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Puberty in cystic fibrosis
Journal of Cystic Fibrosis 18 (2019) S88 S94
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Puberty in cystic fibrosis Bracha Goldsweiga,*, Beth Kaminskib, Aniket Sidhayec, Scott M. Blackmand, Andrea Kellye a
Division of Pediatric Endocrinology, Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA Department of Pediatrics, Division of Endocrinology, University Hospitals Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106, USA Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Suite 333, Baltimore, MD 21287, USA d Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, 200 N Wolfe Street, Baltimore, MD 21287, USA e Division of Pediatric Endocrinology and Diabetes, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, 2716 South Street, Room 14363, Philadelphia, PA 19146, USA b c
A R T I C L E
I N F O
Article history: Received 7 July 2019 Revised 14 August 2019 Accepted 14 August 2019 Keywords: Cystic fibrosis Puberty Delayed puberty Growth
A B S T R A C T
Historically, delayed puberty was considered a common clinical feature of cystic fibrosis (CF). More recent reports have documented normal pubertal progression in the majority of individuals with CF. However, youth with more severe disease are still at risk for delayed puberty. Careful evaluation of pubertal development in children and adolescents with CF is important as pubertal timing impacts linear growth, bone mineral accrual, body image and psychosocial wellbeing, all of which can also be impacted directly by CF. This article reviews the physiology of puberty, timing of puberty in CF, evaluation of pubertal development, and the differential diagnosis, evaluation, and management of delayed and precocious puberty in people with CF. © 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
1. Background Puberty is the gradual development of secondary sexual characteristics and reproductive capability and the developmental stage during which a growth spurt occurs and final adult stature is ultimately achieved. Pubertal development is controlled by the hypothalamicpituitary-gonadal (HPG) axis. This axis is active during fetal development and during the first six months of life in males and the first two years of life in females. The HPG axis then becomes quiescent and remains so for the remainder of the pre-pubertal years. After this period of dormancy, puberty begins when the hypothalamus secretes gonadotropin-releasing-hormone (GnRH) in a pulsatile manner resulting in pulsatile secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increasing levels of LH stimulate testosterone production in males. Increasing levels of FSH trigger growth and maturation of seminiferous tubules involved in sperm production. In females, FSH stimulates estrogen production and ovarian follicle maturation involved in oocyte production while LH largely stimulates ovulation and progesterone production. The stimulus for pulsatile GnRH secretion from the hypothalamus is unclear but is likely multifactorial involving genetic, epigenetic and environmental factors [1]. The trend towards earlier puberty in the *Corresponding author. E-mail addresses: [email protected] (B. Goldsweig), [email protected] (B. Kaminski), [email protected] (A. Sidhaye), [email protected] (S.M. Blackman), [email protected] (A. Kelly).
general population over the past few decades may be due to improved nutrition, obesity, and/or environmental endocrine disruptors [2]. The timing of puberty impacts linear growth, bone mineral accrual, body image, and psychosocial wellbeing. Thus, a comprehensive evaluation of the child with cystic fibrosis (CF) should include consideration of pubertal status. Early reports on growth and pubertal development in children and adolescents with CF suggested that delayed puberty was common. Pubertal delay occurring in CF has largely been considered a manifestation of poor nutrition, but this relationship has not been consistently reported. A 1964 study found that the height and weight deficits in people with CF became pronounced in the pre-adolescent age group due to absence of the preadolescent growth spurt. No correlation between severity of lung disease and either weight gain or linear growth was found [3]. In the early 1970s, nutritional status was reported to be the major factor underlying the mild delay in the pubertal growth spurt in children with CF [4]. Neither study included details on pubertal milestones such as breast development or testicular growth, Table 1. Studies during the 1970s through the early 2000s continued to report delayed puberty in the CF population, Table 1. Findings of delayed breast and testicular development [5 9], delayed age at menarche [5,10 13], and delayed pubertal growth spurt [7,13,14] were reported. Some groups found a correlation between delayed puberty and nutritional status or severity of pulmonary disease while others found no specific associations. Landon et al. reported that in CF subjects with low plasma linoleic acid levels, normalization of their levels after an oral hyperalimentation program resulted in
https://doi.org/10.1016/j.jcf.2019.08.013 1569-1993/© 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
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Table 1 Studies evaluating puberty in CF. Study
N
Ages (y)
Sex
Outcome of interest
Association with pulmonary or nutrition status
Height deficit more prominent in adolescence Delayed skeletal maturity. Mildly delayed growth spurt. Mean onset of puberty: M 15.5 years, F 14.2 years Mean age at menarche: 14.4 y Delayed skeletal maturity Mean age at menarche: 14.2 y Mean age at menarche: 14.5 y Delayed Tanner stages and rise of gonadotropins by 2 4 y Mean age at menarche 14.4 y
Correlation with severity of pulmonary disease
M male F female Sproul and Huang [3]
50
0 14
M and F
Kreissl et al. [4] Mitchell-Heggs et al. [5]
53 45
0 13.8 >12
M and F M and F
Stern et al. [10] 45 Moshang and Holsclaw [11] 63 Reiter et al. [6] 106
8 24
F F M and F
Neinstein et al. [12]
40
>12
F
Landon and Rosenfeld [7]
54
12 30
M
Mahaney and McCoy [8]
50
7.5 17.4 M and F
Johannesson et al. [13]
17
21 36
F
Boas et al. [9] Aswani et al. [14]
33 30
13 17 >16
M M and F
Buntain et al. [16]
85
5 18
M and F
Kelly et al. [17]
82
8 18
M and F
Bournez et al. [18]
729
8 20
M and F
28% had delayed puberty PHV at 15 years Delayed pubertal progression Delayed age at menarche 90% Delayed skeletal age Mean age at PHV 12.9 y Mean age at menarche 14.9 y Average 2 y pubertal delay 20/33 with delayed puberty Age at PHV: M 14.6 y, F 12.6 Reached genetic potential late No difference in age at breast development, testicular growth, or menarche (13 y). M: Lower LH, FSH, testosterone Delayed skeletal age Mean age at each Tanner stage was not significantly different in CF vs controls Mildly delayed skeletal age Growth acceleration and PHV occur at same time in CF and controls
Correlation with severity of malnutrition No correlation with disease severity
Correlation with pulmonary and nutritional disease
Strongest correlation with weight, weaker with age at diagnosis, weight for height index, weight%, height%, body fat%
No correlation with disease severity
No correlation with pulmonary or nutritional status. Abnormal OGTT and homozygous del 508 associated with later age at menarche Correlation with weight < 10th %, height < 25th%, FEV1 < 60th% Correlation with general clinical status (not FEV1).
Delayed skeletal age associated with nutritional status but not lung disease
Abbreviations: PHV = Peak height velocity.
significant weight gain, resolution of primary amenorrhea in 3 girls, and normalization of irregular menses in 2 girls supporting the idea that poor nutrition was driving the delayed puberty in CF [15]. The more recent studies starting in the mid-2000s report normal pubertal timing in youth with CF. Normal age at each Tanner stage was found in CF adolescents compared to healthy controls [16,17], and normal age at menarche was also found [16]. The most recent study in a French cohort published in 2012 demonstrated that the timing of growth acceleration and peak height velocity was the same in the CF population compared to healthy controls [18]. These newer data emphasize that the CF clinician cannot assume that pubertal abnormalities in CF patients are inherent to their underlying disease. Additionally, patients with poorly controlled diabetes and CF-related liver disease are predisposed to malnutrition and may be at higher risk of abnormal pubertal development. Evaluating timing of pubertal milestones in CF patients and referral for endocrine evaluation, if necessary, are important to avoid exacerbating potential problems such as poor body image, sub-optimal linear growth, and compromised peak bone mass. Interestingly, cystic fibrosis transmembrane conductance regulator protein (CFTR) expression is found in the rat [19] and human hypothalamus [20] suggesting that CFTR could play a role in GnRH secretion and pubertal development. A role for CFTR in hypothalamic function is further suggested by an in vitro study demonstrating inhibition of GnRH secretion when CFTR expression is inhibited in a hypothalamic GNRH cell line [21]. Additionally, CFTR knockout mice demonstrated delayed puberty as assessed by timing of vaginal opening compared to wild type mice [22]. CFTR is not expressed in the ovaries and is unlikely to play a direct role in primary ovarian function [23]. Male
infertility in CF is caused by absence of the vas deferens that leads to azoospermia [24]. The mechanism for this anatomical abnormality is unknown. Some researchers have suggested that development of the HPG axis and GnRH secretion in fetal life could play a role, but absence of the vas deferens is not a feature of other disorders of HPG axis including congenital hypopituitarism and Kallman syndrome. Despite these in vivo findings, the majority of CF patients now have normal pubertal timing, even in the absence of functional CFTR, and CFTR is unlikely to have an important direct role in pubertal development. 2. Definitions/clinical presentation: precocious and delayed puberty The progressive physical changes that occur during puberty are described using the Sexual Maturity Rating of Marshall and Tanner (otherwise known as Tanner staging) system (Figs. 1, 2) [25,26] and measurement of testicular volume [27]. 2.1. Female puberty The majority of females begin puberty between 9 and 12 years of age with the first sign being breast enlargement (thelarche). The average age of breast budding in Caucasian females is 10.5 years and in African-American girls approximately 9.5 years. Thelarche is followed by pubic hair growth and menarche. Peak height velocity in girls is approximately 8 cm per year and occurs on average 6 12 month prior to menarche. Mean age at menarche is 12.9 years in Caucasian girls and 12.2 years in African-American girls (Table 2) [28].
