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ARTICLE
Growth hormone supplementation improves
implantation and pregnancy productivity rates
for poor-prognosis patients undertaking IVF
John L Yovich *, James D Stanger
PIVET Medical Centre, 166–168 Cambridge Street, Leederville, Perth 6007, Australia
*Corresponding author. E-mail address: jlyovich@pivet.com.au (JL Yovich).
Dr Yovich presented his MD thesis ‘Human Pregnancies Achieved by In-Vitro Fertilisation’ following research and
clinical work undertaken with Professor Ian Craft at the Royal Free Hospital in London (1976–1980). He returned
to his home town of Perth, Western Australia and established PIVET Medical Centre, the first private
independent fertility management facility in Australia. In 1982, the first child was born as a result of treatment
at PIVET and this child has now become a father himself.
Abstract In a sequential crossover study of IVF conducted from 2002 to 2006, growth hormone (GH) supplementation was assessed
in poor-prognosis patients, categorized on the basis of past failure to conceive (mean 3.05 cycles) due to low response to high-dose
stimulation (<3 metaphase II oocytes) or poor-quality embryos. Pregnancy rates in both fresh and frozen transfer cycles and the
total productivity rates (fresh and frozen pregnancies per egg collection) were compared. In all, 159 patients had 488 treatment
cycles: 221 with GH and 241 without GH. These cycles were also compared with 1572 uncategorized cycles from the same period.
GH co-treatment significantly improved the clinical pregnancy rate per fresh transfer (P<0.001) as well as per frozen–thawed
embryo derived from GH cycles (P<0.05) creating a highly significant productivity rate (P<0.001). The effect was significant
across all age groups, especially in younger patients, and was independent of stimulation modality or number of transfers. GH cycles
resulted in significantly more babies delivered per transfer than non-GH cycles (20% versus 7%; P<0.001) although less than the
uncategorized cycles (53%). The data uniquely show that the effect of GH is directed at oocyte and subsequent embryo quality.
RBMOnline
ª2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
KEYWORDS: embryo quality, growth hormone, implantation, IVF, pregnancy, productivity rate
Introduction
The prognosis for treatment by IVF is highly dependent
upon ovarian responsiveness and the quality of oocytes
recovered, with both factors deciding the number of
good-quality embryos that will be generated. Most IVF
programmes utilize ovarian stimulation schedules which
all focus on capturing secondary follicles that have
reached the early antral stage in the early follicular
phase. At this point the follicles become FSH sensitive
and can be selected for growth in the cyclic recruitment
process.
1472-6483/$ - see front matter ª2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.rbmo.2010.03.013
Reproductive BioMedicine Online (2010) 21,37–49
www.sciencedirect.com
www.rbmonline.com
Fertility treatment by assisted reproductive techniques,
particularly for IVF, has relied upon increasing the amount
of endogenous FSH either by oral agents such as clomiphene
citrate and, more recently, aromatase inhibitors or by giving
exogenous FSH in a concentrated purified form (either uri-
nary-derived or produced by recombinant technology).
Exogenous FSH administration, particularly when supported
by gonadotrophin-releasing hormone analogues to prevent
early luteinization, has been very effective in follicle
recruitment and the generation of pregnancies at satisfac-
tory rates (Homburg et al., 1990a). However there is wide
variability to its responsiveness, such that some patients
will show excessive response with risk of ovarian hyperstim-
ulation syndrome whilst others demonstrate relative de-
grees of ovarian resistance leading to the recovery of few
oocytes. The number of oocytes is quite important given
the age-related phenomenon, which dictates that only a
proportion of oocytes recovered will have the maturational
integrity for generating good-quality embryos with subse-
quent successful implantations and ensuing pregnancies;
e.g. this level might be 20% of oocytes in younger women
(<35 years) but less than 10% of oocytes for older women
(>40 years).
Menstrual cycle dynamics were sufficiently well under-
stood by the 1960s to enable the evolution of successful
ovarian stimulation regimens for fertility treatments includ-
ing the inevitable progression into IVF. However, all stimu-
lation regimens have relied solely upon the importance of
FSH as the key hormone for follicle recruitment and matura-
tion. The last 20 years has seen an intense focus examining
ovarian endocrinology and paracrinology using advances in
molecular biology to better understand folliculogenesis,
cycle dynamics and the age-related process underlying
poorer-quality oocytes in older women. There is an increasing
realization that folliculogenesis involves events prior to, and
other than, FSH dependence, with the role of growth factors
an obvious consideration. Recent suggestions that LH may
improve embryo quality and implantation (Andersen et al.,
2006) and the use of dehydroepiandrosterone (DHEA) for
follicle recruitment (Barad and Gleicher, 2005, 2006)in
low-responder patients are two examples where stimulants
other than FSH may be needed. Critically, past FSH-only
regimens have focused more on oocyte numbers rather than
quality. Poor-responder patients by definition are those who
fail to respond satisfactorily to standard regimens and high-
light the complexity of follicle recruitment and viability and
the problem of a universal stimulation regimen. Growth hor-
mone (GH) is another adjunctive therapy reported to pro-
vide benefit to complex cases (Homburg et al., 1991,
1990b). Currently, reports of its use have been from limited
studies in various patient subgroups (Tesarik et al., 2005)
and as such remains outside routine clinical application.
The first interest in utilizing GH in the human followed
from a series of reports from several independent groups
showing an essential role in various animal species of growth
factors on ovarian function, particularly the amplification of
FSH action (Adashi et al., 1991). The early report, in partic-
ular, that GH could facilitate ovulation induction by meno-
trophins in the human setting (Jacobs, 1972, 1992), caused
some highly fruitful collaborative activity under the leader-
ship of Professor Howard Jacobs in London. However, one
critical area that GH had received little attention was on
poor-prognosis patients in whom, despite increased gonado-
trophin dosages, pregnancies were difficult to achieve. Con-
sequently, the lead author established pilot trials to be
undertaken at PIVET Medical Centre to determine if GH
might have a role in improving the outcome for patients
who had poor responses in IVF. After positive implications
in pilot studies over several years, this report details the po-
sitive outcome of a formalized 5-year study providing GH
therapy to patients deemed to be poor-prognosis cases.
Materials and methods
Study period and participants
PIVET Medical Centre was established in 1980. The study
period includes all cases managed at PIVET Medical Centre
from 1 January 2002 to 31 December 2006. Patients offered
the opportunity to participate in the GH study were those
considered to fulfil one or more of the following criteria:
(i) women who had generated less than 3 metaphase II oo-
cytes despite having been given maximal FSH stimulation
(i.e. 450 IU/day with absolute maximum of 600 IU/day);
(ii) women who had generated embryos of which the major-
ity (>50%) showed marked fragmentation and were graded
as 1.5 in PIVET’s long-standing embryo-grading system;
or (iii) repetitive fresh or frozen embryo transfers without
pregnancy where diminished egg or embryo quality was
identified by the laboratory.
