Impacts of Medications on Male Fertility

By Erma Z. Drobnis and Ajay K. Nangia

The over-arching goal of this volume is to help infertility practitioners evaluate and manage their patients with poor semen quality.  The authors review the existing literature on the effects of medications on male fertility, and provide detailed information about what is known, giving the number of individuals and population characteristics for studies of medication effects on male fertility. Medications are designed to treat illness and reduce symptoms, but all have undesirable adverse effects such as headache or stomach upset. Some adverse reactions can even be life-threatening, so it is no surprise that some drugs have negative effects on male reproduction.  Medical practitioners rarely consider a man’s reproductive plans when prescribing medications. Men are routinely treated with drugs that can impair or abolish fertility.

Although practitioners in the field of reproductive medicine generally realize that certain drugs impact negatively on reproductive health, thereare limited resources providing evidence-based knowledge useful in counseling patients. Tables throughout this volume summarize the information for each drug, providing a handy reference for clinical use.

• Language: English
• Publisher: Springer
• Release date: Dec 18, 2017
• ISBN: 9783319695358

Book preview

Volume 1034

Advances in Experimental Medicine and Biology

Series Editors

Irun R. Cohen

The Weizmann Institute of Science, Rehovot, Israel

Abel Lajtha

N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

John D. Lambris

University of Pennsylvania, Philadelphia, PA, USA

Rodolfo Paoletti

University of Milan, Milan, Italy

More information about this series at http://​www.​springer.​com/​series/​5584

Erma Z. Drobnis and Ajay K. Nangia

Impacts of Medications on Male Fertility

../images/430897_1_En_BookFrontmatter_Figa_HTML.png

Erma Z. Drobnis

Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO, USA

Ajay K. Nangia

Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

ISSN 0065-2598e-ISSN 2214-8019

Advances in Experimental Medicine and Biology

ISBN 978-3-319-69534-1e-ISBN 978-3-319-69535-8

https://doi.org/10.1007/978-3-319-69535-8

Library of Congress Control Number: 2017958959

© Springer International Publishing AG 2017

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Abbreviations

5ARIs

5α-reductase inhibitors

ACE

Angiotensin converting enzyme

ACE1

Somatic ACE, sACE

ACE2

Germinal ACE, gACE, testicular ACE, tACE

Ach

Acetylcholine

ADHD

Attention deficit hyperactivity disorder

ART

Assisted reproductive technology

ASA

Antisperm antibodies

BMI

Body mass index

BPH

Benign prostate hyperplasia

BTB

Blood-testis barrier

CAI

Carbonic anhydrase inhibitor

cART

Combination anti-retroviral therapy

CASA

Computer-assisted sperm analysis

CHF

Congestive heart failure

CI

Confidence interval

CMV

Cytomegalovirus

CNS

Central nervous system

COPD

Chronic obstructive pulmonary disease

COX

Cyclooxygenase

DBI

Diazepam-binding inhibitor

DFI

DNA fragmentation index

DHEAS

Dehydroepiandrosterone sulfate

DHT

Dihydrotestosterone

DM

Diabetes mellitus

DOR

δ-opioid receptor

E 2

Estradiol

EBV

Epstein-Barr virus

ED

Erectile dysfunction

EDC

Endocrine disrupting chemical

FAI

Free androgen index

FDA

U.S. food and drug administration

FSH

Follicle stimulating hormone

GERD

Gastroesophageal reflux disease

GnRH

Gonadotropin releasing hormone

GPI

Glycosylphosphatidylinositol

GSH

Glutathione

HAART

Highly active anti-retroviral therapy

HBV

Hepatitis B virus

hCG

Human chorionic gonadotropin

HCV

Hepatitis C virus

HED

Human equivalent dose

HIV

Human immunodeficiency virus

HPG axis

Hypothalamus-pituitary-gonadal axis

HSV

Herpes simplex virus

HTN

Hypertension

hyperPRL

Hyperprolactinemia

IBD

Inflammatory bowel disease

ICSI

Intracytoplasmic sperm injection

IL

Interleukin

IM

Intramuscular administration

IP

Intraperitoneal administration

IUI

Intrauterine insemination

IV

Intravenous administration

IVF

In vitro fertilization

KO

Gene knock out or knock down

KOR

κ-opioid receptor

LDH-X

Testisisoform of lactate dehydrogenase

LH

Luteinizing hormone

LUTS

Lower urinary tract symptoms

MAC

Mycobacterium avium complex

MAGI

Male accessory gland infections

MAOI

Monoamine oxidase inhibitor

MDA

Malondialdehyde

MI

First meiotic division (spermatogenesis) or myocardial infarction (heart attack)

MII

Second meiotic division

MOR

μ-opioid receptor

mtDNA

Mitochondrial DNA

mTOR

Mammalian target of rapamycin

MX

methylxanthine

NaSSA

Noradrenergic and specific serotonergic antidepressant

NDRI

Norepinephrine-dopamine reuptake inhibitor

NE

Norepinephrine

NMDA

N -methyl- d -aspartate

NNRI

Non-nucleoside reverse transcriptase inhibitor

NRI

Norepinephrine reuptake inhibitor (antidepressant) or nucleoside reverse transcriptase inhibitor (antiviral)

NRTI

Nucleoside analog reverse transcriptase inhibitor

NSAID

Non-steroid anti-inflammatory drug

OATS

Oligoasthenoteratozoospermia syndrome

OPIAD

Opioid-induced androgen deficiency

OR

Odds ratio

OTC

Over the counter (non-prescription)

