Endometrial biopsy. Peri- or menopause: - Due to the high prevalence of organic pathology during this period it is necessary to systematically perform endometrial biopsy (Cornier or Hysteroscopy).

69-year-old woman who comes to your office referring genital bleeding of several months of evolution. She denies hormone replacement therapy and anticoagulation. She provides normal cervicovaginal cytology. General and genital physical examination without findings of interest. BMI of 38kg/m2. Indicate the most correct attitude:

Hormonal assessment with FSH, LH and estradiol.

Transvaginal ultrasonography of the endometrium in women with postmenopausal bleeding: is it always necessary to perform an endometrial biopsy?

This study was undertaken to evaluate whether it was possible to abstain from performing an endometrial biopsy when endometrial thickness according to transvaginal ultrasonography was </=4 mm in women with postmenopausal bleeding or irregular bleeding during hormone replacement therapy. Transvaginal ultrasonography was performed in 361 women aged >/=50 years who were referred because of postmenopausal bleeding or irregular bleeding during hormone replacement therapy. If endometrial thickness was </=4 mm, a Papanicolaou cervical smear was performed and the woman was reexamined with transvaginal ultrasonography after 4 and 12 months. Subjects were also instructed to return if they had recurrent bleeding, in which case transvaginal ultrasonography was performed and an endometrial biopsy specimen was obtained. Women with an endometrial thickness >/=5 mm underwent either curettage or endometrial biopsy. One hundred sixty-three women had an endometrial thickness </=4 mm. In this group one endometrial cancer that was missed by ultrasonography was diagnosed by cervical cytologic examination and two adnexal malignancies were diagnosed by ultrasonography. Endometrial malignancy was diagnosed in 0.6% of the women with an endometrial thickness </=4 mm. Endometrial biopsy was performed because of recurrent bleeding in 6.1% of cases and because of endometrial thickening in 8.1%. No cancer or hyperplasia was subsequently diagnosed among the women with an endometrial thickness </=4 mm. Endometrial cancer was diagnosed in 18.7% of the women with an endometrial thickness >/=5 mm. The corresponding figure when atypical hyperplasia and endometrial metastases were included was 20. 2%. If the false-negative rate of endometrial biopsy techniques is taken into account, then the combination of transvaginal ultrasonography and cervical cytologic examination is an adequate form of management for women with postmenopausal bleeding or irregular bleeding during hormone replacement therapy as long as endometrial thickness is </=4 mm. A randomized prospective study is necessary to verify this finding.

Atypical complex endometrial hyperplasia treated with the GyneLase system.

A 47-year-old premenopausal, para 1, gravida 1 woman complained of menometrorrhagia. She had no risk factors for endometrial hyperplasia or cancer, and office endometrial biopsy indicated focal, nonatypical endometrial hyperplasia. Seven months later the patient was scheduled for hysteroscopic endometrial resection. Instead she was treated by hysteroscopy, curettage, and the GyneLase system. The curetting indicated atypical, complex endometrial hyperplasia. The woman refused hysterectomy and salpingo-oophorectomy and adjunctive therapy with progesterone. She agreed to close surveillance and further treatment if she had any vaginal bleeding. At 13 months she remains amenorrheic, the endometrial echo is 2 mm, and follicle-stimulating hormone level is 63 IU/L. Based on the patient's amenorrhea and ultrasound uterine measurement, it is tempting to assume that GyneLase treatment may have cured her atypical hyperplasia. However, at this time, we have no evidence to substantiate this assumption.

A prospective, controlled trial of six forms of hormone replacement therapy given to postmenopausal women.

This study was undertaken to investigate the effect of various forms of hormone replacement therapy (HRT) upon postmenopausal women while controlling as many variables as possible. It was felt that the age, duration of amenorrhoea and the general health of the patients should be as comparable as possible and that each patient should provide her own pretherapy and post-therapy control data. In addition, it was felt that any placebo effect should be investigated and the patients were therefore randomly allocated to placebo tablets or one of six available forms of HRT. The age/sex registers of two large general practices were scrutinized and all women between 49 and 54 years of age were asked to cooperate; for a variety of reasons only 56 women were suitable and willing to take part in the project, yielding 8 women for each of the seven possible therapy groups. Blood samples were taken at 7-day intervals three times before therapy was given and the mean of the three values was used as the control value. The women returned on day 21 of each subsequent therapy cycle for six consecutive months and finally three months after discontinuing therapy. From the data the following broad conclusions can be drawn: (i) some women have classic symptoms of hot flushes and sweating despite high endogenous oestrogen concentrations; (ii) vaginal cytology is a relatively poor indicator of endogenous oestrogen status; (iii) while follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations are reduced on HRT neither is decreased to anywhere near premenopausal values while prolactin is unaffected; (iv) plasma cholesterol levels are reduced on HRT, the pulse rate is slower and both systolic and diastolic blood pressure are reduced to a small but significant extent; (v) there is no adverse effect upon blood clotting; and (vi) most women experience significant or complete relief of symptoms on all forms of HRT as do some women taking a placebo. The combined preparations containing an oestrogen and progestogen produced vaginal bleeding in only 80 per cent of the women. Thus protection by regular endometrical shedding may not be afforded to all women. As vaginal bleeding is unacceptable to most women if they can achieve the same symptomatic relief without inducing menstruation, it is suggested that women have a low dose oestrogen preparation prescribed cyclically for 6 to 12 months. If therapy is to be maintained for a longer time, uterine curretage should be undertaken at regular intervals to exclude the possibility of endometrial carcinoma developing.

