Endo Reproduction

CLINICAL GUIDELINESCLINICAL GUIDELINES

FOR FOR

EVALUATION AND EVALUATION AND MANAGEMENT OF MANAGEMENT OF

AMENORRHEAAMENORRHEA

CLINICAL GUIDELINESCLINICAL GUIDELINES

FOR FOR

EVALUATION AND EVALUATION AND MANAGEMENT OF MANAGEMENT OF

AMENORRHEAAMENORRHEA

Primary Amenorrhea: State in which menarche does not occur

Secondary Amenorrhea: State in which cessation of menstrual periods occurs after menarche

ENDOCRINOLOGY 2

Primary amenorrhea

Failure of menarche to occur when expected in relation to the onset of pubertal development.

No menarche by age 16 years with signs of pubertal development.

No onset of pubertal development by age 14 years.

Secondary amenorrhea

Absence of menstruation for 3 or more months in a

previously menstruating women of reproductive

age.

CNS-Hypothalamus-PituitaryOvary-uterus Interaction

Neural control Chemical control

Dopamine (-)

Norepiniphrine (+)

Endorphines (-)

Hypothalamus

Gn-RH

Ant. pituitary

FSH, LH

Ovaries

Uterus

ProgesteroneEstrogen

Menses

–± ?

ENDOCRINOLOGY 5

0

50

100

150

200

250

Day1 Day 12 Day 13 Day 14 Day 22 Day 26

LHFSHEstrogenProgestrone

Inadequate hormonal stimulation of the endomerium “Anovulatory amenorrhea”

- Euestrogenic - Hypoestrogenic

Inability of endometrium to respond to hormones “Ovulatory amenorrhea”

- Uterine absence - Utero-vaginal agenesis - XY-Females ( e.g T.F.S) - Damaged endometrium ( e.g Asherman’s syndrome)

Normal androgens Hypothalamic-pituitary

dysfunction (stress, weight loss or gain, exercise, pseudocyesis)

Hyperprolactinemia Feminizing ovarian tumour Non-gonadal endocrine

disease (thyroid, adrenal) Systemic illness

High androgens PCOS Musculinizing ovarian

tumour Cushing’s syndrome Congenital adrenal

hyperplasia (late onset)

Normal androgens- Hypothalamic-pituitary failure - Severe dysfunction - Neoplastic,destructive, infiltrative, infectious & trumatic conditions involving hypothalamus or

pituitary- Ovarian failure - Gonadal dysgenesis - Premature ovarian failure - Enzyme defect - Resistant ovaries - Radiotherapy, chemotherapy

High androgens- Musculinizing ovarian tumour- Cushing’s syndrome- Congenital adrenal hyperplasia (late

onset)

AMENORRHOEA AN APPROACH FOR DIAGNOSIS

• HISTORY• PHYSICAL EXAMINATION• ULTRASOUND EXAMINATION

Exclude PregnancyExclude Cryptomenorrhea

Cryptomenorrhea

Outflow obstruction to menstrual blood

- Imperforate hymen- Transverse Vaginal septum with functioning

uterus- Isolated Vaginal agenesis with functioning

uterus

- Isolated Cervical agenesis with functioning uterus

- Intermittent abdominal pain

- Possible difficulty with micturition- Possible lower abdominal swelling- Bulging bluish membrane at the introitus or absent vagina (only dimple)

Imperforate hymen

Once Pregnancy and cryptomenorrhea are excluded:

The patient is a bioassay for Endocrine abnormalities

Four categories of patients are identified 1. Amenorrhea with absent or

poor secondary sex Characters

2. Amenorrhea with normal 2ry sex characters3. Amenorrhea with signs of androgen excess

4. Amenorrhea with absent uterus and vagina

FSH Serum level

Low / normal

High

Hypogonadotropichypogonadim

Gonadal dysgenesis

- FSH, LH, Prolactin, TSH- Provera 10 mg PO daily x 5 days

+ Bleeding No bleeing Prolactin TSH

FurtherWork-up(Endocrinologist)

- Mild hypothalamic dysfunction - PCO (LH/FSH) Review FSH result

And history (next slide)

