Growth Hormone Deficiency Causing Micropenis:Peter A. Lee, MD, PhD,​a Tom Mazur, PsyD, Lessonsb​ Christopher P. Houk, MD, Learnedc​ Robert M. Blizzard, MD d

From a Well-Adjusted Adultabstract This report of a 46,​XY patient born with a micropenis consistent with etiology from isolated congenital growth hormone deficiency is used to (1) raise the question regarding what degree testicular testosterone exposure aDepartment of Pediatrics, College of Medicine, Penn State to the central nervous system during fetal life and early infancy has on the University, Hershey, Pennsylvania; bCenter for Psychosexual development of male gender identity, regardless of gender of rearing; (2) Health, Jacobs School of Medicine and Biomedical suggest the obligatory nature of timely full disclosure of medical history; Sciences, University at Buffalo and John R. Oishei Children’s Hospital, Buffalo, New York; cDepartment of (3) emphasize that virtually all 46,​XY infants with functional testes and Pediatrics, Medical College of Georgia, Augusta University, a micropenis should be initially boys except some with partial androgen Augusta, Georgia; and dDepartment of Pediatrics, College of Medicine, University of Virginia, Charlottesville, Virginia insensitivity syndrome; and (4) highlight the sustaining value of a positive long-term relationship with a trusted physician (R.M.B.). When this infant Dr Lee reviewed and discussed the extensive medical records with Dr Blizzard, reviewed presented, it was commonly considered inappropriate to gender assign an pertinent medical literature, and wrote each draft infant male whose penis was so small that an adult size was expected to be of the manuscript with input from all coauthors; inadequate, even if the karyotype was 46,​XY, and testes were functional. Dr Mazur reviewed the literature and wrote a chronologic history outline with particular attention Concomitantly, female gender assignment was considered the appropriate to the psychological aspects and comments with decision, believing that parental rearing in the assigned gender was suggestions on each draft of the manuscript; considered the major factor determining established adult gender identity. Dr Houk reviewed and discussed the extensive Full disclosure of medical information was considered inappropriate. medical records in person with Drs Blizzard and Lee, commented and outlined pertinent information Progress in appreciating the complexities of gender identity development, from this case, and reviewed and commented on which is not yet completely understood, and sexuality, coping ability, each draft of the manuscript; Dr Blizzard, who and outcome data has resulted in a change of practice in initial gender cared for this patient for the first 35 years of the patient’s life, created an extensive collection assignment. A 46,​XY individual with functional testes and verified androgen of notes and comments regarding this patient, responsiveness should be assigned and reared as male, regardless of discussed information to be included in this report, penis size. Without androgen responsiveness, the multiple factors must be and approved the manuscript being submitted; and all authors approved the final manuscript as carefully considered and disclosed. submitted. DOI: https://​doi.​org/​10.​1542/​peds.​2017-​4168 CASE SUMMARY Accepted for publication Apr 2, 2018 gender by parents and caregivers, Address correspondence to Peter A. Lee, MD, PhD, Milton S. Hershey Medical Center, PO Box 850, 500 A 46,​XY individual born with a gender adjustment problems developed, and at age 29 years, after University Dr, Hershey, PA 17033-085. E-mail: plee@ stretched penis length of 1.5 cm was psu.edu reassigned female at 5 months of full medical history disclosure, this patient self-reassigned as male. This PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, life. Risks of female reassignment 1098-4275). were discussed; parents signed a patient is now a self-supporting, Copyright © 2018 by the American Academy of detailed hand-written consent. Testes socially active, married, sexually active, – Pediatrics were removed, and the penis was unequivocal heterosexual man. refashioned as a clitoris. With Figs 1 5, During childhood, developmental To cite: Lee PA, Mazur T, Houk CP, et al. Growth we provide a chronological summary milestones were normal, and gender Hormone Deficiency Causing Micropenis: Lessons in which we detail the life events for identity appeared female, but Learned From a Well-Adjusted Adult. Pediatrics. this 39-year-old well-adjusted man. poor self-concept, inattentiveness, 2018;142(1):e20174168 Despite multiple genital surgeries and and hyperactivity were noted a long-term commitment to a female (retrospectively, this perhaps signals Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 142, number 1, July 2018:e20174168 CASE REPORT “ ”

