Lecture Notes on HPG Axis, Sex Differentiation, and Intersex Conditions

Hypothalamus-Pituitary-Gonadal (HPG) Axis

• The HPG axis is an active, ongoing system from puberty until menopause.

• It involves communication between the hypothalamus, pituitary gland, and gonads.

• The system differs slightly between males and females but includes the hypothalamus, pituitary, and adrenal gland in both sexes.

• Definition: The hypothalamus communicates with the pituitary gland, which in turn communicates with the gonads.

Gonadotropin-Releasing Hormone (GnRH)

• Starting at puberty, the hypothalamus releases GnRH approximately every two hours.

• Neurons in the hypothalamus release GnRH into blood vessels rather than synapsing onto other neurons.

• GnRH travels to the anterior pituitary gland.

Gonadotropins: FSH and LH

• In the anterior pituitary gland, secretory cells respond to GnRH by releasing gonadotropins.

• Gonadotropins, specifically follicle-stimulating hormone (FSH) and luteinizing hormone (LH), are released into the bloodstream.

• These hormones travel throughout the body but primarily affect the gonads.

• In males, they influence testosterone production, and in females, they affect estradiol and progesterone production.

Gonadotropins: FSH and LH Explained

• FSH (Follicle-Stimulating Hormone):

  • In males, FSH stimulates sperm production in the testes.

    • Without FSH, sperm production ceases.

  • In females, FSH causes the ovarian follicles to ripen.

• LH (Luteinizing Hormone):

  • In males, LH stimulates testosterone production from specific cells in the testes.

  • In females, LH triggers ovulation and the formation of the corpus luteum.

    • The corpus luteum then produces more hormones.

HPG Axis Regulation in Males

• In males, the HPG axis operates via a negative feedback system, similar to a thermostat.

• This system maintains testosterone levels around a set point, although there is also a circadian rhythm.

• Mechanism:

  • If testosterone levels drop below the set point, the hypothalamus releases GnRH.

  • GnRH triggers the anterior pituitary to release both LH and FSH.

  • FSH stimulates sperm production, and LH stimulates testosterone production in the testes.

  • Testosterone is released into the bloodstream and affects various tissues, including muscles.

Negative Feedback Loop

• Testosterone receptors in the anterior pituitary and hypothalamus respond to high testosterone levels by:

  • Inhibiting the release of GnRH from the hypothalamus.

  • Inhibiting the release of gonadotropins (LH and FSH) from the pituitary.

• This inhibition reduces LH concentration, decreasing testosterone production.

• As testosterone levels fall, the inhibition stops, and the cycle repeats to maintain hormonal balance.

The Impact of Anabolic Steroids on the Male HPG Axis

• Anabolic steroids mimic the effects of testosterone in the body.

• They bind to testosterone receptors, signaling the hypothalamus and pituitary gland that testosterone levels are high.

• This leads to:

  • Reduced GnRH production in the hypothalamus.

  • Decreased LH and FSH production in the pituitary gland.

  • Lowered testosterone production in the testes.

  • Testicular shrinkage due to lack of stimulation from FSH and LH over time.

HPG Axis in Females and the Menstrual Cycle

• The HPG axis in females is more complex than in males, particularly in humans due to the menstrual cycle.

• The menstrual cycle involves the interaction of the hypothalamus, pituitary, and gonads, similar to males, but with different hormonal dynamics.

• The menstrual cycle is approximately 28 days long.

Phases of the Menstrual Cycle

• Follicular Phase (approximately day 5 to day 13):

  • A slight increase in FSH is released from the anterior pituitary gland.

  • FSH stimulates the follicles in the ovaries.

  • One follicle starts to ripen and grow, producing increasing amounts of estradiol (estrogen).

• Ovulation:

  • When estradiol levels reach a threshold, it triggers the hypothalamus to release GnRH.

  • This causes a peak in LH and a smaller peak in FSH.

  • The LH surge triggers ovulation, releasing the ovum (egg) from the follicle.

• Luteal Phase:

  • After ovulation, the remaining follicle transforms into the corpus luteum (yellow body).

  • The corpus luteum produces both estradiol and progesterone.

  • These hormones prepare the uterine lining for potential implantation of a fertilized embryo.

• Premenstrual Period:

  • If fertilization does not occur, the corpus luteum stops producing estradiol and progesterone.

  • The decline in these hormones causes the uterine lining to shed, resulting in menstruation.

• End of Menstruation:

  • A slight increase in FSH occurs, restarting the cycle.

Feedback Mechanisms in the Female HPG Axis

• The female HPG axis operates through feedback loops, but it is not a simple set-point regulation like in males.

• The menstrual cycle involves slower, cyclical changes in hormone levels over approximately 28 days.

