Anabolic steroid misuse and male infertility: management and strategies to improve patient awareness.

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.

Enclomiphene citrate: A treatment that maintains fertility in men with secondary hypogonadism.

INTRODUCTION: Hypogonadism is an important issue among the male population. Treatments such as exogenous testosterone have become very popular. One of the adverse effects of testosterone is its suppression of fertility. This has lead to the use of alternative therapies such as selective estrogen receptor modulators (SERMs) that aim to correct hypogonadism without reducing fertility. Areas covered: The SERM, clomiphene citrate, which is approved by the FDA for the treatment of ovarian dysfunction, has been shown to have beneficial effects on male hypogonadism. Clomiphene citrate exists as a mixture of both the cis-isomer (zuclomiphene) and the trans-isomer (enclomiphene). The literature has suggested that most of the beneficial effects of clomiphene are due to the trans-isomer enclomiphene. Zuclomiphene contributes little to the intended outcomes. The purpose of this drug profile is to examine the available literature on the trans-isomer enclomiphene. Expert opinion: Enclomiphene has been shown to increase testosterone levels while stimulating FSH and LH production. Initial studies demonstrated that enclomiphene maintains the androgenic benefit of clomiphene citrate without the undesirable effects attributable to zuclomiphene. This article reviews the difficulties associated with the FDA approval of a new molecular entity related to the treatment of hypogonadism.

The Effect of Testosterone Topical Solution in Hypogonadal Men With Suboptimal Response to a Topical Testosterone Gel.

This study evaluated the effect of axillary administration of a 2% testosterone solution (Axiron®) in hypogonadal (HGN) men who had had a suboptimal response to treatment with a commercially available topical testosterone gel. HGN men averaging 57 years old, with a mean body mass index of 31.9 kg/m2 and median baseline testosterone level (T-level) of 185.2 ng/dL, who had failed to reach normal T-levels with a topical testosterone gel (Androgel 1.62%, Androgel, Testim, or Fortesta) were treated with a 2% testosterone solution until T-levels reached a normal range (from ≥300 to ≤1,050 ng/dL) or for up to 9 weeks. Outcomes included the cumulative percentage of men with a serum T-level in the normal range during treatment with Axiron and improvement in symptoms of low energy level and low sexual drive. During the study, 95% of HGN men (72/78) attained a T-level in the normal range. The median T-level at endpoint was 495.7 ng/dL, a threefold increase over baseline, p < .001, 70% achieving normal T-levels within the first 2 weeks of treatment. In a post hoc analysis, all subjects with baseline body mass indexes >35 kg/m2 ( n = 19) achieved T-levels in the normal range. Prior to treatment, over 61% of subjects (48/78) reported impairment in either energy level or sexual drive. After treatment (or testosterone normalization), energy level improved in 75% of subjects and sexual drive improved in 70%. Topical 2% testosterone solution is a safe and effective treatment for HGN men who have had a suboptimal response to previous treatment with topical testosterone gels.

Metabolomics Approach in the Study of the Well-Defined Polyherbal Preparation Zyflamend.

Zyflamend is a highly controlled blend of 10 herbal extracts that synergistically impact multiple cell signaling pathways with anticancer and anti-inflammatory properties. More recently, its effects were shown to also modify cellular energetics, for example, activation of fatty acid oxidation and inhibition of lipogenesis. However, its general metabolic effects in vivo have yet to be explored. The objective of this study was to characterize the tissue specific metabolomes in response to supplementation of Zyflamend in mice, with a comparison of equivalent metabolomics data generated in plasma from humans supplemented with Zyflamend. Because Zyflamend has been shown to activate AMPK, the "energy sensor" of the cell, in vitro, the effects of Zyflamend on adiposity were also tested in the murine model. C57BL/6 mice were fed diets that mimicked the macro- and micronutrient composition of the U.S. diet with and without Zyflamend supplementation at human equivalent doses. Untargeted metabolomics was performed in liver, skeletal muscle, adipose, and plasma from mice consuming Zyflamend and in plasma from humans supplemented with Zyflamend at an equivalent dose. Adiposity in mice was significantly reduced in the Zyflamend-treated animals (compared with controls) without affecting body weight or weight gain. Based on KEGG pathway enrichment, purine and pyrimidine metabolism (potential regulators of AMPK) were particularly responsive to Zyflamend across all tissues, but only in mice. Consistent with the metabolomics data, Zyflamend activated AMPK and inhibited acetyl CoA-carboxylase in adipose tissue, key regulators of lipogenesis. Zyflamend reduces adipose tissue in mice through a mechanism that likely involves the activation of AMPK.