FSH

Low / normalHigh

Hypothalamic-pituitaryFailure

Ovarian failure

If < 25 yrs or primary amenorrhea karyoptype If < 35 yrs R/O autoimmune disease

?? Ovarian biopsy

head CT- scan or MRI

- Severe hypothalamicdysfunction

- Intracranial pathology

Amenorrhea Utero-vaginal absence

Karyotype

46-XX

Mullerian Agenesis

(MRKH syndrome)

Andogen Insenitivity

(TSF syndrome)

. Gonadal regressioon. Testocular enzyme defenciecy. Leydig cell agenisis

46-XY

Normal breasts& sexual hair

Normal breasts& absent sexual

hairAbsent breasts& sexual hair

Asherman’s syndrome History of pregnancy associated D&C Rarely after CS , myomectomy T.B

endometritis, bilharzia Diagnosis : HSG or hysterescopy Treatment : lysis of adhesions; D&C or

hysterescopy + estrogen therapy ( ? IUCD or catheter)

Some will prescribe a cycle of Estrogen and Progesterone challenge Before HSG or

Hysterescopy

AmenorrheaSigns of androgen excess

Testosterone, DHEAS, FSH, and LH

DHEAS 500-700 mug/dL DHEAS >700 mug/dLTEST. >200 ng/dL

Serum 17-OHProgesterone level

Late CAH Adrenal hyperfunction

U/S ? MRI or CT

OvarianOr adrenal

tumor

Lower elevations PCOS (High LH / FSH)

Amenorrhea

PRIMARY AMENORRHEA

. Ovarian failure 36%

. Hypogonadotrophic 34%

Hypogonadism.

. PCOS 17%

. Congenital lesions

(other than dysgenesis) 4%

. Hypopituitarism 3%

. Hyperprolactinaemia 3%

. Weight related 3%

SECONDARY AMENORRHEA

. Polycystic ovary syndrome 30%

. Premature ovarian failure 29%

. Weight related amenorrhoea 19%

. Hyperprolactinaemia 14%

. Exercise related amenorrhoea 2%

. Hypopituitarism 2%

Chromosomally incompetent - Classic turner’s syndrome (45XO) - Turner variants (45XO/46XX),(46X-abnormal X) - Mixed gonadal dygenesis (45XO/46XY) Chromosomally competent - 46XX (Pure gonadal dysgeneis) - 46XY (Swyer’s syndrome)

Classic

Turner’s

Turner

Variant

True gonadal

Dysgenesis

Mixed

Dysgenesis

phenotype Female Female Female Ambiguous

Gonad Streak Streak Streak - Streak

- Testes

Height Short - Short

- Normal

Tall Short

Somatic stigmata

Classical ± Nil ±

karyotype XO XX/XO or abnormal X

46-XX(Pure)

46-XY (Swyer)

XO/XY

• Sexual infantilism and short stature.• Associated abnormalities, webbed

neck,coarctation of the aorta,high-arched pallate, cubitus valgus, broad shield-like chest with wildely spaced nipples, low hairline on the neck, short metacarpal bones and renal anomalies.

• High FSH and LH levels.• Bilateral streaked gonads.• Karyotype - 80 % 45, X0 - 20% mosaic forms (46XX/45X0)• Treatment: HRT

Mosaic (46-XX / 45-XO) (Classic 45-XO)

Turner’s syndrome

Ovarian dysgenesis

Steroidogenic enzyme defects (17-hydroxylase)

Ovarian resistance syndrome Autoimmune oophoritis Postinfection (eg. Mumps) Postoopherectomy Postradiation Postchemotherapy

Serum estradiol < 50 pg/ml and FSH > 40 IU/ml on repeated occasions

10% of secondary amenorrhea Few cases reported, where high dose estrogen

or HMG therapy resulted in ovulation Sometimes immuno therapy may reverse

autoimmue ovarian failure Rarely spont. ovulation (resistant ovaries) Treatment: HRT (osteoporosis, atherogenesis)

The most common cause of chronic anovulation

Hyperandrogenism ; LH/FSH ratio Insulin resitance is a major biochemical

feature ( blood insulin level hyperandrogenism )

Long term risks: Obesity, hirsutism, infertility, type 2 diabetes, dyslipidemia, cardiovasular risks, endometrial hyperplassia and cancer

• Treatment depends on the needs of the patient and preventing long term health problems

• Normal height• Normal external and internal

genital organs (infantile)• Low FSH and LH• MRI to R/O intra-cranial pathology.• 30-40% anosmia (kallmann’s

syndrome)• Sometimes constitutional delay• Treat according to the cause

(HRT), potentially fertile.

