Females Males

Thelarche Testicular growth

Pubarche Pubarche

Maximal growth velocity Maximal growth velocity

Menarche

Adult pubic hair

Adult breast

In boys, two Sertoli cell proteins, inhibin B and antimullerian hormone (AMH)/ mullerian inhibiting substance (MIS), are produced in the early neonatal period. Inhibin B (human males have minimal inhibin A) increases soon after birth and peaks at 4-12 months of age, declines to low levels by ages 3-9, and then increases again with the onset of puberty (at lower levels than the neonate). AMH/MIS is evident in the first month of life and peaks about 6 months of age, drops during childhood, and becomes very low with puberty, probably secondary to increased testosterone inhibition. These hormones are useful markers of testicular function in early childhood.

Abnormalities of Puberty

Precocious Puberty

Definitions and Etiology

Precocious puberty is defined as the onset of puberty before the age of 8 in girls and age 9 in boys. These ages are 2.5 standard deviations below the mean age of puberty in North American children. This disorder is five times more common in girls than boys. It is classified as either central (GnRH-dependent) or peripheral (GnRH-independent) depending on whether the inciting event has activated the H-P-G axis. In central precocious puberty (CPP), activation of the hypothalamic-pituitary axis occurs, leading to premature sexual development that typically follows the normal pattern of puberty except that it is early. In peripheral precocious puberty (PPP), steroid production is independent of activation of the central axis, as is the case in gonadal or adrenal tumors or McCune-Albright syndrome. Precocious puberty is often idiopathic, especially in girls, however, a work-up is indicated in order to rule out significant pathology. If left untreated, final adult height will be compromised because of steroid-induced premature closure of the epiphyses. These children have normal reproductive function and do not appear to be at risk for premature menopause. Psychosocial issues should also be addressed because other aspects of development correspond with chronological age. In addition, more benign variants, premature thelarche and premature pubarche, may also occur.

Diagnosis of Precocious Puberty

Precocious puberty may result in a decrease of final adult height; so arresting the growth is an important objective. The history and physical exam are extremely important as are growth charts. A skeletal film of the hand for bone age is very important in assessing the severity of the disorder and need for treatment (Fig. 2.1). Premature thelarche may occur in girls 1-2 years old because of the GnRH pulse generator activity. Normally, this will not result in advanced growth and the bone age is consistent with chronologic age. No treatment is necessary, even though some girls may have follicular activity on ultrasound. Premature adrenarche without other signs of puberty is also a benign process, and if the bone age is normal, these patients can be followed expectantly. Patients with premature adrenarche tend to be taller and heavier than other children their age. These patients may be at risk for polycys-tic ovary syndrome in the future. If they have hirsutism, serum levels of total testosterone, DHEAS, and 17-hydroxyprogesterone may be indicated. If markedly elevated androgens are present or there is evidence of virilization, adrenal or ovarian neoplasms and congenital adrenal hyperplasia should be excluded as in peripheral precocious puberty (Fig. 2.1).

Syndrome Albright
Figure 2.1. An algorithm that can be used as a guide in the diagnosis of precocious puberty (PP). T, testosterone; DHEAS, dehydroepiandrosterone sulfate; 17OHP, 17-hydroxyprogesterone; US, ultrasound; MAS, McCune-Albright syndrome.

For children who develop breasts and have pubic hair suggesting precocious puberty, the history and physical examination including height, weight, Tanner staging, signs of virilization and estrogenization, thyroid exam, and a thorough neurological exam should be performed. A bone age will demonstrate accelerated growth compared to chronological age (for example, if the bone age for a 5-year old is 8 years). A CT or MRI is usually necessary to exclude a CNS tumor in patients with central or peripheral precocious puberty. In particular, patients with precocious puberty who have a rapid course of progression or who have CNS signs should have an MRI of the brain to exclude a tumor. A "GnRH stimulation test" is useful to determine if CPP or PPP is present. A LH response greater than FSH response indicates a central cause, while a primarily FSH response suggests a peripheral, or GnRH-independent cause. Since native GnRH is not available for these tests, a GnRH-agonist such as leuprolide acetate can be used at a dose of 20 |ig/kg S.Q. FSH and LH levels should be drawn at baseline (before agonist administration) and every 15 minutes for 1 hour thereafter. If the LH/FSH ratio exceeds 1 or the maximum level of LH exceeds ~7 mIU/mL (cutoff value should be determined for your own lab), then the etiology is central (mediated through the H-P-G axis). It has also been suggested that if an immunofluorometric LH assay is used, a single unstimulated LH value >0.6 mIU/mL may eliminate the need for a "GnRH stimulation test" (remember there is lab variability and this cutoff level should be determined in your lab). Ovarian volume may also be increased in patients with CPP.

