Endocrinology

Adolescent with Menorrhagia

Dr. Ashwini Bhalerao-Gandhi

Introduction

Menstruation can be seen as the endpoint of an endocrine cascade that begins with thelarche and ends with menarche. All over the world, the age at menarche is decreasing. This may be attributed to many known and unknown factors. The first period occurs because there has been sufficient endometrial stimulation to result in a withdrawal bleed when there is a temporary fall in the estrogen level. Menstrual irregularities often occur in adolescent girls as cycles tend to be anovulatory. This is a stressful condition for the adolescent girl as well as her parents. As the girls cannot differentiate between normal and abnormal menstrual patterns, medical help is sought either too early or too late. Heavy periods lead to a lot of fear, anxiety and stigma.

Normal and abnormal  menstrual pattern during puberty –

Till two years from menarche, most cycles are anovulatory. The length of the cycle varies from 21-40 days, the mean duration is 4-5 days, the average blood loss being 35ml. Whenever the cycle length is less than 21 days, duration is more than 8 days and menstrual blood loss is more than 80ml, the girl requires further evaluation and necessary treatment.

Table 1

Adolescent with excessive bleeding per vaginum – Differential diagnosis

1. Anovulation – Immature H-P-O axis
2. PCOS
3. Stress – mental, physical
4. Eating disorders, obesity
5. Substance abuse
6. Thyroid dysfunction
7. Chronic renal disease
8. Hepatic disorders
9. Congenital adrenal hyperplasia, Cushing's syndrome
10. Haematologic abnormalities (30%) – ITP, Von Willebrand's disease, Factor XI deficiency.
11. Infections – Chlamydia, Kochs
12. Genital tract injuries
13. Pregnancy related bleeding
14. Irregular intake of OCS, progesterone to post-pone / pre-pone periods.
15. Mullerian anomalies
16. Foreign body

Etiopathology

Menstrual problems are common during adolescence due to slow maturation of the hypothalamic pituitary-ovarian axis and can last 2-5 years after menarche. Menorrhagia (excessive bleeding PV either in duration or quantity or both) at regular intervals and metrorrhagia (cycle irregularity) are commonly seen in adolescent girls. In them, Dysfunctional uterine bleeding (DUB) causes menorrhagia in 74%, primary coagulation disorders  are present in 19% and other causes account for 7%. Genital tuberculosis may cause excessive  menstrual bleeding in the beginning of the disease process. Cervical polyp and granulosa cell  tumour of the ovary may rarely cause menorrhagia. Bleeding disorders like thrombocytopenia, Von Willebrand's disease, factor II, V, VII, X & XI deficiency disorders should be ruled out if menorrhagia starts as soon as menarche sets in.

DUB

It is best defined as abnormal bleeding from the uterus in the absence of the organic disease of the genital tract. The bleeding may be abnormal in frequency, amount, duration or any combination of these. This is the commonest cause in adolescent girls suffering from menorrhagia. 40-50% resolve within 2 years and a better prognosis is expected when DUB starts after a period of normal menstruation  than who develops it at menarche itself. In most of the girls with puberty menorrhagia, the cycles are anovulatory though in few they may be ovulatory.

Anovulatory DUB – Causes

1. Inadequate signal – Follicular development is insufficient to produce strong enough signals to induce LH surge.
2. Impaired positive feedback – may lead to proliferation and hyperplasia of the endometrium due to unopposed estrogen.

Ovulatory DUB – Causes

1. Inadequate Luteal phase - The normal luteal phase is over 12-13 days with progestogen around day 20 in excess of 20 nmol/l.  The inadequacy arises from inadequate follicular development, may be due to subnormal secretion of FSH.
2. Idiopathic bleeding – It is because of irregular ripening of the endometrium due to the shift in endometrial conversion of endoperoxide from vasoconstrictor PGF2 to vasodilator PGE2.

Treatment of mild DUB –

In cases with mild DUB, reassurance to the girl as well as her parents is absolutely essential. In this way the iatrogenic factors of anxiety and worry are lessened and relieved. Thus explanation and reassurance are the backbone of therapy.

Points to be covered during counselling

• Explain the anatomy and pathophysiology in brief and easy to understand language.
• Emphasize that puberty menorrhagia is not a very uncommon problem.
• Reassure the patient that there is nothing anatomically wrong with her.
• Sympathize with her concerns for the future including the future prospects of childbirth etc.
• High protein and iron rich diet
• Simple haemostatic agents like gynaec CVP, RCK etc.

Treatment of moderate DUB

Aims - To stop bleeding
To prevent recurrence
To correct anaemia, malnutrition etc.

In these girls, PG synthetase inhibitors like mefenamic acid should be used during period to reduce the amount of bleeding. It acts on cyclo-oxygenase and blocks peripheral PG receptors leading to antiprostaglandin action, dose being 250 to 500 mg 3 times a day. Sometimes ethamsylate can be added. Iron supplementation is a must to treat anaemia. Hormonal  therapy in the form of OCS or progestogens is required in cases with irregular cycles. Regular evaluation of hormonal therapy is done as the H-P-O axis matures.

Management of severe DUB

Sometimes, hospitalisation is required. Smith et al (1998) concluded that 63% hospitalised adolescents  with menorrhagia required blood transfusion. These girls should be assessed for primary coagulation disorder or any medical problem. Anti fibrinolytic agents like Tranexamic acid  which is a potent inhibitor of  fibrinolysis  should  be started in  the dose of  500mg  three times a day. It also can be given parenterally. Combination of mefenamic acid, tranexamic acid and / or ethamsylate may be used judiciously. Hormonal therapy with oral contraceptive pills or plain progestogens is a must. Progestogens counter balance unopposed estrogen action. Three types of progesterones are available  in the market – Dydrogesterone (10mg), Medroxy progesterone acetate (5/10mg) and Norethisterone acetate (5mg). In moderate to severe menorrhagia, Norethisterone acetate or Medroxy progesterone acetate can be given in the dose of 1 BD to 1 TDS for 21 days. This therapy can be given cyclically starting from every 5th day of the period lasting for 21 days for 3 to 4 months. Once the cycles are stabilized, progestogens can be given only in the leuteal phase of the cycle i.e. 1 BD to be started from the 14th day of the cycle for total 10 days. This leuteal phase support can be given for 3-4 months and then the girl is re-evaluated for the necessity of hormones. In cases with mild to moderate menorrhagia, low dose contraceptive pills (OCS with ethinylestradiol 30 ugm)  also can be tried in a cyclical manner for 3 to 6 months duration. If the girl is also suffering from polycystic ovarian syndrome (PCOS), acne and hirsuitism then OCS containing desogestrel or cyproterone acetate should be started. These lipid friendly progestogens help in  reducing the androgenic effects as well.

