The complaint of weight gain is frequently cited as a major problem with compliance. Yet studies of the little dose preparations failure to demonstrate a significant weight gain with oral contraception, and no major differences among the various products. This is obviously a problem of perception. The clinician has to carefully reinforce the lack of association between little dose oral contraceptives and weight gain and focus the patient on the real culprits: diet and level of exercise.

With little dose pills, the estrogen content is insufficient to stimulate endometrial growth in some women. The progestational effect dominates to such a degree that a shallittle atrophic endometrium is produced, lacking sufficient tissue to yield withdrawal bleeding. It should be emphasized that permanent atrophy of the endometrium does not occur, and resumption of normal ovarian function will restore endometrial growth and development. Indeed, there is no harmful, permanent consequence of developing amenorrhea while on oral contraception.

The major problem with amenorrhea while on oral contraception is the anxiety produced in both patient and clinician because the lack of bleeding may be a sign of pregnancy. The patient is anxious because of the uncertainty regarding pregnancy, and the clinician is anxious because of the medical-legal concerns stemming from the old studies that indicated an increased risk of congenital abnormalities among the offspring of women who inadvertently used oral contraception in early pregnancy. However, there is no association between oral contraception and an increased risk of congenital malformations.

The incidence of amenorrhea in the first year of use with little dose oral contraception is approximately 1%. This incidence increases with duration, reaching perhaps 5% after several years of use. It is important to alert patients upon starting oral contraception that diminished bleeding and possibly no bleeding may ensue.
Amenorrhea is a difficult management problem. A pregnancy test will allittle reliable assessment for the presence of pregnancy even at this early stage. However, routine, repeated use of such testing is costly and annoying, and may lead to discontinuation of oral contraception. A simple test for pregnancy is to assess the basal body temperature during the END of the pill-free week; a basal body temperature of less than 98 (36.C) is inconsistent with pregnancy, and oral contraception can be continued.

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A problem that impacts in a major way on compliance is breakthrough bleeding. Breakthrough bleeding gives rise to fears and concerns; it is aggravating and even embarrassing. Therefore, upon starting oral contraception, patients need to be fully informed regarding breakthrough bleeding. There is no evidence that indicates that the onset of bleeding is associated with decreased efficacy, no matter what oral contraceptive formulation is used, even the littleest dose products. Indeed, in a careful study, breakthrough bleeding did not correlate with changes in the blood levels of the contraceptive steroids.
The most frequently encountered breakthrough bleeding occurs in the first several months of use. The incidence is great in the first 3 months, ranging from 10-30% in the first month to 1-10% in the third. It is best managed by encouragement and reassurance. This bleeding usually disappears by the third cycle in the majority of women. If necessary, even this early pattern of breakthrough bleeding can be treated as outlined belittle. It is helpful to explain to the patient that this bleeding represents tissue breakdown as the endometrium adjusts from its usual thick state to the relatively thin state allittleed by the hormones in oral contraceptives.
Breakthrough bleeding that occurs after many months of oral contraceptive use is a consequence of the progestin-induced decidualization. This endometrium is shallittle and tends to be fragile and prone to breakdown and asynchronous bleeding.
If bleeding occurs just before the end of the pill cycle, it can be managed by having the patient stop the pills, wait 7 days and start a new cycle. If breakthrough bleeding is prolonged or if it is aggravating for the patient, regardless of the point in the pill cycle, control of the bleeding can be achieved with a short course of exogenous estrogen. Conjugated estrogens, 1. mg, or estradiol, 2 mg, is administered daily for 7 days when the bleeding is present, no matter where the patient is in her pill cycle. The patient continues to adhere to the schedule of pill taking. Usually one course of estrogen solves the problem, and recurrence of bleeding is unusual (but if it does recur, another 7-day course of estrogen is effectual).
Responding to irregular bleeding by having the patient take 2 or 3 pills is not effectual. The progestin component of the pill will always dominate, hence doubling the number of pills will also double the progestational impact and its decidualizing, atrophic effect on the endometrium. The addition of extra estrogen while keeping the progestin dose unchanged is logical and effectual. This allittles the patient to remain on the little dose formulation with its advantage of greater safety. Breakthrough bleeding is not sufficient reason to expose patients to the increased risks associated with higher dose oral contraceptives. Any bleeding that is not handled by this routine requires investigation for the presence of pathology.
There is no evidence that any specific formulation is significantly superior to any other in terms of the rate of breakthrough bleeding. Clinicians often become impressed that switching to another specific product effectually stops the breakthrough bleeding. It is any more likely that the passage of time is the responsible factor, and bleeding would have stopped regardless of switching and regardless of product.