Although GH had been explored in several pilot studies
over the previous decade, the selected study period
(2002–2006 inclusive) embraces rigid inclusion criteria and
a complete computer-record system that has been sub-
jected to a rigorous, ongoing validation process.
Clinicians had individual flexibility in deciding which
cases fitted the categories and could be offered inclusion
in the study group. Participants were offered GH based upon
experience from previous cycles or history from either PI-
VET or from outside clinics. The decision to utilize GH, when
offered, was made by the patient and included several fac-
tors, one of which was cost (since patients were required to
pay for GH). However, once selected, patients accepted the
sequential crossover design and made their own decision to
commence the next cycle with or without GH on the under-
standing that they could not receive further GH for treat-
ment cycles undertaken within 6 months. There was an
even distribution between women under 36 and over
36 years of age. The majority had undertaken several IVF at-
tempts before GH was offered. It was only in the latter part
of the study period that GH was offered pre-emptively on
the first or second attempt, generally on the basis of ad-
vanced age or limited cycle opportunities. The number of
previous cycles undertaken in outside clinics was not always
clear and therefore the attempt may be understated.
Accreditation
The Reproductive Technology Accreditation Committee
(RTAC), which was formed as a subcommittee under the
Fertility Society of Australia, controls Australian IVF units.
RTAC accredits IVF units to a maximum of 3 years under
an evolving Code of Practice. For accreditation, IVF units
38 JL Yovich, JD Stanger
must provide their data in a continuous and complete form
for central audit. During this period, PIVET has satisfied
RTAC and received full 3-year accreditations continuously.
In Western Australia, there is also state legislation under
the Human Reproductive Technology Act (1991) that pro-
vides a second and separate regulatory requirement. Data
are provided quarterly and each unit is assessed on an annual
basis. One of the requirements under state legislation is that
the IVF unit must have up-to-date accreditation by RTAC as
well as to be overseen by the Reproductive Technology
Council (RTC), established under the state legislation.
Ethical approval
All research at PIVET requires approval from its institutional
ethics committee. The use of GH in ovulation induction was
first approved by the Cambridge Hospital Human Research
Ethics Committee on 15 September 1993. The project was
further scrutinized by the RTC and was granted final ap-
proval on 25 November 1993 (registration number I002).
RTC oversight approvals were further granted on 19 Novem-
ber 2002 and 27 October 2006.
Experimental design
The study was designed as a sequential crossover, where pa-
tients identified as ‘poor-prognosis cases’ were given the
option of using GH. They may or may not have elected to
utilize it in the cycle when initially offered (due to costs
or other concerns), but would be offered it in the next cycle
if unsuccessful in the first. Patients who utilized GH in a cy-
cle, but did not conceive, continued in a crossover process
with no GH on the next cycle, believing that GH had no ben-
efit. PIVET requirement was that a maximum of six injec-
tions were given for a patient within any 6-month period
and patients who utilized GH waited at least 6 months be-
fore considering utilizing it again. Given that the PIVET
clinic requirement is a minimum of only 2 months’ rest be-
tween treatment cycles, this crossover arrangement pre-
sented an issue in that some treatment cycles without GH
may well still have remained under its influence.
Patients who received GH on at least one cycle during
the 5-year period were included in the study group. The
analysis compares the outcome including pregnancy be-
tween the cycles in which GH was given (termed GH+) to
those cycles where GH was not utilized (termed GH). It
also enables a comparison of the outcomes of these two
groups to the treatment cycles for all other uncategorized
patients managed concurrently (termed GHu). This term
was used since it included a group of patients who under-
took IVF and either conceived or withdrew from further
treatment, some of whom may have ultimately been of-
fered GH after the study period. Whilst a sequential cross-
over study has some weaknesses as a research model, it is
highly practicable in a private clinical setting and the com-
parative assessments are believed to be valid.
Patient consent
Patients provided their informed consent using PIVET docu-
ment, file number 18, Information and Consents 22.1 – Consent
to an Innovative Procedure: Use of Saizen (Biosynthetic
Growth Hormone) in ovulation induction. They were also
provided with a patient information sheet ‘What is Growth
Hormone?’. The sheet highlighted potential side-effects
and, particularly, asked patients to report any headaches,
visual problems, nausea, vomiting or joint-swelling. The
document noted a potential association between low GH
and hypothyroidism and the potential precipitation of
diabetes particularly for those with a family history. The
patient information sheet was continuously updated to
indicate information from current reported studies, the
consideration of safety aspects along with biosynthetic
preparation and costings. Patient consent for the use of
GH was in addition to other consents for IVF treatment,
intracytoplasmic sperm injection (ICSI) or other innova-
tions, such as assisted hatching, with each having its own
separate patient information sheet and requiring separate
consent. Participating patients were required to pay for
the use of GH over and above the IVF treatment cycle with
charges levied according to the manufacturer’s charge to
the clinic.
Growth hormone protocol
In the initial phase of the study, the protocol for the com-
mencement of GH was in the cycle preceding the actual
IVF attempt. During 2004–2006, GH was increasingly started
and maintained during the IVF cycle. Therefore the period
2002–2003 represented prior GH exposure, while 2005–
2006 represented concurrent exposure: 2004 may be viewed
as a transition between the two protocols. Twenty-six per-
cent of transfers occurred in 2002–2003 while 57% of trans-
fers occurred in 2005–2006, reflecting the increased usage
of GH supplementation over time.
GH was given in the form of Saizen 10 IU (Serono, Austra-
lia) under two schedules. In the first four years (2000–
2004), the schedule was based on the ideas of Homburg
et al. (1990a,b), attempting to enhance the development
of those secondary oocytes which were in the initial recruit-
ment phase and would be available for FSH capture in the
early follicular phase of the treatment cycle. GH was,
therefore, given in the previous cycle on days 7, 14 and 21
with a final injection on day 2 of the treatment cycle.
With the emergence of other ideas (particularly those
subsequently published by Tesarik et al. (2005), who used
a course of GH injections during the treatment cycle) the
majority of cases in 2005 and 2006 adopted a revised blend
whereby patients received six injections with the first
beginning on day 21 of the preceding cycle and the subse-
quent injections being on days 2, 6, 8, 10 and, if still pro-
gressing, a final injection on day 12.
Patients therefore received either four injections under
the early protocol or a maximum of six injections under
the updated protocol. These were analysed both together
and separately in the results.
