Clinical, biochemical, and genetic findings in a large pedigree of male and female patients with 5 alpha-reductase 2 deficiency.

The present report describes a cluster of eight patients with male pseudohermaphroditism from a large pedigree with steroid 5 alpha-reductase 2 deficiency (5 alpha RD), who reside in Southern Lebanon. They were born with unambiguous female external genitalia and reared as girls until puberty, when masculinization occurred, followed by a change of gender role. Semen analysis and testicular histology revealed maturation arrest of spermatogenesis, with low sperm count and motility. Determination of urinary 5 alpha- and 5 beta-reduced adrenal steroids enabled us to diagnose the disease in a male patient with the full-blown clinical syndrome, in another male patient who had undergone bilateral orchidectomy, and in three female individuals with the biochemical derangement. The female patients were unique in this family with respect to their low degree of virilization, but had normal menstrual cycles. Molecular genetic studies were performed on DNA extracted from peripheral leukocytes and from cultured genital skin fibroblasts. The coding sequence of the 5 alpha R2 gene (SRD5A2) was studied by exon-specific PCR, single strand conformation polymorphism, and direct sequencing. A homozygous point mutation was identified in exon 1, leading to a thymidine for adenine substitution, predicting amino acid substitution of leucine for glutamine at position 55.

Comparison of technetium-99m aminoalkyl diaminodithiol (DADT) analogs as potential brain blood flow imaging agents.

N-ethyl piperidinyl diaminodithiol (NEP-DADT), complexed with 99mTc has been developed as an agent for the measurement of brain blood flow using SPECT. Studies in patients have shown that 99mTc NEP-DADT enters rapidly into the brain, but also clears rapidly (t1/2 = 17 min). In this study nine new aminoalkyl DADT derivatives were synthesized, labeled with 99mTc and tested in mice with the aim of developing an agent with increased retention in the brain. In addition, relationships between chemical properties of the derivatives and their in vivo localization were investigated. The results were as follows: (a) the R-group and its isomeric configuration has a profound influence on the biodistribution; (b) 99mTc aminoalkyl DADT derivatives with apparent pKa values of greater than 6.9 show poor brain uptake (less than 0.40% dose at 5 min); (c) lengthening of the chain between the DADT moiety and the amino-R group from ethyl to hexyl generally increases the apparent pKa and consequently lowers brain uptake; (d) a correlation (r = 0.71) exists between initial brain uptake and the octanol-buffer partition coefficient; (e) 99mTc-4'-methyl NEP-DADT has the highest partition coefficient, relatively high uptake, and longest retention in the mouse brain. This complex has characteristics suited for brain blood flow measurements.

Design, preparation, and biodistribution of a technetium-99m triaminedithiol complex to assess regional cerebral blood flow.

A new ligand (N-piperidinylethyl-DADT, 5) has been prepared which forms two complexes with 99mTc when stannous chloride is used as a reducing agent for [99mTc] pertechnetate. Biodistribution studies of one of the complexes in mice showed that 2.2% of the injected dose of the tracer was in the brain at 5 min postintravenous injection with 0.53% of the dose remaining in the brain at 30 min postinjection. Brain-to-blood ratios at these times were 5.3 and 3.0, respectively. Biodistribution studies of the other complex showed similar behavior with a slightly lower initial uptake by and faster clearance from the brain. Imaging studies of the more promising of the two complexes were conducted in a monkey and a baboon. In both cases, rapid uptake of the tracer in the brain was observed and clear brain images were obtained. Time-activity curves showed peak uptake in the brain at approximately 5 to 7 min postintravenous injection followed by a plateau of about 11 min. The half-lives for clearance of the tracer from the brains of the monkey and baboon were found to be 63 and 58 min, respectively. These results suggest that this tracer may be useful for brain imaging in humans.

Ambiguous genitalia due to partial activity of cytochromes P450c17 and P450c21.

