BMSN2202 - Life Science II

(Physiology & Biochemistry)

Sex determination, Puberty and
Menopause
Calvin KF Lee
L7-49, Laboratory Bock, FOMB
Obstetrics and Gynaecology
Email: ckflee@hku.hk
 Outline
1. List several sex determination systems
2. State the functional roles of Sry gene on sex
determination
3. Describe the developmental changes of
Wolffian and Mullerian ducts
4. Describe the abnormalies in male and female
during sexual differentiation
5. List the changes during puberty in male and
female
6. Describe the role of Estrogen in menopausal
women
1. Human sex
Chromosomal Sex (genetic)
Presence or absence of Y chromosome
Gonadal Sex (1o Sex Determination)
Controlled by presence or absence of testis
determining factor (TDF)
Phenotypic Sex (2o Sex Differentiation)
Determined by the hormonal products
produced by the gonads
1. Sex-determination systems
XX/XY sex-determination system (most
mammals, 23 pairs in humans)
Females (XX), males (XY)
XX/X0 sex determination (some insects)
Females (XX), males (X0), 0 denotes the absence of
a second sex chromosome
ZW sex-determination system (birds, reptiles
and some insects) - reversed compared to the
XY system homo/hetero-zaygous

Females (ZW), males (ZZ)

1. Non-genetic sex-
determination systems
Temperature-dependent sex
determination (some reptiles)
Do not have the SRY gene, but genes such
as DAX1, DMRT1, and SOX9 are expressed
or not expressed depending on the
temperature
Other sex determination systems (fish)
The dominant individual in a group becomes
female while the other ones are male
(chemical effect?)
1. Sex chromatin
All mammalian Females are homogametic
Human oocytes carry 22 autosomes and X
chromosome (22X)
Mammalian embryos of both sexes are
bathed in relatively large amounts of
placental estrogen (E2) during development
Represent the default pathway in sexual
differentiation
 SRY
gene

1. Sex chromatin
Y
All mammalian Males are heterogametic
Human sperms with both 22X and 22Y
Male are considered the differentiated
phenotypic sex
Y chromosome - carries Sex-determining
Region of the Y chromosome (SRY)
Without the presence of SRY, a fetus will
develop into female phenotypic pathway
2. Gonadal differentiation
Begins at the 4th embryonic (6th menstrual)
week
Migration of primordial germ cells from
yolk sac

4th week
2. SRY gene
Intronless gene
protein that binds to DNA for transcription

SRY is a transcription factor

Member of the high mobility group (HMG)-
box family of DNA-binding proteins
Initiates male sex determination
Mutations in this gene give rise to XY
females with gonadal dysgenesis (Swyer
syndrome) hypogonadism
2. SRY activation
The Primordial gonad in the urogenital ridge are
in a bipotential state
SRY up-regulates SOX9, SOX9 in turn up-
regulates fibroblast growth factor 9 (Fgf9) for
Sertoli cell differentiation
Fgf9 then up-regulates SOX9 by positive
feedback; SOX9 can also up-regulate itself by
binding to its own enhancer region
The bipotential cells of the gonad begin to
differentiate into Sertoli cells; cells expressing
SRY will continue to proliferate to form the
primordial testis
2. Mouse Gonad development

Menke et al., 2003 Dev Biol

 M
#3 Mullerian duct Regression at week 8 caused by AMH from sertoli cells
Wolffian duct Development at week 8 caused by testosterone from leydig cells

3. Ductal Differentiation
Mullerian duct
F
Development at week 6
Wolffian duct Regression at week 10
Testis
SRY gene determining
factor gonad
mesonephros
Mullerian duct
Bipotential
gonad Wolffian duct
Y

