Anxiety and depression symptoms in women with polycystic ovary syndrome compared with controls matched for body mass index.

BACKGROUND: Anxiety and depression are more prevalent in women with polycystic ovary syndrome (PCOS) than in those without this disorder. Possible confounding effects of overweight and obesity are suggested. The aim was to compare symptoms of anxiety and depression in women with PCOS and controls matched for age, body weight and body mass index (BMI). METHODS: Women with PCOS (n = 30) and controls (n = 30) were recruited from the community. Persons with ongoing psychotropic medication were excluded. All potential participants underwent gynecological examination to confirm case-control status. Participants completed the self-reported versions of the Brief Scale for Anxiety (BSA-S) and Montgomery Asberg Depression Rating Scale (MADRS-S). RESULTS: Women with PCOS had a higher BSA-S score compared with controls (median, range: 10.5, 1-24 versus 5.0, 0-28, P < 0.001). They scored higher on the following four individual symptoms: reduced sleep (2.0, 0-5 versus 0, 0-2, P < 0.001), worry (1.5, 0-4 versus 0, 0-6, P = 0.004), phobias (1, 0-4 versus 0, 0-3, P < 0.001), and pain (1, 0-3 versus 0, 0-2, P < 0.001). No statistical difference was demonstrated regarding MADRS-S scores (10.0, 0-27 versus 5.5, 0-24, P = 0.053). Only one of the nine MADRS-S symptoms, reduced sleep, which is also included in the BSA-S, differed between cases and controls. CONCLUSIONS: Several anxiety symptoms distinguished women with PCOS from a control group matched on BMI. A better understanding of the symptoms is needed to identify and alleviate anxiety symptoms in this vulnerable group.

Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

BACKGROUND: Low pregnancy rate has been reported in women with congenital adrenal hyperplasia (CAH) and little information on pregnancy and children is known. METHODS: In a Swedish study, 62 adult women with CAH, aged 18-63 years, and 62 age-matched controls were followed-up. Medical records, including those concerning pregnancies and deliveries, were examined and the 21-hydroxylase genotype of patients was noted. All women answered a questionnaire concerning sexual and reproductive health including health of the children. RESULTS: Pregnancy and delivery rates were significantly lower in women with CAH (P < 0.001, P < 0.0056, respectively), and the severity of the 21-hydroxylase-mutation correlated with the reduced number of children born. More women with salt-wasting CAH were single and had not attempted pregnancy. Pregnancies were normal except for a significantly increased incidence of gestational diabetes in CAH patients (P < 0.0024). The children had normal birthweight and no malformations were observed. A later follow-up of the children showed a normal intellectual and social development. The sex ratio of the offspring differed significantly, with 25% boys in the CAH group compared with 56% among controls (P < 0.016). CAH women had more gynaecological morbidity during menopause. CONCLUSIONS: Pregnancy and delivery rates are reduced in women with CAH mainly due to psychosocial reasons. The outcome of children did not differ from controls. The unexpected sex ratio in children born to mothers with CAH warrants further research.

The role of cyclic adenosine 3',5'-monophosphate in the ovulatory process of the in vitro perfused rabbit ovary.

LH alters ovarian steroidogenesis via adenylate cyclase (AC) activation and cAMP production. Although LH also initiates ovarian follicle rupture, evidence is lacking for involvement of cAMP in this process. This work explores the involvement of cAMP in the ovulation of in vitro perfused rabbit ovaries by comparing LH stimulation of ovaries with that of LH plus 3-isobutyl-1-methyl-xanthine (IBMX), (an inhibitor of phosphodiesterase) and of forskolin (a nonreceptor-specific activator of AC). Venous perfusates were analyzed for cAMP, progesterone, 17 beta-estradiol, and testosterone, ovaries were analyzed for cAMP, and ovulations were noted. LH, LH plus IBMX, and forskolin all increased tissue cAMP levels significantly after 0.5 h, the perfusate levels increasing rapidly thereafter reaching plateau levels, while tissue levels returned to control levels after 2.4 h. LH plus IBMX and forskolin significantly increased cAMP release over LH controls, LH plus IBMX increasing and forskolin decreasing the number of ovulations. Forskolin significantly increased progesterone release over LH controls and, although no other significant steroid differences were seen, strong tendencies existed. Although forskolin could induce ovulations and could induce significantly higher release of cAMP than LH, it resulted in a lower ovulation rate than receptor-specific LH. LH plus IBMX also induced significantly higher cAMP release than LH, as did forskolin, and resulted in a higher ovulation rate than both LH and forskolin. These findings suggest, not only that cAMP production alone is sufficient for ovulation, but also that the receptor specificity of the cAMP production is important for the number of ovulations. Since tissue levels of cAMP peak several hours before ovulation, the cAMP is probably inducing a metabolic pathway leading to ovulation.