What should be avoided

Drugs like danazol, GnRh analogues and daflon  which are used in elderly women should be avoided in adolescents. Also, progestogen only pills and LNG system (progestogen containing intrauterine device) are contraindicated. Inj. Depot provera is used rarely.  Unlike in women with perimenopausal menorrhagia, diagnostic or therapeutic  curettage (D&C) is avoided in adolescent girls in spite of USG  finding of thickened endometrium. If endometrial hyperplasia  is suspected then she is put on progesterone for a period of 6-12 months, after which she is re-assessed.

Follow up

Girls requiring hormonal treatment need frequent follow up and evaluation. It may take few years before their cycles get established properly. Till then, they may require to take  natural progestogens like dydrogesterone for many months.

Table 2

Adolescents with Menorrhagia

1 : 5 require hospitalisation
1 : 4 will have Hb of < 10gm%
1 : 3 will require blood transfusion
1 : 2 present at menarche

Girls with menarche menorrhagia fall into a high risk group. They face problems like severe anaemia  and blood transfusion. In the long run, they may develop impaired reproductive potential like infertility, spontaneous abortions  etc. They are also prone to develop endometrial hyperplasia and rarely carcinoma of the endometrium  in later life if neglected. Puberty menorrhagia sometimes can emerge as a therapeutic challenge requiring combined efforts of family physician, gynecologist, paediatrician, endocrinologist and haematologist.

Suggested Reading –

1. Dewhurst's practical paediatric and Adolescent Gynaecology 2nd edition by D. Keith Edmonds. Published by Butterworth & Co. Ltd. Great Britain.
2. Adolescent Girl – An update  (2nd edition), Editors : P. Kotdawala, V. Salvi, U. Krishna; Jaypee, New Delhi.
3. Reproductive Endocrinology – A Clinical Approach. Editors : V. Walvekar, M. Jassawalla & et al; 2nd edition; Jaypee, New Delhi.
4. Practical Gynec Endocrinology by Dr. Geeta Pandya and Dr. Ashwini Bhalerao-Gandhi. 1st edition; Jaypee, New Delhi.

Precocious Puberty

Dr. Ashwini Bhalerao-Gandhi

Puberty is the transition period between childhood & adulthood during which secondary sexual characteristics start developing, menstruation begins & psychosexual outlook of the individual changes.

Puberty: is the rendering of the Latin word Pubertasmeaning, "Grown Up". The Oxford Dictionary defines puberty as - the state of being functionally capable of procreation1.  Puberty is the stage of physical maturation in which an individual becomes physiologically capable of sexual reproduction and is defined by WHO as the age between 10 and 19 years. Normal puberty starts at 8 to 12 years in Indian girls & it takes 3-4 yrs for the completion of the secondary sexual characteristics. Disorder of pubertal development may occur at any stage of the maturational process leading to either precocious or delayed puberty.

Factors affecting the onset of puberty:

1. Genetic, a major influence,
2. Nutritional state,
3. General health,
4. Geographic location,
5. Environmental influence (Exposure  to light, geographic location)
6. Psychological state.
7. Ethinicity
8. Level of activity

Menstruation usually commences after the maximum growth spurt (6-11 cm per year). There is also a relationship between skeletal maturity and onset of menstruation; it is unusual for menstruation to begin before bone age of 12.5 years or after 14.5 years (Sheil & Turner 1997).  Typically the age of menarche is earlier in girls with moderate obesity (upto 30% above ideal body weight), while it is delayed in those with severe malnutrition2. However, the increase in body fat to 23.5% from pre-pubertal 16% is thought to be an important factor influenced by nutrition (Sternleib & Munan 1972). High levels of Leptin, a peptide secreted in adipose tissue that circulates in blood and acts on the CNS regulatory neurons that regulate eating behaviour and energy balance is associated with earlier age of menarche (Matkovic et al, 1997).  Evidence also suggests that, pubertal growth acceleration is due to estrogen and concomitant increases in growth hormone production and secondary stimulation of insulin-like growth factor-I levels.

Precocious Puberty:

If one accepts the mean +/-2.5 standard deviations as encompassing the normal range, then pubertal changes before the age of 8 are regarded as precocious. Increased growth is often the first change in precocious puberty. Occasionally, adrenarche, thelarche, and linear growth occur simultaneously and sometimes menarche may be the first sign. The occurrence of menarche is considered precocious when it occurs prior to 10 years of age.

Precocious puberty can be divided into two classifications:

1. Gonadotropin-Dependent Precocious Puberty (GDPP) /Isosexual/ Central (CPP) or true precocious puberty: This refers to premature awakening and early activation of the hypothalamic-pituitary-gonadal axis.
2. Gonadotropin-Independent Precocious Puberty (GIPP) / Heterosexual/ Peripheral or Pseudoprecocious puberty: Sexual maturation and development of secondary sexual characteristics without maturation of the HPG axis, under the influence of sex steroids, secreted either from the gonads or adrenals and sometimes exogenous steroid ingestion.
3. Intermediate type of precocious puberty: Includes tumors that secrete gonadotropin-like substances (HCG), e.g. from dysgerminomas, teratomas, hepatoblastomas, etc. and do not cause activation of HPG axis.

Precocity occurs 5 times more frequently in girls than boys, and almost three-quarters (80%) of these are idiopathic or constitutional precocity (true sexual precocity), this must be a diagnosis by exclusion with prolonged follow-up in an effort to detect slowly developing lesions of the brain, ovary or adrenal gland. 15% girls and 50% boys with CPP have a lesion of CNS.

