INTRODUCTION
Adolescence is a challenging period in life of an individual and envisages development of new relationships and behaviors that persist throughout life. As per WHO, the world now has more young than past and adolescents are one-sixth of the world's population and make around 42% of the young population worldwide. The clinicians attending to these adolescents face unique challenge, while dealing with this age group, due to their varied and complex physical, psychological, social, gynecological and sexual health concerns.
The concern for future fertility and sexual health may be paramount in this age group. The clinicians need to be well versed with their concerns and must be trained enough to counsel about these. There are many factors which may have a large impact on future fertility and sexual health of adolescent age group and require timely interventions to prevent future permanent implications of these conditions.
The various factors which may act as stealers or thieves of future fertility and sexual health of adolescents are as follows; some conditions may fall in the categories of more than one class.1-6,10-12
- Genetic:
- Kallmann's syndrome:
- Mutations in the follicle-stimulating hormone (FSH) beta gene
- Turner's syndrome (45 XO)
- Galactosemia
- Klinefelter's syndrome (47-XXY)
- 46 XX primary ovarian deficiency:
- Down's syndrome
- Fragile-X permutation
- 46 XX gonadal dysgenesis
- Mutation of sex-determining region of Y chromosome (SRY) such as Swyer's syndrome
- Cystic fibrosis
- Congenital and acquired anatomical abnormalities:
- Congenital absence of uterus and vagina
- Imperforate hymen
- Anorectal malformations
- Transverse vaginal septum
- Cervical atresia
- Mullerian dysgenesis (MRKH syndrome)
- Absolute uterine factors and other Mullerian anomalies
- Asherman's syndrome
- Endometriosis
- Fibroids
- Genital mutilation
- Spina bifida or spinal injuries
- Cerebral palsy
- Bilateral cryptorchidism
- Anorchia/Testicular regression
- Receptor and enzyme defects:
- Congenital adrenal hyperplasia (17 alpha-hydroxylase deficiency)
- Androgen insensitivity syndrome due to defective androgen receptor
- FSH, luteinizing hormone (LH) inactivating mutations leading to gonadotropin resistance
- Aromatase deficiency
- Growth and development problems:
- Isolated gonadotropin-releasing hormone (GnRH) deficiency
- Hypopituitarism
- Constitutional delay of puberty
- Congenital central nervous system defects
- Age-related fecundity decline
- Metabolic and endocrinological problems:
- Polycystic ovary syndrome (PCOS)
- Obesity
- Congenital adrenal hyperplasia
- Hypothyroidism and hyperthyroidism
- Cushing's syndrome
- Hypogonadotropic hypogonadism
- Transgender
- Pseudohypoparathyroidism
- Hyperprolactinemia
- Autoimmune ovarian insufficiency and premature ovarian failure
- Empty sella and Sheehan's syndrome
- Prader-Willi's syndrome and leptin deficiency
- Neoplasia/tumors:
- Craniopharyngioma
- Pituitary adenoma
- Ovarian tumors
- Testicular tumors
- Childhood cancer survivors of acute lymphoblastic leukemia, acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, soft tissue, and germ cell tumors
- Infections:
- Mumps
- Chronic pelvic inflammatory diseases, e.g., chlamydia
- Sexually transmitted infections (STIs)
- Vulvovaginitis
- Genital tuberculosis
- Malaria
- HIV/AIDS
- Human papillomavirus (HPV) infection
- Postpartum and postabortal sepsis (unsafe abortions)
- Immunological and rheumatological:
- Lupus/mixed connective tissue disease
- Vasculitis
- Steroid-dependent nephrotic syndrome
- Rheumatoid arthritis
- Other chronic ailments:
- End-stage renal disease
- End-stage liver disease
- End-stage cardiac disease
- End-stage lung disease
- Dermatological conditions—anogenital warts, lichen planus, lichen sclerosis
- Environmental and social:
- Poor socioeconomic status
- Genital trauma and mutilation
- Poor perineal hygiene and menstrual hygiene
- Use of local irritants, e.g., feminine sprays, soaps, perineal wash, etc.
- Availability of clean toilets in schools and public places
- Dietary factors—over nutrition and under nutrition
- Use of tobacco and smoking
- Excessive caffeine use, alcohol intake and drug abuse
- Sexual abuse and violence
- Exercise and extreme sports activities
- Immunization status, e.g., HPV, etc.
