Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Explain the physiology of female pubertal development.
2. Identify when an investigation of delayed puberty is warranted and understand the basic evaluation.
3. Summarize pharmacologic strategies to manage common causes of delayed female puberty.
This article reviews normal female pubertal physiology, reasons why puberty might be delayed, and how to manage pubertal delay. Puberty is the combination of changes resulting in psychophysical maturity, reproductive capacity, and full adult height. Puberty is influenced by genetics and the environment. During this time of psychosocial growth, adaptive and functional skills incrementally develop and self-identity is established. Puberty typically occurs between the ages of 8 and 13 years. Delayed puberty, occurring in about 2% of adolescents, is the lack of any pubertal development later than 2 to 2.5 standard deviations from the population mean. Delayed puberty is clinically diagnosed when there is no breast development (thelarche) at 13 years, no menarche by age 15 to 16 years, or no menses greater than 3 years after thelarche.1
Genetic factors account for 50% to 80% of pubertal timing variation, and there is ongoing investigation about the interplay between epigenetics and environmental factors. Pubertal timing is highly polygenic. Studies have demonstrated greater concordance of pubertal timing among monozygotic compared with dizygotic twins.2
Physiology of Normal Puberty
Puberty begins with the activation of the hypothalamic-pituitary-gonadal (HPG) axis. The anterior hypothalamus synthesizes and releases gonadotropin-releasing hormone (GnRH), which stimulates the anterior pituitary to release gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which then stimulate gonadal steroid release and gamete production.
The HPG axis has 3 activation periods: during fetal life, a "mini-puberty" from the first week of life to 6 to 9 months of age, and finally, after childhood, which is the period commonly defined as puberty. At about 40 days' gestation, GnRH-secreting neurons originate from the epithelium of the medial olfactory pit and migrate along nerve fibers to the hypothalamus.3 During fetal life, the HPG axis activation allows for reproductive organ development and a theorized central programming process responsible for the sex dimorphic body composition later in life. Placental estrogens increase at 37 to 40 weeks' gestation and suppress the HPG axis in early infancy. After birth, gonadotropin levels initially decline, and then at 6 to 10 days after birth, the GnRH pulse generator temporarily reactivates, resulting in mini-puberty. Mini-puberty is thought to contribute to reproductive organ maturation and the basis of future fertility, though the exact role is poorly understood.4 During mini-puberty, LH is approximately at pubertal levels, with a peak at 1 to 3 months of age, and a drop at 6 to 9 months of age. The mechanism by which the HPG axis then turns "off" is also unclear. The HPG axis remains quiescent through childhood and reactivates during puberty.
At puberty onset, the anterior hypothalamus begins to secrete pulsatile GnRH into the hypophyseal portal system. This process is regulated by the neuropeptide kisspeptin. Kisspeptin is produced by neurons in 2 regions within the hypothalamus: the arcuate nucleus (ARC) and the preoptic area (POA) of the third ventricle. Kisspeptin, through its receptor, acts on GnRH neurons to release GnRH, which in turn stimulates the pituitary to release LH and FSH, which stimulate the ovaries to produce sex steroids. Gonadal steroids stimulate neurons in the POA to release kisspeptin, but inhibit the release of kisspeptin in the ARC, with corresponding feedback loops. The ARC kisspeptin neurons are generally thought to be the GnRH "pulse generator."5 The pulse generator controls the pulsatile secretion of LH and FSH, which is essential for fertility. The ARC also produces neurokinin-B (NKB), which stimulates kisspeptin secretion, and dynorphin (Dyn), which inhibits kisspeptin secretion. Kisspeptin, NKB, and Dyn neurons are collectively referred to as the KNDy neuronal network.6
Other modulators include glutamate, which stimulates GnRH release, and [gamma]-aminobutyric acid (GABA), which inhibits GnRH release.7 Estrogen inhibits GnRH and kisspeptin release.
