Ewa Radwanska

Occult ovulatory dysfunction in women with minimal endometriosis or unexplained infertility

Characteristics of follicular development and hormonal patterns were evaluated in 17 women with minimal endometriosis and 11 with unexplained infertility. The controls were 7 women with male factor infertility and 8 who conceived during an investigational cycle. Women with minimal endometriosis had more and smaller follicles at luteinizing hormone (LH) surge, lower preovulatory estradiol (E2), and lower E2 at LH surge. Women with unexplained infertility had lower LH surges and a trend to a shorter follicular phase. Occult ovulatory dysfunction and may contribute to infertility in women with minimal endometriosis or unexplained infertility.

Bone mineral density in women with endometriosis before and during ovarian suppression with gonadotropin-releasing hormone agonists or danazol * †

Lumbar bone mineral density (BMD) was evaluated by dual photon absorptiometry (DPA) in 38 women with laparoscopically diagnosed and staged endometriosis. DPA was performed before and at the completion of 26 weeks of treatment with either gonadotropin releasing hormone agonist (GnRHa) or danazol. Twenty-five women received GnRHa either nasally or subcutaneously and 13 women received danazol 200 mg four times daily by mouth. During treatment amenorrhea and suppressed estradiol levels were observed in all patients. Each patient took a supplement of oral calcium 1 gm daily. DPA (reproducibility +/- 1.5%) was read by a single observer unaware of the treatment assignment of the patient. The mean (+/- standard error) of the entire group prior to treatment was 98.8% +/- 0.03% of a control population of women from the same geographic area matched for race, age, and weight. At the completion of treatment, BMD was slightly decreased in the GnRHa group and marginally increased in the danazol group but neither change was significant. Women with endometriosis have lumbar BMD in the normal range and ovarian suppression with either GnRHa or danazol produces no significant change in BMD.

Ovarian suppression induced with Buserelin or danazol in the management of endometriosis: a randomized, comparative study.

The effectiveness of Buserelin (Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ) (0.2 mg subcutaneously [SC] or 1.2 mg intranasally [IN] per day) and danazol (800 mg per day) in inducing ovarian suppression for the management of endometriosis was compared in a prospective randomized study. During 6 months of treatment, peripheral follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol concentrations were suppressed to a similar degree in both groups. Symptomatic improvement and laparoscopically assessed regression of endometriotic lesions also were comparable. After treatment, 8 of 18 infertile women treated with Buserelin and 5 of 8 treated with danazol conceived. General and hypoestrogenic side effects were similar in both groups, while androgenic and anabolic were more frequent with danazol. High density lipoprotein (HDL)-cholesterol increased in the Buserelin and decreased in the danazol group. The study indicates that at the dose tested, buserelin and danazol induce a similar degree of ovarian suppression resulting in a comparable clinical improvement and regression of endometriotic lesions.

Mild endometriosis and ovulatory dysfunction: effect of danazol treatment on success of ovulation induction

The effectiveness of ovulation induction with clomiphene citrate or human menopausal gonadotropins was evaluated in 52 infertile women with stage I or stage II endometriosis and ovulatory dysfunction: anovulation or luteinized unruptured follicle (LUF) syndrome before (group I) and after (group II) danazol treatment. The incidence of anovulation and LUF in the endometriosis population was 9% and 34%, respectively. In group I, 10 of 36 patients (27.8%) conceived, with an average of 17.6 induction cycles per pregnancy. In group II, 21 of 30 patients (70%) conceived, with an average of 4.5 cycles per pregnancy (difference significant at P less than 0.001). There was no difference in the average number of ovulation induction cycles per patient between groups I and II (4.9 and 3.1, respectively). Of 14 patients who did not conceive in group I and crossed over to group II, 9 (64.3%) conceived (not different from group II). Spontaneous abortion rates were 20% in group I and 14% in group II. These results indicate that mild endometriosis may interfere with conception through mechanisms other than ovulatory dysfunction and that treatment with danazol appears to more than double the fertility rate.

