Breast cancer and HRT--what are the data?

Breast cancer remains one of women's greatest concerns. When asked regarding the likelihood of contracting a specific disease, most women believe their greatest risk of death is from breast cancer. Interestingly, we have gone from a time when estrogen was utilized as a treatment regimen in advanced breast cancer, to the current question of hormone replacement therapy increasing the risk of breast cancer. When one searches earlier data, it is noted that estrogen in several different forms, including ethinyl estradiol, as well as DES, was used as a therapeutic agent in the management of advanced breast cancer. Indeed, some of the original trials evaluating tamoxifen for adjunctive treatment of breast cancer used estrogen as the "gold-standard" treatment arm. Numerous publications have attempted to address the relationship between hormone replacement therapy and breast cancer. In the last quarter of a century, at least 50 epidemiological studies have been published, with some studies demonstrating slight increases in patients who used hormone replacement therapy for an extended time, while others demonstrated no evidence of a change in incidence. The "Nurses' Health Study" suggested that current users of hormone replacement therapy of 5 or more years' duration have a relative risk of greater than 1.4. While a well-performed and conceived trial, it suffers from limitations like all other studies. In the same time period, multiple additional studies have cast doubt on the likelihood of hormone replacement therapy markedly increasing the risk of breast cancer. When the multitude of studies is combined, the evidence seems to demonstrate that in ever-use of hormone replacement therapy the increase in relative risk is small. It is interesting that, in almost all studies published (even those demonstrating increases such as the "Nurses' Health Study") discontinuation of 2 to 5 years evaporates the increased risk. This seems biologically implausible, given the prior exposure. A recent study by Sellers et al evaluated over 41,000 patients in a prospective cohort. In this study, they closely evaluated patients who were at a higher risk of breast cancer based on a positive family history in first-degree relatives. Interestingly, they, like others, found that HRT was not associated with a significantly increased incidence of breast cancer, but did note a significantly reduced total mortality rate. When one evaluates the sum total data in the world literature regarding hormone replacement therapy and breast cancer, it is difficult to ascertain that any substantial clinical risk exists with the use of hormone replacement therapy and breast cancer. Multiple ongoing trials, including the Women's Health Initiative-a Prospective Protocol, will help to define better if any appreciable risk exists.

Diagnosis of the polycystic ovary syndrome in adolescence: comparison of adolescent and adult hyperandrogenism.

We performed gonadotropin releasing hormone agonist (GnRHag) tests on 23 consecutive hyperandrogenic girls 9.9-17.5 years of age who were referred to our pediatric endocrinology clinic with symptoms suggestive of PCOS. They were compared to contemporaneously studied groups of adult normal and hyperandrogenic women. We found that hyperandrogenic adolescents had clinical and endocrine features similar to those of hyperandrogenic adults. However, there were some noteworthy unique features of adolescent hyperandrogenism, such as presentation in mid-childhood with premature pubarche and the occasional diagnosis before the age of 10 years. Some differences between adolescents and adults were statistically significant, for example, pelvic ultrasonography was not as helpful in the diagnosis of FOH as it is in adults. Nevertheless, a number of questions about the development of the ovarian dysfunction remain to be answered. For example, we are unable to diagnose ovarian dysfunction before puberty or in early puberty, and the relationship of "physiologic adolescent anovulation" to PCOS remains to be defined.

Identification of seminiferous tubule aberrations and a low incidence of testicular microliths associated with the development of azoospermia.

