Polycystic Ovary Syndrome



     François Pralong
 Division of Endocrinology
Definition
   Association of clinical and/or biochemical evidence of androgen
   excess with chronic anovulation
   Hetero...
PCOS: THE TEXTBOOK VIEW I

Pathogenic hypothesis
Abnormal hormonal feedback
mechanisms
PCOS: THE TEXTBOOK VIEW I

                   Hypothalamus




 Tissu                                Ovaire
adipeux




  ...
PCOS: THE TEXTBOOK VIEW II
Pathogenic hypothesis
Obesity and insulin resistance
PCOS: A DEVELOPMENTAL VIEW



Puberty             LH           Insulin




            ANDROGENS

            •Hirsutism
 ...
Gonadotropin Secretion in PCOS

Increased LH secretion:
   •Ratio of LH/FSH: 2-3/1
   •Prevalence: 30 to 90% !



   Impor...
GnRH
                  GnRH


      Pituitary

                  LH

      LH,
       FSH        FSH
E2,
 T
Facilitation                     Inhibition



      GnRH
     neurons




Gonadotrophs
                                  ...
Facilitation
                                                    Inhibition


Metabolic signals
                      GnRH...
?
Puberty           LH           Insulin




          ANDROGENS

          •Hirsutism
          •Acne
          •Alopecia...
Possible Mechanisms of Abnormal LH
          Secretion in PCOS

Altered sex steroid feedback:
   •Increased spontaneous LH...
Study of 5 teenage, post-pubertal girls with PCOS, compared to
age-matched controls


Diagnostic criteria:
    •Chronic an...
Abnormality present in 4 of 5 patients

                                         NEJM 309, 1983
Study of 12 women with PCOS, compared to 21 normal controls


Diagnostic criteria:
    •Perimenarchal onset of oligo/ameno...
Normal   PCOS




         J Clin Endocrinol Metab 66, 1988
J Clin Endocrinol Metab 66, 1988
Study of 13 women (aged 11-18) with hyperandrogenism,
compared to 28 aged-matched normal controls


Patients from Adolesce...
J Clin Endocrinol Metab 79, 1994
J Clin Endocrinol Metab 79, 1994
Study of 61 women with PCOS, compared to 24 normal
controls (EFP)


Diagnostic criteria:
    •Chronic oligoamenorrhea (<9 ...
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
J Clin Endocrinol Metab 82, 1997
High prevalence of gonadotropin secretion abnormalities in
PCOS patients


  Important associations between the elevated L...
CONCLUSIONS
Rapid GnRH pulse frequency probably has a role in the
abnormal LH secretion pattern in PCOS




              ...
CONCLUSIONS
Rapid GnRH pulse frequency probably has a role in the
abnormal LH secretion pattern in PCOS


The defect in hy...
Role of Brain Insulin Receptor in Control of Body
            Weight and Reproduction
                         Body weight...
Role of Brain Insulin Receptor in Control of Body
                 Weight and Reproduction


      Sperm                  ...
Euglycemic hyperinsulinemic clamp
                      studies in mice

Insulin infusion                   Glucose 15 % i...
Insulin Stimulates GnRH Secretion In Vivo


                                       P<0.01
                     1,0

      ...
Insulin Stimulates GnRH Secretion In Vitro

                                     Glucose 0.5 mM                   Glucose ...
Insulin stimulates the expression of
           the GnRH gene



                    300
  (% of controls)


             ...
Hypothalamic GnRH neurons express a
     functional insulin receptor


A                  A   M   B       HT     Gnv-3



...
Insulin signaling and GnRH transcription
           Insulin

 Insulin
receptor                               Hypothalamic ...
ERK1/2 activation (Phospho ERK) in primary hypothalamic cells



                    300                                  ...
PI-3 kinase activation


                                   900                                *
                         ...
ERK1/2 (Phospho ERK) and Akt (Phospho-Akt) activation in GnV-3 cells




                        ERK 1/2                  ...
The insulin effect on GnRH gene expression is dependent
 upon Erk1/2 activation in primary hypothalamic neurons


        ...
The insulin effect on GnRH gene expression is independent
 of PI3-kinase activation in primary hypothalamic neurons



