A Tale of Three Hormones: hcg, Progesterone and AMH

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1 A Tale of Three Hormones: hcg, Progesterone and AMH

2 Download the Ferring AR ipad/iphone app from the Apple Store:

3 Human Ovarian Steroidogenesis and Gonadotrophin Stimulation Johan Smitz Vrije Universiteit Brussels, Belgium 3

4 4 Overview 1. Steroidogenesis in the human ovary 2. Benefits of LH activity 3. hcg is similar but more potent than LH

Key steroidogenic enzymes are expressed in

P450scc P450c17 Antral phase LH LH Luteal

5 Key steroidogenic enzymes are expressed in theca and granulosa cells Preantral phase P450scc P450c17 Antral phase LH LH Luteal phase P450scc P450c17 P450arom LH LH FSH LDL cholesterol camp P450scc P450c17 Progesterone and androgens camp camp P450arom Low tone P450scc High tone LH responsiveness camp P450scc P450c17 Estrogens Progesterone 5

6 The delta 5 pathway Delta 5 pathway Cholesterol Pregnenolone 17α-hydroxypregnenolone Dehydroepiandrosterone Granulosa cells Androstenediol Pandey AV, Miller WL. J Biol Chem 2005;280: ; Miller WL. Endocr Dev 2008,13:1 18 Testosterone Estradiol 6

Androstenedione Estrone Pandey AV, Miller WL.

7 The delta 4 pathway Delta 4 pathway Cholesterol Pregnenolone Progesterone 17α-hydroxyprogesterone Androstenedione Estrone Pandey AV, Miller WL. J Biol Chem 2005;280: ; Miller WL. Endocr Dev 2008,13:1 18 Testosterone Estradiol 7

Ovarian steroids in humans are preferentially

5 pathway Delta 4 pathway Pregnenolone Theca cells

17α-hydroxyprogesterone Dehydroepiandrosterone

8 Ovarian steroids in humans are preferentially produced via the delta 5 pathway Cholesterol Delta 5 pathway Delta 4 pathway Pregnenolone Theca cells only Progesterone 17α-hydroxypregnenolone 17α-hydroxyprogesterone Dehydroepiandrosterone 17,20 lyase 17,20 lyase Androstenedione Estrone Androstenediol Pandey AV, Miller WL. J Biol Chem 2005;280: ; Miller WL. Endocr Dev 2008,13:1 18 Testosterone Estradiol 8

9 LH activity converts androgens to estradiol in the natural cycle, keeping progesterone levels low Normal cycle Pregnenolone FSH (LH) Theca cells Progesterone Granulosa cells PROGESTERONE Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010;21:

10 LH activity converts androgens to estradiol in the natural cycle, keeping progesterone levels low LH Normal cycle Pregnenolone FSH (LH) Theca cells Cyp17 Progesterone Androgens Aromatase Granulosa cells PROGESTERONE Estrogens Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010;21:

11 High FSH activity during COS drives the production of progesterone in follicles COS Pregnenolone PROGESTERONE ( ) by circulating FSH FSH (LH) Theca cells PROGESTERONE Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010;21: Progesterone Androgens Estrogens Aromatase PROGESTERONE ( ) by number of follicles Granulosa cells 11

12 LH activity during COS avoids the elevation of progesterone LH Circulating LH activity restores the balance of progesterone precursors via the delta 5 pathway PROGESTERONE ( ) by circulating FSH COS Pregnenolone FSH (LH) Theca cells PROGESTERONE Cyp17 Adapted from Fleming R, Jenkins J. Reprod Biomed Online 2010;21: Progesterone Androgens Estrogens Aromatase PROGESTERONE ( ) by number of follicles Granulosa cells 12

13 Summary Delta 5 pathway is the preferred ovarian steroid pathway of progestogens to androgens in humans Hypothesis (Fleming and Jenkins) 1 LH activity during COS may reduce premature FSH-induced progesterone increases in the follicular phase 1. Fleming R, Jenkins J. Reprod Biomed Online 2010;21:

14 14 Overview 1. Steroidogenesis in the human ovary 2. Benefits of LH activity 3. hcg is similar but more potent than LH

follicles Expression of LH receptor increases while FSH receptors decrease Theca cells express LH

15 LH determines follicular fate earlier than previously thought 5 mm 5 10 mm >10 mm Granulosa cells No LH receptor expression in granulosa cells Expression of LH receptor observed in granulosa cells of 80% of follicles Expression of LH receptor increases while FSH receptors decrease Theca cells express LH receptors from early antral follicle stage Jeppesen JV, et al. J Clin Endocrinol Metab 2012;97:E1524 E

16 FSH and LH increase with age is variable and patient dependent FSH LH Ferrell RJ, et al. Menopause 2007;14:29 37 Age (year) Age (year) 16

Response to hcg stimulation reduces with increasing age AUC 96h 17-OHP r= 0.

