Brief Report Treatment of infertility and menopause in a patient with multiple sclerosis affecting the pituitary stalk: a case report.

BACKGROUND: Multiple Sclerosis (MS) is an immune-mediated inflammatory disease characterized by demyelination of the CNS that affects women in their child-bearing years. There has been no absolute data to suggest infertility in this population; however, women with MS may exhibit decreased fertility due to various etiologies. Furthermore, their transition into menopause presents unique aspects in patient care. METHODS: We report a case of a 38 year-old female with a diagnosis of MS with subsequent secondary amenorrhea and primary infertility. Multidisciplinary work-up with was consistent with hypothalamic hypogonadism secondary to MS affecting the pituitary stalk. She was treated for infertility in our clinic as well as management of her menopausal symptoms. RESULTS: The patient conceived triplets after 2 cycles of ovarian stimulation with injectable gonadotropins and intrauterine insemination. She underwent fetal reduction to twins. After completion of childbearing, she was treated for menopausal symptoms with various hormonal therapies and ultimately remained on oral conjugated estrogens with no symptoms. CONCLUSION: To our knowledge, this is the first report of infertility caused by suspected MS involvement of the pituitary stalk. In this patient population, infertility treatment can be successful with gonadotropins and alleviation of menopausal symptoms can be achieved with hormone replacement.

Congenital Uterine Malformation by Experts (CUME): diagnostic criteria for T-shaped uterus.

OBJECTIVES: To identify uterine measurements that are reliable and accurate to distinguish between T-shaped and normal/arcuate uterus, and define T-shaped uterus, using Congenital Uterine Malformation by Experts (CUME) methodology, which uses as reference standard the decision made most often by several independent experts. METHODS: This was a prospectively planned multirater reliability/agreement and diagnostic accuracy study, performed between November 2017 and December 2018, using a sample of 100 three-dimensional (3D) datasets of different uteri with lateral uterine cavity indentations, acquired from consecutive women between 2014 and 2016. Fifteen representative experts (five clinicians, five surgeons and five sonologists), blinded to each others' opinions, examined anonymized images of the coronal plane of each uterus and provided their independent opinion as to whether it was T-shaped or normal/arcuate; this formed the basis of the CUME reference standard, with the decision made most often (i.e. that chosen by eight or more of the 15 experts) for each uterus being considered the correct diagnosis for that uterus. Two other experienced observers, also blinded to the opinions of the other experts, then performed independently 15 sonographic measurements, using the original 3D datasets of each uterus. Agreement between the diagnoses made by the 15 experts was assessed using kappa and percent agreement. The interobserver reliability of measurements was assessed using the concordance correlation coefficient (CCC). The diagnostic test accuracy was assessed using the area under the receiver-operating-characteristics curve (AUC) and the best cut-off value was assessed by calculating Youden's index, according to the CUME reference standard. Sensitivity, specificity, negative and positive likelihood ratios (LR- and LR+) and post-test probability were calculated. RESULTS: According to the CUME reference standard, there were 20 T-shaped and 80 normal/arcuate uteri. Individual experts recognized between 5 and 35 (median, 19) T-shaped uteri on subjective judgment. The agreement among experts was 82% (kappa = 0.43). Three of the 15 sonographic measurements were identified as having good diagnostic test accuracy, according to the CUME reference standard: lateral indentation angle (AUC = 0.95), lateral internal indentation depth (AUC = 0.92) and T-angle (AUC = 0.87). Of these, T-angle had the best interobserver reproducibility (CCC = 0.87 vs 0.82 vs 0.62 for T-angle vs lateral indentation depth vs lateral indentation angle). The best cut-off values for these measurements were: lateral indentation angle ≤ 130° (sensitivity, 80%; specificity, 96%; LR+, 21.3; LR-, 0.21), lateral indentation depth ≥ 7 mm (sensitivity, 95%; specificity, 77.5%; LR+, 4.2; LR-, 0.06) and T-angle ≤ 40° (sensitivity, 80%; specificity, 87.5%; LR+, 6.4; LR-, 0.23). Most of the experts diagnosed the uterus as being T-shaped in 0% (0/56) of cases when none of these three criteria was met, in 10% (2/20) of cases when only one criterion was met, in 50% (5/10) of cases when two of the three criteria were met, and in 93% (13/14) of cases when all three criteria were met. CONCLUSIONS: The diagnosis of T-shaped uterus is not easy; the agreement among experts was only moderate and the judgement of individual experts was commonly insufficient for accurate diagnosis. The three sonographic measurements with cut-offs that we identified (lateral internal indentation depth ≥ 7 mm, lateral indentation angle ≤ 130° and T-angle ≤ 40°) had good diagnostic test accuracy and fair-to-moderate reliability and, when applied in combination, they provided high post-test probability for T-shaped uterus. In the absence of other anomalies, we suggest considering a uterus to be normal when none or only one criterion is met, borderline when two criteria are met, and T-shaped when all three criteria are met. These three CUME criteria for defining T-shaped uterus may aid in determination of its prevalence, clinical implications and best management and in the assessment of post-surgical morphologic outcome. The CUME definition of T-shaped uterus may help in the development of interventional randomized controlled trials and observational studies and in the diagnosis of uterine morphology in everyday practice, and could be adopted by guidelines on uterine anomalies to enrich their classification systems. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Diurnal variation of steroid hormones and their reference intervals using mass spectrometric analysis.