Microsurgical enucleation of tripronuclear human zygotes

Polyspermic fertilization of human oocytes in vitro produces genetically abnormal embryos whose replacement in utero represents a potential obstetrical risk. Microsurgical removal of extra male pronuclei offers the possibility that normal ploidy can be restored in these zygotes. Pronuclear removal was attempted in three tripronuclear human oocytes fertilized in vitro. Male pronuclei were distinguished by their larger size and an associated sperm tail piece. Zygotes were pretreated with cytochalasin B and colcemid in phosphate-buffered saline before microsurgery. Enucleation was completed in all embryos; syngamy occurred in one embryo, but cleavage was not observed.

A randomized, prospective comparison of endocrine changes induced with intranasal leuprolide or danazol for treatment of endometriosis.

A prospective, randomized trial compared hormonal changes induced with intranasal leuprolide 1.6 mg/day to danazol 800 mg/day for treatment of endometriosis. Both regimens induced anovulation and ovarian suppression in all subjects. Mean estradiol (E2) and progesterone (P) levels were suppressed with both regimens, but were lower with leuprolide. There was no difference in cumulative follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, although at times during treatment mean levels of these hormones were lower with leuprolide. Higher P levels in the danazol group, most likely of adrenal origin, indicated a suppressive effect on adrenal steroidogenesis. Symptomatic improvement was significant in both groups. Laparoscopy after treatment also demonstrated a decrease in endometriosis scores in both groups. At 12 months after treatment, cumulative pregnancy and live birth rates were similar in both groups. Leuprolide offers an attractive alternative to danazol for the medical treatment of endometriosis.

High progesterone/estradiol ratio in follicular fluid at oocyte aspiration for in vitro fertilization as a predictor of possible pregnancy

Eighteen women undergoing in vitro fertilization (IVF) procedures were studied. All had optimal (900 to 1600 pg/ml) peak serum estradiol (E2) response to the same stimulation regimen with clomiphene citrate and menotropins; fertilization rate was above 64%; and two to four embryos in two to eight cell stages were replaced in each patient. All were considered to have optimal chances for conception. The authors compared progesterone (P), E2, and P/E2 ratio in serum and follicular fluid (FF) at the time of oocyte aspiration in eight patients who conceived (group I) and ten who did not (group II). Mean serum P and E2 levels and serum P/E2 ratio were not significantly different between the groups. In contrast, mean FF P concentrations (ng/ml) were significantly (P less than 0.05) higher in group I (9721 versus 5385), as was FF P/E2 ratio (19.0 versus 11.8; P less than 0.02). There was no significant difference in mean FF E2 concentrations between the groups. These data indicate that in IVF cycles with optimal serum E2 response to the stimulation protocol, FF P and P/E2 ratio at the time of oocyte aspiration may be predictive of subsequent implantation and pregnancy.

Human chorionic gonadotropin rise in normal and vanishing twin pregnancies

OBJECTIVE The purpose of the study was to describe and to compare the rate of rise of human chorionic gonadotropin (hCG) in vanishing twin and normally progressing twin pregnancies during the first trimester. DESIGN All patients with twin pregnancies between 1985 and 1989 were prospectively studied. Human chorionic gonadotropin was measured one to three times per week between days 12 and 52 after luteinizing hormone (LH) surge or day of hCG administration (day 0). Pelvic ultrasound (US) was performed weekly beginning on day 24. SETTING The study was performed at Rush-Presbyterian-St. Lukes Medical Center in an academic private practice setting of the Section of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology. PATIENTS Forty patients who conceived after treatment of infertility and who had two gestational sacs on US examination were included in the study after the following criteria were met: (1) both sacs progressed to exhibit a fetal pole and (2) day of LH surge and/or day of hCG administration was known. MAIN OUTCOME MEASURE The rate of rise of hCG was slower in vanishing twin pregnancies than in normally progressing twin gestations for the entire time period studied (P less than 0.05). RESULTS A vanishing twin occurred in one third of the twin pregnancies. Forty-six percent of these losses occurred after fetal heart activity had been established. CONCLUSIONS Vanishing twin phenomenon occurred in a large proportion of twin pregnancies in this infertility population. Fetal heart activity was not a reliable predictor of continuing fetal viability in early twin gestations. Vanishing twin conceptions were characterized by a slower rate of rise of hCG than normally progressing twin pregnancies.

