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The pubertal process is the period of transitional growth bridging the childhood years and adulthood. The genetic blueprint housed within the genome of the individual has long before set in motion a number of critical processes. The end result is the maturation of a multitude of endocrine axes necessary for (1) secondary sexual development and, (2) the attainment of the immediate capacity for reproduction. Intrinsic to this reproductive maturation is yet another important process of puberty: (3) a secondary wave of skeletal growth and the attainment of adult stature. Abnormal puberty, whether premature or delayed, may adversely influence each of these events resulting in an untimely or altered ability for spontaneous secondary sexual development and spontaneous reproduction or abnormal growth.

In recent years numerous advances have been made in molecular medicine and the assisted reproductive technologies. The impact of these advances has had a tremendous effect on the care of patients with abnormal puberty by: changing the initial counseling provided to our patients; allowing for new treatments during the time of altered pubertal growth; and, providing reproductive options to individuals previously known to be infertile and some considered sterile. In addition, new insight about the genetics of these disorders has been accumulated. The focus of this chapter will be on our expanded knowledge of both the genotypes and phenotypes of the disorders presenting as abnormal puberty.

NORMAL PUBERTY FOR GIRLS (ITS OCCURRING EARLIER!): A BASIS FOR THE DEFINITION OF ABNORMAL PUBERTY

Onset of Normal Pubertal Landmarks

The first somatic change associated with the initiation of puberty in girls is an increase in growth velocity. It is during the initial increment in growth velocity that the first sexual sign of puberty occurs. It has long been held that thelarche (breast budding) develops between ages 9-11 years for American girls and is usually followed by adrenarche, the appearance of pubic hair. Additionally, it was considered that in approximately 15% of adolescent Caucasian girls adrenarche preceded thelarche. However, it is important to remember that the normal sequence of pubertal signs as published by Marshal and Tanner was taken from studies of British Caucasian girls not long after WW II [1, 2]. A study of African girls in the 1970s, however, noted that for the majority of them adrenarche preceded thelarche. Even more important is the recent data published from the Pediatric Research in Office Settings Network [3]. This data was taken from a cross-sectional study of 17,077 American girls of whom 9.5% were African-American and 90.4% were Caucasian (note that Hispanic girls were included in both African-American and white groups). Surprisingly, nearly 30% of the African-American girls had evidence of breast and/or pubic hair development at age 7 years and nearly 50% by age 8 years. For Caucasian girls, 15% had started puberty by age 8 and nearly 40% by age 9. This data suggests that puberty is occurring earlier in American girls than has previously been thought; for both breast and pubic hair development, African-American girls are more advanced that are Caucasian girls at the same age. For African-American girls, pubic hair development begins slightly earlier than does breast development. While it is reasonable to consider that the British data is likely different from the heterogeneous American population at the end of the 20th century, the data of the recent Pediatric Research in Office Settings Network study has also been viewed with mixed feelings. Some have criticized the study for the methodology used in staging pubertal development. The examiners staged pubertal development on visual and not palpatory changes. While pubic hair assessment was likely accurate, it is possible that girls with "chubby chests" may have been miss-staged and, therefore, that the mean timing for onset of breast development reported in this study may be prematurely inaccurate.

After thelarche and adrenarche, growth velocity continues to increase and peak, a landmark termed the adolescent growth spurt. A peak height velocity of 9 cm/year is attained at that time. Subsequently, with near closure of the epiphyses there is a deceleration phase for growth. It is in this deceleration phase of growth that menarche occurs. The first menstrual period was previously reported to occur at an average of 12.8 years for American girls. The recent cross-sectional data demonstrated that while the average age of menarche for Caucasian girls remains unchanged, African-American girls start menstruation earlier and at a mean age of 12.16 years [3]. Since it often is at least 5 years after menarche, (i.e., nearly age 18 years) that the majority of menstrual cycles are ovulatory, we cannot consider that puberty is normal until this reproductive mechanism is well established.

Determinants of Normal Pubertal Growth

From conception to the fusion of epiphyses during the later stages of puberty, a number of maturational processes occur for formation and modeling of the skeleton. Intrinsic to these processes are the initial mesenchymal cell condensation and differentiation into cartilage that serves as a template for subsequent bone formation. Osteoblast differentiation occurs on the surface of this cartilaginous template and endochondral bone formation results when such differentiation occurs on calcified cartilage at the growth plate.

Both genetic and hormonal determinants exist which are critical for the attainment of adult stature. A number of genes have been identified which mediate bone growth. If all of these genes are functional, parental growth genes determine the final adult height attained by an individual. One can estimate this height by a calculation of mid-parental height. For females this is determined by subtracting 5 inches from the father's height, adding this to the mother's height and then dividing by 2. For males, this is determined by adding 5 inches to the mother's height, adding this sum to the father's height and then dividing by 2.

Under pathophysiologic situations, an individual may be taller or shorter than would be dictated by parental height determinants. Sometimes these differences are genetically determined and in other situations abnormal hormonal influences alter an otherwise intact genetic predisposition. For example, some statural genes are present on both X and Y-chromosomes with Y individuals being taller than X individuals. From tallest to shortest one can generalize the following: XYY > (taller than) XY > (taller than) XXX > (taller than) XX > (taller than) X individuals. A few genes have been implicated in these differences. One set of genes, the SHOX genes exist on the distal X chromosome [4-6]. Mutations have resulted in short stature and deletion of this locus is associated with short stature in Turner syndrome (45,X).

Hormonal Determinants of Growth (Some gene mediated)

No doubt, a normal endocrine environment critically influences bone growth. For example it is essential that intact and normal growth hormone and thyroid hormone production, among others, be present. This is demonstrated by the fact that growth hormone and thyroid hormone deficiency separately result in short stature until corrected [7]. Growth hormone excess results in such conditions as a gigantism and acromegaly.

In addition to these known growth-promoting hormones, sex steroids are essential for mediating the pubertal growth spurt and attainment of final adult stature. Premature sex hormone production in children with congenital adrenal hyperplasia causes premature epiphyseal growth and fusion: thus, tall as children and short as adults. Precocious puberty similarly causes premature pubertal growth with the risk of short adult stature unless corrected. The lack of pubertal development (delayed puberty) allows for continued long bone growth since the epiphyseal centers remain open longer than normal. Usually, in these situations, growth is normal until the expected age onset of puberty and the growth spurt is not noticed; however, linear growth continues in the absence of epiphyseal closure. This results in eunuchoid body proportions: an arm span which exceeds the height by >6 cm and disproportionately long legs.

While it had always been accepted that estrogen mediated pubertal bone growth in females, it was only recently that it was established that estrogen and not testosterone mediated the same function for males. Inactivating mutations in either the estrogen receptor gene or the aromatase gene (preventing conversion from androgens to estrogens) in males have resulted in lack of normal bone growth at puberty and lack of epiphyseal closure with resultant tall stature (i.e., taller than predicted) [8-11]. These findings establish that estrogen is essential for initiation of pubertal growth, closure of the growth plate, and augmentation accrual of bone during puberty. The presence of both alpha and beta estrogen receptors have been identified in the growth plate but the exact mechanism of action has yet to be delineated. Studies on estrogen receptor knock out mice are underway.

