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Literature review
Adolesc Pediatr Gynecol (1988) 1:207-209
Adolescent and Pediatric Gynecology © 1988 Springer-Verlag New York Inc.
Literature Reviews Pediatric Endocrinology
Reproductive Endocrinology
Changes in Growth and Serum Growth Hormone and Plasma Somatomedin-C Levels During Suppression of Gonadal Sex Steroid Secretion in Girls with Central Precocious Puberty. Mansfield MJ, Rudlin CR, Crigler IF, Jr., et al. J Clin Endocrinol Metabol 1988; 66:3. Reviewed by: Steven D . Chernausek, M.D., Department of Pediatrics, University of Cincinnati, Children's Hospital Re search Foundation, Cincinnati,OH.
Immunocytochemistry of the Estrogen Receptor in Spontaneous Endometriosis in Rhesus Macaques. Sternfeld M, West N, Brenner R . Fertil Steril 1988; 49:342. (Reproduced with permission of the publisher, The American Fertility Society.) Reviewed by: Joseph S. Sanfilippo, M.D., Associate Professor, Department of Obstetrics and Gynecology, University of Louisville School of Medicine , Louisville , KY .
Spontaneous growth hormone secretion and plasma somatomedin-C (insulin-like growth factor-I ) concentration s were quantitated in 10 young girls with central precocious puberty. Growth velocity and plasma somatomedin levels were increased for age and growth hormone concentration correlated with growth velocity before treatment. During therapy with an LHRH analog, growth velocity declined into the normal range accompanied by a more than 50% fall in spontaneous nocturnal growth hormone secretion measured over a 4-hour period. Plasma level s of somatomedin-C fell similarly. Clinical Correlation. The LHRH analog used here has been shown to halt centrally mediated precocious puberty by attenuating gonadotrophin secretion . From a clinical standpoint, it may be the best treatment available for central precocious puberty . Careful study of patients generates additional information and insight into other areas of human biology . Here we find that LHRH analog therapy induces a fall in the secretion of growth hormone . The circulating concentrations of somatomedin-C (the putative mediator of growth hormone 's growth-promoting effects) decline in tum. Relationships between growth hormone secretion and puberty have been shown before, but seldom as dramatically as here where puberty was "switched off" with the therapy. These data suggest that increases in growth hormone secretion may be partly responsible for producing the pubertal growth spurt. This likely occurs as a result of the effect s of the sex steroids upon the pituitary . The sex steroids also appear to act directly on the skeleton to stimulate skeletal growth in concert with growth hormone.
Endometriosis in the adolescent female remains a challenging subject for the clinician. Exactly how does it occur ? Speculation ranges from Sampson's theory of endometrial reflux to Meyer's theory of totipoten tial cells that become active after puberty, on to considerations of lymphatic and hematogenous spread. In an adolescent, endometriosis may present as punctate hemorrhages , frequently occurring along the uterosacral ligaments . The issue facing the clinician is how aggressive treatment should be. Are oral contraceptives , danazol , or perhaps laser treatment adequate, or is no treatment preferable? Will the disease progress? These are questions without obvious clear-cut answers. Sternfeld et al. have helped us to further understand the mystery of endometriosis. Their information will assist the clinician in treating this disease in adolescents as well as adult populations. In their study , immunocytochemical , biochemical, and histological analysis of endometriotic lesions, as well as uterine endometrium, were evaluated using a Rhesu s macaque animal model. Several distinctions were noted between the two groups . In endometriotic lesions , neither the percentages of estrogen receptor positive (ER +) cells nor the total ER content changed significantly during the menstrual cycle. Estrogen receptor staining in both stromal and epithelial cells increased and decreased synchronously during the menstrual cycle in eutopic endometria. This synchrony was lacking in endometriotic lesions . Furthermore, in the endometriotic lesions , the percentage of ER + cells was low in the stroma and highly variable in the epithelium throughout the cycle . Taken together, the data indicate a defect in the hormonal regulation of ER in endometriotic lesions of macaque monkeys. The state of the art for ER assessment now includes monoclonal
208
Literature Reviews
