eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Androgen Insensitivity Syndrome

Bruce E Wilson, MD, Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine at East Lansing

Updated: Jun 23, 2009

Introduction

Background

Androgen insensitivity syndrome (AIS), formerly known as testicular feminization, is an X-linked recessive condition resulting in a failure of normal masculinization of the external genitalia in chromosomally male individuals. This failure of virilization can be either complete androgen insensitivity syndrome (CAIS) or partial androgen insensitivity syndrome (PAIS), depending on the amount of residual receptor function.

Both individuals with partial androgen insensitivity syndrome and individuals with complete androgen insensitivity syndrome have 46,XY karyotypes. Individuals with complete androgen insensitivity syndrome have female external genitalia with normal labia, clitoris, and vaginal introitus.^1,2,3 The phenotype of individuals with partial androgen insensitivity syndrome may range from mildly virilized female external genitalia (clitorimegaly without other external anomalies) to mildly undervirilized male external genitalia (hypospadias and/or diminished penile size).

Penoscrotal hypospadias is shown. Note the associated ventral chordee and true urethral meatus located at the scrotal level.

Pathophysiology

The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the androgen receptor (AR) gene. This AR gene has been localized to the long arm of the X chromosome (ie, Xq11-13). Over 200 such mutations have been described, including complete and partial gene deletions, point mutations, and small insertions/deletions. These mutations can cause a variety of functional defects, ranging from a complete loss of receptors on the cell surface because of incomplete protein synthesis to alterations in substrate binding affinity. Altered substrate binding affinity causes a signal transmission loss, despite normal cell surface receptor numbers. While the genotypes causing complete androgen insensitivity syndrome are consistent in phenotypic presentation, the genotype/phenotype relationships for the mutations causing partial androgen insensitivity syndrome remain unclear.

Loss of AR function means that, despite normal levels of androgen synthesis, the typical postreceptor events that mediate the effects of hormones on tissues do not occur. This results in the phenotype of prenatal undervirilization of external genitalia, absence of pubic and axillary hair, lack of acne, and absence of voice changes at puberty.

Frequency

United States

Data are currently not available on the specific incidence of complete androgen insensitivity syndrome and partial androgen insensitivity syndrome.

International

The best available data suggest an androgen insensitivity syndrome incidence of approximately 1 case per 20,400 liveborn males. This statistic is based on analysis of a Danish patient registry that included only hospitalized cases; thus, the true incidence of androgen insensitivity syndrome may be higher. Complete androgen insensitivity syndrome appears more common than partial androgen insensitivity syndrome, although exact figures are unavailable.

Mortality/Morbidity

Androgen insensitivity syndrome, either complete or partial, has little medical morbidity or mortality. Over time, untreated patients have a theoretical risk of malignant degeneration and development of gonadoblastoma of the testes. No documentation on the morbidity or mortality of these tumors specifically in individuals with androgen insensitivity syndrome is available. The tumor is considered cured without need for further therapy if it is removed while still limited to the interior of the testes capsule. The tumor is considered curable in most patients even when undetected at this early state.

In contrast to medical morbidity, psychological morbidity is common. Phenotypic females who are discovered to be genetic males may have psychosocial problems. These females require sensitive psychological support. Their psychosocial problems range from identity issues to problems dealing with the gender perceptions of the outside world and the style and sensitivity (or lack thereof) they encounter within the medical system.

Most affected individuals report psychological trauma at diagnosis. Their reactions to the diagnosis frequently are compounded by their interactions with the medical care system, in which they often are treated as oddities and forced to undergo multiple examinations and interviews with students and residents for teaching purposes. Even in nonteaching situations, women with androgen insensitivity syndrome report difficulties identifying offices where physicians and staff are familiar with their condition. Many of these patients have been told that they really are not women but actually are men because of the presence of a Y chromosome and testes. These difficulties and doubts often cause shame and self-doubt as well as anger and frustration with a medical system they had expected to take care of them.

Race

No racial differences in incidence or presentation of androgen insensitivity syndrome have been described.

Sex

All patients with androgen insensitivity syndrome are chromosomally and gonadally male. However, separating the concepts of sex and gender is crucial with these patients. The term sex is usually based on physical attributes, whereas the concept of gender is based on an individual's self-concept and self-identification as well as the role an individual assumes in society.

Most patients with complete androgen insensitivity syndrome have a female gender. This may be due, in part, to the patient's role assignment and upbringing before the diagnosis or to the patient's choice of female "sex/gender" at diagnosis. The significance of the androgen effect's absence is increasingly recognized for its influence on the maturing brain (and other systems) in terms of developing adult gender identity.