OBJECTIVE: Accurate measurement of steroid hormones remains challenging. Mass spectrometry affords a reliable means for quantitating steroid profiles accurately. Our objective was to establish and define (1) the extent of diurnal fluctuations in steroid concentrations that potentially necessitate strict adherence to time of sample acquisition and (2) time-dependent steroid reference intervals. DESIGN: Nine steroid markers were examined in couplets in males and females. METHODS: Using isotope dilution high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) analysis, we developed a multi-steroid profile requiring only a minimal volume of serum (0.1 mL). Couplet (AM and PM) measurements of steroid hormones for 120 healthy females (F) and 62 healthy males (M) were obtained. Patients were recruited from several participating centers. RESULTS: The following diurnal values were noted to be significantly different in both females and males: cortisone, cortisol, corticosterone, 11 deoxycortisol (11 DOC), androstenedione, 17a-hydroxyprogesterone (17 OHP) and dehydroepiandrosterone (DHEA). Testosterone was only found to have significant diurnal variance in males. Progesterone showed no significant difference in AM and PM values for either groups and thus may provide an internal control. CONCLUSIONS: When diagnosing endocrine disorders, it is imperative to acknowledge the 24-h diurnal variation of the biochemical steroid markers. We highlight the importance of standardization of collection times and appropriate implementation of reference intervals. PRECIS: We identify diurnal fluctuations in steroid concentrations with time of day and emphasize the importance of adhering to firm time of sample acquisition.

Expression profiles of the nuclear receptors and their transcriptional coregulators during differentiation of neural stem cells.

Neural stem cells (NSCs) are pluripotent precursors with the ability to proliferate and differentiate into 3 neural cell lineages, neurons, astrocytes and oligodendrocytes. Elucidation of the mechanisms underlying these biologic processes is essential for understanding both physiologic and pathologic neural development and regeneration after injury. Nuclear hormone receptors (NRs) and their transcriptional coregulators also play crucial roles in neural development, functions and fate. To identify key NRs and their transcriptional regulators in NSC differentiation, we examined mRNA expression of 49 NRs and many of their coregulators during differentiation (0-5 days) of mouse embryonic NSCs induced by withdrawal of fibroblast growth factor-2 (FGF2). 37 out of 49 NRs were expressed in NSCs before induction of differentiation, while receptors known to play major roles in neural development, such as THRα, RXRs, RORs, TRs, and COUP-TFs, were highly expressed. CAR, which plays important roles in xenobiotic metabolism, was also highly expressed. FGF2 withdrawal induced mRNA expression of RORγ, RXRγ, and MR by over 20-fold. Most of the transcriptional coregulators examined were expressed basally and throughout differentiation without major changes, while FGF2 withdrawal strongly induced mRNA expression of several histone deacetylases (HDACs), including HDAC11. Dexamethasone and aldosterone, respectively a synthetic glucocorticoid and natural mineralocorticoid, increased NSC numbers and induced differentiation into neurons and astrocytes. These results indicate that the NRs and their coregulators are present and/or change their expression during NSC differentiation, suggesting that they may influence development of the central nervous system in the absence or presence of their ligands.

A model for initial care of the infertile couple.

Infertility affects an estimated 6.1 million women in the United States. Although more than 1.2 million women seek medical care for infertility each year, the majority drop out of the treatment process before achieving a successful pregnancy. An expert panel of five reproductive endocrinologists developed the Individualized Infertility Care Plan model to aid obstetrician-gynecologists and primary care physicians in streamlining the critical period encompassing diagnosis and initial treatment of the patient with uncomplicated infertility. The model emphasizes the importance of the physician's establishing a strong, lasting relationship with the infertile patient.