Clinical management
Infertility patients involved in the IVF programme at PIVET
are treated in a flexible manner (sometimes dictated by cli-
nician preference) utilizing different stimulation regimens.
Growth hormone supplementation in poor-prognosis IVF patients 39
These include a long down-regulation protocol (LDR;
Synarel; Pfizer, Australia; or Lucrin; Abbott, Australia), a
flare-stimulation regimen (FSR; Lucrin) or, increasingly in
recent years, an antagonist protocol (AP; Cetrotide; Serono,
Australia; or Orgalutran; Shering Plough, Australia). All
patients were treated with recombinant FSH (mostly Gonal-F;
Serono, occasionally Puregon; Schering-Plough, previously
known as Organon), Gonal-F being the preferred agent when
dosages of 300 IU are required.
In general, young women (<35 years) undergoing first
treatment utilize LDR progressing to FSR and then AP if
demonstrating ovarian resistance or poor outcomes. Often
older women (>35 years) will commence on FSR, progress-
ing to AP if required. Annualized data at PIVET shows no dif-
ferences in the pregnancy rates or likelihood of a live-born
baby from any of these stimulation protocols in the overall
data.
Recombinant FSH dosage was prescribed in a set formula
for first cycles, based on patient’s age, day-2 FSH and antral
follicle count graded A for high to E for low. Ovulation was
triggered by 10,000 IU human chorionic gonadotrophin
(HCG; Schering-Plough) in all cases included in the GH study
group when the leading follicles reached 18 mm and the co-
hort was matched by a serum oestradiol of around 800–
1000 pmol/follicle 14 mm.
As per long-standing practice, the patients were moni-
tored during the follicular phase, initially with a basal
day-2 concentrations of oestradiol, progesterone and LH,
thereafter from day 7 on alternate days with oestradiol,
progesterone, LH and transvaginal ultrasound for follicle
dimensions. Transvaginal oocyte recovery was undertaken
35 h post trigger under IV sedation using a PIVET-Cook dou-
ble-lumen flushing/aspiration needle (Cook, Australia).
Each follicle was aspirated and flushed to ensure maximum
potential for oocyte recovery.
The luteal phase was managed in all cases under PIVET’s
long-standing protocol of HCG support (1000 units on days 4,
7, 10 and 13 where day 0 is the day of oocyte retrieval. Mid-
luteal hormone check (oestradiol and progesterone) signi-
fied whether additional support hormones may be given
(oestradiol, progesterone or combined oestradiol/proges-
terone pessary; compounded PIVET products). Where 12
oocytes were recovered, progesterone pessaries replaced
HCG injections.
Embryo culture and assessment
All embryo culture was conducted using Sage Biopharma cul-
ture media (Gytech, Melbourne, Australia) with 5 mg/ml hu-
man serum albumin (Gytech) or occasionally patient’s
serum (10%). Oocytes were cultured for 4–5 h post collec-
tion before insemination with 100,000 motile spermato-
zoa/ml for IVF or denuded with hyaluronidase and mature
oocytes injected by ICSI.
Embryo cultures were undertaken as single embryo incu-
bations in 10 ll drops under oil (Gytech). All cultures were
in 60 mm Falcon dishes (BD, Australia) in MINC benchtop
incubators (Cook) under an atmosphere of charcoal filtered
5% CO
2
/5% O
2
/90% N
2
medical-grade gas. Embryos were
graded on day 3 under a four-point system, including half
points (grade 4 = 8+ cells no fragmentation and early
compaction evident; grade 3 = 7–9 cells, no fragmentation
and no compaction; grade 2 = slow cleavage and/or >20%
fragmentation; grade 1 = arrested or significantly fragmented
embryos). Embryos graded 1.5 were discarded. Day 5
embryos were graded using the Gardner’s scoring system
(Gardner and Schoolcraft, 1999) for blastocysts.
On days 2, 3 or 5, one or two embryos were transferred
to the uterus in 10–20 ll of culture media. Embryo transfers
were undertaken using the Cook double-catheter system
(K-JITS-2005; Cook) under transvesical ultrasound control.
The embryos were deposited just short of the fundus with
a clear flash identified in the fundal region and a negative
check on the transfer catheter by the embryologist on
completion.
Although the clinic has a strong policy of single embryo
transfer for most of the study period, such cases catego-
rized as poor prognosis can receive up to two day-3 em-
bryos. When fertilization rates were above expectation
(5 embryos growing) the patient could elect to have blas-
tocyst culture with a single blastocyst transferred on day 5.
In the study period, there were 37 transfers at the blasto-
cyst stage in GH+ and 34 transfers in GHcycles. Assisted
hatching was offered according to RTC approval (i.e. if
three previous transfers had failed to generate a pregnancy
or if the patient was >38 years with an elevated baseline
FSH).
Residual embryos of suitable quality were cryopreserved
on the day of transfer using a slow freezing, propanediol
method (Testart, 1986) using 10% patient serum where pos-
sible or human serum albumin if required. The thawing of
embryos followed the same protocol (Testart, 1986) and oc-
curred on the day of embryo transfer.
Data validation and statistical analysis
PIVET has established an electronic record-keeping system
that integrates demographic data and billing systems (JAM
software) with a data-recording system using Filemaker
Pro database. Data is transmitted electronically annually
to the independent National Perinatal Statistics Unit data-
recording site and quarterly to the RTC.
The main data comparison was between the GH+ and
GHtreatment cycles and where relevant against the GHu
cycles. The main measure used for comparison between
groups was clinical pregnancy (CP) rate per embryo transfer
procedure, either fresh embryo transfer or post-thaw frozen
embryo transfer (FET). A productivity measure was also in-
cluded which summates the total embryo transfer and FET
pregnancies for the relevant group, constituting a produc-
tivity rate as the cumulative pregnancy rate per oocyte
retrieval. Implantation rates are defined as the number of
identifiable gestational sacs in clinical pregnancies arising
as a proportion of the total number of embryos transferred.
A further term, utilization rate, was used to denote the
proportion of ‘usable’ embryos arising from the total
number of two pronucleate embryos created from a single
oocyte retrieval procedure. This denotes the number of
embryos transferred plus the number deemed suitable for
cryopreservation.
Statistical analysis was conducted by comparison of
groups in 2 ·2 contingency tables using chi-squared analysis
40 JL Yovich, JD Stanger
with Pearson’s correction factor where required and t-test
for comparison between means.
