Margareta D. Pisarska, Carolyn Alexander, Ricardo Azziz, Richard P. Buyalos, Jr.
This part of Essentials (Chapters 31 through 36) deals with the normal and abnormal hormonal influences on the female reproductive system. The sequence of events is an excellent example of the “Life-Course Perspective” for women’s health and health care introduced in Chapter 1. This series of events begins with endocrine changes in the fetus, the neonate, and then into childhood and pubertal development, then is followed by the early reproductive years, continuing on through the female climacteric, over the life course of a woman’s reproductive years. This section of the book concludes with a chapter on other common disorders that are influenced by normal and abnormal hormonal changes during the menstrual cycle.
Puberty encompasses the development of secondary sexual characteristics and the acquisition of reproductive capability. During this transition, usually between 10 and 16 years of age, a variety of physical, endocrinologic, and psychological changes accompany the increasing levels of circulating sex steroids.
The onset of pubertal changes is determined primarily by genetic factors, including race, and is also influenced by geographic location (girls in metropolitan areas, at altitudes near sea level, or at latitudes close to the equator tend to begin puberty at an earlier age) and nutritional status (obese children have an earlier onset of puberty, and those who are malnourished or who have chronic illnesses associated with weight loss have a later onset of menses). Excessive exercise relative to the caloric intake can also delay the onset of puberty. It has been proposed that an “invariant mean weight” of 48 kg (106 lb) is essential for the initiation of menarche in healthy girls and that leptin, a peptide secreted by adipose tissue, may be the link between weight and initiation of menarche. Psychological factors, severe neurotic or psychotic disorders, and chronic isolation may interfere with the normal onset of puberty through a mechanism similar to adult hypothalamic amenorrhea.
In the United States and Western Europe, a decrease in the age of menarche (age at first menses) was noted between 1840 and 1970. This trend has plateaued in the past 30 years (Figure 31-1). Presently, the mean age of menarche is about 12.4 years in the United States.
FIGURE 31-1 Decreasing age at menarche, 1840 to 1978, with inset from 1950 to 2008, indicating a leveling off (about 12.4 years in the United States) since 1975.
(Adapted from Styne DM, Grumbach MM: Disorders of puberty in the male and female. In Yen SSC, Jaffe RB, Barbieri RL [eds]: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 4th ed. Philadelphia, WB Saunders, 1999.)
Endocrinologic Changes of Puberty
FETAL AND NEWBORN PERIOD
The fetal hypothalamic-pituitary-gonadal axis is capable of producing adult levels of gonadotropins and sex steroids. By 20 weeks’ gestation, levels of gonadotropins—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—rise dramatically in both male and female fetuses (Figure 31-2). The female fetus acquires the lifetime peak number of oocytes by mid-gestation, and she experiences a brief period of follicular maturation and sex steroid production in response to elevated gonadotropin levels in utero. This transient increase in serum estradiol (a sex steroid) acts on the fetal hypothalamic-pituitary unit, resulting in a reduction of gonadotropin secretion (negative feedback effect), which in turn reduces estradiol production. This indicates that the inhibitory effect of sex steroids on gonadotropin release is operative before birth.
FIGURE 31-2 Changes in the concentration of gonadotropins (LH and FSH), sex steroids (DHEA, androstenedione, and estradiol), and the number of oogonia throughout fetal life and pubertal development. hCG, human chorionic gonadotropin; LH, luteinizing hormone; FSH, follicle-stimulating hormone; DHEA, dehydroepiandrosterone.
(Adapted from Speroff L, Fritz M: Neuroendocrinology. In Speroff L, Fritz M [eds]: Clinical Gynecologic Endocrinology and Infertility, 7th ed. Baltimore, Williams & Wilkins, 2005.)
In both male and female fetuses, serum estradiol is primarily of maternal and placental origin. With birth and the acute loss of maternal and placental sex steroids, the negative feedback action on the hypothalamic-pituitary axis is lost, and gonadotropins are once again released from the pituitary gland, reaching adult or near adult concentrations in the early neonatal period. In the female infant, peak serum levels of gonadotropins are generally seen by 3 months of age and then slowly decline until a nadir is reached by the age of 4 years. In contrast to gonadotropin levels, sex steroid concentrations decrease rapidly to prepubertal values within 1 week after birth and remain low until the onset of puberty.
