Ovarian response to gonadotrophins, optimal method for oocyte retrieval and pregnancy outcome in patients with vaginal agenesis

Ellen G. Wood1, Frances R. Batzer and Stephen L. Corson

Women's Institute for Fertility, Endocrinology and Menopause, Pennsylvania Reproductive Associates, Pennsylvania Hospital, 815 Locust Street, Philadelphia, PA 19107, USA


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The aim of this study is to characterize the ovarian response to stimulation and the optimal method of oocyte retrieval in patients with vaginal agenesis (Mayer– Rokitansky–Küster–Hauser syndrome) in a gestational carrier programme. Twelve patients underwent gonadotrophin stimulation and hormonal monitoring. Forty-nine treatment cycles were initiated; seven cycles were cancelled secondary to poor stimulation. Five patients had undergone surgical neovagina construction; seven patients had utilized vaginal dilators. Oocyte retrieval was achieved in one cycle via transvesical ultrasound, in two cycles via transabdominal ultrasound, in nine cycles via laparoscopy and in 30 cycles via transvaginal ultrasound. Ten pregnancies were achieved which included two clinical pregnancies, two biochemical pregnancies, three singleton births and three sets of twin births. A live birth rate of 45.5% was achieved per patient. Hormonal response to gonadotrophin stimulation in this population was similar to that of patients with normal pelvic anatomy. Pregnancy outcome was comparable to other patients utilizing gestational carriers within the same program (i.e. surgically absent uterus, anatomically non-functioning uterus, etc.). The surgical creation of a neovagina makes transvaginal retrieval technically more difficult than when dealing with a dilator-created vagina, and may require laparoscopy or transabdominal ultrasound for oocyte retrieval.

Key words: gestational carrier/Mayer–Rokitansky–Küster–Hauser syndrome/ovulation induction/vaginal agenesis


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The attainment of genetic offspring for karotypically female patients with vaginal agenesis [Mayer–Rokitansky–Küster–Hauser (MRKH) syndrome] was an impossibility until the introduction of ovulation induction with oocyte retrieval for in-vitro fertilization (IVF) using a gestational carrier. This report profiles the ovarian response to gonadotrophin stimulation in 12 patients with vaginal agenesis undergoing IVF at the Pennsylvania Hospital from April 1988 until October 1998 and the pregnancy outcome of the gestational carrier. A limited number of series reports exist describing successful stimulation, retrieval and IVF of the oocytes from women with vaginal agenesis (Egarter and Huber, 1988Go; Yovich and Hoffman, 1988Go; Utian et al., 1989Go; Batzer et al., 1992Go; Corson et al., 1998Go). To date, this is the largest set of patients with vaginal agenesis, of which we are aware compiled within one programme.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Between 1 April 1988 and 1 October 1998, 12 patients with vaginal agenesis (MRKH syndrome) between the ages of 27 and 39 years underwent gonadotrophin stimulation.

Diagnosis of vaginal agenesis in all patients had been made prior to age 17 via either laparoscopy or clinical correlation of non-invasive studies prior to presentation to the Pennsylvania Hospital. Creation of a functional vagina had been accomplished surgically in five patients and by using mechanical dilators in seven patients.

Monitoring of cyclic ovarian function was carried out using basal body temperature (BBT) charts in conjunction with serial follicle stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and progesterone concentrations. Early experience with the first eight cycles employed oral contraceptive use in the genetic mother to accomplish synchronicity of cycles with the gestational carrier. Later cycles utilized downregulation with a gonadotrophin-releasing hormone agonist (GnRH-a, Lupron; Tap Pharmaceuticals, Chicago, IL, USA) to match the cycles of the genetic parent with her carrier. The stimulation protocol in 33 cycles was with urinary or recombinant gonadotrophins, either follicle stimulating hormone (FSH) alone or mixed follicle stimulating hormone/luteinizing hormone (FSH/LH) following GnRH-a downregulation. Sixteen cycles were not downregulated. Ten of these used gonadotrophins alone and the remaining six cycles used clomiphene citrate in conjunction with gonadotrophins. All cycles were monitored with serial oestradiol concentrations and ultrasound. Human chorionic gonadotrophin (HCG) was administered when at least two follicles were 17 mm in diameter or greater.