Results
Patient profile
The patient profile revealed a total group of 159 women
with an average age of 37.5 ± 4.1 years (Table 1) with sim-
ilar numbers of patients in the various age groups (101 trans-
fers below 35 years; 216 between 35 and 40 years and 78
over 40 years) indicating that age itself did not entirely con-
stitute the prescription for GH. Infertility categories showed
21% of couples had some tubal factor, 32% had endometri-
osis included in their medical history, 42% had some form
of abnormal semen profile and 21% had poorly explained
infertility largely comprising polycystic ovaries or ovulatory
disorders. A single cause was described in 49% of couples
while 51% had more than one reason for infertility.
On average, couples had 3.05 cycles before being offered
GH; however, this was decided on a case-by-case basis. The
average number of cycles per referral case at PIVET during
the study period was 1.96 cycles compared with 3.95 cycles
in those patients receiving GH in one or more cycles.
Fresh and frozen transfers
During the 5-year study period, 159 patients were classified
as fulfilling the criteria for consideration of GH and had 488
IVF cycles. In all, 232 cycles were started with GH and 256
cycles were not (Table 2). This population represented
about 25% of the cycles started during the study period. Sev-
enty-one of the 159 patients had two GH+ cycles with at
least one intervening GHcycle.
The cancellation rates and the egg collection to transfer
rates were similar in both arms of the study leading to 193
transfers in GH+ and 202 transfers in GHcycles. Despite
similar numbers of fresh transfers, significantly more preg-
nancies arose in the GH+ group than the GHgroup (49/
193, 25% versus 19/202, 9%; chi-squared P<0.01).
Eighty-four embryo thaw cycles were undertaken with
embryos generated during GH+ cycles of which 79 resulted
in a transfer, but there were twice as many thaw attempts
(148) and transfers (140) undertaken from GHcycles
(partly due to the latter group recycling back more fre-
quently for transfers as there were fewer pregnancies in
the group). Importantly, there were significantly more clin-
ical pregnancies in the GH+ thawing group (17, 20%) than in
the GHFET group (14, 9%; P<0.05). The resultant preg-
nancy productivity rate (sum of clinical pregnancies from
fresh and frozen transfers per egg collection) in the GH+
group was significantly higher (30% versus 14%; chi-squared
P<0.001). The improved pregnancy rate in the GH+ thaw
cycles was noted as a strong trend across all age groups,
but particularly the younger (24% versus 10% for <35 years)
rather than the older (15% versus 11% for >40 years) age
group.
Of the 1686 IVF cycles undertaken in the GHu group of
patients (Table 2), 1572 had oocytes retrieved and 1311
proceeded to transfer which generated 499 clinical preg-
nancies (38%) and 1528 had thaw cycles which generated a
further 494 clinical pregnancies (32%). The pregnancy pro-
ductivity rate for the non-treatment group was 63% (993
clinical pregnancies from a total of 1572 egg collections).
When the GH treatment groups are compared against this
background population, the pregnancy productivity rate
for the GHgroup of 9% for fresh transfers and 9% for frozen
transfers clearly justifies the classification of these patients
as poor-prognosis cases. Supplementation with GH in the
fresh treatment cycles of this population provided a preg-
nancy rate that approached but remained less than the
background uncategorized population (fresh transfers 25%
versus 38%; P<0.01). This is reinforced by the productivity
rate comparisons for frozen transfers that showed the GH+
group (30%) was significantly improved to a level higher than
Table 1 Basic demographics for patients
receiving growth hormone co-treatment.
Parameter Value
No. of patients 159
Mean age ± SD (years) 37.5 ± 4.1
Type of infertility (%)
Tubal 21
Endometriosis 32
Unexplained 21
Male 42
Additional factors, e.g.
fibroid/adhesions
34
Single cause 49
Multiple causes 51
Table 2 Summary of fresh and frozen treatment cycles
with or without growth hormone (GH) co-treatment.
Parameter GH+ GHGHu Total
Cycles started 232 256 1686 2174
Oocyte retrievals 221 241 1572 2034
Fresh embryo transfers 193 202 1311 1706
Clinical pregnancies 49 19 499 567
Clinical pregnancy rate
per fresh embryo
transfer (%)
25
a,c
9
e
38 33
Thawing cycles 84 148 1528 1760
Clinical pregnancies 17 14 494 525
Clinical pregnancy rate
per thawing cycle (%)
20
b,d
9
e
32 30
Total pregnancies 66 33 993 1092
Clinical pregnancy rate/
oocyte retrieval
30
a,c
14
e
64 54
Values are number or percentage.
GH+ = cycles managed with growth hormone; GH= cycles
managed without growth hormone; GHu = uncategorized
cycles managed concurrently without growth hormone
consideration.
a
GH+ vs GHP<0.001.
b
GH+ vs GHP<0.05.
c
GH+ vs GHu P<0.01.
d
GH+ vs GHu P<0.05.
e
GHvs GHu P<0.001.
Growth hormone supplementation in poor-prognosis IVF patients 41
the GH(14%) and but still less than GHu group (64%)
(P<0.001 and P<0.01, respectively).
Influence of age
Twenty-six percent of the 395 transfers in the GH study
group were for women <35 years of age, 55% for women
aged 35–40 years and 20% for women over 40 years
(Table 3). While the number of transfers with or without
GH was similar in each age group, the pregnancy rate was
significantly higher in those cycles that included GH supple-
mentation (P<0.001). This effect of GH was most signifi-
cant for women under 35 years of age who displayed a
four-fold improvement (38% versus 9%; P<0.001) but also
significant to a moderate level for those aged 35–40 who
displayed a two-fold improvement (21% versus 11%; P<
0.05) and for those over 40 who displayed an eight-fold
improvement on smaller numbers (24% versus 3%; P<0.05).
Women over 40 years generated 29 pregnancies in the GH
group and 131 in the GHu group, providing a rate when
not exposed to GH of 160/1513 (10.6%) rising significantly
when exposed to GH to 50/193 (24%; P<0.001). Given that
the GHu group can also be categorized as poor prognosis,
the true benefit of GH in the over-40 years group is there-
fore more likely a 2.5-fold improvement.
Utilization rate and implantation rate
There was no significant difference in mean FSH concentra-
tion, the number of oocytes recovered nor in their fertiliza-
tion rate or utilization rate between GH+ and GHcycles
(Table 4). The difference in serum FSH at the start of each
cycle was slightly elevated in the GH+ and GHcompared
with the GHu control group but this difference was not sig-
nificant. In this study, the utilization rate was used as a
measure of embryo quality rather than applying an embryo
score and reflects the proportion of embryos deemed suit-
able for transfer or freezing. The average number of em-
bryos transferred was the same in all groups (GH+ 1.78;
GH1.77; GHu 1.64); however, there was a significant in-
crease in the implantation rate in GH+ cycles compared with
GHcycles (Table 4; 15.2% versus 5.1%; P<0.01). The low
implantation rate in GHcycles reinforced the patient’s
definition as poor prognosis and their inclusion in the GH
study. Although the implantation rate was increased under
GH+, the rate remained significantly less than observed in
the GHu group (27.4%; P<0.05).
