Hormones and Reproduction Flashcards

Lecture Objectives

• Describe the role of the hypothalamic-pituitary-gonadal axis in controlling the reproduction.
• Describe the role of the ovaries and testes in producing gametes.
• Describe the role of the gonads as endocrine organs.
• Describe the female reproductive cycle.

Reproductive Potential

• Reproductive life history
• Puberty
• Age
• Menopause
  • Male
  • Female

Hypothalamus

• The hypothalamus contains several key nuclei:
  • Dorsomedial nucleus
  • Paraventricular nucleus
  • Anterior hypothalamus
  • Preoptic region
  • Suprachiasmatic nucleus
  • Arcuate nucleus
  • Mammillary bodies
  • Posterior nucleus
  • Ventromedial nucleus

Gonadotrophin-Releasing Hormone (GnRH) Neurons

• The hypothalamus releases GnRH.
• GnRH travels to the anterior pituitary via blood vessels in the pituitary stalk.
• The posterior pituitary releases oxytocin and ADH.

Anterior Pituitary Hormones

• GnRH stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from gonadotroph cells into the circulation.
  • LH & FSH

The Hypothalamic-Pituitary-Gonadal (HPG) Axis

• Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) are released together into the circulation from the anterior pituitary in response to GnRH.
  • Follicle Stimulating Hormone.
    • Stimulates the production of gametes (eggs, sperm).
  • Luteinizing Hormone.
    • Stimulates the production of steroid hormones.

Gonads

• Male - Testes
• Female - Ovaries
• Two main roles:
  • Production of gametes.
  • Production and release of steroid hormones.

Steroid Hormones

• Cholesterol is the precursor for all steroid hormones.
• Key enzymes involved in steroid hormone synthesis include:
  • Cholesterol side-chain cleavage enzyme
  • 3β-HSD
  • 17α-hydroxylase
  • 21α-hydroxylase
  • 11β-hydroxylase
  • 17,20 lyase
  • 17β-HSD
  • Aromatase
  • 5α-reductase
  • Aldosterone synthase

Steroid Hormones Mechanism of Action

• Pass through cell membranes to act on intracellular receptors.
• Receptor activation leads to changes in gene transcription.

Androgens

• Steroid hormones that stimulate male physical and reproductive characteristics.
• Testosterone is the primary biological androgen.
• Mainly synthesized and released by the testes and the adrenal gland.
• Can be converted into estrogens.

Estrogens

• Steroid hormones that function as the primary female reproductive hormones.
• In non-pregnant women, the primary naturally occurring estrogen is estradiol.
• Mainly synthesized from androgens and released by the ovaries.

Progestagens

• Steroid hormones derived from the same precursor as testosterone and estrogen.
• Involved in the menstrual cycle and pregnancy.

The HPG Axis Feedback Loops

• Negative feedback from gonadal hormones (testosterone, estradiol, and progesterone) inhibits GnRH release from the hypothalamus and LH/FSH release from the anterior pituitary.
• Positive feedback: Estradiol can exert positive feedback on LH release during the ovulatory phase.

Reproductive Potential

• Puberty
• Age
• Menopause
• These are controlled by the HPG axis in both males and females

Male vs. Female Reproductive Differences

• Continuous sperm production in males
• Ovarian cycles in females
• To understand the differences between male and female reproduction, it's important to understand the differences between how the ovaries and the testes produce gametes.

Anatomy of Testes

• Key structures include:
  • Seminiferous tubules
  • Epididymis (head and tail)
  • Vas deferens
  • Leydig cells

Effects of Testosterone

• Male hormone - anabolic
• Primary and secondary male sexual characteristics
• Libido and sexual behavior
• Stimulates spermatogenesis

Seminiferous Tubules

• Spermatogenesis occurs within the seminiferous tubules.
• Seminiferous tubules contain both Sertoli cells and spermatogonial stem cells.

Spermatogonial Stem Cells

• Sperm production

Sertoli Cells

• Support
• Nutrition
• Protection
• Regulation

Spermatogenesis

• Starts at puberty
• Maintains species
• Mitosis followed by Meiosis
• $120$ million sperm / day or $1,500$ / sec
• Regulated by FSH

Mature Sperm

• Key structures:
  • Head (Acrosome, Nucleus)
  • Mid (connecting) piece (Mitochondria, Centriole)
  • Tail (Axial filament, Terminal disc, End piece)
• Mature sperm are produced in the seminiferous tubules and then stored until needed.