Etiological factors:

I) Gonadotropin- dependent precocious puberty:
a. Idiopathic or constitutional

1. 1. 1. Familial
      2. Sporadic

b. CNS Lesions

1. 1. 1. Hypothalamic tumors-hamartomas, astrocytomas, ependymomas, gliomas, neuroblastomas, craniopharyngioma
      2. Infection- encephalitis, brain abscess, meningitis, tuberculous or pyogenic
      3. Head trauma- at birth or accidental
      4. Congenital defects- hydrocephalus, craniostenosis, third ventricular cysts
      5. Irradiation

II) Gonadotropin-independent precocious puberty

1. Gonadal tumors or cysts
2. Adrenal tumors
3. Endocrinopathies- congenital adrenal hyperplasia (CAH), primary   hypothyroidism
4. McCune-Albright syndrome (MAS)
5. Accidental ingestion of oral or topical oestrogen creams, oestrogen containing cosmetics, anabolic drugs, sex steroids
6. Aromatase excess syndrome
7. Peutz-Jeghers syndrome

III) Intermediate type of precocious puberty

Gonadotropin-secreting tumors- teratomas, hepatoblastomas, dysgerminomas, ovarian-granulosa cell tumor, arrhenoblastoma, lipid cell tumor, thecoma etc.

Diagnosis:

A careful history and thorough physical examination is mandatory, along with the required laboratory work-up which will aid in arriving at a proper diagnosis.
History should include the chronology of pubertal events, associated behavioural changes, drug usage or incidental drug ingestion, symptoms suggestive of or past history of intracranial lesions and symptoms of hypothyroidism. The growth velocity should be plotted on appropriate growth charts (cm/yr) to determine growth spurt. A complete systematic examination including palpation for abdominal masses, neurological and endocrinological examination, estimation of visual fields and optic fundi would help in diagnosis of the cause. The clinical stage and type of pubertal development by Tanner's method, the height of the patient, buccal smear (pyknotic nuclei), karyotyping and bone age are the basic investigations. Serum levels of FSH, LH, Oestradiol, Testosterone, TSH, Thyroxine will distinguish complete and incomplete types. High resolution USG of the ovaries and computed tomographic images of the adrenal glands, will be required if peripheral cause is suspected. In CNS disease, MRI of the brain for imaging the hypothalamo-hypophyseal area is indicated.

Recommended Diagnostic approach for Precocious Puberty

Controversy related to age:

• Girls and boys entering puberty before 8 and 9 years of age respectively need evaluation.
• According to Lawson Williams Peadiatric Endocrinological society, the limit for investigations of girls and boys should be lowered to 7 and 8 years.
• American Association of Pediatric recommends that the girls with either breast development or pubic hair should be evaluated if occurring before 7 years in white girls and 6 years in African-American girls.
• It is less common for white girls, to begin pubic hair growth, before breast development.
• A multi variate analysis confirms that, obesity as measured by BMI is significantly associated with early puberty in white girls and is associated with early puberty in black girls as well, but to a lesser extent.

Management:

Treatment depends on the underlying cause. Objectives for management include:

1. To identify a correctable cause, CNS or otherwise and offer its specific management.
2. To arrest pubertal development.
3. To suppress linear growth and further acceleration of skeletal maturation.
4. To prevent sexual abuse and pregnancy.
5. To offer multidisciplinary care for associated conditions like behavioural problems, obesity, hyperandrogenism, etc.
6. Reassurance and counseling to the parents

Gonadal, adrenal, liver or CNS tumors require surgery and /or subsequent chemo/radiotherapy.

For congenital adrenal hyperplasia (CAH), glucocorticoid replacement will suppress production leading to precocity.

Thyroid replacement therapy will suppress precocity by suppressing HPG axis in cases  of primary hypothyroidism.

McCune-Albright syndrome is independent of gonadotropins and does not respond to GnRH therapy. The syndrome may be associated with hyperthyroidism or Cushing's syndrome. Treatment includes medical - administration of testolactone (40 mg/kg/day) to suppress conversion of testosterone to estrogen and Orthopaedic management.

Central precocious puberty is gonadotropin dependent and therapy is directed to suppress its secretion. Treatment includes, giving Medroxyprogesterone acetate (Provera) in doses of 100-200 mg i.m. every 2-4 weeks. Alternatively, Cyproterone acetate, a drug with antiandrogenic and antigonadotropic properties is also used and appears superior to MPA in the treartment of precocious puberty. However, nowadays the mainstay of treatment is the use of LHRH analogues. These are administered 0.2-0.3 mg/kg (max 7.5 mg) i.m. every 4 weeks. They down regulate receptors, causes regression of secondary sexual characteristics, cessation of menses, delay short stature by delaying the closure of epiphyses and normalize growth. Dosage given is Triptorelin i.m. every 28 days or Buserelin with cyproterone acetate to improve height.

Table II

Indications for GnRH analog treatment in CPP:

1. Onset less than 6 years
2. Onset of puberty between 6-8 years
   1. Bone age is more than chronological age by more than 2 years.
   2. Projected height is less than 2 SD from target height
   3. Rapid progression of puberty

Table III

Advantages of GnRH analogue Therapy:

• Preserves height potential especially in younger patients
• Improves final adult height
• Complete recovery of H-P-O axis after Rx
• Good safety profile
• Minimal adverse effects
• No severe long-term consequences
• Combining somatropin (growth hormone) with GnRH analogues
• Introduction of GnRH antagonists as an option

Recent Advances & Controversies:

• Lawson Wilkins Pediatric Endocrino Society suggested that3 the limit for investigations of girls and boys should be lowered to 7 & 8 years respectively. Girls with either breast development or pubic hair should be evaluated if this occurs before age 7 in white girls and before age 6 in African-American girls.
• Girls with premature  adrenarche / pubarche are at risk for PCOS and its long-term sequelae. The prevalence of overweight and obesity in children in the United States has dramatically increased during the past 20 years and there has been a rise in the incidence of type 2 diabetes in youth and higher degree of insulin resistance seen in African-American than in whites contributing to early puberty.
• Girls with premature pubarche are more likely to develop functional ovarian and adrenal hyperandrogenism.
• Long acting GnRh therapy is effective in improving the auxological outcome of patients with CIPP. Maximum benefit is observed in girls with greater  bone age advancement treated at a younger age and for a longer duration of treatment.
• 35 patients (30 girls, 5 boys with CIPP were treated with a long acting GnRH analogue triptorelin by Anurag Bajpai, Jyoti Sharma et al of AIIMS, New Delhi – Triptorelin at a dose of 3.75mg depot administered deep intramuscularly every 28 days. Final height outcomes and factors affecting treatment were analyzed. Treatment was started at the chronological age of 6.5 ± 1.8years in girls and 4.4 ± 1.5 years in boys and continued for a period of 3.7 ± 1.8 years in girls and 6 ± 1.8 years in boys. Follow-up period after discontinuation of treatment was 2.2 ± 0.5 years in girls and 2.6 ± 0.3 years in boys. Long acting GnRH therapy is effective in improving  the auxological outcome of patients with CIPP, maximum benefit is observed in girls with greater bone age advancement treated at a younger age and for a longer duration of treatment. These girls have lower bone age advance at discontinuation of treatment4.
• Very long-term follow up of girls with early and late menarche done by Johansson Ritzen EM revealed that at age 15-16, girls with menarche before age 11 (early) were more norm-breaking, including being delinquents. In addition, they had earlier advanced sexual experiences. Regarding somatic development, at age 43, women with early menarche were shorter & heavier, had worse physical fitness5.

References :

• Keith Edmonds; Dewhurst's practical paediatric and adolescent Gynaecology 2nd edition; Butter Worth & Co (publishers) Ltd. 1989 - 56 to 57.
• Jonathan S. Berek, Novaks Gynecology, 12th edition, Williams & Wilkins 1996 - 772 to 773.
• Kaplowitz PB, Oberfield SE, Drug and Therapeutics and Executive Committees of the Lawson Wilkins Pediatric Endocrine Society Reexamination of the age limit for defining when puberty is precocious in girls in the United States: implications for evaluation and treatment. Pediatrics. 1999; 104:936-941.
• Anurag Bajpai, Jyoti Sharma et al; Long-acting GnRh analogue Triptorelin Therapy in Central Isosexual  precocious puberty, Indian Pediatrics, 2002; 633: 639.
• Johansson Ritzen EM; very long term follow-up of girls with early and late menarche, Endocr Dev. 2005; 8:126-36.

Youth Friendly Health Services

Dr. Ashwini Bhalerao-Gandhi

Adolescent and young people stand at the threshold of adult world. People aged 10 to 24 years are called as ‘young people’ This is a period of rapid and sometimes drastic changes taking place in their body, mind and social life. Many are already exposed to challenges from the adult world. We need to focus our attention towards the health needs of this group (a) to reduce mortality and morbidity now, and during their future lives (b) to respect their rights to health care, in general and reproductive health care, in particular (c) to enable them to pass on good health to their own children as they are the future parents.

Young people face dangers more complex than previous generations faced with less support and safety network.

Newer challenges faced by young people

• Early puberty
• Nuclear familities
• Academic pressures
• Urbanisation
• Industrialisation
• Effect of mass media
• Explosion of technology
• Globalisation
• Experimentation (Internet, mobile phones etc)

Young people come from different strata and communities – being not only of different ages and sexes but also of different cultures and life experiences. When in trouble, they usually do not know where to go and seek help. They often hesitate to visit any health care facility because they are afraid about the stigma and also wonder whether they will be treated well at a clinic. In addition to general health disorders, adolescent and young people face multiple specific problems.

Health problems faced by young people

• General health problems
• Malnutrition / obesity / eating disorders
• Mental health problems
• Scholastic difficulties
• Addictive behaviours, Accidents, violence
• Menstrual problems
• Early and unprotected sex
• Premarital sex, minimal use of contraceptives
• Unwanted pregnancies, abortions
• Prevalence of RTIS, STDS
• Female genital mutilation
• Sexual abuse

Usually it is seen that when young people are looking for urgent treatment for their own problems, public sector health services are often their last resort. There are many barriers in using existing health services.

Barriers

• Lack of knowledge on the part of the youth
• Legal or cultural restrictions
• Physical or logistical restrictions
• Poor quality of clinical services
• Unwelcoming services
• High cost
• Gender barriers
• Peer Pressure

Adolescent and Youth Friendly health services represent an approach which brings together the qualities that young  people demand, with the high standards that have to be achieved in public as well as private services. The characteristics of adolescent and youth friendly health services were discussed during the global consultation process initiated by WHO in 2000, and continued during the discussions by the expert group convened by WHO in Geneva in 2001.

Characteristics of Adolescent Friendly Health Services

Adolescent friendly health services need to be accessible, equitable, acceptable, appropriate, comprehensive, effective and efficient. These characteristics are based on the WHO Global Consultation in 2001 and discussions at a WHO expert advisory group in Geneva in 2002. They require :