The improved effect was present in all three age groups
defined in the study. However, when compared with the non-
treatment GHu group, it was the older women (>35 years)
who demonstrated the most significant improvement with
the use of GH, demonstrating implantation rates which
were equivalent to that of the uncategorized non-treatment
group (i.e. no significant differences; 12.8% versus 22.0%
in 35–40 year group and 13.0% versus 11.0% in >40 year
group). Younger women (<35 years) receiving GH showed
an improved implantation rate (20.6% versus 4.7%; P<0.01)
but this rate still fell significantly short of the GHu young
group (34.3%; P<0.05).
Stimulation regimens
In both the AP and FSR regimens, GH+ cycles had signifi-
cantly higher pregnancy rates than GHcycles (both P<
0.05) but there were no significant differences in pregnancy
rates among any of the stimulation regimens which received
GH augmentation (Table 5). Whilst overall, the pregnancy
rate was similar regardless of whether the stimulation was
AP, FSR or LDR, there were more AP cycles (n= 205) than
FSR (n= 147) and LDR cycles (n= 43) in the GH study group
(n= 395). This reflects the clinic’s policy at that time that
poor responders were increasingly managed by an AP proto-
col. LDR protocols were infrequently used in the patients
who received GH.
Attempt number
There was a significantly better pregnancy rate with GH on
the second (P<0.05) or third transfer (P<0.01; Figure 1)
than without GH. Individually, there was no better outcome
with GH when given for any transfer after the third but col-
lectively the combined pregnancy rate was significantly
higher with GH. The pregnancy rate for combined one–
three cycles was significantly higher for GH+ treatment cy-
cles (33% versus 11%; P<0.001) as well as for the combined
Table 3 Relationships between clinical pregnancies per transfer, patient age and growth hormone (GH)
co-treatment.
Treatment <35 years 35–40 years >40 years Total
nPregnant (%) nPregnant (%) nPregnant (%) nPregnant (%)
GH+ 41 38
a,e
103 21
b,c
49 24
b,e
193 25
a
GH60 9
d
113 11
d
29 3
d
202 9
d
GHu 653 46 527 34 131 16 1311 38
Total 754 43 743 29 209 16 1706 33
GH+ = cycles managed with growth hormone; GH= cycles managed without growth hormone; GHu = uncategorized cycles
managed concurrently.
a
GH+ vs GHP<0.001.
b
GH+ vs GHP<0.05.
c
GH+ vs GHu P<0.05.
d
GHvs GHu P<0.001.
e
GH vs GHu not statistically significant.
42 JL Yovich, JD Stanger
Table 4 Embryology information by age and growth hormone (GH) co-
treatment.
GH+ GHGHu Total
<35 years
Oocytes/retrieval 10.7 9.8 12.2 11.7
Fertilization rate (%) 58.3 58.0 61.9 61.4
Utilization rate (%) 64.4 64.7 84.7 82.2
Implantation rate (%) 20.6
a,c
4.7
b
34.3 29.9
Mean FSH ± SD (IU/l) 7.4 ± 1.6 7.3 ± 1.9 5.3 ± 2.5 5.9 ± 2.4
35–40 years
Oocyte retrievals 126 134 601 861
Oocytes/retrieval 9.3 8.4 9.8 9.5
Fertilization rate (%) 52.7 48.4 61.7 58.0
Utilization rate (%) 68.8 81.0 76.2 75.0
Implantation rate (%) 12.8
a
7.2
b
22.0 18.9
Mean FSH ± SD (IU/l) 8.0 ± 3.1 7.8 ± 3.8 5.6 ± 1.9 6.6 ± 2.9
>40 years
Oocyte retrievals 54 36 167 257
Oocytes/retrieval 7.2 7.9 6.9 7.1
Fertilization rate (%) 57.0 55.0 59.0 58.40
Utilization rate (%) 67.0 77.0 26.0 43.0
Implantation rate (%) 13.0
a
1.3
b
11.0 10.0
Mean FSH ± SD (IU/l) 6.6 ± 3.0 6.5 ± 2.4 6.4 ± 3.7 6.5 ± 3.2
Total
Oocyte retrievals 221 241 1572 2034
Oocytes/retrieval 8.0 8.9 10.7 10.3
Fertilization rate (%) 55.0 53.0 61.0 60.0
Utilization rate (%) 67.10 72.0 78.0 75.0
Implantation rate (%) 15.2
a,c
5.1
b
27.40 22.0
Mean FSH ± SD (IU/l) 7.4 ± 2.7 7.4 ± 2.9 5.4 ± 2.4 6.5 ± 2.7
Utilization rate = percentage of embryos suitable for transfer or freezing.
GH+ = cycles managed with growth hormone; GH= cycles managed without
growth hormone; GHu = uncategorized cycles managed concurrently.
a
GH+ ·GHP<0.01.
b
GH·GHu P<0.05.
c
GH+ ·GHu P<0.05.
Table 5 Relationships between clinical pregnancies per transfer, method of
ovarian stimulation and growth hormone (GH) co-treatment.
Group Antagonist Flare stimulation Long down-regulation
nPregnant (%) nPregnant (%) nPregnant (%)
GH+ 138 30
a
38 21
a,b
17 17
c
GH67 15 109 7 26 4
GHu 251 39 686 39 374 38
n= no. of transfers; Pregnant = percentage clinical pregnancy per embryo transfer.
GH+ = cycles managed with growth hormone; GH= cycles managed without
growth hormone; GHu = uncategorized cycles managed concurrently.
a
GH+ ·GHP<0.05.
b
GH+ ·GHu P<0.05.
c
GH+ ·GHnot statistically significant.
Growth hormone supplementation in poor-prognosis IVF patients 43
Oocyte retrievals 41 71 804 916
four–nine cycles (20% versus 7%; P<0.05). Although the
number of patients who underwent a high number of trans-
fers was low, pregnancies were recorded in all transfer ser-
ies, even after nine or 10 previous unsuccessful attempts
with more pregnancies following the use of GH.
It is worth pointing out that all but ten (Figure 1a) of the
GH+ transfers had at least one prior transfer without GH. All
six of the patients who did have GH+ transfers in their first
IVF cycles were over 40 years of age. The majority of the
GH+ transfers were either the second or third transfer; how-
ever, where GH was administered after high-order multiple
transfers, most were patients referred to PIVET after multi-
ple unsuccessful transfers elsewhere, where GH was not of-
fered. In all, 24% of GH+ transfers were associated with
prior poor outcomes outside of PIVET. This would have the
effect of decreasing the pregnancy rate of the GHcycles
if it were factored into this analysis and further enhance
the differences in the implantation and pregnancy rates be-
tween GH+ and GHcycles.
