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A person with pure gonadal dysgenesis (XY) is described in whom peripheral leukocytes, skin, fascia, and both gonads were subjected to chromosomal analysis, confirming a lack of mosaicism. Previous case reports and the developmental and genetic basis for such an anomaly are reviewed. more...

Five women with endometriosis were given a daily dose of a potent long-acting GnRH agonist, D-Trp6-Pro9-Net-LHRH (GnRH-A) for 28 days in an attempt to suppress ovarian estrogen secretion. The mean level of estradiol (E2) during sampling over 24 hours decreased (P less than 0.01) from 62 +/- 11 to 10 +/- 1 pg/ml at the end of treatment. Mean concentrations of androstenedione, testosterone, estrone and E2 on day 28 of therapy were similar to those measured in oophorectomized women. The level of FSH was decreased (P less than 0.001) during GnRH-a, whereas that of LH was significantly (P less than 0.001) increased, suggesting differing intracellular control mechanisms for release of the two gonadotropins. Desensitization of the pituitary was demonstrated at the end of treatment by a complete lack of acute response of FSH or LH to the daily dose of GnRH-a. "Medical oophorectomy" provides a new approach to the treatment of endometriosis. more...

We conducted a dose-response study in 23 postmenopausal women to compare the physiologic effects of transdermal estradiol and oral conjugated equine estrogens. The doses studied were 25, 50, 100, and 200 micrograms of transdermal estradiol per 24 hours, and 0.625 and 1.25 mg of oral conjugated estrogens. Transdermal estradiol increased circulating concentrations of estradiol and estrone. Oral conjugated estrogens also raised the levels of estrogen, particularly estrone. Both preparations lowered gonadotropin levels, decreased the percentages of vaginal parabasal cells, increased the percentage of superficial cells, and lowered urinary calcium excretion. The effects of 0.625 and 1.25 mg of oral estrogens were similar to those of 50 and 100 micrograms of transdermal estradiol per 24 hours, respectively. Oral estrogens significantly increased circulating levels of renin substrate, sex-hormone-binding globulin, thyroxine-binding globulin, and cortisol-binding globulin; transdermal estradiol had no effect. The higher dose of oral estrogens had favorable effects on concentrations of low-density and high-density lipoproteins, but transdermal estradiol did not. Neither preparation affected any of the four clotting factors studied. These data indicate that transdermal estradiol can elicit many of the desirable actions of estrogen while avoiding the pharmacologic effects of oral estrogens on hepatic proteins. more...

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. more...

Six patients are described with hypothalamic amenorrhea and associated hypercarotenemia. The commencement of the hypothalamic amenorrhea followed weight reduction or stress in each case. The subjects were otherwise healthy and had none of the associated stigmata of anorexia nervosa. None of the subjects had ingested excessive quantities of vegetables or fruits rich in carotene. Although all six patients had elevated serum carotene levels, only three had clinically apparent yellow pigmentation of the skin. The exact mechanism responsible for hypercarotenemia in patients with hypothalamic amenorrhea is not apparent. Mobilization of lipid stores and catabolic changes occurring with weight-loss states appear to be related in some undefined way to the elevated carotene levels. more...

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. more...

