1. (a) T (b) F (c) T (d) F (e) T

Streptococcus pyogenes typically lives in the throat or on the skin. The possibility of asymptomatic pharyngeal colonization has been amply demonstrated. The possibility of rectal colonization is not an explanation for resistance to penicillin derivatives. Failure of treatment with penicillin is generally attributed to other local commensal organisms producing β-lactamase. The use of parenteral ceftriaxone is indicated for the eradication of Gonococcus infection in older girls. In children the use of oral drugs is preferable. The use of a topical antibiotic is correct, but can be limited by the difficulty for the mother in inserting a cannula or catheter beyond the hymen. The age and the genital conformation of the girl are significant variables for this choice.

2. (a) F (b) F (c)T (d) T (e) T

Infection with HPV virus, especially in very young children, is not a definite indicator of sexual abuse; consequently it is better to collect data about this before speaking openly of the possibility. The fact that most abuse takes place inside the family should also be borne in mind. Obtaining information from a very young child about such matters is extremely difficult: non-leading questions and techniques that are appropriately geared to the child’s level of development and language are called for. In the case of grounded suspicions, it is recommended to apply to specially-qualified child abuse professionals, even for assistance in any possible legal proceedings. More information about family organization can be helpful and should be registered in the medical records. The possibility of a vertical transmission at delivery is high, as well as involuntary inoculation via finger skin warts. We have to consider the possibility of a long period of incubation in the child and phases of latency of manifestations in the mother. Considering the high site-specificity of adult HPV infections, the possibility that HPV typing may assist in the diagnosis of warts related to genital-genital abuse in children is undoubtedly interesting. Unfortunately, the published studies on this topic are to date inconclusive, due to the poor quality of data. While awaiting further evidence-based information, HPV typing can be important in assessing the correspondence of the viral types in the child and in the mother or the suspected offender.

3. (a) T (b) F (c) F (d) T (e) F

In all the above conditions the testes produce normal amounts of Testosterone. In 5α reductase deficiency, Testosterone is not reduced into the more potent androgen Dihydrotestosterone, not CAIS where the problem lies in lack of sensitivity of the testosterone receptor. There is no increased risk of malignancy in 5α reductase deficiency. In puberty, virilisation can occur, possibly because of the presence of other isoforms of the 5α reductase enzyme that convert the increasing amounts of Testosterone.

4. (a) F (b) F (c)T (d) T (e) F

The correct answers are c and d. In both conditions the testes produce normal amounts of Testosterone. In 5α reductase deficiency, Testosterone is not reduced into the more potent androgen Dihydrotestosterone, which is responsible for the virilisation of the external genitalia in utero. However, in puberty, virilisation can occur, possibly because of the presence of other isoforms of the 5α reductase enzyme that convert the increasing amounts of Testosterone. Similarly, in PAIS, the androgen receptor retains some activity, and therefore virilisation can occur in puberty. In Frasier syndrome and Swyer syndrome, it is essential to perform a gonadectomy early, as soon as the diagnosis of the condition is made, because of the increased risk of malignancy. In CAIS, there is a small risk of malignancy, in the range of 2-5%, similar to that seen in cryptoorchidism. There is no risk of virilisation.

5. (a) T (b) T (c) F (d) F (e) T

6. (a) T (b) F (c) T (d) F (e) F

HDT in hypogonadism is essential for longitudinal growth of girls, female reproductive system function, bone and lipid metabolism and the immune, central nervous and cardiovascular system. It therefore must be applied in absolute estrogen deficiency states or all of these things will be adversely affected. HDT is required during all reproductive life (and possibly lifelong) and needs increasing doses on an individual basis due to large inter-individual variation in requirements. HDT may be started with estrogens only, the need for progestagens depending upon the age of the patient. In contrast, the aim of menopausal replacement therapy in elderly women is treating negative effects of physiological loss of estrogens as hot flush, lack of well-being and osteoporosis.

7. (a) T (b) F (c) T (d) T (e) F

The maintenance of appropriate stages of sexual development and prevention of osteoporosis and cardiovascular disease in later life are the prime goals of long term HDT. Data on long term risks of HDT is very sparse so if a patient requests cessation then it should be stopped on an individual basis. A pseudo-menopause is well recognised after stopping long term HDT with menopausal symptoms commonly reported. This is more common the younger the woman is. Long term HDT in relative estrogen deficiency states is much more controversial and may well not be necessary in women with relatively mild deficiency. Data is lacking.

