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Risk factors for secondary amenorrhea and galactorrhea.

OBJECTIVE: Analyses were undertaken to identify factors that may predispose women to secondary amenorrhea or galactorrhea, frequent sources of abnormal reproductive function. METHODS: Data were gathered from interviews with 252 women with secondary amenorrhea or galactorrhea from four clinical centers, along with neighborhood controls matched to each case. Univariate comparisons were made for clinical and demographic factors of the study subjects. RESULTS: Patients with amenorrhea and normal prolactin (PRL) levels and their matched controls tended to be younger than those with amenorrhea and elevated PRL or than menstruating patients with galactorrhea alone and their matched controls. Patients with amenorrhea and normal PRL also were significantly more educated and were older at menarche than their controls, while amenorrhea patients with elevated PRL or patients with galactorrhea alone did not differ significantly from their controls in age at menarche or educational level. More patients with galactorrhea alone had reported menstrual pain to their physicians and had significantly longer menstrual periods than their matched controls. Patients with galactorrhea alone also weighed more than their controls 2 years prior to diagnosis, a difference that remained after stratification by parity, although only statistically significant among women who had had one or two pregnancies. Finally, significantly fewer patients with amenorrhea than controls were smokers. Thus, these disorders may not be due to anti-estrogenic effect or to low estrogen levels which have been associated with smoking.

Adolescent↗

Termination of early pregnancy (up to 63 days of amenorrhea) with mifepristone and increasing doses of misoprostol [corrected].

The efficacy and tolerability of mifepristone in combination with misoprostol for termination of early pregnancy (up to 49 days of amenorrhea) are established. We studied the efficacy and tolerability of this combination therapy for termination of pregnancy in women up to 63 days of amenorrhea. We also examined the effect of an additional dose of misoprostol in cases of nonexpulsion within 3 hours after the first dose. The multicenter trial included 1,108 women, mean age 27.9 +/- 6.2 years. The mean duration of pregnancy was 51.7 +/- 9.2 days. On day 1, the women received an oral dose of mifepristone, 600 mg. On day 3, they received an oral dose of misoprostol, 400 micrograms, and were monitored for up to 3 hours. If they did not expel the conceptus within 3 hours, an additional dose of 200 micrograms of misoprostol was given and they were monitored for 2 more hours. From days 10 to 18, the women were followed up with clinical examination, human chorionic gonadotropin measurement, or ultrasound examination. Overall, the procedure was successful in 92.9% of women. Efficacy decreased with the duration of pregnancy, especially after 56 days of amenorrhea. Up to 42 days of amenorrhea, the success rate was 97.6%; between days 42 and 49, 94.8%; between days 50 and 56, 93.4%; between days 57 and 63, 86.8%; and after day 63, 83.3%. The most common side effects were moderate uterine cramps (80.5%) and gastrointestinal (GI) symptoms (34.9%), especially vomiting (18.3%) and diarrhea (10.5%). GI symptoms were generally mild. A second dose of misoprostol was given to 61.6% of the women. In a subgroup analysis, we assessed the efficacy of 600 mg of mifepristone plus 400 or 600 micrograms of misoprostol (one or two doses) in women with up to 49 days of amenorrhea and compared it with the efficacy in women who received mifepristone plus only 400 micrograms (one dose) of misoprostol in a previous study. The overall rate of success (termination of pregnancy) was 95.5% in the current study compared with 95.4% in the previous study. The additional dose of misoprostol did not significantly increase the overall rate of success, but did increase the rate of termination within the monitoring period (69.7% versus 64.9% (and within 72 hours after administration of mifepristone (92.7% versus 90.4%). We have confirmed that the combination of mifepristone and misoprostol was effective, safe, and well tolerated for termination of pregnancies at 49 or fewer days of amenorrhea. The efficacy decreased slightly between 49 and 56 days, and then decreased significantly between 56 and 63 days. For maximal safety and tolerability, we recommend this method only for women with 49 or fewer days of amenorrhea. A second dose of misoprostol did not improve overall efficacy, but did increase the rate of early termination.

Abortifacient Agents↗

A study of postpill amenorrhea.