Persistent suppression of gonadotropin and ovarian steroid production can be achieved in women with polycystic ovarian disease (PCO) by daily administration of a long-acting GnRH agonist (GnRHa). This study was designed to determine the patterns of recovery of clinical responses and hormonal secretion after chronic GnRHa administration in women with PCO. Six women with PCO were treated with daily sc injections of [D-His6(imBzl),Pro9-NEt]GnRHa (100 micrograms) for 6 months. Blood samples were obtained at the time of and three times weakly for 90 days after discontinuation of agonist therapy. In five women who did not ovulate, the suppressed serum FSH levels rose to pretreatment values within 10 days. In contrast, a gradual and progressive increase in serum LH (as measured by bioassay and immunoassay) was apparent by day 18. The LH increase coincided with progressive increases in serum estrone (E1), androstenedione, and testosterone. Serum estradiol (E2) began to rise on day 28. All hormones returned to their pretreatment baseline values within the 90-day recovery interval, with the exception of E2. Trend analysis of the slopes of recovery revealed that the incremental secretion patterns of E1, E2, androstenedione, and testosterone differed significantly from that of FSH, but not from those of bioactive or immunoactive LH. Serum progesterone, dehydroepiandrosterone sulfate, and cortisol did not change after withdrawal of GnRHa. One woman ovulated spontaneously on day 52 before which her hormone secretion patterns were indistinguishable from those of the other women. In summary, 1) during recovery after discontinuation of chronic GnRH agonist therapy the patterns of FSH and LH release suggested resumption of endogenous GnRH action on the pituitary with greater release of FSH than LH, a pattern that would be expected in the absence of ovarian steroid influence; 2) the lack of early estrogen production despite the increase in serum FSH concentrations suggests inadequate FSH secretion, abnormal ovarian responsiveness to FSH, or impaired FSH bioactivity; 3) androgen secretion was provoked by the increase in LH secretion; 4) per unit LH measured by bioassay, greater ovarian androgen secretion was stimulated in PCO than ovulatory women; and 5) the likelihood of spontaneous ovulation during recovery was minimal. more...

This report describes the use of celite partition chromatography to separate the A and E prostaglandins. The stationary phase consists of a glycine-HCL buffer, pH 3.6-3.7. The mobile phase consists of mixtures of ethyl acetate in toluene. At this critical hydrogen ion concentration of the stationary phase, the two prostaglandin groups are clearly separated on the basis of their difference in polarity, with greater than 95% recoveries and only 5% overlap of the elution patterns. It is anticipated that specific radioimmunoassays can be achieved by combining this system with partially specific antisera. more...

Six postmenopausal women, who were experiencing frequent hot flashes, had an 8 h continuous recording of skin temperature over the dorsum of the finger as an objective index of hot flashes. Frequent blood samples were obtained during the time of the recording for the measurement of serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels. During the 48 h of recording 34 significant temperature elevations were recorded and 32 were associated with a subjective hot flash. 3l pulses of LH release were also observed with 26 occurring simultaneously with the temperature rises. Correlation analysis of simultaneous skin temperature and circulating LH levels showed a significant positive correlation (p less than 0.01). FSH levels showed no consistent relationship with skin temperature. These data suggest that LH or the factors that trigger its pulsatile release are related to the mechanism responsible for the initiation of hot flashes. more...

The changes in cutaneous and body temperature and cutaneous conductance during hot flushes in eight postmenopausal women were studied. The vasomotor changes occurred approx. 45 sec after the patients experienced the initial subjective symptoms of the attacks. The rise in skin conductance appeared to be a more reliable index of the flushing episode than did the change in skin temperature. On the basis of the changes recorded it is suggested that the hot flush syndrome may represent a specific thermoregulatory disorder rather than being due to a non-specific central autonomic discharge. The episodes may be triggered by a neuroendocrine imbalance following the disruption of ovarian function and fall in estrogen production. In assessing the frequency and severity of hot flushes, and the effects of treatment, objective measurements of skin and core temperature and skin conductance should replace subjective criteria. more...

Previously, we reported that short term administration of a highly potent GnRH agonist (GnRHa) for 1 month to patients with polycystic ovarian disease (PCO) resulted in complete suppression of ovarian steroidogenesis without measurable effects on adrenal steroid production. This new study was designed to evaluate the effects of long term GnRHa administration in PCO patients with respect to their hormone secretion patterns and clinical responses. Eight PCO patients and 10 ovulatory women with endometriosis were treated daily with sc injections of [D-His6-(imBzl]),Pro9-NEt]GnRH (GnRHa; 100 micrograms) for 6 months. Their results were compared to hormone values in 8 women who had undergone bilateral oophorectomies. In response to GnRHa, PCO and ovulatory women had rises of serum LH at 1 month, after which it gradually declined to baseline. In both groups FSH secretion was suppressed throughout treatment. Serum estradiol, estrone, progesterone, 17-hydroxyprogesterone, androstenedione, and testosterone levels markedly decreased to values found in oophorectomized women by 1 month and remained low thereafter. In contrast, serum pregnenolone and 17-hydroxypregnenolone were partially suppressed, and dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol levels did not change. Clinically, hyperplastic endometrial histology in three PCO patients reverted to an inactive pattern, and proliferative endometrium in two other PCO patients became inactive in one and did not change in the other. Regression of proliferative endometrial histology occurred in all ovulatory women. Vaginal bleeding occurred in all women studied during the first month of GnRHa administration, after which all but one PCO patient became amenorrheic. Hot flashes were noted by all ovulatory women and by four of eight PCO patients. All PCO patients noted subjective reduction of skin oiliness, and five had decreased hair growth. We conclude that in premenopausal women: 1) chronic GnRHa administration results in apparently complete persistent suppression of ovarian steroid secretion; 2) adrenal steroid secretion is not influenced directly or indirectly; and 3) its use may be helpful in the treatment of endometrial hyperplasia and ovarian androgen excess in women with PCO. more...