8. (a) T (b) T (c) T (d) F (e) F

Clinical hyperandrogenism primarily includes hirsutism, acne and male-pattern alopecia. Hirsutism is defined in females as male-type terminal hair growth and distribution. PCOS is a common cause of hirsutism; about 60-80% of women with PCOS have hirsutism. The clinical signs of androgen excess result from the increased exposure to dihydrotestosterone, synthesised in the skin from circulating androgens and affecting hair follicles.Other features of hyperandrogenism include virilisation, which, especially if present as clitoromegaly and rapid in onset, requires exclusion of other causes, including adrenal or ovarian androgen-secreting tumours.Vaginal aplasia is commonly associated with the Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome which is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. Androgens normally have anabolic effect on muscles.

9. (a) T (b) T (c) T (d) F (e) T

According to Genazzani et al, Functional Hypothalamic Amenorrhea (FHA) is defined as a non-organic and reversible disorder in which impairment of GnRH secretion plays an important role. The spectrum of GnRH and LH secretion disturbances is very broad and includes lower mean frequency of LH pulses, complete absence of LH pulsatility, normal-appearing secretion pattern and higher mean frequency of LH pulses. The three main types of FHA are: stress-related FHA, weight loss-related FHA and exercise-related FHA.The exact pathophysiologic mechanisms that lead from the above mentioned disorders to the dysregulation of the pulsativity of GnRH secretion still remain unclear, although it is known, that numerous neurosteroids and neuropeptides -like allopregnanolone, neuropeptide-Y, leptin and ghrelin- play a significant role in GnRH secretion regulation. Streak gonads or gonadal dysgenesis generally refers to a condition where gonadal development is abnormal, often only presenting streaks of connective tissue. The condition may be due to Turner syndrome and its variations (i.e. mosaicism), XX gonadal dysgenesis with 46XX patients, Swyer syndrome with 46 XY patients and Perrault syndrome.

10. (a) T (b) T (c) F (d) F (e) T

Hyperprolactinaemia is a common condition in females, affecting about 1% and is associated with decreased estradiol concentrations (mainly due to GnRH suppression) and oligomenorrhea, or amenorrhea. The severity of the menstrual disorders is positively correlated with the prolactin levels. Hyperprolactinaemia occurs in about 15% of patients with secondary amenorrhea and in 2% of patients with oligomenorrhea. Galactorrhoea is a presenting complaint in about 30% of cases.

11. (a) T (b) T (c) F (d) T (e) T

Type II autoimmune polyglandular syndrome is characterized by adrenal insufficiency, autoimmune thyroid disease, type I diabetes mellitus and POF. Hyperprolactinemia is not a characteristic of this syndrome.

12. (a) T (b) T (c) F (d) F (e) F

Most current research suggests there is an intrinsic ovarian theca cell defect leading to androgen overproduction as well as an impaired hypothalamic-pituitary sensitivity to ovarian steroid feedback. Also the increased LH concentrations appear to result from the androgen-induced impairment of hypothalamic sensitivity to ovarian steroid feedback. GnRH production is generally normal.

13. (a) F (b) T (c) F (d) F (e) F

14. (a) F (b) T (c) T (d) F (e) F

The risk of developing PCOS appears to be higher in girls with exaggerated premature adrenarche and atypical central precocious pubarche. There is no convincing evidence in the other disorders

15. (a) T (b) T (c) T (d) F (e) T

Only IVF has not been specifically implicated in the pathogenesis of PCOS in epidemiological studies.

16. (a) T (b) F (c) F (d) T (e) F

Both high calorific content and high protein diets have been shown to be associated with worsening of the clinical and metabolic sequelae of PCOS.

17. (a) F (b) F (c) T (d) F (e) F

18. (a) F (b) F (c) T (d) F (e) F

Male pseudohermaphroditism is a condition of sex differentiation disorder. There is 46,XY–male genotype and female phenotype. The gonads are testes, but the genital ducts and/or external genitalia are incompletely masculinized. This syndrome is caused by a failure of the sequential process in embryonal development of the testis. In the presence of functioning testes the Müllerian ducts regress, while the mesonephric ducts and urogenital sinus differentiate into the internal and external male genitalia. Female pseudo-hermaphroditism is a condition that patients have 46 XX karyotype with normal ovaries and müllerian structures, but the external genitalia are virilized to a variable degree. The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. It affects at least 1 out of 4500 women. MRKH may be isolated (type I) but it is more frequently associated with renal, vertebral, and, to a lesser extent, auditory and cardiac defects (MRKH type II or MURCS association). The first sign of MRKH syndrome is primary amenorrhea in young women presenting otherwise with normal development of secondary sexual characteristics and normal external genitalia, with normal and functional ovaries, and karyotype 46, XX without visible chromosomal anomaly. The main symptom of McCune-Albright syndrome is premature puberty in girls. CNS tumors are not associated with vaginal aplasia.

