Endocrine Therapy

• GnRH - regulating hormone

  • secreted from the hypothalamus
  • initiates secretion of LH and FSH
• LH - regulating hormones

  • secreted from the anterior pituitary gland
  • triggers ovulation
  • converts the follicle into the corpus luteum
• FSH - regulating hormone

  • secreted from the anterior pituitary gland
  • initiates folicular growth
• The Hypothalamic-Pituitary (HPO) Axis

  • a tightly regulated system controlling female reproduction
  • hypothalamic neurons act in an auto- and paracrine manner to modulate pulsatile GnRH secretion
  • GnRH stimulates FSH and LH secretion from the anterior pituitary gland
  • FSH and LH in turn stimulate the development of ovarian follicles and the production of estradiol by the ovaries
• The Reproductive Cycle

  • average cycle length is about 28 +/-4 days
  • Depends on hormones concentrations in the blood and everything is controlled by the hypothalamus pituitary axis
  • Ovarian and uterine cycles are two different cycles that co-operate together
  • Hormones form the ovarian cycle can influence the uterine cycle
  • Ovarian cycle = follicle maturation and corpus luteum development
• FSH – promotes maturation of ovarian follicle maturation, and secretion of oestrogen leading to ovulation

  • Is active in the first half  of the cycle, after ovulation its secretion is supressed to prevent other follicle to mature
• LH - triggers ovulation also stimulates the development of the corpus luteum and the secretion of progesterone
• phases of the menstrual cycle - ovarian cycle

  • pre-ovulation = follicular phase
  • post-ovulation = luteal phase
• phases of the menstrual cycle - uterine cycle

  • pre-ovulation = period & proliferative phase
  • post-ovulation = secretory phase
• (I) Folicular phase

  • pituitary hormone effect: LH and FSH stimulate several follicles to growth
  • ovarian hormone effects: follicles produce low levels of oestradiol that:
  • (a) inhibit GnRH secretion by the hypothalamus, keeping LH and FSH low
  • (b) cause endometrial artiest to constrict resulting in menstruation
• (II) ovulation

  • pituitary hormone effects: LH and FSH estimulate maturation of the one of growing follicles
  • ovarian hormone effects: growing follicles begin to produce high levels of estradiol which:
  • stimulate GnRH secretion by the hypothalamus
  • LH and FSH levels rise, resulting in ovulation
  • cause the endometrium to thicken
• (III) luteal phase

  • pituitary hormone effects: LH stimulates growth of a corpus lute from follicular tissue left behind after ovulation
  • ovarian hormone effects: the corpus lute secretes estradiol and progesterone that:
  • block GnRH production by the hypothalamus and LH and FSH production by the pituitary
  • cause the endometrium to further develop
• LHRH = luteinising hormone releasing hormone
• reproductive hormones - progesterone

  • source: corpus luteum
  • functions: steroid hormone, helps in the growth of the endometrium, promotes implantation, support pregnancy
  • higher level: irregular periods, lower sexual activities
  • lower level: perimenopause, unable to carry the pregnancy
• reproductive hormones - testosterone

  • source: interstitial cells
  • functions: male sex hormone, stimulates the synthesis of sperm cells, regulate functions of male sex hromone, helps in the metabolism
  • higher level: changes in testicles, PCOS in women, lowering of sperm
  • lower level: decrease in activities secondary sex, depression, loss in sexuality
• reproductive hormones - oestrogen

  • source: ovarian follicles
  • functions: female sex hormone, regulate functions of female reproductive system, development of mammary gland, helps in milk secretion
  • higher level: gynecomastia in males, irregular menstrual cycle, depression, overweight, endometriosis
  • lower level: irregular periods, earlier menopause, osteoporosis
• Disorders of Menstruation

  • Amenorrhea
  • Polymenorrhea
  • Oligomenorrhea
  • Dysmenorrhea
  • Menorrhagia
• Amenorrhea – absence of period in reproductive women (weight loss)
• Polymenorrhea – cycle lasting <21 days
• Oligomenorrhea –cycle lasting >35 days
• Dysmenorrhea – painful period
• Menorrhagia – abnormally prolonged and heavy period associated with increased blood loss
• Kallmann syndrome combines an impaired sense of smell with a hormonal disorder that delays or prevents puberty

