H&H exam 2- Sex development and Males

3 types of sex + brief descriptions

chromosomal sex (established at fertilization), gonodal sex (embryonic gonads develop into either testis or an ovary), phenotypical sex (external and internal genitalia and secondary sex characteristics)

normal sex development label

green boxes: chromosomal sex, gonadal sex, phenotypic sex
left column: ovary-determining genes, gonadal steroids (E2)
right column: testis-determining genes, gonadal steroids and peptides

karyotype for chromosomal sex for males and females

male: 46 XY
female: 46 XX

DHT long

Dihydrogentestosterone

MIS or AMH long

Mullerian inhibiting substance, Anti-Mullerian Hormone

E2 long, what is it (simple)

gonadal steroid, 17β-estradiol

SRY- long, function, what are the implications

Sex-Related gene on the Y chromosome, in the presence of it- testis (activates testis promoting genes), in the absence of it- ovaries, testis-determining factor (TDF), default are ovaries (but not entirely)

top 3 lines label (both red & orange) (left to right, by line)

ovum, spermatozoon
genetic sex (XX or XY genotype)
gonadal sex (~4 weeks, ovary or testis)

label bottom 3 rows (left to right, by line)

phenotypic sex
peripheral sex, brain sex
external genitalia, secondary sex organs, sexual behaviour, pituitary function

sexual differentiation: at 4 weeks

gonads still indifferent, can develop into testis or ovary

How does sexual differentiation happen in males (basic ish) (3 main points)

under the control of SRY gene, genes activated for testoicular development, Sertolli cells produce Mullerian inhibiting hormone (MIH), causing atrophy of the mullerian duct, Leydig cells secrete testosterone (which after conversion to dihydrogentestosterone supports development of the Wolfian duct)

label left to right

male gonad, bipotential gonad, female gonad

label the bipotential gonad (top to bottom)

gonads, wolffian duct, mullerian duct

label the male gonad (top to bottom)

epididymis, testis, vas deferens, seminal vesicle

label the female gonad (top to bottom)

ovary, oviduct, uterus, cervix

How does the expression of SRY induce testis development?

SRY→SOXY9→FGF9→Serolli cells

what happens when there is a mutation of SRY in 46 XY males (eg a deletion)

no testes development

what happens when there is a translocation of SRY into 46 XX females? What is it called?

Induces testis development and a male phenotype, ovo-testicular disorder of sexual development

Difference in sex development: Ovo-testicular disorder of sexual development description, percentages of how it works

formerly called true hermaphroditism, both an ovary and a testis in one individual or an ovotestis, 60% 46XX, 15%XY, 25% mosaicism

ovotestis description

ovarian and testicular tissue combines in the same gonad

Androgen Insensitivity Syndrome (AIS) description, prevalence

mutation in androgen receptor (X linked), 1 in 100,000 chromosomal males (46XY), testosterone levels (usually) normal for males

Complete AIS 5 features

female phenotype, normal breast development, scanty pubic and axillary hair, short vagina (but no uterus), female psychosexual orientation

Partial AIS 3 features

perineoscrotal hypospadias (dislocated urethra), small undescended testes, gynecomastia (increase in male breast tissue during puberty)

Klienefelter syndrome: description, prevalence, percentages when it happens

47XXY, 1 in 1000 men (75% not diagnosed), meiotic non-disjunction of sex hormones during gametogenesis (40% during spermatogenesis, 60% during oogenesis)

Other variants of Klinefelter syndrome description

mosaicism, 48XXYY, 48XXXY- rare and result from chromosomal mitotic non-disjunction within the zygote

clinical features of Klinefelter Syndrome (7)

low T (50-75%↓), High FSH and LH (85%↑), increase of estradiol (conversion of testosterone), infertility, “eunuchoid” proportions, incomplete development of male physical characteristics, gynecomastia

What is incomplete development of male physical characteristics also called

under-virilisation

What happens between 6 and 8 years of age in terms of puberty (2)

adrenal glands produce more androgens (DHEA), reactivation of the H-P-Axis and production of GnRH

GnRh throughout development

active in fetal life and early infancy, quiescent until early puberty when it it is reactivated

Why do obese children enter puberty earlier?

involvement of leptin (from adipose tissues) to enter puberty

tanner scale description

scale of physical development in children, adolescents and adults, based on external primary and secondary sex characteristics

Puberty events in males order

testiscular volume rises earlier than genitalia or pubic hair

What happens in early puberty- males (9)

nocturnal surges of LH and FSH, increase in testicular volume, ↑T levels, deepening of the voice, prostate growth, facial hair growth, initiation of recession of temporal hairline, GH increases IGF-1 and linear bone growth, prolongued pubertal exposure to gonadal steroids causes epiphyseal closure

