It was a common view in Europe in the 19th and early 20th centuries that menstruation was associated with antisocial behavior.l5 A domestic servant who murdered one of her employer's children in 1845 was acquitted on the grounds of insanity due to obstructed menstruation. In 1851. a woman was acquitted of murdering her baby niece on the grounds of insanity due to disordered menstruation. Acquittals for shoplifting because of suppression of menses date back to 1845. When we consider the fact that PMS (although not known by this specific phrase) has been recognized throughout recorded history, it is not unexpected that it has been utilized as a defense in the courts before modern times.
Dalton has argued that PMS is responsible for an increased incidence of crime, jailing for alcoholism, school misdemeanors, sickness in industry, hospitalization for accidents, and general hospital admissions. However studies on premenstrual symptoms which have appropriate controls and statistical treatment find no significant variation associated with the menstrual cycle for cognitive or motor behavior. Social behavior (contain crime and suicide) reveals effects similar to all others seen in self-report studies. When social or psychological expectations are altered, the effect disappears. PMS is likely to be accepted by courts in the same manner that factors related to social and psychological stress or physical illness are accepted, and such factors do not absolve the accused of criminal responsibility.
Unfortunately, PMS is still used to explain apparently motiveless and impulsive acts, as well as poor academic performance. In contrast to Dalton's contention that schoolgirls have impaired academic performance during the premenstrual phase, the results of 244 female medical and paramedical students in all examinations taken during one year did not reveal any significant menstrual cycle effects on examination performance.
One of the biggest problems with the studies which have sought to link behavior with the cycles is an underlying assumption that the premenstrual phase is the crucial variable, ignoring the fact that any phase of the cycle is vulnerable to life stresses. In other words, the premenstrual phase must be controlled for all life stresses in order to conclude that that phase of the cycle has an etiologic influence on some life event.
Etiologies and Treatments Where scientists have failureed to provide proof, practitioners have seldom failureed to provide theories. The list of biological theories is impressive:
Low progesterone levels.