- Education level, gender bias, family, and partner support
- Local cultural, religious, political factors
- Legislation around age of marriage and employment
- Environmental toxin exposer and endocrine disrupting chemicals (EDCs)
- Preconception care and interventions
- Accessibility and availability of adolescent reproductive and sexual health (ARSH) program and fertility preservation facilities
- Mental and psychological state:
- Psychological stress
- Depression
- Anxiety
- High-risk behavior
- Sexuality
- Eating disorders
- Dating violence
- Poor mental health literacy and attending mental health services
- Adolescent responsive quality healthcare:
- ARSH program and sexual and reproductive health services
- Poor treatment adherence—role of apps and other web-based technology
- Fertility preservation services
- Preconception counseling and care during pregnancy
- Availability of HIV/AIDS, tuberculosis and STI treatment
- Mental health services
- School-based health services
- Vaccination for measles, rubella, BCG, Hepatitis-B vaccine, diphtheria-tetanus, influenza, HPV, etc.
- Iatrogenic:
- Gonadotoxic chemotherapy: Alkylating agents, heavy metals
- Gonadotoxic radiotherapy: Pelvic irradiation
- Surgical extirpation of uterus and ovaries, Fallopian tubes for various indications
- Orchidectomy.
The parents of or chronically-ill adolescents may seek inquiry about scope of their future fertility. A systematic history, examination and investigations may be required for prognostication.13
History
A careful history taken in a very empathetic and confidential way is important which includes:
- Detail childhood growth and development
- Age at thelarche
- Age at menarche
- Any history of cyclical pelvic pain or prolonged pain in lower abdomen
- Detailed menstrual history
- Any history of amenorrhea
- Dysmenorrhea or abnormal uterine bleeding
- Past history of alcohol intake
- Any drug intake for prolonged illness
- History of any pelvic or perineal trauma, sexual abuse or violence
- History of smoking or tobacco use or substance abuse
- Sexual history, if relevant and contraceptive use and medical termination of pregnancy done in past
- Any history of irradiation to pelvis in past
- Any history of surgery done in pelvic area
- Dietary history
- History of any psychiatric illness or medication taken for same
- History of excessive hair growth over body or face
- History of galactorrhea, thyroid disease, pituitary or adrenal disease diabetes, tuberculosis, sexually transmitted diseases
- Any history of hot flushes, anxiety, sleep disturbance, night sweats is to be elicited
- Headache or visual field changes
- Any history of bleeding disorder in the adolescent or family
- History of genetic diseases and familial caners in the next of kin
- History of HIV, AIDS, Hepatitis
- Chronic kidney disease.
Examination
A thorough physical examination of adolescent is required which includes looking for:
- Height
- Weight
- Body mass index (BMI)
- Thyromegaly
- Lymphadenopathy
- Tanner staging and breast development
- Systemic examination including respiratory, cardiovascular, neurological system
- Vision and visual field
- Blood pressure
- Signs of virilization/hirsutism
- Striac and pigmentation
- Examination of inguinal canal for any palpable gonads
- Urological and genital tract examination in both male and female adolescent
- Testicular volume by Prader orchidometer
- Evaluation in relevant cases for psychological age as against chronological age.
Investigations
These may be required both for diagnosis of underlying clinical conditions that affect fertility and their follow-up and prognostication of future fertility and reproductive outcomes.
- Hemogram and platelet count
- Erythrocyte sedimentation rate
- Screening for diabetes
- Thyroid function tests
- S prolactin
- FSH, LH, anti-Müllerian hormone (AMH), serum estradiol
- S testosterone, dehydroepiandrosterone sulfate
- Androstenedione, 17-OH progesterone
- Coagulation profile and vonWillebrand disease panel
- Kidney function test
- Liver function test
- Abdominal and pelvic ultrasound
- Magnetic resonance imaging for pituitary and hypothalamus
- Tests for bone age
- Karyotype
- Tumor marker in suspected malignancies, e.g., CA 125, alpha fetoprotein, beta hCG, carcinoembryonic antigen and lactate dehydrogenase, etc.
Counseling
It incorporates involvement of gynecologist, andrologist, geneticist, infertility/IVF specialist, and psychiatrist. Adolescents are made aware about their future fertility concerns along with parents initially 4and later in separate sessions as per requirement of confidentiality. Fertility awareness is generated in adolescents and their misconceptions and doubts are cleared regarding their reproductive and sexual health. This empowers adolescents to make informed reproductive choices and helps them to optimize their future fertility.7 A culture appropriate counseling is done to help parents overcome their emotional turmoil first so that they may help the adolescent later on in dealing with their self-esteem and body image issues in spite of their subfertility in certain conditions.
