Narkwichean, Amarin
(2018)
Efficacy of DHEA to fight against ovarian ageing.
PhD thesis, University of Nottingham.
Abstract
There is an increase in the number of women with subfertility, who seek assisted reproductive technology (ART) treatment to overcome involuntary childlessness due to ovarian ageing, but which is commonly associated with poor response to ovarian stimulation protocols resulting in poor outcomes during ART. A few clinical studies have shown that DHEA, an androgen mainly secreted from the adrenal glands, can improve ovarian response and increase the chances of pregnancy after in vitro fertilisation (IVF) treatment in women affected by ovarian ageing. However, clinical evidence as well as knowledge regarding underlying mechanisms of DHEA on improving ovarian response is still limited.
The research was divided into 2 arms; i) mechanistic experiments where sheep, a monoovulatory species with a long period of folliculogenesis, were used to investigate DHEA mechanisms and ii) a pilot randomised study called DITTO (DHEA intervention to treat ovarian ageing) to evaluate the efficacy of DHEA in clinical IVF practice.
The first animal experiment (chapter 3) utilised an ovarian cortical ‘normograft’ model in which a single ovary (n=6) was taken out operatively. Half of the ovary was prepared for small pieces of ovarian cortical grafts and transferred back onto the cut- ovarian pedicle. The other half was fixed for use as a control. DHEA implants were administered to the animals and left for a 10-week period. The second operation was scheduled to harvest both the remaining ovary and cortical graft. The normograft procedure allows i) destruction of all growing follicular pool and synchronisation of primordial follicle initiation in the autograft without endocrinological disturbance, and ii) retention of the normal follicular hierarchy in the remaining ovary. DHEA stimulates primordial follicle initiation and preantral/early antral follicular development in the gonadotrophin responsive stages by improving granulosa cell proliferation and modulating local growth factors e.g. anti-Müllerian hormone (AMH).
The second animal experiment (Chapter 4) was conducted partly to confirm the effects observed in the first experiment by comparing with the control animals. The animal number was double (12 mature ewes) and they were divided into two groups; animals treated with DHEA implants for 12 weeks and controls with placebo treatment. Moreover, the experiment was designed to compare, between treatment and control, ovarian response to controlled ovarian stimulation mimicking the human IVF cycle. The findings confirm that DHEA treatment increases the rate of follicle initiation as well as stimulating preantral follicular growth. Enhancing granulosa cell proliferation is one of the mechanisms but DHEA treatment also increases follicular response to both FSH and insulin-like growth factor 1 (IGF-1) by positive modulation of receptors expression. Higher follicular P4 production was observed in treated animals after the gonadotrophin stimulation when compared to the controls.
A pilot double-blinded, placebo-controlled, randomised trial was performed over two years with 60 women undergoing IVF. Subjects were randomised to receive either 75 mg/day DHEA or a placebo for at least 12 weeks with both capsules having similar colour, size and appearance. Sixty women were recruited with poor ovarian reserve based on antral follicle count or anti-Mullerian hormone thresholds. Subsequently, all patients were scheduled to the long gonadotrophin releasing hormone (GnRH) agonist IVF protocol with hMG, starting dose at 300 IU/day. Ovarian response, live birth rates and molecular markers of oocyte quality were compared between the study and control groups on the ‘intention to treat’ basis. Unfortunately, the clinical trial could not demonstrate a significant improvement in terms of pregnancy outcomes and ovarian response markers in the treatment group when compared to the control. The numbers of oocytes obtained from the egg collection procedure were similar between the two groups. Also, there was no significant difference in all cumulus and granulosa mRNA expressions concerning oocyte developmental competence.
In conclusion, there is currently no established clinical evidence supporting the use of DHEA as an adjuvant in IVF treatment. In contrast, in vivo animal studies demonstrate that DHEA treatment potentially provides stimulatory effects on folliculogenesis, thus indicating the importanceof androgens at all stages of follicular development. Further investigations are required to confirm these potential findings. If the beneficial effects of DHEA are confirmed, it can provide a safe and less costly intervention to fight against ovarian ageing in terms of infertility treatment and menopausal conditions.
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