17 Response to hcg stimulation reduces with increasing age AUC 96h 17-OHP r= p=0.004 Piltonen T, et al. J Clin Endocrinol Metab 2003;88: Age (years) 17

18 Relationship between theca cell insufficiency and reduced ovarian responsiveness Compromised recruitment of follicles in: Women with profound pituitary downregulation (GnRH agonists long protocol) 1 Women >35 years 2 o Reduced ovarian sensitivity to FSH 3 o Reduced ovarian capacity to secrete androgens under basal LH conditions 4 1. Ferraretti AP, et al. Fertil Steril 2004;82: Humaidan P, et al. Reprod Biomed Online 2004;8: Davison SL, et al. J Clin Endocrinol Metab 2005; Spencer JB, et al. J Clin Endocrinol Metab 2007;92:

of gonadotrophins Differences in endocrine profiles Embryo

19 Different gonadotrophin preparations may lead to differences in live birth rates following IVF/ICSI Different composition of gonadotrophins Differences in endocrine profiles Embryo quality Endometrial receptivity Ongoing pregnancy Live births 19

20 Different gonadotrophin preparations may lead to differences in live birth rates following IVF/ICSI Different composition of gonadotrophins Differences in endocrine profiles Embryo quality Endometrial receptivity Ongoing pregnancy Live births 20

21 MERiT showed that HP-hMG was associated with significantly more top-quality embryos compared with rfshα Top-quality embryos/ oocytes retrieved (%) Ziebe S, et al. Hum Reprod 2007;22: p= HP-hMG 9.0 rfshα 21

22 MERiT showed that implantation rates were significantly higher with HP-hMG versus rfshα when transferring only top-quality embryos Ongoing implantation rate (%) p< Ziebe S, et al. Hum Reprod 2007;22: HP-hMG rfshα 22

23 23 LH activity improves the outcome in poor responders to FSH therapy rlh hcg De Placido G, et al. Hum Reprod 2001;16: Mochtar MH, et al. Cochrane Database Syst Rev 2007;2:CD Lehert P, et al. Reprod Biol Endocrinol 2014;12:17

24 Summary Theca cell insufficiency (i.e. insufficient LH activity) can be iatrogenic Theca cell insufficiency progresses from age of 35 years onwards Consider routine administration of LH activity from the start of stimulation as a precautionary measure Although beneficial for poor responders and older patients, rlh added to rfsh does not improve clinical outcome in the general ART population 1 in contrast to hcg-driven LH activity in hmg 2 1. Mochtar MH, et al. Cochrane Database Syst Rev 2007;2:CD van Wely M, et al. Cochrane Database Syst Rev 2011;2:CD

25 25 Overview 1. Steroidogenesis in the human ovary 2. Benefits of LH activity 3. hcg is similar but more potent than LH

Non-pregnant women produce hcg hcg (IU/L) 14 12 10 8 6 4 2 hcg concentration range and the 97.

26 Non-pregnant women produce hcg hcg (IU/L) hcg concentration range and the 97.5 percentile values for the non-pregnant cohorts in the study Non-pregnant cohort Premenopausal, years Perimenopausal, years Postmenopausal, >55 years n hcg, IU/L 97.5 percentile, IU/L p value 240 <2.0 to <2.0 to * 240 <2.0 to < Age (years) *Compared with the non-pregnant premenopausal cohort Compared with the non-pregnant premenopausal and non-pregnant perimenopausal cohorts Snyder JA, et al. Clin Chem 2005;51:

27 Similarities between LH and hcg LH and hcg are structurally similar 1 Both bind to the same receptor sites 2 1. Rao CV, et al. Mol Cell Endocrinol 2007;269: Cole LA. Reprod Biol Endocrinol 2010;8: hcg 27

28 hcg is more potent than LH 1,2 Serum LH activity hcg LH 1. Stokman PG, et al. Fertil Steril 1993;60: Filicori M, et al. Hum Reprod Update 2002;8: Time Half life of hcg is 6 8 times longer than LH 1,2 hcg is six times more potent than LH 1,2 28

HP-hMG has the highest hcg content of the researched gonadotrophin IVF products 1,2 First generation hmgs HP-hMG PERGONAL HUMEGON rfsh LH (IU/vial) 0.4 13.

29 HP-hMG has the highest hcg content of the researched gonadotrophin IVF products 1,2 First generation hmgs HP-hMG PERGONAL HUMEGON rfsh LH (IU/vial) hcg (IU/vial) Wolfenson C, et al. Reprod Biomed Online. 2005;10: Van de Weijer BH, et al. Reprod Biomed Online 2003;7:

30 Live birth (%) Live birth (%) MERiT showed that hcg, but not LH, on day 6 of stimulation correlates with live birth rates LH on day 6 (IU/L) Arce and Smitz. Gynecol Endocrinol 2013;29:

31 31 Summary HP-hMG contains mainly hcg hcg and LH act differently on target cells hcg but not LH levels on day 6 of COS correlates with live birth

Conclusions hcg-driven LH-activity during COS may reduce the increase of progesterone in follicular phase due to high FSH stimulation acting on many ovarian follicles There is a need for

32 Conclusions hcg-driven LH-activity during COS may reduce the increase of progesterone in follicular phase due to high FSH stimulation acting on many ovarian follicles There is a need for supplementation with LH activity in some patients undergoing ART Implantation Embryo quality hcg is similar but more potent than LH hcg levels on day 6 of COS correlate with live birth 32

A Tale of Three Hormones: hcg, Progesterone and AMH

A Tale of Three Hormones: hcg, Progesterone and AMH Download the Ferring AR ipad/iphone app from the Apple Store: http://bit.ly/1okk74m Interpreting Follicular Phase Progesterone Ernesto Bosch IVI Valencia,