Partial androgen insensitivity syndrome is a more complicated problem for gender identity. Just as the genitalia may be highly varied in the degree of virilization, gender identity may be either female or male. At present, no reliable predictors of eventual gender identity have been identified, including genotype or degree of genital virilization at birth.

Clinical

History

Most cases of androgen insensitivity syndrome (AIS) are identified in the newborn period by the presence of inguinal masses, which later are identified as testes during surgery. Some patients are first seen in the teenage years for evaluation of primary amenorrhea. Many of these patients have a history of surgery for hernias and/or the presence of gonads in the inguinal canals, which were considered ovaries and returned to the abdomen.

Physical

In newborns with complete androgen insensitivity syndrome (CAIS), the most frequent initial finding is unilateral or bilateral masses in the inguinal canals that are found to be testes during surgery. Associated hernias may or may not be present.⁴

In adolescent patients, notable findings include inguinal masses. As with newborns, these masses may or may not be associated with hernias. In addition, adolescent patients have no pubic and axillary hair, with otherwise scanty body hair, and lack acne, although breast is normal as a result of conversion of testosterone to estradiol.

Newborn patients with partial androgen insensitivity syndrome (PAIS) can have a highly variable genital appearance. Adolescents may have pubic hair, although usually less than normal, and may have progressive clitoral enlargement and other signs of masculinization.

Causes

The basic etiology of androgen insensitivity syndrome is a loss-of-function mutation in the AR gene.⁵

Differential Diagnoses

17-Hydroxylase Deficiency Syndrome
3-Beta-Hydroxysteroid Dehydrogenase Deficiency
5-Alpha-Reductase Deficiency
Congenital Adrenal Hyperplasia
Mayer-Rokitansky Syndrome

Other Problems to Be Considered

Testicular dysgenesis
Leydig cell aplasia/hypoplasia
True hermaphroditism

Workup

Laboratory Studies

The following studies may be indicated in patients with androgen insensitivity syndrome (AIS).

• A karyotype is essential to differentiate an undermasculinized male from a masculinized female. Alternatively, the presence of a Y chromosome can be confirmed by fluorescent in situ hybridization (FISH) probes for either the SRY region of the Y chromosome or a subtelomeric Y chromosome probe. These offer a much quicker turnaround time than conventional karyotypes.
• Levels of testosterone and dihydrotestosterone (DHT) establish the presence of normal steroidogenesis.
  • If the testosterone level is low for age, obtain levels of dehydroepiandrosterone (DHEA), androstenedione, and their precursors, 17-hydroxypregnenolone and 17-hydroxyprogesterone. These levels allow identification of errors in the steroid biosynthetic pathways.
  • An elevated ratio of testosterone to DHT indicates a 5-alpha reductase deficiency, a possible differential for patients with partial androgen insensitivity syndrome but usually not for complete androgen insensitivity syndrome. Low levels of testosterone in the absence of evidence of defective steroidogenesis suggest testicular dysgenesis or Leydig cell aplasia/hypoplasia.
• Mutation analysis of the androgen receptor gene is now commercially available. It detects upwards of 95% of the mutations for complete androgen insensitivity syndrome and partial androgen insensitivity syndrome. The analysis is performed on DNA obtained from buccal swabs. However, the testing is slow (about 6 wk for results) and expensive (not covered by some insurance companies).

Imaging Studies

• A pelvic ultrasound examination is frequently useful. Identification of any müllerian structures, such as uterus or fallopian tubes, is inconsistent with a diagnosis of complete androgen insensitivity syndrome or partial androgen insensitivity syndrome.

Histologic Findings

• Histologic examination of the testes in patients with complete androgen insensitivity syndrome or partial androgen insensitivity syndrome should show fairly normal testicular structure, although the numbers of spermatogonia and/or sperm may be reduced markedly in postpubertal patients.
• Given current management recommendations (see Treatment), a histologic examination may be impossible to perform until the patient is in late adolescence or early adulthood.

