Effect of estrogen supplementation on exercise thermoregulation in premenopausal women.

This study examined the effects of 3 days of estrogen supplementation (ES) on thermoregulation during exercise in premenopausal (20-39 yr) adult women during the follicular phase of the menstrual cycle. Subjects (11 control, 10 experimental) performed upright cycle ergometer exercise at 60% of maximal O2 consumption in a neutral environment (25 degreesC, 30% relative humidity) for 20 min. Subjects were given placebo (P) or beta-estradiol (2 mg/tablet, 3 tablets/day for 3 days). All experiments were conducted between 6:30 and 9:00 AM after ingestion of the last tablet. Heart rate, forearm blood flow (FBF), mean skin temperature, esophageal temperature (Tes), and forearm sweat rate were measured. Blood analysis for estrogen and progesterone reflected the follicular phase of the menstrual cycle. Maximal O2 consumption (37.1 +/- 6.2 in P vs. 38.4 +/- 6.3 ml. kg-1. min-1 in ES) and body weight-to-surface area ratio (35.58 +/- 2.85 in P vs. 37.3 +/- 2.7 in ES) were similar between groups. Synthesis of 70-kDa heat shock protein was not induced by 3 days of ES. Neither the threshold for sweating (36.97 +/- 0.15 in P vs. 36.90 +/- 0.22 degreesC in ES), the threshold for an increase in FBF (37.09 +/- 0. 22 in P vs. 37.17 +/- 0.26 degreesC in ES), the slope of sweat rate-Tes relationship (0.42 +/- 0.16 in P vs. 0.41 +/- 0.17 in ES), nor the FBF-Tes relationship (10.04 +/- 4.4 in P vs. 9.61 +/- 3.46 in ES) was affected (P > 0.05) by 3 days of ES. We conclude that 3 days of ES by young adult women in the follicular phase of their menstrual cycle have no effect on heat transfer to the skin, heat dissipation by evaporative cooling, or leukocyte synthesis of 70-kDa heat shock protein.

Cost-effectiveness of infertility treatments: a cohort study.

OBJECTIVE: To determine the cost-effectiveness of infertility treatments. DESIGN: Retrospective cohort study. SETTING: Academic medical center infertility practice. PATIENT(S): All patients treated for infertility in a 1-year time span. INTERVENTION(S): Intrauterine inseminations, clomiphene citrate and IUI (CC-IUI), hMG and IUI (hMG-IUI), assisted reproductive techniques (ART), and neosalpingostomy by laparotomy. MAIN OUTCOME MEASURE(S): All medical charges and pregnancy outcomes associated with the treatments were obtained. Cost-effectiveness ratios defined as cost per delivery were determined for each procedure. The effects of a woman's age and the number of spermatozoa inseminated on cost-effectiveness of the procedures was also determined. RESULT(S): Intrauterine inseminations, CC-IUI, and hMG-IUI have a similar cost per delivery of between $7,800 and $10,300. All of these were more cost-effective than ART, which had a cost per delivery of $37,000. Assisted reproductive techniques in women with blocked fallopian tubes was more cost-effective than tubal surgery performed by laparotomy, which had a cost per delivery of $76,000. Increasing age in women and lower numbers of spermatozoa inseminated were factors leading to higher costs per delivery for IUI, CC-IUI, hMG-IUI, and ART. Use of donor oocytes reduced the cost per delivery of older women to the range seen in younger women with ART. CONCLUSION(S): Our analysis supports, in general, the use of IUI, CC-IUI, and hMG-IUI before ART in women with open fallopian tubes. For women with blocked fallopian tubes, IVF-ET appears to be the best treatment from a cost-effectiveness standpoint.

The effectiveness of sublingual progesterone administration during cryopreserved embryo transfer cycles: results of a matched follow-up study.