19. (a) F (b) T (c) F (d) T (e) T

Male pseudohermaphroditism is classified to subtype according to etiological factors: (1) testicular unresponsiveness to hCG and LH; (2) defect in testosterone biosynthesis; (3) end-organ resistance to androgen; (4) defects in the intracellular metabolism of testosterone; (5) aberrations in testicular organogenesis; (6) defects in anti-Müllerian hormone.

20. (a) T (b) T (c) T (d) F (e) T

Female pseudo-hermaphroditism is a condition that patients have 46 XX karyotype with normal ovaries and müllerian structures, but the external genitalia are virilized to variable degree. The degree of genital ambiguity can range from enlargement of the clitoris or fusion of the posterior labia to a completely male appearance, depending on the timing of androgen production and the concentration of androgens in the fetal circulation. Virilization may be caused by excessive production of either fetal or maternal androgens. The common enzymes that are missing are 21-hydroxylase, 11-hydroxylase, and 3-hydroxysteroid dehydrogenase. All of these children are reared as females and should have normal fertility because they have normal internal genitalia (ovaries, vagina and uterus).

21. (a) F (b) F (c) T (d) T (e) T

McCune-Albright syndrome is a genetic disease that affects the bones and color (pigmentation) of the skin. The syndrome is caused by mutations in the GNAS1 gene. The abnormal gene is present in a fraction, but not all, of the patient’s cells (mosaicism). This disease is not inherited. It is caused by a new change (mutation) to the DNA that occurs in the womb while the baby is developing. This mutation is not passed on to any of the person’s children. The main symptom of McCune-Albright syndrome is premature puberty in girls. Menstruation may begin in early childhood, long before the breasts or pubic hair develop (which normally occur first). Puberty and menstrual bleeding may begin as early as 4 – 6 months in girls. Early sexual development may also occur in boys, but it is not as common as it is in girls. Other symptoms include: bone fractures, deformities of the bones in the face, gigantism, irregular, large patchy cafe-au-lait spots, especially on the back.

22. (a) T (b) T (c) F (d) F (e) T

The Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is characterized by congenital aplasia of the uterus and the upper part (2/3) of the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype.

23. (a) T (b) T (c) T (d) F (e) T

The Vecchietti procedure includes the placement of an acrylic olive in the introital dimple; the olive is dragged with sutures passing through the abdominal area (intra-.or exra-peritoneally) and secured to an apparatus located to the anterior abdominal wall. Traction from the inside elongates the dimple and, within a few days, the neovagina is formed. In the McIndoe operation, a mold covered with a full-, or a split-thickness skin graft is placed in a surgically created space between the patient’s rectum and urethra, in order to create a neovagina. With this technique the created neovagina is functional within 6 to 10 weeks, but the operation is associated with severe complications, like urethra, bladder or rectum injury, hemorrhage, severe postoperative infection and creation of fistulas. Moreover, the patient is obliged to use dilators postoperatively for about a year, even if she has regular sexual activity. Williams vaginoplasty uses a vulval flap to make a vaginal tube. Although this simple procedure does not damage the urethra or rectum, dilation is needed for a lengthy period, and the neovagina has a physiologically abnormal angle. Frank technique involves the use of dilators, progressively increasing in diameter and length, which are placed in the vaginal dimple by the patient herself and are held in place for 20 to 30 minutes, three times a day. In the Creatsas modification of the Williams vaginoplasty a flap of the perineal skin is used to create the neovagina.

24. (a) T (b) F (c) T (d) F (e) T

The possible presence of a rudimentary uterus with functional endometrium, in the Mayer-Rokitansky-Küster-Hauser syndrome, might give rise to a hematometra but it is not associated with the operation. There is no communication of the internal genitals with the exterior in the Mayer-Rokitansky-Küster-Hauser syndrome.

25. (a) T (b) T (c) F (d) F (e) T

Given the risk of ectopic pregnancy, along with the risk of retrograde menses, pain, and endometriosis, rudimentary uterine horns containing endometrium should be surgically removed. Cases of ruptured ectopic pregnancy in non-communicating horns have been reported. Pregnancy in these cases results from transperitoneal migration of sperm. Given the fibrous structure of the uterine septum, studies have shown that implantation rates may be jeopardized by the presence of the septum. Septoplasty should be discussed prior to infertility treatment. Patients with uterus didelphys do have the possibility of carrying a pregnancy past the point of viability. Strassman reunification is not the first step in the approach to patients with uterus didelphys, as this procedure has not been shown to optimize obstetric outcomes in most cases. The cervical portion of a uterine septum may be left in place at the time of septoplasty, although its removal often facilitates the procedure. Debate exists whether removal of the cervical portion of the septum may increase subsequent cervical incompetence during pregnancy. In most cases, resection of an obstructed uterine horn associated with endometriosis will bring about resolution of endometriosis, and should be a first-line therapy in the patient with pelvic pain with an associated mullerian anomaly who has not responded to conservative therapy.