The hypothalamic-pituitary-gonadal axis in the young child is suppressed between the ages of 4 and 10 years. The hypothalamic-pituitary system regulating gonadotropin release has been termed the gonadostat. Low levels of gonadotropins and sex steroids during this prepubertal period are a function of two mechanisms: maximal sensitivity of the gonadostat to the negative feedback effect of the low, circulating levels of estradiol present in prepubertal children, and intrinsic central nervous system inhibition of hypothalamic gonadotropin-releasing hormone (GnRH) secretion. These mechanisms occur independent of the presence of functional gonadal tissue. This is clearly demonstrated in children with gonadal dysgenesis. Agonadal children display elevated gonadotropin concentrations during the first 2 to 4 years of life, followed by a decline in circulating FSH and LH levels by 6 to 8 years of age. By 10 to 12 years of age, gonadotropin concentrations spontaneously rise once again, eventually achieving castration levels. This pattern of gonadotropin secretion in early childhood is similar to that of children with normal gonadal function. These data suggest that an intrinsic central nervous system regulator of GnRH release is the principal inhibitor of gonadotropin secretion from 4 years of age until the peripubertal period.
LATE PREPUBERTAL PERIOD
In general, androgen production and differentiation by the zona reticularis of the adrenal cortex are the initial endocrine changes associated with puberty. Serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione rise between the ages of 8 and 11 years. This rise in adrenal androgens induces the growth of both axillary and pubic hair and is known as adrenarche or pubarche. This increase in adrenal androgen production occurs independent of gonadotropin secretion or gonadal steroid levels, and the mechanism of its initiation is not understood at this time. Recent studies indicate that girls who undergo premature pubarche are more likely to develop polycystic ovary syndrome (PCOS) as adults.
By about the 11th year of life, there is a gradual loss of sensitivity by the gonadostat to the negative feedback of sex steroids (Figure 31-3). As a consequence of this reduced negative feedback effect, GnRH pulses (with their mirroring pulses of FSH and LH) increase in amplitude and frequency. The factors that reduce the sensitivity of the gonadostat are incompletely understood. Some studies indicate that a rise in the concentration of leptin, a hormone produced by adipocytes (fat cells) that mediates appetite satiety, precedes and is necessary for this change. This, in turn, supports the connection between minimum weight or total body fat and the onset of puberty. A further decrease in sensitivity of the gonadostat, combined with the loss of intrinsic central nervous system inhibition of hypothalamic GnRH release, is heralded by sleep-associated increases in GnRH secretion. This nocturnal-dominant pattern gradually shifts into an adult-type secretory pattern, with GnRH pulses occurring every 90 to 120 minutes throughout the 24-hour day.
FIGURE 31-3 Changes in set point of the hypothalamic-pituitary unit (gonadostat) (solid lines) and the maturation of the negative and positive feedback mechanisms from fetal life to adulthood in relation to the normal changes of puberty. This figure does not illustrate the change in the sex steroid–independent intrinsic central nervous system inhibitory mechanism that is observed from late infancy to puberty. GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone.
(Adapted from Styne DM, Grumbach MM: Disorders of puberty in the male and female. In Yen SSC, Jaffe RB [eds]: Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 2nd ed. Philadelphia, WB Saunders, 1991.)
The increase in gonadotropin release promotes ovarian follicular maturation and sex steroid production, which induces the development of secondary sexual characteristics. By mid to late puberty, maturation of the positive-feedback mechanism of estradiol on LH release from the anterior pituitary gland is complete, and ovulatory cycles are established.
Somatic Changes of Puberty
Physical changes of puberty involve the development of secondary sexual characteristics and the acceleration of linear growth (gain in height). The classification of breast and pubic hair development by Marshall and Tanner is employed for descriptive and diagnostic purposes (Figures 31-4 and 31-5).
FIGURE 31-4 Stages of breast development as defined by Marshall and Tanner. Stage 1: Preadolescent; elevation of papilla only. Stage 2: Breast bud stage; elevation of breast and papilla as a small mound with enlargement of the areolar region. Stage 3: Further enlargement of breast and areola without separation of their contours. Stage 4: Projection of areola and papilla to form a secondary mound above the level of the breast. Stage 5: Mature stage; projection of papilla only, resulting from recession of the areola to the general contour of the breast.