Endometrial biopsy

Medical uses There are a number of indications for obtaining an endometrial biopsy in a non-pregnant woman: Women with chronic anovulation such as the polycystic ovary syndrome are at increased risk for endometrial problems and an endometrial biopsy may be useful to assess their lining specifically to rule out endometrial hyperplasia or cancer. In women with abnormal vaginal bleeding the biopsy may indicate the presence of abnormal lining such as endometrial hyperplasia or cancer. In patients with suspected uterine cancer, the biopsy may discover the presence of cancer cells in the endometrium or cervix. In female infertility the assessment of the lining can determine, if properly timed, that the patient ovulated, however, the same information can be obtained by a blood test of the progesterone level.

Endometrial Hyperplasia -- Treatment / Management -- Treatment duration and follow up:

In order to induce the regression of the hyperplasia, treatment should be for at least six months. Endometrial surveillance with office endometrial biopsy is recommended at six-monthly intervals. Before discharging the patient, two consecutive 6 – monthly negative biopsies should be obtained. Women who have a BMI of more than 35 and who were treated with oral progestogens are at a higher risk of relapse and should be advised annual follow -up. All women should be advised to come for a follow -up if they experience the symptoms of abnormal uterine bleeding.[2]

Unopposed estradiol therapy in postmenopausal women: results from two randomized trials.

To estimate the rates of endometrial hyperplasia, bleeding episodes, and interventions among menopausal women receiving unopposed oral estradiol or placebo therapy with ultrasound monitoring over 3 years. Two-hundred eighteen healthy women with intact uteri enrolled in the Estrogen in the Prevention of Atherosclerosis Trial (EPAT) or the Women's Estrogen-Progestin Lipid-Lowering Hormone Atherosclerosis Regression Trial (WELL-HART) were randomly assigned to either 1 mg of micronized 17beta-estradiol (n=96) or placebo (n=122) daily for up to 3 years in a double-blind fashion. Patients were followed with annual measurement of endometrial thickness using transvaginal ultrasonography. Logistic regression was used to identify predictors of uterine bleeding and endometrial biopsy. Over the study periods, nine women (9.4% of patients, 95% confidence interval [CI] 3.6-15.2%) in the estradiol group developed hyperplasia. Eight of the nine cases (88.9%) of hyperplasia were simple without atypia. Women receiving estradiol were more likely than those receiving placebo to have at least one episode of uterine bleeding (67% versus 11% at 3 years, respectively, P<.001). Women in the estradiol group were also more likely to have an endometrial biopsy (48% versus 4% at 3 years, P<.001). Among women on estradiol, obesity (body mass index [BMI] greater than 30 kg/m(2)) significantly increased the odds of uterine bleeding compared with normal-weight patients (BMI 25 or less) (OR 3.7, 95% CI 1.2-11.8). Short-term, unopposed estradiol therapy with gynecologic monitoring may be an option for the treatment of menopausal symptoms. Menopausal women choosing estradiol therapy, especially if obese, should anticipate uterine bleeding and the possibility of an endometrial biopsy. Clinicaltrials.gov, www.clinicaltrials.gov, NCT 00000559 and NCT 00115024. I.

Gynecology_Novak

3. If this hormonal therapy is not effective, the patient should be reevaluated and the diagnosis should be reassessed. The failure of hormonal management suggests that a local cause of bleeding is more likely. In this event, consideration should be given to a pelvic ultrasonographic examination to determine any anatomic causes of bleeding (such as uterine leiomyomas, endometrial polyps, or endometrial hyperplasia) and to assess the presence of intrauterine clots that may impair uterine contractility and prolong the bleeding episode. Although anatomic causes of heavy menstrual bleeding are rare in adolescents, they become increasingly common in women of reproductive age. 4. If intrauterine clots are detected, evacuation of the clots (suction curettage or D&C) is indicated. Although a D&C will provide effective immediate control of the bleeding, it is unusual to reach this step in adolescents.

First_Aid_Step2

First step: Obtain a β-hCG to rule out ectopic pregnancy. Second step: Order a CBC to rule out anemia. Third step: Pap smear to rule out cervical cancer (which can present with bleeding). TFTs to rule out hyper-/hypothyroidism and hyperprolactinemia. Obtain platelet count, bleeding time, and PT/PTT to rule out von Willebrand’s disease and factor XI def ciency. Order an ultrasound to evaluate the ovaries, uterus, and endometrium. Look for uterine masses, polycystic ovaries, and thickness of the endometrium. If the endometrium is ≥ 4 mm in a postmenopausal woman, obtain an endometrial biopsy. An endometrial biopsy should also be obtained if the patient is > 35 years of age, obese (BMI > 35), and diabetic. Heavy bleeding: Since heavy or prolonged uterine bleeding has likely denuded the endometrial cavity, estrogen is needed to rapidly promote endometrial growth.

