Endocrinology Exam II (Lecture 10)

Why do sexes differ: proximate causation

“How” questions that describe the immediate mechanisms. Examples being genes, chromosomes, receptors, etc.

Why do sexes differ: ultimate causation

“Why” questions that address evolutionary consequences and why some differences are selection favored. Examples being sexual selection between mating and competition that drives evolution of mating displays, coloration, larger body size, aggression, and defensive weapons

What are organizational effects?

Hormones early in development that establish relatively permanent characteristics (neural, morphological).

“Building things to use later in life”

What are activational effects?

Later hormones that act on previously differentiated tissues to trigger or end behaviors, alter duration/frequency, or prime animals for a response

What is sex determination?

Development of the bipotential gonad into a testis or ovary (permanent). Key example: SRY gene

What is sex differentiation?

The entire process by which male/female characteristics, including primary and secondary sex characteristics, develop

What are primary sex characteristics?

Internal and external reproductive organs present at birth that are directly involved in the reproductive process that occur later when producing gametes.

What are examples of primary sex characteristics for both males and females?

Male: Penis, testis, scrotum

Females: Vagina, ovaries, labia and clitoris

What are secondary sex characteristics?

Physical and visible traits that emerge later during puberty, not directly apart of the reproductive system

What are examples of secondary sex characteristics for males and females?

Male: Growth of facial and body hair, voice deepens, increase in upper muscle mass

Female: Development and enlargement of breast tissue, pelvis and hips widening, body fat deposits around tights and hips.

What are the three mechanisms of sec determination?

1. Genotypic

2. Temperature-dependent

3. Behavioral

What type of mechanisms are included in biotic sex determination?

Genotypic and behavioral

What type of mechanism is abiotic sex determination?

Temperature-Dependent

What does Genotypic sex determination mean?

Sex of an animal is determined by genetic chromosomes (XX/XY, ZZ/ZW). Found among most mammals, birds, fish, and amphibians.

What does Temperature-Dependent sex determination mean?

Ambient temperature during a critical developmental period determines sex in many reptiles. The temperature pattern differs by species.

What does Behavioral sex determination mean?

Involves social interactions, hierarchy, or behavior cues that trigger an individual’s biological sex to change in adult life.

List the genes involved with male/female gonadal development (6)

1. SRY

2. SOX9

3. SOX3

4. DAX-1

5. FGF9

6. WNT4

What does the SRY gene do?

The Y linked testis-determining factor that initiates testis development

What does SOX9 do?

Gene that regulates testis development. Directly upregulated by SRY gene.

What does SOX3 do?

It is an X-linked factor that can functionally substitute for SRY to induce testis formation in XX individuals

What does DAX-1 do?

It is an X-linked factor that acts as a dosage sensitive regulator. A certain amount is needed to produce a normal male. Too much or too little activity can disrupt testis development and cause male-to-female sex reversal

What does WNT4 do?

Associated with the female ovarian development pattern in the absence of SOX9 expression. Actively suppresses the male-specific SOX9 pathway, allowing for the female pattern to dominate.

What is the male differentiation pathway (internal and external)?

Internally

• SRY → SOX9 → testis

• In testis → Sertoli cells produce MIS (AMH) → Mullein duct regression

• Leydig cells produced testosterone → Wolffian duct development

Externally

• Testosterone → DHT by 5a-reductase → External genitalia differentiation by androgens

What are Wolffian ducts?

A paired embryonic structure that forms in early fetal development in both males and females. Develops as part of the male internal reproductive tract under androgen influence.

What are Mullerian ducts?

A paired embryonic structure that forms in early fetal development in both males and females. Develops from absence of AMH and grows to mature into the fallopian tubes, uterus, cervix, and part of the vagina.

What does MIS stand for?

Mullerian-inhibitory substance

What is another name for MIS?

AMH

What does AMH stand for?

Anti-Mullerian Hormone

What happens to the Müllerian ducts in male development under AMH/MIS influence?

They are suppressed and degenerate. Vice versa in females.

Are any hormones necessary to permit female development?

No, unlike male development

What are the 4 anomalies in male sexual development due to single gene mutations?

1. Defect in SRY

2. Absence of AMH

3. Absence of Androgen receptor/hydroxysteroid dehydrogenase (AR/HSD)

4. Absence 5-a reductase

What would a defect in SRY cause as an anomaly in male sexual development for an XY individual?

Testis will not develop → testosterone will not be produced → No internal genitalia (vas deferent or seminal vesicles)

No testosterone → No DHT conversion → No external genitalia (penis, prostate, scrotum)

An XY individual will develop a uterus and fallopian tubes by default without SRY.

What would a mutation where AMH can’t be produced cause as an anomaly in male sexual development for an XY individual?

Regular development of male genitalia would occur, but the Mullerian inhibiting substance would not be there to stop female development from occurring too.

An individual will present as male at birth, but still have both interfering tubes and vesicles, leading to problems later during puberty.

