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- 1. DHEA & FEMALE INFERTILITY Dr.Sanjay Makwana Vasundhara Hospital & Fertility Centre Jodhpur 342003 www.vasundharafertility.com
- 2. OVERVIEW • How Does Age affect Fertility? • How can the Ovarian reserve be Assessed? • How does DHEA improve Ovarian reserve?
- 3. Is Infertility Affected by Age? YES!! 15 - 20% of all couples will experience difficulties with conception, but this increases up to 50% at age 35 – 40.
- 4. Current trends of marriage and pregnancy Infertile ↑ 1Maria et al. Ann. N.Y. Acad. Sci. 2008; 1127: 27–30. 96(3):638-40. 2Gianaroli et al. Hum Reprod. 2010;25: 2374–2386. 3Schoolcraft et al. Fertil Steril. 2011 Sep;
- 5. The Age Factor • A woman's fertility naturally starts to decline in her late 20's. • After age 35 a woman's fertility decreases rapidly. • A woman is born with all the eggs she'll have, and with time, the supply diminishes.
- 6. Aging & Fertility • • • Decline in AFC Reduced cohort size Decreased oocyte quality & potential fertility • Altered feedback – Reduced inhibin B – Steady rise in FSH – Gradually declining AMH F. J. Broekmans et al., 2009 Miscarriages due to Aneuploidy
- 7. Outcome of IVF in Women 45Years Older • • • • 30% Cancellation Rate Overall PR 21.1% Per Retrieval 85.3% Experienced a Pregnancy Loss Overall Delivery Rate Was 3.1% Steven D. Spandorfer, Zev Rosenwaks, Jan 2007
- 9. What is ovarian reserve? Describe a woman’s reproductive potential with respect to ovarian follicle number and oocyte quality Total Ovarian Reserve Non growing follicles (NGF) This is so called Ovarian Reserve (or FOR) Growing follicles (GF) TOR decreases with time : continuous follicle recruitment 1Gianaroli et al. Hum Reprod. 2010;25: 2374–2386.
- 10. Quantity and quality of follicles % Broekmans et al: Endocrine Reviews, August 2009, 30(5):465–493
- 11. Decreasing ovarian pool with age Reproductive period:Around 400 ovulate
- 12. Decreased ovarian reserve Definition: if the follicle pool, at any given age, is smaller than expected In 2009: DOR was the second most common diagnosis among infertility patients undergoing IVF in the USA (15%; SART-CORS, 2009). One of the least well characterised etiologies of infertility Also encountered in young women
- 13. Factors affecting ovarian reserve
- 14. How to asses ovarian reserve?
- 15. Prediction: Baseline hormones Antimüllerian hormone FSH Estradiol Inhibin B Ultrasound parameters Antral follicle count Ovarian volume •Any day of the cycle •No inter-cycle variation •Low fertility: <2.2 ng/ml •Measured using trans vaginal Us on day 3 •Normal: 15-30 follicles •DOR: <6follicles Dynamic tests Clomiphene citrate challenge test (CCCT)
- 16. Follicle Stimulating Hormone (FSH) Day 3 FSH level FSH interpretation <10 Normal FSH level. Expect a good response to ovarian stimulation. 10 - 12 Borderline FSH. Response to stimulation is somewhat reduced. 13- 15 Elevated FSH. Reduced ovarian reserve. Reduced response to stimulation. 16 - 20 Markedly elevated FSH. > 20 Very poor (or no) response to stimulation. Marked reduction in response to stimulation
- 17. Anti-Mullerian Hormone (AMH) • AMH is a glycoprotein • Appears in females at puberty • Produced by granulosa cells of pre-antral and small antral follicles • Not cycle dependant-can be measured any day • Less cycle to cycle variation than FSH • Nor effected by GnRH agonists- can measure during downregulation • BUT expensive
- 18. AMH and Ovarian Aging AMH Level ng/ml Interpretation Expected Response to FSH Anticipated Anticipated Cancellation Rate Pregnancy Rate with IVF with IVF >3.0 High, often PCOS Very High Low Normal 1.0-3.0 Normal Good Low Normal 0.4-0.9 Low Reduced Increased Reduced <0.4 Very Low Very Poor Very High Very Low
- 19. Antral Follicle Count (AFC) • Follicles 2 to 5mm on Day 1 or 2 • Inter-observer variation • If AFC < 5- significantly worse outcome