To examine the possible relationship between the occurrence of menopausal hot flushes and waking episodes, a study was conducted of nine postmenopausal women with severe hot flushes and five asymptomatic premenopausal women. Measurement of simultaneous changes of finger temperature and skin resistance over the sternum was used as an objective marker of hot flushes. During cumulative sleep 47 objectively measured hot flushes occurred, and 45 were associated with a waking episode measured by polygraphic techniques. In eight of nine subjects, a significant correlation was observed between the occurrence of hot flushes and waking episodes. A similar association was not observed in premenopausal subjects. Estrogen administered to symptomatic patients resulted in significant reductions of both hot flushes and waking episodes. These data suggest the menopausal flushes are associated with a chronic sleep disturbance, and both can be improved by estrogen therapy. more...

Circulating estradiol (E2), estrone (E1), adrostenedione, and testosterone levels were measured in 40 normal postmenopausal women of widely varying body weights. The fasting urinary calcium to creatinine ratio (Ca:Cr) was also quantitated as an index of bone resorption. Significant positive correlations of E2 and E1 were found with body weight and correlations of E2 and E1 were found with body weight and percent ideal weight but not with height, age, or years since menopause. No correlations were observed between circulating androstenedione and testosterone levels and any of these characteristics. Significant negative correlations were noted between Ca:Cr and percent ideal weight and between Ca:Cr and E2 and E1 concentrations. Administration of 10 micrograms ethinyl E2 to 10 postmenopausal subjects for 30 days reduced Ca:Cr to the level observed in 20 premenopausal women. These data suggest that body weight can influence urinary calcium excretion. It is possible that the reduced amounts of endogenous estrogen found in conjunction with low body weight may be a factor contributing to the greater loss of urinary calcium and the more frequent occurrence of osteoporosis in slender postmenopausal women. more...

Pituitary suppression with leuprolide acetate (LA) was used before and during ovarian stimulation with human menopausal gonadotropins in 45 consecutive women having their first cycle of in vitro fertilization embryo transfer (IVF-ET). As anticipated, a low rate of cycle cancellation (6.7%) was necessary for poor responses. Follicles were allowed to develop to a larger diameter than with our prior protocol without LA. On the day of human chorionic gonadotropin (hCG), 11.5 + 0.7 follicles of at least 1.0 cm were visualized; 11.7 + 0.9 oocytes were retrieved; 67.5% fertilized and 6.7 + 0.6 normal embryos were available for transfer. Of the 3.4 + 0.1 embryos transferred per patient, 24.6% implanted. The rates of clinical pregnancy per retrieval and per stimulation were 54% and 47%, respectively, of which 23.8% aborted. Routine use of LA resulted in a highly efficient level of ongoing pregnancy per initiated cycle, and therefore may produce a superior first cycle for IVF-ET. more...