Gynecology_Novak

Endometrial Sampling Endometrial sampling should be performed to evaluate abnormal bleeding in women who are at risk for endometrial pathology, including polyps, hyperplasia, or carcinoma. Such sampling is mandatory in the evaluation of anovulatory bleeding in women older than 35 to 40 years of age, in younger women who are obese, and in those who do not respond to medical therapy or those with a history of prolonged anovulation (143). The technique of D&C, which was used extensively for the evaluation of abnormal bleeding, was largely replaced by endometrial biopsy in the office. The classic study in which a D&C was performed before hysterectomy with the conclusion that less than one-half of the endometrium was sampled in more than one-half of the patients led to questioning the use of D&C for endometrial diagnosis (176,177). Hysteroscopy, either diagnostic or operative, with endometrial sampling, can be performed either in the office or operating room (178).

Management of hypogonadism in adolescent girls and adult women with Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3 ± 7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20 ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53 ng/ml and 6.4 IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult.

[Women's opinion on hormone pills and the main sources of information].

The aim of this paper was to analyze and to evaluate women's opinion on hormone pills and the influence on hormone pill usage and reveal the main sources of information. Women who came for pregnancy termination (Group A) and women who came for consultation on further usage of contraception (Group K) have been interrogated. Interrogation according the special questionnaire has been performed at four consultation centers and three gynecologic clinics of Kaunas city. It was find out that due to the wrong information 25.1% of women in group A and 35% of women in group K thought that hormone pills cause irregular bleeding (p=0.01). Another myth - the possibility to become pregnant when taking pills - was indicated by 17% of women in group A and 32.4% of women in group K (p=0.01). Nine percent in group A and 12% in group K were confident that when taking hormone pills for some period of time one will not be able to become pregnant in the future. Seventy three percent of group A women and 80% of group K women indicated that the use of hormone pills increases the body weight (p=0.01). This research showed that the women that used hormone pills were properly informed about their treatment and side effects. Fifty four percent of group A women and 36% of group K women indicated that hormone pills were not suitable in case of several diseases (p=0.01). Eighty three percent of group A women and 71% of group K knew that hormone pills did not protect from cervical cancer (p=0.01). This information was mainly obtained from medical workers. The main reason why women of fertile age who took part in our research used little of hormone pills was false information received from insufficiently skilled persons and accordingly the negative opinion about hormone pills. Women's opinion on hormone pills is a very important factor for its usage. This opinion depends on sources of information, whether women received correct or false information on hormone pills. The most reliable source of information indicated by investigated women was medical personnel.

Menstrual restoration in severe panhypopituitarism many years after cranial irradiation for suprasellar germinoma.

We report a very rare case showing menstrual restoration in severe pan-hypopituitarism many years after cranial irradiation for suprasellar germinoma. A 30-year-old, almost primarily amenorrheic woman with severe panhypopituitarism presented with cyclic genital bleeding for the previous five months. She had menstruated once, when she was 13 years old. When she was 14 years old, she was diagnosed with a suprasellar germinoma measuring 10 mm in diameter, which led to diabetes insipidus. Cranial irradiation with a total dose of 24 Gy and chemotherapy resulted in complete tumor remission. She developed severe hypopituitarism [luteinizing hormone (LH) = 0.4 mIU/mL, follicle-stimulating hormone (FSH) = 1.7 mIU/mL, and serum estradiol (E2) level < 10 pg/mL]. She had received multiple hormone replacement therapies for many years. When she was 29 years old, she expressed a desire to become pregnant. Serum gonadotropin and E2 levels increased (LH = 5.8 mIU/mL, FSH = 5.9 mIU/mL, and E2 = 58 pg/mL). She conceived with clomiphene therapy, and then delivered a healthy baby. Eight months after parturition, her basal body temperature and serum progesterone levels indicated recovery of ovulatory cycles. Ten months after parturition, she also spontaneously conceived. Menstrual restoration is very rare in severe panhypopituitarism after cranial irradiation. A relatively low dose of irradiation and small tumor size may have contributed to the recovery of menstruation in our patient.

[Evaluation of weight and morphotype of French women in gynecological consultation].

Weight and morphology change with age in proportions which depend on numerous environmental factors. This French study on 3,000 women age between 40 and 70, seeing their gynecologist, has shown that the average body mass index of this population is 23.97 kg/m2, and that the waist hip ratio is 0.81. Those two parameters increase with age and are reduced when women have a physical activity for more than 2 hours a week and are on oral contraception or hormone replacement therapy. Women on percutaneous hormone replacement therapy have a lower body mass index and a lower waist hip ratio. Cigarette smoking goes with a lower body mass index. When it dates back to more than 5 years, menopause is associated with a body mass index increase. In this population, the proportion of women under hormone replacement therapy is 69%, mostly percutaneous estrogenotherapy on a discontinuous sequential rhythm.

Estrogen-secreting adrenocortical tumor in a postmenopausal woman: a challenging diagnosis.