(Adapted from Marshall WA, Tanner JM: Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291, 1969.)
FIGURE 31-5 Stage of female pubic hair development according to Marshall and Tanner. Stage 1: Preadolescent; absence of pubic hair. Stage 2: Sparse hair along the labia; hair downy with slight pigment. Stage 3: Hair spreads sparsely over the junction of the pubes; hair is darker and coarser. Stage 4: Adult-type hair; there is no spread to the medial surface of the thighs. Stage 5: Adult-type hair with spread to the medial thighs assuming an inverted triangle pattern.
STAGES OF PUBERTAL DEVELOPMENT
The first physical sign of puberty is usually breast budding (thelarche), followed by the appearance of pubic or axillary hair (pubarche or adrenarche). Unilateral breast development is not uncommon in early puberty and may last up to 6 months before the development of the contralateral breast. Maximal growth or peak height velocity is usually the next stage, followed by menarche (the onset of menstrual periods). The final somatic changes are the appearance of adult pubic hair distribution and adult-type breasts. In about 15% of normal girls, the development of pubic hair occurs before breast development. The sequence of pubertal changes generally occurs over a period of 4.5 years, with a normal range of 1.5 to 6 years (Figure 31-6).
FIGURE 31-6 Sequence of physical changes during pubertal development.
Race plays a role in determining the age of the onset of puberty. African American girls begin puberty earlier than other racial groups (on average between the ages of 8 and 9 years), followed by Mexican Americans and whites (Table 31-1). In African American girls, thelarche and adrenarche can occur as early as 6 years of age, whereas in whites, they can occur as early 7 years of age.
TABLE 31-1 PUBERTY MILESTONES IN FEMALES
A useful acronym used to remember the usual chronologic order of the stages of female pubertal development is T-A-P-M (thelarche, adrenarche, pubarche, and menarche).
ADOLESCENT GROWTH SPURT
In general, the pubertal girl’s growth spurt is seen 2 years earlier than in boys. Growth hormone, estradiol, and insulin-like growth factor I (formerly somatomedin-C) are involved in the adolescent growth spurt. Peak height velocity occurs about 1 year before the onset of menarche. There is limited linear growth after menarche because gonadal steroid production accelerates fusion of the long-bone epiphyses.
BODY COMPOSITION AND BONE AGE
There are no significant differences in skeletal mass, lean body mass, or percentage of body fat between prepubertal boys and prepubertal girls. After attaining sexual maturity, girls generally have less skeletal and lean body mass and a greater percentage of body fat than boys.
Bone age correlates well with the onset of secondary sexual characteristics and menarche. Bone age is determined by using radiographs of the left (or nondominant) hand and wrist, elbow, or knee and comparing them with an index population. Osseous maturation is particularly useful in the evaluation of adolescents with delayed onset of puberty. Bone maturation, chronologic age, and height can also be used to predict the final adult stature from standardized nomograms.
Precocious puberty refers to the development of any sign of secondary sexual maturation at an age earlier than 2.5 standard deviations less than the expected age of pubertal onset. In North America, these ages are 8 years for girls and 9 years for boys. The incidence of precocious puberty is 1 in 10,000 children in North America, and it is about 5 times more common in girls. In 75% of cases of precocious puberty in girls, the cause is idiopathic. A thorough evaluation to eliminate a serious disease process and to arrest potential premature osseous maturation that may affect the normal growth pattern is mandatory.
The early development of secondary sexual characteristics may promote psychosocial problems for the child and should be carefully addressed. Typically, these girls are taller than their peers as children but ultimately are shorter as adults owing to the premature fusion of the long-bone epiphyses. A classification system for female precocious puberty is shown in Box 31-1.
BOX 31-1 Classification of Female Precocious Puberty
Data from Brenner PF: Precocious puberty in the female. In Mishell DR Jr, Davajan V (eds): Infertility, Contraception and Reproductive Endocrinology, 3rd ed. Cambridge, MA, Blackwell Scientific Publications, 1991, p 349.
