This is because in early ovarian failure FSH and LH are elevated. This is confirmed by the SEGO protocol called Early Menoguia. The rest of the diagnoses are consistent with these analytical parameters.

A 21-year-old woman comes for consultation with a hormonal study showing FSH 0.29 mUl/mL (normal in follicular phase = 3.50-12.50 mUl/mL) and LH < 0.1 mUl/mL (normal in follicular phase 2.40-12.60 mUl/mL). We should make a differential diagnosis between the following clinical situations EXCEPT:

Administration of combined oral contraceptives.

Pituitary and ovarian response to acute stimulation with LH-RH in normal and anovulatory women.

The LH FSH estradiol and progesterone responses to acute stimulation with LH-RH were studied in 12 normal women with ovulatory cycles (4 in the initial follicular phase, 4 in the mid-follicular phase and 4 in the late follicular phase) and in two castrated women, two under hormonal contraception, two with ovarian amenorrhea, twelve with central amenorrhea of no detectable origin (6 with normal and 6 with low basal gonadotrophins), eleven anovulatory patients with pseudomenstruation, two with anorexia nervosa, and two with pituitary amenorrhea. Each woman received a rapid i.v. injection of 100 microgram synthetic LH-RH at 9:00 a.m. Serum levels of LH, FSH, estradiol and progesterone were determined by radioimmunoassay in samples collected before and 60, 120, 240 and 480 minutes after injection. The findings were : 1) A significant rise in estradiol and progesterone levels, in addition to LH and FSH elevation, in normal women; 2) A lack of ovarian steroid response in the castrated women and in ovarian amenorrheas, which suggests that the source of steroid response to stimulation is not extragonadal; 3) Significant differences in the responses of the four hormones to LH-RH in the women with central amenorrhea in comparison with the normal group with great variability of results; the steroid response in the presence of a positive LH response might correlate with the severity and/or prognosis of the disorder, a point deserving further study; 4) In anovulatory women with pseudomenstruation, LH responses for the most part normal, and particularly, progesterone responses.

[Secondary amenorrhea and LH hypersecretion. An unusual report of a granulosa cell ovarian tumor].

Granulosa cell ovarian tumors are infrequent. Since they originate from the gonadal stroma, they retain a high secretory potential and some of their clinical manifestations may be secondary to the production of sexual steroids. A 36 year old woman with an ovarian tumor presenting as a secondary amenorrhea is reported. This patient had a positive progesterone test and her hormonal profile showed a maintained LH hypersecretion (> 75 mUl/ml) which, joined to the presence of a hypophyseal microadenoma lead to suspect the presence of a gonadotrophin secreting tumor. The absence of LH response to TRH and its adequate suppression using oral contraceptives discarded this diagnosis. The histopathology of the excised ovarian tumor demonstrated that it is was a granulosa cell tumor. The physiopathological explanation of the case is based on the maintained levels of estrogens produced by the tumor that, through a positive feed-back mechanism similar to that of the polycystic ovary syndrome, produced a tonic LH elevation and GnRH hyper response. After the tumor excision, ovulatory cycles resumed and the patient became pregnant, facts that confirm the postulated hypothesis.

Functional hypothalamic amenorrhea

In all cases of amenorrhea, pregnancy should be excluded. This can be done by obtaining serum B-hCG levels. In cases of suspected FHA, screening laboratory tests include a complete blood count (CBC), electrolytes, glucose, bicarbonate, blood urea nitrogen (BUN), creatinine, liver panel, and when appropriate, sedimentation rate and/or C-reactive protein levels. Liver function tests may be abnormal in females with extreme energy restriction. The initial endocrine evaluation includes testing for levels of TSH and free T4, prolactin, LH, FSH, estradiol (E2), and anti-Müllerian hormone (AMH). FHA patients may display a combination of the following: FSH concentrations that are normal but lower than LH levels, low or low normal LH, E2 <50 pg/mL, and progesterone <1 ng/mL. LH and FSH are often normal in FHA patients. No single E2 value can confirm FHA as each reflects only a certain time point, but in individuals whose E2 is <20 pg/mL persistently, an acute gonadotropin response to GnRH

Gonadotropin-releasing hormone insensitivity

Diagnosis When suspected on the basis of the clinical presentation or physical findings, the diagnosis of GnRH insensitivity should be confirmed biochemically. The diagnosis requires the following findings: The demonstration of prepubertal serum concentrations of sex steroid hormones (serum testosterone less than 100 ng/dL [3.5 nmol/L] in males or serum estradiol less than 20 pg/mL [73 pmol/L] in females). Inappropriately low or normal serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations (usually less than 4 to 5 international units/L) rather than the high concentrations expected with primary gonadal failure. Otherwise normal anterior pituitary function.

Effect of "missed" pills on oral contraceptive effectiveness.

The purpose of this study was to determine whether missing pills in an oral contraceptive (OC) cycle resulted in folliculogenesis and eventual ovulation. Fifteen women selected from a population requesting tubal reanastomosis were randomized into three groups and issued pill packs missing four consecutive pills in specific sequences, as follows: group I, days 1-4; group II, days 3-6; and group III, days 6-9. Serum was drawn for assay of LH, FSH, estradiol (E2), and progesterone, and serial ovarian ultrasound examinations were done to study follicular development throughout the cycle at 4-day intervals. No subject ovulated, as suggested by serum progesterone concentrations (not exceeding 0.63 ng/mL for any woman) and ultrasound assessment of follicular development (no follicular diameter exceeding 13 mm). The highest (mean +/- standard deviation) serum concentrations of LH and FSH in any group (13.25 +/- 18.71 and 14.40 +/- 7.71 mIU/mL, respectively) and of E2 (44.35 +/- 26.79 pg/mL) were observed during or immediately after the pill-free interval. Ovarian ultrasound examinations suggested suppressed folliculogenesis in all groups. No functional ovarian cysts were detected. Oral contraceptives exerted a similar degree of pituitary and ovarian suppression even when the subjects missed four pills at varying times in a cycle. The anovulatory effect persisted when the OC pills were reinstituted and taken reliably after an interval of noncompliance.

Poor ovarian reserve

Pretreatment with 50 mcg ethinylestradiol three times a day for two weeks, followed by recombinant FSH 200 IU/day subcutaneously. Ethinylestradiol treatment was maintained during FSH stimulation. When at least one follicle reached 18mm in diameter and serum estradiol was greater or equal to 150 pg/ML ovulation was induced with an intramuscular injection of 10,000 IU of hCG (human chorionic gonadotropin hormone). For luteal phase support 5,000 IU of hCG was administered every 72 hours. Out of 25 patients 8 ovulated and 4 became pregnant. In the control group there were no ovulations. The patients ranged in age between 24 and 39 years with an average age of 32.7. All women had amenorrhea for at least 6 months (average 16.75 months) and FSH levels greater or equal than 40 mIU/mL (average FSH 68 mIU/ML). The researchers believe this protocol would work for women in early post menopause as well.

Pharmacodynamics of estradiol

Generally, estrogens are antigonadotropic and inhibit gonadotropin secretion. However, in women, a sharp increase in estradiol levels to about 200 to 500 pg/mL occurs at the end of the follicular phase (mid-cycle) during the normal menstrual cycle and paradoxically triggers a surge in LH and FSH secretion. This occurs when estradiol concentrations reach levels of about 250 to 300 pg/mL. During the mid-cycle surge, LH levels increase by 3- to 12-fold and FSH levels increase by 2- to 4-fold. The surge lasts about 24 to 36 hours and triggers ovulation, the rupture of the dominant ovarian follicle and the release of the egg from the ovary into the oviduct. This estrogen-mediated gonadotropin surge effect has also been found to occur with exogenous estrogen, including in transgender women on hormone therapy and pre-hormone therapy transgender men acutely challenged with a high dose of an estrogen, but does not occur in men, pre-hormone therapy transgender women, or transgender men on

Testicular failure and male infertility in the monogenic Mulibrey nanism disorder.

Few monogenic mutations causing human male infertility have been identified to date. We studied pubertal development and fecundity in males with Mulibrey nanism (MUL) caused by mutations in the TRIM37 gene. Twenty-eight male MUL patients of the Finnish national cohort aged 8.7 to 50.0 yr (median age, 28.8) at the end of observation were followed for 10 yr beginning from 2000-2001. Clinical characteristics, reproductive hormone levels, semen quality, and testicular histology were assessed. The external genital phenotype was normal. In childhood and prepuberty, serum levels of FSH, LH, testosterone (T), and inhibin B were normal. Puberty started spontaneously at a median age of 12.6 yr (range, 11.1-15.0), and FSH, LH, T, and inhibin B levels increased adequately until midpuberty. Thereafter, testicular growth and virilization proceeded slowly. Concomitantly, FSH, and to a lesser extent LH, showed a progressive increase to hypergonadotropic levels in all patients, whereas inhibin B decreased and T leveled off. Testicular size was small (median volume, 8.7 ml; range, 3.5-18.3 ml in adults). All semen samples showed severe oligoasthenozoospermia or azoospermia. None of the patients had a history of spontaneous fertility, but four men had undergone infertility treatment, which in one case was successful. All histological MUL samples showed varying degrees of degeneration. All adult MUL males have a unique disorder of testicular function with small testes, elevated FSH and LH, and low inhibin B. In MUL, mutations in TRIM37 lead to disturbance of sexual maturation, and fertility is severely compromised. Thus, TRIM37 is a novel gene causing male infertility.

[Gonadal function in anorexia nervosa patients in the postcritical phase].

Resuming of menstruation is generally held as a hall mark of recovery in Anorexia Nervosa. Nevertheless, fifteen young women (17 to 28 years old) consulted us about secondary amenorrhea while the acute phase of illness was over. Basal gonadotropins and Estradiol (E2) were measured and a GnRH- TRH stimulation test was performed. Two groups of patients were considered: A - 7 patients with a normal Body Weight Index; B - 8 patients with a Body Weight Index still low. (- 20% - 30%). In group A, 6 out of 7 patients had a early onset of anorexia nervosa (within two years after menarche). In group B, 6 out of 8 patients had a late onset of their disease (more than five years after puberty). As for Body Weight, it seems that the prognosis is better when Anorexia Nervosa occurs within few years after menarche. By comparison with normal women of same age explored in early follicular phase, our population of Anorexia Nervosa showed no significant difference in basal levels of F.S.H., L.H., E2. Cumulative Response F.S. H./L.H. was slightly increased (= 1) compared with normal control (= 0,34). Basal and stimulated Prl were normal. When Body Weight Index was still low, LH and E2 were decreased whereas cumulative response F.S. H./L.H. was dramatically increased. A correlation between E2 and Body Weight Index was shown, low E2 usually fitting well with Low Body Weight Index. Prognosis is poorer for recovery of normal gonadal function in late onset Anorexia Nervosa. Nevertheless, in each group, some patients escaped this rule. Induction of ovulation with Clomifene let us disappointed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Sublingual thyroid gland associated with polycystic ovaries].

