Novel reference range values for serum testosterone: a cross-sectional study of 200,000 males.

PURPOSE: To better understand the effects of aging, metabolic syndrome, diurnal variation, and seasonal variation on serum testosterone levels in the context of current guideline statements on testosterone deficiency. METHODS: This cross-sectional study utilized the United Kingdom Biobank. Physical examination, anthropomorphic measurements, and laboratory evaluation were performed at the time of enrollment from 2006 to 2010. The primary outcomes were the effect of age, the presence of metabolic syndrome, the time of day, and the month of the year on serum testosterone levels. RESULTS: Among 197,883 included men, the 5th, 25th, 50th, 75th and 95th percentile testosterone levels in men without metabolic syndrome were significantly higher than those in men with metabolic syndrome at every decade of life (p < 0.001). The average testosterone level within each group (men without metabolic syndrome vs. men with) was clinically similar across decade of life (12.43 in 40's 12.29 in 50's 12.24 in 60's vs. 10.69 in 40's 10.56 in 50's 10.63 in 60's respectively). Average testosterone levels decreased with blood draws later in the day ranging from 10.91 to 12.74 nmol/L (p < 0.01). Similarly, there was seasonal variation in serum testosterone ranging from 11.86 to 12.18 nmol/L (p < 0.01). CONCLUSIONS: We found significant variation in serum testosterone according to the presence of metabolic syndrome and time of laboratory draw, but not according to age. These data challenge the prior dogma of age-related hypogonadism and favor an individualized approach towards serum testosterone measurement and interpretation. However, further studies are needed to correlate these population-based data with individuals' hypogonadal symptoms.

Infertility Counseling and Misattributed Paternity: When Should Physicians Become Involved in Family Affairs?

Infertility specialists may be confronted with the ethical dilemma of whether to disclose misattributed paternity (MP). Physicians should be prepared for instances when an assumed father's evaluation reveals a condition known for lifelong infertility, for example, congenital bilateral absence of vas deferens (CBAVD). When there is doubt regarding a patient's comprehension of his diagnosis, physicians must consider whether further disclosure is warranted. This article describes a case of MP with ethics analysis that concludes that limited nondisclosure is most consistent with a physician's principled duties to inform, to respect patients' autonomy, and to employ nonmaleficence (including the avoidance of psychosocial harms).

Low total motile sperm in transgender women seeking hormone therapy.

PURPOSE: This study was undertaken to compare semen quality, hormonal status, and social factors in transgender women seeking fertility preservation with those of fertile cisgender men. Long-range goals are to establish standard practice measures ensuring optimum semen quality for cryopreservation and fertility preservation in transgender women. METHODS: This is a case-control study carried out at an academic medical center. Cases are transgender women seeking fertility preservation prior to initiation of hormone therapy. Controls are cisgender men recently fathering a child. All participants completed the Depression Anxiety Stress Scales 21 survey and additional survey questions related to personal behaviors. Complete semen analysis was carried out in a clinical andrology laboratory according to WHO guidelines, 5th edition. Serum follicle stimulating hormone, estradiol, and testosterone were measured at the time of semen analysis. RESULTS: Sperm concentration, total sperm per ejaculate, total motile sperm, volume, and normal sperm morphology were significantly lower in transgender females compared with fertile cisgender men. Other measures of semen parameters and hormone concentrations were not different between groups. Survey results indicated transgender women were more likely to have symptoms of depression, anxiety, and stress and utilize tucking and tight undergarments, compared with controls; however, both groups reported similar numbers of ejaculations per week. CONCLUSIONS: Although semen parameters were low, cryopreservation of sperm prior to hormone therapy is a viable fertility preservation option for most transgender women. The etiology of the differences in semen parameters is not known. Enhanced education related to personal behaviors or treatment to reduce effects of stressors prior to cryopreservation may improve future fertility potential.

Surgically acquired sperm use for assisted reproductive technology: trends and perinatal outcomes, USA, 2004-2015.

