1. Centre For Reproductive Biology University of Edinburgh
Mechanisms of Anovulation Regulation of Ovarian cycle and its disorders
David T Baird
Emeritus Professor of Reproductive Endocrinology
Centre For Reproductive Biology
University of Edinburgh
Scotland

2. OVULATION Extrusion of the appropriate number of eggs of
good quality at a time when they can be
fertilized (developmentally competent )

4. Regulation of the Ovarian Cycles and its Disorders
Folliculogenesis
Physiology of Normal Ovarian Cycle
Disorders of Ovulation
Ovarian Insufficiency(Primary ovarian failure)
Secondary ovarian insufficiency

5. Folliculogenesis inWomen

6. Folliculogenesis inWomen
InA
InB E2
InA
InB
AMH
InB
AMH 

7. Regulation of the Ovarian Cycles and its Disorders
Folliculogenesis
Physiology of Normal Ovarian Cycle
Disorders of Ovulation
Ovarian Insufficiency(Primary ovarian failure)
Secondary ovarian insufficiency

8. Endocrine Control of Ovarian Cycles
Ovarian cyclicity is dependant on intact Hypothalamic-Pituitary-Ovarian Axis.
Maturational change in Hypothalamic Pituitary Unit at puberty manifest by increasing secretion of FSH and LH and ovarian secretion of estradiol
Negative feedback inhibits secretion of FSH (and LH)
Positive feedback induces LH surge

9. Hypothalamic-pituitary-ovarian Axis
Kisspeptide

10. Endocrine Control of Ovarian Cycles
Ovarian cyclicity is dependant on intact Hypothalamic-Pituitary-Ovarian Axis.
Maturational change in Hypothalamic Pituitary Unit at puberty manifest by increasing secretion of FSH and LH and ovarian secretion of estradiol
Negative feedback inhibits secretion of FSH (and LH)
Positive feedback induces LH surge

11. Establishment of ovulatory cycles
Early in puberty anovulatory cycles relatively common
Manifest by irregularity in length of menstrual cycles and duration of bleeding which are often relatively painless
Delay in maturation of H-P to generate LH surge
Within a few months regular monthly periods (often painful) become established

12. Schematic Representation of Hormonal Changes in Human Menstrual Cycle
Marshall & Eagleson 1997

13. Final stage of Follicle Development in Women
Selection

14. Final stage of Follicle Development in Women
Selection

15. Final Selection of the Ovulatory follicle
Threshold
Single Ovulation LH
FSH
Atresia
Baird 1987

16. How does ovulatory follicle survive in environment when FSH falls below threshold ?
Increasingly sensitive to FSH
Paracrine factors within follicle
Can use LH as partial surrogate (LH receptors on granulosa cells)

17. Large Follicles are responsive to LH as well as FSH
Normal Cycle
Ovarian responses in macaques to pulsatile infusion of follicle-stimulating hormone (FSH) and luteinizing hormone: increased sensitivity of the maturing follicle to FSH. Zeleznik AJ Kubic CJ Endocrinology119: (1986) FSH and control of follicle growth in women Glasier AF,BairdDT& Hillier SG J Steroid Biochem 32: (1989) Examination of the relative roles of FSH and LH in the mechanism of ovulatory follicle selection in sheep Campbell BK,DobsonH, BairdDT&Scaramuzzi RJ J Reprod Fertil 117: (1999)

19. Local Follicular Factors

20. Regulation of the Ovarian Cycles and its Disorders
Physiology of the Ovarian Cycles
Disorders of Ovulation
Ovarian Insufficiency(Primary ovarian failure)
Secondary ovarian insufficiency

21. Ovary devoid of oocytes cannot function as an endocrine gland
Ovarian Insufficiency (failure) Michel De Vas,Paul Devroey & Bart Fauser Lancet :376(9744):911-21
Ovary devoid of oocytes cannot function as an endocrine gland
High levels of FSH and LH ,low estradiol and AMH : often amenorrhoea
Reduced number of oocytes may be insufficient to maintain repeated ovarian cyclicity(“incipient ovarian failure”)
Multiple causes of primary ovarian insufficiency

22. Primary ovarian Insufficiency (failure) Michel De Vas,Paul Devroey & Bart Fauser Lancet :376(9744):911-21
Accelerated rate of loss of primordial follicles leads to premature ovarian insufficiency
Reduced concentration of AntiMullerian Hormone(AMH) and small antral follicle count (AFC)
Rarely “resistant ovary” normal number of oocytes but “resistant “ to development eg. due to mutations in FSHR

23. 2 Hypogonadotrophic Hypogonadism(WHO 1)
Secondary ovarian failure Insufficient or inappropriate stimulation of ovary
2 Hypogonadotrophic Hypogonadism(WHO 1)
Low levels of LH,FSH and estradiol
No bleeding in response to gestogen challenge
Hypothalamic causes include Kallman,s Syndrome,craniopharyngioma, and hypothalamic suppression in association with weight loss, stress etc
Pituitary causes: Tumour (prolactinoma)Infarction(Sheehan’s Syndrome
Amenorrhoea or oligomenorrhoea
FSH,LH and Estradiol within normal range but subtle disorder of pattern of pulsatile LH
Gestogen challenge positive
Polycystic or Multicystic Ovaries
Some may be due to failure to respond to estrogen with LH surge leading to anovulatory cycles