Levels of follicle-stimulating hormone, luteinizing hormone and prolactin were evaluated in 52 cases of postpill amenorrhea at the Institute of Post Graduate Medical Education and Research, Calcutta, India. All 52 patients had experienced amenorrhea for one year since discontinuation of oral contraceptive therapy. The incidence of postpill amenorrhea was much higher in patients with histories of oligomenorrhea or irregular menstrual periods. No relationship was seen between the number of cycles of pills used and the incidence of postpill amenorrhea. The ratio of luteinizing hormone to follicle-stimulating hormone in all cases exceeded unity, indicating that postpill amenorrhea is a type of functional secondary amenorrhea.

Amenorrhea↗

Weaning, body weight, and postpartum amenorrhea duration in pigtailed macaques (Macaca nemestrina).

Early permanent infant separation or weaning decreases the time interval between pregnancies and interbirth intervals for many female primates. At least part of the interpregnancy interval consists of postpartum amenorrhea, a period of non-menstruation lasting from the time of birth until the female begins to ovulate. This study investigated the effects of weaning age and dam's body weight on the duration of the interval between pregnancies, the duration of postpartum amenorrhea, and the number of cycles to conception in a year-round breeder. Female pigtailed macaques (Macaca nemestrina) have an observable perineal swelling that fluctuates throughout the menstrual cycle and provides a means of detecting ovulation. The perineal swelling records of socially housed pigtailed macaques were studied from July 1996 to September 1998. Postpartum amenorrhea data were obtained on 44 females who gave birth to normal, viable infants. As weaning age increased and dam's weight decreased, postpartum amenorrhea, and consequently the interval between pregnancies, increased in duration. The interpregnancy interval consisted almost entirely of the postpartum amenorrhea phase. Our finding that a higher dam's body weight decreased the length of postpartum amenorrhea duration lends support to the hypothesis that a minimum body weight is necessary for menstrual cycles to occur. Most females became pregnant on their first ovulation regardless of weaning age and whether or not they were carrying an infant. As the weaning age of the infant and the dam's weight increased, ovulation went from occurring after separation to occurring before separation.

Amenorrhea↗

Incidence of chemotherapy-induced, long-term amenorrhea in patients with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane.

BACKGROUND: Twenty-five percent of all women with breast carcinoma are premenopausal and are at risk for chemotherapy-induced menopause with long-term side effects. Although there is considerable documentation of the rates of chemotherapy-induced amenorrhea with classic adjuvant regimens, there are inadequate data that address the impact of taxanes on menstrual function in this setting. The objective of this analysis was to determine the incidence of long-term amenorrhea (> or = 12 mos) in women with breast carcinoma age 40 years and younger after adjuvant anthracycline and taxane-based chemotherapy, with or without subsequent tamoxifen. METHODS: The authors identified 235 premenopausal women with breast carcinoma age 40 years or younger who were treated with adjuvant anthracycline and taxane-based chemotherapy at Memorial Sloan-Kettering Cancer Center from January 1997 to June 2003. RESULTS: One hundred sixty-six patients met all eligibility criteria and had sufficient follow-up for evaluation. The median age of patients at diagnosis was 36 years (range, 27-40 yrs). All patients had regular pretreatment menses, 25 patients (15%) developed long-term amenorrhea, and 141 patients (85%) resumed menstruation. Eighty-two patients (49%) also received tamoxifen: The incidence of amenorrhea among them was 17%. There was a statistically significant association between age and the development of amenorrhea, with older women at higher risk (P < 0.01). CONCLUSIONS: The sequential addition of a taxane to standard adjuvant anthracycline-based chemotherapy did not appear to produce a high rate of chemotherapy-related amenorrhea compared with historic controls. To increase the information available to assist young patients who are considering adjuvant therapy, prospective studies should incorporate menstrual function ascertainment by patient-reported history and assays of ovarian function.

Adult↗

Galactorrhea and pituitary tumors in postpill and non-postpill secondary amenorrhea.