Adrenocortical carcinoma (ACC) is a malignant disorder with rapid evolution and severe prognosis in adults and most produce cortisol and androgen. Estrogen-secreting adrenocortical carcinomas are extremely rare, especially in women, tend to be larger and have worse prognosis compared with other types of ACCs. We report the case of a 58-year-old woman who presented with bilateral breast enlargement and postmenopausal genital bleeding. She presented high estradiol (818 pg/mL - 25 times above upper normal limit for postmenopausal women) and testosterone (158 ng/dL - 2 times above upper normal limit) levels and no suppression of cortisol after overnight 1 mg dexamethasone test (12.5 µg/dL; normal reference value: < 1.8 µg/dL). The patient had no clinical features of cortisol excess. MRI showed a 12 cm tumor in the right adrenal. Clinical findings of bilateral breast enlargement and postmenopausal genital bleeding with no signs of hypercortisolism associated with hormonal findings of elevated estradiol and testosterone levels would indicate either an ovarian etiology or an adrenal etiology; however, in the context of plasma cortisol levels non-suppressive after dexamethasone test and the confirmation of an adrenal tumor by MRI, the diagnosis of an adrenal tumor with mixed hormonal secretion was made. The patient underwent an open right adrenalectomy and pathological examination revealed an ACC with a Weiss' score of 6. Estradiol and testosterone levels decreased to normal range soon after surgery. She was put on mitotane treatment as adjuvant therapy, but due to side effects, we were unable to up-titrate the dose and she never achieved serum mitotane dosage above the desired 14 µg/mL. The patient remained in good health without any local recurrence or metastasis until 5 years after surgery, when increased levels of estradiol (81 pg/mL - 2.5 times above upper normal limit) and testosterone (170 ng/dL - 2.1 times above upper normal limit) were detected. MRI revealed a retroperitoneal nodule measuring 1.8 × 1.2 cm. The pathological finding confirmed the recurrence of the estrogen-secreting ACC with a Weiss' score of 6. After the second procedure, patient achieved normal estrogen and androgen serum levels and since then she has been followed for 3 years. The overall survival was 8 years after the diagnosis. In conclusion, although extremely rare, a diagnosis of an estrogen-secreting ACC should be considered as an etiology in postmenopausal women presenting with bilateral breast enlargement, genital bleeding and increased pure or prevailing estrogen secretion. Estrogen-secreting adrenocortical carcinomas are exceedingly rare in adults and account for 1-2% of adrenocortical carcinomas. Estrogen-secreting adrenal tumors can be present in females, but are even more rare, we found few cases described in the literature. In women, they present with precocious puberty or postmenopausal bleeding. Feminization in the context of an adrenal tumor is considered almost pathognomonic of malignancy. Feminizing ACCs tend to be larger and with worse prognosis compared with nonfeminizing ACCs.

[Guideline for the diagnosis of postmenopausal bleeding. PMPB Working Group of the SGGG].

2.1. History and clinical-gynecological investigation including a Pap smear are the first step in the clarification. The history should make sure if there is in fact bleeding from the genital and not from the urological or the intestinal region. Drug intake should be recorded, and risk factors for the development of endometrial carcinoma should be considered. This will not affect further investigation. The clinical-gynecological investigation should prove the source of postmenopausal bleeding according to the anatomical site--uterine, infra-, or suprauterine. The causes of infrauterine bleeding may easily be diagnosed by means of inspection of the external genitalia and further by using a speculum. The causes of uterine bleeding are of major importance. Cytology and colposcopy, supported by bimanual investigation, exclude cervical carcinoma as a cause of bleeding. Atypical endometrial cells on the cytological smear arouse suspicion of endometrial carcinoma. 2.2. Transvaginal sonography (TVS) is the next step if the above-mentioned investigations are negative. Both adnexa should always be investigated and the findings sonographically documented, so that solid cystic masses in the adnexal area can be better identified as suprauterine causes of postmenopausal bleeding. Then the uterus should be investigated. Further procedures are decided from the results of measurement of the longitudinal section of the endometrium at the level of maximum endometrial thickness. If the endometrial thickness is _<4 mm, an observant attitude can be assumed. After 3 months the patient should be controlled against using TVS. If bleeding recurs or the endometrial thickness is >4 mm on TVS, the procedure given in subparagraph 2.3 should be followed. In case the endometrial thickness is >4mm or not measurable, a histomorphological investigation according to subparagraph 2.3 should be performed. In such cases, saline infusion sonohysterography(SIS) is useful as a simple method to supplement TVS. It can aid in the decision making as to which further, more invasive measures should be taken (endometrial biopsy/hysteroscopic resection). Computerized tomography or magnetic resonance imaging are, as a rule, not indicated in patients with postmenopausal bleeding. 2.3. A definite diagnosis is possible only on the basis of a histological investigation. If TVS or SS show evidence of a polypoid state, removal under hysteroscopic control is the diagnostic method of choice. In cases of symmetrical or asymmetrical thickening of the endometrium on SIS, a less invasive biopsy may be sufficient. If the biopsy specimen does not yield representative diagnostic material, one should proceed as described above. A fractionated curettage should as a rule not be performed solely, but in combination with hysteroscopy.