Management and counseling of the male with advanced paternal age.

Increasing percentages of children are being born to older fathers. This has resulted in concerns about the potential adverse effects of advanced paternal age. To help clinicians counsel couples, a systemic review was performed to attempt to address questions that these couples may ask: Should routine sperm testing be performed in older males? Should preimplantation genetic diagnosis (PGD) be performed? How do providers counsel patients about risk? Should young males freeze sperm if they plan to delay paternity? Using the terms "advanced paternal age", "semen testing", "preimplantation genetic diagnosis/screening", and "cryopreservation", a comprehensive search was performed in PubMed and the Cochrane Library, and numerous international societal guidelines were reviewed. In total, 42 articles or guidelines were reviewed. There were no limits placed on the timing of the articles. Thirty articles were found to be relevant and beneficial to answering the above questions. Each question was answered separately by the supporting literature. While primary research exists to support the role of semen testing, PGD/preimplantation genetic screening, and sperm banking in males who may be affected by advancing age, comprehensive studies on the possible clinical benefit of these interventions have yet to be performed. As a result, societal guidelines have yet to incorporate distinct best-practice guidelines on advanced paternal age.

The significance of clinical practice guidelines on adult varicocele detection and management.

Varicoceles are the most common correctable etiology of male factor infertility. However, the detection and management of varicoceles have not been standardized. This has led to decades of debate regarding the effect of varicocele on male infertility and subsequently whether repair leads to an improved fertility status. The current body of evidence investigating the role of varicocele and varicocelectomy is weak and conflicting. The stance taken by the AUA and ASRM suggests that there is insufficient outcomes data to support evidenced-based guidelines, citing evidence used to provide current recommendations are generally of a low quality level. On the other hand, the EAU Guidelines give a level 1a of evidence for management of varicoceles that are clinically palpable, associated with subnormal semen analyses and having otherwise unexplained fertility. Besides aiding with clinical varicocele detection and management, clinical practice opinion statements and guidelines aim to direct and strengthen the infrastructure of future studies. We review the current status of opinion statements and guidelines in varicocele and management detection with focus on their application in practice.

Oral enclomiphene citrate raises testosterone and preserves sperm counts in obese hypogonadal men, unlike topical testosterone: restoration instead of replacement.

OBJECTIVES: To determine the effects of daily oral doses of enclomiphene citrate compared with topical testosterone gel treatment on serum total testosterone (TT), luteinising hormone (LH), follicle-stimulating hormone (FSH), and sperm counts in men with secondary hypogonadism. PATIENTS AND METHODS: Two parallel randomised, double-blind, double-dummy, placebo-controlled, multicentre, phase III studies were undertaken to evaluate two doses of enclomiphene citrate vs testosterone gel (AndroGel(®) 1.62%) on TT, LH, FSH, and sperm counts in overweight men aged 18-60 years with secondary hypogonadism. Men were screened and enrolled in the trials (ZA-304 and ZA-305). All enrolled men had early morning serum TT levels in the low or low normal range (≤300 ng/dL; ≤10.4 nmol/L) and had low or normal LH (<9.4 IU/L) levels measured on two separate occasions 2-10 days apart. Serum samples were obtained over the course of the study to determine relevant hormone levels at baseline and after 16 weeks of treatment. Men provided semen samples twice to enroll at the beginning and twice at the end of the study. RESULTS: TT levels increased between baseline and after 16 weeks of treatment in all the treatment groups. FSH and LH levels increased in the enclomiphene citrate groups and decreased in the testosterone gel group at 16 weeks. Enclomiphene citrate maintained sperm concentration in the normal range over the treatment period, while there was a marked reduction in spermatogenesis in the testosterone gel group. CONCLUSIONS: Enclomiphene citrate consistently increased serum TT, LH and FSH, restoring normal levels of serum TT. Enclomiphene citrate treatment maintained sperm concentrations in the normal range. The effects on TT were also seen with testosterone replacement via testosterone gel but sperm counts were not maintained.

