HPV. Changing the Paradigm. June 23, :45 PM 2:00 PM New York, New York. Educational Partner

Transcription

1 HPV Changing the Paradigm June 23, :45 PM 2:00 PM New York, New York Educational Partner

2 Session 3: HPV Changing the Paradigm Learning Objectives 1. Explain the epidemiology and burden of disease associated with human papillomaviruses (HPVs). 2. Identify those HPV types most often associated with particular cancers and genital warts. 3. Discuss strategies to reduce the prevalence of these diseases. Faculty Maura L. Gillison, MD, PhD Professor of Medicine, Epidemiology, and Otolaryngology Jeg Coughlin Chair of Cancer Research Comprehensive Cancer Center The Ohio State University Columbus, Ohio Dr Maura Gillison, professor of medicine, epidemiology, and otolaryngology at the Ohio State University (OSU) in Columbus, is co-director of its Hand and Neck Disease Committee, as well as Jeg Coughlin Chair of Cancer Research in OSU s Comprehensive Cancer Center. Her research involving the biological causes of head and neck squamous cell carcinoma (HNSCC) has transformed how we think about and treat this disease. Dr Gillison was the first to define a causal link between human papillomavirus (HPV) and a distinct subset of head and neck cancers. Her research has further clarified the etiological heterogeneity of head and neck cancers and the effect of this heterogeneity on treatment response and prognosis. She demonstrated, with colleagues, that tumor HPV status is the single greatest predictor of treatment response and prognosis for head and neck cancer patients, leading to distinct paths for clinical trial research for HPV-positive HNSCCs, compared to HPV-negative HNSCCs. Dr Gillison s examination of the effect of HPV-positive disease at the population level has identified a rapid increase in incidence for HPV-positive oropharyngeal cancers, which appear to be especially prevalent among whites, men, and young adults. These findings have shifted the understanding of HPV-associated cancers and sparked debate over whether young boys and men should be routinely vaccinated against the most common types of HPV. Amanda F. Dempsey, MD, PhD, MPH Associate Professor of Pediatrics University of Colorado Denver Denver, Colorado Dr Amanda Dempsey is an associate professor of pediatrics in the Child Outcomes Research Group at the University of Colorado in Denver. She received her medical and doctoral degrees from Vanderbilt University in Nashville, and completed pediatric residency training at the Seattle Children s Hospital and Regional Medical Center. Dr Dempsey was a Robert Wood Johnson Clinical Scholar and received her master s degree in public health at the University of Washington, also in Seattle. Dr Dempsey s long-standing interest in research related to adolescent and childhood immunization covers a broad range of issues, including health policy, implementation strategies, and understanding the biologic and clinical effects of vaccination. Session 3

3 She also uses mathematical modeling strategies to study the comparative economics of vaccination, as well as the potential population-level effects of various vaccination policies. Dr Dempsey s research interests include human papillomavirus (HPV) infection among women and men with a specific interest in prevention interventions and understanding HPV infection and its association with non-melanoma skin cancer and other viral-associated cancers. Faculty Financial Disclosure Statements The presenting faculty reports the following: Dr Gillison has received research funding from Merck & Co., Inc. Dr Dempsey is an advisor for Merck & Co., Inc. Education Partner Financial Disclosure Statement The content collaborators at Miller Medical Communications, LLC, report the following: Lyerka D. Miller, PhD, has no financial relationships to disclose. Suggested Reading List Fryhofer SA. Immunization 2011: expanding coverage, enhancing protection. Ann Intern Med. 2011;154(3): Gillison ML, Chaturvedi AK, Lowy DR. HPV prophylactic vaccines and the potential prevention of noncervical cancers in both men and women. Cancer. 2008;113(10 Suppl): Giuliano AR, Lee JH, Fulp W, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet. 2011;377(9769): Giuliano AR, Lu B, Nielson CM, et al. Age-specific prevalence, incidence, and duration of human papillomavirus infections in a cohort of 290 US men. J Infect Dis. 2008;198(6): Kharbanda EO, Stockwell MS, Fox H, et al. The role of human papillomavirus vaccination in promoting delivery of other preventive and medical services. Acad Pediatr. 2011;11(4): Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila). 2009;2(10): Koshiol JE, Laurent SA, Pimenta JM. Rate and predictors of new genital warts claims and genital warts-related healthcare utilization among privately insured patients in the United States. Sex Transm Dis. 2004;31(12): Litton AG, Desmond RA, Gilliland J, et al. Factors associated with intention to vaccinate a daughter against HPV: a statewide survey in Alabama. J Pediatr Adolesc Gynecol. 2011;24(3): Markowitz LE, Sternberg M, Dunne EF, et al. Seroprevalence of human papillomavirus types 6, 11, 16, and 18 in the United States: National Health and Nutrition Examination Survey J Infect Dis. 2009;200(7): Steben M, Duarte-Franco E. Human papillomavirus infection: epidemiology and pathophysiology. Gynecol Oncol. 2007;107(2 Suppl 1):S2-S5. Session 3