PURPOSE: To compare national trends and perinatal outcomes following the use of ejaculated versus surgically acquired sperm among IVF cycles with male factor infertility. METHODS: This retrospective cohort includes US fertility clinics reporting to the National ART Surveillance System between 2004 and 2015. Fresh, non-donor IVF male factor cycles (n = 369,426 cycles) were included. We report the following outcomes: (1) Trends in surgically acquired and ejaculated sperm. (2) Adjusted risk ratios comparing outcomes for intracytoplasmic sperm injection (ICSI) cycles using surgically acquired (epididymal or testicular) versus ejaculated sperm. (3) Outcomes per non-canceled cycle: biochemical pregnancy, intrauterine pregnancy, and live birth (≥ 20 weeks). (4) Outcomes per pregnancy: miscarriage (< 20 weeks) and singleton pregnancy. (5) Outcomes per singleton pregnancy: normal birthweight (≥ 2500 g) and full-term delivery (≥ 37 weeks). RESULTS: Percentage of male factor infertility cycles that used surgically acquired sperm increased over the study period, 9.8 (2004) to 11.6% (2015), p < 0.05. The proportion of cycles using testicular sperm increased significantly over the study period, 4.9 (2004) to 6.5% (2015), p < 0.05. Among fresh, non-donor male factor ART cycles which used ICSI (n = 347,078 cycles), cycle, pregnancy, and perinatal outcomes were statistically significant but clinically similar with confidence intervals approaching one between cycles involving epididymal versus ejaculated sperm and between testicular versus ejaculated sperm. Results were similar among cycles with a sole diagnosis of male factor (no female factors), and for the subset in which the female partner was < 35 years old. CONCLUSION: Among couples undergoing ART for treatment of male factor infertility, pregnancy and perinatal outcomes were similar between cycles utilizing ejaculated sperm or surgically acquired testicular and epididymal sperm.

Accounting for physicians' gender expectations improves men's health medicine.

The field of men's health seeks to improve men's health outcomes by accounting for the specific ways that gender influences male health behaviors. To meet this goal, physicians must also account for the ways that their own cultural assumptions about masculinity influence their clinical practice. Gender is not solely biological. It is a way of acting out masculinity or femininity that varies across individual and cultural contexts. Thus, doctors and patients might have different ideas about how a man should feel and act. These attitudes can influence whether men's bodily changes are viewed as pathological versus normal. Two simple interventions are proposed to enable physicians to identify their own assumptions about masculinity and differentiate these from their patients' in order to make more appropriate treatment decisions. The first is advocating for medical guidelines for their specialty that account for gender as context-specific rather than universal. The second is incorporating attention to gender into their daily clinical practice by asking rather than assuming what patients want in order to base treatment decisions on patients' rather than physicians' ideas of how men should feel and behave.

El campo de la salud masculina procura mejorar los resultados en materia de salud de los hombres al reconocer las maneras específicas en que el género influye en el comportamiento de los hombres con respecto a la salud. Para alcanzar esta meta, los médicos también deben tener en cuenta la manera en que sus propios supuestos culturales acerca de la masculinidad influyen en su práctica clínica. El género no es solo biológico; es una manera de exteriorizar la masculinidad o la femineidad que varía entre los diversos contextos individuales y culturales. Por consiguiente, los médicos y los pacientes pueden tener ideas diferentes acerca de cómo debe sentirse y actuar un hombre, y estas actitudes pueden influir en que los cambios físicos de los hombres se perciban como patológicos o como normales. Se proponen dos intervenciones sencillas para ayudar a los médicos a tomar consciencia de sus propios supuestos acerca de la masculinidad y distinguirlos de los de sus pacientes, a fin de tomar decisiones terapéuticas más apropiadas. La primera intervención consiste en promover pautas clínicas para su especialidad que reconozcan el género como algo dependiente del contexto en lugar de algo universal. La segunda es incorporar la atención al género en su práctica clínica diaria al preguntar a los pacientes qué desean en lugar de suponerlo, a fin de basar las decisiones terapéuticas en las ideas de los pacientes sobre cómo deben sentirse y comportarse los hombres, en lugar de las ideas del médico.