Definition of Abnormal Puberty

The definitions of abnormal puberty, whether premature or delayed, are based on those times that are considered to be 2.5 standard deviations removed from the mean. Previously, the definition of precocious puberty for girls was the appearance of secondary sexual development before the age of 8 years, an age felt to represent 2.5 standard deviations earlier than the mean. Recent revised recommendations have been made based on the findings of the Pediatric Research in Office Settings Network [12]. These new guidelines propose that precocious puberty be defined by the presence of breast or pubic hair development before age 6 in African-American Girls and before age 7 years in Caucasian girls. In addition to taking into consideration the findings of earlier puberty for American girls, treatment of precocious puberty in girls after age 8 years has not been shown to alter final adult stature. Recent reports of isolated cases of girls who were found to have a significant pathologic etiology which would have been missed had the physicians followed strictly the new definition guidelines, have been viewed by some as reason not to institute them [13, 14]. A more reasonable interpretation of the occurrence of these etiologies during later childhood years would be to follow the new guidelines only in the absence of other CNS findings or behavioral changes that would warrant evaluation and possible treatment and for those children not evaluated to always keep in mind this possibility.

Recommendations based on the findings of the Pediatric Research in Office Settings Network have not been made for revising the definition of delayed puberty in girls as they have for precocious. As such, the absence of thelarche by age 13 years for girls signifies an abnormality, and remains the definition of pubertal delay. While some patients present strictly with the absence of the onset of pubertal development, others have abnormalities in the tempo and sequence of puberty that has seemingly begun on time. For example, the absence of menarche by age 15 or 16 years is considered as 2.5 and 3 standard deviations deviated from the mean, respectively. It is equally as abnormal for a young girl who started puberty on time not to have had menarche by age 16 years as it is for another who never initiated the pubertal process.

Age definitions should be seen as only guidelines, and for delayed puberty, the age at which an evaluation should ideally have already been completed. Rather than wait until these young women meet the strict definitions for delayed puberty to initiate an evaluation, it has been suggested that all adolescents be followed annually throughout the pubertal process. It would be better to begin a partial evaluation during earlier adolescent years at the time that abnormalities are first suspected than it would to wait until these young women are significantly different from their peers. No doubt, adolescence is one of the most difficult time periods in growth and development. It is potentially very harmful for an individual's psychosexual development to allow significant delays in secondary sexual development or onset of menses to continue without evaluation, treatment and appropriate counseling. Given that puberty appears to be initiated earlier than previously recorded and the definition of pubertal delay has not yet been revised, it is even more important that one avoid the time-held reassuring delays of watchful waiting under the guise of being "a late bloomer!"

PRECOCIOUS PUBERTY

Overview

The classic definition of sexual precocity is the appearance of secondary sexual characteristics before the age of 8 years in girls. The overall incidence of sexual precocity for that definition has been estimated to be 1:5,000 to 1:10,000 children. The female to male ratio is approximately 10:1. Recent data from the Herman-Giddens study suggests that this age for girls falls less than two standard deviations from the mean [15]. These findings prompted the suggestion that the definition be changed and that the onset of puberty not be considered precocious unless it occurs prior to age 6 for African American girls or age 7 for Caucasian girls [12]. As discussed above, even when puberty occurs between these ages and age 8, it is important to consider evaluation of all children [13, 14]. The child may be suffering from a serious CNS disorder associated with precocious puberty [14]. In addition, psychosexual maturation remains concordant with chronological age, and unfortunately early physical sexual maturation places these young girls at a significant risk for sexual abuse. It is thus important not only to make a reasoned judgment as to when to initiate an evaluation but also to institute the appropriate therapy and support to prevent these potential long-term sequelae, even in selected girls who fall outside the new recommendations.

The appearance of the secondary sexual characteristics of precocity results from increased sex steroid production. This increase may be secondary to aberrant gonadotropin stimulation or intrinsic disease of the ovary or adrenals. True precocious puberty, also known as complete precocious puberty, refers to puberty that appears early and either progresses through each of the pubertal landmarks including menarche or, in the absence of treatment, would progress through each of these stages. A GnRH challenge test that demonstrates the pubertal response of gonadotropins (i.e., LH response > FSH response) is the hallmark of this diagnosis as is the usual ability to suppress pubertal development with GnRH agonists. Incomplete precocious puberty refers to the appearance of one phase of the pubertal process: thelarche, adrenarche, or menarche. Isolated precocious thelarche, isolated precocious adrenarche, and isolated menarche are the three forms of incomplete precocious puberty. Sexual precocity has been further categorized according to whether the pubertal signs are concordant or discordant with the sex of the individual: isosexual precocity referring to early sexual development consistent with the sex of the individual (i.e., feminization of a female); heterosexual or contrasexual precocity indicating precocious pubertal development that is limited to those physical signs not characteristic for the sex of the individual when presenting as isolated findings (i.e., virilization of a female). GnRH dependent and GnRH independent precocious puberty (GIPP) refer to those causes of precocity that do or do not respond to GnRH analogue treatment, respectively. Finally, central precocious puberty (CPP) refers to precocity of CNS origin. A summary of the causes of sexual precocity is presented in Table I below, followed by a numeric breakdown of the frequency of occurrence of these disorders in Table II.

In this review of 438 girls examined between 1988-1998, the incidence of central precocious puberty (CPP) was noted to be 97.7% and GnRH independent precocious puberty (GIPP) was 2.3% [16]. Neurogenic abnormalities were noted in 18.4%, and idiopathic CPP in 74% of the girls in this study. The frequency of neurogenic CPP tended to be higher in the youngest girls (i.e., those under 4 years of age) and the frequency of idiopathic CPP tended to be higher in girls presenting at older ages (i.e., between 7-7.9 years). Those girls identified with idiopathic precocious puberty after 7 years may, in fact, represent the recent observations of earlier onset of normal puberty by Herman-Giddens [3].

Central Precocious Puberty

This results from early maturation of the hypothalamic- pituitary-gonadal axis. Serum gonadotropins, gonadal pulsitality and sex steroid concentrations are in the normal postpubertal range. As mentioned previously, idiopathic precocious puberty seems to be the most common cause of CPP. Neurogenic CPP seems to be found more frequently in extremely young girls with the earliest onset of puberty. CNS lesions identified include neoplasms, trauma, hydrocephalus, postinfectious encephalitis, congenital brain defects, and such genetic disorders as neurofibromatosis type 1 and tuberous sclerosis. The most commonly identified neurogenic neoplasms found in CPP include hamartomas, astrocytomas, and pituitary microadenomas [16]. Hamartomas are congenital hypothalamic malformations that histologically contain fiber bundles, glial cells and GnRH- secreting neurons and often act as a mini-hypothalamus. Less frequently identified tumors include epipendymomas, gliomas, pinealomas. While the craniopharyngioma has usually been associated with delayed puberty, it can rarely cause precocity as well.

Girls with severe primary hypothyroidism can develop true precocious puberty. These girls have elevated gonadotropins in addition to high TSH levels. The associated precocity may result from cross-activation of the FSH receptor by the high circulating TSH or from direct stimulation of the ovary by the gonadotropins. Occasionally, treatment and correction of long standing virilizing congenital adrenal hyperplasia will be followed by the development of true precocious puberty. It has been hypothesized that GnRH secretion and gonadotropin stimulation of the ovary may ensue in these patients after the removal of hypothalamic androgenic suppression.