1. Adolescent friendly policies that
   • Fulfil the rights of adolescents as stated in the UN Convention  on the rights of the child and other declarations.
   • Do not restrict providing health services on basis of sex, religion, age, disability, race etc.
   • Provide special attention to gender needs.
   • Take into account needs of general population including vulnerable and under served groups.
   • Ensure privacy and confidentiality and promoting autonomy so that adolescents can consent to their own treatment and care.
   • Make sure that services are provided free of cost or at affordable charges  for adolescents.
2. Adolescent friendly procedures to provide
   • Quick as well as confidential registration, storage and retrieval of records of patients.
   • Minimal waiting time and prompt referral, if necessary.
   • Flexibility of availing consultation with or without appointment welcoming walk-in clients.
3. Adolescent friendly health care providers who
   • Are trained to provide specific promotive, preventive and curative services tailor-made to each client's circumstances and maturity level.
   • Are well  motivated and supportive.
   • Have non-judgmental attitude and are trustworthy.
   • Having good communication skills.
   • Can spare adequate amount of time for clients.
   • Act in the best interest of their clients.
   • Can respect as well as care for the clients irrespective of their gender, age, religion, culture etc.
   • Provide information enabling each adolescent to  take a right decision out of their free will.
4. Adolescent friendly support staff who are
   • Trained and motivated.
   • Able to treat each adolescent client with equal care and respect.
5. Adolescent friendly health facilities that
   • Are located at a convenient place with an appealing ambience.
   • Provide safe and clean environment.
   • Have flexible and convenient hours of working.
   • Offer privacy and are devoid of stigma.
   • Provide IEC material.
6. Involvement and participation of Adolescent and youth, so that they are
   • Aware of their rights and services available.
   • Encouraged to respect the rights of others and are involved in giving suggestions regarding variety of services provided.
7. To solicit involvement of gatekeepers eg. parents, teachers, social workers, politicians etc.
   • So that they develop trust in the health care system endorsing its  utilisation by the youngsters.
   • To diffuse opposition by staunch religious, social and cultural authorities.
8. Provision of outreach, as well as Community based services involving peer educators.
9. Appropriate and comprehensive services that
   • Provide umbrella of services looking after physical, mental, social, sexual and spiritual needs of adolescents.
   • Provide majority of services under one roof and referring to higher services only if required.
   • Avoid unnecessary procedures, investigations etc.
10. Effective health services for adolescents
    • Involving evidence-based protocols and guidelines.
    • Having technical expertise, necessary equipments and supplies including medicines, vaccines etc. necessary to deliver adequate health care.
    • Having a process of quality improvement by on-going assessment and evaluation of existing facilities.
11. Efficient services which have
    • A management information system including information on the cost of resources.
    • Ability to foresee evolving issues and health problems and to adapt and incorporate changes to tackle them effectively in time to come.

Locations

Adolescent and Youth friendly health services can be offered at various levels and centres. Making existing services more friendly is one option whereas establishing specific stand alone clinics is yet another option available.

• Services at health centres or hospitals – Existing services can definitely take care of the basic needs of young people provided medical and support staff are given proper training. There are also dedicated health centres which provide a full range of services especially for young people. Such services can provide training and inspiration for other health providers, but they usually only have an impact in that specific area e.g. SHAHN at Safdarjang Hospital in New Delhi.
• Services located at other kinds of centre – As same adolescents are reluctant to visit health facilities, services can also be taken to places where young people already go. e.g. Go 4 Health Youth Clubs of FPA India. Health services in Sweden reach large numbers of adolescents, including an increasing number of boys, through a network of youth centres nationwide.
• Out reach services – These are important to cater for the needs of young people who are unlikely to attend conventional health centres - e.g. Friend corners in Thailand were started in local shopping malls and community housing areas. The first point of contact is with adolescents trained as peer counsellors. Health staff are also on hand to provide counselling or to refer adolescents to specialized services as necessary.
• School / College health clinics – Schools and colleges are ideal places to screen for or treat a range of common illnesses, for health education and referral to a higher centre if required - e.g. – Welingkar – FOGSI Growel centre at Welingkar College of Business Management, Mumbai. Services can be located anywhere where young people go – no single setting should become the only model.

A strategy for planning services –

• Achieve a national consensus for action
• Decide on essential services to be provided
• Identify & set quality standards
• Link related services, Networking, Referrals
• Involve young people , parents & community leaders, professionals, teachers
• Political support
• Marketing, Media, Help-Lines
• Public- Private Sector Co-ordination
• Involvement of NGOS

A variety of services can be provided to young people. Specialised services concentrating on their Reproductive & Sexual health include –

Services

• Screening & advice on nutrition, self-care issues, Body-image
• Counselling services
• Contraceptive services
• Pregnancy test, HIV testing etc
• Safe Abortions
• Prenatal & post natal care
• Mental health services
• Sexual & Reproductive health education
• Space for youth groups to hold meetings
• Referral services

These services can be provided by a team of professionals especially trained in ARSH.

Guidelines for Staff

Staff - Gynecologists, Pediatricians, Physicians, Psychologists, Counsellors, Support Staff, Lab technicians.

Qualities & Skills - Non judgmental & unbiased attitude,Ensure confidentiality, Competence, Warm & Friendly Approach, Optimism & Motivation, Respect for clients irrespective of age, sex, socio-economic & marital status; Adequate time for interaction, Welcome drop-in clients,  Skills in Record keeping, Empathy, Sensitivity

Communicating with young people – Good communication skills are very important to reach out to young people. They create trust and develop bonding.

Communicating with young people

• Take young people seriously
• Offer help quickly
• Give attention & encouragement
• Don't offer false assurance
• Encourage them to talk it out
• Help them to understand the cause of distress
• Maintain continued contact
• Focus on positive behaviour
• Expect rebuffs

Creating awareness and providing specific services catering to adolescent reproductive and sexual health in this manner is the need of the hour. It is essential in transforming today's adolescent boys and girls into tomorrow's responsible citizens, spouses and parents.

Suggested Reading -

Adolescent Friendly Health Services – An Agenda for change, by Peter McInture, Oxford, UK with support from Department of Child & Adolescent Health & Development, WHO, Geneva in 2003.

Hyperprolactinaemia – Cause, Effect and Management

Dr. Ashwini Bhalerao-Gandhi

Hyperprolactinaemia refers to a prolactin level in excess of 20 ng/ml in a non-pregnant woman.

Prolactin

Prolactin is a polypeptide hormone consisting of 198 amino acids. It circulates in three different sizes: the small or monomer form, the big or dimmer form and the big big or polymeric form. A major part (80%) of the hormone is secreted in the small form which is biologically active. The other two forms may be biologically inactive though they are measured by radioimmunoassay. Prolactin is secreted by the chromophobe cells called lactotrophs located in the lateral areas of the pituitary gland and by decidua and endometrium. With a half-life of 20 minutes, Prolactin is both mammogenic (stimulates the growth of mammary tissue) and lactogenic (causes production and secretion of milk).

The secretion of prolactin is controlled mainly by inhibition. Dopamine (prolactin inhibiting factor or PIF) inhibits the synthesis and release of prolactin. On the other hand, the neurotransmitters-serotonin and thyrotropin releasing factor increase the secretion of prolactin. Prolactin is secreted episodically and serum levels fluctuate throughout the day as well as through the menstrual cycle, with peak levels being seen at mid-cycle.

