J. S. D. Winter

Pituitary-ovarian relationships preceding the menopause

Abstract Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, and progesterone concentrations were measured in 58 ovulating women in different age groups (20 to 29, 34 to 39, 40 to 44, and 45 to 50 years) at five- to seven-day intervals through a single menstrual cycle and in 18 postmenopausal women sampled weekly five to six times. The over-all hormone patterns were similar in our premenopausal groups. However, mean serum FSH levels increased with age and significantly higher concentrations were found in the 40 to 50 year group than in the 20 to 29 year group. Serum LH levels did not show a similar rise with age, although follicular LH levels in the oldest group were higher than in the 20 to 29 year group. Prolactin and estradiol concentrations did not change with age prior to the menopause, but luteal progesterone levels were lower in the three older premenopausal groups than in the 20 to 29 year group. Postmenopausal women showed elevated FSH and LH, decreased prolactin, and negligible estradiol and progesterone levels. There was an over-all significant linear correlation between prolactin and estradiol concentrations. It appears that the menopause is preceded by several years of rising gonadotropin, predominantly FSH, levels. During this period, ovarian estrogen production appears to be maintained and ovulation continues, but luteal progesterone levels decline. It is likely that these premenopausal alterations in pituitary-ovarian relationships reflect depletion of ovarian follicles.

Pituitary-Gonadal Relations in Female Children and Adolescents

Extract: Data are provided which concern daytime levels of circulating follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol and progesterone in healthy female children and adolescents. These findings are correlated with sexual and skeletal maturation. Serum estradiol and testosterone levels were low in childhood, but rose to adult levels coincident with the appearance of secondary sexual characteristics. Serum LH levels did not rise above prepubertal levels until these characteristics were already apparent. Serum FSH levels showed a biphasic pattern with age; widely scattered values, some into the adult range, were seen in infancy. Mean FSH levels then declined throughout childhood until the onset of clinical puberty at which time they increased again to adult levels. Serum progesterone concentrations remained low (below 150 ng/100 ml) until menarche. Levels of serum progresterone which suggested possible ovulation and corpus luteum formation (over 200 ng/100 ml) were found in 9 of 30 girls who were less than 3 years postmenarchal.Speculation: The finding of high serum FSH levels in female, but not in male, infants suggests that the infantile ovary may be relatively resistant to FSH stimulation. The decline in FSH levels during early childhood may represent increasing ovarian maturation, at least in terms of ability to secrete as yet unidentified gonadotropin-inhibiting feedback substance (or substances). The onset of female puberty appears to be heralded by increasing FSH secretion; although nocturnal LH release may be characteristic of early puberty, daytime elevation of this hormone is not seen until midpuberty. The surprising finding of luteal range serum progesterone levels in many early postmenarchal girls suggests that anovulatory cycles may not be characteristic of these years. The reported relative infertility of adolescent girls may relate to factors other than ovulation (such as a short corpus luteum life-span, defects in sperm capacitation, or impaired blastocyst implantation).

ENDORPHINS AND THE REGULATION OF THE HUMAN MENSTRUAL CYCLE

In order to assess a possible influence of endogenous opioids upon gonadotrophin secretion in women, we examined the effects of i.v. administration of 10 mg naloxone, a specific opiate antagonist, in ten normal menstruating women, in thirteen women with amenorrhoea and/or hyperprolactinaemia and in two women with putative deficiency of gonadotrophin‐releasing hormone (GnRH). In thirteen subjects, a saline vehicle control study (randomized order of administration) was also performed. In the normal women, naloxone failed to elicit changes in serum gonadotrophin levels when administered during the early follicular phase of the menstrual cycle. However, significant increments of LH were observed from 30 to 165 min following naloxone administration during the late follicular phase. Similar LH responses occurred in the amenorrhoeic and hyperprolactinaemic women. There was a tendency towards a concomitant increment in FSH levels, which reached statistical significance variably from 60 to 105 min post‐naloxone. The LH response to naloxone in individual subjects showed a significant (P > 0·01) quadratic (U‐shaped) relationship to the log basal oestradiol concentration. No response to naloxone was observed in the two patients with GnRH deficiency despite a brisk response to an exogenous GnRH bolus. Taken together, these data suggest that central nervous system inhibitory opioid pathways may be involved in the regulation of LH secretion in normal women and that excessive production of endogenous opioids may play a role in the pathophysiology of some amenorrhoeic conditions.