Contemporary Issues for Management of CPP

The management of true precocious puberty requires identification of underlying CNS lesions, if present, or in other children identification of a pubertal gonadotropin response to GnRH that is usually associated with idiopathic true precocious puberty and occasionally with a hamartoma. The mainstay, therefore, of evaluation is imaging of the CNS and a GnRH challenge test. In addition, bone age X-rays are helpful to identify the advance physiologic age associated with true precocious puberty. Ovarian imaging, thyroid and hCG testing may also compliment the evaluation. While some CNS lesions will need treatment, the majority of remaining causes of true precocious puberty (i.e., idiopathic) respond to GnRH analogues. It has also been demonstrated that precocity associated with hamartomas may be effectively treated with GnRH agonists [17].

Predicted height has been shown to improve with long-term GnRH agonist therapy and the absence of treatment is associated with reductions of these height predicitions, [18, 19]. Studies have consistently demonstrated that not all children with precocious puberty will benefit from the GnRH analogues [20]. Those children who do not benefit may have the following characteristics: slowly progressive puberty, the precocity of which does not adversely affected the child; a normal predicted height prognosis; and a lack of evidence for gonadal activation [21]. While consideration should be given to withholding treatment for these children, studies consistently demonstrate that girls presenting under age six are able to subsequently achieve normal adult height because of the GnRH agonist therapy [22, 23].

GnRH agonist therapy initially increases circulating gonadotropin and estradiol concentrations for short periods of time. Chronic therapy is associated with suppression of pulsatile gonadotropin secretion and a blockade to the LH response of endogenous GnRH. Suppression is best monitored with GnRH challenge tests. Additionally, measurement of serum estradiol (if elevated on prior analysis), height, bone age, and assessment of secondary sexual characteristics may be helpful. Evaluation of ovarian morphology and uterine size by pelvic ultrasonography may, in some cases, provide additional evidence of such suppression. Cessation of menses, regression in physical pubertal signs (i.e., breast size and pubic hair), and a diminution of uterine and ovarian size usually occur within the first 6 months of therapy. True precocious puberty has been associated with the same GH secretory dynamics that accompany normal puberty; use of GnRH agonists generally decreases this aberrant and increased GH secretion. Since some have suggested that GnRH analogue treatment may significantly suppress growth velocity enough to compromise the predicted improvement in height, studies have been performed to evaluate whether addition of GH to GnRH analogue treatment will be beneficial [24].

Incomplete, Isosexual, or Gonadotropic Independent Preococious Puberty (GIPP)

GIPP can originate from the gonads, the adrenals, from extragonadal or intragonadal sources of human chorionic gonadotropin, or from exogenous sources. In girls, functionally autonomous ovarian cysts are the most common cause of GIPP. Ovarian follicles up to 8mm in diameter are common in normal prepubertal girls and may appear or regress spontaneously, but rarely secrete significant amounts of estrogen [25, 26]. A recent finding of the somatic cell mutation associated with McCune Albright syndrome in the cells of one such cyst sheds new light on this occurrence [27]. GnRH agonists are not effective in treating autonomous cysts. Medroxyprogesterone acetate has been utilized.

Juvenile granulosa cell tumors or theca cell tumors of the ovary are a rare cause of GIPP. Other ovarian neoplasms even more rarely seen in this age group that may also secrete either estrogens an/or androgens include gonadoblastomas, lipoid tumors, cystadenomas, and ovarian carcinomas [28]. Peutz-Jeghers syndrome has been associated with GIPP; the mucocutaneous pigmentation and gastrointestinal polyposis seen in this disorder has been rarely associated with gonadal sex-cord tumors [29].

McCune-Albright syndrome classically includes the triad of hyperpigmented café-au-lait spots, progressive polyostotic fibrous dysplasia of the bones and GnRH-independent sexual precocity [30]. At least 2 of these features must be present to consider the diagnosis. This disorder is caused by postzygotic somatic cell mutations of the gene encoding the alpha-subunit of the stimulatory guanine nucleotide binding protein Gs. These activating mutations stimulate constitutive G protein activation in affected cells with aberrant cyclic AMP production [31]. The mutations may occur at various times in fetal development with a patchy tissue distribution of affected cells. Each of the associated findings is affected by these mutations: granulose cells in the ovary, melanocytes of the skin [32], and the dysplastic bone cells [33, 34]. In addition to the classic triad, other endocrine cells may also be similarly affected and associated with their autonomous hyperfunction: pituitary adenomas, usually growth hormone secreting, hyperthyroid goiters [35], and rarely adrenal hyperplasia [36]. Another recent finding is the presence of these same somatic cell mutations in cells from isolated hyperfunctioning ovarian cysts of GIPP patients who do not exhibit other findings of McCune Albright Syndrome [27]. This may account for the findings of "ovarian hyperfunction" in patients with GIPP as reported in the series of Table II above [16].

The sexual precocity of McCune Albright syndrome is due to autonomously functioning follicular cysts. These patients can progress form GnRH independent to GnRH dependent puberty; when their bone age reaches the physiologic age of the normal time-onset for puberty, awakening of the arcuate nucleus for pulsatile GnRH secretion may occur and progress to the establishment of ovulatory cycles. Testolactone, an aromatase inhibitor, has been shown to be effective treatment for the GnRH independent phase of this condition. When the shift from gonadotropin independent to gonadotropin dependent puberty takes place, GnRH analog therapy then becomes effective.

Iatrogenic sexual precocity

In prepubertal children, exogenous intake of estrogen has been shown to cause precocious pubertal development. A number of estrogen containing products have been previously reported including hair products, lotions, and creams. Ingestion of estrogen containing meat has also been implicated. In actuality, these causes are extremely rare today.

Premature Thelarche

Isolated precocious thelarche is a common entity and associated with unilateral or bilateral breast enlargement without other signs of sexual maturation. It occurs at early ages up to 4 years and regresses spontaneously after diagnosis [37]. Gonadotropin levels rise in the newborns after delivery and remain elevated for up to four years of age. While most newborns rarely exhibit a dramatic ovarian response to these elevated levels, it is likely that isolated precocious thelarche is a result of this physiologic process. The uterus remains prepubertal in size during this time, however, the ovaries may develop temporary follicular activity, often correlating with the breast enlargement. This is usually a benign self-limiting disorder not associated with bone age progression.

Premature Menarche

Premature menarche has been reported as periodic vaginal bleeding without other signs of secondary sexual development [38]. While this entity has been repeatedly yet rarely reported, pediatric vaginal bleeding can occur as the first manifestation of sexual precocity in most causes of GIPP listed above. These etiologies should be excluded before one considers premature menarche as the diagnosis.

Contrasexual precocity

Virilizing precocious puberty in girls and isolated precocious adrenarche

Most girls with contrasexual precocious puberty present with early appearance of pubic hair or hirsuitism. The most common cause is a mild form of 21-hydroxylase deficiency, which is present in 0.1-1.0% of the population. Other more rare forms of congenital adrenal hyperplasia have also been identified in these patients. Virilizing adrenal (occasionally malignant) and ovarian tumors (e.g., Leydig or Sertoli cell tumors) in young girls can similarly present with virilizing precocious puberty. In actuality, most girls with appearance of pubic hair likely have isolated precocious adrenarche. While many of them have only early yet normal pubertal development [3], recent evidence shows that the prevalence of ovarian hyperandrogenism, hyperinsulinism and dyslipidemia is increased in this population [39]. These findings suggest that that premature pubarche in girls may be a childhood marker for insulin resistance and polycystic ovary syndrome.