PAD

Peripheral artery disease

PDE

Phosphodiesterase

PE

Pulmonary embolus

PEVR

Perception of ejaculatory volume reduction

PI-PLC

Phosphatidylinositol-specific phospholipase C

PrEP

Pre-exposure prophylaxis

PRL

Prolactin

PTSD

Post-traumatic stress disorder

RA

All-trans retinoic acid

RCT

Randomized, controlled trial

RDBPCT

Randomized, double-blinded, placebo-controlled trial

RPCT

Randomized, placebo-controlled trial

SC

Subcutaneous administration

SCSA

Sperm chromatin structure assay

SEM

Scanning electron microscopy

SGE

Spinal generator of ejaculation

SHBG

Sex hormone binding globulin

SLE

Systemic lupus erythematosus

SNRI

Serotonin-norepinephrine reuptake inhibitor

SOD

Superoxide dismutase

SSRI

Selective serotonin reuptake inhibitor

T

Testosterone

TB

Tuberculosis

TCA

Tricyclic antidepressant

tetraCA

Tetracyclic antidepressant

TMP/SMX

Trimethoprim/sulfamethoxazole

TRH

Thyrotropin releasing hormone

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labeling

WBC

White blood cell

Contents

1 Introduction to Medication Effects on Male Reproduction 1

2 Challenges of Obtaining Evidence-Based Information Regarding Medications and Male Fertility 5

2.​1 Experimental Design 5

2.​2 Species-Specificity and Reproductive Endpoints 7

2.​3 Variation in Effects of Drugs in the Same Class 7

2.​4 Few Studies with Live-Birth and Offspring Health as Outcomes 8

2.​5 Individual Variation in Response 8

2.​6 Illness Can Have Profound Effects on Male Reproductive Function 9

2.​7 Mechanism of Toxicity Is Often Obscure 9

2.​8 Drug Interactions in Humans Have Not Been Studied 9

3 Male Reproductive Functions Disrupted by Pharmacological Agents 13

3.​1 Pre-testicular:​ The Hypothalamic–Pituitary–Gonadal (HPG) Axis 14

3.​1.​1 Endocrine Disrupting Chemicals 14

3.​1.​2 The Hypothalamus–Pituitary–Adrenal Axis and Corticosteroids 14

3.​1.​3 Sex Hormone Binding Globulin 15

3.​1.​4 Medications and Prolactin Levels 15

3.​1.​5 Medications and Thyroid Hormone Levels 17

3.​2 Testicular:​ Spermatogenesis, Spermiogenesis, and Spermiation 18

3.​3 Post-testicular:​ Epididymal Transit 18

3.​4 Post-testicular:​ Ejaculation 19

3.​4.​1 Emission 20

3.​4.​2 Expulsion 20

3.​4.​3 Ejaculatory Dysfunction 21

3.​5 Post-ejaculation Sperm Function 22

3.​5.​1 Sperm Transport in the Female Reproductive Tract 22

3.​5.​2 Fertilization and Offspring Health 23

3.​6 Drug Metabolism 23

4 Exogenous Androgens and Male Reproduction 25

5 Phosphodiesteras​e Inhibitors (PDE Inhibitors) and Male Reproduction 29

5.​1 Methylxanthines 32

5.​2 Specific Phosphodiesteras​e Inhibitors 35

5.​2.​1 PDE5 and Male Reproduction 35

5.​2.​2 PDE5 Inhibitor Effects on Tissues In Vitro 36

5.​2.​3 PDE5 Inhibitor Effects on Testosterone Levels and Semen Quality in Humans 36

5.​2.​4 PDE5 Inhibitors in Experimental and Companion Species 37

6 Pain Medications and Male Reproduction 39

6.​1 Opioids 39

6.​1.​1 Opioids and Testosterone Levels in Men 45

6.​1.​2 Opioids and Circulating PRL Levels 47

6.​1.​3 Pain Management in Men with Hypogonadism Desiring Fertility 48

6.​1.​4 The Endogenous Opioid System in Normal Male Reproduction 49

6.​1.​5 Opioids and Human Semen Quality 50

6.​1.​6 Opioids in Animal Models 50

6.​2 Non-steroid Anti-inflammatory Drugs (NSAIDs) 52

6.​2.​1 NSAIDs and Human Male Reproduction 53

6.​2.​2 NSAIDs and Male Reproduction in Rodents 54

7 5α-Reductase Inhibitors (5ARIs) and Male Reproduction 59

7.​1 5ARIs and Testosterone Levels 60

7.​2 5ARIs and Semen Quality 61

8 Psychotropics and Male Reproduction 63

8.​1 Antidepressants 64

8.​1.​1 SSRIs 75

8.​1.​2 SNRIs, NRIs, NDRIs, Serotonergic and Melatonergic Antidepressants 78

8.​1.​3 TCAs 79

8.​1.​4 MAO Inhibitors 81

8.​2 GABAAergic Anxiolytics 82

8.​2.​1 Endocrine Effects of GABA A ergic Medications 83

8.​2.​2 GABA A ergic Medications, Spermatogenesis, and Semen 84

8.​3 Antipsychotics 85

8.​3.​1 Antipsychotic Drugs and Increase in Peripheral PRL Levels 85

8.​3.​2 Antipsychotics and the HPG Axis 92

8.​3.​3 Antipsychotics and Ejaculatory Dysfunction 93

8.​3.​4 Antipsychotics and Semen Quality 95

8.​3.​5 Antipsychotic Medications in Experimental Animal Models 95

8.​3.​6 Lithium 97

8.​4 Anticonvulsants 98

8.​4.​1 Anticonvulsants and the HPG Axis 98

8.​4.​2 Anticonvulsants and Semen Quality 99

8.​4.​3 Anticonvulsant Medications in Experimental Animal Models 100

9 Cardiovascular/​Pulmonary Medications and Male Reproduction 103

9.​1 Adrenergic Drugs 110

9.​2 α-Adrenergic Agonists 110

9.​2.​1 α-Adrenergic Agonists and In Vitro Studies of Male Reproductive Tract Tissue 111