antiestrophilins as immunocytochemical reagents to analyze and localize ER in the reproductive tract. Clinical Correlation. As part of the continuing effort to bridge the gap between adolescent gynecology and molecular biology, this study is a step in the right direction . The information regarding "degree of positivity of ER" may be a useful link in the further understanding of the pathophysiology of endometriosis. Researchers started with basic information initially supporting a cytoplasmic ER that would bind to the estrogen steroid and translocate to the nucleus . Current thinking suggests that estrogen receptors are located primarily, perhaps exclusively, in the nucleus. Once steroid and receptor link up, there is binding to DNA with attachment at the hormone regulatory element of the steroid-sensitive gene. Recent information identifies structures such as "zinc fingers" which are the actual linkage points between the steroid-receptor and DNA. This complex activates DNA and ultimately causes transcription of mRNA. The mRNA translocates to the ribosomes and becomes responsible for protein synthesis. If we understand the molecular mechanism of action, perhaps this information can help clinicians choose the appropriate treatment. Specifically, laser ablation or coagulation in the adolescent may be the most feasible modus operandi. Though this sounds simplified, needless to say, more research is necessary. The authors do leave us with one interesting thought: The recurrence of endometriosis after medical therapy is likely to be related to the variability that this tissue demonstrates to endocrine influences, but may also be related to the stage of the disease and degree of lesion differentiation. I am not sure if the researchers have made significant progress yet for the clinician, but certainly they are well on the way.
equate sexual histories or give appropriate disease prevention advise. Only one-third of respondents admitted that they took sexual histories during a new patient visit. Although the authors did not include gynecologists or pediatricians in their sample, it is likely that sexual histories and counseling techniques by gynecologists, and in particular pediatricians, are also inadequate regarding HIV infection . Clinical Correlation. Because prevention is currently the key to control of HIV infection, it is imperative for all clinicians who care for sexually active patients to take an adequate sexual history by questionnaire and/or interview in order to assess the need for intervention. Such interviews should include questions on sexual practices, number and sex(es) of sexual partners, history of sexually transmitted diseases, especially hepatitis B, drug use by self or partner stressing I. V. drug practices, and condom use . Patients who by history are "low risk" for HIV acquisition should be encouraged to continue their "safer" sexual practices , to choose partner(s) carefully , and to use condoms . Client'> in a high-risk situation should be counseled regarding the behaviors that place them at risk for HIV infection, and encouraged to engage in low-risk behaviors, including condom use. In addition , the positive and negative arguments for possible HIV antibody screening can be discussed with such high-risk patients . Screening for common sexually transmitted diseases (STDs) should be included during pelvic examinations and women with positive results should be counseled that HIV is acquired sexually like other STDs.
Molecular Biology
The Sexual History-Taking and Counseling Practices of Primary Care Physicians. Lewis CE, Free man HE. West J Med 1987; 47-165-167. Reviewed by: Mary-Ann Shafer, M.D., Division of Adolescent Medicine Department of Pediatrics, University of California, San Francisco, CA .
Isolation of an Abundantly Expressed Sequence from the Human X Chromosome by Differential Screening. M.V. Wiles, C.M. Alexander, P.N. Goodfellow. Somatic Cell and Molecular Genetics 1988; 14(1):31-39. Reviewed by: Leo Plouffe, Jr., M .D ., C .M., Medical College of Georgia, School of Medicine, Department of Obstetrics and Gynecology, Reproductive Endocrinology, and Genetics Section, Augusta, GA
Authors Lewis and Freeman questioned a variety of practicing physicians (internists, family/general practitioners) throughout the state of California regarding their practices of taking sexual histories. Though California is recognized as a leader in both the prevalence of HIV infections as well as in the development of strategies for its prevention, the authors were able to show that even California physicians rarely take ad-
This study is important in as much as it may hold the key to a new understanding of ovarian development and function. However, the important potential implications of the study may be lost in the highly technical and thorough presentation of this paper, especially to readers uninitiated to the source journal. The authors are indeed modest in their discussion of the putative role for the sequence they have isolated.
