Testosterone levels and androgen-producing neoplasms.
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Androgens↗
Biomedical subjects
D R Meldrum
Publications and source records attributed to D R Meldrum.
Danazol inhibits steroidogenesis by the human ovary in vivo.
Gonadotropins, estradiol (E2), and the steroid precursors of ovarian estrogen secretion were examined in women on danazol to clarify actions of the medication on hypothalamic-pituitary-ovarian function. Follicle-stimulating hormone was not altered acutely after a single maximal dose or chronically during therapy, whereas a slight but significant increase in luteinizing hormone was noted during the 6 months of treatment. During danazol treatment, there was a blunted response of E2 to injections of human menopausal gonadotropins. The progestin and androgen precursors of E2 were reduced, with the exception of 17-hydroxypregnenolone, which was significantly increased. This 17-hydroxylase enzyme block persisted in spite of dexamethasone suppression of adrenal function. Therefore, the reduced ovarian secretion of E2 in women receiving danazol is due in part to reductions of ovarian precursor steroids for E2 synthesis, consequent to a direct ovarian action of the medication.
Adult↗
Ethiodol inhibits phagocytosis by pelvic peritoneal macrophages.
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Ascitic Fluid↗
Extracorporeal fertilization and embryo transfer in the treatment of infertility.
The study of human fertilization has assumed greater clinical importance as extracorporeal fertilization has been increasingly used to treat infertility. In vitro fertilization has advanced from years of struggle that preceded a single success to some programs that are able to establish pregnancy in a fifth or more of treatment cycles. The simpler procedure of donation of an early conceptus from an artificially inseminated female, now routine in animal husbandry, has only been recently accomplished in humans. With further refinements in methods of in vitro fertilization, virtually all women with an anatomically intact and healthy uterus may be able to establish a successful pregnancy.
Age Factors↗
Optimization of hydrogen-ion concentration during aspiration of oocytes and culture and transfer of embryos.
Rapid and marked shifts in pH can have deleterious effects on oocytes and embryos. Such shifts are most likely to occur during laparoscopy and examination of gametes and embryos. We studied the rate of pH change of follicular fluid and bicarbonate- and phosphate-based media during exposure to 100% CO2 with a constant surface area to volume ratio. All solutions tested developed a pH below the physiological range of 7.30-7.50 within 2 min of exposure to 100% CO2. We also examined the rate of increase in pH due to CO2 loss from media in room air within standard organ culture dishes and tubes. After exposure to ambient conditions for 2 min, the pH of modified Ham's F-10 medium in organ culture dishes rose above the physiological range. We have used a needle laparoscope to confirm intraperitoneal placement prior to the insufflation of a 5% CO2 gas mixture for laparoscopic oocyte retrieval. We have carried out all examinations of oocytes and embryos within a pediatric isolette equipped with an automatic CO2 controller to maintain a 5% CO2 environment. We have transferred embryos in 15% fetal cord serum to avoid the alkaline pH associated with a high concentration of equilibrated heat-inactivated preovulatory serum. These simple techniques can optimize the hydrogen-ion concentration of media during the entire process of in vitro fertilization and embryo transfer.
Carbon Dioxide↗
Acute ovarian responses to a long-acting agonist of gonadotropin-releasing hormone in ovulatory women and women with polycystic ovarian disease.
A long-acting agonist of gonadotropin-releasing hormone (GnRH-a, 100 micrograms/day) was administered daily for 14 days in four patients with polycystic ovarian disease (PCOD) and eight ovulatory women (OW) to determine acute hormone responses. Initiation of GnRH-a treatment in OW on day 5 of their menstrual cycles (OW-day 5) stimulated a greater acute rise of serum follicle-stimulating hormone (FSH) than that seen in OW beginning treatment on day 2 (OW-day 2) or PCOD patients. FSH levels fell to baseline values with repeated injections, whereas luteinizing hormone levels remained elevated in all patients. An acute rise and progressive fall of estradiol (E2) was found in all groups. The OW-day 5 group demonstrated a secondary increase, which by day 14 was clearly greater than that found in the other groups. This secondary increase of E2 in the OW-day 5 group was associated with lower abdominal pain, whereas OW-day 2 and PCOD patients were asymptomatic. For comparison, human menopausal gonadotropin (150 IU/day for 3 days) stimulated a significantly greater increase of E2 in OW-day 5 than in PCOD patients. These studies indicate that daily GnRH-a administration induced variable effects on ovarian function, which depended on when it was begun during the menstrual cycle and whether it was given to ovulatory or PCOD subjects. In addition, abdominal discomfort associated with GnRH-a use in regularly OW can be avoided by commencing agonist administration earlier in their menstrual cycles.
