Disorders of ovarian function in childhood and adolescence: evolving needs of the growing child. An endocrine perspective
Dr M Zacharin, Department of Endocrinology and Diabetes, The Royal Children’s Hospital, Parkville, Vic. 3052, Australia. Email email@example.com
Please cite this paper as: Zacharin M. Disorders of ovarian function in childhood and adolescence: evolving needs of the growing child. An endocrine perspective. BJOG 2010;117:156–162.
Over the past 15 years there have been changes in the care of children and adolescents paralleling increased longevity of those with chronic illnesses and increased survival after childhood cancer and organ transplantation. A broad understanding of holistic management and long-term risks is required. Optimisation of pubertal progress and normalisation of bone and hormonal health by the end of puberty will reduce the impact of later adult bone loss in chronic disease conditions. Psychosocial issues related to both precocious and delayed puberty can have profound effects on family function.
Over the past 10–15 years, physicians caring for children and adolescents across most disciplines have seen marked changes in their range of practice reflecting increases in the prevalence of many types of chronic illness, such as inflammatory bowel disease; increased survival after childhood cancer; increased longevity of individuals with disorders such as cystic fibrosis; increased use of organ transplantation; and recognition of new genetic disorders associated with loss of ovarian function. As the complexity of disease patterns increases, so does the need for a broad understanding of holistic management and a working knowledge of long-term risks.
As changes in ovarian function with treatment and with physical and emotional stress have assumed new importance, it has become clear that strategies are required to anticipate loss of ovarian function and to provide solutions. Recognition of the pivotal importance of optimising peak bone mass accumulation, to reduce the impact of later adult bone loss in chronic disease conditions,1 has further underlined the need for a detailed understanding of ovarian function and its effects. The intrinsic link between bone mass accumulation and progress through puberty makes it essential to have a thorough understanding of methods of optimising pubertal progress and normalising bone and hormonal health by the end of puberty.
The possibility of achieving new medical outcomes produces new challenges. Bisphosphonate management of bone disorders in childhood generates issues regarding risks in future pregnancies.2 Women with Turner syndrome can now look forward to achieving pregnancy through donor ovum in vitro fertilisation. To maximise the chances of successful pregnancies in individuals with Turner syndrome, uterine size must be optimised using adolescent hormone replacement therapy (HRT).
Gain of ovarian function in childhood results in precocious puberty. Girls with precocious puberty are mainly seen by paediatricians, but there are also extensive ramifications for adult care in terms of fertility and the risk of metabolic syndrome.3
Psychological, social and ethical issues
When the timing and tempo of growth and puberty are altered, major psychosocial and emotional turmoil can occur in families. It is imperative to separate the concerns of the child from the concerns of the parent.
The effect of pubertal disturbance on a child or adolescent can be devastating. When puberty is late, short stature and altered body image may give rise to the fear that appropriate growth might never occur and that the affected girl might never have an adult female appearance. While many parents are knowledgeable about differing growth patterns, communication between parent and child may be lacking. Where puberty is early there are complex interactions between the child and her parents, other children in the family and her peers. Parents’ concerns centre around tall stature, the possibility of stunted final height as a result of early puberty, and the emotional and social chaos that results from the effects of early estrogen production on brain function, and the consequent mature but disordered behaviour of the child. Significant friction within a household is common, and understanding and sympathy can be lacking. Parental attitude and coping ability can be compromised by unresolved concerns. Adequate explanation in terms of patterns of pubertal progress, likely outcome and planning strategies may address these concerns. Specific advice regarding interactions with school staff is also needed.
Where ovarian function is deteriorating, in situations such as Turner syndrome or galactosaemia, with reduced adult fertility prospects, decisions may need to be made by parents on behalf of a child or adolescent below the age of consent. Lengthy discussion is required to enable parents to understand the concepts of unfertilised ovum salvage, with the currently limited potential for future viable ovum salvage.4 Ethical concerns arise regarding removal of gonadal tissue without true informed consent, and where complications could potentially occur, for possible future use in procedures for which there is little positive evidence of effectiveness. Such actions might in future be challenged in a court of law.
