The Ins & Outs of Sexual Medicine Brochure | AUA History Booth 2022

of Sexual Health

Ins & Outs of Sexual Health

The Ins

Female Pelvic Organs

MAY 20221

Welcome to the Ins & Outs of Sexual Health

We have always been passionate about moving the field of sexual medicine forward: developing the next process of care, performing clinical trials on future treatment options, educating providers and the public on sexual medicine issues.

Through the various stakeholder societies, the AUA, SMSNA, ISSM and ISSWSH, we have had the pleasure of seeing the field of sexual medicine grow. Being asked to curate the history exhibit at the AUA has given us a wonderful opportunity to look back and share some of our favorite parts of the 40 plus-year sexual medicine journey. “The Ins and Outs of Sexual Health” has been a genuine labor of love; we hope you get as much enjoyment out of the exhibit as we have had from building it. The history exhibit has morphed into an occasion to educate AUA members on how we got to today in sexual medicine and where we expect to be going tomorrow, all with the unwavering support of the AUA. The “Ins and Outs of Sexual Health”, clearly a play on words, is literally just that. Did you know that hormones were initially given to men by transplanting the testicles of monkeys? Did you know that the first public display of an intracavernosal injection for pharmacologic erection was actually a public display at the AUA? Did you know that the approval of sildenafil sparked the study of women’s sexual health as a biopsychosocial field?

We have always worked as a team—often with Irwin in the foreground and Sue in the background—but this project has allowed us to use each of our strengths to bring to you a labor of love. Come learn something new about men’s sexual health issues, women’s sexual health issues, hormones (well, really testosterone) and regenerative therapies. Leave just a little more knowledgeable about sexual medicine. And maybe a little more passionate about it. After all, sexual health affects people’s overall health. You don’t need to be a specialist to ask about someone’s sexual health—you just need to know there are people out there to whom you can refer your patient, your client, your friend. Don’t be afraid to ask because you won’t know what to do with the answer.

Enjoy the exhibit, check the ins and outs and bone up on some new information.

It’s not hard to do!

Irwin Goldstein, MD & Sue Goldstein, CCRC, CSE 2022 Exhibit Curators

Irwin Goldstein, MD & Sue Goldstein, CCRC, CSE 2022 Exhibit Curators Ronald Rabinowitz, MD AUA Historian 2022 Sponsor

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1000 Corporate Boulevard Linthicum, Maryland 21090 www.UrologicHistory.museum

UrologicHistory.Museum

Barbara Chubak, MD

Common Female Medical Diagnoses: Wandering Womb

In the middle of the flanks of women lies the womb, … closely resembling an animal; in a word, it is altogether erratic. It delights also in fragrant smells, and advances towards them; and it has an aversion to fetid smells, and flees from them.

Aretaeus, a physician from Cappadocia, 81-138 CE

Furor Uterinus

Another term for Nymphomania or Hysteromania.

Medical diagnosis, made exclusively in women, popular during the Victorian era, for women who exhibited a wide array of symptoms including faintness, nervousness, insomnia, fluid retention, heaviness in abdomen, muscle spasm, shortness of breath, irritability, loss of appetite for food or sex, and a “tendency to cause trouble”.

A Comprehensive Medical Dictionary, 1865.

Chlorosis

Chlorosis (from Greek “green”) A disease peculiar to young females under retention or suppression of the menstrual discharge; green-sickness.

A Comprehensive Medical Dictionary, 1865.

From the origins of Western medical history in the Hippocratic Corpus, the uterus has been blamed for various diseases afflicting female patients, the etiology changing with the prevailing understanding of the body. Ancient, medieval, and early-modern doctors worried about uterine suffocation, in which the “wandering womb” compressed and injured other organs, and humoral imbalance related to menstruation or its absence (“chlorosis” or “greensickness”). Modern, mechanistic and neurologic body concepts associated uterine illness, or hysteria, with psychopathy and spasticity.

Sexual activity within the socially acceptable confines of marriage was the recommended treatment for these various uterine ills, ideally resulting in pregnancy, a woman’s best purpose being motherhood. As orgasm was commonly believed to be a reliable aid, if not essential, to conception, medical texts emphasized the importance of sexual pleasure for the wellbeing of women, marriage, family, and society, while simultaneously worrying that sexual satisfaction might be achieved outside of this approved context and thus undermine the social order.

The Ins

The Secrets of Women: Hysteria, Orgasm, and Vibrators

To accommodate the importance of genital stimulation to women’s health while restricting its pleasures to heterosexual marriage, doctors de-eroticized their treatments. When pelvic massage was indicated, ancient, medieval, and earlymodern doctors delegated or referred patients to female healers for treatment.

In the 19th century, when Swedish gynecologist Dr. Thure Brandt popularized bimanual massage for the treatment of pelvic disease, he employed female therapists and advised that they should err on the side of causing pain, rather than pleasure.

The popular origin story of the vibrator – that Victorian doctors used them to masturbate their repressed, hysterical female patients to orgasm – is false, a myth that persists because it titillates the imagination while reinforcing gender stereotypes. Though not explicitly advertised as such, early vibrators likely were used by women to achieve orgasm in the same way they are most commonly used today: at home, by their own choice and in their own hands.

Hysteria

Hysteria (from Greek, the “womb”) Hysteries, attacking in paroxysms or fits, usually preceded by dejection, anxiety, tears, difficulty breathing, sickness, and palpitation of the heart.

A Comprehensive Medical Dictionary, 1865.

Ins & Outs of Sexual Health

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Anatomy of Arousal Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

Gross anatomic and histologic study of the clitoris, vestibular bulbs, labia minora, and urethra show them to contain specialized vascular tissues that are sexually responsive and consist of two histologically distinct types of vascular tissue.

Trabeculated erectile tissue is found in the clitoris and the vestibular bulbs, which allows for engorgement with blood and volume expansion during sexual arousal.

In contrast, the labia minora and glans clitoris are composed of non-erectile vascular tissue, in which the blood vessels are dispersed within a fibrous matrix, with only a minimal amount of smooth muscle. Non-erectile, sexually responsive vascular tissue is also found surrounding the urethral lumen and within the walls of the vagina. During sexual arousal, these tissues increase in blood flow, but the structure of the tissues does not accommodate vascular engorgement as in erectile tissue.

Female Pelvic Nerves: In preparation: Komisaruk BR Goldstein I. Female Sexual Dysfunction after Cystectomy

The urethra, sitting toward the apex of the introitus, demonstrates changes in blood flow during arousal. The distal urethra is flanked by the erectile tissue of the vestibular bulbs. There are anterior vaginal wall periurethral glands along the length of the urethral lumen. These glands stain positively for prostate-specific antigen, consistent with prostate tissue. A region of the anterior wall of the vagina overlying the mid-urethra has been identified as the Gräfenberg zone (or G-spot), an area that - in some women - is particularly sensitive to tactile stimulation. Gräfenberg’s original article identified the erogenous area as arising from the urethra.

Some researchers have further speculated that these glands are responsible for the production of “female prostatic fluid” which is emitted during female ejaculation upon G-spot stimulation and which is distinct from urine. Recent evidence supports the notion that the G-spot likely encompasses a complex of multiple tissues involved in female sexual response, including but not limited to the female prostate.

Female Blood Flow in Arousal: In preparation: Komisaruk BR Goldstein I. Female Sexual Dysfunction after Cystectomy Courtesy Irwin Goldstein, MD

Female Prostate Courtesy Irwin Goldstein, MD

Female Blood Flow in Arousal: In preparation: Komisaruk BR Goldstein I. Female Sexual Dysfunction after Cystectomy Courtesy Irwin Goldstein, MD

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UrologicHistory.Museum

Sue Goldstein, CCRC, CSE

Female Pelvic Organs

William P. Didusch Center for Urologic History

For centuries women were accused of being frigid, likely hypoactive sexual desire disorder (HSDD) or nymphomaniac, possibly persistent genital arousal disorder/ genito-pelvic dysesthesia (PGAD/GPD). Any sexual issue of which a women might complain was considered psychologic. With the FDA approval of sildenafil (Viagra) for men in 1998, women clamored for a solution for their issues; many turned to Irwin Goldstein, first author on the sildenafil NEJM article, for help. In response, he started a course and invited world’s experts on various aspects of women’s sexual function to present. People fed off each other’s knowledge and enthusiasm, sharing information to “figure it out”. By the third year, attendees voted to start a society, and in 2001 the International Society for the Study of Women’s Sexual Health (ISSWSH) was born.

ISSWSH members understand that menopausal women are fearful of hormones in the post-Women’s Health Initiative era, which often results in painful intercourse and urinary tract infections (UTIs), but hormone treatment can be safe and efficacious. Members cringe at stories of patients with uncontrollable orgasms from PGAD/GPD who are told, “I wish my wife had that problem,” or women with HSDD told to have wine, chocolate or a weekend away as a cure. Many attended the FDA advisory panel for flibanserin (2015), stumping on the Hill the day before, to support the need for pharmacologic treatment for our patients who told stories of ruined relationships. The medication was approved—the first for HSDD--but not without accompanying negative press.

The Ins

From Greensickness to Female Sexual Dysfunction

ISSWSH has developed/revised nomenclature useful for clinicians, researchers, and the mental health community as well as guidelines for treating various sexual dysfunctions. Over the years, hundreds of providers have attended courses in women’s sexual health at AUA or ISSWSH, to better manage their patients. With the ICD-11’s new chapter on sexual medicine in 2022, codes are more reflective of the current landscape so perhaps more clinicians will address women’s sexual function and dysfunction.

Second Course Book Courtesy Irwin Goldstein, MD

Agenda from FDA public meeting Courtesy Irwin Goldstein, MD

Ins & Outs of Sexual Health

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Menopause is More than Hot Flashes: Genitourinary Syndrome of Menopause (GSM) Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

15-35 %

Modern medicine has meant women live half their adult lives in menopause.

The decreased ovarian synthesis of estrogen and testosterone in menopause leads to physical changes to the vulva, vestibule, clitoris, vagina, urethra and bladder. These changes can lead to genital dryness; decreased lubrication with sexual activity; discomfort or pain with sexual activity; post-coital bleeding; decreased arousal, orgasm, desire; irritation/burning/itching of the vulva or vagina; dysuria; and urinary frequency/urgency. The previously-used term vulvovaginal atrophy only referred to the vulva and vagina, and not the plethora of menopausal symptoms.

women over 60 HAVE INCONTINENCE women with lower urinary tract symptoms are

The new term used with consensus by the North America Menopause Society and the International Society for the Study of Women’s Sexual Health characterizes both the physical changes and symptoms experienced by menopausal women: “genitourinary syndrome of menopause” (GSM).

