- •Series Editor Foreword
- •Preface
- •Contents
- •Contributors
- •Differential Diagnosis
- •Evaluation
- •Treatment
- •Discussion
- •References
- •Background
- •Normal Pubertal Stages
- •Differential Diagnosis of Precocious Puberty
- •Evaluation [1, 3, 4]
- •Treatment [1, 2]
- •Discussion
- •References
- •Background
- •Differential Diagnosis of Delayed Puberty
- •Evaluation
- •History and Physical Examination
- •Laboratory Investigation and Imaging
- •Treatment
- •Discussion
- •Suggested Readings
- •Discussion
- •Differential Diagnosis
- •References
- •Discussion
- •References
- •Differential Diagnosis
- •Evaluation
- •Treatment
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •Interpretation of Thyroid Function Tests (TFTs)
- •Iodine Supplementation for Pregnancy and Lactation
- •Screening for Maternal Hypothyroidism
- •Maternal Subclinical Hypothyroidism
- •Thyroid Autoimmunity
- •Maternal Hyperthyroidism: Diagnosis
- •Maternal Hyperthyroidism: Treatment
- •Postpartum Thyroiditis
- •Summary
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •Intrauterine Pathology
- •Thin Lining
- •Endometrial Receptivity Analysis (ERA)
- •Chronic Endometritis
- •Conclusion
- •References
- •Discussion
- •References
- •Discussion
- •History
- •Physical Exam
- •Semen Analysis
- •Laboratory Testing
- •Genetic Testing
- •Adjunctive Tests
- •Imaging
- •References
- •Discussion
- •Pathophysiology
- •Evaluation
- •Treatment
- •Lifestyle Changes
- •Medications
- •Phosphodiesterase 5 Inhibitors
- •Vacuum Erection Device
- •Intraurethral Alprostadil
- •Intracavernosal Injections
- •Surgery
- •References
- •Discussion
- •History
- •Semen Analysis
- •Physical Examination
- •Proper Varicocele Examination
- •Laboratory Investigations
- •Additional Investigations for the Pain Include
- •Other Investigations for Infertility in the Context of Varicoceles
- •Treatment
- •Indications for Varicocele Treatment Include the Following
- •Numerous Treatments for Varicocele Exist
- •References
- •Discussion
- •Semen Analysis
- •History and Physical Examination
- •Laboratory Investigations
- •Testicular Biopsy
- •Treatment
- •Surgical Techniques for Sperm Retrieval [13]
- •Fresh Vs. Frozen Sperm
- •Counseling
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Background
- •Epidemiology
- •Evaluation
- •Treatment
- •Non-ART Treatment
- •Accelerated Utilization of ART
- •ART Success Rates
- •Recent Trends in ART
- •Discussion
- •Conclusion
- •Suggested Readings
- •Evaluation
- •Differential Diagnosis
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •References
- •Discussion
- •Suggested Readings
- •Diagnosis
- •Management
- •Discussion
- •References
- •Index
Chapter 2
Precocious Puberty
Nigel Pereira
Case
A 6-year-old African American girl is brought to the of ce by her mother. The girl began breast bud development 5 months ago. Pubic hair began to appear 4 months after the appearance of breast buds. Her mother has not observed any psychosocial or developmental milestone issues. The young girl appears well on examination with Tanner stage III breast development and stage II pubic hair growth. Her height has increased by 5 cm over the last 6 months. How does a physician approach this clinical presentation?
Background
Puberty in humans is a complex physiological process that is characterized by the transition from childhood to adulthood [1, 2]. Following the completion of puberty, young males and females are considered capable of reproducing [3, 4]. Puberty is marked by the maturation of external and internal genitalia, development of secondary sexual characteristics, acceleration of linear growth velocity, and in females, the beginning of menses (menarche) [5, 6]. For the purpose of this chapter, we will limit our discussion to female puberty.