Heavy menstrual bleeding

Pap smear to rule out cervical neoplasia Pelvic ultrasound scan is the first line diagnostic tool for identifying structural abnormalities. Endometrial biopsy in women with high risk endometrial cancer or atypical hyperplasia or malignancy. Hysteroscopy (anaesthesia should be offered) Thyroid-stimulating hormone and thyrotropin-releasing hormone dosage to rule out hypothyroidism

Female infertility

Lab tests Hormone testing, to measure levels of female hormones at certain times during a menstrual cycle. Day 2 or 3 measure of FSH and estrogen, to assess ovarian reserve. Measurements of thyroid function (a thyroid stimulating hormone (TSH) level of between 1 and 2 is considered optimal for conception). Measurement of progesterone in the second half of the cycle to help confirm ovulation. Anti-Müllerian hormone to estimate ovarian reserve. Examination and imaging An endometrial biopsy, to verify ovulation and inspect the lining of the uterus. Laparoscopy, which allows the provider to inspect the pelvic organs. Fertiloscopy, a relatively new surgical technique used for early diagnosis (and immediate treatment). Pap smear, to check for signs of infection. Pelvic exam, to look for abnormalities or infection.

Clinical practice guidelines on menorrhagia: management of abnormal uterine bleeding before menopause.

Normal menstrual periods last 3-6 days and involve blood loss of up to 80ml. Menorrhagia is defined as menstrual periods lasting more than 7 days and/or involving blood loss greater than 80ml. The prevalence of abnormal uterine bleeding (AUB) is estimated at 11-13% in the general population and increases with age, reaching 24% in those aged 36-40 years. A blood count for red cells+platelets to test for anemia is recommended on a first-line basis for women consulting for AUB whose history and/or bleeding score justify it. A pregnancy test by an hCG assay should be ordered. A speculum examination and Pap smear, according to the French High Health Authority guidelines should be performed early on to rule out any cervical disease. Pelvic ultrasound, both abdominal (suprapubic) and transvaginal, is recommended as a first-line procedure for the etiological diagnosis of AUB. Hysteroscopy or hysterosonography can be suggested as a second-line procedure. MRI is not recommended as a first-line procedure. In idiopathic AUB, the first-line treatment is medical, with efficacy ranked as follows: levonorgestrel IUD, tranexamic acid, oral contraceptives, either estrogens and progestins or synthetic progestins only, 21 days a month, or NSAIDs. When hormone treatment is contraindicated or immediate pregnancy is desired, tranexamic acid is indicated. Iron must be included for patients with iron-deficiency anemia. For women who do not wish to become pregnant in the future and who have idiopathic AUB, the long-term efficacy of conservative surgical treatment is greater than that of oral medical treatment. Placement of a levonorgestrel IUD (or administration of tranexamic acid by default) is recommended for women with idiopathic AUB. If this fails, a conservative surgical technique must be proposed; the choices include second-generation endometrial ablation techniques (thermal balloon, microwave, radiofrequency), or, if necessary, first-generation techniques (endometrectomy, roller-ball). A first-line hysterectomy is not recommended in this context. Should a hysterectomy be selected for functional bleeding, it should be performed by the vaginal or laparoscopic routes.

Gynecology_Novak

Table 14.16 Etiology of Postmenopausal Bleeding From Hacker NF, Moore JG. Essentials of obstetrics and gynecology, 3rd ed. Philadelphia: WB Saunders, 1998:635, with permission. Endometrial sampling is indicated for any unexpected bleeding that occurs with hormonal therapy. A significant change in withdrawal bleeding or breakthrough bleeding (e.g., absence of withdrawal bleeding for several months followed by resumption of bleeding or a marked increase in the amount of bleeding) should prompt endometrial sampling. Patient adherence to hormonal regimens is a significant issue with hormone therapy, with the challenges of oral therapy mitigated by nonoral routes of administration (247). Missed doses of oral medication and failure to take the medication in the prescribed fashion can lead to irregular bleeding or spotting that is benign in origin but that can result in patient dissatisfaction (248).

Menopause

The stages of the menopause transition have been classified according to a woman's reported bleeding pattern, supported by changes in the pituitary follicle-stimulating hormone (FSH) levels. In younger women, during a normal menstrual cycle the ovaries produce estradiol, testosterone and progesterone in a cyclical pattern under the control of FSH and luteinizing hormone (LH), which are both produced by the pituitary gland. During perimenopause (approaching menopause), estradiol levels and patterns of production remain relatively unchanged or may increase compared to young women, but the cycles become frequently shorter or irregular. The often observed increase in estrogen is presumed to be in response to elevated FSH levels that, in turn, is hypothesized to be caused by decreased feedback by inhibin. Similarly, decreased inhibin feedback after hysterectomy is hypothesized to contribute to increased ovarian stimulation and earlier menopause.

[Endometrial hyperplasias resistant to progestins: alternatives to traditional treatments].

Endometrial hyperplasias are mainly regarded as a response to unopposed endogenous estrogenic stimulation and concern 12% of perimenopausal women. They are usually diagnosed because of irregular bleeding. They are divided into two categories based on the presence or absence of cytological atypia and further classified as simple or complex according to the extent of architectural abnormalities. Endometrial hyperplasias with cytological atypia are classically treated by hysterectomy. Endometrial hyperplasias without cytological atypia are classically treated by progestins. The bad observance (25% spontaneously stopping), the 30% recurrence rate after stopping progestin and the 12-53% resistance rate to treatment lead to propose a second-line therapy after endocrinological check-up, exploration of haemostasis, pelvic ultrasonography, hysteroscopy and endometrial biopsies. Standard treatments include uterine curettage which is not very effective and hysterectomy. Medical alternatives (gonadotropin-releasing hormone agonists, levonorgestrel-releasing intrauterine device) and surgical alternatives (endometrial resection, thermal balloon endometrial ablation) were developed to avoid treating functional pathology radically. These conservative procedures correct 80% of endometrial hyperplasia symptoms with a low rate of lateral effects. However, these results need to be confirmed by long-term studies. Some economical, legal or material factors can also limit carrying out the procedures. Clinical trials need to be performed to better define the place of medical and surgical alternatives to hysterectomy in the treatment of endometrial hyperplasias resistant to progestins.