Gonadotropin- and cytokine-regulated expression of the chemokine interleukin 8 in the human preovulatory follicle of the menstrual cycle.

Interleukin 8 (IL-8) is a chemotactic cytokine involved in the recruitment and activation of neutrophils as well as in cell proliferation and angiogenesis. Because these events are essential components of folliculogenesis, ovulation, and subsequent repair of the ruptured follicle, the presence and regulation of IL-8 in the human follicle of the menstrual cycle was investigated. The concentrations of IL-8 were higher in follicular fluids from dominant follicles of late follicular/ovulatory phase compared with those of midfollicular phase. IL-8 was detected in the media from cultured granulosa and theca cells, with 10-fold higher levels in the theca cell cultures. Exposure to FSH and LH increased the IL-8 secretion from granulosa cells, but no effect was seen in theca cell cultures. Estradiol and progesterone did not affect IL-8 secretion from any cell type. The cytokines IL-1alpha and IL-1beta, but not tumor necrosis factor alpha, enhanced IL-8 secretion from both cell types. IL-8 levels in cultures of granulosa-lutein cells from hyperstimulated in vitro fertilization cycles were not affected by either gonadotropins or steroids. These data provide evidence that ovarian IL-8 is gonadotropin and cytokine induced and may be involved in the hormonally regulated stages of follicular development and ovulation.

Studies on the mechanism of ovulation using the model of the isolated ovary.

Using the isolated perfused rabbit and rat ovaries as experimental models, we have studied various biochemical aspects of the ovulatory process. In rabbits, ovulations were induced by injecting hCG prior to the perfusion or by adding LH directly to the medium. In PMSG-treated rats, ovulations were induced by adding LH to the perfusion system. Steroids and other metabolites were analyzed in the perfusate and in follicular fluid. Steroid levels in follicular fluid were high early in the preovulatory development, but declined to very low levels 4 hours after LH stimulation. Levels of prostaglandins E and F rose as ovulation approached. In both perfusion models, indomethacin blocked ovulation without affecting steroid release or oocyte maturation. In the rabbit, PGF2 alpha reversed the indomethacin-induced inhibition and was able to induce follicular rupture by itself. Manipulations of the follicular fluid content of progesterone and estradiol to supraphysiological levels did not affect follicular rupture or oocyte maturation in the rabbit model. When the initial increase in LH-induced steroidogenesis was blocked by a 3 beta-ol-dehydrogenase inhibitor, ovulation was not affected. In rats, inhibition of estradiol production by an aromatase blocker did not affect the ovulatory process. When the endogenous formation of cyclic AMP is increased by pretreatment with a phosphodiesterase inhibitor, the LH-induced ovulation frequency increases in rabbits. Furthermore, forskolin, which increased the adenylate cyclase activity, stimulated steroidogenesis and induced follicular rupture. Recent experiments in the rat indicate that cyclic AMP acts on the ovulatory process via an effect on prostaglandin synthesis.

Steroid production in vitro of a hilus cell tumor of the human ovary.

A 69-year-old heavily virilized woman with an androgen-producing tumor of the right ovary is described. After tumor removal, plasma testosterone levels fell from 5 to less than 0.6 ng/ml. Serum gonadotropins were low prior to surgery and rose to high levels postoperatively. Histologic examination of the right ovary revealed a hilus cell tumor. Incubation of small specimens of tumor tissue for 2 hours in oxygenated Krebs bicarbonate buffer containing glucose and bovine serum albumin yielded a release of predominantly testosterone and androstenedione into the medium. Human chorionic gonadotropin (hCG) added to the medium had no effect on steroid release. Incubation of tumor tissue in vitro may provide a useful functional adjuvant to the morphologic characterization of hormone-producing ovarian tumors. Such combined studies may increase our knowledge of the much-debated histogenesis of these tumors.