OBJECTIVE: To evaluate the use of percutaneous testicular sperm aspiration in the assessment of azoospermia and its association with seminiferous tubule microliths. DESIGN: Case report. SETTING: Tertiary care fertility center in a university hospital. PATIENT(S): Male undergoing infertility evaluation. INTERVENTION(S): Testicular biopsy and percutaneous testicular aspiration. MAIN OUTCOME MEASURE(S): Serum hormone analysis, sperm concentration in semen, spermatogenesis in samples from testicular biopsies and aspirations, and microlith composition. RESULT(S): A patient presented for infertility evaluation with a history of severe oligospermia that progressed to azoospermia. The serum testosterone concentration (357 ng/dL) and LH concentration (9.2 mIU/mL) were normal and the serum FSH concentration (18.3 mIU/mL) was elevated. Testicular biopsy results indicated spermatogenic hypoplasia with limited spermatozoa. Seminiferous tubules obtained by percutaneous testicular aspiration were structurally aberrant, with multiple diverticula. Microliths averaging 120 microm in diameter were observed within and blocking the seminiferous tubules. The microliths were composed of calcium phosphate (hydroxyapatite) in both the core and peripheral regions. Electron microscopy revealed a high degree of collagen-like material within the peripheral zone. CONCLUSION(S): The presence of seminiferous tubule microliths is associated with the development of azoospermia. In patients with a low incidence of seminiferous tubule microliths and aberrant seminiferous tubule architecture, percutaneous testicular aspiration may provide a diagnostic advantage over testicular biopsy.

Mononuclear-cell immunisation in prevention of recurrent miscarriages: a randomised trial.

BACKGROUND: Couples with unexplained recurrent miscarriage may have an alloimmune abnormality that prevents the mother from developing immune responses essential for the survival of the genetically foreign conceptus. Immunisation with paternal mononuclear cells is used as a treatment for such alloimmune-mediated pregnancy losses. However, the published results on this treatment are conflicting. In this study (the Recurrent Miscarriage [REMIS] Study), we investigated whether paternal mononuclear cell immunisation improves the rate of successful pregnancies. METHODS: Women who had had three or more spontaneous abortions of unknown cause were enrolled in a double-blind, multicentre, randomised clinical trial. 91 were assigned immunisation with paternal mononuclear cells (treatment) and 92 immunisation with sterile saline (control). The primary outcomes were the inability to achieve pregnancy within 12 months of randomisation, or a pregnancy which terminated before 28 weeks of gestation (failure); and pregnancy of 28 or more weeks of gestation (success). Two analyses were done: one included all women (intention to treat), and the other included only those who became pregnant. FINDINGS: Two women in each group received no treatment, and eight (three treatment, five control) were censored after an interim analysis. In the analysis of all randomised women who completed the trial, the success rate was 31/86 (36%) in the treatment group and 41/85 (48%) in the control group (odds ratio 0.60 [95% CI 0.33-1.12], p=0.108). In the analysis of pregnant women only, the corresponding success rates were 31/68 (46%) and 41/63 (65%; odds ratio 0.45 [0.22-0.91], p=0.026). The results were unchanged after adjustment for maternal age, number of previous miscarriages, and whether or not the couple had had a previous viable pregnancy. Similar results were obtained in a subgroup analysis of 133 couples with no previous livebirth. INTERPRETATION: Immunisation with paternal mononuclear cells does not improve pregnancy outcome in women with unexplained recurrent miscarriage. This therapy should not be offered as a treatment for pregnancy loss.

Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome.

OBJECTIVE: NIDDM occurs commonly among women with polycystic ovary syndrome (PCOS). The prevalence and natural history of its precursor, impaired glucose tolerance (IGT), is less well known. The objective of this study was to characterize the prevalence and incidence of glucose intolerance in a large cohort of women with well-characterized PCOS. RESEARCH DESIGN AND METHODS: A total of 122 women with clinical and hormonal evidence of PCOS were recruited from the Medicine, Endocrinology, Gynecology, and Pediatrics Clinics at the University of Chicago. All women had a standard oral glucose tolerance test (OGTT) with measurement of glucose and insulin levels. A subset of 25 women were subsequently restudied with the aim of characterizing the natural history of glucose tolerance in PCOS. RESULTS: Glucose tolerance was abnormal in 55 (45%) of the 122 women: 43 (35%) had IGT and 12 (10%) had NIDDM at the time of initial study. The women with NIDDM differed from those with normal glucose tolerance in that they had a 2.6-fold higher prevalence of first-degree relatives with NIDDM (83 vs. 31%, P < 0.01 by chi 2) and were significantly more obese (BMI 41.0 +/- 2.4 vs. 33.4 +/- 1.1 kg/m2, P < 0.01). For the entire cohort of 122 women, there was a significant correlation between fasting and 2-h glucose concentrations (r = 0.76, P < 0.0001); among the subset with IGT, the fasting glucose concentration was poorly predictive of the 2-h level (r = 0.25, NS). After a mean follow-up of 2.4 +/- 0.3 years (range 0.5-6.3), 25 women had a second OGTT. The glucose concentration at 2 h during the second glucose tolerance test was significantly higher than the 2-h concentration during the first study (161 +/- 9 vs. 139 +/- 6 mg/dl, P < 0.02). CONCLUSIONS: The prevalence of IGT and NIDDM in women with PCOS is substantially higher than expected when compared with age- and weight-matched populations of women without PCOS. The conversion from IGT to NIDDM is accelerated in PCOS. The fasting glucose concentration does not reliably predict the glucose concentration at 2 h after an oral glucose challenge, particularly among those with IGT, the subgroup at highest risk for subsequent development of NIDDM. We conclude that women with PCOS should periodically have an OGTT and must be closely monitored for deterioration in glucose tolerance.

