C. Hilary Buckley

Effect of two antiprogestins (mifepristone and onapristone) on endometrial factors of potential importance for implantation

OBJECTIVE To investigate the effects of postovulatory administration of antiprogestins on endometrial factors that may be of importance for successful implantation. DESIGN Ten women were given 200 mg mifepristone and an additional 10 women 400 mg of onapristone 48 hours after the LH surge in urine (LH + 2). MAIN OUTCOME MEASURE(S) Biopsies were assessed for histologic dating and the immunolocalization of [1] leukemia inhibitory factor, [2] 15-hydroxyprostaglandin dehydrogenase, and [3] the cell proliferation marker Ki 67. Hormonal measurements in blood and urine were used to monitor the effects on the ovarian cycle. Glycodelin (placental protein 14) concentrations were measured in blood taken on LH + 12. RESULT(S) Treatment with antiprogestins retarded the development of secretory changes without affecting the length of the luteal phase. In addition, there was reduced immunostaining for 15-hydroxyprostaglandin dehydrogenase within glands and a significant reduction in serum levels of glycodelin. Reduced immunostaining for leukemia inhibitory factor also was apparent within glands in biopsies taken on LH + 6 of the treatment cycle. Increased Ki 67 immunostaining was observed on both cycle days after treatment, consistent with P antagonism. CONCLUSION(S) Administration of mifepristone and onapristone adversely affects uterine receptivity. This adds further evidence to support their potential as a method of postovulatory fertility control.

Experience with a ‘physiological’ steroid replacement regimen for the establishment of a receptive endometrium in women with premature ovarian failure

Summary. Eighteen women with a premature menopause underwent assessment of serial serum oestradiol (E2) and progesterone levels and endometrial histology and function. Patients received continuous transdermal E2, and progesterone either orally or vaginally for 14 days. Physiological levels of E2 were attained. Significantly higher levels of progesterone were achieved with vaginal progesterone (P<0.01). Endometrial biopsies obtained during E2 replacement demonstrated normal proliferative features. Expression of an oestrogen related antigen (ER‐Ag) was localized in the cytoplasm of the epithelium. After 3 days of progesterone replacement the endometrium showed normal secretory features and expression of ER‐Ag in the stroma as well as in the glands. After 7 days of progesterone supplementation, vaginal administration produced a more consistent physiological appearance than oral administration. Thus transdermal E2 combined with vaginal progesterone is a highly satisfactory combination for establishing a physiological endometrium in women with premature ovarian failure.

Endometrial structure after superovulation: a prospective controlled study

OBJECTIVE To demonstrate the effect of superovulation using a GnRH agonist (GnRH-a) and hMG and hCG on endometrial structure. DESIGN Prospective, case-controlled study. SETTING Tertiary referral assisted reproduction unit in an academic department. PATIENTS Eleven women undergoing GIFT or IVF, without ET. INTERVENTIONS All women were treated with a long stimulation regimen using the depot GnRH-a Goserelin (ICI, Macclesfield, United Kingdom) and hMG and hCG. MAIN OUTCOME MEASURES Comparison of endometrial biopsy specimens taken 4 days after ovulation in an unstimulated cycle with specimens taken 4 days after oocyte recovery, using standard dating criteria and morphometric analysis. RESULTS There was no difference in endometrial glandular development as assessed by either standard criteria or morphometric analysis. CONCLUSIONS Superovulation preceded by pituitary down regulation is not associated with abnormal endometrial glandular development, even though supraphysiological levels of E2 and P are induced.

HLA expression in pre-invasive cervical neoplasia in relation to human papilloma virus infection

A significant proportion of cervical carcinomas show loss of major histocompatibility complex human leucocyte antigen (HLA) class I expression while upregulating HLA class II expression. These changes may have direct consequences for immune surveillance of the human papilloma virus (HPV) infection which is strongly associated with cervical malignancy. A relationship between changes in HLA expression and HPV infection may be evident in the evolution of premalignant disease. This immunohistological study of 104 colposcopic biopsies establishes that HLA class II expression occurs in a significant proportion of squamous epithelia showing histological evidence of wart virus infection and cervical intraepithelial neoplasia (CIN) I to III. In comparison, alteration of HLA class I expression in cervical premalignant lesions is rare. There is no correlation between the detection of high risk HPV DNA (types 16, 18, 31 and 33) by polymerase chain reaction (PCR) and the MHC class II phenotype of the lesion. This suggests that altered HLA class II expression is neither a consequence nor a prerequisite for HPV infection.

Angiogenesis in normal, hyperplastic, and neoplastic endometrium.

