsatile secretion, thus inhibiting LH and FSH release and disrupting normal HPG axis (El Osta et al., 2016;Jarow and Lipshultz, 1990). (Rahnema et al., 2014) in a meta-analysis that comprised data from men who had taken and ceased taking anabolic steroids for non-pathological purposes, follow-up studies published between 1965 and 2013, concluded that even after anabolic steroid drugs withdrawal, total serum T levels were on pair with agonadal men. ...
Hypogonadism is more frequent among men with common metabolic diseases, notably obesity and type 2 diabetes. Indeed, endocrine disruption caused by metabolic diseases can trigger the onset of hypogonadism, although the underlying molecular mechanisms are not entirely understood. Metabolic diseases are closely related to unhealthy lifestyle choices, such as dietary habits and sedentarism. Therefore, hypogonadism is part of a pathological triad gathering unhealthy lifestyle, metabolic disease and genetic background. Additionally, hypogonadism harbors the potential to aggravate underlying metabolic disorders, further sustaining the mechanisms leading to disease. To what extent does lifestyle intervention in men suffering from these metabolic disorders can prevent, improve or reverse hypogonadism, is still controversial. Moreover, recent evidence suggests that the metabolic status of the father is related to the risk of inter and transgenerational inheritance of hypogonadism. In this review, we will address the proposed mechanisms of disease, as well as currently available interventions for hypogonadism.
... We recently showed that already a single dose of intra-muscular administration of testosterone or nandrolone suppresses the secretion of LH and FSH, but with large inter-individual variations [1,2]. After discontinuation of AAS use, LH and FSH may be suppressed for a long period of time, resulting in anabolic steroid induced hypogonadism (ASIH) [3]. The time of AAS induced hypogonadotropic hypogonadism is highly variable and is dependent on the duration, dose and type of steroids used, co-use of other drugs and age, but may also be influenced by genetic factors [4][5][6]. ...
... Supra-physiological doses of androgens are known to suppress LH and FSH with a fast response that may persist for a long time [3]. The resulting hypogonadism has been associated with the more distressing AAS induced side effects, such as depression and sexual dysfunction [33,34]. ...
Objective
The primary aim of this study was to investigate the association between the vitamin D receptor polymorphisms rs2228570 (Fok1) and rs731236 (TaqI) and LH and FSH levels in relation to anabolic androgenic steroid (AAS) use. ResultsTwo cohorts were analyzed. Cohort 1 comprised healthy volunteers given single supra-physiological doses of 500 mg testosterone (n = 25). Cohort 2 comprised 45 self-reporting AAS users. Healthy volunteers homozygous for the C-allele of the Fok1 polymorphism exhibited 30% higher LH levels than T-carriers at baseline (p = 0.04) and twice the levels 14 days after testosterone administration (p = 0.01). AAS users homozygous for the C-allele had four times higher LH levels than TT-individuals (p < 0.05). FSH levels were not associated with Fok1 polymorphism, nor were LH and FSH levels associated with the TaqI polymorphism. In conclusion, there is an association between LH levels and the Fok1 VDR polymorphism and this difference is even more pronounced in AAS users and subjects with suppressed LH levels.
... The availability and the degree of anomally common to DES sons and daughters differ greatly depending on 1. Timing of mother's first exposure 2. Total dosage at exposure and 3. Length of exposure (Faber et al;1990). ...
Endocrine disruptors are environmental compounds that affect the normal hormones synthesis, secretion, transport, binding, action or elimination. There interference occurs at certain doses of the chemicals and can cause birth anomalies, as well as sexual developmental problems in both males and females. These hormones play significant role in reproduction. Endocrine disruptors are chemical substances which interfere with the natural hormones in the body and thus affect the maintenance of normal cell metabolism. They are also called hormonally active agents, endocrine disrupting chemicals or endocrine disrupting compounds. Biologically, these effects cause obesity, diabetes, reproductive problems as well as hormone sensitive cancers in both male and female. This is because of the release of great quantity of chemical, following the expansion of the industrial revolution which in turn leads to the alteration in the balance of endocrine and reproductive system. Studies in recent times has shown decline in female fecundity and sperm count. Furthermore, in the United States, the average age at menarche, thalarche and sexual development among minors, has speedily progressed, hence the need to identify their place in reproduction and put in control measures to prevent its attendance complications.
... Also, the AAS-induced hypogonadism as reflected by LH and FSH repression correlated to klotho levels. Supra-physiological doses of androgens are known to suppress gonadotropins with fast response (Jarow and Lipshultz, 1990). The degree of suppression and the ability to recover after an AAS cycle depends on the duration of AAS use and the cumulative dose (Tan and Scally, 2009) with most being normalized within 6 months, even though in some cases, it may take up to 1 year as seen in our participants (Borjesson et al., 2020) and elsewhere (Sader et al., 2001). ...
It has been suggested to longitudinally monitor Insulin-like growth factor I (IGF-I) as a biomarker for the detection of recombinant growth hormone (GH). Subsequently, it is of interest to understand any confounders of endogenous IGF-I. Herein we have studied if serum IGF-I concentration is affected by the intake of anabolic androgenic steroids (AAS) and the potential connection between IGF-I and klotho protein. Moreover, the usefulness of klotho as a biomarker for recombinant GH intake was assessed in healthy male volunteers. An ongoing administration of AAS did not affect the levels of IGF-I. Klotho protein was ~30% higher in men with an ongoing AAS use compared to those with previous (>2 months ago) AAS use, and the serum klotho protein correlated negatively with luteinizing hormone (LH) (rs = −0.38, p = 0.04) and follicle stimulating hormone (FSH) (rs = −0.35, p = 0.05) levels. Serum IGF-I and klotho concentrations showed no correlation in the AAS using population but showed a strong negative correlation in healthy volunteers (rs = −0.86, p = 0.006). The intake of recombinant GH did not affect the serum concentrations of the klotho levels. In conclusion, IGF-I was not affected by supra-physiological AAS doses in men. Interestingly, an association between AAS intake and serum klotho was seen. The usefulness of klotho as an androgen biomarker warrants further studies, whereas klotho can be discarded as a promising biomarker for GH doping.
... 7,20 A major effect of extended AAS use is anabolic steroidinduced hypogonadism (ASIH), which refers to the disruption of the hypothalamic-pituitary-testicular (HPT) axis from prolonged exposure to supraphysiologic doses of testosterone esters, synthetic androgens, and accessory performanceenhancing drugs. 21 Men using AAS often attempt to prevent ASIH by taking various compounds such as SERMs and hCG, an unproven strategy referred to as "post-cycle therapy" or "PCT." ASIH is proving to be a significant cause of male hypogonadism, with 20.9% of 6033 hypogonadal men reporting prior AAS use in a recent retrospective study. ...
