Karen D. Bradshaw

Bio: Karen D. Bradshaw is an academic researcher from University of Texas Southwestern Medical Center. The author has contributed to research in topics: Pregnancy rate & Artificial insemination. The author has an hindex of 18, co-authored 31 publications receiving 1762 citations. Previous affiliations of Karen D. Bradshaw include Vanderbilt University & University of Texas Health Science Center at San Antonio.

Male pseudohermaphroditism caused by mutations of testicular 17β-hydroxysteroid dehydrogenase 3

Abstract: Defects in the conversion of androstenedione to testosterone in the fetal testes by the enzyme 17β–hydroxysteroid dehydrogenase (17β–HSD) give rise to genetic males with female external genitalia. We have used expression cloning to isolate cDNAs encoding a microsomal 17β–HSD type 3 isozyme that shares 23% sequence identity with other 1 7β–HSD enzymes, uses NADPH as a cofactor, and is expressed predominantly in the testes. The 17βHSD3 gene on chromosome 9q22 contains 11 exons. Four substitution and two splice junction mutations were identified in the 17βHSD3 genes of five unrelated male pseudohermaphrodites. The substitution mutations severely compromised the activity of the 17β–HSD type 3 isozyme.

An evaluation of the effect of gonadotropin-releasing hormone analogs and medroxyprogesterone acetate on uterine leiomyomata volume by magnetic resonance imaging: a prospective, randomized, double blind, placebo-controlled, crossover trial

Abstract: The purpose of this study was to prospectively compare the effectiveness of administering medroxyprogesterone acetate (MPA; 20 mg/day) in either the first (protocol A) or last (protocol B) 12-week period along with a 6-month course of the GnRH analog (GnRH-a; leuprolide acetate; 1 mg/day, sc) on uterine and leiomyomata volumes and hormone (estradiol, LH, and FSH) and serum lipid (total cholesterol, triglycerides, and high and low density lipoprotein) levels. Sixteen women were randomized into protocol A or B, received either MPA or placebo along with GnRH-a, respectively, and were then crossed over at 12 weeks to placebo or MPA, respectively, for the final 12-week interval of GnRH-a therapy. Total, myoma, and nonmyoma uterine volumes were determined by magnetic resonance imaging, and serum studies were performed at the beginning of the study and at 12 and 24 weeks. In both protocols, LH and estradiol levels declined by 80-90% (P < 0.03) and 55-72% (P < 0.02) of the baseline, respectively, at 12 weeks and remained at this level at 24 weeks. There were no significant changes in the other laboratory tests between protocols or longitudinally over time. Total uterine volume decreased to 73% of the baseline at 12 weeks in protocol B (P < 0.04), but did not change in protocol A. After crossover at 12 weeks, the total uterine volume of women in protocol A decreased to 74% of the baseline (P < 0.02) at 24 weeks. Between-protocol comparisons demonstrated a greater decline in total uterine volume in protocol B than A at 12 weeks, but after cross-over, MPA addition was associated with a significant increase in total uterine volume (protocol B) compared to a decrease in protocol A at 24 weeks (P < 0.005). In contrast, although myoma volume declined in both protocols, no significant changes in myoma volume were detected within or between groups over the treatment period. Nonmyoma volume changes in protocols A and B roughly paralleled total uterine volume changes, with MPA coadministration showing a correlation with a reversal in the GnRH-a-associated decrease in nonmyomatous tissue volume.(ABSTRACT TRUNCATED AT 400 WORDS)

Management of vulvovaginal atrophy-related sexual dysfunction in postmenopausal women: an up-to-date review.

Abstract: Objective Menopause and its transition represent significant risk factors for the development of vulvovaginal atrophy-related sexual dysfunction. The objective of this study was to review the hormonal and nonhormonal therapies available for postmenopausal women with vulvovaginal atrophy-related sexual dysfunction, focusing on practical recommendations through a literature review of the most relevant publications in this field. Methods This study is a literature review. Results Available vaginal estrogen preparations are conjugated equine estrogens, estradiol vaginal cream, a sustained-release intravaginal estradiol ring, or a low-dose estradiol tablet. Vaginal estrogen preparations with the lowest systemic absorption rate may be preferred in women with history of breast cancer and severe vaginal atrophy. Vaginal lubricants and moisturizers applied on a regular basis have an efficacy comparable with that of local estrogen therapy and should be offered to women wishing to avoid the use of vaginal estrogens. Conclusions Oral, transdermal, or vaginal estrogen preparations are the most effective treatment options for vulvovaginal atrophy-related sexual dysfunction. Selective estrogen receptor modulators such as lasofoxifene and ospemifene showed a positive impact on vaginal tissue in postmenopausal women. Vaginal dehydroepiandrostenedione, vaginal testosterone, and tissue selective estrogen complexes are also emerging as promising new therapies; however, further studies are warranted to confirm their efficacy and safety.

The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders.

