Howard E. Kulin

Peutz-Jeghers Syndrome

Peutz-Jeghers syndrome (PJS) is an unusual polyposis syndrome that has enjoyed a rich and somewhat confusing history. Mucocutaneous pigmentation and diffuse gastrointestinal hamartomas are the hallmark features of this autosomal dominant inherited condition. Peutz-Jeghers syndrome is now also recognized as a cancer predisposition syndrome. In this review, we highlight the historical aspects of PJS polyposis with special emphasis on its extraintestinal manifestations, particularly genital tract tumors. A PJS management scheme for clinicians is included.

Hypothalamic hamartoma: a source of luteinizing-hormone-releasing factor in precocious puberty.

The presence of a hypothalamic hamartoma and precocious puberty in a 19-month-old boy provided an opportunity to study their relation. Excised tissue had the ultrastructural characteristics of an independent neuroendocrine unit -- i.e., neurons containing neurosecretory granules and blood vessels with fenestrated endothelium and double basement membranes. Immunofluorescence studies using specific antibody to luteinizing-hormone-releasing factor showed antigenicity to the factor in the hamartoma. The testicular-hypothalamic-pituitary axis was tested. Clomiphene unresponsiveness suggested a lack of maturation of central-nervous-system events characteristic of normal puberty. The negative feedback system between gonad and brain was intact but partially resistant to steroid suppression. These studies suggest that hypothalamic hamartomas may cause precocious puberty by autonomous production and release of luteinizing-hormone-releasing factor into vessels that communicate with the pituitary portal blood system.

Age of puberty: Data from the United States of America

In an attempt to determine whether the secular trend toward an earlier onset of puberty has continued over recent decades in the United States of America, published reports concerning the age of attainment of pubertal events have been reviewed. Such reports are very limited and vary in both design and inclusive ages of study subjects. Among females, two recent large cross‐sectional studies indicate that fifty percent of females in the United States attain Tanner breast stage 2 at 9.5 to 9.7 years of age. This is younger than previously thought, although adequate earlier studies of girls in the United States are not available for comparison. These two studies also indicate that about 14% of girls attain Tanner stage 2 while 8 years of age; one study extends earlier reporting that about 6% exhibit onset of breast development while 7 years of age. There is no evidence that the age of menarche or the attainment of adult (Tanner 5) breast development has decreased over the past 30 years. The data also suggest an earlier onset of Tanner stage 2 pubic hair but no change in attainment of stage 5. Among males, pubic hair may be appearing at younger ages, but data are inadequate or too inconsistent to allow firm interpretation. The lack of standardization of genital criteria of pubertal onset in the male makes any conclusions regarding secular trends impossible. In summary, earlier secular trends over recent decades related to better health, improved nutrition or socio‐economic status, or any putative influence by endocrine disrupters cannot be verified.

The effect of calcium supplementation and tanner stage on bone density, content and area in teenage women

One hundred and twelve Caucasian girls, 11.9±0.5 years of age at entry, were randomized into a 24-month, double-masked, placebo-controlled trial to determine the effect of calcium supplementation on bone mineral content, bone area and bone density. Supplementation was 500 mg calcium as calcium citrate malate (CCM) per day. Controls received placebo pills, and compliance of both groups averaged 72%. Bone mineral content, bone mineral area and bone mineral density of the lumbar spine and total body were measured by dual energy X-ray absorptiometry (DXA). Calcium intake from dietary sources averaged 983 mg/day for the entire study group. The supplemented group received, on average, an additional 360 mg calcium/day from CCM. At baseline and after 24 months, the two groups did not differ with respect to anthropometric measurements, urinary reproductive hormone levels or any measurement of pubertal progression. The supplemented group had greater increases of total body bone measures: content 39.9% versus 35.7% (p=0.01), area 24.2% versus 22.5% (p=0.15) and density 12.2% versus 10.1% (p=0.005). Region-of-interest analyses showed that the supplemented group had greater gains compared with the control group for bone mineral density, content and area. In particular, in the lumbar spine and pelvis, the gains made by the supplemented group were 12%–24% greater than the increases made by the control group. Bone acquisition rates in the two study groups were further compared by subdividing the groups into those with below- or above-median values for Tanner score and dietary calcium intake. In subjects with below-median Tanner scores, bone acquisition was not affected by calcium supplementation or dietary calicum level. However, the calcium supplemented subjects with above-median Tanner had higher bone acqusition rates than the placebo group with above-median Tanner scores. Relative to the placebo group, the supplemented group had increased yearly gains of bone content, area and density which represented about 1.5% of adult female values. Such increases, if held to adult skeletal maturity, could provide protection against future risk of osteoporotic fractures.