Furthermore, removal of part or all of an ovary which is of poor quality and has limited function, may alter the pubertal cascade, leading to a requirement for HRT for adult feminisation.
Donation of maternal ovarian tissue for future potential use by an affected daughter raises issues of possible chromosomal risk. Future potential rejection of this tissue may further complicate the relationship of the parent with the child.
Historical lessons should be learnt. The use of estrogen to hasten epiphyseal closure and to limit final height was common in the 1960s. The issue of true informed consent arose later, with a perception that future risks had not necessarily been adequately addressed in terms of management planning. Individual and class actions against medical practitioners were considered.5 Changing societal views of tall stature in women as a positive rather than a negative trait have had a major impact on changing attitudes. We need to be sensitive to the possibility that decisions taken now may in future have unanticipated outcomes. Legal cases have been brought successfully to trial, with decisions in favour of men with cancer who were not offered appropriate semen storage facilities before chemotherapy.6 In current childhood management protocols, an awareness is needed of evolving medical possibilities as well as attitudes.
Clinical problems associated with ovarian hypofunction
Structural hypothalamic–pituitary disorders
Growth failure, pubertal failure or arrest, defects in vision or hearing, and signs of raised intracranial pressure are all possible presentations of craniopharyngioma or malignant tumours. Prolactinoma is relatively uncommon in early adolescence.
Functional hypothalamic–pituitary disorders
Functional disorders of the hypothalamic–pituitary–ovarian axis, particularly subclinical eating disorders (which can be seen in children as young as seven or eight years old), are extremely common in adolescent girls and present as linear growth failure and failure to enter puberty.7 Chronic illnesses such as Crohn’s disease have a peak incidence between the ages of 9 and 13 years. Severe cerebral palsy and related conditions often result in low weight and consequent pubertal delay. Failure to detect and manage these conditions early results in adverse outcomes in terms of height and bone quality. Nutritional deficits, corticosteroid use with adverse effects on vitamin D and calcium absorption and metabolism, inhibition of adrenal and gonadal steroid synthesis and specific adverse effects on osteoblast function all have a cumulative effect in reducing bone health, linear growth and appropriate pubertal progress.8
Isolated hypogonadotrophic hypogonadism
A large number of genetic associations with hypogonadotrophic hypogonadism (HH) have now been described. Any of these genetic conditions may result in a failure to enter puberty or occasionally pubertal arrest. Changes in pathways of neural networking as a result of mutations in genes controlling brain dopaminergic pathways, Kiss gene mutations, adhesion molecule abnormalities and downstream gene signalling defects have been demonstrated to cause HH, and a Kal gene mutation has been demonstrated to cause HH and anosmia.9
Girls who have HH require induction of puberty. Despite appropriate feminisation, after the trauma of severe pubertal delay, a distorted body image of a childlike appearance may persist for one to two years as a significant psychosocial burden.
High-dose cranial radiation (CXRT; 40–54 Gy) for malignant brain tumours in childhood, lower dose (12–24 Gy) whole-brain radiation as a component of leukaemia chemotherapy protocols, or total body irradiation conditioning before bone marrow transplant may result in evolving hypothalamic–pituitary deficits.10 CXRT also has major global effects on learning, short-term memory and memory processing. When a recipient of childhood CXRT is seen as a young adult, it is important to recognise memory impairment. Such a young woman may appear physically, psychologically and socially normal while having very significant short-term memory problems. This may impinge upon grasping and understanding concepts of endocrine deficits and the need for complex treatment regimens, particularly with regard to fertility. It may also impinge upon regular use of any medication. Physician awareness of such deficits allows tailoring of treatment protocols to these special needs.