OBJECTIVE: To compare cryopreserved ET pregnancy rates in subjects receiving either sublingual parenteral P. DESIGN: Matched follow-up study. SETTING: University-based assisted reproduction program. PATIENTS: Women undergoing cryopreserved ET between January 1993, and December 1994. Cases received a hormone replacement protocol containing oral E2 and sublingual P and controls received a hormone replacement protocol containing oral E2 and parenteral P. Cases and controls were matched one-to-one according to age, number of embryos transferred, embryo grade, and route of ET. INTERVENTIONS: Cryopreserved embryos were thawed and transferred in all patients in an identical manner independent of the route of P administration. MAIN OUTCOME MEASURES: Clinical and ongoing pregnancy rates. RESULTS: Of 61 ET cycles performed in the sublingual P group, there were 16 clinical pregnancies (26.2%) and 12 ongoing pregnancies (19.7%). Of the 61 ET cycles in the parenteral P group, there were 14 clinical pregnancies (23.0%) and 11 ongoing pregnancies (18.0%). A chi 2 test revealed no significant differences in either clinical or ongoing pregnancy rates according to the route of P administration. CONCLUSIONS: This data suggests that sublingual P administration is an effective alternative to parenteral P administration in preparing the endometrium for the implantation of cryopreserved embryos.

Tubal versus uterine transfer of cryopreserved embryos: a prospective randomized trial.

OBJECTIVE: To compare pregnancy rates after fallopian tubal and uterine transfer of cryopreserved embryos. DESIGN: Prospective randomized trial with assignment to treatment groups by a random number table. SETTING: University of Iowa Hospitals and Clinics, a tertiary care academic institution. PATIENTS: Forty patients with patent fallopian tubes and at least three cryopreserved embryos. INTERVENTIONS: Cryopreserved embryos were thawed and transferred to the fallopian tube by laparoscopy or to the uterus by a transcervical catheter. MAIN OUTCOME MEASURES: Clinical and ongoing pregnancy rates. RESULTS: Tubal transfer of cryopreserved embryos resulted in statistically higher clinical (68% versus 24%) and ongoing pregnancy rates (58% versus 19%) when compared with uterine transfer. CONCLUSIONS: Tubal transfer of cryopreserved embryos is highly effective and offers an improved pregnancy rate when compared with uterine transfer of embryos. This method of transfer should be considered in patients with patent fallopian tubes and at least three cryopreserved embryos.

Primary hypothyroidism associated with multicystic ovaries and ovarian torsion in an adult.

BACKGROUND: Primary hypothyroidism is known to be associated with multicystic ovaries in juvenile females, but this association has been reported only once previously in an adult. This report describes an unusual case of bilateral multicystic ovaries occurring in an adult patient with profound hypothyroidism. CASE: A 26-year-old woman presented with an acute abdomen and bilateral adnexal masses. An emergency exploratory laparotomy revealed bilateral enlarged multicystic ovaries with torsion of the right ovary. Because this ovary was necrotic, it was removed; pathology revealed multiple hemorrhagic follicular cysts. Laboratory studies to evaluate the cause of the multicystic ovaries revealed negative serum beta-hCG, LH 0.7 IU/L, FSH 15.7 IU/L, and estradiol 80 pg/mL. The TSH value was greater than 50 IU/L and serum thyroxine was undetectable, demonstrating profound hypothyroidism. Subsequent thyroid hormone replacement was associated with resolution of the cysts in the remaining ovary. CONCLUSION: Profound hypothyroidism can cause multicystic ovaries in an adult. In the absence of ovarian torsion, surgery can be avoided, as thyroid hormone replacement leads to clinical resolution of the cysts within 3 months.

Early diagnosis of ovarian torsion by color Doppler ultrasonography.

Ovarian torsion is often difficult to diagnose because of the nonspecific nature of the clinical findings. We report on the use of color Doppler ultrasonography in diagnosing early ovarian torsion. This technique provides a highly specific finding, the absence of blood flow to the ovary, that greatly facilitates the diagnosis of ovarian torsion.

Long term follow-up of women with surgically treated prolactin-secreting pituitary tumors.

To examine the long term effectiveness of transsphenoidal microsurgery for patients with PRL-secreting pituitary tumors, we studied 54 women at yearly intervals after transsphenoidal surgery. Five years after surgery, 19 women (35%) had normal serum PRL concentrations, and 23 (43%) had persistent hyperprolactinemia. Hyperprolactinemia recurred in 12 of 31 patients (39%) who had normal PRL concentration 6 weeks after surgery. None of the patients with recurrent hyperprolactinemia had radiographic evidence of tumor regrowth, and only 3 of 12 had amenorrhea. A serum PRL level below 6 ng/ml 6 weeks after surgery occurred more frequently in cured patients than in those who had a recurrence. PRL responses to TRH were normal in cured patients 1 and 5 yr after surgery and abnormal in those who had recurrent hyperprolactinemia. The PRL responses to chlorpromazine- and insulin-induced hypoglycemia were blunted in patients with normal as well as elevated PRL levels. Patients with recurrent, as well as those with persistent, hyperprolactinemia had no nocturnal rise in serum PRL 5 yr after surgery. The 39% recurrence rate of hyperprolactinemia and persistent abnormalities in pituitary-hypothalamic regulation of PRL secretion after transsphenoidal surgery raise important questions about the choice of primary therapy for patients with PRL-secreting tumors.