herself lesbian (although sexual orientation itself is not evidence of incorrect gender assignment, this may indicate a struggle with female gender), and related and identified with other similar-aged lesbians (Fig 4). At 22, she reestablished physician contact and indicated that she had previously told doctors what she thought they wanted to hear, rather than how she felt. She still refused hormonal therapy (indication of not wanting female characteristics), was gender-neutral in appearance, FIGURE 1 and began requesting full medical Timeline of events and observations for birth to 6 years (arrows are used to highlight key events). FSH, follicle-stimulating hormone; hCG, human chorionic gonadotropin; IGF-1, insulin-like growth history and records. As was common factor1; LH, luteinizing hormone. in this era, records had not been made available consistent with the perception that disclosure might foster more psychological problems.

Finally, at age 29, her medical history was reviewed and explained by R.M.B. over several sessions (Fig 5). This disclosure was followed by an immediate gender change to male similar to a case in which a person with a diagnosis of partial androgen insensitivity syndrome (pAIS)

changed gender from male to female 1 upon learning of her medical history. Mastectomy was undertaken, and testosterone therapy was initiated. FIGURE 2 After full replacement was achieved, Timeline of events and observations for ages 6.5 to 9 years (arrows are used to highlight key events). orgasmic ability was restored. GH deficiency was reverified, and adult GH replacement therapy was begun. His birth certificate was reissued that a struggle with female gender The patient delayed the male. Now, multiple years after these began during childhood). With Figs 1 recommended onset of estrogen changes, this man continues to be and 2, we outline the medical history; therapy for several years (further gainfully employed, is socially active, genital anatomy; gender assignment; evidence of a struggle with female – maintains fulfilling relationships growth hormone (GH) testing; gender), beginning sex steroids at – with family and friends, has enjoyed pregonadectomy hypothalamic age 11.5 years with vaginoplasty physical intimacy, including 2 pituitary testicular function; the at 14 years. Concerns included an long-term romantic relationships dramatic fivefold phallic growth from atypical reproductive anatomy, with women that included male- 6 mm to 3 cm during GH therapy; noncompliance with estrogen typical sexual activities (with the behavioral, psychological, functional therapy (sign of a gender struggle) inherent limitations imposed by difficulties; and recurrent problems and prescribed vaginal dilation, penile absence), and by his mid-30s from previous genital surgery. and desire for sexual hair (Fig was married. This may imply that, Concerns involved genital differences 3). In early adulthood, during a although fetal testicular testosterone compared with other girls (again 3-year interval without physician was insufficient to stimulate fetal perhaps this signals that a struggle contact, the patient worked as a penis growth in the face of GH with female gender began during nursing assistant, refused hormones deficiency, testosterone exposure childhood), and clitoral erections. and/or medications, declared to the central nervous system (CNS) Downloaded from www.aappublications.org/news by guest on September 23, 2021 2 LEE et al uncertainty, particularly in how individual personality factors, such as resilience, influence outcomes. It is still true that this type of variability in behavioral outcomes makes a perfect gender assignment impossible in all cases. With this current case report, we point to the need for cautious and careful case-by-case management for these patients and, when possible, for such management to be performed

FIGURE 3 by open-minded3 multidisciplinary Timeline of events and observations for ages 10 to 16 years (arrows are used to highlight key events). teams. ADHD, attention-deficit/hyperactivity disorder; FSH, follicle-stimulating hormone; GI, gender idenity; LH, luteinizing hormone. Etiologies of micropenis commonly include pituitary gonadotropin

deficiency, androgen4 biosynthetic defects, and pAIS. Classic teaching is used to instruct us that fetal and neonatal penis growth is primarily driven by androgen stimulation (via dihydrotestostrone). Isolated GH

deficiency is typically not1, mentioned5​ as a cause of micropenis,​ ‍ although penis growth has been reported

among patients with GH deficiency6 who received GH therapy. Authors of textbook chapters may mention isolated GH deficiency as a possible