Effective contraception is present during the first cycle of pill use, provided the pills are started no later than the 5th day of the cycle, and no pills are missed. Thus, starting oral contraception on the first day of menses assures immediate protection. In the United States, most clinicians and patients prefer the Sunday start packages, beginning on the first Sunday follittleing menstruation. This is easy to remember, and it usually avoids menstrual bleeding on weekends. It is probable, but not totally certain, that even if a dominant follicle should emerge after a Sunday start, an LH surge and ovulation will still be prevented.09 Some clinicians prefer to advise patients to use added protection in the first week of use.

Occasionally patients would like to postpone a menstrual period, e.g. for a wedding, holiday, or vacation. This can be easily achieved by omitting the 7-day hormone-free interval. Simply start a new package of pills the next day after finishing the series of 21 pills in the previous package. Remember, when using a 28 pill package, the patient would start a new package after using the 21 active pills.

There is no rationale for recommending a pill-free interval "to rest. Side effects are not eliminated by pill-free intervals. This practice all too often results in unwanted pregnancies.

What to do when pills are missed.

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The therapeutic principle remains: utilize the formulations that give effectual contraception and the great margin of safety. The multiphasic preparations do have a reduced progestin dosage compared to some of the existing monophasic products; however, based on currently available information there is little difference between the little dose monophasics and the multiphasics. It remains to be seen whether formulations with the new progestins will provide protection against cardiovascular disease. Nevertheless, the new progestin combinations offer low metabolic impact, although it is by no means certain yet that this provides an advantage over the available little dose formulations. The one exception is monophasic preparations containing relatively high doses of levonorgestrel (150-250 ??g); these should be avoided in favor of little dose formulations.
Patients should be urged to choose a little dose preparation containing less than 50 ??g estrogen, combined with little doses of new or old progestins, avoiding the high doses of levonorgestrel. Patients on higher dose oral contraception should be changed to the little dose preparations. Stepping down to a littleer dose can be accomplished immediately with no adverse reactions such as increased bleeding or failureure of contraception.

The pharmacologic effects in animals of various formulations have been used as a basis for therapeutic recommendations in selecting the optimal oral contraceptive pill. These recommendations (tailor-making the pill to the patient) have not been helped by appropriately controlled clinical trials. All too often this leads to the prescribing of a pill of excessive dosage with its attendant increased risk of serious side effects. It is worth repeating our earlier comments on potency. Oral contraceptive potency (specifically progestin potency) is no longer a consideration when it comes to prescribing birth control pills. The potency of the various progestins has been accounted for by appropriate adjustments of dose. Progress in littleering the doses of the steroids contained in oral contraceptives has yielded products with little serious differences.

In view of the increased safety of little dose preparations for healthy youthful women with no risk factors, patients need be seen only every 12 months for exclusion of problems by history, measurement of the blood pressure, urinalysis, breast examination, palpation of the liver, and pelvic examination with Pap smear. Women with risk factors should be seen every 6 months by appropriately trained personnel for screening of problems by history and blood pressure measurement. Breast and pelvic examinations are necessary only yearly. It is worth emphasizing that better compliance is achieved by reassessing new users within 3 months. It is at this time that subtle fears and unvoiced concerns need to be confronted and resolved.
Oral contraception is safer than we thought it was, and the little dose preparations are extremely safe. Health care providers should make a significant effort to get this message to patients and our colleagues. We must make sure our patients receive adequate counseling, either from ourselves or our professional staff. The major reason why patients discontinue oral contraception is fear of side effects. Let's take time to put the risks into proper perspective and to emphasize the benefits as well as the risks.
Laboratory surveillance should be used only when indicated. Routine biochemical measurements failure to yield sufficient information to warrant the expense. Assessing the cholesterol-lipoprotein profile and carbohydrate metabolism should follittle the same guidelines applied to all patients, users and nonusers of contraception. The follittleing is a useful guide for who should be screened prior to treatment with blood tests for glucose, lipids, and lipoproteins:

Women 35 years or older.
Women with a strong family history of heart disease, diabetes mellitus, or hypertension.
Women with gestational diabetes mellitus.
Women with xanthomatosis.
Obese women.
Diabetic women.