The pathogenesis of polycystic ovary syndrome: lessons from ovarian stimulation studies.

In polycystic ovary syndrome (PCOS) the ovary produces markedly increased amounts of both androgens and estrogens in response to gonadotropin stimulation. Distinctive responses of 17-hydroxyprogesterone and androstenedione to ovarian stimulation testing suggest that ovarian hyperandrogenism is a result of dysregulation of theca cell androgen production which is intrinsic to the ovary. The occurrence of hyperestrogenism together with hyperandrogenism in PCOS suggests that whatever the abnormality of local regulatory factors of steroidogenesis, it affects granulosa as well as theca cells. Dysregulation is often associated with an increase in the number of follicles which evade atresia and reach the 2-8 mm stage of development. Autocrine/paracrine factors, especially those which are FSH-dependent, likely play an important role in the pathogenesis of the ovarian abnormality. Both LH and insulin hypersecretion probably play a secondary role in PCOS by amplifying the preexisting ovarian dysregulation. Because FSH secretion is under tight long-loop negative-feedback control and LH is not, hyperandrogenism is the primary clinical manifestation of dysregulation of steroid production in PCOS. However, anovulation in PCOS is most likely a result of excessive estrogen and inhibin production by multiple, small follicles which inhibit FSH secretory dynamics sufficiently to prevent selection of a dominant follicle.

Transmission disequilibrium of maternally-inherited CTLA-4 microsatellite alleles in idiopathic recurrent miscarriage.

To elucidate the mechanisms that facilitate tolerance at the maternal-fetal interface, we are investigating the role of genes that are involved in peripheral self-tolerance in couples with idiopathic recurrent miscarriage. CTLA-4 is a negative regulator of T-cell proliferation and has been associated with human autoimmune disease. An AT(n) polymorphism in the 3'-untranslated region (UTR) of the human gene results in AT stretches that vary in length from 16 to 46 bp. We hypothesized that long stretches of AT repeats would result in mRNA instability, and reduced fetal survival in humans. We examined the transmission of AT(n) alleles in 60 couples with a history of > or = 3 unexplained spontaneous abortions to their 51liveborn children and 10 abortuses. The shorter allele was transmitted from heterozygous mothers to 26 of 35 liveborn children (chi2 = 8.3, P = 0.0040) and to three of nine aborted fetuses (chi2 = 1.0, P = 0.317). The shorter allele was transmitted from heterozygous fathers to 15 of 32 liveborn children (chi2 =0.12, P=0.726) and to five of eight aborted fetuses (chi2 = 0.5, P = 0.480). Furthermore, liveborn fetuses who inherited smaller alleles were more likely to represent the first successful pregnancy than liveborn fetuses who inherited larger maternal alleles (Pexact = 0.044) and fetuses of first pregnancies that inherited the smaller allele were significantly more likely to survive to term (Pexact = 0.0086). The preferential transmission of maternally-inherited shorter alleles to liveborn children, but random transmission of paternally-inherited alleles, suggests that CTLA-4 may be imprinted in humans and that this gene may play a role in inducing or maintaining tolerance at the maternal-fetal interface.

A pilot study of the human chorionic gonadotrophin test for ovarian hyperandrogenism.