Hormone receptors and sexuality in the human female.

There is only inferential evidence based on observational studies and deductive reasoning that allows us to suppose there are hormone receptors in the human brain that are associated with libido. Data indicate that sexually active pubescent women have higher testosterone levels than matched controls. However, any number of nonhormonal events in puberty could be related to these changes. Another circuitous way to look at hormone libido receptors in the brain is by evaluating patients on birth control pills, in whom sexual activity paradoxically decreases. Sex hormone-binding globulin (SHBG) levels are increased, and, therefore, free testosterone levels seem to be affected by the use of birth control pills. In addition, the progestins in the pill are 19-nortestosterone derivatives, which may have some androgenic effect in their own right. Women on estrogen replacement therapy with the addition of testosterone seem to report increased libido, and there is subjective information that there is an increase in psychological sense of well-being. It has been well documented that females with adrenogenital syndrome are masculinized in utero, indicating imprinting on behavior. Because of the nature of the end point (e.g., increased libido), it is difficult to draw concrete conclusions on the presence of libido receptors in the human brain. Because the outcomes and end points are so soft, it is difficult to come to a consensus, and in fact this topic polarizes opinions of the pure scientist (objective) against the clinician (subjective).

Administration of progesterone before oocyte retrieval negatively affects the implantation rate.

OBJECTIVE: To compare the efficacy of two clinically accepted methods of progesterone supplementation during IVF. DESIGN: Prospective randomized trial. SETTING: A university-based IVF program. PATIENT(S): Three hundred fourteen stimulated IVF cycles between January 1993 and October 1994. INTERVENTION(S): Patients were assigned to one of two luteal phase progesterone regimens by a random permuted block design. In protocol A, 12.5 mg of IM progesterone was given 12 hours before oocyte retrieval; in protocol B, 25 mg of IM progesterone was given on the day of oocyte retrieval. MAIN OUTCOME MEASURE(S): Clinical pregnancy. RESULT(S): Patient demographic characteristics, including age, diagnosis, number of oocytes retrieved and fertilized, and number of embryos transferred, were not different between the two groups. There was no difference in the rate of cycle cancellation between the groups. One hundred forty ETs were performed in patients assigned to protocol A and 142 in patients assigned to protocol B. The clinical pregnancy rate in group A was 12.9% compared with 24.6% in group B. CONCLUSION(S): The administration of progesterone before oocyte retrieval is associated with a lower pregnancy rate than the administration of progesterone after oocyte retrieval.

Prevention of retrosternal adhesion formation in a rabbit model using bioresorbable films of polyethylene glycol and polylactic acid.

The purpose of this study was to test the efficacy of three bioresorbable films of polyethylene glycol (EO) and polylactic acid (LA) (EO/LA = 1.5, 2.5, and 3.0) in the prevention of adhesion formation between the epicardium and the sternum (retrosternal adhesions) in a rabbit model. Retrosternal adhesions were generated by sternotomy, pericardiotomy, and abrasion of the anterior epicardium. The adhesion barrier was placed between the epicardium and the sternum and sutured to the edge of the pericardium. Epicardial adhesions were evaluated 14-20 days later by assessing the area of the epicardium covered by adhesions. In the control rabbits, tenacious adhesions were observed between sternum and the central portion of epicardium (portion exposed through the pericardiotomy) which were difficult to dissect. When a bioresorbable film was placed over the pericardium, adhesion formation at the central strip of the epicardium (area between the sternum and the epicardium exposed through the pericardium) could be reduced or prevented. At this site, the areas of adhesion formation were 0% (EO/LA = 1.5), 8.4 +/- 2.8% (EO/LA = 2.5), and 5.6 +/- 4.7% (EO/LA = 3.0) of the central strip, significantly less than that observed in the control group, 78.0 +/- 5.8% (P < 0.01). At the anterior left and right and posterior apex of the heart (sites where the film was not placed), there were no differences between control and treatment groups. The films were completely resorbed at the time of necropsy in group EO/LA = 2.5 and 3.0. Small pieces of film were observed in group EO/LA = 1.5. In conclusion, the bioresorbable films [EO/LA = 1.5 (REPEL-CV), 2.5, or 3.0] were efficacious in the reduction of retrosternal adhesions to the epicardium.

