Previously reported better fertilization rate after intracytoplasmic single sperm injection (ICSI) than after subzonal insemination of several spermatozoa was confirmed in a controlled comparison of the two procedures in 11 patients. Intracytoplasmic sperm injection was carried out in 150 consecutive treatment cycles of 150 infertile couples, who had failed to have fertilized oocytes after standard in-vitro fertilization (IVF) procedures or who were not accepted for IVF because not enough motile spermatozoa were present in the ejaculate. A single spermatozoon was injected into the ooplasm of 1409 metaphase II oocytes. Only 117 oocytes (8.3%) were damaged by the procedure and 830 oocytes (64.2% of the successfully injected oocytes) had two distinct pronuclei the morning after the injection procedure. The fertilization rate was not influenced by semen characteristics. After 24 h of further in-vitro culture, 71.2% of these oocytes developed into embryos, which were transferred or cryopreserved. Only 15 patients did not have embryos replaced. Three-quarters of the transfers were triple-embryo transfers. High pregnancy rates were noticed since 67 pregnancies were achieved, of which 53 were clinical, i.e. a total and clinical pregnancy rate of 44.7% and 35.3% per started cycle and 49.6% and 39.2% per embryo transfer. A total of 237 supernumerary embryos were cryopreserved in 71 treatment cycles.

High fertilization and implantation rates after intracytoplasmic sperm injection

On average, the menopause occurs at the age of 50 years,1 with 1 % of women continuing to menstruate beyond the age of 60 years and 1% whose menopause occurs before 40 years. Arbitrarily, a menopause before the age of 40 years is defined as 'premature'. Premature ovarian failure may be caused by any process which reduces the number of oocytes within the ovary. In the embryo, germ cells first appear in the urogenital ridge. These germ cells then migrate to the primitive ovary. Once within the ovary, the germ cells multiply to form 3.5 million potential oocytes in each ovary (Fig. 1). From this time, oocytes are held in suspended animation - meiosis - until required for ovulation perhaps 40 years later. If a woman were to ovulate every month throughout her reproductive life, then she would use fewer than 500 eggs - a tiny proportion of the original 7 million (0.007%). Thus, if a woman were to prevent ovulation, say by taking the combined oral contraceptive

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Premature ovarian failure

Premature ovarian failure (POF) is defined as a syndrome characterized by menopause before the age of 40 yr. The patients suffer from anovulation and hypoestrogenism. Approximately 1% of women will experience menopause before the age of 40 yr. POF is a heterogeneous disorder with a multicausal pathogenesis involving chromosomal, genetic, enzymatic, infectious, and iatrogenic causes. There remains, however, a group of POF patients without a known etiology, the so-called "idiopathic" form. An autoimmune etiology is hypothesized for the POF cases with a concomitant Addison's disease and/or oophoritis. It is concluded in this review that POF in association with adrenal autoimmunity and/or Addison's disease (2-10% of the idiopathic POF patients) is indeed an autoimmune disease. The following evidence warrants this view: 1) The presence of autoantibodies to steroid-producing cells in these patients; 2) The characterization of shared autoantigens between adrenal and ovarian steroid-producing cells; 3) The histological picture of the ovaries of such cases (lymphoplasmacellular infiltrate around steroid-producing cells); 4) The existence of various autoimmune animal models for this syndrome, which underlines the autoimmune nature of the disease. There is some circumstantial evidence for an autoimmune pathogenesis in idiopathic POF patients in the absence of adrenal autoimmunity or Addison's disease. Arguments in support of this are: 1) The presence of cellular immune abnormalities in this POF patient group reminiscent of endocrine autoimmune diseases such as IDDM, Graves' disease, and Addison's disease; 2) The more than normal association with IDDM and myasthenia gravis. Data on the presence of various ovarian autoantibodies and anti-receptor antibodies in these patients are, however, inconclusive and need further evaluation. A strong argument against an autoimmune pathogenesis of POF in these patients is the nearly absent histological confirmation (the presence of an oophoritis) in these cases (< 3%). However, in animal models using ZP immunization, similar follicular depletion and fibrosis (as in the POF women) can be detected. Accepting the concept that POF is a heterogenous disorder in which some of the idiopathic forms are based on an abnormal self-recognition by the immune system will lead to new approaches in the treatment of infertility of these patients. There are already a few reports on a successful ovulation-inducing treatment of selected POF patients (those with other autoimmune phenomena) with immunomodulating therapies, such as high dosages of corticosteroids (288-292).

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Premature ovarian failure and ovarian autoimmunity.

Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study

BACKGROUND
Primary ovarian insufficiency (POI) is characterized by marked heterogeneity, but with a significant genetic contribution. Identifying exact causative genes has been challenging, with many discoveries not replicated. It is timely to take stock of the field, outlining the progress made, framing the controversies and anticipating future directions in elucidating the genetics of POI.

