Dehydroepiandrosterone(DHEA)Therapy is a promising policy for InfertileAged Women to get Spontaneous Conception
1Department of Obstetrics and Gynecology, Menoufia University, Egypt
Submission: April 12, 2019;Published:August 31, 2019
*Corresponding author: Abd-Elhaseib Salah, Department of Obstetrics and Gynecology Faculty of Medicine, Menoufia University, Shibin El-Kom City, Menoufia governorate, Egypt
How to cite this article: Abd-Elhaseib Salah. Dehydroepiandrosterone (DHEA) Therapy is a promising policy for Infertile Aged Women to get Spontaneous002 Conception. J Gynecol Women’s Health. 2019: 16(3): 555936. DOI: 10.19080/JGWH.2019.16.555936
Objectives: Evaluating the clinical pregnancy rate (CPR) after priming of infertile women older than 38 years and have poor ovarian reserve using dehydroepiandrosterone (DHEA).
Patients & Methods: The study included 282 fulfilling inclusion criteria received DHEA (50 mg twice daily for 3 months) and were allowed to get spontaneous pregnancy. Women who failed to get pregnant received oral clomiphene citrate (100 mg for five days starting on day 3 of the menstrual cycle) followed by daily intramuscular injection of 150 IU of human menopausal gonadotropin till ovulation was assured by TVU. Evaluated parameters included bilateral ovarian antral follicular count and hormonal profile were estimated at time of enrollment and at end of each 3-m phases. Chemical and clinical pregnancy rates and abortion rate.
Results: Clinical pregnancy and continued pregnancy till 2nd trimester rates were 6.7% and 5.7% for Phase-1 and for Phase-2 were 16.3% and 14.4%, respectively. Collectively, chemical pregnancy rate was 26.2%, CPR was 21.6%, abortion rate was 13.1% and rate of continued pregnancy till 2nd trimester was 18.8%. CPR with induction after 3-m DHEA priming was significantly (p=0.00039) higher than without induction. The applied protocol allowed getting pregnancy that was continued till 2nd trimester in 71.6% of women who had positive chemical pregnancy and 86.9% of women who had clinical pregnancy. Moreover, DHEA therapy induced significant reduction of serum FSH, LH with significant increase of testosterone, E2 and AMH levels with subsequently higher AFC compared to pretreatment levels.
Conclusion: Priming of infertile aged women with POR using DHEA with or without ovulation induction improves the chance of spontaneous conception and spares the need for assisted reproduction procedures by 21.6% of treated women. Ovulation induction after DHEA priming triples the chance for spontaneous conception.
Ovarian ageing shows great inter-individual variability, is characterized by quantitative and qualitative alteration of ovarian oocyte reserve and about 20% of infertile women show signs of premature ovarian ageing . Premature ovarian failure (POF) may be considered as autoimmune disease secondary to absence of ovarian immunological protection and detection of ovarian autoantibodies strongly support this hypothesis . POF may have a genetic etiopathogenesis as the presence of breast cancer susceptibility gene (BRCA) mutation was found to be linked to accelerated ovarian aging and reduced ovarian reserve . Inflammatory aging refers to a chronic and low-degree proinflammatory status with increasing age and is closely associated with multiple diseases, as POF .
Anti-Müllerian hormone (AMH) is a homo-dimeric glycoprotein produced by granulosa cells of growing ovarian follicles and has an inhibitory effect on primordial follicle recruitment and response of growing follicles to follicle-stimulating hormone (FSH) . AMH levels may predict the ovarian response to ovarian hyDehydroepiandrosterone perstimulation for IVF, timing of menopause, iatrogenic damage
to the ovarian follicle reserve and as surrogate for antral follicle
count (AFC) . Also, for prediction of the ovarian response to
gonadotropin therapy, serum AMH levels are stronger predictor
than ultrasonographic AFC .
Dehydroepiandrosterone (DHEA) is a 19-carbon steroid
and its actions are partially exerted through its metabolites .
