S. S. C. Yen

REVIEW ARTICLE: THE POLYCYSTIC OVARY SYNDROME

An extensive literature dealing with studies on the pathophysiology of the polycystic ovary syndrome (PCO) has accumulated over the years. The great clinical and biochemical variability of PCO, as indicated in several excellent reviews over a decade ago (Goldzieher & Axelrod, 1963; Mahesh & Greenblatt, 1964; Jeffcoate, 1963; Shearman & Cox, 1966), continues as a major problem in defining this syndrome. Further, the pathogenesis of this reversible disorder remains elusive. However, recent advances in our understanding of ovarian physiology, the pathways for androgen-oestrogen secretion and metabolism, and the integrated function of the hypothalamic-hypophyseal-ovarian axis permit a rational description of the pathophysiology of the PCO syndrome. Thus, current evidence regarding the basis for the dysfunction of ovarian steroidogenesis and follicular maturation, and the aberration of gonadotropin secretion as related to the inappropriate steroid feedback system will be reviewed. The long debated issue of the possible role of adrenal androgen in the genesis and persistence of PCO syndrome will also be considered.

The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age‐advanced men and women

The biological role of the adrenal sex steroid precursors ‐ DHEA and DHEA sulphate (DS) and their decline with ageing remains undefined. We observed previously that administration of a 50 daily dose of DHEA for 3 months to age‐advanced men and women resulted in an elevation (10%) of serum levels of insulin‐like growth factor‐I (IGF‐I) accompanied by improvement of self‐reported physical and psychological well‐being. These findings led us to assess the effect of a larger dose (100 mg) of DHEA for a longer duration (6 months) on circulating sex steroids, body composition (DEXA) and muscle strength (MedX).

A simple method for the assay of eight steroids in small volumes of plasma

A simple method is described for the simultaneous radioligand assay of four delta5-3beta-hydroxysteroids adjacent to one another on the biosynthetic pathway (pregnenolone [1], 17alpha-hydroxypregnenolone, dehydroepiandrosterone and 5-androsterone-3beta, 17beta-diol), and their four delta4-3keto products (progesterone, 17alpha-hydroxyprogesterone, 4-androstene-3, 17-dione and testosterone). Two plasma aliquots are extracted and fractionated each for four steroids and individual corrections are made for losses. For fractionation, maximum use is made of the high resolution and reproducibility of celite minicolumns, using propylene glycol as stationary phase, and a discontinuous gradient of ethyl acetate in iso-octane as mobile phase. The fractions are then assayed in the appropriate radioligand end-assay system. Each assay was finally validated by demonstrating coincidence of peaks of immuno- and radioactive steroid in extracts of female plasma. Results in pre-pubertal girls and women in the follicular phase of the menstrual cycle suggest that the major change in adrenal steroid production at puberty may be an increase in 17, 20-desmolase activity. There appears to be little reversal of this change in adrenal function after ovariectomy.

Circulating prolactin levels during the menstrual cycle: Episodic release and diurnal variation☆

Abstract Assessment of temporal relationship between levels of prolactin (PRL), gonadotropins, and ovarian steroids in 14 ovulatory cycles was made. Serum PRL concentrations were determined by a homologous radioimmunoassay. Our data showed that, although the highest mean PRL concentration was found on the day of LH-surge and the day after estrogen peak, a consistent pattern of circulating PRL in daily morning samples was not present in ovulatory cycles; variations in random fluctuation with erratic spikes were observed within cycles and between subjects. In two cycles studied, despite markedly elevated PRL levels (eightfold) induced by amphetamine, optimal ovulatory events occurred in terms of both hormonal patterns and luteal function. These findings implicate a lack of apparent physiologic role of PRL in the regulation of ovarian function in human subjects. The random daily fluctuation of PRL was further characterized in samples obtained at 10 to 30 minute intervals during different days of five ovulatory cycles and continuous sampling during day and night was made in three of five studies; a clear episodic nature of PRL release was disclosed. A circadian rhythm with marked elevation during sleep which was composed of multiple peaks with larger excursions than those found during waking periods was revealed. The event of sleep-induced PRL rise was initiated shortly (30 to 90 minutes) after the onset of sleep and ceased upon wakening. In one subject a quantitatively greater nocturnal PRL release around midcycle (eightfold) than during the follicular and the luteal phases (threefold) was found. These data would facilitate future elucidation of the inapparent role as well as the neuroendocrine regulation of PRL secretion during the human menstrual cycle.

