Oocyte donation: a review

Oocyte donation provides an option for achieving pregnancy in women lacking functioning gonads, or in whom IVF techniques have failed to harvest adequate oocytes, or those who do not wish to use their own gametes because of hereditary disease. In agonadal women, artificial menstrual cycles are required before proceeding to gamete donation. A fixed cyclical steroid replacement schedule of oestradiol (E2) valerate and progesterone (P4) pessaries was initially used, but the need for synchrony between donor and recipient cycles, and the narrow window for implantation limited the transfer of fresh embryos. Donor-recipient cycle asynchrony can be overcome by using frozen-thawed embryos, or by extending the follicular phase in the recipient to widen the transfer window. Twenty-two pregnancies have now been achieved by the Monash/Epworth group, resulting in the birth of 13 healthy infants. There were no statistically significant differences in pregnancy rates (per transfer) between transfers in natural cycles (14%, four pregnancies) and steroid replacement cycles (24%, 16 pregnancies). Five pregnancies (36%) were established in women treated with 2 mg of E2 daily 13-18 days before embryo transfer with P4 starting on the day of or the day following oocyte retrieval. E2 was continued for a median of 85 days (range 49-110) and P4 for a median of 86 days (range 49-133) after the supposed last menstrual period. All but one delivery was by caesarean section. There were no perinatal deaths and no ectopic pregnancies.     

Role of transient hyperprolactinemia in the late follicular phase of the gonadotropin-stimulated cycle

Background: Serum prolactin (PRL) concentration is known to transiently increase in rats; however, its change is obscure and the role of it is also unclear in women. We studied the relationship between estradiol (E₂) and PRL production and the role of transient hyperprolactinemia in the late follicular phase of the gonadotropin-stimulated cycle.
Methods: (1) Serum E₂ and PRL concentrations were measured on an early follicular day and immediately before a human chorionic gonadotropin (hCG) injection in 60 patients with normoprolactinemia. Twelve of the 60 patients also received a gonadotropin injection with bromocriptine, and serum hormone levels were compared with those without bromocriptine. (2) Preovulatory serum E₂ and PRL concentrations were compared between the natural and clomiphene treatment cycles in 14 hormonally normal women. (3) Changes of serum PRL concentrations were measured before and after E₂ loading in five premature ovarian failure (POF) patients. (4) The E₂ production by granulosa cells in the presence of PRL was measured.
Results and Conclusion: Serum E₂ and PRL concentrations were significantly increased by the gonadotropin injection. Bromocriptine treatment completely inhibited the PRL increase, but further increased serum E₂ concentration on the late follicular day. The E₂ loading increased serum PRL levels in POF patients. The clomiphene treatment increased serum E₂ but decreased PRL concentrations. Prolactin significantly decreased E₂ production by granulosa cells. A feedback loop may exist between E₂ and PRL to control the excess E₂ production induced by gonadotropin injection. (Reprod Med Biol 2002; 1 : 69–74)     

Prognostic Value of Plasma Oestradiol-17β and Human Placental Lactogen in High-risk Pregnancies

Summary: Serial estimations of plasma oestradiol-17(E₂) and human placental lactogen (HPL) were made in 58 high-risk pregnancies. In pregnancies complicated by marked hypertension, intrauterine growth retardation, and intra-uterine death, plasma E₂ did not reflect fetal well-being accurately, unlike HPL which was accurate in predicting fetal outcome. In diabetic pregnancy, plasma E₂ and HPL levels were similar to those found in normal pregnancy.     

The treatment of premenstrual tension with mefenamic acid: analysis of prostaglandin concentrations

Summary. Eighty patients with premenstrual tension were treated prospectively with mefenamic acid for a mean period of 13 months. Most of them (86%) reported significant relief of premenstrual tension. Symptoms of dysfunctional menorrhagia or primary dysmenorrhoea were also alleviated. In 19 patients, the plasma concentrations of prostaglandin (PG) E₂, PGF_2α and 13,14-dihydro-15-keto-prostaglandin F_2α (PGFM) were measured at intervals throughout three menstrual cycles. During the first cycle the patients received no treatment; in the subsequent two cycles they received either mefenamic acid or placebo in a randomized double-blind crossover manner. Similar measurements were made in 22 matched control subjects. The plasma concentrations of PGE₂, PGF_2α and PGFM were significantly lower in the 19 patients in all three menstrual cycles compared with the values in the control subjects. Excess synthesis of prostaglandins of the 1 series may occur in premenstrual tension and, by precursor depletion, result in decreased synthesis of the 2-series prostaglandins.     