9.​2.​2 α-Adrenergic Agonists and the HPG Axis 111

9.​2.​3 α-Adrenergic Agonists and Ejaculatory Dysfunction 112

9.​3 α-Adrenergic Antagonists (α-Blockers) 113

9.​3.​1 α-Adrenergic Antagonists and In Vitro Studies of Male Reproductive Tract Tissue 113

9.​3.​2 α-Adrenergic Antagonists and the HPG Axis 114

9.​3.​3 α-Adrenergic Antagonists and Human Ejaculatory Dysfunction 114

9.​3.​4 α-Adrenergic Antagonists and Ejaculation in Other Species 116

9.​3.​5 α-Adrenergic Antagonists and Semen Quality 117

9.​3.​6 α-Adrenergic Antagonists and Fertility 118

9.​4 β-Adrenergic Agonists 118

9.​5 β-Adrenergic Antagonists (β-Blockers) 119

9.​6 Calcium Channel Blockers 121

9.​6.​1 Calcium Channel Blockers and Human Male Reproduction 121

9.​6.​2 Calcium Channel Blockers and Male Rat Reproduction 123

9.​7 Angiotensin Converting Enzyme (ACE) Inhibitors 124

9.​8 Diuretics 126

9.​8.​1 Spironolactone 126

9.​8.​2 Thiazide Diuretics 129

9.​9 Digoxin 129

9.​10 Hydralazine 130

10 Antimicrobials and Male Reproduction 131

10.​1 Anti-parasitics 142

10.​2 Antifungals 144

10.​3 Antibacterials 148

10.​3.​1 Aminoglycosides 149

10.​3.​2 Amphenicols 150

10.​3.​3 Cephalosporin Beta-Lactams 150

10.​3.​4 Macrolides 151

10.​3.​5 Nitrofurans 152

10.​3.​6 Penicillin Beta-Lactams 153

10.​3.​7 Polypeptides 153

10.​3.​8 Fluoroquinolones​ 153

10.​3.​9 Sulfonamides 155

10.​3.​10 Tetracyclines 156

10.​4 Mixed Antimicrobials 158

11 Antivirals and Male Reproduction 163

11.​1 HIV Infection Effects on Semen Quality 169

11.​2 Combination Antiretroviral Therapy (cART) Effect on Semen Quality 171

11.​3 Mitochondrial Inhibition with HIV Medications 172

11.​4 HIV Medication and the HPG Axis 173

11.​5 HIV Medication and Spermatogenesis/​Semen Quality 175

11.​6 Purine Nucleoside Analogs 176

11.​7 Other Antivirals 177

12 Immunosuppressan​ts and Male Reproduction 179

12.​1 Corticosteroids 186

12.​1.​1 Treatment of Antisperm Antibodies 186

12.​1.​2 Treatment of Inflammatory Diseases 187

12.​1.​3 Antirejection Treatment After Organ Transplant 188

12.​1.​4 Studies in Healthy Men 189

12.​1.​5 Studies in Non-human Primates 190

12.​1.​6 Endocrine Studies in Rodents 190

12.​1.​7 Spermatogenesis Studies in Rodents 191

12.​1.​8 Studies in Domestic Species 191

12.​2 Cytostatics 193

12.​2.​1 Azathioprine and 6-Mercaptopurine 193

12.​2.​2 Methotrexate 195

12.​2.​3 Chlorambucil 197

12.​2.​4 Cyclophosphamide​ 198

12.​2.​5 Melphalan 201

12.​3 Immunophilin Modulators 201

12.​3.​1 Calcineurin Inhibitor Effects on the HPG Axis 202

12.​3.​2 mTOR Inhibitor Effects on the HPG Axis 203

12.​3.​3 Immunophilin Modulators in Male Rodents 203

12.​4 TNF-α Inhibitors 206

12.​5 Sulfasalazine 206

13 Miscellaneous Drugs and Male Reproduction 211

13.​1 Cimetidine 211

13.​2 Colchicine 217

13.​3 Ergotamine 218

13.​4 Gastrokinetic Agents 219

13.​5 Hydroxyurea 220

13.​6 Metformin 222

13.​7 Mifepristone 223

13.​8 Propylthiouracil​, Methimazole, Levothyroxine, Liothyronine 224

13.​9 Retinoids 224

13.​10 Statins 225

References227

Index313

© Springer International Publishing AG 2017

Erma Z. Drobnis and Ajay K. NangiaImpacts of Medications on Male FertilityAdvances in Experimental Medicine and Biology1034https://doi.org/10.1007/978-3-319-69535-8_1

1. Introduction to Medication Effects on Male Reproduction

Erma Z. Drobnis¹  and Ajay K. Nangia²

(1)

Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO, USA

(2)

Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

Abstract

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.

There has been an increase in medication use over the years as disease treatments have been researched and developed. In the United States, 68% of men 18–44 and over 80% of those 45–64 years of age are taking prescriptions or OTC medications. The number of medications taken also increases with age (Kaufman et al. 2002; Qato et al. 2008). Medication use in childhood and young adulthood is also increasing , with increased psychotropic medication use, along with diabetes and hypertension treatments. This is related, in part, to the increased world-wide prevalence of obesity (Cox et al. 2008). Older paternal age also must be considered, with 74% of men having their first child between the ages of 18 and 40 years of age, leaving 26% having their first child after that age (Martinez et al. 2012). The age at paternity has particularly increased in the developed countries (Bray et al. 2006; Sartorius and Nieschlag 2010; Zweifel 2015).

