Primary amenorrhoea

Ans. is b i.e. Ovarian dysgenesis 

Primary amenorrhea is a condition when a female has not attained menarche by the age of 14° in the absence of growth or development of secondary sexual characteristics.

OR

No menarche by the age of 16 years° regardless of the presence of normal growth and development of secondary sexual characteristics.

“Mullerian agenesis – is a relatively common cause of primary amenorrhea. more frequent than congenital androgen insensitivity and second only to gonadal dysgenesis.”

Remember-Most common cause of Primary Amenorrhea = Gonadal dysgenesis°

Ilnd most common cause of Primary Amenorrhea = Mullerian Agenesis (Mayer Rokitansky Kuster Hauser Syndrome). °

Also know :

Causes of Primary Amenorrhea

Friends most of the textbooks have given an exhaustive list of the causes of Primary amenorrhea which is quite difficult to mug, but if you try to understand and then learn. I think you will be able to recall them better during exams.

Let’s first see what are the basic requirements for a female to menstruate normally.

• An intact out flow tract which connects the uterine cavity with outside and a normally developed uterus with its endometrium lining.
• Proper quantity and sequence of steroid hormones i.e. Estrogen and Progesterone which inturn originate from ovary.
• The maturation of follicular apparatus is guided by Gonadotropins – FSH and LH (released by pituitary).
• The secretion of these hormones is inturn dependant on Gonadotropin Releasing Hormone (released by hypothalamus).

So, broadly we can classify the causes of amenorrhea into the following compartments.

Ans. is a i.e. Kallman Syndrome 

Friends, you know the answer to this question quite well. Here I would like to point out that in solving PGMEE Questions of previous years, it is not only important to know the correct answer with its details, it is equally important to know the details of incorrect options (as Questions might be asked on these incorrect options in future).

So, let’s know :

Laurence Moon Biedl Syndrome

It is an autosomal recessive disorder characterized by GnRH deficiency (hypogonadism) (FSH < 40 mIU/m1) and associated with :                                     

• Obesity
• Mental retardation
• Polydactyly
• Retinitis Pigmentosa

Ans. is d i.e. Prolactinoma  

This child is presenting with – Primary amenorrhea with :

• Negative progesterone challenge test – which rules out PCOD – (otherwise too, PCOD is a cause of secondary amenorrhea).
• When next step was done i.e., estrogen, progesterone combined test – It comes out to be positive i.e., compartment I system (uterus, endometrium and outflow tract) is normal if properly stimulated by estrogen which rules out mullerian agenesis and ashermann syndrome.
• Positive estrogen progesterone combined test means the defect is in the production of estrogen i.e., either ovaries, pitutary or hypothalmus.

So from the given options we have to look for a cause which involves either of the above sites. which in this case is prolactinoma.

Testicular feminization syndrome – complete androgen resistance, presents as phenotypic young woman without sexual hair but with normal breast development and primary amenorrhoea Complete testicular feminization is a common form of male pseudohermaphroditism. It is the 3rd most common cause of primary amenorrhea after gonadal dysgenesis and congenital absence of the vagina. The features are characteristic. Namely,  a  ”woman”  is  ascertained  either  because  of  inguinal  hernia  (prepubertal)  or  primary amenorrhea (postpubertal). The development of the breasts, the habitus, and the distribution of body fat are female in character so that most have a ”truly” feminine appearance. Axillary and pubic hairs are absent or scanty, but some vulval hairs are usually present. Scalp hairs are that of a normal woman, and facial hairs are absent. The external genitalia are unambiguously female, and the clitoris is normal. The vagina is short and blind-ending and may be absent or rudimentary. All internal genitalia are absent except for testes that contain normal Leydig cells and seminiferous tubules without spermatogenesis. The testes may be located in the abdomen, along the course of the inguinal canal, or in the labia majora.