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B. Goldsweig et al. / Journal of Cystic Fibrosis 18 (2019) S88 S94 Table 2 Age (y) of average, delayed, and precocious pubertal onset.
Females Thelarche (TS 2 breast) Menarche
Average Onset
Delayed
Precocious
African American: 9.5 y Caucasian: 10.5 y African American: 12.2 y Caucasian: 12.9 y
13 y
African American: 7 y Caucasian: 8 y
>4 years
Time from TS 2 breast to menarche
Fig. 1. Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In Sperling M, ed. Pediatric endocrinology. 3rd Edition. Philadelphia, PA: Elsevier;2008:530 609.
2.1.1. Delayed puberty Delayed puberty in girls is defined as the absence of breast development by 2 to 2.5 standard deviations later than the population mean. Absence of breast buds by age 13 years or slow progression towards further stages of sexual maturity are signs of this delay. Development of pubic hair is not considered in the definition because pubarche results from maturation of the adrenal gland (adrenarche) and occurs independently of activation of the HPG-axis. Axillary hair, acne, and adult body odor are manifestations of adrenal gland maturation as well. Any female with absence of breast buds by age 13 years, or primary amenorrhea at age 16 years, or >4 years after thelarche, should be referred for endocrine evaluation.
2.1.2. Precocious puberty On the other end of the spectrum, precocious puberty is defined as the onset of puberty at an age that is 2 to 2.5 standard deviations earlier than the population mean. Typically, precocious puberty is defined as breast development in girls prior to age 8 years [28] and is an indication for endocrine referral. African-American girls are more likely to start pubertal development before age 8 years than Caucasian girls; thus, precocious puberty tends to evaluated in African-
Males Testes >3 cc Time from testes>3 cc to testicular volume 20 25 cc
16 y
11.5 y
14 y >4 y
<9 y
Abbreviations: TS = Tanner stage.
dPTage merican girls only if puberty starts prior to age 7 years [29] (Table 2). A Puberty that begins at the normal time but progresses unusually rapidly is also considered precocious. 2.2. Male puberty Pubertal development starts later in males—generally, between the ages of 10 and 13 years. The first observable change is testicular enlargement; pubic hair development and penile growth then manifest. Testicular enlargement is first seen at an average age of 11.5 years. Peak height velocity is about 9 cm per year and occurs at approximately 13.5 years of age [28] (Table 2). 2.2.1. Delayed puberty Delayed puberty in boys is defined as the absence of testicular enlargement at an age that is beyond 2 to 2.5 standard deviations from the population mean. Absence of testicular development by age 14 years or early testicular development with a long lag before further testicular enlargement, penile growth, or pubic hair development define this delayed pubertal status. Frequently boys present for short stature alone, and further history and physical exam reveal delayed pubertal milestones. The growth chart often shows faltering linear growth around 11 13 years of age due to absence of the pubertal growth spurt that typically starts around that time. Boys without testicular development by age 14 years, with slowly progressing puberty, or with a decline in height percentiles in the preteen or early teen years should be referred for endocrine evaluation. 2.2.2. Precocious puberty Precocious puberty in boys is defined as the onset of puberty at an age that is 2 to 2.5 standard deviations earlier than the population mean. Typically, precocious puberty is defined as testicular development in boys prior to age 9 years. The presentation of precocious puberty may include early onset of physical development, accelerated growth, or rapid progression of pubertal milestones and always requires an endocrine evaluation. 3. Prevalence 3.1. Delayed puberty
Fig. 2. Rosen DS. Physiologic growth and development during adolescence. Pediatr Rev 2004 Jun;25 [6]:194 200. https://doi.org/10.1542/pir.25-6-194.
The prevalence of delayed puberty in healthy individuals is by definition 5%. In a retrospective study of adolescents presenting to an academic pediatric endocrinology center 53% of subjects had constitutional delay (63% of males and 30% of females), 19% had functional hypogonadism, 13% had primary hypogonadism, 12% had various causes of permanent hypogonadotropic hypogonadism and 3% were undetermined [30]. The studies of puberty timing in CF measured various aspects of pubertal timing in CF (Table 1) but only a few have
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looked at prevalence. However, the earlier findings of delayed pubertal milestones in CF compared to healthy controls suggests a higher prevalence of delayed puberty. In 1991, a group investigating the psychological impact of short stature and delayed puberty in people with CF found a prevalence of delayed puberty in 20% of the subjects [31]. Other studies found prevalence rates of 28% [7] and 60% [9]. More recently in 2008, in a study measuring bone mineral content in CF youth, the mean age at each Tanner stage was found to be the same in people with CF and healthy controls [17]. This report suggests that the prevalence of delayed puberty in CF should be around that of the general population. Studies examining causes of delayed puberty in CF report varying degrees of association with BMI, general nutritional status, pulmonary health and glucose tolerance. No studies have sought to determine the prevalence of other organic etiologies of delayed puberty in CF. 3.2. Precocious puberty No studies have documented the prevalence of precocious puberty in CF. During the years when malnutrition was common in CF patients, rates were likely to be extremely low. With current improvements in nutritional status the numbers may be similar to the general population with a prevalence of 5%. 4. Differential diagnosis 4.1. Delayed puberty Delayed puberty results from either a lack of pubertal maturation of the HPG axis (also called hypogonadotropic hypogonadism) or primary gonadal dysfunction (also called hypergonadotropic hypogonadism). Pubertal delay may be a manifestation of permanent hypogonadism requiring lifelong treatment or may be transient with potential for subsequently normal gonadal function. Hypogonadotropic hypogonadism, also called central hypogonadism or secondary hypogonadism, is characterized by deficient GnRH secretion from the hypothalamus leading to decreased LH and FSH secretion from the pituitary gland and inadequate testosterone or estradiol production. The most common cause of delayed puberty is constitutional delay of growth and puberty (CDGP) which is temporary and more common in boys than in girls. People with constitutional delay have a transient functional defect in GnRH production and often have a family history of pubertal and growth delay also referred to as late bloomers. Hypogonadotropic hypogonadism may also be caused by functional hypogonadism in the context of an eating disorder, excessive exercise or chronic disease such as inflammatory bowel disease or CF. In functional hypogonadism, inadequate weight gain is usually a contributing factor. Decreased body fat results in decreased leptin concentrations and gonadotropin deficiency [32]. A critical weight may also be necessary before menarche can occur [33]. Malnutrition causing functional hypogonadism is likely the etiology of delayed puberty seen in some individuals with CF. Another possible etiology for delayed puberty is isolated gonadotropin deficiency. Constitutional delay and gonadotropin deficiency present similarly and may be difficult to distinguish, but in the absence of testicular development or breast development by age 17 years constitutional delay becomes unlikely and permanent hypogonadism should be expected. Lastly, other diseases of the pituitary gland or hypothalamus such as tumors, congenital malformations, or hyperprolactinemia may lead to GnRH or gonadotropin deficiency (Table 3). Hypergonadotropic hypogonadism caused by primary gonadal failure is characterized by low testosterone or estradiol with elevated LH and FSH levels. Primary gonadal failure may be secondary to Turner syndrome in girls or Klinefelter syndrome in boys. Turner syndrome (karyotype 45,X or mosaicism) occurs in approximately 1 in 2500 live female births and usually causes primary gonadal failure along with short stature, an increased risk of congenital heart disease
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Table 3 Delayed Puberty Causes and evaluation of Delayed Puberty Primary (hypergonadotropic hypogonadism) Congenital: Turner syndrome (45, X) Klinefelter syndrome (47, XXY) Anorchia or cryptorchidism Disorders of testosterone biosynthesis LH or FSH receptor defects Acquired: Autoimmune gonadal failure Trauma Chemotherapy or radiation Bilateral testicular torsion Secondary (hypogonadotropic hypogonadism) Congenital: Congenital malformations (optic nerve hypoplasia syndrome, etc) Isolated GnRH deficiency (with anosmia – Kallmann syndrome) Multiple pituitary hormone deficiencies Acquired: Constitutional delay of growth and puberty Chronic disease (inflammatory bowel disease, cystic fibrosis) Malnutrition (eating disorder, poverty) Hypothyroidism Hyperprolactinemia Tumors (craniopharyngioma, etc) Head trauma Chemotherapy or cranial radiation
Evaluation Medical History Physical Exam Weight, height, growth velocity pubertal staging Laboratory Testing CBC Comprehensive metabolic panel Celiac screening LH, FSH Estradiol/testosterone IGF-1, IGFBP-3 TSH, free T4 Prolactin Karyotype Imaging Bone age x-ray Brain MRI (hypothalamus/pituitary)
and lymphedema among other features. Two women with CF and Turner syndrome have been reported in the literature. Both women were diagnosed with CF in infancy and Turner syndrome in their teenage years as part of an evaluation for short stature [34]. Klinefelter syndrome (karyotype 47,XXY or XY/XXY mosaicism) occurs in approximately 1 in 1000 live male births and causes primary gonadal failure along with tall stature and sometimes behavioral problems and learning difficulties. A man with mosaic Klinefelter syndrome and cystic fibrosis has been reported [35]. These reports are important reminders to not assume delayed puberty and infertility are solely attributable to CF. Additional causes of hypergonadotropic hypogonadism are listed in Table 3. 4.2. Precocious puberty Precocious puberty can be divided into central causes secondary to premature activation of the HPG axis and peripheral causes secondary to secretion of sex hormones that is independent of stimulation from the pituitary. Several variants of normal puberty present with features of precocious puberty but are non-progressive and considered benign. Central precocious puberty (CPP) caused by early maturation of the HPG axis leads to early onset of puberty that progresses with a normal pattern and timing. CPP is idiopathic in 80 90% of girls and 25 60% of boys [36]. The major worry is that a CNS mass requiring urgent evaluation underlies CPP. Additional potential acquired and genetic defects that are associated with CPP are listed in Table 4. Peripheral precocious puberty occurs in the absence of activation of the HPG axis and is caused by autonomous production of sex
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determined based on the differential diagnosis generated by the history and physical exam (Tables 3 and 4).