[Two cases of myasthenia gravis associated with transient amenorrhea].

Two cases of acquired autoimmune myasthenia gravis (MG) presenting transient amenorrhea were reported. Case 1, 28 years old, developed blepharoptosis and generalized fatigability at the age of 20 years. She had been treated only by anti-cholinesterase. Amenorrhea appeared at the age of 26 years. Then, physical examinations showed normal secondary sexual development and moderate myasthenic features. On laboratory examinations, SLE findings such as leucopenia (1,600/mm3), biologically false positivity in the serological tests for syphilis, negative Mantoux reaction, positive anti-nuclear and -DNA antibodies, were noted. Anti-AChR antibody was highly positive (max.: 353 nmol/l). Decreased E2 (13-15 pg/ml) and progesterone (0.21-0.29 ng/ml) values in serum, elevated LH (110-160 mIU/ml) and FSH (78-90 mIU/ml) and highly reactive LH-RH loading test were consistent with the hypergonadotropic hypogonadism. Thymus pathology of thymectomy which was done during amenorrhea, showed hyperplasia. Bilateral ovarian biopsy revealed a number of arrested primordial follicles, but neither inflammatory changes nor fibrosis. Immune complexes were not localized in the ovarian biopsy. The Kaufmann's therapy aggravated myasthenic symptoms. Menstruation recurred after 13 months of thymectomy. Amenorrhea continued for 18 months. Case 2, 37 years old, has had anti-epileptic regimens since the age of 4 years. She has been highly myasthenic for 15 years and treated by thymectomy, steroid hormone, plasmapheresis and some other therapies for 10 years. Amenorrhea occurred at the age of 34 years. Sexual development was normal. Myasthenia was very severe. On laboratory examinations, anti-AChR antibody was positive (max.: 941 nmol/l). Transient elevation of serum LH (37 mIU/l) and FSH (14 mIU/l) values was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Postmenopausal bleeding should be referred urgently.

Postmenopausal bleeding is an episode of bleeding 12 months or more after the last menstrual period. It occurs in up to 10% of women aged over 55 years. All women with postmenopausal bleeding should be referred urgently. Endometrial cancer is present in around 10% of patients; most bleeding has a benign cause. The peak incidence for endometrial carcinoma is between 65 and 75 years of age. Causes of postmenopausal bleeding include: endometrial carcinoma; cervical carcinoma; vaginal atrophy; endometrial hyperplasia +/- polyp; cervical polyps; hormone-producing ovarian tumours; haematuria and rectal bleeding. The aim of assessment and investigation of postmenopausal bleeding is to identify a cause and exclude cancer. Assessment should start by taking a detailed history, with identification of risk factors for endometrial cancer, as well as a medication history covering use of HRT, tamoxifen and anticoagulants. Abdominal and pelvic examinations should be carried out to look for masses. Speculum examination should be performed to see if a source of bleeding can be identified, assess atrophic changes in the vagina and look for evidence of cervical malignancy or polyps. Ultrasound scan and endometrial biopsy are complementary. Ultrasound scan can define endometrial thickness and identify structural abnormalities of the uterus, endometrium and ovaries. Endometrial biopsy provides a histological diagnosis. The measurement of endometrial thickness aims to identify which women with postmenopausal bleeding are at significant risk of endometrial cancer. If the examination is normal, the bleeding has stopped and the endometrial thickness is < 5 mm on transvaginal ultrasound scan, no further action need be taken.

Gynecology_Novak

Differential Diagnosis The causes of postmenopausal bleeding and the percentage of patients who seek treatment for different conditions are presented in Table 14.16. Hormone therapy may be used to manage troublesome menopausal symptoms; it is recommended to treat with the lowest effective dose with the risks versus benefits regularly reviewed by a woman and her doctor (246). Women who are taking hormone therapy during menopause may be using a variety of hormonal regimens that can result in bleeding (see Chapter 34). Because unopposed estrogen therapy can result in endometrial hyperplasia, various regimens of progestins are typically added to the estrogen regimen; they are given in a continuous fashion, although they may be given in a sequential fashion for women within 1 year of menopause (246). Table 14.16 Etiology of Postmenopausal Bleeding From Hacker NF, Moore JG. Essentials of obstetrics and gynecology, 3rd ed. Philadelphia: WB Saunders, 1998:635, with permission.

A Case of Uterine Cervical Adenocarcinoma in Which Initial Total Laparoscopic Hysterectomy Was Performed for Suspected Atypical Endometrial Hyperplasia.

The patient was a 69-year-old multiparous female (gravida/para, 3/3) who had hypertension and arrhythmia. Her history included cerebral infarction treated with conservative therapy. She visited our hospital for atypical genital bleeding. She was diagnosed with atypical glandular cells (AGC) based on cervical cytology, atypical cells in endometrial cytology, and atypical endometrial hyperplasia on preoperative endometrial biopsy, and underwent total laparoscopic hysterectomy. However, in a postoperative pathologic examination, she was diagnosed with stage IB1 cervical adenocarcinoma without endometrial abnormality. AGC appeared in cervical cytology before surgery, but a surgical plan was not made with consideration of cervical adenocarcinoma.