To describe a young woman with polycystic ovary syndrome and a lingual thyroid gland. A 19-year old woman with secondary amenorrhea whose previous history had been uneventful. She had a normal spontaneous puberty with menarche at 13 years, followed by cyclical menstruations until six months before, when a period of four months of amenorrhea occurred. Physical exploration disclosed a normal young adult woman, without goiter, galactorrhea, acne, nor hirsutism. A pelvic ultrasound showed bilateral enlargement of the ovaries. Hormonal studies showed FSH 4 mUl/mL (nl = 2-12), LH 6 mUl/mL (nl = 2-14) and PRL 12 ng/mL (nl = < 25); TSH 8 microU/mL (nl < 5) and a free thyroxine level of 8.4 ng/dl (nl = 0.75-1.8). A thyroid gammagram with radioiodine disclosed a 6% caption (nl = 8.15%) and a small nodular gland at the base of the tongue. Levothyroxine 100 micrograms/day was initiated and a month later the TSH level was normal but cyclical menstruations were not established after six months of follow up. The polycystic ovary syndrome is the main endocrine cause of secondary amenorrhea in young women.

[Usefulness of determining serum levels of prolactin in women with menstruation disorders].

In 173 women with oligomenorrhea or amenorrhea, serum level of prolactin (PRL) was determined by radioimmunoassay method. In 22 cases (12.7%) the concentration of PRL was above 15 ng/ml. From the above women in 9 cases (5.2%) of all examined patients pituitary microadenoma was diagnosed. In 1 patient with pituitary microadenoma, coexisting partially empty sella was diagnosed. The mean basal PRL concentration in women with menstruation disturbances without hyperprolactinemia (group I) was found to be 7.1 +/- 3.1 ng/ml while the women with hyperprolactinemia without pituitary microadenoma (group II) was 32.9 +/- 5.8 ng/ml. In women with diagnosed pituitary microadenoma (group III) PRL concentration was 131.8 +/- 47.7 ng/ml. The group II and III demonstrated statistically significant increase of serum prolactin level in comparison to group I. Moreover in comparison with group I, statistically significant reduction of serum level of FSH, LH and estradiol 17 beta was confirmed in group with pituitary microadenoma. In group II significant decrease of serum concentration of LH and estradiol 17 beta was stated as well as lack of significant difference in serum level of FSH, in comparison to group I.

[Diagnosis of pregnancy before the menstrual period is delayed. Interest of the determination of plasma chorionic gonadotropin (HCG) in fertility disorders].

Estimating plasma HCG levels in the last days of the menstrual cycle have very early diagnosis of pregnancy. In 86 cycles occurring in 65 women being treated for sterility the levels were estimated between the 10th and the 15th day following the low point in the temperature curve for the purpose of trying to estimate the practical use of this method. In 30 cycles studied one case of fertilisation took place and was confirmed by the evolution of a pregnancy. From the 11th day onwards with the exception of one solitary case the concentrations of HCG ranged between 15 and 405 mUl-2 degrees-IS-hCC/ml. These levels, therefore are higher than the apparent concentrations found in a  group of women used as controls who were not pregnant (0 to 4.5 mUl/ml.). In 56 other cycles apparently normal periods followed on the expected date. All the same, the apparent concentration of HCG (2 to 32 mUl/ml) is far higher often than in the control group. The interference of LH in the level makes it impossible to decide between two hypotheses: whether raised levels of LH are associated with irregular menstrual function or with fertilisation, followed by premature expulsion of the oocyte.

Gynecology_Novak

Brain imaging (MRI is the gold standard) to exclude  Pituitary microadenoma  Pituitary macroadenoma  Other abnormal brain mass Hypothyroidism  Exclude secondary causes  Treat condition  Supplement with thyroid hormone if indicated  Spontaneous ovulation will occur when thyroid function normalizes  Treat underlying condition  When prolactin normalizes, spontaneous ovulation should occur Anovulation Normal or high day 3 FSH and LH Ovarian disorders (see Figure 30.3) Low LH, FSH, TSH, GH, ACTH High serum prolactin levels Abnormal TSH or T4Low FSH, LH, E2 Hypothalmic disorders Thyroid disease Hyperprolactinemia Panhypopituitarism Assess and treat condition Repeat test to exclude false positive Elevated prolactin If a pituatary microadenoma is diagnosed  Bromocriptine or cabergoline to normalize prolactin level  Spontaneous ovulation should occur when prolactin is normal Anorexia  Medical and psychiatric assessment  Treat condition  Aim to increase BMI to allow spontaneous

Premature ovarian insufficiency and early depletion of the ovarian reserve in the monogenic Mulibrey nanism disorder.

What is the timing of onset and clinical course of premature ovarian insufficiency (POI) in patients with Mulibrey nanism (MUL), a monogenic disorder caused by mutations of the peroxisomal TRIM37 gene? The number of ovarian follicles is highly reduced already in infant and young MUL girls and the majority of them will have early depletion of follicles resulting in clinical and biochemical signs of POI. Both female and male patients with MUL show failure of sexual maturation, signs of hypogonadism and infertility. We studied the gonadal function, pubertal development and ovarian reserve in 33 MUL patients aged 5.1-47.3 years (median age 22.3) at the end of observation. The patients were followed between 2004 and 2014 and 19 pubertal or postpubertal patients were enrolled in a cross-sectional study. The period of postnatal activation of the hypothalamic-pituitary-gonadal axis (minipuberty), pubertal development and menstrual history were assessed longitudinally. The cross-sectional study included gynecological examination, analysis of reproductive hormones and ultrasonography with evaluation of ovarian volume and antral follicle count. Infant girls experienced a transient minipuberty with a high FSH surge. In childhood, gonadotropins were normal or slightly elevated but began to rise to hypergonadotropic levels in prepuberty. Anti-Müllerian hormone (AMH) levels remained undetectable or low throughout childhood. The onset of puberty occurred spontaneously and the median age at menarche was 12.5 years. Of the patients, 54% never attained regular menses and 10 years from menarche, only 8% of the women menstruated regularly. In the cross-sectional study, none of the patients had normal ovarian morphology under ultrasonography. Ovaries were hypoplastic and 82% had no or fewer than two visible antral follicles. AMH levels were undetectable in the vast majority (89%). The Finnish MUL patients genotypically form a homogenous group and therefore it is possible, that different TRIM37 mutations lead to different hypogonadal phenotypes. However, to date there is no known genotype-phenotype correlation in MUL. In MUL, AMH is a useful marker of ovarian function. MUL should be added to the list of syndromes associated with POI and correspondingly, TRIM37 should be added to the list of genes associated with POI. To our knowledge, TRIM37 is the first known gene coding for a peroxisomal membrane protein associated with female gonadal failure and infertility. Elucidating the role of syndromic genes in reproduction may aid in a greater understanding of ovarian biology. This study was supported by the Finnish Foundation for Pediatric Research, Finska Läkaresällskapet, the Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds. The authors declare no conflicts of interest. Not applicable.

Menstrual abnormalities in a woman with ACTH-dependent pituitary macroadenoma mimicking polycystic ovary syndrome.

Here, we present a case of ACTH-dependent pituitary macroadenoma (Cushing's disease) resulting in secondary amenorrhea mimicking polycystic ovary syndrome (PCOS). A 20-year-old nulligravid woman had been suffering from oligomenorrhea, amenorrhea, and moderate hirsutism since the age of 18 years. She visited a gynecologic clinic where PCOS was impressed according to the clinical manifestation and ultrasound finding. The patient responded to medication in the 1st year, but gradually failed to induce menses. She was advised to visit the endocrinology department for secondary amenorrhea and endocrine survey. Physical examination revealed central obesity, supraclavicle fatpad, abdominal striae, and myopathy of four limbs. Endocrine studies revealed: serum prolactin 21 ng/mL (3.0-20 ng/mL), FSH 5.69 mIU/mL (3.4-10.0 mIU/mL), LH 1.01 mIU/mL (1.1-11.6 mIU/mL), E2 < 20 pg/mL (follicular phase 53-258 pg/mL), ACTH 110 pg/mL (0-46.0 pg/mL), cortisol 26.7 microg/dL at 8 a.m. (5.0-25 microg/dL), cortisol 21.3 microg/dL at 11 p.m. (half of normal morning value). Right pituitary macroadenoma was diagnosed through a series of dexamethasone tests and MRI. The patient received staging surgery including transsphenoidal adenomectomy and right frontotemporal craniotomy. As a result, the patient's physical condition gradually improved, and her menstrual cycle became regular with medication after the operation in the outpatient follow-up. PCOS is a common disease resulting in secondary amenorrhea. However, Cushing's syndrome resulting from pituitary macroadenoma should also be considered. Therefore, a careful history, observation, physical examination, and endocrine studies can differentiate between patients with PCOS and Cushing's disease.

Evidence for ovarian "inhibin": suppression of the secondary rise in serum follicle stimulating hormone levels in proestrous rats by injection of porcine follicular fluid.

The present studies were carried out to see if porcine follicular fluid could inhibit increases in serum follicle stimulating hormone (FSH) levels when injected into the rat. For these studies the pentobarbital-treated proestrous rat was chosen as the major test animal model. If an artificial surge of luteinizing hormone (LH) is administered to these rats, it can induce a synchronized secondary rise in FSH secretion rate. Normal saline-treated rats were also used as test animals. They exhibit preovulatory endogenous "surges" of LH and FSH, and also a secondary FSH rise. Porcine follicular fluid was harvested from medium-sized and large (3- to 10-mm diameter) follicles and treated with charcoal to remove endogenous steroids. Charcoal-treated porcine serum served as a control solution. The fluid was injected intraperitoneally in two 0.5-ml doses into pentobarbital-treated proestrous rats immediately and 3 hr after LH injection. Follicular fluid, but not the serum, suppressed the secondary, LH-induced FSH rise (P < 0.01) in a dose-dependent manner, without altering the effects of LH upon serum ovarian steroid levels or follicular rupture. It was effective down to a total dose of 200 mul. Porcine follicular fluid also blocked the secondary FSH surge in normal proestrous rats exhibiting endogenous LH/FSH primary surges. Thus, it would appear that porcine follicular fluid contains a non-steroidal substance(s) that can block the secretion of FSH that is secondary to a natural or artificial LH surge.

Ovarian hyperstimulation caused by gonadotroph adenoma secreting follicle-stimulating hormone in 28-year-old woman.