   ...
Treatment options

•Oral contraception: retablish menstrual cycles, decrease
hyperandrogenism

•Association with an anti-a...
Division of Endocrinology       Department of Medicine and
Lausanne                        Botnar Center of Clinical
Miche...
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  1. 1. Polycystic Ovary Syndrome François Pralong Division of Endocrinology
  2. 2. Definition Association of clinical and/or biochemical evidence of androgen excess with chronic anovulation Heterogeneous condition with a spectrum of clinical/biochemical features Estimated prevalence : 25% of all women, full blown syndrome in ~5% of women of reproductive age Clinical presentation · Hirsutism (95%), acne, alopecia · Enlarged ovaries (95%) · Sterility (75%) · Amenorrhea (55%) · Obesity (40%) · Dysmenorrhea (28%) · Chronic anovulation (20%)
  3. 3. PCOS: THE TEXTBOOK VIEW I Pathogenic hypothesis Abnormal hormonal feedback mechanisms
  4. 4. PCOS: THE TEXTBOOK VIEW I Hypothalamus Tissu Ovaire adipeux Surrénale
  5. 5. PCOS: THE TEXTBOOK VIEW II Pathogenic hypothesis Obesity and insulin resistance
  6. 6. PCOS: A DEVELOPMENTAL VIEW Puberty LH Insulin ANDROGENS •Hirsutism •Acne •Alopecia Adapted from S Franks, 2002
  7. 7. Gonadotropin Secretion in PCOS Increased LH secretion: •Ratio of LH/FSH: 2-3/1 •Prevalence: 30 to 90% ! Importance of assessing LH secretion in relation to recent menses
  8. 8. GnRH GnRH Pituitary LH LH, FSH FSH E2, T
  9. 9. Facilitation Inhibition GnRH neurons Gonadotrophs LH Childhood years
  10. 10. Facilitation Inhibition Metabolic signals GnRH neurons Gonadotrophs LH Post-pubertal Period
  11. 11. ? Puberty LH Insulin ANDROGENS •Hirsutism •Acne •Alopecia Adapted from S Franks, 2002
  12. 12. Possible Mechanisms of Abnormal LH Secretion in PCOS Altered sex steroid feedback: •Increased spontaneous LH pulse amplitude •Increased LH response to GnRH •Normal FSH response to GnRH Inherent neuroendocrine abnormality
  13. 13. Study of 5 teenage, post-pubertal girls with PCOS, compared to age-matched controls Diagnostic criteria: •Chronic anovulatory syndrome •Exclusion of other virilizing syndromes (Cushing, CAH…) •Normal TFTs and PRL NEJM 309, 1983
  14. 14. Abnormality present in 4 of 5 patients NEJM 309, 1983
  15. 15. Study of 12 women with PCOS, compared to 21 normal controls Diagnostic criteria: •Perimenarchal onset of oligo/amenorrhea •Hirsutism and/or acne •Raised LH/FSH ratio •Raised T/androstenedione levels •E2 lower than controls in MFP and LFP •Estrone higher than controls in EFP and MFP, lower in LFP J Clin Endocrinol Metab 66, 1988
  16. 16. Normal PCOS J Clin Endocrinol Metab 66, 1988
  17. 17. J Clin Endocrinol Metab 66, 1988
  18. 18. Study of 13 women (aged 11-18) with hyperandrogenism, compared to 28 aged-matched normal controls Patients from Adolescent Medicine/Repro Endo clinics, UCSD Diagnostic criteria: •Chief complaint: hirsutism •No hormonal medication for 3 months J Clin Endocrinol Metab 79, 1994
  19. 19. J Clin Endocrinol Metab 79, 1994
  20. 20. J Clin Endocrinol Metab 79, 1994
  21. 21. Study of 61 women with PCOS, compared to 24 normal controls (EFP) Diagnostic criteria: •Chronic oligoamenorrhea (<9 cycles/yr) or amenorrhea •Hyperandrogenism (clinical or biochemical) •Exclusion of late-onset CAH •Normal TFT and PRL •Off all medication for at least 2 months J Clin Endocrinol Metab 82, 1997
  22. 22. J Clin Endocrinol Metab 82, 1997
  23. 23. J Clin Endocrinol Metab 82, 1997
  24. 24. J Clin Endocrinol Metab 82, 1997
  25. 25. J Clin Endocrinol Metab 82, 1997
  26. 26. High prevalence of gonadotropin secretion abnormalities in PCOS patients Important associations between the elevated LH secretion and recent ovulation or LH pulse frequency, but NOT sex steroids Strong association between LH pulse frequency and pool LH levels or LH/FSH ratio may suggest an etiologic relationship J Clin Endocrinol Metab 82, 1997