etiology of micropenis7,8​ but without specific case citation. ‍ Thus, this case represents the first published FIGURE 4 report of isolated congenital GH Timeline of events and observations for ages 17 to 22 years (arrows are used to highlight key events). deficiency causing micropenis, and, with it, we demonstrate the impressive phallic growth noted after GH therapy and highlight this may have occurred as expected. exposure or surgical procedures as a treatable etiology. However, Among the many factors he feels GH treatment does not guarantee ’ and more a consequence of the fostered his positive adjustment, complex interplay between multiple that adult penis size will be in the he cites his and his family s long- experiences (eg, having chronic normal range or that psychological term relationship with his pediatric condition and attendant experiences, challenges and dissatisfaction will endocrinologist (R.M.B.) as the most reaction of parents, medical decision- not occur. important and supportive. making, lack of disclosure and We demonstrate that isolated Case reports, such as this one, in feelings of secrecy and shame, and GH deficiency is an etiology which the influence of medical, effects of possible peer rejection) of micropenis on the basis of hormonal, psychological, and cultural that modulate the outcomes within2 unequivocal evidence of GH mediating factors are highlighted and across developmental stages. deficiency (GH stimulation testing in can be used to provide valuable Although excellent progress has infancy and adulthood, subnormal information, in part to respond to been made in our management of pretreatment growth velocity, justifiable criticism by patients and these patients, our understanding of normalization of the linear growth advocates that poor psychosocial the biological and social factors that rate after GH therapy was initiated, and sexual outcomes may be less contribute to healthy psychosexual a normal adult height [176 cm], a function of atypical sex hormone development remain an area of and fivefold phallic growth noted Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 142, number 1, July 2018 3 abnormalities of nonhormonal origin (including penile agenesis, cloacal and classic exstrophy of the bladder, and penile ablation) carry a high risk of gender self-reassignment that is considerably higher than the

