Genetics of Human Sexual Development

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#evels of Sexual Development

$ %!ere are & levels to sexual development' ( chromosomal sex' presence or absence of t!e ) c!romosome ( gonadal sex *primary sex determination+' w!et!er t!e gonads develop as testes or ovaries depends on t!e presence or absence of t!e S,) gene usually found on t!e ) c!romsome ( phenotypic sex *secondary sex determination+' all of t!e internal and external structures develop along male or female lines depending on w!ic! !ormones are secreted by t!e gonads" $ -!enotypic sex also !as a couple of distinct systems' t!e internal ducts and t!e external genitalia $ %wo important times' pre-natal development and puberty

.!romosomal Sex Determination

$ $ We !ave /0 c!romosomes' 1& pairs one set from eac! parent" 2ne pair of c!romosomes is t!e sex c!romosomes 3 and )"
( t!e ot!er c!romosomes 4ust !ave numbers' 5-11"

6 person wit! 1 3 c!romosomes */0 33+ is female and a person wit! an 3 and a ) */0 3)+ is male"

Human 7aryotype' c!romsomes stained to s!ow bands from a male

8eiosis
$ ,eproduction involves putting one copy of eac! c!romosome into eac! sperm cell or egg cell' t!e process of meiosis" So meiosis starts wit! /0 c!romosomes c!ooses one from eac! pair and puts 1& c!romosomes in eac! sperm or egg"
( 9or males 5:1 t!e sperm get an 3 c!romosome and t!e ot!er 5:1 get a ) c!romosome"

Sometimes meiosis goes wrong *non-dis4unction+ and a sperm or egg mig!t get 1 sex c!romosomes or ; sex c!romosomes leading people wit! /< or /= c!romosomes" 8ore on t!is later"""

9ertili>ation
$ 9ertili>ation means t!e sperm 4oins t!e egg creating t!e >ygote w!ic! is t!e first cell of t!e new individual person"
( 1& c!romosomes from sperm plus 1& from t!e egg restores t!e total of /0 c!romosomes" ( 6nd t!e new individual is now eit!er /0 33 *female+ or /0 3) *male+

%!e S,) Gene

$ $ How t!e ) c!romosome determines sex" %!e S,) gene located on t!e ) c!romosome is t!e primary determinant of sexual development"
( %!at is if a developing embryo !as a functional S,) gene in its cells it will develop as a male" 6nd if t!ere is no functional S,) t!e embryo develops as female"

6lt!oug! t!e S,) gene is usually on t!e ) c!romosome it occasionally gets transferred to t!e 3"
( t!is leads to /0 33 males

6lso sometimes t!e S,) gene is inactivated by mutation"

( #eading to /0 3) females *Swyer syndrome+ ( it is also possible to !ave a partially inactive S,) gene leading to ambiguous genitalia

?arly Gonad Development

$ @efore 0-< wee7s of development t!e gonad is indifferent' neit!er male nor female" It develops from t!e same tissue as t!e 7idneys and adrenal glands" 6lso developing by t!is time' 1 sets of ducts t!at will eventually lead to t!e outside world" ( Wolffian ducts A male ( 8ullerian ducts A female

Gonad Differentiation
$ If S,) is present in t!e indifferent gonad at 0 wee7s it gets activated" %!is in turn activates ot!er genes and t!e indifferent gonad is converted to a testes" In t!e absence of S,) a different set of genes is activated and t!e indifferent gonad becomes an ovary" %!e germ cells w!ic! actually become sperm or eggs migrate into t!e gonad about t!is time"

Development of -!enotypic Sex

$ %!e cells of t!e newly formed testes start secreting t!e !ormone testosterone"
( %estosterone secretion pea7s about wee7 50 wit! levels similar to t!ose found in adult males" 6fter t!is t!e testosterone level drops to about t!e same level as female fetuses" ( %!e testes also secrete anot!er !ormone' 8ullerian in!ibiting substance *8IS+ *a7a anti-8ullerian !ormone 68H+"

$ 6not!er important process in t!e developing male' during t!e last trimester of pre-natal life t!e testes migrate *BdescendC+ from t!e 7idney region into t!e scrotum"
( Dnder t!e control of a t!ird testes !ormone' Binsulin-li7e !ormone &C

$ %!e developing ovary secretes estrogen w!ic! is important after birt! but estrogen from t!e mot!er completely swamps it out before birt!"