Heterosexual Precocious Puberty
Congenital adrenal hyperplasia (adrenogenital syndrome)
Exogenous androgen exposure
Isosexual Precocious Puberty
Incomplete Isosexual Precocious Puberty
Complete Isosexual Precocious Puberty
True isosexual precocious puberty
Organic brain disease
Central nervous system tumors
Central nervous system infection (abscess, encephalitis, meningitis)
Pseudoisosexual Precocious Puberty
Exogenous estrogen exposure
Precocious puberty may be divided into two major subgroups: heterosexual precocious puberty (development of secondary sexual characteristics opposite those of the anticipated phenotypic sex) and isosexual precocious puberty (premature sexual maturation that is appropriate for the phenotype of the affected individual).
Investigations for females with precocious puberty are shown in Box 31-2.
BOX 31-2 Laboratory Tests Used Selectively to Evaluate Female Precocious Puberty
Serial bone age (isosexual precocity)
Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain with optimal visualization of hypothalamic region and sella turcica (true isosexual precocity)
MRI, CT, or ultrasonography of the abdomen, pelvis, or adrenal gland (heterosexual precocity, pseudoisosexual precocity)
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Dehydroepiandrosterone sulfate (DHEA-S), testosterone (heterosexual precocity)
17-OH progesterone, 11-deoxycortisol (suspected congenital adrenal hyperplasia [CAH] causing heterosexual precocity)
Thyroid function tests [TSH, free T4] (isosexual precocious puberty)
Gonadotropin-releasing hormone (GnRH) stimulation test: LH measurement after 100 μg of GnRH given intravenously (to differentiate gonadotropin-dependent from gonadotropin-independent isosexual precocity)
In females, heterosexual precocity results from virilizing neoplasms, congenital adrenal hyperplasia, or exposure to exogenous androgens.
Androgen-secreting neoplasms in females are either ovarian (most commonly Sertoli-Leydig cell) or adrenal in origin and are exceedingly rare in childhood. They are diagnosed by abdominal physical and radiologic examinations and are treated by surgical removal.
Congenital adrenal hyperplasia most commonly results from a defect of the adrenal enzyme 21-hydroxylase leading to excessive androgen production. More severe forms of this defect cause the birth of a female with ambiguous genitalia. If untreated, progressive virilization during childhood and short adult stature will result. The treatment of this disorder includes replacement of cortisol with a related glucocorticoid and surgical correction of any anatomic abnormalities in the first few years of life. A less severe form of this defect, referred to as nonclassic (late-onset adrenal hyperplasia), can cause premature pubarche and an adult disorder resembling PCOS.
ISOSEXUAL PRECOCIOUS PUBERTY
Complete isosexual precocious puberty results in the development of the full complement of secondary sexual characteristics and increased levels of sex steroids. It may arise from premature activation of the normal process of pubertal development involving the hypothalamic-pituitary-gonadal axis, which is called true isosexual precocity. Exposure to estrogen, independent of the hypothalamic-pituitary axis (such as from an estrogen-producing tumor), is called pseudoisosexual precocity.
True Isosexual Precocity
In females, 75% of cases are constitutional. It may be diagnosed by the administration of exogenous GnRH (a GnRH stimulation test) with a resultant rise in LH levels equivalent to that seen in older girls who are undergoing normal puberty. In about 10% of girls with the true form of precocious puberty, a central nervous system disorder is the underlying cause. This includes tumors, obstructive lesions (hydrocephalus), granulomatous diseases (sarcoidosis, tuberculosis), infective processes (meningitis, encephalitis, or brain abscess), neurofibromatosis, and head trauma. It is postulated that these conditions interfere with the normal inhibition of hypothalamic GnRH release. Children with precocious puberty secondary to organic brain disease often exhibit neurologic symptoms before the appearance of premature sexual maturation. Evaluation of true isosexual precocity should include magnetic resonance imaging of the head for lesions.
Pseudoisosexual precocity occurs when estrogen levels are elevated and cause sexual characteristic maturation without activation of the hypothalamic-pituitary axis. In these girls, a GnRH stimulation test does not induce pubertal levels of gonadotropins. Causes include ovarian tumors and cysts, exogenous estrogenic compound use, McCune-Albright syndrome, severe prolonged hypothyroidism, and Peutz-Jeghers syndrome. Curiously, when the initial cause of pseudoisosexual precocity is eliminated, some girls go on to develop true isosexual precocity.