Ovarian hyperstimulation caused by a gonadotroph adenoma in premenopausal women has been described only twice before this report. A 28-yr-old woman presented with menstrual disturbances and pelvic pains that began after stopping the use of contraceptive pills. Transvaginal ultrasound revealed enlarged ovaries with multiple cysts. The patient had elevated serum estradiol (up to 2900 pmol/L; normal, 80-300 pmol/L in the follicular phase) and inhibin (6.4 kU/L; normal, 0.5-2.5 kU/L) levels. Serum LH was appropriately suppressed (0.6 IU/L), but serum FSH varied from 4.9-8.1 IU/L. Both gonadotropins as well as the free alpha-subunit showed a paradoxical response to the stimulus by TRH. A nuclear magnetic resonance study unraveled a pituitary tumor, 12-14 mm in diameter, extending up to the suprasellar cistern. After pituitary surgery, all hormone values normalized, and the patient resumed regular ovulatory cycles. In immunostaining, 20-30% of the cells of the tumor stained positively for FSHbeta. We conclude that a gonadotropin-producing adenoma must be considered in the differential diagnosis of a patient presenting with large multicystic ovaries and high estradiol levels in the absence of exogenous gonadotropins.

Elagolix

In clinical trials, elagolix produced dose-dependent decreases in gonadotropin, estradiol, and progesterone levels in women. Median levels of estradiol were partially suppressed to 42 pg/mL (follicular phase levels) with 150 mg once daily and were fully or near-fully suppressed to 12 pg/mL (postmenopausal levels) with 200 mg twice daily. In a 21-day study in premenopausal women, the effects of elagolix on FSH levels were found to be maximal at a dosage of 300 mg twice per day or above, whereas its effects on LH and estradiol levels were maximal at a dosage of 200 mg twice per day or above. Levels of progesterone were maintained at anovulatory levels (<2 ng/mL) across the 21-day study period at dosages of elagolix of 100 mg twice per day and above. A dosage of elagolix of 400 mg twice per day appears to produce no greater suppression in gonadotropin or estradiol levels than a dosage of 300 mg twice per day in premenopausal women. Suppression of gonadotropin and sex hormone levels with

[A study with diagnostic standard of occult hyperprolactinemia (OHP) and the effect of bromocriptine administration].

It is well known that the transient excessive increase of serum prolactin level is harmful for the mechanism of ovulation or the steroidogenesis of the ovaries. The pathogenesis of latent or occult hyperprolactinemia (OHP) has been investigated recently. The present study was conducted to determine the diagnostic standard of OHP, and to elucidate the efficacy of bromocriptine administration for the treatment of OHP and other ovulatory disturbances. 110 cases of hypothalamic anovulations were selected from 385 cases of infertile patients by the LH-RH and TRH loading tests. Bromocriptine (5mg/day) was administered to all of the subjects for more than three months, and the efficacy of the bromocriptine administration was investigated. Follicular development was observed by transvaginal ultrasonography (mature follicular diameters > or = 20mm), and also luteal function was estimated by the duration of the luteal phase in the BBT charts (high phase > or = 12 days), the mid-luteal serum estradiol (> or = 200pg/ml) and progesterone (> or = 10ng/ml) levels. The subjects were divided into two groups: group A, bromocriptine effective patients (63 cases) and group B, bromocriptine non effective patients (47 cases). The results of the LH-RH and TRH loading tests were compared between these two groups. Serum prolactin levels at 30 min. after TRH loading (PRL30) in group B (61.5 +/- 28.3 vs. 38.0 +/- 19.3ng/ml, p < 0.01). At the cut-off points of 50, 60 and 70ng/ml over in the values of the PRL, the efficacies of the bromocriptine administration were 77.4, 78.9 and 88.5%, respectively. From these facts, it was thought suitable that the diagnostic standard of OHP was PRL30 > or = 70ng/ml, and values of PRL30 from 50 to 70ng/ml were borderline cases of OHP. The efficacy of the bromocriptine administration in the cases without OHP (n = 57) was also investigated. Serum LH levels at 30 min. after LH-RH loading (LH30) were compared between the cases of the bromocriptine effective (n = 22) and non effective (n = 35). As a result, the LH30 of the former was significantly higher than that of the latter (96.5 +/- 64.2 vs. 45.1 +/- 31.5mIU/ml, p < 0.005). In conclusion, the diagnostic standard of OHP was determined as PRL30 > or = 70ng/ml (borderline: 50 > 70ng/ml), and bromocriptine administration was effective not only in cases of OHP, but also in cases of hyperreactivities of LH (so-called endocrinological PCOD).

Pharmacokinetics of progesterone

Progesterone can be taken by mouth, in through the vagina, and by injection into muscle or fat, among other routes. A progesterone vaginal ring and progesterone intrauterine device are also available as pharmaceutical products. Normal levels Progesterone is used as part of hormone replacement therapy in people who have low progesterone levels, and for other reasons. For purposes of comparison with normal physiological circumstances, luteal phase levels of progesterone are 4 to 30 ng/mL, while follicular phase levels of progesterone are 0.02 to 0.9 ng/mL, menopausal levels are 0.03 to 0.3 ng/mL, and levels of progesterone in men are 0.12 to 0.3 ng/mL. During pregnancy, levels of progesterone in the first 4 to 8 weeks are 25 to 75 ng/mL, and levels are typically around 140 to 200 ng/mL at term. Production of progesterone in the body in late pregnancy is approximately 250 mg per day, 90% of which reaches the maternal circulation. Routes of administration

InternalMed_Harrison

Onset of Breast/ Age of Peak woman is ±2 days. Luteal phase length is relatively constant between 12 and 14 days in normal cycles; thus, the major variability in cycle length is due to variations in the fol-White 10.2 11.9 12.6 14.3 17.1 licular phase. The duration of menstrual bleeding in ovula-Black 9.6 11.5 12 13.6 16.5 tory cycles varies between 4 and 6 days. There is a gradual Source: From FM Biro et al: J Pediatr 148:234, 2006. Abbreviations: CNS, central nervous system; GnRH, gonadotropin-releasing hormone; hCG, human chorionic gonadotropin. The differential diagnosis of precocious and delayed puberty is similar in boys (Chap. 411) and girls. However, there are differences in the timing of normal puberty and differences in the relative frequency of specific disorders in girls compared with boys.

Pituitary stalk portal blood collection in rhesus monkeys: evidence for pulsatile release of gonadotropin-releasing hormone (GnRH).

Hypothalamic-pituitary stalk portal blood was collected from 12 female rhesus monkeys. The pituitary stalk was approached transorbitally and cut at the level of the diaphragma sellae under direct visualization. After complete heparinization of the animal, stalk portal blood was obtained continuously, for periods of 30 minutes to 9 hours, using a constant exfusion pump at a rate of 30 to 40 mul/min. The mean GnRH in portal blood, as measured by radioimmunoassay, was 66 +/- 6.6 pg/ml (+/- SE) in 7 ovariectomized animals and 51 +/- 5.3 pg/ml (+/- SE) in 2 monkeys during the early follicular phase. Fluctuations in portal blood GnRH were most prominent in ovariectomized animals, with peak levels of 200-800 pg/ml and intervals of 1 to 3 hours between pulses. Peaks of GnRH during the early follicular phase did not exceed 200 pg/ml. The administration of estradiol (1000 ng, iv) to 3 monkeys did not decrease GnRH levels within the next 2 hours. These data provide direct evidence for a hypothalamic mediation of pituitary LH pulsatile release.

Premature ovarian failure in the early age 20s: 3 case reports.

Premature ovarian failure in the early age 20s is a very rare phenomenon. In a woman presenting with amenorrhea and symptoms of hypoestrogenism, the confirmatory diagnosis of premature ovarian failure relies upon the finding of postmenopausal level of the follicle-stimulating hormone (FSH > 40 mIU/ml). Three women at the age of 25, 30 and 32 years presented with 5, 6 and 10 years secondary amenorrhea, respectively. They used to have regular menses, and two of them gave birth to a healthy baby(ies). Although the etiology remains enigmatic, their gonadotropin and estradiol serum values were found to be in the postmenopausal range. Serum FSH values in the three cases were 135.4, 41.9 and 86.5 mlU/ml. Both combined oral contraceptive pills and progesterone challenge test were administered but couldn't bring about recommencement of menstrual flow. These three women who were diagnosed as a case of premature ovarian failure, evidenced by long standing secondary amenorrhea, secondary infertility, signs and symptoms of postmenopause and biochemical evidences of hypergonadotropic hypoestrogenism, were put on continuous combined oral contraceptive pills and felt better. Literature on the potential serious complications of premature menopause and treatment options in low setting areas is revised.

[Ovarian cysts and tumors as the cause of isosexual pseudoprecocious puberty].

Precocious puberty in girls is generally defined as appearance of secondary sexual characteristics before eight years of age. Menarche before the ninth birthday may serve as an additional criterion. Precocious puberty is divided in central precocious puberty and pseudoprecocious puberty. Central precocious puberty (GnRH dependent) occurs because of premature activation of hypothalamic-pituitary-gonadal axis and activity of gonadotrophins. Pseudoprecocious puberty (GnRH independent) is caused by activity of sexual steroids that are not the result of gonadotrophin activity. Objective of our study was to examine the etiology, clinical and laboratory manifestations of isosexual pseudoprecocious puberty in girls. In the period between 1995 and 2004, clinical and laboratory sings of 34 girls with precocious puberty were studied at the Endocrine Department of the Institute of Mother and Child Health Care of Serbia. Initial evaluations included height measurement, staging of puberty, bone age assessment and pelvic ultrasound. Important diagnostic sonographic parameters of precocious puberty were the volumes of ovaries and uterus as well as ovarian structure. The initial hormonal evaluation included measuring of plasma oestradiol, luteinizing hormone (LH) and follicle stimulating hormone (FSH). The luteinizing hormone releasing hormone (LHRH) stimulation test was used to evaluate LH and FSH responsiveness (60 microg/m2 LHRH-Relefact LHRH, Ferring). Blood samples were collected at 0, 20 and 60 minutes. Basal and GnRH stimulated LH and FSH were determined by immunoradiometric assay. Estradiol concentration was measured using the fluoroimmunometric assay. Thirty-four girls aged 6 months to 9 years (mean age 4.5 years) with precocious puberty were studied during the period of 9 years. Eleven girls presented with breast development, six with vaginal bleeding and seventeen with signs of puberty. On the basis of clinical signs, bone age, estradiol levels and LHRH test, premature thelarche was diagnosed in eleven patients (32.4%), premature menarche in six (17.6%) and central precocious puberty in ten girls (29.4%). Seven girls (20.6%) presented with pseudoprecocious puberty. Pelvic ultrasound examination revealed unilateral ovarian cysts in six patients and granulosa cell tumor in one. Elevated estrogen serum levels and failure of gonadotropin responses after gonadotropin releasing hormone were the classical findings in patients with isosexual pseudoprecocious puberty during the acute period of disease. In four patients, the cyst decreased spontaneously after several months, while in two patients, the cyst was removed by laparotomy. Surgical treatment was performed in a patient with granulosa cell tumor. Our work demonstrates that autonomous functional ovarian follicle cyst is the most often cause of isosexual pseudoprecocious puberty. Short period of observation is suggested because the cyst can resolve spontaneously. On the other hand, juvenile granulosa cell tumor, as highly malignant tumor, should be removed as soon as diagnosis is established.