The absence of positive feedback between estrogen and luteinizing hormone in sexually immature girls.

Extract: The development of estrogen-mediated luteinizing hormone (LH) release (positive feedback) was studied in prepubertal, pubertal, and adult females. The optimum means of eliciting positive feedback was established by administering graded doses of 17β-estradiol (E2) for 5 days to 11 women during the early follicular phase of 14 menstrual cycles. Three groups of adult subjects were formed based on the peak levels of E2 in plasma attained: 100–200 pg/ml, 200–300 pg/ml, and >300 pg/ml. In all groups, LH values in plasma fell to a nadir at a mean time of 2 days after the initiation of injections and then rose sharply while plasma E2 levels in plasma still remained elevated. The magnitude of the LH elevations appeared to relate to the levels of E2 in plasma.In contrast to the results in adult women, three prepubertal girls and an 11-year-old girl with gonadal dysgenesis did not evidence positive feedback when given similar estrogen courses. Levels of E2 in plasma in the prepubertal subjects ranged between 100 and 300 pg/ml and both LH and follicle-stimulating hormone (FSH) remained suppressed. One early pubertal girl displayed a small increment in LH in the presence of elevated exogenous estrogen levels. One midpubertal, premenarchal girl with adult levels of gonadotropins and precocious puberty due to an hypothalamic cyst revealed a large LH rise during E2 administration both before and after drainage of the cyst. Finally, a 14-year-old girl with gonadal dysgenesis and adult castrate levels of gonadotropins also displayed positive feedback.Speculation: Puberty in women is a multistage process which involves alterations in the hypothalamic-pituitary-gonadal axis. A change in sensitivity of the negative feedback system is associated with rising gonadotropin levels early in the course of sexual maturation. Ovulatory potential is dependent on the development of positive feedback, an event which occurs later in the course of pubescence.

Age of puberty: Data from the United States of AmericaNote . Review article

In an attempt to determine whether the secular trend toward an earlier onset of puberty has continued over recent decades in the United States of America, published reports concerning the age of attainment of pubertal events have been reviewed. Such reports are very limited and vary in both design and inclusive ages of study subjects. Among females, two recent large cross‐sectional studies indicate that fifty percent of females in the United States attain Tanner breast stage 2 at 9.5 to 9.7 years of age. This is younger than previously thought, although adequate earlier studies of girls in the United States are not available for comparison. These two studies also indicate that about 14% of girls attain Tanner stage 2 while 8 years of age; one study extends earlier reporting that about 6% exhibit onset of breast development while 7 years of age. There is no evidence that the age of menarche or the attainment of adult (Tanner 5) breast development has decreased over the past 30 years. The data also suggest an earlier onset of Tanner stage 2 pubic hair but no change in attainment of stage 5. Among males, pubic hair may be appearing at younger ages, but data are inadequate or too inconsistent to allow firm interpretation. The lack of standardization of genital criteria of pubertal onset in the male makes any conclusions regarding secular trends impossible. In summary, earlier secular trends over recent decades related to better health, improved nutrition or socio‐economic status, or any putative influence by endocrine disrupters cannot be verified.

