Endocrine Signalling & Reproductive Biology 7

Introduction to Reproductive Research in Mice

  • Focus on the theme of reproduction going wrong, particularly endocrine control.
  • Use of mice as a primary model for study, acknowledging limitations.

Advantages and Limitations of Mouse Models

  • Mice allow gene modifications (knockouts, overexpression, etc.).
  • Not a perfect model for understanding human reproductive development due to differences in timing and processes.

Ovarian Development in Mice vs. Humans

  • Diagram aligns gestation weeks in humans with days post-coitum in mice.
  • Female mouse ovaries born at ~gestation week 17 (human equivalent).
    • Shared process: primordial germ cells migrate to gonads.
    • Gonadal sex determination leads to testis (XY) or ovary (XX).
  • Proliferation and arrangement of primordial germ cells occurs:
    • In mice: easier to observe meiotic division and follicle assembly; ovary maturity achieved quickly.
    • In humans: more extended gestational period for ovarian development.

Follicular Genesis and Timing Differences

  • Timing differences in primordial follicle assembly:
    • Mice: Days 1-2 postnatal.
    • Humans: Gestation weeks 17-28.
  • Concerns arise regarding developmental accuracy and impacts on reproduction due to these differences.

Hypothalamus-Pituitary-Gonad Axis in Mice vs. Humans

  • Active in fetal life in humans, postnatal activation in mice.
  • Example: Knockout mice with destroyed pituitary show normal testis development at birth but abnormal development afterwards.

Investigating LH Receptor Knockout Mice (Loka Mice)

  • Histology shows differences between wild type and knockout mice:
    • Wild Type: Healthy follicles and oocytes.
    • Knockout: Antral follicles in arrested development, no ovulation, and lack of corpora lutea.
  • Importance of LH for final maturation stages in females.

Male Loka Mice Observations

  • Similar histological structure between knockout and wild type until ~2 weeks postnatal.
  • Adult knockout males exhibit:
    • Thin seminiferous tubules, arrested spermatogenesis, absence of granulosa cells.
    • Leydig cells require LH for development, indicating further developmental failure in knockout.

Summary of Effects of Gonadotrophin Modification

  • Overexpression or underexpression of various hormones leads to specific reproductive outcomes:
    • FSH Overexpression in Males: Elevated testosterone, enlarged seminal vesicles, infertility.
    • FSH Overexpression in Females: Infertility, cystic ovaries, elevated estradiol and progesterone, broader health impacts (e.g., kidney defects).
    • LH Overexpression in Males: Small testes, reduced germ cells leading to infertility.
    • LH Underexpression: Similar detrimental traits leading to small testes and infertility, but varied responsiveness to treatment such as LH injections.

Disorders of Sexual Differentiation (DSD)

  • Examples include cryptorchidism, MRKH syndrome, and hypospadias.
  • Manifestations indicate wide-ranging hormonal impact and mechanisms involved in sexual differentiation.

XX Male and XY Female Phenotypes

  • XX male mice vs. XY male mice behavior and phenotype comparison:
    • Differences suggest that the gonadal sex influences broader sexual dimorphism.
    • XX males show different behavioral and physiological traits compared to XY counterparts, underscoring importance of genetic and hormonal contributions.

Conclusion

  • The lecture underscores the complexities of reproductive research using mouse models and their implications for understanding human reproduction. Recommendations for further reading and understanding gonadotropin receptors in humans were provided.