• Common cause (20%)• Under stature and

delayed bone age ( X-ray Wrist joint)• Positive family history• Diagnosis by exclusion

and follow up • Prognosis is good (late developer)• No drug therapy is

required – Reassurance (? Hormone replacement therapy [HRT] )

Pituitary inability to secrete gonadotropins Pituitary necrosis following massive

obstetric hemorrhage is most common cause in women

Diagnosis : History and E2,FSH,LH + other pituitary deficiencies (MPS test) Treatment : Replacement of deficient hormones

1o or 2o Amenorrhea is often first sign A body mass index (BMI) <17 kg/m²

menstrual irregularity and amenorrhea Hypothalamic suppression Abnormal body image, intense fear of

weight gain, often strenuous exercise Mean age onset 13-14 yrs (range 10-21 yrs) Low estradiol risk of osteoporosis Bulemics less commonly have amenorrhea

due to fluctuations in body wt, but any disordered eating pattern (crash diets) can cause menstrual irregularity.

Treatment : body wt. (Psychiatrist referral)

Common in women who participate in sports (e.g. competitive athletes, ballet dancers)

Eating disorders have a higher prevalence in female athletes than non-athletes

Hypothalamic disorder caused by abnormal gonadotrophin-releasing hormone pulsatility, resulting in impaired gonadotrophin levels, particularly LH, and subsequently low oestrogen levels

Post-pill amenorrhea is not an entity Depot medroxyprogesterone acetate Up to 80 % of women will have amenorrhea after

1 year of use. It is reversible (estrogen deficiency)

A minority of women taking the progestogen-only pill may have reversible long term amenorrhoea due to complete suppression of ovulation

Autosomal recessive trait Most common form is due to

21-hydroxylase deficiency Mild forms Closely resemble

PCO Severe forms show Signs of

severe androgen excess High 17-OH-progesterone

blood level Treatment : cortisol

replacement and ? Corrective surgery

Clinical suspicion : Hirsutism, truncal obesity, purple striae, BP

If Suspicion is high : dexamethasone suppression test

(1 mg PO 11 pm ) and obtaine serum cortisol level at 8 am :

< 5 µg/ dl excludes cushing’s 24 hours total urine free cortisol

level to confirm diagnosis 2 forms ; adrenal tumour or ACTH

hypersecretion (pituitary or ectopic site)

15% of 1ry amenorrhea Normal breasts and Sexual Hair

development & Normal looking external female genitalia

Normal female range testosterone level Absent uterus and upper vagina & Normal

ovaries Karyotype 46-XX 15-30% renal, skeletal and middle ear

anomalies Treatment : STERILE ? Vaginal creation

( Dilatation VS Vaginoplasty)

X-linked trait Absent cytosol receptors Normal breasts but no

sexual hair Normal looking female

external genitalia Absent uterus and upper

vagina Karyotype 46, XY Male range testosterone

level Treatment : gonadectomy

after puberty + HRT ? Vaginal creation (dilatation

VS Vaginoplasty )

. Attempts to restore ovulatory function

. If this is not possible HRT (oestrogen and progesterone) is given to hypo-estrogenic amenorrheic women (to prevent

osteoporosis; atherogenesis). Periodic progestogen should be taken by euestrogenic

amenorrheic women (to avoid endometrial cancer). If Y chromosome is present gonadectomy is indicated. Many cases require frequent re-evaluation

To achieve pubertal development

Premarin 5mg D1-D25 + provera 10mg D15-D25 X 3 months; 2.5mg premarin X 3 months and

1.25mg premarin X 3 monthsMaintenance therapy

0.625mg premarin + provera OR ready HRT preparation OR 30µg oral contraceptive pill

Although the work-up of amenorrhea may seem to be complex, a carefully conducted physical examination with the history, and Looking to the patient as a bioassay for endocrine abnormalities, should permit the clinician to narrow the diagnostic possibilities and an accurate diagnosis can be obtained quickly.

