[Assisted reproduction and risks of superovulation].
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Biomedical subjects
Publications and source records attributed to A Tiitinen.
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OBJECTIVE: To study serum levels of placental protein 14 (PP14) in relation to endometrial function in women with a history of habitual abortion. DESIGN: Prospective study. SETTING: Departments I and II of Obstetrics and Gynecology, University Central Hospital of Helsinki, Helsinki, Finland. PATIENTS: Fifty patients (26 primary and 24 secondary habitual aborters) and 38 controls without a history of abortion studied during a regular cycle. RESULTS: Habitual aborters as a whole or when subgrouped into those with normal cycles (n = 40) or with a luteal phase defect (LPD; n = 10) and control women demonstrated a distinct increase in PP14 levels from late follicular to late luteal phases. In the luteal phase, serum PP14 levels were lower in the patients than in the controls (27.2 +/- 3.1 versus 48.5 +/- 10.1 micrograms/L), but the differences in PP14 levels between habitual aborters with or without LPD was not significant (16.3 +/- 4.3 versus 29.9 +/- 3.7 micrograms/L). CONCLUSIONS: Habitual aborters exhibit lower serum PP14 levels in the late luteal phase compared with normal fertile women.
Products of the corpus luteum have targeted actions on the endometrium. Besides steroid hormones, the corpus luteum produces biologically active substances which may be either unique or shared by the endometrium and other tissues. Here we review selected markers of the corpus luteum and the endometrium as candidates for functional markers of the interplay between the two sites and relative to various treatment modalities. In clinical routine, the assessment of luteal phase is performed by morphological criteria. The timing of endometrial biopsy is important because specimens taken at different stages of the luteal phase give different results. After human menopausal gonadotrophin (HMG) superovulation, there is dyssynchrony in the morphological maturation of endometrial glands and stroma, and a marked difference has been found in endometrial development between progesterone-supplemented and non-supplemented cycles. The expression of steroid hormone receptors in endometrium is affected by ovarian stimulation regimens. After gonadotrophin-releasing hormone analogue/HMG superovulation, the progesterone receptor (PR) has been found less frequently in progesterone-supplemented cycles than in non-supplemented cycles. The relative distributions of oestrogen receptor and PR between epithelium and stroma have been reported to vary according to the number of days of progesterone exposure. Thus, the detection of PR in endometrial glands in the late luteal phase indicates that exposure of the endometrium to the action of progesterone is short. Certain biochemical changes in the uterus are not reflected in endometrial morphology. Under the influence of progesterone, secretory glandular epithelium synthesizes placental protein 14, more recently named glycodelin. Glycodelin inhibits the innate immune system and also has contraceptive actions. Endometrial glands secrete glycodelin into glandular lumen, uterine fluid and blood, where the concentrations rise during the last week of the secretory phase. The effects of various ovarian stimulation protocols on serum glycodelin concentrations are reviewed, along with recent studies on relaxin, prolactin and insulin-like growth factor binding protein 1, all products of the secretory endometrium.
OBJECTIVE: To evaluate the effect of elective cryopreservation of all embryos in the prevention of severe ovarian hyperstimulation syndrome in women at increased risk, following superovulation for in vitro fertilisation. DESIGN: Three hundred and ninety women undergoing superovulation for in vitro fertilisation between September 1991 and December 1992. SETTING: University Infertility Clinic, Helsinki, Finland. INTERVENTIONS: Twenty-three women were considered to have an increased risk of developing ovarian hyperstimulation syndrome. They were characterised by more than 20 retrieved oocytes and/or by serum oestradiol levels exceeding 10,000 pmol/l on the day of administration of human chorionic gonadotrophin. Instead of cancelling the cycle the oocytes were harvested and fertilised, and all good quality embryos were cryopreserved. The embryos were thawed and replaced during subsequent natural cycles. MAIN OUTCOME MEASURES: Occurrence of ovarian hyperstimulation syndrome and pregnancy rate. RESULTS: One out of the 23 patients at increased risk developed a moderate degree ovarian hyperstimulation syndrome, while the others had only mild symptoms. Two of the remaining 367 women with no risk developed ovarian hyperstimulation syndrome, both during early pregnancy. Among the 23 patients at increased risk there have been 15 clinical pregnancies after transfer of two to three frozen-thawed embryos in natural cycles, with a 32.6% pregnancy rate. CONCLUSIONS: Withholding embryo replacement and elective cryopreservation of the embryos is effective in preventing severe ovarian hyperstimulation syndrome. After subsequent replacement in natural cycles the implantation rate per embryo is good (22.7%).