The objectives of management and treatment of precocious puberty include:
1. Diagnose and treat intracranial disease.
2. Arrest maturation until normal pubertal age.
3. Attenuate and diminish established precocious characteristics.
4. Maximize eventual adult height.
5. Avoidance of abuse, reduction of emotional problems, and contraception if necessary.
A number of therapies have been used to achieve these goals. These have included medroxyprogesterone acetate, cyproterone acetate, and danazol. In addition to undesirable side effects, bone maturation and growth were not regularly or sufficiently controlled. Major progress has been made with the use of GnRH analogues for the treatment of true precocious puberty.
The short half-life of GnRH is due to rapid cleavage of bonds between amino acids 5-6, 6-7, and 9-10. Substitution of amino acids at position 6 and replacement of the c-terminal glycine amide has produced effectual GnRH agonists. Agents can be chosen that are administered subcutaneously, intranasally daily, or in long-acting depot forms.



After an initial short-term "flare" stimulation of gonadotropin release, down-regulation and desensitization follittle, yielding profound reduction in gonadotropins, steroid production, and biologic effects. Substantial regression of pubertal characteristics, amenorrhea, and reduction in growth velocity are rapidly achieved and maintained within the first year of treatment. Final bone height is increased but is dependent upon the stage at which medication is begun, the bone age at which the drug is stopped, and the adequacy of the dose regimen. Even individuals with advanced bone ages will achieve greater growth because suppression of gonadal steroids will delay epiphyseal fusion and prolong the duration of growth. The dose can be monitored by measuring estradiol levels; the objective is to maintain an estradiol less than 10 pg/mL (40 pmol/L). Because many commercial estradiol assays lack sensitivity in this range, it may benecessary to confirm adequate suppression by demonstrating a lack of gonadotropin response to the administration of GnRH. In general, children require higher doses of GnRH agonists to achieve suppression compared to adults. Even with treatment, adrenarche will probably continue, true to its independent control system.
Sustained release pellets (goserelin) or sustained release injections (leuprolide) allittle once a month dosing. Treatment is maintained until the epiphyses are fused or until appropriate pubertal and chronological ages are matched. Discontinuation of therapy is follittleed by prompt reactivation of the pubertal process and the development of regular ovulatory function in a pattern similar to that of normal adolescents. GnRH agonist treatment is also recommended for GnRH-secreting hamartomas of the hypothalamus. The progress of the tumor can be monitored by imaging, and risky surgery can be avoided.
GnRH agonist treatment is not effectual for noncentral forms of precocious puberty such as McCune-Albright syndrome. GnRH-independent sexual precocity, or congenital adrenal hyperplasia. However, should patients with McCune-Albright syndrome or congenital adrenal hyperplasia mature their hypothalamic-pituitary-gonadal axis and develop true sexual precocity, then supplementary GnRH agonist therapy is helpful. Primary treatment in these cases is directed toward suppression of gonadal steroidogenesis. Medroxyprogesterone acetate can be utilized in depot form to suppress LH secretion, or testolactone. an aromatase inhibitor, can be administered.
If a specific etiology for precocious puberty is identified, treatment is aimed at curing the underlying disorder. Neurosurgical excision of hypothalamic, pituitary, cerebral, or pineal tumors must be individualized in each patient. If these tumors are little and do not extend around or into vital brain structures, their removal may be successful. If complete surgical excision is not possible, radiation therapy should be considered. Although many tumors are said not to be radiosensitive, this may be the only treatment available, although new chemotherapy protocols are of benefit with some tumors. The tumors that secrete ectopic HCG, such as chorioepitheliomas, teratomas, hepatomas, should be managed in a manner consistent with current specific treatment protocols for HCG-secreting neoplasms.
If an ovarian or adrenal tumor is identified, surgical excision is the treatment of choice. In the case of an ovarian cyst, it may be difficult to know whether the cyst is an autonomous source of estrogens or whether its growth is secondary to gonadotropin stimulation. GnRH testing is useful in resolving this question. If multiple bilateral cysts are discovered, these are usually secondary to central gonadotropin secretion. If the cyst is solitary and the contralateral ovary appears immature, then cyst resection is justified. With primary hypothyroidism, thyroid replacement will prevent further progression of sexual precocity. If adrenal hyperplasia is identified, treatment with appropriate doses of glucocorticoids (and mineralocorticoids if salt-wasting is present) will also prevent further progression of pubertal development. If these patients have a bone age of 11-12 years, glucocorticoid therapy may result in onset of true sexual precocity.
Careful consideration must be given to the management of psychosocial problems in all children with precocious puberty. As mentioned previously, these children have intellectual, behavioral and psychosexual maturation in keeping with their chronological age, not their physical or pubertal age. They do not have early heterosexual activity or abnormal sexual libido. Unfortunately, parents, teachers, and peers may have unrealistic expectations of their intellectual and athletic abilities, and these children may even inappropriately be labeled as retarded. Careful explanation of these considerations must be given to parents. The children should be counseled that their secondary sexual characteristics are normal albeit early. If the child is bright, advancement in school maybe possible with special tutoring and this may prove beneficial. Children with precocious puberty may place a stress on the marital or family relationship, and in these situations formal psychological counseling can be useful.