Histologic alterations in dermal repair after thermal injury effects of topical angiotensin II.

Previously, we determined that quantitative assessment of epithelialization of the burn site could be performed using quantitative immunohistochemistry with an antibody to the protein cyclin. In this study, the effect of administration of angiotensin II (AII) on two histologic parameters of healing-the number of vascular channels at the burn site and the number of cells proliferating in hair follicles at the edge of the burn and within the burn-were evaluated. Beginning on day 4, vascular channels were noted within the burn site. Significantly more channels were noted in the burns treated with AII than those treated with placebo. With the exception of 3 postinjury days, this increase continued through day 17. Thereafter, the number of vascular channels peaked, and no differences were noted between control and treated burns. The number of cells proliferating in the hair follicle was also evaluated. At the edge of the burn, on average, 126 cells per microscope field (10x) were undergoing proliferation in the AII-treated burn on days 1 through 16 after burn injury. This is approximately a 50% increase over the number of cells proliferating in the placebo-treated burns. On day 12 (approximately 5 days before that observed in control burns), this AII-dependent proliferative response began to increase and peaked on day 19 at a level comparable to control. Thereafter, the proliferative response remained at this level through day 28. Within the area of the burn on days 1 through 15, 21 cells per medium power field on average (approximately 50% more than control) were undergoing proliferation. As on the edge of the burn, an AII-dependent increase in the number of cells proliferating in the hair follicles was observed during the latter phase of healing (on day 16 after the initiation of injury). However, unlike the edge of the burn, administration of AII led to a continued increase (approximately 50%) in the number of cells per field undergoing proliferation. AII increased neovascularization and cellular proliferation after burn injury. Through an increase in these two cellular events, AII may in turn accelerate healing of tissues after thermal injury.

Expression of cyclin protein after thermal skin injury in a guinea pig model.

In this study, an immunohistochemical stain for cyclin was used to quantitate proliferating elements in hair follicles at the edge of and within thermal burn areas. Biopsy specimens from thermal injury in the guinea pig (day 1 through day 28) were sectioned and stained with MIB-1 antibody, which recognizes cyclin, a protein expressed during epithelial cell proliferation. At the edge of the burn, 89 +/- 6.1 (SD) cells per medium power field (x 10, mpf) were MIB-1-positive on days 1 through 16. On day 17, the number of positive cells increased, reaching peak values on days 20 to 28 (271 +/- 12.7 cells/mpf). Within the burn, minimal staining was observed from day 1 to day 15 (12.7 +/- 1.6 cells/mpf). Thereafter the number of MIB-1-positive cells increased and plateaued with an average of 96.4 +/- 9.0 cells/mpf on days 20 through 28. In conclusion, immunohistochemical staining of dermal biopsy specimens with MIB-1 antibody may provide a quantitative method for the evaluation of tissue damage and healing after thermal injury.

Results of conventional and hysteroscopic surgery.

Müllerian anomalies usually come to medical attention when they become problematic and require treatment. Most of these complications require surgical correction. The most commonly presenting anomaly is the double uterus which can be the source of recurrent abortion and preterm deliveries. The Strassman, Jones and Tompkins metroplasties have been shown to greatly improve the rate of successful deliveries in these patients. Hysteroscopic metroplasty, using either scissors, resectoscope or laser is now the recommended treatment for most septate uteri due to its relative simplicity, low morbidity and excellent reproductive outcome.

Clinical problem of intraperitoneal postsurgical adhesion formation following general surgery and the use of adhesion prevention barriers.

Because of multiple studies demonstrating barrier efficacy, adhesion prevention adjuvants have received widespread acceptance in appropriate surgical settings. Many investigators are incorporating adhesion prevention barriers into their routine clinical practice and are achieving good results. Although both Seprafilm and Interceed barriers were shown to be safe and effective in all human clinical trials, their use did not eliminate adhesions in all patients. Efficacy of these barriers is limited to surgical situations in which the area in question can be completely covered. Physician acceptance is constrained by technical difficulties, including the need for hemostasis and removal of excess peritoneal fluid (Interceed), as well as limitations in application and handling properties within the surgical field (Seprafilm).

Inhibin, activin, and follistatin in reproductive medicine.