Treatment

Medical Care

• HRT
  • HRT is the first and less complex aspect. All patients with complete androgen insensitivity syndrome (CAIS) and most patients with all but the mildest forms of partial androgen insensitivity syndrome (PAIS) undergo gonadectomy at some point in their treatment (see Surgical Care). Adolescent and adult patients with androgen insensitivity syndrome require hormone replacement.
  • For patients with complete androgen insensitivity syndrome, hormone therapy almost always consists of estrogen replacement. The general belief is that these women do not require progesterone because they have no uterus. Some evidence suggests that progesterone therapy combined with estrogen replacement may lessen the long-term risk of breast cancer, although this type of therapy is debatable. More recent meta-analyses suggest progesterone administration may have little or no advantage for patients without a uterus. Therapy usually is initiated with a low dose of estrogen alone, then is increased to routine adult dosing. Progesterone is added, if considered appropriate, after maintenance therapy with estrogen is established.
  • For individuals with partial androgen insensitivity syndrome , traditional therapy has mirrored therapy for individuals with complete androgen insensitivity syndrome. Patients with partial androgen insensitivity syndrome who have a male gender identity, however, may be treated with testosterone and/or dihydrotestosterone (DHT). The advantage of DHT is that it cannot be aromatized to estrogen. No medical consensus has been reached about this therapy; no dosage schedules have been established. Therapy may vary depending on the nature of the gene defect.
• Psychological support
  • Psychological support is probably the most important aspect of medical care from the patient's point of view. In a family with an affected infant, the parents are the primary clients. Parents need genetic counseling to understand the nature of the condition and the risk of recurrence (25% for each subsequent pregnancy) as well as to identify other potential carriers. In addition, parents often benefit from the services of a pediatric psychologist or child and adolescent psychiatrist to help adjust to their child's condition, including support on how to inform the child, over time and in an age-appropriate manner, about the condition. Genetic counselors do not provide this type of ongoing family support.
  • In a family with an affected older child, the patient is the primary client, although family members also may require psychological services. In these cases, too, pediatric psychologists or child and adolescent psychiatrists are the preferred clinicians because of their medical background and ability to help address medical, emotional, and psychological issues or questions. If at all possible, the therapist also should have experience dealing with patients who have intersex conditions, even if this experience is not specific to androgen insensitivity syndrome. The patient needs to establish a long-term relationship with the therapist to discuss new issues that arise as the child matures. (At times, these visits will be infrequent.) For adults with androgen insensitivity syndrome and other intersex conditions, lack of emotional and psychological support has been a major criticism of the medical care system.
  • The primary care practitioner can coordinate medical care for a child with androgen insensitivity syndrome, or coordination may be performed by a pediatric endocrinologist, especially as part of a multidisciplinary team. Carefully maintain communication and coordination among primary care, genetic, endocrinologic, and surgical services to avoid trauma to the child and family.
  • Contact with other individuals who have androgen insensitivity syndrome is another source of psychological and emotional support for the patient. The Androgen Insensitivity Syndrome Support Group (AISSG) has constituent organizations in the United States, United Kingdom, and Australia, as well as contacts and/or smaller groups in many European countries. AISSG maintains an excellent Web site at www.medhelp.org/www/ais that provides a large amount of medical information, AISSG contact points, and patients' accounts of their experiences with AIS. This type of contact can markedly decrease feelings of "freakishness" and "being the only one," which patients and families frequently experience.

Surgical Care

• For individuals with androgen insensitivity syndrome, the standard of care is an orchidectomy to prevent possible malignant degeneration of the testes.⁶ The timing of such surgery has been debated. Historically, early surgery was assumed preferable to avoid raising uncomfortable psychosexual issues during adolescence or young adulthood. More recently, surgery during the late teenage years or early 20s has been preferred. Later orchidectomy allows pubertal development to occur spontaneously with the production of estrogen from the aromatization of the high levels of testosterone normally produced.
• In addition, many women with androgen insensitivity syndrome require vaginal lengthening procedures. Orchidectomy and vaginal lengthening procedures may be performed concurrently if surgery is postponed until the patient matures. Ultrasound examination of the gonads can monitor potential tumor development.
• Vaginal lengthening procedures have stirred ongoing debate. In the past, many vaginal lengthening procedures were performed before or at onset of puberty. Many patient advocates now support delaying these procedures until the patient is sufficiently mature to participate actively in treatment decisions (ie, whether to undergo surgery, what type of procedure).
• Similarly, in female gender patients with partial androgen insensitivity syndrome who have some degree of masculinization of the genitalia at birth, cosmetic reconstructive surgery traditionally has been performed in infancy. Patient advocates, including medical ethicists and intersex advocates, now endorse delaying this reconstructive surgery until children are old enough to decide for themselves. Medical practice and court decisions appear to be moving in this direction as the new standard of care.

Consultations

• Initial consultation for the child with androgen insensitivity syndrome should include a geneticist and a pediatric endocrinologist. These individuals order and interpret the tests required to confirm the diagnosis. Additionally, these clinicians can provide appropriate information about the child's condition. An endocrinologist helps set the future course for medical and surgical therapy.
• Because this is a particularly stressful diagnostic possibility for many families, consult an appropriate mental health professional to provide psychological and emotional support. Part of the mental health professional's role is to facilitate communication between the medical team and the family.