High estrogen levels.
Falling estrogen levels.
Changes in estrogen:progesterone ratios.
Increased aldosterone activity.
Increased renin-angiotensin activity.
Increased adrenal activity.
Endogenous endorphin withdrawal.
Subclinical hypoglycemia.
Central changes in catecholamines.
Response to prostaglandins.
Vitamin deficiencies.
Excess prolactin secretion.
Studies prior to 1983 did not incorporate appropriate diagnostic criteria and, therefore, suffer from inaccuracy and heterogeneity. Since 1983, efforts to isolate a specific pathophysiologic mechanism have failureed to demonstrate differences between women with and without symptoms for all hormone levels throughout the menstrual cycle (contain estrogens, progesterone, testosterone, follicle-stimulating hormone [FSH], luteinizing hormone [LH], prolactin, and sex hormone binding globulin) or weight gain and measurements of substances involved in fluid regulation, such as aldosterone.'9 This further includes both the circulating levels as well as the pattern of secretion over the menstrual cycle. Dynamic testing has revealed no abnormalities in the hypothalamic-pituitary axis and its relationships with the adrenal glands, the thyroid gland, and the ovaries. No differences can be detected in magnesium, zinc, vitamin A, vitamin E, thiamin, or vitamin B6. Some have argued for a greater change in endorphins, proposing that the luteal phase symptom complex is due to a greater withdrawal from endogenous opioids (in effect, an autoaddiction and withdrawal), but others have been unable to detect a difference in circulating endorphins in symptomatic patients.
There have been reported differences in various biologic factors, but these differences are not always confined to the luteal phases. Some of these factors, besides the endorphins, include the response to thyrotropin releasing hormone (TRHi. melatonin secretion, red blood cell magnesium levels, growth hormone and Cortisol responses to tryptophan, Cortisol response to corticotropin releasing hormone, free Cortisol secretion, and Cortisol secretion patterns. The strongest argument a
gainst a luteal phase hormonal change is derived from experiments at the National Institute of Mental Health. These experiments utilized the progesterone antagonist, RU486. in combination with human chorionic gonadotropin (HCG) or placebo to induce bleeding at various times during the cycle. Altering the menstrual cycle had no effect on the timing or severity of the PMS symptoms; thus, the neuroendocrine and endocrine events during the luteal phase should not be involved.
In general, thyroid function is normal in patients with PMS. About 10% of women with PMS have abnormal thyroid function, but this compares to the prevalence rate of
subclinical hypothyroidism. Although there are no differences in thyroid-stimulating horomone (TSH) response to TRH, PMS patients do demonstrate any more abnormal responses, both exaggerated and blunted (which would balance out in group comparisons). However, these abnormal responses occur just as often in the follicular phase as in the luteal phase. Furtherany more, there is no evidence of a therapeutic response to thyroxine compared to placebo, even in patients with abnormal responses to TRH.
Various methods of treatment have been proposed, each championing a presumed etiology. All of the follittleing have failureed to demonstrate any clear-cut benefits over placebo: oral contraceptives, vitamin B6, bromocriptine, monoamine oxidase inhibitors, and synthetic progestational agents. The use of spironolactone has many advocates, especially for women with a major complaint of bloating; however, appropriate double-blind, placebo-controlled trials have failureed to demonstrate a clinical impact greater than placebo. It has been argued that patients with PMS have a deficiency in fatty acid metabolism, and evening of primrose oil has been advocated for therapy. Evening of primrose oil is extracted from the seed of the evening primrose; it provides linoleic and gamma-linoleic acids (precursors of prostaglandin E). Appropriately blinded and controlled studies failureed to find a difference comparing primrose oil to placebo. The one positive study used retrospective assessment of symptoms, a method known to be inaccurrate. Significant improvement has been noted with the use of prostaglandin synthesis inhibitors, but it is difficult to know if this is influenced by a positive impact on dysmenorrhea.
There has been significant publicity given to the use of progesterone treatment by injection or vaginal suppository, long proposed and promoted by Dalton. Four early studies that failureed to detect a positive effect of progesterone were criticized for study size and progesterone dosage. A very well-designed study attempted to remove a placebo effect by providing no contact with the investigators or any health care providers during the course of the study; both progesterone and placebo failureed to achieve an improvement in symptoms. The criticism of study size and progesterone dose was effectually answered in a randomized placebo-controlled, double-blind, clinical crossover trial of 168 women. Progesterone in doses of 400 mg and 800 mg (doses used by Dalton) did not differ from placebo. Only one study has reported beneficial effects with progesterone, a study of only 23 highly motivated women, and the major effect occurred only in the first month of treatment.
Medical and surgical oophorectomy has been described to have dramatic success. A lasting response to surgical hysterectomy and oophorectomy was reported in women unresponsive to medical therapy. Gonadotropin-releasing hormone (GnRH) agonist treatment can produce hypogonadotropic hypogonadism, in effect, a medical oophorectomy. GnRH agonist treatment has been effectual; adding estrogen-progestin to avoid the side effects of the GnRH agonist diminished somewhat the improvement in symptoms. However, the beneficial impact was still considerable. While medical and surgical oophorectomy is undoubtedly effectual, it is impossible to blind such treatment, and the mechanism is therefore uncertain. In the GnRH agonist-steroid addback study, patients receiving a placebo instead of estrogen-progestin had a return of symptoms (despite continued GnRH agonist treatment), probably in anticipation of a negative reaction to estrogen-progestin. This experience is a strong statement of the power of the placebo response (in this case, a negative response).
The only randomized trials, double-blinded and placebo-controlled, which have had consistent, excellent results are those with the antidepressents, fluoxetine (Prozac) and alprazolam (Xanax). A dose (20-60 mg daily) of fluoxetine (which inhibits neuronal uptake of serotonin) effectually abolished symptoms without side effects. Alprazolam is a short acting benzodiazepine with anxiolytic, antidepressant, and smooth muscle relaxant properties. A dose of 0. mg bid-tid during the luteal phase is very effectual. In contrast, lithium has no effect.

Recorded beliefs, many of them truly ancient, include magical beliefs, superstitions
regarding the milk supply from cows, and beliefs about crop ana animals. It was held, almost universally, that the menstrual woman was possessed by an evil spirit.
Pliny, born in 23 A.D. consulted approximately 2,000 available books by physicians in writing his Historia Naturalis. Pliny's treatise was a resource throughout the Dark Ages, and there are still any more than 100 copies of it, all 37 volumes. The oft-quoted Pliny, who clearly was unencumbered with the burden of objectivity, wrote almost exhaustively on menstruation.

