Obstetrics and Gynecology

Pubertal Delay

Delayed Puberty in Girls / Primary Amenorrhea

1. What every clinician should know

Puberty is the period of growth where sexual maturity and fertility are established. The timing and tempo of normal puberty are dependent on genetic and environmental factors. In the female, puberty follows a progressive and predictable sequence of estrogen and androgen related physical changes that typically begin with accelerated growth, followed by breast development (thelarche), pubic hair growth (adrenarche), and finally the first menstrual event (menarche); the complete sequence on average takes 4.5 years.

Delayed puberty is defined clinically by either the failure to initiate thelarche or menarche by an age at which 98.5% (2.5 standard deviations (SD)) of children of one's own sex and culture have initiated sexual maturation, or a failure of sexual development to progress in a timely manner. Such failures may represent a temporary delay in normal gonadal function or may indicate permanent hypogonadism.

The clinical staging of puberty is performed by the criteria established by James Tanner, which was initially established using data accumulated from healthy European girls. Contemporary data suggests that North American standards are approximately 6 months earlier for each stage. Secondary sex characteristics typically develop earlier in African American girls than in Caucasian girls. The median age of onset for Tanner II breast development is 10.3 years in whites, 9.5 years in African Americans, and 9.8 years in Hispanics, with the ages at which 98.5% of girls have initiated development in each group being 12.8, 12.4, and 12.8 years, respectively.

The median age of onset for menarche is 12.7 years in whites, 12.1 years in African Americans, and 12.2 years in Hispanics, with the ages at which 98.5% of girls have initiated development in each group being 14.8, 14.6 and 14.7 years, respectively. Therefore, a lack of breast development by age 13 or lack of menarche by age 15 fulfills criteria for pubertal delay in most American girls.

About one third of girls who present with delayed onset of puberty are at the extreme end of the normal spectrum of pubertal timing, or have constitutional delay. Constitutional delay is a diagnosis of exclusion. Nearly 70% of girls who present with pubertal delay have underlying pathology, and therefore a genetic, anatomic, hypothalamic, or pituitary disorder must be suspected. In one large case series, 19% of girls presenting with pubertal delay had hypogonadotropic hypogonadism secondary to a systemic disease, 20% had permanent hypogonadotropic hypogonadism, 26% had permanent hypergonadotropic hypogonadism, and 3% had an unclassified form of pubertal delay.

Individuals with a family history of pubertal delay may be at increased risk for initiating thelarche and/or menarche 2.5 SD later than the mean age. Constitutional delay appears to follow an autosomal-dominant pattern, although no gene or family of genes have yet been identified. Specific inheritable gene defects associated with abnormal or absent production of gonadotropin releasing hormone (GnRH) have been identified in several families, and may be associated with a lack of a sense of smell (anosmia), midline defects including cleft lip/palate or scoliosis.

Young girls with systemic disease, physical or emotional stress, a history of vigorous exercise, malnutrition, eating disorders, clinical evidence of hypothyroidism or hypercortisolism are at increased risk of pubertal delay due to defective GnRH release by the hypothalamus resulting in diminished gonadotropin secretion from the anterior pituitary (hypogonadotropic hypogonadism). Failure to initiate menarche due to polycystic ovary syndrome (PCOS) is uncommon, as this endocrine disorder is typically associated with a normal initiation and tempo of pubertal events with accompanying irregular, but not absent, menses.

However, PCOS should be suspected in young girls who fail to initiate menarche and have other sequelae of the disease. Girls at increased risk for permanent pubertal delay due to premature ovarian insufficiency include those with early evidence of Turner syndrome, autoimmune ovarian failure, galactosemia, prior radiation and/or chemotherapy. Known reproductive or renal anomalies that could be associated with outflow tract obstruction or an absent uterus must also be considered risk factors for the diagnosis of pubertal delay.

2. Diagnosis and differential diagnosis

Many disorders of pubertal delay have a functional defect in GnRH secretion and/or its action, and therefore no single test except for observation over time reliably distinguishes patients with constitutional delay of puberty from patients with other causes, particularly GnRH deficiency. Therefore, a history and physical examination are very useful in the initial evaluation and should precede any biochemical testing or imaging studies.