Abdomen↗
Management of endometriosis with gonadotropin-releasing hormone agonists.
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Cholesterol, HDL↗
Treatment of hot flashes with transdermal estradiol administration.
A randomized prospective double blind study was performed to assess the ability of a transdermal therapeutic system (TTS) delivering estradiol (E2) to suppress hot flashes (HFs) in symptomatic postmenopausal women. Patients were given placebo or E2 in four doses for a 20-day period, and serum gonadotropin and estrogen levels and the occurrences of HFs were measured. Administration of placebo had no measurable effect on either estrogen or gonadotropin levels or the occurrence of HFs. A dose-response relationship was found between the rate of E2 administered and the circulating level of E2, with 25, 50, 100, and 200 micrograms/24 h dosages raising the mean E2 concentrations from mean baseline levels of 5-8 pg/ml to 18, 38, 73, and 100 pg/ml, respectively. Estrone levels also increased with TTS application, but to a lesser extent than did E2 levels. Dose-response reductions of FSH and LH with increasing amounts of E2 administration occurred, but gonadotropin levels were not lowered in any of the patients into the ranges found in premenopausal women. TTS application significantly suppressed the occurrence of HFs at the 50 micrograms/24 h dosage and higher. A significant negative correlation (r = 0.6045; P less than 0.001) between E2 levels and the rates of occurrence of HFs was found during hormone administration. Based on this regression, 50% and 100% reductions of HFs should occur at 61 and 122 pg/ml E2. These data indicate that the transdermal delivery of E2 with these systems significantly reduced the occurrence of HFs and allowed definition of the therapeutic range of hormone replacement in terms of lost ovarian function, as reflected by circulating E2 levels.
Administration, Topical↗
NIH conference. Therapeutic applications of luteinizing-hormone-releasing hormone and its analogs.
The chemical structure of luteinizing-hormone-releasing hormone (LHRH) was discovered in 1971 after more than a decade of intensive effort. Subsequent physiologic studies in primates and humans showed that the biologic activity of LHRH depends on the way in which the hormone is administered. Pulsatile administration of LHRH, which mimics the natural secretory pattern, causes sustained secretion of the gonadotrophins. This method of administration has been used to induce ovulation in women with hypothalamic amenorrhea and to induce puberty and spermatogenesis in men with hypogonadotrophic hypogonadism. Continuous infusion, however, produces only transient stimulation of gonadotrophin secretion, followed by a "desensitization" response in which gonadotrophin secretion is inhibited. Thus, LHRH can either augment or inhibit gonadotrophin secretion depending on the mode of administration. Recently, long-acting synthetic analogs of LHRH have been shown to desensitize the pituitary gland and inhibit gonadotrophin release when administered as a single daily subcutaneous injection. These LHRH analogs have proved highly effective in the treatment of prostatic carcinoma and central precocious puberty. They are also being studied as a new approach to contraception and to the treatment of endometriosis and polycystic ovary syndrome.
Animals↗
Direct action of androgen on hot flushes in the human male.
Hot flushes (HF) were demonstrated definitively in a hypogonadal man by continuous recordings of finger temperature, skin resistance and subjective symptoms. The magnitudes and temporal interrelationships of these physiological changes were similar to those previously observed in oophorectomized women. HF were abolished by injections of methyl testosterone (MT) and during oral administration of fluoxymesterone (FM), a non-aromatizable androgen. Increases of the non-SHBG bound fractions of T and E2 were noted during MT therapy, either of which may have been responsible for suppression of HF. No significant changes of the non-SHBG bound levels of E2 were observed during FM ingestion. These data confirm that typical HF occur in the male and support the concept that androgen acts directly on the central nervous system without requiring aromatization to estrogen in the brain or other tissues.
Adult↗
Transvaginal ultrasound scanning of ovarian follicles.