One hundred sixty-seven women with secondary amenorrhea were observed from six months to four years. In 66 patients, the amenorrhea followed the discontinuation of oral contraceptives (postpill) while in the remaining 101 the amenorrhea was not temporally pill related (non-postpill). Galactorrhea was present in 43 (65%) of those with postpill amenorrhea and in 32 (32%) of those with non-postpill amenorrhea (p less than 0.001). Tomography of the sella turcica was performed in the 75 women with galactorrhea and in the 35 without galactorrhea who did not have withdrawal uterine bleeding following progesterone administration and who had low or normal serum follicle-stimulating hormone levels (hypothalamic-pituitary failure). Forty of the 75 patients with amenorrhea and galactorrhea had radiographic evidence of a pituitary tumor whereas only eight of 35 patients with hypothalamic-pituitary failure without galactorrhea had an abnormal sella turcica (p less than 0.01). The incidence of radiographic abnormalities in those with galactorrhea was similar in both the postpill and non-postpill groups.

Adolescent↗

A schematic approach to the work-up of amenorrhea.

Amenorrhea is a symptom having many possible causes. Since amenorrhea can result from disturbed function anywhere in the hypothalamic-pituitary-ovarian-uterine axis, a specific etiologic diagnosis must be made if treatment is to be effective. For this purpose, a diagnostic scheme for the differential diagnosis of the etiology of primary and secondary amenorrhea is proposed. This scheme includes a progestin test, a cyclic estrogen and progestin test, a luteinizing hormone-releasing hormone (LH-RH) loading test, and a gonadotropin (human menopausal gonadotropin and human chorionic gonadotropin) loading test. A specific pattern of responses to LH-RH and gonadotropins exists in patients with hypothalamic, pituitary, and ovarian amenorrheas, respectively, and the character of the response may facilitate the etiologic diagnosis of amenorrhea. The clinical usefulness and/or value of the scheme in the diagnosis and treatment of amenorrheas is discussed.

Adult↗

Effectiveness of the lactational amenorrhea method in Pakistan.

OBJECTIVE: To determine the efficacy of the lactational amenorrhea method of family planning (amenorrhea during full or nearly full breastfeeding for 6 months postpartum). DESIGN: Prospective noncomparative study. SETTING: Normal breastfeeding women in Karachi and Multan, Pakistan, most delivered at home by a midwife. PATIENTS: Three hundred ninety-nine newly delivered mothers who successfully had breastfed a previous child and chose the lactational amenorrhea method to prevent a subsequent pregnancy, 391 of whom were followed for a full year. INTERVENTIONS: Mothers were taught, before or shortly after delivery, to use the method and were interviewed in their homes each month by a Lady Health Visitor. MAIN OUTCOME MEASURE: Life-table pregnancy rates. Periods of postpartum or lactational abstinence were excluded in the calculation of the pregnancy rates. RESULTS: During full or nearly full breastfeeding, while the women were amenorrheic and not otherwise contracepting, the rate of pregnancy was 0.6%. The pregnancy rate during lactational amenorrhea alone was 1.1% at 1 year postpartum. CONCLUSION: The lactational amenorrhea method was found to be highly effective for 6 months. A high degree of contraceptive protection endures for a full year during lactational amenorrhea, but not after the return of menses during breastfeeding.

Adolescent↗

Amenorrhea and bone health in adolescents and young women.

PURPOSE OF REVIEW: We present an update on amenorrhea in adolescent girls and young women. Amenorrhea may herald the onset of estrogen deficiency, which can adversely affect peak bone mass and ultimate risk of osteoporosis. RECENT FINDINGS: Adolescence is a critical period for bone accretion. Important modifiable factors that optimize bone accretion during this time are calcium intake, vitamin D, nutrition, and exercise. Another modifiable factor in the hands of the clinician is the prompt recognition and therapy of amenorrhea associated with estrogen deficient states, caused by conditions such as hyperprolactinemia and ovarian failure. An important recent observation is that adolescents with amenorrhea who diet, but who do not meet diagnostic criteria for anorexia nervosa, are nonetheless at significant risk for low bone density. Also, multiple factors contribute to the bone loss experienced by patients with anorexia nervosa, and the associated estrogen deficiency may not be the major contributor. Recent evidence also suggests that the contraceptive depot medroxyprogesterone acetate may contribute to impaired bone accretion. While estrogen/progestin replacement therapy has a clear role in the management of girls and young women with primary ovarian insufficiency, the exact role of this therapy in the amenorrhea associated with anorexia nervosa or exercise remains controversial. SUMMARY: Increasingly, osteoporosis prevention is recognized as an important role for health care providers of adolescent girls and young women. Viewed from this perspective, there is a need for more aggressive evaluation and management of amenorrhea, and research is needed to define sound and cost effective strategies.

