sex determination and differentiation. lots to talk about... gender determination gender...

SEX DETERMINATION AND

DIFFERENTIATION

Lots to talk about . . .Lots to talk about . . .

Gender DeterminationGender DeterminationGender DifferentiationGender Differentiation– GonadsGonads– BrainBrain

Gender Differences in the Gender Differences in the HPG axisHPG axis– Menstrual CycleMenstrual Cycle– Male Gonadal Hormone Male Gonadal Hormone

RegulationRegulation

Disorders of Sexual Disorders of Sexual DifferentiationDifferentiation

Sexual DeterminationSexual Determination

Chromosomal sexChromosomal sex: : XXXX XYXY

– Determines Determines gonadal sex gonadal sex – Determines Determines hormonal sexhormonal sex

Gonadal differentiation occurs during the 5Gonadal differentiation occurs during the 5thth and 6 and 6thth weeks of fetal development . . . weeks of fetal development . . .

Sexual DifferentiationSexual Differentiation

A complex process . . .A complex process . . .

fa llop ian tu b escervixu te ru s

M u lle rian d u c t sys tem

L ow es trog en h orm on e sec re tionN o T - fem in iza tion

N o M IH - d em ascu lin iza tion

O vary d eve lop m en tG erm in a l rid g e o f p ro tok id n ey

X X

vas d e fe ren ssem in a l ves ic les

W olffian d u c t sys tem

A n d rog en s & P ep tid es sec re tedT - m ascu lin iza tion

M u lle rian in h ib ito ry h orm on e (M IH )- d e fem in iza tion

Tes tis d eve lop m en tG erm in a l rid g e o f p ro tok id n ey

tes tis d e te rm in a tion fac to r (TD F )X Y

X X / X YS R Y g en e exp ress ion ?

S ex-d e te rm in in g reg ion on th e Y ch rom osom e

Gonadal Development of the EmbryoGonadal Development of the Embryo

Mullerian and Wolffian Duct Mullerian and Wolffian Duct SystemsSystems


A masculine-feminine continuum . . .A masculine-feminine continuum . . .

MasculinizationMasculinization = induction of male traits. = induction of male traits.

DefeminizationDefeminization = removal of the potential for female = removal of the potential for female traits.traits.

FeminizationFeminization = induction of female traits. = induction of female traits.

DemasculinizationDemasculinization = removal of the potential for = removal of the potential for male traits.male traits.


Androgens are responsible for the differentiation of Androgens are responsible for the differentiation of the external genitalia . . . the external genitalia . . .

– AndrogensAndrogens

Testosterone Testosterone 5 5α-reductase α-reductase DHT DHT penis, penis, scrotumscrotum

– No AndrogensNo Androgens clitoris, vaginal labia clitoris, vaginal labia

In the absence of androgens, the “default” gonadal In the absence of androgens, the “default” gonadal development isdevelopment is

Temperature-dependent Sex Temperature-dependent Sex Determination?Determination?

Reptiles & FishReptiles & Fish: Temperature of egg incubation is an important : Temperature of egg incubation is an important factor in determining gender!!factor in determining gender!!

Lizards / AlligatorsLizards / Alligators: Temperatures > 30: Temperatures > 30° C produce males and < ° C produce males and < 28° C produce females in some lizards and alligators!! 28° C produce females in some lizards and alligators!! Temperatures may inactivate enzymes like aromatase and 5α-Temperatures may inactivate enzymes like aromatase and 5α-reductase. reductase.

And humans?And humans? The DMRT1 gene required for male development in The DMRT1 gene required for male development in humans and mice is similar to the mab-3 and doublesex genes of humans and mice is similar to the mab-3 and doublesex genes of animals whose sex is determined by temperature . . . An animals whose sex is determined by temperature . . . An evolutionary link? evolutionary link?

Sexual Differentiation of the Brain

The POTENTIAL for feminine or masculine behavior appears to be organized by early exposure to hormones.

Like the body, the brain is initially programmed to develop in the FEMALE direction.

Sexual Organization of the Brain

GONADS Testosterone

Estrogen

aromatase

Estrogen-receptor

reductase

Dihydrotestosterone

Androgen-receptor

++

Creation of the male rat brain


Gonads Estrogen

EstrogenSequestered by alpha-fetoprotein

Creation of the female rat brain

End-result : Estrogen is removedfrom placenta and metabolized bymaternal liver

Less estrogen to get to brainand defeminize the brain

Female : less testosterone toaccess brain and aromatize to estrogenso again, no possibility of masculinization

Summary: Sexual Organization of the BrainSummary: Sexual Organization of the Brain

Male RatsMale Rats: Testosterone aromatized to estrogen (E) appears to : Testosterone aromatized to estrogen (E) appears to be especially important for masculinizing the male rat brain!!be especially important for masculinizing the male rat brain!!

Female RatsFemale Rats: Exposed to high levels of E from mom’s ovaries : Exposed to high levels of E from mom’s ovaries and own E from fetal ovaries, and own E from fetal ovaries, so why are they not so why are they not masculinizedmasculinized? ?