In patients who do not have evidence of a central cause, ovarian ultrasound or adrenal CT may be helpful to evaluate the presence of a neoplasm. For boys, tes-ticular palpation may indicate a mass needing biopsy. Thyroid studies (TSH and total T4), prolactin, estradiol, DHEAS, testosterone, estradiol, and hCG levels should be considered.

Causes and Treatment of Precocious Puberty

Central Precocious Puberty

A number of factors can activate the hypothalamic production of GnRH, leading to stimulation of pituitary gonadotrophs and gonadal steroid production. Tumors can impinge on inhibitory neurons causing increased secretion of GnRH. A suspected malignancy should be followed by biopsy for identification. Benign tumors, such as hamartomas (hyperplastic malformations of the tuber cinerum which elaborate GnRH), can be successfully treated with GnRH agonist therapy. Long standing hypothyroidism can cause central precocity (usually associated with retarded bone age). Treatment will curtail symptoms. A careful history may illicit a previous history of an infectious process (i.e., meningitis), trauma, radiation, or developmental abnormalities (hydrocephalus). Ectopic gonadotropin production by tumors accounts for less than 0.5% of the causes of central precocity. The most common of these tumors include chorioepithelioma, dysgerminoma, and hepatoblastomas.

Therapy is directed toward arresting further sexual development and skeletal growth. GnRH agonist therapy has become the standard for children with central precocious puberty. The depot form of leuprolide acetate is given at a dose of 300 |ig/kg every four weeks. Be aware that 7.5 mg or more may be necessary for treatment in some children rather than the standard 3.75 mg dose. Therapy with leuprolide is continued until an age agreed upon by the patient, family, and the physician, usually 11-12 years of age. Adequate suppression of the H-P-G axis should be assessed by drawing an LH level by a standard GnRH agonist test or by a single LH value 2 hours after a dose of GnRH agonist. The maximal LH should be suppressed to less than 2-5 mIU/mL depending upon the assay used, although most suggest <2 mlU/mL. Follow-up visits should be scheduled every 3 months to assess growth velocity and every 6 months to assess Tanner staging and bone-age at least initially, and then less often.

Peripheral Precocious Puberty

Peripheral precocity can be caused by a number of disorders. A careful history will eliminate rare iatrogenic causes such as hormone containing lotions or meat from animals fed steroids. Gonadal neoplasms occur in about 10% of both boys and girls diagnosed with precocious puberty. The most common cause of precocity from gonadal estrogen production in girls is a follicular cyst. Careful follow up (including ultrasound to document ovarian size) and observation is appropriate. Surgery should be avoided because it might lead to an unnecessary oophorectomy. The most common malignant tumor that causes peripheral precocity is the granulosa-theca cell tumor, although these are very rare. They are almost always unilateral and diagnosed at an early stage,. In boys, tumors that produce hCG can cause precocious puberty. Treatment is usually surgical, and if malignant, adjuvant therapy may be indicated. Hepatoblastomas and hepatomas usually present with bilateral testicular enlargement and have a poor prognosis.

Mc Cune-Albright syndrome is associated with precocity and is five times more common in girls than in boys. The diagnosis is made with the findings of cafe-au-lait spots, precocious puberty and polyostotic fibrous dysplasia. The order of pubertal development is sometimes completely haphazard. Skeletal fractures may occur in the regions of polyostotic fibrous dysplasia because fibrous tissue replaces normal bone. The femur and skull are the most frequent fracture sites. The risk of fractures usually does not persist into adulthood. Hearing loss may occur if there is involvement of the temporal bone. McCune-Albright syndrome is caused by a somatic cell mutation of the Gsa gene, which encodes for a G-protein. Abnormal activation of other organs utilizing cAMP can occur so these patients should be screened for hypercortisolism, hyperthyroidism, and growth hormone excess. Testolactone, an aromatase inhibitor, at a dose of 20-40 mg/kg/day in four divided doses has been used successfully. Newer aromatase inhibitors have been used as well, but there is much more experience with testolactone. Adult height is not compromised and these adults have normal reproductive function.

