IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister.
ABSTRACT Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF) with donor oocytes is currently the only treatment known to be effective.
A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the recipient's husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day three.
A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks' gestation. Additionally, four embryos were cryopreserved for the recipient's future use. The sister-donor achieved another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery.
POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the circumstance of sister oocyte donation.
Article: [NR5A1 and ovarian failure].[show abstract] [hide abstract]
ABSTRACT: Primary ovarian insufficiency (POI) is characterised by the arrest of normal ovarian function before the age of 40 years and affects 1 % of all women. POI shows familial inheritance suggesting a genetic contribution. NR5A1 is nuclear receptor that regulates the transcription of many genes involved in sexual developmental and reproduction. 18 NR5A1 mutations have been published associated with either anomalies of adrenal or testis development. We have identified NR5A1 mutations associated with POI, including familial cases with affected 46,XY individuals. This demonstrates that NR5A1 plays an important role in ovarian development and function. However several questions remain. What is the incidence of NR5A1 mutations in POI? Is there a genotype/phenotype relationship? Are mutations associated with a progressive loss of reproductive function? Answering these questions will lead to a better understanding of ovarian function and dysfunction and could lead to new therapies for treating POI.Medecine sciences: M/S 10/2009; 25(10):809-13. · 0.56 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The gene responsible for Fragile X syndrome, fragile X mental retardation-1 (FMR1), contains an unstable sequence of CGG trinucleotide repeats in its promoter region. Expansions of >200 trinucleotide repeats are considered full mutations and typically lead to abnormal methylation of the region resulting in loss of FMR1 expression. Males with loss of FMR1 protein are expected to be affected by Fragile X syndrome while females may or may not clinically manifest features of the condition. The protocols in this unit outline the complementary use of polymerase chain reaction (PCR) and methylation-sensitive Southern blot hybridization to accurately measure trinucleotide repeat size and methylation status. These protocols are also used to evaluate CGG repeat size in two adult-onset conditions known for their association with FMR1 premutation alleles, Fragile X Tremor/Ataxia (FXTAS) syndrome and Premature Ovarian Failure (POF).Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 10/2009; Chapter 9:Unit 9.5.
- [show abstract] [hide abstract]
ABSTRACT: Elucidation of the causes of premature ovarian failure (POF) is difficult due to the heterogeneity of the condition. Inhibin is a potential candidate gene for POF based on its dual actions on FSH secretion by the pituitary and gametogenesis in the gonads. A missense mutation in the inhibin alpha subunit gene (INHA G769A) is associated with POF in several populations. However, there is phenotypic heterogeneity in INHA G769A mutation carriers. Relevant studies were identified by searching PubMed and mutational frequencies combined for meta-analysis. Meta-analysis of published studies revealed a risk difference of 0.04 (-0.030 to 0.11). The occurrence of asymptomatic carriers in populations suggests incomplete penetrance and/or a multi-genetic cause of POF. We propose that a decline in inhibin bioactivity caused by the mutation could increase FSH levels; and in a susceptible individual, the heightened sensitivity to gonadotrophins causes POF. Impaired paracrine effects of inhibin could impact folliculogenesis due to reduced antagonism of activin, bone morphogenetic protein 15 and growth differentiation factor 9. Functional studies of this mutation indicate normal production of dimeric inhibin A and B and impaired bioactivity of inhibin B. The identification of an autosomal mutation in the inhibin alpha subunit gene that is significantly linked to POF in certain ethnic populations highlights the role of inhibin in the regulation of ovarian biology and fertility. Although the reduction of inhibin B bioactivity by the INHA G769A mutation is clearly not the only cause, evidence suggests that this change may serve as a susceptibility factor, increasing the likelihood of POF.Human Reproduction Update 09/2009; 16(1):39-50. · 9.23 Impact Factor
Sills et al. Reproductive Biology and Endocrinology 2010, 8:31
IVF for premature ovarian failure: first reported
births using oocytes donated from a twin sister
© 2010 Sills et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons At-
tribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited.