Table 4 Precocious Puberty Causes and evaluation of Precocious Puberty
6. Routine management
Central (gonadotropin-dependent) Congenital: Optic nerve hypoplasia Hydrocephalus Arachnoid cysts Acquired: Idiopathic Hamartomas, other tumors CNS trauma CNS radiation Pituitary inflammation Peripheral (gonadotropin-independent) Congenital Activating LH receptor mutation (testotoxicosis) McCune-Albright Syndrome Congenital adrenal hyperplasia Acquired: Follicular ovarian cysts Tumors (granulosa cell, Leydig cell, germ cell, adrenal, HCG-secreting) Hypothyroidism Exogenous sex steroids
6.1. Delayed puberty
Evaluation Medical History Physical Exam Weight, height, growth velocity pubertal staging Laboratory Testing LH, FSH Estradiol/testosterone TSH, free T4 17 hydroxyprogesterone, DHEAS Imaging Bone age x-ray Brain MRI (hypothalamus/pituitary) Ovarian, testicular, or adrenal ultrasound
steroids from the gonads or adrenal glands, exogenous sources of sex steroids, or from stimulation of the gonads by hormones that crosstalk with the gonadotropin receptors (beta-hCG, TSH). Physical signs of puberty may occur in an unusual order or more rapidly than is normal. Causes include follicular ovarian cysts, hormone secreting tumors, exposure to exogenous sex steroids, hypothyroidism and rare genetic disorders (Table 4). Several normal variants of puberty present similarly to precocious puberty but do not require intervention. Premature thelarche is isolated, non-progressive breast development that typically occurs in the first two years of life or between 6 and 8 years of age. No other signs of puberty are present, growth velocity is normal, skeletal age is not advanced, and gonadotropins and estradiol are in the pre-pubertal range. Premature adrenarche is characterized by development of pubic hair, axillary hair, acne and/or body odor prior to the normal age of puberty. Signs of central puberty are absent. Mild acceleration of linear growth and a mildly advanced skeletal age may be present. Dehydroepiandrosterone sulfate (DHEAS) may be mildly elevated, but gonadotropins and other androgens are in the pre-pubertal range. 5. Diagnostic work up Monitoring of pubertal status in people with CF is important in order to avoid negative sequelae of early or late development. The evaluation for both delayed and precocious puberty starts with a careful medical history and physical exam. Specific attention should be given to the neurological exam to evaluate for central nervous system causes of pubertal abnormalities. Breast development/testicular enlargement and pubic hair growth should be staged separately as shown in Figs. 1 and 2. Endocrinologists measure testicular size using a Prader orchidometer. Outside endocrinology clinics, a self-assessment questionnaire is sometimes used to categorize pubertal stages [37]. While this questionnaire is a validated tool for pubertal assessment, physical exam by a medical provider is more accurate particularly for measuring testicular size [30]. When the clinical assessment is consistent with delayed or precocious puberty in a patient with CF, a biochemical evaluation of the HPG axis is necessary. Additional laboratory measurements and imaging should be
Treatment of delayed puberty depends on the underlying etiology and whether puberty is expected to progress spontaneously. If a specific cause is identified such as hypothyroidism, inflammatory bowel disease or a prolactinoma, addressing the underlying issue will often be all the treatment that is required for puberty to progress normally. For patients with CF, determining if coexisting malnutrition is a contributing factor in delayed pubertal development is important. In girls, if permanent hypogonadism is suspected, pubertal induction using exogenous hormones is indicated to ensure typical development of secondary sexual characteristics, normal pubertal growth spurt, appropriate psychosocial adjustment and optimal bone mineral accrual. Estrogen is replaced in small doses transdermally; the dose is then gradually increased every 6 months over 3 4 years until an adult dose is reached [38]. After two years of estradiol therapy or when menstruation starts, cyclic progesterone is added to the regimen. In boys, when permanent hypogonadism is suspected, pubertal changes are induced using exogenous testosterone. Testosterone is started in low doses and then increased every 6 12 months to mimic the physiologic increases in testosterone levels that would occur if the HPG axis were functioning properly. Testosterone is available as an intramuscular (IM) injection and as a transdermal gel or patch. In some countries, although not the United States, it is available in an oral form. In adolescents, the injectable form has been the most well studied and is used most commonly. Alternative modes of treatment for delayed puberty in males and females that more closely mirror physiological processes are being investigated. These options include GnRH, hCG (with biological activity of LH), recombinant FSH and kisspeptin-10 [1]. If constitutional delay is suspected based on family history and normal diagnostic work-up the options are either watchful waiting or a short-term course of testosterone or estrogen to attempt to stimulate central puberty. The above described regimens with estradiol or testosterone can be initiated for 6 12 months and then discontinued. Patients with permanent hypogonadism usually have minimal pubertal progression on low doses of sex steroids. However, patients with CDGP will often have activation of the HPG system and will continue to progress through puberty once exogenous sex steroids are discontinued. This method is more effective in boys than in girls. 6.2. Precocious puberty Treatment of precocious puberty depends on the etiology. If the inciting cause is identified it should be addressed medically or surgically as indicated. Central precocious puberty is treated with a GnRH agonist which inhibits gonadotropin secretion. GnRH agonists are available as an intramuscular injection administered monthly, every 3 months or every 6 months or as a subcutaneous implant that is placed surgically and lasts for at least 12 months. Treatment of peripheral precocious puberty is specific to the underlying cause. 7. Complications and their management Delayed puberty is often associated with delayed growth and sometimes with short adult stature in boys and girls [39,40]. People with CF have other risk factors for poor growth including malnutrition, chronic inflammation, and frequent steroid courses which may be exacerbated by delayed puberty [41]. Thus, evaluation of growth parameters and growth hormone axis are important. Use of growth hormone as an adjunct therapy in otherwise healthy patients with pubertal delay is controversial and benefits are unclear. Some
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evidence suggests use of growth hormone in people with CF, regardless of pubertal timing, leads to improvements in height, weight, and lean body mass [42]. However, the data are inconsistent, and use of growth hormone should only be considered on a case by case basis. Further discussion of growth hormone is covered in article 11, section 4, Growth Failure and Treatment in CF, [50]. Several studies have found that delayed increase in sex steroids is associated with lower bone mineral density and an increased risk of fracture in adolescence and adulthood [43,44]. People with CF are already at increased risk for osteopenia and osteoporosis [17], and gonadal issues may compound this underlying predisposition for CF bone disease. McCormack et al. demonstrated that healthy adolescents gain a substantial proportion of their bone mineral content during pubertal growth [45]. Similarly, Bianchi et al. showed that the maximum increase in bone mineral content and density occurred during puberty in people with CF, data that highlight the critical role of hormonal changes during puberty and their potent stimulus on bone mineral accrual [46]. Treatment of delayed puberty caused by functional hypogonadism with supplemental hormones has not been shown to improve bone mineral density in the general population but has not been studied specifically in CF. Therefore, bone health alone may not be an indication to start hormonal treatment. Delayed puberty and hypogonadism may be a factor to include when considering whether a specific patient with CF would benefit from treatment of osteopenia and in the interpretation of dual energy x-ray absorptiometry [47]. Further discussion of CF bone disease and vitamin D supplementation are discussed in separate articles in this issue [51]. Lastly, delayed puberty can impact the psychosocial well-being of the individual and potentially contribute to lower self-image, increased internalizing symptoms, and poorer academic performance although long lasting effects into adulthood have not been demonstrated [43]. Delayed puberty may compound already existing feeling of isolation and difference in people with CF. One study showed patients with CF and delayed growth and puberty were less likely to participate in certain social activities and had a less positive body attitude [31]. The psychological impact of delayed pubertal development should be considered when deciding if or when to start supplemental hormones for pubertal induction. 8. Potential impact of CFTR modulation CFTR modulator therapies are improving clinical outcomes in people with CF. CFTR potentiator and corrector therapies improve lung function and nutritional status in patients with CF [48]. If the main cause of delayed puberty in CF is due to malnutrition and low weight, then improvement in CFTR function could lead to a normalization in pubertal timing. However, some studies found that delayed puberty in CF was not associated with nutritional status [13]. This finding along with evidence that CFTR is expressed in the human hypothalamus raises the possibility that delayed puberty in CF could be secondary to abnormal CFTR function involved in the HPG axis. In addition, a study in a CF mouse model showed that mice with truncated CFTR mRNA had delayed pubertal timing measured by vaginal opening [22]. Whether delayed puberty in CF is secondary to malnutrition or CFTR dysfunction, CFTR modulators have the potential to impact pubertal timing. Within the next decade it will be possible to study pubertal timing in CF patients who are on CFTR modulators from a young age. 9. Future directions Based on available data, significant pubertal delay appears to occur much less commonly in CF and is restricted to the sickest patients. With the introduction of CFTR modulators at younger ages, pubertal delay may become even less common. With improving health, overweight and obesity are emerging complications in our youth with CF; overweight was reported in 15% and obesity in 8% of pediatric patients
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at one center [49]. Given that obesity is associated with earlier onset of puberty in girls but later onset of puberty in boys [2], pubertal timing may also be impacted in youth with CF. A large, multicenter study investigating pubertal timing in CF patients, including those who start on modulator drugs at a young age, will help clarify the current prevalence of delayed and precocious puberty in CF and if there is any association with malnutrition or obesity. Timing of puberty could potentially be tracked through the Cystic Fibrosis Foundation Patient Registry. 10. Clinical practice points Patients with CF should be screened for delayed puberty due to the impact on growth, bone health and psychosocial well-being. Special attention should be directed at screening for delayed puberty in groups that may be higher risk such as malnourished patients, those with abnormal glucose tolerance, or CF liver disease. A diagnosis of delayed puberty should be considered in pre-teens or adolescents with poor linear growth. Pubertal abnormalities in people with CF require full evaluation and should not be attributed to CF alone.