4 Drug List Pre-? Generic Name HPV4 HPV2 Trade Name Gardasil Cervarix For which group is HPV vaccination recommended to prevent genital warts? 1. Males and females aged <9 years 2. Males and females aged 9-26 years 3. Females aged years, sexually 4. Males aged years, sexually For which group is HPV vaccination recommended to prevent anal cancer? Pre-? Pre-? How often do you currently vaccinate or recommend HPV vaccination for both males and females? 1. Males and females aged <9 years 2. Males and females aged 9-26 years 3. Females aged years, sexually 4. Males aged years, sexually 1. Never or rarely 2. Some of the time 3. Most of the time 4. Always 5. Only in males and females who are at high risk for HPV infection 6. Only in males and females who are sexually Pre-? Pre-? How often do you currently talk about HPV vaccination with your patients who are parents or relatives of adolescents? In your opinion, the BEST reason to immunize males against HPV is: 1. Never or rarely 2. Some of the time 3. Most of the time 4. Always 5. Only if my patients ask me about it 1. To prevent genital warts in males 2. To prevent male-to-female transmission of HPV 3. To prevent female-to-male transmission of HPV 4. To prevent head and neck, penile, and anal malignancies in males 1

5 Human Papillomavirus (HPV) HPV Infection and Associated Diseases Maura L. Gillison, MD, PhD Professor of Internal Medicine & Epidemiology Jeg Coughlin Chair of Cancer Research Comprehensive Cancer Center The Ohio State University Columbus, Ohio Small, circular DNA viruses Humans only known host More than 130 unique types Cutaneous and mucosal types High- and Low-risk types HPV Genome Organization HPV Oncoproteins: p53 and prb HPV is a double stranded, closed circular (episomal) DNA virus with a genome size of 8000 base pairs E6 E7 E1 E5 L2 E2 L1 E4 early genes late genes URR* *URR=upstream regulatory region 12 Alani RM, et al. J Clin Oncol. 1998;16(1): Prevalence of Low-risk and High-risk HPV Among Women in the United States, Genital HPV Infection in Men The HIM Study, N=3909 Overall, 42.5% HPV16, 4.7% HPV type Prevalence (%) Any HPV 66.8 High-risk HPV 29.7 Low-risk HPV only 22.7 HPV Hariri S, et al. J Infect Dis. 2011;204(4): HIM=History of HPV in men Akogbe GO, et al. Int J Cancer. 2012; 131(3):E282-E

6 Prevalence Of Oral HPV Infection United States, Sexual Behaviors And Oral HPV Infection Prevalence (%) Prevalence Ratio Men Women PR 95% CI Overall High-risk HPV Adjusted for: Age Race/ethnicity Gender Marital status Smoking Gillison ML, et al. JAMA. 2012;307(7): Gillison ML, et al. JAMA. 2012;307(7): Infection From Time of First Sexual Intercourse Genital HPV Infection in Couples, N=263 Cumulative Incidence of HPV Infection Study of female college students (N=603) No. Couples Percent concordant No. Infections % in both partners All % % HR % % LR % % 0 Months Since First Intercourse Winer RL, et al. Am J Epidemiol. 2003;157(3): Burchell AN, et al. Epidemiology. 2010: 21(1): Incidence Rates (IR) for Genital HPV Infection in Sexual Partners, 179 Couples Persistence of Incidence Type-specific HPV Infections Variable IR, Per 100 Person-months 95% CI Overall Men to women Women to men High-risk HPV Burchell AN, et al. J Infect Dis. 2011; 204(11): Winer RL, et al. Cancer Epidemiol Biomarkers Prev. 2011;20(4):

