CH0576: The Biology of Disease-Dr Richard N. Ranson

1. Endocrine Disorders 3: Reproductive pathophysiology CH0576: The Biology of Disease-Dr Richard N. Ranson

2. Alterations of reproductive systems: Overview ● Changes in sex hormone level-Synthesis/secretion ● Alterations in receptor sensitivity/number of receptors ● Congenital

3. Alterations of reproductive systems: Timeline ●6 weeks post conception: Sex Differentiation -Errors can cause Intersex conditions ●By age 13-14 Puberty (sex hormone production by testis and ovary) -May be delayed or precocious – could be due to tumour sometimes requires hormone treatment. ●Post 14 yrs – First Point of sexual maturity. -Array of potential disorders – Carcinoma, impotence, infertility etc.

4. Endocrinology of Sex Differentiation and Development

5. Sex may be determined by Chromosomes ‘Sex Chromosomes’ XX – female genotype XY - Male Key to sex determination Fig 2.7 Levay Human sexuality Gene: sex-determining region of the Y chromosome (SRY) -codes for the protein testis-determining factor (TDF) ●Individuals with Y chromosome with SRY gene will develop as males ●In the absence of Y Female development is the ‘default pathway’

6. DAX-1 (make ovary) Sexual differentiation and the role of SRY Stage 1: Chromosomes dictate development of gonads When single copies of genes are present SRY overrules DAX-1 SRY (make testis) Fig 6.9. Levay. Human Sexuality ● Mesenephros: A transitory embryonic kidney, provides tissue to gonads ●SRY genes produce transcription factor (protein). ● Transcription factor acts on genes in genital ridge cells-sertoli cells –develop testis

7. Sex Hormones and critical (time) periods for sexual differentiation 1. Development of the reproductive tract: Prior to 6 weeks both sexes 6 weeks post conception Male Gonad ●Sertoli cells- Anti Mullerian Hormone (AMH) ●Leydig cells- Testosterone Wolffian duct androgen receptors (normal) Mutation in PG-21 receptor Intersex condition

8. Intersex Condition: Androgen insensitivity syndrome Look/identify as female - Characterised by mutation in gene for androgen receptor - Mutation- prevents androgen binding to receptor or receptor binding to DNA response elements - 1:10000 live born with complete AIS Develop testes XY sex chromosomes with SRY From Human Sexuality, Levay. AMH Mullerian ducts atrophy Testosterone No ovaries (infertile) No effect ●Amenorrhea (No menstrual periods), No pubic hair ●Breast growth due to testis and adrenals secreting estradiol ●Shallow vagina

9. Sexual Dimorphism

10. Sex Hormones and critical (time) periods for sexual differentiation 2. 9 and 12 weeks testosterone leads to male genitalia development Development of External Genitalia Testosterone surge in this period also had crucial effects on brain structure Brain Dimorphisms Fig 30.2 B from Purves et al neurosciences

11. Brain/spinal neurons Estradiol (oestrogen) Testosterone Aromatase Binds to estradiol receptors Testosterone and the ‘Masculinization’ of the brain (basis of sexual dimorphisms?) During mid gestation (critical period)-Testosterone surge Enhanced transcription of estrogen responsive genes Promotes cell survival, plasticity – increased dendritic spines- connectivity Figs from Purves et al Neuroscience

12. Other human brain regions that are dimorphic The cerebral cortex ‘Red’ areas depict regions that are volumetrically larger in females whilst ‘green’ areas relate to that in males ●Differences linked to cognitive processing The Hypothalamus Regions include SDN, sexually dimorphic nucleus (INAH 1) INAH, Interstitial nuclei of anterior hypothalamus-2,3 and 4 SCN, Suprachiasmatic nucleus SON, supraoptic nucleus Para ventricular nucleus Ventromedial nucleus

13. Sexual dimorphism…Anatomy INAH3 is much larger in men than in women Dendritic spines ●Neurotransmitter content ●Enzyme activity ●mRNA levels encoding for different proteins Hippocampal neurons increase spine density-Estradiol treatment

14. Brain nuclei, gender identity and sexual orientation 1. Hypothalamus S. Levay (1991). Science. 253:1034-7 ●A more recent study refutes this and finds no link between INAH-3 size and sexual orientation. (refer Byne et al (2001) Horm. Behav 40, 86-92 ● Studies are scant-great care should be drawn in basing conclusions on small numbers of studies ●Also pathologizing Homosexuality and gender dysphoria raises many ethical issues!