Initial laboratory studies should include serum levels of gonadotropins (follicle stimulating hormone (FSH) and luteinizing hormone (LH)) and estradiol to determine if circulating levels are elevated (indicating primary hypogonadism), low or normal (indicating secondary hypogonadism or an anatomic etiology with delayed menarche). The first tier evaluation (history, physical, circulating gonadotropins, and estradiol) can then be followed by directed studies according to the findings.

History and physical examination

The history should focus upon the initiation and tempo of sexual development, and whether it has been completely absent, or whether events were initiated and then delayed, commonly associated with a constitutional delay. Key points include nutritional habits, bowel habits suggestive of inflammatory bowel disease, exercise intensity, psychosocial issues, prior medical illnesses and/or treatments, current medications, and a family history of constitutional delay or congenital GnRH deficiency. Older siblings can often provide height and pubertal milestones for the individual at risk.

Neurologic symptoms such as headache, dyskinisia, seizures, and mental retardation suggest a disorder of the central nervous system. A reduced or absent sense of smell (anosmia) strongly suggests Kallmann syndrome, a form of hypogonadotropic hypogonadism associated with a genetic defect in several identified genes including KAL1, FGF8, FGFR1, PROK2, and PROKR2.

Physical examination should include careful review and plotting of growth charts to determine height velocity, arm span, and Tanner staging of any secondary sexual characteristics. An arm span that exceeds height by more than 5 cm can suggest delayed epiphyseal closure secondary to hypogonadism. Short stature suggests many possibilities; isolated growth hormone (GH) deficiency, hypopituitarism, and gonadal dysgenesis, most commonly Turner syndrome (45, X).

Turner syndrome is associated with other physical findings such as a broad chest, lymphedema of the hands and feet at birth, webbed neck, nail dysplasia, low set ears, hearing loss, hypothyrodism, hypertension, cardiac and renal anomalies, and difficulty with visuospatial organization. Midline defects such as cleft lip/palate, or scoliosis can suggest congenital GnRH deficiency. Persistent deciduous teeth are suggestive of hypothyroidism. Neurologic exam should include visual field testing and documentation of a sense of smell.

Laboratory testing

Gonadotropins and estradiol

The diverse etiologies of delayed puberty are best categorized by the levels of circulating gonadotropins (FSH and LH) and estradiol. Three categories, hypergonadotropic hypogonadism, hypogonadotropic hypogonadism, and eugonadism, exist.

Hypergonadotropic hypogonadism

Elevated serum FSH (greater than 20 mIU/ml) and LH (greater than 25 mIU/ml) are indicative of primary hypogonadism, indicating that there are diminished or absent levels of estradiol and inhibin (A and B) being produced by the gonads in order to regulate gonadotropin secretion by providing negative feedback to the hypothalamus and pituitary. Hypergonadotropic hypogonadism is always indicative of pathology, and represents permanent causes of delayed puberty. FSH provides the greatest discriminate value in comparison to the referent population. These measurements do not need to be corrected for age, but should be run by a reliable laboratory with adequate normative data.

The most common disorder associated with these findings is gonadal dysgenesis, and chromosomal evaluation is indicated. Turner syndrome (45,X) is the most common karyotype associated with gonadal dysgenesis, however genetic mosaicism, structural deletions of the X chromosome, and normal 46,XX and 46,XY are not infrequent findings. A Y-bearing cell line requires surgical removal of the gonads as prophylaxis against malignancy as outlined below.

A hypergonadotropic 46,XX individual may have pure gonadal dysgenesis, but other possibilities such as sickle cell disease (diagnosed by hematologic evaluation), 17-alpha-hydroxylase deficiency (associated with hypertension and elevated serum progesterone), aromatase gene mutations and androgen insensitivity syndrome (with absent internal reproductive organs and elevated serum testosterone), must be considered, as well as all causes of premature ovarian insufficiency, including autoimmune ovarian failure (often associated with autoimmune polyendocrine syndrome type II), previous radiation or chemotherapy, or galactosemia. Fragile X premutation carriers typically undergo normal pubertal development and may encounter premature ovarian insufficiency before 40 years of age.