O ramo da saúde masculina procura melhorar os desfechos de saúde do homem ao levar em consideração as maneiras inerentes como o gênero influencia os comportamentos masculinos com relação à saúde. Para esta finalidade, os médicos também devem levar em conta que seus próprios pressupostos culturais sobre masculinidade influenciam a prática clínica. O gênero não é meramente um aspecto biológico. É uma forma de exteriorizar a masculinidade ou a feminilidade que varia dependendo do contexto individual e cultural. Assim, médicos e pacientes podem ter noções distintas sobre como um homem deve se sentir e agir e estas atitudes podem influir na maneira como são consideradas as mudanças físicas no corpo de um homem, se patológicas ou normais. São propostas duas intervenções simples para ajudar os médicos a se conscientizarem dos próprios pressupostos sobre masculinidade e diferenciá-los dos pressupostos dos pacientes a fim de que possam tomar decisões de tratamento mais apropriadas. A primeira intervenção consiste em defender orientações médicas para a especialidade que reconheçam o gênero como próprio para um contexto, em vez de algo universal. A segunda consiste em incorporar a atenção ao gênero à prática clínica diária, perguntando ao paciente o que ele quer, em vez de fazer suposições, a fim de fundar as decisões de tratamento nas noções do paciente, não nas do médico, de como um homem deve se sentir e se comportar.

Trends in Testosterone Replacement Therapy Use from 2003 to 2013 among Reproductive-Age Men in the United States.

PURPOSE: Although testosterone replacement therapy use in the United States has increased dramatically in the last decade, to our knowledge trends in testosterone replacement therapy use among reproductive-age men have not been investigated. We assessed changes in testosterone replacement therapy use and practice patterns among 18 to 45-year-old American men from 2003 to 2013 and compared them to older men. MATERIALS AND METHODS: This is a retrospective, cross-sectional analysis of men 18 to 45 and 56 to 64 years old who were enrolled in the Truven Health MarketScan® Commercial Claims Databases throughout each given calendar year from 2003 to 2013, including 5,094,868 men in 2013. Trends in the yearly rates of testosterone replacement therapy use were calculated using Poisson regression. Among testosterone replacement therapy users, the Cochran-Armitage test was used to assess temporal trends in age, formulation type, semen analysis and serum testosterone level testing during the 12 months preceding the documented use of testosterone replacement therapy. RESULTS: Between 2003 and 2013, there was a fourfold increase in the rate of testosterone use among 18 to 45-year-old men from 29.2/10,000 person-years to 118.1/10,000 person-years (p <0.0001). Among testosterone replacement therapy users, topical gel formulations were initially most used. Injection use then doubled between 2009 and 2012 (23.5% and 46.2%, respectively) and surpassed topical gel use in 2013. In men 56 to 64 years old there was a statistically significant threefold increase in testosterone replacement therapy use (p <0.0001), which was significantly smaller than the fourfold increase in younger men (p <0.0001). CONCLUSIONS: In 2003 to 2013, testosterone replacement therapy use increased fourfold in men 18 to 45 years old compared to threefold in older men. This younger age group should be a focus for future studies due to effects on fertility and unknown long-term sequelae.

Introduction to Medication Effects on Male Reproduction.