- 20. P O R Definition Criteria by ESHRE working group (at least 2 should be present) (i) Advanced maternal age or any other risk factor for poor ovarian response (POR) (ii) A previous POR (iii) An abnormal ovarian reserve test (ORT) In general Failure to respond adequately to standard protocols and to recruit adequate follicles is called ‘poor ovarian response’ ESHRE: European Society of Human Reproduction and Embryology
- 21. Prevalence and outcomes Varies between 9 and 24% Successful pregnancy rate in these patients is as low as 2-4% ↓ oocyte production Cycle cancellation A significantly diminished probability of pregnancy Keay SD et al. Br. J Obstet. Gynecol., 104, 521-527
- 22. Classification of low responders
- 24. Premature ovarian failure Can be seen in reproductive age Characterized by amenorrhea or oligomenorrhia with hyper gonadotropic and hypo estrogenic hormonal changes Affects 1%–5% of women Causes: genetic, iatrogenic, viral and autoimmune disease Success rate- only 6%
- 25. How to Improve Ovarian Reserve??
- 26. Challenges in management Older ovaries have few antral follicles, high rates of atresia, and ↑ “resistance” to OI Despite various predictive tests - poor responder revealed definitively only during ovarian stimulation Need for a drug which acts in the preliminary stages of follicle development and can avoid the first cycle failure itself
- 28. Role of androgens in follicle maturation Androgens affect follicle maturation at very early stages DHEA
- 29. DHEA concentration wrt. age
- 30. Role of androgens in follicular maturation High concentration of androgen receptors in pre-antral and antral stage Stimulate granulosa cells •Follicular maturation •Steroidogenesis
- 31. DHEA TO IMPROVE OVARIAN FUNCTION Reprod Biomed Online. 2009 Oct;19(4):508-13.
- 33. Who require DHEA? • Women with – Physiological ovarian ageing ( all above age 40 ) – Premature ovarian ageing ( Below the age of 38)
- 34. DEHYDRO EPIANDROSTERONE (DHEA) Physiological Ovarian Ageing • All women above age of 40 with decreased fertility • Poor ovarian reserve due to age
- 35. DEHYDRO EPIANDROSTERONE (DHEA) Premature ovarian ageing • Function of the ovary is impaired • FSH level above 95 % tile • AMH below 95 %tile for her age
- 36. DEHYDRO EPIANDROSTERONE (DHEA) PREMATURE OVARIAN AGEING TESTOSTERONE EVALUATED • UPPER 1/3 OF NORMAL • LOW 2/3 OF NORMAL • NO DHEA • DHEA GIVEN
- 37. DEHYDRO EPIANDROSTERONE (DHEA) • AMH increases in parallel with length of DHEA supplementation • This increase is more pronounced in younger POF than older DOR patients • Improvement in AMH levels predicts pregnancy success. Gleicher et al, rep.biomed online 2010.,
- 38. Reduces IVF cancellation rates • DHEA supplementation shows increase in IGF1 concentrations to potentiate gonadotrophin action in women with diminished ovarian reserves Hum Reprod. 2010 Oct;25(10):2496-500. Epub 2010 Aug 21. • Increase in average embryo scores per oocyte in IVF cycle outcomes and reduces IVF cancellation rates Hum Reprod. 2000 Oct;15(10):2129-32. • DHEA supplementation facilitates gonadotrophins effect, it also reduces the dose of gonadotrophins in IVF cycles Human reproductions sep 2006
- 39. Effect of dehydroepiandrosterone on oocyte and embryo yields, embryo grade and cell number in IVF (Ref. 1 Human Reproduction 2006; 21: 2845-2849
- 40. Reduces miscarriage rates • DHEA supplementation has shown to have progestogenic effects in women with age related poor ovarian function to support conception and prevent miscarriages • DHEA augument gonadotrophin secretion augment HCG secretion to support corpus luteum for production of progesterone to support pregnancy • Overall reduces miscarriages and improve cumulative pregnancy outcome Fertility and sterility sep 2006