All patients underwent oocyte retrieval via laparoscopic directed guidance or via transvesical, transabdominal or transvaginal ultrasound guidance. Fresh or frozen embryo transfer into a gestational carrier was then carried out at either 48 or 72 h after retrieval. Measurement of ß-HCG was performed 12 days after embryo replacement and considered confirmed after ultrasound documentation of fetal viability.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Forty-nine treatment cycles were initiated in 12 patients; seven cycles were cancelled due to poor stimulation. A summary of all patients' stimulations is given in Table IGo. An average of 32 ± 13.5 (SD) ampoules of urinary or recombinant gonadotrophins were required per patient/retrieval. HCG was administered cycle day 10.8 (1.4 SD) with an oestradiol concentration of 1807.3 pg/ml (± 833.9) (conversion factor to SI units = 3.67). Oocyte retrieval was accomplished in one cycle via transvesical ultrasound, in two cycles via transabdominal ultrasound, in nine cycles via laparoscopy; 30 of the retrievals were carried out via transvaginal ultrasound. Table IIGo illustrates the presence of a surgically created or dilator-created vagina as related to the method of retrieval necessary.


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Table I. Summary of stimulated cycles
 

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Table II. Relationship of type of retrieval with type of neovagina
 
The seven cancelled cycles occurred in four patients. All cycles were downregulated with GnRH agonist and stimulated with urinary gonadotrophins. Three cancellations were in one patient prior to HCG administration secondary to poor stimulation. Two other cancelled cycles were in another patient due to a drop in oestradiol greater than 15% the day after HCG. The two other cancelled cycles occurred in two patients, one due to poor stimulation and the other to a low oestradiol concentration after HCG administration. The average age of these four patients at the initiation of the cycle was 36 years (range 27–39).

No oocytes were obtained in three cycles. The fertilization rate per oocyte was 49%. Fertilization failure occurred in two cycles. Embryo development arrested on day 2 in one cycle. Transfer was cancelled in one cycle due to contamination. Embyros were cryopreserved in three cycles due absence of an available carrier; the embryos from one of these cycles were thawed with no survival and the embyros for the two remaining cycles remain frozen. Nine extra embryos from two additional cycles were cryopreserved and thawed with no survival.

Embryo transfer to an appropriately chosen carrier with fresh embryos occurred in 32 cycles. The mean number of embryos transferred was 3.4 (± 1.0). Ten pregnancies were achieved which included two clinical pregnancies, with one ending in spontaneous abortion and one ongoing, two biochemical pregnancies, three singleton births and three sets of twins with two sets delivered and one set ending in spontaneous abortion. Conception cycles are presented in Table IIIGo. A live birth pregnancy rate of 45.5% was attained per patient.


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Table III. Pregnancy cycles
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Since 1978 when Steptoe and Edwards reported the birth of Louise Brown, IVF has steadily become an accessible treatment option for the infertile couple (Steptoe and Edwards, 1978Go). Growing public acceptance of advanced reproductive technologies brought about the advent of involving third parties as gestational carriers to aid in the accomplishment of genetic offspring for females devoid of a functional uterus either congenitally or surgically.

Although MRKH is a rare disorder with the prevalence being reported as one in 4000–5000 female births (Capraro and Gallego, 1976Go; Evans et al., 1981Go), an increasing number of patients with MRKH syndrome are entering IVF carrier programmes, allowing for certain conclusions about this population to be made. Comparisons between patients utilizing carriers for different indications can now be made regarding the ovarian function of patients with vaginal agenesis and those patients with a surgically absent or non-functional uterus. Analysis of mean number of eggs attained, mean number of eggs fertilized, mean number of embryos transferred and the implantation rate in this set of patients has been comparable to other patients utilizing gestational carriers within our programme for other indications such as surgically absent uterus and severe uterine abnormalities after diethylstilboestrol (DES) exposure with comparable pregnancy rates (Corson et al., 1998Go).

Normal spontaneous cyclic pituitary gonadotrophin concentrations and ovarian endocrine function in patients diagnosed with congenital absence of the uterus have been documented (Coyotupa et al., 1973Go). Since these patients are otherwise normal females with functioning ovaries, a 46, XX chromosomal complement, and normal secondary sex characteristics (Griffin et al., 1976Go), emphasis on treatment had been primarily placed on sexual identity and body image issues (Foley and Morley, 1992Go). In addition, the vast majority of the existing literature focuses specifically on the multiple anatomic anomalies afflicting females with vaginal agenesis: renal ectopy or agenesis reported in one-third of patients (Speroff et al., 1989Go), urinary tract malformations (Rock and Keenan 1992Go), pelvic kidney (Evans et al., 1981Go) and skeletal abnormalities (Griffin et al., 1976Go). In our series, two patients exhibited anomalies in concert with vaginal agenesis: one with a pelvic kidney and one with multiple skeletal anomalies.