Some ovarian tumors can be felt on abdominal examination and are usually unilateral. Other lesions may require radiologic imaging for diagnosis. Treatment of these lesions is surgical.
The McCune-Albright syndrome (polyostotic fibrous dysplasia) represents 5% of cases of female precocious puberty and consists of sexual precocity, multiple cystic bone defects that fracture easily, café au lait spots with irregular borders (most frequently on the face, neck, shoulders, and back), and adrenal hypercortisolism. Hyperthyroidism and acromegaly may also occur in this syndrome. The pathophysiology involves a somatic mutation in affected postzygotic tissues, which causes them to function independent of their normal stimulating hormones.
Prolonged severe hypothyroidism has been hypothesized to cause pituitary gonadotropin release in response to the persistently elevated secretion of thyroid-releasing hormone (TRH).Concomitant elevated prolactin levels may also occur with the development of galactorrhea. Ovarian cysts may occasionally develop, and bone age may be retarded. This is the only form of precocious puberty associated with delayed bone age. Treatment is with thyroid replacement therapy.
The Peutz-Jeghers syndrome has been associated with a rare sex cord tumor with annular tubules, which may be estrogen secreting. Because this syndrome of gastrointestinal tract polyposis and mucocutaneous pigmentation has also been reported in association with a granulosa-theca cell tumor, children with this disorder should be screened for the development of gonadal neoplasms.
Incomplete isosexual precocity is the early appearance of a single secondary sexual characteristic. These conditions include premature thelarche, the isolated appearance of breast development before the age of 4 years (unilateral or bilateral) that resolves spontaneously within months and that is probably secondary to transient estradiol secretion; premature adrenarche, the isolated appearance of axillary hair before the age of 7 years that is the result of premature androgen secretion by the adrenal gland; and premature pubarche, the isolated appearance of pubic hair in girls before 8 years of age.
In general, premature thelarche and premature adrenarche are associated with appropriate sexual maturation, although they may be associated with the development of nonclassic adrenal hyperplasia and perhaps polycystic ovary syndrome. Therapy for these conditions is not required. Both conditions are more common in girls than in boys. It is not possible to diagnose an incomplete form of sexual precocity on a single evaluation, and interval examinations of bone age are necessary to rule out true precocious puberty.
TREATMENT OF TRUE ISOSEXUAL PRECOCIOUS PUBERTY
About 75% of cases of precocious puberty in girls prove to have a constitutional or idiopathic cause, and these patients are candidates for GnRH agonist (e.g., leuprolide acetate) therapy. These girls require treatment to prevent further sex steroid release and accelerated epiphyseal fusion. If the condition is left untreated, fewer than 50% of girls with idiopathic precocity will attain an adult height of 5 feet.
GnRH agonists are the most effective therapy for idiopathic precocity. Long-term GnRH agonist treatment suppresses pituitary release of LH and FSH, resulting in the decline of gonadotropin levels to prepubertal concentrations and arrest of gonadal sex steroid secretion. Clinically, normal gonadotropin release, sex steroid production, and pubertal maturation resume 3 to 12 months after discontinuation of GnRH agonist therapy.
The final adult stature of girls with GnRH-dependent causes of precocious puberty is strongly influenced by their chronologic age at diagnosis and initiation of treatment. When GnRH agonist treatment is initiated before the chronologic age of 6 years, the final adult height is increased by 2% to 4% (Figure 31-7). In contrast, the final adult height is usually not affected when the chronologic age at diagnosis and treatment is greater than 6 years of age.
FIGURE 31-7 Scatter diagram of final height vs age at diagnosis of girls with gonadotropin-releasing hormone (GnRH)–dependent precocious puberty who were treated with GnRH agonist therapy (top). The shaded arearepresents the range of normal adult height for North American women. Bottom, Percentage target height (final target height/target height × 100) vs the age at diagnosis.
(Modified from Kletter GD, Kelch RP: Effects of gonadotropin-releasing hormone analogue therapy on adult stature in precocious puberty. J Clin Endocrinol Metab 79:333, 1994.)