Adolescent↗

Secondary amenorrhea after Hodgkin's lymphoma is influenced by age at treatment, stage of disease, chemotherapy regimen, and the use of oral contraceptives during therapy: a report from the German Hodgkin's Lymphoma Study Group.

PURPOSE: Long-term survivors of successfully treated Hodgkin's lymphoma (HL) are at risk for late complications. Among these, infertility for female patients is of major importance. The subject of this analysis is to evaluate the menstrual status after HL therapy. PATIENTS AND METHODS: From 1994 to 1998, the German Hodgkin's Lymphoma Study Group conducted clinical trials for early-, intermediate-, and advanced-stage HL (trials HD7 to HD9) involving a total of 3,186 patients. A survey was carried out to evaluate the menstrual status after therapy. The following factors were assessed concerning their influence on amenorrhea: age, treatment, stage, and the use of oral contraceptives during chemotherapy. RESULTS: A total of 405 women aged younger than 40 years answered the study questions. After a median follow-up of 3.2 years, 51.4% of the women receiving eight cycles of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) had continuous amenorrhea. Amenorrhea was significantly more frequent after dose-escalated BEACOPP compared with doxorubicin, bleomycin, vinblastine, and dacarbazine; cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, and dacarbazine; or standard BEACOPP (P = .0066). Amenorrhea after therapy was most pronounced in women with advanced-stage HL (P < .0001), in women older than 30 years at treatment (P = .0065), and in women who did not take oral contraceptives during chemotherapy (P = .0002). CONCLUSION: Most women who are treated for advanced-stage HL experience amenorrhea after therapy. Amenorrhea is significantly more frequent in women with advanced-stage HL receiving eight cycles of dose-escalated BEACOPP and in women older than 30 years at first treatment. Furthermore, the data show a statistical association between the use of oral contraceptives and return of menstrual cycle, which is subject to further investigation.

Adolescent↗

Amenorrhea in premenopausal women after adjuvant chemotherapy for breast cancer.

Chemotherapy and ovarian ablation both independently improve survival in premenopausal women with hormone-sensitive breast cancer. Amenorrhea is a well-recognized occurrence after chemotherapy. The rate of chemotherapy-induced amenorrhea varies with patient age and chemotherapy regimens administered. However, the impact of chemotherapy-induced amenorrhea on prognosis is still being defined. Older studies in premenopausal women argue that the benefit with chemotherapy is a result of direct cytotoxicity alone. However, studies that restrict outcome analysis to hormone receptor-positive tumors suggest that chemotherapy has a dual mechanism in women with hormone-responsive tumors; indirect endocrine manipulation secondary to chemotherapy-induced ovarian suppression and direct cytotoxicity. The significant health ramifications involved with the induction of premature menopause as well as potential benefits necessitate a comprehensive evaluation of chemotherapy-induced amenorrhea. This review will discuss the incidence of amenorrhea with commonly-used adjuvant chemotherapeutic regimens, the possible benefits of chemotherapy-induced amenorrhea, and the challenges of interpreting the existing data in breast cancer trials.

Amenorrhea↗

Gonadotropin responses to gonadotropin-releasing hormone and prolactin responses to thyrotropin-releasing hormone and metoclopramide in women with amenorrhea and insulin-treated diabetes mellitus.