DHEA acts as prohormone, endogenous precursor of ovarian and
adrenal androgens and a metabolic intermediate in ovarian follicular
steroidogenesis . Metabolically, DHEA affects oocyte
metabolism and its elevated systemic levels may contribute to
poor pregnancy outcomes in women with hyperandrogenism
Considering the fact that androgens can influence ovarian
follicular growth, augment steroidogenesis, promote follicular
recruitment and increase number of primary and pre-antral follicles
. The current study hypothesized that priming of infertile
women with poor ovarian reserve using dehydroepiandrosterone
(DHEA) may improve clinical pregnancy rate (CPR) in
women older than 38 years seeking for pregnancy
The current study was conducted since March 2016 till Oct
2018 to allow a minimum follow-up period of 6 months for the
last case enrolled in the study. All women in age range of 38-40
years and complaining of failure to get spontaneous pregnancy
since more than one-year despite of the regular intercourse, no
use of contraceptives, and absence of male factor for infertility.
Women with endocrinopathy, tubal factor, had previous attempts
of assisted reproduction, presence of male factor, uterine abnormalities,
had diabetes mellitus, renal or cardiac disease were excluded
from the study to equalize enrolment criteria.
All women eligible for evaluation undertook full clinical examination,
transvaginal ultrasonography (TUV), hystrosalpingography,
and gave blood samples for evaluation of hormonal
profile. Husbands were asked to perform seminal analysis for
assurance of fertility and were sent for andrology clinic for evaluation of potency sufficient to commit intercourse. Enrolment
criteria included primary or secondary infertility for >1-year
duration, serum anti-Müllerian hormone (AMH) level of ≤1 ng/
ml, and ultrasonographic manifestations of poor ovarian reserve
(POR). Enrolled couples signed written fully informed consent
prior to enrolment. Diagnostic criteria for poor ovarian reserve
included old age or presence of other risk factor for POR, history
of previous POR, abnormal ovarian reserve including low AFC
and/or AMH .
The study protocol comprised two-phase, during Phase-1,
all enrolled women received DHEA therapy in a dose of 50 mg
twice daily for three months and women were allowed to get the
trial for getting spontaneous conception. Women who failed to
get pregnant underwent induction of ovulation using 100 mg of
oral clomiphene citrate (Clomifene; Young Poong Pharmaceutical,
Incheon, Korea) for five days starting on day 3 of the menstrual
cycle, followed by daily intramuscular injection of 150 IU
of human menopausal gonadotropin (Pregnyl; Organon, Oss, the
Netherlands) till ovulation was assured by TVU.
I. Bilateral ovarian AFC using TVU on day 2–3 of cycle
by counting number of antral follicles reaching 2–10 mm
in transverse axial section of each ovary and count was
summed. AFC was determined at time of enrollment, after
DHEA therapy (End of Phase-1), and after induction of ovulation
(End of Phase-2).
II. Hormonal profile was re-checked at the end Phase-1
III. Chemical and clinical pregnancy rates (CPR) and abortion
Obtained data were presented as mean±SD, numbers and
percentages. Results were analyzed using paired t-test and Oneway
ANOVA Test. and Chi-square test (X2 test). Statistical analysis
was conducted using the IBM SPSS (Version 23, 2015) for
Windows statistical package. P value <0.05 was considered statistically
The study included 341 infertile women eligible for evaluation,
59 women were excluded for not fulfilling inclusion criteria
and 282 women were included in the study (Figure 1); inclusion
criteria were shown in Table 1, Table 2.
At the end of phase-2 of the study, hormonal profile of women
included in phase-2 continued to improve with ovulation induction
after 3-m course of DHEA especially serum FSH, LH and
E2 that were improved significantly at the end of phase-2 (Figure
2), while serum testosterone and AMH were improved non-significantly
compared to levels estimated at the end of phase-1
(Table 3, Figure 3). AFC at the end of phase-2 was significantly higher than at end of phase-1 for women included in phase-2 of
the study. Through phase-2, 49 women got chemical pregnancy
(19%) and pregnancy was assured clinically in 42 women for a
CPR of (16.3%) and during 1st trimester 5 women (11.9%) got
abortion and 37 women continued pregnancy till the 2nd trimester
for a trial success rate of 14.4% (Figure 1).
