Scientific Programme

TUESDAY 23 JUNE 17.30 – 18.30

What does feminisation surgery entail?

Pierre Mouriquand

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Aims of surgery:
Restore functional genital anatomy to allow future penetrative intercourse,
Facilitate future reproduction,
Reduce urological hazards related to abnormal genito-urinary anatomy i.e. urinary tract infections with its potential upper urinary tracts consequences and urinary incontinence,
Reduce the risk of gonadal cancers,
Help construction of individual and social identities.
Avoid social stigmatisation.

The genital tubercle
Clitoral reduction consists of reducing the length of the genital tubercle whilst trying to preserve the nerves and vessels leading to the clitoris. A more precise description of the anatomy of these nerves in the late 90s allows a much finer dissection of the afferent fibres leading to the clitoris. Most techniques of clitoral reduction remove a variable segment of the corpora cavernosa. As this is an irreversible step of the procedure, some surgeons tried to preserve the full length of each corpus and bury them around the vaginal opening with the idea that they could be reused in the future should the patient choose the male gender. However, the procedure of reversion has not been reported to date.
Once the corpora cavernosa have been removed or displaced the clitoris is reattached to the corporeal stumps near the lower edge of the pelvis.
The skin shaft of the genital tubercle is split vertically to refashion the labia minora.
This is clearly delicate surgery. The potential damage on the clitoral sensitivity and the irreversible character of this procedure are the two main criticisms made. This is the reason why clitoral reduction should be restricted to significantly overgrown clitoris, knowing that in the CAH group, a well conducted substitutive hormonal treatment permits a significant reduction in size. Attempts to avoid this surgery with prenatal hormonal substitution (Dexamethasone) in the CAH group have been successfully reported as long as the treatment starts before week 6 of gestation although potential side effects of steroids on the foetus and the mother during gestation is the source of discussions.

The vaginal cavity
It is important de figure out what happens during the embryogenesis (5-10 WG) and more specifically during the delimitation process which divides and separate the cloacal cavity in three compartments – urological, genital and intestinal – which will be individually connected to the outside with a proper opening and sphincter. This cavitation and separation process fails in most DSD situations described before. The vagina which represents the mid compartment is said to come from two different embryonic structures: Mullerian ducts for its top two thirds and ectoderm for its bottom third. In the CAH group, the upper two thirds need to be connected to the pelvic floor and separated from the urological compartment wrongly called uro-genital sinus. In the 45,X0/46,XY DSD group, the retro-urethral cavity is narrower and more rigid than in the CAH group. When the female gender is chosen, this cavity also needs to be connected to the pelvic floor and separated from the urological path. In all other DSD groups, there is either no genital cavity (17βHSD) i.e. no mullerian structures or a vaginal cupule which probably represents the lower third of the vagina. The complete absence of genital tract implies the creation of a new vagina using various techniques (intestine, peritoneum etc …). The presence of a genital deep can be subjected to progressive dilatations allowing the creation of a full length neo-vagina. Current surgical techniques to connect the vagina to the pelvic floor and to separate it from the urethra are based on two types of procedures which can be combined: The “top-down” approach (Total or partial uro-genital sinus mobilization: TUM or PUM) consists of mobilizing downwards the urethral conduit up to the confluence with the vagina and connect both independently on the perineal surface using the urethral tissue sitting distal to the confluence. The “down –top” approach consists of creating a mucosal funnel (introitoplasty) between the perineal floor and the vaginal cavity using the urethral tissues sitting under the GT.

The gonads are an issue when the assigned gender is different from the gonadal sex mostly in the 46,XY DSD group, the 45,X0/46,XY DSD group and the ovo-testicular group and when there is a risk of tumour related to the testicular tissue.
Gonad (testis) can either be partially or totally removed, or brought down (orchidopexy), or simply watched with regular clinical examination, ultrasound scans or biopsies.
Gonadal preservation in the prepubertal testis, although possible, has not proved yet to be efficient for future fertility.
Tumour risk is very low before puberty although recent reports showed that gonadoblastomas have been identified early in life. This risk is particularly significant in dysplastic gonads and in any cases in all undescended testes.
The role of testicles after puberty in the bone maturation and the breast development in the complete androgen insensitivity syndrome is well acknowledged and the tumor risk is low in this group although probably equals to undescended testes.
The timing of gonadal removal is therefore a critical issue particularly in the DSD groups where pubertal virilisation is expected (17βHSD and 5α reductase deficits).