DELAYED PUBERTY

An Overview of Delays within the H-P-O Circuit (Delays of Secondary Sexual Development and Menarche)

Several large descriptive studies have been published which have categorized the causes of pubertal/ menarchal delay. In 1981, a series of 252 female adolescents evaluated over 20 years at the Medical College of Georgia from a large referral area in Georgia was published [40]. It included all patients seen with either delay of the onset of puberty or menarchal delay. The series was subsequently expanded to include 326 patients. In this series the most common causes of abnormal puberty were: (1) ovarian failure (42%); (2) congenital absence of the uterus and vagina (14%), and (3) constitutional delay of puberty (10%). While these 3 disorders comprised 2/3 of all patients seen, a host of less frequent disorders was also diagnosed (see Table III below); the most common of these included PCOD and idiopathic hypogonadotropic hypogonadism (IHH), both at 7% each.

In April of 2002, a contemporary series of both male and female patients evaluated for delayed puberty at Children's Hospital in Boston between 1/96 and 7/99 was published [42]. This study, like the MCG study, included patients with delayed onset of puberty; it, however, did not include patients with menarchal delay. For the females reported (N=74), the 3 most common causes were: (1) constitutional delay of puberty (30%); (2) ovarian failure (26%); and permanent hypogonadotropic hypogonadism (20%). Over 20 other numerically less frequently reported disorders were identified and listed below (see Table IV).

Numerical and physical clues to the disorders presenting with delays in pubertal development: organizing the approach to the patient

The numerical findings in these series point out several useful facts. First, most practitioners confronted with females presenting with pubertal delays can identify a few disorders that present in the majority of patients: ovarian failure, constitutional delay, and permanent hypogonadotropic hypogonadism (as frequent causes of delayed onset of puberty) and vaginal agenesis (as the most frequent cause of menarchal delay). Rather than wait until the ages defining female pubertal or menarchal delay (ages 13 and 15 or 16, respectively), a physical examination with inspection of the introitus, plotting the patients on growth charts (longitudinal and velocity), and obtaining gonadotropins values will identify many of these disorders even before these age definitions are met. Idiopathic hypogonadotropic hypogonadism (IHH), however, is the exception being more difficult to diagnose in the younger patients. It is often a diagnosis of exclusion in the late teenage years. Second, the "late bloomer" occurs in less than 1/3 of patients in any series. While constitutional delay is a frequent cause of delayed puberty in females it does not occur with the very high frequency seen in males (i.e., approximately 2/3 of patients). For 2/3 of female patients, disorders with more serious implications are usually found! Finally, pubertal delay can be an ascertainment for the identification of a rare disorder (See Table 2). Similarly, should any diagnosis be made during childhood years and in advance of the time for normal puberty, plans can be made prior to the pubertal years to allow for the most normal pubertal progression as is possible. At least in the Children's Hospital setting, this appears to be the case for Turner syndrome.

The physical findings of the patients in these series also provide clues for helping us to form a differential diagnosis and organizing our diagnostic approach. First, classification according to estrogen as in the MCG series allows for a separation of major etiologies.

The absence of breast development suggests a cause of hypogonadism: ovarian failure or a hypothalamic-pituitary problem. The practitioner can further narrow these possible etiologies by obtaining an FSH level; high levels suggest ovarian failure and low normal values direct one to etiologies that have their effect at the level of the hypothalamus or pituitary. The presence of breast development usually directs one towards causes of menarchal delay suggesting the ongoing production of estrogen. One should remember, however, that some patients may have initiated puberty only then to have this process (and estrogen production) suppressed. A vaginal smear which demonstrates greater than 15% superficial cells or a positive progestin challenge test will confirm the suspicion of ongoing estrogen production. Patients demonstrating breast development but not evidence of ongoing estrogen production by either of these two tests should be treated like any other hypogonadal patients.

Second, absence of pubic hair after age 13 years is a very significant clue of several specific abnormalities. Pubic hair growth results from both adrenal and gonadal androgen production. One should remember that even when the H-P-O circuit appears delayed, the H-P-A (adrenal) circuit should still be functioning and providing adrenal androgens. For most disorders of delayed onset of puberty, at least some pubic hair should be present because this H-P-A circuit is unaffected by the defect (ovarian failure and IHH). When pubic hair is absent after 13 years, it suggests a defect of: (1) pituitary function (i.e., the inability to stimulate both ovarian and adrenal androgen production as in pituitary insufficiency); (2) steroidogenesis (i.e., the inability to convert cholesterol to androgens as in 17-hydroxylase deficiency); or (3) androgen receptors (i.e., the inability to translate the hormone signal into end organ androgenization as in androgen insensitivity syndrome or AIS). The first two of these disorders occur in the hypogonadal patients (Tables III and IV) and demonstrate defects within both H-P-O and H-P-A circuits, the common denomonator being pituitary insufficiency or a steroid enzyme block. When examined they are found to have a nomal mullerian system. Androgen receptor defects are found in patients with normal breast development and absence of the vagina (i.e., Androgen Insensitivity Syndrome (AI S)). Thus, for the patient with absent pubic hair after age 13, the most critical portions of the examination include the breasts and introitus.

Third, the apparent absence of a mullerian system (i.e., vaginal agenesis) can occur for either 46,XX or 46,XY patients. However, an examination, not a karyotype, is the most cost effective initial screen. Patients may present with absence of the vagina yet also demonstrate normal pubertal breast and pubic hair development. If a rectal examination is unrevealing for them, the likely diagnosis is congential absence of the uterus and vagina (CAUV) also known as mullerian aplasia or Rokitansky-Keuster-Hauser syndrome. If, instead, a bulging midline mass is identified just above the "absent vagina," the patient likely has either a transverse vaginal septum (TVS) or imperforate hymen. None of these findings warrant chromosomal studies as they clinically suggest the presence of a 46,XX karyotype. The patient found to have breast development and absence of both pubic hair and a mullerian system likely has AIS. These later findings alone warrant a karyotype to confirm the 46,XY compliment and the need for gondadal extirpation.
Fourth, identification of stature significantly shorter than one would expect for an individual whose growth was interrupted only by the delayed onset of puberty often reveals a genetic cause of both disorders (e.g., Turner syndrome) or an endocrine cause which stopped growth several years earlier than the usual time onset for puberty in addition to preventing or slowing the onset of secondary sexual development (i.e., growth hormone deficiency, thyroid deficiency, or pituitary insufficiency).

DISORDERS IDENTIFIED IN PATIENTS WITH EITHER DELAYED PUBERTY OR MENARCHE

The remainder of this chapter will address specific concerns of the most common causes of the pubertal abnormalities identified in the two series described above. It will primarily refer to the data of the MCG updated series of 326 patients presenting with either delayed pubertal onset or delayed menarche tabulated in Table III and classified according to Table V above [41]. In addition to discussing the common findings associated with these etiologies it will point out recent findings from molecular medicine and summarize contemporary treatment strategies.