We describe a patient with male pseudohermaphrodism who has normal basal serum concentrations of cortisol and high basal levels of progesterone and 17 hydroxyprogesterone. Serum concentrations of androstendione, dehydroepiandrosterone sulfate and testosterone were low. On adequate human chorionic gonadotropin (HCG) stimulation, no rise in serum androstendione, dehydroepiandrosterone sulfate or testosterone concentrations was observed. After ACTH stimulation there was an excessive rise in progesterone and 17 hydroxyprogesterone with no rise in androstendione, dehydroepiandrosterone sulfate, testosterone, deoxycorticosterone or cortisol. These clinical and laboratory data suggest that the patient has a combined defect in both cytochromes P450c17 and P450c21. The genes coding for these cytochromes are on different chromosomes, 10 and 6, respectively. Unlike isolated 21 hydroxylase deficiency where all identical HLA siblings suffer from the disease, HLA typing of the patient's family revealed a healthy brother with identical HLA. This suggests that the gene coding for P450c21 on chromosome 6 is not affected and that the lesion might be on a common enzyme which donates an electron to both cytochromes, most probably a flavoprotein.

A review of 35 endometrial ablations using the Nd:YAG laser for recurrent menometrorrhagia.

Endometrial ablation with the Nd:YAG laser can be used to treat recurrent dysfunctional uterine bleeding. Two series of patients were studied. All suffered for at least 1 year with recurrent menometrorrhagia that was unresponsive to other treatments such as hormonal therapy or removal of polyps or fibroids. In the first series, 75 patients presenting with menometrorrhagia were considered for endometrial ablation using Nd:YAG laser, and 23 met conservative requirements. In the second series, 12 of the 25 patients considered met the conservative requirements. The patients in series I received danazol for 30 days before and 30 days after the procedure; patients in series II received leuprolide acetate. All patients were followed for at least 1 year after treatment was discontinued. Of the 35 patients in both series, 21 (60%) were found to have complete cessation of menstruation. Eleven (31.43%) resumed menstruating but at acceptable levels. Three patients (8.57%) had unsatisfactory results, one who later had a repeat ablation and two who had hysterectomies. Thus, 32 of 35 patients were successfully treated without further intervention after laser ablation. Nd:YAG endometrial ablation is efficacious and cost-effective for recurrent menometrorrhagia in selected patients. The additional benefit of this procedure is the avoidance of hysterectomies and postsurgical complications as well as the psychological consequences of a hysterectomy.

Pulmonary accumulation of neutral diamine dithiol complexes of technetium-99m.

Twenty-two neutral, lipid-soluble 99mTc complexes have been synthesized from diamine dithiol (DADT) ligands which vary in alkyl substitution pattern on nitrogen and carbon. The logarithm of the partition coefficients (log PC), as well as the capacity factor k', of the purified complexes increased linearly with molecular weight. The biodistribution of these complexes was determined in normal mice, and several of the complexes selectively accumulated in the lungs as compared to the liver or other organs. Pulmonary accumulation varied greatly with subtle changes in structure, and a 30-fold range of lung uptake (1-31% of the injected dose/organ) was observed for isomeric technetium complexes which have identical molecular weights and similar log PC. Further, a parabolic relationship between lung uptake and log PC was observed for a subset of the complexes which are derived from a homologous series of tetramethyl-DADT ligands. Neutral and lipophilic radiopharmaceuticals labeled with technetium can therefore be developed which exhibit structurally specific uptake in the lung.

Tibial arteriovenous fistula: successful use for limb salvage.

Embolization of atheromatous material from abdominal aortic aneurysms to the distal arterial circuit is a well-recognized clinical entity causing the "blue toe syndrome." A case is presented in which this phenomenon resulted in obliteration of the pedal arch and thrombosis of the tibial arteries. As a result, forefoot gangrene, severe leg ischemia and anterior and posterior compartment syndromes occurred. Salvage of the extremity required an extraordinary approach with the construction of an arteriovenous fistula between the posterior tibial vessels. The literature on the use of therapeutic and adjunctive arteriovenous fistulas and their physiology is discussed.

Comparison of 99Tcm complexes (NEP-DADT, ME-NEP-DADT and HMPAO) with 123IAMP for brain SPECT imaging in dogs.