For male patients in general, reproductive health is underappreciated during health evaluations. We are becoming increasingly aware that reproductive health in men is related to their general health. Low semen quality and infertility are biomarkers for poor general health (Salonia et al. 2009; Omu 2013; Tarín et al. 2015; Ventimiglia et al. 2015), and men with poor semen quality have shorter lifespans than those with normal semen (Groos et al. 2006; Jensen et al. 2009; Eisenberg et al. 2014, 2015a).

In addition to the connection between general health and semen quality, medical practitioners rarely consider a man’s reproductive plans when prescribing medications. Exposure of men to medications is often inadequately addressed, even during male infertility work-up by specialists (Samplaski and Nangia 2015). Men are treated with drugs that can impair or abolish fertility without counseling on adverse fertility effects. A recent German study determined that 46% of men presenting to an infertility clinic were taking at least one medication ; of those, the average was 2.3 medications; and of these drugs, adverse effects on male reproduction had been reported in the literature for 51% (Pompe et al. 2016). In a study of 1768 men with infertility of at least 3 years duration, 165 were taking medications believed to impair male fertility for chronic conditions, and had no other medical explanation for their infertility (Hayashi et al. 2008). Of these, 73 patients were switched to less toxic medications while 92 were maintained on their current therapy. Male and female partner ages were equivalent between the groups. Over the subsequent 3 years in the intervention group, semen quality normalized in 93% of men and conception occurred in 85%, compared with 12% semen normalization and 10% conception rate in the men continuing on their initial medications. Although this was not a randomized, blinded, or placebo-controlled trial, and the men remaining on their medications were undoubtedly less healthy than those who were able to change medication, these results emphasize that consideration of drug effects is quite important in the work-up of male infertility .

One significant challenge is that countries with regulations for evaluation of medications have insufficient requirements for inclusion of reproductive toxicity in men. Starting in 2011, the US Food and Drug Administration began requiring evaluation of male reproductive toxicity as part of premarketing studies, and two recent draft guidances have been released (US FDA 2015a; b). However, most of the drugs in current use were approved before such testing was required, and FDA -required labeling is inconsistent with current knowledge (Ding et al. 2017). The medications we discuss in this volume are currently used in one or more countries; some of the drugs covered are not used world-wide. Interestingly, some medications discussed here are not currently approved for use in the United States or Canada, but are nevertheless included on the WHO Model List of Essential Medicines (WHO 2017) which presents a list of minimum medicine needs for a basic health-care system.

The primary focus of this book is medications used by adult men on a routine basis that may underlie male factor infertility in patients presenting to the fertility clinic. Although practitioners in the field of reproductive medicine generally realize that certain drugs impact negatively upon reproductive health in men, considerably more research has been conducted in women. Comparatively limited resources have been devoted to providing evidence-based knowledge useful in counseling male infertility patients on their medication use . In some cases, a drug is widely believed to impact male infertility, but when the literature is evaluated, the belief is based on minimal clinical data or even stems from an early case report. This volume reviews the literature in the English language, and provides detailed information about what is known, giving the number of individuals and population characteristics for studies of medication effects on male fertility. Human studies are described when available. In cases where scant data are available in humans, studies in experimental species are detailed. Tables are provided to summarize the information for each drug. We also direct the reader to a marvelous bibliography by Kraus (2008) that covers many publications reporting medication effects on male reproduction, along with the number of study subjects, a description of the population, and a ranking of the quality of the study.

Beyond the scope of this volume, but covered in recent research and reviews, are drugs used to treat cancer, that are intentionally cytotoxic (Wallace et al. 2005; Magelssen et al. 2006; Howell and Shalet 2009; Dohle 2010; Meistrich 2013; Vij and Gilligan 2016); herbal and dietary supplements (Olayemi 2010; Gabrielsen and Tanrikut 2016); drugs of abuse or recreational drugs (Fronczak et al. 2012; Stearns and Turek 2013; Samplaski et al. 2015; du Plessis et al. 2015; Sharma et al. 2016); and drug effects on prenatal and pre-pubertal male development. Also not covered specifically are medications administered acutely to hospitalized patients and topical medications with relatively minor systemic effects. A final medication-associated source of toxicity not covered here are excipients (inactive ingredients) that are associated with medications, such as paraben and phthalates (Hauser et al. 2004; Dodge et al. 2015).

The mechanism and drugs that affect erectile function are beyond the scope of this book, and we direct readers to excellent reviews published on this topic (Brock and Lue 1993; Doumas and Douma 2006; Serretti and Chiesa 2011; Ludwig and Phillips 2014; Gandaglia et al. 2014; Cai et al. 2014; Gandhi et al. 2017). Although not covered specifically in this volume, libido and erectile function are essential constituents of successful male reproduction. Indeed, these factors contribute to overall sexual function, even when reproduction is not being considered. Medications along with endocrine, vascular, neurological, and psychological factors can affect erectile function. Of course there are many diseases that cause erectile dysfunction directly through the same mechanisms, including DM, hypertension , and hypercholesterolemia/hyperlipidemia . As a result, the correlation or additional effect of medications for the treatment of such diseases makes it difficult to differentiate the medication effect as an independent variable. Medications can be endocrine disrupters, can affect erectile function by disruption of the required vasculature of the penis and also can affect psychological desire. Psychotropic and hypertension medications in particular have been implicated in these adverse effects . Medications used to treat benign prostate hyperplasia and lower urinary tract symptoms, such as finasteride , and less selective alpha blockers are of particular concern.