Male HPG Axis

• Hypothalamus releases GnRH, stimulating the anterior pituitary.
• Anterior pituitary releases LH and FSH.
• LH stimulates Leydig cells to produce testosterone.
• FSH and testosterone stimulate sperm production in the seminiferous tubules.
• Testosterone exerts negative feedback on GnRH and LH release.

Leydig Cells and Seminiferous Tubules

• The Leydig cells and the seminiferous tubules work together to maintain male reproductive function.

Male Reproductive Function

• New sperm produced continuously throughout adult life
• Testosterone released at a constant level

Anatomy of Ovaries

• Key structures include:
  • Ovarian stroma cells
  • Surface of ovary
  • Follicles (Primordial follicle, Oocyte, Squamous follicular cells)

Effects of Estradiol

• Female hormone
• Primary and secondary female sexual characteristics
• Effects on bone development and growth
• Controls the ovarian cycle and ovulation

The Ovarian Cycle

• Unlike in males, female reproductive function is cyclic with one oocyte released per cycle
• 3 Phases:
  • Follicular phase: Days $1-10$
    • A follicle grows in preparation for ovulation
    • The growing follicle releases estradiol
  • Ovulatory phase: Days $11-14$
    • High estradiol causes the LH surge
    • Ovulation
  • Luteal phase: Days $14-28$
    • Remains of the follicle release progesterone – Corpus Luteum
    • The interaction between changing levels of LH / FSH and estrogen / progesterone drives the cycle

Follicular Phase (Days $1-10$)

• FSH causes follicles to grow.
• LH stimulates the release of estradiol from the follicles.
• As the follicles grow estradiol levels increase…

Primordial Follicle ($40\mu m$)

• Immature dormant oocytes.
• Surrounded by flat granulosa cells.

Mature Follicle ($20mm$)

• Dependant on FSH to grow.
• Competition for limited FSH means that only one follicle is left by day 10.
• As the follicle grows, the theca cells and granulosa cells release estradiol in response to LH.

Ovulatory Phase (Days $11-14$)

• Normally estradiol has a negative feedback effect on LH release.
• BUT – during ovulation estradiol stimulates LH causing the “LH surge”.
• The LH surge triggers ovulation.

Luteal Phase (Days $15-28$)

• The follicle becomes the corpus luteum and releases estradiol and progesterone to prepare for pregnancy.
• If the egg is not fertilized, the corpus luteum degenerates.
• The cycle starts again…

Female HPG Axis

• Hypothalamus releases GnRH, stimulating the anterior pituitary.
• Anterior pituitary releases LH and FSH.
• FSH stimulates follicle growth and estradiol release.
• High estradiol levels trigger the LH surge, leading to ovulation.
• After ovulation, the corpus luteum releases estradiol and progesterone.
• Estradiol and progesterone exert negative feedback on GnRH, LH, and FSH release.
• If pregnancy does not occur, the corpus luteum degenerates, and the cycle starts again.

Differences Summarized

• Male
  • New sperm produced continuously throughout adult life
  • Testosterone released at a constant level
• Female
  • A limited supply of eggs which are released in cycles until the menopause
  • Estradiol and progesterone levels change in cycles
• However, both are controlled by the HPG axis

Disturbances in HPG Axis Function

• Can be beneficial when disturbed intentionally – e.g. contraception.
• Clinical problems with the HPG axis can have major physiological effects.

Contraception - Female

• Progestogen-only pills
  • Progesterone inhibits GnRH, LH and FSH
  • No follicle growth and no ovulation
• Combined oral contraceptive pill (Estrogen and Progesterone)
  • Estrogen added to help control cycles

Contraception - Male

• Currently not available – ongoing research
• Synthetic testosterone works, but not $100\%$

Clinical Problems with Reproductive Function

• The HPG axis is complex and steroid hormones affect many different tissues.
• Clinical problems can occur at many points.
  • Hypothalamus: Kallman syndrome
  • Target tissues: Androgen insensitivity syndrome

Kallman Syndrome

• The GnRH neurons originate from the olfactory region of the brain.
• Genetic mutations affecting the development of the olfactory bulb also stop GnRH neurons developing.

Androgen Insensitivity Syndrome

• Genetic defects in the androgen receptors reduce sensitivity to testosterone.
• Complete androgen insensitivity can result in female body development despite XY chromosomes.

Take Home Message

• Male steroid release and sperm production is constant
• Female steroid release and ovulation is cyclical
• However, both are controlled by the HPG axis
• Steroid hormones have many effects on the body – can be useful (e.g. contraception), but also the source of clinical problems