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Late Effects of Parasellar Lesion Treatment: Hypogonadism and Infertility
Emilia Sbardellaa Marianna Minnettia Riccardo Pofia Alessia Cozzolinoa Ermanno Grecob Daniele Gianfrillia Andrea M. Isidoria
Abstract
Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options, and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.
Introduction
The parasellar region is a highly complex and fragile area without any strong anatomic boundaries. It comprises structures and spaces surrounding the sella turcica, namely the suprasellar cistern, the cavernous sinus, the hypothalamus, and the third ventricle [1, 2]. In the long term, patients with a parasellar lesion are likely to develop endocrine disorders, resulting from either the tumorous or infiltrative process itself or its treatments, which can have both local and distal side effects. Masses occupying the parasellar region are normally due to a pituitary adenoma extending from the sella. Less frequently, they may arise from a primary parasellar tumour or a nontumorous cystic lesion [1]. The most common malignant lesions occupying the parasellar region are gliomas, followed by germ cell tumours, primary lymphomas and metastases. Other potentially malignant tumours include craniopharyngiomas, chordomas, chondrosarcomas, haemangiopericytomas and Langerhans cell histiocytosis, while benign tumours include meningiomas, epidermoid cysts, dermoid cysts and Rathke cysts [2].
The diagnostic approach to a suspected suprasellar/ parasellar lesion should start with radiological imaging. Computed tomography scans are generally considered to offer the most information, as they enable an accurate assessment of bony details and calcifications. However, magnetic resonance imaging is the imaging technique of choice, as it produces multiplanar high-contrast images, while more recent advanced magnetic resonance imaging techniques such as diffusion-weighted imaging and perfusion-weighted imaging [3–5] can better define the morphological characteristics of the lesion. 18F-fluoro-deoxyglucose and 68Ga-positron emission tomography can be used for functional imaging, but only in specific tumour settings [6, 7].
The second diagnostic step is a complete pre-treatment evaluation of hormone deficiencies, to help establish the prognosis and initiate a suitable therapy. A complete description of the tests used to investigate the hypothalamic-pituitary axis in men and women was previously provided [8–11]; a brief summary is reported in Table 1.
Parasellar Lesions: The Effects of Treatment
Radiotherapy and Its Effects on the HypothalamicPituitary-Gonadal Axis
Chemotherapy, Immunological Treatment and Their Effects on the Hypothalamic-Pituitary-Gonadal Axis
Long-Term Effects of Parasellar Lesion Treatments on Male Gonad Function
Male Central Hypogonadism
Male Infertility
Long-Term Effects of Parasellar Lesion Treatments on Female Gonad Function
Female Central Hypogonadism
Female Infertility
Other Endocrine Effects Affecting Fertility
Managing Pregnancy
Conclusions
In recent decades, progress in parasellar tumour diagnosis and treatment has led to a great improvement in survival rates. Strategies for identifying patients with delayed puberty and instituting timely pubertal induction in adolescence can significantly improve long-term sexual and reproductive function. Correct identification of delayed puberty and personalization of puberty induction therapy with androgens and/or gonadotropins are crucial with these patients. Long-term physiological testosterone replacement is necessary for men with permanent HH, to substitute HPG function and to reduce comorbidities associated with HH.
In girls with a diagnosis of HH secondary to parasellar lesion treatment, oestrogen replacement therapy should be promptly started with the proposed protocols; if hypogonadism arises after puberty, HRT is necessary until or beyond the age of natural menopause to protect female patients from metabolic, cardiovascular and bone diseases associated with HH.
Post-treatment preservation of fertility and quality of life is therefore crucial. Whenever possible, fertility aspects should be discussed before starting therapies leading to hypogonadism and infertility. Unfortunately, about 40% of cancer survivors report that no fertility counselling was offered after their diagnosis. Fertility preservation strategies are available, and several studies are evaluating further new alternatives. A multidisciplinary approach involving oncologists, radiotherapists, endocrinologists, gynaecologists and fertility specialists is essential to improve the awareness and availability of these options. As ART regimens continuously change and fertility options improve, future studies on patients with hypopituitarism are needed to find a patient-tailored strategy for restoring hormonal function, when possible, and preserving the patient’s reproductive potential.