The Operating Characteristics of the Hypothalamic–Pituitary System during the Menstrual Cycle and Observations of Biological Action of Somatostatin

Publisher Summary This chapter focuses on the investigations conducted over the past few years on the interaction between the hypothalamic hormone(s) and gonadal steroids in the regulation of cyclic gonadotropin output by the adenohypophysis in humans. It describes hypothalamus as a neuroendocrine regulator. It also reviews the observations on the biological actions of hypothalamic somatostatin in humans. The description of the hypothalamic-hypophysial portal system and the subsequent presentation of a number of anatomical and physiological observations led to the proposal that the hypothalamus is critically involved in the control of anterior pituitary function. The chapter presents the three elements of the hypothalamic-hypophysial portal system: (1) the CNS-hypothalamus complex that may be regarded as a signal generator, (2) the pituitary as a signal transmitter, and (3) the cyclic ovarian steroid output as a signal modulator. It reviews the regulation of the hypothalamic-hypophysial- gonadal system in humans within this general context.

Pattern of increase in circulating prolactin levels during human gestation

Serum prolactin concentrations, determined serially at weekly intervals from the fifth week of gestation, increase in an approximately linear pattern. It is suggested that in human gestation the increase in prolactin secretion is related to supramaximal estrogen augmentation at all times and is a functional reflection of hypertrophy and hyperplasia of pituitary lactotrophs.

Neuroendocrinology of opioid peptides and their role in the control of gonadotropin and prolactin secretion

Substantial evidence now exists to indicate that the endogenous hypothalamic opioidergic mechanism(s) represents one of the important controlling systems for release of gonadotropin-releasing hormone. Modulations of frequency and amplitude of the secretory activity of gonadotropin-releasing hormone appears to be mediated through an inhibitory action of endogenous opioids, and the functional coupling of the opioidergic and gonadotropin-releasing hormone systems is an ovarian steroid-dependent event. There is also evidence to implicate suprahypothalamic mechanism(s) that enhance endogenous opioid inhibition of secretion of gonadotropin-releasing hormone. Although exogenous opioid peptides and their synthetic analogs consistently induce the secretion of prolactin, blockade of opioid receptors in humans by naloxone failed to elicit a decrement in the levels of prolactin under a variety of conditions. On the contrary, naloxone induced a remarkable increment in the secretion of prolactin via an increased frequency of pulsatile release which is synchronized with pulses of luteinizing hormone. These observations suggest that a common neuroendocrine mechanism is involved in the opioidergic control of the secretion of both luteinizing hormone and prolactin in women.

Regression of uterine leiomyomata to the antiprogesterone RU486: dose-response effect.