The over-arching goal of this volume is to help infertility practitioners evaluate and manage their patients with poor semen quality. Medications can negatively impact on male reproduction and these effects are of increasing concern. People world-wide are using more medications than in the past, including men of childbearing age. In addition, men are fathering children later in life than previously, which is associated with greater medication use in the reproductive population. Finally, people are experiencing more chronic disease at earlier ages, particularly in developed countries. Taken together, these factors have increased the number of prescribed and over-the-counter (OTC) drugs being taken by men attempting fatherhood. There is some evidence in the literature that medications, even some common OTC medications, can negatively impact male reproduction, and yet, medication use is inadequately addressed in the evaluation of male infertility and fertility plans are rarely considered by providers before prescribing medications. In this volume, we systematically consider medications being used world-wide, focusing on those that might cause poor semen quality in men with otherwise idiopathic infertility. Extensive tables are provided in this volume that summarize the research for each specific medication, and it is our hope that these tables will be useful in day-to-day counseling of infertility patients and of men desiring fertility. Although some specialist practitioners are aware that there are pharmacological negative effects on male fertility, most practitioners are not, and the published evidence is surprisingly sparse. We hope that this volume will encourage our readers to conduct robust, well-designed studies to inform clinical practice.

Challenges of Obtaining Evidence-Based Information Regarding Medications and Male Fertility.

In the clinic, the existing literature is insufficient to counsel our infertile men on medication use. Most studies have flaws that limit their application to evidence-based practice. In this chapter, we discuss the limitations of the current literature and the challenges to designing more useful studies. Among the most important weaknesses of existing studies is lack of power; that is, too few men are included to draw conclusions about the existence and size of medication effects. Adequate power is particularly important when confirming an absence of medication effect. Bias is also a problem in most studies. Early studies were rarely randomized, placebo-controlled, or blinded; a common example is patients receiving different medication regimes based on the severity of their symptoms-making it impossible to attribute differences between treated and untreated men to the medications. Additional bias is introduced by failing to include other factors that influence the outcome in the experimental design. A uniform population amenable to randomization and placebo-control are experimental species, and useful information has been gained from these models. However, application to humans is limited by differences from other species in route of drug administration, absorption of the drug, concentration in the male genital tract tissues, and genital tract physiology. To a lesser degree, there is variation among individual men in their response to drugs. In addition, drugs in the same class may have different effects, limiting the applicability of data across drugs of a single class. Complicating matters further, a toxic medication may seem to improve fertility endpoints by improving a disease condition that diminishes fertility. Finally, drug interactions have not been studied, and actual fertility data (pregnancy/fecundity) in humans are rare. A healthy dose of skepticism is warranted when evaluating studies of medications and male reproductive health.

Male Reproductive Functions Disrupted by Pharmacological Agents.

In this chapter, we review the male reproductive functions disrupted by medications. Medications can affect the hypothalamic-pituitary-gonad axis, acting as endocrine disrupting chemicals (EDCs). Disturbances may be directly at androgen receptors, modifying the activity of endogenous androgens at the target tissue, or may disrupt feedback loops at the hypothalamus or pituitary resulting in modification of gonadotropin release. Impaired testosterone production and/or spermatogenesis result. Other EDC activities can be indirect via effects on levels of prolactin (PRL), estrogen, cortisol, thyroid hormone, or sex hormone binding globulin (SHBG). Appropriate regulation of these hormones and SHBG are essential for normal reproductive function. An increase in circulating PRL levels is a common adverse medication effect. The consequence is lower gonadotropin and testosterone secretion. Drugs can also have direct toxicity on the seminiferous tubule epithelium, including effects on Leydig cells, Sertoli cells, or germ cells. In some cases, spermatogenesis is severely impaired. After leaving the testis, sperm spend a week or more in the epididymis. It is clear from the timing of some drug effects that sperm are damaged during epididymal transit. There can also be impairment of the ejaculatory reflex, resulting in alterations of emission or expulsion of semen. Even after ejaculation, exposure to seminal plasma can alter sperm function, and some drugs may affect sperm at this stage. The most critical effects on male reproduction are decreased fertility and/or health effects on offspring. These endpoints have received little research attention. Another consideration is the metabolism of drugs. Medications may become more toxic if metabolic systems are suboptimal due to comorbid conditions.

Exogenous Androgens and Male Reproduction.