11. Summary Historically, delayed puberty was considered a common complication of CF. Studies were mixed regarding whether delayed puberty was associated with poor nutrition, low weight or other factors. However, newer data in more recent cohorts of CF patients show normalization of pubertal timing which may be secondary to improved nutrition. Delayed puberty has important effects on growth, bone health and psychological well-being. These issues make screening CF teens for delayed puberty important even if pubertal delay only occurs at the same prevalence as the general population (5%). Future, larger studies evaluating pubertal timing in CF patients, including those who have been on CF modulators from a young age, will further clarify the current prevalence of delayed and precocious puberty in CF. Declaration of Competing Interest None. Funding This paper is part of a Supplement supported by the Cystic Fibrosis Foundation. Acknowledgements The authors would like to express appreciation to the Cystic Fibrosis Foundation for grant support through the EnVision: Emerging Leaders in CF Endocrinology Program. Thank you to the EnVision faculty members for their continuing support and mentorship of the program awardees. References [1] Wei C, Crowne CE. Recent advances in the understanding and management of delayed puberty. Arch Dis Child 2016;101(5):481–8. [2] Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? Lancet Child Adolesc Health 2019;3(1):44–54. [3] Sproul A, Huang N. Growth patterns in children with cystic fibrosis. J Pediart 1964;65:664–76. [4] Kreissl T, Bender SW, Morchen R, Hovels O. The physical development of children with cystic fibrosis. Z Kinderheilkd 1972;113(2):93–110. [5] Mitchell-Heggs P, Mearns M, Batten JC. Cystic fibrosis in adolescents and adults. Q J Med 1976;45(179):479–504. [6] Reiter EO, Stern RC, Root AW. The reproductive endocrine system in cystic fibrosis. Am J Dis Child 1981;135(5):422–6. [7] Landon C, Rosenfeld RG. Short stature and pubertal delay in male adolescents with cystic fibrosis. Androgen treatment. Am J Dis Child 1984;138(4):388–91.
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[8] Mahaney MC, McCoy KS. Developmental delays and pulmonary disease severity in cystic fibrosis. Hum Biol 1986;58(3):445–60. [9] Boas SR, Fulton JA, Koehler AN, Orenstein DM. Nutrition and pulmonary function predictors of delayed puberty in adolescent males with cystic fibrosis. Clin Pediatr (Phila) 1998;37(9):573–6. [10] Stern RC, Boat TF, Doershuk CF, Tucker AS, Primiano FP, Matthews LW. Course of cystic fibrosis in 95 patients. J Pediatr 1976;89(3):406–11. [11] Moshang T, Holsclaw Jr. DS. Menarchal determinants in cystic fibrosis. Am J Dis Child 1980;134(12):1139–42. [12] Neinstein LS, Stewart D, Wang CI, Johnson I. Menstrual dysfunction in cystic fibrosis. J Adolesc Health Care 1983;4(3):153–7. [13] Johannesson M, Gottlieb C, Hjelte L. Delayed puberty in girls with cystic fibrosis despite good clinical status. Pediatrics 1997;99(1):29–34. [14] Aswani N, Taylor CJ, McGaw J, Pickering M, Rigby AS. Pubertal growth and development in cystic fibrosis: a retrospective review. Acta Paediatr 2003;92(9):1029–32. [15] Landon C, Kerner JA, Castillo R, Adams L, Whalen R, Lewiston NJ. Oral correction of essential fatty acid deficiency in cystic fibrosis. J Parenter Enteral Nutr 1981;5 (6):501–4. [16] Buntain HM, Greer RM, Wong JC, Schluter PJ, Batch J, Lewindon P, et al. Pubertal development and its influences on bone mineral density in Australian children and adolescents with cystic fibrosis. J Paediatr Child Health 2005;41(7):317–22. [17] Kelly A, Schall JI, Stallings VA, Zemel BS. Deficits in bone mineral content in children and adolescents with cystic fibrosis are related to height deficits. J Clin Densitom 2008;11(4):581–9. [18] Bournez M, Bellis G, Huet F. Growth during puberty in cystic fibrosis: a retrospective evaluation of a French cohort. Arch Dis Child 2012;97(8):714–20. [19] Mulberg AE, Resta LP, Wiedner EB, Altschuler SM, Jefferson DM, Broussard DL. Expression and localization of the cystic fibrosis transmembrane conductance regulator mRNA and its protein in rat brain. J Clin Invest 1995;96(1):646–52. [20] Mulberg AE, Weyler RT, Altschuler SM, Hyde TM. Cystic fibrosis transmembrane conductance regulator expression in human hypothalamus. Neuroreport 1998;9 (1):141–4. [21] Weyler RT, Yurko-Mauro KA, Rubenstein R, Kollen WJ, Reenstra W, Altschuler SM, et al. CFTR is functionally active in GnRH-expressing GT1-7 hypothalamic neurons. Am J Physiol 1999;277(3):C563–71. [22] Jin R, Hodges CA, Drumm ML, Palmert MR. The cystic fibrosis transmembrane conductance regulator (Cftr) modulates the timing of puberty in mice. J Med Genet 2006;43(6):e29. [23] Tizzano EF, Silver MM, Chitayat D, Benichou JC, Buchwald M. Differential cellular expression of cystic fibrosis transmembrane regulator in human reproductive tissues. Clues for the infertility in patients with cystic fibrosis. Am J Pathol 1994;144 (5):906–14. [24] Kaplan E, Shwachman H, Perlmutter AD, Rule A, Khaw KT, Holsclaw DS. Reproductive failure in males with cystic fibrosis. N Engl J Med 1968;279(2):65–9. [25] Rosen DS. Physiologic growth and development during adolescence. Pediatr Rev 2004;25(6):194–200. [26] Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In: Sperling MA, editor. Pediatric endocrinology. 3rd ed. Philadelphia, PA: Elsevier; 2008. [27] Biro FM, Lucky AW, Huster GA, Morrison JA. Pubertal staging in boys. J Pediatr 1995;127(1):100–2. [28] Bordini B, Rosenfield RL. Normal pubertal development: part II: clinical aspects of puberty. Pediatr Rev 2011;32:281–92. [29] Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatric research in office settings network. Pediatrics 1997;99(4):505–12. [30] Sedlmeyer IL, Palmert MR. Delayed puberty: analysis of a large case series from an academic center. J Clin Endocrinol Metab 2002;87(4):1612–20.