A controlled clinical study was designed to investigate the value of human chorionic gonadotrophin (HCG) challenge as a test for functional ovarian hyperandrogenism. Dexamethasone administration was followed by 5000 IU HCG and blood samples for steroid hormone assay were obtained 0, 8, 16, and 24 h thereafter. Study subjects were normal women (n = 13); women with functional ovarian hyperandrogenism, defined by androgen excess, amenorrhoea and an increased 17-hydroxyprogesterone response to nafarelin (n = 6); and normal men (n = 4). The responses of 17-hydroxyprogesterone, androstenedione and testosterone to HCG in women with functional ovarian hyperandrogenism were significantly greater than in normal women. However, the 17-hydroxyprogesterone response to HCG in functional ovarian hyperandrogenism was significantly lower after HCG than after nafarelin. The oestradiol response was also significantly lower after HCG than nafarelin, although oestradiol concentration more than doubled in normal women as well as in women with functional ovarian hyperandrogenism. The responses to HCG confirm that functional ovarian hyperandrogenism abnormalities are luteinizing hormone (LH)-dependent. Therefore, the 17-hydroxyprogesterone response to HCG could represent a useful test for the diagnosis of ovarian hyperandrogenism. The lower 17-hydroxyprogesterone response to HCG than to nafarelin in functional ovarian hyperandrogenism suggests that a follicle-stimulating hormone (FSH)-responsive factor modulates thecal 17-hydroxyprogesterone secretion. The oestradiol response to HCG is consistent with HCG directly stimulating the oestradiol secretion by thecal cells.

Diagnosis and therapy of hyperandrogenism.

Diagnostic categories in hyperandrogenism include polycystic ovary syndrome (PCOS) and its variants, adrenal and ovarian steroidogenic enzyme deficiencies, adrenal and ovarian androgen secreting tumours and other endocrine disorders such as hyperprolactinaemia, Cushing syndrome and acromegaly. About 95% of hyperandrogenic women will have PCOS. Endometrial hyperplasia can be prevented in hyperandrogenic, anovulatory women by the oral contraceptive pill or progestins. Hirsutism is best treated by a combination of the oral contraceptive pill and an anti-androgen. The first line of therapy for ovulation induction is clomiphene citrate, with human menopausal gonadotrophins (hMG) or laparoscopic ovulation induction reserved for clomiphene failures. hMG together with gonadotrophin-releasing hormone agonist may decrease the risk of spontaneous abortion following ovulation induction in PCOS. Weight loss should be vigorously encouraged to ameliorate the metabolic consequences of PCOS.

Pathophysiology of ovarian steroid secretion in polycystic ovary syndrome.

The ovary in polycystic ovary syndrome (PCOS) produces markedly increased amounts of steroids in response to gonadotropin stimulation. Because FSH secretion is under tight long-loop negative-feedback control and LH is not, hyperandrogenism is the primary clinical manifestation of excess steroid production in PCOS. However, estrogen production by multiple, small follicles may inhibit FSH secretion sufficiently to prevent selection of a single, dominant follicle. Ovarian stimulation testing has suggested that ovarian hyperandrogenism is a result of dysregulation of the androgen producing enzyme P450c17. ACTH stimulation testing is consistent with dysregulation of adrenal P450c17 in about two-thirds of hyperandrogenic women. In most cases dysregulation appears to be due to an intrinsic abnormality of P450c17, or to an abnormality of autocrine/paracrine factors which regulate P450c17. Both LH and insulin hypersecretion are most often a result of the steroid secretory abnormalities. Once present they may amplify the underlying cause of dysregulation of P450c17.

Anterior abdominal wall adhesions after laparotomy or laparoscopy.

