Female Reproductive Physiology. Dr Raelia Lew CREI, FRANZCOG, PhD, MMed, MBBS Fertility Specialist, Melbourne IVF

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1 Female Reproductive Physiology Dr Raelia Lew CREI, FRANZCOG, PhD, MMed, MBBS Fertility Specialist, Melbourne IVF

2 REFERENCE Lew, R, Natural History of ovarian function including assessment of ovarian reserve and premature ovarian failure Best Practice & Research Clinical Obstetrics and Gynaecology, July 2018

3 1 in 6 couples are affected by infertility Infertility is a W.H.O. medical condition, it is not a choice!!

4 Normal Time to Conceive Advice to couples: 100% 80% Cumulative Pregnancy Rate (%) 11% Seek advice after 12 months trying to conceive Seek advice earlier if: 60% 14% Maternal age is >35 40% 20% Known fertility concerns: STIs 20% Anovulation 0% 40% Sexual problems Endometriosis Known male factors Months or cycles of treatment

5 Physical Structures of Female Reproductive System Fallopian tube Ovary Sigmoid colon Uterus Bladder Pubic bone Cervix Rectum Anus Urethra Vagina

6 Uterine lining - endometrium Ovulated oocyte in the oviduct Sperm swimming through cervical mucous

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8 A lot goes on inside an ovarian follicle as an oocyte matures To produce a mature oocyte To assist the sperm to reach the egg To prepare and support the lining of the uterus To allow an embryo to hatch out and implant To support the luteal phase until placental transition Fertility & Sterility Cover; July 2009, Vol. 92, No.1.

9 A lot goes on inside an ovarian follicle as an oocyte matures Achieves this by: Oogenesis: to produce female gametes Secretion of hormones A pregnancy is dependent on the corpus luteum until 8 to 9 weeks gestation Fertility & Sterility Cover; July 2009, Vol. 92, No.1.

10 Early Folliculogenesis: the factors involved This process starts between 8 and 13 weeks of gestation

11 Oocyte Development At birth: Primary oocytes Oocytes arrest in prophase I of meiosis I Diploid (46 chromosomes) After puberty: Cyclic recruitment Developing oocytes complete meiosis I Haploid (23 chromosomes) secondary oocyte Extrusion of 1st polar body Around ovulation: Meiosis II begins Metaphase II oocyte Around fertilization: Meiosis II completed Extrusion of 2 nd polar body Text goes here Text goes here Text goes here Text goes here Text goes here Text goes here Text goes here The LH surge is critical for final oocyte maturation HCG can be used in ART

12 Connection between the Brain and the Female Reproductive System A feedback system of hormones secreted by the ovary, hypothalamus and pituitary

13 FSH and LH production in an orderly fashion is key to the development of a mature oocyte that can become a baby

14 FSH and LH only act in the final weeks of the development of a mature surviving oocyte Folliculogenesis occurrs independently of gonadotrophin stimulation McGee and Hsueh (2000).

15 Antral Follicle Thecal Cells Granulosa Cells Cumulus Cells Egg - Oocyte

16 FSH and LH Granulosa cells are the only cells in women to possess FSH receptors Antral formation becomes FSH dependent, when follicles reach about 0.25mm in diameter antrim Granulosa cells develop LH receptors when the follicle is >11mm in diameter ~ day 8 or 9 of follicular phase The pre-ovulatory surge of gonadotropins (FSH and LH) is essential to induce the resumption of meiosis

17 Ovarian steroidogenesis is LH dependent LH receptors are present in ovarian theca and granulosa cells. antrim Theca cells produce androgens in response to LH FSH induces aromatisation of androgens to estrogens in granulosa cells.

18 Two cell, two gonadotrophin theory FSH alone is required for follicular growth Some LH is essential: achieves steroidogenesis develops the capacity of a follicle to ovulate and luteinise Inhibin B secreted by granulosa cells in response to FSH, directly suppresses pituitary secretion. Activin originating in both pituitary and granulosa, augments FSH secretion and action.

