[Oncoplastic techniques for immediate reconstruction with nipple-areolar preservation following radical resection of a centrally located breast cancer]. / Onkoplastische Sofortrekonstruktions-Technik unter Erhalt des Mamillen-Areola-Komplexes nach radikaler Resektion eines Mammakarzinoms mit zentralem Sitz.

There are few breast-conserving therapies (BCT) for centrally located breast cancer. The present paper describes a BCT for breast cancers in such a location, which permits conservation of the nipple-areola complex (NAC), provided this has not been infiltrated. After histological detection of the breast cancer by punch biopsy, a central segmental mastectomy and an axillary dissection are performed. An immediate reconstruction of the subareolar defect is carried out by means of a local flap technique, thus conserving the NAC.

Psychological and endocrine correlates of chronic pelvic pain associated with adhesions.

Chronic pelvic pain (CPP) is a frequent and often unexplained gynecological complaint. We attempted to evaluate stress history, psychological features and hypothalamic-pituitary-adrenal (HPA) axis function in a group of patients suffering from CPP associated with pelvic adhesions. We recruited 10 patients with CPP and adhesions and 14 painfree, infertile control patients who underwent gynecological examination and diagnostic laparoscopy in a general hospital. Psychological assessment included structured interviews on sexual and physical abuse experiences and major life events as well as questionnaires on pain characteristics and depression. To evaluate HPA axis function, we measured plasma adrenocorticotropin (ACTH) and salivary cortisol responses to the administration of 100 micrograms human corticotropin-releasing factor (CRF). Results revealed high, but not statistically increased, prevalence rates of sexual and physical abuse for patients with CPP and adhesions as compared to controls. Patients with CPP and adhesions reported a significantly higher total number of major life events. Mean depression scores were normal in both groups. Patients with CPP and adhesions demonstrated normal plasma ACTH, but decreased salivary cortisol levels in the CRF stimulation test. These preliminary findings suggest that stress and neuroendocrine changes may also contribute to the pathophysiology of CPP with an identified organic correlate.

Abuse-related posttraumatic stress disorder and alterations of the hypothalamic-pituitary-adrenal axis in women with chronic pelvic pain.

OBJECTIVE: Although numerous organic conditions may cause chronic pelvic pain (CPP), diagnostic laparoscopy reveals a normal pelvis in many patients with CPP. However, psychological studies yield a high frequency of psychopathology and increased prevalences of chronic stress and traumatic life events, ie, sexual and physical abuse, in women with CPP, suggesting a relationship between posttraumatic stress disorder (PTSD) and CPP. As chronic stress and PTSD have been associated with specific alterations of the hypothalamic-pituitary-adrenal (HPA) axis, we explored stress history, psychopathology and HPA axis alterations in women with CPP. METHOD: We recruited 16 patients with CPP and 14 painfree, infertile controls from a general hospital where diagnostic laparoscopy was performed. Psychological assessment included standardized interviews on clinical symptoms, abuse experiences and major life events as well as psychometric testing for PTSD-like symptoms and depression. Endocrinological evaluation involved determinations of diurnal salivary cortisol levels and hormonal responses to a corticotropin-releasing factor (CRF) stimulation test (100 microg human CRF) and a low-dose dexamethasone suppression test (0.5 mg). RESULTS: We observed increased prevalences of abuse experiences and PTSD in women with CPP as well as a higher total number of major life events, whereas the mean extent of depression was within the normal range. With respect to endocrine measures, women with CPP demonstrated normal to low diurnal salivary cortisol levels, normal plasma-adrenocorticotropin (ACTH), but reduced salivary cortisol levels in the CRF stimulation test, and an enhanced suppression of salivary cortisol by dexamethasone. CONCLUSION: Women with CPP demonstrate HPA axis alterations, that partly parallel and partly contrast neuroendocrine correlates of PTSD, but show marked similarity to findings in patients with other stress-related bodily disorders. These findings suggest that a lack of protective properties of cortisol may be of relevance for the development of bodily disorders in chronically stressed or traumatized individuals.

Episodic variations of prolactin, thyroid-stimulating hormone, luteinizing hormone, melatonin and cortisol in infertile women with subclinical hypothyroidism.