Management aims at restoring ovulatory cycles if possible, replacing estrogen when deficient and Progestogegen to protect endometrium from unopposed estrogen.

• Frequent re-evaluation and reassurance of the patient.

Androgen Insensitivity Syndrome Hypogonadism Klinefelter’s Syndrome (XXY) Swyer syndrome (XY but no gonads,

treated as a girl e.g. with estrogen etc.) 5 alpha-reductase deficiency (5-ARD) –

(XY) vagina and labia, as well as penis that can ejaculate

– androgenic insensitivity 1. XY: X chromosome is responsible for the testosterone receptors

i. These receptors become insensitive to testosterone

ii. Child is born with appearance of female genitalia

**Mullerian inhibiting system is okay; so internal organs are not female**

Klinefelter’s syndrome Gonadotropin receptor

mutations Cryptorchidism Androgen biosynthesis

disorders Varicocele Congenital anorchia

Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic

Congenital Acquired

Isolated hypogonadotropic hypogonadism

Kallman’s syndrome DAX1 mutation GPR 54 mutation Leptin or leptin receptor

mutations Gonadotrope receptor mutations Hypopituitarism

Hyperprolactinemia Androgen therapy GnRH analog therapy Glucocorticoid therapy Critical illness Chronic illness Diabetes mellitus Opiates Pituitary mass lesions Infiltrative diseases Sellar surgery Sellar radiation

Congenital Acquired

How would you evaluate this patient?

Total testosterone: 134 ng/dL (176-781)

Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)

What is the initial diagnosis?

Primary hypogonadismWhat is the next step in work up?

Klinefelter’s syndrome Gonadotropin receptor

mutations Cryptorchidism Androgen biosynthesis

disorders Varicocele Congenital anorchia

Mumps orchitis Radiation Antineoplastic drugs Ketoconazole Glucocorticoid excess Trauma Testicular torsion Autoimmune orchitis Cirrhosis Chronic renal failure HIV infection Idiopathic

Congenital Acquired

Confirmed low testosterone

Check LH+FSH (SA if infertility)

High gonadotropins – 1o Low/low nl gonadotropins – 2o

Karyotype Prolactin, other pituitary hormones, iron studies, sella MRI

How would you evaluate this patient?

Total testosterone: 134 ng/dL (176-781)

Luteinizing hormone (LH): 26.3 mIU/mL (1.3-13.0)What is the initial diagnosis?

Primary hypogonadism

What is the next step in work up?

Karyotype: 47 XXY

Incidence ~ 1/1,000 live male births Extra X chromosome, usually 47 XXY Phenotype strongly influenced by CAGn repeat

in the androgen receptor gene Manifestations

› Hypogonadism› Gynecomastia› Behavioral disorders› Bronchiectasis/emphysema/bronchitis› Mediastinal germ cell tumors› Non-Hodgkin’s lymphoma› Diabetes mellitus› Lower extremity varicosities

Abnormality Frequency (%)

Abnormal testicular histology 100

Decreased testicular length 99

Azoospermia 93

Low testosterone 79

Decreased facial hair 77

Increased gonadotropins 75

Decreased sexual function 68

Gynecomastia 55

Decreased axillary hair 49

Decreased penis length 41

Gordon DL et al. Arch Intern Med (1972) 130:720

Primary goal is to restore testosterone levels to the laboratory reference range

Prescribe only for patients with confirmed hypogonadism

Role in “treating” decline in testosterone levels with aging uncertain

Multiple preparations› Oral› Intramuscular› Transdermal› Buccal

Signs and symptoms of hypogonadism depend on when the condition occurs in development

Initial evaluation focuses on distinguishing between primary and secondary hypogonadism› Primary: LH elevated, testosterone low› Secondary: LH low, testosterone low

Goal of testosterone replacement is physiological testosterone levels and preservation of testosterone-dependent physiological functions

Idiopathic

Kallmann’s syndrome (X-linked): impaired migration of GnRH neuronesanosmia, disturbance colour vision, dyskinesis

Prader-Willi syndrome (aut. dom., chromosome 15): obesity, muscle hypotonia, mental retardation, short stature, small hands/feet, cryptorchidism, HH

Mutations in pathway for GnRH secretion and action (KAL, DAX1, GnRH receptor, etc….)