Hyperprolactinemia and contraception: a prospective study.

The authors measured serum concentrations by single and multiple sampling techniques in 347 women before, during, and after treatment with either hormonal or barrier methods of contraception. The prolactin responses to an intramuscular injection of estrogen also were evaluated in control and selected study patients. The incidence of hyperprolactinemia in oral contraceptive users was higher than control subjects (12 versus 5%). Hyperprolactinemia was best assessed by multiple blood sampling, it is often transient and resolves spontaneously in about 50% of women. The estrogen provocation study suggests that some women who develop hyperprolactinemia while taking oral contraceptives are more sensitive to the effects of exogenous estrogen and may be at greater risk of developing pill-related menstrual aberrations and hyperprolactinemia.

Hyperprolactinemia in polycystic ovary syndrome.

With the use of multiple blood sampling, the prevalence of hyperprolactinemia in 150 consecutive patients with polycystic ovary syndrome (PCO) was found to be 17%. To further compare these two groups of PCO patients, the pituitary responses to gonadotropin-releasing hormone and thyrotropin-releasing hormone and the adrenal responses to dexamethasone suppression and adrenocorticotropic hormone stimulation were evaluated in 40 normoprolactinemic and 10 hyperprolactinemic PCO patients. Adrenal and pituitary perturbation tests were normal in both groups of PCO patients. Besides the higher levels of prolactin, the hyperprolactinemic patients also had higher blood levels of thyrotropin and testosterone, a higher luteinizing hormone/follicle-stimulating hormone ratio, lower levels of follicle-stimulating hormone, and lower follicle-stimulating hormone responses to gonadotropin-releasing hormone. Our data are consistent with the hypothesis that in some cases, the pathogenesis of PCO may be due to a central deficiency in dopaminergic activity at the basal hypothalamus. The hyperprolactinemia observed in a significant number of PCO patients may reflect a greater deficiency of hypothalamic dopamine, as manifested by the basal elevations of both prolactin and thyrotropin levels.

Effects of danazol on plasma lipid and lipoprotein levels in healthy women and in women with endometriosis.

Previous studies of the effects of danazol on lipid and lipoprotein levels have been conflicting and limited to women with endometriosis. In the present study, plasma levels of lipids and lipoprotein-cholesterol and triglycerides were determined in 25 infertile women with endometriosis and in eight normal women before, during, and after treatment with danazol at daily doses of 200 to 800 mg for 2 to 6 months. Pretreatment values of cholesterol, triglycerides, and lipoprotein were within the normal range in all subjects except three (one with type III and two with type IV hyperlipoproteinemia). During treatment, the mean levels of total cholesterol and triglycerides decreased slightly, while no significant changes in low-density and very low-density lipoproteins were seen. However, a marked (40%) reduction in the mean levels of high-density lipoprotein cholesterol and triglycerides occurred (P less than 0.001) within 4 weeks of therapy in all subjects, which persisted for the duration of the treatment. Patients with pretreatment hyperlipoproteinemia experienced a substantial fall in plasma lipids and lipoprotein and had normal lipoprotein profiles during treatment. Within 4 weeks after danazol was discontinued, all changes in plasma lipid and lipoprotein levels returned to pretreatment levels. These findings have important implications for the atherogenic potential of danazol, a new treatment for hyperlipidemia, and the relationship between gonadal hormones and lipoprotein levels.

Danazol: endocrine consequences in healthy women.