Preliminary data have suggested that female infertility due to corpus luteum insufficiency may be caused by subclinical hypothyroidism [exaggerated thyroid-stimulating hormone (TSH) response to thyrotrophin-releasing hormone (TRH) stimulation]. L-Thyroxine supplementation has been recommended to achieve pregnancies in subclinical hypothyroid women. This controlled study was carried out in order to investigate the biochemical diagnosis of subclinical hypothyroidism as a possible infertility factor. Five infertile patients (aged 25-36 years) with subclinical hypothyroidism (n = 4, stimulated TSH >20 microU/ml) or primary hypothyroidism (n = 1) and five healthy controls (aged 22-39 years) with normal thyroid function (stimulated TSH <15 microU/ml), regular cycles and no history of infertility were studied in the early follicular phase. In the pre-study evaluation, eight of 23 volunteers (34.8%) had to be excluded because of subclinical hypothyroidism with stimulated TSH values (TSHs) >15 microU/ml. Cycle function of patients and controls was compared by the method of LH pulse pattern analysis. Therefore blood samples were drawn every 10 min during a 24 h period. Sleep was recorded from midnight to 7 a.m. Repetition of the TRH tests at the end of the 24 h blood sampling period confirmed the difference in stimulated TSH values of the two study groups. Pulse analysis for luteinizing hormone (LH), TSH and prolactin showed no differences between patients and controls for pulse frequency, amplitude, height, length, area under curve (AUC) and the 24 h mean. Even the hypothyroid patient had a normal LH pulse pattern. Additional measurement of melatonin in pooled sera every 30 min gave the well-documented diurnal profiles during day and night for both groups. Patients had significantly higher melatonin values at seven time points during the night. Peaks for LH, TSH, prolactin and cortisol were correlated with the sleep stages wake, rapid eye movement, 1 + 2 and 3 + 4. We concluded that corpus luteum insufficiency in female infertility cannot be explained by subclinical hypothyroidism and thus should not be treated with L-thyroxine for fertility reasons.

A multicenter, uncontrolled clinical investigation of the contraceptive efficacy, cycle control, and safety of a new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel over six treatment cycles.

The aim of the trial was to demonstrate the contraceptive efficacy of a new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel and to observe cycle control and safety. Data from 805 treated women resulted in 4400 treatment cycles. One pregnancy occurred while on the trial medication as a result of method failure, resulting in a Pearl index of 0.29. Cycle control was good, and cycle length as well as duration and intensity of withdrawal bleeding were not significantly changed during the trial. Intermenstrual bleeding usually occurred as spotting and decreased considerably during the treatment phase. Spotting alone was reported in 12.4% of cycles, breakthrough bleeding alone in 4.5% of cycles, and breakthrough bleeding and spotting together in 1.4% of treatment cycles. The rate of absence of withdrawal bleeding declined throughout the trial to 2.4% in cycle 6. There were no serious adverse events related to treatment, and most adverse events were those commonly observed in clinical trials with oral contraceptives. Headache, breast tension, and nausea were reported by 17.3%, 11.0%, and 7.7% of the women, respectively. There were no clinically relevant changes in laboratory parameters, blood pressure, or weight. In this trial, the new low dose oral contraceptive containing 20 micrograms ethinyl estradiol and 100 micrograms levonorgestrel was shown to be effective, safe, and well tolerated. Cycle control was found to be good and there was a low incidence of adverse events.

PIP: The contraceptive efficacy, cycle control, and safety of a new low-dose oral contraceptive (OC) containing 20 mcg of ethinyl estradiol and 100 mcg of levonorgestrel were investigated in a multicenter clinical study involving 805 German women (average age, 25.6 years) and a total of 4400 treatment cycles. There was one case of method failure, yielding a Pearl index of 0.29. A regular withdrawal bleed occurred in 95.5% of all treatment cycles. Cycle length and the duration and intensity of withdrawal bleeding were not significantly altered by use of the low-dose OC. Spotting alone occurred in 12.4% of treatment cycles and breakthrough bleeding alone was reported in 4.5%; both symptoms occurred in 1.4% of cycles. Headache, breast tension, and nausea were reported by 17.3%, 11.0%, and 7.7% of women, respectively. Only 8.4% of women discontinued OC use due to adverse events. Finally, there were no clinically relevant changes in laboratory parameters, blood pressure, or body weight. Overall, these findings suggest that substantial reductions in the estrogen and progestogen doses of OCs do not compromise contraceptive efficacy or cycle control.