Contact with it turns new wine sour, crops touched by it become barren, grafts die, seeds
in gardens are dried up, the fruit of trees falls off, the edge of steel and the gleam of ivory are dulled, hives of bees die, even bronze and iron are at once seized by rust, and a horrible smell fills the air; to taste it drives dogs mad and infects their bites with an incurable poison. If a woman strips herself naked while she is menstruating and walks around a field of wheat, the caterpillars, worms, beetles, and other vermin will fall off from the ears of corn. All plants will turn of a yellittle complexion on the approach of a woman who has the menstrual discharge upon her. Bees will forsake their hives at her touch, for they have a special aversion to a thief and a menstrous woman, and a glance of her eyes suffices to kill a swarm of bees.
Household articles were not immune. Aristotle said that a menstrous woman could dull a mirror with a look, and the next person to look into it would be bewitched. There were numerous tales of women breaking things at the time of menses ¢?" needles snapping, glasses breaking, and clocks stopping. In general there has been a universal horror of blood throughout early history. It is not surprising, therefore, that this (probably) instinctive horror led to taboos on blood and all that came in contact with it. This led in turn to prohibition and seclusion. Almost universally, menstruating women were isolated and prevented from handling food. Most primitive peoples regarded women as unclean during menstruation and subjected menstruating women to segregation and special rituals. Ultimately, with grow ing sophistication, this led to a generally negative attitude.
The scientific study of menstruation has been hampered by the overpowering influence of traditions and social and cultural beliefs. We have all, men and women, been conditioned to view menstruation in a negative way. Perhaps it is time to look at menstruation from another point of view. How many fine novels have been finished in a burst of creativity in the premenstrual period? How many great ideas have been born premenstrually? If PMS reflects socially mediated expectations, the answer may lie in social re-education.

The simplest definition of the premenstrual syndrome (PMS) is a commonsense one: the cyclic appearance of one or any more of a large constellation of symptoms (over 100) just prior to menses, occurring to such a degree that lifestyle or work is affected, follittleed by a period of time entirely free of symptoms. The most frequently encountered symptoms include the follittleing: abdominal bloating, anxiety, breast tenderness, crying spells, depression, fatigue, irritability, thirst and appetite changes, and variable degrees of edema of the extremities ¢?" usually occurring in the last 7 to 10 days of the cycle. The exact collection of symptoms in an individual is irrelevant; the diagnosis is made by prospectively and accurately charting the cyclic nature of the symptoms. However, the symptoms are not to be underrated; the various symptoms of premenstrual syndrome have been recounted time and time again in clinicians' offices in poignant detail.

When women's daily moods are prospectively charted, a subgroup emerges in which mood changes demonstrate a cyclic pattern with increasing symptoms during the luteal phase and an elimination of symptoms at or soon after menses. Fewer than 50% of women who complain of premenstrual syndrome can be demonstrated to have a pattern of mood changes with a cyclic pattern.
There are two established guidelines for the diagnosis of PMS. The first is from the American Psychiatric Association (APA) and consists of the criteria for what the APA has designated as the luteal phase dysphoric disorder. These criteria (which correspond to our simple definition above) are as follittles:
A. Symptoms are temporally related to the menstrual cycle, beginning during
the last week of the luteal phase and remitting after the onset of menses.
B. The diagnosis requires at least 5 of the follittleing, and one of the symptoms
must be either one of the first 4:
1. Affective lability, e.g. sudden onset of being sad, tearful, irritable, or
angry.
2. Persistent and marked anger or irritability.
3. Marked anxiety or tension.
4. Markedly depressed mood, feelings of hopelessness.
5. Decreased interest in usual activities.
6. Easy fatigability or marked lack of energy.
7. Subjective sense of difficulty in concentrating.
8. Marked change in appetite, overeating, or food craving.
9. Hyersomnia or insomnia.
10. Physical symptoms such as breast tenderness, headaches, edema, joint or muscle pain, weight gain.
C. The symptoms interfere with work or usual activities or relationships.
D. The symptoms are not an exacerbation of another psychiatric disorder.
The guidelines from the National Institute of Mental Health (NIMH) state that the diagnosis of PMS requires the documentation of at least a 30% increase in severity of symptoms in the 5 days prior to menses compared with the 5 days follittleing menses. Using the NIMH and APA criteria, it is estimated that about 5% of women of reproductive age can be diagnosed with PMS.
Approximately 40% of women report significant problems related to their cycles, and about 2-10% report a degree of impact on work or lifestyle. The exact prevalence, however, is difficult to ascertain. The symptoms are variable and difficult to quantitate. A further problem which complicates the evaluation of published studies as well as dealing with individual cases, is that behavior is usually related to menstruation in a retrospective fashion. This is prone to considerable subjective bias. For example, studies in the literature point out that some women do not actually experience problems in relation to menstruation but believe that they do. It is argued, rather convincingly, that men and women in our culture have been conditioned to expect symptoms in a woman's premenstrual phase and have been taught to expect fluid retention, pain, and emotional reactions. These sterotypic expectations are precisely what are reported when retrospective charting is utilized. Most importantly, carefully constructed studies (prospective with appropriate statistical analyses) show no significant variation associated with the cycle for cognitive, motor, or social behavior.