The evolving nature of endocrine losses after CXRT needs to be explained to patients and their parents. Early radiation results in early disinhibition of pubertal restraint, with pubertal onset occurring two years earlier than average. Normal ovarian function follows, with slow evolution to gonadotrophin deficiency in many cases.11 Moderate elevation of prolactin can exacerbate cycling abnormalities. Failure to present for care for this type of problem is common, with people who have undergone CXRT having the misplaced and erroneous belief that it is an inevitable and untreatable consequence of past cancer therapy.12
Early high-dose CXRT can cause cerebral arteritis,13 which increases late thrombotic stroke risk. When planning hormone replacement in this group, the possibility should be explored of using transdermal estrogen with cyclical progestogen as a preferred modality of treatment, to reduce coagulation risk. Concomitant use of low-dose aspirin may be desirable.
Chronic diseases of childhood often follow a fluctuating course. Intervention to improve growth rate and optimise bone mass accumulation is partly dependent on choosing a window of opportunity during an episode of remission of the disease process. However, where remission is unlikely or slow, such as in an eating disorder, juvenile chronic arthritis or cystic fibrosis, it may ultimately be necessary to choose a course that permits induction of puberty at the expense of optimising final height.8
Treatment of concurrent growth hormone deficiency may require a delay in pubertal induction. Appropriate counselling is necessary to enable girls and their parents to make an informed choice as to whether to delay the induction of puberty in these circumstances.
Survival of young people with major midline brain malformations is now common. Chronic disability and immobilisation increase the risk of poor bone health, which is complicated by pubertal disorder. Appropriate induction of puberty may be indicated, with a specific aim of improving adolescent bone mass and of reducing lifetime fracture risk.14
Occasionally parents of affected children with global developmental delay may wish for the child to remain prepubertal.15 Judicious intervention with HRT, where appropriate, results not only in improved growth and physical development, with a concomitant reduction in fracture risk through improved bone health, but also in a significant improvement in brain maturity and understanding. This can have a major positive effect on the parent–child interaction.16
Bone health is dependent on the complex interaction of normal nutrition and growth factors, appropriate pubertal progress and maintenance of adult hormonal requirements, together with the ability of bone to respond to loading. Adverse circumstances for bone health include use of anticonvulsants, immobility, corticosteroids and the presence of inflammatory cytokines. The concept of the ‘muscle–bone unit’ involves understanding of mechanical contributors to bone strength.17 Optimal intake of calcium, phosphate, magnesium and vitamin D, together with normalisation of linear growth, contribute to improvement in bone health but the largest effect is produced by ensuring normal pubertal progress and maintenance of adult sex hormone levels.18
Primary ovarian failure
Primary ovarian failure as a cause of short stature and pubertal delay or arrest is common, frequently as the result of Turner syndrome (1 in 2500 live births), and is most likely to present in late childhood or early adolescence with these features. Thirty to forty percent of girls with this condition enter puberty normally,19 but only around 4% achieve spontaneous menarche and 1% are spontaneously fertile. Most do not have the classical phenotypic features of Turner syndrome. Very minor ‘soft’ features of narrow, deep-set nails with mild hyperextension of terminal phalanges and puffiness of interphalangeal dorsal fat pads are common.
Karyotyping is an essential component of any investigation of short stature and pubertal delay in girls. If diagnosed, Turner syndrome requires specialist investigation and management, including full cardiac evaluation and screening for associated autoimmune diseases such as hypothyroidism and coeliac disease.20 Thirty percent of girls with Turner syndrome have some form of associated cardiovascular anomaly, most commonly a bicuspid aortic valve. Coarctation only occurs in around 4% of girls with Turner syndrome. Hypertension in the absence of a structural anomaly is also common, with increased risks during adult life.21 The finding of a bicuspid aortic valve, particularly when posteriorly placed, increases the risk of aortic dissection. With in vitro fertilisation technology, prospects for fertility are good. It is therefore of increasing importance that adequate visualisation of the cardiovasculature is undertaken, particularly before consideration of a pregnancy.21 The current practice of evaluation using echocardiography may be inadequate, with better visualisation of valves and the aortic arch being obtained using magnetic resonance imaging.22,23 Normograms based on body surface area, for evaluation of the aortic root, can be valuable, to provide evidence of stable or increasing aortic diameter and hence risk for dissection. This risk is currently estimated to be around 2%, and risk of death during pregnancy for a woman who has Turner syndrome is increased as much as 100-fold.24 Cardiological review every three to five years is advised for all girls with this condition, from adolescence onwards. Adequate advice regarding potential pregnancy risks is also necessary.