Intermittent Cushing's disease in hirsute women.

Clinical symptoms of Cushing's syndrome were recognized in approximately 23 of 97 successive hirsute women attending the Endocrinological Department of the Women's Hospital. Endocrine and radiological examinations ultimately confirmed Cushing's syndrome caused by pituitary microadenomas (Cushing's disease) in only 2 women. In 17 of the remaining 21 patients suspected of having Cushing's disease hypercortisolism could not be diagnosed by classical endocrine tests. Thus further endocrinologial tests as corticotrophin releasing hormone (CRH)-tests (100 micrograms i.v.) and insulin tolerance tests were initiated including serum and stress-free salivary cortisol profiles during the day. Diurnal cortisol profiles showed higher values in the morning than during the night, but intermittent elevated cortisol concentrations could be detected. Finally, seven patients could be classified as suffering from a special form of pituitary ACTH-dependent hypercortisolism, named intermittent Cushing's disease (ICD). It is characterized by severe Cushingoid symptoms like marked central adiposity, purple striae, hirsutism and acne, intermittently increased cortisol concentrations, no cortisol response to hypoglycaemia, but preservation of some diurnal variation of serum or saliva cortisol. Three of these seven patients had diagnostic transsphenoidal neurosurgery and pituitary ACTH-producing microadenomas were removed in two women. Repeated determinations of the circadian rhythm of cortisol in saliva samples in combination with an overnight 1 mg dexamethasone suppression and an insulin stimulation test, are recommended to diagnose patients with suspicion on ICD even in an outpatient clinic.

Predictive parameters for ovarian response to hyperstimulation with exogenous gonadotropins after suppression of gonadotropin secretion of the pituitary using a long-acting GnRH agonist.

Individually adapted gonadotropin dosage is more successful than standardized schemes for ovarian stimulation prior to in vitro fertilization and embryo transfer. Unfortunately, differences in ovarian response can not be predicted reliably. In order to develop predictive parameters for ovarian response the data from 99 cycles in 69 patients were analysed retrospectively. Before initiating ovarian stimulation for in vitro fertilization, an untreated menstrual cycle was examined using a commonly used endocrinological screening protocol. The ovaries were then stimulated with exogenous gonadotropins after previous suppression of endogenous gonadotropin secretion using a long-acting GnRH-analogue. The predictive value of this endocrinological screening protocol for ovarian response was evaluated. Ovarian response was defined as the logarithmically transformed ratio of the serum estradiol concentration at ovulation induction, divided by the number of ampoules of exogenous gonadotropins administered. Comparison of the various hormone characteristics with ovarian response led to identification of two distinct groups of patients showing reduced ovarian response: those with elevated serum levels of FSH on the third cycle day (> 9 units/l, P < 0.0001), and those with elevated serum levels of estradiol on the third cycle day (> 190 pmol/l, P < 0.02). Patients with high serum levels of TSH in the TRH test responded poorly to ovarian stimulation (P < 0.05), but also showed significantly higher serum concentrations of FSH (P < 0.01). No parameter correlated positively with ovarian response.

[Disorders of thyroid function and sterility in the woman]. / Schilddrüsenfunktionsstörungen und Sterilität der Frau.