The purpose of this study was to quantify vascular density in the stroma of normal, hyperplastic, and neoplastic endometria and to explore its relationship to other prognostic features of endometrioid adenocarcinoma. Curettage specimens of proliferative and mid‐secretory endometrium; simple, complex, and atypical endometrial hyperplasia; and grade I endometrioid adenocarcinoma were stained with Factor VIII‐related antigen. The number of vessels per mm2 of stroma was calculated for each case. The stroma of mid‐secretory and hyperplastic endometrium was more vascular than that of proliferative endometrium. The stroma of adenocarcinoma, though reduced in proportion to the epithelium, was significantly more vascular than that of normal or hyperplastic endometrium. Stromal vascular density was not related to the depth of invasion, the presence of lymphovascular space permeation, or the state of the adjacent endometrium, whether atrophic or hyperplastic.

Disseminated leiomyomatosis peritonealis in association with oestrogen secreting ovarian fibrothecoma

A 59 year old nulliparous woman presented with a two year history of irregular vaginal bleeding. She was not taking hormone replacement therapy. She was found to have an abdominopelvic mass and ultrasound con®rmed an enlarged uterus, measuring 16x13cm with the appearance of multiple ®broids. There was also gross endometrial thickening of 5cm and a loculated cystic adnexal mass measuring 13cm in diameter. Laboratory investigations revealed iron de®ciency anaemia (Hb 5.5 g/dL, MCV 54.0 ̄, MCH 15.8 pg) and elevated serum CA125 (115 U/L). There was also biochemical evidence of abnormal oestrogen secretion. Serum oestrogen levels (156 pmol/L) were in the premenopausal range and gonadotrophin secretion was suppressed (FSH 1.5 iu/L, LH 6.3 iu/L). Serum electrolytes and liver function tests were normal as was a chest X-ray. Four units of blood were transfused prior to undertaking a laparotomy. A midline incision was performed. A grossly enlarged uterus containing several large intramural nodules, right ovarian cyst measuring 20cm in diameter and a left ovarian cyst, 3 cm in diameter, were found (Fig. 1). There was a small amount of clear ascites. On opening the retroperitoneum the appearance was of bilateral parametrial and pelvic side wall lymph node masses, the largest measuring 10cm and ®lling the left obturator fossa (Fig. 2). The omentum, peritoneal surfaces and upper abdomen appeared normal. Total hysterectomy, bilateral salpingo-oophorectomy, bilateral pelvic lymphadenectomy and infracolic omentectomy were performed. It was possible to develop a plane around the nodal masses in the parametrium and on the pelvic side wall such that there was no remaining macroscopic tumour at the conclusion of surgery. Operative blood loss was 3000ml and a further six units of blood were transfused. Post-operatively she developed a mild degree of disseminated intravascular coagulation which was corrected with fresh frozen plasma. She became hypoproteinaemic with a protracted ileus and required intravenous nutritional support. She was discharged on the 16 day after her operation.

Luteal phase defect: The possibility of an immunohistochemical diagnosis

Monoclonal antibody D9B1 has been shown to bind to a carbohydrate epitope associated with high molecular weight secretory sialoglycoprotein(s) of human endometrium. The authors demonstrate that, in a group of 28 patients diagnosed on the basis of histopathologic assessment as exhibiting luteal phase defect, 68% reveal significantly diminished expression of the epitope. Furthermore, histologic assessment of the secretory activity in single glands does not correlate simply with the level of expression of the epitope. Of specimens from patients complaining of infertility, 92% showed defective production of the D9B1 epitope. Thus, D9B1 immunohistochemistry provides a new molecular criterion for defective endometrial function.

Involvement of the vulval skin appendages by intraepithelial neoplasia

Summary. In the treatment of vulval intraepithelial neoplasia (VIN) by laser, the extent to which the skin appendages are involved is an important factor in determining the depth of tissue to be destroyed. An investigation of 50 patients with VIN revealed that in 28 the skin appendages were involved and the maximum depth of involvement reached 4.6 mm from the surface of the epidermis. It is suggested that eradication of tissues to a depth of 5·0 mm would eliminate all atypical epithelium in the skin appendages.

A fatal case of stilboestrol associated clear cell adenocarcinoma of the vagina

SummaryIn the United States of America, over 400 cases of clear cell adenocarcinoma of cervix and vagina have been reported (Herbst, 1981), two-thirds of these having a documented association with prenatal exposure to stilboestrol. The first description of a stilboestrol associated neo-plasma of this type from the United Kingdom was in 1978 and it was then estimated that there were a further 10 latent cases in Great Britain (Monaghan and Sirisena, 1978); two of these have since become overt (Dewhurst et al., 1980; Davis et al., 1981) and we record here a third in which there were several unusual features and which proved to be the first reported fatality from this type of neoplasm in Britain.