- 41. Miscarriage rates after dehydroepiandrosterone (DHEA) supplementation Ref. 1 Reproductive Biology and Endocrinology 2009, 7:108 )
- 42. Effect on pregnancy rate and speed of conception Study gp : 88 women with poor ovarian reserve evidenced by inadequately poor response to OI Control gp : 101 patients selected for IVF supplementation in Conclusion : DHEA women with diminished ovarian reserve, independent of age, leads toIVF (microdose agonist/gn max increased, and DHEA 25mg TID for 3.7± 0.3 months Had more rapid, conception rates 450-600IU 62 had IVF, 9 had atleast one prior OI, 17 missed Outcome – Cumulative preg rate of 27% IVF cancellation rate of 10% Miscarriages 24% Outcome –cumulative preg rate of 11 % IVF cancellation rate 26 % Miscarriages 44% Fertility and sterility vol 86,suppl 2, sep 2006
- 43. DEHYDRO EPIANDROSTERONE (DHEA) REPORTED REPRODUCTIVE BENEFITS Improves egg/embryo numbers & quality Spontaneous pregnancies High IVF pregnancy rates Shortens time to conceive Cumulative pregnancy rates increases Barad et al,j Assist.rep. Genet 2007
- 44. DOSAGE FOR USE IN INFERTILITY • Administration of DHEA for 2 months 80µg/day increased the level of DHEA to 544+/- 55µg • Administration of DHEA ,four months prior to IVF cycles increases the response of the ovaries to gonadotrophin treatment and also improves the overall outcome Fertility and sterility sep 2005
- 45. DEHYDRO EPIANDROSTERONE (DHEA) Dosage - 25 mg three times a day - Stay with DHEA till pregnancy - Stop after pregnancy is confirmed
- 46. Is there a role in PCOS ? • All patients with PCOS have increased senstivity to androgens upto 70% have elevated androgen levels and other 30% are in the high normal range • Hence initial conversion of DHEA to androgens does not favour its use in treatment of PCOS
- 47. DEHYDRO EPIANDROSTERONE (DHEA) ROLE IN PCOs Poorly responding PCOS Where testosterone is decreased Better response with DHEA
- 48. Conclusions • Age is the main determinant of success of infertility treatments • AMH is the most promising method of assessing ovarian reserve • DHEA acts by Rejuvenating Ovarian Environment in women with DOR and POA • It significantly improves pregnancy rates in IVF • It decreases miscarriages and pregnancy losses
Notes de l'éditeur
- Career Late marriage Postpone pregnancy Late consultation: hesitation, ignorance, There is shocking evidence on how big an influence age has on fertility and pregnancy outcomes
- After about age 32, a woman's fertility potential gradually declines. Infertility in older women may be due to a higher rate of chromosomal abnormalities that occur in the eggs as they age. Older women are also more likely to have health problems that may interfere with fertility. The risk of miscarriage also increases with a woman's age. A gradual decline in fertility is possible in men older than 35. The reason is straightforward. A woman is born with all the eggs she'll have. And with time, the supply diminishes. The remaining eggs also age along with the rest of the body.
- FIG. 10. Schematic representation of the changes in average early follicular levels of endocrine and ovarian ultrasound markers for ovarian aging according to the STRAW phases of reproductive aging. Note the late decrease in estradiol and inhibin A levels, the gradual decrease in AMH across the subsequent stages, and the abrupt decrease in inhibin B in the menopausal transition. Drawing is based on several sources (46, 66, 95, 109, 122, 124, 155, 329).
- Define Classify TOR decreases with time. Let us look at the shocking rate of depletion of TOR in the following slides
- Dotted line: proportion of poor quality oocyte rising constantly This is the normal decline. Cases of accelerated decline are a major concern. These patients have DOR wiz essentially lower ovarian reserve wrt the age normal at any stage.