Gonadotropin responses to GnRH and PRL responses to TRH and metoclopramide (MTC) were investigated in nine consecutive women with amenorrhea and insulin-treated diabetes mellitus. Nine normal menstruating diabetic women, 12 normal women in the early follicular phase, and nine consecutive nondiabetic women with functional amenorrhea served as controls. No significant differences were found in relation to diabetes regulation within the two diabetic groups. Amenorrheic patients with diabetes mellitus had significantly lower basal PRL levels than normal women and estradiol levels compared to the other groups. Basal plasma LH concentrations were significantly lower in women with amenorrhea and diabetes mellitus than in nondiabetics with amenorrhea, whereas plasma FSH levels were similar in all groups. The LH response to GnRH was significantly lower in amenorrheic patients with diabetes mellitus than in normal women, and a significant correlation (r = 0.81, P less than 0.01) was found between the LH response to GnRH and the basal estradiol level in these women. The FSH response to GnRH and the PRL response to TRH were similar in all groups. Amenorrheic diabetics had significantly lower PRL responses to MTC compared to other groups, and nondiabetics with amenorrhea had significantly lower PRL response than normal women. It is concluded that diabetic patients with functional amenorrhea have low basal and MTC-stimulated PRL levels, low basal LH levels, and decreased LH response to GnRH despite low estrogen levels. These hormonal changes may in part be caused by a raised central dopaminergic activity leading to a depression of pituitary ovulatory mechanisms.

Adult↗

Osteopenia in exercise-associated amenorrhea using ballet dancers as a model: a longitudinal study.

Few longitudinal studies have investigated the effects of amenorrhea and amenorrhea plus exercise on bone mineral density (BMD) of young women. We carried out a 2-yr comparison of dancers and nondancers, both amenorrheic and normal, that investigated the role of hypothalamic amenorrhea on bone in this context. We studied 111 subjects (mean age, 22.4 +/- 4.6 yr; age of menarche, 14.1 +/- 2.2 yr), including 54 dancers, 22 with hypothalamic amenorrhea, and 57 nondancers, 22 with hypothalamic amenorrhea. Detailed hormonal and nutritional data were obtained in all groups to determine possible causal relationship to osteoporosis. The amenorrheic groups, dancers and nondancers, both showed reduced BMD in the spine, wrist, and foot, which remained below controls throughout the 2 yr. Only amenorrheic dancers showed significant changes in spine BMD (12.1%; P < 0.05) but still remained below controls, and within this subgroup, only those with delayed menarche showed a significant increase. The seven amenorrheic subjects (three dancers and four nondancers) who resumed menses during the study showed an increase in spine and wrist BMD (17%; P < 0.001) without achieving normalization. Delayed menarche was the only variable that predicted stress fractures (P < 0.005), which we used as a measure of bone functional strength. Analysis of dieting and nutritional patterns showed higher incidence of dieting behavior in this group, as manifested by higher Eating Attitudes Test scores (16.3 +/- 2.00 vs. 11.5 +/- 1.45; P < 0.05) and higher fiber intakes (30.7 +/- 3.00 vs. 17.5 +/- 2.01 g/24 h; P < 0.001). We concluded that low bone mass occurs in young women with amenorrhea and delayed menarche, both exercisers and nonexercisers. Crucial bone mass accretion may be compromised by their reproductive and nutritional health.

Adult↗

[Endocrinological analysis of hypothalamic primary amenorrhea (author's transl)].

Primary amenorrhea, in which serum concentrations of gonadotropins are low or normal, has been considered to be relatively rare. Recent analysis in our outpatient clinic revealed that the incidence of hypothalamic primary amenorrhea is higher than previously appreciated, comprising 26.7% of the total primary amenorrheas. Endocrinological functions of the hypothalamo-hypophyseo-ovarian axis in these patients were therefore investigated. Studies on gonadotropin secretion indicated that a disturbance in LH-RH secretion and a lack of estrogen positive feedback were principle features of this disease. In addition to the dysfunction of gonadotropin secretion, the control of PRL secretion was disturbed in this disease since there was a poor PRL response to chlorpromazine in spite of normal responsiveness to TRH. Thus, "isolated gonadotropin deficiency" hitherto used to describe this disease is not pertinent. Furthermore, these results suggest that PRL might be involved in the onset of puberty in humans. Clinically, the induction of ovulation with HMG (Human Menopausal Gonadotropin) is possible in hypothalamic primary amenorrhea, although the ovarian responsiveness to gonadotropin is poor. Therefore, an endocrinologically precise diagnosis of hypothalamic primary amenorrhea is important in the gynecological clinic because fertility has been considered to be almost impossible in primary amenorrhea.

Amenorrhea↗

Childhood's enuresis in the history of women with hyperprolactinemic amenorrhea.