OBJECTIVE: To study the occurrence and mechanisms of gonadal dysfunction in women with alcohol abuse. DESIGN: Prospective study. SETTING: Helsinki University Central Hospital. SUBJECTS: Fifteen consecutive chronic female alcoholics without liver cirrhosis admitted for withdrawal treatment, were studied after cessation of alcohol intake. Twelve women had regular menstrual cycles, two appeared to be menopausal and one had hypothalamic amenorrhoea. The women with regular cycles were compared with eleven healthy controls. INTERVENTION: Blood was sampled for hormone measurements three times on cycle days 5 to 7, 11 to 14, and 19 to 22, and ultrasonography was performed on the same days as the first two hormonal studies. MAIN OUTCOME MEASURES: Serum LH, FSH, prolactin, estrone, estradiol, progesterone, testosterone, androstenedione, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), the ovarian volume, the follicular diameter, the endometrial thickness. RESULTS: During the luteal phase of the menstrual cycle the serum concentration of testosterone was 65% (p < 0.01) higher and that of progesterone 23% (p > 0.05) lower in patients than in controls. During the follicular phase serum DHEAS level was decreased by 39% (p < 0.05) in patients. Otherwise the serum concentrations of the hormones studied were similar in patients and in controls. As assessed by ultrasonography, patients and controls did not differ with regard to size of the ovaries, follicle development, or the endometrial thickness. CONCLUSIONS: Even heavy alcohol use has only minor permanent effects on ovarian function, at least until development of liver cirrhosis.
To evaluate the efficacy and safety of nafarelin before hysterectomy in a prospective placebo-controlled trial, we randomized 188 pre-menopausal women with uterine fibroids (n = 111), menometrorrhagia (n = 58) or pelvic pain (n = 19) to receive either nafarelin (200 micrograms twice daily as a nasal spray) or a placebo for 3 months before abdominal hysterectomy. The data analysis could be performed in 166 women, of whom 107 received nafarelin and 59 a placebo. Nafarelin led to a rise in blood haemoglobin (5.5 g/l) and to a decrease in uterine volume (23.7%). This, however, gave no objective benefit during surgery (similar operative durations and blood losses). The uteri from patients treated with nafarelin (255.5 +/- 12.6 g, mean +/- SD) were significantly lighter (P = 0.029) than those from patients treated with a placebo (346.2 +/- 35.7 g). Histological examination of the fibroids or uteri revealed changes typical for hypo-oestrogenism, but no specific histological pattern could be established. The endometrium was proliferative in 56% and showed mild hyperplastic features in 10% of patients given nafarelin, whereas the respective figures for the placebo group were 41 and 0%. Hot flushes were the most common side-effects, being reported by 61% in the nafarelin group and 35% in the placebo group. Nafarelin can be useful as a pre-surgical adjunct in a patient scheduled for abdominal hysterectomy if there is a need to raise the haemoglobin concentration or to reduce the size of the uterus.
Previous studies suggest that, in pregnancies after in-vitro fertilization (IVF) and embryo transfer following pituitary down-regulation with a gonadotrophin-releasing hormone analogue (buserelin) and ovulation induction with human gonadotrophins, the serum placental protein 14 (PP14) concentration is lower than in normally conceived pregnancies. We studied serum PP14 concentrations in two groups of women: (i) in 17 infertile women whose pregnancy followed IVF and embryo transfer using buserelin (long protocol) and human menopausal gonadotrophin for ovulation induction; (ii) in 15 women whose pregnancy followed transfer of frozen-thawed embryos. Similar PP14 concentrations were found in both groups on days 9-10, 14-15 and 70-77 after human chorionic gonadotrophin administration (buserelin, IVF/embryo transfer) or spontaneous luteinizing hormone surge (frozen-thawed embryo transfer). Our results show that PP14 secretion is not compromised by pituitary down-regulation with buserelin in infertile women with functional ovaries.
