Discussion
This is the first prospective study to evaluate the effectiveness of
adjuvants with DHEA combining Metformin in poor ovarian responders
(PORs) undergoing IVF. This study demonstrated that after
supplementation pretreatment, the number of oocytes retrieved, the
clinical pregnancy rate and the live birth rates significantly improved
in poor ovarian responders. However, larger prospective studies and
randomized controlled trials are necessary to confirm the possible
benefit of this approach.
Despite the fact that in the last two decades several clinical trials on
the topic of poor ovarian response have been made, so far it has been
impossible to identify any efficient treatment to improve the ovarian
response and the clinical outcome of this group of patients.
Dehydroepiandrosterone (DHEA) is currently widely used worldwide and is
considered a potential agent to improve the IVF outcomes of PORs. DHEA
is an endogenous steroid generated by the adrenal glands and ovarian
theca cells (7). Evidence shows that DHEA levels decrease with age (2).
DHEA may influence ovarian follicular growth, not only by acting as a
metabolic precursor for steroid production, but also by serving as
ligands for androgen receptors (18). Indeed, androgen has been reported
to play roles in recruitment and initiation of primordial follicles (27,
20), promotion of follicular growth by increasing FSH receptor
expression, and prevention of follicular atresia by reducing apoptosis
(26). DHEA could improve mitochondrial function and reduce apoptosis in
the cumulus cells and human granulosa cell line (19). Another possible
mechanism was described by Casson et al. (8), who described a transient
increase in insulin-like growth factor 1 (IGF-1) in patients undergoing
exogenous gonadotrophin ovulation induction after pre-treatment with
DHEA. The IGF-I amplifies the effect of FSH at the level of both
granulosa and theca cells (10, 29). This beneficial effect of IGF-1 has
been reported to be correlated with oocyte quality and embryo
development (13). Barad and Gleicher postulated that the effect of DHEA
was due to the creation of polycystic ovarian syndrome (PCOS)-like
characteristics in the aging ovary (4). Long-term androgen exposure can
induce histological and sonographic changes in normal ovaries similar to
PCOS (17). The effect of DHEA is cumulative as more of the antral
follicles become exposed to treatment, as described by Barad and
Gleicher (5). The theory of PCOS-like environment can explain the
increase in response from cycle to cycle under DHEA exposure.
Patients receiving DHEA supplements should be informed of the potential
negative side effects associated with DHEA, such as acne, oily skin,
deepening of the voice, hirsutism and hair loss. Long-term effects of
DHEA supplementation remain unknown. Possible risks include masculinized
daughters and sex steroid dependent malignancies.
Metformin is a biguanide that lowers blood glucose levels in
hyperglycemic individuals with type-2 diabetes mellitus but has no
effect on glucose levels in normal subjects (3). Beginning in the 1990s,
a series of studies indicated that metformin reduced insulin resistance
in women with PCOS and increased the likelihood of ovulation and
pregnancy (28). Hyperinsulinemia, as observed in PCOS subjects, may
contribute to the aberrant response of granulosa cells to gonadotropins
(9) and to the consequent arrest of follicle growth (12). However, the
exact role of metformin in the management of women with PCOS has been
quite controversial. Metformin modifies the ovarian morphology in PCOS
(11), enhances intraovarian androgen levels (24), and improves systemic
and local insulin resistance (25).
Therapy with metformin does not lead to weight gain and may be
associated with modest weight loss, largely because of a slight
anorectic effect as well as gastrointestinal side effects, including
abdominal discomfort, diarrhea, nausea, and vomiting.