OBJECTIVE: To review the available information regarding the polypeptide factors inhibin, activin, and follistatin in reproductive physiology. DESIGN: The protein structure, tissue expression, regulation, and effects of these factors are outlined, with an emphasis on the reproductive tissues in both females and males. Although some information is only available in animal model systems, human data has been selected whenever possible. CONCLUSIONS: Inhibin and activin are closely related peptides with opposing actions, whereas follistatin is a structurally unrelated peptide that may act indirectly through modulation of inhibin-activin effects. These three peptides are secreted in highest levels by the adult gonads; however, they are also present in a wide variety of reproductive and nonreproductive tissues where they are believed to exert local, tissue-specific effects. Within the reproductive system, these peptides play a role in the regulation of gonadotropin biosynthesis and secretion, ovarian and placental steroidogenesis, and oocyte and spermatogonial maturation.

Bone-sparing properties of oral contraceptives.

Postmenopausal osteoporosis is a major health care problem that affects 20 million women in the United States and accounts for > 1 million fractures per year. Hormone replacement therapy is effective for reducing bone loss in the postmenopausal women. However, intervention before menopause may delay or prevent the decline in bone mass that begins between ages 30 and 40 years. The effects of oral contraceptives on bone mass have been investigated, and a positive association between oral contraceptive use and bone mass that is directly related to the duration of oral contraceptive use was observed. The effects of oral contraceptives on bone mass may be related to the specific formation. The effect of estrogens is dose related, and the optimal dose appears to be 25 to 35 micrograms of ethinyl estradiol or its equivalent. Results from several studies show that norethindrone has a positive effect on bone mass. An oral contraceptive may offer optimal birth control for the older premenopausal woman who currently uses other forms of birth control.

PIP: A review of the research literature on the effects of oral contraceptives (OCs) on bone mass suggests that premenopausal OC use may exert as beneficial an effect on preserving bone mass as hormone replacement therapy does on stabilizing bone mass loss in menopausal and postmenopausal women. Of the 12 studies reported in the literature, 9 found some positive correlation between these two variables in postmenopausal and/or premenopausal and perimenopausal women. The most significant increases in bone mineral density were recorded among women who had used OCs for more than 3 years. One study found that bone mineral density increased by 1% for each year of OC use. The three studies that failed to confirm any differences between OC users and nonusers in bone mineral density could be criticized methodologically for their focus on subjects with less than 5 years of pill use. Clinical studies have indicated that an OC containing 20-35 mcg/day of ethinyl estradiol in combination with the progestin norethindrone produces the optimal bone-sparing effect in premenopausal women while minimizing the risk of venous thrombosis. Since osteoporosis affects close to 20 million women and results in over 1 million bone fractures each year, this is yet another noncontraceptive benefit of OC use.

Ultrasound prediction of follicle volume: is the mean diameter reflective?

OBJECTIVE: To evaluate the relationship between 2 dimensional sonographic measurement of ovarian follicles and their actual volume. DESIGN: Prospective clinical study. SETTING: The in vitro fertilization (IVF) program of a University based, tertiary care hospital. PATIENTS AND INTERVENTIONS: Sonographic categorization by shape, and measurement of 96 individual ovarian follicles immediately prior to aspiration for IVF. Each follicle was aspirated under direct ultrasound guidance and the volume recorded. The 96 follicles were visualized in a total of 14 patients from whom 2 to 27 oocytes were obtained. MAIN OUTCOME MEASURE: Total volume of each follicle. RESULTS: Round and polygonal follicles exhibited a highly significant relationship between sonographically measured mean diameter and total follicle volume. The volume of follicles that were categorized as ellipsoid was not predicted by measurement of the longest diameter, shortest diameter or mean diameter. CONCLUSION: The mean diameter of round and polygonal follicles accurately predicts total follicular volume. However, clinical decisions in ovulation induction should be modified when the follicle shape is predominantly ellipsoid because the traditionally held belief that the sonographic measurement of the follicular diameter correlates with the follicular volume does not apply in those circumstances.

Aberrant estradiol flare despite gonadotropin-releasing hormone-agonist-induced suppression is associated with impaired implantation.

Our results confirm the previous report that rapid suppression by GnRH-a is favorable relative to delayed suppression (1). They further indicate that the pattern of E2 production during GnRH-a-induced ovarian suppression may be predictive of cycle outcome. We suggest that imperfect pituitary suppression of bioactive LH as indicated by an aberrant rise in E2 during GnRH-a down-regulation may compromise oocyte quality and ultimately impair implantation. Further study of follicular phase E2 response to GnRH-a suppression may provide a prognostic marker for implantation.