Effects of electro-acupuncture on corticotropin-releasing factor in rats with experimentally-induced polycystic ovaries.

The aims of the present study were to investigate corticotropin-releasing factor (CRF) concentrations in the brain, the adrenal glands, and the ovaries in rats with estradiol valerate (EV) induced polycystic ovaries (PCO). The effect of 12 electro-acupuncture (EA) treatments on CRF concentrations was also investigated. The CRF concentrations in the median eminence (ME) were significantly increased in rats with PCO (both the PCO control group and the PCO group receiving EA) compared with the healthy control group (veichle control group), indicating increased activity in the hypothalamus-pituitary axis. The CRF concentrations in the ovaries were significantly reduced in the PCO group receiving EA compared with the PCO control group. Also, there was a decrease in comparison withthe healthy control group but the decrease was not as significant. This finding indicates that repeated EA treatments change the neuroendocrinological state in the ovaries, which may play an important role in reproductive failure.

Collection of human oocytes by the use of sonography.

A technique for ultrasonically guided percutaneous oocyte aspiration was developed utilizing standard real-time, linear-array ultrasound equipment. Forty-four patients attending our in vitro fertilization and embryo transfer (IVF-ET) program were included in this study. In 38 patients, follicular puncture was performed under general anesthesia and in 6 cases performed under local anesthesia. Fifty-two follicles with a mean diameter greater than or equal to 18 mm were punctured, and 40 mature oocytes were recovered corresponding to a success rate of 77% per follicle. Six of the punctured follicles were considered cystic when the aspirated granulosa cells were examined microscopically and, if these were excluded, the corrected recovery rate was 87% per follicle. In two patients, ovulation had occurred at the time for oocyte collection. In one of these patients, a mature oocyte was, however, recovered from the pouch of Douglas by the use of sonography. On the basis of these results, ultrasonically guided puncture of follicles for collection of human oocytes in our IVF-ET program seems suitable for use in all cases where laparoscopy is presently used and, moreover, in cases with severe adhesions, where laparoscopy may fail.

Hemostatic and metabolic variables in women with polycystic ovary syndrome.

OBJECTIVE: To study whether a previously demonstrated increased morbidity in cardiovascular disease (CVD) and diabetes mellitus in women with polycystic ovary syndrome (PCOS) is associated with certain hemostatic variables that are known to be markers for CVD. DESIGN: The study was a trans-sectional follow-up study from a cohort of women with PCOS. SETTING: The women with PCOS were recruited from hospital clinics and referents were randomized from a population study of women from the same area. PARTICIPANTS: The investigation involved 28 women aged 43 to 62 years diagnosed to have PCOS on ovarian histopathology at wedge resection 25 to 34 years previously and 56 referents who were matched by age and body mass index. MAIN OUTCOME MEASURES: In connection with a clinical investigation, the hemostatic variables fibrinogen, von Willebrand factor antigen, factor VII procoagulant activity, factor VII antigen, and plasminogen activator inhibitor as well as the metabolic variables serum insulin and serum triglycerides were assayed. RESULTS: There was a strong positive correlation between serum concentrations of triglyceride, basal insulin, and abdominal obesity on the one hand, and plasminogen activator inhibitor, fibrinogen, and von Willebrand factor on the other, among women with PCOS as well as among referents. There were significantly higher mean concentrations of fibrinogen and factor VII:Ag among referents, but the mean values of most hemostatic variables studied showed no differences between the groups. CONCLUSION: Women with an altered metabolic profile were also found to have affected hemostatic factors, but PCOS in itself did not seem to influence them.

Women with polycystic ovary syndrome wedge resected in 1956 to 1965: a long-term follow-up focusing on natural history and circulating hormones.