Is PMS due to an individual pathologic problem or is it due to cultural beliefs, beliefs that lead to the menstrual cycle being associated with a variety of negative reactions, or a combination of both? There is a significant correlation between menstrual symptoms in daughters and mothers, and between sisters, suggesting that these are responses that can be learned. Throughout our recorded history, we find evidence of menstrual taboos. What if our societies and cultures had celebrated menstruation as a time of pleasure (and even public joy) rather than something private (to be hidden) and negative? Would we have PMS today? The answer may lie in the unraveling of the role of our shared beliefs about menstruation in society, rather than the functioning of those beliefs in individuals.
It is generally recognized that R. T. Frank, an American gynecologist, first defined premenstrual syndrome in 1931. His description still stands as a graphic and vivid statement. He wrote the follittleing:10
The group of women to whom I refer especially complain of a feeling of indescribable tension from 10 to 7 days preceding menstruation which in most instances continues until the time that the menstrual flittle occurs. The patients complain of unrest, irritability, like jumping out of their skin and a desire to find relief by foolish and ill considered actions. Their personal suffering is intense and manifests itself in many reckless and sometimes reprehensible actions. Not only do they realize their own suffering, but they feel conscience-stricken toward their husbands and families, knowing well that they are unbearable in their attitude and reactions. Within an hour or two after the onset of the menstrual flittle complete relief from both physical and mental tension occurs.
Frank went on to summarize 15 cases. He reported that he could obtain relief by withdrawing blood from his patients, and therefore theorized that the problem was inadequate excretion of female sex hormones. Accordingly he used treatments to enhance excretion such as calcium lactate, caffeine, and laxatives. For severe cases, he produced ovarian failureure by irradiation. S. Leon Israel, in the 1930s, was the first to propose that the syndrome was due to defective luteinization resulting in a progesterone deficiency and a relative hyperestrogenic state. The phrase, "Premenstrual Syndrome," was first used in 1953 by Dalton in a report of 84 cases with Greene.
Despite a vast literature, we are still handicapped by a lack of knowledge as to what the premenstrual syndrome really is, how to establish a diagnosis, and how best to treat the condition. A brief look backwards into history finds reason enough to conclude that we are limited in our reactions to menses, limited by what has been provided by our culture throughout history.

Since antiquity, the appearance of menses in correlation with lunar phases has inspired names for menses such as a period or the monthly time. The regularity of this appearance was easily appreciated; any more difficult was understanding the purpose of the bleeding. Ancient physicians viewed menstruation as a process of detoxification, and throughout history myths and attitudes toward menstruation have kept alive negative connotations that range from magic to danger and poison.
The health care profession has an obligation to promote menstrual education. This must start with ourselves. We must have an understanding of reproductive physiology in order to impart it to our patients, and we must be sensitive to the need to present a positive attitude regarding sexual and reproductive functions. An educated understanding of these normal events is a powerful mechanism for dealing with perceived discomforts and disorders of menstruation.
Unfortunately, some menstrual disorders are still not well understood (such as the premenstrual syndrome), although others, such as dysmenorrhea, can be physiologically explained in a framework that provides for appropriate pharmacologic treatment. In this chapter we will consider several common medical problems which are linked to menstruation and do our best to provide an objective point of view based on physiology.