risk of gender self-reassignment14, in15​ patients initially raised as boys. There has also been a concern regarding the indelible effect of – androgen on brain masculinization during mid fetal life and the effect this may have on gender identity development. Although this concept is supported by patients with FIGURE 5 Timeline of events and observations for ages 23 to 29 years (arrows are used to highlight key events). complete androgen insensitivity, who almost universally identify as women in adulthood, the degree of influence in those with a normally functioning “ androgen receptor remains an area during the first 1.5 years of GH effect first11 noted in gonadotropin ” therapy). This patient, with no deficiency and by way of the data of controversy. This androgen other anterior pituitary hormone presented in this case in those with imprinting concept, together with deficiencies, demonstrated dramatic GH deficiency. Outcome data are outcome impressions, has also growth of the phallic corpora from even less clear and are perplexing resulted in higher rates of male nonpalpable to 3.0 cm during the for those with pAIS, ovotesticular gender assignments for individuals first 1.5 years of GH therapy. The disorders of sex development (DSD), with 46,​XY DSD during the last 2 genital surgery precluded not only and testicular agenesis or regression decades, particularly in those13 with the documentation of the impact of syndrome. less severe undervirilization. In short-term growth response to GH addition, dramatic refinement of in a small penis as a consequence A female assignment was long surgical techniques for masculinizing of GH deficiency but also made it considered the ultimate alternative genitoplasty have also occurred impossible to speculate whether a in patients with a micropenis with a over the same interval. However, normal adult size would have been forecasted penile growth expected to because long-term health and quality be well below the normal adult range. of life outcomes of such changes are reached with long-term GH therapy. “ ” Although penile growth acceleration This was based on the rationale that not available for at least 2 decades, is obvious during periods of a penis of sufficient size was a further systematic confirmation of androgen treatment, there is no significant factor in the well-being the benefits of these shifts remain. It evidence that testosterone treatment of a man (on the basis of proposed is critical to point out that the ethical dilemmas involved in medical and before puberty increases9 the eventual benefits of standing to urinate, for size of the adult penis. As is seen traditional penetrative intercourse, surgical management of persons in human growth in stature, adult and the unverified implication that with congenital atypical genital penis size in those with a micropenis penis size is an index of masculinity). development will persist regardless cannot always be specifically From the surgical standpoint, it was of improved surgical techniques predicted because of the multiple also naively considered more feasible or cosmetic outcomes, because factors involved; however, some to create a penetrative12 conduit than surgery is not the primary driver of outcome data reveal that adult penis a penetrating organ. The gradual outcome in these cases but should length can be within 2 SD of normal trend away from female assignment be considered complementary to a thoughtful initial gender in patients without GH deficiency10 was based in part on the negative born with a micropenis. consequences of feminizing genital management and is maximally surgery (clitoris by reduction of beneficial when it aligns with the Hence, depending on etiology of phallus, inadequacy of vaginal future adult sexual identity. congenital micropenis, penis growth construction) and 3,a13​ higher risk of potential cannot be easily predicted gender dysphoria. ‍ Female gender With this case, we suggest that, in at presentation and may4 be greater assignment in 46,​XY infants and addition to prenatal testosterone than initially forecasted ; this is an young children with severe genital CNS exposure, the presence of a Downloaded from www.aappublications.org/news by guest on September 23, 2021 4 LEE et al 46,XY​ karyotype may also be a development or responses to certain adjustment, and psychopathology factor in the development of a male hormonal stimulus, and socialization suggest that men born with a gender identity. Because gender is known to heavily influence micropenis have similar outcomes identity is a complex construct 16 many sex-related behavioral to men in9 control groups in these involving multiple components,​ characteristics. domains. This, of course, should many additional factors should Nevertheless, with this case, we not imply that 46,​XY individuals be considered when trying to strongly support rearing 46,XY​ with a micropenis reared as male understand the reasons 17for self- infants with functional testes, a do not experience psychosexual and reassignment of gender. Empirical normal androgen receptor, and psychosocial problems. Satisfactory evidence of the extent of influence micropenis as male, regardless of genitosexual function was found exerted by prenatal testosterone on 18 penis size. Among those with pAIS, among those reared as male, but gender identity remains inconclusive,​ extensive feminizing surgery was ’ only those patients who fail to with more definitive evidence demonstrate phallic growth after associated with a negative outcome for testosterone s role in gender7 exogenous testosterone should be for those reared as female. With this role interests and behavior,​ and, considered for female assignment. report, we found that, regardless of recently, in influencing sexual19 Although there are not good criteria the initial assignment, the majority of attraction toward women. for a normal phallic response (a patients indicated satisfaction with Although, with this case report, we general rule has been a 100% their assigned gender and showed provide evidence used to reinforce increase in penis length), clinically, similar degrees of dissatisfaction the role of androgen (and functioning a positive response is unequivocally with genital appearance and function, androgen receptors) in influencing apparent by inspection. Outcome leading to the conclusion that male masculine-typical brain and gender data for those with pAIS include assignment is preferable because24 identity development, any significant genital surgery is not needed. These individuals who self-initiated21 gender role of an XY karyotype on sexual change in both directions. This results must be taken within the development, although intuitive, highlights the lack of data used to context that studies on psychosexual remains speculative. For example, 46,​ provide guidance on which gender to development and psychosocial XY women with complete androgen initially assign among