In t!e early embryo two duct systems form" 6fter t!e gonad differentiates into a testis or ovary one set of ducts develops furt!er w!ile t!e ot!er set degenerates" %estosterone causes t!e Wolffian ducts to develop into male structures' epididymus vas deferens seminal vesicles"
( In t!e absence of testosterone t!e Wolffian ducts disappear *except a bit becomes t!e adrenal glands in bot! sexes+

Internal Ducts

8ullerian in!ibiting substance causes t!e 8ulerian ducts to disappear" ( In t!e absence of 8IS t!e 8ullerian ducts develop into t!e 9allopian tubes uterus and upper vagina"

6not!er Duct -icture

Development of t!e ?xternal Genitalia

$ %!is process is controlled by t!e presence or absence of di!ydrotestosterone *DH%+"
$ %estosterone gets converted into DH% by t!e en>yme =-alp!a reductase w!ic! is found in t!e testes and t!e s7in" @ot! sexes start out wit! t!e same structures w!ic! develop along different lines under t!e influence of testosterone and DH%" %!e default condition in female' in t!e absence of DH% t!e external genital structures develop along female lines" DH% also causes !air loss' male pattern baldness" %estosterone is converted to DH% locally" ,ogaine wor7s by bloc7ing =-alp!a reductase

In t!e absence of DH% t!e genital swellings form t!e labia ma4oraE t!e genital folds remain unfused and form t!e labia minoraE t!e genital tubercle forms t!e clitoris and t!e urogenital sinus forms t!e lower part of t!e vagina" Wit! DH% present t!e genital swellings migrate and become t!e scrotumE t!e urogenital folds enlarge and enclose t!e penile uret!ra and become t!e s!aft of t!e penisE t!e genital tubercle becomes t!e glans penisE and t!e urogenital sinus forms t!e prostate gland

?xternal Development

Side Fiew

.!ild!ood and -uberty

$ During c!ild!ood sex !ormone levels are very low in bot! sexes"
( %!ere is a surge of sex !ormones in bot! boys and girls for a few wee7s 4ust after birt!" Significance is un7nown"

-uberty begins w!en t!e brain and !ypot!alamus start producing t!e neuro!ormone Gn,H *gonadotropin releasing !ormone+" %!is !ormone t!en stimulates production of #H and 9SH by t!e pituitary gland" #H and 9SH stimulate t!e testes and ovaries to start producing large amounts of testosterone and estradiol *a form of estrogen+"
( In boys some of t!e testosterone is converted to estradiol w!ic! causes a growt! spurt and sometimes leads to temporary breast development"

%!e adrenal glands also secrete male sex !ormones in bot! boys and girls starting in late c!ild!ood"
( 6fter puberty starts t!e ovaries also produce androgens"

,eview of Gormal Sexual Development

$ %!e default condition is female" 8ale development occurs only w!en t!e S,) gene *on t!e ) c!romosome+ is present"
( %!e primary sex organ t!e gonad becomes an ovary in t!e absence of S,) and a testis in t!e presence of S,)"

$ $

%!e testes secrete two !ormones' testosterone and 8ullerian-in!ibiting substance" %!ese control t!e development of t!e internal reproductive ducts" %wo duct systems are present in t!e embryo' Wolffian and 8ullerian
( In males testosterone causes t!e Wolffian ducts to develop into t!e vas deferens seminal vesicles and epididymus" 6lso in males 8IS causes t!e 8ullerian ducts to degenerate" ( In females t!e absence of 8IS causes t!e 8ullerian ducts to develop into t!e fallopian tubes uterus and upper vagina" %!e absence of testosterone causes t!e Wolffian ducts to degenerate"

$ $

%!e external genitalia develop in t!e male pattern if di!ydrotestosterone *DH%+ is present" 9emale genitalia develop in t!e absence of DH%" Fery little c!ange occurs in c!ild!ood but puberty brings a big surge in sex !ormones w!ic! modify t!e structures formed before birt!"

Fariant .onditions
$ %!e large ma4ority of people develop as eit!er completely male or completely female" However 5H or more of t!e population !as some variant condition"
( ( ( .!romosomal variations Gene mutations ?xternal conditions

6 few important terms'

( Gynecomastia' development of breasts in a male ( Hypospadias' t!e uret!ra exits t!e male body at t!e base of t!e penis instead of at t!e tip due to failure of t!e uret!ra to become enclosed by t!e urogenital folds" ( Hermap!rodite' a person ex!ibiting bot! male and female c!aracteristics $ a true !ermap!rodite !as bot! testicular and ovarian tissue sometimes as separate organs but more frequently as an ovotestis' a single organ wit! different parts" Fery rare" $ 8ale pseudo-!ermap!rodite !as testes and no ovariesE a female pseudo-!ermap!rodite !as ovaries and no testes" ( Worth noting' t!e Intersex Society of Gort! 6merica finds t!e term B!ermap!roditeC offensive and prefers BintersexC"