Most children with sexual precocity have few significant behavioral problems, but emotional support is important in these children. Behavioral expectations by family members and teachers should be based on the child’s chronologic age, which determines psychosocial development, and not on the presence of secondary sexual characteristics.
Although there is a wide variation in normal pubertal development, most girls in the United States begin pubertal maturation by the age of 13 years. Failure to undergo thelarche by age 14 years requires evaluation. A physiologic delay in the onset of puberty occurs in only 10% of girls with delayed puberty, and exclusion of other diagnoses is necessary. Physiologic delays in puberty tend to be familial. A careful history must be taken, with special attention to the patient’s past general health, height, dietary habits, and exercise patterns. Details about the pubertal development of the patient’s siblings and parents should be obtained. Box 31-3 lists tests that should be performed to evaluate girls with delayed puberty.
BOX 31-3 Radiologic and Laboratory Tests Used to Evaluate Female Delayed Puberty
Magnetic resonance imaging (MRI) or computed tomography (CT) of the brain with optimal visualization of hypothalamic region and sella turcica (hypogonadotropic hypogonadism)
Follicle-stimulating hormone (FSH)
Karyotype (delayed puberty, ambiguous genitalia)
Progesterone (delayed puberty secondary to 17-hydroxylase [P450c17] deficiency)
Prolactin (hypogonadotropic hypogonadism)
In general, the causes of delayed onset of puberty can be subdivided into two categories: hypogonadotropic hypogonadism and hypergonadotropic hypogonadism. Disorders resulting in hypogonadotropic hypogonadism that may cause primary or secondary amenorrhea are discussed in Chapter 32. Of note, anorexia nervosa, which can result in hypogonadotropic hypogonadism and delayed puberty, can affect 0.5% to 1.0% of young women. It is important to recognize this disorder in the evaluation of these patients. Chromosomal abnormalities or injury to the ovaries by surgery, chemotherapy, or radiation may cause hypergonadotropic hypogonadism. When the patient’s abnormal karyotype includes the presence of a Y chromosome, gonadectomy is recommended to prevent potential malignant neoplastic transformation.
A growing list of single gene disorders resulting in delayed or absent female puberty is being documented in the literature.
Kallmann syndrome presents with hypogonadotropic hypogonadism and anosmia or hyposmia. It may result from a mutation of the KAL gene on the X chromosome or from autosomal mutations that prevent the embryologic migration of GnRH neurons into the hypothalamus. These individuals may have other anomalies of midline structures of the head. One in 50,000 females is affected.
Mutations of the GnRH receptor gene in females have resulted in low gonadotropin levels with primary amenorrhea or delayed puberty.
FSH β-subunit gene mutations and FSH receptor gene mutations have been associated with primary amenorrhea and varying degrees of incomplete development of secondary sexual characteristics.
Females with aromatase deficiency present at puberty with progressive virilization, absence of thelarche, and primary amenorrhea.
17-Hydroxylase (P450c17) deficiency interferes with production of the androgenic and estrogenic steroids, resulting in deficient or absent pubertal development. The accumulation of progesterone before the block leads to excessive synthesis of the mineralocorticoid, 11-deoxycorticosterone, that generally causes hypertension and hypokalemia.
Leptin and leptin receptor gene mutations are associated with retarded pubertal development and childhood morbid obesity.
Mutations in the steroidogenic acute regulatory (StAR) gene result in complete loss of adrenal steroidogenesis and delayed puberty, which is called congenital lipoid adrenal hyperplasia. The StAR protein is necessary in the transport of cholesterol from the outer mitochondrial membrane to the inner mitochondrial membrane, which is the rate-limiting step in steroidogenesis.
Adolescents who present with permanent hypoestrogenism require estrogen therapy as described in Chapter 32, to complete the development of secondary sexual characteristics. Hormone therapy with estrogen plus a progestin or with a low-dose oral contraceptive after establishment of secondary sexual characteristics is required to avoid menopausal symptoms and to prevent osteoporosis. To further maximize bone mineral accretion, 1500 mg of elemental calcium and 400 mg of vitamin D daily are recommended. This should be combined with regular weight-bearing exercises.
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