– Mom has high levels of the carrier protein Mom has high levels of the carrier protein α-fetoproteinα-fetoprotein in in circulation which binds estrogens well, but NOT androgens. circulation which binds estrogens well, but NOT androgens.

– Αlpha-fetoproteinΑlpha-fetoprotein sequesters, or removes, E via the sequesters, or removes, E via the placenta to be metabolized by mom’s liver. It protects the placenta to be metabolized by mom’s liver. It protects the female rat brain from any masculinizing effects of E. female rat brain from any masculinizing effects of E.


GONADS Testosterone Estrogen

EstrogenSequestered in brainby alpha-fetoprotein

Estrogen

aromatasereductase

Dihydrotestosterone

Any dysfunction in genetic and hormonal pathways will lead to problems in sexual differentiation in both animals and humans . . .

GnRH

LH/FSH

Pulsatile Release

Pulsatile Release

Sex Steroids-

-

-

Gender Differences in HPG regulationBack to the axes . . .

Gender Differences in HPG Regulation

Females: Females: CyclicCyclic gonadal function gonadal function– Estrogens and ProgesteroneEstrogens and Progesterone

Males: Males: TonicTonic gonadal function gonadal function– TestosteroneTestosterone

Secretion of Sex Steroids

GnRH

LH/FSH

Pulsatile Release

Pulsatile Release(every 60 mins for humans)

Sex Steroids-

-

-

Females : Steady Increasein Estrogen

How???

+

Surge+

The more estrogen you have, the higher the probability to induce POSITIVE FEEDBACK and surges of GnRH and LH / FSH.

What do you predict?

GnRH

LH/FSH

Sex Steroids-

-

-

+

+OVX + low doses Estrogen

LH

GnRH

OVX + high doses Estrogen

LH

GnRH

Conclusion : High doses of estrogen in females overcomes negative feedback

.. evidence that this only applies to females

GnRH

LH/FSH

Sex Steroids-

-

-

+

+Castration + low doses Estrogen

LH

GnRH

Castration + high doses Estrogen

LH

GnRH

Conclusion : High doses of estrogen in females overcome negative feedback

The Menstrual CycleThe Menstrual Cycle

Amazing Ovarian FunctionAmazing Ovarian Function

1-2 million follicles in each ovary at birth 1-2 million follicles in each ovary at birth only about 400 oogonia (potential ovum) only about 400 oogonia (potential ovum) used during female reproductive lifespan!used during female reproductive lifespan!

Ovulation is a result of a careful Ovulation is a result of a careful orchestration of LH, the FSH:LH ratio, orchestration of LH, the FSH:LH ratio, receptor systems, and the availability of receptor systems, and the availability of estrogens, androgens, plus other estrogens, androgens, plus other neurochemicals (eg., inhibin – a peptide that neurochemicals (eg., inhibin – a peptide that feeds back to inhibit FSH)feeds back to inhibit FSH)

Quick Facts about Ovarian FunctionQuick Facts about Ovarian Function

Follicular PhaseFollicular PhaseFollicular cell Follicular cell – Stimulated by FSHStimulated by FSH– Produces estradiol and Produces estradiol and

other estrogensother estrogensE synthesis hypothesis . . .E synthesis hypothesis . . .– Thecal cells surrounding Thecal cells surrounding

the follicle have LH the follicle have LH receptors and produce receptors and produce androgensandrogens

– Granulosa cells Granulosa cells surrounding the follicle surrounding the follicle have FSH receptors and have FSH receptors and convert androgens to convert androgens to estradiolestradiol

Luteal PhaseLuteal PhaseCorpus LuteumCorpus Luteum– An endocrine glandAn endocrine gland– Produces progesterone Produces progesterone

(and some estrogen)(and some estrogen)– Progesterone suppresses Progesterone suppresses

LH and GnRHLH and GnRH– Progesterone down-Progesterone down-

regulates estradiol regulates estradiol receptorsreceptors

– Capillaries in the Capillaries in the endometrial lining endometrial lining constrict when E and P constrict when E and P rapidly withdraw on days rapidly withdraw on days 27-28, leading to 27-28, leading to menstruation. menstruation.

How about Testicular Function?How about Testicular Function?Testes produce many trillions of spermatozoa in a Testes produce many trillions of spermatozoa in a lifetime!lifetime!

Leydig cells:Leydig cells:– Have LH receptorsHave LH receptors– Produce testosteroneProduce testosterone– Initiate paracrine interactions with seminiferous tubules and Initiate paracrine interactions with seminiferous tubules and

Sertoli cells to influence spermatogenesis.Sertoli cells to influence spermatogenesis.