The transvaginal approach to ultrasound scanning is a practical method complementary to the transabdominal technique for the minority of cases where, regardless of technological refinements, anatomic constraints require an alternative port of access to the pelvic cavity.
Female↗
The effects of naloxone on hot flashes and gonadotropin secretion in postmenopausal women.
Hot flashes have a close temporal relationship with the initiation of LH pulses, suggesting that factors stimulating gonadotropin release are involved in the mechanism of this disturbance. It has been reported that the opiate antagonist naloxone acutely blocked subjective hot flashes, a seemingly paradoxical effect, since the use of this agent in premenopausal women increases the magnitude and frequency of LH pulses. We, therefore, studied the effects of naloxone in 16 postmenopausal women with frequent hot flashes using continuous recordings of finger temperature and skin resistance as objective indices of flushing and perspiration, respectively. After baseline recordings, the subjects were randomized into equal groups, and the recordings were repeated during 8-h infusion of either saline or naloxone (22 micrograms/min). Serum gonadotropin levels were measured at 15-min intervals before and during the last 4 h of the infusion. Naloxone did not change the rate of objectively measured hot flashes, mean serum LH or FSH levels, or the frequencies or amplitudes of gonadotropin pulses. These data suggest that there is a very low input of endogenous opiates on gonadotropin secretion in postmenopausal women and that opioid peptides do not play a role in the initiation of the postmenopausal hot flash.
Aged↗
Stimulation of LH fragments with reduced bioactivity following GnRH agonist administration in women.
In eumenorrheic women with endometriosis and in oligo-amenorrheic women with polycystic ovarian disease (PCO), chronic administration of a long-acting GnRH agonist (GnRH-a) reduced the circulating concentrations of estrogens and androgens to levels similar to those of castrated women. The concommittant elevation of LH in both groups suggested that the measured immunoreactive LH had reduced bioactivity. In seven women with endometriosis, bioactive LH (BA LH) measured as the in-vitro secretion of testosterone by dispersed Leydig cells, was significantly (p less than 0.001) reduced from 10.8 +/- 1.2 (SEM) to 4.4 +/- 0.2 mIU/ml at the end of 28 days of GnRH-a therapy. In five women with PCO, BA LH decreased from 44.2 +/- 15.5 to 5.7 +/- 0.6 mIU/ml (p = 0.06). These changes of BA LH appeared to be responsible for the suppression of ovarian androgen secretion during GnRH-a treatment and in turn may have contributed to the profound decreases of estrogen production by reducing the amount of precursor androgen available for aromatization. Free alpha subunit levels increased simultaneously with the decrease of BA LH at the end of therapy, suggesting a post-receptor effect of GnRH-a. Beta subunit levels became undetectable. Cross-reaction of alpha subunit in the RIA for LH was sufficient to only partially account for the LH levels measured. On sephadex G-100 chromatography the excess immunoreactive material was detected at and immediately following the alpha subunit tracer. Further studies will be necessary to elucidate the chemical nature of the immunoreactive LH secreted during GnRH-a therapy.
Endometriosis↗
Further delineation of hypothalamic dysfunction responsible for menopausal hot flashes.
An association exists between pulsatile LH release and hot flashes (HFs). To further delineate the hypothalamic mechanism(s) responsible for HF, the basal levels and pulsatile release of LH, FSH, estradiol, and estrone and the rate of occurrence of HFs (measured objectively) were evaluated in patients with a defect of GnRH secretion [isolated gonadotropin deficiency (IGD)], patients with abnormalities of afferent input to GnRH neurons [hypothalamic amenorrhea (HA)], and postmenopausal women with severe HFs. Patients with IGD had received estrogens, which were discontinued before study. Patients with HA had experienced regular menses before disease onset, which followed emotional stress or weight loss. Studies were limited to HA patients with estrogen levels in the postmenopausal range. Pulsatile LH release was absent in patients with IGD and was absent or greatly reduced in women with HA. Objectively measured and subjectively experienced HFs occurred in IGD but not in HA patients. These results suggest that HFs are not an obligatory consequence of low endogenous estrogen levels and that the absence of episodic LH and GnRH release (IGD) does not influence the occurrence of HFs. It is possible that the dysfunction of afferent input to GnRH neurons in HA somehow prevents HFs in these women with low endogenous estrogen secretion.