What would a mutation where the absence of Androgen receptors/ hydroxysteroid dehydrogenase cause as an anomaly in male sexual development for an XY individual?

HSD is required to make testosterone: No testosterone → No internal genitalia development

AR will bind with DHT: No AR → No external genitalia development

AMH will still suppress female development

Individual will look completely neutered.

What would a mutation where the absence of 5-a reductase cause as an anomaly in male sexual development for an XY individual?

5-a reductase converts testosterone → DHT (which develops external genitalia

Testosterone is still produced from the testis so the internal genitalia will still develop.

AMH will still suppress female development

The individual will look like a female externally at birth, but contain male internal genitalia.

When can you differentiate the XY individuals that have a mutation where AR/HSD are absent and where 5-a reductase is absent?

During puberty since testosterone is still present to perform during that development

Name some examples for disorders of sex differentiation?

Chromosomal/aneuploidy disorders

• Turner Syndrome: X

• Klinefelter syndrome: XXY

Germ-line disorders (genetically inherited)

• Congenital adrenal hyperplasia (female presenting → masculinization)

• Androgen insensitivity syndrome (male presenting → develop female genitalia)

How does hermaphroditism or pseudohermaphroditism occur in germ-line disorders?

Androgens changes the structure external genitalia from either F→M or M→F. These individuals are usually infertile.

How can androgen insensitivity syndrome occur?

When tissues do no possess functional androgen receptors, XY individuals develop female external genitalia, but not internal female gonads

What process do striped parrot fish possess regarding behavioral sex determination?

Sequential hermaphroditism

What happens in sequential hermaphroditism in stripped parrotfish?

Younger stage: females apart of the reef edge territory

— Internal structures adapt —

Later stage: Males (mature female) who defends a large territory harem of females

What happens in sequential hermaphroditism in social development?

Aquatic animals with external fertilization can change the type of gametes produced and switch sex roles

Examples:

• Clown fish (M→F in absence of harem defense where females disappear)

• Belted Sandfish: can switch back and forth between sexes and associated courtship behaviors within minutes to quickly deposit sperm or eggs.

What is puberty?

When the gonads attain their full hormonal and gamete-genetic capacity for reproduction

What is the most critical factor in puberty?

The increase in frequency of GnRH pulses

What is the active inhibition hypothesis?

Proposes that the body actively inhibits GnRH secretion during childhood, essentially put on hold. Once the brain gets a signal that the body is ready for reproduction processes (puberty), inhibition of GnRH secretion is reduced.

This allows increased GnRH pulse frequency and activation of the HPG axis.

What affects timing of puberty?

Many genetic and environmental factors that can lead to precocious or delayed/absent onset

Examples: Receptor mutations or disorders

What neural signals stimulate GnRH? (3)

GABA, glutamate, norepinephrine

what neural signals inhibit GnRH?

B-endorphin and GABA

How is GnRH secreted?

Pulsatilely. This pulse pattern drives pulsatile LH/FSH secretion

What does LH do in the testis?

Acts directly on Leydig cells to stimulate testosterone synthesis and supports spermatogenesis

How does LH stimulate testosterone synthesis?

Binds to surface receptor → activates cAMP of PKA pathway → induces StAR synthesis → moves cholesterol into mitochondria → testosterone synthesis

What does FSH do in the testis?

Acts directly on the Sertoli cells through a G-Protein/cAMP pathway, stimulating AMP and inhibit production to support spermatogenesis

What is ABP?

Androgen binding protein

What is inhibin?

A Sertoli cell product involved in negative feedback, especially suppression of FSH

What is StAR and what does it do?

Steroidogenic acute regulatory protein that binds cholesterol to mitochondria as a precursor in testosterone synthesis

How is testosterone transported ?

Mostly protein bound, mainly to albumin and sex hormone binding globulin (SHBG)

What does 90-95% of testosterone produced from LH and Leydig cells end up in?

Binding to Androgen receptors in muscle tissue

what happens to 5-10% of testosterone?

It gets converted to DHT by 5a-reductase and binds to AR and ends up in the skin or prostate tissue to maintain growth

What happens to .1% of testosterone?

It gets converted to estradiol by aromatase and binds to estrogen receptors in the brain and in bone.

What are the stages of spermatogenesis?

Spermatogonia (2N) → Mitosis → Primary spermatocyte (2N, 4N) → Meiosis I → Secondary spermatocyte (N, 2N) → Meiosis II → Spermatid (N) → Sperm

Recall the 4 major types of clinical disorders…What is the 5th one regarding the HPGn axis?

1. Hormone overproduction

2. Hormone underproduction

3. Altered tissue responses

4. Tumors'/ defects of endocrine glands

5. Misuse of anabolic steroids

What is male hypogonadism?

a clinical syndrome resulting from a failure of the testes to produce enough testosterone

What is affected from a primary disorder in male hypogonadism?

The testis

What is affected from a secondary disorder in male hypogonadism?

The pituitary or hypothalamus