Interruption of first trimester human pregnancy following Epostane therapy. Effect of prostaglandin E2 pessaries

Summary. The effect of Epostane, a competitive inhibitor of the 3β hydroxy steroid dehydrogenase enzyme system in combination with prostaglandin E₂ (PGE₂) for induction of abortion in early first trimester pregnancy has been studied in a group of 20 women awaiting termination of pregnancy. The women were consecutively assigned to four treatment groups. The first group was treated with PGE₂ alone, administered vaginally as a lipid based (Witepsol) pessary. The remaining three groups received Epostane at differing doses for 5 days, and were treated with PGE₂ on the fourth day. Significant falls in serum progesterone and oestradiol occurred in the Epostane-treated patients. Abortion was induced in one of the five control patients and in three of 10 patients treated with low doses (300–400 mg) of Epostane. Intra-utrine pressure monitoring showed an increased reactivity to PGE₂ in the treated groups. At the highest dose (600 mig) of Epostane, serum progesterone and oestradiol showed the greatest decline to 8% and 21% of the pretreatment values, a prompt and sustained pressure response occurred to PGE₂ and abortion was induced in all five patients. A critical degree of progesterone suppression appears to sensitize the myometrium to exogenous prostaglandin. This combined treatment is an effective method of early pregnancy termination and may have a role in the management of mid-trimester abortion.     

Lack of effect of circulating prostacyclin on contractility of the non-pregnant human uterus

Summary. To study the effect of prostacyclin (PGI₂) on the contractility of the non-pregnant human uterus, the intrauterine pressures in the isthmus and fundus of the uterus were recorded before, during and after intravenous PGI₂ at different phases of two consecutive menstrual cycles in eight women. Infusions of 1–8 ng of PGI₂ mur⁻¹ kg⁻¹ for 20 min caused no changes in intrauterine pressure either during menstruation or any other phase of the cycle when compared with the contractility patterns in the same woman during the control infusion. Thus these data suggest that circulating PGI₂ is not involved in regulating the contractility of the non-pregnant human myometrium.     

Phytoestrogens and reproductive biology

Phytoestrogens are naturally occurring plant substances that can either mimic or antagonize the action of endogenous estrogens. This is because of the similarity of the functional structure of phytoestrogens and endogenous estrogens. In premenopausal women, phytoestrogen intake might induce a decrease in luteinizing hormone, follicle-stimulating hormone and estradiol (E₂), which are associated with a longer follicular phase. The circulating transport protein, sex hormone-binding globulin, is increased, resulting in less cellular availability of E₂. Phytoestrogens inhibit the activities of E₂ synthetic enzymes through adenylate cyclase and tyrosine kinase cascades. This might decrease of risk of hormone dependent cancers. A phytoestrogen-rich diet might reproduce normal body composition, affecting the course of polycystic ovary syndrome (PCOS). Some herbs used in traditional Japanese medicine contain phytoestrogens that influence endogenous hormone levels to directly regulate the pituitary-ovarian system, in particular, the chemotactic effects on ovaries. (Reprod Med Biol 2005; 4 : 225 –229)     

Quantitative production of prostaglandin E2 and its metabolites by human fetal membranes

Summary. Cultured amnion, choriodecidua and intact fetal membrane produced similar quantities of prostaglandin E₂ (PGE₂) (1–5 ng/ml). Choriodecidua and intact fetal membrane also produced very high levels of PGE₂ metabolites (100–1000 ng/ml). The total production of PGE (PGE₂ metabolites) was similar in intact fetal membrane and in choriodecidua, suggesting that the amnion, although a source of PGE₂ contributes little to the overall PGE production by fetal membranes.     