Hypogonadotropic hypogonadism

Low or normal FSH and LH values are indicative of diminished hypothalamic and/or pituitary function, or secondary hypogonadism. Impaired secretion of GnRH is involved in transient causes of delayed puberty, such as constitutional delay, malnutrition, eating disorders, excessive exercise, chronic illness, psychogenic stress, hypothyroidism, hypercortisolism, as well as hypothalamic or pituitary pathology including tumors, most commonly craniopharyngiomas or prolactinomas. Permanent causes of hypogonadotropic hypogonadism include genetic causes of impaired GnRH secretion such as idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, CNS defects, and benign or malignant pituitary tumors and/or the consequences of their treatment.

Eugonadism

Mullerian tubal segment discontinuities resulting in outflow tract obstruction or mullerian agenesis, as well as androgen insensitivity syndrome, can present as delayed menarche despite normal development of an adult female karyotype. PCOS and androgen-producing adrenal tumors can also cause delayed menarche.

Additional laboratory tests

A karyotype should be obtained in every patient with primary hypogonadism to evaluate for gonadal dysgenesis. Multiple cells (at least 30), with consideration of multiple sources (i.e., peripheral blood lymphocytes and skin fibroblasts) should be evaluated to investigate for genetic mosaicism including the Y chromosome. A random measurement of serum prolactin should be measured to rule out hyperprolactinemia, which may be indicative of a prolactinoma or other cause of interruption of hypothalamic inhibition of anterior pituitary lactotrophs.

Elevated prolactin levels should be repeated, and evaluated by MRI of the pituitary to assess for lactotroph adenoma. Thyroid stimulating hormone (TSH) and a free T4 level should be measured to evaluate for hypothyroidism. Insulin-like growth factor- 1 (IGF-1) can be drawn to identify isolated growth hormone deficiency. Normal adrenal androgens, including dehydroepiandrostenedione sulfate (DHEA-S), may favor congenital GnRH deficiency over constitutional delay, but the values in the two groups often overlap, so this is rarely helpful from a clinical standpoint.

GnRH stimulation

As individuals with constitutional delay have the same low/normal gonadotropin levels as those with hypogonadotropic hypogonadism, GnRH stimulation with or without a GnRH agonist has been evaluated as a means to help differentiate these two groups. Such testing is currently not recommended as there is significant overlap in gonadotropin responses between the two groups. Such differentiation is best determined over time with serial evaluations, and in some cases therapy may be indicated even before discerning the true diagnosis.

Imaging studies

Skeletal age

A conventional X-ray of the left hand and wrist can be used as a crude indicator of biologic maturity that is independent of chronologic age. The baseline X-ray provides information in regard to the relationship between skeletal maturation and chronologic age, the potential for future growth, and a preliminary prediction of adult height. It can be used as a reference that can be repeated over time if indicated. Puberty can be expected to occur when the skeletal age is consistent with the expected age of pubertal onset, and therefore is helpful in identifying constitutional delay. The female hypothalamic-pituitary-ovarian axis typically becomes pubertal at a bone age between 10 and 11 years, regardless of chronologic age.

Pelvic ultrasound

Trans-abdominal, trans-perineal, or trans-vaginal ultrasound can be used to determine the presence or absence of a uterus and/or ovaries.

Head MRI

If laboratory studies, neurologic signs or symptoms suggest a central process consistent with hypothalamic or pituitary pathology, a MRI of the pituitary should be ordered.

3. Management

The primary cause of delayed puberty in an individual, to some degree, dictates the management options that are available to the clinician. The primary distinction should be made between those etiologies that result in permanent disruption of hormonal function and those that will be transient or modifiable. The primary treatment options are medical therapies that allow the adolescent to undergo normal secondary sexual characteristic development at an appropriate time while maintaining, if there is any possibility of such, fertility options in the future.