7 Cervical Infection Persistence and Risk of CIN2+ Natural History of HPV Infection and Potential Progression to Cervical Cancer 0 1 Year 0 5 Years 1 20 Years Initial HPV Infection Continuing Infection CIN 2/3 Invasive Cervical Cancer CIN 1 Cleared HPV Infection CIN=cervical intraepithelial neoplasia Chen HC, et al. J Natl Cancer Inst. 2011;103(18): Pinto AP, et al. Clin Obstet Gynecol. 2000;43(2): Pathologic Progression of Cervical Cancer Estimated Annual Burden of HPV-Related Diagnoses in the United States Cervical intraepithelial neoplasia (CIN) 1 CIN 1: Mild dysplasia; includes condyloma (anogenital warts) CIN 2: Moderate dysplasia CIN 3: Severe dysplasia; includes CIS CIN 1 Histology of squamous cervical epithelium 1 Basal cell Normal CIN 1 (condyloma) CIN 1 (mild dysplasia) CIN 2 (moderate dysplasia) CIN 3 (severe dysplasia/cis) Invasive Cancer 9710 new cases of cervical cancer 330,000 new cases of high-grade cervical dysplasia (CIN 2/3) 1.4 million new cases of low-grade cervical dysplasia (CIN 1) 3700 deaths estimated in Basal membrane CIS=carcinoma in situ Bonnez W. In: Richman DD, Whitley RJ, Hayden FJ, eds. Washington, DC: American Society for Microbiology Press; 2002: Ostör AG. Int J Gynecol Pathol. 1993;12(2): million new cases of genital warts American Cancer Society. Cancer Facts and Figures Atlanta, GA: American Cancer Society; 2006:4. Schiffman M, et al. Arch Pathol Lab Med. 2003;127(8): Fleischer AB Jr, et al. Sex Transm Dis. 2001;28(11): HPV and Anogenital Warts in the United States HPV Types in Cervical Cancer HPV 6 and 11 responsible for >90% of anogenital warts Rate of ~1.2 per 1000 in the United States 340,000 cases in 2004 Median duration of 95 days Recurrence common Estimated cost of $220 million Hoy T, et al. Curr Med Res Opin. 2009;25(10: Franceschi S, et al. Int J Cancer. 2006;119(11): Copyright 2002 BMJ Publishing Group Ltd. 27 4

8 Classification of HPV Types by Cervical Oncogenicity Annual Burden of HPV-Associated Cancers Among Women and Men High-risk: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82 Probable high-risk: 26, 53, 66 Low risk: 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, CP610 Undetermined risk: 34, 57, 83 Number of cases 12,000 10, Cervix Women Noncervical cancers Men Penis Vagina Oropharynx Vulva Anus Cervix Burden of noncervical cancers ~ burden of cervical cancers Burden of noncervical cancers is equal among men and women Oropharyngeal cancers contribute to a substantial burden of HPV-associated cancers among men (75%) and a considerable burden of noncervical HPV-associated cancers among women (26%) Muñoz N, et al. N Engl J Med. 2003;(348(6): Gillison ML, et al. Cancer. 2008;113(10 suppl): Annual Burden of HPV-Associated Cancers in the United States, Incidence Trends in the United States Annual number of cases 12,000 10, Non-HPV 16/18 genotype associated HPV 16/18-associated cancers 10, Cervix Oropharynx Anus Vulva Vagina Penis Surveillance, Epidemiology and End Results Program (SEER), National Cancer Institute Evaluate changes in prevalence and incidence of HPV-pos and HPV-neg oropharynx cancer 271 cases of oropharynx cancer from from Residual Tissue Repository Program in Iowa, LA, Hawaii Cervical and gastric cancer cases used as positive and negative controls and used to adjust sensitivity Assays specifically designed to account for DNA and RNA degradation in formalin fixed paraffin. Gillison ML, et al. Cancer. 2008;113(10 suppl): HPV Prevalence, Oropharynx Cancer United States Oropharynx Incidence Trends by HPV Status HPV status per LiPa Reweighted to age, gender, race, ethnicity, distribution of all cases in 3 registries Consistent with trends in all SEER registries Chaturvedi AK, et al. J Clin Oncol. 2011;29(32): LiPa=assay used in HPV genotyping Chaturvedi AK, et al. J Clin Oncol. 2011;29(32):