Oestrogen increases the levels of prolactin and, thus, prolactin levels rise in hyperoestrogenic states such as puberty and pregnancy. The rise in prolactin is proportionate to the levels of oestrogen and in the third trimester of pregnancy, prolactin concentration is 200 ng/ml. However, lactation does not occur since oestrogen inhibits the action of prolactin on the breast. After delivery, the levels of oestrogen rapidly decline and lactation is established. Each act of breastfeeding is associated with a rise in prolactin levels.

Pathologic Causes of Hyperprolactinaemia

Hyperprolactinaemia is seen in 15% of all anovulatory women and in 20% of women with indeterminate amenorrhoea. Thirty to eighty per cent of women with hyperprolactinaemia will have galactorrhoea. The incidence of hyperprolactinaemia is higher in women with galactorrhoea and amenorrhoea with low oestrogen levels as compared to women with galactorrhoea and normal or abnormal menses with normal oestrogen levels.

AETIOLOGY

Prolactin levels are physiologically elevated by either nipple or breast stimulation, exercise, sleep, stress and following the noonday meal. The maximum levels are observed during sleep at night.

Pathologic Causes of Hyperprolactinaemia

Pituitary Adenomas

Of all pituitary adenomas, 80% secrete prolactin and the commonest pituitary tumours are prolatinomas. These tumours have been arbitrarily divided into microadenomas (< 1 cm diameter) and macroadenomas which are larger. In the absence of an adenoma even lactotroph hyperplasia can cause hyperprolactinaemia.

Only 5% of women with hyperprolactinaemia will have a prolactinoma and if the prolactin level exceed 200 ng/ml, there is almost always a prolactinoma.

Prolactinoma should be ruled out in women wih > 100 ng/ml prolactin level. Microadenomas rarely grow in pregnancy. They do not progress to macroadenoma.

Hypothroidism

Reduced thyroxine (T4) levels in hypothyroidism causes an elevation in thyrotrophin releasing hormone(TRH). This results in increased levels of thyroid stimulating hormone (TSH) and prolactin. Hypothyroidism is found in 3% to 5% of individuals with hyperprolactinaemia. Therefore, a TSH assay is recommended in all cases of hyperprolactinaemia.

In any case of drug-induced galactorrhoea, the drug is discontinued for one month and prolactin measured thereafter. If the medication cannot be discontinued then a prolactin assay is performed as such and CT /MRI is advised if prolactin levels exceed 100 ng/ml.

Management

It is essential to remember that hyperprolactinaemia is in itself simply an abnormal “lab value” that reflects the presence of an underlying pathophysiologic cause and all possible causes must be considered and either identified or ruled out before therapy is initiated (Olive)1. The indications for treatment include -

1. The presence of significant symptoms, such as infertility, ovulatory dysfunction or galactorrhoea in women and infertility or gynecomastia in men.
2. The presence of significant signs, such as visual field defects or cranial nerve palsies.
3. Abnormal test results, including visualization of a pituitary mass or lesion or detection of osteopenia.

Expectant

A patient with idiopathic hyperprolactinaemia or with a microadenoma who has no wish to conceive may be managed expectantly with yearly prolactin levels and CT scan every 2 years. If the woman is hypoestrongenic, oestrogen-progesterone combination therapy or bromocryptine can be used.

Radiation

Radiation is not the primary mode of therapy. Both external therapy (cobalt, proton beam, heavy particles) and brachy therapy (yttrium 90 rads as pituitary implants) have been used. The results are inconsistent; and delayed. Radation may damage the surrounding normal pituitary tissue causing diabetes insipidus and also damage the optic nerve.

Surgery

Trans-sphenoidal microsurgical resection of prolactinomas is also performed, but is once again not the treatment of first choice. Surgery should be reserved for those uncommon tumours that do not respond to medical therapy or have a large cystic component or for the occasional patient who cannot tolerate dopamine agonists or who experiences pituitary apoplexy (Biller)2. Though the initial cure rates for micro-and macroadenomas are 65 to 85% and 20 to 40%, respectively, the tumour recurs in 20 to 50% of microadenomas and 20 to 80% of macroadenomas.

Medical Management

Dopamine receptor agonists such as bromoergocryptine, methysergide and metergoline form the main stay of therapy with bromocryptine being the drug of choice. Bromocryptine is a semi-synthetic ergot alkaloid which stimulates dopamine receptors. It is rapidly absorbed orally, peak blood levels being reached in 1 to 3 hours and prolactin levels are depressed for 14 hours, therefore, it is given in a twice daily dosage form. Bromocryptine causes orthostatic hypotension resulting in faintness, dizziness, nausea and vomiting. Other adverse effects include headache, nasal congestion, fatigue, constipation or diarrhoea. Prolactin levels normalize in 90% of patients, fertility is resorted in 80% and galactorrhoea suppressed in 60% of idiopathic hyperprolactinaemia and microadenomas.

Therapy is commenced with a dose of 1.25 mg per day (half tablet) and gradually increased in weekly increments. In 10% of microadenomas, prolactin does not normalize even at a dose of 20 mg/day but many patients conceive and ovulate. After 1 year of bromocryptine therapy, only 10 to 20% of patients permanently normalize. After 2 years of therapy, 75% of microadenomas and 80 to 90% of macroadenomas regress. Bromocryptine is also used in postoperative or postirradiation failure or recurrence of hyperprolactinaemia. With a dose of 5 mg, 95% of patients with no adenomas resume normal menstrual function and galactorrhoea reduces over a period of 4 to 6 weeks and fertility is restored by 8 to 10 weeks duration If an adenoma is present, 50% will normalize menstrual function and galactorrhoea gets corrected by 12 weeks while fertility is restored by 14 to 18 weeks with the same dose. The rest of the patients may require higher doses ( up to 20 mg)m of bromocryptine.

A trial with bromocryptine therapy for up to 6 months is warranted even in macroadenomas. There may be a slow or rapid response, but usually the results are excellent. Of those with macroadenomas who conceive, 20% may have visual disturbances or headache during pregnancy and bromocryptine may be necessary. There is no evidence of teratogenesis, increased rate of abortions or multiple gestation with bromocryptine.

Once a patient with an adenoma conceives, no monitoring is required for microadenomas unless the patient is sympotomatic, while in macroadenomas, monthly visual fields suffice. In the non-pregnant state, macroadenomas should be monitored by 6 monthly visual fields and CT scans.