Abstract: Steroidogenesis entails processes by which cholesterol is converted to biologically active steroid hormones. Whereas most endocrine texts discuss adrenal, ovarian, testicular, placental, and other steroidogenic processes in a gland-specific fashion, steroidogenesis is better understood as a single process that is repeated in each gland with cell-type-specific variations on a single theme. Thus, understanding steroidogenesis is rooted in an understanding of the biochemistry of the various steroidogenic enzymes and cofactors and the genes that encode them. The first and rate-limiting step in steroidogenesis is the conversion of cholesterol to pregnenolone by a single enzyme, P450scc (CYP11A1), but this enzymatically complex step is subject to multiple regulatory mechanisms, yielding finely tuned quantitative regulation. Qualitative regulation determining the type of steroid to be produced is mediated by many enzymes and cofactors. Steroidogenic enzymes fall into two groups: cytochrome P450 enzymes and hydroxysteroid dehydrogenases. A cytochrome P450 may be either type 1 (in mitochondria) or type 2 (in endoplasmic reticulum), and a hydroxysteroid dehydrogenase may belong to either the aldo-keto reductase or short-chain dehydrogenase/reductase families. The activities of these enzymes are modulated by posttranslational modifications and by cofactors, especially electron-donating redox partners. The elucidation of the precise roles of these various enzymes and cofactors has been greatly facilitated by identifying the genetic bases of rare disorders of steroidogenesis. Some enzymes not principally involved in steroidogenesis may also catalyze extraglandular steroidogenesis, modulating the phenotype expected to result from some mutations. Understanding steroidogenesis is of fundamental importance to understanding disorders of sexual differentiation, reproduction, fertility, hypertension, obesity, and physiological homeostasis.

The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature.

Abstract: We provide here a list of 221 P450 genes and 12 putative pseudogenes that have been characterized as of December 14, 1992. These genes have been described in 31 eukaryotes (including 11 mammalian and 3 plant species) and 11 prokaryotes. Of 36 gene families so far described, 12 families exist in all mammals examined to date. These 12 families comprise 22 mammalian subfamilies, of which 17 and 15 have been mapped in the human and mouse genome, respectively. To date, each subfamily appears to represent a cluster of tightly linked genes. This revision supersedes the previous updates [Nebert et al., DNA 6, 1–11, 1987; Nebert et al., DNA 8, 1–13, 1989; Nebert et al., DNA Cell Biol. 10, 1–14 (1991)] in which a nomenclature system, based on divergent evolution of the superfamily, has been described. For the gene and cDNA, we recommend that the italicized root symbol "CYP" for human ("Cyp" for mouse), representing "cytochrome P450," be followed by an Arabic number denoting the family, a letter designating...

Overview of Steroidogenic Enzymes in the Pathway from Cholesterol to Active Steroid Hormones

Abstract: Significant advances have taken place in our knowledge of the enzymes involved in steroid hormone biosynthesis since the last comprehensive review in 1988. Major developments include the cloning, identification, and characterization of multiple isoforms of 3β-hydroxysteroid dehydrogenase, which play a critical role in the biosynthesis of all steroid hormones and 17β-hydroxysteroid dehydrogenase where specific isoforms are essential for the final step in active steroid hormone biosynthesis. Advances have taken place in our understanding of the unique manner that determines tissue-specific expression of P450aromatase through the utilization of alternative promoters. In recent years, evidence has been obtained for the expression of steroidogenic enzymes in the nervous system and in cardiac tissue, indicating that these tissues may be involved in the biosynthesis of steroid hormones acting in an autocrine or paracrine manner. This review presents a detailed description of the enzymes involved in the biosynthe...

Molecular Biology of Steroid Hormone Synthesis

Abstract: Introduction STEROID hormones are familiar clinically and physiologically as regulators of physiological processes. Five groups of steroid hormones are generally recognized according to their physiological behavior: mineralocorticoids, which instruct the renal tubules to retain sodium; glucocorticoids, which are named for their carbohydratemobilizing properties but have many other effects as well; estrogens, which induce female secondary sexual characteristics; progestins, which are essential for reproduction; and androgens, which induce male secondary sexual characteristics. These classes of steroid hormones are structurally similar and arise from a common series of pathways. They are distinguished by their actions on one or more specific steroid hormone receptors. The hormone/receptor complexes function as tissue-specific transcriptional regulators of distinct domains of genes and, consequently, exert their broad array of physiological effects. (For reviews, see Refs. 1 and 2.) The pathways by which the...

Short-chain dehydrogenases/reductases (SDR).

Abstract: Short-chain dehydrogenases/reductases (SDR) constitute a large protein family. Presently, at least 57 characterized, highly different enzymes belong to this family and typically exhibit residue identities only at the 15-30% level, indicating early duplicatory origins and extensive divergence. In addition, another family of 22 enzymes with extended protein chains exhibits part-chain SDR relationships and represents enzymes of no less than three EC classes. Furthermore, subforms and species variants are known of both families. In the combined SDR superfamily, only one residue is strictly conserved and ascribed a crucial enzymatic function (Tyr 151 in the numbering system of human NAD(+)-linked prostaglandin dehydrogenase). Such a function for this Tyr residue in SDR enzymes in general is supported also by chemical modifications, site-directed mutagenesis, and an active site position in those tertiary structures that have been characterized. A lysine residue four residues downstream is also largely conserved. A model for catalysis is available on the basis of these two residues. Binding of the coenzyme, NAD(H) or NADP(H), is in the N-terminal part of the molecules, where a common GlyXXXGlyXGly pattern occurs. Two SDR enzymes established by X-ray crystallography show a one-domain subunit with seven to eight beta-strands. Conformational patterns are highly similar, except for variations in the C-terminal parts. Additional structures occur in the family with extended chains. Some of the SDR molecules are known under more than one name, and one of the enzymes has been shown to be susceptible to native, chemical modification, producing reduced Schiff base adducts with pyruvate and other metabolic keto derivatives. Most SDR enzymes are dimers and tetramers. In those analyzed, the area of major subunit contacts involves two long alpha-helices (alpha E, alpha F) in similar and apparently strong subunit interactions. Future possibilities include verification of the proposed reaction mechanism and tracing of additional relationships, perhaps also with other protein families. Short-chain dehydrogenases illustrate the value of comparisons and diversified research in generating unexpected discoveries.