9 Oropharyngeal and Cervical Cancer Incidence Projections, United States Head and Neck Cancer Incidence Projections Chaturvedi et al, unpublished. 34 Chaturvedi et al, unpublished. 35 HPV Attributable Cancers GLOBOCAN 2008 Conclusions Cancer Total No. HPV-PAF No. Attributable to HPV Males only Cervix 530, , Oropharynx 85, ,000 17,000 Anus 27, ,000 11,000 Vulva 27, , Penis 22, ,000 11,000 Vagina 13, HPV is the most common sexually transmitted infection Majority clear infection without consequence Benign warts and cervical pre-cancers are associated with substantial morbidity and cost Approximately 20,000 cancers in the United States each year Approximately 5% of worldwide cancer burden Vaccination is important because we can not distinguish those who will get cancer from those who will not PAF=population attributable fraction de Martel C, et al. Lancet Oncol. 2012;13(6): Gillison, Cancer Many HPV related diseases could be prevented by HPV vaccination Proportion of Cancers Attributable to HPV Reducing the HPV Disease Burden Amanda Dempsey, MD, PhD, MPH Associate Professor of Pediatrics University of Colorado Denver Denver, Colorado 38 Adapted from Gillison et al. Cancer. 2008;113: ; MMWR. 2012;61(15):

10 Overview HPV Vaccines and Indications HPV vaccines and their indications Current vaccine recommendations Why adolescent vaccination is important Reasons for not using sexual history in making the vaccine recommendation Side effects, real and imagined Talking with parents about the vaccine Strategies to increase vaccination rates HPV4 HPV types included 6, 11, 16, 18 16, 18 Availability in United States Clinically proven indications + Other diseases possibly prevented by vaccine ++ Females since 2006 Males since 2010 Prevention of: Genital warts Cervical cancers* Anal cancers* Vaginal cancers* Vulvar cancers* Respiratory papillomatosis Some head and neck cancers HPV2 Since 2009 (females only) Prevention of: Cervical cancers* Anal cancers* Vaginal cancers* Vulvar cancers* *Caused by vaccine-specific HPV types + Demonstrated efficacy in clinical trials ++ Biologically plausible, but has not been studied in a clinical trial Current Vaccine Recommendations (ACIP) Why is it important to vaccinate adolescents in particular? Females Males HPV years at doctor/parent discretion years routine vaccination years catch up vaccination 9 10 years at doctor/parent discretion years routine vaccination years catch up vaccination years at doctor/patient discretion HPV years at doctor/parent discretion years routine vaccination years catch up vaccination Not licensed Biological reasons Epidemiologic reasons Behavioral reasons Programmatic reasons Pediatrics. 2012;129(3): Biological Immunogenicity Biological Adolescent Cervix Higher antibody levels with younger age at vaccine administration Occurs with both the bivalent and quadrivalent HPV vaccines ~3 log orders of magnitude difference between 9-year-olds and 26-year-olds Large transformation zone of squamous metaplasia on surface of cervix Single layer columnar epithelium multilayered squamous epithelium Susceptible to epithelial breaks that allow for entry of HPV virus to basal layer Active cell replication during metaplasia also likely contributes Reisinger et al. Pediatr Infect Dis J. 2007;26(3): ; Pedersen et al. J Adol Health. 2007;40: Moscicki et al. Adol Med. 2010;21:

