Marc A. Fritz

The endocrinology of the menstrual cycle: the interaction of folliculogenesis and neuroendocrine mechanisms

(1) The gonadotropins are secreted in a pulsatile fashion in response to the similar pulsatile release of GnRH from neurosecretory neurons centered in the arcuate nucleus of the medial basal hypothalamus. (2) The gonadal steroids appear to exert their feedback effects both directly on the pituitary and through modulation of the pulsatile pattern of GnRH secretion. They may also influence the degree of sialylation and subsequent biologic activity of the gonadotropins. (3) GnRH release is under the control of catecholaminergic neurotransmitters. Norepinephrine appears to act as an excitatory agent, whereas dopamine inhibits GnRH secretion. (4) Dopamine also directly inhibits PRL release and may be the prolactin-inhibiting factor. (5) The endorphins are endogeneous opiate peptides and are derived from a common ACTH/ beta-lipotropin precursor. Through modulation of neurotransmitter mechanisms, the endorphins may affect both PRL and gonadotropin secretion. (6) The catecholestrogens, by virtue of their structural similarity to the neurotransmitters, may mediate the central feedback actions of the gonadal steroids.

Direct effect of sex steroid-binding protein (SBP) of plasma on the metabolic clearance rate of testosterone in the rhesus macaque

We report direct evidence for the effect of the sex steroid-binding protein (SBP) on the metabolic clearance rate of testosterone (MCRT). Pure rhesus SBP or human SBP was infused intravenously into three different cycling female rhesus monkeys. MCRT was measured before and after SBP had reached 150-300% of basal levels. A decrease in MCRT was observed in all cases. The effect of SBP on MCRT was tested further in four additional cycling females by infusing immunoaffinity-purified monospecific human SBP antibodies known to cross-react with rhesus SBP. SBP dropped to 54, 40, 4 and 2% of basal levels with a concomitant increase of 118, 190, 320 and 640% of basal MCRT. In one of these animals, pure rabbit SBP was administered after the anti-human SBP infusion resulting in a decrease in MCRT. The magnitude of the SBP effect on MCRT is related to the distribution of testosterone (T) bound to SBP and albumin in the plasma. Calculations show that as long as the percent of T bound to SBP is equal or higher than the percent of T bound to albumin, the influence on MCRT is small. However, if SBP is reduced to the extent that T is bound mostly to albumin, the redistribution of T is associated with a dramatic increase in MCRT. We conclude that under normal conditions each animal has an optimum concentration of plasma SBP which binds a maximum amount of T. If SBP increases above this level, little effect on MCRT will result. However, a drop below the optimum level, as is the case in certain physiological or clinical conditions, will produce a large increase in the clearance of T.

Soy protein isolate with isoflavones does not prevent estradiol-induced endometrial hyperplasia in postmenopausal women: a pilot trial.

ObjectiveTo test the hypothesis that soy protein isolate (SPI) with isoflavones opposes the proliferative effects of exogenous estradiol (E2) on the endometrium after menopause. DesignThirty-nine postmenopausal women were randomized to receive daily for 6 months either 0.5 mg E2 + placebo, 1.0 mg E2 + placebo, 0.5 mg E2 + 25 g SPI with 120 mg isoflavones, or 1.0 mg E2 + 25 g SPI with 120 mg isoflavones. Primary outcome measures were endometrial histology, ultrasound endometrial thickness, and Ki67 staining quantification, a marker of cellular proliferation. Secondary outcome measures were serum lipids and markers of bone resorption. ResultsEndometrial hyperplasia, endometrial stromal and epithelial cellular proliferation, and sonographically measured endometrial thickness were similarly affected in all groups. SPI did not lessen the beneficial effects of E2 on lipids and markers of bone resorption. ConclusionIn this pilot study, SPI with isoflavones did not protect the endometrium from E2-induced hyperplasia in postmenopausal women. If higher, long-term doses of isoflavone supplementation are found to be safe for postmenopausal women, then future studies combining E2 with isoflavones may be feasible as an alternative to traditional hormone replacement therapy.

Influence of corpus luteum age on the steroidogenic response to exogenous human chorionic gonadotropin in normal cycling women

OBJECTIVEnThe null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment.nnnSTUDY DESIGNnTwenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects.nnnRESULTSnSerum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days.nnnCONCLUSIONnThe human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.

Current concepts of the endocrine characteristics of normal menstrual function: The key to diagnosis and management of menstrual disorders

Obviously, the endocrine mechanisms involved in producing the normal, cyclic pattern of menstrual bleeding are exceedingly complex. A review of even our current, far from complete, knowledge of the regulation of follicular growth, cyclic selection of a single dominant follicle, ovulation, and the neuroendocrine control of all three mechanisms only serves to emphasize the myriad of endogenous and exogenous factors that may adversely affect such a delicate balance and be manifest in menstrual disturbance. Indeed, one may wonder that the menstrual cycle is cyclic and predictable at all. Nevertheless, the efficiency with which the system normally operates is striking. Its very complexity often makes disorders of menstrual function a not infrequent symptom of disease outside the reproductive tract, a fact that should stress the need for prompt and thorough evaluation.