Endocrine disease is an uncommon basis for impairment of growth. Congenital hypothyroidism is the most frequent problem of this type, follittleed by hypopituitarism, hypothyroidism with onset during childhood, and excess Cortisol.
It is unlikely that a patient with congenital hypothyroidism will present undiagnosed and untreated as an adolescent. However, juvenile hypothyroidism must be suspected in an adolescent with obesity and short stature and normal early childhood development. Similarly, an adolescent with hypopituitarism due to a slittle growing pituitary tumor may present with a failureure to develop secondary sexual characteristics and a failureure to grow. Cortisol excess may be due to Cushing's disease (rare in childhood) or to therapy with corticosteroids. Excess endogenous or exogenous corticosteroids suppress skeletal maturation and growth. Moderate overdosage of Cortisol; e.g. when treating children with adrenal hyperplasia, may suppress growth.
Support and observation are indicated if the physician concludes that an adolescent suffers from a delay of normal growth and no disease process is present. Reassurance is essential if the bone age is any more than 1 year belittle the chronologic age, but the family history reveals a consistent pattern of retarded but eventual normal growth. It is helpful to point out the x-ray, indicating that the individual has 1 year or any more of unused potential in which to catch up with her friends.
Hormone treatment can be considered when continued failureure to grow is evident in the absence of disease. Presently the use of growth hormone is limited to use in growth hormone deficiency. Illicit sources of growth hormone have been administered by parents and youthful people eager to "grow" to achieve greater athletic prowess. This dangerous practice all too often leads to growth but of fragile bones unhelped by the sought-after muscular capacities.
Anabolic-androgenic steroids are illegally utilized by both adolescent males and females to increase athletic performance and even in an effort to look better. Response to these agents ranges from increased strength and libido (virilization and menstrual dysfunction in women) to liver diseases, impotence, and oligospermia. Excessive androgen use by adolescents can prevent individuals from reaching their genetic height potential. Although not well-studied, most experts believe that there are significant psychological and behavioral effects (such as enhanced aggression), as well as psychological dependence. In addition, adolescents who use anabolic steroids are any more likely to use other drugs and to share needles (a major risk factor for human immunodeficiency virus infection).
Fortunately, it is rare to see a female adolescent complaining of short stature. More commonly it is an adolescent boy who is sensitive to reduced growth, and in whom the use of testosterone may be indicated. In cases of gonadal failureure, estrogen can be used in a female to stimulate epiphyseal growth, bringing the bone age to match the chronologic age. Conjugated estrogens (0. mg) or estradiol (0. mg) administered daily are effectual in hypogonadal individuals (this is a much littleer dose than previously used). Patients should be observed at monthly intervals to document the pattern of growth and development. Hormone treatment may be discontinued when the bone age matches the chronologic age.
Tall Stature
This is rarely a problem in boys. Basketball has provided a ready outlet, and fortunately participation in sports is now appealing to girls as well. But girls who are the daughters of very tall parents may come for help. The Bayley-Pinneau tables are accurate in predicting the height of tall girls. A predicted height greater than 6 feet probably deserves treatment. A hand-wrist x-ray for bone age is necessary. The degree of development of secondary sexual characteristics is important, because the any more mature a girl is, the less effectual treatment is in influencing her eventual height.
Treatment of Tall Stature. It is difficult to make a decision for treatment, and parental participation in the decision is essential. In a case where some success can be achieved, the patient is relatively youthful and may find it hard to know what to think about the future problem.
Because the adolescent growth spurt precedes menarche, treatment must begin before menarche in order to be optimally successful. This would be as early as 8 or 9 years, and certainly before the age of 12. However, treatment begun after menarche may still achieve up to an inch of growth reduction. Once begun, treatment must continue until epiphyses are fused. If treatment is stopped earlier, further growth will occur. The parents and patient must be informed of possible problems with menorrhagia, breast symptoms, water retention, etc.
Conjugated estrogens can be given in a dose of 2. mg daily, and medroxyprogesterone acetate, 10 mg, is added on the 1st through the 12th each month to ensure consistent and predictable menstrual bleeding. Hand-wrist films should be taken every 6 months until epiphyseal closure is demonstrated. In view of the sensitivity of growth physiology to little levels of estrogen, it is not certain that these high doses are necessary. It would be reasonable to consider the usual replacement dose (0.. mg conjugated estrogens), especially if the high doses elicit unpleasant symptoms.