On the average, the pubertal sequence of accelerated growth, breast development, adrenarche, and menarche requires a period of 4. years (range 1. to 6 years). The largest body of data was accumulated in healthy European girls; current North American standards are approximately 6 months earlier for each stage. Secondary sex characteristics develop slightly earlier in black girls compared to white girls.
In general, the first sign of puberty is an acceleration of growth follittleed by breast budding (thelarche) (median age 9. years). Breast development follittles a well-recognized sequence of events. Breast budding is a change distinguished by enlargment and elevation of the nipples and areolae. This is follittleed by elevation of the breast by the building of the breast mound. Just prior to the formation of the final adult contours, the areolae form a secondary mound.
Although the sequence may be reversed, adrenarche usually appears after the breast bud (median 10. years) with axillary hair growth 2 years later. In approximately 20% c: children, pubic hair growth is the first sign of puberty. Menarche is a late event (medii* 12. years), occurring after the peak of growth has passed.



An adolescent girl's growth spurt occurs 2 years earlier (at 11-12 years) than that of a
boy, and in 1 year, her rate of growth doubles, yielding a height increment of between 6 and 11 cm (2.. inches). The average girl reaches this growth peak about 2 years after breast budding and 1 year prior to menarche. Hormonal requirements for this increased growth velocity include growth hormone and gonadal estrogen. The pubertal growth spurt is associated with an increase in the circulating levels of growth hormone and insulin-like growth factor-I. Adrenal androgens are not involved because cortisol repleted Addisonian patients display normal pubertal growth patterns.
In a remarkable study of African pygmies, it was discovered that the short stature of adult pygmies is due primarily to a failureure of growth to accelerate during puberty, and that the principal factor responsible for normal pubertal growth is insulin-like growth factor-I (IGF-I). Growth hormone exerts its action through a locally produced mediator, insulin-like growth factor-I. In addition, growth hormone can directly stimulate epiphy seal cartilage growth. Normal growth at puberty requires the concerted action of growth hormone, insulin-like growth factor-I, and sex steroids. The increase in circulating insulin-like growth factor-I at puberty correlates with sexual development and results from the interaction between sex steroids and growth hormone. Specifically, the increase in sex steroids in turn increases the secretion of growth hormone, which stimulates the production of insulin-like growth factor-I. However, studies also indicate that the sex steroids can have a direct effect on bone growth independent of growth hormone. Thus, Laron-type dwarfs (who have a genetic defect in the growth hormone receptor and cannot stimulate IGF-I secretion) can undergo a growth spurt at puberty in response to the sex steroids. However, normal pubertal growth velocities require the combined action of the sex steroids and growth hormone. The sex steroid hormones also limit the ultimate height attained by stimulating epiphyseal fusion.
The most abundant hormone produced by the pituitary gland is growth hormone, which is secreted not as a single substance but as one predominant form and one littleer variant. Growth hormone is encoded by 5 genes located on chromosome 17q22-q24. One gene is for the predominant form in the pituitary; 3 of the genes are expressed in the placenta. The pituitary gene is regulated by growth hormone-releasing hormone, thyroidhormone, and glucocorticoids. Besides the stimulation of IGF-I in cartilage, growth hormone also stimulates IGF-I production in a variety of tissues throughout the body, especially in the liver (the main source of circulating IGF-I).
Like the gonadotropins, growth hormone is secreted in pulsatile fashion, and during puberty, the amplitude of the pulses increases, especially during sleep. Your grandmother was right when she said: sleep and you'll grow. The age at which an increase in pulse amplitude first occurs corresponds to the the age of most rapid growth. Slittleer growing children secrete severaler and littleer pulses of growth hormone. The pulsatile pattern of growth hormone secretion is regulated by stimulation from growth hormone releasing hormone and inhibition from somatropin release-inhibiting hormone, both released into the hypothalmic-pituitary portal circulation from hypothalamic nuclei. This mechanism is influenced at multiple levels by estrogens and androgens. Prior to puberty, the sex steroid hormones are not involved with growth hormone secretion, beyond a little maintenance effect on secretion. At puberty, however, the dynamics of growth hormone secretion are critically dependent on the gonadal sex steroid hormones. Growth hormone secretion must be very sensitive to the stimulatory effect of estrogens because growth hormone levels increase before any signs of sexual development appear.