Several new lipophilic 99Tcm complexes have recently been described as alternatives to N-isopropyl (123I) iodoamphetamine (123IAMP) for measurement of regional cerebral blood flow (RCBF). In this study we have compared brain uptake and blood clearance of 99Tcm-N-ethylpiperidine-diamino dithiol (99Tcm-NEP DADT), its 4-methylated derivative (99Tcm-Me-NEP-DADT) and 99Tcm-hexamethyl-propylene-amine-oxime (99Tcm-HMPAO) with that of 123IAMP in two dogs. Single photon emission tomography (SPECT) was employed to measure brain accumulation and retention of the four radiopharmaceuticals. Cerebral uptake of the 99Tcm complexes (0.8-1.1%) was lower than that of 123IAMP (1.6% of the injected dose). There was considerable extracerebral activity in the dog's head, especially in the olfactory and snout regions. Because of slow blood clearance 99Tcm-HMPAO showed high uptake in these regions. Brain uptake of 99Tcm-HMPAO reached a plateau 5 to 10 min after intravenous injection and remained constant for the entire study period (1 h). 99Tcm-NEP-DADT, on the other hand, showed significant clearance from the brain after reaching maximal uptake at 10 to 15 min after injection. However, brain imaging with these agents was possible during the first 20 min. The mechanism of brain uptake, as well as the relationship between brain uptake and RCBF need to be evaluated for each of the four radiopharmaceuticals.

Myoma coagulation (myolysis).

Myoma coagulation or myolysis by way of the laparoscope or hysteroscope is a valuable addition to the armamentarium of treatments for a problem that remains pervasive among women: uterine leiomyomata. Likewise, surgical techniques include the use of the Nd:YAG laser as well as the bipolar needle. The addition of myolysis to earlier uterine-sparing endometrial ablation or resection markedly improves the success rate of these minimally invasive alternatives to hysterectomy. Myoma coagulation when combined with endometrial ablation among women with symptomatic fibroids and bleeding also reduces all subsequent surgery rates compared with endometrial ablation alone. The continued goal for therapy of fibroids and debilitating menorrhagia must take into consideration the needs and desires of the patient in terms of her lifestyle (e.g., days lost from work because of symptoms) and childbearing plans. Hysterectomy continues to be costly in billions of dollars spent annually as well as in the more fundamental terms of morbidity and mortality when compared with the less invasive alternatives of myomectomy, ablation, and myolysis.

Nd:YAG laser laparoscopic coagulation of symptomatic myomas.

The Nd:YAG laser dispersion effect, 2-5 mm in diameter, is utilized in a new laparoscopic procedure to coagulate and reduce symptomatic serosal and intramural myomas of moderate size (less than or equal to 10 cm). Depot leuprolide pretreatment for 2-6 months resulted in 40-60% shrinkage. Seventy-five patients 35-50 years old with symptomatic myomas, pain and pressure then underwent Nd:YAG laser coagulation for thorough devascularization of uterine myomas. Postoperative transvaginal ultrasound one, three and six months later showed the myomas reduced an average of 50-70% beyond the effect attributable to leuprolide. In two groups of patients whose myomas measured 5-10 cm and 3-5 cm after leuprolide pretreatment, laser coagulation subsequently reduced the myomas an average of 50%. In patients with postleuprolide myomas of 2-3 cm, virtually no myomas were identified postoperatively. The patients were followed up to 14 months. This laparoscopic procedure can be used in patients approaching menopause who wish to avoid abdominal myomectomy or hysterectomy.

Laparoscopic leiomyoma coagulation-myolysis.

Leiomyomas, the most common solid pelvic tumors, occur in 25% to 30% of women during their reproductive years. Approximately 20% to 50% of these women experience symptoms that require treatment, with the most common complaints being menorrhagia, metrorrhagia, pelvic pressure, and the appreciation of a pelvic mass.

Combining myoma coagulation with endometrial ablation/resection reduces subsequent surgery rates.