Year of treatment
GH+ significantly increased pregnancy rates compared with
GHtransfers in the same year in both the 2002–2003
and 2005–2006 intervals (Figure 2a). In 2004, the preg-
nancy rate between GH+ and GHcycles was not significant
although the same trend existed. During 2002–2003, there
were 12 clinical pregnancies from 30 transfers in GH+ cycles
compared with only 8% in GHcycles (40% versus 8%;
P<0.001) while in 2005–2006, there were slightly less
clinical pregnancies with GH+ (24% versus 7%; P<0.01).
The pregnancy rate in GHcycles was the same in both
periods, indicating the referral of patients was similar over
the review period, although the proportion of cases taking
up GH treatment was higher in the years 2005–2006
(Figure 2b).
Side effects
No case of diabetes or hypothyroidism emerged during GH
administration. Two patients described joint swellings of
the hands – one after a single GH injection, another after
a series of four injections. Both ceased further GH treat-
ment and their symptoms resolved spontaneously over 1 or
2 weeks. There were no cases of clinically significant ovar-
ian hyperstimulation syndrome, although for two patients
receiving GH, all embryos were frozen as per PIVET protocol
as they had 12 oocytes recovered at oocyte retrieval. They
were monitored during the luteal phase and did not develop
significant symptoms or other features of ovarian hyper-
stimulation syndrome.
Pregnancy outcome
The analysis of the clinical outcomes combined the pregnan-
cies from both fresh and frozen transfers (Table 6). There
was no difference in the number of clinical pregnancies
per positive HCG pregnancy test (66/73, 90.4% versus 33/
37, 89.2%) or live births per clinical pregnancy (43/66,
65.2% versus 17/33, 51.5%) between GH+ and GHcycles.
In this study, the multiple pregnancy rate (two twin preg-
nancies after GH+ and one after GHstimulation) was low
regardless of treatment but there was no difference in the
pregnancy loss rate between GH+ and GHcycles (35% ver-
sus 48% miscarriage rate per clinical pregnancy) both higher
than the rate in the GHu group. The multiple pregnancy rate
from the patient population utilizing GH on some cycles
(two sets of twins from the GH+ group and one set from
the GHgroup) was lower than the non-treatment group
Figure 2 Clinical pregnancy rates (a) and number of transfers
(b) in poor prognosis cases with or without GH supplement
during individual years of the study period.
Figure 1 The number of transfers by attempt number (a) and
the attempt number in which pregnancy ensued (b) for poor
prognosis patients receiving growth hormone.
44 JL Yovich, JD Stanger
(5.0% versus 9.2%) over the same period reflecting, once
again, the group’s lower implantation potential. In all, sig-
nificantly more babies were delivered in GH+ cycles than
in GHcycles (P<0.05).
There were three abnormalities identified from the GH+
derived pregnancies (one anencephaly terminated in the
first trimester, one complex congenital heart anomaly,
one diamniotic twin/twin transfusion syndrome and one
case of fetal growth retardation). There were two abnor-
malities from the GHpregnancies (one tetraploidy and
one trisomy 15, both terminated in the second trimester).
These cases represented a similar profile to the background
of subfertility pregnancies managed at PIVET although the
‘highish’ aneuploidy rate and pregnancy loss rates might
well reflect the poorer prognosis status of those cases se-
lected for consideration of GH treatment.
Discussion
This report represents the application of GH as an adjuvant
to ovarian stimulation and follicle recruitment in highly se-
lected, poor-prognosis cases deemed to be poor responders
or patients with suboptimal embryo development. The clear
observation arising from this study is that implantation rates
and resultant pregnancy rates along with the numbers of
healthy babies delivered are significantly higher when GH
co-treatment is given to the defined categories of poor-
prognosis cases. The results confirm a role for GH treatment
during an IVF stimulation cycle and the benefits apply to wo-
men categorized as poor prognosis regardless of age, stimu-
lation regimen or attempt number. The results not only
confirm a benefit in fresh transfer cycles involving GH co-
treatment but reveals an extension to subsequent frozen
embryo transfers. This appears therefore to arise as a con-
sequence of improved oocyte quality rather than numbers
of oocytes and embryos, which were not influenced. The re-
port is the first to span such a long time period reinforcing
its efficacy and is the first to include aspects of a whole-
of-cohort analysis that views the total productivity from
an egg collection incorporating both fresh and frozen trans-
fers. The information reported in this study was collected
over a 5-year period and applied to patients in a private
clinical environment who have demonstrated via past per-
formance a reduced prognosis due to poor embryo numbers
and/or quality and to a lesser extent response to FSH.
There are several reports of small, limited randomized
studies involving GH in ovulation induction and IVF. An early
study with GH on anovulatory or amenorrhoeic women
showed less gonadotrophin was required in the presence
Table 6 Summary of pregnancy outcomes between growth hormone (GH) co-treatment
groups.
Parameter GH+ GHGHu
Cycles started 232 256 1686
Cancelled cycles 11 15 114
Oocyte retrievals 221 241 1572
Nil oocytes retrieved 4 4 28
Nil fertilization 17 17 80
Deferred transfer 4 5 175
Fresh transfer cycles with embryos frozen 95 103 879
Cycles with freezing (%) 49 50 56
Fresh transfers 193 202 1311
Frozen transfers 73 145 1528
Total transfers 266 347 2839
Total biochemical pregnancies 7 4 33
Total clinical pregnancies 66 33 993
Failed pregnancies 23 16 228
Live births from fresh embryo transfer 33 11 387
Live births from frozen embryo transfer 10 6 378
Total live births 43 17 765
Multiple pregnancies 2 1 70
Total babies delivered 45 18 836
Miscarriage rate/positive HCG (%) 30/73 (41) 20/37 (54) 261/1026 (25)
Miscarriage rate/clinical pregnancies (%) 23/66 (35) 16/33 (48) 228/993 (23)
Babies/oocyte retrieval (%) 20
a
753
Mean birthweight ± SD (g) 3111 ± 738 3271.3 ± 446 3043 ± 732
b
Mean gestation ± SD (weeks) 38.0 ± 3.2 38.9 ± 0.91 37.6
c
Males:females 20:25 7:11 431:405
GH+ = cycles managed with growth hormone; GH= cycles managed without growth hormone;
GHu = uncategorized cycles managed concurrently.
a
GH+ ·GHP<0.001.
b
Mean birthweight for all births between 2002 and 2008.
c
National Perinatal Statistics Unit data for 2006: average gestational age for all births from all
transfers.