To examine the relationship between the occurrence of menopausal hot flashes and the pulsatile release of LH, we have investigated the serum hormone levels and the occurrence of hot flashes by objective recordings in five women with endometriosis given daily injections of a long-acting GnRH agonist (GnRH-a) for 28 days. Results were compared to the findings made in 25 young women 6-8 weeks after bilateral oophorectomy. Serum levels of estrone and estradiol were similar in the subjects given GnRH-a and the women who underwent a surgical castration. In comparison with values before GnRH-a administration, the mean FSH level was lower whereas the mean LH concentration was significantly higher (P less than 0.01) on the last day of therapy. The coefficients of variations of both gonadotropins measured during 4-h sampling periods at 20-min intervals before and at the end of GnRH-a administration were significantly reduced (P less than 0.01) with therapy. During the total of 20 h of frequent sampling in the 5 subjects, 15 pulses (20% rise from nadir) of LH and 12 pulses of FSH were detected before GnRH-a, whereas only 2 and 8 pulses, respectively, were observed on day 28 of treatment. Hot flashes were observed in both groups of patients. The proportion of women experiencing hot flashes, the rate of occurrence/h and the characteristics of the physiological changes were similar in the 2 groups of women. These data indicate that hot flashes can occur in the absence of prominent LH pulses, suggesting the pulsatile release of this hormone is merely associated with the hot flash rather than being etiological. more...

Five women with prior suboptimal ovarian stimulation for in vitro fertilization and embryo transfer (IVF-ET) were pretreated with a long-acting gonadotropin-releasing hormone (GnRH) agonist beginning in the midluteal phase of the preceding menstrual cycle. The four women with normal luteal function had castrate estrogen levels following regression of the corpus luteum, whereas one woman with an abnormal luteal phase and perimenopausal levels of gonadotropins had an agonistic response. In the three women with adequate stimulation, 20 oocytes were obtained and one women became pregnant. Initiation of GnRH agonist therapy during the luteal phase of a normal menstrual cycle may be an efficient way of obtaining ovarian suppression without an agonistic response. more...

To determine whether vaginal administration of conjugated equine estrogens (VCE) could provide physiological replacement while avoiding effects on hepatic function, as occurs with oral administration, a study was conducted in which 20 postmenopausal women were evaluated before and after the vaginal administration of CE. The dosages studied were 0.3, 0.625, 1.25, and 2.5 mg/day for 4 weeks. Twenty premenopausal women were also studied, and their values were presumed to reflect normal physiological function. The findings in the postmenopausal women were compared with previously reported results obtained in a similar group of subjects given oral CE (OCE). Vaginal cytology returned to premenopausal values with 0.3 mg VCE. This response was similar to that exerted with 1.25 mg OCE. Stepwise increases in circulating estrone and estradiol occurred with increasing dosages. The 2.5-mg dosage of VCE raised estrone levels to values similar to those in premenopausal women in the late follicular phase, and estradiol concentrations were similar to early follicular phase concentrations. Limited or no responses of the systemic markers of estrogen action occurred with all doses of VCE. Small decreases in LH and FSH levels occurred, but no dosage significantly reduced the level of either gonadotropin. Although the urinary calcium to creatinine ratio was significantly reduced by the two largest dosages of VCE, the effect of the 2.5-mg dosage was less than that observed with 0.625 mg OCE, the lowest dosage that protects against osteoporosis. Hepatic protein synthesis was significantly increased only by the higher dosages tested. No dosage had a significant effect on circulating levels of triglycerides or total or fractionated cholesterol levels. These data suggest that the vaginal administration of CE exerts mainly a local effect, with limited or no measurable changes in systemic markers of the action of estrogen. more...

The present study was designed to validate and standardize a technique of continuous recording of skin temperature of the finger as an objective index of hot flashes. Significant skin temperature rises (greater than 1 degree C) were recorded in close temporal relationship to 69% of subjective hot flashes experienced by seven postmenopausal women. The temperature elevations occurred at an interval of 54 +/- 10 minutes (mean +/- standard error) and lasted an average of 31 minutes. The mean increase was 2.7 degrees +/- 0.2 degrees C. The extent of the temperature elevations found in the postmenopausal subjects was significantly greater than in premenopausal control subjects (P less than 0.05) and was reduced by estrogen treatment (P less than 0.02). This study substantiates that the recording of skin temperature changes of the finger provides an objective index of hot flashes. This should assist in the investigation of the underlying disturbance and provide more accurate evaluation of modes of therapy. more...

Addition of serum to culture medium during washing of sperm was shown to significantly improve sperm motility upon subsequent 24-hour incubation, distinct from the beneficial effects of adding serum after washing. Commercial sources of human and bovine albumen tested did not preserve motility as well as serum, but addition to serum showed that the lesser effect was probably due to toxic contaminants. One of the most commonly available disposable plastic syringes was found to be markedly toxic to sperm. The materials found to have sperm toxicity also manifested toxicity to mouse embryos. These findings show that a similar degree of caution is advisable in testing of materials contacting sperm in vitro to that which has become standard practice for culture of human embryos. more...