An important cause of PPP in boys is familial male precocious puberty (FMPP), previously known as testotoxicosis. This often presents at age 2-3 and occurs via an activating mutation of the luteinizing hormone receptor (LHR) gene that results in increased testosterone production without an increase in the LH ligand. These patients have prepubertal levels of gonadotropins, but adult-sized testes and adult levels of testosterone. It is inherited in an autosomal dominant mode, but interestingly, does not affect females. This can be treated by ketoconazole, a P450 cytochrome inhibitor of adrenal and gonadal steroidogenesis at doses of 400-600 mg/day. Liver enzymes must be followed to avoid hepatotoxicity. Antiandrogens such as flutamide may be added, but may also be hepatotoxic.

Less common causes of peripheral precocious puberty include adrenal tumors (virilizing in boys; feminizing in girls), such as adrenal adenomas and cancer. Adrenal cancer has a poor prognosis.

Delayed Puberty Diagnosis

Delayed puberty is defined as no signs of puberty by age 14 in boys. In girls, it is defined as either the absence of thelarche by age 13 or menarche by age 15. These are 2.5 standard deviations above the mean for North American children. In boys, delayed puberty signifies that there is a hypogonadal state. In girls, the differential diagnosis is complex and may include a hypogonadal state, anatomic abnormalities, such as absence or obstruction of the outflow tract, and certain disorders with ongoing estrogen production most commonly polycystic ovary syndrome (PCOS). An algorithm is shown in Figure 2.2. Note that the evaluation and diagnostic categories are similar for males with the exception of an obstructed genital tract.

All patients with delayed puberty should have a TSH, total T4 (more robust assay than the problematic free T4), and serum prolactin, and detailed psychosocial history. Hypothyroidism (central, rather than primary) hyperprolactinemia, and hypothalamic disorders (eating disorders/stress/exercise) may occur in patients who are eugonadal or hypogonadal depending upon the duration of the process.

A careful history and physical exam of the patient with delayed puberty are extremely important to ascertain if there are any initial signs of puberty and estrogen production. If there are no signs of breast development, the patient clearly has

J. TSH,T4,PRL Z. Determine if hi

Normal I PCOS I

No Vagina

Eugonadal | Pelvic exam ypogonadal

I Hypogonadal"]

No Vagina

Mullerian

Complete

Aplasia

Nd pubic hair 46.XV

Obtain FSH 4 LH

I Hypergonadotropic Hypogonadism | j Hypogonado tropic Hypogonadism |

Karyotype

Pubic hair 4Î.XX

Nd pubic hair 46.XV

Karyotype

Normal +

Abnormal +

Normal +

Abnormal +

Hypothalamic

Pituiary

Cause

Tumor

Consider 17-OHase *

46rXy) f f eoting disorder.

If no breasts. Evaluate for Abnl Stress, exercise, do pelvic exam (Renal & Cardiac) CDP. IHH

Consider 17-OHase, LHft mutation

' Vagina present Vagina absent ■ (46. XX) (46, XY)

Figure 2.2. An algorithm that can be used as a guide in the diagnosis of delayed puberty. AIS, androgen insensitivity syndrome.

hypogonadism. If she has breast development, she has evidence of at least previous estrogen production, but her estrogen status must be determined at the time of presentation (she could now be hypogonadal). One of two tests is recommended: a vaginal maturation index or a progestin challenge test. Estradiol levels are not very helpful since it may be difficult to discriminate between low and low-normal. A vaginal smear (or vaginal maturation index) can be performed using a Q-tip to swab the vagina. The swab is gently rolled onto a slide and set with Urine Sedi-Stain or another quick prep stain. The ratio of parabasal, intermediate, and superficial (P/I/S) cells is reported, usually in that sequence. A predominance of parabasal cells (such as 70/30/0) indicates that the patient is probably hypogonadal (hypoestrogenic). If there are superficial cells present (as in 0/30/70), the patient is probably making estrogen or is eugonadal. The second screening test for the eugonadal state is the progestin challenge test. It is usually performed by administering medroxyprogesterone acetate 10 mg for 5-10 days (after a negative pregnancy test, if the patient has normal breast development). If the patient is hypogonadal, she may spot, but will not have a menstrual bleed after the medication is completed. This test can be repeated if negative the first time. The progestin challenge test does not need to be performed in patients with no breast development or who have a vaginal smear indicating no estrogen production (predominant parabasal cells).