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In addition to the physical changes from menopause and aging, such women experience sexual dysfunction. Many menopausal women report dryness and painful intercourse (dyspareunia), bleeding or spotting with sexual activity, burning, discomfort and irritation. In the Menopause Epidemiology Study, women were at four-fold greater risk of experiencing sexual dysfunction.

x

MORE LIKELY TO HAVE SEXUAL PAIN DISORDERS

During menopause, women experience urinary problems including frequency, urgency, nocturia, dysuria, and recurrent urinary tract infections. Urinary frequency and urgency are common midlife complaints; incontinence occurs in 15% to 35% of women over 60 years of age. Women with lower urinary tract symptoms have a sevenfold greater risk of sexual pain disorders and a fourfold greater risk of sexual arousal disorders than women without such symptoms.

The decrease in diversity of the vaginal microbiome and in acid-generating bacteria and the increase in coliform species within the vagina in menopause may predispose to infection and urogenital symptoms. Urogenital tissues are responsive not only to estrogen but to androgens as well. GSM may be successfully treated by restoring the hormonal milieu, reducing risk of UTIs and ameliorating dyspareunia.

GSM Is Undertreated 0%

Vaginal pH Levels in GSM

100%

Women without GSM

Women with GSM

3.8-4.2

>5.5

Only

20-25%

of women seek medical attention

Source: Portman et al. Genitourinary syndrome of menopause: new terminology for vulvovaginal from the for Source: Portman et al. Genitourinary syndrome of menopause: newatrophy terminology International Society for the Study of Women's Sexual Health and the North American Menopause Society. Menopause 2014;21(10)1063-1068.

vulvovaginal atrophy from the

International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause 2014;21(10)1063-1068.

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ACIDIC

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Source: Phillips N, Bachmann G. Genitourinary syndrome of menopause: Common Source: Phillips N, Bachmann G. Genitourinary syndrome of menopause: Common problem, effective treatments.

Cle Clinic J ofeffective Med 2018;85(5):390-398. problem, treatments.

Cle Clinic J of Med 2018;85(5):390-398.

UrologicHistory.Museum

Neuroproliferative Vestibulodynia Rachel Rubin, MD; Meredith Wasserman, MD, MS

The Vestibule

The vestibule, the opening to the vagina, looks totally normal or has some redness on visual exam, but is quite painful throughout the entire vestibule on physical examination with Q-tip testing —so is your patient’s pain with penetration in her head?

Neuroproliferative vestibulodynia was first described by gynecologist Dr Edward Friedrich in 1987; it was then called vulvar vestibulitis syndrome, with three main criteria: exquisite tenderness when the vestibule is palpated with a cotton-tip swab; vestibular erythema; severe pain with attempted vaginal penetration Neuroproliferative vestibulodynia is a peripheral neurologic vestibular pain disorder identified by an increase in the density of C-afferent nociceptors within the vestibular endoderm, and was first discovered by Bohm-Starke and colleagues in 1999. This paved the way for research identifying: the presence of increased innervation and sensitization of nociceptors within the mucosa

The Ins

Penetration Pain—It’s Not in Your Head

a 10-fold increase in density of these afferent fibers increased mast cell activation Since the increase in nerves and mast cells are only visible on histologic staining on biopsy or excised vestibular tissue and not on physical exam, many physicians presume that the penetration pain is psychological.

Courtesy Irwin Goldstein, MD

Nina Bohm-Starke

With the 1999 findings, researchers identified conservative treatments including oral antihistamines, topical analgesics, gabapentin and capsaicin. When conservative treatments fail, complete vestibulectomy has been shown to be successful and can be offered as the primary treatment when patients specifically exhibit hyperpathia and allodynia of the entire vestibule without hormonal factors contributing.

Complete vestibulectomy was first described by Woodruff and Parmley in 1981. It involves excision of the vestibular endoderm and coverage by a vaginal advancement flap. As evidenced by immunohistochemical staining of the entire vestibular specimen, neuroproliferative vestibulodynia affects the entire vestibule.

Performing only a posterior vestibulectomy does not make sense, as the remaining vestibular tissue is a recognized source of failed surgery.

Ins & Outs of Sexual Health

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Does the Pill Cause Pain? Hormonally Mediated Vestibulodynia Rachel Rubin, MD; Meredith Wasserman, MD, MS

The vestibule, endodermal tissue, can be adversely affected by sex-steroid deficient states, generally due to low testosterone. Approximately 10 million women in the US use oral contraceptive pills (OCPs). OCPs significantly increase sex hormone binding globulin levels and decrease synthesis of total testosterone, resulting in significant reduction of calculated free testosterone.

In 2007, Johannesson et al. found that endodermal vestibular epithelium was hormonally sensitive – altered in women on OCPs. The morphological pattern was consistent with low/sparse dermal papillae; the interlocking dermal papillae of women on OCPs made their vestibular epithelium more sensitive to stress (i.e., mechanical strain). Furthermore, the mucin-secreting minor and major vestibular glands depend, in part, on testosterone acting on androgen receptors. This translates into vestibulodynia—the potential price of OCPs. Women with hormonally mediated vestibulodynia and a low calculated free testosterone are found to have the following on physical examination:

Locations of q-tip testing during vulvoscopy Courtesy Irwin Goldstein, MD

diffuse vestibular tenderness of the vestibule ostia of the minor and major vestibular glands that are frequently erythematous diffuse pallor of vestibular epithelium with superimposed erythema Studies have shown increased risk of developing provoked vestibulodynia with OCP use, worse with early use. The first step in treatment involves discontinuing OCPs and identifying an alternative contraception, typically a long-acting reversible contraceptive such as an IUD, or etonogestrel implant.

Described in 2013, local treatment of hormonally mediated vestibulodynia involves applying daily local estradiol 0.03%/testosterone 0.1% in a hypoallergenic base to the vestibule. Additionally, patients may use systemic testosterone, typically a tube of 1% testosterone gel used over 10 days, applied to the back of the calf. The ideal calculated free testosterone goal is 0.6-0.8 ng/dl. Symptomatic improvement may be realized after 6 – 12 weeks of hormone treatment.

Erythema and pallor consistent with hormonally mediated vestibulodynia Courtesy Irwin Goldstein, MD

Outside of OCP use, hormonally mediated vestibulodynia may be associated with low calculated free testosterone related to hormonal control of endometriosis or hirsutism, breast-feeding, infertility treatments or treatments for breast cancer.

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UrologicHistory.Museum

Hypoactive Sexual Desire Disorder (HSDD) Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

ISD to HSDD

In 1968, the Diagnostic and Statistical Manual of Mental Disorders, Second Edition (DSM-II) did not address the existence of desire disorders in either gender; all sexual disorders were grouped into one diagnostic category labeled psychophysiological genitourinary disorders. Masters and Johnson did not recognize desire disorders in their famous text Human Sexual Inadequacy (1970).

Two highly influential psychiatrists, Harold Lief and Helen Singer Kaplan, introduced the concept of low sexual desire in 1977, citing “inhibited sexual desire” (Lief) and “hypoactive sexual desire disorder” (Kaplan); inhibited sexual desire, defined as “persistent inhibition of sexual desire”, was included in the DSM-III (1980).

The DSM-III-R (1987) replaced inhibited sexual desire with hypoactive sexual desire disorder (HSDD), which was more descriptive and did not imply etiology.

HSDD was defined as ”persistent or recurrent deficient or absent sexual fantasies or desire for sexual activity.” Sexual aversion disorder was added to sexual desire disorders with the additional requirement that the disorder cause significant personal or interpersonal distress for both diagnoses; this ensured normal variations in sexual behavior would not be diagnosed as mental disorders.

The Ins

How Low Can You Go?

In 2000, the Sexual Function Health Council of the American Foundation for Urologic Disease, a committee of The American Urological Association (AUA), added to the definition of HSDD “an absence of sexual thoughts and a lack of desire in response to sexual stimulation.”

In response to the DSM-5 combining sexual arousal and desire disorders into a single entity, Female Sexual Interest/Arousal Disorder (FSIAD), the International Society for the Study of Women’s Sexual Health argued for a return to the diagnosis of HSDD for which there is a large body of empirical experimental and clinical evidence. The definition was more broadly described and published in 2016 as part of a larger nomenclature paper.

Courtesy Irwin Goldstein, MD

Two drugs, flibanserin and bremelanotide, are now FDA-approved for the treatment of pre-menopausal women with acquired HSDD.

Manning Up for Women in America Sue Goldstein, CCRC, CSE Ever try to explain something intangible to someone who has never experienced it? Hypoactive sexual desire disorder (HSDD) can be when someone no longer desires sex, but it can also be when you get distracted during sex or when you no longer fantasize about it, and it bothers you. Complicated, right? But to someone experiencing HSDD, it’s not so complicated—they just want to be treated before they lose their relationship. When the doctor says, “Go home and have a glass of wine,” or “Go away for the weekend without the kids,” how do you think patients feel?

Before the first drug to treat HSDD went before the FDA, a group of experts AND their patients went to Washington to speak to their congressmen and the senators. Patients told their stories, and we think our leaders listened, but no one explained what HSDD felt like, only the consequences. So that was my job, as an educator and a woman with HSDD. Sometimes we have to “man up” to help our patients!

Ins & Outs of Sexual Health

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How Much is Too Much?

History of Persistent Genital Arousal Disorder (PGAD/GPD) Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE Leiblum and Nathan first reported “persistent sexual arousal syndrome” (PSAS) in 2001 with a case series of five women. The main features of PSAS were symptoms of unremitting genital - primarily clitoral - arousal observed in “the absence of conscious feelings of sexual desire.” Diagnostic testing revealed “no obvious hormonal, vascular, neurological, or psychological causes.”

PSAS to PGAD/GPD

Five years later, Leiblum revised the name to persistent genital arousal disorder (PGAD), in part because “the condition was more a problem of genital, rather than sexual, arousal.” Many patients with PGAD were found to have high levels of distress including suicidal ideation, especially since management strategies often defied usual psychological and biological treatments.

In 2016, the International Society for the Study of Women’s Sexual Health (ISSWSH) organized a meeting to redefine sexual health nomenclature, including PGAD. Two years later ISSWSH convened an expert panel to develop an evidencebased comprehensive management strategy for PGAD. The term “genito-pelvic dysesthesia” (GPD) was introduced, defined as an unpleasant, atypical sensation in the genito-pelvic region that may also include lower extremity dysesthesia due to involvement of common sacral nerve roots. PGAD would now be referred to as PGAD/GPD. PGAD/GPD is characterized as persistent or recurrent, unwanted or intrusive, distressing sensations of genital arousal >3 months and may include other types of genito-pelvic dysesthesia. The symptoms are most commonly experienced in the clitoris but also in other genito-pelvic regions. These sensations may be accompanied by the experience of uncontrollable orgasms and/or having an excessive number of orgasms. These sensations are not associated with concomitant sexual interest, thoughts, or fantasies.