May be difficult to distinguish from constitutional delay

GnRH tests can sometimes help but results may be unreliable

CASES

Case 1 Answer: Full physical examination

Serum endocrinology:FSH, LH, prolactin, thyroid

functionpregnancy test

Ultrasound scan of the pelvis (uterus and ovaries)

Case 1 Results

FSH of 2.2 iu/L

LH 15.0 iu/L

normal prolactin and thyroid function

The ultrasound scan demonstrated the presence of polycystic ovaries and an endometrial thickness of 15 mm.

Case 1 What should the management be?

Case 1Endometrial hyperplasia is a risk factor for oligo / amenorrhoeic women with PCOS because of unopposed oestrogen stimulating progressive hyperplasia and potentially malignancy / adenocarcinoma. Regular withdrawal bleeds should be induced either with cyclical progestogens or the COC pill.

If fertility is required then ovulation induction should be instituted with clomifene citrate followed by gonadotrophin therapy if this is unsuccessful.

If the patient is overweight she should be encouraged to lose weight. Women with polycystic ovary syndrome have insulin resistance and at an increased of cardiovascular disease and type II diabetes.

Case 2 An 18 year old woman presents with primary amenorrhoea (she has never had a period).

She has developed small breasts and has some pubic hair. She is very overweight with a body mass index of 39 kg/m2.

What investigations should be performed in order to make the diagnosis?



function(pregnancy test)


Case 2 Results FSH of 0.5 iu/LLH of 0.5 iu/L

normal prolactin and thyroid function

The ovaries appear small on ultrasound scan, as does the uterus. What is the diagnosis?

Case 2

Hypogonadotrophic hypogonadism

Usually of hypothalamic origin and may be congenital, such as Kallmann's Syndrome (association with lack of smell)

The low gonadotrophin concentrations have failed to stimulate ovarian development and adequate puberty.

The small amount of breast development and pubic hair can be explained by oestrogen being produced in the peripheral fat and adrenal androgen secretion.

Overall this patient will be oestrogen deficient and bone mineral densitometry should be performed to exclude osteoporosis.

Case 2 What is the treatment?

Case 2

If the patient wishes to be pregnant, first line treatment would be pulsatile GnRH or gonadotrophin stimulation of the ovaries with a preparation that contains both FSH and LH bio-activity (ie, one of the traditional hMG preparations rather than recombinant FSH).

Otherwise HRT should be given.

Case 2

Do you need to image the pituitary / hypothalamus?

Case 2

Do you need to image the pituitary / hypothalamus?

Yes in adults with secondary amenorrhoea and hypog/hypog or hyperPRL, but tumours less common in adolescents if no other symptoms and normal PRL

Case 2

The patient was administered HMG at increasing high doses, but failed to produce any demonstrable follicular growth as assessed both by ultrasound scan and persistently low serum oestradiol concentrations.

Can you explain?

Case 2

This patient appears to have a second pathology and may well have primary ovarian failure combined with hypothalamic hypogonadotrophic hypogonadism, thus explaining the combination of ovarian failure with low gonadotrophin concentrations.


She has a normal body mass index and no other obvious problems.






Case 3 Results FSH of 0.5 iu/LLH of 0.5 iu/L

serum prolactin concentration: 5,000 mu/L What is the diagnosis?What further investigations should be done?

Case 3

Hyperprolactinaemia

A repeat prolactin should be measured.

The diagnosis is likely to be that of a macro-adenoma of the pituitary gland and therefore either MRI or CT imaging of pituitary should be performed.

What treatment should be provided?

Case 3

Dopamine agonists: Bromocriptine or Cabergoline

Check visual fields


She has a normal body mass index and no other obvious problems.






Case 4 Results FSH of 40 iu/LLH of 30 iu/L

What is the diagnosis?What further investigations should be done?

Case 4

Primary ovarian failure / premature ovarian failure

What further investigations should be performed?

Case 4

• repeat FSH & LH• karyotype • bone mineral densitometry• auto-antibody screen

Treatment should be with hormone replacement therapy combined with egg donation is fertility is required.

THANK YOUFOR YOUR ATTENTION

Health & Medicine

Endo Reproduction