Cabergoline and quinagolide are two new dopamine agonists that seem to have considerable advantages over bromocriptine (Webster)3. Cabergoline is an ergoline D2 agonist which has a long plasma half-life that enables once or twice weekly administration. Quinagolide, in contrast, is a nonergot D2 agonist with an elimination half-life intermediate between those of bromocriptine and cabergoline. Quinagolide can be administred once daily. Comparative studies here indicated that cabergoline is superior to bromocriptine in efficacy (prolactin suppression, restoration of gonadal function) and in tolerability ( Biller et al)2.. In similar studies, quinagolide appeared to have similar efficacy and superior tolerability to that of bromocriptine. A small crossover study has indicated that cabergoline is better tolerated and has superior activity than quinagolide.

Pregnancy with pituitary adenoma

Usually no monitoring is required for microadenomas unless the patient develops symptoms; where as in macroadenomas monthly evaluation of visual field should be done. Bromocriptine can be used  in pregnancy if women complain of headache and visual disturbances. Rarely surgery may be required. Following pregnancy, Prolactin levels decrease in 50% of idiopathic hyperprolactinaemia  and 40% with adenomas. Breast feeding should be encouraged.

Bibliography

1. Olive D: Indications for hyperprolactinemia therapy. J Reprod Med 44(12 suppl): 1091-94:1999.
2. Biller BM: Diagnostic evaluation of hyperprolactinemia. J Reprod Med 44(12 suppl): 1095.9:1999.
3. Webster J: Dopamine agonist therapy in hyper PRL. J Reprod Med 44(12 suppl):1105-10:1999.
4. Walvekar VR, Jassawalla MJ, Salvi Vinita: Reproductive Endocrinology – A Clinical Approach, FOGSI, 224-33; 2001.
5. Gordon JP, Rydfors J: Obstetrics, Gynecology & Infertility-Handbook for clinicians, Scrub Hill Press, 509 – 517; 2001.
6. Gunasheela Sulochana: Principles & Practice of Obstetrics and Gynecology for Post graduates, Jaypee, 670 – 674; 2008.

Primary Amenorrhoea

Dr. Ashwini Bhalerao-Gandhi

BASIC PRINCIPLES OF MENSTRUAL FUNCTION

There are five basic factors involved  in the onset and continuation of normal menstruation. These are: anatomical patency of the genital tract; normal female chromosomal pattern; co-ordinated hypothalamic-pituitary-ovarian axis; active support by two other endocrine glands, namely thyroid and adrenal  cortex and responsive endometrium. Defect in one or more of these factors will therefore, be responsible for amenorrhoea, either primary or secondary⁽¹⁾.

PATHOLOGICAL AMENORRHOEA

It is defined as absence of menstruation for at least 6 months, not due to pregnancy, in a woman of childbearing age. The usual age limits of menarche and menopause are 16 and 44 years respectively.

Primary Amenorrhoea

Absence of menarche by age  14 in the absence of development of secondary sexual characteristics, or absence of menarche by age 16, regardless of the presence of normal growth, development and presence of secondary sexual characteristics.

Physiological Amenorrhoea

Before menarche, after menopause and during pregnancy.

ETIOLOGY OF PRIMARY AMENORRHOEA

Disorders of H-P-O Axis(2)

Hypothalamic

• Primary failures: Compression by tumours (Kallmann syndrome).
• Functional disorders: Psychological disturbances, weight loss, extreme exercise, pseudocyesis.

Pituitary

• Primary failures: Compression by tumours, Damage by surgery, Radiotherapy, Infarction (e.g. Sheehan syndrome), Hyperprolactinemia
• Functional failure secondary to hypothalamic failure or disorder.

Ovarian

Primary failures: Dysgenesis (genetic/chromosomal), damage by surgery, radiotherapy, chemotherapy.
Autoimmune disease

• Premature menopause
• Resistant ovary syndrome

Anatomical Causes of Amenorrhoea

Simple Developmental Defects

• Absent ovaries (extremely rare),
• Absent uterus / severely hypoplastic, with or without absent vagina.
• Imperforate hymen (lower vaginal aplasia).

Developmental Defects of Endocrine Origin

• Androgen-resistant syndrome (Testicular feminization), pseudohermaphrodites (genetic and gonadal males) including inhibition of uterovaginal  development.

Summary of Primary Investigations(3)

1. History:
   1. Previous  weight loss (h/o  rigorous exercises-athletes), or weight gain
   2. Psychological disorder: Change of environment, emotional disturbances.
   3. Prolactinergic drugs
   4. Thyroid symptoms
   5. Hirsutism
2. Examination
   1. General hirsutism
      • Thyroid swelling.
      • Secondary sex characters: Breast development, axillary / pubic hair
   2. Abdominal: Lumps, tumours, haematometra, enlarged uterus.
   3. Local perineal region
      • Clitoris, vulva, Hymen - Bulge or partially imperforate.
      • Vagina absent / dimple.
      • PV in secondary amenorrhoea
3. Laboratory investigations:
   1. Routine blood, urine, and stool.
   2. Special for tuberculosis
4. Hormonal evaluation
   1. FSH / LH
   2. Serum prolactin
   3. Plasma testosterone
   4. DHEAS
   5. Thyroid stimulating hormone (TSH) and T3, T4
   6. Serum progesterone
   7. Estradiol
      
      The hormonal tests must be done at an appropriate time of the menstrual cycle.
   
   
5. X-ray: Chest and bone age.
6. USG: The availability of USG has become the most important diagnostic tool. Especially in young girls when PS / PV examination is difficult. Also in obese patients where assessment of uterus and adnexae are difficult. It also helps in assessing tumours in pelvic region.
7. Progesterone challenge test: Usually Medroxyprogesterone acetate (10mg) or Norethisterone (5mg) is given BID for 5 to 7 days. Withdrawal bleeding will occur within 7 to 15 days provided the patient has enough estrogen.  If following progesterone there is no withdrawal and patient has enough estrogen then look for a cause in end organ, namely endometrium. Progesterone challenge test per se has not much value. This is because USG gives much more information. Whenever patient has tuberculosis, full anti Koch's treatment must be given. It is preferred that this should be done in consultation with a physician.
8. E + P challenge test- T: Ethinyl estradiol 0.02 mg (Lynoral-0.01 / 0.05mg) or conjugated estrogen 1.25 mg (Premarin-0.625 / 1.25mg tabs) daily for 25 days. T Medroxyprogesterone acetate (10mg) daily to be added from day 15-25.