  • The hormonal disorder is due to underdevelopment of specific neurons, or nerves, in the brain that signal the hypothalamus
• Polycystic Ovarian Syndrome (PCOS)

  • It is a complex and heterogenous, endocrine disorder whereby polycystic ovaries are one of an array of possible symptoms caused by an underlying hormone imbalance
  • One of the most common endocrine-reproductive-metabolic disorders in females since prehistory and remains a major cause of infertility
• The term polycystic ovaries describes ovaries that may contain many small “cysts”

  • Usually, no bigger than 8 millimetres each (2-10 mm)
  • located just below the surface of the ovaries
  • fluid-filled sacs
  • they are actually follicles that have not matured to be ovulated
  • Increased stromal echo Increased ovarian volume
• • PCOS is linked to reproductive and metabolic disturbances as well as to psychiatric conditions such as anxiety and depression
  • Women with PCOS also have hyperinsulinaemia independent of obesity, which further stimulates theca cells of ovary to produce testosterone, exacerbates LH hypersecretion and lowers the production of sex hormone-binding globulin (SHBG) in the liver, thereby further increasing hyperandrogenaemia
  • increased risk of obesity, which not only worsens all symptoms of this syndrome but also causes PCOS
• Macrophages, neutrophils, T lymphocytes, DCs and NK cells are involved in pathogenesis of PCOS (MUST KNOW)

  • The abnormal expression of immune cells can cause immune function disorder or the imbalance of the proportion of immune-related factors
• Clinical and/or Biochemical Signs of PCOS

  • Oligomenorrhoea
  • Anovulatory infertility
  • Hyperandrogenism
  • Obesity or overweight
  • Insulin resistance
  • Irregular menstruation
• Symptoms of PCOS

  • Excessive body hair growth
  • Weight changes and trouble losing weight
  • Ovarian cysts
  • Low sex drive
  • Irregular or missed periods
  • Male pattern baldness thinning hair
  • High testosterone levels
  • Insulin resistance
  • Fatigue
  • Acne
  • Mood changes
  • Trouble conceiving or infertility
• PCOS Early Signs – Adolescence

  • Insulin resistance has reportedly increased in last decade
  • Paediatric Endocrinologists trending towards an earlier work-up then compared to traditional practice of waiting 2-years post-menarche (first menstruation) 
  • Diagnosing PCOS is challenging given the developmental issues in this group
  • Many features of PCOS are common in normal puberty, for example, acne, menstrual irregularities, and hyperinsulinemia
  • Menstrual irregularities with anovulatory cycles occur due to the immaturity of the HPO axis during the first 2 to 3 years after menarche
• PCOS phenotype A

  • hyperandrogenism
  • ovulatory dysfunction
  • polycystic morphology
• PCOS phenotype B

  • hyperandrogenism
  • ovulatory dysfunction
• PCOS phenotype C

  • hyperandrogenism
  • polycystic morphology
• PCOS phenotype D

  • ovulatory dysfunction
  • polycystic morphology
• Anti-Mullerian Hormone (AMH)

  • A peptide growth factor of the transforming growth factor-β family, is a reliable marker of ovarian reserve
  • AMH is supposed to regulate the number of growing follicles and their selection for ovulation
  • AMH decreases with age
• Influencing Factors in the Development of PCOS

  • Chronic anovulation
  • Oxidative stress
  • Abnormal gut microflora
  • Autoimmune response
  • Chronic inflammation
  • Lipid metabolism disorder
  • Insulin resistance
  • Hyper-androgemia
• complications of PCOS

  • endometrial cancer
  • sleep apnea
  • depression
• complications of PCOS - endometrial cancer

  • Long-term follow-up of 786 PCOS women found an increased risk of endometrial cancer
  • Women >50 yrs of age with endometrial cancer, PCOS (62.5%) more prevalent than not (27.3%; P=0.033)
• complications of PCOS - sleep apnea

  • Increased Sleep Disordered Breathing (SDB) and daytime sleepiness in PCOS vs. controls
• complications of PCOS - depression

  • Higher prevalence in PCOS patients, associated with higher body mass index (BMI, P=0.05) and greater insulin resistance (P=0.02)