OBJECTIVE To study the response of uterine leiomyomata to three daily doses of RU486 (5, 25, and 50 mg). DESIGN Prospective nonrandomized trial of women with symptomatic leiomyomata. SETTING Patients from the clinical practice of the authors at the University of California, San Diego Medical Center. PATIENTS Ten patients with symptomatic leiomyomata previously reported after treatment with 50 mg of RU486 daily for 3 months. Eleven patients treated with 25 mg of RU486 daily and nine patients placed on 5 mg of RU486 daily for 12 weeks. MAIN OUTCOME MEASURES Changes in leiomyomata volume as measured with vaginal ultrasounds at baseline and monthly thereafter. Frequent blood samples for hematology, chemistry, and hormone levels were obtained. Twenty-four-hour urine collections for free cortisol and creatinine were obtained at baseline and at 12 weeks. RESULTS All three doses induce ovarian acyclicity. Administration of 50 mg of RU486 decreases leiomyomata volume to 78.1% +/- 4.8% of baseline at 4 weeks, 60.5% +/- 6.6% at 8 weeks, and 51.0% +/- 9.2% after 12 weeks of treatment. Regressive response in patients treated with 25 mg of RU486 daily was 76.3% +/- 5.0% of baseline at 4 weeks, 54.0% +/- 5.1% at 8 weeks, and 44.0% +/- 5.0% after 12 weeks. At 5 mg of RU486 leiomyomata volume was 80.6% +/- 8.3% of baseline after 4 weeks, 63.7% +/- 14.6% after 8 weeks, and 74.4% +/- 19.8% after 12 weeks of therapy. CONCLUSIONS Although acyclicity is seen at all three doses, an effective dose to cause a clinically significant (50%) decrease in leiomyomata volume appears to be 25 mg daily.

Augmentation by naloxone of efflux of LRF from superfused medial basal hypothalamus

The effects of naloxone and β-endorphin (β-EP) on the efflux of luteinizing hormone releasing factor (LRF) from superfused rat medial basal hypothalamus (MBH) were determined. After an equilibration period of 2.5 hrs with Medium 199 at 37°C 0.5 ml fractions were collected. Infusion of medium containing 150 mM KCl for 10 min produced a prompt 4-fold rise in LRF efflux. Injection of naloxone, but not medium alone, into the system significantly increased the effluent concentration of LRF from female (N = 6) MBHs by 177% (P < 0.01) and from male (N = 5) MBHs by 108% (P < 0.05). Administration of β-EP did not significantly alter LRF efflux. However, β-EP did nullify the LRF-stimulating effect of naloxone, when an equimolar mixture of β-EP and naloxone was injected. We conclude that naloxone-sensitive opiate receptors exert a tonic inhibitory effect on tuberoinfundibular LRF neurons. This action does not require the intermediation of brain centers outside the MBH.

The 24-hour excursion and diurnal rhythm of glucose, insulin, and C-peptide in normal pregnancy☆☆☆

Abstract A longitudinal study to quantitate the progressive effects of the second and third trimesters of normal pregnancy on the levels of plasma glucose, immunoreactive insulin (IRI), and C-peptide (C-P) at hourly intervals throughout the 24-hour “metabolic clock” was made. Identical studies were conducted in each subject at 6 to 11 weeks post partum and these data were used as nonpregnant control values. Data analyses were made to determine the role of meal-activity-sleep cycles as physiologic modifiers. A diurnal rhythm of plasma glucose, IRI, and C-P was demonstrated in all study periods. During meals anabolic values of plasma glucose (increments above the 24-hour mean) in response to meal intake were remarkably small, ranging between 30 and 35 mg/100 ml in the postpartum state, and were not significantly modified by pregnancy. The corresponding IRI levels were similarly small with a mean increase on only 31% in pregnancy. However, during the third but not the second trimester of pregnancy, the peak anabolic values for both plasma glucose and IRI were significantly (p a.m. ) plasma glucose and 24-hour integrated glucose levels. This relative nocturnal hypoglycemia was associated with synchronous IRI values but without concomitant reduction of absolute IRI levels. Consequently, the fasting, premeal, and 24-hour IRI/glucose ratios were increased. Thus, basal insulin secretion is significantly augmented relative to levels of plasma glucose, but a quantitative increase in insulin secretion following food intake is relatively small during pregnancy. These observations together with the finding of a marked diurnal rhythm of plasma glucose and relative nocturnal hypoglycemia provide important insights for the formulation of guidelines for the timing, amount, and mode of delivery of exogenous insulin necessary for the management of diabetic patients during pregnancy.