Puberty is also linked to metabolic and neuroendocrine signals. For example, kisspeptin interacts with leptin. Leptin, secreted from adipose tissue, increases appetite and food intake, which are essential for GnRH pulsatility. Leptin also stimulates KNDy neurons.3
GnRH pulse frequency affects the action of the anterior pituitary. High-frequency pulsation favors LH secretion, whereas low-frequency pulsation favors FSH secretion. When stimulated by FSH and LH, the ovaries release estrogen (primarily estradiol). Estrogen induces breast development (thelarche), growth acceleration, skeletal maturation, and eventually, menarche. High estrogen levels stimulate endometrial lining growth and negatively feedback on the HPG axis. This negative feedback creates cyclical troughs in estrogen, progesterone, and gonadotropin levels that result in endometrial shedding (menses). Mid-cycle, estrogen triggers a large GnRH release, via the POA, and a subsequent LH surge that triggers ovulation. For the first 2 years after menarche, this feedback loop is often not fully mature, resulting in variable menstrual cycle length and anovulation.
Timing and Components of Puberty
The normal pubertal duration is approximately 5 to 6 years. In females, puberty onset occurs at an average age of 10.5 years, with a range of 8.5 to 12.5 years. The phases of puberty occur in an ordered fashion: gonadarche, thelarche, maximum growth velocity, and menarche. Gonadarche, the growth and maturation of the ovaries, is the earliest pubertal change. The first visible sign of puberty is generally considered to be breast bud appearance (thelarche), occurring at a mean age of about 10 years. Estradiol rises 12 to 18 months preceding visible breast development. Puberty culminates with menarche, which happens at an average age of 12.4 years in the United States.8
Adrenarche, the activation of the adrenal gland, occurs concurrently, beginning at an average age of 6 to 8 years. This process is separate from the HPG axis; individuals with gonadal insufficiency will still undergo adrenarche. The zona reticularis of the adrenal cortex secretes dehydroepiandrosterone (DHEA), DHEA sulfate (DHEA-S), and androstenedione. Adrenal androgens increase about 24 months before breast development. Adrenal androgens cause acne, pubic hair development (pubarche), axillary hair, and body odor.9
Vertical growth is an important aspect of puberty. Sex steroids appear to stimulate the growth hormone (GH) axis through insulin-like growth factor-1 (IGF-1), causing a growth spurt that accounts for 20% of final adult height. GH and IGF-1 rise in response to increased estrogen, and then fall when puberty is complete. Growth also depends on other factors including thyroid hormones, cortisol, and insulin. Gonadal steroids stimulate the final fusion of epiphyseal growth cartilage discs. Females gain an average of 10 inches of height during puberty; only about 1 to 2 inches are added after menarche. The most rapid growth occurs at an average age of 11.5 years, during Tanner breast stages 2 to 3. Growth begins with enlargement of hands and feet, then arms and legs, followed by widening of hips; trunk lengthening happens last. The skeletal mass nearly doubles by the end of adolescence. In females, peak bone mass is reached at an average of 22 years. Although females gain bone mineral density at slower rates than males, both males and females gain the greatest amount of bone mineral density in the 1 year before and 2 years after peak height velocity. Older age of puberty onset is associated with persistently lower bone mineral density.10 During puberty, females experience a decrease in lean body mass and an increase in adipose tissue. Other normal pubertal changes include increasing uterine and ovarian volume, vaginal lengthening, physiologic vaginal discharge, thickening and color change of vaginal mucosa, thickening of labia minora and majora, and clitoral enlargement.
Delayed Puberty
Delayed puberty is defined as greater than 2 to 2.5 standard deviations from the population mean, a lack of breast development by age 13 years, no menarche by age 15 to 16 years, or no menarche greater than 3 years after thelarche. Delayed puberty may hinder social development and is associated with negative self-beliefs, peer stress, social isolation, bullying, depression, difficult intimate relationships, and mental health issues in adulthood.11 Weighing the psychological impact on the adolescent is essential when evaluating delayed puberty and making treatment decisions. The most common cause of pubertal delay is constitutional delay of growth and puberty (CDGP), diagnosed when puberty starts beyond 2 standard deviations from the mean, but otherwise progresses normally. Typically, patients and parents should be reassured when this diagnosis is made; extensive evaluation and treatment are not usually indicated.
Evaluation of Delayed Puberty
Evaluation begins with a comprehensive history. Family history is particularly important, as up to 80% of those with CDGP have a family member with delayed puberty. When available, a family history of childhood growth patterns, use of sex steroids to induce puberty, and mid-parental height should be collected. The mid-parental height is a projected estimate of adult height; for girls, this is calculated by subtracting 5 inches (13 cm) from father's height, and averaging that number with mother's height. This number can then be plotted on the child's growth chart for comparison to actual height and the trend over time.