Causes of precocious puberty description, 2

age <9, premature sexual development, gonadotropin-dependant (central precoucious puberty), gonadotropin independent (androgens from the testes or adrenals)

delay puberty when, causes (5)

not started by 14, constitututional delay of growth and puberty, systemic disorders (malnutrition, anorexia- bc leptin is very low), CNS tumors, H-P causes (low gonadotropin- can be congenital or aquired), androgen insensitivity

Male hormones: acronyms & long (5+1)

GnRH- Gonadotropin releasing hormone
LH- Luteinizing Hormone
FSH- Follicle Stimulating Hormone
DHEA: Dehydro-epiandrosteron
DHT: Dihydrotestosterone
and estrogens

Leydig cells description

stimulate testosterone synthesis, regulatory control of androgen synthesis is mediated by testosterone feedback on both hypothalamus and the pituitary gland

Sertolli cells description

nurture germ cells to divide, differentiate and mature into sperm (spermatogenesis), secrete inhibin B which suppresses pituitary FSH

How is GnRH released?

in distinct pulses every 2 hrs, resulting in discrete pulses of LH and FSH

ABP long

androgen binding protein

How do Leydig cells work?

activated by LH (binds to membrane receptor), cAMP and PKA - leads to new protein synthesis, creates enzymes that convert cholesterol into testosterone

What is the result of Leydig cells function

local T concentration is very high around them, (in circulation is a lot more diluted), has a paracrine effect on Sertolli cells

How do Sertolli cells work? (from diagram) (4 ish steps)

activated by FSH - cAMP and PKA - new protein synthesis which creates: inhibins, aromatase (which converts T to estradiol), ABP, then high ABP and T [] induces production of sperm cells

Maturation of the sperm cells (3 points)

occurs gradually from the basal lamina to the lumen of the tubule, complete maturation requires 74 days, spermatozoa spend 21 days in the epididymis for further maturation

how many sperm cells does an adult testes produce in a day? Why is this relevant?

100 million, makes it a lot more difficult to make a male reproductive pill

Percentages of T binding

0.5-3% - unbound
50-70% - albumin
30-45% - SHBG (Sex hormone binding globulin)

circulating testosterone, where is how big percentage derived from?

95% of circulating T is derived from the testis

DHT vs testosterone

DHT is more powerful than Testosterone

Where is T mainly metabolized and excreted?

mainly metabolized in the liver and excreted in the kidneys

Influence of T on: skin (2), male sex organs (3), muscle (1)

skin: growth of facial and body hair, supports collagen
male sex organs: sperm production, prostate growth, erectile function
muscle: increased muscle mass and strength

Influence of T on: brain (3), bone marrow (1), bone (1)

brain: sex drive, positive feelings, aids cognition and memory
bone marrow: red blood cell production
bone: bone density and maintenance

DHT & hair

causes hair loss- decreases blood flow to hair follicle and decreases keratin production, finasteride can block conversion of T to DHT

disorders of the male reproductive axis during adulthood (3 + sub points)

Hypogonadism- primary testicular cause of hypogonadism, androgen insensitivity syndrome, hypogonadotropic hypogonadism (secondary)
gynecomastia, aging-related changes in male reproductive function

T levels and aging

they decrease natural over time as you age, can be beneficial to boost it later on with T treatments

total testosterone levels testing results

<200ng/dl - T deficiency
200-350ng/dl - repeat testing
>350ng/dl - androgen deficiency unlikely

What to do if testosterone deficiency found (how to determine if primary or secondary hypogonadism)

test the LH level- high level LH→ primary hypogonadism, low/inappropriately normal level of LH→secondary hypogonadism

signs of hypogonadosim both severe and partial

severe: absence puberty, sexual infantilism (hypospadias, undescended testes)
partial: delayed/arrested sex development, abnormalities in LH pulse frequency/amplitude

aquired hypogonadotropic disorders: reversible (6ish)

stress, severe illness (HIV, COPD, etc.), malnutrition, opioids & marijuana, exercise-induced (only women)

Obesity associated secondary hypogonadism

1- leptin increases→ SHBG decreases→testosterone long =, later decrease
2- testosterone → aromatization in adipose tissue → increase in estradiol

Adverse effects of (ab)use of anabolic steroids

suppression of LH and FSH,

Testing for abuse of steroids

high ration of T to epitestosterone, (normal ratio is 1:1, anything higher than 4:1 indicates doping use)