26. (a) T (b) F (c) T (d) T (e) F

Abnormal uterine vasculature with compromised cervical blood flow has been posited as a possible cause of adverse obstetrics outcomes associated with mullerian anomalies. Patients with mullerian anomalies such as unicornuate uterus have a higher muscle to connective tissue ratio, and in fact have hypermuscular cervices with insufficient connective tissue. Operative deliveries are more common in patients with mullerian anomalies given the high rate of malpresentation, owing to a restricted uterine cavity. Preterm labor may be more common in mullerian anomaly patients given the diminished gestational capacity associated with incomplete uterine formation, though data is limited and of poor quality. Mullerian anomalies are associated with multifactorial inheritance patterns and are not commonly thought to be secondary to genetic mutations, although rarely cases within families have been described.

27. (a) F (b) T (c) T (d) T (e) T

Rudimentary horns which do not contain endometrium do not need to be removed as they do not pose a risk for ectopic pregnancy or endometriosis. Several configurations of unicornuate uterus have been identified. The rudimentary horn may or may not be connected to the body of the unicornuate uterus. Variation occurs in the presence of endometrial tissue and whether the two cavities are connected. Endometriosis is extremely common in obstructed rudimentary horns secondary to retrograde menses. Surgical correction of the obstructed anatomy often resolves the endometriosis depending on the extent of the patient’s disease. Transperitoneal migration of sperm has been well described. Ectopic pregnancy can and does occur in non-communicating rudimentary horns, and thus these horns should be removed if they are shown to contain functional endometrium. Laparoscopy remains the gold standard for definition of mullerian anatomy in cases of anomalies. While MRI and 3D ultrasound are useful diagnostic tools, laparoscopy is invaluable in cases in which conventional imaging strategies are inconclusive.

28. (a) T (b) F (c) T (d) T (e) F

Moderate physical activity can improve lean mass and consequently bone mineral density, only if the energetic balance is positive and the girl has a BMI in the normal range. Consequently, it is necessary to continue careful monitoring of nutritional intake and to check over time that physical exercise does not become a surrogate for weight control practice. Despite widespread use, there is little evidence of the positive effects of estro-progestins on bone health in girls with previous history of anorexia nervosa; moreover these subjects are generally not favorable to hormonal treatments for fear of the weight and body modifications induced by the drugs. Calcium supplements can be useful if the composition of the diet indicates a deficiency of dairy products, fish and vegetable oils. Watch out for the possibility that oral calcium formulations may aggravate gastro-intestinal symptoms, very frequent in the recovery phase. Bisphosphonates have a great affinity for bone tissue and remain in mineralized bone for several years. Based on animal data they are contraindicated in pregnancy (FDA category C pregnancy risk); consequently their use in young women prior to conception may pose a teratogenic risk.

29. (a) T (b) F (c)T (d) T (e) F

The possibility that traumatic lesions of the central nervous system affecting the hypothalamus-pituitary system can promote an increase in weight is well-documented. Various antiepilectic drugs may aggravate the problem, but not topiramate which generally induces weight loss. A period of sudden physical inactivity certainly contributes to a net reduction of energy expenditure, with consequent increase in weight. A genetic predisposition, probably associated with unhealthy family eating habits, acts as favorable background for being overweight. Diabetes insipidus is not strictly related to weight gain, although it is a possible indication of a transient post-traumatic hypopituitarism.

30. (a) F (b) F (c) T (d) T (e) F

This prevalence only exists in the African countries with highest adolescent fecundity rates, in the Occupied Territories of Palestine and in 5 countries in Eastern Europe.

In all the other countries, prevalence in use goes over 40%. There are 20 countries in 3 Regions that have averages of 43.2, 55.6, 55.8 and 57.2 of use and which belong to the groups of countries with lowest fecundity rates. Quantitative information shows that the greatest reductions can be seen in the less developed countries with a fall of 24% between 1995 and 2008. But, when separated by Regions, Europe and North America have the lowest reductions. The less developed countries of the African and Latin American region are the countries that have contributed most to this reduction.

The only exception to this relationship of lower adolescent fecundity to greater prevalence of contraceptive use are the 5 countries of the occupied Palestinian Territories and the 10 countries with the highest fecundity rate in Asia and the 5 Latin American countries with the lowest rates of adolescent fecundity. Political and cultural factors probably explain these differences, as is the case of the distribution of traditional ethnic groups of Peru and Haiti. In other cases, the legalisation of abortion must be an important factor, as is the case of Trinidad and Tobago. 78 countries in the 7 Regions classified in accordance with adolescent fecundity show a lower ratio of Adolescent Fecundity when there is a higher prevalence of use of contraceptives.