Whipple, Leiblum and Rutgers University psychology professor Barry Komisaruk (Whipple’s co-author of their 2006 book, “The Science of Orgasm”) are using MRIs to examine the brains of women suffering from PGAD in hopes of discovering how the central nervous system might play a role.

2013 NBC News

Furthermore, PGAD/GPD could be associated with: limited resolution, no resolution, or aggravation of symptoms by sexual activity compromised orgasm quality aggravation by certain circumstances despair, emotional lability, catastrophizing, and/or suicidality absent overt evidence of genital arousal on physical examination

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UrologicHistory.Museum

Helen L. Bernie, DO, MPH; Ronald Rabinowitz, MD

Min

Min, the 4th millennium BCE Egyptian god of fertility and harvest, appeared on tomb walls with his right hand on an erect penis.

Bes

In the 2nd century CE, Romans often had a statue of a small man with an enormous erect penis to protect their gardens. This god of fertility (Bes) from Asia Minor, was imported by Roman soldiers from the former Greek empire and eventually became known as Priapus, the dwarf son of Dionysus and Aphrodite. His penis was larger than his body.

The erect penis has been depicted since antiquity. Min, the 4th millennium BCE Egyptian god of fertility and harvest, appeared on tomb walls with his right hand on an erect penis. In the 2nd century CE, Romans often had a statue of a small man with an enormous erect penis to protect their gardens. This god of fertility (Bes) from Asia Minor eventually became known as Priapus, the dwarf son of Dionysus and Aphrodite. His penis was larger than his body. Depictions of gods or men with an erect penis appeared on Greek pottery vases, and statues, and on Roman oil lamps and wall frescoes.

Egyptians and Romans ate animal testes to increase erections. In China, the Yellow Emperor texts from 2500 BCE described mixtures of many herbs to improve erectile function. Hippocrates (460-375 BCE) described impotence in Scythians secondary to horseback-riding perineal trauma. As well as consuming animal male genitalia, men have taken Chinese Ginseng root and Cantharidin (Spanish Fly) to improve erectile function. It is unclear whether ginseng helps and Spanish Fly (an extract from a green beetle) is nephrotoxic and can cause intestinal hemorrhage.

Leonardo da Vinci (1452-1519) was the first to describe increased blood flow to the penis causing erection. Although the corpora cavernosae were described by Galen (129-216 CE), this information was lost for a time until Costanzo Varolio (1543-1575), physician to Pope Gregory XIII, described the mechanisms of erection. French surgeon Ambroise Paré (1510-1590) wrote detailed instructions of how to perform sex to achieve pregnancy and was credited with the first penile implant made of wood, though this was used to aid in voiding and not erections.

In 1668, Dutch physician Regnier de Graaf (1641-1673) reported that injecting water into the hypogastric artery in a corpse caused an erection. Electrical stimulation of the brain and spinal cord producing erection in animals was reported in 1863 by German physiologist Conrad Eckhard (1822-1905). In 1873, Italian physician Francesco Parona (1842-1907) injected hypertonic saline into the dorsal penile vein to induce erection. In 1902, J.S. Wooten reported dorsal penile vein ligation to treat impotence. The precursor to the modern vacuum device to induce erection was first reported in 1874 by American physician John King. In 1913, Austrian physician Otto Lederer (1872-1944) added a compression ring to improve the success of vacuum erection.

The Outs

Erections: Size Matters and History Matters

Priapus

Priapus with Phallus Hat, Bronze Figurine

Priapus from fresco found at Pompeii, 89 BCE to 79 CE

Naples Museum, Italy

Naples National Archaeological Museum

Ins & Outs of Sexual Health

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The earliest penile implant to treat impaired erections was performed by Russian surgeon Nikolaj Bogoraz (1874-1952) in 1936 where he used rib cartilage to provide rigidity to the penis. Peter L. Scardino is most likely the first to use a synthetic implant but his work was never published. Urologists Willard E. Goodwin (1915-1998) and William Wallace Scott (1913-2000) described the first acrylic penile prosthesis in 1952. But it wasn’t until 1973 that F. Brantley Scott (1930-1991) described the first inflatable penile prosthesis. And in 1974 Michael Small and Hernan Carrion developed a penile implant made up of a pair of silicone rods from which the first malleable implant would arise. In 1996, the Medicated Urethral System for Erection (MUSE) Study Group presented the first use of a transurethral alprostadil to help with erections. It wasn’t until 1998 when the serendipitous development of a pill originally for angina would obtain approval by the Food and Drug Administration to become the very first oral treatment for men with ED: sildenafil citrate (Viagra). This revolutionized the treatment of erectile dysfunction.

Phallic Protection

Depictions of gods or men with an erect penis appeared on Greek pottery vases and statues, and on Roman oil lamps and wall frescoes. The fascinum, a talisman in the shape of an erect penis, was the most common protective magic symbol in ancient Roman art, providing protection from the evil eye (malevolent energy caused by envy).

Phallic object in the form of a Roman lamp.

Graeco-Roman bronze phallic pendant.

Wellcome Images

Wellcome Images

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UrologicHistory.Museum

Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

In 1873, the Italian physician Francesco Parona injected the dorsal penile vein of a young impotent patient with hypertonic saline to cause sclerosis and reduce excessive venous outflow. Two decades later, American doctors started performing surgical dorsal vein ligation or resection. In the early 1930s, Oswald Lowsley combined simple dorsal vein plication with a surgically more advanced perineal crural technique, plicating the bulbocavernous and ischiocavernous muscles with several mattress sutures for corporal veno-occlusive dysfunction.

OS Lowsley

In 1948, the French surgeon Leriche first mentioned arterial vascular impotence in thrombotic obliteration of the aortic bifurcation, a syndrome he described in detail in the 1920s, now named after him. Moving forward, several strategies were outlined to save or reconstruct the internal iliac artery during abdomino-pelvic vascular surgery to maintain or restore erectile function.

In 1973 in Prague, Michal reported the first microsurgical treatment of vascular erectile dysfunction by revascularization with direct anastomosis of the inferior epigastric artery to the corpus cavernosum. He was one of the first to observe that failure of the hemodynamics of erection played an important role in the pathogenesis of impotence in many patients and discussed use of phalloarteriography with saline-filled erection to visualize the proximal arterial disease. Further techniques were introduced later by Michal himself, as well as Virag, and Hauri. Michal taught his techniques to a young Goldstein in Boston.

The Outs

Impotence and Penile Revascularization

Around 1970, physicians were dealing with issues of sexual medicine, its definition and establishment in the medical community, including the start of societies. The “First International Conference on Corpus Cavernosum Revascularization” was a key event that took place in New York in 1978. Zorgniotti, a visionary urologist from New York and AUA Historian 1980-1988, identified and invited experts on vasculogenic impotence from all over the world for this meeting. Over the course of time this organization developed into the “International Society of Impotence Research,” that later reincarnated as the “International Society for Sexual Medicine.”

Lowsley William P. Didusch Center for Urologic History

V. Michal

Michal anastomosis Courtesy Irwin Goldstein, MD

Ins & Outs of Sexual Health

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From Bones To Boners Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

Findings from eighth century BCE India attested that erectile dysfunction (ED) had its roots in psychogenic, religious, and supernatural causes with treatments involving potions, aphrodisiacs, ointments, and prayers. In early 1900s, psychologists/psychiatrists treated ED as primarily psychogenic in origin. For cases with obvious biologic causes, such as penile amputation, Bogoras described using extracorporeal rib cartilage for reconstruction (1936), but postoperative complications included infection, extrusion, pain and reabsorption over time. In 1952, Goodwin and Scott described using synthetic material for an extracorporeal acrylic penile implant, however these were eventually abandoned due to difficulties with penetration, irritation of the glans, intractable pain, and extrusion of the implant through the skin or urethra. In 1966, Beheri described a paired intracavernosal polyethylene penile implant inserted into the corpora cavernosal bodies. Few urologists were then involved in the management of ED. 1974 saw the birth of a new era in the treatment of ED with the use of two safe and efficacious intracavernosal penile prostheses: the Small-Carrion semirigid prosthesis and the Scott-Bradley-Timm inflatable penile prosthesis. At one point, there were at least 15 different types of prostheses available. Currently, only two companies manufacture implants in the United States: Coloplast and Boston Scientific. The penile prosthesis remains the gold standard for the treatment of patients with medical refractory ED. The contemporary three-piece inflatable penile prosthesis provides optimal tumescence and detumescence, mimicking normal penile erectile physiology; use of the semirigid rod penile implant is somewhat limited in the United States.

The success of the intracavernosal penile implant sparked global interest by urologists and other specialists to study, diagnose and treat patients with ED, and eventually initiated the field of sexual medicine. In 1974, only five physicians presented on treatment of ED at the AUA--today, we have a plethora of presentations and various societies dedicated to the study of sexual medicine.

Nikolay Bogoras

Penile Prostheses

Scott-Bradley-Timm prosthesis

ERECTILE DYSFUNCTION (ED) GUIDELINE American Urological Association

Small-Carrion prosthetic William P. Didusch Center for Urologic History

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UrologicHistory.Museum

Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE

G. Brindley Courtesy Johan Mattelaer

Aphrodisiacs have been used to treat sexual dysfunction since ancient times, but the first milestone in effective medical treatment of severe organic erectile dysfunction (ED) was the intracavernous injection (ICI) of vasoactive drugs.

In 1982, the French vascular surgeon Ronald Virag accidentally discovered the pro-erectile effect of papaverine during a revascularization surgery of the penis and suggested therapeutic injection into the corpus cavernosum. In 1983, Giles Brindley described the possibility of getting an efficient erection through “cavernosal alpha-blockade.” He reported that large doses of oral phenoxybenzamine caused penile tumescence lasting 24-48 hours. He proposed ICI for patients with ED, and stated that ICI could be a diagnostic tool, with a good response ruling out vascular but not neurogenic causes. At the 1983 annual AUA meeting, Brindley made history when he showed off the effect of ICI of phenoxybenzamine on his own penis. Wearing bulging sweatpants, he paraded through the aisles asking people to feel it to make sure it wasn’t a penile implant.

Prior to 1983, there was limited knowledge about penile erectile physiology.