Human ovarian follicular fluid contains a number of insulin-like growth factor binding proteins (IGFBP) of which IGFBP-3 is the most abundant. IGFBP-3 synthesis is growth hormone-regulated. We studied the effect of prostaglandin F2 alpha (PGF2 alpha) on IGFBP-3 secretion by cultured human granulosa-luteal cells from follicular aspirates of women participating in an in-vitro fertilization programme. The IGFBP-3 concentration was measured using a specific monoclonal immunofluorimetric assay. Contrary to a previous report on unstimulated follicles, this study demonstrated a positive correlation between follicular fluid IGFBP-3 concentration and follicular size. PGF2 alpha was found to stimulate in a dose-dependent fashion the secretion of IGFBP-3. Significant (P < 0.05) effects were found at PGF2 alpha concentrations of 10(-8), 10(-7) and 10(-6) M. Because IGFBP-3 inhibits progesterone production stimulated by insulin-like growth factor (IGF)-I, the PGF2 alpha-induced stimulation of IGFBP-3 production may be one of the mechanisms whereby PGF2 alpha exerts its luteolytic effect via the IGF system.
The therapies presently available for treating ovarian hirsutism are not uniformly effective, and therefore, much has been expected from GnRH agonists. These inhibit the secretion of gonadotropins and thereby suppress ovarian function, but at the same time cause hypoestrogenic side-effects. We, therefore, administered goserelin, a long-acting GnRH agonist, for treatment of 20 hirsute women (18 with polycystic ovaries) for 9 months; half of them were randomized to receive cyclic estradiol and medroxyprogesterone replacement from the fourth month onward. Seventeen patients completed the study. Goserelin suppressed ovarian function, as evidenced by a profound reduction in serum estradiol levels. The circulating levels of total testosterone, free testosterone, and androstenedione were lowered at 3 months by 29%, 31%, and 38%, respectively, but there was no effect on the levels of sex hormone-binding globulin (SHBG) or dehydroepiandrosterone sulfate. Ovarian suppression, maintained for the duration of the trial, alleviated hirsutism, as evidenced by a decrease in Ferriman-Gallwey hirsutism scores. Estrogen plus progestin replacement restored estradiol levels and increased SHBG levels, but did not potentiate the therapeutic effect of goserelin or reduce free testosterone levels. Replacement therapy abolished or alleviated hypoestrogenic vasomotor symptoms, but it also caused bleeding and premenstrual symptoms, which necessitated the withdrawal of 3 of 10 women from the treatment. Thus, goserelin is an effective treatment for ovarian hyperandrogenism. Simultaneous estrogen replacement abolishes the hypoestrogenic side-effects, but does not potentiate the effect of goserelin on hirsutism. Interestingly, the estrogen-induced increase in SHBG did not affect free testosterone. Thus, the suppression of gonadotropins, rather than the increase in SHBG, appears to be of primary significance in the alleviation of ovarian hyperandrogenism by estrogens.