24. Regulation of the Ovarian Cycles and its Disorders
Disorders of Ovulation
Hypergonadotrophic hypogonadism (Primary ovarian failure or insufficiency)
Hypogonadotrophic Hypogonadism( WHO1)
Hyperprolactinaemia
Normogonadotrophic anovulation (WHO2)
Baird DT 1997 Lancet 350:9073,

25. Mechanisms of Anovulation- Normoganadotrophic
Inability to generate LH surge in response to estrogen challenge
Lack of maturation of HPO axis at puberty
Steroids “ectopic” to HPO axis eg adrenal androgens,progestogens (eg CAH)
Dysfunction of Follicle maturation
Premature acquisition of LH receptors by small antral follicle
Relative lack of FSH at critical point when follicle selected for final ovulatory maturation eg PCO

26. Mechanisms of Anovulation
Failure of follicle rupture LUF
Inappropriate LH surge (Stouffer 1999)
NSAID (Killick & Elstein 1987 Fert Steril 47: 773-7
Clomiphene (Randall & Templeton 1991 Hum Rep 6: )
Progesterone antagonists (PRMS)
Dysfunction of Follicle maturation
Premature acquisition of LH receptors by small antral follicle
Relative lack of FSH at critical point when follicle selected for final ovulatory maturation eg Polycystic Ovary Syndrome

27. 4 Normogonadotrophic anovulation (WHO 11)
Secondary ovarian failure Insufficient or inappropriate stimulation of ovary
4 Normogonadotrophic anovulation (WHO 11)
Amenorrhoea or oligomenorrhoea
FSH,LH and Estradiol within normal range but subtle disorder of pattern of pulsatile LH
Gestogen challenge positive
Polycystic or Multifollicular Ovaries
Some may be due to failure to respond to estrogen with LH surge leading to anovulatory cycles

28. Recent reviews on Polycystic Ovary Syndrome
Human Reproduction Update, pp. 1–12, 2008doi: /humupd/dmn015Follicle dynamics and anovulation in polycystic ovary syndromeStephen Franks1,3, Jaroslav Stark2 and Kate Hardy1
Clin Endocrinol (Oxf) Apr;74(4): doi: /j x.PCOS Forum: research in polycystic ovary syndrome today and tomorrow.Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, Homburg R, Hickey T, Franks S, Tapanainen JS, Balen A, Abbott DH, Diamanti-Kandarakis E, Legro RS.

29. Polycystic Ovary Syndrome Phenotype and Endocrine response
Menstrual irregularity
Obesity
Anovulation
Signs of androgen excess –hirsutism, acne
Enlarged polycystic ovaries with presence of > 10 follicles 4- 8mm diameter in each ovary
But up to 25 % of ovaries have evidence of ovulation(Stein Leventhal) and 25% cycles ovulatory
Women with PCO show intact negative and positive feedback response to estrogen(Baird et al 1977)

30. Polycystic Ovary Syndrome Phenotype and Endocrine response
High basal LH with fast frequency of LH pulses
Hyper-responsive to GnRH
Relatively low FSH
Women with PCO show intact negative and positive feedback response to estrogen(Baird et al 1977)

31. Women with PCO have normal levels of estrogen
Baird et al 1977

32. PCO have intact positive feedback to Estrogen
Baird et al 1977 JCEM

33. Anovulatory PCO have raised LH and are hyper-responsive to GnRH
Baird et al 1977

34. Negative and positive feedback to estrogen is intact in PCO
Baird et al 1977

35. Animal Models for PCO
Whereas androgen excess in non-primates(eg rodents and sheep) primarily disengages the ability of the hypothalamus–pituitary to generate an ovulation-inducing LH surge, this is not the case in primates. In the latter, altered steroid negative feedback regulation of LH and compensatory hyperinsulinaemia from insulin resistance may disrupt ovulatory function, causing anovulation (Abbott et al., 2002).

36. Recent reviews on Polycystic Ovary Syndrome
Human Reproduction Update, pp. 1–12, 2008doi: /humupd/dmn015Follicle dynamics and anovulation in polycystic ovary syndromeStephen Franks1,3, Jaroslav Stark2 and Kate Hardy1
Clin Endocrinol (Oxf) Apr;74(4): doi: /j x.PCOS Forum: research in polycystic ovary syndrome today and tomorrow.Pasquali R, Stener-Victorin E, Yildiz BO, Duleba AJ, Hoeger K, Mason H, Homburg R, Hickey T, Franks S, Tapanainen JS, Balen A, Abbott DH, Diamanti-Kandarakis E, Legro RS.

37. Polycystic Ovary Syndrome : aetiology of anovulation
Endocrine :Abnormal endocrine HPO axis
Low FSH,
High LH,Androgens, AntiMullerian Hormone (AMH)
Intraovarian
Hypertrophied theca
Multiple small follicle arrested at 10mm
Heterogenity in antral fluid content
Low estrogen and high androgen
But granulosa cells in vitro can produce estrogen

38. Granulosa cells Theca cell
Polycystic Ovary Syndrome What is the cause of arrest of follicle growth?
Granulosa cells
Premature luteinization: aquisition of LH receptors ?insulin, IGF
Androgens
AMH causes reduced response to FSH in vitro. AMH production from GC in anovulatory higher than in ovulatory(Pellat et al 2007 JCEM ,92,240)
Theca cell
Hypertrophied(Franks, Willis) Greater production of androgens and progesterone in vitro