Hypogonadism

Hypergonadotropic Hypogonadism

The single most common cause of delayed puberty in all prior delayed puberty series has been primary ovarian failure [40, 41]. Forty three % of all patients seen in the MCG series had hypergonadotropic hypogonadism. The fact that ovarian failure presenting at puberty was numerically less frequent (i.e., 26%) in the recent Children's Hospital series suggests that more children are being diagnosed with Turner syndrome and other forms of ovarian failure before the adolescent years and that treatment may be presently initiated at an earlier age [42].

Turner syndrome

Numerically, more patients with ovarian failure and delayed puberty have a form of Turner syndrome than they do with either 46,XX or 46, XY gonadal dysgenesis. Approximately 30% of the Turner patients have the classic 45,X karyotype with the remainder of patients having mosaic forms of Turner syndrome (Table VI below). Mosaicism refers to the presence of two or more cell lines, which originated from a single cell line. Patients with mosaic forms of Turner syndrome usually have a 45,X cell line associated with another cell line such as 46,XX or 46,XY. Other cell lines exist which represent structural abnormalities of the X chromosome such as isochromosome for the long arm of X, i.e., [i(Xq)] ; they may occur either as single cell lines or as mosaicism in association with 45,X.

All of the chromosomal findings in mosaic and non-mosaic patients with Turner syndrome have a common denominator: privation of either the entire X chromosome or a portion of the X chromosome. Fetuses with Turner syndrome have as many germ cells at mid gestation as do 46,XX fetuses. However, because of the absence of ovarian determinant genes accelerated loss of germ cells occur. Many of these individuals lose all of their germ cells before birth. Some of them lose the remaining germ cells during childhood years and before puberty. Less than 15% of patients with Turner syndrome will lose their germ cells either during or after the pubertal process [40]. Five % of patients with Turner syndrome will have enough germ cells remaining at puberty to not only initiate the pubertal process but also have regular, cyclic menses during at least a portion of their adolescent or adult years and 1% may spontaneously become pregnant.

Once the germ cells are prematurely depleted from the ovaries, the only remaining tissue present is the connective stroma of the gonads. It is usually a ribbon of white connective stroma located beneath the fallopian tubes and along the pelvic sidewalls. These residual gonads have the appearance of "streaks" and are referred to as streak gonads. The presence of a Y cell line in a patient with Turner syndrome brings with it a 15-25% risk of developing malignant germ cell tumors within those streak gonads. In those particular patients the streaks need to be surgically removed as soon as a diagnosis is made. For all other patients with Turner syndrome, privation of X chromosomal material is associated with the variable stigmata noted in Turner patients, cardiovascular and renal abnormalities, and the development of a number of specific medical problems. Turner stigmata include high arched palate, low hair line and webbed neck, multiple pigmented nevi, short fourth metacarpals, shield chest, increased carrying angle of the arms (cubitis valgus) and lymphadema of ankles to name a few. While these stigmata related to loss of X-chromosomal material are variably present and phenotypic-karyotypic correlations cannot be made [43], one consistent finding for these patients is limited adult height [40]. The MCG series was reported prior to the treatment of Turner patients with growth hormone. The fact that none of the patients in that series was taller than 63 inches in height supported the tenet that statural genes were surely located on both arms of the X chromosome. The knowledge of consistent short adult stature, often under 5 feet, and the potential psychological effect it has in combination with other features of Turner syndrome, provided impetus for identifying therapies independent from estrogen treatment for these patients. Many hundreds of Turner patients have now been treated with growth hormone pushing the final adult stature beyond this 63-inch mark for some and certainly past the predicted final height for many other women. Cardiac malformations have been reported to exist in up to 50% of patients and include coarctation and bicuspid aortic valves (separately between 30 and 45% incidence), and dilation of the ascending aorta [44]. The later pathophysiologic entity appears to be acquired in at least 10% of patients in one series and unfortunately has usually resulted in the past in misdiagnosis and death after dissection and rupture of the ascending aorta [44]. It is associated with the pathohistologic entity of cystic medical necrosis of the vessel wall, the culprit of similar clinical outcomes in patients with Marfan syndrome [44]. The recent reports of at least 4 deaths during or immediately after pregnancy in Turner patients who became pregnant from oocyte donation and embryo transfer suggests a special risk to these patients from the increased cardiovascular demands of pregnancy [45].

Horseshoe kidney is the most common renal abnormality seen in Turner patients. A number of autoimmune disorders have been identified in patients with Turner syndrome, the most common being Hashimoto thyroiditis and rarely diabetes.

Normal Chromosomes

The second largest group of young women with primary ovarian failure has a 46,XX karyotype (46,XX gonadal dysgenesis). For them, a few have a genetic etiology. In particular, an autosomal recessive form of this disorder was previously suggested by the presence of sibships reported in which several non-twin sisters are affected with ovarian failure [40]. While an autosomal recessive form may well exist, the recent finding that approximately 14% of familial cases of 46,XX ovarian failure have permutations for the fragile X syndrome makes this genetic cause identifiable [46]. A number of known genetic disorders have also been associated with ovarian failure including myotonia dystrophica, ataxia telangectesia, galactosemia, and more recently and numerically more frequently, permutations of the fragile X gene. Infiltrative diseases such as mucopolysaccharidoses have also been associated with primary ovarian failure. It is considered that environmental etiologies such as childhood viral illnesses may also cause premature depletion of oocytes from the ovaries. This is suspected in identical twins reported to be discordant for ovarian failure [40]. While mumps can cause orchitis in males, it is suspected that viruses such as mumps may cause oophoritis and loss of oocytes as well. Patients previously treated for childhood malignancies such as Wilms tumor, may develop germ cell depletion as a result of radiation therapy or chemotherapy (e.g., alkylating agents). Probably the most common cause of premature primary ovarian failure in women with a 46,XX karyotype is autoimmune. For the group of patients for whom an abnormality is not identified, autoimmune is considered the most likely cause. These patients have an increased risk for developing other autoimmune endocrine abnormalities such as Hashimoto thyroiditis, hypoparathyroidism and adrenal insufficiency. In addition, pernicious anemia has been reported in some of these patients. They should be screened on a routine basis for hypothyroidism and the other endocrinopathies if symptomatic.

As one would suspect, in the absence of a genetic etiology for depletion of the oocytes, more patients present at puberty with residual germ cells after the initial insult. In the MCG series of patients, nearly 40% of them had enough follicles at puberty to mount a pubertal response before presenting with amenorrhea and ovarian failure [40]. A number of patients with 46,XX gonadal dysgenesis will actually go through the pubertal process and have cyclic menses before developing ovarian failure and amenorrhea in their late teens or 20's.

Rare patients present with 46,XY gonadal dysgenesis. These are patients who likely have mutations in a gene controlling testicular morphogenesis such as the SRY gene, which initiates testicular development in-utero. In the absence of testicular development, the germ cells that arrive at the genital ridge will organize in the cortical, rather than medullary region of the undifferentiated gonad. For these patients with a 46,XY karyotype, however, germ cell loss is complete before birth. Since they never develop testes, they will not produce mullerian inhibiting substance to ablate the developing mullerian system. They will also not produce androgens to allow for masculinization of the external genitalia. These 46,XY individuals have Swyer syndrome and at birth have a normal female phenotype with a normal vagina, uterus and fallopian tubes. At puberty, they do not initiate pubertal development and are found to have elevated gonadotropin levels. These 46,XY individuals have the highest risk for developing germ cell tumors of their streak gonads of any individuals with gonadal dysgenesis and a Y chromosome cell line. The streaks must be removed as soon after diagnosis as is reasonable. They do not have other phenotypic abnormalities like the patients with Turner syndrome. They are often tall because of the presence of a Y chromosome.