  27. 27. CONCLUSIONS Rapid GnRH pulse frequency probably has a role in the abnormal LH secretion pattern in PCOS Marshall and Eagleson, 1999
  28. 28. CONCLUSIONS Rapid GnRH pulse frequency probably has a role in the abnormal LH secretion pattern in PCOS The defect in hypothalamic GnRH secretion seems to be intrinsic to PCOS patients Could there be a role of elevated insulin levels/insulin resistance in this abnormal GnRH secretion pattern?
  29. 29. Role of Brain Insulin Receptor in Control of Body Weight and Reproduction Body weight 80 Leptin 40 35 * ** 60 Gramms ng/mL 30 40 25 20 20 15 0 6 10 14 18 23 Age (weeks) WAT 40 Body weight 120 100 ** 35 * mg/g BW Gramms 80 30 * 60 40 * 25 20 20 0 15 WT KO WT KO 150 Food uptake Male Female ** mg/g BW 100 50 0 WT KO WT KO Brüning et al., Science 289, 2000 Male Female
  30. 30. Role of Brain Insulin Receptor in Control of Body Weight and Reproduction Sperm Plasma LH Plasma LH one hr after count i.p GnRH agonist 0.5 40 14 0.4 30 * ng/mL 12 ng/mL 0.3 10 * 0.2 20 8 * 10 6 0.1 ** 4 0 0 WT KO WT KO WT KO WT KO WT KO Male Female Male Female Brüning et al., Science 289, 2000
  31. 31. Euglycemic hyperinsulinemic clamp studies in mice Insulin infusion Glucose 15 % infusion Glycemia
  32. 32. Insulin Stimulates GnRH Secretion In Vivo P<0.01 1,0 0,8 LH (ng/mL) 0,6 0,4 0,2 0,0 Glucose (mM) 5.5 2.5 5.5 20 Insulin - + + + Burcelin et al, Endocrinology 2003
  33. 33. Insulin Stimulates GnRH Secretion In Vitro Glucose 0.5 mM Glucose 20 mM Insulin 2.5 mg/mL Insulin 2.5 mg/mL A GnRH (pg/mL) 40 30 20 10 0 5 10 15 20 25 30 35 40 45 50 B Fractions 350 ** 300 GnRH (% of BL) 250 200 C 150 * 100 50 0 Basal 0.5 1 2.5 5 Insulin (mg/mL) Burcelin et al, Endocrinology 2003
  34. 34. Insulin stimulates the expression of the GnRH gene 300 (% of controls) * * GnRH mRNA 200 6 hours 24 hours 100 0 Ct Ins Burcelin et al, Endocrinology 2003
  35. 35. Hypothalamic GnRH neurons express a functional insulin receptor A A M B HT Gnv-3 B M B HT Gnv-3 B Vollenweider et al, Bern 2003
  36. 36. Insulin signaling and GnRH transcription Insulin Insulin receptor Hypothalamic neurons IRS P85 Shc P110 Grb2 Akt Sos PI3 Kinase Ras ? GnRH Raf ERK 1/2
  37. 37. ERK1/2 activation (Phospho ERK) in primary hypothalamic cells 300 n = 5-6 * p-ERK/total ERK (% over basal) 200 * 100 0 2 min 5 min 10 min 30 min Time
  38. 38. PI-3 kinase activation 900 * * PI3 kinase activity * (% over basal) * IP IRS-1 450 * PI3-kinase 0 Basal 5 min 15 min 30 min 60 min 120 min 250 * * PI3 kinase activity * (% over basal) * 125 IP IRS-2 PI3-kinase 0 Basal 5 min 15 min 30 min 60 min 120 min Time (min)
  39. 39. ERK1/2 (Phospho ERK) and Akt (Phospho-Akt) activation in GnV-3 cells ERK 1/2 Akt 2000 * n = 5-6 700 ** p-ERK1/2/ERK (% over basal) 1500 (% over basal) ** p-Akt/Akt 1000 350 * * 500 * 0 0 1 min 5 min 10 min 30 min Basal 5 min 15 min 60 min Time Time
  40. 40. The insulin effect on GnRH gene expression is dependent upon Erk1/2 activation in primary hypothalamic neurons GnRH mRNA levels * 500 ** 400 % of CT 300 200 100 0 Ct Ins Ins + PD PD DMSO
  41. 41. The insulin effect on GnRH gene expression is independent of PI3-kinase activation in primary hypothalamic neurons GnRH mRNA 300 250 200 % of CT 150 100 50 0 CT Ins Ins + Wort Wort DMSO
  42. 42. Treatment options •Oral contraception: retablish menstrual cycles, decrease hyperandrogenism •Association with an anti-androgen •Insulin sensitizers: metformin, thiazolidinediones Usually good clinical response to clomiphene citrate when seeking fertility
  43. 43. Division of Endocrinology Department of Medicine and Lausanne Botnar Center of Clinical Micheline Glauser Investigation Marie-Jeanne Voirol Peter Vollenweider Marco Giacomini Pascal Nicod Einar Castillo Roberto Salvi Rolf Gaillard Institute of Pharmacology and University of Toulouse Toxicology, Lausanne Rémy Burcelin Bernard Thorens
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