This book represents a complete review of medications with known effects on male fertility using the methods described here. Reviews including this topic were read to identify drugs suspected of causing male infertility, and a list of all drugs in the same class as those identified was compiled. Medline searches were then conducted for each individual medication, limited to English language publications, using the following search terms:

[individual medication]

AND

Prostate/ or prostate.mp. or Genitalia, Male/ or male genitalia.mp. or Seminal Vesicles/ or seminal vesicles.mp. or Semen/ or semen.mp. or Semen Analysis/ or semen analysis.mp. or Spermatozoa/ or sperm?.mp. or Spermatogenesis/ or Male reproduce?.mp. or Testis/ or testis.mp. or testis.mp. or testicle.mp. or testicular.mp. or Epididymis/ or epididym?.mp. or Ejaculation/ or Prolactin / or prolactin.mp. or Testosterone/ or testosterone.mp or Infertility, Male/ or male infertility.mp. or male fertility.mp. or Luteinizing Hormone/ or LH .mp. or luteinizing or hormone.mp. or Follicle Stimulating Hormone/ or FSH .mp or follicle stimulating hormone.mp. or Fertilization / or fertilization.mp. or Acrosome/ or Acrosome Reaction / or acrosome.mp. or acrosome reaction.mp.

NOT

Child/ or childhood.mp. or children.mp. or Pediatrics/ or pediatric.mp. or Pregnancy, Ectopic/ or ectopic pregnancy.mp. or biopsy.mp. or Biopsy, Fine-Needle/ or Image-Guided Biopsy/ or Biopsy/ or Biopsy, Needle/ or Biopsy, Large-Core Needle/ or Carcinoma, Ductal, Breast/ or Breast Diseases/ or Breast/ or Breast Neoplasms/ or breast cancer.mp. or Prenatal Exposure Delayed Effects/ or prenatal.mp. or Infant, Premature/ or Infant, Newborn/ or Respiratory Distress Syndrome, Newborn/ or Polycystic Ovary Syndrome/ or polycystic ovarian.mp. or Infertility, Female/ or Case Reports/ or case report.mp. or case study.mp. or Placenta/ or placenta.mp. or Cytochrome P-450 Enzyme System/ or CYP?.mp. or liver microsomes .mp. or Microsomes, Liver/ or Prostatic Neoplasms/ or Prostatectomy/ or prostate surgery .mp. or prostate cancer.mp. or Miscarriage/ or mammary gland.mp. or congenital adrenal hyperplasia.mp. or Adrenal Hyperplasia , Congenital/ or tumor.mp. or tumour.mp. or Neoplasms, Germ Cell and Embryonal/ or testicular cancer.mp. or Testicular Neoplasms/ or fetal.mp. or carcinoma.mp. or lactation.mp.

The resulting titles were reviewed by one author for relevant material. Research papers and additional reviews were also found as citations in the discovered publications and by using the related articles function of PubMed.

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© Springer International Publishing AG 2017

Erma Z. Drobnis and Ajay K. NangiaImpacts of Medications on Male FertilityAdvances in Experimental Medicine and Biology1034https://doi.org/10.1007/978-3-319-69535-8_2

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

Erma Z. Drobnis¹  and Ajay K. Nangia²

(1)

Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO, USA

(2)

Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

Abstract

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.

2.1 Experimental Design

For most drugs, there is a paucity of large, well-designed clinical trials evaluating effects on male fertility. The majority of human studies are small and observational, often retrospective, with inconsistency in study populations, doses, and endpoints. Although we may suspect that a pharmacologic agent has a negative impact, it is rare that this can be stated with certainty. Following are some important aspects of experimental design.

Size and power: Limited clinical information is provided from underpowered studies (Ioannidis 2005; Meldrum and Su 2017). A prospective power analysis to determine the required number of study subjects is important for evaluating a medication’s effects. This is critical for studies showing no effect of the medication. For example, if a decrease in testosterone level of 25% was considered clinically significant in the power analysis, an appropriately powered study allows the conclusion that it is unlikely that the drug causes testosterone to decrease by 25% or more. But the study is underpowered to comment on the potential for smaller testosterone changes in the population of treated men. Small sample size is also problematic when a statistically significant difference is determined, as the effect size can be overestimated (Wacholder et al. 2004; Meldrum and Su 2017). Thus, there may actually be a difference in testosterone level, as determined by the study, but it may only be 2% on average, instead of the 25% reported. The bottom line is that a high proportion of pharmacological studies are underpowered, and the results of an individual study of this type do little to inform evidence-based clinical practice.

Randomization, placebo-control, and blinding: The gold standard for experimental design in clinical trials is a randomized, double-blinded, placebo-controlled trial (RDBPCT) . For most medications, such studies have not been published for male fertility outcomes. It is not unusual to have medication effects detected that are later determined to result from bias introduced by population differences between treatment and control groups or by differences in the treatment of patients in the medication group versus the controls. Nevertheless, adequately powered, observational studies (e.g., cohort, case-control, and cross-sectional) are valuable and can sometimes provide more applicable clinical information than randomized, controlled trials (RCTs) because they may better reflect the patient population and/or the flexible dosing that is used in a clinical setting. Because such studies are more subject to bias, observational studies must be interpreted with caution.

Lack of negative reports: There are fewer reports of drugs having no effect on male reproduction than reports of a positive or negative effect. This phenomenon, commonly known as publication bias, has been improving over time as the value of negative results is better appreciated (e.g., Lenson et al. 2017); however, there remain fewer reports of no drug effect, particularly in the older literature.

Confounding: Sexual health and fertility are impacted by many confounding variables in addition to the medication under evaluation. Useful studies must control for a plethora of variables known to effect male reproduction, not the least of which is female sexual health and fertility. Medication studies have more clinical value if a representative population is studied and factors known to influence male fertility are considered in the experimental design. At a minimum, this includes age, smoking status, alcohol consumption, body mass index (BMI) , other disease conditions, other medications, reproductive tract anomalies (e.g., varicocele), and history of genital infection.