Academic interest had focused around the creation of a functional vagina. The non-surgical Frank technique (Frank, 1938Go) as well as the McIndoe split-thickness skin graft vaginoneoplasty (McIndoe and Bamister, 1938Go) were both described in 1938 for creating a functional vagina. The Ingram `bicycle seat' (Ingram et al., 1981) technique of passive dilatation was later heralded in the early 1980s. Functional success rates approach 95% for these procedures (Rock and Keenen, 1992). Currently, it is suggested that a dilatation procedure be used as initial management in all patients with vaginal agenesis, reserving surgical procedures for unsuccessful mechanical outcomes.

In our series, the surgical creation of a neovagina notably amplified the technical difficulty of oocyte retrieval already existing in these patients. Seven of the nine laparoscopic oocyte retrievals and the two ultrasound-guided transabdominal retrievals were performed in patients who had previously undergone surgical vaginal reconstruction as shown in Table IIGo. When analysing these numbers via the Chi-squared test with the Fisher's exact correction for small numbers, our conclusions are statistically significant with a P value = 0.0157 as shown in Table IVGo. Although an artificial vagina may serve the purpose for coitus, we have found that the usual vaginal elasticity and relaxation is absent. High lateral placement of the ovaries, far removed from a shortened, thickened vagina can make transvaginal ultrasound monitoring and retrieval unpleasant, technically challenging, and at times impossible.


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Table IV. Method of egg retrieval in patients with vaginal agenesis
 
In 1988, Egarter and Huber described the first experience of successful stimulation and laparoscopic retrieval of oocytes situated laterally, high above the linea terminalis in a patient with MRKH syndrome (Egarter and Huber, 1988Go) and a similar case was reported (Yovich and Hoffman, 1988Go) with ovaries sited on the pelvic sidewall where the oocytes were recovered by transvaginal ultrasound technique in a patient with vaginal agenesis.

The establishment of a formalized gestational carrier programme was pioneered by (Utian et al., 1989Go) and initially reported two live genetic births in carriers for patients with uterine agenesis. Two of the patients in our series have been previously described (Batzer et al., 1992Go) while highlighting the medical-legal challenges involved in a gestational carrier programme. In a 1996 survey of IVF programmes in the United States, seven programmes providing gestational carrier services reported experience with women with congenital absence of the uterus and vagina (Petrossa et al., 1997Go). Fifty-eight women undergoing 162 cycles delivered 34 live births (17 female/17 male). No congenital anomalies of the female offspring were found; one male child with a middle-ear defect was reported.

Reports describing stimulation protocols in patients with vaginal agenesis are also scarce. Ben-Rafael et al. (1998) reports utilizing GnRH-agonist downregulation as a part of their routine approach once ovulation is determined by progesterone concentrations >6 nmol/l in their four patients with vaginal agenesis (Ben-Rafael et al., 1998Go). Utilizing GnRH-agonist downregulation in the luteal phase has simplified the synchronization of cycles between genetic patient and gestational carrier. This approach was undertaken in all of our cycles after 1990 where clomiphene citrate was not used. A similar response to gonadotrophins, as well as comparable oocyte retrieval rates, fertilization rates and pregnancy rates in patients with vaginal agenesis compared with DES-exposed patients and patients' status post-hysterectomy also requiring a gestational carrier has been highlighted (Corson et al., 1998Go).

MRKH syndrome can therefore be regarded as a purely developmental abnormality and should not preclude the birth of normal offspring utilizing appropriate treatments with a gestational carrier.


    Notes
 
1 To whom correspondence should be addressed Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Batzer, F.R., Corson, S.L., Gocial, B. et al. (1992) Genetic offspring in patients with vaginal agenesis: specific medical and legal issues. Am. J. Obstet. Gynecol., 167, 1288–1292.[ISI][Medline]

Ben-Rafael, Z., Bar Hava, I., Levy, T. and Orvieto, R. (1998) Simplifying ovulation induction for surrogacy in women with Mayer–Rokitansky–Küster–Hauser syndrome. Hum. Reprod., 13, 1470–1471.[Abstract]

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Speroff, L., Glass, R.H. and Kase, N.G. (1989) Amenorrhea. In Speroff, L., Glass, R.H. and Kase, N.G. (eds), Clinical Gynecological Endocrinology and Infertility. Williams & Wilkins, Baltimore, pp. 165–211.

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Submitted on July 28, 1998; accepted on January 12, 1999.