Kerstin Hagenfeldt

Gender Role Behavior, Sexuality, and Psychosocial Adaptation in Women with Congenital Adrenal Hyperplasia due to CYP21A2 Deficiency

CONTEXT Gender-atypical behavior has been described in young girls as well as in women with congenital adrenal hyperplasia (CAH) due to a CYP21A2 deficiency. OBJECTIVE The aim of the study was to assess health-related, psychosexual, and psychosocial parameters and correlate the results to CYP21A2 genotype. DESIGN AND PARTICIPANTS Sixty-two Swedish women with CAH and age-matched controls completed a 120-item questionnaire and a validated quality of life instrument [psychological general well-being (PGWB) formula] to identify psychosexual and psychosocial parameters. The patients were divided into four CYP21A2 genotype groups. RESULTS The women with CAH held more male-dominant occupations (30%) compared to controls (13%) (P = 0.04), especially those in the null genotype group (55%) (P = 0.006). They also reported a greater interest in rough sports (74%) compared to controls (50%) (P = 0.007). Eight women with CAH (14%) reported a prime interest in motor vehicles, compared to none of the controls (P = 0.002). Non-heterosexual orientation was reported by 19% of women with CAH (P = 0.005), 50% in the null genotype group (P = 0.0001), 30% in I2 splice (NS), and 5% in I172N (NS). PGWB total score did not differ between patients and controls. CONCLUSION We identified increased gender-atypical behavior in women with CAH that could be correlated to the CYP21A2 genotype. This speaks in favor of dose-dependent effects of prenatal androgens on the development of higher brain functions. The impact of the disease on upbringing and interpersonal relationships did not correlate with disease severity, indicating that other factors, such as coping strategies, are important for psychosocial adaptation. This illustrates the need for psychological support to parents and patients.

Intrauterine contraception with the Copper-T device

Abstract By means of neutron activation analysis, the concentrations of copper, zinc, manganese, sodium and potassium were estimated in the endometrium and cervical mucus in sixteen women using the Cu-T device. Copper and zinc levels in plasma were also determined as well as the protein concentration of the endometrium. Specimens were taken both in the proliferative and in the secretory phase before the insertion, during one years use and in the first two cycles after the removal of the device. The release of copper from the devices was also assessed. The use of a Cu-T resulted in a significant increase in the protein concentration of the endometrium, which remained elevated after the removal of the device. The copper concentration of the proliferative endometrium was increased during the first three cycles, but not thereafter, whereas in the secretory endometrium, it was significantly elevated even after 11–12 cycles with the Cu-T in situ . There was a marked increase in the copper concentration of the cervical mucus during the first six treatment cycles, especially during the proliferative phase. No changes occurred in the plasma levels of copper. There was a gradual decrease in the zinc concentration of the secretory endometrium. Furthermore, there was a significant decrease in the manganese concentration of both proliferative and secretory endometrium following 11–12 cycles with the Cu-T, which did not normalize after the removal of the device. There was no consistent and systematic change in endometrial sodium; however, the potassium concentration of the proliferative endometrium was diminished. The release of copper from the devices was estimated to be 10.3 mg per year (range 7.4–13.5 mg). The data obtained indicate that — after the first two months of use — the daily release of copper from the device (approximately 45 μg) is almost constant during one year (Cu-T 200).

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.

Ovarian epithelial neoplasia after hormonal infertility treatment: long-term follow-up of a historical cohort in Sweden

OBJECTIVE To study the association between hormonal infertility treatment and ovarian neoplasia. DESIGN Historical cohort study. SETTING Three university hospitals in Sweden. PATIENT(S) A total of 2,768 women assessed and treated for infertility and infertility-associated disorders between 1961 and 1975. INTERVENTION(S) Exposed women received clomiphene citrate and/or gonadotropins. MAIN OUTCOME MEASURE(S) Incidence of ovarian neoplasia. RESULT(S) No overall excess risk of invasive ovarian cancer emerged compared with the general population. In women with gonadotropin treatment for non-ovulatory disorders, the risk was elevated (standardized incidence ratio [SIR] = 5.89; 95% confidence interval [CI] 1.91-13.75); four of the five cases reported hCG treatment only, rendering the biological plausibility uncertain. Multivariate analysis within the cohort indicated that treatment with gonadotropins only was associated with an increased risk of invasive cancer (relative risk = 5.28; 95% CI 1.70-16.47). For borderline tumors, a more than threefold overall increase of tumors (SIR = 3.61; 95% CI 1.45-7.44) was noted; women exposed to clomiphene because of ovulatory disorders showed the highest risk (SIR = 7.47; 95% CI 1.54-21.83). CONCLUSION(S) Our findings of increased risk of ovarian cancer after gonadotropins and of borderline tumors after clomiphene treatment need to be interpreted with caution. However, concern is raised, and further research on the long-term safety particularly of modern hormonal infertility treatment in IVF programs is warranted.