BACKGROUND: This study compares results of endometrial ablation alone and in combination with myoma coagulation. Subsequent surgery rates were 38% for ablation alone and 12% for combined therapy. OBJECTIVE: The purpose of this study was to compare hysterectomy rates following various surgical procedures to treat profuse uterine bleeding as well as myomatous uteri. STUDY DESIGN: This is a descriptive study of women who underwent endometrial ablation alone, endometrial ablation with myoma coagulation, or endometrial resection with myoma coagulation to treat profuse uterine bleeding as well as myomatous uterus. From 1986 to 1995, the author performed 52 endometrial ablation procedures; 88 myoma coagulation and endometrial ablation procedures; and 28 myoma coagulations with resection of submucous myomas in patients who were subsequently available for follow-up. Patients were followed up for up to ten years. RESULTS: Of the patients undergoing ablation alone, 20 (38%) of 52 required a second surgery for continued symptoms during a mean follow-up of 47 months. Five of these patients (9.6%) underwent hysterectomy. Of the patients who underwent endometrial ablation plus myoma coagulation (myolysis), 11 (12.5%) of 88 required a repeat surgical procedure during a mean follow-up of 25 months. Five of these patients (5.7%) underwent hysterectomy. Volumetric measurements revealed an average reduction in fibroid volume of 54.5% in this patient group following treatment with a gonadotropin-releasing hormone (GnRH) agonist and combined myoma coagulation and endometrial ablation surgery. Of the 28 patients who underwent myoma coagulation plus resection, five (18%) required a repeat procedure. Of these five, one (4%) required hysterectomy. Fibroid volume in this group was reduced by a mean of 72.6% following administration of a GnRH agonist and combined laparoscopic and hysteroscopic surgery as described. The rate of reoperation was significantly lower among patients receiving endometrial ablation with myoma lysis with or without resection compared with those undergoing endometrial ablation alone (P<0.01). CONCLUSIONS: Myoma coagulation (myolysis), when combined with endometrial ablation among women with symptomatic fibroids and bleeding, reduces all subsequent surgery rates compared with endometrial ablation alone. Myolysis with endometrial resection also results in a reduced need for hysterectomy.

Laparoscopic-assisted vaginal myomectomy: a case report and literature review.

The purpose of this article is to present a case of laparoscopic myomectomy (LM) that led to the identification of a new minimally invasive technique [laparoscopic-assisted vaginal myomectomy (LAVM)] for removing multiple transmural uterine myomas and facilitating uterine suturing. In addition, we reviewed the literature to (1) describe the history leading up to LAVM, (2) relate the benefits of this technique to other more widely performed myomectomy procedures [LM and laparoscopic-assisted myomectomy (LAM)], and (3) identify criteria for LM and LAVM.

D&C results improved by hysteroscopy.

A review of the records of 287 women examined hysteroscopically prior to dilatation and curettage (D&C) and a review of the international literature on hysteroscopy indicate that there is significant evidence to support the routine use of hysteroscopy as an adjunct to D&C.

Comparison of carbon dioxide with continuous-flow technique for office hysteroscopy.

STUDY OBJECTIVES: To determine the effectiveness of lactated D5W-lactated Ringer's solution as the distention medium for office hysteroscopy, and to compare it with carbon dioxide (CO2) DESIGN: Observational, comparative study. SETTING: Private practice. PATIENTS: 50 women with fibroids or recurrent bleeding. INTERVENTIONS: Hysteroscopies with CO2 and with dextrose 5% D5W-lactated Ringer's solution. MEASUREMENTS AND MAIN RESULTS: Visualization and distention were adequate with both CO2 and fluid in women with no uterine pathology and those with polyps. In 24 women with submucous leiomyomas CO2 distention was relatively inadequate due to bubbling, bleeding, and inability to determine intracavitary penetration. CONCLUSION: Although CO2 hysteroscopy is a valuable assessment procedure, significant intrauterine pathology may be missed. Instilling lactated D5W-lactated Ringer's solution through small-diameter continuous-flow instruments makes fluid office hysteroscopy practical and desirable for precise diagnosis.