Anabolic androgenic steroid (AAS) and performance-enhancing drug (PED) use is a prevalent medical issue, especially among men, with an estimated 2.9–4 million Americans using AAS in their lifetime. Prior studies of AAS use reveal an association with polycythemia, dyslipidemia, infertility, hypertension, left ventricular hypertrophy, and multiple behavioral disorders. AAS withdrawal syndrome, a state of depression, anhedonia, and sexual dysfunction after discontinuing AAS use, is a common barrier to successful cessation. Clinical resources for these patients and training of physicians on management of the patient using AAS are limited. Many men are hesitant to seek traditional medical care due to fear of judgment and lack of confidence in physician knowledge base regarding AAS. While proposed approaches to weaning patients off AAS are published, guidance on harm reduction for actively using patients remains sparse. Medical education regarding the management of AAS use disorder is paramount to improving care of this currently underserved patient population. Management of these patients must be non-judgmental and focus on patient education, harm reduction, and support for cessation. The approach to harm reduction should be guided by the specific AAS/PEDs used.
... In one case, even with HCG treatment, the pituitary response was clearly compromised. On the other case, the test showed no response from the pituitary gland (Jarow & Lipshultz, 1990). ...
The anabolic-androgenic steroids (AAS) are clinically used as an androgen replacement, in hypogonadism treatment, to induce puberty, and also in the treatment of chronic degenerative diseases. The AAS use out of clinical context is becoming massively, being used merely for aesthetic reasons. AAS abuse may cause severe disarrangement on the HPG axis and generate a significant decrease in testosterone synthesis and secretion by the testes. This review aims to evaluate whether the hypogonadism induced by AAS abuse is reversible and under what circumstances the reversibility is possible. For this, PRISMA guidelines and several databases are used between July and September 2020. Altogether, this systematic review identified and analysed 179 cases of AAS users. Of these, 168 cases had the hypogonadism clearly diagnosed and proven to be linked exclusively to AAS abuse. However, between these 168 cases, only 38 cases presented fully known outcomes and among these, merely in 4, the hypogonadism was completely reversible (2 based on drug therapy) with HPG axis recovery. In conclusion, this review presents evidences that AAS-induced hypogonadism is a seriously underestimated problem, and in the majority of cases, full recovery is very difficult to succeed.
... Serum levels of testosterone were examined at euthanasia (PID15) to verify that the rats consumed adequate Met treatment, as AAS use results in a suppression of the hypothalamic-pituitary-gonadal axis, thereby reducing endogenous testosterone production [38]. The two-way ANOVA showed a main effect of Met treatment (F (1,67) = 39.71, ...
Background: Repetitive mild traumatic brain injury (RmTBI) is increasingly common in adolescents. Anabolic–androgenic steroid (AAS) consumption among younger professional athletes is a significant risk factor for impaired neurodevelopment. Given the increased rates and overlapping symptomology of RmTBI and AAS use, we sought to investigate the behavioural and neuropathological outcomes associated with the AAS Metandienone (Met) and RmTBI on rats. Methods: Rats received either Met or placebo and were then administered RmTBIs or sham injuries, followed by a behavioural test battery. Post-mortem MRI was conducted to examine markers of brain integrity and qRT-PCR assessed mRNA expression of markers for neurodevelopment, neuroinflammation, stress responses, and repair processes. Results: Although AAS and RmTBI did not produce cumulative deficits, AAS use was associated with detrimental outcomes including changes to depression, aggression, and memory; prefrontal cortex (PFC) atrophy and amygdala (AMYG) enlargement; damaged white matter integrity in the corpus callosum; and altered mRNA expression in the PFC and AMYG. RmTBI affected general activity and contributed to PFC atrophy. Conclusions: Findings corroborate previous results indicating that RmTBI negatively impacts neurodevelopment but also demonstrates that AAS results in significant neuropathological insult to the developing brain.
... Использование ААС оказалось широко распространенным явлением среди непрофессиональных спортсменов. Впервые стероид-индуцированный гипогонадизм был описан J. Jarow и L. Lipshultz в 1990 г. [3]. Установлено, что в мужской популяции моложе 50 лет -это наиболее частая причина гипогонадизма [4]. ...
Background:
The widespread use of AAS for non-medical purposes is more than often becoming the cause of secondary hypogonadism. The study of the formation of the negative attitude towards the use of AAS among the gym visitors is quite relevant.
Aims:
To identify the frequency of the formation of a motivated refusal to continue taking androgenic anabolic steroids among men who voluntarily declared their use.
Materials and methods:
The study included 44 men, all users of AAS. There has been estimated the effectiveness of the clinical examination: how ready they were to disclose information about the use of AAS (drugs, doses, regimens, duration) or how much they were aware of the mechanisms of action of AAS and their effects on the body. The participants were also asked to evaluate their psychological and emotional state (on the scale Index of life satisfaction, Hamiltons depression, aggressiveness). The experience of our informational lectures on the topic Risks of using AAS prior to the selection of volunteers for research, anonymous surveys and interviews with potential participants in the clinical trial, the clinical work itself with the selected volunteers, the characteristic features of a medical history and tests that we identified were compared with clinical recommendations for hypogonadism diagnostic (domestic and foreign).
Results:
More than 105 gym visitors responded positively to a motivated offer (free medical consultation and laboratory tests) to participate in a clinical study. Based on the results of the individual interview, 54 men (51.4%) who indicated the use of AAS signed an informed consent. 44 volunteers (41.9%) completed all stages of the study. Among them, 32 participants (72.7%) were aware of the mechanisms of action and side effects of AAS. 21 volunteers (47.7%) filled in the scales. The index of life satisfaction was determined as high, equal to 34 [29; 38] points; the index of aggressiveness was higher than the generally accepted standard and composed 27 [25; 29] points, the level of depression corresponded to a mild depressive disorder, equal to 9 [3; 12] points. Over the use of AAS 22.7% (n = 10) of the examined noted an increase in aggressiveness, which they themselves associated with the use of steroids. The clinical symptoms of hypogonadism (decreased libido, erectile dysfunction) after the cancellation of AAS were indicated by 25% (n = 11) of the volunteers and that was one of the reasons they continued to use anabolics. 31.8% (n = 14) of the participants were ready to completely stop using the steroids.
Conclusions:
Individual informational interviews aimed at providing knowledge about the negative effects of steroids on the body motivated the desire to stop using them amongst 31.8% of AAS users. The obtained data points out to a developed AAS addiction which requires the involvement of psychiatrists to get rid of it.
... Typically, chronic AAS users experience a suppression of the hypothalamic-pituitary-gonadal (HPG) axis as a result of negative feedback inhibition, reducing the amount of naturally produced testosterone in circulation (73,74). Met treatment was found to lower serum testosterone levels, verifying that in our study Met treatment did suppress the HPG axis. ...