Prostaglandins in the human endometrium: Gas chromatographic-mass spectrometric quantitation before and after IUD insertion

Prostaglandin F2alpha and its major metabolite in plasma, 15-keto-13, 14-dihydro-PGF2alpha were quantitated in biopsies from human endometrium using gas-liquid chromatography-mass spectrometry. In four of the five cases studied, the levels of both compounds were higher in the secretory phase than in the proliferative phase regardless of whether the IUD was present or not. Before insertion of an IUD the levels of PGF2alpha ranged from 65 to 8,280 pg. per milligram of tissue and those of 15-keto-13,14-dihydro-PGF2alpha ranged from less than 4 to 1,940 pg. per milligram. After insertion of an IUD the levels of the compounds ranged from 260 to 2,100 and from 5 to 109 pg. per milligram, respectively. In four of the five individual cases the IUD caused a decrease rather than an increase of the prostaglandin content of the tissue. These data do not indicate an increased biosynthesis of prostaglandins in the human endometrium after insertion of an IUD.

Menstrual disorders and associated factors among adolescent girls visiting a youth clinic

Background. Menstrual disturbances are common among teenagers and are often explained by immaturity of the hypothalamic‐pituitary‐gonadal axis. However, little is known about the underlying causes. The aim of this study was to evaluate endocrine mechanisms of menstrual disturbances and associated factors among adolescent girls visiting a Swedish youth clinic. Methods. All adolescent girls visiting the youth clinic during a five‐year period due to menstrual disturbances, except those with primary amenorrhea, were included in this retrospective study. These 203 girls were evaluated in a standardized manner by the same gynecologist. One third also met a psychologist and/or a dietician at the clinic. Results. Secondary amenorrhea was diagnosed in 117 girls (58%) and oligomenorrhea in 86 girls (42%). Menarcheal age was 13 in both groups. Hypothalamic inhibition of the gonadal axis was more frequent in the girls with secondary amenorrhea, whereas a hyperandrogenic hormonal pattern as a feature of polycystic ovary syndrome was more common in the oligomenorrheic girls. Different types of eating disorders were diagnosed in 68% of the amenorrheic girls and in 38% of the oligomenorrheic girls. Conclusions. We found hypothalamic amenorrhea and hyperandrogenism to be frequent endocrine mechanisms of menstrual disorders in teenagers. Concomitant eating disorder was highly frequent and secondary amenorrhea was associated with anorectic behavior. It is important to evaluate endocrine patterns and eating behavior in adolescents with menstrual disturbances to ensure adequate medical care and treatment.

Prospective follow‐up of menstrual disorders in adolescence and prognostic factors

Objective. Clinical follow‐up of menstrual status and eating behavior in grown‐up women diagnosed with menstrual disturbance in adolescence. Design. Prospective follow‐up study six years after the initial study. Setting. A youth clinic that is part of the school health system in Stockholm. Population. Eighty‐seven women diagnosed with secondary amenorrhea or oligomenorrhea in adolescence. Methods. Subjects underwent gynecological examination, evaluation of eating behavior and endocrine status. Main outcome measures. Menstrual status and eating behavior changes. Results. Menstrual disturbances were still present in 62% of the subjects not using hormonal contraception, 59% of which fulfilled the criteria for polycystic ovary syndrome (PCOS). The frequency of persistent menstrual disturbance was significantly more common in women with previous oligomenorrhea than secondary amenorrhea. The occurrence of eating disorders was decreased by half to 31% in women diagnosed with secondary amenorrhea at the initial study, whereas it was unchanged (40%) in women with previous oligomenorrhea. Recovery from anorectic behavior, primarily in the group of secondary amenorrhea, significantly predicted resumption with menses. Conclusion. Menstrual disturbances and eating disorders were still frequent after six years in a follow‐up of women who had menstrual disturbance in adolescence. PCOS was the main cause explaining persistent menstrual disorder, whereas recovery of anorectic eating disorders predicted resumption of menses. The findings call for a continued follow‐up of women diagnosed with menstrual disturbance in their teens.