The modern infertility evaluation

The modern diagnostic evaluation of the infertile couple reflects a growing reliance on assisted reproductive technologies and the trend toward a more evidence-based medical practice. The recommended evaluation no longer includes some of the traditional diagnostic tests, applies other tests more selectively, and includes a new test that helps to define a couples prognosis and best choice of treatment. All tests are easily performed, allowing clinicians to complete a basic but still thorough evaluation quickly and easily.

Maternal estradiol response to alterations in uteroplacental blood flow

Low levels of maternal estrogens are commonly regarded as indicators of fetal stress. We continuously monitored distal aortic blood flow by flowmeter, fetal heart rate, and amniotic fluid pressure in seven pregnant baboons near term. Four of the animals received a constant intravenous infusion of [7-3H]dehydroepiandrosterone and [4-14C]estradiol for 270 minutes. A 50% reduction in mean distal aortic blood flow was imposed after 60 minutes by means of partial occlusion of the aorta with a snare device and released at 180 minutes. Blood was collected at 10-minute intervals from 30 to 60 minutes, 120 to 180 minutes, and 240 to 270 minutes. Concentrations of dehydroepiandrosterone, dehydroepiandrosterone sulfate, estradiol, and cortisol in maternal plasma were determined by radioimmunoassay. Metabolic clearance rates of dehydroepiandrosterone and estradiol were calculated from plasma concentrations of [3H]dehydroepiandrosterone and [14C]estradiol. There was no significant change in maternal levels of dehydroepiandrosterone, dehydroepiandrosterone sulfate, or cortisol with alterations in distal aortic blood flow. Three animals exhibited no fetal heart rate evidence of fetal stress; estradiol levels declined during occlusion and returned toward control after release of the snare. Four animals exhibited repetitive late decelerations under conditions of reduced flow; estradiol was unchanged or rose slightly during occlusion but increased three- to 10-fold after release whereas the metabolic clearance rate of both dehydroepiandrosterone and estradiol remained stable. We conclude that placental hypoperfusion without fetal stress results in decreased conversion of aromatizable substrate and elevated maternal estradiol levels during acute hypoxemic fetal stress probably represent increased production of fetal androgen.

The Role of Progestational Agents in Hormone Replacement Therapy

Women seeking medical attention for complaints of vasomotor phenomena and symptoms related to the deterioration of estrogen-dependent tissues comprise an ever-increasing proportion of gynecologic care as the population ages and life expectancy beyond reproductive age continues to rise. There can be no question that estrogen replacement therapy can effectively relieve many of the disturbing and sometimes disabling symptoms of the perimenopausal and postmenopausal periods. The value of estrogen replacement in the arrest and prevention of osteoporosis and in reducing the general incidence of malignant disease and overall mortality has also become apparent. Enthusiasm over the benefits of postmenopausal estrogen has been tempered, however, by an appreciation for its causative link to the rise in incidence of endometrial cancer. Legitimate concerns have also been raised over estrogen-induced alteration of carbohydrate and lipid metabolism, its influence on clotting mechanisms, and impact on both benign and malignant breast disease.

Relationship of uteroplacental blood flow to placental clearance of maternal plasma C-19 steroids: Evaluation of mathematical models

The concept that the placental clearance of maternal plasma dehydroepiandrosterone sulfate through estradiol formation is a function of uteroplacental blood flow in women has been disputed. We obtained data on the clearance of maternal plasma dehydroepiandrosterone through placental estradiol formation in the baboon and used these data to evaluate some mathematical models of placental clearance. Our evaluation shows that the placental clearance of dehydroepiandrosterone is proportional to uteroplacental blood flow in the baboon.

Current Concepts of the Endocrine Characteristics of Normal Menstrual Function: The Key to Diagnosis and Management of Menstrual Disorders

Obviously, the endocrine mechanisms involved in producing the normal, cyclic pattern of menstrual bleeding are exceedingly complex. A review of even our current, far from complete, knowledge of the regulation of follicular growth, cyclic selection of a single dominant follicle, ovulation, and the neuroendocrine control of all three mechanisms only serves to emphasize the myriad of endogenous and exogenous factors that may adversely affect such a delicate balance and be manifest in menstrual disturbance. Indeed, one may wonder that the menstrual cycle is cyclic and predictable at all. Nevertheless, the efficiency with which the system normally operates is striking. Its very complexity often makes disorders of menstrual function a not infrequent symptom of disease outside the reproductive tract, a fact that should stress the need for prompt and thorough evaluation.