Pituitary-gonadal function in Klinefelter syndrome before and during puberty.

ABSTRACT: Serum concentrations of follicle-stimulating hormone, luteinizing hormone, testosterone, and estradiol were determined at intervals before and during puberty in 40 individuals with Klinefelter syndrome (47,XXY karyotype), of whom 27 had been detected in neonatal cytogenetic screening programs. Prior to the appearance of secondary sexual changes, basal serum hormone concentrations and acute responses to stimulation with gonadotropinreleasing hormone and human chorionic gonadotropin were normal. The timing of the onset of clinical puberty was normal. Early pubertal boys showed initial testicular growth and normal serum testosterone levels, while serum follicle-stimulating hormone and estradiol concentrations were significantly elevated. By midpuberty, the Klinefelter subjects were uniformly hypergonadotropic and their testicular growth had ceased. Serum testosterone concentrations after age 15 remained in the low-normal adult range. Serum estradiol levels remained high, irrespective of the presence or absence of gynecomastia. Exaggerated responses to gonadotropin-releasing hormone are seen in pubertal subjects with elevated basal gonadotropin values.

The application of a serum 17OH-progesterone radioimmunoassay to the diagnosis and management of congenital adrenal hyperplasia

Serum concentrations of 17OH-progesterone were studied serially over 24 hours in 13 treated and untreated patients with the C21 hydroxylase form of congenital adrenal hyperplasia. The results were correlated with measurements of plasma renin activity, serum electrolytes, and urinary 17-ketosteroids and pregnanetriol. In 500 healthy subjects from birth to adult life, serum 17OH-pregesterone levels ranged from 5 to 315 ng/dl. In untreated CAH, serum 17OH-progesterone was markedly elevated (2,000 to 80,000 ng/dl). Treatment with cortisol (20 to 30 mg/m2/day in 3 doses) resulted in normal serum 17OH-progesterone levels in both non-salt-losing and salt-losing patients receiving adequate mineralocorticoid. Even slightly inadequate mineralocorticoid therapy (shown by high plasma renin activity with normal serum electrolytes) was associated with elevated 17OH-progesterone (to 65,000 ng/dl) in spite of usually effective doses of cortisol. Some patients showed isolated 17OH-progesterone elevations (usually early morning), a situation which requires only revision of the cortisol dosage schedule without an increase in total dosage. The data confirm the value of 17OH-progesterone assays in both the diagnosis and management of CAH. Taken together with determinations of plasma renin activity, serum 17OH-progesterone assays can permit more exact control of CAH without excessive doses of glucocorticoid.

CONGENITAL 11β‐HYDROXYSTEROID DEHYDROGENASE DEFICIENCY ASSOCIATED WITH JUVENILE HYPERTENSION: CORTICOSTEROID METABOLITE PROFILES OF FOUR PATIENTS AND THEIR FAMILIES

Four children with 11bT‐hydroxysteroid dehydrogenase deficiency are described. All patients had severe hypertension, hypokalaemia, and low plasma aldosterone and renin activities. Two of the patients were siblings and two were unrelated. The most noticeable biochemical feature of these individuals was the extremely low excretion of cortisol metabolites containing an 11‐carbonyl group compared to the excretion of the 11β‐hydroxyl containing metabolites. Although this condition is readily diagnosed in affected individuals by urinary steroid analysis, carriers of the defect do not differ from normal in their urinary steroids. Both parents of the affected siblings had normal 11‐oxo‐steroid/11bT‐hydroxysteroid ratios under baseline conditions and the lesions could not be revealed by ACTH administration.