Permanent causes

Turner syndrome

Turner syndrome is diagnosed in 1:4,000 births, making it one of the more common diagnosable genetic causes of premature ovarian failure in girls and associated with delayed puberty. About one third of girls with TS will initiate pubertal development spontaneously but less than one half of these will initiate menarche. Girls with Turner Syndrome are often diagnosed in infancy or childhood due to delayed growth and short stature. As such growth hormone (GH) therapy is considered standard of care to maximize height development. On average girls treated for an average of 5.7 years with GH will be 7.2 cm taller than if untreated. Start of GH therapy at an early age may allow for maximization of height while not delaying the onset of induction of puberty.

Puberty is induced with initiation of estrogen therapy. As estrogen will initiate the closure of the epiphyses, it is important to delay therapy with estrogen until maximization of height with GH therapy has been reached. The goals of estrogen therapy are to normalize secondary sex characteristic development such as breast development, uterine size and shape, as well as bone accrual and cardiovascular function. Typically to induce puberty it is best to start with low doses of estradiol and gradually increase. Transdermal delivery systems may offer the most physiologic replacement. Typical commercially available doses of transdermal estrogen range from 37.5 mcg/day to 100 mcg/day.

If the induction of puberty is begun prior to any spontaneous pubertal development, it is best to start with 37.5 mcg patch cut in half to deliver <20 mcg of estradiol daily (which will result in serum estradiol concentration of about 15-20 pg/mL) for 6 months then gradually increase to the 100mcg patch. Patches are typically changed twice a week. Progestin therapy in the form of oral progesterone 200 mg/day for 7-10 days monthly to induce menses is indicated after attainment of Tanner III-IV breast development or if breakthrough bleeding occurs or 2 years into therapy. Oral combination hormone replacement therapy can be initiated after menses for ease of administration.

Surgical therapy for delayed puberty in Turner Syndrome is not indicated routinely. Uterine anomalies are not more common in Turner Syndrome. In rare circumstances, a remnant of the Y chromosome is identified in an otherwise 45X individual or there is a mosaic cell line with a portion of the Y chromosome in it. In this circumstance gonadectomy is indicated for prevention of dysgenesis of the nonfunctioning streak gonad.

Premature ovarian insufficiency, non-Turner syndrome

In the case of 46XX premature ovarian insufficiency (POI), diagnosed by elevated FSH levels as outlined above, there is typically no concern about short stature as the genes responsible for height on the X chromosome are intact. Pubertal induction therefore does not need to be delayed to maximize height growth. Pubertal induction protocols with transdermal estrogen similarly physiologic to those with Turner Syndrome, and may be preferred. Typical estrogen induction again occurs over 2 years in the absence of evidence of prior spontaneous pubertal development. Progestin therapy is begun to induce menstrual withdrawal monthly once breast development is adequate or if breakthrough bleeding is noted.

Mullerian agenesis

Structural absence of the uterus will result in primary amenorrhea but are typically associated with normal ovarian function. Therefore these individuals have spontaneous development of secondary sexual characteristics but do not undergo menarche. Hormone therapy is therefore not required as ovulation and ovarian hormone production progresses normally. Usually in the complete absence of Mullerian development, the vagina will vary from just a dimple to several cms in length but will be blind ending. Sexual function will not be normal however as the vagina is not at a functional length. Therefore treatment of mullerian agenesis requires creation of a neovagina.

First line therapy for vaginal creation is typically use of vaginal dilator therapy. The dilators are a series of molded plastic dilators that are graduated in length and width. Typically they are inserted and pressure applied to stretch the vaginal tissue over a period of months. It is generally advisable to do this 20-30 minutes daily. In a majority of cases an adequate length is achievable in 6-12 months but this varies by motivation and commitment.

In a small portion of cases, neovagina creation is made via surgical reconstruction of the vagina using either peritoneum pulled down via the abdomen and connected to the opened vaginal space, or skin grafting into the neovaginal space. Success rates vary for stability of the neovagina but often molds are required to maintain the shape. If there are remnants of Mullerian structures containing functional endometrium present in the abdomen, these require surgical removal due to the high incidence of pain and endometriosis seen if there is functional endometrium in a non communicating structure.

Permanent hypogonadotropic hypogonadism

Individuals with permanent hypogonadotropic hypogonadotropism may have congenital disease resulting in no initiation of pubertal development or have a lesion or disease process that permanently destroys GnRH or gonadotropin secretion resulting in arrest of puberty. In these cases, estrogen replacement therapy should be given. In cases of initiation of pubertal development, scaled low dose estrogen should be used with progestin therapy after appropriate interval with adequate breast development. In those with arrested pubertal progression, combination hormone replacement can be initiated to induce cyclic menses.