Emilia Sbardellaa Marianna Minnettia Riccardo Pofia Alessia Cozzolinoa Ermanno Grecob Daniele Gianfrillia Andrea M. Isidoria
Abstract
Central hypogonadism, also defined as hypogonadotropic hypogonadism, is a recognized complication of hypothalamic-pituitary-gonadal axis damage following treatment of sellar and parasellar masses. In addition to radiotherapy and surgery, CTLA4-blocking antibodies and alkylating agents such as temozolomide can also lead to hypogonadism, through different mechanisms. Central hypogonadism in boys and girls may lead to pubertal delay or arrest, impairing full development of the genitalia and secondary sexual characteristics. Alternatively, cranial irradiation or ectopic hormone production may instead cause early puberty, affecting hypothalamic control of the gonadostat. Given the reproductive risks, discussion of fertility preservation options, and referral to reproductive specialists before treatment is essential. Steroid hormone replacement can interfere with other replacement therapies and may require specific dose adjustments. Adequate gonadotropin stimulation therapy may enable patients to restore gametogenesis and conceive spontaneously. When assisted reproductive technology is needed, protocols must be tailored to account for possible long-term gonadotropin insufficiency prior to stimulation. The aim of this review was to provide an overview of the risk factors for hypogonadism and infertility in patients treated for parasellar lesions and to give a summary of the current recommendations for management and follow-up of these dysfunctions in such patients. We have also briefly summarized evidence on the physiological role of pituitary hormones during pregnancy, focusing on the management of pituitary deficiencies.
Introduction
The parasellar region is a highly complex and fragile area without any strong anatomic boundaries. It comprises structures and spaces surrounding the sella turcica, namely the suprasellar cistern, the cavernous sinus, the hypothalamus, and the third ventricle [1, 2]. In the long term, patients with a parasellar lesion are likely to develop endocrine disorders, resulting from either the tumorous or infiltrative process itself or its treatments, which can have both local and distal side effects. Masses occupying the parasellar region are normally due to a pituitary adenoma extending from the sella. Less frequently, they may arise from a primary parasellar tumour or a nontumorous cystic lesion [1]. The most common malignant lesions occupying the parasellar region are gliomas, followed by germ cell tumours, primary lymphomas and metastases. Other potentially malignant tumours include craniopharyngiomas, chordomas, chondrosarcomas, haemangiopericytomas and Langerhans cell histiocytosis, while benign tumours include meningiomas, epidermoid cysts, dermoid cysts and Rathke cysts [2].
The diagnostic approach to a suspected suprasellar/ parasellar lesion should start with radiological imaging. Computed tomography scans are generally considered to offer the most information, as they enable an accurate assessment of bony details and calcifications. However, magnetic resonance imaging is the imaging technique of choice, as it produces multiplanar high-contrast images, while more recent advanced magnetic resonance imaging techniques such as diffusion-weighted imaging and perfusion-weighted imaging [3–5] can better define the morphological characteristics of the lesion. 18F-fluoro-deoxyglucose and 68Ga-positron emission tomography can be used for functional imaging, but only in specific tumour settings [6, 7].
The second diagnostic step is a complete pre-treatment evaluation of hormone deficiencies, to help establish the prognosis and initiate a suitable therapy. A complete description of the tests used to investigate the hypothalamic-pituitary axis in men and women was previously provided [8–11]; a brief summary is reported in Table 1.
Parasellar Lesions: The Effects of Treatment
Radiotherapy and Its Effects on the HypothalamicPituitary-Gonadal Axis
Chemotherapy, Immunological Treatment and Their Effects on the Hypothalamic-Pituitary-Gonadal Axis
Long-Term Effects of Parasellar Lesion Treatments on Male Gonad Function
Male Central Hypogonadism
Male Infertility
Long-Term Effects of Parasellar Lesion Treatments on Female Gonad Function
Female Central Hypogonadism
Female Infertility
Other Endocrine Effects Affecting Fertility
Managing Pregnancy
Conclusions
In recent decades, progress in parasellar tumour diagnosis and treatment has led to a great improvement in survival rates. Strategies for identifying patients with delayed puberty and instituting timely pubertal induction in adolescence can significantly improve long-term sexual and reproductive function. Correct identification of delayed puberty and personalization of puberty induction therapy with androgens and/or gonadotropins are crucial with these patients. Long-term physiological testosterone replacement is necessary for men with permanent HH, to substitute HPG function and to reduce comorbidities associated with HH.
In girls with a diagnosis of HH secondary to parasellar lesion treatment, oestrogen replacement therapy should be promptly started with the proposed protocols; if hypogonadism arises after puberty, HRT is necessary until or beyond the age of natural menopause to protect female patients from metabolic, cardiovascular and bone diseases associated with HH.
Post-treatment preservation of fertility and quality of life is therefore crucial. Whenever possible, fertility aspects should be discussed before starting therapies leading to hypogonadism and infertility. Unfortunately, about 40% of cancer survivors report that no fertility counselling was offered after their diagnosis. Fertility preservation strategies are available, and several studies are evaluating further new alternatives. A multidisciplinary approach involving oncologists, radiotherapists, endocrinologists, gynaecologists and fertility specialists is essential to improve the awareness and availability of these options. As ART regimens continuously change and fertility options improve, future studies on patients with hypopituitarism are needed to find a patient-tailored strategy for restoring hormonal function, when possible, and preserving the patient’s reproductive potential.
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