In 118 successive infertile women (aged 22-40 years, median 30 years) with longstanding infertility from our infertility clinic we performed an endocrinological (TRH-test, TT3, TT4, TBG, antibodies) as well as a morphological thyroid examination (sonography and 99mTc-scintigraphy. The same endocrinological investigations except TRH-test and a thyroid sonography was performed in the control group (50 fertile women, aged 24-39 years, median 33 years). Two patients were hyperthyroid and one patient had primary hypothyroidism. Antibodies against thyroglobulin (TgAK) and thyroid peroxidase (TPO) or microsomal antibodies (MAK) were found in 19 patients (19%). The incidence of biochemical immunological thyroiditis was not significantly different from the control group. But thyroid volume was significantly higher in patients (21 versus 15.6 ml, p < 0.03). Goitre (> 18 ml) was diagnosed in 52% (n = 57) of the patients, although 43 had normal TRH-test results with delta TSH 2.5-12.5 microU/ml. So-called subclinical (latent) hypothyroidism (delta TSH > 12.5 microU/ml) was found in 29 patients; 18 of these infertile women had no goitre. Iodine avidity (99mTc-uptake) increased significantly with the increase in thyroid volume, but showed a tendency to lower values with increasing delta TSH-values and higher iodine avidity in women with thyroid enlargement (n = 109). During follow-up of 12-24 months 10 women with goitre conceived spontaneously after initiation of iodine and/or L-thyroxine 100 micrograms treatment. These data support recent studies, that factors other than TSH cause thyroid enlargement.(ABSTRACT TRUNCATED AT 250 WORDS)

Gastrointestinal disease and oral contraception.

Oral contraceptive steroids play a major role in modern family planning. With the present tendency to decrease the doses of both estrogens and progestogens, any factor that reduces the bioavailability of the lower-dose preparations may have an impact on contraceptive protection. Although ethinyl estradiol, the most commonly used oral estrogen, is liable to an enterohepatic circulation as unchanged drug, the commonly used progestogens are not. At present, no convincing evidence exists in the human subject that disruption of the enterohepatic circulation by antibiotics or antacids does reduce contraceptive efficacy of the pill. Oral contraceptive steroids are mainly absorbed from the small bowel, and contraceptive efficacy depends on its absorptive capacity. Enhanced passage of gastrointestinal contents or impaired absorption may thus contribute to contraceptive failures in patients who have chronic inflammatory disease, diarrhea, ileostomy, or jejunoileal bypass.

PIP: THe recent trend toward decreased dosages of estrogen and progestogen in oral contraceptives (OCs) makes it especially important that attention be directed toward additional factors-- dietary factors, gastrointestinal disturbances or diseases, or drugs that interact with OCs--that may further reduce the bioavailability of steroids and thus compromise contraceptive protection. At present, there is no evidence that antibiotics interfere with OC steroids at the level of enterohepatic circulation; also unlikely is a clinically significant interaction between OCs and antacids. Unlike estrogens, progestogens do not undergo enterohepatic recirculation as unchanged drugs; presumably due to the lack of direct conjugation at the 17 position. Thus, no impact on contraceptive efficacy is produced by disruptions in progestogen metabolism. On the other hand, there is an ample body of research suggesting a link between OCs and chronic inflammatory bowel disease, especially Crohn's disease. The finding of reduced bioavailability of estrogen and progestogen in women who have undergone jejunoileostomy demonstrates that OCs are mainly absorbed in the small bowel and that contraceptive efficacy is related to its absorptive capacity. Overall, it is recommended that careful attention be given to OC acceptors with chronic inflammatory disease, non-colonic diarrhea, ileostomy, and jejunoileal bypass.

LH-RH agonist (buserelin): treatment of endometriosis. Clinical, laparoscopic, endocrine and metabolic evaluation.

To investigate the effects of the LH-RH agonist Buserelin [D-Ser (But)6 des-Gly10-LHRH ethylamide] on endometriosis, 64 patients were treated with 900 micrograms/d Buserelin intranasally over 6 months after histological verification of the disease. As shown by the follow-up operation at the end of treatment, 73% of cases showed regression of implants, whereas adhesions seemed to be unaffected. The uncorrected pregnancy rate of the 45 patients with a history of infertility was 40%, while the overall recurrence rate--confirmed by histological examination--was 9.4%. The endocrine parameters demonstrated a highly significant suppression of estradiol (E2) and a sharp decline of progesterone (Prog), indicating anovulatory cycles. Follicle-stimulating hormone (FSH) was unchanged, while luteinizing hormone (LH) and prolactin (Prl) decreased significantly. The androgenic parameters testosterone (T), dehydroepiandrosterone sulfate (DHEA-S), and sex-hormone-binding globulin (SHBG) revealed no relevant changes. Influence on bone metabolism could not be detected by measuring calcitonin and parathyroid hormone fragments (PTH-C and PTH-MM). Negative metabolic effects were absent in terms of hematology, clotting system, liver enzymes, renal parameters and lipid metabolism. Remarkable was a significant increase of high-density-lipoprotein cholesterol (HDL). Subjective complaints were mostly attributed to the therapy-induced hypoestrogenism. We consider Buserelin to be an effective drug in the treatment of endometriosis, with a low incidence of relevant side effects.

