Infertility, Female Clinical Trial
Official title:
Efficacy of Growth Hormone Supplementation With Gonadotrophins in IVF/ICSI for Poor Responders; a Randomized Controlled Trial
The objective of this study is to assess the effectiveness of adjuvant growth hormone injection during controlled ovarian stimulation, in poor responder women undergoing intracytoplasmic sperm injection (ICSI) procedures.
Infertility is defined as the failure to achieve a clinical pregnancy after 12 months or more
of regular unprotected sexual intercourse (and there is no other reason, such as
breastfeeding or postpartum amenorrhoea). Primary infertility is infertility in a couple who
have never had a child. Secondary infertility is a failure to conceive following a previous
pregnancy.
Subfertility, usually defined as the absence of conception after one year of regular
intercourse, subfertility is a common problem affecting as many as one in six couples.
According to the European Society of Human Reproduction and Embryology (ESHRE)
recommendations, couples with an estimated live birth rate of 40% or higher per year are
encouraged to continue aiming for a spontaneous pregnancy .
Treatment methods for infertility may be grouped as medical, complementary and alternative
treatments. Some methods may be used in concert with other methods. Drugs may be used for
both women and men.
If conservative medical treatments fail to achieve a full term pregnancy, the physician may
suggest the patient undergo assisted reproductive fertilization (ART). Methods for ART
include artificial insemination (IUI), gamete intrafallopian transfer (GIFT), zygot
intrafallopian transfer (ZIFT) or ICSI.
Intracytoplasmic sperm injection (ICSI) is an in vitro fertilization procedure in which a
single sperm is injected directly into an oocyte. During the past decade, ICSI has been
applied increasingly around the world to alleviate problems of severe male infertility
because too few motile and morphologically normal sperm were present in the ejaculate of the
male partner.
Although there have been several improvements in techniques of ART during the last three
decades clinical pregnancy and live-birth rates remain at approximately 30-40%.
Increasing these rates is desirable for couples undergoing ART, as treatment failure is a
source of psychological distress, and the most common cause of drop-out before achieving
pregnancy.The most common interventions to improve ART outcome are the use of maximized
controlled ovarian stimulation (COS), transference of multiple embryos into the uterus and
cryopreservation of surplus oocytes/embryos. However, the first two of these interventions
might increase the risk of ovarian hyperstimulation syndrome and multiple pregnancy.
In-vitro fertilization (IVF) protocols are constantly under review in an attempt to decrease
hormone (gonadotrophin) requirement, improve follicular recruitment, whilst primarily to
increase live birth rates.
Implantation failure is thought to result from impairment of embryo development and/or from
abnormal uterine receptivity.
Some protocols have considered the role of growth hormone in IVF. Growth hormone is a
biological peptide hormone, synthesized, stored and secreted by somatotroph cells located in
the anterior pituitary gland. Growth hormone can be synthetically produced using recombinant
DNA technology and is licensed to be used in the human population. There is currently no
consensus as to the route, dose or timing of growth hormone administration in IVF protocols.
Poor Ovarian Response (POR) is defined by the Bologna criteria, with an incidence between 9
and 24% of all cycles of IVF, usually it indicates a reduction in follicular response,
resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to
define the poor response in IVF, at least two of the following three features must be
present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and
(iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation
are sufficient to define a patient as poor responder in the absence of advanced maternal age
or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore,
one stimulated cycle is considered essential for the diagnosis of POR. However, patients of
advanced age with an abnormal ORT may be classified as poor responders since both advanced
age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of
ovarian stimulation cycle outcome. In this case, the patients should be more properly defined
as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal'
criteria needed to select patients for future clinical trials, more homogeneous populations
will be tested for any new protocols. Finally, by reducing bias caused by spurious POR
definitions, it will be possible to compare results and to draw reliable conclusions.
How the intervention might work? The administration of growth hormone may potentiate the
effect of exogenous gonadotrophins. Growth hormone is reported to modulate the action of
follicular stimulating hormone on granulosa cells by up-regulating the local synthesis of
insulin-like growth factor-I (IGF-1). This interest has been stimulated by animal studies
which suggest that growth hormone may increase the intra-ovarian production of the IGF-1.
IGF-1 displays growth hormone dependence both in-vivo and in-vitro The interaction between
growth hormone and IGF-1 is of significance since IGF-1 has been shown to play an important
part in ovarian function in both animal and human models. The addition of IGF-1 to
gonadotrophins in granulosa cell cultures increased gonadotrophin action on the ovary by
several mechanisms including augmentation of aromatase activity, 17 beta-oestradiol and
progesterone production and luteinising hormone receptor formation. IGF-1 has also been found
to stimulate follicular development, oestrogen production and oocyte maturation.
Improving the outcomes of ICSI by the use of growth hormone adjuvant therapy is important
particularly in those women who are considered poor responders. The aim of this study is to
establish the role of growth hormone in ICSI.
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