Polsters or cushions around penile vessels were reported to relax to let blood in, and thought to contract to trap blood during sexual arousal - the role of penile smooth muscle was not appreciated. The Brindley injection lecture forever changed the sexual medicine world. His passion and personal attention to detail allowed the field of sexual medicine to evolve exponentially. Physiology and pharmacology of the erectile process was understood once the critical role of cavernosal smooth muscle relaxation became evident. ICI therapy became the first pharmacologic, non-surgical treatment for ED. Zorgniotti (1985) introduced the bimix combination of papaverine and phentolamine. Ishii et al. (1989) published on treatment with prostaglandin E1 (PGE1). PGE1 has been added to the bimix, making trimix formulations.

The Outs

A Hard Act To Follow: THE BRINDLEY INJECTION

Almost 40 years after Brindley’s demonstration, we continue to use ICI as a safe and effective treatment for ED. Irwin Goldstein, MD I was going to be speaking in a few minutes at the Urodynamics Society meeting at the 1983 AUA in Las Vegas. I was only a couple of years out of my fellowship, so this was a big deal. I went to the bathroom before it was my turn on stage, and out of the stall next to me came an older man wearing a jogging suit. It seemed strange until he walked on stage a few minutes later. Giles Brindley— demonstrating his intracavernosal injection—literally. Obviously, he had injected himself in the stall next to me in the bathroom.

As part of his demonstration, Brindley walked up and down the aisles of chairs filled with physicians and their spouses all dressed in black tie, and offered them the opportunity to touch his erection to confirm it was real and was not a prosthesis. How was I supposed to follow that act? I followed it by returning to my practice and starting patients on intracavernosal injection therapy the following week, and almost 40 years later, I continue to use this therapy.

Ins & Outs of Sexual Health

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From Heartache to Hard On: The History of Viagra

Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE The development of sildenafil for the treatment of erectile dysfunction (ED) was serendipitous. How could adequate doses of an oral medication cause clinically effective pharmacologic changes exclusively to the erectile tissue and not cause clinically significant systemic side effects? The endogenous neurotransmitter responsible for penile smooth muscle relaxation during sexual stimulation causing erection was not known until 1991 and 1992 when three independent research groups discovered the molecule that turned out to be a gas: nitric oxide (NO). ED was likely the result of reduced ability to release NO by dysfunctional cavernosal nerves and endothelial cells.

In 1986, Pfizer was focused on identifying PDE5 inhibitors to treat angina.

With preclinical testing showing that sildenafil produced coronary artery dilation in animals, clinical trials with sildenafil commenced in 1991. Sildenafil showed no clinically significant effect on hemodynamic outcomes, but erections were noted as a side effect. In Pfizer’s research, the most prevalent expressed PDE in corporal erectile tissue was PDE5, highly expressed in the corpus cavernosum and vasculature, but not in the myocardium. Sildenafil selectively inhibits PDE5, elevating the cGMP signal initiated by release of NO in response to sexual stimulation, producing smooth muscle relaxation and inflow of blood to the corpus cavernosum. Thus, sildenafil is only effective in the presence of sexual stimulation.

The first trial of sildenafil for the treatment of ED was initiated at the end of 1993.

Both diary and RigiScan data showed a clear difference between sildenafil and placebo. The onset of penile tumescence occurred within a few minutes of visual sexual stimulation, or about 30 minutes post dose, corresponding with the peak plasma concentration of the drug. The International Index of Erectile Function was developed/validated as an endpoint for clinical trials. Sildenafil (Viagra) was approved by the FDA for the treatment of ED in March 1998—converting an unremarkable angina drug into a successful ED treatment.

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Sildenafil, the active ingredient in Viagra.

Annie Cavanagh, Wellcome

Viagra pill Wikimedia

UrologicHistory.Museum

La Peyronie and ‘His’ Disease Ronald Rabinowitz, MD; Sutchin Patel, MD

Peyronie

Peyronie’s Disease, a wound-healing disorder of the tunica albuginea that causes the formation of scar tissue or plaque resulting in penile deformity and curvature, occurs in approximately 3 to 20% of adult men.

Who was Peyronie and why is this condition named after him? François Gigot de La Peyronie (1678-1747) was a French surgeon. He was born in Montpellier, where he studied surgery before moving to Paris for additional training with leading surgeon Georges Mareschal de Bièvres (1658-1736). La Peyronie studied anatomy and surgery and founded the Royal Society of Sciences of Montpellier in 1706. He returned to Paris in 1715, where he treated Peter the Great as well as other European Royalty. Along with Mareschal, La Peyronie founded the Acadèmie Royale de Chirurgie in 1731. In 1737, he succeeded his mentor to become First Surgeon to King Louis XV, whom he influenced to separate surgeons from the barbers’ guild, thus leading to the independence of French surgeons. From 1736 until his death in 1747, he was chairman of the Acadèmie Royale de Chirurgie. Having no heirs when he died in 1747 at age 69, La Peyronie divided his estate of land, library, and money to the surgical communities of Montpellier and Paris.

Wellcome

Tulp

The disease that bears his name was described by the Italian surgeon Theodoric Borgognoni (1205-1298) in 1267. He described firm penile tubercles that did not fall off. The Italian surgeon Guilielmus de Saliceto (1210-1276) described Peyronie’s Disease, which he called ‘nodus in virga’ in his work Chirurgia in 1275. It was also described by Italian Gabriele Falloppio (1523-1562) and Belgian Andreas Vesalius (1514-1564) in the same patient in 1561. The Italian surgeon Giulio Cesare Aranzi (1530-1589) described Peyronie’s Disease in 1579, calling it ‘nodus penis’. The Dutch physician Claes Pieterszoon, who later changed his name to Nicolaes Tulp, (1593-1674) described Peyronie’s Disease as ‘coles incurvates’ in 1652. He described a patient with a bent penis without the nodules that were usually seen with this condition. Thus, he clearly recognized ‘Peyronie’s Disease’ before it became known by that name.

The Outs

Caution! Curve Ahead!

So why does La Peyronie deserve the honor of having his name as the eponym for this condition described half a millennium prior? In 1743, La Peyronie published “On Some Obstacles Opposing the Natural Ejaculation of Semen” and reported on patients who had lost the ability to ejaculate normally. One of his patients, who had a urethral stricture and retrograde ejaculation, also had developed dorsal penile curvature with erection secondary to beads of scar tissue along the dorsum of his penile shaft. In his detailed description of the condition, La Peyronie reported other patients with lesions of the cavernous bodies having ‘nodes or ganglia sometimes extending like a string of beads from one end to the other of the two corpora.’ He also reported that these painful erectile deformities were different from those resulting from venereal disease.

La Peyronie’s detailed description of the condition in multiple patients is the likely reason for the eponym ‘Peyronie’s Disease’.

Ins & Outs of Sexual Health

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Flattening the Curve: Peyronie’s Disease Today Irwin Goldstein, MD; Sue Goldstein, CCRC, CSE Peyronie’s disease (PD), a localized fibrosing disorder involving the tunica albuginea, is characterized by deposition of collagenous plaques restricting expansion of the tunica at that location, resulting in one cavernosal body expanding more than the other and subsequent erect penile curvature. Presence of excessive collagen in PD appears to be a consequence of dysregulated collagen synthesis, appreciated since the 1960s.

Data from multi-site, placebo-controlled, clinical trials support the use of nonsurgical treatment with intralesional intraplaque injection with collagenase.

Collagenase Clostridium histolyticum (CCH) was FDA-approved in 2013 to treat PD. Using collagenase to treat deforming penile scarring of PD arose from a combination of factors: lack of available treatments and knowledge that plaques were primarily collagen. CCH injected into the primary plaque at the point of maximum penile curvature deformity, along with penile modeling, has been shown to improve penile curvature deformity and the PD bother score of the Peyronie’s Disease Questionnaire (PDQ). Of note, female partners of men with PD were not bothered by the PD unless it made intercourse difficult. Although treatment-related adverse events following CCH treatment of PD in clinical studies have largely been mild to moderate in severity and resolving without intervention, corporal rupture or severe penile hematoma have been documented. While oral therapies and low intensity shockwave therapy for Peyronie’s disease have been suggested, limited data support their use.

When considering surgery for PD, if erectile quality is important, a penile prosthesis should be considered. Plaque excision and grafting with PD were reported as early as 1950 by Lowsley and Boyce. The Nesbit plication procedure was first described in 1965, excising tunica on the side contralateral to the curvature. Modifications of plication procedures include the 16-dot procedure reported by Lue in 2002. Plaque excision and grafting can also be combined with a plication procedure to achieve erect penile straightening.

Peyronie’s

Penile Structure Courtesy Irwin Goldstein, MD

Lowsley

PEYRONIE’S DISEASE GUIDELINE American Urological Association

William P. Didusch Center for Urologic History

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UrologicHistory.Museum

History of Premature Ejaculation Stanley Altof, MD

Praecox

Karl Abraham, Sigmund Freud, colleagues at Hague Congress.

Greek mythology contains the first recorded description of premature ejaculation “ejaculato ante portas.” In 1901, the eminent German sexologist R. von KrafftEbing described a case of abnormally fast ejaculation but did not employ the terms premature or praecox. Psychoanalysts Abraham and Stekel considered “ejaculation praecox” as a neurosis stemming from unconscious conflicts requiring classical psychoanalysis. Contemporaneously, in Berlin, Hirschfield ‘s Institut für Sexualwisenschaft began treating patients with sexual dysfunctions and researching efficacy of drug treatments for various conditions. Approximately 20 years later, Schapiro, a German endocrinologist, proposed that PE was a psychosomatic disturbance caused by a psychologically overanxious constitution combined with an “inferior ejaculatory apparatus,” thereby describing two subtypes later recognized as lifelong and acquired PE.

Library of Congress

In the 1960s, Masters and Johnson proposed that PE was learned behavior from rushed early intercourse experiences. Alternatively, Helen Kaplan considered ‘‘lack The Premature Ejaculation of sexual sensory awareness’’ to be the immediate cause. Investigations into Prevalence and Attitudes neurobiological and genetic factors began in the 1980s. Evolving theories included hypersensitivity of the glans penis, disruptions of the serotonin, dopamine and Multi-National Survey oxytocin transporters, and genetic polymorphisms related to PE; however, the PE ED etiology remains unknown.

PREVALENCE (%)

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The Outs

Too Soon For You?

40 30 20 10

0!

18-24

25-34

35-44

45-54

55-64

65-70

AGE GROUP (YRS) PE definition: Self-reported ejaculation on last sexual event occurred before or within 2 minutes of penetration

Typical IELT is less than or equal to 2 minutes PE definition: Self-reported ejaculation on last sexual Self-reported IELT is longer than 2 minutes but they claim: control over ejaculation is fair or poor, time to ejaculation is a problem for him and/or his partner eventincreased occurred before or within 2 minutes of penetration Rosen RC et al (2004) The Premature Ejaculation Prevalence and Attitudes (PEPA) Survey: A Multi-National Survey.