STUDY OBJECTIVE: To determine the frequency of postoperative adhesions to the anterior abdominal wall peritoneum that could affect safe placement of the initial laparoscopic umbilical cannula at subsequent procedures. DESIGN: Prospective cohort study. SETTING: Reproductive endocrinology and infertility service of a tertiary care referral hospital. PATIENTS: Two hundred fifteen women, 124 with prior abdominal surgery and 91 with no prior surgery. INTERVENTIONS: Surgical histories were reviewed, abdominal skin scars noted, and extent of anterior abdominal wall adhesions prospectively recorded. Statistical analysis was performed with the chi2 test. MEASUREMENTS AND MAIN RESULTS: No anterior abdominal wall adhesions were present in 91 patients with no previous surgery or 45 patients with previous laparoscopy (12 had more than 1 laparoscopy; p <0.001 vs laparotomy). Seventeen (59%) of 29 patients with a midline vertical incision had anterior wall adhesions (p <0.05 vs suprapubic transverse incision). Eleven (28%) of 39 with a suprapubic transverse incision had anterior wall adhesions (p <0.001 vs no surgery or laparoscopy). Ninety-six percent of adhesions involved omentum and 29% included bowel. CONCLUSION: Prior laparotomy, whether through a midline vertical or suprapubic transverse incision, significantly increased the frequency of anterior abdominal wall adhesions, and these adhesions may complicate the placement of the laparoscopic cannula through the umbilicus.

Response to challenge with gonadotropin-releasing hormone agonist in a mother and her two sons with a constitutively activating mutation of the luteinizing hormone receptor--a clinical research center study.

The pituitary-gonadal axis was evaluated in a mother after two of her sons with familial male-limited pseudoprecocious puberty were found to have a constitutively activating mutation of the LH receptor (LHR). Genotyping demonstrated that all showed a mutation in one of the two alleles, a substitution of Gly for Asp578 in the sixth transmembrane segment of the LHR. Ovarian function was normal in the 36-yr-old mother as assessed by LH dynamics and FSH and androgen levels throughout the menstrual cycle. Hormonal responses to acute GnRH agonist (nafarelin) challenge, chronic GnRH agonist administration, and dexamethasone were also normal. Studies of the boys upon presentation at 2.4 and 3.5 yr of age revealed that acute LH responses to nafarelin were in the hypogonadotropic range, and the FSH responses were prepubertal despite the presence of late pubertal testosterone blood levels. Upon the inception of true puberty at 11 yr of age in the older brother, gonadotropin responses normalized for the state of development. The data show that this activating LHR mutation does not cause functional ovarian hyperandrogenism and causes only incomplete pubertal activation of Leydig cells. The results are compatible with relatively low constitutive activity associated with this structural abnormality of LHR.

Acute hormonal responses to the gonadotropin releasing hormone agonist leuprolide: dose-response studies and comparison to nafarelin--a clinical research center study.

The hormonal responses to single subcutaneous injection of the GnRH agonist nafarelin have been shown to have considerable potential as a diagnostic test in a number of settings. Since nafarelin injection is no longer produced, studies were conducted to determine the dosage of leuprolide that would yield equivalent responses. Nafarelin 100 micrograms stimulates LH and FSH for 24 h, releasing about 7-fold more gonadotropin than this dose of natural GnRH, which accounts for its ability to elicit gonadal steroid responses. Normal adult men and women were randomized to receive leuprolide doses of 0.1, 1.0, or 10 micrograms/kg; a study extension evaluated doses up to 20 micrograms/kg in men. The responses of LH, FSH, testosterone, and estradiol were monitored for 24 h, and the data were compared to those previously obtained on nafarelin. Leuprolide dose of 10 micrograms/kg yielded LH responses similar to 1-1.5 micrograms/kg nafarelin. However, this leuprolide dose unexpectedly released less FSH than nafarelin. Nevertheless, the gonadotropin responses were sufficient to elicit equivalent or greater sex steroid responses to leuprolide. These studies also further delineated sex-specific differences in pituitary responsiveness to challenge with GnRH agonists: men had a significantly lower baseline FSH level, greater LH release within the first hour, and lesser secretion of LH and FSH over the 24-h period. These studies indicate that leuprolide in a dosage of 10 micrograms/kg would be expected to be efficacious in testing the pituitary-gonadal axis in men and women.

Studies of the nature of 17-hydroxyprogesterone hyperresonsiveness to gonadotropin-releasing hormone agonist challenge in functional ovarian hyperandrogenism.