Effective bleeding control and symptom relief by lower dose regimens of continuous combined hormone replacement therapy: a randomized comparative dose-ranging study.

We compared two different continuous combined hormone replacement therapy (HRT) regimens of estradiol valerate (E(2)V) and medroxyprogesterone acetate (MPA) with a combination of micronized estradiol (E(2)) and norethisterone acetate (NETA) to determine bleeding pattern, control of climacteric symptoms, lipid profile, endometrial and general safety in a 1-year multicenter study. 440 postmenopausal women were randomized to three treatment groups to receive: 1 mg E(2)V+2.5 mg MPA; 1 mg E(2)V+5 mg MPA; or 2 mg of E(2)+1 mg NETA. After the first 6 months, the E(2)V dose was increased to 2 mg in both E(2)V/MPA groups. Information on bleeding was recorded on diaries by the women and intensity of climacteric symptoms was assessed using VAS scales. Physical and laboratory examinations, endometrial biopsy and vaginal ultrasonography were performed at baseline and follow-up visits. Significantly fewer bleeding days were experienced in the first 3 months by women taking E(2)V/MPA compared with women taking E(2)/NETA. When the dose of E(2)V was increased in the E(2)V/MPA groups, an increase in maximum bleeding intensity was observed in the group receiving 2.5 mg of MPA, but not in the group taking 5 mg of MPA. All dose combinations effectively relieved climacteric symptoms and beneficial effects on the lipid profile were seen after 6 months in all groups. Tolerability and endometrial safety were good and no cases of hyperplasia were observed. More women discontinued treatment prematurely in the E(2)/NETA group compared with either of the E(2)V/MPA groups. The overall continuation rates ranged from 70 to 86%. These results confirm that lower dose combinations of continuous combined HRT are usually sufficient to control symptoms or avoid breakthrough bleeding. However, if higher E(2)V dose is needed for symptom control, it should be combined with the higher dose of progestin (5 mg) to avoid bleeding disturbances. Flexible treatment regimens should be available for individualized HRT.

Cyclic Progesterone Therapy in Androgenic Polycystic Ovary Syndrome (PCOS)-A 6-Month Pilot Study of a Single Woman's Experience Changes.

<iBackground and Objectives:</i Women with androgenic Polycystic Ovary Syndrome (PCOS) have increased endometrial cancer risk that cyclic progesterone will prevent; it may also reverse PCOS's neuroendocrine origins. This pilot study's purpose was to document 6-month <iexperience changes</i in a woman with PCOS taking cyclic progesterone therapy because she was intolerant of combined hormonal contraceptive therapy, the current PCOS standard of care. A 31-year-old normal-weight woman with PCOS had heavy flow, irregular cycles, and was combined hormonal contraceptives-intolerant. She was prescribed cyclic oral micronized progesterone (OMP) (300 mg/<ih.s.</i cycle days 14-27). She kept Menstrual Cycle Diary© (Diary) records, starting with the 1st treatment cycle for six cycles; she was on no other therapy. Statistical analysis <ia priori</i hypothesized progesterone decreases high estradiol (E2) experiences (flow, cervical mucus, fluid retention, front-of-the-breast tenderness and anxiety); analysis focused on these. Our objectives: (1) changes from cycles 1 to 6 in E2-related experiences; and (2) follicular phase E2-related changes from cycle 1 (no therapy) to cycles 3 and 6. <iMaterials and Methods:</i Data from consecutive Diaries were entered into an SPSS database and analyzed by Wilcoxon Signed Rank Test (Objective #1) within-person whole cycle ordinal data, and (Objective #2 follicular phase) repeated measures ANOVA. <iResults:</i Cyclic OMP was associated with regular, shorter cycles (±SD) (28.2 ± 0.8 days). Comparison of cycles 1-6 showed decreased fluid retention (<ip</i = 0.001), breast tenderness (<ip</i = 0.002), and cervical mucus (<ip</i = 0.048); there were no changes in flow or anxiety. Fluid retention in the follicular phase also significantly decreased over time (F (1.2, 14.7) = 6.7, <ip</i = 0.017). <iConclusions:</i Pilot daily Diary data suggest women with PCOS have improved everyday experiences on cyclic progesterone therapy. Larger prospective studies with more objective outcomes and randomized controlled trials of this innovative PCOS therapy are needed.

[Endometrial biopsy in hormonal imbalance].