Male Anti-mullerian Female

hormone from Sertoli cell

suppress the development of Wolffian duct

Testosterone

DHT
Regression of Mullerian duct Regression of Wolffian duct
3. Ductal Differentiation
Ductal systems are bipotential
Male
Sertoli cells produces Mullerian inhibiting hormone
(anti-Mullerian hormone, AMH) -> atrophy of the
Mullerian ducts
Leydig cells secrete testosterone -> Wolffian ducts
develop -> epididymis, seminal vesicles and ductus
deferens
Removal of testis from developing fetus:
Mullerian ducts develop & Wolffian ducts wither
 3. Human prenatal sexual
differentiation Fetal age
Weeks Crown-rump length Sex differentiating events
(mm)
0 blastocyst Inactivation of one X chromosome
4 2-3 Development of wolffian ducts
5 7 Migration of primordial germ cells in the undifferentiated gonad
6 10-15 Development of mllerian ducts
8 30 Regression of mllerian ducts in male fetus
8 32-35 Appearance of Leydig cells. First synthesis of testosterone
9 43 Total regression of mllerian ducts. Loss of sensitivity of mllerian ducts in the
female fetus
9 43 First meiotic prophase in oogonia
10 43-45 Beginning of masculinization of external genitalia
10 50 Beginning of regression of wolffian ducts in the female fetus
14 90 Appearance of first spermatogonia
16 100 Appearance of first ovarian follicles
17 120 Numerous Leydig cells. Peak of testosterone secretion
20 150 Regression of Leydig cells. Diminished testosterone secretion
28 230 Cessation of oogonia multiplication
28 230 Descent of testis *
4. Abnormalities in male
Congenital bilateral absence of the vas
deferens (CBAVD): Unilateral or bilateral
Infertile X ejaculation
Cystic fibrosis patient with CFTR mutation (>98%)
Other (e.g. renal agenesis)
Pseudo-hermaphroditism ()
Primary sex characteristics of one sex but develops
that are different from what would be
the secondary sex characteristicsexpected on the basis of the gonadal
tissue (ovary or testis).
Sometimes not identified until Puberty
e.g. 5a-reductase deficiency
4. 5-alpha reductase deficiency
(5-)
Testosterone is converted to the more potent
DHT by 5a-reductase
5-alpha reductase
Testosterone --------------------------> 5-dihydrotestosterone (DHT)

DHT is a potent androgen, and is necessary for

the development of male external genitalia
Individual can have normal male external
genitalia, ambiguous genitalia, or normal female
genitalia -> hormone treatment at puberty
4. Abnormalitis in Males
Cryptorchidism (): undescented testis
(3% in newborn); absence of one or both testes
from the scrotum -> infertility & cancer risk ->
surgery
Hypospadias (): Abnormally placed
urinary meatus (the opening) at the ventral
surface of the penile shaft (1/125 to 1/4000) ->
surgery
4. Abnormalities in female
Many are asymptomatic (e.g. structural
abnormalies of the uterus, cervix and vagina) ->
abnormalities of Mullerian system development
Congenital adrenal hyperplasia (CAH)
Several autosomal recessive diseases
Mutations of genes for enzymes on production of
cortisol from cholesterol by the adrenal glands
(steroidogenesis)
Excessive or Deficient production of sex steroids;
produces excess androgen in female
21-hydroxylase deficiency accounts for about 95% of
diagnosed CAH -> Hormone treatment
X
4. Turner syndrome
(45,X), (46,XdelXp), (46XiXq)
1 in 2000 1 in 5000
Physical abnormalities
Short stature, swelling, broad chest
Low hairline, low-set ears, and webbed necks
Congenital heart disease, hypothyroidism
Diabetes, vision problems, hearing concerns, and
many autoimmune diseases
Gonadal dysfunction (non-working ovaries)
Absence of menstrual cycle
Sterility (premature ovarian failure)
4. Clinical presentation
XY Female karyotypes - with a single
locus deletion in the Y chromosome (i.e.
SRY) results in ovarian development and
a phenotypic female
XX Male karyotypes - with aberrant
presence of SRY sequence developed into
male phenotype
4. Caster Semenya
This was invoked in
August 2009 with the
mandated testing of
South African athlete
Caster Semenya
Semenya won gold in the
women's 800 meters at
the 2009 World
Championships in
Athletics with a time of
1:55.45 in the final 2009
2010
4. Male or Female athletes?
For gender verification at the Olympic Games
(1992), athletes with a SRY gene were not
permitted to participate as females
The screening was eliminated as of the 2000
Summer Olympics
inaccurate and discriminating
reserved for specific cases in Olympic sports
Gender verification tests typically involve
evaluation by gynecologists, endocrinologists,
psychologists, and internal medicine specialists
4. Androgen insensitivity
syndrome (AIS)
Testicular feminisation (46,XY genotype)
1 in 500-600 female
Androgen receptor (AR) mutation
Xq11-Xq12
Complete AIS (CAIS) -> female
Partial AIS (PAIS), and
Mild AIS (MAIS) -> male
Management of AIS
Limited to symptomatic management
Correct AR gene mutation not currently available
 5. Puberty