[Ovarian stimulation for in vitro fertilization using LHRH agonists: comparison of plasma and intra-follicular hormone profiles using "short" and "long" protocols].

Plasmatic estradiol (E2), progesterone (P) and LH were measured during the follicular phase of 343 cycles induced for in vitro fertilization (IVF) using a LHRH agonist in a "long protocol" (Group I) and 76 cycles in a "short protocol" (Group II). Moreover measurements in the plasma and follicular fluid (FF) of E2, P, LH, Delta-4-androstenedione (A), Testosterone (T) and prolactin (PRL) were performed on the day of oocyte retrieval (DO) in 46 women of the group I (111 FF) and 27 of the group II (67 FF). In the group I, plasma LH always remains below 3 mUl/ml, whatever the type of agonist (Buserelin or DTRP6-LHRH) and the type of stimulation (HMG or FSH) are used. On the other hand in the group II, mean plasma LH and P levels from D-5 to D-2 and those of FF LH, T and A on DO are significantly higher than in the group I. These changes are associated with a significant decrease of retrieved oocytes (5.8 versus 7.8 p less than 0.0001), pregnancy rate (15% versus 30%, p less than 0.01) and ongoing pregnancy rate (10% versus 22%, per oocyte retrieval, p less than 0.01). They suggest that the pituitary desensitization could be unsatisfactory with the short protocol use of agonist.

LH as a diagnostic criterion for polycystic ovary syndrome in patients with WHO II oligo/amenorrhoea.

Elevated LH is common in polycystic ovary syndrome (PCOS), but is not part of the diagnostic criteria. LH concentrations are usually assessed in the early 'follicular' phase when it is suppressed, and therefore the prevalence is underestimated. In this study, LH is measured during the 'specific oligomenorrhoeic phase', when LH is least suppressed, and its importance as a diagnostic tool for PCOS is evaluated. Patients presenting with oligo- or amenorrhoea between 2002 and 2006 were selected, with the exclusion of women with WHO III oligoamenorrhoea, hyperprolactinaemia or with wrongly timed endocrine measurements. A total of 252 patients were included (198 oligo/amenorrhoeic PCOS patients and 54 oligo/amenorrhoeic controls). Mean LH concentrations were higher in PCOS patients than in controls (11.0 versus 4.1 IU/l, P < 0.001). The receiver operating characteristics (ROC) curve showed an optimal cut-off for LH of > or =6.5 IU/l, resulting in a sensitivity of 84%, specificity of 78% and a likelihood ratio of 3.8, and elevated LH concentrations predicted PCOS accurately in 93%. In conclusion, elevated LH concentrations are found in a large majority of PCOS patients when measured at the appropriate time, and could be used as an additional diagnostic test to differentiate between oligo/amenorrhoeic PCOS patients and other causes of oligo- or anovulation.

Estrone sulfate

Levels E1S levels have been characterized in humans. E1S using radioimmunoassay (RIA) have been reported to be 0.96 ± 0.11 ng/mL in men, 0.96 ± 0.17 ng/mL during the follicular phase in women, 1.74 ± 0.32 ng/mL during the luteal phase in women, 0.74 ± 0.11 ng/mL in women taking oral contraceptives, 0.13 ± 0.03 ng/mL in postmenopausal women, and 2.56 ± 0.47 ng/mL in postmenopausal women on menopausal hormone therapy. In addition, E1S levels in pregnant women were 19 ± 5 ng/mL in the first trimester, 66 ± 31 ng/mL in the second trimester, and 105 ± 22 ng/mL in the third trimester. E1S levels are about 10 to 15 times higher than those of estrone in women. References Further reading Estranes Estrogens Estrone esters Human metabolites Prodrugs Phenol esters Sulfate esters

[Hypergonadotropic ovarian failure in three patients with pituitary hyperplasia].

Three patients with ovulatory disturbances associated with increased production of gonadotropins and normal excretion of estrogen were endocrinologically examined. Patient A was 25 years old and had irregular menstruation of 13 years' duration. Patients B and C were 32 and 36 years old, the former with secondary amenorrhea of 19 years' duration and the latter with one of 2 months. Endocrinological analyses revealed a markedly increased plasma concentration of both LH (greater than 117 mIU/ml) and FSH (greater than 113 mIU/ml) in all three patients. The plasma concentration of estradiol was over 56 pg/ml in A and C before medication, and in the other patient (case B) the plasma estradiol level rose to 53 pg/ml after the administration of clomiphene. There was excessive LH and FSH response in the LH-RH stimulation test. Episodic gonadotropin secretions were observed and two weeks' administration of estrogen plasma concentrations of LH and FSH were suppressed. Computerized tomography revealed a high density area about 9-11 mm in diameter in the sella turcica of all three patients. Patient A underwent surgery via the transsphenoidal approach. Histology shows pituitary hyperplasia. After operation, the elevated LH and FSH concentration decreased to below 30 mIU/ml and the plasma concentration of estradiol and progesterone was increased to 260 pg/ml and 2 ng/ml, respectively.

[Analysis of cause and test treatment of amenorrhea in teenagers].

The population of 49 young, secondary amenorrheic women aged 17 to 20 was divided according to reaction on i.m. injection of progesterone in oil. The positive category was subdivided into I--polycystic ovarian disease with elevated serum LH and II--hypothalamic-pituitary dysfunction (HPD) with normal (or decreased) level of LH. The negative category consists of subgroup, III--hypothalamic-pituitary failure (HPF) with normal or low serum FSH and IV--ovarian failure with elevated level of FSH (two patients were noted). The bleeding response was obtain in two third of the patients, and also two third of them ovulated after clomiphene citrate treatment, including all six women with POC. The ovulatory response in patients with hypothalamic pituitary failure was noted in more than 40%. The low concentration of serum FSH (below 5 mU/ml) was more frequent in HPF (57%) in comparison with HPD (48%). The resistance to clomiphene citrate treatment was correspondingly 62.5% and 70%. When the ovulation occurred no difference in the regular function of corpus luteum in POC, HPD and HPF patients was noted.

[Effect of the steroid sex hormones on the LH and FSH responses to LHRH in the normal subject].

In man both basal gonadotrophin levels and the pituitary responses to LHRH remained relatively constant throughout life. In women the pituitary sensitivity varied in the menstrual cycle due to the typical cyclic variation of oestradiol and progesterone. The max delta LH increase to 100 mug LHRH was observed in the periovulatory period (183 +/- 41 mU/ml); it was also significantly higher in the luteal (49 +/- 7 mu/ml) than in the early follicular phase (18 +/- 3 mU/ml). The effect of exogenous sex steroid hormones taken as contraceptive drugs was then studied in 15 women. Significantly lower LH and FSH basal values as well as responses to LHRH were observed in 8 normal women under oral combined contraceptives. Conversely, in 7 women under oral sequential contraceptives, basal LH and FSH remained in the normal range. The LH-FSH responses were increased and delayed when these tests were performed during the period of estrogen treatment. Thus, with combined oral contraceptives, constant and high levels of estrogens and progesterone not only inhibit the LH peak, but also decrease the basal LH-FSH levels and responses to releasing hormone. Conversely, with sequential oral contraceptives, the low level of estradiol does not inhibit these responses and even enhances them. In menopausal women both basal and gonadotrophin responses to LHRH were increased indicating an important pituitary reserve. In menstruating women a significant estradiol increase is observed 2 and 4 hours after a 100 mug LHRH injection, both during the follicular and the luteal phases whereas progesterone increases only in the luteal phase. In men, testosterone was found to increase 4 hours after a 100 mug LHRH injection. These studies show that in normal subjects, sex steroid hormones are important regulators of the sensitivity of the pituitary responsiveness to releasing hormone.

Evolution of clinical symptoms in a young woman with a recurrent gonadotroph adenoma causing ovarian hyperstimulation.

To demonstrate the clinical course in a young female with gonadotroph adenoma causing ovarian stimulation. Our patient was a 23-year-old woman with a history of oligomenorrhea who had previously undergone bilateral ovarian wedge resection owing to the clinical appearance of polycystic ovaries. Two years later, she sought treatment for headache, galactorrhea, history of spotting and lower abdominal distension. FSH, LH, beta-LH, inhibin A and B, estradiol, prolactin (PRL), and beta-chorionic gonadotrophin (beta-CG) were measured, and the responses of FSH, LH and beta-LH to thyrotrophin-releasing hormone (TRH) were documented. Immunohistochemical analysis of the tumor tissue was performed after surgery. Five years after the trans-sphenoidal surgery, the patient again became oligomenorrheic. A large recurrent adenoma was diagnosed on CT one year later. Transvaginal ultrasound showed ovaries of normal size with multiple small cystic formations simulating a polycystic pattern, While the patient was awaiting surgery, a pituitary apoplexy occurred. Emergency decompressive surgery was performed and the patient fully recovered. Enlarged ovaries were found on ultrasound examination simulating a hyperstimulation-like pattern. At that time, elevated levels of FSH (13.4IU/l) and marginally elevated levels of beta-LH (1.43ng/ml) were found, whereas the level of LH (0.5IU/l) was subnormal. Plasma estradiol was markedly supranormal (6150pmol/l). Levels of inhibin A and B were elevated (326pg/ml and 588pg/ml respectively). The prolactin level (70ng/ml) was increased, whereas beta-chorionic gonadotrophin (beta-CG) was normal. Significantly increased FSH, LH, and beta-LH responses to TRH stimulation were documented. Pituitary macroadenoma was found on MRI scan and removed by trans-sphenoidal surgery. Immunohistochemical examination showed high positivity for beta-CG and LH, and slight positivity for FSH. Five years after the surgery, estradiol was elevated (1160pmol/l), whereas basal levels of LH (4.65IU/l) and FSH (3.98IU/l) were not suppressed. After the second operation, immunostaining of the adenoma tissue confirmed the previous findings. Measurement of gonadotrophins in our case did not prove to be a method for identifying a large recurrent gonadotroph pituitary adenoma. The sonographic ovarian imaging varied from a polycystic- to an ovarian hyperstimulation-like pattern during the evolution of the tumour.