Growth hormone increases final height and is commonly prescribed for girls with Turner syndrome. Its use does not alter the lipid profile or glucose tolerance in the long term, although short-term changes have been seen.
Autoimmune disease is common in Turner syndrome. Lifetime risk for coeliac disease is approximately 10%. Two-yearly surveillance is advised, with transglutaminase antibody being specific for diagnosis, provided that immunoglobulin A is normal. In particular, if pregnancy is not being achieved at the expected rate for a girl with Turner syndrome, review of coeliac disease screening status is desirable.
Hashimoto’s thyroiditis risk requires pre-pregnancy screening for possible elevation of thyroid-stimulating hormone.
Because of increased lifetime risk for hypertension, it is preferable to use natural estrogens when planning HRT regimens. The ethinyl radical of most estrogen components of commonly used oral contraceptive pills causes a 40-fold increase in renin substrate induction, compared with a natural estrogen.25 Simply using natural estrogens significantly reduces the risk of hypertension in these girls. Pubertal induction should be at a peer-appropriate age, and not delayed unduly for statural growth. Induction should be slow, with minimal estrogen dosing, to mimic normal puberty over two to three years, with the addition of cyclical progestogen by the end of that time.19,26
Most large, recent studies show a slightly reduced uterine volume in women with Turner syndrome.27 First-trimester miscarriage is common, and is largely attributable to uterine factors. Adolescent HRT protocols need to ensure that estrogen is delivered at the appropriate age to optimise uterine growth potential.28 Questions regarding early ovum salvage are similar to those for galactosaemia (see following section).
Galactosaemia causes almost inevitable ovarian failure with time, which presents as pubertal failure or amenorrhoea with raised follicle-stimulating hormone levels, and requires long-term HRT.29,30 Questions regarding early ovum salvage are commonly raised. Parents may elect for attempted ovum salvage at an age at which informed consent is not possible or for a girl whose understanding may be significantly limited by intellectual disability induced by the underlying condition. Careful counselling should be undertaken to explain the advantages and disadvantages of such a course of action, before ovum salvage is attempted.
Limitation of lactose intake is mandatory for this condition. Lactose is used as the vehicle in most tablet preparations, so transdermal estrogen is the preferred choice. However, adolescents sometimes refuse to use a medication which is visible to themselves and potentially to others and most dislike gel preparations. When choosing the type of preparation to use, the effects of daily intake of small amounts of lactose must be weighed against the possible effects of major noncompliance.
Survival after childhood cancer
Survival after childhood cancer is 70% overall and up to 90% for some conditions. Surveillance planning after chemotherapy and radiation exposure is required.
Consideration needs to be given for possible risks of metaplasia and cancer following past exposure of bowel, bladder31 and endometrium to pelvic irradiation. These risks are currently unknown. Future breast cancer risk, after early exposure of the breast to radiation as part of childhood cancer protocols, is estimated at 100-fold higher than that for other young women. Formulation of new guidelines for those who were exposed to radiation during childhood or adolescence is needed.32
Conditioning treatment before bone marrow transplant, with total body irradiation, exposes the ovary to 12 Gy radiation bilaterally. Where pelvic irradiation has occurred, for example for treatment of Wilms’ tumour, Ewing’s sarcoma or chondrosarcoma, ovarian exposure to radiation may only be unilateral with relative preservation of the contralateral ovary.