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OBJECTIVE: We studied the effects of ovarian electrocauterization on the serum levels of luteinizing hormone (LH), testosterone, insulin, sex hormone-binding globulin (SHBG) and insulin-like growth factor binding globulin-1 (IGFBP-1) in women with polycystic ovarian disease (PCOD). DESIGN: Prospective. PATIENTS: Ten women with PCOD admitted to a University Infertility Clinic. MEASUREMENTS: Fasting blood samples for determination of hormone levels were taken during the follicular phase before and one month after laparoscopic ovarian electrocauterization. RESULTS: One month after electrocauterization the serum mean +/- SE LH levels had decreased from 14.4 +/- 1.9 to 10.9 +/- 1.1 U/l (P < 0.05), while the serum insulin levels showed no significant change (10.3 +/- 2.0 and 8.1 +/- 1.3 mU/l). The levels of IGFBP-1 (33.9 +/- 8.2 and 38.4 +/- 13.7 micrograms/l) and SHBG (48 +/- 10.4 and 43 +/- 5.7 nmol/l) showed no significant changes. Testosterone decreased from 3.9 +/- 2.6 to 2.9 +/- 0.3 nmol/l (P < 0.001) and androstenedione from 15.0 +/- 1.2 to 12.0 +/- 1.5 nmol/l (P = 0.05). After electrocautery seven out of ten PCOD patients ovulated either spontaneously (n = 3) or with clomiphene citrate (n = 4), and two of them conceived. CONCLUSIONS: Ovarian electrocautery leads to resumption of ovulatory cycles in some but not all PCOD patients. This effect seems to be mediated by reduction of serum LH and androgen levels, while the insulin-driven pathway via SHBG and IGFBP-1 remains unaffected.
We describe two women who suffer from recurrent fever up to 40 C in association with progesterone action and who have continuously elevated serum levels of immunoreactive tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6). In patient 1, recurrent fever began at age 17 yr and has now continued for 11 yr. The patient has had three early pregnancy terminations because of continuous fever and, thereafter, three early pregnancy losses associated with fever. In patient 2, fever first appeared at age 18 yr, and the attacks have now continued for 3 yr. The association between fever and progesterone action is supported by the following facts. 1) The episodes of fever appear in the midluteal phase of the menstrual cycle concomitantly with the highest concentration of serum progesterone. 2) Fever is further exaggerated in early pregnancy. 3) Synthetic progestins induce fever regardless of the day of the menstrual cycle. 4) The progesterone antagonist RU 486 and an agonist of GnRH, nafarelin, are capable of preventing the fever, with no effect on serum cytokine levels. Although the underlying mechanism of elevated TNF alpha and IL-6 levels in our patients remains unknown, the data suggest that these cytokines cooperate with progesterone in exerting a pyrogenic response in the hypothalamic thermoregulatory center.
Pregnancy tests have sufficiently low detection limits (25-200 IU/L of human chorionic gonadotropin, hCG) and good specificity as judged by lack of cross-reaction with lutropin (LH) and follitropin (FSH). However, little information is available on the specificity of the tests for subunits and fragments of hCG. The dominating form of hCG immunoreactivity in pregnancy urine is actually a 10 kD fragment of the beta chain of hCG called the core fragment. We have evaluated ten commonly used pregnancy test with respect to specificity for various forms of hCG and detection limit. Our results show that the detection limits of the tests are close to that claimed by the manufacturers and that the main form of hCG immunoreactivity detected is intact hCG. Four of the tests also measure the free beta subunit of hCG and one method also the hCG beta core fragment, but the detection limits were 7-70 fold those for hCG.
UNLABELLED: Insulin-like growth factor-I (IGF-I) stimulates ovarian androgen production. Insulin-like growth factor binding protein-1 (IGFBP-1) inhibits IGF actions in vitro. OBJECTIVE: To investigate the effect of oral contraceptive (OC) pills, given for 3 months, on serum gonadotropin, androgen, IGF-I, and IGFBP-1 concentrations, and glucose tolerance in seven women with polycystic ovarian disease (PCOD) and in five healthy control subjects. PATIENTS: Seven women with PCOD and five healthy control subjects. INTERVENTIONS: An oral glucose tolerance test (OGTT) was performed before and after treatment with OC. RESULTS: After treatment with OC, serum luteinizing hormone, androstenedione, and free testosterone levels decreased, and sex hormone-binding globulin concentration increased in the women with PCOD as well as in the control subjects. The cumulative response of serum insulin to OGTT was larger in the women with PCOD than in the control subjects both before and after treatment. Serum IGF-I concentration, which was unchanged during OGTT, decreased from basal level of 326 +/- 70 micrograms/L to 199 +/- 28 micrograms/L after treatment with OC in the women with PCOD, whereas no change was found in the control subjects (from 235 +/- 11 micrograms/L to 226 +/- 11 micrograms/L). Treatment with OC caused an increase of the mean basal IGFBP-1 concentration from 24 +/- 7 micrograms/L to 73 +/- 14 micrograms/L in the women with PCOD. This increase was constant during the OGTT. In the control subjects, treatment with OC did not result in any significant change in IGFBP-1 concentrations (from 44 +/- 11 micrograms/L to 61 +/- 9 micrograms/L). CONCLUSION: The combination of decreased total IGF-I concentration and increased IGFBP-1 concentration induced by OC may decrease ovarian androgen production in PCOD.