The pubertal transition in females occurs due to two processes: gonadarche and adrenarche [6]. The former is associated with the growth and maturation of the ovaries which, in turn, results in increased sex steroid hormone synthesis, follicular development, and ovulation. The latter involves maturation of the adrenal cortex,
N. Pereira (*)
Reproductive Medicine and Ob/Gyn, The Ronald Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Medical College of Cornell University, New York, NY, USA e-mail: nip9060@med.cornell.edu
© Springer Nature Switzerland AG 2023 |
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P. H. Chung, Z. Rosenwaks (eds.), Problem-Focused Reproductive Endocrinology and Infertility, Contemporary Endocrinology, https://doi.org/10.1007/978-3-031-19443-6_2
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N. Pereira |
thereby increasing adrenal androgen production, leading to the appearance of pubic hair (pubarche). The re-activation of the hypothalamic–pituitary–ovarian (HPO) axis is thought to drive gonadarche. Speci cally, increased pulsatile gonadotropin- releasing hormone (GnRH) secretion is noted during puberty, which stimulates follicle-stimulating hormone (FSH) and luteinizing hormone (LH) synthesis, resulting in downstream ovarian activity and consequently breast development (thelarche). The mechanism of adrenarche remains unknown. Of note, the absence of adrenarche in humans does not seem to impact fertility or impede the process of gonadarche [6].
Normal Pubertal Stages
In general, puberty encompasses the following sequential events: accelerated linear growth, thelarche, adrenarche, and menarche. Population-based studies have indicated that African American girls begin puberty between age 8 and 9, while Caucasian girls do so by age 10 [5, 6]. However, thelarche and/or adrenarche can occur as early as age 6 and 7 in African American and Caucasian girls, respectively. Growth spurt generally occurs 2 years prior to thelarche and can be associated with a 6–11 cm increase in height within 1 year. This phase of linear acceleration is mediated by increasing estrogens from the ovary and the secretion of growth hormone from the pituitary gland. Gonadarche and adrenarche often occur concomitantly; however, there can be discordance between the two phases even in normal pubertal development. The changes during gonadarche and adrenarche are classi-ed into ve distinct stages called the Tanner stages, ranging from stage I (prepubertal) to stage V (adult) [3, 5, 6]. These stages have been summarized in Fig. 2.1 and Table 2.1. Menarche usually occurs about 2 years after thelarche. Menstrual cycles during the rst 1–2 years are usually anovulatory and irregular, ranging between 21 and 45 days. However, within 3–5 years of menarche, most menstrual cycles are ovulatory and regular, varying between 21 and 35 days [5, 6].
Differential Diagnosis of Precocious Puberty
The most commonly accepted de nition of precocious puberty is the development of secondary sexual characteristics before the age 8. It is known that a proportion of girls can attain secondary sexual characteristics before age 8. In such girls, clinical evaluation can be considered based on clinical presentation or the anxiety of parents. However, thelarche or adrenarche before age 6 should warrant immediate clinical evaluation [3, 4]. Precocious puberty occurs ve times more often in females when compared to males, with an estimated incidence of 1 in 5000–10,000. The differential diagnoses of precocious puberty can be classi ed into two distinct categories: central precocious puberty (CPP) and peripheral precocious puberty (PPP)
2 Precocious Puberty |
13 |
Breast |
Pubic Hair |
Tanner Stage 1
Tanner Stage 2
Tanner Stage 3
Tanner Stage 4
Tanner Stage 5
Fig. 2.1 Summary of Tanner stages, ranging from stage I (pre-pubertal) to stage V (adult)
Table 2.1 Summary of the Tanner stages of pubertal development
Tanner |
|
|
stage |
Breast |
Pubic hair |
1 |
Pre-pubertal |
No pigmented hair |
|
|
|
2 |
Breast budding |
Some pigmented, coarse hair over labia majora |
|
|
|
3 |
Enlargement of breast and areolae |
Extension of pigmented, coarse hair over mons pubis |
4 |
Secondary mound of areolae |
Nearing adult pattern |
5 |
Mature contour |
Adult pattern |
[1]. CPP is also called GnRH-dependent precocious puberty, complete precocious puberty, or true precocious puberty. All these precocious puberty terms signify the same mechanism, i.e., premature activation of the HPO axis [3, 4]. Approximately, 80% of all precocious puberty cases are CPP, of which 75–90% are idiopathic in nature. PPP occurs when there is excessive secretion of sex steroids independent of the HPO axis [3, 4]. Therefore, PPP is also called GnRH-independent precocious puberty or incomplete precocious puberty. The source of sex steroids in PPP can be from exogeneous sources, tumors or genetic mutations. Table 2.2 summarizes the various causes of CPP and PPP [1, 3, 4].