[31] Sinnema G, Van der Laag H, Stoop JW. Psychological development as related to puberty, body height and severity of illness in adolescents with cystic fibrosis. Isr J Med Sci 1991;27(4):186–91. [32] Welt CK, Chan JL, Bullen J, Murphy R, Smith P, DePaoli AM, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351 (10):987–97. [33] Frisch RE, Revelle R. Height and weight at menarche and a hypothesis of menarche. Arch Dis Child 1971;46(249):695–701. [34] Steppberger K, Schuster V, Kiess W. Growth failure and diabetes in cystic fibrosis: have you considered turner syndrome? Acta Paediatr 2003;92(9):1111. [35] Shwachman H, Lamarche PH, Dartley SE. Mosaic Klinefelter syndrome in an adult with cystic fibrosis. Johns Hopkins Med J 1982;150(3):120–2. [36] Choi KH, Chung SJ, Kang MJ, Yoon JY, Lee JE, Lee YA, et al. Boys with precocious or early puberty: incidence of pathological brain magnetic resonance imaging findings and factors related to newly developed brain lesions. Ann Pediatr Endocrinol Metab 2013;18(4):183–90. [37] Morris NM, Udry JR. Validation of a self-administered instrument to assess stage of adolescent development. J Youth Adolesc 1980;9(3):271–80. [38] Torres-Santiago L, Mericq V, Taboada M, Unanue N, Klein KO, Singh R, et al. Metabolic effects of oral versus transdermal 17b-estradiol (E₂): a randomized clinical trial in girls with turner syndrome. J Clin Endocrinol Metab 2013;98(7):2716–24. [39] Crowne EC, Shalet SM, Wallace WH, Eminson DM, Price DA. Final height in boys with untreated constitutional delay in growth and puberty. Arch Dis Child 1990;65(10):1109–12. [40] Crowne EC, Sm Shalet, Wallace WH, Eminson DM, Price DA. Final height in girls with untreated constitutional delay in growth and puberty. Eur J Pediatr 1991;150(10):708–12. [41] Wong SC, Dobie R, Altowati MA, Werther GA, Farquharson C, Ahmed SF. Growth and the growth hormone-insulin like growth factor 1 axis in children with chronic inflammation: current evidence, gaps in knowledge, and future directions. Endocr Rev 2016;37(1):62–110. [42] Thaker V, Carter B, Putman M. Recombinant growth hormone therapy for cystic fibrosis in children and young adults. Cochrane Database Syst Rev 2018(12). [43] Zhu J, Chan YM. Adult consequences of self-limited delayed puberty. Pediatrics 2017;139(6). [44] Cousminer DL, Mitchell JA, Chesi A, Roy SM, Kalkwarf HJ, Lappe JM, et al. Genetically determined later puberty impacts lowered bone mineral density in childhood and adulthood. J Bone Miner Res 2018;33(3):430–6. [45] McCormack SE, Cousminer DL, Chesi A, Mitchell JA, Roy SM, Kalkwarf HJ, et al. Association between linear growth and bone accrual in a diverse cohort of children and adolescents. JAMA Pediatr 2017;171(9). [46] Bianchi ML, Romano G, Saraifoger S, Costantini D, Limonta C, Colombo C. BMD and body composition in children and young patients affected by cystic fibrosis. J Bone Miner Res 2006;21(3):388–96. [47] Shepherd JA, Schousboe JT, Broy SB, Engelke K, Leslie WD. Executive summary of the 2015 ISCD position development conference on advanced measures from DXA and QCT: fracture prediction beyond BMD. J Clin Densitom 2015;18(3): 274–86. [48] Wu HX, Zhu M, Xiong XF, Wei J, Zhuo KQ, Cheng DY. Efficacy and safety of CFTR corrector and potentiator combination therapy in patients with cystic fibrosis for the F508del-CFTR homozygous mutation: a systematic review and meta-analysis. Adv Ther 2019;36(2):451–61. [49] Hanna T, Roth CL. Overweight and obesity in patients with cystic fibrosis: a center-based analysis. Pediatr Pulmonol 2015;50(1):35–41. [50] Le TN, Anabtawi A, Putman MS, Tangpricha V, Stalvey MS. Growth failure and treatment in cystic fibrosis. J Cyst Fibros 2019;18(S2):S82–7. [51] Daley T, Hughan K, Rayas M, Kelly A, Tangpricha V. Vitamin D deficiency and its treatment in cystic fibrosis. J Cyst Fibros 2019;18(S2):S66–73.
Contents lists available at ScienceDirect
Journal of Cystic Fibrosis journal homepage: www.elsevier.com/locate/jcf
Puberty in cystic fibrosis Bracha Goldsweiga,*, Beth Kaminskib, Aniket Sidhayec, Scott M. Blackmand, Andrea Kellye a
Division of Pediatric Endocrinology, Children's Hospital and Medical Center, 8200 Dodge Street, Omaha, NE 68114, USA Department of Pediatrics, Division of Endocrinology, University Hospitals Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106, USA Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Suite 333, Baltimore, MD 21287, USA d Division of Pediatric Endocrinology, Johns Hopkins University School of Medicine, 200 N Wolfe Street, Baltimore, MD 21287, USA e Division of Pediatric Endocrinology and Diabetes, Children's Hospital of Philadelphia, University of Pennsylvania, Perelman School of Medicine, 2716 South Street, Room 14363, Philadelphia, PA 19146, USA b c
A R T I C L E
I N F O
Article history: Received 7 July 2019 Revised 14 August 2019 Accepted 14 August 2019 Keywords: Cystic fibrosis Puberty Delayed puberty Growth
A B S T R A C T
Historically, delayed puberty was considered a common clinical feature of cystic fibrosis (CF). More recent reports have documented normal pubertal progression in the majority of individuals with CF. However, youth with more severe disease are still at risk for delayed puberty. Careful evaluation of pubertal development in children and adolescents with CF is important as pubertal timing impacts linear growth, bone mineral accrual, body image and psychosocial wellbeing, all of which can also be impacted directly by CF. This article reviews the physiology of puberty, timing of puberty in CF, evaluation of pubertal development, and the differential diagnosis, evaluation, and management of delayed and precocious puberty in people with CF. © 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
1. Background Puberty is the gradual development of secondary sexual characteristics and reproductive capability and the developmental stage during which a growth spurt occurs and final adult stature is ultimately achieved. Pubertal development is controlled by the hypothalamicpituitary-gonadal (HPG) axis. This axis is active during fetal development and during the first six months of life in males and the first two years of life in females. The HPG axis then becomes quiescent and remains so for the remainder of the pre-pubertal years. After this period of dormancy, puberty begins when the hypothalamus secretes gonadotropin-releasing-hormone (GnRH) in a pulsatile manner resulting in pulsatile secretion of the pituitary gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Increasing levels of LH stimulate testosterone production in males. Increasing levels of FSH trigger growth and maturation of seminiferous tubules involved in sperm production. In females, FSH stimulates estrogen production and ovarian follicle maturation involved in oocyte production while LH largely stimulates ovulation and progesterone production. The stimulus for pulsatile GnRH secretion from the hypothalamus is unclear but is likely multifactorial involving genetic, epigenetic and environmental factors [1]. The trend towards earlier puberty in the *Corresponding author. E-mail addresses: [email protected] (B. Goldsweig), [email protected] (B. Kaminski), [email protected] (A. Sidhaye), [email protected] (S.M. Blackman), [email protected] (A. Kelly).