We studied the effects of danazol on pituitary and gonadal function in seven normal women who volunteered to take danazol, 400 mg twice daily, for 2 months. We measured circulating levels of sex steroids, gonadotropins, and prolactin on alternate days throughout a control menstrual cycle and during treatment. Danazol inhibited ovulation in all subjects. The amenorrheic state induced by danazol was characterized by normal basal levels of gonadotropins, prolactin, and estrogen. Serum androgen levels were significantly increased as was the urinary excretion of 17-ketosteroids. The LH and FSH responses to gonadotropin-releasing hormone were enhanced during treatment, and there was a normal LH rise following administration of estradiol valerate, indicative of intact positive feedback. These observations fail to support the contention that danazol suppresses pituitary gonadotropin secretion or directly inhibits steroidogenesis. The results suggest that danazol may have a primary site of action at the ovary by suppressing the normal, orderly process of follicular maturation.

Endocrine consequences of continuous antiestrogen therapy with tamoxifen in premenopausal women.

Daily administration of estrogen antagonists to premenopausal women has been incorporated into the adjuvant treatment of breast cancer. We have studied the changes in reproductive hormones, pituitary responses to hypothalamic-releasing hormones, and endometrial histology during treatment with the antiestrogen tamoxifen in five healthy, premenopausal women. These studies were carried out during one menstrual cycle before and during two cycles of antiestrogen treatment. All subjects continued to have regular menses with biphasic basal body temperature records. During treatment, estradiol (E2) levels were increased but followed the usual pattern reflecting follicular maturation and corpus luteum formation. The mean E2 concentration at the midcycle peak and during the luteal phase was twice that observed during the non-treatment cycle. By contrast, the concentrations and secretory patterns of luteinizing hormone and follicle-stimulating hormone were not greatly changed, and the gonadotropin responses to gonadotropin-releasing hormone were not suppressed. Endometrial biopsies obtained during the follicular phase of control and tamoxifen treatment cycles showed no differences whereas biopsies obtained during the luteal phase of tamoxifen cycles uniformly showed a lack of changes attributed to progesterone action with no progression of histologic changes beyond those expected on day 7-8 of the luteal phase. These observations are consistent with maturation of multiple ovarian follicles, a surprising finding considering the normal gonadotropin concentrations. The retarded development of the endometrium in the presence of supranormal serum E2 and progesterone concentrations is a morphologic demonstration of the antiprogestational effect of antiestrogens. The lack of gonadotropin suppression in the presence of hyperestrogenemia suggests a major antiestrogen action on the hypothalmus and pituitary gland.

PIP: Administration of antiestrogen has recently been incorporated into the management of breast cancer. To explore the endocrine consequences of this therapy 5 healthy premenopausal volunteers were observed and treated with daily administration of the antiestrogen Tamoxifen. During the treatment period all subjects continued to have regular menses and basal body temperature; estradiol (E2) levels increased but followed a regular pattern, and its concentration at midcycle and during the luteal phase were twice as high as during nontreatment. On the other hand, concentrations of LH and of ESH were not greatly changed. In the presence of higher concentrations of E2 and of progesterone the endometrium showed a retarded development, thus demonstrating the antiprogestational effect of Tamoxifen. The lack of gonadotropin suppression also suggests a major antiestrogen action on the hypotalamus and pituitary glands.

Coexistent empty sella and prolactin-secreting microadenoma.

The empty sella turcica may be found in people with no antecedent history of intracranial disease, as well as in those with known pituitary pathology or following therapy to the pituitary gland. We have evaluated 3 women with galactorrhea and hyperprolactinemia, 2 of whom had amenorrhea. Each had an empty sella. In all cases polytomograms demonstrated asymmetry of the sella floor with focal bony erosion, conventional pneumoencephalography showed intrasellar air, and polytomographic pneumoencephalography confirmed air limited to one side of the pituitary fossa with tumor and/or residual normal tissue on the opposite side. In 2 patients who had extensive endocrine evaluation, pituitary function was normal with the exception of hyperprolactinemia. Transsphenoidal excision of microadenomas resulted in postoperative normalization of the serum prolactin concentration and resumption of regular menses in the previously amenorrheic women.

Pathogenesis of prolactin-secreting pituitary adenomas.