Plasma 17-hydroxyprogesterone (17PROG) hyperresponsiveness to GnRH agonist (nafarelin) testing is typical of polycystic ovary syndrome and other functional ovarian hyperandrogenism (FOH) that does not meet customary criteria for the diagnosis of polycystic ovary syndrome. We have postulated that this results from abnormal regulation of androgen secretion. Whether this dysregulation is the result of a normal physiological response to ovarian hyperstimulation or escape from down-regulation of steroidogenesis is unknown. To distinguish between these possibilities, we have analyzed the ovarian steroid responses to nafarelin for the apparent efficiency of the steroidogenic steps and the apparent dose-response relationships between blood LH and steroid levels. We compared normal women (n = 18) with three groups of hyperandrogenic women (n = 15-19/group): patients with 17PROG hyperresponsiveness with or without elevated LH levels (type 1 and type 2 FOH, respectively) and patients with normal 17PROG responses to nafarelin (nafarelin negative). Subjects were pretreated with dexamethasone to suppress coincidental adrenal contributions to plasma steroid levels. The pattern of steroid secretion was similarly abnormal in both types of FOH, with the high LH group having generally more severe abnormalities in the levels of steroid intermediates. Baseline 17PROG and 17-hydroxypregnenolone and the ratio of 17PROG to androstenedione (AD) were increased (P < 0.05). In addition, the apparent slope of the 17PROG response to LH was significantly increased. Baseline levels of both AD and dehydroepiandrosterone and the AD response to nafarelin were increased, yet the ratio of peak minus baseline (delta) AD/delta 17PROG (another index of 17,20-lyase activity) was subnormal in FOH. The apparent slope of the testosterone (T) response to LH was significantly increased, and indexes of aromatase activity [estradiol (E2)/T and delta estradiol/delta T] were significantly decreased. Nafarelin stimulated plasma E2 in all groups to rise along an apparently similar LH-E2 dose-response slope. We interpret these results as indicating that FOH patients have generalized overactivity of thecal steroidogenesis, but nevertheless compensate so as to maintain a normal dose-response relationship between blood levels of LH and E2. FOH patients, whether they have LH excess or not, seen to form excessive 17PROG and incompletely dampen (down-regulate) thecal cell 17PROG, AD, and T secretion in response to LH stimulation. 17PROG hyperresponsiveness to nafarelin seems to be prominent both because it is formed in excess and because 17,20-lyase efficiency is rate limiting. The T elevation seems to arise mainly from overactive steroidogenesis, but also partly from an additional functional decrease in aromatase efficiency, which is secondary to negative feedback by the substrate-driven tendency toward estrogen excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Ovarian hyperandrogynism as a result of congenital adrenal virilizing disorders: evidence for perinatal masculinization of neuroendocrine function in women.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome, consisting of hyperandrogynism, infertility, menstrual irregularities, and elevated LH levels. This is generally considered secondary to poor control of the congenital adrenal hyperplasia. However, our experience led us to suspect that ovarian hyperandrogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy. Therefore, we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyperandrogenism. We studied eight women with congenital adrenal virilizing disorders, seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age. We also studied six women with late-onset 21-hydroxylase deficiency, without signs of congenital virilization. An ovarian source of androgens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist (nafarelin) test. Five women with congenital adrenal virilizing disorders (four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma) and one women with late-onset 21-hydroxylase deficiency had ovarian hyperandrogenism as determined by subnormal suppression of free testosterone after dexamethasone and/or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone. All women with congenital adrenal virilization and ovarian hyperandrogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin, which suggests that LH excess is the cause of their ovarian hyperandrogenism. This was not the case for the late-onset 21-hydroxylase-deficient woman. Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty. This is postulated to frequently cause ovarian hyperandrogenism even when adrenal androgen excess is subsequently controlled by glucocorticoid therapy.

Menstrual disorders in adolescence.

Current concepts of normal and pathologic puberty have been reviewed because menstrual abnormalities are usually due to abnormal maturation of the reproductive endocrine system. Schema are presented for the initial evaluation of patients with amenorrhea or oligomenorrhea based upon whether they are hypoestrogenic or estrogenized. The role of the bone age in the differential diagnosis of delayed puberty is emphasized. The differential diagnosis and management of excessive genital bleeding and dysmenorrhea in adolescence are given.