2.2 Species-Specificity and Reproductive Endpoints

Although there are studies in other species for all medications approved for human use, and recently reproductive endpoints have received more attention, species differ in their reproductive response to drugs. Different species are inherently dissimilar in reproductive physiology. There are also significant species differences in pharmacokinetics , including variation in absorption of medications, metabolic considerations, and concentration in the reproductive tract tissues. The dosages used in trials with experimental species are often high so that toxicity will be seen if present; however, that approach limits provision of clinically valuable information. Often, the dose-response curve for an exogenous chemical is non-linear and can be similar at low and high doses (Vandenberg et al. 2012), so a response may be missed at some doses.

In this volume, the human equivalent doses (HED) were calculated using human dosages found at FDA .gov or drugs.​com, and the equivalent animal dose was based on differences in surface area among species as described by Reagan-Shaw et al. (2008). Pharmacokinetic data would be the most appropriate method for determining HED (Blanchard and Smoliga 2015); however, the data required are not readily available. The calculated value using body surface area is influenced by the weight of the experimental animal, which is often omitted from publications; in these cases, adult weights were estimated at 250 g for rats and 20 g for mice. The route of administration in humans is included in square brackets, indicating all routes if the human dose is equivalent for oral, intramuscular (IM), intravenous (IV), subcutaneous (SC), or metered dose inhaler (MDI) administration as indicated for humans . For drugs that are used at high doses to treat cancer, and lower doses for other conditions, HED were based on the lower dose that men of childbearing age might be taking chronically.

Endpoints measured after administration of pharmacological doses in an experimental species are unlikely to provide information useful for counseling patients. Nevertheless, such results can indicate drugs deserving clinical trials.

2.3 Variation in Effects of Drugs in the Same Class

In some cases, there are a variety of drugs in a given class, and data only exist for some of them. Included in the tables of this book are lists of comparable medications with little (e.g., case reports) or no data for male reproductive endpoints. Occasionally there is only one or a few drugs in a class that have reproductive toxicity, and those with scant data can represent alternative medications for use when fertility is desired. In other cases, drugs with no published data have not been evaluated sufficiently and have unknown impact on male reproduction.

2.4 Few Studies with Live-Birth and Offspring Health as Outcomes

Although fertility and offspring health are our dominant interests, the outcomes used in most in vivo human studies look at endocrine or semen outcomes. Aside from the large literature questioning the relevance of semen analysis in evaluation of male fertility, there are also examples from the pharmacology literature that illustrate the challenges associated with reliance on these outcomes. In some studies, a negative effect on fertility is seen in the absence of reduced semen (or epididymal sperm in rodents) quality. Similarly, decreased semen quality is not necessarily associated with impaired fertility. Another challenge of using semen quality measures, and also reproductive hormone levels, to measure treatment outcomes is that these factors have large variability in fertile men and most are highly skewed in distribution (Cooper et al. 1991, 2010). Without adequate power and appropriate statistical techniques, effects of treatments can be difficult to detect. Generally, studies are underpowered to reach conclusions regarding a lack of medication effect. As such, the scarcity of reliable evidence for a fertility effect is profound when using changes in semen parameters or reproductive hormones as a surrogate for the effect on fertility or cause of male infertility. This is a significant limitation of reproductive pharmacotoxicology studies in men.

2.5 Individual Variation in Response

Not every individual responds comparably to medications. This can be due to demographic factors, drug interactions , other health conditions, environmental exposures, and differences in genetic predisposition . The most valuable information for counseling our patients is the proportion of men with fertility effects from a given medication . Instead, the literature commonly reports mean values for endpoints, even in cases of data that are not normally distributed (e.g., total sperm count; testosterone level), where nonparametric measures (e.g., medians) would be more appropriate. In most cases, we do not have the information required to inform evidence-based clinical practice. As with all medications, some individuals will have more severe adverse effects than others, and the mechanism for this is often obscure. No significance in mean values for a reproductive endpoint does not mean that there are no men suffering infertility due to the medication. Differences can also relate to clearance of the drug or the mechanism underlying the adverse reaction.

2.6 Illness Can Have Profound Effects on Male Reproductive Function

We now know that male infertility and poor semen quality are associated with reduced general health, many chronic illnesses, and even a shorter lifespan. As listed in Table 2.1, a medication that treats an illness can improve reproductive symptoms as the man’s general health improves, while at the same time exerting a toxic effect on reproductive function. Four approaches have been used to separate the effects of disease from the effects of a medication: (1) Randomized, placebo-controlled trials of men being treated for the condition; (2) measuring outcomes before and after new administration of the drug; (3) measuring outcomes during drug exposure then after cessation of the drug; and (4) treating healthy individuals with the drug. In the latter case, information is provided on the effect of the drug alone, but this may not be as useful for making clinical decisions because it doesn’t address what is happening in the patients who present with infertility while under treatment for a disease condition. RPCTs are not always possible for men with disease.

Table 2.1

Medical conditions with negative reproductive effects in which medication benefit may mask its toxicity

5ARIs 5α-reductase inhibitors, BPH benign prostate hyperplasia, CHF congestive heart failure, HCV hepatitis C virus, HIV human immunodeficiency virus, IBD inflammatory bowel disease, LH luteinizing hormone, LUTS lower urinary tract symptoms, NNRIs non-nucleoside reverse transcriptase inhibitors, NRIs nucleoside reverse transcriptase inhibitors, PDE phosphodiesterase, T testosterone

How an illness affects male reproduction can be related to the constitutional effects of the illness, like a chronic inflammatory state (e.g., fever, hypertension ), or to destruction/functional effects on male reproductive tissues (e.g., BPH, genital tract infection ). Molecular spermatogenic genetic predisposition can also be involved. Clearly, medications can play an important role in the entire multi-factorial process of reproduction.