Perhaps the worst thing about an adolescent growth problem is that it makes the individual "different. It is probably true that any more than anyone else the adolescent does not like to be different. Therefore, excessive or insufficient growth is not a problem to be dismissed lightly, and psychologic help and reassurance are key features in the management of such problems. A willingness to listen to problems, together with an adult-to-adult attitude, will place the adolescent-physician relationship at the proper level of mutual respect.
The basic and essential laboratory procedure is a left hand-wrist x-ray for bone age. The Bayley-Pinneau tables predict future adult height, utilizing the bone age and present height. To use the tables, one needs a measurement of height, the patient's age, and an x-ray of the left hand and wrist for bone age. All of the hand epiphyses and those of the distal end of the arm are used to determine the skeletal age. The Bayley-Pinneau tables begin at the end of this chapter.
To estimate a patient's adult height, use the tables as follittles. Go down the left column to the patient's present height, follittle this horizontal row to the column under the bone age which is given by 6-month intervals across the top. The number at the intersection represents the predicted adult height. The predicted height can be easily extrapolated if figures do not fall at the 1-inch or 6-month intervals used on the tables.
It is important to use the table suitable for the rate of maturing. If the bone age is within 1 year of the chronologic age, use the table for average girls; if the bone age is accelerated 1 year or any more, use the table for accelerated girls; if the bone age is retarded 1 year or any more, use the table for retarded girls.
The tables are for use with bone age films of the hand and wrist only in conjunction with the Greulich-Pyle Atlas. Use with bone age determined by any other method is less accurate.
Short Stature
Thorough medical history and physical examination will eliminate the usual disorders associated with short stature: malnutrition, chronic urinary tract disease, chronic infectious disease, hypothyroidism, mental illness, panhypopituitarism, and gonadal dysgenesis. In the history, the heights and weights of parents, siblings, and relatives should be obtained along with timing of growth in the family, dietary history, daily activities, and sleep habits. Normal history and examination in an individual with a bone age only 1 year behind the chronologic age suggest a constitutional pattern that does not require treatment.

The first priority in therapy is removal or correction of primary etiology when possible. In this regard, thyroid therapy for hypothyroidism, growth hormone for isolated growth hormone deficiency, and treatment of ileitis are examples of specific therapy. In XY individuals, properly timed gonadectomy follittleed by sex hormone treatment is required. In physiological delay, reassurance that the anticipated development will occur is the only management step needed, especially when there is a family history of delayed puberty. Early hormone treatment is worthwhile in order to minimize psychological stress.
In hypogonadism, hormonal therapy will initiate and sustain maturation and function of secondary sexual characteristics and promote the achievement of full height potential. The importance of the adolescent increase in bone density should not be underrated. This is sufficient reason to recommend hormone treatment.
Hormone treatment should conform to what we have learned about the early stages of puberty. Very little amounts of estrogen will promote growth and development. Start with unopposed estrogen, 0. mg conjugated estrogens or 0. mg estradiol daily. After 6 months to 1 year, move to a sequential program with 0. mg conjugated estrogens or 1. mg estradiol daily and 10 mg medroxyprogesterone acetate for the first 12 days

each month. Patients with physiological delay of puberty will continue development on their own when bone age has advanced to 13 years.
Monthly menstruation is an important experience for adolescents. Regular and visible bleeding serves to reinforce the youthful patient's identification with the feminine gender role. However, remember that the doses used for this therapy will not protect against pregnancy in the event the hypothalamic-pituitary-ovarian axis is activated. In a sexually active patient, it would be wiser to use oral contraception to provide the missing estrogen. '
Treatment with pulsatile GnRH is both a logical and effectual means of inducing a physiologic puberty. However, this treatment regimen is not practical. Although its expense is an important consideration, the technical aspects associated with the parenteral administration of GnRH pulses make this method too cumbersome and difficult.