• Changes in hormone levels during the menstrual cycle can be useful for psychologists to study the organizational versus activational effects of hormones.

Hormonal Contraceptives

• Contraceptive pills and implants often maintain steady hormone levels, preventing the natural fluctuations of the menstrual cycle.

• Progesterone-only pills prevent pregnancy by maintaining high progesterone levels, which inhibit ovulation.

• During a natural menstrual cycle, progesterone levels are very low during ovulation; high progesterone levels prevent ovulation.

Intersex Conditions

• Intersex conditions deviate from typical patterns of sexual differentiation and maturation.

• The lecture focuses on three main examples:

  • Androgen Insensitivity Syndrome (AIS)

  • 5-Alpha Reductase Deficiency

  • Congenital Adrenal Hyperplasia (CAH)

• Studying these conditions provides insights into sex differences and the complexities of sex and gender.

Androgen Insensitivity Syndrome (AIS)

• In AIS, the body is insensitive to androgens due to non-functional or improperly functioning testosterone receptors.

• Typically described in 46, XY individuals (those with an X and a Y chromosome).

Mechanism in 46, XY Individuals

• Testes develop due to the presence of the Y chromosome, producing anti-Müllerian hormone and testosterone.

• However, testosterone cannot bind to its receptors, preventing the differentiation of the Wolffian system (male internal genitalia).

• External genitalia do not masculinize because dihydrotestosterone (DHT), another androgen, also cannot bind to its receptors.

• Anti-Müllerian hormone functions normally, inhibiting the development of female internal genitalia.

Phenotype of AIS

• Individuals with AIS (46, XY) are anatomically female at birth and grow up as girls/women.

• They have testes located in the body cavity but lack a uterus, fallopian tubes, penis, and scrotum.

• At puberty, the testes produce enough estradiol to cause female secondary sexual characteristics to develop, but high levels of testosterone remains ineffective.

Management and Considerations

• Testes may be removed due to potential cancer risk, after which hormone treatment is administered to maintain female hormonal balance.

AIS in 46, XX Individuals

• In 46, XX individuals, androgen insensitivity has minimal effect because fertility is independent of testosterone.

• The only noticeable difference may be the absence of pubic and axillary hair, which are androgen-dependent.

5-Alpha Reductase Deficiency

• Five-alpha reductase is an enzyme that converts testosterone into DHT (dihydrotestosterone), which is necessary for the development of external male genitalia during embryonic development.

Mechanism of 5-Alpha Reductase Deficiency

• In 46, XY children with this deficiency, the external genitalia appear female at birth, while the internal genitalia are male (Wolffian system).

• This occurs because anti-Müllerian hormone still functions, preventing the development of female internal structures.

• The external genitalia is not masculinized because DHT cannot be produced.

Pubertal Changes

• At puberty, high levels of testosterone can affect receptors that are normally sensitive to DHT.

• This leads to the development of a penis and scrotum, causing individuals who were raised as girls to develop male characteristics.

Cultural Context

• In certain populations (e.g., some areas of Guatemala and Turkey), this condition is relatively common due to genetic factors within intermarrying groups.

• In these cultures, it is accepted for individuals to transition from being raised as girls to living as boys at puberty.

Congenital Adrenal Hyperplasia (CAH)

• CAH affects intersex phenotypes through the hypothalamic-pituitary-adrenal (HPA) axis.

Role of the Adrenal Gland

• The adrenal gland produces cortisol, which is involved in stress response, salt and water balance, and energy balance.

• Congenital adrenal hyperplasia typically involves a deficiency in the enzyme 21-hydroxylase, which is required for cortisol production.

Mechanism of CAH

• When 21-hydroxylase is deficient, the precursors to cortisol are instead converted into androgens, including testosterone.

• In developing female embryos (46, XX), this excess of androgens results in the masculinization of external genitalia.

Treatment and Management

• Treatment involves administering external cortisol, which suppresses the HPA axis and reduces the production of both cortisol precursors and excess testosterone.

• This treatment is usually initiated shortly after birth, particularly in females where masculinized genitalia are easily identified.

Effects on Gender Identity

• 46, XX individuals with CAH may undergo corrective surgery to make their genitalia appear fully female.

• However, approximately 5% of these individuals experience gender dysphoria.

• In cases where the external genitalia are significantly masculinized, parents and doctors may assign the child as male.

• A study showed that about 12% of 46, XX individuals assigned male at birth later expressed a gender identify that was not male.

Implications for Gender Identity

• Gender identity is influenced by multiple factors, including prenatal hormone exposure, external anatomy, and upbringing.

• The outcomes in CAH suggest that prenatal hormone exposure can play a role in gender identity, although it is not the sole determinant.