Sport-related concussion is an increasingly common injury among adolescents, with repetitive mild traumatic brain injuries (RmTBI) being a significant risk factor for long-term neurobiological and psychological consequences. It is not uncommon for younger professional athletes to consume anabolic-androgenic steroids (AAS) in an attempt to enhance their performance, subjecting their hormonally sensitive brains to potential impairment during neurodevelopment. Furthermore, RmTBI produces acute neuroendocrine dysfunction, specifically in the anterior pituitary, disrupting the hypothalamic-pituitary adrenal axis, lowering cortisol secretion that is needed to appropriately respond to injury. Some AAS users exhibit worse symptoms post-RmTBI if they quit their steroid regime. We sought to examine the pathophysiological outcomes associated with the abrupt cessation of the commonly abused AAS, Metandienone (Met) on RmTBI outcomes in rats. Prior to injury, adolescent male rats received either Met or placebo, and exercise. Rats were then administered RmTBIs or sham injuries, followed by steroid and exercise cessation (SEC) or continued treatment. A behavioral battery was conducted to measure outcomes consistent with clinical representations of post-concussion syndrome and chronic AAS exposure, followed by analysis of serum hormone levels, and qRT-PCR for mRNA expression and telomere length. RmTBI increased loss of consciousness and anxiety-like behavior, while also impairing balance and short-term working memory. SEC induced hyperactivity while Met treatment alone increased depressive-like behavior. There were cumulative effects whereby RmTBI and SEC exacerbated anxiety and short-term memory outcomes. mRNA expression in the prefrontal cortex, amygdala, hippocampus, and pituitary were modified in response to Met and SEC. Analysis of telomere length revealed the negative impact of SEC while Met and SEC produced changes in serum levels of testosterone and corticosterone. We identified robust changes in mRNA to serotonergic circuitry, neuroinflammation, and an enhanced stress response. Interestingly, Met treatment promoted glucocorticoid secretion after injury, suggesting that maintained AAS may be more beneficial than abstaining after mTBI.
... Jarrow and Lipshultz first reported ASIH in 1990, by describing two cases of men with low testosterone levels 3 months and 2.5 years after discontinuing use of AAS. 4 Rahnema et al 5 published a comprehensive review of this phenomenon in 2014, describing the secondary hypogonadotropic hypogonadism by feedback suppression of the hypothalamicpituitary-gonadal (HPG) axis via inhibition of pulsatile GnRH. Only male patients were described, and there was no mention of vocal symptoms. ...
Key Clinical Message
Anabolic steroids and androgenic steroids (AAS) can have long‐term effects on the female voice. These changes are clinically relevant since they are difficult to treat and therefore should be disclosed to patients using AAS or receiving androgenic steroid therapy.
... However, the use of AAS was not free from the characteristic sequelae of the use of androgen and resulted in an unfavorable side effect of anabolic steroid-induced hypogonadism (ASIH). ASIH is common as a cause of secondary hypogonadism in young men, especially because young men often use AAS (Coward et al., 2013;Jarow and Lipshultz, 1990). In young men, hypogonadism not only is a problem but also can cause a more serious problem such as infertility. ...
... One physiologic change is a dose-dependent impairment of normal testicular androgen secretion and spermatogenesis [7][8][9] . This effect is believed to result from the suppression of circulating luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a feedback loop system of the hypothalamic-pituitary-gonadal (HPG) axis 9,10 . ...
A randomized, double-blind clinical trial was conducted to investigate long-term abuse effects of testosterone cypionate. Thirty-one healthy males were randomized into a dose group of 100, 250 or 500mg/wk and received 14 weekly injections of TC. A PK-PD model was developed to characterize testosterone concentrations and link exposure to change in luteinizing hormone and spermatogenesis following long-term TC administration. A linear one-compartment model best described the concentration-time profile of total testosterone. The population mean estimates for testosterone were 2.6 kL/day for clearance and 14.4 kL for volume of distribution. Weight, albumin and their changes from baseline were identified as significant covariates for testosterone. The estimated potency of total testosterone with respect to suppression of LH synthesis was 9.33 ng/ml. Simulation based on the indirect response model suggests the suppression of endogenous testosterone secretion, LH synthesis and spermatogenesis was more severe and of greater duration in 250mg and 500mg dose groups. This article is protected by copyright. All rights reserved.
Anabolic androgenic steroids (AAS) they are the synthetic type of the natural male sex hormone(testosterone), they are widespread used amongst athletes to enhance performance. Abuse of AAS is commonamongst players and it is usually accompanied by a many medically based complications. It was reportedthat hepatic problems include cholestasis, elevation of liver enzymes e.g. aminotransferases, as well as,benign hepatic adenomas, jaundice and to less extent of hepatocellular carcinoma was associated with theiruse.A total of (12) adult New Zealand rabbits (Oryctolagus cuniculus) male, aged one year was selected. 2control animals and 10 were treated with injections intramuscularly of the AAS, nandrolone decanoate(15 mg/kg) three times a week for 12 weeks. At the end of experiment the animals were sacrificed and theliver was dissected out and fixed using 10% buffered formalin-saline to prepare blocks for staining withhaematoxylin and eosin for histological examination using the light microscope.The liver of treated animals reveals that there are a mild to severe vascular congestion. There is swelling ofhepatocytes, and inflammatory cell infiltration. Perivascular fibrosis, cellular necrosis was observed in otherslides with sinusoidal congestions and extrabiliary bile pigments deposits.The benefit of AAS comes with unwanted side effects. The total volume of the hepatocytes and sinusoidswere increased in the studied animals. The total number of hepatocytes nuclei in experimental group alsoincreased. The damage of the liver cells or at least increased permeability of the hepatocellular membranewhich is noticed in the present work could explain the increment of plasma levels of liver enzymeswhich was studied by other researchers, as they notice an elevation liver enzymes activity such as alanineaminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AP), gamma glutamyltranspeptidase (GGT), and lactate dehydrogenase(LDH)..Patients and physicians must kept in mind that the sequelae of AAS abuse are life threatening. So peopleshould be aware about the complications of AAS use and a periodic examination of liver function and checkout should be done to those treated groups.
Background and Aims
Androgenic‐anabolic steroid (AAS) abuse is a global health concern, studies revealing an increasing trend of abuse and deleterious effects on reproductive health. Unfortunately, there is no consensus about management pathways due to the lack of specific guidelines.
Methods
A prospective study, multicentre, online survey, composed of 30 questions, was conducted to investigate the current trend of AAS abuse and the management followed by practitioners from different specialities dealing with this condition.
Results
A total of 151 respondents were included. The majority were general urologists (68.21%), andrologists (22.51%), and endocrinologists (9.28%). An increasing trend of AAS abuse was noticed by 90.73% of participants mostly in young age populations. Most of AAS abusers were presented with infertility (64.24%) and erectile dysfunction (59.60%), and their investigations showed abnormal semen analysis (77.48%), abnormal hormones (follicle‐stimulating hormone, luteinizing hormone, testosterone, and estradiol) (94.70%), and reduction in testicular size (50.33%). Most of respondents expected: the need of long duration for spontaneous recovery (6–12 months), relapse of AAS abuse in one‐third of patients, less knowledge about the adverse effects (39.74%), and risk of drug dependence (54.30%). Immediate treatment was the most offered plan of management (44.37%) followed by a waiting spontaneous recovery (32.45%), while the remaining would refer the patients to an either endocrinologist or andrologist. The treating physicians did not follow specific guidelines and most of participants (44.44%) reverted to their personal experience in the management.
Conclusions
Our study revealed an increasing trend of AAS abuse, deleterious effects of AAS use on reproductive health, and lack of consensuses among the treating physicians regarding the management of related adverse effects. Our study could be considered a call to the scientific bodies to have more studies, establish guidelines for management, and to have better awareness of this serious public health concern.