Adolescents are counseled about modifiable risk factors for infertility and are advised to make lifestyle modifications to conserve and preserve their future fertility and reproductive outcomes. They are given nutritional counseling and deficiencies are corrected. Adolescents are empowered to stop smoking, tobacco use, caffeine and alcohol intake in adequate number of counseling sessions. They are advised to optimize their BMI and moderate exercises are encouraged keeping into consideration their underlying clinical disease and exercise tolerance. Effort should be made to minimize their exposure to environmental toxins, EDCs and self-harming practices. The importance of good psychological assistance, support to allay stress and anxiety, and cognitive behavioral therapy, as and when required, cannot be underemphasized to maintain optimism for future fertility. Counseling about availability of fertility preservation options is important and is discussed ahead.9
Transgender adolescents pose challenges to counselors as their concern may depend on their parenthood desires, family perceptions about biological child, fertility information specific to them and finances involved in the process.8
MANAGEMENT OF SOME COMMON STEALERS OF FUTURE FERTILITY
Reproductive Tract Anomalies
Anomalies of female genital tract may be due to agenesis/hypoplasia, vertical fusion or canalization, and contact abnormalities with urogenital sinus, lateral fusion defects or resorption. Adolescents may present with amenorrhea, pain in lower abdomen or pelvis, unhealthy vaginal discharge or abnormal vaginal bleeding specially with obstructive anomalies. Adolescents into acute abdomen may be diagnosed with obstructive anomalies and need surgical intervention.
Many Mullerian anomalies remain undiagnosed during adolescence. They may present later on in life, when pregnancy is contemplated, with either recurrent pregnancy loss or infertility. Diagnosis of Mullerian agenesis may be a traumatizing experience to the adolescent or her family. Counseling by expert team is important as already mentioned and family should be informed about potential reproductive function due to normal ovarian function, including production of sex steroids and fertility options of assisted reproduction technologies and surrogacy is discussed. Creation of neovagina is delayed till adolescent is mature enough to understand nature of treatment and its timing. Most uterine fusion defects do not require surgical correction until there is specific concern of poor reproductive outcome in form of infertility or recurrent pregnancy loss. Absolute uterine factors may need surrogacy.
Sexually Transmitted Diseases
Adolescent females are more prone to develop sexually transmitted diseases than adult females and males. They may have asymptomatic infection and may not seek health care due to sociocultural barriers. This may have long-term reproductive implications, as may later on lead to pelvic inflammatory disease, which is an important cause of infertility and ectopic gestation. Timely diagnosis and treatment of STI such as Neisseria gonorrhoeae, chlamydia, trichomoniasis can prevent this. Young, sexually active adolescents may develop HPV infection. Persistence of high risk subtypes of HPV with oncogenic potential may lead to development of high grade cervical intraepithelial neoplasia and carcinoma cervix, if screening and timely intervention is not done HPV vaccination can prevent this dreadful consequence which may cause subfertility and may be fatal.
Abnormal Uterine Bleeding
Abnormal uterine bleeding due to varied causes, as discussed earlier, may give a hint to underlying pathology which may affect later fertility in adolescents. A careful evaluation needs to be done as per PALM-COEIN classification and cause specific treatment is instituted, as abnormal uterine bleeding may indicate irregular ovulation and dwindling fertility later on in life. Adolescents need correction of associated anemia for general health well-being and better reproductive outcomes later on in life.
Polycystic Ovary Syndrome and Other Conditions Associated with Hyperandrogenemia
Counseling of PCOS patients should be started early in adolescence regarding life style management to avoid development of metabolic syndrome later on in life. Metabolic syndrome can compromise fertility. PCOS 5itself causes infertility due to associated oligo-ovulation or anovulation. The association of unopposed estrogen exposure to development of endometrial hyperplasia and endometrial cancer later on in life may hamper fertility due to clinical condition itself or due to treatment given for the same, which may need medical or surgical interventions. Overzealous treatment of PCOS by ovarian drilling may itself cause decreased ovarian reserve, ovarian in-sufficiency and premature ovarian failure, so it must be avoided except in specific situations associated with infertility in late adolescence.