Androgen insensitivity syndrome [Ref. Harrison 16⁶¹/e p 2218, 2219 & 15^th/e p 2182]

• It is a case of Testicular feminisation syndrome.
• The characteristic features of these disorders are that they are genotypically male (XY) while phenotypically they are female.
• These cases usually present as female with abdominal testis.

Prepubertal children with this disorder are often detected when inguinal masses prove to be a testis or when a testis is unexpectedly found during herniorrhapy in phenotypically female.

• It is called testicular feminisation syndrome but the name is both stigmatising and inaccurate (the testes do not produce feminising factors).
• The preferred name, complete androgen insensitivity syndrome (CAIS) reflects the underlying aetiology.
• The cause of androgen insensitivity syndrome is the abnormality of the androgen receptor.
• In the fetus with CA1S testes forms normally due to the presence of the (SRY gene) on chromosome Y.
• At the appropriate time, these testes secretes anti Mullerian hormone leading to the regression of mullerian ducts. Hence CAIS ‘women’ do not have a uterus.
• Testosterone is also produced at the appropriate time. However due to the complete inability of the androgen receptor to respond, the external genitalia do not virilise and instead undergo female development.
• These patients have vagina instead of penis .
• Other areas where testosterone may have important fetal effects, such as the brain, will also develop along the female path.
• The result is a female (both physically and psychologically) with no uterus, testis present which is found at some point in their line of descent through the abdomen front the pelvis to the inguinal canal.
• During puberty, breast development will be normal; however, the effects of androgens will not be seen, so pubic and axillary hair growth will be minimal.
• Majority of women with CATS have shortened vagina, when compared with normal average length of 10-12 cm.
• The cause of this lies in the embroyological development of the vagina,

– Upper portion of vagina                                    develops from mullerian ducts

– Lower portion of vagina                                    develops from urogenital sinus.

In CATS mullerian duct regresses, under the effect of mullerian inhibiting hormone, leaving just the part derived from the urogenital sinus.

Patient described in the question is most likely a case of Turner’s syndrome as indicated by the clinical features.

Turner’s syndrome results from complete or partial loss of one X chromosome resulting in the karyotype 45X.

It is primarily characterized by hypogonadism in phenotypic females.

Ref: Robbins Pathologic Basis of Disease, 6th Edition, Page 174-5.

The genotype XO belongs to the Turner’s syndrome which is characteristic of gonadal dysgenesis, short stature and external and internal dysmorphic features. The gonadal dysgenesis leads to primary amenorrhea.

This is a case of Kallmann syndrome.

It is a form of isolated idiopathic hypogonadotropism associated with anosmia and colour blindness.

There may be associated cleft lip and palate.

In these patients, GnRH neurons are absent due to partial or complete agenesis of olfactory bulb.

Patients present with primary amenorrhoea. Menstruation can be induced with combined oestrogen and progestin therapy.

Induction of ovulation is successful with exogenous gonadotrophins.

Ref: Textbook of Gynaecology by D.C.Dutta, 4th Edition, Page 426

Turner Syndrome: 45,X Gonadal Dysgenesis:

• Müllerian agenesis
• Vaginal septum
• Imperforate hymen
• Androgen insensitivity syndrome
• PCOS
• Congenital adrenal hyperplasia
• Cushing and thyroid disease

Müllerian agenesis (Mayer-Rokitansky-Küster-Hauser syndrome) is the second most common cause of primary amenorrhea.

Clinical features:

• Normal ovarian development
• Normal endocrine function
• Normal female sexual development
• Shortened or absent vagina in addition to absence of the uterus
• Individuals have 46,XX karyotype

Ref: Rosen M.P., Cedars M.I. (2011). Chapter 13. Female Reproductive Endocrinology and Infertility. In D.G. Gardner, D. Shoback (Eds),Greenspan’s Basic & Clinical Endocrinology, 9e.