19 Two cell, two gonadotrophin theory The maturing follicle reduces its dependence on FSH by acquiring LH receptors

20 OVULATION LH Surge >20IU/l required for Ovulation Continuation of meiosis in the oocyte Frees oocyte from follicular attachments luteinisation of the granulosa synthesis of progesterone Progesterone + proteolytic enzymes + prostaglandins rupture of the follicular wall E 2 LH Early progesterone rise premature luteinisation adversely affects pregnancy potential

21 Endocrine Testing Follicular phase: LH and FSH Follicle growth Oestrogen Timing Ovulation LH, Progesterone Luteal phase Progesterone

22 Maternal Age and Oocyte Numbers A woman has her maximal quota of eggs when her mother is 6 months pregnant

23 Assessing a Woman s Fertility Potential Antral follicle count normal 6 to 12 Antral Follicle

24 Assessing a Woman s Fertility Potential Early Follicular phase FSH Normal <10IU/L Inhibin A&B secreted by granulosa cells in response to FSH, directly suppresses pituitary secretion.

25 Assessing a Woman s treatment options: Anti Mullerian Hormone Text goes here.. Antral Follicle Anti-mullerian hormone is secreted by granulosa cells

26 Anti-Müllerian Hormone (AMH) Testing in Women

27 What is the role of Anti-Müllerian Hormone (AMH) in Women? Inhibition on follicle recruitment into the antral cohort Reduces the sensitivity of growing follicles to FSH.

28 Why test Anti-Müllerian Hormone (AMH) in Women? Simple blood test Estimates ovarian reserve Estimates ART fertility potential Predicts response to controlled ovarian hyperstimulation

29 AMH: Pitfalls Patient and cyclic variation Assay variation COCP suppresses Does not reflect egg quality Does not influence spontaneous fecundity as a stand alone measure

30 Anti-Müllerian Hormone Age Relationship AMH levels pm 100 Probable PCOS Upper 10 Median Lower 1 Diminishing Ovarian Reserve Guideline only. Statistical analysis on data from Natural Conception Patients Age Values of AMH below the optimal range indicate a low antral follicle count and therefore reduced reproductive capacity.

31 Very high levels AMH Unilateral pleural effusion What is this??

32 AMH Usefulness as a Predictor of Live Birth 88 women, aged 25 to 40 years, TTC with AMH levels <1.1pmol/L 5 year follow-up: Cumulative pregnancy rate 61% 57 pregnancies, includes spontaneous and ART Low AMH does not mean a woman cannot conceive naturally or on treatment Yarde et al, Eshre, July Anti-Müllerian hormone as predictor of live birth in imminent ovarian failure.

33 To Conclude What to Believe AMH is a useful screening tool for measuring a woman s ovarian reserve. AMH testing can be done at any time in the menstrual cycle. However AMH it is not an absolute indicator of ovarian reserve, just a guideline. AMH is not a measure of a woman s chance of actually conceiving in the immediate future. Therefore, a woman should never be advised she is unable to have a child or treatment on the basis of an AMH level alone!

34 Fertility Rate (per 100 women) Effect of Maternal Age Fertility and Miscarriage Rates Miscarriage Rate (percentage) Fertility As a woman s age increases her fertility decreases and her risk of miscarriage increases Miscarriage >45 Maternal Age (Years)

35 Effect of Maternal Age on Live Birth Rates after IVF Using a Woman s Own Oocytes Live Births (percentage) Woman s Age (years)

36 A woman is only half the baby It takes two to tango A male factor is present in 50% of infertile couples In 30%, a male factor is the main issue

37 Time to Conception for a 25 year old Woman vs. Male Partners Age Time to Pregnancy (months) 25 4x longer x longer 5 0 Hassan et al, F&S 2003, 2006 < >40 Male Partner s Age (Years) Likelihood of conception following IVF is halved for women 38 to 40 years if their partner is aged 40 years or older.

38 An egg and sperm contribute an equal amount of genetic material to a pregnancy. The placenta is largely dependent on the expression of genes from the paternal chromosomes. Miozzo and Simoni, 2002, Biol. Neonate; 81:

39 Questions? Fertilised egg in fallopian tube