J. Sex Med 1 (Supp 1): 57-58

Typical IELT is less than or equal to 2 minutes Self-reported IELT is longer than 2 minutes but they claim: control over ejaculation is fair or poor, increased time to ejaculation is a problem for him and/or his partner Rosen RC et al (2004) The Premature Ejaculation Prevalence and Attitudes (PEPA) Survey: A Multi-National Survey. J. Sex Med 1 (Supp 1): 57-58

Since the early 2000s, the International Society for Sexual Medicine and AUA have led development of evidence-based definitions and guideline documents for medical and mental health clinicians. Presently, there are no FDA-approved medications to treat PE, while dapoxetine is approved in over 60 countries. Offlabel pharmacological treatments include: daily/as needed SSRIs, clomipramine, or topical numbing agents. Mental health clinicians treating PE in individual and/ or couples psychotherapy generally integrate interventions such as stop-start and sensate-focused exercise. Combining pharmacological and psychological interventions leads to better outcomes.

PE investigations have evolved from authority/expert opinion to evidencebased studies allowing for accurate determination of prevalence, investigations into etiology, impact on partners, development of validated Patient Reported Outcomes, regulatory authority oversight, and treatment efficacy.

DISORDERS OF EJACULATION: AN AUA/SMSNA GUIDELINE American Urological Association

Ins & Outs of Sexual Health

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Discovery of Testosterone Abraham Morgentaler, MD

From the beginning of recorded history, there has been an awareness that men experience a loss of vigor, sexual ability and desire as they reach their middle to later years. Although testosterone would not be identified until the mid-1930s, it was clear from experience with eunuchs that testicles were responsible for producing “some product” that contributed to muscle, vigor, and sexuality.

Aristotle ascribed pubertal changes to the gonads.

Testosterone

A number of interesting procedures in the 19th and early 20th century were designed to improve this loss of “vigor” situation for affected men. In 1848, Arnold Berthold, physiologist and curator of the Gottingen zoo, realized that the rooster’s coxcomb must be an androgen-dependent structure because castration resulted in atrophy of the comb, disappearance of aggressive behavior, and loss of interest in hens. He also castrated roosters and placed one testis intraabdominally in two of them. Six months later, “these animals remained male in regard to voice, reproduction instinct, fighting spirit, and growth of comb and wattles.” He concluded the testicles acted “upon the blood and organism.” This experiment demonstrated endocrine secretion, although the substances produced by the testes were unknown.

In 1889, Charles Edouard Brown-Sequard reported results on self-injections of testicular extracts, stating, “his vigor and feeling of well-being were markedly restored but the effects were transient,” suggesting the extract contained a substance promoting rejuvenation. Within a year, more than 12,000 physicians were administering the extract to patients.

Arnold Berthold

Eugen Steinach, nominated for six Nobel Prizes, developed a procedure called unilateral vasal ligation for physical and mental rejuvenation. By obstructing sperm outflow, the testicle would be spurred to secrete more testicular products into the body. It is believed that WB Yeats and Sigmund Freud underwent this procedure.

Charles Brown-Sequard

Steinach Operation

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UrologicHistory.Museum

Abraham Morgentaler, MD

In early 1900s, Serge Voronoff began organ transplants, first transplanting testicles of criminals into millionaires, and later using monkey testicles instead.

Between 1917 and 1926, Voronoff performed over 500 transplantations on sheep, goats, and bulls, grafting testicles from younger animals into older ones, and concluded that older animals regained the vigor of the younger ones. His first official transplantation of monkey testicular tissue into a human was in 1920. Thin slices - a few millimeters wide - of testicles from chimpanzees and baboons were implanted inside the patient’s scrotum. The thinness of the tissue samples was believed to allow foreign tissue to fuse with human tissue.

Serge Voronoff

By early 1930s, over 500 men had been treated in France by Voronoff’s rejuvenation technique, including Voronoff’s younger brother, Georges. By 1935, rejuvenation procedures involving testes were obsolete due to criticisms of lack of verifiable data.

In 1927, Gallagher and Koch extracted 20mg of a substance from 40 pounds of bull testes and showed remasculinization when injected into castrated roosters.

In 1931, Butenandt isolated androsterone, the first androgen, from 15,000 liters of urine from policemen. In 1935, Laquer isolated 10mg of a more androgenic substance from 100kg of bull testes, which he called “testosterone.” The determination of the androgenic potential of these extracts used the coxcomb assay: the first bioassay!

Sheep During Transplant

The 1939 Nobel Prize was awarded to two individuals who separately synthesized testosterone: Butenandt (Germany), a member of the Nazi Party who rejected the award, and Ružička (Switzerland). The synthesis of testosterone led to its clinical use within a few short years.

The Hormone T

From Monkey to Man: The Ef fects of Testosterone

Sheep Before and After Transplant

Ins & Outs of Sexual Health

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The Evolution of Testosterone Preparation Abraham Morgentaler, MD

Within several years of the synthesis of testosterone in the mid-1930s, a variety of testosterone preparations were already available. This was prior to the formation of the modern version of the FDA, so no rigorous trials to demonstrate either efficacy or safety were required.

Testosterone propionate appears to have been the most frequently used formulation for testosterone therapy. Injections were given daily. The short halflife of testosterone propionate led to the development of longer-acting esters, including testosterone cypionate and testosterone enanthate in the 1950s. For many years, testosterone enanthate and testosterone cypionate were routinely given at the physician’s office at monthly intervals.

Oral testosterone was found to be rapidly metabolized and was soon abandoned (until recently). Along with testosterone, Ružička synthesized 17 -methyl testosterone in 1935. The addition of the methyl group resulted in longer half-life, and this oral form of testosterone proved to be reasonably effective. Although methyltestosterone is still available today, its use has been almost completely abandoned in the US due to liver toxicity.

Compressed crystalline testosterone in the form of pellets was an early and effective form of testosterone therapy. Pellets were placed subcutaneously and were similar to pellets used today. The FDA approved compressed crystalline testosterone pellets in 1972, though they were not used extensively until this century.

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Ružička, 1939

UrologicHistory.Museum

Abraham Morgentaler, MD

Since men have more heart disease and more testosterone (T) than women, it was believed in the 1960s and 1970s that T likely contributed to heart disease.

However, population-based studies in the 1980s showed the opposite. Men with the lowest T had an increased risk and greater severity of coronary artery disease compared with men with higher levels of T. Meta-analyses have shown that low endogenous T is associated with increased mortality. Testosterone therapy in individuals with T deficiency increased muscle mass, reduced fat mass, and could contribute to resolution of metabolic syndrome, with studies supporting the concept that normal testosterone was healthy for the CV system.

This changed in 2013 with publication in JAMA of an observational study by Vigen et al reporting increased risk of heart attacks, stroke, and death in men with serum T <300ng/dl who received a prescription for T compared with men who did not receive a prescription. All of a sudden, T was seen as dangerous. The FDA called a special advisory board meeting to review the CV risks of T. Rates of T prescriptions dropped precipitously. However, the study by Vigen et al was riddled with critical errors. The actual value of adverse events was less than half in men who received T (10.1% for the T group vs 21.2% for those not receiving T): JAMA published a formal correction. Meanwhile, it was revealed that 9% of the all-male study population was female!

In response, the Androgen Study Group met with the FDA, published a critical review of the CV literature, and spearheaded an international awareness campaign, petitioning JAMA to retract the article by Vigen et al, but JAMA declined. This single article, amplified by the media, created a false impression among the public and medical community that T therapy is dangerous for the CV system, despite a wealth of data to the contrary. Recent literature has been highly reassuring that T therapy is not associated with CV risk.

Ins & Outs of Sexual Health

The Hormone The Ins T

You Can’t Spell Heart Attack without “T” – Or Can You?

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Testosterone: A Magnificent Molecule Abraham Morgentaler, MD

Testosterone (T) therapy has come a long way since the times of monkey testis transplants. Today physicians understand that T deficiency is highly prevalent as men reach their middle years and is associated with a wide variety of symptoms and physical changes that negatively impact quality of life and general health.

The Testosterone Trials

Urologists have played a critical role in research, education, and clinical practice in this field, and urologists are often the first healthcare providers to make the diagnosis of T deficiency (also called hypogonadism), since sexual complaints such as decreased libido or erectile dysfunction are prominent presenting symptoms of T deficiency.

High-level evidence now supports the use of T therapy for a number of sexual and non-sexual symptoms. In addition, two recent large, randomized controlled studies have shown important benefits for T therapy unrelated to sexuality. For example, in the Testosterone Trials, comprised of 790 men 65 years or older with low T values, men were randomized to one year of either T gel or placebo gel.

Men who received T showed greater improvement in bone density and resolution of pre-existing anemia.

In the T4DM trial, more than 1000 men with low T values and an abnormal glucose tolerance test result underwent two years of behavioral intervention (the Weight Watchers program) with or without T undecanoate injections every 3 months. The group that received T injections demonstrated improved glucose metabolism parameters, lower rates of type 2 diabetes mellitus, greater resolution of diabetes, greater muscle mass, and lower fat mass. In neither of these studies was there any indication of increased cardiovascular events or prostate cancer in the groups that received T therapy.

Testosterone is one of the most powerful and interesting molecules within the body. It will be fascinating to observe how testosterone will be used within medicine in the future.

TESTOSTERONE DEFICIENCY GUIDELINE American Urological Association (AUAnet.org)

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UrologicHistory.Museum

Abraham Morgentaler, MD

Oral testosterone undecanoate (TU), available outside the US since the 1970s, has an 11-carbon chain attached to the testosterone (T) molecule and is not associated with liver toxicity. Two new oral TU products have been approved by the FDA in the last few years, showing greater absorption and serum T concentrations because formulations contain lipid emulsifiers within the capsule.

Topical T formulations were most common from about 2001 to 2015. The gel, cream or solution is applied to the chest, upper arms, axillary regions, flank, or thighs, depending on formulation. The main limitation has been cost, unreliable absorption, and potential of transference to female partners or children. Compounded creams have also been popular, and are less expensive but less reliable.

In 1998, the FDA approved the patch Testoderm, applied to the scrotum—not popular.

Androderm was developed to be applied to non-scrotal skin, like the abdomen, however this patch was plagued by skin irritation and suboptimal absorption.

Injections of T cypionate and T enanthate have been available since the 1950s and continue to be a mainstay of T therapy. Instead of every 4 weeks, injections are now given every week. They provide robust T levels, dosages are easily adjusted, and injections can be self-administered.

A long-acting form of TU, available in most of the world since 2004, was approved in the US in 2014 at a lower dose (Aveed), to be given every 10 weeks after an initial booster.