Despite the new techniques of biochemical evaluation of steroid hormones in the plasma and urines, the endometrial biopsy remains an easy valuable method of evaluation of ovarian activity. The clinical indications of the endometrial biopsy are mainly a history of sterility or an abnormal uterine bleeding if we exclude the diagnosis of cancer. Different technical procedures should be followed carefully in order to get a valuable answer. The biopsy should be taken at the right time of the cycle which means 10 to 12 days after ovulation. The danger of interrupting a pregnancy is minimal but in a case of sterility, the biopsy can be performed 4 to 6 days after ovulation to prevent any interference with a early pregnancy. Proper fixation, embedding and staining must be the rule. A fragment of the middle layer of the functionalis must be present to evaluate accurately the hormonal stimulation. Isthmic or cervical tissues are unsuited for functional diagnosis. The existence of an endometritis or the administration of steroid hormones are clinical circumstances which prevent any functional evaluation. The normal menstrual cycle can be divided into different functional phases: the early, the middle and the late proliferative phases, and the early and late secretory phases followed by the menstruation period. The different cellular components of the endometrial mucosa will exhibit various changes corresponding to each of the phases. The interpretation of the endometrial biopsy lies in the correlation between the observed image and the image corresponding to that date of the cycle. The functional disturbances are associated with absent, deficient or excessive function of the ovarian hormonal secretion. The endometrial mucosa will reflect these anomalies revealing atrophic, hypoplastic or hyperplastic conditions of the glandular and stromal components. It is essential to obtain the clinical informations including the knowledge of any hormone administration to provide a valuable diagnosis. Properly interpreted, the endometrial biopsy remains a very useful technique in the study of hormonal ovarian disturbances.

[A "no-bleeding" substitute hormone treatment with an oral microdose progesterone. A prospective multicenter study].

Study of influence of different sequences of oral micronized progesterone (Pg) on endometrial morphology and the incidence of bleeding. Prospective comparative multicentric study conducted in 101 post-menopausal patients. 98 patients who did not wish any regular withdrawal bleeding were given percutaneous oestradiol 17-beta (E2) (1.5 mg/d) associated with micronized Pg (100 mg/d) at bedtime during either 21 out of 28 days (group I), or 25 days per calendar month (group III), during a minimum of 6 months. For those wishing withdrawal bleeding (n = 3), E2 (3 mg/d) during 25 days was associated with Pg (300 mg/d) from the 16th to the 25th day of the month (group III). Endometrial biopsies were performed after 6 months of the same treatment and blindly analysed; transvaginal ultrasonography (measurement of endometrial mucosa thickness) was done in case of insufficient amount of tissue. Groups I and II: 61% of the endometrium were quiescent without mitosis, 23% were slightly active with rare mitoses, 8% partly secretory and 4% subatrophic. Sampling was inadequate in the remaining 4%. Mitotic activity of glands was low on the overall samplings (average < 0.53/1,000 cells). The average mucosa thickness was at 3.9 mm. No bleeding (spotting or withdrawal bleeding) occurred in 73.3% and 82.1% of cycles at the 3rd and 6th months of administration, respectively. Group III: endometrium were quiescent or slightly active and combined with frequent withdrawal bleeding. A relatively low dose of oral progesterone (100 mg/d) combined with E2 during 21d/28d or 25 d/month efficiently controls proliferation, induces a very low endometrial cyclic activity--while reducing spottings--and maintains an amenorrhea in the majority of women. This simple treatment is likely to improve compliance.

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

What is the recurrence rate of postmenopausal bleeding in women who have a thin endometrium during a first episode of postmenopausal bleeding?

To determine the incidence and significance of recurrent postmenopausal bleeding among women diagnosed with an endometrial thickness < or =4 mm after a first episode of postmenopausal bleeding. Consecutive patients not using hormone replacement therapy (HRT) presenting with a first episode of postmenopausal bleeding and an endometrial thickness < or =4 mm at transvaginal ultrasonography (TVU) were managed expectantly. In case of recurrent bleeding, the patient was evaluated according to the hospital's local policy with TVU, office endometrial sampling, hysteroscopy or dilatation and curettage (D&C) or a combination of these tests. We evaluated the incidence of recurrent bleeding, potential risk factors for recurrent bleeding, and the diagnosis made after recurrent bleeding. A total of 607 patients were registered with a first episode of postmenopausal bleeding, of whom 249 had an endometrial thickness < or =4 mm. Follow-up took place with a median of 174 weeks (range: 4-250 weeks). During follow-up, 25 of the 249 patients (10%; 95% CI: 6.6-14%) had recurrent bleeding. Median time until recurrence of bleeding was 49 weeks (range: 9-186 weeks). Two patients with recurrent bleeding turned out to have an endometrial carcinoma (8%; 95% CI: 2.2-25%), and 1 patient had a malignant melanoma. Time since menopause, age, body mass index, hypertension, diabetes and anticoagulants were not predictive for recurrent bleeding. The recurrence rate after a first episode of postmenopausal bleeding managed expectantly is low and cannot be predicted by patient characteristics. Patients with recurrent bleeding should be re-evaluated, as they bear a considerable risk of carcinoma.

Anorgasmia

Women suffering from anorgasmia with no obvious psychological cause would need to be examined by their GP to check for absence of disease. Blood tests would also need to be done (full blood count, liver function, oestradiol/estradiol, total testosterone, SHBG, FSH/LH, prolactin, thyroid function, lipids and fasting blood sugar) to check for other conditions such as diabetes, lack of ovulation, low thyroid function or hormone imbalances. The normal thresholds for these tests and timing in a woman's menstrual cycle is detailed in Berman et al., 2005. They would then need to be referred to a specialist in sexual medicine. The specialist would check the patient's blood results for hormonal levels, thyroid function and diabetes, evaluate genital blood flow and genital sensation, as well as giving a neurological work-up to determine the degree (if any) of nerve damage.