Pharmacokinetics of estradiol

Different estradiol routes and dosages can achieve widely varying circulating estradiol levels (see the table below). For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase. Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle are in the range of 80 to 150 pg/mL, according to some sources. In postmenopausal women, circulating levels of estradiol are below 15 pg/mL. During normal human pregnancy, estrogen production increases progressively and extremely high estrogen levels are attained. Estradiol levels range from 1,000 to 40,000 pg/mL across pregnancy, are on average 25,000 pg/mL at term, and reach levels as high as 75,000 pg/mL in some women. Oral administration


Prerenal acute renal failure due to NSAIDs seems the most plausible option in this case. Tubulointerstitial nephritis due to methotrexate is less likely due to the absence of rash, fever or eosinophilia, which although rare in the MIR usually appear. Although GMN and renal amyloidosis are relatively frequent in RA, the anodyne urine sediment and the absence of proteinuria make these options unlikely.

Prerenal acute renal failure due to NSAIDs seems [HIDDEN]. Tubulointerstitial nephritis due to methotrexate is less likely due to the absence of rash, fever or eosinophilia, which although rare in the MIR usually appear. Although GMN and renal amyloidosis are relatively frequent in RA, the anodyne urine sediment and the absence of proteinuria make these options unlikely.

In a patient with rheumatoid arthritis treated with methotrexate, prednisone and indomethacin who acutely presents edema and increased plasma creatinine with a poorly expressive urine sediment and proteinuria less than 100 mg/24 h the most likely cause is:

Glomerulonephritis secondary to rheumatoid arthritis.

Renal failure due to non-steroidal anti-inflammatory drugs.

Interstitial nephritis due to methotrexate.

[Chronic interstitial nephritis caused by analgesics].

Interstitial nephritis secondary to analgesic ingestion is apparently an uncommon subject in pediatric literature. Two cases are reported in this article: case 1 is a girl followed for the last fifteen years when she had lipoid nephrosis which was treated initially with corticosteroids; she responded satisfactorily, but presented frequent relapses. After 8 years, she was given cyclophosphamide plus prednisone and lately, she responded and has remained well. Further on, her urinalysis showed specific gravity of 1,033 and no proteinuria. Five years ago, because of protracted headache due to psychological disturbance, she started to ingest a variety of analgesics in progressively increasing doses. For the last 2 years, abdominal pains, paleness, polydipsia and polyuria have been observed; at present, her blood pressure, serum chemistry, and urine sediment are normal, but there is a marked failure in the renal concentration capacity, as well as marked sodium urinary losses. A percutaneous renal biopsy showed tubulo-interstitial fibrosis and edema with normal glomeruli. Case 2 is a girl with rheumatoid arthritis which appeared 3 years ago; for over one year, the patient was given 15 mg/day prednisone plus 1.5 g. acetylsalycilic acid. She was admitted to the hospital because her osteoarticular problem did not improve. Her blood pressure, blood chemistries and urinary sediment were also normal. LE tests were negative. Renal concentrating capacity was reduced and the renal biopsy showed tubular atrophy; there was intestinal edema and mononuclear infiltration. Chronic interstitial nephritis, secondary to analgesics is supported in both cases; polyuria and a marked defect of renal concentrating capacity are the earliest and most characteristic features. Normal urinary sediment is a common finding leading to erroneous assessment of a lack of renal involvement. Pathological lesions are located in the interstice of the renal medulla and sometimes in the papilla. Early arrest of analgesic ingestion may stop and even reverse the renal lesion and the renal insufficiency.

[Renal tubular dysfunction in patients with rheumatoid arthritis starting with low dose of methotrexate].

The elevation of N-acetyl-beta-D-glucosaminidase (NAG) in urine has been shown to be associated with reversible renal tubular damage. The aim of the study was to examine the effect of first oral low dose methotrexate (MTX) on urinary excretion of NAG comparing with MTX concentration in serum and urine in a cohort of patients with rheumatoid arthritis (RA). Urinary NAG to urinary creatinine ratio (NAG index) determined in 43 patients (5 males, 38 females) with RA who started taking the first oral dose of 10 mg of MTX. Urinary NAG index was observed at 24 h and 48 h after the first MTX dose. MTX concentration was measured in blood at 90 minutes and in blood and urine at 24 h after the drug administration. NAG-enzymuria was increased in 72.1% of the patients before administration of MTX therapy (10.8 UI/g creatinine). There was no change in NAG index at 24 and 48 h after first dose of MTX (9.1 and 10.7 UI/g of creatinine). No differences of NAG-enzymuria in non-steroidal anti-inflammatory drug (NSAID)-treated patients and NSAID-free patients before and after MTX administration were revealed. The patients with decreased creatinine clearance had before treatment higher NAG index than those with normal creatinine clearance but there was not any significant increase of NAG activity after first dose of MTX in the patients with decreased creatinine clearance. Continued treatment with MTX resulted in a decrease in NAG activity accompanied by serum C-reactive protein concentration. The use of low dose MTX with or without NSAIDs does not influence the renal tubular function in patients with RA.

[Kidney involvement in rheumatoid arthritis].

Rheumatoid Arthritis (RA) is a widespread disease and its renal involvement, relatively common, is clinically significant because worsens course and mortality of the primary disease. There is still no agreement on the prevalence of renal disorders in RA: data analysis originates from different sources, as death certificates, autopsies, clinical and laboratory findings and kidney biopsies, each with its limitations. Histoimmunological studies on bioptical specimens of patients with RA and kidney damage, led to clarify prevalent pathologies. In order of frequency: glomerulonephritis and amyloidosis (60-65% and 20-30% respectively), followed by acute or chronic interstitial nephritis. Kidney injury during RA includes secondary renal amyloidosis, nephrotoxic effects of antirheumatic drugs and nephropathies as extra-articular manifestations (rheumatoid nephropathy). Amyloidosis affects survival, increases morbidity and is the main cause of end stage renal disease in patients with RA and nephropathy. Strong association between RA activity and amyloidosis needs the use of immunosuppressive and combined therapies, to prevent this complication and reduce risk of dialysis. Long-lasting and combined RA pharmacotherapy involves various renal side effects. In this review we describe NSAIDs and DMARDs (Disease-Modifying Antirheumatic Drugs) nephrotoxicity, particularly by gold compounds, D-penicillamine, cyclosporine A and methotrexate. Rare cases of IgA glomerulonephritis during immunomodulating therapy with leflunomide and TNF blocking receptor (etanercept) are reported; real clinical significance of this drug-related nephropathy will be established by development of RA treatment. In RA nephropathies, mesangial glomerulonephritis is the most frequent histological lesion (35-60 % out of biopsies from patients with urinary abnormalities and/or kidney impairment), followed by minimal change glomerulopathy (3-14%) and p-ANCA positive necrotizing crescentic glomerulonephritis.

Spectrum of glomerulonephritis in Egyptian patients with rheumatoid arthritis: A University Hospital experience.

Rheumatoid arthritis (RA) is accompanied by a variety of nephropathies. It is often difficult to distinguish between disease-associated and drug-associated renal diseases. Three hundred and seventy-six RA patients with renal involvement were included in our study; they were subjected to full history and clinical examination, kidney function, 24-h urinary protein, and kidney biopsy. All our patients were on methotrexate, low dose steroids, and nonsteroidal anti-inflammatory drugs, in addition to the previous medications. About 79.3%, 20.7%, 6.9%, and 5.9% of our patients were on leflunomide, hydroxychloroquine, etanercept, and infliximab, respectively. Renal presentation was in the form of nephrotic syndrome (33.5%), persistent subnephrotic proteinuria (12.2%), persistent proteinuria and recurrent hematuria (13.3%), acute nephritis (23.9), recurrent hematuria (7.4%), and creatinine >1.5 mg/dL (10.6%). Renal biopsies were glomerular amyloidosis (28.1%), mesangioproliferative (19.1%), membranous (6.1%), crescent (16.8%), focal segmental glomerulosclerosis (18.6%), and minimal changes (11.7%). There was a statistically significant difference in the incidence of membranous nephritis between patients who took leflunomide, and hydroxychloroquine and those did not. Etanercept in our study seems not to be related to any form of renal involvement, while infliximab is related to focal segmental sclerosis and amyloidosis of tubulointerstitial type. Kidney involvement in RA is not a rare complication. Any type of histopathological changes can be present, with amyloidosis on top of the list. Hydroxychloroquine and leflunomide are accused in membranous nephropathy. Infliximab is associated with focal segmental sclerosis and amyloidosis of tubulointerstial type, and etanercept appear to be safe as regards kidney affection.

Proliferative glomerulonephritis with acute renal failure-a rare manifestation in seronegative rheumatoid arthritis.

A 55 years old lady with advanced rheumatoid arthritis (RA) presented with severe acute renal failure with significant proteinuria preceded by fever for 14 days. She had no history of taking drugs usually responsible for glomerulonephritis, neither had she any clinico-biochemical evidence of peri-infectious glomerulonephritis. Acute interstitial nephritis (AIN) was excluded by absence of eosinophilia and eosinophils in urine. Renal biopsy reveled absence of amyloidosis and showed Focal segmental proliferative glomerulonephritis (FSGN). Patient was successfully managed with methyl-prednisolone followed by steroid and immunosuppressive and patient came over renal failure. So FSGN should be considered as one of the causes of acute renal failure in a patient with seronegative RA which may respond to immune-therapy like rapidly progressive glomerulonephritis.

[Renal involvement in patients with rheumatoid arthritis].

In rheumatoid arthritis (RA) kidney is commonly affected organ with clinical presentation characterised by proteinuria (often nephrotic range) and microhematuria followed by chronic renal failure. This condition is well recognized as a rheumatoid nephropathy (rheumatoid glomerulonephritis), which is mediated by an immunological inflammation and by nephrotoxic effects of numerous drugs usually used in rheumatoid arthiritis treatment, such as NSAID, DMARD. In the patohistological examination various kinds of associated renal lesions could be seen. The most often are amyloidosis, glomerulonephritis, interstitial nephritis. In this study, we presented 15 patients, 10 women and 5 men, mean age of 60.2 with average rheumatoid arthritis duration of 19.4 years and signs of rheumatoid nephropathy. In all patients renal biopsy was performed with frequency of histopathological findings as follows: amyloidosis in 5 patients, IgA nephropathy in 3 patients, FSGS in 3 patients, mesangial proliferative glomerulonephritis in 3 patients, minimal change disease, pauci-immune glomerulonephritis and thin membrane disease in 1 patient. In all patients (except patient with thin membrane nephropathy) we started immunossuppresive therapy with glucocorticoids in combination with cyclophosphamide or cyclosporin or azatioprine. In conclusion, in all patients with rheumatoid arthritis, parameters of renal function should be monitored and in the case of patologic results, renal biopsy should be be performed. In the treatment of RA patients with related renal disorder, suspected causal drug should be removed from the treatment and specific immunosuppressive therapy initiated.