Oocyte donation

Oocyte donation affords women with ovarian failure, advanced reproductive age, heritable conditions or recurrent implantation failure the ability to conceive. Recipients must be medically screened carefully prior to attempting pregnancy. Egg donors should also be healthy and pose no infectious or genetic risk to the recipient or offspring. Donor and recipient menstrual cycles are synchronized so that embryos are transferred to a receptive endometrium. Donors are prescribed injectible gonadotrophins to achieve multifollicular growth. Recipient endometrial priming begins with 2 weeks (or more) of oestradiol, with progesterone added to the regimen 3-4 days prior to the transfer of embryos. Pregnancy rates following egg donation are among the highest observed following assisted reproduction. Despite advanced reproductive age, perinatal and obstetric outcomes are generally good. Techniques (i.e. germinal vesicle transfer, donor ooplasm, and ovarian cryopreservation and transplantation techniques) may permit the recipient to provide some genetic contribution to offspring and are currently under investigation.     

Primary and myoma-associated menorrhagia: role of prostaglandins and effects of ibuprofen

Summary. The release of 6-keto-prostaglandin F_1α(6-keto-PGF_1α), a metabolite of prostacyclin (PGI₂) and thromboxane B2 (TxB2), a metabolite of thromboxane A2 (TxA2), was estimated in endometrial biopsies taken from 12 menorrhagic and 12 healthy women during the luteal phase of the cycle. The releases of 6-keto-PGF_1α and TxB2 were normal, but the ratio TxB2/6-keto-PGF_1α was inversely related to menstrual blood loss in women with measured menstrual blood loss exceeding 70 ml. In the second part of the study, 24 women with excessive menstrual bleeding (13 with primary menorrhagia, 10 with uterine fibro-myomas, one with haemostatic factor VIII deficiency) were treated at random with ibuprofen (600mg/day and 1200mg/day) and with a placebo. Ibuprofen 1200 mg/day reduced (P<0.01) median blood loss from 146 ml (range 71–374 ml) to 110 ml (30–288 ml) in primary menorrhagia but had no effect on blood loss in women with uterine fibroids and factor VIII deficiency. Blood loss was normal in six women and was not affected by ibuprofen. Thus, our data suggest that there is a PGI₂ dominance in the endometrium of patients with menorrhagia. In addition, primary, but neither fibromyoma nor coagulation defect-associated menorrhagia, can be treated by ibuprofen.     

Tibolone and low-dose continuous combined hormone treatment: vaginal bleeding pattern, efficacy and tolerability

Objectives  The primary objective was to compare the vaginal bleeding pattern during administration of tibolone and low-dose continuous combined estradiol plus norethisterone acetate (E₂/NETA). The secondary objectives were efficacy on vasomotor symptoms and vaginal atrophy.
Design  A randomised, double-blind, double-dummy, group comparative intervention trial.
Setting  Multicentre study executed in 32 centres in 7 European countries.
Sample  Five hundred and seventy-two healthy symptomatic postmenopausal women, aged 45–65 years.
Methods  Participants were randomised to receive 2.5 mg tibolone or 1 mg 17β estradiol plus 0.5 mg norethisterone acetate (E₂/NETA) daily for 48 weeks.
Main outcome measures  Prevalence of vaginal bleeding, hot flushes and adverse events.
Results  The incidence of bleeding was significantly lower in the tibolone group during the first 3 months of treatment (18.3 versus 33.1%; P < 0.001) when compared with the E₂/NETA group. This effect on the bleeding pattern was sustained throughout the study, although reaching statistical significance again only in 7–9 months of treatment (11 versus 19%; P < 0.05). In both treatment groups, vasomotor symptoms and vaginal atrophy were significantly reduced to a similar extent when compared with baseline. The prevalence of breast pain/tenderness was significantly lower with tibolone compared with E₂/NETA (3.2 versus 9.8%; P < 0.001).
Conclusion  Tibolone reduces menopausal symptoms to a similar extent as conventional low-dose continuous combined hormone therapy but causes significant less vaginal bleeding in the first 3 months of treatment. This constitutes an important argument for woman adherence to therapy.     