general population over the past few decades may be due to improved nutrition, obesity, and/or environmental endocrine disruptors [2]. The timing of puberty impacts linear growth, bone mineral accrual, body image, and psychosocial wellbeing. Thus, a comprehensive evaluation of the child with cystic fibrosis (CF) should include consideration of pubertal status. Early reports on growth and pubertal development in children and adolescents with CF suggested that delayed puberty was common. Pubertal delay occurring in CF has largely been considered a manifestation of poor nutrition, but this relationship has not been consistently reported. A 1964 study found that the height and weight deficits in people with CF became pronounced in the pre-adolescent age group due to absence of the preadolescent growth spurt. No correlation between severity of lung disease and either weight gain or linear growth was found [3]. In the early 1970s, nutritional status was reported to be the major factor underlying the mild delay in the pubertal growth spurt in children with CF [4]. Neither study included details on pubertal milestones such as breast development or testicular growth, Table 1. Studies during the 1970s through the early 2000s continued to report delayed puberty in the CF population, Table 1. Findings of delayed breast and testicular development [5 9], delayed age at menarche [5,10 13], and delayed pubertal growth spurt [7,13,14] were reported. Some groups found a correlation between delayed puberty and nutritional status or severity of pulmonary disease while others found no specific associations. Landon et al. reported that in CF subjects with low plasma linoleic acid levels, normalization of their levels after an oral hyperalimentation program resulted in
https://doi.org/10.1016/j.jcf.2019.08.013 1569-1993/© 2019 The Authors. Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society. This is an open access article under the CC BY-NC-ND license. (http://creativecommons.org/licenses/by-nc-nd/4.0/)
B. Goldsweig et al. / Journal of Cystic Fibrosis 18 (2019) S88 S94
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Table 1 Studies evaluating puberty in CF. Study
N
Ages (y)
Sex
Outcome of interest
Association with pulmonary or nutrition status
Height deficit more prominent in adolescence Delayed skeletal maturity. Mildly delayed growth spurt. Mean onset of puberty: M 15.5 years, F 14.2 years Mean age at menarche: 14.4 y Delayed skeletal maturity Mean age at menarche: 14.2 y Mean age at menarche: 14.5 y Delayed Tanner stages and rise of gonadotropins by 2 4 y Mean age at menarche 14.4 y
Correlation with severity of pulmonary disease
M male F female Sproul and Huang [3]
50
0 14
M and F
Kreissl et al. [4] Mitchell-Heggs et al. [5]
53 45
0 13.8 >12
M and F M and F
Stern et al. [10] 45 Moshang and Holsclaw [11] 63 Reiter et al. [6] 106
8 24
F F M and F
Neinstein et al. [12]
40
>12
F
Landon and Rosenfeld [7]
54
12 30
M
Mahaney and McCoy [8]
50
7.5 17.4 M and F
Johannesson et al. [13]
17
21 36
F
Boas et al. [9] Aswani et al. [14]
33 30
13 17 >16
M M and F
Buntain et al. [16]
85
5 18
M and F
Kelly et al. [17]
82
8 18
M and F
Bournez et al. [18]
729
8 20
M and F
28% had delayed puberty PHV at 15 years Delayed pubertal progression Delayed age at menarche 90% Delayed skeletal age Mean age at PHV 12.9 y Mean age at menarche 14.9 y Average 2 y pubertal delay 20/33 with delayed puberty Age at PHV: M 14.6 y, F 12.6 Reached genetic potential late No difference in age at breast development, testicular growth, or menarche (13 y). M: Lower LH, FSH, testosterone Delayed skeletal age Mean age at each Tanner stage was not significantly different in CF vs controls Mildly delayed skeletal age Growth acceleration and PHV occur at same time in CF and controls
Correlation with severity of malnutrition No correlation with disease severity
Correlation with pulmonary and nutritional disease
Strongest correlation with weight, weaker with age at diagnosis, weight for height index, weight%, height%, body fat%
No correlation with disease severity
No correlation with pulmonary or nutritional status. Abnormal OGTT and homozygous del 508 associated with later age at menarche Correlation with weight < 10th %, height < 25th%, FEV1 < 60th% Correlation with general clinical status (not FEV1).
Delayed skeletal age associated with nutritional status but not lung disease
Abbreviations: PHV = Peak height velocity.
significant weight gain, resolution of primary amenorrhea in 3 girls, and normalization of irregular menses in 2 girls supporting the idea that poor nutrition was driving the delayed puberty in CF [15]. The more recent studies starting in the mid-2000s report normal pubertal timing in youth with CF. Normal age at each Tanner stage was found in CF adolescents compared to healthy controls [16,17], and normal age at menarche was also found [16]. The most recent study in a French cohort published in 2012 demonstrated that the timing of growth acceleration and peak height velocity was the same in the CF population compared to healthy controls [18]. These newer data emphasize that the CF clinician cannot assume that pubertal abnormalities in CF patients are inherent to their underlying disease. Additionally, patients with poorly controlled diabetes and CF-related liver disease are predisposed to malnutrition and may be at higher risk of abnormal pubertal development. Evaluating timing of pubertal milestones in CF patients and referral for endocrine evaluation, if necessary, are important to avoid exacerbating potential problems such as poor body image, sub-optimal linear growth, and compromised peak bone mass. Interestingly, cystic fibrosis transmembrane conductance regulator protein (CFTR) expression is found in the rat [19] and human hypothalamus [20] suggesting that CFTR could play a role in GnRH secretion and pubertal development. A role for CFTR in hypothalamic function is further suggested by an in vitro study demonstrating inhibition of GnRH secretion when CFTR expression is inhibited in a hypothalamic GNRH cell line [21]. Additionally, CFTR knockout mice demonstrated delayed puberty as assessed by timing of vaginal opening compared to wild type mice [22]. CFTR is not expressed in the ovaries and is unlikely to play a direct role in primary ovarian function [23]. Male
infertility in CF is caused by absence of the vas deferens that leads to azoospermia [24]. The mechanism for this anatomical abnormality is unknown. Some researchers have suggested that development of the HPG axis and GnRH secretion in fetal life could play a role, but absence of the vas deferens is not a feature of other disorders of HPG axis including congenital hypopituitarism and Kallman syndrome. Despite these in vivo findings, the majority of CF patients now have normal pubertal timing, even in the absence of functional CFTR, and CFTR is unlikely to have an important direct role in pubertal development. 2. Definitions/clinical presentation: precocious and delayed puberty The progressive physical changes that occur during puberty are described using the Sexual Maturity Rating of Marshall and Tanner (otherwise known as Tanner staging) system (Figs. 1, 2) [25,26] and measurement of testicular volume [27]. 2.1. Female puberty The majority of females begin puberty between 9 and 12 years of age with the first sign being breast enlargement (thelarche). The average age of breast budding in Caucasian females is 10.5 years and in African-American girls approximately 9.5 years. Thelarche is followed by pubic hair growth and menarche. Peak height velocity in girls is approximately 8 cm per year and occurs on average 6 12 month prior to menarche. Mean age at menarche is 12.9 years in Caucasian girls and 12.2 years in African-American girls (Table 2) [28].
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B. Goldsweig et al. / Journal of Cystic Fibrosis 18 (2019) S88 S94 Table 2 Age (y) of average, delayed, and precocious pubertal onset.
Females Thelarche (TS 2 breast) Menarche
Average Onset
Delayed
Precocious
African American: 9.5 y Caucasian: 10.5 y African American: 12.2 y Caucasian: 12.9 y
13 y
African American: 7 y Caucasian: 8 y
>4 years
Time from TS 2 breast to menarche
Fig. 1. Rosenfield RL, Cooke DW, Radovick S. Puberty and its disorders in the female. In Sperling M, ed. Pediatric endocrinology. 3rd Edition. Philadelphia, PA: Elsevier;2008:530 609.
2.1.1. Delayed puberty Delayed puberty in girls is defined as the absence of breast development by 2 to 2.5 standard deviations later than the population mean. Absence of breast buds by age 13 years or slow progression towards further stages of sexual maturity are signs of this delay. Development of pubic hair is not considered in the definition because pubarche results from maturation of the adrenal gland (adrenarche) and occurs independently of activation of the HPG-axis. Axillary hair, acne, and adult body odor are manifestations of adrenal gland maturation as well. Any female with absence of breast buds by age 13 years, or primary amenorrhea at age 16 years, or >4 years after thelarche, should be referred for endocrine evaluation.
2.1.2. Precocious puberty On the other end of the spectrum, precocious puberty is defined as the onset of puberty at an age that is 2 to 2.5 standard deviations earlier than the population mean. Typically, precocious puberty is defined as breast development in girls prior to age 8 years [28] and is an indication for endocrine referral. African-American girls are more likely to start pubertal development before age 8 years than Caucasian girls; thus, precocious puberty tends to evaluated in African-
Males Testes >3 cc Time from testes>3 cc to testicular volume 20 25 cc
16 y
11.5 y
14 y >4 y
<9 y
Abbreviations: TS = Tanner stage.
dPTage merican girls only if puberty starts prior to age 7 years [29] (Table 2). A Puberty that begins at the normal time but progresses unusually rapidly is also considered precocious. 2.2. Male puberty Pubertal development starts later in males—generally, between the ages of 10 and 13 years. The first observable change is testicular enlargement; pubic hair development and penile growth then manifest. Testicular enlargement is first seen at an average age of 11.5 years. Peak height velocity is about 9 cm per year and occurs at approximately 13.5 years of age [28] (Table 2). 2.2.1. Delayed puberty Delayed puberty in boys is defined as the absence of testicular enlargement at an age that is beyond 2 to 2.5 standard deviations from the population mean. Absence of testicular development by age 14 years or early testicular development with a long lag before further testicular enlargement, penile growth, or pubic hair development define this delayed pubertal status. Frequently boys present for short stature alone, and further history and physical exam reveal delayed pubertal milestones. The growth chart often shows faltering linear growth around 11 13 years of age due to absence of the pubertal growth spurt that typically starts around that time. Boys without testicular development by age 14 years, with slowly progressing puberty, or with a decline in height percentiles in the preteen or early teen years should be referred for endocrine evaluation. 2.2.2. Precocious puberty Precocious puberty in boys is defined as the onset of puberty at an age that is 2 to 2.5 standard deviations earlier than the population mean. Typically, precocious puberty is defined as testicular development in boys prior to age 9 years. The presentation of precocious puberty may include early onset of physical development, accelerated growth, or rapid progression of pubertal milestones and always requires an endocrine evaluation. 3. Prevalence 3.1. Delayed puberty
Fig. 2. Rosen DS. Physiologic growth and development during adolescence. Pediatr Rev 2004 Jun;25 [6]:194 200. https://doi.org/10.1542/pir.25-6-194.