Calcitonin secretion was studied in 50 normal females from 20--69 yr of age, with 10 subjects in each decade. Hormone measurements were made by RIA during response to a 10-min infusion of calcium (as the chloride salt) at 3 mg/kg BW. There was a progressive decrease of the calcium-stimulated plasma calcitonin with age. Linear regression analysis demonstrated a significant (P less than 0.05) negative correlation (r = 0.29) between calcitonin response and age. Postmenopausal females had a significantly (P less than 0.01) smaller calcitonin response than premenopausal females. The time of maximum calcitonin response progressively shifted from 10 min in the younger subjects to 20 min in the older subjects. These studies demonstrated that calcitonin secretion decreases with age in females. This decrease may play some role in the pathogenesis of the progressive loss of bone mass which occurs with aging in females. more...

During the first 2 1/2 years of operation of the University of California at Los Angeles in vitro fertilization-embryo transfer program, 47 clinical pregnancies were achieved in 154 laparoscopies for oocyte aspiration (31%). Two of these pregnancies were achieved through transfer of cryopreserved embryos when ongoing pregnancy did not result from embryo transfer in the stimulated cycle. An increase in clinical implantation was noted with a reduction of transfer volume and proportion of air, with 34% of laparoscopies being followed by clinical pregnancy over the last 18 months. No difference in the rate of clinical pregnancy was noted relative to uterine depth or position. The high rate of multiple implantation (47%) suggested a high level of embryo quality. The success rate was attributed to a strong ovarian, human menopausal gonadotropin stimulation, accurate timing of human chorionic gonadotropin, a high oocyte retrieval rate, meticulous laboratory technique, atraumatic, high-fundal transfer of embryos, and initiation of embryo cryopreservation. more...

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. more...

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. more...

Tubal reanastomosis was performed in 32 patients using microsurgical techniques. In 25 women, occlusion was due to prior sterilization. A splint was not used during or after repair. Intrauterine pregnancy occurred in 21 (84%) and fetal loss in 6% of 17 potentially viable pregnancies. The mean midluteal serum progesterone level of previously sterilized patients (13.4 +/- 1.0 ng/ml) was similar to the level in normal partners of infertile men (12.9 +/- 1.5 ng/ml) and in women with other tubal causes of infertility (14.3 +/- 1.1. ng/ml). Seven patients with occlusion due to disease achieved postoperative patency; there were 4 (57%) intrauterine pregnancies and 1 tubal gestation. The author concludes that a splint is not necessary in performing tubal reanastomosis and that there is no clinical or laboratory evidence of luteal insufficiency in this group of previously sterilized women. more...

Following menopause, some women are troubled by hot flashes (episodes of flushing and perspiration), whereas others do not experience the symptom. To determine whether the extent of estrogen deficiency influences the occurrence of the disturbance, the authors measured the levels of estradiol (E2), estrone (E1), and sex-hormone binding globulin (SHBG), and the percent and total non-SHBG-bound E2 in 24 women with frequent hot flashes and 24 women who had never experienced the symptom. Significantly lower levels of E2 (P less than .002), E1 (P less than .05), percent non-SHBG E2 (P less than .05), and total non-SHBG-bound E2 (P less than .01) were found in the symptomatic women. Similar differences were confirmed in 18 subject pairs matched for age, years since menopause, and presence or absence of ovaries. The finding of a significantly (P less than .05) lower percent ideal body weight in the women with hot flashes suggests that the known effects of body weight on the rate of extraglandular estrogen production and the level of SHBG in postmenopausal women may be important variables determining the occurrence of hot flashes. more...