Molecular Findings

While Turner syndrome is considered to result from haploinsufficiency of critical loci or regions of the X chromosome and a number of putative genes have been identified, a molecular understanding of mechanisms involved is far from understood. A number of the stigmata and malformations of Turner syndrome have been thought to be caused by edema present during development because of an abnormal lymphatic drainage to the heart. As such, the abnormalities are actually deformations. For example, edema of the nail beds causes nail hypoplasia, edema of the neck causes cystic hygromas and webbed neck, and edema of the kidneys prevents them from migrating around the aortic bifurcation and results in horseshoe kidney. The presence of cystic hygromas during fetal life is also associated with coarctation of the aorta; lymphatic drainage back to the heart is sufficiently abnormal during development to cause this cardiac malformation. One region of the X chromosome, Xp11.2-p22.1, has been thought to include "Turner syndrome loci", as a number of associated features including ovarian failure, short stature, high-arched palate, and autoimmune disease have been mapped here [47]. Deletions of the X-chromosome linked SHOX gene has explained many of the dysmorphic skeletal features of Turner syndrome including the short stature [6].

Prior karyotypic/pheontype correlations have suggested that the proximal regions of both the p and q arms of the X chromosomes are most critical for maintenance of the germ cell compliment [43]. However, terminal deletions at the telomeric regions of these arms are also associated with oocyte depletion, although to a lesser degree. Deletion of these regions are more likely to result in premature ovarian failure after some period of ovarian function rather than a complete loss of germ cells evident at the start of the teenage years as is seen with the proximal deletions. While putative genes such as POF1 [48], POF2 [49, 50], the human homologue of the Drosophila melanogaster diaphanous gene, and the fragile X locus have been recently implicated for these ovarian determinants, the mechanisms mediated by their gene products which normally allows for ovarian development and preservation are far from understood [46]. It would appear that a double dosage of these genes is required for normal ovarian function. Interruption, deletion and likely mutation of such ovarian determinant genes, even on one X chromosome, results in premature loss of germ cells from the ovaries. It is possible that mutations within these loci are responsible for ovarian failure in women with intact X chromosomes. The most studied of them is the FMR 1 gene, the locus mutated by a CGG triple nucleotide repeat expansion in fragile X syndrome. As in many triple nucleotide repeat disorders, areas of normal repeat sequence may be predisposed to expansion during or before meiosis. Function of the gene is maintained within a given number of these triple repeats but when a certain threshold is reached gene function may be adversely altered. For the fragile X gene, a CGG repeat sequence occurs with up to 60 such repeats being normal. Expansion to over 200 such repeats leads to fragile X syndrome; the high level of repeats causing hypermethylation of the promoter and silencing of the gene. Interesting observations were made that female carriers of the permutation of this locus, an unstable intermediary level of repeats (i.e., 60-199), often had premature ovarian failure. Recent evidence suggests that this premutaton is associated with a 21 fold greater chance of developing premature ovarian failure and that 2% of sporadic and 14% of familial ovarian failure patients harbor this unstable intermediate trinucleotide repeat. Another triple repeat disorder that has been associated with premature ovarian failure is myotonic dystrophy.

Our understanding of Swyer syndrome (46,XY gonadal dysgenesis/ sex reversal) together with 46,XX sex reversal helped to identify the SRY gene on the Y chromosome short arm [51]. Expression of this gene appears to be one of the first signals in the process of testicular morphogenesis. Approximately 15% of women with 46,XY gonadal dysgenesis have been found to have mutations in this gene [52, 53]. The fact that the remaining 46,XY gonadal dysgenesis patients have intact Y chromosomes and that only rare 46,XX true hermaphrodites studied have been found to harbor SRY sequences provides evidence that other genes are present and necessary either upstream or downstream in expression to SRY. Mutations of WT 1 [54, 55], SOX9 [54, 56-59], DSS [60], SF-1 [61], and DAX-1 [59] have all been associated with specific syndromes and 46,XY sex reversal. Of these, the most frequently reported and best characterized involves the SOX-9 gene and the accompanying syndrome of Campomelic dwarfism.

A molecular understanding of genes involved in steroid signaling and production has clarified better those disorders that present as pseudo-ovarian failure. Several classic hypergonadotropic hypogonadal syndromes have been long described for which germ cell depletion is not the cause of the elevation of gonadotropins. Rather, in these patients, the inability for steroid production is the cause of the hypergonadotropic state; hence the classification of ovarian failure. The first such classic syndrome, Savage syndrome, was initially described as gonadotropin resistance. More recently a number of families have been identified in Finland in which 46,XX individuals with gonadotropin resistance have been found to be homozygous for a single mutation of the FSH receptor gene [62-64]. Subsequently, other 46,XX hypergonadotropic patients have been identified with mutations in the LH receptor [65-69], the FSH b [70, 71], and the LH b genes. Overall the result of these disorders is a lack of estrogen production and variable hypergonadotropic states. 46,XY individuals with homozygous or compound heterozygous mutations of the LH receptor gene do not masculinize in-utero and present during adolescence with a female phenotype, delayed puberty, and hypergonadotropic hypogonadism. Their gonads, however, are testes not ovaries. The second classic hypergonadotropic state that has long been described in association with otherwise normal gonads is 17 a-hydroxylase deficiency. Both 46,XX and 46,XY individuals present with delayed puberty and a female phenotype, and ovaries and testes, respectively. Mutations have been also found in this gene [72, 73]. More recently mutations of the aromatase gene in 46,XX individuals have been similarly identified and associated with delayed puberty and hypergonadotropism in these individuals [8, 74-76]. In contradistinction to the other hypoestrogenic syndromes, aromatase deficiency, however, is associated with elevations of androgens in-utero and at puberty and the predictable but variable degrees of masculinization in these otherwise phenotypic females.

Contemporary Issues for Management

Patients identified with ovarian failure will need evaluation for associated medical disorders. For Turner syndrome, the most commonly identified acquired medical condition is Hashimoto thyroditis. For them, the most dangerous abnormalities involve cardiovascular malformations. While previously it has been well known that coarctation of the aorta occurs more frequently for these patients as does bicuspid aortic valves, it is now evident that these patients are at increased risk of developing dilation of the ascending aorta (and less commonly at other vascular sites) with subsequent dissection and, if undiagnosed and untreated, rupture. Like patients with Marfan syndrome, they appear to have cystic medial necrosis as the predisposing vascular histopathology. Similar to Marfan syndrome, the increased cardiovascular demands of pregnancy also appear to increase significantly this risk. It is recommended that cardiac ultrasound studies be performed every 3 - 5 years and perhaps during each trimester of pregnancy if patients are willing to take a risk estimated to be at least 2% for maternal mortality. Recommendations for counseling and pregnancy by donor oocytes are being developed and will be forthcoming from the American Society of Reproductive Medicine. All Turner patients should be counseled about their increased risk of dilation, dissection and rupture of the ascending aorta. Since most previous deaths occurred after misdiagnosis, Turner patients should be counseled to make health care providers aware of this possible diagnosis when being evaluated for disproportionate symptoms of indigestion and upper abdominal or chest pain. It is possible that most deaths could have been avoided with timely diagnosis and surgical repair. Turner syndrome patients need evaluation for horseshoe kidney and occasionally for other less frequently diagnosed autoimmune disorders such as diabetes.