Testosterone supplementation in men: a practical guide for the gynecologist and obstetrician.

PURPOSE OF REVIEW: Prescribing habits for the treatment of symptomatic hypogonadism have recently stirred controversy surrounding testosterone replacement therapy. As a result, the gynecologist will need to recognize this iatrogenic form of decreased sperm production in couples seeking fertility advice. We have compiled a review of the current literature on testosterone supplementation pertaining to the gynecologic practice. RECENT FINDINGS: Over the last decade, testosterone use has seen a recent increase including in men desiring to become fathers. Many physicians and hypogonadal men do not recognize that testosterone replacement therapy can have a detrimental effect on spermatogenesis. Fortunately, the cessation of treatment will yield predictable recovery of sperm production for most men. A growing body of evidence supports the use of selective estrogen receptor modulators, such as clomiphene citrate, or human chorionic gonadotropin for the treatment of hypogonadism in men who wish to maintain fertility potential. Recently, the Food and Drug Administration has recommended a labeling update on testosterone products to warn of possible increased risk of venous thromboembolism, cardiovascular events and stroke. SUMMARY: Clinicians should be familiar with current practices involving testosterone replacement therapy and the implications on male factor fertility.

Treatment of hypogonadotropic male hypogonadism: Case-based scenarios.

The aim of this study is to review four case-based scenarios regarding the treatment of symptomatic hypogonadism in men. The article is designed as a review of published literature. We conducted a PubMed literature search for the time period of 1989-2014, concentrating on 26 studies investigating the efficacy of various therapeutic options on semen analysis, pregnancy outcomes, time to recovery of spermatogenesis, as well as serum and intratesticular testosterone levels. Our results demonstrated that exogenous testosterone suppresses intratesticular testosterone production, which is an absolute prerequisite for normal spermatogenesis. Cessation of exogenous testosterone should be recommended for men desiring to maintain their fertility. Therapies that protect the testis involve human chorionic gonadotropin (hCG) therapy or selective estrogen receptor modulators (SERMs), but may also include low dose hCG with exogenous testosterone. Off-label use of SERMs, such as clomiphene citrate, are effective for maintaining testosterone production long-term and offer the convenience of representing a safe, oral therapy. At present, routine use of aromatase inhibitors is not recommended based on a lack of long-term data. We concluded that exogenous testosterone supplementation decreases sperm production. It was determined that clomiphene citrate is a safe and effective therapy for men who desire to maintain fertility. Although less frequently used in the general population, hCG therapy with or without testosterone supplementation represents an alternative treatment.

Combination of tadalafil and finasteride for improving the symptoms of benign prostatic hyperplasia: critical appraisal and patient focus.

The evidence suggests that combination therapy for benign prostatic hyperplasia (BPH)-lower urinary tract symptoms (LUTS) using an α-blocker and a 5α-reductase inhibitor has become well accepted. The combination of daily tadalafil and an α-blocker has also demonstrated benefit. This paper addresses combination therapy with daily tadalafil and finasteride for the treatment of BPH-LUTS. Our results demonstrate that use of tadalafil and finasteride represents a logical extension of combination therapies. We analyze a landmark study by Casabé et al that demonstrates improved voiding symptoms as assessed by International Prostate Symptom Scores with a combination of tadalafil and finasteride compared with finasteride and placebo. Study patients had moderate to severe LUTS and prostate volumes >30 g. The additional benefit of improved erectile function as assessed by International Index of Erectile Function-erectile function domain scores with the addition of tadalafil was a secondary benefit. We propose that the ideal patient for combination therapy with tadalafil and finasteride has a prostate volume >30 g and desires additional benefit over monotherapy. For these men, improved erectile function without sexual side effects was a secondary benefit.

Endovascular treatment of vasculogenic erectile dysfunction.