Ovarian failure after irradiation is dose and age dependent. After total body irradiation, 50% of treated adolescents will have sufficient ovarian function to progress through puberty, although reduced ovarian function with time is almost inevitable and early menopause is universal. It is usual to advise such women to plan a family before the age of 30 years.33,34
Local pelvic irradiation during childhood or adolescence alters uterine growth, which results in adverse pregnancy outcomes.33
Chemotherapy with alkylating agents is common as a component of treatment protocols for some types of childhood leukaemia or cancer; in particular, cyclophosphamide, melphalan and busulfan are commonly used before bone marrow transplantation. All cause dose-dependent ovarian failure.
Ovarian failure after treatment with cyclophosphamide is common but usually resolves somewhere between two and ten years after childhood administration. With early childhood exposure, resolution of normal ovarian function by the time of expected puberty is likely. If administered later, at eight to 12 years, ovarian failure may still be present at the time of peer-appropriate pubertal development and in this case HRT induction of puberty will be required.33
Genetic disorders associated with ovarian dysfunction
As the number of genetic diagnoses for complex congenital disorders increases, so too does the number of genetic associations with either hypothalamic–pituitary abnormalities (18p del)35 or primary ovarian failure (3q del).36 Intrauterine growth restriction with 11p15 methylation defects,37 fragile X carrier state38 and steroidogenic factor 1 (NR5A1) mutations39 are also linked to ovarian failure, together with chronic transfusion dependence and iron overload.
In all cases where HRT is required for pubertal induction, if the initial estrogen dose is too high or the rate of increase is too rapid, breast development is altered, with permanent deformation of normal breast shape and an unusually large nipple. Specialist paediatric endocrine management is therefore required to optimise growth and development.
Clinical problems associated with ovarian hyperfunction in childhood
Presentation with precocious puberty is not uncommon in childhood. Parents are alerted to the possibility of estrogen excess by premature thelarche, a common, usually benign, self-limiting condition occurring any time from birth to the second year of life. Links have been made with maternal estrogen, soy milk products and other estrogen-containing vehicles but most cases are not found to have a satisfactory explanation.
Differentiation of benign premature thelarche from true central precocious puberty (CPP) is imperative. CPP usually has a sudden onset, often in childhood at age three years or above rather than in infancy, although it can occur at any time and usually shows a rapid progression. Where estrogen levels are clinically significant, increasing growth velocity is always associated with CPP, in addition to mood change, emotional lability and a type of ‘mature’ adolescent behaviour.
Severe hypothyroidism should be considered. It is difficult to diagnose clinically in early to mid childhood, with few obvious signs. A cross-over effect of thyroid-stimulating hormone and follicle-stimulating hormone can result in estrogen excess and breast development.40 If this effect is extreme, very large ovarian cysts can occur, which usually regress on treatment of the underlying condition.
Where pubertal progress is of sudden onset under the age of five years, associated with a rapid growth spurt, elevated gonadotrophins and estrogen, magnetic resonance imaging of the hypothalamic–pituitary axis is imperative. Midline lesions include hamartoma of any size, germinoma, glioma, astrocytoma and occasionally craniopharyngioma. The association of neurofibromatosis type 1 and optic chiasmal glioma with CPP is well known but precocious puberty in this condition can occur in the absence of tumour.41
Intervention for precocious puberty usually uses a luteinising hormone-releasing hormone (LHRH) agonist. Where treatment is commenced after the age of eight years in a girl, the outcome, in terms of remaining growth potential, is not altered. Progestogen is a useful alternative but has less effect on bone age advance. It is commonly used for children with a major brain abnormality, with associated precocious puberty.18 Use of high-dose progestogen after puberty to suppress menstruation results in hypothalamic–pituitary–ovarian axis switch-off, with resultant hypo-estrogenaemia. This is highly undesirable in terms of bone mass preservation, and this type of treatment should therefore always be accompanied by estrogen replacement. By contrast, when progestogen is used unopposed during childhood, there are no such concerns regarding bone mass accumulation, because estrogen is not required in children.