Allgrove syndrome: an autosomal recessive syndrome of ACTH insensitivity, achalasia and alacrima

Allgrove syndrome (Isolated glucocorticoid deficiency, achalasia and alacrima) was found in eight members of an inbred French Canadian/North American Indian pedigree. The high degree of consanguinity supports an autosomal recessive mode of inheritance for this disorder. Six patients presented with hypoglycaemia and other evidence of cortisol deficiency between 2·5 and 8 years of age; however, two others became cortisol deficient after Initial testing showed normal cortisol responses to ACTH, evidence that the glucocorticoid Insufficiency of this syndrome may not be congenital, but may develop as late as the third decade. No evidence of mineralocorticoid deficiency has been found during 65 patient‐years of follow‐up. Aiacrima was the earliest and most consistent clinical sign of Allgrove syndrome. Other manifestations of peripheral or autonomic neuropathy were found in four patients. The patients showed similar facial features, and three had significant veto‐pharyngeal Incompetence. Ail showed oesophageal dysmotility even in the absence of symptomatic dysphagia. In‐vitro studies of lymphocyte ACTH binding showed no differences from normal controls. If such lymphocyte binding, as has been suggested, reflects adrenal ACTH receptor activity, these data would suggest that the glucocorticoid deficiency of Allgrove syndrome is not the result of a defect in that receptor. However, the observation that ACTH does not elicit increased adenylate cyclase activity even in normal lymphocytes casts considerable doubt on the physiological significance of ACTH binding to lymphocytes. It seems likely, therefore, that true ACTH receptors are not expressed on peripheral lymphocytes, and any conclusions regarding a possible receptor defect in Allgrove syndrome must await studies of receptor expression on adrenal cell membranes

Pituitary-ovarian interrelationships during the puerperium

Abstract This study examines and correlates serial serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (human chorionic gonadotropin) (LH [HCG]) prolactin, estradiol, and progesterone in 2 lactating (one unsuccessful) and 2 nonlactating women during the first 45 to 68 days of the puerperium. Prolactin concentrations, which were high at delivery, declined but with marked fluctuations. Over-all prolactin levels were highest in the successful lactator. LH (HCG) concentrations decreased to normal menstrual cycle values by 2 weeks. Serum FSH levels were suppressed for the first 10 to 12 days and rose rapidly to normal over the next 2 to 6 days. Estradiol and progesterone values declined to low levels during the first week following delivery. Levels of estradiol remained low in spite of rising FSH values—for one week in both nonlactating women, 12 days in the unsuccessful lactating woman, and 18 days in the successful lactating woman. The first menses observed in 2 subjects during the study were preceded by subnormal serum progesterone increments and in one case by a subnormal gonadotropin peak.

Identification of a common molecular basis for combined 17α-hydroxylase/17,20-lyase deficiency in two Mennonite families

SummaryDuring the course of studies to characterize mutations of the CYP17 gene that cause the 17α-hydroxylase-deficient form of congenital adrenal hyperplasia we have discovered two ostensibly unrelated Mennonite families in which affected individuals are homozygous for the same mutation. The defect is a four-base duplication in exon 8 of the CYP17 gene, which alters the reading frame encoding the C-terminal 26 animo acids of cytochrome P45017α.

Influence of restraint and ketamine anesthesia on adrenal steroids, progesterone, and gonadotropins in rhesus monkeys.

Abstract Changes in gonadotropins, progesterone, Cortisol, DHA, and DHAS were monitored in 10 female rhesus monkeys (Days 20-23 of the menstrual cycle) subjected to cage restraint with or without ketamine anesthesia for successive venipunctures. All animals were bled without sedation for 2 hr at 30-min intervals. Then 4 of the animals were anesthetized with ketamine-HCl and bleedings in all animals were continued for an additional 2.5 hr. FSH and progesterone were not appreciably affected by either restraint technique. LH declined steadily for the duration of the bleedings (P < 0.05). Serum levels of Cortisol and the adrenal androgens increased twofold (P < 0.05). Anesthesia with ketamine had no effect on any of the six variables when compared with saline controls. Cortisol and dehydroepiandrosterone (DHA) levels tended to plateau (P < 0.01) after 2 hr in both treated and control groups. In contrast, dehydroepiandrosterone sulfate (DHAS) levels increased continuously throughout the entire study period. These data indicate that ketamine anesthesia does not alter endocrine responses to venipuncture when administered following cage restraint of conscious animals. These findings further confirm the difficulties in obtaining estimates of basal levels of hormones which are responsive to stress and suggest that the first sample may provide the best estimate.