[Clinicopathological study of nephropathy in patients with rheumatoid arthritis].

We carried out a retrospective study to investigate the clinical and pathological findings in 31 patients with rheumatoid arthritis (RA). In clinical findings, 17 patients showed nephrotic syndrome, five had isolated proteinuria, two had proteinuria and hematuria and seven had renal failure. In pathological findings, there were 16 patients with membranous nephropathy (MN), two with proliferative glomerulonephritis (DPGN), two with minor glomerular abnormality (MGA), six with amyloidosis, 2 with tubulointerstitial nephritis, and three patients had accompanying lupus nephritis. Eleven of 16 with MGN had been treated with gold, bucillamine or D-penicillamine, so they were diagnosed as drug induced MGN. In the other five patients, we could not decide which drugs induced the nephropathy. The 2 cases of MGA were associated with nephrotic syndrome and acute renal failure, which were caused by non-steroidal antiinflammatory drugs. There were two cases of non-Ig A DPGN, which was regarded as the native nephropathy in RA. The three cases with lupus nephritis were diagnosed as systemic lupus erythematosus by the criteria of the American Rheumatism Association (ARA). In conclusion, the nephropathy in patients with RA was varied and renal biopsy was a useful examination.

Severe reversible renal failure due to naproxen-associated acute interstitial nephritis.

Acute interstitial nephritis is uncommon in children and has very rarely been described with naproxen treatment. We report the occurrence of severe acute renal failure in a 10-year-old girl with juvenile rheumatoid arthritis after 1 month of naproxen therapy. Renal biopsy showed severe acute interstitial nephritis. The patient recovered completely after discontinuation of naproxen and administration of methylprednisolone. A review of the literature regarding non-steroidal anti-inflammatory drug-associated acute interstitial nephritis is provided. In an era of increasing popularity of non-steroidal anti-inflammatory drugs for use in children, paediatricians should be aware of the potential renal complications of this class of drugs.

Renal involvement in rheumatoid arthritis: analysis of renal biopsy specimens from 100 patients.

Abstract  We analyzed renal biopsy specimens from 100 patients to evaluate the characteristics of renal involvement in patients with rheumatoid arthritis (RA). Membranous nephropathy (MN) was the most common renal histological pattern (31%). Mesangial proliferative glomerulonephritis (GN) was found in 21% of cases (IgA nephropathy 12%, non-IgA GN 9%), minor changes in 17%, renal amyloidosis in 11%, interstitial nephritis in 9%, sclerotic GN in 4%, and crescentic GN in 2%. MN was relatively more frequent in men than in women, and most developed nephrotic syndrome, while a few developed renal failure. Disease-modifying antirheumatic drugs (DMARDs) correlated with MN in 26 of 31 cases. Mesangial proliferative GN showed high-grade hematuria. Amyloidosis correlated with long duration of RA; approximately half of the cases with amyloidosis also had nephrotic syndrome, and 82% developed renal failure. Of the 100 patients, 82% showed some tubulo-interstitial changes, which might be related to non-steroidal anti-inflammatory drugs. Because renal lesions in RA are very diverse, and early stage cases of MN and amyloidosis can be detected only by histological examinations, renal biopsy should be performed in cases with continuous urinary abnormalities or progressive renal failure.

Remission of the nephrotic syndrome in a patient with renal amyloidosis due to rheumatoid arthritis treated with prednisolone and methotrexate.

A 46-year-old woman developed nephrotic syndrome secondary to rheumatoid arthritis (RA). A renal biopsy showed deposition of amyloid fibrils in the subendothelial space of the glomerular capillary walls. After treatment with prednisolone (PSL, 40 mg/day), the levels of C-reactive protein (CRP) and serum amyloid A decreased to within normal limits for 2 weeks. However, the nephrotic syndrome persisted for 6 months after the therapy. To maintain the suppression of disease activity and to reduce PSL, methotrexate (5 mg/week) was added. The nephrotic syndrome resolved gradually, and the level of serum albumin returned to normal. Although renal prognosis of patients with nephrotic syndrome due to amyloidosis caused by RA has been considered poor, adequate and long-term treatment of RA with antiinflammatory drugs, including PSL and methotrexate, is useful for patients with secondary amyloidosis complicated by RA.

Renal function in rheumatoid arthritis patients treated with methotrexate and infliximab.

This study was aimed at monitoring the early and late effects of infliximab on renal proximal function in RA patients treated with methotrexate. N-acetyl-3-D-glucosaminidase (NAG) activity in urine served as an indicator of proximal tubular damage NAG activity was estimated in 21 patients during the course of treatment with infliximab and methotrexate. In every patient NAG-enzymuria was estimated directly before and 60 min after infliximab infusions and 62 weeks after starting the therapy. The total of mean NAG activities observed before each infusion of infliximab was significantly lower (p < 0.02) than NAG-enzymuria before the start of infliximab treatment (7.4 UI/g vs 11.8 UI/g). The proportion of patients in whom NAG activity rose by more than 50% during treatment ranged from 5.3% to 25%. Administration of infliximab did not significantly change the mean serum creatinine levels or creatinine clearance. No significant differences were observed in the mean values of NAG values before and 60 min after infliximab infusion. Patients who demonstrated elevated NAG activities during the course of the whole treatment demonstrated significantly more pronounced NAG enzymuria before treatment and one hour after the first infusion (p < 0.0005), as well as higher RA activity (p < 0.05). There was no observed influence of NSAIDs or prednisone on the frequency of elevated NAG activities. Raised creatinine concentrations (> 1.3 mg/dL) were noted before and during the course of infliximab treatment in 3 patients. In 16 patients abdominal fat aspiration biopsy was performed and in 3 the presence of amyloid deposits was demonstrated. In these patients NAG activity exceeded twice the upper normal limit. The introduction of infliximab during methotrexate therapy demonstrated no early or delayed nephrotoxicity of the drug in patients with rheumatoid arthritis.

A Case Report Describing a Rare Presentation of Simultaneous Occurrence of MPO-ANCA-Associated Vasculitis and Rheumatoid Arthritis.

<iBackground</i. Renal-limited myeloperoxidase vasculitis with simultaneous rheumatoid arthritis is reported as a rare occurrence. Review of literature suggests that most patients had a diagnosis of rheumatoid arthritis for several years prior to presenting with renal failure from myeloperoxidase vasculitis. <iCase Presentation</i. A 58-year-old Caucasian male presented to the hospital experiencing malaise, fevers, decreased oral intake, nausea, and vomiting for one week duration. His past medical history consisted of newly diagnosed but untreated rheumatoid arthritis, hypertension, and non-insulin-dependent diabetes mellitus. He was found to have acute renal failure, proteinuria, and hypoglycemia. Standard therapy, including intravenous fluids, did not improve his acute renal failure. A vasculitis workup resulted in a positive myeloperoxidase anti-neutrophil cytoplasmic antibody (MPO-ANCA). Renal biopsy revealed crescentic glomerulonephritis (GN) pauci-immune type, suggestive of MPO-ANCA-associated vasculitis (MPO-AAV). Treatment consisted of prednisone, cyclophosphamide, and seven cycles of plasmapheresis, in addition to hemodialysis for uremia. Upon discharge, he received hemodialysis for another week and continued treatment with cyclophosphamide and prednisone. <iConclusion</i. Patients with longstanding rheumatoid arthritis may develop renal failure due to nonsteroidal anti-inflammatory medication use and AA type amyloidosis; however, necrotizing glomerulonephritis with crescent formation has been rarely reported. This stresses the importance of early recognition and swift initiation of treatment.

[Focal segmental glomerulosclerosis presenting nephrotic syndrome and acute renal failure in a patient with rheumatoid arthritis].

A 45-year-old woman with rheumatoid arthritis(RA) who developed nephrotic syndrome and acute renal failure was reported. She first noticed polyarthritis in June 1990, and was diagnosed as RA. Since her RA was not controlled with nonsteroidal anti-inflammatory drugs (NSAID), she started taking prednisolone 10 mg daily and received 100 mg of D-penicillamine from October 1990 with improvement of the RA. In March 1991, she noticed edema of the face and legs, at which time massive proteinuria and hematuria were first noted. Because of her nephrosis, she was referred to our hospital for further evaluation. Laboratory investigations revealed 24-hour urine proteinuria of 37 g, serum creatinine, 2.7 mg/dl, blood urea nitrogen, 43.5 mg/dl, total protein, 4.1 g/dl, albumin, 1.5 mg/dl, and total cholesterol, 600 mg/dl. The rheumatoid factor and anti-nuclear antibody were positive. Renal biopsy showed focal segmental glomerulosclerosis (FSGS). Her nephrotic syndrome and renal dysfunction recovered after the administration of prednisolone at 60 mg/day. The possible pathogenesis of FSGS in patients with RA was discussed.

A prospective study of renal disease in patients with early rheumatoid arthritis.

This prospective study was designed to clarify the frequency, causes, and clinical course of renal disease in patients with early rheumatoid arthritis (RA). 235 patients (185 women, mean age 49.4 years) with early RA of less than one year's duration were enrolled and assessed monthly. Proteinuria was defined as a positive dipstick result and microscopic haematuria was defined as the presence of > or =5 red blood cells per high power field. Urinary abnormalities lasting three months or longer were defined as persistent abnormalities. At entry, 40 patients exhibited haematuria, two had a raised serum creatinine concentration, and none had proteinuria. During the observation period (average 42 months), persistent haematuria was found in 43, persistent proteinuria in 17, and a raised serum creatinine concentration in 14 patients. Persistent proteinuria was caused by drugs in 14 of 17 patients and disappeared in most cases. Risk factors for drug induced proteinuria included a raised C reactive protein and erythrocyte sedimentation rate and age over 50 at entry. Drugs resulted in a raised serum creatinine concentration in eight of 14 patients. The incidence of haematuria at entry did not differ among patients who had been treated with non-steroidal anti-inflammatory drugs, disease modifying antirheumatic drugs, or no drugs. In some patients with isolated haematuria, the haematuria appeared when the activity of RA was high and resolved when it was low. This study suggests that a raised serum creatinine concentration or persistent proteinuria in patients with early RA is predominantly drug related whereas, in contrast, isolated haematuria is more directly associated with the activity of the disease process.

[Clinico-immunological aspects of renal lesions in rheumatoid arthritis].