Cholesterol is the precursor of all steroid hormones, and the entry of cholesterol into the mitochondria is the rate-limiting step of steroidogenesis. Voltage-dependent anion channel (VDAC1) is an outer mitochondrial protein part of a multiprotein complex that imports cholesterol. We previously reported that intratesticular administration of a 25 amino acid peptide blocking the interaction between 14-3-3ϵ with VDAC1 increased circulating levels of testosterone. This fusion peptide was composed of a HIV-1 transactivator of transcription (TAT) protein transduction domain cell-penetrating peptide, a glycine linker, and amino acids 159-172 of VDAC1 (TV159-172). Here, we describe the development of a family of small molecules that increase circulating testosterone levels after an oral administration. We first characterized an animal model where TV159-172 was delivered subcutaneously. This subcutaneous model allowed us to study the interactions between TV159-172 and the hypothalamus-pituitary-gonadal axis (HPG) and identify the biologically active core of TV159-172. The core consisted of the tetrapeptide RVTQ, which we used as a platform to design synthetic peptide derivatives that can be administered orally. We developed a second animal model to test various derivatives of RVTQ and found 11 active compounds. Dose-response experiments identified 4 synthetic peptides that robustly increased androgen levels in a specific manner. We selected RdVTQ as the leading VDAC1-core derivative and profiled the response across the lifespan of Brown-Norway rats. In summary, we present the development of a new class of therapeutics that act within the HPG axis to increase testosterone levels specifically. This new class of small molecules self-regulates, preventing abuse.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
The new edition of this canonical text on male reproductive medicine will cement the book's market-leading position. Practitioners across many specialties - including urologists, gynecologists, reproductive endocrinologists, medical endocrinologists and many in internal medicine and family practice – will see men with suboptimal fertility and reproductive problems. The book provides an excellent source of timely, well-considered information for those training in this young and rapidly evolving field. While several recent books provide targeted 'cookbooks' for those in a male reproductive laboratory, or quick reference for practising generalists, the modern, comprehensive reference providing both a background for male reproductive medicine as well as clinical practice information based on that foundation has been lacking until now. The book has been extensively revised with a particular focus on modern molecular medicine. Appropriate therapeutic interventions are highlighted throughout.
Male hypogonadism can be congenital or acquired and categorized into hypergonadotropic and hypogonadotropic based on the concomitant luteinizing hormone and follicle-stimulating hormone levels. Acquired causes of hypogonadotropic hypogonadism in male patients include anabolic steroid use, hyperprolactinemia, and any pathology that can disrupt hypothalamic–pituitary–gonadal axis such as sellar/suprasellar masses, infiltrative or infectious disorders, trauma, and radiation of the sella or nearby structures. Congenital causes are rare and include idiopathic gonadotropin-releasing hormone (GnRH) deficiency, also termed Kallmann syndrome when there is accompanying anosmia. Hypergonadotropic causes can be of genetic etiology (Klinefelter’s syndrome) or acquired as with a history of epididymitis, orchitis, varicocele, testicular trauma, chemotherapy, or radiation. Although testosterone replacement therapies can improve libido and sexual function, they will not restore fertility and can lead to oligo- or azoospermia; hence, additional options should be weighed in collaboration with the patient. Those patients with primary testicular failure desiring fertility may need to explore assisted reproductive technologies such as testicular sperm extraction, microsurgical testicular sperm extraction, and intracytoplasmic sperm injection. For patients with central hypogonadism, aromatase inhibitors, selective estrogen receptor modulators, or human chorionic gonadotropin can be considered, in the context of underlying etiology of hypogonadism, to improve intrinsic testosterone production and spermatogenesis. Additional lifestyle approaches such as weight loss and treatment of sleep apnea may also contribute to improved gonadal health.KeywordsHypogonadotropic hypogonadismHypergonadotropic hypogonadismMale infertilityClomipheneHuman chorionic gonadotropinKallmann syndromeAnosmiaSERM
Hypogonadism commonly occurs during withdrawal from anabolic-androgenic steroid (AAS) use, particularly when users have been taking AAS for prolonged periods. Mounting evidence now suggests that AAS-induced hypogonadism may persist for months or even years after last AAS use, and in some cases may be partially or completely irreversible. Treatment with human chorionic gonadotropin and clomiphene may help to restore hypothalamic-pituitary-testicular axis function, and these substances are widely used illicitly by AAS users at the end of a course of AAS as so-called postcycle therapy. Many endocrinologists still have only limited experience in diagnosing and treating AAS-induced hypogonadism.
Fertility preservation among men with secondary hypogonadism is an extensive topic with contemporary regimens emerging. The original approach of testosterone replacement therapy has long been replaced by a variety of therapies as the understanding of the hypothalamic-pituitary-gonadal axis continues to develop. Preservation and stimulation of fertility in men with hypothalamic or pituitary diseases focuses on the use of gonadotropins and the agile manipulation of testosterone, providing men with multiple therapeutic options. Human chorionic gonadotropin, recombinant human FSH, selective estrogen receptor modulators, and aromatase inhibitors, among other agents, have been shown to preserve and induce fertility by repleting testosterone and stimulating spermatogenesis. Recent pharmacologic advancements using an intranasal form of testosterone have shown early promise in allowing maintenance of serum testosterone levels with minimal effect on spermatogenesis. For those men who have previously been treated with testosterone supplementation therapy (TST) and anabolic androgenic steroids (AAS), who are currently on treatment or anticipate starting therapy, and who also desire restoration or maintenance of their fertility, these same agents have demonstrated efficacy in reversing or preventing the negative feedback of exogenous androgen on the hormonal axis. A number of treatment strategies such as hCG, aromatase inhibitors, and selective estrogen receptor modulators often used with hCG have been shown to elevate total testosterone levels and maintain spermatogenesis in hypogonadal man.
At the Swedish national forensic toxicology laboratory, a measured testosterone/epitestosterone (T/E) ratio ≥12 together with testosterone/luteinizing hormone (T/LH) in urine >400 nmol/IU is considered as a proof of exogenous testosterone administration. However, according to the rules of the World Anti-Doping Agency (WADA), samples with T/E ratio >4 are considered suspicious and shall be further analyzed by gas chromatography-combustion-isotope-ratio mass spectrometry (GC-C-IRMS) to confirm the origin of testosterone and its metabolites. The aim of this study was to investigate the possibility of false negative results and to estimate the frequency of negative results using the current criteria for detection of abuse of testosterone in forensic investigations. Urine and serum samples were collected by the police at suspected infringement of the doping law in Sweden. Fifty-eight male subjects were included in the study. Urinary testosterone was determined by GC-MS, serum testosterone and LH - by immunoassay. The origin of testosterone and its metabolites was confirmed by means of GC-C-IRMS. Twenty-six of the 57 analyzed subjects tested positive for exogenous testosterone using the criteria T/E ≥12 combined with T/LH >400 nmol/IU. The IRMS analyses confirmed 47 positives, thus 21 were considered false negatives. Negative predictive value was 32% (95% CI: 16-50%) and sensitivity 55%. No false positive subjects were found. The number of false negative cases using the current criteria for the detection of testosterone abuse and hence the low sensitivity indicates a need to discuss introduction of new strategies in forensic doping investigations.