.!romosomal Fariants
$ $ 8eiosis t!e form of cell division t!at generates t!e sperm and eggs carefully puts exactly 5 copy of eac! c!romosome pair into eac! cell" Sometimes meiosis goes wrong and puts ; or 1 copies of some c!romosome into a sperm or egg cell"
( t!e best example of t!is' Down syndrome w!ic! starts wit! a sperm or egg wit! 1 copies of c!romosome 15" ( 8aternal age effect' more frequent in older mot!ers

$ $ $

%!e sex c!romosomes are quite tolerant of variants" 8ost common types involve /= or /< c!romosomes %!ere are many ot!er rarer types wit! /I or even /J c!romosomes suc! as /J 3333)" Suc! conditions almost always lead to serious mental deficiencies" The general rule: if the Y is present, the person is internally and externally male.

Klinefelter Syndrome' /< 33)

$ $ 2ccurs about 5 per =;; male birt!s" It is t!e most common type of sex c!romosome variant" %!e presence of t!e ) c!romosome causes a /< 33) person to be male bot! externally and internally because t!e testes are formed" ,oot symptom' small testes leading to low testosterone levels" 8ost but not all are sterile" 6t puberty reduced facial and body !air broader !ips breast development" /< 33) c!ildren tend to be taller less p!ysically strong and coordinated and more quiet and s!yer t!an t!eir peers" Some language and learning problems are common' often slow to learn to spea7 and read" %estosterone replacement t!erapy !elps wit! some of t!e p!ysical symptoms" Speec! t!erapy and educational services also !elp" /0 33 males wit! t!e S,) gene on t!e 3 !ave t!e Klinefelter appearance"

$ $ $

%urner Syndrome' /= 3
$ $ 2nly one 3 c!romosome sometimes called 32" Since t!ere is no ) c!romosome t!e primary gonad is t!e ovary and /= 3 people are female" 6bout 5 in 1=;; live female birt!s"
( 5;H of all spontaneous abortions *miscarriages+ are due to %urner syndromeE about JIH of all %urnerLs embryos die before birt!

2varies completely non-functional so /= 3 women are sterile wit! no production of sex !ormones and development of secondary sexual c!aracteristics at puberty" Some c!aracteristic p!ysical abnormalities' s!ort stature low !airline webbed s7in at nec7" Kidney and circulatory system problems 2ften !ave problems wit! spatial reasoning and mat!ematics" 6lso social difficulties' inability to understand ot!ersL emotions" .an be treated wit! growt! !ormone and estrogen"
)ou need 1 3 c!romosomes for proper ovarian development" /0 3) females *non-functional S,)gene+ resemble %urnerLs

/< 3))
$ $ $ 6bout 5 in 5;;; live male birt!s" 8ost 3))Ls are never detected' a very mild condition" since 5J0; newly discovered c!romosome variants arenLt given t!e discovererLs name It was once t!oug!t to create !yper-aggressive males wit! a tendency towards criminal be!avior" ( ,ic!ard Spec7 t!e 7iller of eig!t student nurses in 5J00 pretended *falsely+ to be an 3)) to obtain leniency" ( 6 5J0I letter to t!e Lancet claimed t!at 3)) men were in prison at a rate M1=-0; times as !ig! as t!e prevalence in t!e general populationC based on finding 1 3))Ls" ( t!e plot of 6liens & involves a prison planet for 3))Ls" 3))Ls are generally normal in appearance but wit! average !eig!t about < cm above expected and normal build" -er!aps acne is more common t!an average but t!is is disputed" %!ey are often more p!ysically active somew!at delayed in emotional maturity and !ave a slig!t increase in learning and speec! problems" 9ertile normal sex drive very rarely pass 1 )Ls to sons"

5J<;Ls @ritis! %F series' He !ad an extra ) w!ic! made !im a mac!o criminal!

