Robert P.S. Jansen

Nonpigmented endometriosis: Clinical, laparoscopic, and pathologic definition☆☆☆

Abstract We describe the morphologic characteristics and clinical importance of peritoneal lesions that have the histologic features of endometriosis but are devoid of the pigmented stigmas typical of this disease. A total of 137 laparoscopic biopsy specimens were taken of nonpigmented peritoneal lesions in 77 patients, among whom 70 were infertile. Seventy-three biopsy specimens showed endometrium-like glands and stroma, and another 12 showed only endometrioid stroma; no such histologic features of endometriosis were present in 10 biopsy specimens of normal uterosacral ligament peritoneum (p = 0.005, Fishers test). Nonpigmented lesions that were commonly endometriotic were: (1) white opacified peritoneum (endometriosis in 81% of n = 52 biopsy specimens). (2) red flamelike lesions (81% of n = 16), and (3) glandular lesions (resembling endometrium at hysteroscopy) (67% of n = 21). Lesions that were sometimes endometriotic were: (1) subovarian adhesions (50% of n = 4), (2) yellow-brown peritoneal patches (47% of n = 19), and (3) circular peritoneal defects (45% of n = 11). However, thickened cribriform peritoneum usually was not endometriotic (9% of n = 11) and vesicular excrescences were, in every case, reactions to oil-based salpingographic medium (n = 5). Six patients underwent another laparoscopy within 6 to 24 months and each had developed pigmented endometriotic lesions in previously nonpigmented but abnormal areas. Visualization of pigment is not necessary to diagnose endometriosis, and definition of its early, nonpigmented appearance keeps the clinical category of “unexplained infertility” exclusive.

The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate

Molecular geneticists and ovarian physiologists today face the challenge of defining and reconciling two major biological imperatives that each center on oogenesis, folliculogenesis and competition between ovarian follicles: (1), defining how the mitochondrial genome--important in both aging and a number of serious mitochondrial diseases--is refreshed and purified as it passes, via the oocytes cytoplasm, from one generation to the next; and (2), endeavouring to discover what cytoplasmic factor(s) it is that permits some eggs but not others to produce viable embryos and ongoing pregnancies. We review here in detail the passage of mitochondria through the female germ cell line. For mitochondria, the processes of oogenesis, follicle formation and loss constitute a restriction/amplification/constraint event of the kind predicted by L. Chao for purification and refinement of a haploid genome. We argue that maintaining the integrity of mitochondrial inheritance is such a strong evolutionary imperative that we should expect at least some features of ovarian follicular formation, function and loss to be primarily adapted to this specific purpose. We predict, moreover, that to prevent accumulation of mild mitochondrial genomes in the population there is a need for physiological female sterility prior to total depletion of ovarian oocytes, a phenomenon for which there is empirical evidence and which we term the oöpause.

What next for preimplantation genetic screening (PGS)? Experience with blastocyst biopsy and testing for aneuploidy

Blastocysts more commonly have a normal karyotype than cleavage-stage embryos do. Moreover, blastocysts have also made a metabolic transition from catabolism and recycling of the oocytes reserves and resources, processes that fuel the first 3 days of cleavage. Although not all blastocysts are karyotypically equal, it is still to be determined to what extent a mosaic karyotype might be a normal feature among embryos, both at the cleavage stage and the blastocyst stage--and when looking for karyotypic abnormalities by embryo biopsy might help the chance of implantation rather than harm it. It is also still impractical to look at all the chromosomes that can, through their aneuploidy, stand in the way of successful embryonic and fetal development. We report a randomized clinical trial of blastocyst biopsy followed by preimplantation genetic screening (PGS) for aneuploidy using 5-colour FISH. The trial was suspended and then terminated early when we were unable to show an advantage for PGS. If we are correct in assuming that mitotic non-disjunction is common by the stage of the blastocyst (and that it is much less ominous than meiotic non-disjunction), then further studies of effective PGS of blastocysts for aneuploidy require methods of analysis that cover all the chromosomes and can differentiate the triallelic and monoallelic states of meiotically derived aneuploidies from the biallelic state of mitotic aneuploidies.

Cyclic changes in the human fallopian tube isthmus and their functional importance

Morphologic studies in rabbits have indicated that a column of tenacious mucus occupies the isthmic lumen in estrus. This secretion disappears after ovulation, and cilia are prominent at the time of ovum transport through the isthmus. This study was designed to seek evidence of similar mucus in the human fallopian tube isthmus. Isthmic segments were taken from 18 normally ovulating women throughout the menstrual cycle. Specimens were also obtained from 10 other women further to elucidate endocrine dependence of observed morphologic variations. Appearances consistent with luminal isthmic mucus were obtained in two women in the late follicular phase and in one woman immediately after ovulation. Observable mucus was absent and cilia were prominent in women in the early follicular phase, in the luteal phase, postmenopausally, in late pregnancy, and in the puerperium. The results described are consistent with the hypothesis that differential sperm and ovum transport in the human fallopian tube isthmus is at least partially determined by the presence or absence of estrogen-dependent luminal mucus.

