Sexual Development and Sexuality William McNett, MD Associate Professor of Pediatrics Jefferson Medical College A.I. duPont Hospital for Children December 15,2015

Clinical Case 3 ½ yr old male is fascinated with Disney Princesses, plays dress up frequently. Physically healthy. Product of a full term, uncomplicated pregnancy Non-verbal gender expression fluctuated between genders At 5 yrs, expresses that God made a mistake and gave her a penis, when will it go away?

Goals and Objectives Understand the development of Sex Characteristics Learn Disorders of Sex Development and Initial Therapeutic Approach Understand gender and sexual orientation development

Goals Know the physical changes associated with puberty (Sexual Maturity Rating) Understand the basis of evaluation and treatment of Disorders of Sex Development Know the basis of gender identity and sexual orientation

Physical Sex Development Embryological Genitalia Brain Development Infant/Childhood Puberty Pre-pubescence Pubescence Post-pubescence

Embryologic Sex differentiation Occurs by 7th week Y chromosome essential for testicular development Wolffian ducts Sertoli Cells: Mullerian Inhibitory Factor Leydig Cells: Testosterone Lack of Y chromosome essential for ovarian development Mullerian ducts develop into uterus and fallopian tubes Female sexual development does not depend on presence of ovaries (default setting)

Embryonic Sex organs Sexual Differentiation of the Brain External sex organs fully formed by 12th week Testes descend from posterior abdominal wall to deep inguinal ring by 28th week Sexual Differentiation of the Brain Occurs after the 20th week of gestation High levels of testosterone in male fetus and continues through first three months of life Combination of genes, sex hormones, and developing brain cells

Undifferentiated Sex Organ gt: genital tuber uf: urogenital fold gs: gonadal sac

Embryonic Male Organ gt: genital tuber (penis) sf: scrotal fold *: urethral groove

Physical sex development: Infant/Childhood External sex characteristics don’t change until pre-pubescence Hypothalamic-pituitary-gonadal axis is dormant Low levels of sex hormones

Puberty: Pre-pubescence Gonadotropin and sex steroids are still low but on the rise Gonadotropin Releasing Hormone (GnRH) stimulates Luteinizing Hormone (LH) which stimulates ovaries or testes Secondary sex characteristics begin to appear Girls: growth spurt begins, pelvic girdle widens, breast start developing, pubic hair begins to appear, axillary hair begins to appear Boys: growth spurt begins, voice begins to change, testicles begin to enlarge, pubic hair begins to appear, axillary hair begins to appear Some behavioral changes

Puberty: Pubescence Reproductive organs become functional Secondary sex characteristics become more apparent and adult Significant behavior changes

Puberty: Post-pubescence Skeletal maturation occurs Males mature slower (18 yrs) then females (15 yrs) Secondary sex characteristics Females: is completed soon after onset of menses Males: hair growth continues: extend up linea alba, beard growth, body hair growth, increase muscle mass through most of teen years

Sexual Maturation Rating Male Genitalia (Tanner Stage) Preadolescent- testes, scrotum, and penis are similar in size to early childhood Stage 2 Testes and scrotum are enlarged, scrotum skin shows change in texture Stage 3 Penis has enlarged, mainly in length, testes and scrotum continue to enlarge Stage 4 Penis is further enlarged in length and breadth with development of glans, scrotal skin becomes darker Stage 5 Penis is adult in size, no further growth occurs

Sexual Maturation Rating Male Pubic Hair (Tanner Stage) Preadolescent, no hair Stage 2 Sparse growth of long, slightly pigmented, straight hair (vellus) above base of penis Stage 3 Hair is darker, coarser, curlier, spreads sparsely over pubis Stage 4 Hair is adult in type but covers less area then an adult Stage 5 Hair is adult type, in inverse triangle, spreads to medial surface of the thighs

Sexual Maturation Rating Female, Breasts (Tanner Stage) Preadolescent, elevation of papilla (nipple) Stage 2 Breast bud stage- elevation of breast and papilla, areolar slightly enlarges Stage 3 Further enlargement of breast and areolar, with no separation of their contours Stage 4 projection of areolar and papilla to form a secondary mound above the level of the breast Stage 5 Mature stage, papilla projection only. Recession of areolar to general contour of breast

Sexual Maturation Rating Female, Pubic Hair (Tanner Stage) Preadolescent, no hair Stage 2 Sparse growth of long, slightly pigmented, straight hair on labia majora Stage 3 Hair is darker, coarser, curlier, spreads sparsely over labia Stage 4 Hair is adult in type but covers less area then an adult Stage 5 Hair is adult type, in inverse triangle, spreads to medial surface of the thighs

Sequence of Development Males (9-17 yrs) Testicular growth Pubarche- onset of pubic hair Penile growth Peak height velocity Females (8-16 yrs) Breast budding Pubarche- onset of pubic hair Peak height velocity Menarche (average age is 12.5, typically when Tanner 4)

Puberty Time Line: Male

Puberty Time Line: Female

Abnormal Sex Development Precocious Puberty Disorders of Sex Development

Precocious Puberty Any pubertal changes if less then 8 yrs in females, 9 yrs in males Types Central resulting in Hypothalamic-pituitary-gonadal axis stimulation (Gonadotropin Releasing Hormone) Starts entire puberty process including maturation of sex organs/fertility Results in short stature due to premature closing of growth plates in long bones Pseudoprecocious puberty- release of sex hormones Premature thelarche (breast development) Premature adrenarche (pubic hair, axillary hair, or body odor)