2.7 Mechanism of Toxicity Is Often Obscure

The best information available about the comparative toxicities of required medications is important for reaching the goal of minimizing adverse drug reaction while enabling our patients to become fathers. Although there are hypotheses and models explaining the mechanism of drug toxicity in most cases, we are rarely certain, which hinders our ability to treat or manage medication-induced infertility.

2.8 Drug Interactions in Humans Have Not Been Studied

At best, studies are designed to look at the effect of a single drug, to compare multiple drugs, or to compare drug mixtures as is common for chemotherapeutic and antiviral regimens. Information about drug interactions is completely lacking. The result of poly-pharmacy, an increasing concern in medicine, is unknown . Generally younger patients in their reproductive years are taking fewer medications compared with older patients. However, the effect of multiple medications, that may or may not have other systemic effects and adverse reactions, could still have a role in male reproduction/spermatogenesis. We cannot forget that illness, especially chronic illness that affects men’s health, may result in general compromise of reproduction along with the medications as mentioned above.

References

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Blanchard OL, Smoliga JM. Translating dosages from animal models to human clinical trials–revisiting body surface area scaling. FASEB J. 2015;29:1629–34. https://​doi.​org/​10.​1096/​fj.​14-269043. PMID: 25657112.CrossrefPubMed

Cooper TG, Jockenhövel F, Nieschlag E. Variations in semen parameters from fathers. Hum Reprod. 1991;6:859–66. PMID: 1757526.CrossrefPubMed

Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–45. https://​doi.​org/​10.​1093/​humupd/​dmp048. PMID: 19934213.CrossrefPubMed

Ioannidis JP. Why most published research findings are false. PLoS Med. 2005;2:e124. https://​doi.​org/​10.​1371/​journal.​pmed.​0020124. PMID: 16060722.CrossrefPubMedPubMedCentral

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Meldrum DR, Su HI. There’s no difference-are you sure? Fertil Steril. 2017;108(2):231–2. pii: S0015-0282(17)30481-8. https://​doi.​org/​10.​1016/​j.​fertnstert.​2017.​06.​022. PMID: 28711153.

© Springer International Publishing AG 2017

Erma Z. Drobnis and Ajay K. NangiaImpacts of Medications on Male FertilityAdvances in Experimental Medicine and Biology1034https://doi.org/10.1007/978-3-319-69535-8_3

3. Male Reproductive Functions Disrupted by Pharmacological Agents

Erma Z. Drobnis¹  and Ajay K. Nangia²

(1)

Obstetrics, Gynecology and Women’s Health, University of Missouri School of Medicine, Columbia, MO, USA

(2)

Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA

Abstract

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.

It is traditional to view pharmacological effects on male reproduction as pre-testicular, testicular, or post-testicular . Pre-testicular effects disrupt the hypothalamus–pituitary –gonad (HPG) axis, generally by interfering with endocrine function. Testicular effects are direct gonadotoxicity, in which spermatogenesis is disrupted by actions on the germ cells , Sertoli cells, and/or Leydig cells. Post-testicular effects occur from the time the sperm leave the seminiferous tubules until they are released from the body at ejaculation. Modification of final transport and maturation of sperm during the post-testicular phase can result in sperm with abnormal physiology and function. This classical mechanistic differentiation is not always reflected by the measured outcomes. For example, pharmacological effects resulting in poor semen quality can involve multiple organ systems and tissues.

3.1 Pre-testicular: The Hypothalamic–Pituitary –Gonadal (HPG) Axis

Some medications are endocrine disrupting chemicals (EDCs) and can exert reproductive toxicity via the HPG axis. These mechanisms are complex and sometimes interact with elements of the other pituitary axes. Recently, considerable attention has focused on exposure of the male to environmental chemicals, particularly during prenatal and pre-pubertal development (Bonde et al. 2016), but EDCs can also affect the adult male (Hauser et al. 2015; Buck Louis et al. 2016).

3.1.1 Endocrine Disrupting Chemicals

For purposes of evaluating the effects of EDC medications on adult males, the most direct exposure is drugs that act on the androgen receptors , providing negative feedback for testosterone at the hypothalamus and/or pituitary, thus inhibiting secretion of gonadotropin releasing hormone (GnRH) or gonadotropins, respectively. Alternatively, effects can be indirect on endocrine and/or nervous system elements that regulate secretion of GnRH or the gonadotropins (Hotaling and Patel 2014). Drugs can also modulate the feedback effects of activin or inhibin on pituitary secretion of FSH .

Another EDC effect of drugs is agonist activity at estrogen receptors, or stimulation of endogenous production of estrogens. Estrogen receptors provide negative feedback at the hypothalamus and pituitary, decreasing gonadotropin secretion. Gynecomastia and/or breast pain are common adverse reactions of some medications and indicate an imbalance in the testosterone to estrogen ratio.

3.1.2 The Hypothalamus–Pituitary–Adrenal Axis and Corticosteroids

The hypothalamus–pituitary–adrenal axis can also be modulated by exogenous drugs that affect cortisol levels. Cortiso l can have a negative impact on reproduction owing to its metabolic effects, its immunomodulatory effects, and its negative feedback inhibition of the HPG axis . There is evidence that stress is associated with higher cortisol levels, lower testosterone levels , and poorer semen quality in humans (Roberts et al. 1993; Fenster et al. 1997; Hackney 2008; Gollenberg et al. 2010; Janevic et al. 2014), and rats (Retana-Márquez et al. 2003), including increased sperm DNA fragmentation (Radwan et al. 2016). This is believed to result, in part, from adrenal glucocorticoid negative feedback on GnRH and gonadotropin secretion (Geraghty and Kaufer 2015), and, as we discuss in Chap. 12, exogenous corticosteroids can also have this negative feedback effect, decreasing levels of gonadotropins.