Adolescent Medicine
Literature Reviews
This well-established and respected group has developed a cDNA library (i.e., an extremely large collection of expressed DNA sequences) from a line of cells that contain mouse-human DNA hybrid. This means that individual somatic cells in culture were originally derived from mice cells containing native mouse DNA only. Through special techniques, sequences of human DNA have been integrated into the mouse DNA, thus giving rise to what is known as a "mouse-human hybrid cell line." This is a relatively common technique. In this particular study, the only human DNA sequence that was integrated into mouse DNA was a translocation between regions of chromosomes 6 and X [t(X;6)(qter-q13;p21-qter)]. One of the results of these molecular manipulations was to isolate a DNA sequence that corresponds to a portion of the q 13 to the q22 region of the human X chromosome, most probably Xq13- Xq13.3 or Xq21.3-Xq22; this sequence is named SCRIO. Next in order was to develop a probe (a sequence of complementary DNA that will pair with constitutive DNA) from a fragment of this full sequence. The final result is a fragment made up of about 1,000 bases (lKb) known as SCAR. Computerized comparison of this sequence with previously described ones shows it to be a novel sequence. The authors then go on to detect the presence of this specific region in various species by DNA analysis, using Southern blot techniques and its expression in the form of RNA production, by Northern blot analysis. They demonstrate the presence of sequences corresponding to SCAR in primates, rodents, avians, and even in as primitive a species as Xenopus (a small African frog used extensively in research). The SCAR sequence appears to encode for a protein of 27.5 kd. The role of this protein will now be the focus of work for these investigators. It is now well established that a fair number of specific DNA sequences are well preserved throughout the phylogenetic scale. Subsets of these sequences are thought to play a critical role in development and also in the pathogenesis of malignancies, as a manifestation of disordered developmental processes. These sequences belong to two large groups: the proto-oncogenes (named for the potential to cause malignancies) and homeobox genes. The reader is referred to recent reviews on the subject. 1,2 At least three protooncogenes have already been mapped on the X chromosome (ARAFljXp13-pll; PKS2jXpll.4; MCF2;Xq27). The finding of a new sequence, highly preserved from primitive to advanced species, raises the exciting prospect of a new gene with a critical role
209
in development. This role would not necessarily be related to reproductive processes or ovarian development but must clearly be explored. In addition, its absence in individuals with partial or total deletions of this region of the X chromosome could correlate with specific phenotypic anomalies, Secondly, the sequence described is located on the long arm of the X chromosome, either at Xq13-Xq13.3 or Xq21.3-Xq22, if the authors' assumption is correct. This corresponds to a portion of X thought by many to be important for ovarian function. 3 Recent reports have ascribed the "Ovarian Determining Gene" to Xq26-q27,4,5 This does not rule out the potential for other regions of X to be significant, perhaps in a different fashion. One region may be critical for morphological arrangement and another is preoccupied with function following normal development. The sequence described in this paper may be such a candidate, especially when one considers its potential role in development, as outlined in the preceding paragraph. Clinical Correlation. This paper presents a newly isolated sequence located on the long arm of the X chromosome. The sequence can be mapped with a probe (SCAR - lKb) and is preserved in the phylogenetic scale. The characteristics ascribed to this sequence make it a good candidate for a critical role in development. Further work in this area may provide a better understanding of the phenotypic manifestations of individuals bearing deletions of the long arm of the X chromosome. Eventually, this might be one of the critical DNA probes used to scan patients with 46,XX ovarian failure for molecular deletions.
References 1. Slamon DJ: Proto-oncogenes and human cancers (editorial). N Engl J Med 1987; 317:955 2. Gehring WJ: Homeo boxes in the study of development. Science 1987; 236: 1245 3. Skibsted L, Westh H, Niebuhr E: X long-arm deletions: A review of non-mosaic cases studied with banding techniques. Hum Genetics 1984; 67:1 4. Kraus Clvl, Turskoy RN, Atkins L, et al: Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987; 317:125 5. Federman DD: Mapping the X-chromosome: Mining its p's and q's (editorial). N Engl J Med 1987; 317:161
Adolescent and Pediatric Gynecology © 1988 Springer-Verlag New York Inc.