/< 333
$ 6bout 5 in 5;;; live female birt!s" So mild as to be only rarely detected" 6lso called triplo-3" 2riginally called BsuperfemaleC *early 5J0;Ls+" Nrolls eyesO Widely varying symptoms including none at all" Slig!tly more passive and quiet as babies less assertive delayed motor and linguistic s7ills" Delayed emotional maturity and social s7ills" Some !ave slig!tly decreased intelligence and learning difficulties" #ower bac7 problems are common" 9ertility normal donLt generally pass 1 3Ls to c!ildren" $ $ $

@ot! terms refer to people w!o !ave 1 different c!romosome sets in different cells" 9or example a /0 33:/< 33) person !as some cells wit! /0 c!romosomes and ot!er cells wit! /<" 6 mosaic starts out wit! a single fertili>ed egg" During an early cell division in t!e embryo one cell gained or lost a c!romosome" *%!is is non-dis4unction t!e same event t!at !appens in meiosis to generate KlinefelterLs etc"+ 6 chimera starts out wit! two separate fertili>ed eggs fraternal twins" %!e two embryos fuse toget!er to form a single individual" ( It is not uncommon to !ave fraternal twins s!aring some blood cells a Bblood c!imeraC ( fused embryo c!imeras are very rare' t!ere are about &;-/; 7nown 33:3) c!imeras *and undoubtedly an equal number same sex c!imeras+" Btetragametic c!imeraC ( .!imerism is probably t!e way most true !ermap!rodites w!o !ave bot! ovarian and testicular tissue are formed" However actual 33:3) c!imeras !ave been everyt!ing from normal male t!roug! various degrees of ambiguous genitalia to normal female" Sexual development can be quite variable in suc! people because t!e c!aracteristics depend on w!ic! cells !ave w!ic! c!romosome complement"

8osaics and .!imeras

Gene 8utations
$ %!e variants up to now all involve w!ole c!romosomes w!ic! !ave lots of genes on t!em" %!e effects of c!anging t!e dosage of many genes tend to be widespread but mild" *or completely let!al as wit! most non-sex c!romosomes+" Gow we are going to loo7 at several gene mutations" In t!ese cases only one gene is affected but it is completely 7noc7ed out" %!is can lead to large effects but limited to a few subsystems in t!e body" ,ates are different' for c!romosome c!anges about 5 in 5;;; birt!s is a typical frequency" 9or gene mutations eac! parent needs to contribute a mutated copy of t!e gene so rates are usually 5 in 5; ;;; birt!s or less" In!eritance is also a factor !ere' most c!romosomal variants are spontaneous events and donLt run in families" Gene mutations are usually in!erited variants' t!ere is often a family:community !istory of t!e variant type"
( Gew mutations do occur spontaneously but itLs rare" 8ost gene variants are in!erited from t!e parents"

=-alp!a ,eductase Deficiency *=-6,D+

$ =-alp!a reductase is t!e en>yme t!at converts testosterone into DH%" If bot! copies of t!e gene t!at ma7es t!is en>yme are defective t!e person !as =-6,D" ( ,ecall t!at DH% is responsible for t!e development of male external genitalia 6t birt! people wit! =-6,D !ave undescended testes and male ducts *wit! no female ducts+ but genitalia t!at appear somew!ere between female and ambiguous including a a very small penis wit! !ypospadias *w!ic! appears to be an enlarged clitoris+ and a s!ort vagina" 2ften raised as girls 6t puberty t!e increase in testosterone is large enoug! t!at some DH% gets made and t!ey develop a male appearance' t!e testes descend t!e penis enlarges facial !air appears t!e voice deepens muscles develop" #arge group in t!e Dominican ,epublic' maybe 5 in J; men" .alled Guevedoces a corruption of B!uevos a los doceC *eggs-testicles- at age 51+" ,aised as girls t!ey easily switc! to t!e male role" ( 2t!er groups found in 8alta Pordan -a7istan Gew Guinea
6lso a c!aracter on t!e %F s!ow Nip and Tuck !as t!is condition

Guevodoces .ase

6ndrogen Insensitivity
$ $ Incidence about 5 in 1; ;;; birt!s Dsed to be called Btesticular femini>ationC" /0 3) wit! normal *undescended+ testes" %!e testes secrete testosterone but t!e cells lac7 a receptor for it" Go receptor A no response to t!e !ormone" .omplete androgen insensitivity .6IS" 6s a result t!e male ducts *vas deferens epididymus seminal vesicles+ are not present" However t!e testes secrete 8IS w!ic! causes t!e female ducts *uterus fallopian tubes upper vagina+ to degenerate"

?xternal genitalia develop as male if DH% is present but testosterone and DH% use t!e same receptor" So female external genitalia including t!e lower 1:& of t!e vagina"
6t puberty t!e testes again secrete testosterone" %!e en>yme aromatase converts it into estradiol" %!us female secondary sexual c!aracteristics develop" 2ften Bvoluptuously feminineC" Go menstruation of course' no ovaries and no uterus" -ubic and armpit !air is usually scant or absent"
( 2ccasionally t!e undescended testes can become cancerous so t!ey are often surgically removed after puberty is complete *so as to get normal female development+"