The prevalence of delayed puberty in healthy individuals is by definition 5%. In a retrospective study of adolescents presenting to an academic pediatric endocrinology center 53% of subjects had constitutional delay (63% of males and 30% of females), 19% had functional hypogonadism, 13% had primary hypogonadism, 12% had various causes of permanent hypogonadotropic hypogonadism and 3% were undetermined [30]. The studies of puberty timing in CF measured various aspects of pubertal timing in CF (Table 1) but only a few have
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looked at prevalence. However, the earlier findings of delayed pubertal milestones in CF compared to healthy controls suggests a higher prevalence of delayed puberty. In 1991, a group investigating the psychological impact of short stature and delayed puberty in people with CF found a prevalence of delayed puberty in 20% of the subjects [31]. Other studies found prevalence rates of 28% [7] and 60% [9]. More recently in 2008, in a study measuring bone mineral content in CF youth, the mean age at each Tanner stage was found to be the same in people with CF and healthy controls [17]. This report suggests that the prevalence of delayed puberty in CF should be around that of the general population. Studies examining causes of delayed puberty in CF report varying degrees of association with BMI, general nutritional status, pulmonary health and glucose tolerance. No studies have sought to determine the prevalence of other organic etiologies of delayed puberty in CF. 3.2. Precocious puberty No studies have documented the prevalence of precocious puberty in CF. During the years when malnutrition was common in CF patients, rates were likely to be extremely low. With current improvements in nutritional status the numbers may be similar to the general population with a prevalence of 5%. 4. Differential diagnosis 4.1. Delayed puberty Delayed puberty results from either a lack of pubertal maturation of the HPG axis (also called hypogonadotropic hypogonadism) or primary gonadal dysfunction (also called hypergonadotropic hypogonadism). Pubertal delay may be a manifestation of permanent hypogonadism requiring lifelong treatment or may be transient with potential for subsequently normal gonadal function. Hypogonadotropic hypogonadism, also called central hypogonadism or secondary hypogonadism, is characterized by deficient GnRH secretion from the hypothalamus leading to decreased LH and FSH secretion from the pituitary gland and inadequate testosterone or estradiol production. The most common cause of delayed puberty is constitutional delay of growth and puberty (CDGP) which is temporary and more common in boys than in girls. People with constitutional delay have a transient functional defect in GnRH production and often have a family history of pubertal and growth delay also referred to as late bloomers. Hypogonadotropic hypogonadism may also be caused by functional hypogonadism in the context of an eating disorder, excessive exercise or chronic disease such as inflammatory bowel disease or CF. In functional hypogonadism, inadequate weight gain is usually a contributing factor. Decreased body fat results in decreased leptin concentrations and gonadotropin deficiency [32]. A critical weight may also be necessary before menarche can occur [33]. Malnutrition causing functional hypogonadism is likely the etiology of delayed puberty seen in some individuals with CF. Another possible etiology for delayed puberty is isolated gonadotropin deficiency. Constitutional delay and gonadotropin deficiency present similarly and may be difficult to distinguish, but in the absence of testicular development or breast development by age 17 years constitutional delay becomes unlikely and permanent hypogonadism should be expected. Lastly, other diseases of the pituitary gland or hypothalamus such as tumors, congenital malformations, or hyperprolactinemia may lead to GnRH or gonadotropin deficiency (Table 3). Hypergonadotropic hypogonadism caused by primary gonadal failure is characterized by low testosterone or estradiol with elevated LH and FSH levels. Primary gonadal failure may be secondary to Turner syndrome in girls or Klinefelter syndrome in boys. Turner syndrome (karyotype 45,X or mosaicism) occurs in approximately 1 in 2500 live female births and usually causes primary gonadal failure along with short stature, an increased risk of congenital heart disease
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Table 3 Delayed Puberty Causes and evaluation of Delayed Puberty Primary (hypergonadotropic hypogonadism) Congenital: Turner syndrome (45, X) Klinefelter syndrome (47, XXY) Anorchia or cryptorchidism Disorders of testosterone biosynthesis LH or FSH receptor defects Acquired: Autoimmune gonadal failure Trauma Chemotherapy or radiation Bilateral testicular torsion Secondary (hypogonadotropic hypogonadism) Congenital: Congenital malformations (optic nerve hypoplasia syndrome, etc) Isolated GnRH deficiency (with anosmia – Kallmann syndrome) Multiple pituitary hormone deficiencies Acquired: Constitutional delay of growth and puberty Chronic disease (inflammatory bowel disease, cystic fibrosis) Malnutrition (eating disorder, poverty) Hypothyroidism Hyperprolactinemia Tumors (craniopharyngioma, etc) Head trauma Chemotherapy or cranial radiation
Evaluation Medical History Physical Exam Weight, height, growth velocity pubertal staging Laboratory Testing CBC Comprehensive metabolic panel Celiac screening LH, FSH Estradiol/testosterone IGF-1, IGFBP-3 TSH, free T4 Prolactin Karyotype Imaging Bone age x-ray Brain MRI (hypothalamus/pituitary)
and lymphedema among other features. Two women with CF and Turner syndrome have been reported in the literature. Both women were diagnosed with CF in infancy and Turner syndrome in their teenage years as part of an evaluation for short stature [34]. Klinefelter syndrome (karyotype 47,XXY or XY/XXY mosaicism) occurs in approximately 1 in 1000 live male births and causes primary gonadal failure along with tall stature and sometimes behavioral problems and learning difficulties. A man with mosaic Klinefelter syndrome and cystic fibrosis has been reported [35]. These reports are important reminders to not assume delayed puberty and infertility are solely attributable to CF. Additional causes of hypergonadotropic hypogonadism are listed in Table 3. 4.2. Precocious puberty Precocious puberty can be divided into central causes secondary to premature activation of the HPG axis and peripheral causes secondary to secretion of sex hormones that is independent of stimulation from the pituitary. Several variants of normal puberty present with features of precocious puberty but are non-progressive and considered benign. Central precocious puberty (CPP) caused by early maturation of the HPG axis leads to early onset of puberty that progresses with a normal pattern and timing. CPP is idiopathic in 80 90% of girls and 25 60% of boys [36]. The major worry is that a CNS mass requiring urgent evaluation underlies CPP. Additional potential acquired and genetic defects that are associated with CPP are listed in Table 4. Peripheral precocious puberty occurs in the absence of activation of the HPG axis and is caused by autonomous production of sex
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determined based on the differential diagnosis generated by the history and physical exam (Tables 3 and 4).
Table 4 Precocious Puberty Causes and evaluation of Precocious Puberty
6. Routine management
Central (gonadotropin-dependent) Congenital: Optic nerve hypoplasia Hydrocephalus Arachnoid cysts Acquired: Idiopathic Hamartomas, other tumors CNS trauma CNS radiation Pituitary inflammation Peripheral (gonadotropin-independent) Congenital Activating LH receptor mutation (testotoxicosis) McCune-Albright Syndrome Congenital adrenal hyperplasia Acquired: Follicular ovarian cysts Tumors (granulosa cell, Leydig cell, germ cell, adrenal, HCG-secreting) Hypothyroidism Exogenous sex steroids
6.1. Delayed puberty
Evaluation Medical History Physical Exam Weight, height, growth velocity pubertal staging Laboratory Testing LH, FSH Estradiol/testosterone TSH, free T4 17 hydroxyprogesterone, DHEAS Imaging Bone age x-ray Brain MRI (hypothalamus/pituitary) Ovarian, testicular, or adrenal ultrasound
steroids from the gonads or adrenal glands, exogenous sources of sex steroids, or from stimulation of the gonads by hormones that crosstalk with the gonadotropin receptors (beta-hCG, TSH). Physical signs of puberty may occur in an unusual order or more rapidly than is normal. Causes include follicular ovarian cysts, hormone secreting tumors, exposure to exogenous sex steroids, hypothyroidism and rare genetic disorders (Table 4). Several normal variants of puberty present similarly to precocious puberty but do not require intervention. Premature thelarche is isolated, non-progressive breast development that typically occurs in the first two years of life or between 6 and 8 years of age. No other signs of puberty are present, growth velocity is normal, skeletal age is not advanced, and gonadotropins and estradiol are in the pre-pubertal range. Premature adrenarche is characterized by development of pubic hair, axillary hair, acne and/or body odor prior to the normal age of puberty. Signs of central puberty are absent. Mild acceleration of linear growth and a mildly advanced skeletal age may be present. Dehydroepiandrosterone sulfate (DHEAS) may be mildly elevated, but gonadotropins and other androgens are in the pre-pubertal range. 5. Diagnostic work up Monitoring of pubertal status in people with CF is important in order to avoid negative sequelae of early or late development. The evaluation for both delayed and precocious puberty starts with a careful medical history and physical exam. Specific attention should be given to the neurological exam to evaluate for central nervous system causes of pubertal abnormalities. Breast development/testicular enlargement and pubic hair growth should be staged separately as shown in Figs. 1 and 2. Endocrinologists measure testicular size using a Prader orchidometer. Outside endocrinology clinics, a self-assessment questionnaire is sometimes used to categorize pubertal stages [37]. While this questionnaire is a validated tool for pubertal assessment, physical exam by a medical provider is more accurate particularly for measuring testicular size [30]. When the clinical assessment is consistent with delayed or precocious puberty in a patient with CF, a biochemical evaluation of the HPG axis is necessary. Additional laboratory measurements and imaging should be