15. Brain nuclei, gender identity and sexual orientation 2. Limbic system Somatostatin staining in bed nucleus of stria terminalis Heterosexual female Heterosexual Man Male to female transsexual Homosexual man Kruijver et al (2000). JCEM.85, 2034

16. Disorders Post-Maturation

17. The Female Reproductive cycle

18. Disorders of the Female reproductive system: 1. Primary Amenorrhea (lack of menstruation-16 yrs) Compartment I : Anatomical defects of outflow tracts. Congenital absence of vagina and uterus (normal ovarian – 2o sex traits) Compartment II: Ovarian defects Congenital e.g. AIS or Turners Syndrome ( 45 X/46 XX, one X or incomplete)– Ovaries lack gametes- no oestrogen secretion-infertile and do not enter puberty Compartment III: Anterior pituitary disorders, tumours- Interruption of FSH and LH release thus ovary not stimulated to produce oestrogens Compartment IV: CNS disorders-hypothalamic Often congenital-Hypothalamic neurons do not secrete GnRH and thus no action on anterior pituitary-no FSH/LH release-no oestrogens Levay

19. Disorders of the Female reproductive system: 2. Secondary Amenorrhea ● Absence of menstruation for 3 or more cycles (6 months) Anorexia Pregnancy is most common cause of secondary amenorrhea McCance & Huether

20. Disorders of the Female reproductive system: 2. Secondary Amenorrhea- altered gonadotrophin secretion in female athletes Weight Loss/decreased body fat-lean ratios (availability of metabolic fuel decreases) Menstrual Disturbances GnRH (hypothalamus) decreased Hypogonadotropic hypogonadism Repeated release of stress and steroid hormones Exercise

21. http://www.endotext.org/female/female4/figures/figure4.jpg 3. Polycystic Ovarian Syndrome

22. PCOS details 1-Symptomology Affects 5-10% of women – resulting in infertility (inherited) Characterised by ● Anovulation (absence of ovulation) ● Elevated androgen levels ● Polycystic ovaries Enlarged Cyst http://www.mja.com.au/public/issues/180_03_020204/nor10314_fm.html

23. PCOS details 2-Pathophysiology: Key role for Hyperinsulinemia Obesity Hirsutism PCOS, linked to Diabetes mellitus type 2 and cardiovascular disease

24. Disorders of the Female reproductive system: 4. Hirsutism and Virilization Often a consequence of PCOS Hyperandrogenic http://www.mja.com.au/public/issues/180_03_020204/nor10314_fm.html Abnormal Adrenal Cortex metabolism Ovarian Tumour ● Increased muscle mass ● Clitoral Enlargement ● Increased libido Treatment – use of androgen antagonist- Cyproterone Acetate

25. Disorders of the Female reproductive system: 5. Premenstrual Syndrome (PMS) and premenstrual dysphoric disorder (PMDD)

26. Disorders of the Female reproductive system: 5. Premenstrual Syndrome (PMS) and premenstrual dysphoric disorder (PMDD) - aetiology PMS: occurs in luteal phase (menstrual cycle) producing behavioural changes that can affect relationships. PMDDis PMS in extreme form (2% of women) ►No hormonal pathology discovered Mental: ● Major depression ● Anxiety ● Irritability ● Anger dyscontrol ● Impairment of concentration Physical: ● Bloating ● Breast tenderness ►May be linked to abnormal response in CNS- linked to 5-HT ►SSRI’s can treat PMDD when prescribed in luteal phase

27. Hormone release and control of male gonad function Regulate bone growth in male

28. Male reproductive pathophysiology: ●Hypogonadism e.g. - Adult Leydig cell failure – fall in serum testosterone-sexual dysfunction (primary) - Gonadotropin deficiency - GnRH defect, hypothalamus (secondary) ●Hypergonadism e.g. - Virilizing (androgen secreting) tumour - Leydig Cell - Feminizing (estrogen secreting) Secondary – tumour in hypothalamus or pituitary (increased GnRH) ●Benign Prostatic hyperplasia (inflammation of prostate) - Up to 80% men, increases with age. May be a consequence of hormone imbalance and enhanced binding of androgen to receptors

29. ● Impotence – lack of circulating testosterone Postganglionic Prolonged Stimulation Viagra Multiple transmitter release

30. References: Boron, W. F. and Boulpaep (2005) Medical Physiology. Elsevier saunders Byne, W. (2001) The interstitial nuclei of the human anterior hypothalamus: An investigation of variation with sex, sexual orientation, and HIV status. Horm.Behav. 40, 86-92 Hadley, M. C. & Levine (2007) Endocrinology. 6th Edit, Pearson. Kruijver, FPM et al (2000) male to female transsexuals have female neuron numbers in a limbic nucleus. Journal of Clinical Endocrinology and Metabolism. 85:2034-2041 Levay S. and Valente, S.M. (2006) Human Sexuality, Sinauer Associates, Inc. Levay, S. (1991). A difference in hypothalamic structure between heterosexual and homosexual men. Science. 253:1034-7 McCance, K. L. & Huether, S. E. (2006). Pathophysiology. (The Biologic Basis for Disease in Adults and Children). 5th Edit. Elsevier Mosby. Purves et al (2008) Neuroscience, 4th Edit, Sinauer Sowell, E.R. et al (2007) Sex differences in cortical thickness mapped in 176 healthy individuals between 7 and 87 years of age. Cereb Cortex. 17 (7):1550-60 Tortora G. J. & Derrickson B.(2006). Principles of Anatomy and Physiology. 11th Edit, Wiley.