Due in part to aggressive marketing, the prevalence of exogenous androgen use has increased to disturbing levels. Prescribing practitioners are often unaware of the severity of the anti-fertility effects. Exogenous androgens should only be prescribed if hypogonadism has been established by appropriate investigation, and preferably the patient does not intend to father a child. There are alternative medications, or combinations of medications, that can be used if hypogonadism is present and fertility is desired.It is somewhat counterintuitive that testosterone treatment will decrease or abolish fertility. Exogenous testosterone inhibits spermatogenesis by removing the feedback response to low testosterone at the hypothalamus and pituitary. This results in reduced synthesis and secretion of gonadotropins required to stimulate endogenous testosterone production and to support spermatogenesis. It is important to realize that the normal testicular levels of testosterone are approximately 100 times the concentration in circulation. These high levels are required locally to support spermatogenesis. So even with circulating androgen levels within the normal range, spermatogenesis fails due to insufficient gonadotropin and local testosterone support. Androgenic herbal supplements and illicit use of anabolic steroids have contributed to this serious challenge in the treatment of infertile men. Most men will recover normal spermatogenesis after cessation of exogenous testosterone treatment, but this requires 6 months or more in most men. In rare cases fertility is permanently impaired.

Phosphodiesterase Inhibitors (PDE Inhibitors) and Male Reproduction.

The nonspecific PDE inhibitors, particularly the methylxanthines: caffeine, pentoxifylline (PTX), and theophylline, are known to stimulate sperm motility in vitro and have been used to treat sperm prior to insemination. The in vivo effects are less dramatic. A beneficial effect of caffeine, which is a constituent of some medications, remains controversial. Very high doses of caffeine do have negative effects on fertility endpoints in men and experimental species. The specific PDE5 inhibitors, particularly sildenafil and tadalafil, are prescribed for erectile dysfunction, as well as pulmonary hypertension, lower urinary tract symptoms, and premature ejaculation. PDE5 is expressed throughout the contractile tissues of the male reproductive tract, generally increasing contractility. Some PDE5 inhibitors tend to increase circulating testosterone levels somewhat. For short-term exposure consistent with use prior to intercourse, there appears to be minimal effects on semen quality. Several large, randomized controlled trials (RCTs) in healthy men have not found adverse effects of long-term use of these drugs on semen quality. RCTs in infertile men have demonstrated a modest increase in semen quality. Animal studies at human equivalent doses (HED) have produced similar results in young males, but a study in aging male rats found progressive decreases in epididymal sperm quality accompanied by consistent degeneration of the seminal tubules suggesting that studies in older men might be warranted. A concerning study in mice found lower fertilization rates in males treated with HED of sildenafil and mated the next day to untreated females than for control males. Fertility studies in humans are needed.

Pain Medications and Male Reproduction.

The increasing use of opioid medications has become a crisis in developed countries. The profound negative effects of opioids on male reproduction are well known, but this topic is absent from the current conversations about these medications. In the fertility clinic, a significant proportion of our patients are using opioids for pain management, and the options for these men are unclear. Opioids exert their negative effects by a variety of mechanisms. At high doses, testosterone levels fall significantly and hypogonadism is seen. In part, this results from increased prolactin and inhibition of gonadotropin production/secretion by the pituitary. However, negative effects on the testis are seen even in the absence of decreased androgen levels. As we review in this chapter, Leydig and germ cells produce endogenous opioids, and receptors for these substances are present throughout the testis. For example, endogenous opioids produced by Leydig and germ cells provide paracrine inhibition at Sertoli cell receptors, decreasing the production of androgen binding protein, which is required for intra-testis transport of androgens. Morphine also increases the expression of aromatase in the brain and testis and acts directly on the testis and germ cells to decrease testicular function. Exogenous opioids in men reduce semen quality, including increased DNA fragmentation. All opioids have these effects, but less damage is caused by lower doses, shorter-acting opioids, and by some drugs with mixed receptor activity, such as tramadol and tapentadol. The non-steroid anti-inflammatory drugs (NSAIDS) have much less effect on the male reproductive system, although there is a paucity of human studies. Paracetamol has been shown to cause sperm abnormalities, including DNA fragmentation, and to increase time to pregnancy and may prove to be of greater concern. In rodents, paracetamol has negative impacts on seminiferous tubule histology and fertility. Robust, well-designed studies in humans are needed.