The aim of this study was to examine the incidence of different renal lesions in rheumatoid arthritis (RA) and to determine their relationships with the type of previous drug therapy and with the specific features of immune disorders. Ninety four patients, 84 (89.9%) females and 10 (10.6%) males) with RA whose mean age was 45.2 +/- 11.9 years and duration of the disease 7.5 +/- 6.5 years were examined. Most of them had degrees 2 and 3 PA (62.7 and 24.4%, respectively). Systemic manifestations were encountered in 60 (63.8%) patients. Eighty one patients took nonsteroidal antiinflammatory drugs (NSAID) continuously: 18 patients for a year, 32 for 5 years, 14 for 6 to 10 years, and 17 for over 10 years. All the patients underwent clinical, laboratory, and instrumental study of partial functions of the kidney. Immunological study involved solid-phase immunoassay of IgA and IgM rheumatoid factor, von Willebrand factor antigens (WF:Ag), C-reactive protein. The serum concentrations were measured by the Mancini method. Changes in urinalysis and/or signs of decreased glomerular and tubular functions were found in 69 (73.%) patients, 25 (26.6%) had arterial hypertension. Tubular dysfunctions were more common [31 (32.9%) patients]. Signs of early renal failure were detected in 20 (21.2%) patients. There were no cases of acute renal failure. Amyloidosis, glomerulonephritis, pyelonephritis were diagnosed in 5 (5.3%), 16 (17%), and 13 (13.8%) patients, respectively. The above renal lesions were concurrent in some patients. Renal lesion correlated with the progression and severity of RA, the presence of systemic manifestations, and age. There was no relationship of both 5- and 10-year use of NSAID to the symptoms of renal disease. The use of these drugs for over 10 years was concurrent with the signs of chronic renal failure and arterial hypertension. Analyzing immunological disorders showed an association of increased erythrocytic sedimentation rates and WF:Ag with amyloidosis, that of higher IgA concentrations with proteinuria and tubular dysfunctions. It is concluded that renal lesion is common in RA, there is a predominance of tubular interstitial changes. In rare cases nephropathy is characterized by a benign course and fails to result in uremia. The symptoms of renal diseases are largely associated with RA progression and severity and the patients' age. Prolonged continuous use of NSAID may contribute to the development of renal failure. Different immune mechanisms are involved in the pathogenesis of glomerular and tubular nephropathy in RA.

[Methotrexate treatment of amyloidosis secondary to rheumatoid arthritis].

Amyloidosis secondary to rheumatoid arthritis is a complication with a poor prognosis and as yet an undefined medical therapy. In the last decades the use of different cytostatics has been advocated to avoid renal function deterioration. The clinical characteristics and course in eight patients with amyloidosis secondary to rheumatoid arthritis are here reported after therapy with low dosage methotrexate. In twelve patients who followed a 12-month therapy a clinical improvement was observed, with a marked decrease in proteinuria; in one of them proteinuria disappeared. These results suggest that methotrexate at low doses might be an alternative in the early treatment of amyloidosis secondary to rheumatoid arthritis in patients with preserved renal function.

Idiopathic membranous nephropathy preceding the onset of rheumatoid arthritis: a case report.

Membranous nephropathy (MN) in the context of rheumatoid arthritis (RA), is often an iatrogenic complication due to the nephrotoxic effects of antirheumatic drugs. Rare cases of non-iatrogenic association between these two diseases were reported in the literature. A 30-year-old female patient presented in September 2005 with nephrotic syndrome. Renal biopsy showed features consistent with MN. Search for etiology was negative, particularly lupus serology which remained negative throughout the course of her illness. Accordingly, she was diagnosed as a case of idiopathic MN. Initially, she was treated with angiotensin converting enzyme inhibitors and angiotensin receptor blockers which maintained her protein excretion below nephrotic range for two years. Her nephrotic syndrome then relapsed and was treated with steroids and chlorambucil, according to the Ponticelli protocol. A few months later, she presented with early morning joint stiffness, polyarthritis involving the small joints of the hands, and strongly positive rheumatoid factor, fulfilling the diagnostic criteria of rheumatoid arthritis (RA). Her serum creatinine remained normal and a second renal biopsy revealed the same features of MN. Her RA was treated with pulsed methylprednisolone followed by oral steroids and methotrexate resulting in remission of the joints disease and the nephrotic syndrome. Remission was maintained for the last two years up to the time of this report. We hereby report a case of secondary membranous nephropathy that preceded the onset of rheumatoid arthritis by three years.

Acute interstitial nephritis with membranous nephropathy in bucillamine-treated rheumatoid arthritis.

In bucillamine-treated patients, persistent proteinuria caused by membranous nephropathy (MN) is a major adverse effect affecting the kidneys. We experienced a case of acute interstitial nephritis (AIN) with MN caused by bucillamine. An 81-year-old Japanese woman with a past medical history of rheumatoid arthritis and hypertension presented with a fever, epigastric pain, and nausea of 1 week's duration. She had commenced bucillamine 4 months earlier. At the time of admission, her baseline creatinine (0.8 mg/dl) had risen to 6.8 mg/dl. A renal biopsy revealed AIN with concomitant MN. Renal function gradually improved after bucillamine administration was stopped. In addition to MN, bucillamine can cause AIN, which requires a renal biopsy for definitive diagnosis. Given the host of pathological findings that tend to develop in patients using bucillamine, patients receiving the drug who present with symptoms of acute kidney injury should undergo a renal biopsy to determine the presence of AIN.

Effect of indomethacin and selective cyclooxygenase-2 inhibitors on proteinuria and renal function in patients with AA type renal amyloidosis.

Because the cardiovascular system (CVS) side-effects of cyclooxygenase-2 (COX-2) selective inhibitors have recently been questioned, we aimed to compare the renal and haemodynamic effects of cyclooxygenase selective (celecoxib and rofecoxib) and non-selective non-steroidal anti-inflammatory drugs (NSAIDs) (indomethacin) in patients with renal amyloidosis secondary to rheumatological diseases who required anti-inflammatory agents and are taking maximum tolerable dose of angiotensin-converting enzyme inhibitors. The present study was performed on 11 patients with stable proteinuria who were diagnosed as AA amyloidosis secondary to rheumatological diseases confirmed by renal biopsies. The study had three consecutive stages (celecoxib 200 mg/day; indomethacin 100 mg/day; rofecoxib 25 mg/day.) Each was given for 4 weeks and a wash-out phase of 3 weeks was allowed between consecutive stages. Although the decrease of proteinuria in the celecoxib period was higher than in the rofecoxib and indomethacin periods, the difference was not statistically significant. No statistically significant differences were found between serum urea, creatinine, creatinine clearance and urinary sodium excretion. In this study, no differences were found between indomethacin and the two selective COX-2 inhibitors in respect to proteinuria and renal functions in 11 patients with renal amyloidosis secondary to rheumatological diseases with varying degrees of proteinuria. Routine doses of NSAIDs brought no additional benefit to the ACE inhibitor use in terms of proteinuria and renal functions. The use of selective COX-2 inhibitors should be limited to their anti-inflammatory and analgesic effects in this population.

[Rheumatoid arthritis and the kidney. Pinpointing an aspect of confusing contours].

In literature there are only a few papers about renal involvement in rheumatoid arthritis. The scarcity of reports is due to the difficulties of pinpointing this subject; in fact a bloody investigation like kidney biopsy is necessary to obtain an exact diagnosis. Moreover it is often clinically hard to distinguish renal injury provoked by rheumatoid arthritis from nephropathy caused by drugs, either non steroidal antiinflammatory drugs or disease modifying antirheumatic drugs. This topic is perhaps neglected because primary renal involvement in rheumatoid arthritis is not considered to influence the survival, with the exception of renal amyloidosis. Pathologic examination of kidney biopsy shows in order of frequency: mesangial nephritis, renal amyloidosis, membranous nephritis, focal proliferative nephritis, minimal nephritis, interstitial nephritis. Both immune complexes and antineutrophil cytoplasmic antibodies may play a pathogenetic role. The mesangial nephritis with IgA or IgM deposits is linked to high levels of rheumatoid factor of IgA or IgM class; it has been hypothesized that the ability of mesangium to remove circulating immune complexes provokes the mesangial damage. Moreover it has been observed that rheumatoid arthritis with renal involvement shows positivity for perinuclear antineutrophil cytoplasmic antibodies more frequently than rheumatoid arthritis without nephropathy. Also in the former cases the title of these autoantibodies is higher. The aim of this paper is to bring the terms of the problem into focus by the revision of the literature. Further and wider studies are necessary to obtain more available data.

[A case of malignant rheumatoid arthritis complicated by secondary amyloidosis and membranous nephropathy].

A 30-year-old man had been treated for malignant rheumatoid arthritis from 1989 with a non-steroidal anti-inflammatory drug, then bucillamine for six months and prednisolone. Mild proteinuria appeared in May 1994, 4 years after bucillamine therapy was conducted. The patient was admitted to our hospital for a renal biopsy in July 1994. The specimen revealed secondary amyloidosis and membranous nephropathy (MGN). These findings suggest that MGN unrelated to bucillamine therapy might have occurred with secondary amyloidosis in rheumatoid arthritis.

Use of biologic agents and methotrexate improves renal manifestation and outcome in patients with rheumatoid arthritis: a retrospective analysis.

We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.

[Biologics-Induced Kidney Injury -with Special Attention to Anti-Rheumatic Drugs -].

A variety of anti-rheumatic drugs including biologics are currently used to treat rheumatoid arthritis (RA). These drugs, as well as RA itself, can cause kidney injury. RA may trigger mesangial proliferative glomeru- lonephritis (MesPGN), membranous nephropathy (N), thin basement membrane disease, and renal amyloi- dosis. As for anti-rheumatic drugs, non-steroidal anti-inflammatory drugs (NSAID) increase serum Cr lev- els due to a reduction of glomerular circulation, particularly in the presence of dehydration. Among disease- modifying anti-rheumatic drugs (DMARD), methotrexate as an anchor drug for RA rarely causes tubular ob- struction as a result of its crystallization, and bucillamine occasionally elicits IN. Calcineurin inhibitors induce vasoconstriction of the afferent arteries. Recently developed anti-rheumatic drugs, biologics, include biological inhibitors of TNF-a, IL6, and CD80/26. These can generally induce the remission of RA, while they have been reported to albeit uncom- monly trigger autoimmune renal disorders (AIRD). A recent meta-analysis identified a total of 29 cases with biologics-induced AIRD, 62% of who manifested AIRD within 12 months after treatment with biologics. AIRD cases were classified into 3 different groups: isolated autoimmune renal disorders (IARD, n =13), glo- merulonephritis with systemic vasculitis (GNSV, n= 12), and glomerulonephritis with lupus-like syndrome (GNLS, n=4). The IARD cases had 4 MesPGN, 4 MN, and 2 crescentic GN, while the GNSV cases had 8 crescentic GN and 3 purpura GN, and the GNLS cases had all MesPGN. To detect these renal disorders early in RA patients, urinalysis and serum Cr measurement should be peri- odically performed. New urinary biomarkers (L-FABP and Ngal) may be more sensitive for kidney injury. Notably, in RA patients receiving biologics, ANA, anti-dsDNA, and ANCA should also be tested at the base- line and regular intervals. [Review].