Growth hormone supplementation in poor-prognosis IVF patients 45
of GH (Homburg et al., 1991,1990b), a result confirmed by
Owen et al. (1991) for polycystic ovary patients. These stud-
ies argued that GH was acting in an augmentation role to
FSH in follicle development via increased insulin-like growth
factor (IGF)-I activity. Younis et al. (1992), in a limited ran-
domized study on 42 young, tubal patients, found no differ-
ence in the FSH required nor in the number of oocytes or
embryos recovered. The implantation rate and pregnancy
rate differed slightly but was not significant. Bergh et al.
(1994) also found similar oocyte numbers with GH but im-
proved fertilization rates in 40 ‘poor responders’ in a ran-
domized, placebo-controlled study. Schoolcraft et al.
(1997) suggested that a protocol utilizing a flare stimulation
regimen with GH whilst using similar amounts of FSH
appeared to deliver a better pregnancy outcome. More
recently, Sugaya et al. (2003) confirmed in nine poor-
responder patients increased oocyte recovery and embryo
quality than in their previous cycles and that, while IGF-I
concentrations were higher after GH, there were no adverse
effects noted. Finally, Hazout et al. (2009) observed an im-
proved response to GH co-treatment in a large sample of
245 ‘poor’ responder patients with increased oocyte and
embryo numbers and increased pregnancy rate when com-
pared with other similar patients.
Rajesh et al. (2007) reported a similar outcome in 20
poor-prognosis patients. Kolibianakis et al. (2009),ina
meta-analysis study, argued that GH may improve preg-
nancy rate in poor-responder patients but there remains
insufficient information to confirm these observations. This
meta-analysis supported a previous study in 2003 from the
Cochrane database (Harper et al., 2003) and a recent review
(Kyrou et al., 2009). Together, these reports suggest that
while oocyte recovery is a variable outcome measure, most
studies have found that more pregnancies occur with GH co-
treatment.
These data also do not confirm an increase in oocyte
recovery or fertilization rate as reported elsewhere (Bergh
et al., 1994). There may be several reasons for the lack of
difference in oocyte numbers; the one most likely is that
the poor-responder groups are normally on high dose FSH
regimens. If one of the roles of GH is to facilitate the ac-
tions of FSH at normal serum concentrations (Volpe et al.,
1992), then the prescription of maximal doses may override
this role (Kyrou et al., 2009). Alternatively, this result was
not surprising given the similar starting FSH concentrations,
reinforcing the view that these patients were not poor
responders relative to other patients in the same age group.
Future studies may need to elucidate the interaction be-
tween FSH dose and GH exposure.
In all age groups, the implantation rate in GHcycles
was highly significantly poorer compared with the implanta-
tion rate in GHu cycles. This observation supports the pa-
tient categorization of poor prognosis. This report did find
that within the study group, co-treatment of GH signifi-
cantly improved the chance of pregnancy and specifically
the implantation rate compared with the cycles without
GH. Importantly, the implantation rate with GH+ cycles in-
creased to levels only marginally less than the uncatego-
rized group, especially so for women over 40 years.
A key observation was that in the thaw cycles with em-
bryos originating from the GH+ cycles, the pregnancy rate
per thaw cycle was significantly higher compared with the
cycles where the frozen embryos arose from the GHgroup.
This was evident across all ages implying better-quality
embryos arise following GH co-treatment in poor-prog-
nosis cases. The best measure of GH effectiveness is the
cumulative number of pregnancies expressed against the
number of collections since it is the cohort of embryos that
is important, not just the fresh transfer. In this study, the
cumulative pregnancy rate per collection (productivity rate)
was significantly higher after GH augmentation than without
GH, although this was still less than the rate of 64% in the
uncategorized group, which, of course, benefited by exclu-
sion of those poor-prognosis cases selected out for the GH
study. This analysis again supports the argument that the
patients referred for GH indeed have a significantly poorer
prognosis. In the cycles without growth hormone, only
13.7 clinical pregnancies were achieved per 100 collections.
It may be surmised from this data that GH significantly im-
proves the outcome in the poor-responder and other poor-
prognosis groups but its application does not restore these
patients to a ‘normal’ responder. The higher implantation
rate with GH and the higher productivity over fresh and fro-
zen cycles argues the effect of GH augmentation was on oo-
cyte competency rather than on uterine interactions.
The beneficial effect of GH was apparent over all at-
tempt numbers and over time, with the observation that
the provision of GH in 2002–2003 in the cycle preceding
the IVF cycle generated better outcomes compared with the
GHcycles than in the later part of the study in 2004–
2005 when GH was given during the treatment cycle. Most
of the published studies administered GH after the start of
ovarian stimulation and continued exposure until ovulation
induction trigger. The two differing exposure periods in this
study reflect this study’s endeavours to explore whether
one regimen was superior and the results suggest that both
pre- or peri-treatment cycle administration provided a ben-
efit. It does not, however, imply that the mode of action is
the same. There have been no reports comparing the timing
of GH exposure, yet there are two proposed modes of
action: either a supportive effect on FSH stimulation on
follicle recruitment and development or a role in oocyte
maturation and maturity.
The requirement of GH in follicle development can be
demonstrated by the management of patients who have
either GH deficiency (Giampietro et al., 2009) or GH excess
women, GH replacement therapy of 4–6 months results in
natural conceptions without the addition of any other
stimulatory means. There have been many reports docu-
menting that GH supplementation increases IGF-I serum
and follicle concentrations in normal ovulating women
(Carson et al., 1989; Volpe et al., 1992) and that its action
was largely to promote FSH activity by IGF-1 (Homburg
et al., 1988). As such, the early studies focused on whether
GH supplementation increased follicle recruitment and
oocyte numbers mainly for poor-responder patients. Whether
this applies to the poor-prognosis patients in this study who
are already receiving high dose gonadotrophin stimulation is
unclear. Sugaya et al. (2003) did find, even at 450 IU/day,
that GH treatments resulted in more oocytes recovered
but only in patients with low IGF-I binding protein-3. This
observation suggests that where GH involves an action via
IGF-I, it is mediated by associated binding proteins. Recent
46 JL Yovich, JD Stanger
(Esfandiari et al., 2005). In the report of four eugonadotrophic
articles demonstrating that DHEA may augment the ovarian
action of FSH in poor responders by increasing oocyte recov-
ery rates and embryo quality (Barad and Gleicher, 2006;
Casson et al., 2000) appear to be different observations
made in this study and suggest that DHEA and GH may differ
in some modes of action. If so, combining both DHEA and GH
may warrant specific investigation.