42 women with amenorrhoea and hyperprolactinaemia had trans-sphenoidal surgery and resection of histologically verified pituitary adenomas. 74% of these patients developed amenorrhoea and/or galactorrhoea in immediate association with the use or discontinuation of oral contraceptives or post partum. There was enough adenomatous tissue for immunocytochemical studies in 35 specimens and specific localisation of prolactin was possible in 31. There is evidence that about 10% of the population have small pituitary tumours, and the majority of these tumours, though asymptomatic, are potentially prolactin-secreting. It is suggested that oestrogens, which are known to modulate prolactin secretion in normal human beings and in animals, can induce the growth and expression of otherwise silent pituitary lesions and that this should be considered a risk of oral-contraceptive use.

The effects of an antihistamine and/or a glucocorticoid on the prolactin response to surgical procedures.

Prolactin (PRL) release in response to surgical stress has been demonstrated in a variety of species. Previous studies in rats indicate this response is blunted or blocked by pretreatment with either glucocorticoids or antihistamines. The present study was designed to investigate this phenomenon in man. Serum PRL levels before, during, and after major gynecologic surgery were measured in 20 women randomly assigned to one of four pretreatment regimens: (1) dexamethasone, (2) promethazine, (3) both agents, and (4) neither agent. Type of operation, preanesthetic medication, anesthetic agents, and estrogen status of patients were similar in all groups. Untreated controls exhibited the expected five- to tenfold increase in serum PRL concentration with surgery. Pretreatment with either dexamethasone or promethazine alone failed to suppress this response (in contrast to reported findings in the rat) and in fact promethazine appeared to cause an augmented response. However, patients given dexamethasone and promethazine together exhibited only a two- to threefold PRL increase, a significantly lesser response than that in any of the other groups. Thus, PRL release in response to general anesthesia and surgery is inhibited by the combination of an antihistamine (H-l) receptor antagonist and a glucocorticoid, whereas either agent alone has no suppressive effect.

Evaluation of the pituitary. Patients with suspected prolactin-producing tumors.

We have reviewed our experience in the radiographic and ophthalmologic evaluation of 1001 patients with symptoms suggesting the presence of a pituitary, prolactin-secreting adenoma. Twenty-seven patients had abnormal or suspicious radiographic examination of the sella turcica. Twenty-two of those had hyperprolactinemia. In only one instance was an abnormality noted on polytomography that was not seen on a conventional four-view study of the skull. Based on these findings, a four-view plain conventional radiographic assessment of the skull suffices as a screening procedure in patients with amenorrhea, galactorrhea, or both. Thin section tomography should be reserved to more thoroughly evaluate those patients with elevated serum prolactin concentrations and/or abnormal conventional radiographs. We found visual field testing to be of little value as an initial screening procedure in these patients.

Spontaneous pregnancy in women with a prolactin-producing pituitary adenoma.

The occurrence of spontaneous pregnancy in patients with amenorrhea-galactorrhea, hyperprolactinemia, and radiographic evidence of a pituitary tumor is unusual. We present here two patients who conceived spontaneously. One had an uneventful pregnancy. Following delivery, transsphenoidal pituitary surgery was performed, confirming the presence of a prolactin-producing adenoma. The second patient had an early pregnancy termination (at 12 weeks of gestation). These patients provide evidence that ovulation and pregnancy can occur in spite of elevated prolactin levels.

The treatment of hyperprolactinemia with a new ergot derivative, lergotrile mesylate.

Lergotrile mesylate is an ergot alkaloid derivative modified to eliminate the vasoconstrictive properties of the parent compound while preserving the properties that inhibit pituitary secretion. Administration of the drug to women with amenorrhea-galactorrhea resulted in the lowering of serum prolactin concentrations. The duration of action was short, so that prolactin levels were near base line 6 to 8 hours after a 2.0-mg dose and morning prolactin concentrations were not persistently suppressed. Initial therapy was accompanied by the development of postural hypotension. Tolerance to this side effect of the drug developed after several days of treatment with gradually increasing doses. In one patient, long-term treatment resulted in reduction of breast secretions, resumption of menses, and conception.

Renal anomalies in the "XY female".

Renal and urinary tract anomalies have been reported to occur with a number of chromosomal abberations and a variety of müllerian developmental anomalies. Historically, the XY female has been privileged to remain free from these associated urologic complications. Presented are two types of the XY female in whom a major renal anomaly was found. It is possible that a potentially more frequent association of developmental anomalies has been overlooked. The urinary systems of XY females, when identified, should be investigated.