Enhancing the fertility of poor responders by treatment with estrogen rebound combined with a short protocol

Aim:  To assess the efficacy of estrogen rebound (ER) plus flare-up by gonadotropin releasing hormone agonist (GnRH-a) in poor responders who failed to become pregnant prior to a long protocol treatment.
Methods:  The patients comprised of thirty-one infertile patients with oocyte retrieval levels of less than five, who had undergone several long protocol treatment cycles. The efficacy of treatment with the ER plus flare-up from GnRH-a was compared with the prior long protocol treatment. The main outcome measures are: confirmation of ER, maximal serum E₂ levels prior to human chorionic gonadotropin (hCG) administration, follicular development, dose, and duration of gonadotrophins in a clinical setting.
Results:  The ER was confirmed by estrogen levels; FSH increased with ER plus flare-up from GnRH-a. Although the 31 patients included in the study had undergone frequent prior treatment cycles, including the long protocol, the pregnancy rate per embryo transfer following ER plus flare-up by GnRH-a was 37.5% (nine of 24). The number of follicles, number of oocytes retrieved, and the E₂ level was higher than those found in prior treatment cycles.
Conclusion:  Exogenous estrogen administration with Premarin^R plus flare-up by GnRH-a may represent an alternative and effective protocol for poor responder patients who had previously undergone several prior long protocol treatments. (Reprod Med Biol 2003; 2 : 127–131)     

A double-blind, randomised trial comparing the effects of tibolone and continuous combined hormone replacement therapy in postmenopausal women with menopausal symptoms

Objective To compare the effects of two postmenopausal regimens on menopausal symptoms, bleeding episodes, side effects and acceptability.
Design Double-blind, randomised controlled trial.
Setting Twenty-nine sites in Denmark, nine in Norway and six in Sweden.
Participants Four hundred and thirty-seven postmenopausal women with menopausal complaints. None of these women had had a hysterectomy.
Interventions Daily treatment with tibolone 2.5 mg (  n = 218  ) or 17β-oestradiol 2 mg plus norethisterone acetate 1 mg (E₂/NETA) (  n = 219  ).
Main outcome measures Hot flushes, sweating episodes, vaginal dryness, assessment of sexual life and bleeding patterns; at baseline and after 4,12,24 and 48 weeks.
Results Treatment with either preparation significantly reduced mean scores for hot flushes, sweating episodes and vaginal dryness. The overall discontinuation rate was 28% (tibolone 25%, E₂/NETA 31%; P = 0.14), mostly during the first six months. There was a markedly lower cumulative incidence of bleeding or spotting episodes with tibolone compared with E₂/NETA (  P < 0.0001  ), mainly during the first six treatment cycles.
Conclusions Both tibolone and E₂/NETA effectively alleviate menopausal symptoms. However, tibolone caused significantly fewer bleeding or spotting episodes, which were reflected by lower overall rates of bleeding, as well as lower drop-out rates due to bleeding.     

Prostaglandin D2 release by endometrium and myometrium

Summary. Prostaglandin D₂ (PGD₂) release was studied using a super-fusion technique in endometrium and myometrium obtained at hysterectomy from 36 women with measured menstrual blood loss (range 4–840 ml). PGD₂ was produced by both tissues with greater rates from endometrium. Cyclical changes in release were found only in the endometrium with increased rates during menstruation and the midluteal phase. In the myometrium the highest release rates were present during menstruation at the start of the superfusion. No significant correlation was found between menstrual blood loss and endometrial or myometrial PGD₂ release.     

Determination of the stage of gestation by the assay of chorionic gonadotrophin and Schwangerschaftsprotein 1

Summary. Serial assays of Schwangerschaftsprotein 1 (SP1), SP1_α, SP1_β and human chorionic gonadotrophin were performed in 12 subjects from ovulation until the pregnancies had reached 16 weeks. From these data formulae were devised for deducing the stage of gestation from the concentration of the placental protein. These formulae were then tested by assays on 34 women not included in the original study. Assays of hCG do not give reliable indications of the stage of gestation when this has progressed beyond 9–10 weeks but SP1 assays give predictions of gestation corresponding closely to that derived from the last menstrual period up to 16 weeks gestation.     

