The reproductive lifespan - PDF Free Download

The reproductive lifespan Reproductive potential Ovarian cycles Pregnancy Lactation Male Female Puberty Menopause Age

Menstruation is an external indicator of ovarian events controlled by the hypothalamicpituitary axis Feedback Hypothalamus GnRH (gonadotrophin Pituitary releasing hormone) LH FSH + ( gonadotrophins ) Ovaries (oestradiol, progesterone). Steroids Roles of the ovary 1. Gametes (ova) 2. Hormones MENSTRUATION Reproductive tract Other targets

What are oestrogens? Oestradiol-17b OH CH 3 Ovaries Testes Placenta HO Brain Bone Answer: Steroids with characteristic effects, esp. on female reproductive tract. Some are more potent than others. ` Breast Cardovascular system Reproductive tract

Hypothalamus GnRH pulse generator Pulsatile activity of GnRH neurones Pituitary GnRH Pulses of GnRH + LH FSH Pulses of LH Plasma LH Ovaries 24 hours

Natural suppression Before puberty Lactation Diet induced Anorexia Malnutrition Exercise Hypothalamic neurones GnRH pulse generator Modulation during menstrual cycle Diet Stress? Pituitary Frequency and amplitude of GnRH pulses Changing patterns of LH and FSH

Timing events in the menstrual cycle. 1. Onset of menstruation Day 1 Day 1 0 4 8 12 16 20 24 28 Menstruation

Timing events in the menstrual cycle. 2. LH surge Days before Days after LH Day 1 Follicular phase Luteal phase Day 1 0 4 8 12 16 20 24 28 Menstruation OVULATION

Animated ovarian events Key events in the ovarian cycle Day 1 1. Follicular growth LH 0 4 8 12 16 20 24 28 Menstruation Oestradiol OVULATION

Animated ovarian events Key events in the ovarian cycle Day 1 1. Follicular growth 2. Ovulation LH 0 4 8 12 16 20 24 28 Menstruation Oestradiol OVULATION

Animated ovarian events Key events in the ovarian cycle 2. Ovulation LH Day 1 1. Follicular growth 3. Luteal function 0 4 8 12 16 20 24 28 Menstruation Oestradiol OVULATION Progesterone (and oestradiol)

Animated ovarian events Key events in the ovarian cycle 2. Ovulation LH Day 1 1. Follicular growth 3. Luteal function 4. Luteal regression 0 4 8 12 16 20 24 28 Menstruation Oestradiol OVULATION Progesterone (and oestradiol)

The follicle is the fundamental element of the ovary: Blood vessels Theca Granulosa cells Antrum Cumulus cells Oocyte Zona pellucida (non-cellular glycoprotein coat)

Oocyte Cumulus cells Cytoplasmic bridges from cumulus cells to oocyte for transport Zona pellucida (non-cellular glycoprotein coat)

Where do follicles come from?

Male Female Spermatogonia Primordial germ cells (oogonia) Continuous replacement in adult Mitoses stop in fetal life Mitoses Meiosis All enter MEIOSIS Spermatozoa This means there is a fixed, Continuous limited sperm pool of production oocytes. Arrested in 1st meiotic division Primary oocytes in primordial follicles

~7 m (Fig adapted from Johnson & Everitt, 2000) Continuous loss No. of germ cells (millions) 99.9% by Atresia Ovulation (post-puberty) BIRTH Puberty ~ 300,000 Conception 3 6 9 months 1 10 20 40 years Age from conception

Growth of follicles: Antral follicle Graafian follicle Primordial follicle Oocyte Granulosa cells Thecal cells Antrum (fluid filled space) Ovulation

Lets look at follicular growth first There are a number of questions to ask How many follicles reach this point? Normally 1 Ovulation Menstruation

Many! 30-50 How many follicles are growing at the start of the cycle? Ovulation Menstruation

Many! 30-50 How many follicles are growing at the start of the cycle? Why is only 1 selected and becomes dominant? When do follicles start growing? Ovulation 2-3 months earlier! Menstruation

What controls follicular growth? Hypothalamus Pituitary GnRH (gonadotrophin releasing hormone) Steroid feedback Ovaries + LH FSH ( gonadotrophins ) Oestradiol (E 2 ) + Reproductive tract Other targets

What controls follicular growth? OVULATORY FOLLICLE?????? Gonadotrophin independent FSH + LH Ovulation Menstruation

OVULATORY FOLLICLE FSH + LH Ovulation Menstruation OESTRADIOL As each follicle grows, it produces increasing amounts of oestradiol.