Hypogonadism

If hypogonadism is suspected on the basis of physical exam (Tanner 1 breasts), vaginal maturation index, or negative progestin withdrawal, serum gonadotropins should be obtained. If elevated, they should be repeated in several weeks for confirmation because of the pulsatile secretion of gonadotropins. When gonadotropins are persistently elevated, gonadal failure, also known as hypergonadotropic hypogonadism, is present. A karyotype should be performed in all children with elevated gonadotropins to rule out a chromosomal abnormality (see below). If gonadotropins are low or normal (in the face of hypogonadism), the patient has hypogonadotropic hypogonadism due to hypothalamic or pituitary disease. Since sex steroids are necessary for growth, performing a bone age should be considered in hypogonadal patients. These patients can have delayed bone age compared to chronological age. They do not usually have a bone age beyond 11-12 years, however, if bone age is markedly delayed, growth hormone deficiency and/or hypothyroidism should be strongly considered.

Hypergonadotropic Hypogonadism

Females

Patients with hypergonadotropic hypogonadism will either have a normal female karyotype (46,XX), a normal male karyotype of 46,XY (Swyer syndrome) or an abnormal karyotype. About half of females with gonadal failure and amenor-rhea will have an abnormal karyotype as compared to only 10-15% of boys with delayed puberty due to hypergonadotropic hypogonadism. In females with a chromosome abnormality, about half are found to have a 45,X cell line and the remainder possess a 45,X cell line plus a second mosaic cell line. The second cell line can be a 46,XX, 47,XXX, 46,XY, 46,X, i(Xq) or a number of structural abnormalities of the X chromosome including deletions. Turner stigmata may or may not be present. The most common feature is short stature (usually <5 feet), while absent puberty occurs in 90-95%. Cardiac anomalies (coarctation, dilated aortic root, bicuspid aortic valve) occur in ~50% of patients and renal anomalies in 30%. Therefore, patients should be evaluated for these abnormalities with a cardiac echo and an IVP or renal ultrasound. A cardiac echo has been suggested to be performed every three years for the rest of her life since patients may develop a dilated aortic root that is prone to rupture.

It should also be kept in mind that about 10% of patients with a 45,X cell line will have some menstrual function, even if short-lived. It is therefore wise to karyo-type all women who develop hypergonadotropic hypogonadism with short stature (<5'3"). Patients who have 45,X/46,XY karyotype can have a phenotype that ranges from completely absent sexual development to normal appearing male external genitalia depending on whether streak gonads or testes are present. Girls with a 46,XY cell line are at increased risk of developing gonadal tumors, such as gonadoblastomas or germ cell tumors like dysgerminomas. These tumors occur in about 15% of patients with a 45,X/46,XY cell line and in 20-25% of those with a pure 46,XY cell line (Swyer syndrome or 46,XY gonadal dysgenesis), and therefore, removal of the gonads is indicated when the diagnosis is made. Most patients with gonadal dysgenesis and a Y cell line, including Swyer syndrome, are pheno-typic females with normal vagina, uterus, and cervix since their nonfunctioning testes (streak gonads) do not make AMH/MIS. They are not short as are the patients with a 45,X cell line. Regular follow up of patients with ovarian failure due to gonadal dysgenesis should also include thyroid studies, as there is an increased risk of developing disease.

Women with hypergonadotropic hypogonadism and normal female chromosomes (46, XX) are phenotypic females with or without breast development. They can present with completely absent puberty (sexual infantilism), or with secondary sexual development and amenorrhea, or they may have normal sexual development and abbreviated reproductive capacity. This disorder is termed 46,XX gonadal dys-genesis, premature ovarian failure, or hypergonadotropic amenorrhea. These patients have normal female internal and external genitalia as well as normal female height. Autoimmune disorders are present in about 20% of these patients, most frequently hypothyroidism and Addison's disease. It is therefore reasonable to obtain a TSH, T4 and 8 AM cortisol level. The cortisol level should be 17-20 |ig/dL to rule out Addison's disease, and should be followed up with an ACTH stimulation test if low. A serum calcium, phosphorus and antinuclear antibody are also reasonable, although autoimmune parathyroid disease is less common. Premature ovarian failure can be associated with a number of genetic abnormalities. It is therefore important to get a good genetic history. Fragile X syndrome carrier status may be observed in -3-4% of women with sporadic 46,XX ovarian failure, but in up to 10-15% of patients if two or more women in the family are affected with gonadal failure. It is reasonable to determine if there is a family history of mental retardation, which increases the likelihood for Fragile X syndrome. Fragile X syndrome may be tested by DNA (not cytogenetics) for the permutation allele. Although a patient with ovarian failure is unlikely to get pregnant spontaneously, there could be a risk for other family members to have a child with Fragile X syndrome.