11 Epidemiologic Behavioral Onset of Sexual Debut There are more than 6 million new genital HPV infections in the United States each year ~75% of those occur among 15- to 24-year-olds Age adjusted Rates of HPV Cumulative Survival White Female 0.4 White Male African American Female 0.3 African American Male Hispanic Female 0.2 Hispanic Male 0.1 Asian Female 0.0 Asian Male Age (years) NHANES Dunne et al. JAMA. 2007;297: Cavazos-Rehg,PA et al. Contraception. 2009; 80: Behavioral Rapid Exposure After Sexual Debut Programmatic 1.0 Study of female college students (N=603) Pre-adolescent health care visit recommended at age years Cumulative Incidence of HPV Infection ~50% of women had HPV within 5 years of becoming sexually!! Builds on adolescent platform of other vaccines routinely recommended Tdap MCV4 Flu Implementation of 3-dose regimen to adolescents difficult at any age start early! Months Since First Intercourse Winer et al. Am J Epidemiol. 2003;157(3): Pediatrics Mar;129(3): Sexual History Should NOT Influence Vaccine Recommendation Vaccine Efficacy Among an Unrestricted* Population of Women Vaccine is likely to still be effective even in women with known prior HPV infection This is because most women will not have been exposed to all of the HPV types found in the vaccines Outcome Adjusted Vaccine Efficacy Cervical pre cancers ** 69% Vulvar pre cancers ** 69% Vaginal pre cancers ** 83% Genital warts** 79% *Unrestricted population: Includes HPV naïve women as well as those with past and current exposures: Females years old involved in an HPV4 vaccine clinical trial in 24 countries Had received at least 1 dose of vaccine (may or may not have completed the 3 dose series) Had at least 1 follow up visit **associated with HPV types 6, 11, 16 and/or 18 Dillner et al. BMJ. 2010;340:c

12 Sexual History Should NOT Influence Vaccine Recommendation Common Side Effects From Vaccination Clinical Trials Who is best to vaccinate? Unclear whether sexually or sexually naïve individuals would confer the highest benefit If vaccinate those WITH risk factors, a proportion of those vaccinated will have already been exposed If vaccinate those WITHOUT risk factors, then a high proportion of women will not be vaccinated, but WILL be exposed in the future Injection site* Pain Swelling Erythema Pruritus HPV4 HPV2 Placebo 83.9% 26.0% 24.7% 4.1% 90.5% 42.0% 43.8% N.R. ~75% ~15% ~16% ~3% Fever** 14.8% 12.4% ~11% * 1-5 days post vaccination ** 1-15 days post vaccination Dempsey et al. Vaccine. 2008; 26: Side Effects Uncovered in the Real World Population Reported Adverse Experiences That Have Been Disproven? Fainting Not specific to HPV Vaccine CDC recommends a 15-minute waiting period after any vaccine given to an adolescent Anaphylaxis VERY rare 2.6/100,000 doses May be more likely to occur with co-administration of other vaccines Guillain-Barré Syndrome Seizures Movement Disorders Other autoimmune processes Death Agorastos et al. Vaccine. 2009;27(52): ; Brotherton et al. CMAJ. 2008;179(6): Centers for Disease Control and Prevention. Vaccine Adverse Event Reporting System (VAERS) Vaccine Adverse Event Reporting System (VAERS) Results for HPV4 From 06/06 12/08 there were: 12,424 reports submitted regarding HPV4 20% of cases had other vaccines co-administered Of these, 772 were serious adverse events. Of these, only ~120 were considered medically important (ie, Not headache, fever, fainting, dizziness, nausea, vomiting, or fatigue) Rates of Serious Adverse Events Identified via VAERS Event Rate associated with HPV vaccination (per 100,000) Anaphylaxis 0.1 Venous Thrombo embolus 0.2 Autoimmune Disorder 0.2 Guillain Barré 0.2 Transverse Myelitis 0.04 Pancreatitis 0.04 Death None of these are significantly different from population background rates Slade BA et al. JAMA. 2009;302(7): Slade BA et al. JAMA. 2009;302(7):

