Newsletter

Table of Contents

05.06.2006

Newsletter No. 10

Endometriotic and adenomyotic lesions are derived from the basal endometrium with stem cell potential: further insights into the pathophysiology of endometriosis
Single embryo transfer: value of cryopreservation
Acne and hyperandrogenemia
Use of human gametes obtained from donors for the production of human embryonic stem cell lines

1. Endometriotic and adenomyotic lesions are derived from the basal endometrium with stem cell potential: further insights into the pathophysiology of endometriosis.

Recent data indicate that both, adenomyotic and endometriotic lesions are composed of epithelium, stroma and peristromal smooth muscle cells. In adenomyosis it is reasonable to assume that the lesions are derived from basal endometrium and it is believed that the surrounding muscular tissue represents hyperplastic myometrium resulting from the infiltrative process. Endometriosis is believed to result from dislocated fragments of superficial endometrium and the origin of peristromal smooth muscle cells of endometriotic lesions is unclear. The hypothesis was tested that both adenomyotic and endometriotic lesions are derived from basal endometrium and that the surrounding myometrium results from metaplasia of the ectopic endometrial stroma and is therefore, as the normal archimyometrium of paramesonephric origin. Normal and uteri with adenomyosis obtained by hysterectomy, excised endometriotic lesions and menstrual blood of women with endometriosis were used. All women had normal menstrual cycles and aged 32-49 years. Estrogen receptor (ER), progesterone receptor (PR) and progesterone receptor isoform B (PRB) immunohistochemistry was performed with the use of specific monoclonal antibodies. In the outer myometrium, in the archimyometrium, in zones I-III of the endometrium the typical pattern of ER and PR expression could be demonstrated with a constantly high expression in the outer myometrium and a cyclically changing expression in the archimetrial components of the uterine wall with high expression during most of the proliferative and progressively decreasing expression in the secretory phase of the cycle. Basal endometrium of zone IV displayed a specific cyclic pattern resulting in a significantly different ER and PR expression between the functionalis and the basalis during the late secretory phase (SP). PRB expression was high in the functional and basalis of the eutopic endometrium during the late proliferative phase and was virtually absent both layers during the late SP. The ectopic endometrium of endometriotic and adenomyotic lesions completely mimicked the cyclical pattern of the zone IV basalis. In menstrual blood of women without endometriosis endometrial fragments with strong staining (basalis) could be demonstrated in 7% of the cases, while fragments of basalis could be found in menstrual blood in 64% of women with endometriosis. The peristromal muscular tissue of endometriotic and adenomyotic lesions displayed the same cyclical pattern of ER and PR expression as the archimyometrium. These data suggest that both endometriosis and adenomyosis are derived from the basal layer of the endometrium. It is furthermore proposed that dislocated basal endometrium has stem cell character capable of resuming embryonic growth potential and resulting in the ectopic formation of all archimetrial components such as epithelium, stroma and paramesonephric smooth muscle cells. The cause of the shedding of fragments of basalis is viewed in the uterine peristaltic activity, which has been shown to dramatically increased in infertile women with endometriosis. Thus, the development of endometriosis by shedding and transplantation of fragments of basal endometrium appears to be caused by auto-traumatisation of the uterus via its proper function.

G Leyendecker, M Herbertz, G Kunz, G Mall (2001) Endometriotic and adenomyotic lesions display the same cyclical estrogen (ER), progesterone (PR) and progesterone isoform B receptor (PRB) expression as the functional unit of basal (zone IV) endometrium and archimyometrium (Abstract, Endocrine Society Meeting, Denver)