5α-Reductase Inhibitors (5ARIs) and Male Reproduction.

The 5ARIs, finasteride and dutasteride, are used to treat benign prostate hyperplasia and lower urinary tract symptoms. At much lower doses, 5ARI treatment reduces male hair loss. These drugs inhibit the conversion of testosterone to the more active dihydrotestosterone (DHT). In men taking these medications, DHT levels are reduced by some 90% while testosterone levels remain relatively stable. Well known for their negative effects on libido and erectile function, 5ARIs also cause ejaculatory dysfunction in some men, having the potential to decrease semen quality. In fact, some studies of men treated with these drugs have reported lower total sperm count, along with lower sperm motility, although the changes are probably insufficient to reduce fertility in men with normal semen before treatment. There is a population of men with more severely decreased sperm numbers; as low as 10% of pretreatment values. Fewer studies have looked at the lower doses used for male alopecia, indicating little affect in men with normal semen quality, but a negative effect on sperm numbers in men with oligozoospermia. There have been no studies looking at fertility endpoints for these medications.

Psychotropics and Male Reproduction.

Psychotropic drugs, including antidepressants, antipsychotics, and anticonvulsants, all have negative effects on sexual function and semen quality. These adverse events vary among men and are less pronounced for some medications, allowing their effects to be managed to some extent. Use of specific serotonin reuptake inhibitors (SSRIs) is prevalent in men of reproductive age; and application to treat premature ejaculation increases the number of young men on SSRI therapy. Oxidative damage to sperm can result from prolonged residence in the male reproductive tract. The increase in ejaculatory latency seen with SSRIs likely underlies some of their negative effects on semen quality, including higher sperm DNA fragmentation, seen in all SSRIs evaluated thus far. These medications increase prolactin (PRL) levels in some men, and this is often credited with inhibitory effects on male reproduction; however, testosterone levels are generally normal, reducing the likelihood of direct HPG axis inhibition by PRL. The tricyclic antidepressants have also been shown to increase PRL levels in some studies but not in others. The exception is the tricyclic antidepressant clomipramine, which profoundly increases PRL levels and may depress semen quality. Other antidepressants modulating synaptic levels of serotonin, norepinephrine, and/or dopamine may have toxicity similar to SSRIs, but most have not been evaluated. In limited studies, norepinephrine-dopamine reuptake inhibitors (NDRIs) and serotonin agonist/reuptake inhibitors (SARIs) have had minimal effects on PRL levels and on sexual side effects. Antipsychotic medications increase PRL, decrease testosterone, and increase sexual side effects, including ejaculatory dysfunction. The greatest evidence is for chlorpromazine, haloperidol, reserpine, risperidone, and thioridazine, with less effects seen with aripiprazole and clozapine. Remarkably few studies have looked at antipsychotic effects on semen quality, and this is an important knowledge gap in reproductive pharmacology. Lithium increases PRL and LH levels and decreases testosterone although this is informed by few studies. The anticonvulsants, many used for other indications, generally decrease free or bioavailable testosterone with variable effects on the other reproductive hormones. Valproate, carbamazepine, oxcarbazepine, and levetiracetam decrease semen quality; other anticonvulsants have not been investigated for this adverse reaction. Studies are required evaluating endpoints of pregnancy and offspring health for psychotropic medications.

Cardiovascular/Pulmonary Medications and Male Reproduction.

