Reproductive Physiology II

- Begins with perimenopause: irregular and unpredictable menses (early >7 days; late 3-11 months amenhorrhea)
- Increased levels of FSH (follicular phase), no effect on LH
- Driven primarily by decreased inhibin B secretion (cessation of negative FB)
- This can cause spontaneous development (recruitment) of many follicles, but atresia at of these follicles is also common
- LH surge can fail to trigger ovulation which leads to decline in oestrogen and progesterone production

1 year of amennhorrhea

Clinical decline in total testosterone, and free testosterone, as well as sexual symptoms (reduced libido, activity and spontaneous erections)

Vascular instability
Hot flushes and night sweats Migraine
Vaginal
itching dryness bleeding watery discharge Urinary prblems Increased susceptibility to inflammation and infection, for example vaginal thrush and UTI
Skeletal
Osteopenia and increased risk of osteoporosis Joint pain, muscle pain Back pain
Skin, soft tissue
Breast atrophy Skin thinning and reduced elasiticity Redistribution of adipose tissue and obesity
Psychological
Mood swings Irritability Fatigue Memory loss Depression and/ or anxiety Sleep disturbances
Sexual
Reduced libido Vaginal dryness Problems reaching orgasm and painful intercourse

- Vasomotor disorder (constriction of blood vessels supplying skin) occurs late in transition to early menopause
- Caused by declining levels of oestrogen
- Oestrogen therapy provides best treatment

- Decreased bone density, increased fracturing and compressing of vertebrae
- Caused by declining levels of oestrogen
- Pregnancy, lactation and lack of exercise can also be causes

- Post menopausal women are more likely to have central fat distribution, which can increase the risk of type II diabetes, cardiovascular disease, coronary heart disease, stroke, atherosclerosis (thickening of artery wall) and poor immune function

Premarin is a combination of oestrogens (oestradiol, oestrol and oestrone) used with or without progestin

-Symptoms of menopause can be alleviated, can prevent osteoporosis in women suffering osteopenia (below normal bone density)
-Can decrease cholesterol and incidence of hypertension

Increased risk of:
- a coronary event (age dependent)
- breast cancer
- venous thromboembolism
- Stroke
- Uterine cancer (oestrogen alone)
- Ovarian Cancer
- Vaginal Bleeding
- Breast Tenderness
- Prostate cancer

These naturally occurring compounds (found in plants/ food) have very similar chemical structure to oestrogen and can bind to ER and mimic E actions

- Menstrual history: how many days between 1st day of bleeding – 1st day of next cycle
- Painful periods (dysmenorrhoea)? Can indicate ovulation has occurred
- PMS? Indicates elevated progesterone
- Mucus changes can indicate ovulation (volume increases as oestrogen levels rise)

- Progesterone levels in blood
- Ultrasound to see follicle
- Temperature: increases after ovulation
- Vaginal cytology: changes throughout cycle

Ampulla

It blocks the negative feedback of oestrogen at the pituitary, thereby increasing FSH levels and inducing follicle development and ovulation (monitor temperature changes)
Sperm count and tubes should be tested prior to treatment

- Injection of FSH can induce ovulation
- Injection of human chorionic gonadotrophin mimics LH surge
- Multiple pregnancy rates still occur
- Sperm count and tubes should be tested prior to treatment

1. Controlled stimulation of ovaries so many eggs are released
2. Monitoring (Ultrasound and oestrogen assay)
3. Oocyte collection
4. Fertilise and culture eggs in vitro
5. Embryo transfer day 3-5

Cause of 60% IHH cases (ideopathic hypogonadotrophic hypogonadism): low reproductive hormones, X-linked disorder, malfunction of factor involved with migration of GnRH (and olfactory) neuron to brain

- Hyperandrogenism and menstrual dysfunction (anovulation/ irregular ovulation) and/or polycystic ovaries
- Other causes must first be excluded

- Elevated oestrogen levels
- Insulin resistance (hyperinsulinaemia)
- Obesity
- Chronic anovulation

- Hyperinsulinaemia (excessive insulin production)
- Rapid GnRH pulsatility (both of which cause)
- increased LH production
- Increased androgen production (by thecal cells)
- Decreased FSH production
- Decreased progesterone

Hormone binds GPCR - 2nd messenger activated (IP3) - IP3 allows release of Ca++ from endoplasmic reticulum - Ca++ opens ligand gated Na+ channels - rapid depolarisation - voltage gated Ca++ channels open --> Ca++ allows contraction

Ca++ binds to calmodulin and this complex binds to myosin light chain kinase (MLCK), entire complex then phosphorylates myosin releasing energy and allowing contraction

- Binding if certain GPCRs activates cAMP which activates PKA
- PKA prevents Ca/Cam from binding to MLCK thus prevents contraction
- PKS also targets plasma membrane and ER Ca++ pump
- PKA hyperpolarises membrane by phosphorylating K+ channels

Innervation releases ATP which acts on P2X receptors to cause initial fast contraction and NA acts on alpha-adrenoreceptors to cause slower contraction.

Parasympathetic stimulation: Ca++ activates NOS - NO synthesised - (NO acts on guanlyl cyclase - cGMP produced - PKG activated) NO is dilator

Adipocity

Adipose Cells

Fasting or chronic under nutrition and low body weight

Control group where food is reduced matches the appetite reducing effects of Leptin (ie to observe effects are not only due to reduced food intake)

As well as a control group (ad lib fed) and a leptin treated group, there would need to be a group fed the same amount as the leptin treated group (who have decreased food intake).
(This group would experience decreased LH secretion)

Leptin administration can restore LH pulsatile secretion, by 'fooling' the brain that there is not a negative energy balance

Leptin effects GnRH neurons (indirectly) as well as the anterior pituitary and the gonads

- Increased positive feedback of oestrogen on HPG axis
- Increased LH secretion
- Early pubertal maturation
- More sexually active
- Have more pregnancies, higher number of offspring

Adrenaline increases immediately and rapidly, and decreases rapidly;
Cortisol increases and decreases more slowly. Layered stress keeps cortisol elevated.

Elevated cortisol, decreased LH pulse amplitude, no LH surge, no follicular development of ovulation.

Reduces pituitary responsiveness to GnRH, and decreases GnRH pulse amplitude

Phytoestrogens are naturally occurring compounds linked to a protective effect on the prostate - they can cause cell death of prostate cancers and have a preventative or therapeutic potential.
Phytoestrogens stimulate ERβ, which has apoptitic effect on tumours.