these infants, well-being in men with DSD or other insensitivity syndrome show brain beyond the general principle that genital atypicality are rare, and, as in responses to sexual images similar lack of physical (genital) response to the studies cited above, the authors to 46,​XX women and markedly testosterone may also indicate lack of of such studies include only a small different from XY men, with whom responsiveness in other organs such number of participants, with large they share a Y chromosome and a as the CNS, hence a lack of whatever numbers of potential participants declining participation, such that high prenatal20 and infant testosterone effect androgen has to impart male secretion. Those with complete gender development. With this case, conclusions should be interpreted androgen insensitivity syndrome lack we also highlight the perils of the with caution. functional androgen receptors, which previous management paradigm in precludes a cellular response to which the assertion was made that In this case, adequate penile length, testosterone; however, testosterone initial gender assignment, when or even having a penis, was not is readily aromatized to estradiol associated with consistent rearing shown to be a prerequisite for a man resulting in normal feminization at and psychosocial input from others, to have successful sexual contact; this puberty, via normally functioning would establish a desired gender would appear to be a consequence estrogen receptors. With these identity regardless of etiology. of an adjustment to face reality. This findings and our current report, we coping mechanism is similar to that The current approach to these suggest multivariate contributions to reported for a25 group of men with gender-specific brain development patients is outlined22 in a recent small penises who also seemed while emphasizing the importance publication and reflects the shift to have learned to de-emphasize of both nature and nurture. Prenatal from female assignment in any 46,​ the importance of intercourse gonadal hormonal exposure, as XY individual. Authors of a recent and had found alternative ways well as exposure during early summary do not mention the 2 for themselves and their partners infancy and puberty may provide possibility of female assignment,​ to pleasure each other and reach additional sensitive periods when sex whereas those of another publication23 orgasms. In other reports, however, steroids are able to influence human only note the controversy of such. when small penis size persists into neurobehavioral organization. Sex- Researchers of outcome data adulthood it was a8 major cause linked genes could also contribute regarding gender issues, body image, of dissatisfaction. This can be to sex-related variability in brain social fitness, sexuality, work, family interpreted to mean that, generally, Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 142, number 1, July 2018 5 ” penis size matters, particularly if an imparted? The issue is no longer establish rapport (an essential individual focuses on this and lacks whether to disclose the information component of successful counseling); the affirmation that, for this as well but when and how to tell it. It has (2) assess normal domains of as other situations in life that cannot been shown that informing children26 development for age, including be altered, accepting this fact and of their condition is beneficial. gender identity; (3) address issues de-emphasizing its importance is the Generally, information should be relevant to developmental age; (4) only reasonable way forward. The given in small increments at different provide education about endocrine challenge for both parents and health times. For the mature child, the oldest conditions by answering questions professionals is how to help such a appropriate age to begin would and concerns; (5) provide a setting person develop the kind of resilience be just before puberty or during to reiterate what has been learned demonstrated by the person in this puberty. For years, parents, despite about condition, medications, etc; report. fears, agreed that their children had (6) begin sex education relevant ’ During several instances beginning the right to know the full details of to development age to be used as a during childhood, there were their DSD condition and treatment template on which to place patients signals (noted above), that this and that the information27 should be DSD; (7) discuss romantic and sexual person was struggling with the given in stages. Such a step-by-28 interests, fears, etc; (8) introduce the assigned female gender. It was full step approach was suggested,​ and, topic of DSD support groups; and (9) education and disclosure regarding today, there are many educational provide opportunities to meet others her DSD condition and treatment resources, some for specific DSD with similar conditions. Although the that provided the knowledge to conditions, for children, adolescents, noncategorical approach follows a make sense of what she had been and young adults (eg, www.​ generic protocol, it recognizes that struggling with for years (the accordalliance.​org). This link also has the patient and family come first assigned female gender). This a list of support groups by specific and that flexibility along with long- confirmed the conviction that she DSD condition. term monitoring and rapport are “ ” had a male gender identity. Although It has become clear that best key assets to best practice. The goal routine psychological checkups practice must include psychosocial of both medical and psychological were generally not done or available, management that is not only used to care via an interdisciplinary team this evidence also would suggest that, focus on gender development and is a person who is well adjusted in if these had occurred, this person sexually related aspects of care but the face of unchangeable physical may have been spared years of also other quality of life domains. characteristics. distress and uncertainty. Fortunately, This approach, referred to29 as a R.M.B. was able to provide this noncategorical approach,​ views ABBREVIATIONS vital educational history within the DSD as a chronic condition similar context of a 35-year relationship to other pediatric conditions. This with this patient and his family. model of care is patient and family CNS: central nervous system Unfortunately, such physician-patient focused and emphasizes that quality DSD: disorders of sex relationships are not“ common today. of life encompasses many aspects of development ” GH: growth hormone The questions are, At what age development. “ pAIS: partial androgen insensi- should information be given? and The purpose of such protocol-driven tivity syndrome How should the information be psychological monitoring is to (1) FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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