Eric Scott Sills*1,2,3, Adam C Brady2, Ahmed B Omar1, David J Walsh1,2, Umme Salma1 and Anthony PH Walsh1,2
Background: Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF)
with donor oocytes is currently the only treatment known to be effective.
Methods: A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of
failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister
were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total
of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the
recipient's husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day
Results: A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks'
gestation. Additionally, four embryos were cryopreserved for the recipient's future use. The sister-donor achieved
another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery.
Conclusion: POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister
who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from
an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while
sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte
donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the
circumstance of sister oocyte donation.
Patient age and number of prior failed fertility treatments
have trended upward in recent years, and both factors
have an adverse impact on pregnancy rates with IVF.
Among women presenting for fertility treatment, those
with premature ovarian failure (POF) comprise an impor-
tant subset as about 1% of all women will have this diag-
nosis . Because POF is characterised by early loss of
normal ovarian function before age 40, the unrecoverable
loss of oocytes results in a bleak fertility prognosis unless
oocyte donation with IVF is used.
Contemporary research has identified some genetic
causes of POF, implicating a close association with Fragile
× syndrome  and mutations in the inhibin alpha sub-
unit gene . Fragile × mental retardation-1 (FMR1) con-
tains an unstable sequence of CGG trinucleotide repeats
in its promoter region, with expansions of >200 trinucle-
otide repeats typically leading to abnormal methylation
and silencing of FMR1 expression . Therefore, in
monozygotic (identical) twin sisters, any genomic anom-
aly linked to POF would be expected to negatively affect
reproductive outcome in both siblings. The present
report describes successful IVF for a POF patient where
donated oocytes were obtained from her dizygotic (non-
identical) twin sister.
Methods and Results
A 33 year-old nulligravida presented with her husband
for reproductive endocrinology evaluation. The couple
had been attempting to achieve a pregnancy for 2 1/2
years. They had undergone two unsuccessful IVF cycles
and a diagnosis of premature ovarian failure had been
made after the second attempt. Neither partner smoked
and both were in good general health. All screening labo-
ratory tests were normal for husband and wife, however
* Correspondence: firstname.lastname@example.org
1 Division of Reproductive Endocrinology, Sims IVF, Dublin, Ireland
Full list of author information is available at the end of the article
Sills et al. Reproductive Biology and Endocrinology 2010, 8:31
Page 2 of 3
her serum FSH was elevated at 42 mIU/ml. Her karyo-
type was 46,XX. Intrauterine contours assessed via saline
infusion sonogram were normal. The husband's semen
analysis at our centre identified mild asthenozoospermia
but was otherwise normal. Considerable patient counsel-
ling had already occurred after the two previous failed
IVF treatments, and the couple understood that further
cycles of IVF using native oocytes would probably be
futile. However, the wife had a sister who had volunteered
to serve as a known oocyte donor.
This sister (donor) was the dizygotic twin of the patient
(recipient). She was married, had previously conceived
without medical assistance and had a 10-month old child.
The sister did not smoke, had a normal menstrual pattern
and had discontinued breastfeeding four months before
assessment. Her cycle day three FSH was 8.8 mIU/ml; all
infectious disease and hormonal screening tests were
normal. Additional counselling was undertaken for both
couples (together and separately) in advance of the
planned treatment and written informed consent was
obtained from all parties . Supplementary genetic test-
ing for recipient and donor were declined.
After pituitary down-regulation with GnRH-agonist,
the donor began a combined 225 IU/d FSH (Puregon®,
Organon [Ireland] Ltd, Swords) plus 75 IU/d LH (Luv-
eris®, Merck Serono Europe Ltd, London) superovulation
regime. She received 10,000 IU hCG via subcutaneous
injection on stimulation day eight with an uneventful
transvaginal ultrasound-guided oocyte retrieval 36 h
later. Ten oocytes were obtained and eight of these were
metaphase II. Following ICSI with fresh sperm obtained
from the recipient's husband, normal 2 pn fertilisation
was noted in seven embryos.