Medication

Hormone replacement therapy (HRT) with estrogens has been the standard of practice for postorchidectomy patients with androgen insensitivity syndrome (AIS). Although most physicians prescribe estrogen alone, some physicians have begun adding progesterone to the regimen, based upon a relatively small amount of data that suggests progesterone may lower the risk of breast cancer, have a role in the ductal development of the breast, or have some role in bone mineral accretion. (These potential benefits are hypothetical.)

Administration of androgens in more masculinized patients with partial androgen insensitivity syndrome (PAIS) has been suggested but remains highly controversial. Because some patients now are assigned male gender and are identifying as males in adulthood, this treatment probably will be described more extensively soon. No data currently describe dosage, administration, benefits, or adverse effects of androgen administration to patients with androgen insensitivity syndrome. Dosage and response likely depends on the severity of the receptor defect. Dihydrotestosterone (DHT) or androgen analogues that cannot be aromatized to estrogen appear to be the treatments of choice.

Estrogens

These agents are used as hormone replacement for women with androgen insensitivity syndrome who are postgonadectomy to support development and maintenance of secondary sexual characteristics and to prevent osteoporosis.

Conjugated estrogens (Premarin)

Represents the average composition of estrogens in pregnant mare urine. Composed of estrone, equilin, 17-alpha estradiol, equilenin, and 17-alpha dihydroequilenin (in small amount). Rapidly biotransformed after administration.

Dosing

Adult

0.3-0.625 mg PO qd
If cycling with progesterone, administer on days 1-21 of cycle

Pediatric

In girls who are orchidectomized prepubertally, start estrogens at lowest available dose, preferably when bone age is at least 13 y
Appropriate beginning dose: 0.3 mg qod; then gradually increase dose to mimic normal female puberty until adult levels achieved

Interactions

May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; increased pharmacologic and toxicologic effects of corticosteroids may occur via inactivation of hepatic P450 enzyme; loss of seizure control has been observed when administered concurrently with hydantoins

Contraindications

Documented hypersensitivity; avoid in patients diagnosed with breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis or thromboembolic disorders, or in patients with history of such disorders with previous estrogen use (except when used in treatment of breast or prostatic malignancy)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause some degree of fluid retention and require careful observation; certain patients may develop undesirable manifestations of excessive estrogenic stimulation

Ethinyl estradiol (Estinyl)

Bioequivalence of various estrogens is quite unclear, but 5-10 mcg of ethinyl estradiol equals approximately 300 mcg of conjugated estrogens in terms of quantifiable metabolic effects on sex hormone binding globulin and gonadotropins.

Dosing

Adult

20 mcg PO qd

Pediatric

20 mcg PO qod

Interactions

May reduce hypoprothrombinemic effect of anticoagulants; coadministration of barbiturates, rifampin, and other agents that induce hepatic microsomal enzymes may reduce estrogen levels; increased pharmacologic and toxicologic effects of corticosteroids may occur via inactivation of hepatic P450 enzyme; loss of seizure control has been observed when administered concurrently with hydantoins

Contraindications

Documented hypersensitivity; avoid in patients diagnosed with breast cancer, undiagnosed abnormal genital bleeding, active thrombophlebitis or thromboembolic disorders, or in patients with history of such disorders with previous estrogen use (except when used in treatment of breast or prostatic malignancy)

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

May cause some degree of fluid retention and require careful observation; certain patients may develop undesirable manifestations of excessive estrogenic stimulation

Follow-up

Further Inpatient Care

• Patients with androgen insensitivity syndrome (AIS) require further inpatient care only for postoperative management.

Further Outpatient Care

• Outpatient follow-up medical care for patients with androgen insensitivity syndrome focuses on hormone replacement therapy (HRT). Appropriate continued treatment with estrogen is required to prevent osteoporosis. Perform assessments of bone mineral density every few years to ensure treatment is adequate.
• Many patients may require ongoing long-term psychotherapy to resolve psychosexual identity issues raised by the diagnosis of androgen insensitivity syndrome. Therapy should be provided on a continuing or recurrent basis for the patient and family, beginning at the time of diagnosis. A helpful resource is the Handbook for Parents written by the Consortium on the Management of Disorders of Sexual Development.⁷

Deterrence/Prevention

• Androgen insensitivity syndrome prevention revolves around the identification of women who may carry the gene.
• Provide appropriate nondirective counseling, including information about the condition and the woman's risk of having an affected child, so that she can make an informed decision about whether to have children.

Complications

• Osteoporosis and psychological sequelae are the 2 major complications of androgen insensitivity syndrome, and their risk can be decreased significantly by appropriate therapeutic intervention. These interventions involve HRT with estrogen to prevent osteoporosis and early and continuing involvement with an appropriate mental health professional for psychological and emotional support.