Adult↗
Effects of the (imBzl)D-His6, Des-Gly analog of GnRH on gonadotropin and estradiol secretion in normal women.
The acute gonadotropin and estradiol responses following single subcutaneous injections of 10, 50, 100 and 200 micrograms of [(imBzl)]D-His6,Pro9-NEt]-GnRH were compared to those after 100 micrograms of [D-Trp6, Pro9-NEt]-GnRH. The gonadotropin responses after 50-100 micrograms of the D-His analog of GnRH were equivalent to those following 100 micrograms of the D-Trp analog. The ovarian E2 response, a reflection of the total cumulative secretion of gonadotropins, was similar at 100 micrograms of each analog. The estradiol response paralleled the increasing gonadotropin response accompanying the graded doses of the D-His analog, indicating the lack of a direct inhibitory action of this GnRH agonist on the ovary. Assessment of both gonadotropin and estradiol responses appears to be satisfactory for assessing relative potency among GnRH agonistic analogs.
Adolescent↗
Pituitary hormones during the menopausal hot flash.
Eighteen postmenopausal women with severe hot flashes had continuous recordings of finger temperature and skin resistance as objective indexes of flushing episodes, and serial measurements of anterior pituitary hormones as indirect indexes of hypothalamic neurotransmitter activity. Significant increases of growth hormone, adrenocorticotropic hormone (ACTH), and luteinizing hormone (LH) occurred with maximal concentrations at 30, five, and 15 minutes, respectively, after the onset of the skin temperature rises. No significant fluctuations of prolactin (PRL), thyroid-stimulating hormone (TSH), or follicle-stimulating hormone (FSH) were observed. The mean serum cortisol concentration increased 15 minutes after the hot flash, presumably consequent to the preceding elevation of ACTH. Pituitary ACTH release may be secondary to hypothalamic cooling, whereas increased growth hormone and LH output and the thermoregulatory adjustments comprising the flushing episodes are all consistent with cyclic episodes of increased hypothalamic norepinephrine activity.
Adrenocorticotropic Hormone↗
Origin of serum progestins in polycystic ovarian disease.
The glandular origin of excess circulating steroid hormones in women with polycystic ovarian disease has been difficult to establish with previously described perturbation techniques. Recently it was demonstrated that daily administration of a potent gonadotropin-releasing hormone agonist achieves complete and reversible suppression of ovarian steroid secretion. To examine the source of C-21 steroid hormones, circulating levels were measured before and after administration of the same agonist in polycystic ovarian disease subjects and normal control subjects. Serum levels of these hormones were also determined after administration of dexamethasone and adrenocorticotropic hormone (ACTH) as well as bilateral oophorectomy. Subjects with polycystic ovarian disease exhibited significant elevations of serum pregnenolone, 17OH -pregnenolone, and 17OH -progesterone by comparison with normal control subjects. The glandular origins of the excess levels of pregnenolone and 17OH -pregnenolone were more difficult to determine and appear to be different from that of 17OH -progesterone.
17-alpha-Hydroxypregnenolone↗
Estrogen replacement therapy by transdermal estradiol administration.
To determine whether the nonoral administration of estradiol (E2) might provide physiologic replacement without alteration of hepatic function, 20 postmenopausal women were studied before and after 3 weeks of treatment with either E2-containing transdermal therapeutic systems or placebo. Twenty premenopausal women were also studied. With E2-containing systems, serum E2 and estrone levels were restored to the premenopausal range. Variable responses of the different biochemical and biologic markers of the actions of E2 were observed. The most sensitive marker was vaginal cytology, with the E2 dosage reverting the maturation index to premenopausal values. Hot flashes, measured objectively, were reduced in frequency but not abolished. Serum levels of follicle-stimulating hormone and luteinizing hormone were lowered but remained higher than the premenopausal range. No significant changes were noted in urinary calcium/creatinine and hydroxyproline/creatinine ratios, which were used as markers of bone resorption. With active systems, no significant changes were noted in the concentrations of the hepatic proteins renin substrate and thyroxine-binding globulin or in the binding capacities of cortisol-binding globulin and sex hormone-binding globulin. These results indicate that transdermal E2 administration may be used to provide estrogen replacement while exerting limited effects on hepatic function.
Calcium↗