Transient pubertal delay

Constitutional delay

The individuals with constitutional delay will undergo puberty outside of the normal range of pubertal development but will not have pathology. There is often a family history of this. They will often demonstrate signs of early pubertal progression. In these cases reassurance can be provided with reassessment in 4-6 months. If there is no progression re-evaluation of the diagnosis should be made at that time. For those that request intervention, a short course of estrogen therapy may be considered however there are little data on the long term impact of this and some data suggest possible impact on long term reproductive function for high dose estrogen in this setting. Therapy should be given for no more than 6 months and discontinued to reassess pubertal progression.

Functional gonadotropin deficiency

Delayed puberty due to chronic disease will likely respond to improvements in the medical condition. Eating disorders require careful assessment and management as mortality rates have been reported as high as 20% in some studies.These women present with weight loss >15% of ideal body weight, behavioral changes and delayed or interrupted pubertal progression. Individuals should work with counselors specially trained in the management of eating disorders. Hormone therapy is generally not recommended until response to behavioral therapy is seen but may not be needed if puberty resumes spontaneously.

Intense exercise as is seen in elite athletes can result in functional pubertal delay. Generally these individuals exhibit low body fat and delay of development which is related to the age and intensity of the exercise. Puberty resumption will usually occur with reduced activity or increase in body fat. Hormone therapy in these individuals can be considered particularly in the setting of low bone density.

4. Complications

Consequences of delayed puberty

Permanent causes

Skeletal abnormalities

Permanent causes of pubertal delay result in significant hypoestrogenism over a lifetime if they remain untreated as these individuals have no spontaneous production of estrogen. Since the majority of bone deposition occurs in adolescence and young adulthood under the influence of the normal hormonal milieu, the risk of significant bone loss is one of the major complications of delayed puberty. Hormone therapy has been shown to ameliorate the bone loss that is seen in this condition. Bone density should be monitored at periodic intervals to assess the risk for osteoporosis and monitor treatment.

Fertility

If the etiology of delayed puberty is due to premature ovarian insufficiency, there is little likelihood of spontaneous conception. Ovulation induction therapy is also not likely to result in ovulation. Oocyte donation is very successful in the management of the fertility concerns in this condition although girls with Turner Syndrome have significant cardiovascular concerns in pregnancy and morbidity and mortality are increase in these women. Consultation with cardiology prior to pregnancy is indicated in women with Turner Syndrome. Those individuals who have gonadotropin insufficiency but normal ovaries, can be successfully managed with ovulation induction using gonadotropin therapy.

Other endocrine dysfunction

Thyroid dysfunction is very common in women with premature ovarian insufficiency and should be monitored in adolescence and on a regular basis thereafter. In individuals with autoimmune cause of ovarian failure, adrenal insufficiency has been seen in approximately 4%. Monitoring for adrenal disease in these women is warranted.

Psychosocial concerns

There is some evidence that in women with premature ovarian insufficiency there is increased risk of anxiety, depression and psychological distress. They also report lower rates of sexual satisfaction. Psychological support of these individuals is very important to manage the impact the permanent nature of the condition and lack of spontaneous fertility.

Transient conditions

Skeletal impact

Reversible causes of pubertal delay will also impact the deposition of bone and lead to skeletal problems such as osteopenia and osteoporosis. Athletes are at particularly high risk of stress fractures. Without the attainment of peak bone mass hypoestrogenism seen with pubertal delay may cause irreversible low bone density over a lifetime.

Psychosocial concerns

Eating disorders are prevalent in those presenting with hypothalamic amenorrhea. There is need for continued psychological support even after treatment of the eating disorder as there is a high rate of recurrence. Stress reduction and behavioral changes have been beneficial in those diagnosed with functional hypothalamic amenorrhea.