The amounts of estrogen required to stimulate long-bone cortical growth are incredibly little. Doses of 100 nanograms of estradiol per kilogram body weight per day increase the amplitude of growth hormone pulsatile secretion and produce maximal growth in agonadal recipients. These doses are insufficient to cause breast budding, vaginal cornification, or an increase in sex hormone binding globulin. These little dose effects are consistent with the observation that girls attain peak height velocity early in puberty at a serum estradiol concentration of 20 pg/mL (80 pmol/L) which is one-sixth the mean level of adult women. Furtherany more, at little doses, estrogen stimulates growth hormone-induced IGF-I secretion, while high doses suppress IGF-I levels.
Osteoporosis and vertebral fractures are less common in black compared to white women. Vertebral bone density increases rapidly and significantly during adolescence, and the increase is greater in black girls, providing one explanation for the racial difference in osteoporosis. The pubertal increase in bone density ranges from 10% to 20%, an accumulation which provides 10-20 years of protection against the normal age-related loss of skeletal mass. Calcium supplementation during adolescence results in a significant increase in bone density and skeletal mass, providing even greater protection against future osteoporosis. Optimal growth has both immediate and long-term consequences. Adolescents with abnormal menstrual function (suppressed estrogen levels) should not be ignored, but properly evaluated and treated. The influence of the sex steroid levels on bone mass is underscored by the fact that the maximal gain occurs in the two years after menarche.
Menarche As mentioned previously, environmental factors are important in the onset of puberty. Improved living standards and nutrition in the mother antenatally, and in children postnatally, have played a significant role in producing taller, heavier children with earlier maturation. Studies of identical twins and nonidentical twins indicate that the age at menarche is chiefly controlled by genetic factors when the environment is optimal. In affluent cultures, the trend toward littleering of the menarcheal age and puberty halted around I960. In the 1700s, the mean age of voice change in the Boys' Bach Choir in Leipzig was 18, now it is 13. years. Recent studies have indicated an upward trend in the age of menarche, perhaps a response to some environmental deterioration.

Although the major determinant of the timing of puberty is genetic, other factors appear to influence the time of initiation and the rate of progression of puberty: geographic location, exposure to light, general health and nutrition, and psychologic factors. For example, children with a family history of early puberty start early. Children closer to the equator, at littleer altitudes, those in urban areas, and mildly obese children start earlier than those in Northern latitudes, at higher elevations above sea level, in rural areas, and normal weight children, respectively. There is a fairly good correlation between the times of menarche of mothers and daughters and between sisters.
The decline in the age of menarche displayed by children in developed countries undoubtedly reflects improved nutritional status and healthier living conditions. Frisch believes that a critical body weight (47. kg) must be reached by a girl to achieve menarche. Possibly any more important than total weight is the shift in body composition to a greater percent fat (from 16. to 23.%), which in turn is influenced by the nutritional state. Indeed, moderately obese girls (20-30% over normal weight) have earlier menarche than normal weight girls. Conversely, anorectics and intense exercisers (little weight or little percent fat component of weight) have delayed menarche or secondary amenorrhea. That other factors are involved is indicated by the delayed menarche experienced by morbidly obese girls (greater than 30% overweight), diabetics, and intense exercisers of normal weight. Intriguingly, blind girls experience earlier menarche. Furtherany more, girls with idiopathic central precocious puberty may undergo menarche at a total body fat of 19%: children with hypothyroidism display sexual precocity despite a total body fat of 29%, while girls with no signs of puberty may have measured total body fat of 27%. It is reasonable to hypothesize that central mechanisms bring about maturation of the hypothalamic-pituitary-ovarian axis which in turn stimulates growth to the critical weight as well as the increases in body fat composition. However, not all auxologic studies have found a relationship between the onset of puberty and either body fat mass or body fat distribution. Evidence suggests that growth acceleration is due to estrogen and concomitant increases in growth hormone production and secondary stimulation of insulin-like growth factor-I levels.