Introduction: Anabolic androgenic steroid use is an uncommon but important cause of male infertility. As paternal age and anabolic steroid use increases, providers are more likely than ever to encounter men with infertility and prior or concurrent anabolic steroid use. In this review, we outline the background, epidemiology and pathophysiology of anabolic steroid induced male infertility and provide recommendations regarding the diagnosis, management, and future prevention of this condition.
Areas covered: Male reproductive physiology is a tightly regulated process that can be influenced by exogenous sources such as anabolic steroids and selective androgen receptor modulators (SARMs). Data suggest that a combination of selective estrogen receptor modulators (SERMs), human chorionic gonadotropin (hCG), aromatase inhibitors (AIs), and recombinant follicle-stimulating hormone (rFSH) may lead to spermatogenesis recovery.
Expert opinion: Anabolic steroid and SARM users continue to exhibit lack of understanding regarding the potential side effects of their use on male fertility. Current literature suggests that spermatogenesis can be safely recovered using a combination of SERMs, hCG, AIs and rFSH although additional studies are necessary. While anabolic steroid prevention strategies have largely been focused on the individual level, further investigation is necessary and should be approached in a socioecological manner.
As has been shown, when well-defined pathophysiology such as hypogonadotropic hypogonadism exists in subfertile men, reasonably successful treatment options are available. When subfertility is unexplained or idiopathic, treatment is less successful. At present, numerous conditions of varying pathophysiology are lumped together as “idiopathic subfertility” and treated with the same nonspecific therapeutic modalities with minimal success. As further research elucidates the biochemical abnormalities causing these conditions, rational and specific therapies may be developed. In addition, advances in assisted reproductive technologies will allow treatment for many patients for whom no therapy currently exists.
Infertility effects one in seven couples and in 50% of cases the cause will be attributable to an abnormality with the man's sperm. We discuss the epidemiology, etiology and pathophysiology of male infertility and provide an evidence-based overview of the main therapeutic strategies. Moreover, we discuss the pathogenesis and management of both erectile dysfunction and late onset hypogonadism.
This article aims to define the optimal endocrine workup of male factor infertility, including evaluation and treatment of men who have previously been on exogenous testosterone or anabolic steroids. Future directions include the expansion of genetic testing for infertility to include endocrine gene products.
Hormonal regulation contributes significantly to spermatogenesis through interactions between the hypothalamic-pituitary-gonadal axis, testosterone synthesis, Sertoli cell function, androgen receptor, and other hormonal influences, such as estrogen. Congenital or acquired causes of endocrine dysfunction can affect spermatogenesis and male fertility. The purpose of this chapter is to discuss the endocrine regulation of spermatogenesis with consideration of its genetic basis.
Klinefelter syndrome (KS) is the most common X chromosome abnormality encountered in men with infertility. The classic form 47,XXY accounts for 80–90% of cases. An error of nondisjunction during gametogenesis provides the extra X chromosome in KS men. The various karyotype variants of KS share the same features of hypergonadotropic hypogonadism but present with more distinct physical, medical and psychological features than the classic form. Spermatogenesis appears to be intact during infancy up to the prepubertal period; however, it progressively declines during adulthood. Learning and behavioural challenges are frequent at an earlier age, while androgen deficiency and infertility are usually encountered at an advanced age. Testosterone replacement therapy is the cornerstone to address hypogonadism to enhance the quality of life and prevent the long-term complications of the androgen-deficient state. Intracytoplasmic sperm injection (ICSI) is a major breakthrough in the treatment of infertility, particularly in KS men. Sperm can be found in the ejaculate in patients with KS and can be used for assisted reproductive technology. However, microdissection testicular sperm extraction (TESE) is the mainstay procedure of choice for sperm retrieval for ICSI, as most KS men present with non-obstructive azoospermia. This procedure provides significantly superior overall outcomes compared to other sperm retrieval techniques. Although men with sex chromosomal abnormalities have a low risk of producing offspring with the same abnormalities after ICSI, genetic counselling should be performed in a multidisciplinary approach to enhance the quality of life and overall health status of KS men.
Background:
A growing body of evidence suggests that anabolic androgenic steroids (AAS) are used globally by a diverse population with varying motivations. Evidence has increased greatly in recent years to support understanding of this form of substance use and the associated health harms, but there remains little evidence regarding interventions to support cessation and treat the consequences of use. In this scoping review, we identify and describe what is known about interventions that aim to support and achieve cessation of AAS, and treat and prevent associated health problems.
Methods:
A comprehensive search strategy was developed in four bibliographic databases, supported by an iterative citation searching process to identify eligible studies. Studies of any psychological or medical treatment interventions delivered in response to non-prescribed use of AAS or an associated harm in any setting were eligible.
Results:
In total, 109 eligible studies were identified, which included case reports representing a diverse range of disciplines and sources. Studies predominantly focussed on treatments for harms associated with AAS use, with scant evidence on interventions to support cessation of AAS use or responding to dependence. The types of conditions requiring treatment included psychiatric, neuroendocrine, hepatic, kidney, cardiovascular, musculoskeletal and infectious. There was limited evidence of engagement with users or delivery of psychosocial interventions as part of treatment for any condition, and of harm reduction interventions initiated alongside, or following, treatment. Findings were limited throughout by the case report study designs and limited information was provided.
Conclusion:
This scoping review indicates that while a range of case reports describe treatments provided to AAS users, there is scarce evidence on treating dependence, managing withdrawal, or initiating behaviour change in users in any settings. Evidence is urgently required to support the development of effective services for users and of evidence-based guidance and interventions to respond to users in a range of healthcare settings. More consistent reporting in articles of whether engagement or assessment relating to AAS was initiated, and publication within broader health- or drug-related journals, will support development of the evidence base.
Testosterone has long been touted as the panacea for men wishing to restore their vitality, sexuality, and masculinity to that of their youth. While the benefits of testosterone are not mythical, they are definite. In this article we will review the various benefits of testosterone as it pertains to men's health and male infertility.
Increasing numbers of men in the United States are seeking treatment for symptomatic hypogonadism with testosterone supplementation therapy (TST). In addition, the use of anabolic-androgenic steroids (AAS) is also increasing. Our current knowledge of the male hypothalamic-pituitary-gonadal axis demonstrates that exogenous androgen use suppresses intratesticular testosterone (T) concentration and consequently shuts down spermatogenesis in the overwhelming majority of cases, leading to potential infertility. Men who are hypogonadal who have not completed their family have several medical options that will allow both the treatment of their symptoms and the preservation of spermatogenesis. Human chorionic gonadotropin, recombinant human FSH, selective estrogen receptor modulators, and aromatase inhibitors, among other agents, have been shown to increase low serum T in appropriate candidates with ondary hypogonadism. For those men who have previously been treated with TST/AAS, are currently on treatment or anticipate starting therapy, and who also desire restoration or maintenance of their fertility, these same agents have demonstrated efficacy in reversing or preventing the negative feedback of exogenous androgen on the hormonal axis. In this chapter, we propose treatment algorithms when a patient desires restoration or maintenance of his fertility in the setting of TST.