Parallel to this, an appropriate endometrial response in
the recipient was established by supplementary estrogen
administration and verified by serial transvaginal ultra-
sound assessments. On day three, two fresh embryos
were transferred to the recipient 11 mm inferior to the
uterine fundus under ultrasound guidance; four embryos
were cryopreserved the same day. Luteal support post-
transfer was administered as previously described .
Pregnancy was confirmed 13 days post-transfer by posi-
tive hCG test, with a twin intrauterine gestation identi-
fied on follow-up obstetrical sonogram at seven weeks.
The patient had an unremarkable obstetrical course.
Following a failed labour induction, she had a caesarean
delivery at 39 weeks' gestation resulting in the birth of
healthy male/male twins. Mother and babies were dis-
charged from hospital five days post-partum in good con-
dition; all continue to do well. Of note, an unassisted
pregnancy was achieved by the sister-donor within six
months of oocyte retrieval, which resulted in another sin-
gleton delivery of her own.
In the setting of the advanced reproductive technologies,
the difficult diagnosis of premature ovarian failure is
often followed by discussions about donor oocyte IVF.
This treatment modality has become an important com-
ponent of the comprehensive assisted fertility treatment
programme, and has been available in Ireland for several
years. Patient survey results from Irish patients have gen-
erally agreed with findings reported elsewhere, showing a
strong preference for sister-donor over anonymous-
donor oocyte approach in IVF . Although successful
sister-donor oocyte IVF has been available in Australia
 and USA  for several years, this is the first descrip-
tion of IVF births resulting from this technique in Ire-
land. Indeed, because all prior births reported from sister
oocyte donors involved a non-twin sibling as the gamete
source, the current case appears to be the first in the
medical literature validating a specific role for twin sister
oocyte donation in IVF. Although IVF incorporating
oocytes donated from a twin sister does not usually differ
from ordinary (non-twin) sister oocyte donation, this
case does extend the range of therapeutic options in POF
to include a dizygotic twin as the oocyte source.
Although most POF cases probably result from de novo
mutations , the genetics of this disorder are complex
and have not yet been fully elucidated. Accordingly, any
POF patient who contemplates sister oocyte donation
should be advised about the possibility that any oocytes
donated by a sister might carry a POF mutation [11,12].
Anonymous donor oocyte IVF is generally regarded as
having a better reproductive outcome than IVF involving
a related oocyte donor , and special ethical consider-
ations exist with sibling gamete donation that do not
apply in anonymous oocyte donation. Perhaps the most
important of these is awareness of the resultant family
dynamic following a birth of a child conceived from sis-
ter-donor oocyte IVF . While counselling fully devel-
oped these issues, our patient nevertheless regarded the
proven fertility of her (dizygotic) twin sister as sufficiently
reassuring to proceed safely in the absence of genetic
data. In this case satisfactory psychological assessments
were completed, no absolute contraindication to known
oocyte donation IVF was present, and ongoing counsel-
ling resources were available throughout the IVF
It must be acknowledged that few POF patients will
have a sister willing and able to serve as a known oocyte
donor for IVF. Accordingly, for most POF patients repro-
ductive success will be achieved clinically from IVF using
oocytes from an anonymous oocyte donor. But against
the background of "routine" donor oocyte therapy for
POF, the current report describes an IVF approach for
the exceptional case where a dizygotic twin oocyte donor
Sills et al. Reproductive Biology and Endocrinology 2010, 8:31
Page 3 of 3
The authors declare that they have no competing interests.
ESS, ABO, DJW, US and APHW were consultants; ACB was medical student asso-
ciated to the case. All authors read and approved the final manuscript.