Literature Reviews Pediatric Endocrinology
Reproductive Endocrinology
Changes in Growth and Serum Growth Hormone and Plasma Somatomedin-C Levels During Suppression of Gonadal Sex Steroid Secretion in Girls with Central Precocious Puberty. Mansfield MJ, Rudlin CR, Crigler IF, Jr., et al. J Clin Endocrinol Metabol 1988; 66:3. Reviewed by: Steven D . Chernausek, M.D., Department of Pediatrics, University of Cincinnati, Children's Hospital Re search Foundation, Cincinnati,OH.
Immunocytochemistry of the Estrogen Receptor in Spontaneous Endometriosis in Rhesus Macaques. Sternfeld M, West N, Brenner R . Fertil Steril 1988; 49:342. (Reproduced with permission of the publisher, The American Fertility Society.) Reviewed by: Joseph S. Sanfilippo, M.D., Associate Professor, Department of Obstetrics and Gynecology, University of Louisville School of Medicine , Louisville , KY .
Spontaneous growth hormone secretion and plasma somatomedin-C (insulin-like growth factor-I ) concentration s were quantitated in 10 young girls with central precocious puberty. Growth velocity and plasma somatomedin levels were increased for age and growth hormone concentration correlated with growth velocity before treatment. During therapy with an LHRH analog, growth velocity declined into the normal range accompanied by a more than 50% fall in spontaneous nocturnal growth hormone secretion measured over a 4-hour period. Plasma level s of somatomedin-C fell similarly. Clinical Correlation. The LHRH analog used here has been shown to halt centrally mediated precocious puberty by attenuating gonadotrophin secretion . From a clinical standpoint, it may be the best treatment available for central precocious puberty . Careful study of patients generates additional information and insight into other areas of human biology . Here we find that LHRH analog therapy induces a fall in the secretion of growth hormone . The circulating concentrations of somatomedin-C (the putative mediator of growth hormone 's growth-promoting effects) decline in tum. Relationships between growth hormone secretion and puberty have been shown before, but seldom as dramatically as here where puberty was "switched off" with the therapy. These data suggest that increases in growth hormone secretion may be partly responsible for producing the pubertal growth spurt. This likely occurs as a result of the effect s of the sex steroids upon the pituitary . The sex steroids also appear to act directly on the skeleton to stimulate skeletal growth in concert with growth hormone.
Endometriosis in the adolescent female remains a challenging subject for the clinician. Exactly how does it occur ? Speculation ranges from Sampson's theory of endometrial reflux to Meyer's theory of totipoten tial cells that become active after puberty, on to considerations of lymphatic and hematogenous spread. In an adolescent, endometriosis may present as punctate hemorrhages , frequently occurring along the uterosacral ligaments . The issue facing the clinician is how aggressive treatment should be. Are oral contraceptives , danazol , or perhaps laser treatment adequate, or is no treatment preferable? Will the disease progress? These are questions without obvious clear-cut answers. Sternfeld et al. have helped us to further understand the mystery of endometriosis. Their information will assist the clinician in treating this disease in adolescents as well as adult populations. In their study , immunocytochemical , biochemical, and histological analysis of endometriotic lesions, as well as uterine endometrium, were evaluated using a Rhesu s macaque animal model. Several distinctions were noted between the two groups . In endometriotic lesions , neither the percentages of estrogen receptor positive (ER +) cells nor the total ER content changed significantly during the menstrual cycle. Estrogen receptor staining in both stromal and epithelial cells increased and decreased synchronously during the menstrual cycle in eutopic endometria. This synchrony was lacking in endometriotic lesions . Furthermore, in the endometriotic lesions , the percentage of ER + cells was low in the stroma and highly variable in the epithelium throughout the cycle . Taken together, the data indicate a defect in the hormonal regulation of ER in endometriotic lesions of macaque monkeys. The state of the art for ER assessment now includes monoclonal
208
Literature Reviews