Direct intraperitoneal or intrauterine insemination in combination with superovulation was used randomly as the treatment of infertility that was unexplained or due to male subfertility or mild endometriosis in 124 couples during 326 cycles. The pregnancy rate per couple was 24% in the direct intraperitoneal insemination group and 31% in the IUI group. The difference was not significant. The pregnancy rates with both treatments were significantly higher than those seen during the 326 control cycles of the same couples (1.1% and 0.6%).
Hyperinsulinaemia is common patients with polycystic ovaries (PCO), and a relationship between hyperinsulinaemia and hyperandrogenaemia has been suggested. We studied the effect of increased circulating insulin in response to an oral glucose tolerance test (OGTT) on plasma levels of androgens and oestradiol in PCO patients and in healthy control subjects. A 75 g, 3 h oral glucose tolerance test (OGTT) was performed in eight non-obese and seven obese PCO patients, and in 10 non-obese control subjects. An additional group of five women were fasting during the study period. The increase in insulin concentration was higher in obese and non-obese PCO patients than in non-obese control subjects, and the peak values were observed at 30 or 60 min. In the fasting control subjects, the mean concentration of androstenedione decreased slightly due to a diurnal variation. During the OGTT, mean concentrations of androstenedione decreased in all groups at 30 min, after which a slight increase was observed in PCO patients and a plateau in control subjects. Similarly, mean testosterone increased after an initial decrease in obese PCO patients whereas no change was found in non-obese PCO patients. No statistically significant differences were found in the responses of androstenedione or testosterone levels to OGTT in obese or non-obese PCO patients compared to normals. No significant responses of plasma oestradiol levels to OGTT were found. These findings failed to demonstrate any significantly abnormal acute androgen responses to OGTT-stimulated hyperinsulinaemia in PCO patients, but did not exclude possible long-term effects of hyperinsulinaemia.
Previous studies have demonstrated expression of insulin-like growth factor-binding protein (IGF BP-1) in secretory and decidualized endometrium, in adult and fetal liver, and in HepG2 liver cancer cells. We have studied the expression of IGF BP-1 in various types of ovarian neoplasias, normal ovary, and granulosa cells from hyperstimulated human ovarian follicles by RNA blot hybridization. A single 1.6 kb mRNA species, similar to that present in human decidua, was identified in poly(A)RNA-containing preparations of granulosa cells and of a borderline malignant ovarian cystadenoma. This finding verifies the postulated production of IGF BP-1 by the human ovary.
Vaginal sonography and determination of serum hCG levels were carried out in 22 healthy pregnant women every 2 to 4 days after the first positive pregnancy test until a living fetus was observed. Gestational age was calculated from the day of ovulation, assessed by LH surge or hCG administration, plus 14 days. A gestational sac of 1-3 mm was detected at a mean (SEM) of 31.2 (0.2) days of gestation (range 30-33 days). The corresponding mean hCG level was 730 iu/l (30) and the range 467-935 iu/l (International Reference Preparation). The yolk sac was detected at a mean of 36.0 (0.2) days, range 34-38 days, at a mean hCG level of 4130 iu/l (370), range 1120-7280 iu/l. Fetal heart motion was visible at a mean of 41.1 (0.3) days, range 39-43 days and the corresponding mean hCG level was 12,050 iu/l (1240), range 5280-22,950, iu/l. The yolk sac and the fetal heart motion were always seen when the sac exceeded 10 and 18 mm in mean diameter, respectively.