Approved in 2018, Xyosted is a self-injector for weekly subcutaneous administration of a fixed dose of T enanthate, easily self-administered.

Natesto is a highly concentrated testosterone gel applied to the insides of both nostrils 2-3 times daily, showing excellent peak T concentrations. Between doses, T levels decline to baseline. Studies have shown smaller impact on LH, FSH, hematocrit, and sperm parameter reductions than injections or topical gels.

Ins & Outs of Sexual Health

The Hormone The Ins T

Testosterone Today

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Regenerative Therapies: Fraud or the Future?

Sue Goldstein, CCRC, CSE

Patients are prey to advertisements, promising cures for erectile dysfunction, anorgasmia and vaginal rejuvenation. The Sexual Medicine Society of North America (SMSNA) has issued a position statement on restorative therapies including stem cell therapy, low intensity shockwave therapy (LiSWT) and platelet rich plasma (PRP), stating “Restorative therapies should be reserved for clinical trials and not offered in routine clinical practice.”

Many providers, however, currently use these therapies for their patients routinely in their practices. The infusion or injection of human blood products (PRP) is exempt from FDA regulation. The combination of PRP with a drug or other tissue product (stem cells) would fall under current regulatory restrictions to be used only under a clinical trial or with a manufacturer’s license.

While there are double-blind sham control data showing improvement with some of the regenerative therapies with specific devices, including shockwaves and lasers, not all therapies are alike—there is not necessarily a class effect when it comes to devices. The FDA sent warning letters to many of the manufacturers of “rejuvenation” devices, but not all warning letters were alike.

Regenerative therapies must all be considered experimental, but it is up to the provider to clarify this with patients—explaining the experimental nature of the device, potentially explaining what is known about the science behind the tissue changes, and never guaranteeing results. Or we can opt to treat patients through a research protocol, which is recommended by our societies. It is imperative that FDA guidelines are followed. In addition, be aware of the FDA clearances for the specific device being used. Patients may benefit, but they need to be given full disclosure with regard to the experimental nature of the treatment. Clearly, more double-blind, sham-controlled clinical trials are needed.

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UrologicHistory.Museum

Trinity Bivalacqua, MD

Female Pelvic Organs

Courtesy Irwin Goldstein, MD

Stem cell therapy (SCT) is an exciting application of restorative medicine with a theoretical promise of disease “cure.” Stem cells are unspecialized, undifferentiated cells found in both embryonic (placental/umbilical) and adult (mesenchymal: bone marrow, adipose, penile corpora cavernosa) tissue. Given their precursory nature, these cells harbor self-renewal potential and the ability to differentiate into other cell types. Stem cells exhibit regenerative effects by releasing growth factors, cytokines, and chemokines; upregulating pathways to reduce inflammation, inhibit apoptosis, improve wound healing, and drive angiogenesis and neuritogenesis.

Within the scope of sexual medicine, mesenchymal stem cells have been of particular interest. Mesenchymal cells, derived from bone marrow and adipose tissue, are more readily available and have minimal ethical considerations.

However, due to difficulty of isolating a pure stem cell population, in sexual medicine we have moved to the use of stromal vascular fraction (SVF). SVF is a heterogeneous mixture from which adipose mesenchymal progenitor cells are derived, including stem cell populations. SVF is isolated via centrifugation from liposuction aspirate after the adipose tissue is digested by enzymes and includes not only adipose derived stem cells, but also preadipocytes, lymphocytes, smooth muscle cells, and endothelial progenitor cells. By including the milieu along with stem cells, there is synergistic activity that drives cellular adhesion, tissue remodeling, angiogenesis, and cell differentiation in the penile microenvironment.

These attributes provide exogenous stem cells with an ideal regenerative microenvironment following intracavernous injection.

At the current time, phase 1 and 2a trials have been performed using SVF and SCT for treatment of erectile dysfunction and each have shown this is a safe approach.

Future trials using SVF will need to be designed to demonstrate efficacy in men with severe ED. Restorative therapies such as SCT and SVF represent an exciting therapy for ED; for patients it represents an opportunity to restore normal penile vascular function.

Ins & Outs of Sexual Health

TheThe Future Ins

Stem Cells—Are We There Yet?

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The Shocking Truth Ranjith Ramasamy, MD

Shockwave research began after World War II, based on a curious observation: depth charges caused lung damage despite no outward physical trauma.

Research followed in the 1960s and 1970s on shockwave safety and the influence of distance on efficacy. In 1971, the first non-contact disintegration of a kidney stone was described; in 1980, the first stone patient was treated; in 1983, the first commercial lithotripter became available in Germany; in 1985, the first gallbladder stone was treated, and in 1988, use in human orthopedic fracture treatment began.

As a contemporary outpatient alternative to invasive surgical procedures for renal calculus treatment, minimally invasive extracorporeal shockwave therapy (ESWT) has been extremely efficacious and associated with less side effects, complications, and recovery time. ESWT is first line treatment for stones under 20 mm.

Shockwave therapy has come full circle from urological use busting kidney stones to orthopedic use (plantar fasciitis and Achilles tendinitis) and cardiovascular use (myocardial revascularization), and back to urology to battle the erectile dysfunction (ED) epidemic. Although not yet FDA-approved specifically for ED, low intensity-ESWT (LI-ESWT) has been shown safe in recent studies. Research proposes a mechanism of shockwave microtrauma inducing multifarious effects including NO/chemokine release, among other pro-angiogenic effects. Some rare and fleeting side effects may include bruising, swelling, and pain. Clinical trials have shown benefit in ED. A meta-analysis found significant improvement in treatment over control groups. Different LI-SWT treatment protocols were compared in a phase 2 clinical trial. The number of shocks may be more important than delivery mechanism. LI-SWT appears safe and probably benefits certain ED patients. Research continues, and further applications may include dyspareunia, female stress incontinence and persistent genital arousal disorder/genito-pelvic dysesthesia in women and men.

Courtesy Irwin Goldstein, MD

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UrologicHistory.Museum

Irwin Goldstein, MD

Platelet-rich plasma (PRP) is an autologous plasma fraction produced by centrifuging whole blood. The PRP contains higher platelet and growth factor concentrations than whole blood. Due to the beneficial properties of growth factors, numerous medical specialties use PRP injections. PRP intracavernosal injections have emerged as a potentially promising, angiogenic, vasculogenic and regenerative treatment modality for ED. Animal studies postulate that PRP injections may improve key elements of the pathophysiologic mechanisms leading to ED through anti-inflammatory, reparative, neuroprotective and neurotrophic effects, although these mechanisms are not yet adequately understood.

PRP centrifuge Courtesy Irwin Goldstein, MD

Platelet-rich plasma Courtesy Irwin Goldstein, MD

Platelets have an important role in promoting wound healing and coagulation and include several growth factors responsible for regenerative functions including fibroblast, platelet-derived, vascular endothelial (VEGF), epidermal, and insulinlike. These growth factors improve angiogenesis stimulation, stem cell recruitment and inflammatory response, meaning PRP has the potential to support the regenerative matrix, healing damaged tissues. Some of these growth factors have been shown to improve erectile function in preclinical and clinical studies.

In animal studies with cavernous nerve injury ED, VEGF injection improved erectile function more than placebo. The endothelial nitric oxide synthase pathway mediates erectile function recovery caused by VEGF administration.

This mechanism is the main component of the hypothesis explaining how growth factors in PRP can improve erectile function in an animal model, with decreased apoptotic markers, decreased fibrosis, and improved erectile function four weeks after a single injection.

In a clinical study, two PRP intracavernosal injections in a one-month interval were shown to be safe and effective for the improvement of erectile function in patients with mild to moderate ED. PRP seems to improve erectile function by regenerating cavernosal nerves and increasing nitric oxide synthesis: PRP may be effective for neurogenic ED. Despite initial favorable outcomes in clinical use, limited data support PRP being part of the established ED algorithm. More research is needed.

TheThe Future Ins

The Power of Platelet-Rich Plasma

PRP injection Courtesy Irwin Goldstein, MD

Ins & Outs of Sexual Health

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CO2 Fractional Laser of the Future Irwin Goldstein, MD

Albert Einstein introduced the concept of stimulated emission for energy balance, the primary principle of the laser (light amplification by stimulated emission of radiation). The interaction between an electromagnetic wave and biological tissue depends on the wavelength and optical properties of the tissue: CO2 laser is infrared (wavelength 10,600 nm) with high water absorption, giving it superficial action. The laser mode of delivery can be fractional to avoid tissue damage to adjacent tissues.

Tissue modifications produced by laser vary depending on the setting. Rapid reconstitution of the epidermis from adjacent epidermal cells contrasts with healing after traditional resurfacing in which new epidermis is derived from cells that migrate from adnexal structures. A prolonged period of new dermal collagenesis follows.

Fractional CO2 laser for vestibulodynia Courtesy Irwin Goldstein, MD

Different studies have described the successful effect of fractional CO2 laser in treating aging-related and atrophic conditions through micro-ablative and thermal effects. The former induces tissue regeneration, whereas the latter induces changes in cell metabolism. The heating shock induces the production of some proteins called heat shock proteins. Heat shock protein 70 stimulates the action of transforming growth factor-beta in activating fibrocytes to become fibroblasts that are responsible for the synthesis of new extracellular matrix, collagen, and elastic fibers. This process of tissue remodeling takes 30 days to occur.

Regarding the vagina and vestibule, menopausal or premenopausal women with estrogen deficiency (e.g. chemotherapy post breast cancer) may have decreased superficial epithelial cells, decreased collagen content and hyalinization, decreased elastin, altered appearance and function of smooth muscle cells, fewer blood vessels, and loss of vaginal rugae and elasticity resulting in vaginal narrowing and shortening. The vaginal epithelium becomes thinner and more fragile, resulting in tears leading to bleeding and fissures during sexual activity.

Fractional CO2 laser, a non-hormonal strategy, regenerates vaginal and vestibular tissue in estrogen-deficient women, significantly alleviating symptoms related to atrophy and improving sexual function.

Markings on the vestibule and vagina immediately after CO2 laser treatment Courtesy Irwin Goldstein, MD

Fractional CO2 laser in the vagina for GSM Courtesy Irwin Goldstein, MD

30

UrologicHistory.Museum

Sue Goldstein, CCRC, CSE; Irwin Goldstein, MD

Regenerative therapies make us think twice about language and FDA approval.

For pharmaceuticals, the pathway is clear: pre-clinical (animal) studies, phase 1 small studies in a healthy population, phase 2 larger studies in the desired population but potentially with different doses or dosing regimens, and finally large phase 3 studies in the specific population indicated with very specific endpoints. The medication can then be approved for a specific disease state in a specific population, although the clinician can prescribe that medication off label—to a different population or for a different disease state.