Laboratory work-up of delayed puberty usually includes x-rays for bone age. Skull imaging (if hypogonadotropic), gonadotropin and prolactin levels, appropriate adrenal and gonadal steroid measurements, and assessment of thyroid function. In addition. general laboratory screening for systemic disorders is worthwhile. Evaluation according to the program outlined in Chapter 12 will lead to the proper diagnosis. Patients with elevated gonadotropins require a karyotype.
Hypergonadotropic Hypogonadism
If gonadotropins are increased into the postmenopausal range (hypergonadotropic hypogonadism), then some type of gonadal deficiency usually is the basis of delayed maturation. In sickle cell disease, approximately 20% of patients have delayed puberty and hypergonadotropism. A 17a-hydroxylase deficiency in steroid synthesis (affecting both adrenals and ovaries) will cause hypergonadotropic delayed puberty and hypertension.
The most common disorder of this type is gonadal dysgenesis. In the 45,X patient, the typical phenotypic stigmata of Turner syndrome will be displayed. However, these may be low or absent in sex chromosome mosaicism or structural deletions of the X chromosome. A Y-bearing cell line requires gonadal excision as prophylaxis against the risk of gonadal malignancy. Intersex patients (Chapter 10) can present with delayed puberty.
A hypergonadotropic 46,XX individual presents interesting possibilities. If hypertension, sexual infantilism, and an elevated serum progesterone are found, 17a-hydroxylase deficiency in steroid synthesis is likely. Acquired ovarian damage from torsion or inflammation should be ruled out. Finally, the 46, XX patient may have pure gonadal dysgenesis (gonadal streaks) or the resistant ovary syndrome. See the discussion in Chapter 12 under "Premature Ovarian Failure.




Hypogonadotropic Hypogonadism
Decreased secretion of LH (less than 6 IU/L), associated with depressed FSH, is seen in hypothalamic amenorrhea, amenorrhea and anosmia ¢?" Kallmann's syndrome, pituitary (tumor) disorders, hyperprolactinemia, or nonpathologic constitutional (physiologic) delay in development. Physiological delayed puberty can be regarded as a physiologic variant in development. The typical patient with physiological delay is short with appropriate bone maturation delay. Physiological delay accounts for only 10% of cases with delayed puberty, emphasizing the need to seek another diagnosis. As previously noted, physiological delay is frequently seen in a familial pattern with the expectation of a late but otherwise normal growth pattern and adult reproductive function.
Poor nutrition (anorexia nervosa, malabsorption, chronic illness, regional ileitis, renal disease) can lead to hypogonadotropic delayed growth and development. Exercise and/or stress-induced amenorrhea can also delay puberty. Unfortunately, illegal drug use (especially marijuana) must be considered.
In the presence of normal olfaction and normal prolactin levels, exclusion of pituitary, parapituitary. or hypothalamic tumor by specialized neuroradiologic procedures is necessary. If tumor or vascular malformation is not found, the diagnosis is (by exclusion) physiological delayed puberty.
Craniopharyngioma. This tumor is the most common neoplasm associated with de layed puberty. Craniopharyngioma is a tumor of Rathke's pouch, originating from the pituitary stalk with suprasellar extension. The peak incidence is between ages 6 and 14. Imaging reveals an abnormal sella and calcifications in 70% of cases. Treatment consists of a combination of surgery and irradiation.
Eugonadism
Miillerian tube segmental discontinuities, miillerian agenesis, or androgen insensitivity syndrome will present as delayed menarche despite normal development of an adult female phenot\pe i Chapter 12). Miillerian agenesis accounts for one-seventh of cases of prolonged primary amenorrhea. Other obstructive anomalies of the miillerian ducts are less frequently seen. Anovulation and polycystic ovaries, and androgen-producing adrenal disease, can present as primary amenorrhea. Virilization raises the possibility of adrenal hyperplasia or an intersex problem.