Prognosis

• The medical and psychological prognosis for a woman with androgen insensitivity syndrome is excellent if she has appropriate support and counseling.

Patient Education

• Educate patients and families about the full nature of androgen insensitivity syndrome. Information for children can be provided in an age-appropriate format, taking care to be as accurate and understandable as possible.
• As the child matures, education should include information about issues such as vaginal hypoplasia and osteoporosis. Encourage patient participation in decisions about medical and surgical alternatives.
• Patient-oriented educational materials are available through the AISSG Web site.⁸

Miscellaneous

Medicolegal Pitfalls

• Legal challenges to the management of patients with complete androgen insensitivity syndrome (CAIS) have not been a problem to date, and such management appears to have little likelihood of becoming a legal problem. However, in partial androgen insensitivity syndrome (PAIS) cases, intersex activists are pursuing the possibility of suing physicians who perform early genitoplasty. Legal challenges appear likely in cases involving demonstrable loss of sexual function or in which the adult gender identity conflicts with the surgically created sex. Physicians providing care for children with partial androgen insensitivity syndrome and genital ambiguity should be aware of this possibility, although enlightened management should lead to outcomes that make lawsuits unlikely.
• In March 2006, androgen insensitivity syndrome (AIS) was given its own IDC code: 259.5. This change seems small but represents recognition by the medical community of the unique blend of issues that patients with androgen insensitivity syndrome represent.

Special Concerns

• In addition to osteoporosis and gender identity issues, women with AIS consistently mention a further concern about their medical care. These women often describe medical visits as traumatic experiences; consequently, they often avoid medical care, including HRT. These issues relate to the relative rarity of their condition as follows:
  • First, these women find that physicians and staff frequently are unfamiliar with AIS, resulting in repeated questioning about the nature of their condition that start at the registration desk. Many of these women feel frustrated and embarrassed by being required to explain the diagnosis to a stranger in such a public place as the registration desk in an office waiting room, only to have to explain it again to the nurse and sometimes yet again to the physician.
  • Second, patients who are seen in a teaching facility often find multiple students or residents participating in their visit, particularly during the genital examination. Group examinations become a problem for the teaching environment because they increase the woman's feeling of being "part of a freak show" and create attendant embarrassment. While students need to be exposed to these conditions and learn about them, the patient's feelings and sense of privacy, even in childhood, must be protected.
• A healthcare provider who is an AISSG member suggests (1) involving only a single trainee in any visit, (2) obtaining the patient's permission for the trainee's involvement before the start of the visit, and (3) giving the trainee time to get to know the patient as a person before any examination, a process that can be combined with obtaining the patient's history. At all costs, avoid group showings of the patient's genitalia, regardless of the patient's age.

Multimedia

Media file 1: Penoscrotal hypospadias is shown. Note the associated ventral chordee and true urethral meatus located at the scrotal level.

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Keywords

androgen insensitivity syndrome, AIS, complete androgen insensitivity syndrome, CAIS, partial androgen insensitivity syndrome, PAIS, testicular feminization, androgen receptor deficiency, androgen resistance syndrome, feminizing testes syndrome, Reifenstein syndrome, Morris syndrome, Goldberg-Maxwell syndrome, hypospadias, clitorimegaly, diminished penile size, gonadoblastoma, hernias, acne, clitoral enlargement, masculinization, treatment, diagnosis

Contributor Information and Disclosures

Author

Bruce E Wilson, MD, Associate Professor, Department of Pediatrics and Human Development, Michigan State University College of Human Medicine at East Lansing
Bruce E Wilson, MD is a member of the following medical societies: American Diabetes Association, Association of Clinical Scientists, Lawson-Wilkins Pediatric Endocrine Society, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology
Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society, Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research
Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds PI, also occasional consultant

CME Editor

Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences
Merrily P M Poth, MD is a member of the following medical societies: American Academy of Pediatrics, Endocrine Society, and Lawson-Wilkins Pediatric Endocrine Society
Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital
Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, and Southern Society for Pediatric Research
Disclosure: Genentech, Inc. Honoraria Speaking and teaching; Pfizer, Inc. Honoraria Consulting

• Relevant clinical guidelines include the following:
  • Androgen therapy in women: An Endocrine Society clinical practice guideline ⁹
  • Micropenis. In: Guidelines on paediatric urology ¹⁰
• Related eMedicine topics include the following:
  • Amenorrhea (Pediatrics: Surgery)
  • Childhood Cancer, Epidemiology
  • Sexuality, Gender Identity

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