Biochemical and morphological changes in the human endometrium induced by the progestasert device

Abstract The influence of sustained intrauterine release of progesterone on the biochemistry and the morphology of the endometrium was investigated in 19 women using the Progestasert x xTrade name (Progestasert Uterine Therapeutic System, Alza Corp., Palo Alto, California, U.S.A.). device for a period of one year. Fourteen women using an inert device of the same shape and material served as a control group. The progesterone releasing device suppressed the proliferative activity of the endometrium, abolishing completely the cyclic changes of the endometrial tissue. The circulating levels of progesterone and estradiol remained unchanged. Following the continuous use of the device, 57 per cent of the women examined showed predecidual reaction and atrophy of the glands of the endometrium, whereas the rest displayed a complete atrophy with a fibrous stroma. Alkaline phosphatase, beta-glucuronidase and total lactic dehydrogenase were decreased to levels normally observed in human endometrial tissue without cyclic activity. The endometrial trace elements, copper, zinc and and manganese, showed minor variations during the period of observation. The only consistent finding was a decrease in the zinc levels during the postovulatory phase. The present findings in the morphology and the biochemistry of the endometrium following the insertion of the progesterone-releasing device are consistent with a suppression of the proliferative activity of the uterine mucosa which may explain the contraceptive action of the device.

Intrauterine contraception with the Copper-T device: 4. Influence on protein and copper concentrations and enzyme activities in uterine washings

The concentrations of protein and copper and the activities of acid and alkaline phosphatase and beta-glucuronidase were measured in the uterine fluid of 8 25-38 year old women using the copper-T (Cu-T) 200 device for intrauterine contraception. Specimens were obtained in the proliferative phase on Cycle Days 10-12 of 1 menstrual cycle, and in the secretory phase on Days 20-23 during the next cycle prior to the insertion of the Cu-T, and during the same cycle days in Cycles 2 or 3 or 6 or 7 following insertion. Uterine fluid was obtained by irrigating the uterine cavity with physiological saline, while endometrial biopsies were taken for histological dating of the endometrium. The protein concentration of the uterine washings did not change significantly as a result of the Cu-T insertion. There was a significant difference (p.001) in Cycles 2 or 3 and 6 or 7 following insertion. Acid phosphatase activity was not influenced by the presence of the device. The betaglucuronidase in the fluid obtained during the proliferative phase showed a significant increase (p .001) DURING THE TIME WHEN the device was situ. The device caused a significant increase in the copper concentration in both phases, while the copper level in the blood serum remained unchanged. There was as increased number of white blood cells in the washings obtained during the secretory phase. The increase in the copper concentration of the uterine fluid might be the cause of the Cu-T antifertility effect due to a spermatotoxic and/or blastotoxic effect, as may the enzymic changes and increase of white blood cells.

Intrauterine contraception with the Copper-T device: 2. Influence on endometrial acid and alkaline phosphatase, beta-glucuronidase and lactic dehydrogenase activities

Protein and nucleic acid concentrations and activities of acid and alkaline phosphatase, beta-glucuronidase, and lactic dehydrogenase were systematically studied in endometrial biopsy specimens obtained from 10 24-35 year old women in this investigation. The biopses were taken during the proliterative phase on Cycle Days 10, 11, or 12 and during the luteal phase on Cycle Days 20, 21, 22, and 23 during the 2 consecutive cycles prior to insertion of the Cu-T, during several cycles of year 1 following insertion, and during the first 2 cycles after removal of the device. A significant increase in endometrial protein concentration occurred during Cycle 11-12 with the device in situ. No change was found in DNA or RNA concentrations. A significant decrease in alkaline phosphatase activity occurred in the secretory phase during and following Cycle 6 with the Cu-T in situ. The acid phosphatase activity was significantly increased in the proliferative phase during and following Cycle 6 with the device in utero. A significant decrease in beta-glucuronidase activity occurred with the Cu-T in situ, but no significant change in lactic dehydrogenase activity occurred. Since the enzymes examined are involved with the implantation of the ovum, their alterations may be the mode of action of the Cu-T.