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Genetics of primary ovarian insufficiency: new developments and opportunities

In 43 patients without ovaries, endometrial biopsies at day 21 of 75 substituted cycles were studied by light and electron microscopy. The morphology of the endometrium was compared after oral, vaginal or intramuscular administration of progesterone, and correlated with the serum levels of 17-beta oestradiol and progesterone and the pregnancies obtained after oocyte donation. After vaginal application of micronized progesterone, endometrial morphology closely matched that of a natural cycle. This therapy was able to support two ongoing pregnancies. No adequate endometrial response was noted after oral ingestion of progesterone. The maturation of the endometrium after intramuscular injections of progesterone in oil was heterogeneous. It was concluded that the vaginal route for administering micronized progesterone can be advised as the treatment of choice in patients without ovarian function.

Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure

An 18-month survey of infertility treatment by in vitro fertilization (IVF) and related procedures at the Centre for Reproductive Medicine of the Vrije Universiteit Brussel is described. During this period, 1326 treatment cycles were started in patients with long-standing infertility and 1135 oocyte retrievals were performed in 771 different patients. IVF and embryo transfer (ET) after laparoscopic (N=793) or ultrasonically guided (N=342) ovum pickup, gamete intrafallopian transfer (GIFT;N=284), or zygote intrafallopian transfer (ZIFT;N=15) combined with IVF as well as the replacement of cryopreserved embryos yielded an overall pregnancy rate of 21.8% per started cycle. Echographic and laparoscopic oocyte retrieval gave similar results except for a higher fertilization rate after echographic-guided retrieval. For in vitro fertilization and embryo transfer an overall pregnancy rate of 26% per transfer was obtained. For GIFT and ZIFT the pregnancy rates were, respectively, 27.8 and 46.7% per replacement. For each procedure onethird of the pregnancies aborted. After the replacement of frozen and thawed embryos, during a natural cycle, a significantly lower fetal loss was observed.

An 18-month survey of infertility treatment by in vitro fertilization, gamete and zygote intrafallopian transfer, and replacement of frozen-thawed embryos

Primary ovarian failure occurs under different circumstances as ovarian dysgenesis, premature menopause, and surgical menopause.’ The first pregnancy and birth after steroid-substitution therapy and in vitro fertilization (IVF) and embryo transfer (ET) in a patient with primary ovarian failure was reported in 1984: The transfer can be done with fresh embryos, if the ovarian cycles from donor and recipient are s y n c h r o n o u ~ ~ ~ ~ ; if their cycles are asynchronous, pregnancy can be obtained by replacing frozen-thawed embryos.’ The results of oocyte and embryo donation at the Centre for Reproductive Medicine of the Medical Campus of the Vrije Universiteit Brussel are reported.

Primary ovarian failure. Embryo donation after substitution therapy.

In vitro fertilization and embryo transfer or gamete (or zygote) intra-Fallopian transfer after ovum donation were performed in 16 patients with primary or secondary amenorrhea, associated with chromosome abnormalities. The patients showed the wide range of (mostly X) chromosome abnormalities characteristic for women with primary or premature ovarian failure. Four of these patients became pregnant and three of them have delivered healthy infants with a normal karyotype. This pregnancy rate is far superior to the accepted fertility figure in these patients. When these results were compared with the fertility treatment results of three other groups of women with absent ovarian function (1. ovarian dysgenesis; 2. surgical castration; 3. premature menopause) but with a normal 46,XX karyotype, no difference in treatment efficiency could be detected. These results offer a promising approach for the treatment of infertility in agonadal patients with chromosome aberrations.

Chromosome studies and fertility treatment in women with ovarian failure.

The clinical, hormonal and cytogenetic findings in 36 women with primary ovarian failure, referred for oocyte or embryo donations are reported. Fifteen women were suffering from ovarian dysgenesis and 11 from premature menopause. Six of these 26 patients showed X-chromosome abnormalities. One patient had a Noonan syndrome. The remaining 10 had surgical menopause. The mean duration of their infertility was 6.5 +/- 3.2 years (+/- SD). All patients had elevated serum gonadotrophins within the menopausal range. Hypothalamic, pituitary and thyroid function were found to be intact. In one of the 15 ovarian biopsies on the patients with chromosomal competent ovarian failure, primordial follicles were found. Hysterosalpingograms revealed a normal uterine cavity in all patients. In view of oocyte donation, careful evaluation of the obstetric risk was mandatory in the six patients with X-chromosome aberrations and in the patient with the Noonan syndrome, because of their short stature and possible concomitant cardiovascular and renal disease. After substitution therapy with oestradiol valerate and natural progesterone, 13 pregnancies were established, seven patients delivered (one set of twins), eight healthy children were born, three pregnancies aborted and three pregnancies are progressing normally.

L. Van Waesberghe

Papers

Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure

An 18-month survey of infertility treatment by in vitro fertilization, gamete and zygote intrafallopian transfer, and replacement of frozen-thawed embryos

Primary ovarian failure. Embryo donation after substitution therapy.

Chromosome studies and fertility treatment in women with ovarian failure.

Oocyte donation in patients without ovarian function