Additional history includes medications, nutritional status, exercise, birth history, surgeries, social history, and developmental milestones. Chronic illnesses such as celiac disease, inflammatory bowel disease, renal insufficiency, cystic fibrosis, hypothyroidism, and anorexia nervosa may cause functional hypogonadotropic hypogonadism (FHH; Table 1). Autoimmune conditions and neoplasms requiring radiation or chemotherapy may cause hypergonadotropic hypogonadism. A complete review of systems must include questions about fatigue, weight loss, headache, and visual changes, which may indicate chronic illness or an intracranial mass.
The physical assessment includes height, weight, growth charts, and an overall examination. Tanner staging, or Sexual Maturity Rating (SMR), is an objective classification system developed from observational data, which is used to describe the stepwise appearance of external genitalia in males, breasts in females, and pubic hair.12 There is generally an increase in height velocity in the 6 to 12 months before pubertal onset. Those with delayed puberty often present with short stature and absent increased height velocity. Genetic syndromes may have visible characteristic examination findings. Signs or symptoms of neurologic disease or malignancy may be noted.
Initial laboratory and radiologic evaluation include LH, FSH, prolactin, thyroid-stimulating hormone (TSH), and bone age. Free thyroxine (T4) may be added if central hypothyroidism is suspected. Bone age radiographs are usually performed on the nondominant hand and wrist, as the hand has many ossification centers that fuse in a predictable pattern. After comparing the image to a set of standards, the bone age is calculated and compared to the patient's chronologic age. A normal bone age is within 2 standard deviations of the mean for that age, and considered abnormal if it is more than 20% above or below the chronologic age.13 Children with CDGP achieve adult height later than peers and may have a bone age that is initially lower than the chronologic age but then normalizes over time. Children with short stature and a bone age similar to chronologic age are more likely to have familial short stature.14
Diagnosis of Delayed Puberty
Hypogonadotropic hypogonadism is associated with low or normal FSH and LH. Hypogonadotropic hypogonadism can be further subcategorized into 3 groups (Table 1). FHH is a transient pubertal delay due to an underlying condition. Congenital hypogonadotropic hypogonadism (CHH) is permanent and usually present from birth. CDGP is a benign delay of puberty.
If FSH is low, further testing may be done to assess for underlying illness or undernutrition, to include complete blood count, basic metabolic panel, liver function tests, erythrocyte sedimentation rate, blood urea nitrogen, and creatinine. Screening for celiac disease may be considered. A serum estradiol is usually not helpful to screen for early puberty. If GH deficiency is suspected, IGF-1 and IGF-1-binding protein-3 may be assessed. If a tumor is suspected, serum markers like human chorionic gonadotropin may be elevated.
Those with hypergonadotropic hypogonadism have elevated levels of FSH and LH; this is gonadal failure or insufficiency. If FSH is greater than 30 mIU/mL, the level is generally repeated in a few weeks for confirmation, and estradiol may be evaluated in this case to confirm premature ovarian insufficiency (POI). A karyotype is the next step in females, primarily to diagnose Turner syndrome. If the karyotype is 46,XX, testing for thyroid antibodies, adrenocortical antibodies, and FMR-1 premutation are indicated.15FMR-1 premutations are responsible for fragile X syndrome.