Normal anatomy Courtesy Irwin Goldstein, MD

Abnormal anatomy corporal fibrosis Courtesy Irwin Goldstein, MD

With devices, however, that path is not so clear. A device may be considered equivalent to another already approved device and be granted a 510K. In that case, assuming it is considered “non-significant risk”, no further work is needed.

However, this will result in FDA clearance, meaning a device may be used for a general purpose such as smooth tissue activation and increased blood flow (e.g. shockwave device) or incision, excision, ablation, vaporization and coagulation of the body soft tissues (e.g. CO2 fractional laser). Clinicians have taken these clearances and used them within their practices.

For a device to claim that it treats erectile dysfunction (which may be treated by smooth tissue activation and increased blood flow) or dyspareunia (which may be treated by incision, excision, ablation, vaporization and coagulation of the body soft tissues), a company would need to complete phase 1 and phase 3 trials and apply to the FDA for the specific indication to be approved. While phase 1 proof of principle trials are small, and phase 3 trials are often smaller than phase 2 pharmaceutical trials, few devices actually perform these rigorous clinical trials, operating with just a clearance. Hence, societies are leery of supporting use of devices for regenerative therapies as anything but experimental.

TheThe Future Ins

Understanding FDA Clearance

Beware of unsubstantiated claims!

After Regenerative Therapy Courtesy Irwin Goldstein, MD

Ins & Outs of Sexual Health

31

How Do Researchers Study Orgasm?

Barry R. Komisaruk, PhD

Early mock-ups of forcecalibrated vaginal/cervical selfstimulators

These were eventually replaced with the device shown connected to the electronic force monitor. Each of the three has a different range of force calibration. The head holding the early form of stimulator has the forcetransducer embedded in the transition to the handle of the stimulator. The blue instrument is a force-calibrator.

Setup for vaginal self-stimulation

Published version: construction of the force-calibrated selfstimulator tip and its use for cervical (C) and vaginal (D) self-stimulation. This study, using functional MRI, provided the world’s first published evidence (2004) of where in the brain women’s orgasm is represented. Essentially, all major brain systems are highly activated at orgasm.

None of these was ever used in our studies.

Clitoral/Vaginal/Cervical Selfstimulator

Self-stimulator connected to force recorder

Stimulation force was monitored to ensure that the women with complete spinal cord injury would not injure their cervix or vagina. Setup for cervical self-stimulation using a gynecologist-fitted diaphragm connected by Velcro to the stimulator tip to protect and center the stimulator over the cervix.

32

We used this type of disposable Plexiglas self-stimulator in the study in which we mapped the projection of the clitoris, vagina, and cervix onto the sensory cortex using functional MRI. Each woman was given her own stimulator. The women used the short end for clitoral and vaginal self-stimulation, and the long end for cervical selfstimulation.

This was the first evidence that the vaginal and cervix project to the sensory cortex; they are certainly sensate.

UrologicHistory.Museum

When locked into the fMRI scanner, head movement is restricted to less than 2mm before, during, and after orgasm. We now use this design routinely in our fMRI orgasm studies.

First, a tracheostomy collar is fitted to the participant.

Then a thermoplastic panel is heated in hot water and molded to the back of the collar and back of the head, becoming semi-rigid as it cools. Next, a second thermoplastic panel is heated and molded to the face of the participant and to the front of the collar. The position of the eyes, nose, and mouth are marked on the front, and cut-outs are made using a side-cutting bit in a portable drill. The assembly is held together with tape.

Rectal and Prostate Selfstimulator

The research participants hold the straight portion of the Plexiglas self-stimulator, insert the curved end, and twist it toward the posterior rectal wall. Then they twist it further toward the posterior rectal wall until they detect a different quality of sensation, described as a slight burning sensation.

In our fMRI data analysis, we electronically subtract the brain activity of just the rectal stimulation from the brain activity of the combined stimulation, when the men perceive the burning sensation. We report that the projection sites to the sensory cortex are different for rectal and prostate self-stimulation but both project to the genital sensory cortex.

True Stories behind Sex Research Barry R. Komisaruk, PhD

I can still recall three salient events in my sexuality research experience.

After getting IRB approval for my first project on humans as a faculty member of the Institute of Animal Behavior, a delegation of Institute faculty petitioned the Director to block my research because it would give the Institute a bad name. The Director refused them, claiming it would violate my academic freedom.

When applying for an NIH grant for Vaginal Stimulationproduced Analgesia, I was told me they would fund me on one condition...I change the title. Despite being sorely tempted to tell them to keep their money, I changed the title and got the grant. The new title?

Stimulation-produced Analgesia.

Ins & Outs of Sexual Health

In 2002, I was asked to write a book on orgasm. I figured I could write about the neural aspects, my former student and current colleague Beverly Whipple would write clinical aspects, and my long-term colleague Carlos Beyer-Flores would write endocrine and pharmacological aspects. It would be fast and easy because there wasn’t much literature to review.

The Orgasm The Ins

Semi-rigid mask custom-made to each research participant

Three years and more than 600 articles later, we submitted the manuscript, The Science of Orgasm.

33

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Hormonally-Mediated Vestibulodynia Johannesson U, Blomgren B, Hilliges M, Rylander E, Bohm-Starke N. The vulvar vestibular mucosa - morphological effects of oral contraceptives and menstrual cycle. Br J Dermatol 2007;157(3):487-93.

Bohn-Starke N, Johannesson U, Hiliges M, et al. Decreased mechanical pain threshold in the vestibular mucosa of women using oral contraceptives: a contributing factor in vulvar vestibulitis? J Reprod Med 2004; 49:888.

Johannesson U, de Broussard CN, Jansen GB, et al. Evidence of diffuse noxious inhibitory controls (DNIC) elicited by cold noxious stimulation in patients with provoked vestibulodynia. Pain 2007;130:31.

Bazin S, Bouchard J, Brisson J, et al. Vulvar vestibulitis syndrome: an exploratory case-control study. Obstet Gynecol 1994;83:47.

Bouchard C, Brisson J, Fortier M, et al. Use of oral contraceptive pills and vulvar vestibulitis: a case-control study. Am J Epidemiol 2002;156:102.

Harlow BL, Vitonis AF, Stewart EG. Influence of oral contraceptive use on the risk of adult-onset vestibulodynia. J Reprod Med 2008; 53:102.

Burrows L, Goldstein A. The treatment of vestibulodynia with topical estradiol and testosterone. Sex Med 2013;1:30-33.

Goldstein S, Minton J, Gagnon C, Kim N, Goldstein I. 018 Open-Label Pilot, Prospective vulvoscopic study during four months of administration of daily prasterone (6.5 mg DHEA) vaginal inserts in women with moderate to severe dyspareunia from vulvar vaginal atrophy (VVA) due to menopause: an interim analysis. Sex Med 2020;17(1):S8-9.

Parish SJ, Goldstein AT, Goldstein SW, Goldstein I, Pfaus J, Clayton AH, Giraldi A, Simon JA, Althof SE, Bachmann G, Komisaruk B, Levin R, Kellogg Spadt S, Kingsberg SA, Perelman MA, Waldinger MD, Whipple B.. Toward a More Evidence-Based Nosology and Nomenclature for Female Sexual Dysfunctions – Part II, J Sex Med. 2016 Dec;13(12):1888-1906.

PGAD Goldstein I, Komisaruk BR, Pukall CF, Kim NN, Goldstein AT, Goldstein SW, Hartzell-Cushanick R, Kellogg-Spadt S, Kim CW, Jackowich RA, Parish SJ, Patterson A, Peters KM, Pfaus JG, International Society for the Study of Women’s Sexual Health (ISSWSH) Review of Epidemiology and Pathophysiology, and a Consensus Nomenclature and Process of Care for the Management of Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia (PGAD/GPD), J Sex Med 2021;18;665-697.

GSM Portman D, Gass M, Kingsberg S, Archer D, Bachmann G, Burrows L, Freedman M, Goldstein A, Goldstein I, Heller D, Iglesia C, Kagan R, Spadt SK, Krychman M, Nachtigall L, Nappi R, Pinkerton J, Shifren J, Simon J, Stuenkel C. Genitourinary syndrome of menopause: new terminology for vulvovaginal atrophy from the International Society for the Study of Women’s Sexual Health and the North American Menopause Society. Menopause. 2014;21:1063-8.

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Erections: Size Matters and History Matters

Murphy, L.J.T.: Peyronie’s Disease (Fibrous Cavernositis). In: The History of Urology. 1st ed. Springfield, Illinois. Charles C Thomas. Pages 485-486, 1972.

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Kuss, R., and Gregoir, W.: L’Induration Plastique des Corps Caverneux. In Histoire Illustrée de L’Urologie de l’Antiquite a nos jours. 1st ed. Paris: Roger Dacosta. Pages 461-464, 1984.

Polkey, H.J.: Induratio penis plastica. Urol. Cutan. Rev., 32:287, 1928.

LaPeyronie, F.: Sur quelques obstacles qui s’opposent a l’ejaculation naturelle de la semence. In: Mein de l’Academie Royale de Chir. New Edition. Paris.

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Dunsmuir, W.D., and Kirby, R.S.: Francois de LaPeyronie (1678-1747): the man and the disease he described. Brit. J. Urol. 78:613-622, 1996.

Campbell, E., and Colton, J.: Warts and tubercles occurring on the penis and other parts of the body: corns and black warts. In The Surgery of Theodoric ca A.D. 1267. 1st ed. Vol II. New York: Appleton-Century-Crofts. Pages 109-114, 1960.

History of Premature Ejaculation Ehrentheil O. A case of premature ejaculation in Greek mythology. Journal of Sex Research. 1974;10: 128-31.

Kraft-Ebing R. Psychopathia sexualis, 11th edition. Stuttgart: Enke; 1901.

Abraham K. Uber Ejaculatio Praecox. Zeitschrift Aerztiche Psychoanalyse.

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Stekel W. Impotence in the male. The psychic disorders of sexual function in the male. New York: Boni & Liveright; 1927.

Schapiro B. Premature ejaculation: a review of 1130 cases. Journal of Urology.

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Masters, Johnson. Human sexual inadequacy. Boston: Little, Brown; 1970.

Kaplan H. How to overcome premature ejaculation. New York: Bruner/Mazel; 1989.

Waldinger MD. The neurobiological approach to premature ejaculation. J Urol.

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Waldinger MD, Janssen PK, Schweitzer DH. Re: Polymorphisms of the serotonin transporter gene and their relation to premature ejaculation in individuals from Iran. M. R. Safarinejad. J Urol 2009; 181: 2656-2661. J Urol. 2009;182: 2983; author reply 83-4.