Persistent ovarian cysts following administration of human menopausal and chorionic gonadotropins: an attenuated form of ovarian hyperstimulation syndrome

Ovarian cysts persisting after the onset of menses were demonstrated by ultrasound (US) in 40 of 71 (56%) nonconception cycles following ovulation induction with human menopausal gonadotropins (hMG) and human chorionic gonadotropin (hCG). Persistent cysts were self-limited and all resolved spontaneously within two cycles. They developed more frequently during stimulation cycles with (1) higher mean pre-hCG serum estradiol (E2), (2) a greater number of medium and large follicles at peak pre-hCG E2, and (3) a larger leading follicle diameter at peak pre-hCG E2. Persistent ovarian cysts frequently occurred despite a peak pre-hCG E2 lower than 1000 pg/ml. Although ovarian enlargement in the presence of cysts exceeded 5 X 5 cm in 25% of cases, no patient developed clinical symptoms of ovarian hyperstimulation syndrome (OHSS). Repeated induction of ovulation with hMG/hCG in the presence of nonfunctional, persistent cysts resulted in pregnancies in 6 of 15 cases (40%). Asymptomatic persistent ovarian cysts frequently follow an hMG/hCG regimen and, when nonfunctional, are not a contraindication to repeated ovarian stimulation. Persistent ovarian cysts appear to be an attenuated form of OHSS.

Current concepts on pathology, histogenesis and etiology of endometriosis

Endometriosis is a disease characterized by ectopic growth of the endometrium, i.e. outside of the uterine cavity. Typically, the disease is limited to menstruating women, although two reports of endometriosis developing in men treated with estrogens are on record (23,24). On occasion, active endometriosis has been described in women after menopause, in teenagers, in patients with gonadal dysgenesis and even in women with primary amenorrhea associated with mullerian anomalies. Endometriosis is also known to occur in other species of primates. The term ‘endometriosis’ was introduced relatively recently, in 1921, by Sampson (27). However, the condition has been recognized as an unnamed entity for many decades and the possibility of endometriosis has probably been present for as long as women have menstruated. The first reference to what could have been the characteristic symptoms of endometriosis was made in the Egyptian Papyrus Ebers dating back to the year 1600 BC and describing treatment for the painful ‘disorder of her menstruation’ (9). In medical literature the first references to cystic lesions of the female reproductive system, most likely endometriotic in nature, were made during the last century. Cruveilhier (5) referred in 1835 to the existence of cysts of the adnexa, uterus and vagina; Von Rokitansky (34) published in 1860 the first pathologic description of endometrioma, referring to it as ‘adenomyoma’ and Breus (3) in 1894 used for the first time the term ‘chocolate cysts’. Our knowledge of the pathophysiology of endometriosis has advanced significantly during this century. The histopathologic changes characteristic of endometriosis are well known. The diagnosis is made early and effectively by means of laparoscopy, the clinical course is well understood and there are several effective approaches to the treatment. However, there are still many aspects of this disease that are poorly understood. In spite of many proposed theories, the histogenesis of endometriosis is obscure. Although Sampson’s theory has become generally accepted, other concepts of the mechanisms of its development are equally plausible and supported by clinical and experimental evidence. The etiology of this disease is unknown. Recent studies seem to suggest that endometriosis may develop through several different mechanisms in susceptible individuals and various etiologic factors have been postulated. This article reviews the current knowledge of the pathology, histogenesis and etiology of this fascinating disease.