Treatment of delayed puberty depends on the underlying etiology and whether puberty is expected to progress spontaneously. If a specific cause is identified such as hypothyroidism, inflammatory bowel disease or a prolactinoma, addressing the underlying issue will often be all the treatment that is required for puberty to progress normally. For patients with CF, determining if coexisting malnutrition is a contributing factor in delayed pubertal development is important. In girls, if permanent hypogonadism is suspected, pubertal induction using exogenous hormones is indicated to ensure typical development of secondary sexual characteristics, normal pubertal growth spurt, appropriate psychosocial adjustment and optimal bone mineral accrual. Estrogen is replaced in small doses transdermally; the dose is then gradually increased every 6 months over 3 4 years until an adult dose is reached [38]. After two years of estradiol therapy or when menstruation starts, cyclic progesterone is added to the regimen. In boys, when permanent hypogonadism is suspected, pubertal changes are induced using exogenous testosterone. Testosterone is started in low doses and then increased every 6 12 months to mimic the physiologic increases in testosterone levels that would occur if the HPG axis were functioning properly. Testosterone is available as an intramuscular (IM) injection and as a transdermal gel or patch. In some countries, although not the United States, it is available in an oral form. In adolescents, the injectable form has been the most well studied and is used most commonly. Alternative modes of treatment for delayed puberty in males and females that more closely mirror physiological processes are being investigated. These options include GnRH, hCG (with biological activity of LH), recombinant FSH and kisspeptin-10 [1]. If constitutional delay is suspected based on family history and normal diagnostic work-up the options are either watchful waiting or a short-term course of testosterone or estrogen to attempt to stimulate central puberty. The above described regimens with estradiol or testosterone can be initiated for 6 12 months and then discontinued. Patients with permanent hypogonadism usually have minimal pubertal progression on low doses of sex steroids. However, patients with CDGP will often have activation of the HPG system and will continue to progress through puberty once exogenous sex steroids are discontinued. This method is more effective in boys than in girls. 6.2. Precocious puberty Treatment of precocious puberty depends on the etiology. If the inciting cause is identified it should be addressed medically or surgically as indicated. Central precocious puberty is treated with a GnRH agonist which inhibits gonadotropin secretion. GnRH agonists are available as an intramuscular injection administered monthly, every 3 months or every 6 months or as a subcutaneous implant that is placed surgically and lasts for at least 12 months. Treatment of peripheral precocious puberty is specific to the underlying cause. 7. Complications and their management Delayed puberty is often associated with delayed growth and sometimes with short adult stature in boys and girls [39,40]. People with CF have other risk factors for poor growth including malnutrition, chronic inflammation, and frequent steroid courses which may be exacerbated by delayed puberty [41]. Thus, evaluation of growth parameters and growth hormone axis are important. Use of growth hormone as an adjunct therapy in otherwise healthy patients with pubertal delay is controversial and benefits are unclear. Some
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evidence suggests use of growth hormone in people with CF, regardless of pubertal timing, leads to improvements in height, weight, and lean body mass [42]. However, the data are inconsistent, and use of growth hormone should only be considered on a case by case basis. Further discussion of growth hormone is covered in article 11, section 4, Growth Failure and Treatment in CF, [50]. Several studies have found that delayed increase in sex steroids is associated with lower bone mineral density and an increased risk of fracture in adolescence and adulthood [43,44]. People with CF are already at increased risk for osteopenia and osteoporosis [17], and gonadal issues may compound this underlying predisposition for CF bone disease. McCormack et al. demonstrated that healthy adolescents gain a substantial proportion of their bone mineral content during pubertal growth [45]. Similarly, Bianchi et al. showed that the maximum increase in bone mineral content and density occurred during puberty in people with CF, data that highlight the critical role of hormonal changes during puberty and their potent stimulus on bone mineral accrual [46]. Treatment of delayed puberty caused by functional hypogonadism with supplemental hormones has not been shown to improve bone mineral density in the general population but has not been studied specifically in CF. Therefore, bone health alone may not be an indication to start hormonal treatment. Delayed puberty and hypogonadism may be a factor to include when considering whether a specific patient with CF would benefit from treatment of osteopenia and in the interpretation of dual energy x-ray absorptiometry [47]. Further discussion of CF bone disease and vitamin D supplementation are discussed in separate articles in this issue [51]. Lastly, delayed puberty can impact the psychosocial well-being of the individual and potentially contribute to lower self-image, increased internalizing symptoms, and poorer academic performance although long lasting effects into adulthood have not been demonstrated [43]. Delayed puberty may compound already existing feeling of isolation and difference in people with CF. One study showed patients with CF and delayed growth and puberty were less likely to participate in certain social activities and had a less positive body attitude [31]. The psychological impact of delayed pubertal development should be considered when deciding if or when to start supplemental hormones for pubertal induction. 8. Potential impact of CFTR modulation CFTR modulator therapies are improving clinical outcomes in people with CF. CFTR potentiator and corrector therapies improve lung function and nutritional status in patients with CF [48]. If the main cause of delayed puberty in CF is due to malnutrition and low weight, then improvement in CFTR function could lead to a normalization in pubertal timing. However, some studies found that delayed puberty in CF was not associated with nutritional status [13]. This finding along with evidence that CFTR is expressed in the human hypothalamus raises the possibility that delayed puberty in CF could be secondary to abnormal CFTR function involved in the HPG axis. In addition, a study in a CF mouse model showed that mice with truncated CFTR mRNA had delayed pubertal timing measured by vaginal opening [22]. Whether delayed puberty in CF is secondary to malnutrition or CFTR dysfunction, CFTR modulators have the potential to impact pubertal timing. Within the next decade it will be possible to study pubertal timing in CF patients who are on CFTR modulators from a young age. 9. Future directions Based on available data, significant pubertal delay appears to occur much less commonly in CF and is restricted to the sickest patients. With the introduction of CFTR modulators at younger ages, pubertal delay may become even less common. With improving health, overweight and obesity are emerging complications in our youth with CF; overweight was reported in 15% and obesity in 8% of pediatric patients
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at one center [49]. Given that obesity is associated with earlier onset of puberty in girls but later onset of puberty in boys [2], pubertal timing may also be impacted in youth with CF. A large, multicenter study investigating pubertal timing in CF patients, including those who start on modulator drugs at a young age, will help clarify the current prevalence of delayed and precocious puberty in CF and if there is any association with malnutrition or obesity. Timing of puberty could potentially be tracked through the Cystic Fibrosis Foundation Patient Registry. 10. Clinical practice points Patients with CF should be screened for delayed puberty due to the impact on growth, bone health and psychosocial well-being. Special attention should be directed at screening for delayed puberty in groups that may be higher risk such as malnourished patients, those with abnormal glucose tolerance, or CF liver disease. A diagnosis of delayed puberty should be considered in pre-teens or adolescents with poor linear growth. Pubertal abnormalities in people with CF require full evaluation and should not be attributed to CF alone.
11. Summary Historically, delayed puberty was considered a common complication of CF. Studies were mixed regarding whether delayed puberty was associated with poor nutrition, low weight or other factors. However, newer data in more recent cohorts of CF patients show normalization of pubertal timing which may be secondary to improved nutrition. Delayed puberty has important effects on growth, bone health and psychological well-being. These issues make screening CF teens for delayed puberty important even if pubertal delay only occurs at the same prevalence as the general population (5%). Future, larger studies evaluating pubertal timing in CF patients, including those who have been on CF modulators from a young age, will further clarify the current prevalence of delayed and precocious puberty in CF. Declaration of Competing Interest None. Funding This paper is part of a Supplement supported by the Cystic Fibrosis Foundation. Acknowledgements The authors would like to express appreciation to the Cystic Fibrosis Foundation for grant support through the EnVision: Emerging Leaders in CF Endocrinology Program. Thank you to the EnVision faculty members for their continuing support and mentorship of the program awardees. References [1] Wei C, Crowne CE. Recent advances in the understanding and management of delayed puberty. Arch Dis Child 2016;101(5):481–8. [2] Reinehr T, Roth CL. Is there a causal relationship between obesity and puberty? Lancet Child Adolesc Health 2019;3(1):44–54. [3] Sproul A, Huang N. Growth patterns in children with cystic fibrosis. J Pediart 1964;65:664–76. [4] Kreissl T, Bender SW, Morchen R, Hovels O. The physical development of children with cystic fibrosis. Z Kinderheilkd 1972;113(2):93–110. [5] Mitchell-Heggs P, Mearns M, Batten JC. Cystic fibrosis in adolescents and adults. Q J Med 1976;45(179):479–504. [6] Reiter EO, Stern RC, Root AW. The reproductive endocrine system in cystic fibrosis. Am J Dis Child 1981;135(5):422–6. [7] Landon C, Rosenfeld RG. Short stature and pubertal delay in male adolescents with cystic fibrosis. Androgen treatment. Am J Dis Child 1984;138(4):388–91.
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