In patients with hypogonadotropic hypogonadism, additional imaging can be used to evaluate for anatomic central nervous system abnormalities and tumors, particularly when associated with symptoms such as headaches or visual disturbances. Cranial MRI can assess the pituitary and characterize brain neoplasms and is the preferred first step in such cases. If FSH and LH are normal in the setting of isolated delayed menarche, a structural anomaly must be considered. Ultrasonography is the first-line test to evaluate the ovaries and uterus in these patients, though MRI is often indicated for more detailed imaging of the pelvis and abdomen. Patients with structural anomalies may need surgical management. Patients with Turner syndrome or gonadal dysgenesis will generally have elevated gonadotropins and may have streak ovaries diagnosable with ultrasound or MRI.16
Inhibin B has been proposed as a test to distinguish between CHH and CDGP. The lowest concentrations of inhibin B have high specificity for CHH, and high pretest probability, though without clinical features, low inhibin B carries low sensitivity and therefore utility is limited. Genetic testing is emerging as a potential method to diagnose CHH, though only 50% of cases of CHH have known genetic causes. Other promising tests include kisspeptin-stimulating LH levels and FSH-stimulated inhibin-B concentrations.17
Hypogonadotropic Hypogonadism
CDGP is the most frequent cause of delayed puberty. In a large 2002 study, 53% of males and females with delayed puberty were diagnosed with CDGP.18 CDGP is benign, temporary, and highly influenced by genetics. CDGP is a diagnosis of exclusion, and difficult to prospectively distinguish from CHH if no underlying illness is found in the evaluation.19 Those with CDGP often present with short stature, as they have not yet experienced the pubertal growth spurt. Typically, the bone age is lower than chronologic age by 2 or more years.14 Short stature is defined as a height below the third percentile or less than 2 standard deviations below the mean for age and sex. Over 50% of patients with CDGP have one or both parents, or a sibling, with CDGP. It is postulated that CDGP has an autosomal dominant pattern of inheritance without complete penetrance.1 If puberty ultimately begins by age 16 to 18 years, CDGP is diagnosed and CHH is excluded.20
About 20% of females with delayed puberty have FHH. FHH is a transient suppression of the HPG axis in the setting of underlying illness. Underlying illness may include celiac disease, inflammatory bowel disease, juvenile idiopathic arthritis, sickle cell disease, cystic fibrosis, persistent asthma, anorexia nervosa, and malnutrition. Chronic illness may cause physiologic stress, undernutrition, and emotional stress. Medications such as chemotherapy, cranial radiation, or inflammation, such as occurs in autoimmune disease, may also affect puberty. Pubertal delay from undernutrition is one of the most common causes of FHH. Undernutrition can result from poor intake, malabsorption, or increased calorie output.
A disruption of the structure and function of the hypothalamus and/or pituitary gland may result in hypogonadotropic hypogonadism. Causes include hypothalamic or pituitary tumors, craniopharyngioma, septo-optic dysplasia, Rathke's cleft cyst, trauma, histiocytosis, damage from surgery or radiation, infection, and iron deposition from, for example, transfusion-dependent hemoglobinopathies. Empty sella syndrome and combined pituitary hormone deficiency (CPHD) are 2 rare causes of hypogonadotropic hypogonadism. CPHD is the lack of production of at least 2 anterior pituitary hormones. Panhypopituitarism is a deficiency of all hormones produced by the pituitary or, of all hormones produced by the anterior pituitary (GH, TSH, LH, FSH, adrenocorticotropic hormone, and prolactin). Symptoms of panhypopituitarism vary based on which hormones are deficient.21
Kallman syndrome, hypogonadism with anosmia or hyposmia, accounts for up to 60% of CHH. Kallman syndrome is associated with many gene mutations; 15% of these individuals have a mutation in ANOS1 (KAL1) or FGFR1. ANOS1 codes for a neural cell adhesion protein molecule, anosmin-1, that is essential for normal neuronal migration to the hypothalamus. ANOS1 mutations are often X-linked recessive and associated with renal agenesis and bimanual synkinesis.22,23FGFR1 mutations are autosomal dominant and associated with cleft palate, dental agenesis, and skeletal anomalies. Prader-Willi syndrome is a rare genomic imprinting disorder in which the paternal long arm is deleted from chromosome 15, resulting in short stature, hypogonadism, hypothyroidism, and obesity. Bardet-Biedl syndrome results from autosomal recessive mutations in BBS1 and BBS10 genes and is associated with retinal dystrophy, polydactyly, obesity, developmental delays, renal anomalies, genitourinary malformations in females, and hypogonadotropic hypogonadism in males. A loss of function mutation in TAC3 and TAC3R genes that encode for NKB and its receptor can result in normosmic isolated hypogonadotropic hypogonadism. A mutation in the DNA-binding protein-7 CHD7 gene expressed in the pituitary gland can cause CHARGE syndrome: a combination of colomba, heart disease, atresia of the choanae, restricted growth and mental development, genital anomalies and ear malformations, hearing loss, and CHH.