antiestrophilins as immunocytochemical reagents to analyze and localize ER in the reproductive tract. Clinical Correlation. As part of the continuing effort to bridge the gap between adolescent gynecology and molecular biology, this study is a step in the right direction . The information regarding "degree of positivity of ER" may be a useful link in the further understanding of the pathophysiology of endometriosis. Researchers started with basic information initially supporting a cytoplasmic ER that would bind to the estrogen steroid and translocate to the nucleus . Current thinking suggests that estrogen receptors are located primarily, perhaps exclusively, in the nucleus. Once steroid and receptor link up, there is binding to DNA with attachment at the hormone regulatory element of the steroid-sensitive gene. Recent information identifies structures such as "zinc fingers" which are the actual linkage points between the steroid-receptor and DNA. This complex activates DNA and ultimately causes transcription of mRNA. The mRNA translocates to the ribosomes and becomes responsible for protein synthesis. If we understand the molecular mechanism of action, perhaps this information can help clinicians choose the appropriate treatment. Specifically, laser ablation or coagulation in the adolescent may be the most feasible modus operandi. Though this sounds simplified, needless to say, more research is necessary. The authors do leave us with one interesting thought: The recurrence of endometriosis after medical therapy is likely to be related to the variability that this tissue demonstrates to endocrine influences, but may also be related to the stage of the disease and degree of lesion differentiation. I am not sure if the researchers have made significant progress yet for the clinician, but certainly they are well on the way.
equate sexual histories or give appropriate disease prevention advise. Only one-third of respondents admitted that they took sexual histories during a new patient visit. Although the authors did not include gynecologists or pediatricians in their sample, it is likely that sexual histories and counseling techniques by gynecologists, and in particular pediatricians, are also inadequate regarding HIV infection . Clinical Correlation. Because prevention is currently the key to control of HIV infection, it is imperative for all clinicians who care for sexually active patients to take an adequate sexual history by questionnaire and/or interview in order to assess the need for intervention. Such interviews should include questions on sexual practices, number and sex(es) of sexual partners, history of sexually transmitted diseases, especially hepatitis B, drug use by self or partner stressing I. V. drug practices, and condom use . Patients who by history are "low risk" for HIV acquisition should be encouraged to continue their "safer" sexual practices , to choose partner(s) carefully , and to use condoms . Client'> in a high-risk situation should be counseled regarding the behaviors that place them at risk for HIV infection, and encouraged to engage in low-risk behaviors, including condom use. In addition , the positive and negative arguments for possible HIV antibody screening can be discussed with such high-risk patients . Screening for common sexually transmitted diseases (STDs) should be included during pelvic examinations and women with positive results should be counseled that HIV is acquired sexually like other STDs.
Molecular Biology
The Sexual History-Taking and Counseling Practices of Primary Care Physicians. Lewis CE, Free man HE. West J Med 1987; 47-165-167. Reviewed by: Mary-Ann Shafer, M.D., Division of Adolescent Medicine Department of Pediatrics, University of California, San Francisco, CA .
Isolation of an Abundantly Expressed Sequence from the Human X Chromosome by Differential Screening. M.V. Wiles, C.M. Alexander, P.N. Goodfellow. Somatic Cell and Molecular Genetics 1988; 14(1):31-39. Reviewed by: Leo Plouffe, Jr., M .D ., C .M., Medical College of Georgia, School of Medicine, Department of Obstetrics and Gynecology, Reproductive Endocrinology, and Genetics Section, Augusta, GA
Authors Lewis and Freeman questioned a variety of practicing physicians (internists, family/general practitioners) throughout the state of California regarding their practices of taking sexual histories. Though California is recognized as a leader in both the prevalence of HIV infections as well as in the development of strategies for its prevention, the authors were able to show that even California physicians rarely take ad-
This study is important in as much as it may hold the key to a new understanding of ovarian development and function. However, the important potential implications of the study may be lost in the highly technical and thorough presentation of this paper, especially to readers uninitiated to the source journal. The authors are indeed modest in their discussion of the putative role for the sequence they have isolated.