In patients with hypergonadotropic hypogonadism who do not have breast development, a pelvic exam should be performed to determine if a vagina is present (Fig. 2.2). Rarely, 17-hydroxylase deficiency (17-OHase) may be observed in females (who will have a uterus/vagina) or in males (who will have a blind vaginal pouch). It is a wise precaution to draw an 8 AM cortisol to exclude adrenal failure secondary to 17-OHase deficiency. Also, rare inactivating mutations in the LHR gene should be considered in a patient with gonadal failure, no breast development, and no vagina.

Treatment of Gonadal Failure

Estrogen can be used to initiate breast development in these patients. Unopposed conjugated estrogens are usually administered in a dose of 0.3 mg/day for a few months and then increased to 0.625, 0.9, then 1.25 mg/day until breast development is adequate. Initial low dose administration may allow for a more normal looking breast with early treatment. Low doses of ethinyl estradiol can be used beginning at 1 |ig/day and gradually increased. Alternatively, estradiol 0.5 mg may be started and increased by 0.5 mg increments. Once breast development is achieved, progestins should be added. Medroxyprogesterone acetate 5-10 mg/day for 10-12 days/month is added for endometrial protection. The patient can then be switched to oral contraceptives. Pregnancy is extremely unlikely in these patients even with ovulation induction or estrogen withdrawal. The chances are not zero since ovarian function may wax or wane in those with a 46,XX karyotype. In vitro fertilization with oocyte donation allows many of these patients the chance to reproduce. Care must be taken in patients with a 45,X cell line because their risk of death due to aortic rupture in pregnancy is 1-2%. For patients with a 45,X cell line, treatment with recombinant growth hormone may also be considered. Although there is significant cost associated with its use, some evidence indicates that height gains of 2-3 inches may occur with long term treatment.

Males

The most common karyotype of males with gonadal failure is a normal 46,XY. However, 10-15% may have a 47,XXY (Klinefelter syndrome) or 46,XX karyotype (sex-reversed male). Patients with a 47,XXY karyotype are usually in the 50 th per-centile for normal male height and eunuchoid due to lack of epiphyseal closure (decreased upper to lower body ratio). Puberty is often initiated, but the tempo is disrupted and they become hypogonadal. The most consistent finding in this syndrome is testicular fibrosis which leads to azoospermia in >95% of pure 47,XXY males. If mosacism is present, about half of these males will have azoospermia. Gy-necomastia occurs in about one-third to one-half of patients and frequently does not respond to hormonal therapy. Medical care should include evaluation for diabetes mellitus, breast cancer, leukemias, lymphomas, and germ cell tumors. Males with a 46,XX karyotype have a normal male phenotype since they have the sex determining region of the Y chromosome (SRY) initially, but they commonly develop gonadal failure and are azoospermic.

Treatment for males with hypergonadotropic hypogonadism (regardless of karyo-type) is comprised of replacing androgens to induce secondary sexual characteristics and normal sexual function and to prevent osteoporosis. When diagnosed in the newborn period, treatment with testosterone cypionate 25 mg IM is given several times to induce penile growth. If treatment is initiated at puberty, testosterone enanthate 50-100 mg IM should be given every 2-4 weeks. The usual adult dose for maintenance is 200 mg administered every two weeks. Topical testosterone gel or patches can also be utilized.

Similar to females with gonadal failure, fertility is highly unlikely and donor insemination generally offers the best chance for pregnancy. In some circumstances, if a testicular biopsy or epididymal aspiration demonstrates mature sperm, IVF with ICSI may be an option.