Hormonal Assessment

• Serum FSH, LH, estradiol-if low then the cause lies in the pituitary.
• If FSH and LH are low but estrogen is normal then it is delayed puberty.
• If FSH, LH are high and estrogen is low then
  1. Go for the bone age. If bone age is lower than chronological age, then wait and watch.
  2. Do karyotyping to rule out Turner's syndrome etc.

Practical Aspects of Management of Primary Amenorrhoea

• Firstly it is important to assess whether it is primary amenorrhoea or delayed puberty.
• USG must be done to see the pelvic organs. This way one can rule out mullerian anomalies and absence of ovaries.
• If the USG is normal then go for general examination to rule out chronic conditions causing delayed puberty (e.g. Koch's, anaemia, worm infestations, thalassemia, renal failure, etc.)

Management

The common principles in the management are(5) :

1. Identification of underlying diseases like systemic, nutritional, endocrine and cytogenetic. Serious space occupying CNS lesions should also be ruled out or diagnosed and treated. Treatment of the primary disease may reverse the process and allow progression of puberty in some of these for example, bromocryptine therapy for hyperprolactinemia or adequate nutritional management in nutritionally deprived /imbalanced girls. Speciality referrals for specific underlying diseases are advocated.
2. Reassurance to the child and her parents regarding  anticipated normal pubertal development in cases of CDGP (Combination delay of growth and puberty).
3. Short-term therapy with sex steroids (estrogens) may be needed in girls with CDGP to trigger the onset of puberty.
4. Induction and maintenance of puberty: Late initiation is beneficial in prevention of early epiphyseal closure and thus not compromising  final adult height (FAH). However, to avoid  psychological embarrassment vis-à-vis their peers, the therapy should be initiated at 13 years of age.  The starting dose of ethinyl  estradiol is 1-2 mg/day, which is gradually increased every 2-3 months. The addition of progestin  should be either on full breast development or when break through bleeding occurs. Girls with permanent  hypogonadism will need this sex steroid therapy till they reach average age of menopause in the population.
5. Growth promoting, potentiating strategies: Abnormal physical growth  like short stature in Turner's syndrome (TS) and Prader-Willi syndrome (PWS) or tall stature of Kallmann's syndrome (KS) and Swyer's syndrome (SS) can be appropriately managed. Girls with TS and PWS are known to respond to growth hormone therapy and achieve an increase in  FAH.17 In order to assure maximum height gain, estrogen replacement can be timely added for achieving optimum synergestic  action and preventing early epiphyseal closure. In patients of KS and SS it is important to start estrogen replacement therapy (ERT) well in time to prevent eunichoid tall stature. Growth hormone therapy in girls with PWS is not only beneficial for improving stature but also for reducing obesity and increasing lean body mass and exercise capacity.18
6. Prevention of osteoporosis: Adolescence is critical period for bone acquisition , which is dependent upon  nutrition, estrogen and lifestyle. Low bone mineral density-osteopenia/osteoporosis can result from either estrogen deprivation or permanent estrogen deficiency due to hypogonadism. Therefore, girls with permanent gonadal failure need estrogen replacement therapy not only for  maintenance of puberty but also for prevention of osteoporosis.
7. Future fertility: With current advances in reproductive medicine the majority of cases of pubertal disorders can be assured of future fertility. Induction of ovulation  by gonadotropins in hypogonadotropic hypogonadism advanced reproductive technology with donor eggs in hypergonadotropic hypogonadism  and bromocriptine/transphenoidal surgery in cases of hyperprolactinemia, pituitary adenoma etc. provide fertility potentiation. Even in girls with  mullerian  agenesis, in vitro  fertilization programmes  employing the woman's own eggs and husband's sperm can utilize surrogate motherhood.
8. Surgical therapy: Gonadectomy is indicated in cases of pure (Swyer's syndrome) or mixed gonadal dysgenesis as well as in girls with testicular feminisation syndrome (TFS). In TFS it should be done after achieving  full breast development. Creation of neo-vagina  is required in cases of TFS and mullerian agenesis.

CONCLUSION

Primary amenorrhoea is a symptom of some underlying disease or disorder. In majority  of cases, diagnosis of the specific disorder is possible by its clinical expression. Cytogenetic, biochemical, biophysical and interventional diagnostic procedures are necessary only to corroborate the clinical diagnosis and in few cases where the clinical diagnosis remains disputed. Hence, the indications of special investigations should be oriented on the  basis of clinical approach. So far as the results of treatment are concerned, only a few of the disorders are curable, majority are crippling in nature while some may appear life -threatening . Primary amenorrhoea due to polycystic ovarian disease, congenital adrenal hyperplasia or transverse septum of vagina with haematocolpos and haematometra (cryptomenorrhoea)  are curable disorders. Chromosomal anomaly leading to primary amenorrhoea is a crippling disease. Intracranial space occupying lesion associated with primary amenorrhoea is a life –threatening condition. Hence, early diagnosis and correct counselling may save these young girls from unnecessary expensive investigations and injudicious treatment. Every possible effort must be done to restore menstrual, coital and reproductive functions in such cases.

REFERENCES :

1. Chakravarty B N. Reproductive Endocrinology – A Clinical Approach. 2nd ed. New Delhi. Jaypee Brothers 2001: 120-132.
2. Shaw R W, Stanton S L. Gynaecology. 3rd ed. UK. Churchill Livingstone 2003: 229-244.
3. Pandya Geeta. Practical Gynec-Endocrinology. 1st ed. New Delhi. Jaypee Brothers 2003: 16-23.
4. Dutta D.C. Text Book of Gynaecology. 2nd ed. Calcutta. New Central Book Agency (P) Ltd 1994: 401-418
5. Vaidya Rama, Shringi Meena et al. Adolescent  Girl – An Update. 1st ed. New Delhi. Jaypee Brothers 2004: 23-35.