The treatment of erectile dysfunction (ED) has been a fascination involving multiple medical specialities over the past century with urologic, cardiac and surgical experts all contributing knowledge toward this multifactorial disease. With the well-described association between ED and cardiovascular disease, angiography has been utilized to identify vasculogenic impotence. Given the success of endovascular drug-eluting stent (DES) placement for the treatment of coronary artery disease, there has been interest in using this same technology for the treatment of vasculogenic ED. For men with inflow stenosis, DES placement to bypass arterial lesions has recently been reported with a high technical success rate. Comparatively, endovascular embolization as an approach to correct veno-occlusive dysfunction has produced astonishing procedural success rates as well. However, after a thorough literature review, arterial intervention is only recommended for younger patients with isolated vascular injuries, typically from previous traumatic experiences. Short-term functional outcomes are less than optimal with long-term results yet to be determined. In conclusion, the hope for a minimally invasive approach to ED persists but additional investigation is required prior to universal endorsement.

Cardiovascular disease and male sexual dysfunction.

Erectile dysfunction (ED) is a form of sexual dysfunction that is estimated to affect > 30% of men between the ages of 40 and 70. As a result of an improved understanding about the pathophysiology of ED and improved treatment options, an increasing number of men are presenting for evaluation than several decades ago. In fact, many of these men are visiting their health care professional for the first time with ED as their primary complaint. Most of these men are unaware of the link between ED and cardiovascular disease (CVD).

Impact of low testosterone on response to treatment with tadalafil 5 mg once daily for erectile dysfunction.

OBJECTIVE: To evaluate, posthoc, the relationship between serum total testosterone and response to therapy in a study of tadalafil once daily for erectile dysfunction (ED). METHODS: Men were aged ≥18 years, with ≥3-month history of ED and partial prior response to on-demand (PRN) phosphodiesterase type 5 inhibitor (PDE5I) therapy. A 4-week maximum-dose PRN PDE5I run-in was followed by a 4-week nondrug washout period, then randomization to tadalafil 2.5 mg titrated to 5 mg or tadalafil 5 mg (pooled for analyses) or placebo once daily for 12 weeks. Analyses compared endpoint efficacy results between low- (<300 ng/dL) vs normal-testosterone (≥300 ng/dL) level subgroups. RESULTS: Improvements for tadalafil vs placebo were significant for the International Index of Erectile Function (IIEF) Erectile Function domain, Intercourse Satisfaction domain, Overall Satisfaction domain, and Question 15 (confidence in the ability to get and keep an erection; all P<.001), and for the Sexual Encounter Profile Questions 1-5 (all P≤.011). Analysis of covariance modeling identified significant treatment-by-subgroup interactions for the IIEF-Overall Satisfaction domain and erection confidence question and Sexual Encounter Profile Question 3. Comparing between tadalafil-treated testosterone subgroups, the IIEF-Erectile Function domain scores improved significantly more in men with normal vs low testosterone (P=.022); no other significant differences were identified for either placebo or tadalafil. No significant differences in pre-existing conditions were observed between tadalafil and placebo within the normal- and low-testosterone subgroups. CONCLUSION: In men with partial response to a PRN PDE5I, tadalafil 5 mg once daily significantly improved ED and sexual function vs placebo irrespective of testosterone levels.

Anabolic steroid-induced hypogonadism: diagnosis and treatment.

OBJECTIVE: To develop an understanding of hypogonadal men with a history of anabolic-androgenic steroid (AAS) use and to outline recommendations for management. DESIGN: Review of published literature and expert opinions. Intended as a meta-analysis, but no quality studies met the inclusion criteria. SETTING: Not applicable. PATIENT(S): Men seeking treatment for symptomatic hypogonadism who have used nonprescribed AAS. INTERVENTION(S): History and physical examination followed by medical intervention if necessary. MAIN OUTCOME MEASURES(S): Serum testosterone and gonadotropin levels, symptoms, and fertility restoration. RESULT(S): Symptomatic hypogonadism is a potential consequence of AAS use and may depend on dose, duration, and type of AAS used. Complete endocrine and metabolic assessment should be conducted. Management strategies for anabolic steroid-associated hypogonadism (ASIH) include judicious use of testosterone replacement therapy, hCG, and selective estrogen receptor modulators. CONCLUSION(S): Although complications of AAS use are variable and patient specific, they can be successfully managed. Treatment of ASIH depends on the type and duration of AAS use. Specific details regarding a patient's AAS cycle are important in medical management.