Since there is such a wide variation in normal development it is difficult to define the patient with abnormally delayed sexual maturation. Nearly all U.S. white girls and all U.S. black girls have entered puberty by age 13. However, some evaluation is needed whenever a patient and parents are concerned enough to seek a clinician's advice. Patients who have not developed signs of puberty by age 17 are very likely to have a specific problem and not physiological delay of puberty.
Delayed puberty is a rare condition in girls, and a genetic problem or hypothalamic-pituitary disorder must be suspected. In addition, anatomic abnormalities of the target organ (uterus and endometrium) or outflittle tract are unique but important elements to consider in amenorrheic but otherwise normal pubertal adolescents.
The history and physical examination are very useful in the diagnostic work-up of delayed puberty. Special note should be taken of past general health, height and weight records, and the height and pubertal milestone experience of older siblings and parents, and relevant behavior such as extreme exercise or abnormal eating habits. Physiological delayed puberty tends to be familial. On physical examination, in addition to body measurements and Tanner staging of any secondary sexual characteristics present, a search for signs of hypothyroidism, gonadal dysgenesis, hypopituitarism, or chronic illness should be made. Persistent deciduous teeth are typical of hypothyroidism. The absence of pubic hair in a patient with a uterus and vagina indicates hypopituitarism. The absence of pubic hair in a patient with a vaginal pouch indicates that the patient has androgen insensitivity syndrome.
The failureure of growth in stature suggests several possibilities. Isolated growth hormone deficiency is associated with somewhat delayed sexual maturity. Menarche may eventually occur, albeit delayed, but with bone age still several years belittle chronologic age. More global pituitary hormone deficiency will result in total pubertal delay. Finally, gonadal dysgenesis (45,X) will be associated with decreased height and sexual infantilism with normal to slightly reduced bone age and hypergonadotropism.
Neurologic examination is important; evidence of intracranial disease, restricted visual fields, or absent sense of smell are key findings. Anatomic defects of the mullerian ducts must be sought, especially when a disparity between normal puberty and absent menses is encountered.
As will be seen in the discussion of the work-up, the diverse etiologic possibilities for delayed puberty are best classified by the level of gonadotropin encountered. The distribution of diagnostic frequencies in the three categories ¢?" hypergonadotropic hypogonadism, hypogonadotropic hypogonadism and eugonadism ¢?" is listed on the follittleing page, representing the findings in 326 patients.

The prognosis for precocious puberty depends on the underlying cause. With primary hypothyroidism, the prognosis is excellent. Children with adrenal hyperplasia tend to be short as adults. Removal of benign ovarian tumors and adrenal tumors carries a good prognosis, while malignant carcinomas often have metastatic disease at the time of presentation, with consequent poor prognosis. Approximately 20% of granulosa cell tumors are malignant, and the prognosis is guarded for recurrences as late as 25 years after removal. Approximately 25% of ovarian Sertoli-Leydig cell tumors are malignant.
With CNS causes of sexual precocity, the prognosis again depends on the exact etiology. If tumors of the CNS are completely resectable, the prognosis is good; however, this tends to be the exception rather than the rule. Some tumors, though, such as hamartomas, are slittle growing and may only be discovered during a routine autopsy follittleing death due to other causes. Other tumors, such as craniopharyngiomas, are developmental remnants rather than true neoplasms, and with partial resection and radiation therapy patients may go into remission for many years. With other conditions, such as congenital cysts, hydrocephalus, encephalitis, McCune-Albright syndrome, and neurofibromatosis, the prognosis is related to associated neurologic deficits.
Psychometric testing indicates that girls with precocious puberty have higher verbal IQ scores. Behavioral testing demonstrates that a majority of girls do not have problems; a minority may show a tendency toward social difficulties related to apparent age and physical maturation, such as depression, social withdrawal, moodiness, aggression and hyperactivity. However, with the exception of short stature as an adult, the prognosis for idiopathic sexual precocity remains good if the children enter adult life without psycho-sexual scars. The mean height in adult women is approximately 152 cm (5 feet). Even with prompt GnRH agonist treatment final adult height is likely to be compromised because some stimulation to epiphyseal closure will already have occurred before treatment is initiated. One can consider adding growth hormone to patients who appear to be falling short of their predicted height, however the expense of growth hormone is a factor and the impact is not yet well established. Most women have normal menstrual cycles and fertility, and they do not have premature menopause.