Cardiovascular and respiratory medications are used by men of reproductive age although use of the former is most prevalent in advanced age. Many of these drugs have been associated with sexual dysfunction, including erectile and ejaculatory dysfunction, but for most there is insufficient evidence to link their use with testicular dysfunction, reduced semen quality or infertility. Some exceptions are the irreversible α1-adrenergic antagonist phenoxybenzamine, which carries a high risk of retrograde ejaculation; the specific α1A-adrenergic antagonists silodosin and tamsulosin, used primarily to treat BPH/lower urinary tract symptoms, which can cause retrograde ejaculation; and the peripheral ß1-adrenergic antagonist atenolol, used to treat hypertension, which may decrease testosterone/free-testosterone levels. In this chapter, we review the evidence available regarding adverse reactions on male reproduction of adrenergic receptor agonists/antagonists, calcium channel blockers, angiotensin converting enzyme (ACE) inhibitors, diuretics, digoxin, and hydralazine. For some of these medications, there is some evidence for male reproductive effects, along with some solid work in experimental and companion animal species suggesting negative effects. In contrast, and of special note, are calcium channel blockers, which have long been included on lists of medications with the potential to cause male infertility. This turns out to be a good example of a substance with profound effects on sperm function in vitro, but with limited evidence for in vivo effects on semen quality or fertility, even in experimental species. We hope that the evidence provided in this chapter will stimulate additional studies for these important classes of medications.

Antimicrobials and Male Reproduction.

Antibiotics have long been suspected of contributing to male infertility; however, there are remarkably limited data to support this premise. A major challenge for evaluating antibiotic effects is that the diseases they treat often have negative impacts on male reproduction, so treatment with the antimicrobial can improve reproductive endpoints. This is particularly true for diseases of the male reproductive tract. As a class, anti-parasitic drugs are toxic to eukaryotic cells and have significant potential for reproductive toxicity. A variety of these medications are also used in companion and food animal species; in this chapter we review the literature on anti-parasitic drugs on male reproduction in these species. In humans, only niridazole has been shown to cause reversible spermatogenic arrest in 20 men with schistosomiasis. Of the antifungal medications, ketoconazole has been shown in some studies to transiently decrease testosterone levels in men, but work is lacking for semen quality or fertility. We review studies of antibacterial medications in the chapter, with some minimal human data available for decreased semen quality in men taking nitrofurantoin, ciprofloxacin, ofloxacin, or sulfamethoxazole. These and some other antibacterials have been studied in other species with results suggestive of negative impacts on male fertility endpoints. In light of the common assumption of reproductive toxicity for antimicrobial medications, and the decided lack of supporting evidence, there is a substantial need for well-designed clinical trials in this area.

Antivirals and Male Reproduction.

The use of antiviral medications has increased with the recognition and treatment of HIV infections, and these drugs are the main focus of this chapter. HIV has become a chronic disease, and many men with HIV desire children. The disease itself has profound negative effects on semen quality, as does infection with hepatitis C virus (HCV), so treatment with antivirals generally improves semen quality in men with longer duration of infection and/or greater symptoms. Several changes in medical practice have allowed studies of pharmacopathology of antiviral medications and brought focus on medication effects in asymptomatic men: (1) the successful practice of specialized sperm washing of asymptomatic men with HIV infection for insemination of their HIV-negative partner; (2) the recommendation that men begin anti-retroviral treatment before HIV symptoms appear; and (3) the recommendation that men without HIV infection who have HIV-seropositive partners take HIV prophylaxis. Early cases of HIV infection were generally treated by monotherapy with the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine (AZT). Currently, men with HIV infections take combination anti-retroviral therapy (cART), involving three or more medications, making it difficult to assess the toxicity of individual medications. In general, zidovudine alone or cART have minimal negative effects on semen quality; the most common being decreased rapid swimming of motile sperm. We review studies with other outcomes and animal studies in this chapter. Peginterferon-α, which is utilized together with ribavirin to treat HCV, does appear to decrease testosterone levels and semen quality although studies showing these effects have been small. Antiviral medications used to treat viral infections other than HIV and HCV have received little experimental attention for male reproductive effects, even in experimental species.

Immunosuppressants and Male Reproduction.