Hypergonadotropic Hypogonadism
Hypergonadotropic hypogonadism, or primary hypogonadism, is due to abnormal gonadal function. LH and FSH are elevated because the gonads do not produce estradiol to provide negative feedback on the pituitary. Hypergonadotropic hypogonadism accounts for about a third of delayed puberty in females, and is often due to genetic abnormalities. Therefore, a karyotype is the first study that should be ordered. Approximately 25% of such patients are found to have Turner syndrome, the incidence of which is about 1 in 2500 live births. People with Turner syndrome have a 45,X karyotype, with full or partial X chromosome deletion. Those with partial X deletions or translocations may have primary or secondary amenorrhea, spontaneous breast development, and may be of average height. About one-third of those with monosomy X have spontaneous breast development and most have primary amenorrhea and short stature; however, the phenotype varies. Most patients require hormone replacement for pubertal changes and bone health. Other features associated with monosomy X are a webbed neck, broad chest, low posterior hairline, cleft renal pelvis or horseshoe kidney, cardiac anomalies, hearing impairment, and multipigmented nevi. A small percentage of those with Turner syndrome have Y chromosomal DNA, which may increase the risk for gonadoblastoma. Multispecialty evaluation is usually warranted.24
POI can also be idiopathic or a result of gonadal damage from radiation, trauma, chemotherapy, or autoimmune disease. About 50% to 90% of POI is idiopathic, and about 14% of cases are due to autoimmune disease. Autoimmune polyglandular syndromes (APS) are a group of endocrine and nonendocrine autoimmune diseases associated with genetic mutations and primary ovarian insufficiency. Diagnosis is through genetic analysis for homozygous inactivating mutations of the autoimmune regulator gene, AIRE for APS type 1, and mutations in the HLA DQ/DR genes for APS types 2 and 3.25
Chemotherapy and/or radiation therapy may physically disrupt or damage ovarian tissue and function. Effects may be transient or permanent; 6.3% of childhood cancer survivors experience ovarian insufficiency. The risk of POI is higher for those with an older age at cancer treatment, Hodgkin's lymphoma, pelvic radiation, and exposure to higher doses of chemotherapy, particularly alkylating agents.26 Viral and bacterial infections may cause ovarian damage and destruction.
Persons with differences of sexual development may have hypergonadotropic or normogonadotropic hypogonadism. Pure gonadal dysgenesis refers to those with underdeveloped, or "streak," gonads. Karyotype may be 46,XX or 46,XY (Swyer syndrome). Those with 46,XXX may also have POI. A rare gene mutation at CYP17A1 results in 17[alpha]-hydroxylase deficiency and causes adrenal insufficiency and a lack of sex steroids, including estrogen. These individuals may have a 46,XX karyotype, typical female genitalia and delayed pubertal development, or 46,XY karyotype with a phenotype similar to androgen insensitivity syndrome (AIS).27 Fragile X premutation carriers, those with myotonic dystrophy, trisomy 21, and ataxia telangiectasia are at risk for POI. Aromatase deficiency is extremely rare.
Structural Anomalies
Structural anomalies may present with primary amenorrhea. Mullerian agenesis, or Mayer-Rokitansky-Kuster-Hauser syndrome, is an embryologic underdevelopment or absence of Mullerian duct structures (uterus, cervix, fallopian tubes, and upper vagina). Ovaries are present, and even if fallopian tubes are atrophic, fimbriae are typically present. Renal malformations may also be seen. These individuals have a 46,XX karyotype, normal gonadotropins, normal progression of thelarche and growth, and absent menarche. If there is Mullerian and vaginal agenesis, dilation is considered first line for neovagina creation, though surgical options exist. For those with partial Mullerian agenesis, if there is functional endometrium in an obstructed uterine remnant, estrogen stimulation during puberty may lead to painful accumulation of hematometra.28 Hematometrocolpos presenting as primary amenorrhea can also occur if there is a normal uterus and cervix, but an obstruction in the lower vagina or an imperforate hymen; these obstructions are relieved surgically. In 2021, the American Society for Reproductive Medicine published a comprehensive classification system for Mullerian anomalies to standardize terminology and raise awareness.29
Individuals with AIS have a 46,XY karyotype and appear phenotypically female with breast development, and scant pubic hair. The prevalence is 1 in approximately 20,000 to 64,000 live births.30 An X-chromosome-linked mutation in the androgen receptor gene renders peripheral tissues unresponsive to testosterone. The gonads are usually undescended testes. There are no Mullerian structures and patients may present with primary amenorrhea. Androgen resistance may be partial or complete with a varying phenotype based on the level of resistance. Gonadectomy for these individuals has historically been recommended due to the increased risk of malignancy. If gonadectomy is delayed after shared decision-making, screening for signs of malignancy is recommended.31,32 Vaginal length in those with AIS can vary from a dimple in the perineum to a blind-ending vaginal pouch of normal length. Dilation is generally considered first-line treatment for neovagina creation, though surgical options exist.