1 Folicle stimulating hormone

2 Luthenizing hormone
3 Progesterone
4 Estrogen
5 Hypothalamus
6 Pituitary gland
7 Ovary
8 Pregnancy?
9 Testosterone
10 Testes
11 Incentives (?)
12 Prolactin - PRL
5. Adrenarche ()
The contribution of adrenal gland
(androgen) to puberty in girls and boys
Begins at ages 6-8 yrs in girls
Weak adrenal androgens secretion:
Initiating growth of pubic and axillary hair; and
growth of axillary sebaceous glands (breast
development)
Intrinsic, programmed event within the
adrenal gland?
5. Puberty in boys
Testes enlargement between ages 9-14
Secondary sexual characteristics progressively
appear over 2-2.5 yr until ages 20-25
Secondary sexual characteristics:
Increased laryngeal size;
Deepening of the voice;
Increased bone mass;
Increased mass and strength of skeletal muscle
Thickened skin;
Increased and thickened hair on the trunk, pubis,
axillae and face.
5. Testicular maturation
Initiation of androgen production by the
Leydig cells
Growth of the seminiferous tubules and
initiation of spermatogenesis
Controlled by FSH and LH
Clinically: Individuals lack hypothalamic
GnRH pulse generator do not undergo
puberty (Kallman syndrome)
5. Somatic growth
Complex interaction between gonadal sex
steroids, growth hormone (GH) and
insulin-like growth factor (IGF-1)
Absence of GH, IGF-1 or IGF-1 receptor
will cause somatic dwarfism
GH production is controlled by estrogen
and maintained by testosterone -> bone
growth (T->E2, increase GH production)
Testosterone increase muscle mass
5. Somatic growth
Adult height are determined by:
Genetic factor (distal short arm of X chromosome)
47, XXY karyotype (Klinefelter syndrome) men are
unusually tall (double dose of X-lined stature
determinants)
BMI at the onset of puberty children with increased
body fat tend to enter puberty earlier but may not
reach the full genetically predetermined adult height
Nutrition
Length of puberty
5. Puberty in girls
Breast development between ages 8-10
Secondary sexual characteristics progressively
appear over 2.5 yr
Onset of menstruation
Secondary sexual characteristics:
Pubic hair;
Keratinization (cornification) of the vaginal mucosa;
Enlargement of labia minora and majora;
Uterine enlargement;
Increased fat deposition in hips and thighs
5. Menarche ()
Onset of menstrual cycles or first menstrual
bleeding
Maturation of the hypothalamic-pituitary-ovarian
(HPO) axis: Pituitary Follicle-stimulating
hormone (FSH) & Luteinzing hormone (LH);
Ovarian estrogen and progesterone
Produce mature ova and endometrium to
support zygote if fertilization taken place
Average age of menarche is 11.75 years
Follicular Reserve vs Ages
1 to 2 million immature
- eggs at born
400,000 remains at
puberty
Thousand will lost in
each cycle
> about 400 will
mature
little or no follicles
remain at menopause
6. Menopause ()
Fertility of women decreases from age 35, but
accelerating after age 40
Ovulation induction after age 45 by gonadotropin
are largely unsuccessful
3-4 yr before menopause - serum FSH ,
estrogen, inhibin & progesterone
Estrogen withdrawal syndrome
Loss of menses
Around age 50
Smokers enter menopause at an earlier age
6. Menopause
Appearance of
hot flashes ()
Insomnia ()
vaginal atrophy
decreased breast size and
reduced skin elasticity
no follicles > serum estrogen lv. decreases

Long-term estrogen deficiency ->Osteoporosis

and cardiovascular disease
6. Osteoporosis
Bone loss in women begins at about age 30
Most rapid bone loss occurs in the first 3-4 yr
after menopause

Bone formation by osteoblast is normal; but

bone resorption rate by osteoclast
Most common site: vertebral body (back pain),
upper femur, humerus, ribs and distal forearm
6. Cardiovascular changes
Fat, liver and kidney express aromatase which
convert circulating androgens to estrogen
(mostly estrone, a very weak estrogen)
Estrogen appears to vascular resistance and
increase blood flow by production of
endothelin (a vasoconstrictor)
Estrogen therapy will in HDL & LDL
6. HRT
Hormone replacement therapy (HRT) :
oestrogens, progesterone or progestins, and
sometimes testosterone
Prolonged exposure of endometrium to estrogen
stimulation (without progesterone) - risk for
endometrial hyperplasia and carcinoma ( risk of
HRT)
Given as a short-term relief (often one or two
years, usually less than five) from menopausal
symptoms
References
1. Textbook of Medical Physiology (Eds.
A.C. Guyton and J.E. Hall) Physiology
(Eds. R.M. Berne and M.N. Levy)
2. Essential Reproduction (Eds. M.H.
Johnson and B.J. Everitt)
3. The Endocrine System at a Glance (Eds.
B. Greenstein and D. Wood)