Hyperprolactinemia, or elevated levels of prolactin in blood, is a normal physiologic post-partum response in lactating women. Non-lactating women with hyperprolactinemia often present during the reproductive years since they may have amenorrhea, galactorrhea, or both. Hypersecretion of prolactin is most commonly due to pituitary adenomas. Women with hyperprolactinemic amenorrhea are often quite anxious, depressed and hostile. It has been hypothesized that these psychological symptoms might antecede the onset of hyperprolactinemia and that hyperprolactinemia may be associated with early developmental problems and may be psychogenic in origin. Twenty patients with hyperprolactinemic amenorrhea and twenty-one normoprolactinemic patients with amenorrhea had an interview covering psychiatric history in order to establish whether they had ever met DSM-III criteria for functional nocturnal enuresis at one time during their childhood. While seven out of twenty (35%) patients with hyperprolactinemic amenorrhea were found to have had functional enuresis during their childhood, only two out of twenty-one (9.5%) normoprolactinemic amenorrheic women reported having had functional enuresis. The difference between the two groups was statistically significant (chi-squared: 3.88; p less than 0.05). We postulate that early stress and developmental problems may present in children as psychological distress and functional enuresis and in women as psychological symptoms (e.g., anxiety and depression) and hyperprolactinemic amenorrhea.

Adult↗

Secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis : report of two cases.

Amenorrhea is rarely presented as a manifestation of endocrinological disturbances in patients of chronic hydrocephalus. We describe two cases of secondary amenorrhea caused by hydrocephalus due to aqueductal stenosis. Two female patients of age 30 and 20 yr presented with amenorrhea and increasing headache. Magnetic resonance images revealed marked, noncommunicating hydrocephalus without any tumorous lesion. In one patient, emergent extraventricular drainage was necessary because of progressive neurological deterioration. Each patient underwent surgical intervention for the hydrocephalus-ventriculoperitoneal shunt and endoscopic third ventriculostomy. Both resumed normal menstruation continuing so far with further normal menstrual bleeding. These two cases and others reported in the literature indicated that the surgical intervention for hydrocephalus resolves amenorrhea in all the cases of amenorrhea due to hydrocephalus. The suspected role of the surgery is the correction of increased intracranial pressure, which is an important pathogenetic factor in the development of amenorrhea.

Adult↗

Transient secondary amenorrhea in women treated by thalidomide.

Compared with other side effects induced by thalidomide, amenorrhea has been relatively poorly investigated although it was first reported in 1989. The aim of this study was to determine the prevalence of amenorrhea in consecutive women treated with thalidomide in our institution from 1995 to 1999. During that period, 21 women received thalidomide associated with progestin contraception. Their clinical and biological data were retrospectively reviewed. Data concerning their genital life were systematically checked by phone with a simple questionnaire. Transient secondary amenorrhea occurred in 5 women (24%) treated for refractory cutaneous lupus erythematosus (4 cases) or complex aphthosis (1 case). The link between thalidomide and amenorrhea was suggested by the resumption of menses 2 to 3 months after drug withdrawal, recurrence of amenorrhea after reintroduction of thalidomide (1 case) and high serum levels of pituitary gonodotrophins. Amenorrhea secondary to ovarian failure is frequently observed in women treated with thalidomide. Its precise mechanism remains to be elucidated.

Adolescent↗

[The risk of sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy].

OBJECTIVE: To determine the risk of sustained amenorrhea in premenopausal women with systemic lupus erythematosus (SLE) receiving intermittent pulse cyclophosphamide (CTX) therapy. METHODS: Prospectively comparing the amenorrhea rate of 51 cases receiving intermittent pulse cyclophosphamide therapy versus that of 22 cases receiving intermittent pulse methylprednisolone (MP) therapy. RESULTS: The amenorrhea rate was higher in the CTX group (19.6%) than in the MP group (P = 0.025). In the CTX group, the amenorrhea rate of patients aged over 30 was higher than that of patients aged 30 or below 30 (P = 0.0018). CONCLUSION: Pulse CTX therapy in fertile women with SLE is associated with increased rate of sustained amenorrhea, and the older the patient is, the higher risk for sustained amenorrhea the patient runs.

Adult↗