1Division of Reproductive Endocrinology, Sims IVF, Dublin, Ireland,
2Department of Obstetrics and Gynaecology, School of Medicine, Royal
College of Surgeons in Ireland, Dublin, Ireland and 3The Sims Institute,
Rosemount Hall, Dundrum Road, Dundrum, Dublin 14, Ireland
1.Bashamboo A, Ravel C, Brauner R, McElreavey K: NR5A1 and ovarian
failure. Med Sci (Paris) 2009, 25:809-813.
2. Basehore MJ, Friez MJ: Molecular analysis of Fragile × syndrome. Curr
Protoc Hum Genet 2009, Chapter 9(Unit 9.5):.
3.Chand AL, Harrison CA, Shelling AN: Inhibin and premature ovarian
failure. Hum Reprod Update 2010, 16:39-50.
4.Godler DE, Tassone F, Loesch DZ, Taylor AK, Gehling F, Hagerman RJ,
Burgess T, Ganesamoorthy D, Hennerich D, Gordon L, Evans A, Andy Choo
KH, Robert Slater H: Methylation of novel markers of fragile × alleles is
inversely correlated with FMRP expression and FMR1 activation ratio.
Hum Mol Genet in press.
5.Lessor R: Behavioral research on oocyte donation recipients, donors
and the social context. In Progress in Reproductive Medicine Edited by:
Asch RH, Studd J. London: Parthenon Publishing Group Ltd; 1993:19-26.
6.Walsh AP, Shkrobot LV, Coull GD, Peirce KL, Walsh DJ, Salma U, Sills ES:
Blastocyst transfer for multiple prior IVF failure: a five year descriptive
study. Ir Med J 2009, 102:282-285.
7.Sauer MV, Rodi IA, Scrooc M, Bustillo M, Buster JE: Survey of attitudes
regarding the use of siblings for gamete donation. Fertil Steril 1988,
8.Leeton J, Chan LK, Trounson A, Harman J: Pregnancy established in an
infertile patient after transfer of an embryo fertilized in vitro where the
oocyte was donated by the sister of the recipient. J In Vitro Fert Embryo
Transf 1986, 3:379-382.
9.Rosenberg SM, East JM, Wood SC, Crain JL: Ovum donation by sisters in
ovarian failure: simplified priming and early withdrawal of exogenous
support. J In Vitro Fert Embryo Transf 1989, 6:228-231.
10. Wöhrle D, Kotzot D, Hirst MC, Antonella M, Korn B, Schmidt A, Barbi G, Rott
HD, Poustka A, Davies KE, Steinbach P: A microdeletion of less than 250
kb, including the proximal part of the FMR-1 gene and the fragile-X
site, in a male with the clinical phenotype of fragile-X syndrome. Am J
Hum Genet 1992, 51:299-306.
11. Conway GS, Payne NN, Webb J, Murray A, Jacobs PA: Fragile ×
premutation screening in women with premature ovarian failure. Hum
Reprod 1998, 13:1184-1187.
12. Rybak EA, Bevilacqua K, Veit CR, Klugman SD, Santoro N: Sibling and self
ovum donation for sisters with an intermediate FMR1 mutation: what's
a program to do? Fertil Steril 2009, 92:394.e9-394.e12.
13. Sung L, Bustillo M, Mukherjee T, Booth G, Karstaedt A, Copperman AB:
Sisters of women with premature ovarian failure may not be ideal
ovum donors. Fertil Steril 1997, 67:912-916.
14. Ethics Committee of the American Society for Reproductive Medicine:
Family members as gamete donors and surrogates. Fertil Steril 2004,
Cite this article as: Sills et al., IVF for premature ovarian failure: first reported
births using oocytes donated from a twin sister Reproductive Biology and
Endocrinology 2010, 8:31
Received: 18 February 2010 Accepted: 25 March 2010
Published: 25 March 2010
This article is available from: http://www.rbej.com/content/8/1/31© 2010 Sills et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Reproductive Biology and Endocrinology 2010, 8:31