Treatment of patients with Turner syndrome includes not only hormone replacement for pubertal progression and health maintenance at least through age 50 years, but an even earlier consideration for growth hormone treatment. While there have been some conflicting reports, general consensus is that the use of growth hormone for enhancing adult stature is a worthwhile endeavor [77-84]. The initiation of estrogen therapy at an age concordant with normal endogenous ovarian production, i.e., at least by ages 9 to 11 years, has always been considered important for normal psychosexual development of the adolescent. However, it is also believed that such early estrogen replacement might also result in an earlier closure of epiphyses and a potential limitation of final adult stature. The use of growth hormone therapy initiated during the childhood years may allow a more normal childhood stature (concordant with mid parental height) and the earlier initiation of estrogen therapy obviating these concerns [80, 85, 86].

Patients with 46,XX gonadal dysgenesis should be evaluated for premutations of the fragile X gene. This finding should prompt counseling for themselves and other family members and limit use of their similarly affected sisters as oocytes donors. In addition, 46,XX ovarian failure patients should be screened regularly for the development of Hashimoto thyroiditis and, with symptoms, for hypoparathyroidism, adrenal insufficiency, and other autoimmune disorders such as pernicious anemia. All gonadal dysgenesis patients with a Y cell line need extirpation of their gonads including Turner patients with 45,X/46,XY (or those with a Y chromosome fragment) gonadal dysgenesis and the 46,XY Swyer syndrome patients. One should remember that rare patients with seeming 45,X single cell line Turner syndrome might have undetected mosaicism for a Y cell line. Screening 45,X single cell line patients and those individuals with an unidentified chromosomal fragment with Y-DNA centromeric probes may be prudent to uncover those additional individuals at-risk for gonadal malignancies.

All patients with premature gonadal failure need estrogen therapy for initiation and completion of pubertal progression and subsequently for the maintenance of a multitude of health processes. While the continued accrual and remodeling of bone is of utmost importance, it remains likely that numerous other physiologic processes are dependent on normal estrogen status as well, at least through 50 years of age. The recent findings and concerns for long term hormone replacement of the Women's Health Initiative do not apply to these or any other patient prior to the age of 50 years and should not be used to prematurely stop their hormone replacement. Counseling is of utmost importance for these individuals and should cover expectations for all aspects of these young women's lives including alternatives for reproduction. While the use of donor oocytes and IVF has proven safe for 46,XX and 46,XY gonadal dysgenesis patients, a maternal death rate of up to 2% may exist for the Turner syndrome patients. While it is often easier to include this form of pregnancy as an alternative during counseling, until more information is available such discussions should be framed with these concerns. One should also turn to patient guidelines of national organizations such as the American Society for Reproductive Medicine (ASRM) and the American College of Obstetricians and Gynecologists (ACOG) as they are developed about these issues. The use of "buddy programs" in which these patients are paired with others who have previously confronted the same issues during adolescence and support groups (e.g., Turner Syndrome Society) is an excellent compliment to this counseling.

Hypogonadotropic Hypogonadism

A number of young women will present with delay of the onset of pubertal development who have no evidence of ongoing estrogen production, because something has interrupted either GnRH or gonadotropin secretion from the hypothalamus/pituitary. Patients with constitutional delay of puberty represent the most common of these disorders. Other disorders are clearly congenital or acquired.

Constitutional delay

Constitutional delay of puberty refers to a common condition for which patients will go through puberty but at a time that is more than 2.5 standard deviations delayed from the mean (Tables III and IV) [40-42]. A number of these patients often have a family history of delayed puberty [42]. Their physiologic age (i.e., bone age) lags behind that of their peers and is manifested by a delay in the adolescent growth spurt and temporary short stature. At a physiologic age of 9-11 years, they will enter the pubertal process. Most of these patients present between 13 and16 years of age and at that time have very early signs of thelarche. Their gonadotropins are in the low to normal range and their workup is otherwise unrevealing. An intravenous GnRH challenge test will usually confirm early awakening of the hypothalamic-pituitary-ovarian circuit by demonstrating a pubertal gonadotropin response, i.e., a greater release of LH than FSH. Such a response is seen only after endogenous GnRH secretion occurs and puberty is in its very early stages. At the same time, this early gonadotropin release produces the multifollicular ovarian appearance of early puberty; the ultrasound appearance of which is likely as reassuring that puberty will march onward as is the LH response of a GnRH challenge.
In males, 60% of pubertal delay is constitutional. In females, however, no more than 30% have this benign reproductive condition. While constitutional delay represents a leading cause of female pubertal delay, prior emphasis on this statistic has led to the false diagnosis for many young women and the misguided reassurance that they were simply "late bloomers." As many as 2/3 of females presenting with delayed puberty will have an irreversible etiology for reproductive failure, not constitutional delay [40]. For this reason, any patient presenting with delayed puberty and given the label of constitutional delay should be scrutinized very carefully for other etiologies, especially if they are beyond age 16 years and have yet to initiate pubertal development. Hopefully, in this century, it will be the exception that an adolescent would reach mid adolescence without spontaneous or exogenously induced pubertal development!

Acquired Abnormalities

A number of acquired medical conditions may interfere with either the production of GnRH and/or gonadotropin secretion producing a hypogonadotropic hypogonadal state (Tables III and IV) [40, 42]. The Children's Hospital series refers to many of these as functional disorders [42]. Endocrine disorders such as hypothyroidism, congenital adrenal hyperplasia, Cushing syndrome, and idiopathic hyperprolactinemia that begin before or during the early pubertal process may arrest gonadotropin secretion. While only some cases of growth hormone deficiency are acquired, this disorder is included here with the other endocrinopathies. Patients with particularly short stature, pubertal delay, and low gonadotropin levels should be considered as having one of the endocrinopathies that also affects growth (i.e., hypothyroidism and growth hormone deficiency). Treatment of these disorders will allow the resumption of puberty. Systemic illnesses including malabsorption states, eating disorders, active autoimmune diseases, and the rare hypoxemic states related to congenital heart malformations or severe anemias (i.e., sickle cell) are also occasionally etiologic for hypogonadotropism and pubertal delays. Most of these conditions are similarly reversible. Finally, pituitary tumors are consistently reported in rare patients of all descriptive delayed puberty series [40]. The craniopharyngioma occurs usually between the ages of 6-14 years prior to the usual time onset of puberty. It is an aggressive tumor that causes early destruction of the pituitary and suprasellar regions and usually delays any pubertal development. On the other hand, it can also be an indolent tumor not becoming apparent until the late teenage years or even the mid 20's. The typical calcification of these tumors makes them easily diagnosed radiologically. Unlike the craniopharyngioma, the prolactinoma usually does not develop until after puberty is initiated. Estrogen is known to increase messenger RNA for prolactin and its increase at puberty is seemingly associated with the development of prolactinomas. For these patients, the prolactinoma usually arrests a pubertal process that has begun on time. These tumors are extremely slow growing and rarely interfere with other pituitary functions, if at all. If a dopamine agonist is given to lower the prolactin levels, puberty or menstrual function will usually proceed normally. In most recent series, the prolactinoma outnumbers the craniopharyngioma as a cause of hypogonadotropic hypogonadism.