Cyclic changes in composition and volume of the breast during the menstrual cycle, measured by magnetic resonance imaging

Summary. The volumes and spin-lattice (T₁) relaxation times of breast tissues and parenchymal water content were measured non-invasively by magnetic resonance imaging (MRI) in eight healthy women during four to eight consecutive menstrual cycles. Total breast volume, and parenchymal volume, T₁ relaxation time and water content were lowest between days 6 and 15. Between days 16 and 28, parenchymal volume, T₁ relaxation time and water content rose sharply by 38·9%, 15·1% and 24·5%, respectively, and peaked after day 25. Within 5 days of the onset of menses, parenchymal volume fell sharply by 30·3%, while water content declined by 17·5%. Rising parenchymal volume in the second half of the menstrual cycle is not solely due to increased tissue water content and provides in vivo evidence for both growth and increased tissue fluid at this time.     

The influence of spontaneous and induced labour on the rise in prostaglandins at amniotomy

Summary. Maternal peripheral plasma levels of 13, 14-dihydro-15-keto-prostaglandin F (PGFM) were measured immediately before and 5 min after amniotomy. Three groups of women were studied: women in late pregnancy; women in spontaneous labour; and women who had received intravaginal prostaglandin E₂ (PGE₂) pessary. There was no significant difference in the magnitude of the rise in PGFM after amniotomy in late pregnancy or during spontaneous labour suggesting that labour has no influence on the release of prostaglandin F_2α (PGF_2α) induced by artificial rupture of the fetal membranes. However, local administration of PGE₂ before amniotomy caused a greater rise in PGFM suggesting that PGE₂ can influence the release and/or metabolism of PGF_2α.     

Cigarette smoking in pregnancy results in marked decrease in maternal hCG and oestradiol levels

Summary. We have examined serum levels of oestradiol (E₂), sexhormone binding globulin (SHBG) and human chorionic gonadotrophin (hCG) during early pregnancy in relation to smoking status at the time of sampling in a series of 147 women. Smoking was associated with significantly depressed serum levels of E₂, SHBG and hCG: in smokers, E₂ levels were on average 17·6% lower ( P =0·037), SHBG levels were 12·4% lower ( P =0·15), and hCG levels were 21·5% lower ( P =0·044). There appeared to be a steady decline in these values with increasing cigarette consumption. These lower hormone levels in smokers may explain certain adverse effects of smoking in pregnancy.     

Primary dysmenorrhoea: the importance of both prostaglandins E2 and F2α

Summary. Menstrual fluid was collected in a contraceptive diaphragm from 16 women with primary dysmenorrhoea and 12 matched control subjects without dysmenorrhoea. Prostaglandins F_2α (PGF_2α), E₂ (PGE₂) and 6-oxo-prostaglandin F_1α (6-oxo-PGF_lα) were extracted and measured using gas-chromatography: mass spectrometry (GC:MS). The concentrations of both PGF_2α and PGE₂ were higher on days 1 and 2 in the dysmenorrhoea group than in the control group and the concentration of PGF_2α was higher on day 1 than on day 2 in the dysmenorrhoea group. The concentrations of 6-oxo-PGF_1α (the stable metabolite of PGI₂) were low in both groups. These results confirm suggestions that PGF_2α is important in the aetiology of dysmenorrhoea and also indicate that PGE₂ may be involved.     

Pregnancies after replacement of frozen-thawed embryos in a donation program

Eighteen patients with primary (n = 8) or secondary (n = 10) ovarian failure were enrolled in a donation program. In 15 cases, the oocytes were donated anonymously; in 3 cases, they were donated by the sister of the recipient. All the recipients had cyclic steroid replacement therapy that included estrogens and progesterone administered by the transdermal and tranvaginal routes, respectively. The embryos obtained were cryopreserved and replaced with no attempt at synchronization between donor and recipient. Steroid hormonal patterns were within the range for the normal menstrual cycle and endometrial biopsies taken on day 21 or 22 of the treatment cycles were independently assessed as being representative of day 21 +/- 2. Four of 12 transfers were successful (31%): 1 patient aborted at 6 weeks, and the three others were delivered, one normally and two by cesarian sections. The authors' practice suggests the following: (1) steroid supplementation by transdermal and transvaginal routes is effective, (2) synchronization between donor and recipient is no longer required with the use of frozen-thawed embryos, and (3) the "temporal window" is large since all the replacements were done on day 14 of the cycle.