Ans. is ‘d’ i.e., 45 X

TURNER’S SYNDROME

o Turner’s syndrome is the most common sex chromosomal disorder in phenotypic females.

o Turner’s syndrome results from complete or partial loss of one X chromosome (45, X) and is characterised by hypogonadism in phenotypic females

Features of Turner syndrome in children

o The most severely affected patients generally present during infancy with edema (owing to lymph stasis) of the dorsum of the hand and foot and sometimes swelling of the nape of the neck.

• Swelling of the neck is related to markedly distended lymphatic channels, producing so called cystic hygroma. o As these infants develop, the swelling subsides but often leave bilateral neck webbing and persistent looseness of skin on the back of the neck.

o Congenital heart disease is also common, particularly preductal coarctation ofAorta and bicuspid Aortic valve.

• C. VS abnormalities are most important cause of mortality in children with Turner’s syndrome. Features of Turner’s syndrome in Adolescents and Adult

o At puberty there is failure to develop normal secondary sex characteristics.

o The genitalia remains infantile, breast development is inadequate and there is little pubic hair. Nipples are widely spaced.

o Turner syndrome is the single most important cause of primary amenorrhoea accounting for approximately  ¹/3 of the cases.

o Short stature (height rarely exceeds 150 cm).

o The mental status of these patients is usually normal but subtle defects in nonverbal, visual spatial information processing have been noted (mental retardation is associated with the presence of extra chromosome not with loss of X chromosome).

o About 50% of the patients develop autoantibodies directed to the thyroid gland and upto one half of these patients develop hypothyroidism.

o Other features include low posterior hairline, webbing of neck, cubitus valgus, streak ovaries. o Glucose intolerance, obesity and insulin resistance are also seen.

Answer is D (Complete androgen insensitivity syndrome)

The patient in question presents as a 21 year old women (truly feminine appearance) with well-developed breasts, no hiruitism, no pubic or axillary hair with primary amenorrhea. All features thus mentioned lead to a diagnosis of complete androgen insensitivity.

Complete androgen insensitivity syndrome : syn: complete testicular feminization:  (Common form of male pseudohermaphroditism)

A 46 XY karyotypic male presents with a truly feminine appearance with complaints of primary amenorrhea (third most common cause of primary amenorrhea after gonadal dysgenesis and congenital absence of vagina)

Mature breast development

Habitus and distribution of body fat are female in character

Scalp hair is that of normal women and facial hair is absent (no hiruitism) External genitalia is unambiguously female and clitoris is normal

Internal genitalia : All internal genitalia are absent except testes that contain normal leydig cells and seminiferous tubules but without spermatogenesis.

Also remember:

The testes may be located in the abdomen, along the course of inguinal canal or in the labia majora (undescended testes)Q

The major complication of undescended testes in this disorder is the development of tumors.

Syndrome :Gonadal dysgenesis

A phenotypic female presents with primary amenorrhea. Pubic and axillary hair remain sparse and breasts are infantile (patient in question has mature breasts)

Stein Leventhal syndrome: Polycystic ovarian disease: Harrison 15^th / 2163

This is characterized by Hirsuitism (patient in question has no hiruitism) along with amenorrhea / oligomenorrhea, obesity and infertility.

Premature ovarian failure: Presents with secondary amenorrhea and not primary amenorrhea.

Answer is C (Testicular feminization syndrome):

Presence of well developed breast (tanner stage 4) with scanty axillary or pubic hair in a phenotypic ‘female’ with primary amenorrhea (? no uterus) suggests the diagnosis of Testicular feminization syndrome.

Answer is A (Occurrence of Turner’s syndrome is influenced by maternal age) :

Maternal age constitutes an important influence on the incidence of Down’s syndrome. Occurance of Turner’s syndrome is not affected by maternal age.

• Turner’s syndrome is the most common cause of primary amenorrhea. At puberty sexual maturation fails to occur and primary amenorrhea is common.
• Short stature is characteristic of Turner’s syndrome.
• Lymphoedema of the dorsum of hands and feet is also a characteristic finding in patients with Turner’s syndrome.

Ans. B i.e. Stein Leventhal syndrome