- Starts in 4th month intra uterine life Read stats Interesting: folicles do not deplete because they are getting used up. The die by apoptosis. So anovulatory women are not spared from the rapid loss of resources either. This is only numbers. Let us look at the quality of the available oocytes in the next slide. This is determined by pregnancy outcomes in these age groups.
- Define DOR High prevalence Seen in young women as well!
- Enumerate How to predict who really needs to be tested? Age is the biggest determinant of ovarian reserve. Concomitant conditions like PID, Endometriosis, …. Also deplete the ovarian reserve faster than expected.
- The most promising predictor of OR- AMH- produced by granulosa cells- poor response a/w low AMH levels- . Can be measured on any day of the cycle. No inter-cycle variation. Lower cut off varies with doctors, 2.2 ng/mL is agreed upon and widely used. FSH is always co related with Estrogen. Varies throughout the cycle. Day3 most reliable. N=3-10. High levels imply poor response/ OR. The reference values vary wrt age. Generally a very high level > 25 mIU/ml suggests failure. E2 is secreted in response to FSH. Normal E2- 200-300 pg/ml. in downregulated ovaries: <50mIU/ml is desired but DOR : E2 >75 mIU/ml on day 3 D3 inhibin test.: Produced by granulosa cells. Inhibin levels directly proportional to OR. Typically N= 45-200 pg/ml. DOR <45 pg/ml Imaging in the form of USS is also routinely poerformed in all patients. Antral follicle count and OV are tested in all pts with infertility. AFC- TV-USG. On day 3. N=15-20 and DOR: <6 follicles OV: both combined. <4ml : DOR Dynamic tests widely used are CCCT and EFFORT CCCT: D3 +D10 FSH >25 :ovarian failure. CC given from day 5 to 9.
- The criteria of poor responders by ESHRE.
- Low responders consist of: Elderly women with abN endocrinological profile make the biggest chunk of low responders Young women with abN profile also respond poorly. Eg: hypo/hyperthyroidism etc Young women with N basal hormonal profile. These comprise women with h/o pelvic sx, radiation for any reason, PID Lets look into the third category more closely
- Poor responders
- Stretching the limit of poor responders too far. NO therapy can help Premature ovarian failure.
- Now the problem here is that: inspite of invasive therapy, no substantial benefit is seen. ART is a costly affair. Failure of a cycle, apart from the emotional trauma means a loss of about 50k Rs for the patient. Moreover, there is less documented evidence about management protocols for infertility in poor ovarian reserve patients. We are dealing with poor responders. Specific challenges we face are: The trial and error method- losing more time and oocytes rapidly with age. With time: resistance to OI increases ART- disappointing success rates beyond 30yr To overcome these challenges, we need to check where we are going wrong. Quick recap of the hormonal play in oogenesis.
- A woman is born with primordial follicles arrested in prophase 1- FSH- primary follicle – FSH androgen – antral follicle– matured follicle– LH – ruptured follicle– CL- progesterone. In our current strategies of management, we give GnRH, exogenous FSH, HCG for LH and progesterone for endometrial support. What we miss out on is androgens for antral follicle maturation. 1 point before getting deeper into this– Androgen does not give immediate relief. Pre treatment is necessary. Let me take u deeper into the maturing follicle now
- Androgen’s role is majorly in but not limited to: Synergism with FSh. As we can see– androgen receptors with a V on the top and FSH receptors with a U. Androgen receptors more abundant in the pre antral and early antral follicles. Definite need to give androgens to make the environment more salubrious to the oocyte’s development. DHEA is an androgen produced by the adrenal gland. Along with its metabolite DHEA-S, it acts with FSH to stimulate the androgen receptors in pre antral follicle cells. Action is mainly on the granulosa cells and not on the oocyte directly. This provides a good environment for the oocyte enclosed by the follicular cells. Having established the fact that DHEA is nearly indispensable to the follicle for normal growth, it will be interesting to see what happens with the levels of DHEA with age.
- DHEA levels begin to decline in the late 20s itself. After that, there is a rapid decline in the amoutn of DHEA. Why? It is speculated that this is parallel to age related deterioration of functioning of the adrenals. Let us take a minute to understand how DHEA/ androgens affect the follicle growth.
- To summarize the actions of DHEA: