Selna L. Kaplan

Growth and Growth Hormone

Abstract Human growth hormone (HGH) deficiency was documented by radioimmunoassay in 35 patients — 16 with isolated HGH, 7 HGH and TSH, 4 HGH and ACTH, and 8 HGH, TSH and ACTH deficiencies. Of 15 p...

The ontogenesis of pituitary hormones and hypothalamic factors in the human fetus: maturation of central nervous system regulation of anterior pituitary function.

Publisher Summary Early in fetal life there is relatively autonomous secretion of hypothalamic hypophysiotropic releasing factors and later in development the maturation of inhibitory or restraining influences, mediated via the central nervous system (CNS), modulates pituitary secretion. Even at birth, CNS regulation of pituitary function is incomplete. Therefore, the maturation of CNS control of anterior hypophysial function can be looked upon as a continuum, extending from fetal life into a variable period in infancy and in relation to gonadotropin secretion, into adolescence. This chapter emphasizes on the limitations of measuring pituitary content and serum concentration of hormones in human fetuses obtained largely after therapeutic abortion. It also provides an overview of some of the factors that can influence the plasma concentration of pituitary hormones. The chapter discusses the morphological changes in the hypothalamic-pituitary complex in the fetus, human fetal hypothalamic-hypophysiotropic factors, hypothalamic content and concentration of releasing factors in human fetuses, human fetal pituitary hormones, placental polypeptide hormones, and pituitary hormones in anencephaly. The developmental pattern of secretion of fetal pituitary hormones is not only diverse, but the hormones apparently develop independently of each other.

CHORIONIC GROWTH HORMONE-PROLACTIN (CGP): SECRETION, DISPOSITION, BIOLOGIC ACTIVITY IN MAN, AND POSTULATED FUNCTION AS THE “GROWTH HORMONE” OF THE SECOND HALF OF PREGNANCY*

It is now firmly established that the human placenta synthesizes and secretes a polypeptide hormone that is chemically and immunologically similar to human pituitary growth hormone and that has prolactin-like and growth hormone-like activity (see Josimovich & Brande, 1964; Grumbach & Kaplan, 1964a & b; and Kaplan & Grumbach, 1964, for historical review and a summary of early observations). A comparable simian placental hormone was identified (Kaplan & Grumbach, 1964) that bears an even closer immunochemical relationship to the human placental hormone than either has to its respective pituitary growth hormone. Josimovich isolated this hormone and emphasized its prolactin and luteotropic activity in animals (Josimovich & MacLaren, 1962; Josimovich et at., 1963; Josimovich & Atwood, 1964) and named it “human placental lactogen.” In our early studies, we obtained data suggesting that this placental polypeptide also exhibited growth hormone-like activity on bioassay. The hypothesis was advanced that changes in carbohydrate, fat, and protein metabolism in the last half of pregnancy, previously ascribed to pituitary growth hormone, were effected, a t least in part, by the placental hormone (Grumbach & Kaplan, 1964a & b; Kaplan & Grumbach, 1964). I t was postulated that the placental polypeptide, rather than pituitary hormone, functioned as an important “metabolic hormone” of late pregnancy; the adaptive and homeostatic advantages to the mother and fetus of such a placental function were pointed out. To indicate the duality of biologic properties of the placental protein which simulated those of human pituitary growth hormone and its origin in the syncytiotrophoblast, we proposed the tentative designation human “chorionic growth hormone-prolactin” (CGP) . Subsequently, additional evidence was obtained in this laboratory to support the growth hormone-like properties of CGP in man and its metabolic role in pregnancy (Grumbach, 1965; Kaplan & Grumbach, 1965b; Grumbach et al . , 1966). *Supported by grants from the National Institute of Child Health and Human Development and the National Institute of Arthritis and Metabolic Diseases, NIH, USPHS

Growth Hormone Treatment for Short Stature

Fifteen short but otherwise normal children, 4.3 to 15.5 years old, with heights greater than 3 S.D. below the mean value for age, growth rates less than or equal to 5.0 cm per year, and normal serum levels of immunoreactive growth hormone in response to provocative stimuli (peak greater than or equal to 10 ng per milliliter) were treated with intramuscular injections of pituitary growth hormone (0.1 U per kilogram) three times weekly for six months, as were 14 children with documented growth hormone deficiency. In all the latter children growth rate increased by more tan 2.0 cm per year during treatment. In 6 of the 14 short normal children who remained prepubertal, growth rate also increased, by 2.2 to 4.2 cm per year during treatment; four of these children had normal base-line serum somatomedin C concentrations. In both short normal children and children with growth hormone deficiency, the increment in serum somatomedin C concentrations after 4 or 10 daily injections of growth hormone correlated with bone age but not with later growth or growth hormone levels. Among the short normal children, those who responded to growth hormone were younger and had a greater delay in bone age and a slower pretreatment growth rate than the nonresponders. These observations suggest that a dose of growth hormone comparable to that used for the treatment of hypopituitarism increases growth rate in some short normal children.

Endocrine and neurologic outcome in childhood craniopharyngioma: Review of effect of treatment in 42 patients

Forty-two cases of craniopharyngioma in children reviewed. Only 9.5% had sought medical attention because of symptoms suggesting hormonal deficit; however, growth retardation was present in 53% and growth hormone deficiency was documented in 72% before treatment. Multiple hypothalamic-pituitary hormone deficiencies were present in all patients after treatment. Eleven percent had normal skull radiographs at presentation; pneumonencephalograms and computed tomographic brain scans were abnormal on every occasion on which they were performed. Recurrence and mortality rates as well as the neurologic outcome of survivors were similar in children treated by radical excision and those treated by limited excision plus radiotherapy. The neurologic prognosis was poorest in those children who had limited excision or drainage without radiotherapy. Additional hypothalamic-pituitary dysfunction following treatment was less common in children who had limited excision plus radiotherapy than in children who had either limited excision or attempted total removal. Unless gross total tumor excision can be readily achieved, limited excision by transsphenoidal microsurgery or craniotomy plus radiotherapy appears to be the treatment of choice for craniopharyngioma in childhood.

Hormonal changes in puberty. I. Correlation of serum luteinizing hormone and follicle stimulating hormone with stages of puberty, testicular size, and bone age in normal boys.

Extract: The concentration of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in serum was determind using a double antibody radioimmunoassay method in each of 106 normal boys aged 5-16 years. The boys were grouped according to the stage of puberty (P1-P5) using the classification of TANNER.The serum LH and FSH, LH/FSH ratio, and testicular volume index (TVI) for boys prepuberty (P1) and at different stages of puberty (P2-P5) are shown in figure l and table. The mean value of LH in prepubertal boys was 4.2 ng/ml, which steadily rose to a concentration of 5.3 ng/ml at P4-5. The differences between the values for LH in early puberty (P2) and at a more advanced stage of puberty (P4-5) were statistically significant. The mean value for serum FSH in the prepubertal boy was 1.4 ng/ml. Serum FSH rose steadily through the early stages of puberty (P1-P3) with no further rise from P3 to P4-5. These changes were reflected in the LH/FSH ratio which fel between P1 and P2, but increased between P2 and P4. Tesricular size (TVI) showed a gradual increase from P1 through P4-5.A comparison of serum LH and FSH, LH/FSH ratio. and TVI with chronological age is indicated in table II. A slight increase in the mean levels of serum LH and FSH was observed from age 9 to age 12 with a continued rise to 15 years and older. Serum LH and FSH was obsereved from age 9 to age 12 with a continued rise to 15 years and older. Serum LH seemed to rise at an earlier age than serum FSH. The TVI showed a definite increase from chronologic age 8 through 11. A pronounced change in testicular size from age 11 through 15 was observed during the period of sharp rise in serum FSH.The correlation of bone age with concentrations of LH and FSH in serum, LH/FSH ratio, and TVI is shown in table III. A significant rise in LH was seen in boys with a bone age of 9-10 years, with a further increase at a bone age of 13-15 years and older. Serum FSH showed a steady increment from a bone age of 11 to 14 years. The most pronounced increase in TVI was seen at a bone age of 11 through 15 years.The relation of concerntrations of LH and FSH in serum and LH/FSH ratio to the TVI is presented in table IV. Mean LH and FSH showed a gradual rise from a TVI of <2 to 10.1-12. Serum LH rose and serum FSH fell, however, with the increase in TVI from 10.1-12 to 12.1-16.In four patients with chromatin-positive seminiferous tubular dysgenesis (Klinefelters syndrome), the mean serum LH concentration was 11.3 ng/ml and the mean serum FSH concerntration was 21.6 ng/ml.The mean serum LH in 14 patients with multiple pituitary hormone deficiencies was 2.1 ng/ml and the mean serum FSH was 1.5 ng/ml. The small diffrences in the concentration of LH and FSH in prepubertal boys compared with that observed in children with hypopituitarism stress the need for further definition of the sensitivity of the assay for serum samples. The serum values reported are of relative not absolute significance.Speculation: The detection of serum FSH and LH prior to puberty, and the increase in serum FSH and LH coincident with advancing puberty suggests 1) that the hypothalamic-pituitary-testicular axis is functional befor puberty, and 2) that the onset of puberry may be associated with a change in sensitivity of the hypothalamus to feedback by testicular steriods.

CONGENITAL ADRENAL HYPERPLASIA DUE TO DEFICIENT CHOLESTEROL SIDE‐CHAIN CLEAVAGE ACTIVITY (20, 22‐DESMOLASE) IN A PATIENT TREATED FOR 18 YEARS

Two siblings, a 9‐week‐old female and an 18‐year‐old male pseudohermaphrodite are described with deficient cholesterol side‐chain cleavage activity. The female died untreated in 1954; the second sibling, a phenotypically female infant with 46 XY karyotype, was diagnosed at age 5 weeks. Massive adrenal hyperplasia was revealed by intravenous pyelography showing downward displacement of the kidneys. Secretion rates of cortisol, aldosterone, deoxycor‐ticosterone and corticosterone were unmeasurable. Urinary 17‐hydroxycorti‐costeroids (17‐OHCS), tetrahydrocortisol, 17‐ketosteroids (17‐KS), pregnanetriol, pregnanediol, and Δ5‐3β‐ol steroids were not detected during prolonged administration of ACTH. Plasma concentrations and urinary excretion of gonadotrophins were increased. Gonadal mitochondria did not convert radioloabelled cholesterol to pregnenolone. The gluccocorticoid and mineralo‐corticoid deficiencies have been controlled well by steroid replacement therapy. Plasma ACTH concentrations and plasma renin activity remained strikingly elevated even when supraphysiologic doses of glucocorticoids and mineralocor‐ticoids were given. Oestrogen replacement alone induced a pubertal growth spurt. The differential diagnosis, the effects of long‐term steroid replacement therapy, and comparison with previously reported findings are discussed.

Treatment of Cushing's Disease in Childhood and Adolescence by Transsphenoidal Microadenomectomy

Fifteen unselected children and adolescents with Cushings disease were treated by transsphenoidal exploration and microadenomectomy. In only three patients was radiographic examination of the sella turcica, including computed tomography, useful in indicating the presence and location of a pituitary microadenoma. Transsphenoidal microadenomectomy corrected hypercortisolism in 14 of the 15 patients; no adenoma was detected in one patient, and one required a second operation six months after the first because of incomplete removal of the adenoma. All 14 lost weight and cushingoid stigmata and had normal or catch-up growth (if epiphyses were not fused) and progression of puberty. In one patient, a recurrence was successfully treated by repeat microadenomectomy six years after the first procedure. The low morbidity and failure rate of the procedure, the low recurrence rate, the rapid amelioration of signs of hypercortisolism, and the preservation of pituitary function in the present study support transsphenoidal microadenomectomy as a low-risk approach to the initial treatment of Cushings disease in childhood and adolescence.

Congenital hypopituitarism associated with neonatal hypoglycemia and microphallus : Four cases secondary to hypothalamic hormone deficiencies

The association of hypoglycemia and microphallus in the male neonate is presumptive evidence of congenital hypopituitarism. This was observed in four male infants with normal birth weight and length, optic discs, and intelligence, and without gross central nervous system malformations. Plasma and urinary cortisol values were low. Stimulation with metyrapone and insulin hypoglycemia failed to elicit a rise in plasma corticoids, but multiple doses of ACTH evoked a response. Growth hormone responses to arginine, insulin, sleep, L-dopa, and glucagon were uniformly less than 2.5 ng/ml. In three patients, however, length remained within 2 SD of the mean until two years of age; in one, there was a sharp decrease in growth by three months. Two patients had low plasma TSH and thyroxine concentrations within the first month of life. In the other two patients, whose thyroxine levels were measurable, intravenous administration of thyrotropin-releasing factor evoked a normal rise in plasma TSH; serum thyroxine decreased into the hypothyroid range in one after GH therapy was initiated. Plasma prolactin was normal in the first two patients receiving thyroxine replacement therapy. The other two patients had elevated baseline prolactin levels and had an augmented rise in plasma prolactin after administration of TRF. Human chorionic gonadotropin induced a 10- to 15-fold rise in plasma testosterone in the two patients tested. The changes in plasma FSH and LH after luteinizing hormone-releasing factor were either low or in the prepubertal range. In three patients, treated with testosterone enanthate intramuscularly, phallic growth occurred. In addition, all three had a transient increase in height but no acceleration of skeletal maturation. The data suggest a deficiency of hypothalamic hypophysiotropic hormones rather than a primary pituitary defect. Early recognition of this syndrome complex is critical for prompt treatment of the life-threatening cortisol deficiency. The diagnosis is more difficult in affected females because their external genitals are normal. The microphallus is a remediable manifestation of hypopituitarism.

Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated.

Micropenis is commonly due to fetal testosterone deficiency. The clinical management of this form of micropenis has been contentious, with disagreement about the capacity of testosterone treatment to induce a functionally adequate adult penis. As a consequence, some clinicians recommend sex reversal of affected male infants. We studied 8 male subjects with micropenis secondary to congenital pituitary gonadotropin deficiency from infancy or childhood to maturity (ages 18 to 27 years). Four patients were treated with testosterone before 2 years of age (group I) and four between age 6 and 13 years (group II). At presentation, the mean penile length in group I was 1.1 cm (-4 SD; range, 0.5 to 1.5 cm) and in group II it was 2.7 cm (-3.4 SD; range, 1.5 to 3.5 cm). All patients received one or more courses of 3 intramuscular injections of testosterone enanthate (25 or 50 mg) at 4-week intervals in infancy or childhood. At the age of puberty the dose was gradually increased to 200 mg monthly and later to an adult replacement regimen. As adults, both group I and II had attained a mean final penile length of 10.3 cm 2.7 cm with a range of 8 to 14 cm (mean adult stretched penile length for Caucasians is 12.4 2.7 cm). Six of 8 men were sexually active, and all reported normal male gender identity and psychosocial behavior. We conclude that 1 or 2 short courses of testosterone therapy in infancy and childhood augment penile size into the normal range for age in boys with micropenis secondary to fetal testosterone deficiency; replacement therapy at the age of puberty results in an adult size penis within 2 SD of the mean. We found no clinical, psychologic, or physiologic indications to support conversion of affected male infants to girls. Further, the results of this study do not support the notion, derived from data in the rat, that testosterone treatment in infancy or childhood impairs penile growth in adolescence and compromises adult penile length.