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.