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N. Pereira |
Table 2.2 Non-exhaustive differential diagnoses of central and peripheral precocious puberty
Central precocious puberty
Idiopathic
Central nervous system tumors: Craniopharyngioma, astrocytoma, hypothalamic hamartoma, ependymoma, neuro broma, luteinizing hormone-secreting adenoma
Central nervous system congenital malformations: Arachnoid cyst, hydrocephalus, myelomeningocele, suprasellar cyst, ectopic posterior pituitary lobe
Central nervous system acquires diseases: Infammatory processes such as abscess, encephalitis, meningitis, sarcoidosis, radiation, trauma
Activating genetic mutations in the KISS1R and/or KISS1 genes
Inactivating genetic mutations in the MKRN3 gene
Peripheral precocious puberty
Adrenal tumors or congenital adrenal hyperplasia Primary hypothyroidism
McCune-Albright syndrome Endocrine disruptors
Ovarian cysts or tumors Aromatase excess
Evaluation [1, 3, 4]
The evaluation of precocious puberty should always begin with a detailed clinical history, which should include the age of onset of each clinical symptom and progression of physical changes. A detailed pediatric and neonatal history should be noted. Emphasis should also be placed on any symptoms associated with central nervous system disease (CNS) such as personality changes, visual changes, polyuria, or polydipsia. Any history of CNS infectious, trauma, or accidental ingestion of hormonal contraception or supplementation should be elicited. A detailed family history should also be reviewed, including the age of puberty in parents, and/or any family members with a history of precocious puberty.
Physical examination begins with a detailed skin examination to look for any café-au-lait spots. The examination should also consist of measurements of linear growth velocity and secondary sexual characteristics as per Tanner staging. Heights should be plotted over time on a growth chart and should also be compared to mid- parental height. As noted earlier, thelarche is generally the rst sign of puberty, and therefore, the presence of rm glandular tissue under the areolae is indicative of thelarche. Basic hormonal measurement should include FSH, LH, estradiol (E2), adrenal hormones, and thyroid function tests. Assessment of bone age with a radiograph of the left hand and wrist is recommended given that bone age is advanced in precocious puberty. In general, advancement of bone age of more than 1 year or 2 standard deviations from chronological age is considered signi cant. Magnetic resonance imaging (MRI) of the brain is generally warranted for all girls below age 6 years with suspected precocious puberty. Pelvic ultrasonography is important when precocious puberty due to ovarian cysts or tumors is suspected. Testing of
2 Precocious Puberty |
15 |
Detailed History
Breast |
|
Pubic Hair |
|
No other signs |
Pubertal Signs |
No other signs |
|
of puberty |
of puberty |
||
|
Premature |
Normal |
Rapid |
Premature |
Thelarche |
Progression |
Progression |
Adrenarche |
Café-Au-Lait |
Inc LH with |
Ovarian or Adrenal |
Spots |
GnRH stim |
Tumor |
McCune Albright |
Central |
Syndrome/ |
Precocious |
Neurofibromatosis |
Puberty |
Fig. 2.2 A putative approach to investigate precocious puberty in young girls
MKRN3, DLK1, or KISS1 mutations is generally reserved for the investigation of familial precocious puberty, de ned by the occurrence of precocious puberty in more than one family member. Figure 2.2 summarizes a putative approach to investigate precocious puberty in young girls.
Clinicians should make every effort to distinguish true precocious puberty from isolated thelarche or adrenarche. Isolated thelarche is associated with the appearance of breast tissue without other signs of puberty. It is generally benign, self- limited and does not progress to precocious puberty. Isolated adrenarche is characterized by an increase in adrenal androgens, resulting in the development of axillary and pubic hair, as well as apocrine body odor, and acne. Isolated adrenarche is also benign in nature. Adrenal tumors can manifest with virilizing features such as clitoromegaly and increased pubic hair, as well as signs of glucocorticoid excess such as hypertension, weight gain, striae, and hirsutism. Due to the pulsatile nature of GnRH, random measurements of FSH or LH may provide limited information