-artial 6ndrogen Insensitivity

$ Sometimes t!e testosterone receptors wor7 inefficiently due to less drastic mutations t!an in .6IS" In t!ese cases t!e body cells respond in a variable manner to testosterone leading a a wide variety of ambiguous genitalia" -6IS A partial androgen insensitivity" 6lso called ,eifenstein syndrome"
( t!ere is also mild androgen insensitivity *86IS+ w!ic! leads to completely male appearance internally and externally but wit! some impairment of masculini>ation at puberty"

$ $

Fariable symptoms' can be predominantly male *wit! !ypospadia abnormal scrotum small penis+ predominantly female *wit! enlarged clitoris fused labia separate vaginal and uret!ral openings+ or ambiguous genitalia *microp!allus--less t!an 5 cm long+ labia-li7e scrotum !ypospadia gynecomastia" Similar variability in male internal ductsE females ducts are usually absent due to 8IS secretion" Sometimes people wit! -6IS c!ange gender identity after puberty in eit!er direction"

.ongenital 6drenal Hyperplasia

$ $ %!e adrenal glands sit on top of t!e 7idneys and secrete a variety of steroid !ormones including cortisone *stress response+ aldosterone *salt balance+ and androgens *male sex !ormones+" Steroid !ormones are made from c!olesterol t!roug! a series of bioc!emical steps" 6ny one of t!ese steps can be inactivated by mutation" However about J=H of .6H cases involve defects in t!e en>yme 21-hydroxylase" 15-!ydroxylase is needed to ma7e cortisol and aldosterone *but not androgens+" .ortisol is secreted in response to t!e pituitary !ormone 6.%H in a feedbac7 loop" So if t!ere isnLt enoug! cortisol being made more 6.%H is made and t!is causes t!e adrenal gland to grow larger *!yperplasia+" 6nd all of t!ose steroid molecules t!at were destined to become cortisol and aldosterone get diverted into male sex !ormones *androstendione and testosterone+ w!ic! donLt need t!e 15!ydroxylase" Fery little effect on male fetus w!ic! is already ma7ing testosterone except t!at after birt! t!e lac7 of salt regulation can lead to deat! from excess salt secretion *salt-wasting+"

9emale fetuses wit! 15-!ydroxlase deficiency !ave some problems due to t!e flood of androgens released by t!e adrenal gland" %!e ovaries are normal and t!e female *8ullerian+ ducts are also normal *since no 8IS is made+" 8ain effects are on t!e external genitalia' enlarged clitoris sometimes wit! an enclosed uret!ra *i"e" li7e t!e penis+ labia can fuse and become scrotum-li7e vaginal opening can be partly or completely closed" 6ppearance at birt! varies a lot" Some appear to be normal male wit! undescended *because non-existent+ testes" However t!e c!romosomes are 33 t!e gonads are ovaries and t!e uterus and fallopian tubes are usually intact" Gormally very little androgen is made in c!ild!ood" .6H causes excess androgens t!roug!out life leading to rapid growt! but an early closure of t!e bone growt! plates' a very s!ort adult" 6lso' early puberty wit! menstrual problems *and poor sperm production in males+" %!e ot!er !ormones aldosterone and cortisol need to be replaced" %!e cortisol replacement calms t!e 6.%H activity leading to less androgen production"

.6H

.6H is t!e most frequent cause of non-standard genitals in genetically female *33+ c!ildren"

Some ?nvironmental .auses

$ Progestin-induced irili!ation" -rogestin was used to prevent miscarriages in t!e 5J=;Ls and 0;Ls" ,elated to t!is is t!e use of androgens to treat endometriosis during t!at time period and occasional accidental use of androgens" 50; 7nown cases"
( 33 fetuses develop as normal females wit! functioning ovaries but t!ey may develop some male secondary c!aracteristics and often !ave enlarged clitorises" ?ffects are very similar to .6H"

"reemartin' usually seen in cattle' female and male twins wit! testosterone from male lea7ing over to t!e female due to a s!ared placenta" Gormal female appearance but undeveloped ovaries and masculini>ed be!avior" ,are or un7nown in !umans" ( 6ldous HuxleyLs boo7 @rave Gew World !as !uman freemartins created by !ormone treatment of fetuses"

6nd #ots 8oreQ

$ We !ave covered t!e main causes of variation in !uman biological sex" However t!ere are many ot!er rarer conditions t!at also affect t!is" $ 6s always wit! biology t!ere are exceptions to every rule exceptions to everyt!ing I said !ere today" $ W!at any individual feels about t!eir body and !ow society reacts to t!ese variations is more a matter for psyc!ology and sociology t!an for biology"