OBJECTIVE: To determine if the hormonal imbalance in women with polycystic ovary syndrome (PCOS) continues into and after menopause and to analyze factors constituting an increased risk for developing metabolic disorders. DESIGN: The study was a transectional retrospective cohort follow-up of patients with PCOS. SETTING: The women with PCOS were recruited from hospital clinics, and referents were randomized from a population study of women. PARTICIPANTS: Thirty-three women ages 40 to 59 years with ovarian histopathology typical of PCOS at wedge resection 22 to 31 years previously; 132 age-matched referents were analyzed. MAIN OUTCOME MEASURES: Clinical data were collected via a questionnaire supplemented with an interview in connection to a clinical examination that also included fasting venous sampling. RESULTS: Infertility, hirsutism, and oligomenorrhea were more common among the subjects with PCOS, but there was a considerable spontaneous restitution of cyclic regularity with time. Women with PCOS were more often hysterectomized and entered menopause later compared with referents. The hormone data show a typical profile for PCOS. Compared with referents women with PCOS showed marked increase in prevalence of central obesity, higher basal serum insulin concentrations, and a higher prevalence of diabetes mellitus and hypertension. CONCLUSION: Perimenopausal women with PCOS have an increased morbidity in hypertension and diabetes mellitus that adds to the classic symptoms, such as anovulation, hirsutism, and infertility.

A method for longitudinal microscopic in vivo examinations of morphology, vascularity, and motility in the ovary and the oviduct of the rat.

OBJECTIVE: We developed an in vivo model to enable observation of dynamic changes in morphology, vascularity, and motility of the rat adnexa. METHODS: Immature Sprague-Dawley rats (n = 16) were primed with equine chorionic gonadotrophin (eCG;15 IU) followed by human chorionic gonadotrophin (hCG; 15 IU) 48 hours later to induce ovulation. The experiments were performed during prolonged (up to 12 hours) thiobarbiturate anesthesia. During laparotomy the periovarian bursa was retracted, whereafter the oviductal-ovarian complex was submerged into an organ chamber. Water immersion lenses (4x-40x; final magnification up to 810x) enabled detailed observations that were recorded on Beta-SP videotape. RESULTS: Capillary flow was monitored easily. At the level of the follicle, top blood flow velocity variations (8-10 per minute) were observed in the microvasculature. Ovulations were followed in detail, and oocyte-cumulus complexes were seen later in the oviductal ampulla. Regular contractions in the oviduct were synchronous with the oocyte-cumulus complexes moving back and forth in the oviductal lumen over a distance of about 900 microm. These contractions were more frequent (13-16 per minute) in the postovulatory phase compared with the time before ovulation (9-10 per minute). The oviductal contractions were initiated alternately from either end of the ampulla and were accompanied by a denudation of the oocytes, with a stream of cumulus cells seen moving in an abovarian direction in between contractions. CONCLUSION: High-magnification video recording in vivo was useful for capturing microcirculatory events as well as structural and functional changes of the ovary and the oviduct.

Ovulation in the isolated perfused rat ovary as documented by intravital microscopy.

Surface cell changes at the apices of preovulatory follicles and ovulations were documented in isolated perfused ovaries from immature rats treated with pregnant mare serum gonadotropin (20 IU) and 48 h later with human chorionic gonadotropin (hCG) (10 IU). A video camera coupled to an inverted microscope and a video recorder captured the preovulatory and ovulatory events at a cellular level. At around 8 h post-hCG, the follicular apex changed from a smooth and optically homogeneous appearance into a rough surface with bleb formation and extrusions of single cells through minute perforations (early stigma formation). At approximately 10 h, a sticky material formed a basketlike structure with trapped cells (late stigma formation). At 12 to 15 h, ovulation took place at a constant speed and with no contractions of the follicular wall. This indicates that ovulation can occur with no visible circumfollicular muscular activity. Furthermore, the observations of a leakage of cells over an extended period of time indicates that the follicular wall is partly digested several hours before ovulation occurs.

Gynaecological history, complaints and examinations in a middle-aged population.