Gonadotropin and Testosterone Measurements after Estrogen Administration to Adult Men, Prepubertal and Pubertal Boys, and Men with Hypogonadotropism: Evidence for Maturation of Positive Feedback in the Male

Extract: Nineteen male subjects were given five daily injections of 17β-estradiol and circulating levels of estradiol (E2), testosterone (T), and gonadotropins were determined by radioimmunoassay before, during, and after the steroid course. Peak levels of E2 attained during the 5 days of treatment ranged from 173–577 pg/ml. Four of seven normal adult men and one castrate man demonstrated suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) with a subsequent rise in LH (positive feedback) while E2 levels remained elevated. A rise in T was associated with the LH increment in the four normal men. Nine pre-, early, or midpubertal boys and two men with hypogonadotropic hypogonadism displayed only gonadotropin suppression after E2 administration. The difference in LH response to estrogen (i.e., positive feedback) between the adult men with normal or elevated gonadotropin levels as compared with the endocrinologically normal boys is significant (P < 0.01).Speculation: Positive feedback between estrogen and LH is present in intact adult men, although the magnitude and consistency of this response is less than in women. Testosterone in men may act like progester-one in the female rhesus monkey to blunt the magnitude of the LH rise during estrogen administration. The potential for positive feedback appears to be a maturational event occurring during puberty in men as well as in women.

The effect of growth hormone on the Leydig cell response to chorionic gonadotrophin in boys with hypopituitarism.

Eleven boys with growth hormone (hGH) deficiency received human chorionic gonadotrophin (hCG) stimulation tests for the assessment of Leydig cell function before, during, and after 1 year of treatment with somatotrophin. Two patients entered puberty during the course of the study protocol. Analysis of the data in nine prepubertal boys revealed an augmentation of testosterone (T) responses to hCG in the presence of hGH. In six of these individuals in whom dihydrotestosterone (DHT) was determined, a similar augmentation in responsiveness of this steroid was found in the presence of hGH. Three prepubertal boys exhibited poor T responses to the basal hCG test with only partial improvement following hGH. In man growth hormone may be an important permissive factor in Leydig cell activity during periods of changing testicular function such as occur in utero or during puberty.

Inborn error in the terminal step of aldosterone biosynthesis. Corticosterone methyl oxidase type II deficiency in a North American pedigree

Profound salt wasting developed in a male infant who had marked reductions in serum and urinary aldosterone concentrations despite striking hyperreninemia. Coincident elevations in plasma and urinary levels of specific 18-hydroxysteroids localized the defect to corticosterone methyl oxidase Type II, the adrenal enzyme responsible for the final step of aldosterone synthesis. Salt replacement but not hydrocortisone ameliorated the clinical and metabolic abnormalities. Evaluation of 33 other family members disclosed the biochemical disorder in six other subjects who were affected in an autosomal-recessive pattern with variably severe clinical manifestations and abnormal ratios of 18-hydroxycorticosterone (or its metabolites) to aldosterone. This inborn error in aldosterone biosynthesis must be distinguished from other heritable, salt-losing defects in adrenal steroidogenesis.

Timed urinary gonadotropin measurements in normal infants, children, and adults, and in patients with disorders of sexual maturation

Timed urine collections-mostly over a three-hour period-were obtained from 58 newborn, 68 prepubertal children, 27 adolescents, and 51 adults. For comparison, similar samples were collected from 69 patients with presumptive abnormalities of sexual maturation. Follicle-stimulating hormone and luteinizing hormone were extracted by acetone precipitation and measured by radioimmunossay. Adult nem and women excreted approximately 11 times as much FSH and 33 times as much LH as perpubertal children. Elevated and/or diminished excretory values of gonadotropins were associated with appropriate diagnoses of abnormal pubertal advance or delay. Timed urinary FSH and LH measurements can provide a simple, sensitive, and accurate test of gonadotropin function in children.