Congenital Abnormalities

A number of irreversible disorders are found in patients with hypogonadotropic hypogonadism, some of which are associated with fractional or complete pituitary insufficiency; the majority are not. Previously, this later group was categorized as idiopathic hypogonadotropic hypogonadism (IHH), of which many patients were felt to have isolated deficiency of GnRH. However, unlike the hypogonadal mouse found to have deletion of a large portion of the GnRH gene, such mutations in humans have yet to be found. A few specific gene mutations have been identified in some of these patients to better understand the disorders. While mutations of the X-linked Kal gene are associated with the anosmia and hypogonadotropic state of some men with Kallmann syndrome, they have yet to be identified in female patients. The most common mutations in other patients with IHH have been found in the GnRH receptor gene. Other disorders are also associated with the hypogonadotropic state and include mutations of DAX 1 and Prop1 genes [87-91]. A number of other genetic defects have been found to cause hypogonadotropic hypogonadism including congenital forms of hypopituitarism, genetic disorders such as Prader-Willi Syndrome, the CHARGE syndrome, and Laurence-Moon and Bidel-Bardet Syndromes. Finally, other forms of hypopituitarism exist some of which are associated with anatomic abnormalities such as Rathke's pouch cysts, anterior encephalocele, and hydrocephalus [40].

Molecular Findings

As in the patients with hypergonadotropic hypogonadism, molecular research has provided new insight into the clinical findings of a number of patients with hypogonadotropism. In particular, these studies have helped to better understand the variation of clinical presentation and gonadotropin levels, and the different responses to exogenous GnRH reported in these patients. For men with Kallman syndrome, mutations of a cell surface adhesive gene, the KAL gene, have helped to understand the anosmia and hypogonadotropic state; they prevent development of the neurologic tract responsible for transport of GnRH to the median eminence and normal olfactory bulb development [90, 92-94]. Subsequently, a number of these men were also found to have unilateral renal agenesis. While similar mutations have not yet been identified in anosmic females, it is likely that a few will ultimately be uncovered. The most common molecular finding in patients with very low gonadotropins has been mutations in the GnRH receptor gene [95-98]. Finally, mutations of DAX1 and PROP1 have more recently been described in patients with hypogonadotropic hypogonadism [87-91].

Contemporary Issues for Management

Numerous different disorders exist for patients presenting with hypogonadotropic hypogonadism. Many of these are rare and best managed by specialists who treat the specific disorder, each disorder having very specific individual clinical concerns. It should be determined early whether treatment of the disorder will allow subsequent pubertal progression or whether an irreversible form of hypogonadotropism exists which warrants sex steroid replacement to allow as timely a pubertal progression as possible. A part of treatment involves individual counseling about expectations for pubertal development, associated problems, reproductive options, and chance of recurrence. No doubt, this may require a multidisciplinary team approach. An interesting finding of the Children's Hospital study was that it provided evidence that there may be an association between hypogonadotropic hypogonadal causes of delayed puberty and attention deficit disorder with or without hyperactivity [42].

Eugonadism

The MCG series presented a third group of females with pubertal abnormalities and evidence of ongoing estrogen production. These patients primarily present with delayed menarche.

Anatomic abnormalities

Congenital absence of the uterus and vagina (CAUV), also known as mullerian aplasia or Rokitansky-Kuster-Hauser-syndrome, is the second most common cause of pubertal aberrancy in the MCG series [41]. In particular, these patients present with delayed menarche. They have fusion failure of the two mullerian anlagen during embryogenesis. The normal fusion process is usually followed by canalization of the vagina. In its absence, small uterine remnants and their attached normal fallopian tubes remain; the vaginal plate is uncannalized. These patients progress through puberty at the normal time. They present with delayed menarche and on examination are found to have absence of the vagina. They have normal ovarian function. Nearly 30% of these patients have concomitant renal abnormalities, the most common being unilateral renal agenesis. From 12-50% of these patients will have associated skeletal abnormalities, scoliosis being the most common. Other abnormalities may also occur.

Another group of patients who present with an anatomic cause of delayed menarche have an imperforate hymen or a transverse vaginal septum. These patients also initiate the pubertal process at the normal time and even menstruate. Their menses, however, are concealed behind the obstructing membrane or septum producing initially a hematocolpus and later a hematometra. These patients usually present within one year of normal menarche with cyclic pelvic pain. On examination they are found to have an obstructing membrane, the imperforate hymen often bulging on valsalva maneuver. Once these obstructing membranes are surgically excised normal menstrual function usually follows.

Molecular Findings

Because patients with CAUV were never previously able to have children, the inheritance pattern for most of them has been generally unknown and clues for potential candidate genes have remained elusive. The majority of these patients are sporadic occurrences within their family. Rare sibships with several nontwin sisters affected have been reported and twins both concordant and discordant for CAUV also exist [40]. A recent report of the outcome of pregnancy for these patients who were able to have their own biological children through IVF utilizing a gestational host suggests that this condition is not commonly autosomal dominant; none of the female babies were found to be similarly affected [99]. Our laboratory has performed mutation analyses for a number of candidate genes in these patients including the cystic fibrosis transmembrane conductance regulator (CFTR) [100], WNT7, anti-Müllerian hormone (AMH) [101], anti-Müllerian hormone receptor (AMHR) [101], HOXA10 [102], HOXA13 [103], galactose-1-phosphate uridyl transferase (GALT), PAX2 [104], and Wilms tumor transcription factor (WT1) [105]. To date none of these analyses have revealed a convincing association. For the transverse vaginal septum and imperforate hymen patients, molecular analysis has been essentially nonexistent.

Contemporary Issues for Management

The diagnosis of CAUV is essentially clinical. The classic finding of vaginal absence or a vaginal pouch (usually developed through prior coital attempts) associated with otherwise Tanner V breast and pubic hair development is unlikely anything else but CAUV. A search for associated physical findings of bony malformations (commonly scoliosis) and rarely inguinal hernias or scars from prior repair should be conducted. The inguinal hernias occur because the round ligaments can pull the unconnected uterine remnants and associated fallopian tubes and ovaries into the inguinal canals. The diagnosis of CAUV can be confirmed simply by a pelvic ultrasound study that demonstrates the presence of ovaries with follicular activity. The midline uterus will not be seen. Neither a karyotype nor laparoscopy is necessary for the diagnosis in the majority of CAUV patients. The prepubertal patient could be misdiagnosed with androgen insensitivity syndrome (AIS). However, postpubertally the clinical findings for CAUV and AIS are sufficiently different that diagnosis of each is usually straightforward. If in doubt, a serum total testosterone level is the least expensive method of resolving the confusion; levels within the female and male ranges will differentiate the two conditions.

Treatment of this condition has previously been surgical; a number of different surgical techniques have been utilized for creation of the vagina. In the United States, the McIndoe vaginoplasty remains the most commonly performed surgery for neovaginal creation. This is the classic procedure in which a skin graft is sewn around a mold and inserted into a newly dissected vaginal space. After a skin graft take the patient wears a vaginal mold for an extended period of time and until regular coitus to prevent scarring down of the neovagina. In other parts of the worl