How is oestradiol production controlled? Theca Granulosa cells LH (Note: the production of androgens is a normal part of ovarian physiology) Androgens FSH Inhibin (protein) Androgens are converted (aromatized) to oestradiol by the granulosa cells OESTRADIOL (steroid)

_ Hypothalamus Pituitary GnRH (gonadotrophin releasing hormone) Increasing amounts of oestradiol. Ovaries + FSH LH Oestradiol (E 2 ) + Reproductive tract Other targets

Increasing negative feedback Increasing amounts of oestradiol. _ Hypothalamus Pituitary INHIBIN (suppresses FSH) Ovaries + GnRH Decreased FSH (gonadotrophin releasing hormone) Oestradiol (E 2 ) + Reproductive tract Other targets

As the follicles grow, FSH levels fall due to the negative feedback FSH Oestradiol 0 4 8 12 16 20 24 28

Many follicles at the start of the cycle Why is only 1 selected and becomes dominant? Ovulation Menstruation

Hypothalamus Pituitary GnRH Ovaries + FSH Small follicles: very dependent on FSH Oestradiol (E 2 ) Large follicles: less dependent on FSH Population of growing follicles

Hypothalamus Pituitary GnRH + FSH Small follicles: very dependent on FSH Ovaries Oestradiol (E 2 ) Large follicles: less dependent on FSH

Oestradiol Hypothalamus Increasing _ negative feedback Pituitary INHIBIN Ovaries + GnRH Decreased FSH Insufficient FSH Small follicles: very dependent Oestradiol (E 2 ) on FSH Large follicles: less dependent on FSH Growth factors Oestradiol + + Dominant follicle

FSH secretion suppressed FSH Oestradiol Dominant follicle(s) can survive Insufficient FSH to keep smaller follicles going they become atretic. 0 4 8 12 16 20 24 28

Theca Granulosa cells LH (Note: the production of androgens is a normal part of ovarian physiology) Androgens FSH Androgens are converted (aromatized) to oestradiol by the granulosa cells OESTRADIOL (steroid)

4. The disturbed steroid feedback may re-inforce the abnormal LH/FSH secretion 1. Raised LH, lowered FSH 3. The high LH induces high androgen secretion from the theca HIRSUTISM 2... leads to disturbed follicle growth ANOVULATION Disturbed cycles

4. The disturbed steroid feedback re-inforces the abnormal LH/FSH secretion 1. Raised LH, lowered FSH 3. The high LH induces high androgen secretion from the theca HIRSUTISM 2... leads to disturbed follicle growth ANOVULATION Disturbed cycles

What causes ovulation? 0 4 8 12 16 20 24 28

What causes ovulation? LH 0 4 8 12 16 20 24 28

What effects does it have? What causes the LH surge? 0 4 8 12 16 20 24 28

NOT HUMANS! What causes the LH surge? Reflex ovulation 0 4 8 12 16 20 24 28 Mating Neuroendocrine reflex LH

Oestradiol 0 4 8 12 16 20 24 28

For most of the cycle, negative feedback operates _ Hypothalamus _ GnRH Pituitary Oestradiol Ovary LH FSH Inhibited by oestradiol

BUT, with high levels of E2 maintained for long enough + Hypothalamus + Pituitary GnRH Oestradiol Ovary LH FSH LH surge

BUT, with high levels of E2 maintained for long enough + Hypothalamus Increased GnRH Oestradiol + Pituitary Ovary Increased GnRH sensitivity to GnRH LH FSH LH surge

How does the LH surge affect the follicle? About 36 h between LH surge and oocyte release..