Prolonged use of immunosuppressant medications is occasionally seen in infertile men with chronic inflammatory conditions; autoimmune disorders; or an organ or hematopoietic stem cell transplant. Chronic inflammation impacts negatively on male reproductive endpoints, so immunosuppressant therapy can produce improvements. Corticosteroids have been used to treat antisperm antibodies and even as an empirical treatment for male infertility in general. Trials of these methods have provided mixed results on semen quality and fertility, with improvement, no change and negative effects reported by different investigators. In a substantial number of observational studies, patients on long-term therapy with prednisone for chronic inflammatory disease, testosterone levels were lower compared to untreated controls, though randomized controlled trials have not been conducted. Similarly decreases in testosterone have been reported in men receiving corticosteroids to minimize transplant rejection; however, most were treated with multiple immunosuppressive medications that may have contributed to this effect. A large number of trials of healthy men treated with corticosteroids have shown some disruption in reproductive hormone levels, but other studies reported no effect. Studies in monkeys, rats (at human equivalent dose), cattle, sheep, and horses have shown endocrine disruption, including low testosterone with dexamethasone treatment. Of the cytostatic immunosuppressives, which have high potential for cellular damage, cyclophosphamide has received the most attention, sometimes lowering sperm counts significantly. Methotrexate may decrease sperm numbers in humans and has significant negative impacts in rodents. Other chemotherapeutic drugs used as immunosuppressants are likely to impact negatively on male fertility endpoints, but few data have been collected. The TNF-α Inhibitors have also received little experimental attention. There is some evidence that the immunophilin modulators: cyclosporine, sirolimus, and everolimus cause endocrine disruption and semen quality impairment. As we review in this chapter, results in experimental species are concerning, and well-designed studies are lacking for the effects of these medications on reproductive endpoints in men.

Miscellaneous Drugs and Male Reproduction.

In addition to main categories of medications believed to have negative impacts on male reproduction, there are a number of miscellaneous drugs with some evidence for such adverse reactions. Because of its widespread use and over-the-counter availability, the H2 receptor antagonist cimetidine is most concerning. As a competitive antagonist at androgen receptors, it can impact the HPG axis and semen quality. In this chapter, we review the studies of this drug and other histamine H2 receptor antagonists in men and experimental species. Several other medications are concerning and the evidence for negative effects on reproduction are covered: colchicine, domperidone, hydroxyurea, metformin, metoclopramide, mifepristone, retinoids, and statins.

Current Practices of Measuring and Reference Range Reporting of Free and Total Testosterone in the United States.

PURPOSE: The evaluation and management of male hypogonadism should be based on symptoms and on serum testosterone levels. Diagnostically this relies on accurate testing and reference values. Our objective was to define the distribution of reference values and assays for free and total testosterone by clinical laboratories in the United States. MATERIALS AND METHODS: Upper and lower reference values, assay methodology and source of published reference ranges were obtained from laboratories across the country. A standardized survey was reviewed with laboratory staff via telephone. Descriptive statistics were used to tabulate results. RESULTS: We surveyed a total of 120 laboratories in 47 states. Total testosterone was measured in house at 73% of laboratories. At the remaining laboratories studies were sent to larger centralized reference facilities. The mean ± SD lower reference value of total testosterone was 231 ± 46 ng/dl (range 160 to 300) and the mean upper limit was 850 ± 141 ng/dl (range 726 to 1,130). Only 9% of laboratories where in-house total testosterone testing was performed created a reference range unique to their region. Others validated the instrument recommended reference values in a small number of internal test samples. For free testosterone 82% of laboratories sent testing to larger centralized reference laboratories where equilibrium dialysis and/or liquid chromatography with mass spectrometry was done. The remaining laboratories used published algorithms to calculate serum free testosterone. CONCLUSIONS: Reference ranges for testosterone assays vary significantly among laboratories. The ranges are predominantly defined by limited population studies of men with unknown medical and reproductive histories. These poorly defined and variable reference values, especially the lower limit, affect how clinicians determine treatment.