Chemotherapy

Some chemotherapy drugs are used in diseases other than cancer, such as in autoimmune disorders, and noncancerous plasma cell dyscrasia. In some cases they are often used at lower doses, which means that the side effects are minimized, while in other cases doses similar to ones used to treat cancer are used. Methotrexate is used in the treatment of rheumatoid arthritis (RA), psoriasis, ankylosing spondylitis and multiple sclerosis. The anti-inflammatory response seen in RA is thought to be due to increases in adenosine, which causes immunosuppression; effects on immuno-regulatory cyclooxygenase-2 enzyme pathways; reduction in pro-inflammatory cytokines; and anti-proliferative properties. Although methotrexate is used to treat both multiple sclerosis and ankylosing spondylitis, its efficacy in these diseases is still uncertain. Cyclophosphamide is sometimes used to treat lupus nephritis, a common symptom of systemic lupus erythematosus. Dexamethasone along with either bortezomib or

Should a patient with rheumatoid arthritis be a kidney donor?

We cared for a woman with sero-positive rheumatoid arthritis (RA), in clinical remission on oral methotrexate (MTX) and hydroxychloroquine, who wished to donate a kidney to a brother with end-stage renal disease (ESRD). We could find scant literature about this unusual clinical circumstance, and therefore review pertinent aspects of renal disease in RA, perioperative medical management, maintenance of disease remission, outcomes for RA patients who have donated kidneys, and relevant ethical issues. Renal complications in RA are not uncommon, with as many as 50% of patients at risk of reduced eGFR. This reflects anti-rheumatic and analgetic medication use (non-steroidal anti-inflammatory drugs, acetaminophen, DMARDs [cyclosporine and, historically, D-penicillamine and gold compounds], and others), glomerulitis, interstitial nephritis, complicating Sjogren's syndrome, vasculitis, or amyloidosis, and/or emergence of an "overlap" syndrome or other rheumatic disorder. The literature suggests that MTX need not be interrupted for surgery. The risk of perioperative infection to our patient would be low and remission should be sustained. We are aware of one study of six patients with RA who donated kidneys; they experienced no complications, ESRD, or deaths after a median follow-up of 8.2 years. Our ethical responsibilities are to balance patient autonomy of decision-making while assuring clinical beneficence and minimizing potential maleficence. Our perspective was that it would not be unreasonable to support this patient donating a kidney if, when fully informed, that remained her wish.

Juvenile rheumatoid arthritis and renal amyloidosis (case report).

Clinical renal abnormalities, including haematuria, proteinuria, abnormal urinary sediment, decreased renal functions and hypertension are relatively common in children with juvenile rheumatoid arthritis (JRA). These findings may be due to renal amyloidosis or administration of drugs that are potentially nephrotoxic. The case of an 11 years old boy diagnosed as JRA at 4.5 months of age and treated with steroids for 10 years is presented. In his history he had hypertension for 5 years and cataract for one year. Renal biopsy was done to evaluate the aetiology for proteinuria, which was overlooked before his admission to our Department. Secondary renal amyloidosis due to JRA was found at biopsy. The importance of investigation for amyloidosis during the long-term follow-up of JRA is reemphasized.

Necrotizing glomerulonephritis in rheumatoid arthritis.

Rheumatoid arthritis may be associated with several glomerular lesions including amyloidosis, mesangial proliferation and membranous glomerulonephritis. Systemic vasculitis is a well-recognized extra-articular complication of rheumatoid arthritis, but necrotizing glomerulonephritis, the glomerular expression of vasculitis, has been described infrequently. This report comprises four patients with rheumatoid arthritis who underwent renal biopsy for declining renal function, proteinuria and active urine sediments. Pathology revealed that three patients had segmental necrotizing glomerulonephritis without significant glomerular immunoglobulin deposition. The fourth had segmental necrosis associated with diffuse membranous glomerulonephritis. We conclude that necrotizing glomerulonephritis is part of the spectrum of glomerular lesions seen in patients with rheumatoid arthritis. Because of therapeutic considerations involving the use of cyclophosphamide, necrotizing glomerulonephritis should be a diagnostic consideration in the rheumatoid arthritis patient with signs of glomerulonephritis and rapidly deteriorating renal function.

[A case of necrotizing crescentic glomerulonephritis with arteritis due to secondary amyloidosis following rheumatoid arthritis].

A 47-year-old woman was admitted on August 4th, 1995, because of edema of the lower extremities. She had been suffering from RA for about 20 years and underwent total knee-replacements 5 years previously. On admission, nephrotic syndrome and rapidly progressive glomerulonephritis had developed in association with ileus, melena, diarrhea, dyspnea and hemoptysis. She showed a high titer of serum rheumatoid factor (357.0 IU/ml) and amyloid A protein (83.9 micrograms/ml) with positive antinuclear antibodies (homogeneous and speckled patterns). However, anti-neutrophil cytoplasmic autoantibody (ELISA), immune complexes and anti-glomerular basement membrane antibody (ELISA) were negative. Renal biopsy showed microscopic PN overlapping A-type positive amyloidosis. Although the maintenance of hemodialysis was necessary, aggressive immunosuppressive therapy with steroid pulse therapy and frequent plasma exchange provided a rapid improvement of systemic symptoms possibly due to vasculitis. We suggested that in this case, massive necrotizing crescentic glomerulonephritis with systemic arteritis developed on the basis of secondary amyloidosis due to rheumatoid arthritis. In such a case, even if various serum autoantibodies and immune complexes were negative, plasma exchange was suggested to be effective to remove not only pathogenic autoantibodies but also various serum inflammatory cytokines which may be related with severe vasculitis and glomerulitis, in addition to aggressive steroid therapy which may suppress the invasion of inflammatory cells producing these cytokines.

Mixed connective tissue disease

For arthritis, non-steroidal anti-inflammatories or low dose prednisone are usually used, which can be used in association with methotrexate or hydroxychloroquine. Temporomandibular joint arthritis has been shown to be successfully treated with condylar reconstruction using chondral grafts. Higher doses of corticosteroids (0.25 to 1 mg/kg/day) are used in complications such as myositis, meningitis, pleuritis, pericarditis, myocarditis, interstitial lung disease, or hematologic abnormalities. On the contrary, Raynaud’s phenomenon, acrosclerosis or peripheral neuropathies are usually resistant to corticosteroids. Cyclophosphamide are useful in interstitial lung disease and in the eventual serious renal involvement. In cases of myositis or thrombocytopenias resistant to corticosteroids, intravenous immunoglobulins may be useful. For Raynaud, general measures (such as tobacco cessation, protection against the cold), calcium antagonists, endovenous prostaglandins or endothelin-2

Crescentic glomerular nephritis associated with rheumatoid arthritis: a case report.

Rheumatoid arthritis is a systemic disorder where clinically significant renal involvement is relatively common. However, crescentic glomerular nephritis is a rarely described entity among the rheumatoid nephropathies. We report a case of a patient with rheumatoid arthritis presenting with antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis. A 54-year-old Sri Lankan woman who had recently been diagnosed with rheumatoid arthritis was being treated with methotrexate 10 mg weekly and infrequent nonsteroidal anti-inflammatory drugs. She presented to our hospital with worsening generalized body swelling and oliguria of 1 month's duration. Her physical examination revealed that she had bilateral pitting leg edema and periorbital edema. She was not pale or icteric. She had evidence of mild synovitis of the small joints of the hand bilaterally with no deformities. No evidence of systemic vasculitis was seen. Her blood pressure was 170/100 mmHg, and her jugular venous pressure was elevated to 7 cm with an undisplaced cardiac apex. Her urine full report revealed 2+ proteinuria with active sediment (dysmorphic red blood cells [17%] and granular casts). Her 24-hour urinary protein excretion was 2 g. Her serum creatinine level was 388 μmol/L. Abdominal ultrasound revealed normal-sized kidneys with acute parenchymal changes and mild ascites. Her renal biopsy showed renal parenchyma containing 20 glomeruli showing diffuse proliferative glomerular nephritis, with 14 of 20 glomeruli showing cellular crescents, and the result of Congo red staining was negative. Her rheumatoid factor was positive with a high titer (120 IU/ml), but results for antinuclear antibody, double-stranded deoxyribonucleic acid, and antineutrophil cytoplasmic antibody (perinuclear and cytoplasmic) were negative. Antistreptolysin O titer <200 U/ml and cryoglobulins were not detected. The results of her hepatitis serology, retroviral screening, and malignancy screening were negative. Her erythrocyte sedimentation rate was 110 mm in the first hour, and her C-reactive protein level was 45 mg/dl. Her liver profile showed hypoalbuminemia of 28 g/dl. She was treated with immunomodulators and had a good recovery of her renal function. This case illustrates a rare presentation of antineutrophil cytoplasmic antibody-negative crescentic glomerular nephritis in a patient with rheumatoid arthritis, awareness of which would facilitate early appropriate investigations and treatment.

Rheumatoid arthritis and renal light-chain deposition disease: long-term effectiveness of TNF-α blockade with etanercept.

A 68-year-old woman diagnosed with erosive rheumatoid arthritis (RA) was treated with intramuscular methotrexate 15 mg weekly and oral prednisone 5 mg daily. A favorable outcome of 6 years was followed by RA flare and nephrotic syndrome (NS). Renal biopsy revealed non-amyloid light-chain deposition disease. Laboratory analysis and bone marrow biopsy excluded monoclonal protein and plasma cell dyscrasia. Addition of subcutaneous etanercept, 25 mg twice weekly allowed rapid control of both arthritis and NS. To date, after over 7-year follow-up, RA is in clinical remission, 24-h albuminuria is consistently below 0.5 g, and serum creatinine is 0.9 mg/dl.

Pulmonary-renal syndrome

Other causes include systemic lupus erythematosus, eosinophilic granulomatosis with polyangiitis, microscopic polyangiitis, dermatomyositis, polymyositis, mixed connective tissue disease, poststreptococcal glomerulonephritis, rheumatoid arthritis, and systemic sclerosis. Less common causes also include IgA vasculitis and cryoglobulinemic vasculitis. Other etiologies include toxic injury such as paraquat poisoning, infection with hantavirus, leptospirosis, or legionella, or vascular, as seen in nephrotic syndrome when a renal vein thrombosis embolizes to the lungs. Diagnosis Differential diagnosis Cardiogenic shock can mimic a pulmonary renal syndrome and lead to coughing up blood due to pulmonary edema and kidney failure from inadequate blood flow. Treatment Treatment is primarily by corticosteroids and immunosuppressive medications like cyclophosphamide, methotrexate, and azathioprine. Plasmapheresis can be used in some circumstances. References Lung disorders Syndromes