Clinical pregnancy rate, as the study primary outcome, was
21.6% and success rate for having continued pregnancy till 2nd
trimester was 18.8%. Such outcome illustrated the benefit of
priming with DHEA with or without induction of ovulation and
indicated that the applied protocol could spare the need for
assisted reproduction procedures in 21.6% of infertile women
aged >38. Moreover, the applied protocol allowed getting pregnancy
that was continued till 2nd trimester in 71.6% of women
who had positive chemical pregnancy and 86.9% of those who
had clinical pregnancy. Furthermore, priming by DHEA did favorably
with induction of ovulation than without induction as the
reported CPR with induction was significantly higher.
Unfortunately, few previous studies tried DHEA for improving
the chance of spontaneous conception, but got similar outcome,
where Malik et al.  reported increased ovulation rate
from 48% to 86.3% and CPR of 24% after 3-m DHEA therapy
compared to women did not receive DHEA and Agarwal et al.
 reported significantly higher AFC after DHEA therapy than
before treatment and these changes were manifested clinically
as improvement in menstrual abnormality and spontaneous conception
in 10% of cases.
The obtained results go in hand with multiple studies tried
DHEA for women with POR, prepared for assisted reproduction
procedures, where Lin et al.  reported greater number of
transferred embryos and higher fertilization rate in women aged
>37 years received DHEA prior to IVF than women who did not
receive DHEA. Recently, Chern et al.  reported significantly
greater number of retrieved, metaphase II and fertilized oocytes
with higher CPR in women received DHEA 90 mg/day for
3 months before the IVF cycles than in women had IVF cycles
without DHEA. Also, Al-Turki  found DHEA supplementation
for women with POR undergoing IVF/ICSI cycles significantly
improved the endometrial quality, number of retrieved oocytes,
quality of embryos, and CPR and live birth rates. Moreover,
Schwarze et al.  performed meta-analysis for published articles
to determine the effect of use of DHEA on the likelihood
of success in patients with POR undergoing IVF/ICSI and found
DHEA use was associated with significant increase in pregnancy
likelihood with significant reduction in the likelihood of abortion,
but showed no association with the number of oocytes retrieved.
Secondary outcomes of the current study included changes
in AFC and hormonal levels, DHEA therapy induced significantc reduction of serum FSH, LH with significant increase of testosterone,
E2 and AMH levels with subsequently higher AFC compared
to pretreatment levels. Similarly, Malik et al.  and
Agarwal et al.  detected significantly improved serum AMH,
FSH and E2 levels and AFC. Recently, Al-Turki  reported that
DHEA supplementation had positive effect on hormonal profiles.
The mechanisms of the beneficial effect of priming of women
with POR with DHEA were variable and were extensively studied;
experimentally, Chimote & Chimote  documented that DHEA
play significantly vital role as intermediate in androgen and estrogen
formation and behave as endogenous agonists triggering
calcium oscillations required for oocyte activation through
regulation of Ca2+ passage through the calcium channels in
oocyte cytoplasm. Chu et al. found supplement DHEA increased
the number of primordial and primary follicles in aged mice by
inhibiting follicle apoptosis and tended to delay the decrease in
levels of cohesion, which may be responsible for age-related aneuploidy
in oocytes. Moreover, Eftekhari et al. detected a positive
and improvement effect on of DHEA on the meiotic spindle in old
Clinically, Lin et al. , found DHEA treatment resulted in
significant reduction of senescence-associated β-galactosidase,
which is was used as marker of senescence in cumulus cells obtained
after oocyte retrieval. Hu et al.  studied the expression
of androgen and FSH receptor in granulosa cells of women
received DHEA or not prior to IVF and found DHEA supplementation
significantly increased serum levels of testosterone and
sulfated DHEA with increased mRNA expression and protein of
both receptors in granulosa cells. Lin et al.  found DHEA supplementation
for women with PORs decreased DNA damage and
apoptosis, while enhanced the mitochondrial mass and dehydrogenase
activity and transcription factor A expression in cumulus
Priming of infertile aged women with POR using DHEA with
or without ovulation induction improves the chance of spontaneous
conception and spares the need for assisted reproduction
procedures by 21.6% of treated women. Ovulation induction
after DHEA priming triples the chance for spontaneous conception.
However, wider scale multicenter comparative studies are
mandatory to establish these outcomes.