Oocyte: Completion of the 1st meiotic division (unequal division; extrusion of 1st polar body) 2nd meiotic division starts but becomes arrested before completion. Microvilli across the zona pellucida are withdrawn. Loosening of cumulus cells

Enzyme induction in the follicle wall

Transformation of ruptured follicle into corpus luteum (CL) Ruptured follicle becomes solid corpus luteum Thecal cells and blood vessels invade Granulosa cells hypertrophy and terminally differentiate ( luteinisation ). Steroid secretion changes Progesterone + Oestradiol

Follicular phase: Oestradiol domination Oestradiol Progesterone Luteal phase: Progesterone domination What maintains the CL? Why does the CL degenerate at the end of the cycle? 0 4 8 12 16 20 24 28 OVULATION

What maintains the CL? 8 hr between LH pulses Hypothalamus Pituitary GnRH + LH (low levels) CL Progesterone + E 2 CL very sensitive to LH

What maintains the CL? Hypothalamus Steroid negative feedback keeps LH and FSH levels relatively low Progesterone + E 2 Reproductive tract etc - - Pituitary + CL GnRH LH (low levels in luteal phase) CL very sensitive

Towards the end of the cycle, the sensitivity to LH reduces. The low levels of LH are insufficient to keep the CL going Hypothalamus Pituitary LH GnRH Progesterone + E 2 CL degenerates

Hypothalamus As CL degenerates steroid negative feedback reduces... Pituitary FSH + LH GnRH Progesterone + E 2

Hypothalamus As CL degenerates steroid negative feedback reduces Pituitary FSH + LH GnRH New wave of follicles stimulated by rising FSH and LH Progesterone + E 2

Oestradiol Progesterone 0 4 8 12 16 20 24 28 OVULATION

Other changes in the cycle a) Outer muscle layer the myometrium b) Inner glandular mucosa the endometrium

Uterine changes in the menstrual cycle. Endometrial depth Oestradiol causes an increase in thickness (the proliferative phase ) More secretion from the glands hence the term secretory phase 0 4 8 12 16 20 24 28 Menstruation OVULATION

Terminal differentiation of stromal cells decidualisation Characteristic spiral arteries 0 4 8 12 16 20 24 28 Optimal time for Menstruation implantation

What causes the onset of menstruation? Steroid levels fall This is followed by the onset of menstruation

1. At end of the luteal phase, steroid production declines. 2. Loss of oedema and gradual shrinking of endometrial tissue. The spiral arteries become more highly coiled 3. Gradual reduction in blood flow to superficial layers leading to ischaemic hypoxia and damage to the epithelial and stroma cells. 4. 4-24 hours prior to menstrual bleeding, an intense constriction of spiral arteries occurs. 5. Individual arteries re-open at different times, tearing and rupturing the ischaemic tissues. 6. Bleeding into the cavity occurs via: 1. red cells diapedese between surface epithelial cells; 2. tears develop in the surface epithelium 3. pieces of weakened superficial endometrium crumble away 7. About 50% of degenerating tissues is resorbed and 50% is lost as 'menstrual bleeding'.

Onset of menstruation is rapid. Probably 95% of women have a total blood loss of less than 60 mls. This blood loss can represent a significant loss of iron (leading to anaemia) especially in women on marginal diets

Menstruation - WHY? In preparation for pregnancy, the human uterine stromal cells go through complex changes and the stromal cells terminal differentiate - Decidualization. If implantation and pregnancy do not occur, this tissue is lost - and the uterus prepares itself again for another possible pregnancy.

38 37.8 37.6 37.4 37.2 37 36.8 36.6 36.4 36.2 36 Basal body temperature A small (0.5 o C) rise in BBT typically follows ovulation. 0 4 8 12 16 20 24 28 LH Menstruation OVULATION

Fertility Oestradiol Progesterone LH Ovulation 0 4 8 12 16 20 24 28 OVULATION