Complications and fetal outcome in diabetic pregnancy. Intensified conventional versus insulin pump therapy.

From 1978 to 1986 a total of 189 pregnant diabetic women gave birth at our hospital. In this randomized prospective study the influence of maternal diabetes treatment in normoglycemic patients, continuous subcutaneous insulin infusion (n = 48) versus intensified conventional treatment (n = 41), is evaluated. These two groups of patients are further compared to patients (n = 28) who underwent conventional diabetes treatment during pregnancy. It can be shown from our data that the rate of complications such as preeclampsia, intrauterine growth retardation, premature labor and premature delivery can be reduced by intensified conventional and insulin pump treatment as compared to conventionally treated patients with late onset of pregnancy care. As expected, in the groups of CSII and ICT patients no difference in the rate of pregnancy complications nor in fetal outcome could be demonstrated. Among CSII pregnancies 12/48 were complicated, in the ICT population the respective figure was 13/41 (CT: 20/28). The mean gestational age at the time of delivery ranged between 38 and 40 weeks, depending on the severity of maternal diabetes. CT patients were delivered earlier in all White classes. Fetal morbidity was nearly equal in CSII and ICT children, in CT patients it was greatly enhanced. Also the mortality (perinatal and neonatal) was considerably larger in CT patients (6/28), again, in the CSII and ICT population the mortality was nearly identical (2/48 and 3/41). We conclude, from our prospective information, that insulin pump therapy during pregnancy is indicated if intensified conventional treatment does not lead to normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrasound-controlled gonadotropin therapy of anovulatory infertility.

Real-time ultrasound scanning of follicular development was performed during 45 cycles of 15 patients receiving gonadotropin therapy for treatment of anovulatory infertility. The amount of gonadotropins administered was based exclusively on the results of the ultrasound examinations. Fourteen pregnancies were obtained, with 10 singletons, 2 sets of twins, and 1 set of triplets, resulting in a cumulative pregnancy rate of greater than 93%. Mild hyperstimulation occurred in two cases. Ultrasound alone can be used effectively to control gonadotropin therapy in the majority of cases.

[Sonographic diagnosis of ectopic interstitial pregnancy. Case report]. / Sonographische Diagnose einer ektopen interstitiellen Gravidität. Ein Fallbericht.

The authors present a case of an interstitial extrauterine pregnancy in the intramural portion of the left oviduct after preceding ipsilateral adnectomy. Sonographic diagnosis was confirmed by the site at operation.

[Effects of a chlormadinone acetate-containing ovulation inhibitor on androgenization pictures and liver and lipid metabolism in young females]. / Auswirkungen eines chlormadinonazetathaltigen Ovulationshemmers auf Androgenisierungs-erscheinungen sowie den Leber- und Fettstoffwechsel junger Frauen.

Twenty-two patients, average age 22 years, were treated for androgenization phenomena with a combination preparation containing ethinyl estradiol and chlormadinone acetate (Neo-Eunomin) over a period lasting 12 cycles. Under this therapy acne, seborrhea, alopecia and hirsutism improved. The hepatic metabolism parameters checked before and during the study (alkalic phosphatase, SGPT, gamma-GT and total bilirubin) showed no pathologic changes and decreased significantly toward the end of the treatment period. SGOT remained uninfluenced. The effects on the lipoproteins checked were favorable, as the atherogenic index (LDL/HDL) dropped from 2.2 prior to therapy to 1.7 in the twelfth cycle of the treatment period. The HDL fraction increased significantly in the very first cycle, while the LDL fraction remained almost constant. There was a significant increase in cholesterol and triglycerides. The serum androgen count (testosterone and DHEA-S) was significantly lowered. There was a clear decrease in testosterone in saliva.