Precocious Puberty Age 3 11/12 yrs, 5 8/12 yrs, 8 ½ yrs

Causes of Precocious Puberty Central Idiopathic Hypothalamic hemartoma Brain tumor Brain insult: trauma, meningitis, hydrocephalus Hypothyroidism Pseudoprecocious or peripheral idiopathic Sex hormone secreting tumor (adrenals, testes, ovaries) McCune-Albright Syndrome Congenital Adrenal Hyperplasia Exogenous estrogen or testosterone

Treatment of Precocious Puberty Determine and treat underlying cause If idiopathic, use of Gn RH antagonist Desensitizes gonadotropin cells in pituitary Monthly injection, very effective Determine with family when to allow puberty to progress If slow progression, may monitor bone age and allow to progress Assess psycho-social concerns with family

Disorders of Sex Development Potential for mischief at anytime in the embryonic development Nomenclature changes: previously referred to as intersex, hermaphrodite, and ambiguous genitalia Determined by chromosomal analysis Described by chromosome and sex organs ( i.e. ovotesticular 46/XY)

Disorders of Sex Development Clitoromegaly , posterior labial fusion Hypospadias and scrotal fusion

Disorders of Sex Development Penile hypospadias, chordee, and absent testicles Partial androgen insensitivity, 46 XY

Disorders of Sex Development

Classification of DSD

Work up of Infant with DSD Chromosomes Analysis Sex hormone levels are usually not helpful Radiographic- Assessing for sex organs: testes, ovaries, uterus, vagina Ultrasound Abdominal MRI Genitogram (dye study)

Treatment of DSD Challenges Multi-discipline Psycho-social dilemma for families Multi-discipline Pediatrician, endocrinologist, urologist, gynecologist, psychiatrist, family therapist Consider delaying definitive treatment (surgery) Hormone therapy, when reaching puberty

Incompletely Viralized Male, 46 XY 5α-reductase deficiency

Congenital Adrenal Hyperplasia Karyotype 46 XX, elevated 17-Hydroxyprogesterone

Healthy 6 month old infant

Androgen Insensitivity Syndrome, Karyotype 46 XY (Previously called Testicular Feminization)

Sexual Behavior Sex identity Gender identity Anatomy based: Vagina or Penis Gender identity Female or Male Physiology: typically determines gender Culture: system of rules/customs dictates behavior Sexual identity/Orientation Fantasy/Arousal Behavior Culture Developmental Goal To be able to form loving and satisfying sexual relationships that benefit self and partner

Origin of Sexual Orientation and Gender Identification Amount of Testosterone exposure in utero Impact on genitalia development Impact on brain development Threshold necessary in XY to establish attraction to women Illustrated by CAH on XX,46 Physical differences in areas of the hypothalamus Genetic component Twin studies No ‘gay’ gene identified Different models: epigenetic Lack of evidence involving environmental factors

Theoretical model illustrating how fluctuations around an average concentration of testosterone (T) during embryonic life could lead to a homosexual or heterosexual orientation. Theoretical model illustrating how fluctuations around an average concentration of testosterone (T) during embryonic life could lead to a homosexual or heterosexual orientation. Balthazart J Endocrinology 2011;152:2937-2947 ©2011 by Endocrine Society

Gender Identity Disorder Gender evolves from a combination of physiology and culture, but mostly physiology Children learn to master and internalize system Think about accepting androgyny as an alternative to GID

DSM-IV Criteria for GID Strong and persistent cross-gender identification Persistent discomfort with his or her sex or sense of inappropriateness in the gender role of that sex Disturbance is not concurrent with Developmental Sex Disorder Disturbance causes clinically significant distress or impairment in important areas of functioning

Gender Identity Disorder Often onset is during preschool age Is brought to medical attention in early school age Is brought to medical attention when: Parents realize behavior is not transient Becomes source of concern or embarrassment Causes deteriorating social relationships Long term outcomes no data for women 65% identify as gay men,10% transgender, 25% heterosexual Clinical treatment No evidence that actions will alter sex/gender identity pathway Support, foster strengths, model behavior Demystify through discussion: sibs, extended family

Resources Sexual differentiation of the human brain in relation to gender identity and sexual orientation. Savic I, Garcia-Falgueras A, Swaab DF. Prog Brain Res. 2010;186:41-62. Sexual orientation in women with classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal androgen excess. Meyer-Bahlburg H, Dolezal C, Baker S, New M Arch Sex Behav 2008 37: 85-99 Homosexuality via canalized sexual development: A testing protocol for a new epigenetic model. Rice W, Friberg U, Gavrilets S. Bioessays 35: 764-770 Sexual differentiation of the human brain: Relation to gender identity, sexual orientation, and neuropsychiatric disorders. Bao A, Swaab D. Frontiers in Neuroendocrinology 32 (2011) 214-226

Questions

Test Question Sample The following is the TYPICAL sequence for males progressing through puberty: A: breast bud development, axillary hair growth, emotional lability, masturbates 5 times a day B: testes enlargement, pubic hair development, penis length growth, ht growth velocity C: pubic hair development, testes enlargement, ht growth velocity, penis length growth D: testes enlargement, penis length growth, pubic hair development, ht growth velocity

Answer: B

Sequence of Development Males (9-17 yrs) Testicular growth Pubarche Penile growth Peak height velocity Females (8-16 yrs) Breast budding Pubarche Peak height velocity Menarche (average age is 12.5, typically when Tanner 4)

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