Blastocyst trophectoderm biopsy and preimplantation genetic diagnosis for familial monogenic disorders and chromosomal translocations.

Modern in vitro fertilization practices involve transfer of embryos as blastocysts, when anabolic metabolism is well established and pregnancy rates can be maintained while transferring embryos singly to avoid multiple pregnancies. Embryo biopsy for preimplantation genetic diagnosis (PGD), however, is generally performed on day 3, when the embryo comprises just 6 to 8 cells, one or two of which are removed for testing. Implantation rates and clinical pregnancy rates have remained relatively low and a harmful effect from losing one or more cells from such early embryos has not been excluded.

Treatment of Recurrent Spontaneous Abortion by Immunization With Paternal Lymphocytes: Results of a Controlled Trial

PROBLEM: It remains unclear whether maternal immunization with paternal lymphocytes prior to conception improves the reproductive outcome in women with recurrent abortion in whom all secondary causes have been excluded.

A comparative treatment trial of endometriosis using the gonadotrophin-releasing hormone agonist, nafarelin, and the synthetic steroid, danazol

Summary: : A randomized and double‐blind trial was carried out comparing intranasal nafarelin acetate (400 μg daily) and oral danazol (600 mg daily), given over 6 months, in the treatment of 49 patients with laparoscopically proven endometriosis. Both drugs produced a highly significant and similar reduction (of 60 to 70%) in objective American Fertility Society scoring, even in severe disease. No effect was seen on adhesions. Both drugs suppressed oestradiol levels to a similar extent, although nafarelin caused a substantial rise in the first 2 weeks after the initiation of therapy. Nafarelin suppressed LH substantially and FSH, testosterone and prolactin to a small degree, whereas FSH and LH increased slightly during danazol. Pregnancies occurred in 12 of 22 infertile women in the 12 months following nafarelin, and in 6 of 14 in the danazol group. Side‐effects were reported at a similar rate with both drugs, but the pattern was different. Hot flushes were the predominant side effect with nafarelin, although oestradiol levels were not suppressed to the extent expected. Small amounts of spotting or light bleeding were experienced with both drugs, but these tended to decrease with time with nafarelin and increase with danazol.

Relative Bradycardia: A Sign of Acute Intraperitoneal Bleeding

Summary: Acute intraperitoneal bleeding with hypotension may be accompanied by a relatively normal pulse rate instead of the tachycardia usually produced by blood loss. Four cases of intraperitoneal bleeding of diverse, though pelvic, origin, are described. In each patient, symptomatic hypotension occurred with a pulse rate less than 80 per minute, thereby initially confusing the diagnosis of internal bleeding. The hypotension and relative bradycardia responded to atropine followed by fluid replacement. Response to atropine implies that the reflex that produces bradycardia is mediated by the parasympathetic nervous system. It is concluded that relative bradycardia occurring with intraperitoneal haemorrhage may be the cause of both diagnostic difficulty and disproportionately severe hypotension.

Single Embryo Transfer in IVF to Prevent Multiple Pregnancies

As the success rates of IVF clinics improve, one of the adverse consequences is the increased incidence of twins, due largely to the number of embryos transferred. Even if the number of embryos transferred is restricted to two, the twinning rate can exceed 40% of the pregnancies. An obvious way to reduce this high twin rate would be to transfer only one embryo. This would require that cryopreservation of the supernumerary embryos be efficacious enough so that the chance of achieving an ongoing pregnancy is not diminished by transferring a single embryo in the stimulated cycle. Previous studies utilising embryos on day 2 and 3 of development have shown that the pregnancy rates can be acceptable (about 40%) and that the cumulative rate can be up to 60%. Most of these studies, however, do not include a comparison with the cumulative pregnancy rate with two embryos transferred in the stimulated cycle. Therefore, the efficacy has not been proven. We present clinical data from the past few years to illustrate the increase in success rates and the concomitant increase in twinning rates. The increased success in the cryopreservation program has enabled us to trial a single embryo transfer program and compare the results to the transfer of two embryos. The results strongly suggest that the transfer of a single embryo is the better clinical option.

Surgery-pregnancy time intervals after salpingolysis, unilateral salpingostomy, and bilateral salpingostomy.

Pregnancy rates and time intervals to achieve pregnancy were determined in 144 patients treated for infertility by lysis of bilateral tubal or peritubal adhesions. The pregnancy rate after bilateral salpingostomy for hydrosalpinges was low (18.7%; n = 91). The eventual pregnancy rate after unilateral salpingostomy with bilateral division of adhesions (43.8%; n = 16), however, was comparable to that after bilateral salpingolysis for purely peritubal adhesions (54.1% n = 37). In contrast, the mean surgery-pregnancy time interval was substantially longer after unilateral salpingostomy (104 weeks) than after bilateral salpingolysis (45 weeks) (P < 0.01). These findings indicate that salpingo-oophorectomy may be preferable to salpingostomy for unilateral hydrosalpinx.