The ovarian-peripheral gradients of various delta4 and delta5 steroids were determined for a patient with virilizing arrhenoblastoma. The high peripheral testosterone level accompanying this tumor results from increased precursor supply from both the delta4 and delta5 pathways, with the delta5 pathway predominating, and from negligible aromatase activity. A review of 45 cases of androgen-producing ovarian tumors with measurement of peripheral venous testosterone, and of 24 cases with measurement of ovarian venous testosterone, and a comparison with findings in 159 patients with hirsutism of functional origin reveal the following 1) An androgen-producing tumor must be ruled out when peripheral testosterone exceeds 2 ng/ml; 2) an ovarian venous testosterone level exceeding 20 ng/ml generally accompanies a tumor, particularly when the tumor is less than 5 cm in diameter; and 3) virtually all (98%) of the tumors reviewed were accompanied by virilization, regardless of the peripheral concentration of testosterone. more...

Sixteen women with endometriosis were treated with daily subcutaneous injections of a potent agonist of gonadotropin-releasing hormone (GnRH) for six months. Ovarian estrogen secretion was reduced to castrate levels during most of the course of treatment. Blinded evaluation of laparoscopic photographs confirmed marked suppression of visually apparent disease, but biopsy specimens showed occult, inactive endometriosis in most cases. Marked pain relief was noted by all patients. As a result of this "medical oophorectomy," the women experienced severe hot flashes, and many had insomnia and emotional disturbances. Vaginal cytology showed menopausal changes but related symptoms were generally mild. Calcium excretion rose to menopausal levels. High-density lipoprotein and total cholesterol remained unchanged. These results indicate that GnRH agonist administration has impressive effects on endometriotic implants, and these actions may be enhanced with longer therapy. Further development of this new form of therapy should involve either use of lesser degrees of ovarian suppression or adjunctive therapy to counter the side effects of "medical oophorectomy." more...

The effectiveness of clonidine in suppressing the occurrence of postmenopausal hot flashes was examined using a dose-response study design and objective recordings of hot flashes. Patients with frequent flashes were studied before and after oral administration of placebo and 0.1, 0.2, and 0.4 mg of clonidine daily for 2 weeks at each dose level. Finger temperature and skin resistance were recorded as indices of hot flash episodes. Four of 10 subjects beginning the study withdrew because of drug-related side effects. Clonidine was found to reduce significantly the frequency of hot flashes as compared with baseline (P less than .005) and with effects of the placebo (P less than .05). At the maximum dosage the mean rate of hot flash occurrence decreased 46%. It was concluded that clonidine does reduce the frequency of postmenopausal flashes. more...

The present study was undertaken to evaluate objective methods of monitoring postmenopausal hot flashes. Continuous recordings of finger and core temperature and sternal skin conductance were carried out in 8 postmenopausal and 4 premenopausal women. Four postmenopausal patients were studied a second time following 30 days of daily oral administration of ethinyl estradiol 0.05 mg. One hundred twenty flashes were subjectively noted and recorded during 104 hours of study in the postmenopausal women. Eighty-two, 98, and 81% of subjective flashes were associated with changes in finger temperature, skin conductance, and core temperature, respectively. The rate of occurrence and magnitude of changes of physiologic markers were significantly greater (P less than .01) in postmenopausal than premenopausal women. Estrogen replacement therapy not only eliminated the subjective sensations but also significantly reduced (P less than .02) the frequency and magnitude of the changes in physiologic function measured by finger temperature. Measurement of skin conductance changes was the single most sensitive and specific indicator of hot flashes. The simultaneous change of both skin conductance and finger temperature, although less sensitive, was a very specific indicator of a hot flash. These results support the concept that the measurement of physiologic changes can be used to assess objectively the occurrence of this symptom complex. more...

To avoid the risks of oestrogen therapy in post-menopausal women, we have examined the effects of a progestin, megestrol acetate (MA), on hot flushes and bone metabolism. Ten normal post-menopausal women were studied before and after the oral administration of 20, 40 and 80 mg of MA daily for 4 wk at each dose level. Finger temperature and skin resistance were recorded for 8 h as objective indices of flushing and perspiration, respectively. The fasting ratios of urinary calcium: creatinine (Ca/Cr) and hydroxyproline: creatinine (OHPr/Cr) were used as indices of bone resorption. A reduction (P less than 0.01) of flushing episodes was noted on all dose levels of MA, with 56, 11, 6 and 1 flushes occurring on 0, 20, 40 and 80 mg of medication. A decrease (P less than 0.05) of Ca/Cr was noted only with 80 mg of MA, whereas OHPr/Cr remained unchanged. We conclude that progestin therapy may provide an alternative mode of treatment for post-menopausal hot flushes. Definitive demonstration of an effect on post-menopausal bone resorption will require a long-term study of bone density. more...