Sertoli cells:Sertoli cells:– Have FSH receptorsHave FSH receptors– Produce estradiol from testosteroneProduce estradiol from testosterone– Produce proteins like androgen-binding protein, nourish Produce proteins like androgen-binding protein, nourish

developing spermatozoa, phagocytosis of damaged sperm, developing spermatozoa, phagocytosis of damaged sperm, produce sperm transport fluid.produce sperm transport fluid.

The TestisThe Testis

Disorders of Sexual Differentiation

Experiments of nature . . .

HERMAPHRODITE :

A person born with both male and female sex organs. This is a vague, confusing and inaccurate definition. There are 3 labels of Hermaphrodites: True, Male Pseudo and Female Pseudo.

PSEUDOHERMAPHRODITE :

Human babies born with ambiguous genitalia. Usually one set of gonads is present.

http://users.southeast.net/~help/sexdiff.html

Disorders of Sexual DifferentiationDisorders of Sexual Differentiation

TRUE HERMAPHRODITE

A person born with both ovary and testicular tissue, this could be 2 separate gonads ( one of each) or a combination of both in one (an ovotestes).

The chromosome compliment can be XX (female), XY (male), XX/XY (mosaic) or even XO (extremely rare). Those XX with female genitalia are raised female (some have even given birth). Those XY with male genitalia are raised male ( a few have fathered children). The children born XX/XY or XO (with genitalia male or female are raised in the sex they look most like). Those born with ambiguous genitalia have many medical tests for the doctors to determine which sex they should be assigned. Doctors then recommend early surgery to make the child look physically like the sex assigned to them.

CAUSES: The causes are not known, The medical community does know this is a very rare condition but do not have accurate figures to how many people have this condition (depending on the literature between 350-450 known cases).

2. FEMALE PSEUDOA person born XX with normal female internal organs but with "masculinized" genitalia. They can appear more male than female or a combination of each.

CAUSESThe most common is Congenital Adrenal Hyperplasia (CAH) it occurs approximately 1:14,000 births.This is when the adrenal glands overproduce testosterone. It also has been recorded that some persons with this disorder had been exposed to progesterone-like drugs before they were born (diethylstilbestrol and medroxyprogesterone acetate used to maintain pregnancies).


No cure as of today,but treatment is available (cortisol).

3. MALE PSEUDO

A person born XY with testes (usually in the abdominal cavity). The external genitalia are usually female but can be ambiguous.

CAUSES

The most common cause is Androgen Insensitivity Syndrome (AIS). This is when the body doesn't respond to the androgen being produced because the androgen receptors do not function. There are different variations: Complete (CAIS) , and Partial (PAIS). This condition has a variety of names and occurrence rates.



Another related syndrome : Turner Syndrome

A disorder in women caused by an inherited chromosomal defect. This disorder inhibits sexual development and causes infertility. Ovarian development is impaired, preventing gonadal estrogen and androgen production!!

Cause : Abnormality in or absence of the second X chromosome.

It affects 1 out of 3,000 live births. There are many manifestations of this syndrome:-Short Stature-Webbing of the skin of the neck-Absent or retarded development of secondary sexual characteristics-Absence of menstruation

Gender Dimorphism in Cognitive Gender Dimorphism in Cognitive FunctionFunction

Female Advantages:Verbal tasks

Perceptual Skills

Fine Motor Skills

Mathematical Calculation

Male Advantages: Quantitative tasks

Directed Motor Skills

Visuospatial Abilities

Mathematical Reasoning

TS Cognitive Findings . . .TS Cognitive Findings . . .

Normal verbal skills

Impaired visual-spatial ability

Impaired visual-perceptual ability

Nonverbal memory < Verbal memory

Impaired on attention tasks

Impaired on tests of arithmetic

Impaired on tests of motor function

A unique sex hormone-deficient model that can be be used to investigate hormone effects on cognition.

Estrogen Treatment for TS GirlsEstrogen Treatment for TS Girls . . . . . .Ross et al., 2000

Double-blind, placebo Double-blind, placebo controlled study:controlled study:

29 children (7-9 years)

placebo estrogenGH GH / Econtrols

RESULTS:

Controls > Estrogen-treated girls > Placebo girls on recall of word lists (verbal memory) . . . But only the difference between normal controls and placebo girls was significant; also small sample size, low E-dose . . .

Androgen Treatment for TS Girls . . .Androgen Treatment for TS Girls . . .Ross et al., 2003

Double-blind, placebo controlled Double-blind, placebo controlled study:study:

51 children (10-14 years)

placebo/GH

Oxandrolone / GH(androgen that does not aromatize to estrogen)

controls

RESULTS:

Androgen group > placebo on tests of working memory over two years of treatment.

No differences on tests of verbal ability, spatial cognition, and executive function.

BUT, effects of GH? practice effects of testing twice? . . .

Other Clinical Neuroendocrine Other Clinical Neuroendocrine ModelsModels

PCOS (Polycystic Ovary Syndrome)PCOS (Polycystic Ovary Syndrome)

Transsexual studies . . .Transsexual studies . . .

The ENDThe END

sex determination and differentiation. lots to talk about... gender determination gender...

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