[Clinical aspects of 7 pregnancies following in vitro fertilization and embryo transfer (IVF/ET)]. / Klinische Aspekte von sieben Schwangerschaften nach In-vitro-Fertilisation und Embryotransfer (IVF/ET).

Between September 1, 1983 and June 15, 1984 69 patients were treated by in-vitro fertilization as part of a clinical research project. The scientific questions were aimed at optimizing the principal methodological aspects of the new technique. One hundred and sixty-nine follicle punctures were performed under laparoscopic or ultrasonographic control. A total of 207 preovulatory oocytes were obtained, 57 of which were transferred to the uterus as cleaving embryos following in-vitro fertilization. Seven clinical pregnancies were diagnosed. Two resulted in spontaneous abortion in the fifth and sixth week of gestation, the remaining five as three single and two twin births. The infrastructure of reproduction medicine has been broadened successfully within a short time. Considering the results of current clinical and experimental research, the efficiency of the methods used is likely to be improved.

Hypothalamic site of progesterone action on gonadotropin release.

Tonic gonadotropin secretion was monitored at 20 min intervals for a total of 9 hours in 3 female volunteers during the mid-luteal phase of an ovulatory cycle. This control period was followed by repeated LH-RH stimulation (12 micrograms LH-RH as i.v. bolus once every hour for another 5 hours). During the control period spontaneous albeit low-frequent pulsatile secretion was observed for LH (a pulse occurring once every 3-8 hours) but not for FSH. While intermittent exogenous LH-RH stimulation was being performed at circhoral LH-RH pulse frequency pulsatile gonadotropin release was established at synchronous episodicity and systemic gonadotropin levels consecutively increased. These data provide indirect evidence that the pituitary gland is not rendered refractory to LH-RH by luteal progesterone secretion but readily responds to LH-RH stimuli even when these simulate a follicular phase LH-RH pulse frequency. Thus, it is concluded that spontaneous pulsatile LH release at low frequency during the luteal phase of the cycle reflects low frequent LH-RH discharges from the hypothalamus. Underlying mechanisms are discussed.

Frequency-varied versus unvaried pulsatile LH-RH substitution in hypothalamic amenorrhea.

In 26 patients with hypothalamic amenorrhea cyclic ovarian function was reestablished by pulsatile LH-RH substitution. Two LH-RH regimens were tested. In group A (n = 13) LH-RH pulses (12 micrograms i.v.) were administered by means of a portable mini-pump (Auto-Syringe) at the unvaried frequency of one pulse every 96 min throughout the follicular phase. In group B (n = 13) LH-RH pulse intervals of 4 h (for 2 consecutive days), 3 h (for 1 day) and 96 min (for the rest of the follicular phase) were selected for initiation of follicle growth. After ovulation pump-assisted pulsatile LH-RH substitution was either maintained at the 96-min rhythm or replaced by LH-RH nasal-spray (200 micrograms/sniff) applied once every 4 h until the onset of menstruation or detection of pregnancy. While in group A patients changes in the pattern of luteal LH-RH support (pump-assisted versus nasal-spray assisted) resulted in rapid luteolysis, such effects did not occur in group B patients. It is suggested that LH-RH pulse frequency at the initial stage of follicular development is of importance for the quality of follicular development and thus luteal function. Both LH-RH regimens resulted in pregnancies (six times singletons and once twins). In the meantime, all children have been born and are healthy.

[Pregnancy after treatment of ejaculate with alpha-chymotripsine because of failure to liquefy]. / Schwangerschaft nach Behandlung des Ejakulates mit alpha-Chymotrypsin wegen fehlender Liquefizierung.

Failure of the human ejaculate to liquefy can be the cause of infertility. We report one such case in which liquefaction of the coagulated ejaculate was effected by alpha-chymotrypsin in-vitro and led to pregnancy after homologous in semination.