13 Talking to Parents About the Vaccine Common Concerns: Parents don t have enough information Short-term safety issues (ie, media stories) Long-term safety not proven Vaccine not needed child not sexually Vaccine not needed child already exposed Vaccination will promote sexual activity Vaccine will cause infertility Vaccine will give your child HPV Vaccine is delivered into cervix directly Changing the Minds of Vaccine Hesitant (VH) Parents Recognize the 5 types of VH parents Uninformed but educable want education to counter anti-vaccine information Misinformed but correctable Need information about vaccine benefits Well-read and open-minded Want to intelligently discuss pros and cons Strongly vaccine-hesitant Willing to listen but not to change mind right away Strong-willed and committed against vaccines Want to sway provider to their line of thinking 58 Harrington. Consultant Ped. 2011;10(11):s General Strategies for Talking With Vaccine Hesitant Parents 1. Do not be dismissive of concerns, even if they are unfounded. 2. Try to figure out the parents specific concerns, rather than provide generic information. 3. Provide a strong recommendation. Do not suggest the vaccine is optional or somehow different from the other vaccines recommended at that age. 10 General Strategies for Talking With Vaccine Hesitant Parents 4. Make the recommendation personal. 5. Draw on parental experiences with HPV-related diseases, if possible. 6. Provide written information that the parents can bring home with them. 7. Acknowledge possibility of side effects rather than glossing over them. 8. Explain the biological advantages of vaccinating at a younger age General Strategies for Talking With Vaccine Hesitant Parents 9. Have ready responses for the common concerns and for any media stories about the vaccine. 10.Work with hesitant parents over time it is a marathon, not a sprint. 12 Clinical Strategies for Improving Vaccination Rates 1. Reminder-recall systems 2. Extended office hours 3. Immunization-only appointments 4. Standing orders 5. Minimizing missed opportunities 6. Knowing the true contraindications to vaccination Lumen et al. Am J Prev Med. 2009;36(2):

14 12 Clinical Strategies for Improving Vaccination Rates 7. Make vaccination a known priority for the practice Word-of-mouth can promote vaccination 8. Automated systems Vaccine reminder systems Standing orders Flu + HPV Helps to make every visit count 9. Consider having special clinics or appointments just for vaccination Back-to-School season One weekend morning a month 10. Insurance hotline 12 Clinical Strategies for Improving Vaccination Rates 11. Be aware of reputable and nonreputable Web sites about vaccination One Google search will get you a lot of information 12. Use the momentum of the adolescent platform Normalize vaccination as an expected part of adolescent preventive care Set up expectations for vaccination preemptively This can diffuse focus on any 1 vaccine Vaccination can signal parents to come to clinic Other preventive care services can then be provided Female Specific Ideas Male Specific Ideas Educate patients about benefits to vaccination even if sexually or prior HPV infection Many women unclear about this point Discuss why promoting vaccination well before any thoughts of sexual activity occur is important Fluoride example Be familiar with commonly held concerns about vaccine safety Have reputable educational resources for parents Describe risk clearly and in a compelling way Pictures speak 1000 words Discuss link between HPV and H&N cancer, which occurs in M>F Discuss what is known about transmission Most heterosexual men consider HPV a female problem Many mothers may be more amenable to HPV vaccination of their sons if they also consider the possibility of decreasing transmission to females Dempsey et al. Sex Transm Dis. 2011;38(8): Putting It All Together Post-? HPV vaccines have been shown to prevent a myriad of diseases. Biologic plausibility suggests additional diseases may also be avoided. Vaccinating younger adolescents gives the best chance of PREVENTING the clinical sequelae from HPV vaccination Systems, communication, and clinical strategies can all increase the likelihood that adolescents receive the vaccine For which group is HPV vaccination recommended to prevent genital warts? 1. Males and females aged <9 years 2. Males and females aged 9-26 years 3. Females aged years, sexually 4. Males aged years, sexually 68 11

15 For which group is HPV vaccination recommended to prevent anal cancer? Post-? Post-? Moving forward, how often will you vaccinate or recommend HPV vaccination for both males and females? 1. Males and females aged <9 years 2. Males and females aged 9-26 years 3. Females aged years, sexually 4. Males aged years, sexually 1. Never or rarely 2. Some of the time 3. Most of the time 4. Always 5. Only in males and females who are at high risk for HPV infection 6. Only in males and females who are sexually Post-? Post-? Moving forward, how often will you talk about HPV vaccination with your patients who are parents or relatives of adolescents? In your opinion, the BEST reason to immunize males against HPV is: 1. Never or rarely 2. Some of the time 3. Most of the time 4. Always 5. Only if my patients ask me about it 1. To prevent genital warts in males 2. To prevent male-to-female transmission of HPV 3. To prevent female-to-male transmission of HPV 4. To prevent head and neck, penile, and anal malignancies in males Questions & Answers? 12