An alternative mode of action may be a direct effect of
GH on oocyte maturation. In the bovine model for instance,
GH has been shown to promote nuclear maturation of oo-
cytes in vitro via cumulus cell interaction (Izadyar et al.,
1996) in a manner that is independent of IGF-1 (Izadyar
et al., 1997). In this model, GH receptors have been identi-
fied on both the cumulus cells and the oocyte along with GH
mRNA expression in the oocyte (Bevers and Izadyar, 2002).
In-vitro co-culture of GH with bovine oocytes promoted em-
bryo development (Izadyar et al., 2000), possibly by improv-
ing cytoplasmic aspects of the oocyte during maturation.
Izadyar et al. (1998a,b) further demonstrated that GH and
FSH acted via separate pathways since the FSH effect on oo-
cyte maturation was cAMP dependent, unlike the GH effects
that were not. Together, these articles argue that GH has a
specific stimulatory role in oocyte maturation via GH recep-
tors to activate transcription and that this may be in part
mediated via the oocyte. There are no reports of GH recep-
tor activity on human oocytes and species variations make
extrapolation difficult, since oocyte-specific factors may
promote granulosa cell proliferation in the mouse, but in
the bovine and porcine models this effect involves IGF-1
(Gilchrist et al., 2008). This study’s data, demonstrating im-
proved implantation rates for both fresh and frozen em-
bryos, suggest that GH has an active role in human
embryo quality and this would most likely reflect a role in
oocyte maturation rather than oocyte numbers. There are
other reports of an association between GH concentrations
in follicular fluid and IVF outcomes. Mendoza et al. (1999)
reported elevated GH concentrations in the follicular fluid
of women were associated with improved oocyte maturity,
fertilization and embryo quality. A follow-up study by
Mendoza et al. (2002) confirmed that elevated GH concen-
trations were also found within the follicle fluid of oocytes
that were selected for transfer and that gave rise to preg-
nancy. In other studies, the concentrations were at the
low end of the normal range in females and the concentra-
tion of serum GH was not described (Mendoza et al., 2002).
Mendoza et al. (1999) suggested that the differing concen-
tration of GH in follicular fluid may arise from the local ac-
tion of cytokines on the permeability of the follicle wall to
serum concentrations. Little is known about the relative
concentrations of GH in serum after co-treatment and
whether the concentrations are raised significantly near
the time of ovulation induction to influence oocyte matura-
tion. The phase of GH administration may therefore produce
different outcomes, depending on whether GH was pre-
scribed before treatment, and therefore acts on follicle
selection and response to FSH, or later in treatment where
the effects may be more to do with oocyte competency.
There are three studies in humans that support the
observations presented here. Tesarik et al. (2005) found
GH administration in women over 40 years of age signifi-
cantly increased the pregnancy rate. The clinical pregnancy
rate for women greater than 40 years in the current study
was 12/49 and 1/29 for GH+ and GH, respectively, and
the combined results showed a 24% pregnancy rate in GH-
treated older women compared with 3% for all women over
40 years treated without GH during the 5-year study period.
These results are consistent with the observations by
Tesarik et al. (2005) who reported clinical pregnancy rates
of 32/50 and 6/50, respectively. These observations support
the nature of this study’s sequential crossover design and
confirm that GH administration in older women can be
beneficial. Rajesh et al. (2007) reported that GH increased
embryo numbers and pregnancy in poor-prognosis patients
and Hazout et al. (2009) also demonstrated a better out-
come with GH in poor-prognosis groups (more than three
transfers) when compared against other patients of similar
background. Sugaya et al. (2003) identified a subgroup of
patents who did not have elevated concentrations of IGF-I
binding protein-3 that appeared to produce more oocytes
with GH treatment.
The type of patient who may benefit from GH augmenta-
tion remains unclear. While this study has demonstrated a
positive role that in patients who clinically present with re-
duced prognosis, usually after three or more IVF attempts,
clarification on how it may improve outcomes may better
elucidate those patients who may benefit. The better out-
comes in younger women argue their poor reproductive po-
tential may be due to processes that depend on GH.
Addition of GH appears to improve their prognosis but does
not fully restore it to levels seen in the uncategorized GHu
group. In other words, GH deficiency is only part of the
problem. In older women, while the need for GH remains,
other effects of oocyte ageing may make GH supplementa-
tion harder to demonstrate if given universally. This study
has shown that GH improves clinical outcomes in both youn-
ger women (<35 years) and older women. It would, how-
ever, seem logical to separate the aetiologies of these
two groups since women over 40 years have lower ovarian
reserve and decreased oocyte quality. In contrast, poor
responders under 35 years of age represent women with
either premature reduction of ovarian reserve or elevated
FSH threshold.
This paper also is the first to report on the outcome of
children conceived from a treatment cycle involving GH dur-
ing IVF. The results suggest a similar miscarriage rate consis-
tent with the poor outcome feature of this group of patients,
a rate still higher than in the GHu group suggesting that GH
may not address some key reproductive failings in such pa-
tients. However, a higher clinical pregnancy rate and live
birth rate per egg collection has been demonstrated in the
GHu group. Birthweights and sex ratio were normal. One re-
port (Esfandiari et al., 2005) documents healthy triplets
after GH treatment for acromegaly and another (Salle
et al., 2000) documents a normal birth after GH treatment
for panhypopituitarism. The similar miscarriage rate differs
from a recent observation that DHEA may reduce the miscar-
riage rates in poor responders (Gleicher et al., 2008) again
suggesting DHEA and GH may not act in the same manner.
In summary, this 5-year comprehensive study of IVF/ICSI
treatment in a large group of patients categorized as having
a poor prognosis, co-treatment with GH was shown to signif-
icantly increase the clinical pregnancy and live birth rate
over treatment cycles without GH, albeit to rates lower
than observed with all other patients not categorized as
Growth hormone supplementation in poor-prognosis IVF patients 47
poor responders. The effect was apparent across time peri-
ods, in all age groups, regardless of previous attempts and
independent of stimulation protocols. The benefit of GH
was also expressed in subsequent frozen embryo transfers
implying improved qualitative aspects for oocytes. There
appeared to be no adverse effects in the children born after
GH exposure. The study does support other reports for a
role for GH supplementation for various poor-prognosis
cases and further research is required to ascertain whether
the effects observed are due to improved follicle health or
improvements in the peri-ovulatory environment.
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Declaration: The authors report no financial or commercial
conflicts of interest.
Received 23 September 2009; refereed 2 November 2009; accepted
4 February 2010.
Growth hormone supplementation in poor-prognosis IVF patients 49