Gonadotrophin-independent precocious puberty is rare, most commonly associated with McCune–Albright syndrome42 (polyostotic fibrous dysplasia and café au lait markings). Various endocrine hyperfunctions occur, including precocious puberty, as a result of Gsα mutations causing constitutive activation of affected cells. In the ovary this may be unilateral or bilateral. Treatment uses aromatase inhibitors to prevent estrogen effects on bone age advance but their effect is inconsistent and inefficient at preventing continuing bone age advance.43 Secondary stimulation of the hypothalamic–pituitary–ovarian axis can result in CPP with the added need for an LHRH agonist later. When treatment is withdrawn, continuing unremitting estrogen production from the ovary without cyclicity can result in endometrial hypertrophy, irregular endometrial shedding, menorrhagia and infertility.44
Inhibition of precocious puberty with an LHRH agonist or progestogen is relatively simple to address in mechanical terms. The major problems encountered by families relate to psychological and emotional issues. Universal expectations of ‘mature’ behaviour are inevitable, putting an intolerable burden on a very young child. This can result in significant psychosocial disturbance. It is imperative that school staff are informed about the condition and about the needs of the child. Parents can be extremely irritated by emotional behaviour more suited to a young adolescent. Lack of understanding of this feature can cause major turmoil within families. Parental concerns about rapid physical maturation are often accompanied by covert concerns about psychosexual maturation and inadvertent risk of exposure to inappropriate sexual advances. This type of problem is very unusual. Early appropriate discussion, at the onset of intervention, can be very helpful in allaying family anxiety.
A history of CPP may predispose to later development of polycystic ovarian syndrome, with its implications for adult care.3
Use of new treatments for a number of childhood conditions has raised new concerns regarding their subsequent impact on these children later in life. Bisphosphonates are now commonly used for the treatment of primary and secondary bone disorders of childhood, including osteogenesis imperfecta, and disorders resulting from chronic corticosteroid use, and are also used around the time of organ transplantation. Bisphosphonate use, particularly in the treatment of osteogenesis imperfecta, has resulted in major changes in outcome, in terms of quality of life, growth and bone health and also in expectations for the future.45,46 Pregnancy is now a possibility for those who previously had such severe bone problems that they may never have grown to a physical size where pregnancy was considered realistic, or health was simply a barrier to pregnancy.
Bisphosphonates are pyrophosphate derivatives that are taken up into bone and released at a slow rate over a number of years. To date there is no evidence of any adverse effect on the fetuses or children of women exposed in the past to bisphosphonate treatment, although few such studies have been carried out.2 It is currently advised that bisphosphonate use should be stopped at least one year before contemplation of a pregnancy.
Women with Turner syndrome can now look forward to fertility. Recognition of aortic dissection risk during pregnancy has underlined the need for the most up-to-date (i.e. magnetic resonance imaging) surveillance for this risk.
Childhood LHRH agonist use may be linked to later fertility impairment. There is currently no evidence to suggest this to be a problem. With an increase in the number of children treated with this agent, continuing surveillance is required.
Increased survival after childhood cancer treatment has brought into focus the risks of subsequent adverse effects of such treatment, particularly radiation exposure. For example, spinal irradiation may have subsequent adverse effects on the breast, pelvic radiotherapy may have effects on pelvic organs and both chemotherapy and radiotherapy may subsequently result in complex evolving fertility impairment.
It is incumbent upon gynaecologists and obstetricians caring for young women who have undergone such treatments to be aware of this broad range of new and complex medical circumstances. As much as gynaecologists require new understanding of areas previously in the domain of paediatricians, so paediatricians require new understanding of the evolving complexities of the adult care of their young patients.
Disclosure of interest
The author has no conflicts of interest to disclose.
Contribution to authorship
M Zacharin is solely responsible for authorship.
Details of ethics approval
No funding or other financial support was obtained for researching or writing this article.