Complications of therapy

Medical therapy

For permanent causes of pubertal delay, estrogen therapy is indicated for both pubertal induction and long term management. There is evidence however that estrogens increase thrombotic potential by increasing resistance to activated protein C and decrease antithrombin III. All types of estrogen have been associated with increased thrombotic potential but the absolute risk of deep vein thrombosis or pulmonary embolus are low. The risk of hormone replacement therapy that have been reported in postmenopausal women such as increased risk of breast cancer or cardiovascular disease are not seen in adolescents treated with hormone therapy. As in all cases where a uterus is present, there is a need for cyclic progestin therapy to allow for menstrual withdrawal as the use of unopposed estrogens is associated with an increased risk of endometrial neoplasia.

Surgical therapy

Oophorectomy is not indicated in premature ovarian insufficiency or Turner Syndrome unless there is the presence of a Y chromosome due to increased risk of gonadal tumors. In the management of vaginal agenesis, surgical neovagina construction can be associated with vaginal scarring if not well maintained. Sexual function has not been adequately compared between dilator therapy and surgical correction. Vaginal prolapse has been reported in both of these treatments.

5. Prognosis and outcome

Long-term prognosis

In individuals with premature ovarian failure as a cause of delayed puberty, amenorrhea is likely permanent and the possibility of spontaneous pregnancy is <5%.There is a possibility of pregnancy, however, while on hormone replacement therapy as there have been case reports of spontaneous ovulation while on therapy in those previously diagnosed with ovarian failure. In gonadotropin deficient patients due to hypothalamic/pituitary destruction, there is permanent amenorrhea however fertility can be restored with exogenous gonadotropins. Hormone replacement in all forms of permanent pubertal failure is indicated over reproductive life and is associated with higher bone density.

Overall treatment of the predisposing cause of pubertal delay is successful in improving reproductive and hormonal dysfunction in a majority of cases. Permanently lower bone density can be seen in those individuals who remain amenorrheic through adolescence that may be related to overall lower peak bone density achieved. Early intervention is recommended. Fertility potential in these individuals is generally normal although some studies have demonstrated ovulatory dysfunction that persists throughout adulthood in patients with eating disorders.

Impact on long-term health

The main impact on long term health in those with pubertal delay is the risk of skeletal impact with lower bone density and increased fracture risk over a lifetime. Long term hormone therapy is often required to maximize bone health. While fertility may be impacted on a permanent basis the availability of reproductive technologies allows for parenthood in most patients. Psychological support is important in the management of the condition due to the suggestion of increased psychosocial concerns.

6. What is the evidence for specific management and treatment recommendations

Mauras, N, Shulman, D, Hsiang, HY, Balagopal, P, Welch, S. "Metabolic effects of oral versus transdermal estrogen in growth hormone-treated girls with turner syndrome". J Clin Endocrinol Metab. vol. 92. 2007. pp. 4154-60.

(Trial demonstrating physiologic benefit of transdermal hormone therapy for pubertal induction.)

Davenport, ML. "Approach to the patient with Turner Syndrome". J Clin Endocrinol Metab. vol. 95. 2010. pp. 1487-95.

(Comprehensive update on the evaluation and treatment of Turner syndrome.)

Crowne, EC, SHalet, SM, Wallace, WH, Eminson, DM, Price, DA. "Final height in girls with untreated constitutional delay in in growth and puberty". Eur J Pediatr. vol. 150. 1991. pp. 708-12.

(Support for expectant management in constitutional pubertal delay in final adult height but raises the possibility of psychological concerns in these girls.)

"ACOG Committee Opinion No. 335: Vaginal Agenesis: diagnosis, management, and routine care". Obstet Gynecol. vol. 108. 2006. pp. 1605-9.

(Most recent recommendation guideline on treatment, both medical and surgical, for neovaginal creation.)

Warren, MP, Stiehl, AL. "Exercise and female adolescents: effects on the reproductive and skeletal systems". J Am Womens Assoc. vol. 54. 1999. pp. 115-20.

(Classic article on functional hypothalamic amenorrhea and impact on the reproductive and endocrine system.)

Sedlmeyer, IL, Palmert, MR. "Delayed Puberty:analysis of a large case series from an academic center". J Clin Endocrinol Metab. vol. 87. 2002. pp. 1613.

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