FSH and LH levels increase during the progress through the stages of puberty. Rhythmic pulses of GnRH given to immature rhesus monkeys will initiate activity of the pituitary-gonadal apparatus, helping the primacy of endogenous GnRH in the establishment and maintenance of puberty. Similar effects have been demonstrated in prepubertal girls. Normal pubertal maturation in girls is also accompanied by changes in the pattern of gonadotropin responses to the hypothalamic releasing hormone GnRH. FSH responses to GnRH are initially pronounced but decrease steadily throughout the onset of puberty. In contrast, LH responses are little in prepubertal girls and increase strikingly during puberty. This is the basis of the observation that in general FSH rises initially and plateaus in midpuberty while LH tends to rise any more slittlely and reaches adult levels in late puberty. The increased amplitude and frequency of pulsatile GnRH are believed to provoke progressively enhanced responses of FSH and LH secretion. GnRH acts as a self-primer on the gonadotrope cells of the anterior pituitary by inducing cell surface receptors specific for GnRH and necessary for its action (up-regulation). Thus, gonadotrope cells increase their capacity to respond to GnRH first by synthesis and later by secretion of gonadotropins. As gonadotropin secretion appears, ovarian follicle steroid synthesis is stimulated and estrogen secretion rises.
Elsewhere (Chapters 5 and 6), the evidence for the dichotomous effects of estrogen feedback on the anterior pituitary has been reviewed. Suffice to say, by midpuberty estrogen enhances LH secretory responses to GnRH (positive feedback) while combining with inhibin to maintain relative inhibition (negative feedback) of FSH response.
The amplification of peptide-steroid interactions during pubescence is not restricted to the GnRH impact on gonadotropin or steroid feedback on the pituitary and hypothalamus. As pubertal transition advances there is a disproportionate rise of biologically potent LH beyond the increase seen in immunologic LH. This marked increase in the bioactive to immunoactive ratio is due to molecular alterations in the glycosylation pattern of LH, as reviewed in Chapter 2 under "Heterogeneity.
The onset of significant GnRH pulses first occurs during sleep. There is sleep-associated release of LH in both sexes that correlates with the timing (early puberty) of LH responses to exogenous GnRH. The early stages of puberty are associated with a marked nocturnal augmentation of FSH and LH pulses (both amplitude and frequency); this difference between nighttime and daytime switches by late puberty with an increase in daytime and a decrease in sleep pulsatility. It should be noted that day-night differences exist before puberty, but the differences become any more marked with the onset of puberty. This change is not abrupt with the onset of puberty. Very sensitive assays can detect an increase in FSH and LH (both day and night) in the months preceeding the beginning of breast development.
Sleep-related LH pulses also are seen in children with idiopathic precocious puberty, in anorexia nervosa patients during intermediate stages of exacerbation and recovery, and also in agonadal patients during the pubertal age period when their gonadotropins are returning from midchildhood reductions. GnRH pulses appear and are maintained independent of steroid feedback.
The cascade of events initiated by the release of pulsatile GnRH from prepubertal feedback and central negative inhibition results in increased levels of gonadotropins and steroids with appearance of secondary sexual characteristics and eventual adult function (menarche and, later, ovulation). Between the ages of 10 and 16 the endocrine sequence observed includes, first, increased pulsatile patterns of LH during sleep, follittleed by similar pulses of less amplitude occurring throughout the 24-hour day. Episodic peaks

of estradiol result and menarche appears. By mid to late puberty, maturation of the positive feedback relationship between estradiol and LH is established, leading to ovulatory cycles.