In addition to the central activity of cortisol , tissues of the male reproductive system are rich in glucocorticoid receptors, allowing direct effects on Leydig cells; Sertoli cells; and tissues of the epididymis, vas deferens, and prostate (Schultz et al. 1993; Whirledge and Cidlowski 2013). Glucocorticoids acting at receptors in Leydig cells inhibit testosterone production and responsiveness to LH . In rats, when the primary endogenous adrenal corticosteroid , corticosterone , increases above basal levels, it is associated with decreased testosterone levels and Leydig cell apoptosis . However, the Leydig cells also express 11β-hydroxysteroid dehydrogenases , which inactivate intracellular glucocorticoids at high glucocorticoid levels, protecting Leydig cells unless stress is extreme (Monder 1991; Hardy et al. 2005). A similar system is present in Leydig cells of the mouse pig , horse , and human (Tannin et al. 1991; Condon et al. 1998; Claus et al. 2007; Herrera-Luna et al. 2013; Li et al. 2015).

3.1.3 Sex Hormone Binding Globulin

Another drug-sensitive pathway is the production of sex hormone binding globulin (SHBG). This important molecule is secreted by the liver and acts as a storage mechanism by tightly binding testosterone, and carrying it in circulation in a form not readily available to target tissues. If SHBG levels are high, bioavailable testosterone, which is generally associated with serum albumin, and free-testosterone will decrease. Medications that interfere with normal hepatic function can affect circulating SHBG levels.

3.1.4 Medications and Prolactin Levels

One hormone often involved in medication-associated male infertility is prolactin (PRL), which can act by inhibition of the HPG axis . Many medications increase PRL levels, but the mechanism for drug-induced hyperprolactinemia (hyperPRL) varies (Madhusoodanan et al. 2010). PRL synthesis and secretion is tightly controlled by complex central mechanisms . Dopamine exerts primary control of PRL secretion through tonic inhibition. Stimulation of dopamine D2 receptors of the CNS or pituitary results in decreased synthesis and release of PRL by lactotrophs. Medications that antagonize D2 receptors can disrupt this system, leading to hyperPRL. The prevalence of this pharmacologic effect can be underestimated by providers prescribing these drugs (La Torre and Falorni 2007). Medications that inhibit dopamine synthesis can also increase circulating PRL. Drugs with limited occupancy of dopamine receptors, that act as agonists/antagonists depending on endogenous dopamine levels, are less likely to cause profound induction of PRL release (Shapiro et al. 2003). Serotonin stimulates PRL secretion indirectly by increasing hypothalamic PRL releasing factors, including oxytocin , thyrotropin releasing hormone (TRH) , and vasoactive intestinal peptide (VIP ) produced by neurosecretory cells. Another mechanism suggested for increased PRL besides serotonergic stimulation is attenuation of dopamine-induced extracellular signal regulated kinase (ERK) phosphorylation (Bruins Slot et al. 2006). Stimulation of GABAergic neurons by serotonin may also inhibit the dopamine signals responsible for decreasing PRL production (Emiliano and Fudge 2004). Other modulators of PRL secretion include stimulation by estrogen and inhibition by endorphins.

PRL has pre-gonadal anti-fertility effects in both males and females (Molitch 2008; Madhusoodanan et al. 2010). Basal secretion of PRL in normal men varies diurnally and is pulsatile, with approximately 3 pulses per day and 8 per night. PRL secretion by lactotroph cells of the pituitary is inhibited centrally by dopaminergic neurons projecting on the median eminence. Gamma-amino butyric acid (GABA), norepinephrine, and acetylcholine act centrally to inhibit lactotrophs. Thyrotropin releasing hormone (TRH) stimulates PRL secretion while serotonin increases PRL secretion indirectly via neurosecretory cells of the hypothalamus. Modulation of central dopamine and serotonin presynaptic reuptake and/or postsynaptic receptor activity by some drugs causes elevated PRL secretion, resulting in negative feedback on pulsatile gonadotropin releasing hormone (GnRH) release and lower levels of LH and FSH (Emiliano and Fudge 2004; Madhusoodanan et al. 2010; Bjelic et al. 2015). Stimulation of GABA receptors by some drugs also modulates PRL secretion. Estradiol and histamine can increase PRL synthesis and release by a variety of mechanisms including decreasing dopamine-mediated inhibition of pituitary lactotroph cells.

Normal values of PRL will vary depending on the analytic platform (i.e., specific instrument or assay), but the upper limit of normal for men is usually between 7.4 and 20 ng/mL (Le et al. 2014). Most publications on this topic provide average PRL values for groups of study subjects, but the proportion of men falling into the hyperPRL range is reported less frequently, and can be more useful clinically. Women tend to have a greater PRL response to medications. The majority of papers include both genders, and the results for male subjects are not always given separately. Overall, it can be unclear how to manage the medications of a male patient with high PRL levels and infertility. There is debate as to when to investigate and/or treat increased PRL in men. Treatment ranges from cessation of medication and lifestyle adjustments, to MRI of the pituitary gland to rule out and treat a potentially life threatening prolactinoma.

In rats with drug-induced hyperPRL, at a dose that did not decrease total testosterone, estradiol , or inhibin ; the LH and FSH levels were low, associated with poor testicular histology , abnormal acrosomal morphology, and higher DNA fragmentation (Gill-Sharma et al. 2003).

Because of its anti-gonadotropic activity, hyperPRL can cause hypogonadism and negatively impact on most reproductive functions in men, including libido, sexual function, spermatogenesis, epididymal transit , and ejaculation (Carter et al. 1978; Segal et al. 1979). Semen quality can be affected with lower sperm count, motility, and normal morphology although this has not been seen consistently. HyperPRL can also have direct testicular effects. The Leydig cells have PRL receptors and PRL is required for normal Leydig cell function; however, PRL can