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. more...

Estrogen replacement therapy is one of the most controversial issues in the field of reproductive medicine. Indications for its use include hot flashes, vaginal atrophy, and risk of osteoporosis. Risk of heart disease may also be an indication but this use has not been firmly established. The role of estrogen replacement therapy in aging changes of skin needs clarification. Complications of therapy include endometrial cancer, breast cancer, hypertension, hyperlipidemia, and gallbladder disease. The last three complications presumably result from hepatic actions of estrogen replacement therapy. more...

The hormonal effects of danazol and of a long-acting gonadotropin-releasing hormone analogue (GnRH-a) were studied in women with endometriosis and those with oophorectomy. During danazol treatment, total serum concentrations of estrone and estradiol, and free, dialyzable estradiol were reduced to the low follicular phase range for premenopausal women. Corresponding estrogen levels were suppressed to a significantly greater degree (P less than .02) at the end of GnRH-a administration, to concentrations which were twofold to fourfold lower than with danazol therapy and similar to values in the oophorectomized women. Sex hormone binding globulin was markedly suppressed (P less than .001) throughout danazol treatment, resulting in a threefold elevation (P less than .01) of free testosterone. These data suggest that danazol may affect endometriosis by mechanisms other than by inducing a pseudomenopause. The increased tissue availability of testosterone may be responsible for acne and hirsutism observed in some women during danazol treatment and may inhibit proliferation of the ectopic endometrium. Medical oophorectomy using GnRH-a may have improved effects on endometriosis without the androgenic side effects of danazol. more...

The time course of suppression of ovarian estrogen production and follicular development with leuprolide was examined in 40 normal women before ovarian stimulation for in vitro fertilization (IVF). Initiation of leuprolide during the midluteal phase caused a significantly more prompt suppression than when treatment was started during the early follicular phase (day 1). Injection of the same total amount of leuprolide in two divided doses also caused a significantly more prompt suppression. These two methods were consistent enough to make routine use of leuprolide practical before ovarian stimulation for IVF. more...

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. more...

The responses of the blood coagulation and related systems were studied in 23 postmenopausal women, all of whom received, in randomized order, therapy with conjugated oral estrogens (0.625 and 1.25 mg daily) and transdermally administered estradiol in doses of 25, 50, 100, and 200 micrograms/24 hr. Neither plasma fibrinopeptide A determinations nor plasma fibrinogen chromatographic findings were altered; thus there is no evidence of accelerated fibrinogen turnover with either form of therapy. However, alpha 1-antitrypsin and plasminogen concentrations were significantly increased with the higher dosage of oral but not with transdermally administered estrogen. Similarly, ceruloplasmin concentration was significantly elevated with both oral doses but was unchanged by transdermal therapy. more...

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. more...

to examine the possible effects of aging on circulating steroid hormones in postmenopausal women, blood samples were drawn from 155 women, aged 34 to 83 years, with spontaneous ovarian failure. The C-21 steroids, pregnenolone and 17-hydroxypregnenolone; the delta 4 progestins, progesterone and 17-hydroxyprogesterone; and cortisol did not change with age and were similar in concentration to the levels measured during the follicular phase of premenopausal women. The delta 5 androgens, dehydropiandrosterone and dehydroepiandrosterone sulfate, declined significantly (P less than .001) with age, whereas no change was noted in the delta 4 androgens, androstenedione and testosterone. The levels of estradiol (E2) and estrone (E1) were strongly correlated with percent ideal weight but did not change with age. The authors conclude that 1) The production of progestins does not change with age in normal adult women, other than that resulting from the loss of secretion associated with ovarian corpus luteum function. 2) The decline of delta 5 androgens without corresponding changes in their precursors suggests an age-related change of adrenal 17,20 desmolase activity. 3) The levels of E2 and E1 reflect an effect of body size but not of age on peripheral aromatization of precursor androgens. more...

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. more...