2. Single embryo transfer: value of cryopreservation

Following the transfer of two to three embryos in-vitro fertilization is associated with a high rate of multiple pregnancies. Not only multiple pregnancies such as triplets but also twin pregnancies constitute a high risk. Thus, there is a challenge in avoiding even twin pregnancies in assisted reproduction, and this can be accomplished with elective single embryo transfer and a good cryopreservation programme. In a follow-up study of a Finnish group, all elective single embryo transfers during 1998-1999 were analysed. In all these cycles at least one embryo was frozen. A total of 127 elective single embryo transfers were performed with a clinical pregnancy rate of 38.6%. The highest implantation rate was obtained with four-cell embryos with <10% fragmentation (39.8%). Thirty-four patients have delivered (26.8%), one of these being a monozygotic pregnancy. In total 129 frozen-thawed cycles have been achieved in 83 patients. One frozen-thawed embryo has been transferred in 46 cycles with a clinical pregnancy rate of 17.4%, and two embryos have been transferred in 83 cycles, with a clinical pregnancy rate of 37.3%. Up until now, 66 of 125 patients in the single embryo transfer programme have delivered or have on-going pregnancies, and 77 still have embryos frozen. The cumulative delivery rate per oocyte retrieval is 52.8% and the twin rate 7.6%.It is concluded that elective single embryo transfer with a good cryopreservation programme results in very acceptable pregnancy rates with a low risk of twins. This is a cost-effective practice that substantially reduces all risks associated with multiple pregnancies and lowers the cost per delivery.

Tiitinen A, Halttunen M, HÃ¤rkki P, Vuoristo P, Hyden-Grnasko C (2001) Elective single embryo transfer: the value of cryopreservation. Hum Reprod. 16: 1140-1144

3. Acne and hyperandrogenemia

To determine whether acne is associated with hyperandrogenemia in a prospective controlled study thirty consecutive unselected women presenting with acne and no hirsutism and 24 eumenorrheic healthy controls were studied. Serum samples was taken in all patients, and an acute 60-minute ACTH-(1-24) test was performed in 19 patients. Total and free Testosterone (T), sex hormone-binding globulin (SHBG), and DHEAS levels in basal samples, and ACTH-stimulated 17-hydroxyprogesterone (17-HP) response to exclude 21-hydroxylase (21-OH)-deficient non-classical adrenal hyperplasia (NCAH) were determined. Non-hirsute patients with acne demonstrated significantly lower levels of SHBG and higher free-T and DHEAS levels than controls. Nineteen (63%) acneic patients had at least one androgen value above the 95% of controls. In patients aged 12-18 years, 7/8 (88%) had at least one increased androgen value, compared with 12/22 (55%) patients aged 19-43 years. One patient (5.3%) was found to have 21-OH-deficient non-classical adrenal hyperplasia. Hyperandrogenemia was evident in a majority of non-hirsute acneic patients studied, regardless of age. These data show the role of elevated androgen levels in non-hirsute acne and suggest that androgen suppression may be useful in treating acne in many of these patients.

Slayden SM, Moran C, Sams WM, Boots LR, Azziz R (2001) Hyperandrogenemia in patients presenting with acne. Fertil Steril 75: 889-892

4. Use of human gametes obtained from donors for the production of human embryonic stem cell lines.

Oocytes were aspirated from oocyte donors (n = 12) and inseminated with frozen-thawed donor (n = 2) sperm followed by culture of embryos to day 5 or 6 in sequential media. The inner cell masses of expanded blastocysts were isolated using immunosurgery and cultured for 4-11 days. Immunosurgery of 40 blastocysts resulted in the culture of 18 inner cell masses, which have produced three cell lines. One of these cell lines has been shown to stain positive for alkaline phosphatase and stage-specific embryonic antigen (SSEA)-4 and negative for SSEA-1, express telomerase activity, and produce hCG when allowed to differentiate. These findings demonstrate that the future production of human embryonic stem cell lines for thetherapeutic use is possible with the use of donated gametes. Many ethical issues were considered before the initiation of this study, and it was the goal of the investigators to ensure that both oocyte and sperm donors understood the nature and purpose of the research before their participating in the study.

Lanzendorf SE, Boyd CA, Wright DL, Muasher S, Oehninger S, Hodgen GD (2001) Use of human gametes obtained from anonymous donors for the production of human embryonic stem cell lines. Fertil Steril 76: 132-137

Gerhard Leyendecker