Adolescent Medicine
Literature Reviews
This well-established and respected group has developed a cDNA library (i.e., an extremely large collection of expressed DNA sequences) from a line of cells that contain mouse-human DNA hybrid. This means that individual somatic cells in culture were originally derived from mice cells containing native mouse DNA only. Through special techniques, sequences of human DNA have been integrated into the mouse DNA, thus giving rise to what is known as a "mouse-human hybrid cell line." This is a relatively common technique. In this particular study, the only human DNA sequence that was integrated into mouse DNA was a translocation between regions of chromosomes 6 and X [t(X;6)(qter-q13;p21-qter)]. One of the results of these molecular manipulations was to isolate a DNA sequence that corresponds to a portion of the q 13 to the q22 region of the human X chromosome, most probably Xq13- Xq13.3 or Xq21.3-Xq22; this sequence is named SCRIO. Next in order was to develop a probe (a sequence of complementary DNA that will pair with constitutive DNA) from a fragment of this full sequence. The final result is a fragment made up of about 1,000 bases (lKb) known as SCAR. Computerized comparison of this sequence with previously described ones shows it to be a novel sequence. The authors then go on to detect the presence of this specific region in various species by DNA analysis, using Southern blot techniques and its expression in the form of RNA production, by Northern blot analysis. They demonstrate the presence of sequences corresponding to SCAR in primates, rodents, avians, and even in as primitive a species as Xenopus (a small African frog used extensively in research). The SCAR sequence appears to encode for a protein of 27.5 kd. The role of this protein will now be the focus of work for these investigators. It is now well established that a fair number of specific DNA sequences are well preserved throughout the phylogenetic scale. Subsets of these sequences are thought to play a critical role in development and also in the pathogenesis of malignancies, as a manifestation of disordered developmental processes. These sequences belong to two large groups: the proto-oncogenes (named for the potential to cause malignancies) and homeobox genes. The reader is referred to recent reviews on the subject. 1,2 At least three protooncogenes have already been mapped on the X chromosome (ARAFljXp13-pll; PKS2jXpll.4; MCF2;Xq27). The finding of a new sequence, highly preserved from primitive to advanced species, raises the exciting prospect of a new gene with a critical role
209
in development. This role would not necessarily be related to reproductive processes or ovarian development but must clearly be explored. In addition, its absence in individuals with partial or total deletions of this region of the X chromosome could correlate with specific phenotypic anomalies, Secondly, the sequence described is located on the long arm of the X chromosome, either at Xq13-Xq13.3 or Xq21.3-Xq22, if the authors' assumption is correct. This corresponds to a portion of X thought by many to be important for ovarian function. 3 Recent reports have ascribed the "Ovarian Determining Gene" to Xq26-q27,4,5 This does not rule out the potential for other regions of X to be significant, perhaps in a different fashion. One region may be critical for morphological arrangement and another is preoccupied with function following normal development. The sequence described in this paper may be such a candidate, especially when one considers its potential role in development, as outlined in the preceding paragraph. Clinical Correlation. This paper presents a newly isolated sequence located on the long arm of the X chromosome. The sequence can be mapped with a probe (SCAR - lKb) and is preserved in the phylogenetic scale. The characteristics ascribed to this sequence make it a good candidate for a critical role in development. Further work in this area may provide a better understanding of the phenotypic manifestations of individuals bearing deletions of the long arm of the X chromosome. Eventually, this might be one of the critical DNA probes used to scan patients with 46,XX ovarian failure for molecular deletions.
References 1. Slamon DJ: Proto-oncogenes and human cancers (editorial). N Engl J Med 1987; 317:955 2. Gehring WJ: Homeo boxes in the study of development. Science 1987; 236: 1245 3. Skibsted L, Westh H, Niebuhr E: X long-arm deletions: A review of non-mosaic cases studied with banding techniques. Hum Genetics 1984; 67:1 4. Kraus Clvl, Turskoy RN, Atkins L, et al: Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome. N Engl J Med 1987; 317:125 5. Federman DD: Mapping the X-chromosome: Mining its p's and q's (editorial). N Engl J Med 1987; 317:161