Waldinger MD, Rietschel M, Nothen MM, Hengeveld MW, Olivier B. Familial occurrence of primary premature ejaculation. Psychiatr Genet. 1998;8: 37-40.

Disorders of Ejaculation: An AUA /SMSNA Guideline. https://www.auanet.org/ guidelines/disororders-of-ejaculation.: American Urological Association; 2020.

Serefoglu EC, McMahon CG, Waldinger MD, et al. An evidence-based unified definition of lifelong and acquired premature ejaculation: report of the second International Society for Sexual Medicine Ad Hoc Committee for the Definition of Premature Ejaculation. J Sex Med. 2014;11: 1423-41.

UrologicHistory.Museum

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McMahon CG, Althof SE, Kaufman JM, et al. Efficacy and safety of dapoxetine for the treatment of premature ejaculation: integrated analysis of results from five phase 3 trials. J Sex Med. 2011;8: 524-39.

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Althof SE. Psychological approaches to the treatment of premature ejaculation.

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Valchanow, V., Michailow, P., & Patrashkov, T. (1989). New possibilities of HM-3 lithotriptor for treatment of disturbed bone union. Paper presented at the 7th World Congress on ESWL and Endourology.

Althof SE, McMahon CG, Rowland D. Advances and missteps in diagnosing premature ejaculation; Analysis and future directions. Journal of Sexual Medicine- online. 2021.

The Hormone Testosterone History of Testosterone

Nieschlage E and Nieschlag S. Endocrine History: the history of discovery, synthesis and development of testosterone for clinical use. Eur J Endocrinology 2019, 180:R201-212 Freeman, Bloom, D. A., & McGUIRE, E. J. (2001). A BRIEF HISTORY OF TESTOSTERONE. The Journal of Urology, 165(2), 371–373.

Morgentaler, & Traish, A. (2020). The History of Testosterone and the Evolution of its Therapeutic Potential. Sexual Medicine Reviews, 8(2), 286–296.

Prostate cancer Huggins, & Hodges, C. V. (2002). Studies on prostatic cancer: I. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. 1941. The Journal of Urology, 168(1), 9–12. (originally published 1941 in Cancer Research) Morgentaler, & Traish, A. M. (2008). Shifting the Paradigm of Testosterone and Prostate Cancer: The Saturation Model and the Limits of Androgen-Dependent Growth. European Urology, 55(2), 310–321.

Morgentaler, Abello, A., & Bubley, G. (2021). Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer: Initial Observations. Androgens: Clinical Research and Therapeutics, 2(1), 121–128.

Khera, Crawford, D., Morales, A., Salonia, A., & Morgentaler, A. (2013). A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications. European Urology, 65(1), 115–123.

Baillargeon, Kuo, Y.-F., Fang, X., & Shahinian, V. B. (2015). Long-term Exposure to Testosterone Therapy and the Risk of High Grade Prostate Cancer. The Journal of Urology, 194(6), 1612–1616.

Testosterone and cardiovascular risk Morgentaler, Abraham, MD, Miner, Martin M., MD, Caliber, Monica, MSc, Guay, Andre T., MD, Khera, Mohit, MD, & Traish, Abdulmaged M., PhD. (2015).

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies.

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Miner, Morgentaler, A., Khera, M., & Traish, A. M. (2018). The state of testosterone therapy since the FDA’s 2015 labelling changes: Indications and cardiovascular risk. Clinical Endocrinology (Oxford), 89(1), 3–10.

Guidelines and clinical recommendations Mulhall, Trost, L. W., Brannigan, R. E., Kurtz, E. G., Redmon, J. B., Chiles, K. A., Lightner, D. J., Miner, M. M., Murad, M. H., Nelson, C. J., Platz, E. A., Ramanathan, L. V., & Lewis, R. W. (2018). Evaluation and Management of Testosterone Deficiency: AUA Guideline. The Journal of Urology, 200(2), 423–432.

Morgentaler, Abraham, et al. “Diagnosis and Treatment of Testosterone Deficiency: Updated Recommendations From the Lisbon 2018 International Consultation for Sexual Medicine.” Sexual Medicine Reviews, vol. 7, no. 4, ELSEVIER, 2019, pp. 636–49.

Other resources: Androgen Society- www.androgensociety.org International multi-disciplinary society dedicated to research and education regarding testosterone deficiency and its treatment Androgens: Clinical Research and Therapeutics - www.liebertpub.com/loi/andro Official journal of the Androgen Society. This journal is dedicated entirely to androgen research and health-related topics in humans

The Future Shockwave

Tailly, G. G. (2013). Extracorporeal shock wave lithotripsy today. Indian journal of urology: IJU: journal of the Urological Society of India, 29(3), 200.

Lawler, A. C., Ghiraldi, E. M., Tong, C., & Friedlander, J. I. (2017).

Extracorporeal shock wave therapy: current perspectives and future directions.

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Al-Abbad, H., & Simon, J. V. (2013). The effectiveness of extracorporeal shock wave therapy on chronic achilles tendinopathy: a systematic review. Foot & ankle international, 34(1), 33-41.

Aqil, A., Siddiqui, M. R., Solan, M., Redfern, D. J., Gulati, V., & Cobb, J. P. (2013). Extracorporeal shock wave therapy is effective in treating chronic plantar fasciitis: a meta-analysis of RCTs. Clinical Orthopaedics and Related Research®, 471(11), 3645-3652.

Alunni, G., Marra, S., Meynet, I., D’amico, M., Elisa, P., Fanelli, A., et al. (2015).

The beneficial effect of extracorporeal shockwave myocardial revascularization in patients with refractory angina. Cardiovascular Revascularization Medicine, 16(1), 6-11.

Bechara, A., Casabé, A., De Bonis, W., & Ciciclia, P. G. (2016). Twelve-month efficacy and safety of low-intensity shockwave therapy for erectile dysfunction in patients who do not respond to phosphodiesterase type 5 inhibitors. Sexual medicine, 4(4), e225-e232.

Sokolakis, I., Dimitriadis, F., Teo, P., Hatzichristodoulou, G., Hatzichristou, D., & Giuliano, F. (2019). The basic science behind low-intensity extracorporeal shockwave therapy for erectile dysfunction: a systematic scoping review of pre-clinical studies. The journal of sexual medicine, 16(2), 168-194.

Clavijo, R. I., Kohn, T. P., Kohn, J. R., & Ramasamy, R. (2017). Effects of low-intensity extracorporeal shockwave therapy on erectile dysfunction: a systematic review and meta-analysis. The journal of sexual medicine, 14(1), 27-35.

Patel, P., Katz, J., Lokeshwar, S. D., Molina, M., Reis, I. M., Clavijo, R., et al. (2020). Phase II randomized, clinical trial evaluating 2 schedules of lowintensity shockwave therapy for the treatment of erectile dysfunction. Sexual medicine, 8(2), 214-222.

Hurt, K., Zahalka, F., Halaska, M., Rakovicova, I., Rakovic, J., & Cmelinsky, V. (2021). Extracorporeal shock wave therapy for treating dyspareunia: A prospective, randomized, double-blind, placebo-controlled study. Annals of Physical and Rehabilitation Medicine, 64(6), 101545.

Long, C.-Y., Lin, K.-L., Lee, Y.-C., Chuang, S.-M., Lu, J.-H., Wu, B.-N., et al.

(2020). Therapeutic effects of Low intensity extracorporeal low energy shock wave therapy (LiESWT) on stress urinary incontinence. Scientific reports, 10(1), 1-10.

Wang, C.-J., Cheng, J.-H., Kuo, Y.-R., Schaden, W., & Mittermayr, R. (2015).

Extracorporeal shockwave therapy in diabetic foot ulcers. International Journal of Surgery, 24, 207-209.

The Orgasm

Komisaruk BR, Whipple B, Crawford A, Liu WC, Kalnin A, Mosier K. Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the vagus nerves.

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PMID: 15451368.

Komisaruk BR, Wise N, Frangos E, Liu WC, Allen K, Brody S. Women’s clitoris, vagina, and cervix mapped on the sensory cortex: fMRI evidence. J Sex Med. 2011 Oct;8(10):2822-30. doi: 10.1111/j.1743-6109.2011.02388.x. Epub 2011 Jul 28. PMID: 21797981; PMCID: PMC3186818.

The References The Ins

McMahon CG, Althof SE, Waldinger MD, et al. An evidence-based definition of lifelong premature ejaculation: report of the International Society for Sexual Medicine (ISSM) ad hoc committee for the definition of premature ejaculation.

Journal of Sexual Medicine. 2008;5: 1590-606.

Wise NJ, Frangos E, Komisaruk BR. Brain Activity Unique to Orgasm in Women: An fMRI Analysis. J Sex Med. 2017 Nov;14(11):1380-1391. doi: 10.1016/j. jsxm.2017.08.014. Epub 2017 Oct 3. PMID: 28986148; PMCID: PMC5675825.

Allen K, Wise N, Frangos E, Komisaruk B. Male Urogenital System Mapped Onto the Sensory Cortex: Functional Magnetic Resonance Imaging Evidence. J Sex Med. 2020 Apr;17(4):603-613. doi: 10.1016/j.jsxm.2019.12.007. Epub 2020 Jan 15. PMID: 31953029.

Chaussy, C. (2017). Extracorporeal Shockwave Lithotripsy: An Eyewitness`s

Ins & Outs of Sexual Health

35

A HISTORY OF BRINGING INNOVATION

TO LIGHT FOR PATIENTS 2004

Founding of UroGen® Pharma

2016

Transformed potential for medicine delivery with innovative RTGel™, reverse-thermal hydrogel technology

APRIL 2020

Breakthrough FDA approval of JELMYTO® (mitomycin) for pyelocalyceal solution, the first and only therapy of its kind

DEVELOPING FUTURE TREATMENT PARADIGMS

2019

Bolstered patient and physician knowledge of kidney preservation through awareness and education

2021

Announced final results from OPTIMA II Phase 2b trial Accelerated research through strategic clinical partnerships

UGN-102: ENVISION Phase 3 trial Low-grade intermediate-risk NMIBC UGN-301: Phase 1 Monotherapy or combination therapy UGN-301 + UGN-201: Nonclinical High-grade NMIBC

A partnership that stands the test of time: UroGen is a proud sponsor of the William P. Didusch Center for Urologic History

NMIBC = non-muscle invasive bladder cancer.

UGN-102, UGN-301, and UGN-301 + UGN-201 are investigational agents. Their safety and efficacy have not been established.

JELMYTO® and UroGen® are registered trademarks and RTGelTM is a trademark of UroGen Pharma, Ltd. © 2022 UroGen Pharma, Inc. All rights reserved. US-UGN-00093 03/22