A sample of women aged 40-56 years (n = 1349) was selected at random from the Census Register of Göteborg, Sweden. Altogether, 1095 (81%) filled out a questionnaire concerning gynaecological data. A control group (n = 170) was established and 135 women from this group (79%) underwent an extensive personal interview and pelvic examination. One aim was to investigate the representativity of the control group for the initial random sample and to compare the information obtained from the questionnaire with the information acquired by personal interview. An additional aim was to obtain information related to pelvic examination and FSH concentrations in the serum of middle-aged women. In general there was a good agreement between information from questionnaires and from personal interviews. The pelvic examination revealed that 53% of the post-menopausal women showed signs of genital atrophy and this condition was more common in sexually inactive than active women. Weakness of the pelvic floor was encountered in 16%. The uterus was of normal size in 94%, anteflexed in 76%, mid-positioned in 8% and retroflexed in 16%. There was a positive correlation between a pathological smear and cervical ectopy. Serum FSH values in menstruating women ranged from 6.4 to 47 IU/l. A cut-off value of 50 IU/l gave a complete separation between menstruating and post-menopausal subjects.

Gynaecology of middle-aged women--menstrual and reproductive histories.

The aim of this study was to investigate menstrual history, reproductive functions, fertility regulation and gynaecological operations is a representative sample of middle-aged women. A sample consisting of 1746 women aged 40-66 was randomly selected. Of those initially selected, a total of 1413 (81%) were investigated. Gynaecological data were acquired by means of questionnaires. Eighty-six percent of menstruating women reported a cycle length of 22-30 days and menstrual flows lasting 4-7 days. The median age at natural menopause was 50.9 yr. The oldest menstruating women were 57 yr old. Curettage had been performed in 53%, and 9% were hysterectomised. Every fourth woman had had three or more children, and 15% were nulliparous. Abortion (spontaneous or induced) was reported by 28% of the women. Of 714 menstruating women, 62% were utilising contraceptive methods, among which barrier or natural methods predominated. Nine percent of women aged 40-44 used combined oral contraceptives. Previous or current use of contraceptive pills was reported by 32% of all the women, and of these 20% had been on the pill for 10 or more yr.

Toxicity testing using the isolated in vitro perfused ovary.

This article discusses the use of in vitro perfusion techniques as a tool for toxicity testing in the ovary and how the rat ovary has been adapted for this purpose. A brief review of the development of in vitro ovarian perfusion is provided, focusing on steroidogenesis and physiology of ovulation. Adaptation of this model for use as a toxicologic model is discussed in the context of other isolated organ models, (that is, liver, heart, lung). Surgical procedures, perfusate and criteria for viability are outlined. Advantages of this technique are highlighted including ability to administer high doses of drugs directly to intact organ devoid of other influences. Applications of this model are discussed and data from studies of glutathione depleted ovaries perfused with hexachlorobenzene (HCB) are presented. Increased oxygen consumption after addition of HCB is suggestive of a disordered respiratory metabolism and is an example of future markers of ovarian injury using this innovative technique.

The effect of estrous cycle and buthionine sulfoximine on glutathione release from the in vitro perfused rat ovary.

There is little known regarding the intracellular mechanisms of modification of damage in the ovary. Ovarian perfusion of en block dissections of the rat right ovary with aorta and vena cava were done to determine (a) if glutathione (GSH) is released by the ovary, (b) if the release is cycle dependent, and (c) if GSH released is the product of de novo ovarian synthesis. All perfused ovaries released GSH and the release was maximal at estrus and least at metestrus. Perfusion with buthionine sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, resulted in a dose-dependent reduction in GSH released, indicating inhibition of de novo synthesis during perfusion.

The invisible wounds: the occurrence of psychological abuse and anxiety compared with previous experience of physical abuse during the childbearing year.