Hypogonadotropic Hypogonadism

When the patient is hypogonadal (absent breast development, without an estrogen withdrawal bleed, or a negative progestin challenge) and serum gonadotropins are low or normal ("normal" is inappropriate given the hypogonadism), the diagnosis is hypogonadotropic hypogonadism (HH). An MRI of the brain is necessary to exclude a pituitary tumor, most commonly a prolactinoma or craniopharygioma. If a tumor is present, it is usually treated medically (dopamine agonist for a prolactinoma), but surgery may be required for a craniopharyngioma, which may be malignant. If a tumor is not present, the cause is generally hypotha-lamic by exclusion. Although it is possible to perform a triple test (insulin induced hypoglycemia, GnRH, and TRH stimulation and check baseline and hormone levels every 15 minutes for 1-2 hours—TSH, prolactin, cortisol, LH, FSH, and GH), the cost is great and the yield is very low except in patients who have extreme short stature, which could suggest pituitary failure. If the patient has a height below the 5th percentile, particularly if there is a family history of pituitary failure, then combined pituitary hormone deficiency (CPHD) should be considered. Genetic counseling and testing for mutations in genes such as PIT1, PROP1, HESX1, or LHX3 should be considered.

In the absence of a tumor, strong consideration must be given to the history and physical exam with particular attention to BMI, eating and exercise patterns, and stress. Eating disorders such as anorexia nervosa or bulimia must be sought because of the significant morbidity and mortality. A history of extreme exercise such as prolonged running or ballet must also be elicited, as should a history of stress. Morning cortisol levels are elevated in patients with eating disorders, and reverse T3 levels may be elevated (preferential conversion of T4 to rT3 instead of the more active T3). Correction of the underlying problem with an increase in weight, reducing the exercise, or trying to relieve the stress will often lead to menstruation.

For patients with hypogonadotropic hypogonadism who have no pituitary tumor and are of normal weight, two diagnoses must be considered. They may have constitutional delay of puberty (CDP) if they initiate puberty spontaneously before age 17 in girls and age 18 in boys (CDP is more common in boys). If they are older than 17 for girls and 18 for boys, the diagnosis is idiopathic or isolated hypogonadotropic hypogonadism (IHH). A history should be sought for anosmia/ hyposmia, midline facial defects, associated neurologic deficits such as synkinesia (tested by raising both arms for example when asked to raise one-corticospinal tract abnormality), hearing loss, or visual abnormalities. When IHH is combined with anosmia/hyposmia, the patient has Kallmann syndrome. Mutations in the KAL1 gene on the X chromosome account for about 5-10% of the causes in males (not females since it is X-linked recessive). Males with mutations in the KAL1 gene may also have unilateral renal agenesis (50% in one series), which should be tested. Mutations in the FGFR1 (KAL2) gene occur in about 10% of patients (male and female) with Kallmann syndrome. This autosomal dominant form of Kallmann syndrome can lead to individuals with mutations who are not affected (reduced penetrance), which can complicate the diagnosis. Midline facial defects and dental agenesis may occur in patients with FGFR1 mutations.

For patients with normosmia, mutations in the gonadotrophin releasing hormone receptor (GNRHR) comprise approximately 5-10% of the cases and are inherited in an autosomal recessive fashion. Although mutations in other genes have been reported, they are thought to be rare. Testing for deletions of KAL1 may be performed commercially, but testing FGFR1 and GNRHR are generally performed only by research laboratories.

Treatment for patients with hypogonadotropic hypogonadism involves administration of estrogen for girls (testosterone for boys) as described above. In contrast to patients with gonadal failure, patients with IHH can be given S.Q. FSH and LH (see ovulation induction chapter) for ovulation induction in females and cycle fecundity is similar for age-matched fertile women. For men who have testes larger than prepubertal size (>4 mL by Prader orhidometer), 2000-3000 IU of hCG may be given S.Q. three times/weekly. If there is little or no response, recombinant FSH 150 IU may be added to this regimen. Most males will have evidence of spermatogenesis and fertility although it may take 6-12 months and their semen analysis parameters are often lower than what would be considered normal.

Eugonadism (in Females)

If breast development is normal and amenorrhea is present, the exam will determine if there is an outflow tract obstruction. The exam may identify an anatomic abnormality, such as absence of the uterus and vagina with either complete androgen insensitivity syndrome (CAIS) or mullerian aplasia (Mayer-Rokitansky-Kuster-Hauser syndrome) or obstruction of the outflow tract. A karyotype will serve to distinguish CAIS (46,XY) vs mullerian aplasia (46,XX), as will a testosterone (normal male levels in CAIS and normal female levels in mullerian aplasia). However, this is often not necessary. CAIS patients usually have absent pubic hair because of an X-linked recessive mutation in the androgen receptor gene, while females with mullerian aplasia are normal appearing females and should have pubic hair, since the defect involves uterine, renal, vaginal, and skeletal development. Remember that about 1/3 of women with mullerian aplasia will have unilateral renal agenesis and may have skeletal spinal fusion defects (Klippel Fiel syndrome) and need some form of evaluation for this. Treatment is usually successfully accomplished with progressive vaginal dilation initiated when the patient is sexually mature and interested in intercourse (usually later teenage years or early 20s). Typically, lubricated, increasing sized vaginal dilators are used for 20-30 minutes/day over a period of 3-6 months until achievement of the final desired vaginal depth and size. Surgical creation of a neovagina, such as the McIndoe procedure, may also be utilized, but patients should understand that wearing a vaginal mold for 6-9 months postoperatively may still be necessary.