Management of Delayed Puberty
Therapeutic decisions are based on the underlying cause. Bone health, fertility, height, psychological factors, and the goals of the patient must also be considered. In a 2020 survey of pediatric endocrinologists, 45% reported treating males earlier than females, citing stress alleviation for males and bone density preservation for females as the most common reasons for initiating treatment.33
In most cases of FHH, treatment of underlying illness results in puberty progression. In some cases, for example, in prolonged anorexia nervosa, a 4- to 6-month course of sex steroid therapy may be reasonable to support bone health while calorie intake is restored.
When hypogonadism is permanent, hormone replacement is indicated. Those with Turner syndrome are usually treated with GH, and sometimes oxandrolone, in addition to estrogen.34,35 Age of treatment for permanent hypogonadism is often guided by age of diagnosis. Estradiol, oral or transdermal, is started at a low dose and slowly escalated to full adult sex steroid levels over approximately 3 years to optimize height and bone health and induce the growth and progression of secondary sexual characteristics. Transdermal estradiol is preferred over oral therapy for ease of use, increased compliance, reduced risk of venous thromboembolism, improved bioavailability, and skipped first-pass metabolism by the liver. A commonly used regimen for therapy begins with a 17-[beta] estradiol patch designed to deliver 25 [mu]g/day, cut in quarters, such that the patient applies 6.25 [mu]g/day continuously for 6 months. Every 6 months thereafter, the dose is increased by 1/4 patch until the dose is a 25 [mu]g/day (1 full patch). This dose is usually reached after 18 months and continued through pubertal induction. Around month 24, cyclic progestin (usually oral micronized progesterone 200 mg daily) is added to induce menstruation and protect against endometrial hyperplasia.16,24 Cyclic progestin is generally not started until breast development plateaus at the full contour, or until vaginal bleeding occurs, due to concern for development of tuberous breasts. Once pubertal induction is complete, maintenance sex steroid therapy is individualized to the needs of the patient, and can be provided via an estrogen patch with cyclic progestin, or oral contraceptive pills. Long-term hormonal treatment at replacement doses reduces risks of osteoporosis, heart disease, and urogenital atrophy and should be continued through age 50 to 51 years, the average age of menopause.36 Calcium and vitamin D for bone health should be encouraged.
The American Academy of Pediatrics historically has recommended watchful waiting and reassurance for CDGP. However, there may be a role in some cases for estrogen therapy to "jump-start" puberty based on shared decision-making with patients and families, in cases where pubertal delay causes significant psychological distress. Treatment does not appear to alter the final adult height, but can initiate secondary sexual characteristic development faster.37
Counseling, reassurance, and support are key components in managing all cases of delayed puberty. Communication between providers, patients, and families is important. Questions and information about fertility and future options should be reviewed and shared. Support groups, conferences, and online resources may be helpful. Although CDGP is the most common cause of delayed puberty, a thorough workup is indicated if delay is suspected, as an underlying illness or anatomic variation may warrant treatment.
Practice Pearls
* Delayed puberty is the lack of any pubertal development later than 2 to 2.5 standard deviations from the population mean, no breast development at 13 years, no menarche by age 15 to 16 years, or no menses greater than 3 years after thelarche.
* The most common cause of delayed puberty is a benign, likely genetic, CDGP: a normal pubertal progression with a delayed timeline. Treatment is observation and reassurance.
* Initial evaluation of delayed puberty includes LH, FSH, prolactin, TSH, and a bone age x-ray. Based on FSH levels, delayed puberty can be categorized into hypogonadotropic, hypergonadotropic, or normogonadotropic.
* Patients with ovarian failure or CHH require exogenous estrogen replacement therapy to induce puberty and provide support for bone and heart health.
References