The aim of this study was to measure the prevalence, effects and character of psychological abuse in women visiting antenatal clinics. A standardized questionnaire based on four different established scales (PMWI, SVAW, TSC-33, and STAI) was used to estimate the frequency of psychological, physical and sexual abuse, anxiety and depression. In the study 207 pregnant Swedish born women married to or cohabiting with Swedish born men were consecutively chosen from three different antenatal clinics from the city of Göteborg, Sweden. Personal interviews were conducted in connection to their regular visit to the antenatal clinic, ranging from the first to the third trimester. Fifty-one (24.5%) women out of 207 reported threats and/or acts of violence during the last year according to the Severity of Violence Against Women Scale (SVAW). There was 89.4% who had experienced dominance/isolation according to the Psychological Maltreatment of Women Inventory (PMWI) and 44.4% of the women reported emotional/verbal abuse. Occupational status, but not age income or education, was found to be significantly correlated to physical violence, dominance/isolation and to emotional/verbal factor according to Psychological Maltreatment of Women Inventory (PMWI). Threats of moderate violence' and 'serious violence' were strongly correlated to physical violence (correlation coefficient 0.9433 and 0.9405, respectively). Sexual abuse demonstrated a high correlation to physical violence and emotional/verbal factor. The results indicate that sexual violence is highly represented in the abusive relationship and also that depression and anxiety in the childbearing year may be caused by domestic violence. This study emphasises the importance of incorporating screening for threats and actual acts of psychological, physical and sexual abuse into routine care for women, enabling health care providers to identify high-risk patients and improve quality of care.

Endometrial carcinoma; ovarian dysfunction--a risk factor in young women.

From a referral area comprising one-fifth of the Swedish female population we investigated possible risk factors for endometrial cancer (EC) in different age groups. Seventy-seven women aged 31-45 with EC were collected retrospectively, and 99 women aged 46-65 were consecutively collected. Both groups were compared to referents randomly selected from a population based study from the city of Göteborg. The referents consisted of 1746 women aged 39-65 years. All cases were studied by hospital record and 82% of the women aged 31-45 years and 85% of those aged 46-65 years were studied by an extensive questionnaire. Among the referents 1409 (81%) were investigated by the above-mentioned questionnaire. Hirsutism, increased body mass index (BMI) and hypertension were significantly more common in both EC groups compared to referents. Nulliparity and infertility were significantly more common in the young EC group. Referents used combined oral contraceptives significantly more often than women developing EC. There was, however, no difference between the groups with respect to the duration of medication with combined oral contraceptives. There was a significant negative correlation between cigarette smoking and the development of EC. These findings indicate that untreated ovarian dysfunction like that present in polycystic ovarian disease (PCO) with unopposed estrogen action on the endometrium is associated with EC in younger women, and that smoking may protect against EC by an 'anti-estrogenic' effect.

Global importance of infertility and its treatment: role of fertility technologies.

Understanding the reasons for infertility and the development of new techniques for its treatment is one of the fields within medicine which has undergone a dramatic development during the last two decades. In the past, gynecologists seemed more successful in the treatment of female problems than urologists and andrologists on the male side, while in the last couple of years this scenario has changed due to the development of both operative procedures to harvest spermatozoa from the epididymis and the testis and the ability to micro-inject single spermatozoa (ICSI) or even spermatides directly into metaphase II oocytes. It should, however, be emphasized that the successful development of in vitro fertilization (IVF) and other assisted reproduction technologies (ART), could not have taken place without the development of diagnostic innovations, such as immunoassays of hormones, high resolution ultrasound and various endoscopic techniques. Today, treatment of the infertile couple is less of a medico-technical problem and more a socio-economic dilemma. This communication is an attempt to summarize the more prominent steps in reproductive medicine during the last decades and one more general conclusion of global relevance which can be drawn, is that less money must be spent on diagnosis and more resources transferred to treatment options.

[Don't miss prolactinoma! On the importance of measuring prolactin and how it is done]. / Missa inte prolaktinomen! Om vikten av mätning av prolaktin och hur den utförs.

Prolactinoma is the most common functional pituitary tumor. Since appropriate treatment is often pharmacological rather than surgical, all patients with a tumor within or close to the sella turcica should be evaluated for prolactinoma before being sent for neurosurgery. Preanalytical factors affecting serum prolactin concentration should be taken into account when planning blood sampling. Diagnostic laboratories should aim for the use of common international calibrators and a common unitage for expressing concentrations. Assays should be carried out in such a way that the risk of falsely high or low values is minimized. Any patient with high values due to an immunometric method should be evaluated for the possible presence of endogenous antibodies against prolactin ("macroprolactinemia").