Other obstructive causes such as a transverse vaginal septum or imperforate hymen will present as cyclic, worsening pelvic pain since uterine contents collect in the vagina (hematocolpos) and in the uterus (hematometra). These disorders present urgently or emergently. If an imperforate hymen is present, a hymenectomy may be performed, which is a relatively straightforward procedure in which the hymen is excised. A transverse vaginal septum presents a much more challenging operative procedure since the septum may be much thicker and higher in the vagina than appreciated; however, the septum must be opened and removed. A vaginal mold is also necessary postoperatively with this procedure.

If no outflow obstruction is observed in a eugonadal patient and thyroid studies and prolactin are normal, the patient very likely has polycystic ovary syndrome (PCOS) as the cause of amenorrhea. These patients are at risk for diabetes and endometrial hyperplasia so treatment with oral contraceptives or acyclic progesterone, such as medroxyprogesterone acetate, if pregnancy is not desired. Ovulation induction is indicated for attempting pregnancy.

Key Points

1. The onset of puberty should occur over a three to four year period, with the usual first sign of puberty being breast budding (thelarche).

2. Sexual development prior to the age of 8 years in girls and 9 years in boys is considered early, and mandates an evaluation. It is often idiopathic and is five times more common in girls than boys.

3. Precocious puberty can be classified as being central (activation of the hypothalamic-pituitary-gonadal axis), which may be treated with GnRH agonists, or peripheral, which will not respond to GnRH agonists. If precocious puberty is not treated, final adult height may be compromised.

4. Delayed puberty is defined as absent puberty by age 14 in boys (no testicu-lar development). For girls, no thelarche by age 13 or no menarche by age 15 is considered delayed.

5. All patients with delayed puberty should have a TSH, T4, prolactin, and girls should have a test for the presence of estrogen (a progestin withdrawal test or vaginal maturation index).

6. If a delayed puberty patient has evidence of estrogen, a pelvic exam will distinguish if there is an outflow tract abnormality vs. polycystic ovary syndrome.

7. In hypoestrogenic girls with delayed puberty, it is necessary to obtain FSH and LH levels. If gonadotropins are elevated, ovarian failure is present and a karyotype is warranted to exclude the presence of a Y chromosome. If gona-dotropins are low or normal, a central (hypothalamic or pituitary) etiology is present, and an MRI is necessary to exclude a tumor.

Suggested Reading

1. Grumbach MM. The neuroendocrinology of human puberty revisited. Horm Res 2002; 57(Suppl 2):2-l4.

Grumbach MM. A window of opportunity: The diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab 2005; 90(5):3122-7. Hayes FJ, Crowley Jr WF. Gonadotropin pulsations across development. Horm Res 1998; 49(3-4):163-8.

Layman LC, Reindollar RH. Diagnosis and treatment of pubertal disorders. Adolesc Med 1994; 5(1):37-56.

Layman LC. Genetics of human hypogonadotropic hypogonadism. Am J Med Genet 1999; 89(4):240-8.

Layman LC. Mutations in human gonadotropin genes and their physiologic significance in puberty and reproduction. Fertil Steril 1999; 71(2):201-18. Layman LC. Human gene mutations causing infertility. J Med Genet 2002; 39(3):153-61.

Lee PA. The effects of manipulation of puberty on growth. Horm Res 2003; 60(Suppl 1):60-7.

Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: A study of 252 patients. Am J Obstet Gynecol 1981; 140(4):371-80. Reiter EO, Lee PA. Delayed puberty. Adolesc Med 2002; 13(1):101-18, (vii). Sun SS, Schubert CM, Chumlea WC et al. National estimates of the timing of sexual maturation and racial differences among US children. Pediatrics 2002; 110(5):911-9.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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