DR.SATHYA BALASUBRAMANYAM MD,DNB,MRCOG,FNB(REPROD MED)

INSTITUTE OF REPRODUCTIVE MEDICINE

AND WOMEN’S HEALTH, MADRAS MEDICAL MISSION, CHENNAI

DHEA- WONDER DRUG?

What is DHEA?

History of use in poor responders

Review of literature

Our experience in IRM&WH

Conclusions

What is DHEA?

DHEA is an important  endogenous steroid hormone.

 It is the most abundant circulating steroid in humans.

It is produced in the  adrenal glands, the gonads, and the brain, where it functions predominantly as a  metabolic intermediate in the biosynthesis of the androgens and estrogens.

Place in the steroid synthetic pathway.

Cholesterol--- Pregnenolone---17 alpha Pregnenolone----DHEA---- Androgens---- Estrogens

Are DHEA and DHEAS different?

DHEAS is the sulfate ester of DHEA. This conversion is reversibly catalyzed by sulpho transferase primarily in the adrenals, the liver, and small intestine.

In the blood, most DHEA is found as DHEAS with levels that are about 300 times higher than those of free DHEA.

Orally ingested DHEA is converted to its sulfate when passing through intestines and liver.

Whereas DHEA levels naturally reach their peak in the early morning hours, DHEAS levels show no diurnal variation.

From a practical point of view, measurement of DHEAS is preferable to DHEA, as levels are more stable.

History of use in poor responders

Casson et al.2000 Self-controlled trial, five women, previous

poor responders.Increased peak E2 levels (939.8 versus 266.3

pg/ml, P = 0.02) and yielded more oocytes (2.2 versus 1) following DHEA treatment .

Criticized due to methodological errors - bias caused by the change in the stimulation protocol, as well as the type and dose of gonadotrophins administered.

POSSIBLE MECHANISM OF ACTION

Direct effect of DHEA on the aging ovaryA) by increasing the pool of follicles up to the

pre-antral stage orB) reducing apoptosis of the originally

recruited follicles (Gleicher et al 2010)DHEA does not appear to exert influence via

recruitment of pre-antral or very small antral follicles (no change in AMH and inhibin B) but rather by rescue from atresia of small antral follicles (increased AFC). Hyman et al 2013

Review of literature

Barad and Gleicher42.7 Year old woman, self medication. 9 IVF in 11

months -66 embryos!(2005)

Self-controlled study ,25 patients ,DOR defined as a history a prior IVF cycle with less than four oocytes and uniformly poor quality embryos.

. Following DHEA, an increased oocyte yield, a higher fertilization rate and a higher embryo grade were achieved.(2006) 

Case–control study , 89 patients with DOR who had used DHEA with 101 matched controls (2007)

DOR was defined as the presence of an elevated age-specific FSH concentration.

The treatment group showed an increased pregnancy rate (28.4 versus 11.9%,P < 0.05) following DHEA use for a mean duration of 73 days .

Same authors also compared miscarriage rates in patients who had used DHEA with those rates reported in the National US IVF database and suggested that the DHEA-supplemented group had significantly lower miscarriage rates (2009).

Gleicher et al 2010Self controlled trial Increase in AMH after DHEA use in

proportion to duration of use, more in younger women.

Increase in pregnancy when AMH rise occurred.

Gleicher 2010Case controlled study(22 women who had

been using DHEA with 44 age-matched women serving as controls)

Lower aneuploidy rates after DHEA intake((38.2 versus 61%).

Those on DHEA produced a mean of 9.6 eggs versus 11.7 in the control group.

A case series Greece Five patients with post-menopausal FSH

levels who conceived following 45–189 days of DHEA supplementation (Mamas and Mamas 2009)

Prospective self-controlled pilot study of 8 women failed to observe any difference in the number of oocytes and embryo quality following 3 months of DHEA supplementation (Motta et al 2006).

Borman et al. found no difference in the mean DHEA levels in poor and relatively good responder patients (2010).

RCT

33 women younger than 42 years of age who either yielded fewer than five oocytes, had poor quality embryos or had cycle cancellation due to poor ovarian response were randomized to receive 75 mg DHEA or nothing for an average duration of 13.5 weeks prior to undergoing repeat treatment using the same ovarian stimulation protocol (Wiser et al., 2010).

No significant difference between the DHEA and control groups in terms of primary outcome measures (peak E2 levels, mean number of retrieved oocytes and embryo quality).

Among 17 patients in the DHEA group, there were seven pregnancies (26.9%) and six live births (23.1%) following 26 treatment cycles.

However, among 16 patients in the control group, there were only three pregnancies (12%) and a single live birth (4%). The difference between live birth rates was reported as statistically significant (P = 0.05).

The use of androgens or androgen-modulating agents in poor responders undergoing in vitro fertilization: a systematic review and meta-analysis. (HR UPDATE 2012)

There is insufficient data to support a beneficial role of, DHEA administration in the probability of pregnancy in poor responders undergoing ovarian stimulation for IVF.

OUR EXPERIENCE IN IRM&WH

Retrospective analysis of IVF records (May 2012- May 2013)

All patients who fulfilled Bologna criteria were identified.

All women who fulfilled the criteria and had taken DHEA for at least 12 weeks prior to their IVF/ICSI were included in the study groups.

Others were taken in the control group.

DHEA (n=32) Non DHEA (87) P

Age 34.3 +/- 6.5 34.6 +/- 4.3 0.68

Duration 6.7+/- 4.1 8.3+/-4.6 0.873

Duration of Gn 10+/-1.3 10.1+/-1.6 0.85

Total dose of Gn 4143+/-816 4030+/-980 0.80No: of eggs 2.9+/-1.5 3+/-1.3

0.58No: of embryos tr 1.65+/-1.2 2+/-1.4

0.23

DHEA Non DHEA

No: of cancelled cycles 6/32 11/87 No of clinical pregnancy 5 7No of ongoing pregnancy 4 2No: of miscarriage 1 4No: of ectopic/PUL 2 3

No: delivered 2 1

Conclusion

We need more multicentre RCTs before DHEA can be recommended for routine use in expected poor responders.

Lack of harm is not sufficient to promote the use of a drug in any given clinical situation and the practice of poly pharmacy should be reduced.

THANK YOU!