Serum concentrations of testosterone, 17-hydroxyprogesterone, estradiol and several other unconjugated and sulphated steroids were analyzed before and after a single dose of hCG in 6 power athletes, who had used high doses of testosterone and anabolic steroids for 3 months. The study was carried out 3 weeks after cessation of drug use, but the study subjects were still characterized by hypogonadotrophic hypogonadism. The mean concentrations of serum LH and FSH were 2.6 +/- 0.3 and 1.1 +/- 0.03 mIU/ml (mean +/- SEM), respectively, and the concentrations of several precursors and metabolites of testosterone were lower than those before drug use. In contrast, circulating concentrations of steroid sulphates were not decreased, with the exception of dehydroepiandrosterone sulphate. After hCG injection serum testosterone and 5 alpha-dihydrotestosterone concentrations increased significantly, whereas no increases in estradiol and 17-hydroxyprogesterone concentrations were observed. These results demonstrate that during transient hypogonadotrophism in adult men, the testicular responsiveness to a single injection of hCG is similar to that in prepubertal boys without any sign of steroidogenic lesion at the 17,20-desmolase step. Therefore, the appearance of the possibly estradiol-mediated inhibition at the level of C21-steroid side-chain splitting in testosterone biosynthesis seems to be dependent on priming by gonadotrophins.
The 5th edition of this world renowned textbook is the result of a thorough updating of every chapter with respect to the mechanism of action and use of older agents and the addition of important new drugs. The philosophy and objectives of the earlier editions are continued, however, together with the same thoughtful organization, clarity and authority that have long made 'Goodman and Gilman' the standard book in the field. Although less dynamic or outmoded sections have been condensed or eliminated, the basic organization remains the same, with major attention being given to the well established, safe and effective prototypal drugs. After a discussion of the general principles of pharmacokinetics, special attention is given to drugs acting on the CNS, local anesthetics, drugs acting at synaptic and neuroeffector junctions, autacoids, cardiovascular drugs, water, salts and ions, drugs affecting renal function and electrolyte metabolism, drugs affecting uterine motility, gases and vapors, heavy metals and antagonists, locally acting drugs, antiparasitic drugs, antimicrobial drugs, antineoplastic drugs, drugs acting on the blood and hematopoietic system, hormones and hormone antagonists, vitamins and even the principles of prescription writing and patient compliance instruction. There is a detailed subject index referring to both medical concepts and drug names, generic as well as proprietary. This book will prove invaluable to both students and graduates in many areas of the biomedical sciences.
The use of anabolic-androgenic steroids (AS) is perceived by the media, by segments of the sports medicine and athletic communities, and by the public to have grown to epidemic proportions. Unfortunately, the incidence and prevalence of AS use among elite, amateur, and recreational athletes is poorly documented. This study was designed to help identify AS use patterns among the male portion of the general adolescent population. The overall participation rate on a schoolwide basis was 68.7% and on an individual basis reached 50.3%. Participants in this investigation were 12th-grade male students (N = 3403) in 46 private and public high schools across the nation who completed a questionnaire that established current or previous use of AS as well as user and nonuser characteristics. Results indicate that 6.6% of 12th grade male students use or have used AS and that over two thirds of the user group initiated use when they were 16 years of age or younger. Approximately 21% of users reported that a health professional was their primary source. The evidence indicates that educational intervention strategies should begin as early as junior high school; the intervention should not be directed only toward those individuals who participate in school-based athletics.
(JAMA 1988;260:3441-3445)
The effects of a one-month course of treatment with a potent anabolic steroid, methandienone (5 and 10 mg daily), and a very weak androgen and hormone precursor, dehydroepiandrosterone sulphate (DHEAS, 20 and 40 mg daily) and placebo on plasma testosterone, LH and FSH levels, red cell volume and red cell 2,3-diphosphoglycerate (2,3-DPG) concentration in endurance sportsmen were studied using a double-blind test system. A highly significant decrease in mean plasma testosterone was observed after the 5 and 10 mg methandienone regimen (66 and 73%). Treatment with 40 mg of DHEAS decreased mean testosterone levels by 41% (not statistically significant). Pre-test testosterone levels were reattained about 10 days after the end of the treatment period with the higher doses of both compounds, while 2–6 weeks afterwards a significant over-compensation in mean plasma testosterone levels was observed. No significant changes in plasma gonadotropins were seen immediately after treatment with either of these steroids but later a tendency towards decreased FSH and LH levels was observed in the subjects who received the higher doses of both compounds. No significant changes in red cell volume were observed. Red cell 2,3-DPG concentration was unaffected by methandienone, but the 40 mg dosage of DHEAS caused a highly significant decrease in 2,3-DPG (by 26%, which is an unwanted effect for top sportsmen).
To quantitate the inhibitory effect of a prolonged increase in serum testosterone concentration on the serum LH and FSH concentrations in men, testosterone enanthate was administered every seven days for eight doses to 12 normal men and to seven men with primary hypogonadism. Serum testosterone and estradiol concentrations were measured on days 0 to 7, 14, 21, 28, 35, 42, 49 to 56, and 84. Serum LH and FSH concentrations, both basal and in response to gonadotropin-releasing hormone (GnRH), were measured on days 0, 7, 14, 28, 56, and 84. In six normal men who received 50 mg of testosterone enanthate every seven days, the mean (±SE) serum testosterone concentration increased from 572 ± 98 ng/dl on day 0 to an average of 768 ± 87 ng/dl on days 1 to 7 (P <0.05), and was maintained at an average of 810 ± 137 ng/dl on days 50 to 56. Serum estradiol concentrations did not change during the time of testosterone administration. The mean (±SE) LH response area following GnRH decreased from 6670 ± 753 mIU.min/ml on day 0 to 4482 ± 240 mIU.min/ml (P <0.025) by day 28, but the mean basal LH and FSH concentrations and the mean FSH response area did not change. In six normal men who received 200 mg of testosterone enanthate every seven days, the mean serum testosterone concentration increased from 507 ± 53 ng/dl on day 0 to an average of 1199 ± 86 ng/dl (P <0.001) on days 1 to 7, and was maintained at an average of 1333 ± 144 ng/dl, on days 50 to 56. By thin-layer chromatography, unhydrolyzed testosterone enanthate was found to make no detectable contribution to the measured testosterone levels in these men. The mean serum estradiol concentration increased from 26 ± 1 pg/ml on day 0 to an average of 39 ± 4 pg/ml (P <0.05) on days 1-7 and to 60 ± 18 (P <0.001) on days 49-56. The basal LH concentration was 8.8 ± 1.3 mIU/ml on day 0, had decreased signifcantly by day 14, and by day 56 was 4.9 ± 0.5 mIU/ml (P <0.01). The LH response area was 5955 ± 558 mIU. min/ml on day 0, was not significantly reduced until day 28, but by day 56 was virtually obliterated, 247 ± 125 mIU.min/ml. The basal serum FSH concentration had decreased by day 14, but the FSH response area did not decrease until day 28. In the seven men with primary hypogonadism, who received 200 mg of testosterone enanthate every seven days, the mean serum testosterone concentration increased from 184 ± 53 ng/dl on day 0 to an average of 1033 ± 346 ng/dl (P <0.01) on days 1 to 7, and was maintained at an average of 1132 ± 260 ng/dl on days 50 to 56. The mean serum estradiol concentration almost tripled during this time. The basal LH and FSH concentrations and the mean LH and FSH response areas all decreased markedly during the treatment period, but even by day 56 one man still had supranormal basal LH and FSH concentrations, and three men had normal or supranormal LH and/or FSH responses to GnRH. The authors conclude that, in order to inhibit markedly the LH and FSH responses to synthetic GnRH, the serum testosterone concentration must be raised to 150% above the mean normal level for 28 days in normal men and for 28 to 56 days or longer in men with primary hypogonadism.
Description is given of six body-builders who had been taking Methandrostenolone (up to 20 mg/day in intermittent courses for a year or more). At the time of examination there was no subjective disturbance of sexual function, but testosterone levels were low relative to laboratory standards and luteinizing hormone levels were also reduced - particularly in relation to testosterone concentrations. Abnormal liver function tests were seen in three of the six subjects, and one had mild diabetes with high serum cholesterol, triglycerides and uric acid. The weight gain of the group was not outstanding, and the only possible finding was a high haemoglobin and haematocrit in one of the six subjects.
Plasma levels of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) as well as the response of LH and FSH to the intravenous administration of 100 μg of luteinizing hormone releasing hormone (LRH) were measured in 16 well-trained athletes (mean age 30 years) before and after 2 months of daily oral intake of 15 mg of metandienon, an anabolic steroid (Anabolin®, 17α-methyl-17β-hydroxy-1,4-androstadien-3-one, Medica, Finland). All athletes continued to train regularly, just as they had done for several years.
During administration of metandienon the mean plasma testosterone level fell 69%, from 29.4 ± 11.6 nmol/l to 9.1 ± 7.5 nmol/l. The mean plasma levels of LH and FSH also fell significantly ( P < 0.001 and P < 0.01, respectively), both about 50%. Because LH and FSH levels were low after administration of the steroid the maximum stimulation values after LRH administration were also lower than pre-treatment values although the mean increments did not differ significantly before and after administration of the anabolic steroid. However, after treatment, the FSH response curve had a biphasic pattern in most subjects, with peaks at 10 to 20 and 50 to 60 min after the iv injection of LRH. Administration of LRH after the treatment period had no effect on FSH secretion in two subjects and no effect on LH secretion in one. Our results show that administration of an anabolic steroid causes a pronounced lowering of plasma levels of testosterone, LH and FSH but causes no gross alteration in the response of LH secretion to stimulation by LRH. The reason for the biphasic response pattern of FSH to LRH administration in most subjects is not known.
The effect of long-term testosterone administration on male reproductive function has been investigated in seven healthy young men age 20 to 27 years. Testosterone oenanthate (TOe) was administered in doses of 250 mg per week for 21 weeks. No toxic side-effects were observed. Libido, sexual potency, frequency of sexual intercourse and body hair development generally remained unaffected, but there was a reversible mean weight gain of 3.6 kg during TOe administration. Seminal fluid parameters and radioimmunoassayable serum FSH, LH, testosterone, and androstenedione levels were monitored before, during, and after TOe administration. The serum testosterone rose approximately by a factor of two, while the serum FSH and LH were rapidly suppressed after the initiation of the TOe therapy. The mean sperm concentration fell to values below three million spermatozoa per ml, and changes in sperm motility, the percentage of normal sperm morphology, and seminal fructose concentrations generally paralleled those of the mean sperm concentrations. In contrast, the mean seminal fluid volume and serum androstenedione levels did not change significantly during TOe administration. The mean sperm concentration showed a marked recovery 13 to 16 weeks after TOe withdrawal, but sperm counts remained below pre-treatment levels in three out of seven subjects 25 to 28 weeks after discontinuation of TOe.
Endocrine effects of self-administration of high doses of anabolic steroids and testosterone were investigated in five power athletes during 26 wk of training, and for the following 12-16 wk after drug withdrawal. After 26 wk of anabolic steroid and testosterone administration, serum testosterone concentrations had increased 2.3-fold. This was associated with increased concentrations of serum estradiol, which rose 7-fold to values (0.48 nmol X 1(-1) typical for females. There was a major decrease in serum FSH and LH concentrations, but they returned to control levels following drug withdrawal. However, serum testosterone concentrations stayed at low levels (9 nmol X 1(-1) ) during this follow-up period, indicating long-lasting impairment of testicular endocrine function. Serum ACTH concentrations were also decreased during steroid administration, possibly due to a corticoid-like effect of some of the anabolic steroids taken in high doses. However, no changes were seen in serum cortisol. The only consistent change in the control group was an increase in serum LH concentrations during the most intensive training, suggesting that a decreasing tendency of serum testosterone was compensated for by augmented LH secretion.
The influence of high doses of testosterone and anabolic steroids on testicular endocrine function and on circulating steroid binding proteins, sex hormone binding globulin (SHBG) and cortisol binding globulin (CBG), were investigated in power athletes for 26 weeks of steroid self-administration and for the following 16 weeks after drug withdrawal. Serum testosterone and androstenedione concentrations increased (P less than 0.05) but pregnenolone, 17-hydroxypregnenolone, dehydroepiandrosterone, 5-androstene-3 beta, 17 beta-diol, progesterone and 17-hydroxyprogesterone concentrations strongly decreased (P less than 0.001) during steroid administration. Serum pregnenolone, 17-hydroxypregnenolone and dehydroepiandrosterone sulphate concentrations followed the changes of the corresponding unconjugated steroids but 5-androstene-3 beta, 17 beta-diol and testosterone sulphate concentrations remained unchanged during the follow-up time. During drug administration SHBG concentrations decreased by about 80 to 90% and remained low even for the 16 weeks following steroid withdrawal. Steroid administration had no influence on serum CBG concentrations. In conclusion, self-administration of testosterone and anabolic steroids soon led to impairment of testicular endocrine function which was characterized by low concentrations of testosterone precursors, high ratios of testosterone to its precursor steroids and low SHBG concentrations. Decreased concentrations of SHBG and testicular steroids were still partly evident during the 16 weeks after drug withdrawal. The depressed circulating levels of dehydroepiandrosterone and its sulphate may indicate that the androgenic-anabolic steroids also suppress adrenal androgen production.
Esterified 19-nortestosterone, an anabolic steroid which has been in clinical use for over 20 years, was administered intramuscularly to five healthy volunteers in doses of 100 mg/week for 3 weeks followed by 200 mg/week for a further 10 weeks. Azoospermia occurred 7 to 13 weeks after initiation of treatment and persisted for 4-14 weeks after the last injection. Serum gonadotropin and testosterone levels were reduced, but androgenic effects were maintained as indicated by unchanged libido and potency. No serious side-effects were noted. 19-nortestosterone appears to be a potential agent for male fertility control.
Monoclonal anti-DNA antibodies prepared by the hybridoma technique were used for an analysis of idiotypes of anti-DNA antibodies in systemic lupus erythematosus (SLE). Serum levels of one idiotypic marker, 16/6/R, were higher than normal in 40 of 74 patients (54%) with active SLE, compared with only 6 of 24 patients (25%) with inactive SLE, 9 of 38 patients (25%) with rheumatoid arthritis, and 4 of 96 normal subjects (4%). Levels of the 16/6/R idiotypic marker were determined in serially collected serum samples from 12 patients with SLE. Concordance was found between idiotype levels and clinical activity in 8 of the 12 patients. Levels of the 16/6/R idiotype tended to correlate with levels of antibodies to double-stranded DNA, but in some cases the clinical status was reflected better by the idiotype levels than by the levels of anti-double-stranded-DNA antibodies. Measurement of idiotypes of anti-DNA antibodies may provide information valuable in monitoring the clinical course of patients with SLE.
Anabolic steroids have widespread metabolic effects but, to date, their proven clinical indications have been limited. Recently the 17 alpha-alkylated steroid, stanozolol, has been shown to be of value in a variety of commonly occurring vascular diseases. Its endocrine effects have received little attention and we have investigated the effect of administering a 14 d course of stanozolol (10 mg orally per day) on a variety of important hormonal pathways in nine healthy male subjects. Significant changes occurred as follows: a 55% reduction in serum testosterone levels was noted and was accompanied by reductions in 'derived' free testosterone, sex hormone binding globulin and LH levels; total T4 and T3 levels fell in association with a decrease in thyroxine binding globulin, but no alteration was detected in TSH or free T4 levels. Changes in vitamin D status, with falls in 25-hydroxycholecalciferol and vitamin D binding globulin were also observed. These effects were reversible on stopping treatment. Stanozolol therapy therefore leads to a number of hormonal changes, probably by an action at both pituitary and hepatic levels.
Adult anesthetized male rats were submitted to in vivo micropuncture of the seminiferous and epididymal tubules and reproductive tract vasculature to obtain fluids for analysis of testosterone, 5 alpha-dihydrotestosterone, and androgen-binding protein (ABP). Androgen and ABP concentrations were determined by RIA. The highest concentrations of testosterone (73.14 +/- 5.12 ng/ml) were in testicular interstitial fluid. A significant downhill concentration gradient exists between testosterone concentrations in testicular interstitial fluid and seminiferous tubule fluid (50.24 +/- 2.26 ng/ml); another significant decrease occurs between seminiferous tubule fluid and rete testis fluid (17.85 +/- 2.11 ng/ml). 5 alpha-Dihydrotestosterone concentrations were highest in intraluminal caput epididymidal fluids (58.73 +/- 6.48 ng/ml) as were ABP concentrations (33.30 +/- 2.40 mu leq/microliter). Intraluminal sperm concentrations were also determined, and from these data, fluid reabsorption by the efferent ducts and epididymal tubules were calculated. Eighty-nine percent of the fluid leaving the testis is reabsorbed between the rete testis and caput epididymidis, and 96% is reabsorbed between rete and cauda. It was calculated that large losses of androgen and ABP also occur from the lumen of the excurrent duct system. These losses may be due to metabolism, diffusion from the lumen, or uptake by cells.
The use of anabolic steroids by athletes is becoming increasingly wide-spread in the attempt to develop muscular strength, although the efficacy of anabolic administration to improve athletic performance is still controversial and androgen therapy itself is not free of risks. The present study was undertaken in 9 male athletes undergoing anabolic treatment in the course of their seasonal training. Methandrostenolone was administered in a single dose in the morning (20 to 35 mg) for 14 days during a period of intense physical activity. Blood samples were taken prior to starting anabolic treatment, then at frequent intervals during drug administration and during the week subsequent to drug discontinuation. The serum levels of the following hormones were measured, using radioimmunoassay procedures: testosterone (T), LH, FSH, PRL, cortisol (F), thyroxine (both total, TT4 and free fraction, FT4); in addition, the serum levels of myoglobin (M) and TBG were also measured. A significant reduction of the serum levels of LH, FSH and T was observed during methandrostenolone administration; while LH and FSH fully recovered 7 days after discontinuation of the drug, the T serum levels had not reached their baseline values at that time, though normal physicological circadian variation of this hormone was maintained during drug administration. Moreover, significant correlations were found for all the pairs of values obtained for FSH vs T in 8 subjects, for LH vs T in 3, and for FSH vs LH in 6 of the subjects. The serum PRL levels showed a trend to decrease during drug administration, without reaching statistical significance however, while the F serum levels appeared not to be affected by the anabolic treatment, also in terms of circadian variation. While FT4 did not show any significant change during drug administration, both TT4 and TBG decreased significantly (TBG was still reduced 7 days after discontinuation of the drug). A peak in the M serum levels was observed in the first day of methandrostenolone assumption followed by a sudden decrease and by a subsequent slow, but significant increase. The results obtained in the present study indicate that treatment with anabolic agents in male athletes has certainly some significant side-effects on the pituitary-gonadal axis and that these effects are reversible in the short run and with the dosage used in this study. However, medical control during anabolic assumption by healthy male subjects (as such athletes) appears to be strictly necessary to monitor both the well known side effects on liver function and those on testicular activity.
Different anabolic steroids can exercise different effects on the pituitary-gonadal axis in males. During a pilot study regarding the possible beneficial effect of the anabolic steroid nandrolondecanoate (ND) on bone metabolism in patients with rheumatoid arthritis additional endocrinological parameters were studied. A significant decrease was found in the serum levels of testosterone, androstenedione and FSH and the ratio of testosterone/oestradiol. There was a significant increase in the serum levels of oestrone. The levels of oestradiol, SHBG, LH and cortisol remained unchanged.
An inhibitory effect of ND on testicular testosterone secretion is assumed. The decrease in androstenedione levels is explained by the diminished testosterone secretion. The rise in oestrone levels is explained by peripheral aromatizing of ND to oestrogens. The presented findings are in accordance with the hypothesis that sex steroids can act directly on the pituitary resulting in selective FSH and LH secretion. The possible role of the ratio testosterone/oestradiol in controlling gonadotrophin output is discussed.
Because testosterone is rapidly metabolized by the liver, it is necessary either to administer androgens by injection in the form of testosterone esters that are absorbed slowly into the circulation or to administer by mouth derivatives that are slowly metabolized by the liver. The later derivatives, however, have deleterious side effects that limit their usefulness. Long-acting parenteral androgen esters are the treatment of choice in the replacement therapy of male hypogonadism. Because these esters must be hydrolyzed to the free hormone prior to exerting their cellular actions the effectiveness of therapy can be monitored by following plasma testosterone levels. All known effects of the endogenous hormone can be duplicated except for the induction and maintenance of normal spermatogenesis. Androgens have been tried in a variety of clinical situations other than male hypogonadism in the hopes that the nonvirilizing actions would outweigh any detectable side effects. The only disorders in which a salutary effect has been documented are hereditary angioneurotic edema and some patients with anemia due to failure off the bone marrow.