Endometriosis
Young adolescents may be diagnosed with this disease when their chronic pelvic pain does not respond to nonsteroidal anti-inflammatory drugs. Endometriosis in adolescents is usually associated with some obstructive Mullerian anomaly. As endometriosis is a progressive disease, patient may later on develop endometriomas and deep infiltrating endometriosis which may cause infertility due to decreased ovarian reserve, distortion of pelvic anatomy and disturbed tubo-ovarian relationship. Goal of therapy in young adolescents is symptomatic relief, suppression of disease progression, and protection of future fertility. Medical management with oral contraceptive pills, progestin therapy or GnRH agonist is preferred and surgery in adolescents is reserved only for patients who do not respond to medical management of chromic pelvic pain. As such, due to inherent progressive nature of disease, she may need multiple surgeries later on in life, may be as a part of infertility management. Patient can be put on continuous hormonal suppression till she is desirous of and contemplates pregnancy. Surgical treatment involves fulguration or complete excision of clear white vesicular and red lesions. Cystectomy, if needed, should involve complete cyst removal except near hilum to preserve ovarian reserve. Levonorgestrel-releasing intrauterine device (LNG-IUD) may be inserted at the time of laparoscopy to prevent recurrence of disease or patient may be given medical treatment as discussed before or etonogestrel subdermal implant may be given.14
Ovarian Cysts and their Torsion
Adolescents may present with simple or complex ovarian cysts. Conservative approach is desirable in form of simple observation or organ sparing surgery to protect their future fertility. Simple cysts less than 6 cm may be observed with or without giving combined oral contraceptive pills for around 3 months, to prevent recurrence. Cysts more than 10 cm will not regress usually and need laparoscopic intervention. Ovarian cysts may undergo torsion and may need conservative surgery in form of untwisting of ovarian pedicle and simple observation. Cystectomy at same sitting is avoided as it may lead to more traumas of friable ovarian tissues. The untwisted ovary usually regains its functions and looks normal on follow-up.15
Hemorrhagic cysts need observation and surgical treatment only in exceptional cases to protect fertility.
Adolescents with Cancer
Oncofertility is a developing science. Survivors of childhood cancers and newly diagnosed adolescents with hematological or genital malignancy will need comprehensive reproductive evaluation and follow-up regarding ensuing gonadal insufficiency, sexual dysfunction, and infertility. The disease itself or its management may cause disturbances in attainment of puberty which may be precocious or may get delayed.
As there is finite number of follicles in ovary, there may be age-related decline in fertility. Moreover, adolescents receiving alkylating agents such as cyclophosphamide and procarbazine or heavy metals as chemotherapeutic agents, have detrimental effect on their ovarian reserve in dose dependent and cumulative way. Prepubertal or pubertal gonadal irradiation may be a risk factor for hypogonadism. Older adolescents, due to their less number of oocyte stores, may develop acute ovarian failure (within 5 years of cancer treatment) or premature menopause or primary ovarian insufficiency. This causes sexual dysfunction due to vulvovaginal cicatrization or narrowing, dysfunction of ovary in form of dwindling hormonal function, and less lubrication and dryness caused by vestibular gland dysfunction.
It is prudent to discuss future fertility concerns at the start of cancer treatment to avoid any repentance later on. All “fertility preservation options” such as oocyte cryopreservation, ovarian cortex cryopreservation are discussed with adolescent and family. Option of embryo cryopreservation is offered if the adolescent has a partner. Some experimental studies are going on in vitro maturation of immature oocytes retrieved without any ovarian stimulation.
Ovarian transposition or oophoropexy before pelvic irradiation may be offered but future reproductive outcome is not ensured as uterus is not protected and may have irreversible endometrial and blood supply damage.
Studies are going on about use of GnRH agonist use during chemotherapy to quieten the ovary, as it will 6suppress ovarian function and decrease blood supply, minimizing the exposure of ovary to chemotherapeutic agents but results are not favoring it as standalone option. Menstrual lightening may be tried with combined hormonal contraceptives, LNG-IUD or depot medroxyprogesterone acetate injections. This will correct anemia of patient as well and provide contraception during cancer treatment as added advantage.
Male adolescents are offered sperm cryopreservation.
The follow-up assessment for fertility potential should continue closely during and after cancer treatment. The ethical and social issues of fertility cryopreservation must be discussed with parents and adolescents, as some adolescents later on in life may not be well enough to provide optimum parenting due to health issues and some may unfortunately not survive till embarking on conception.16-18
CONCLUSION
Most adolescents expect to have their biological children in future if properly counseled and given an option. The prognosis of fertility potential in future will depend upon underlying pathophysiology of their disease and effect of its treatment involved. The thieves and stealers of reproductive future of adolescents can only be conquered by timely diagnosis and management of the disease and therapy optimization. Fertility preservation option should be offered to adolescents diagnosed with cancer. Expert quality counseling regarding perception and priorities of adolescents about decision making for future fertility is the corner stone of treatment.
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