The external genitalia
Although DSD surgery has been restrictively considered by some as “cosmetic surgery”, the cosmetic aspect of genitalia is also an important issue for many patients. Perineoplasty and reconstruction of the genital tubercle are parts of the techniques mentioned above and play an important role in the patient’s satisfaction or dissatisfaction after DSD surgery.

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TUESDAY 23 JUNE 18.30 – 19.30

Central Precocious Puberty Management and long-term outcome?

Juliane Léger

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Precocious puberty (PP) is defined as the onset of clinical signs of puberty before age 8 years in girls and 9.5 years in boys. However, the onset of puberty may be subject to constitutional (genetics, ethnicity) environmental (secular trends, adoption, absence of the father and possible exposure to estrogenic endocrine-disrupting chemicals) and nutritional (body mass index) variations (1-3), with implications for the definition of precocious puberty. The signs of puberty include breast development in girls and testicular enlargement in boys (testicular volume greater than 4 ml or testicular length greater than 25 mm). Precocious puberty leads to the progressive development of secondary sexual characteristics, together with the development of pubic hair, and an acceleration of growth velocity and bone maturation, resulting in premature fusion of the growth plates, potentially responsible for adult height deficit. It may have consequences for growth and psychosocial development. PP may be caused by central or peripheral mechanisms (1). Central precocious puberty (CPP), which is much more common in girls than in boys (4), results from premature reactivation of the hypothalamo-pituitary-gonadal axis and pulsatile GnRH secretion, with a hormonal pattern similar to that of normal puberty. CPP may be due to hypothalamic lesions, but is idiopathic in most cases, particularly in girls (1). Recent studies have implicated the activation of Kisspeptin and its receptor, and the inactivation of Makorin ring finger 3 (MKRN3) genes in “idiopathic” CPP (5-6). MKRN3 is an imprinted gene located on the long arm of chromosome 15, with a potentially inhibitory effect on GnRH secretion. MKRN3 gene defects have been identified as a cause of paternally transmitted familial CPP, but such defects do not underlie maternally transmitted CPP and are rarely involved in sporadic forms. Premature sexual maturation is a frequent cause for referral. Clinical evaluation is generally sufficient to reassure the patients and their families, but premature sexual maturation may reveal severe conditions and thorough evaluation is therefore required to identify its cause and potential for progression, so that appropriate treatment can be proposed. If a non-progressive form of PP is suspected, it is recommended to wait a few months and then to reassess the patient, to avoid unnecessary treatment. The heterogeneity of CPP, in terms of its clinical presentation and definition, can be accounted for by the gradual nature of the transition to puberty. Indeed, in many girls with idiopathic CPP, puberty progresses very slowly, and may even be regressive, resulting in an unchanged predicted final stature and a normal adult height close to parental target height (7, 8). Therapeutic abstention is appropriate in most cases, because puberty progresses slowly, with the menarche occurring, on average, 5.5 years after the onset of clinical signs of puberty, and normal adult height relative to parental target height being reached. However, in some cases (about one third of subjects), final stature prognosis may worsen during the progression of puberty, in parallel with the emergence of evident biological signs of estrogenization. Clinical assessments should therefore be systematically carried out in children for whom no treatment is justified at the initial assessment, at least until the age of nine years, to identify girls subsequently requiring treatment to block precocious puberty (1, 8, 9). In both sexes, the central cause of precocious puberty is demonstrated by an increase in pituitary gonadotropin levels. Indeed, the mechanism of precocious puberty involves premature activation of the hypothalamic-pituitary-gonadal axis, with the initiation of pulsatile LH secretion and an increase in the secretion of pituitary gonadotropins, both in basal conditions and after stimulation with LHRH. Before the onset of puberty, the FSH peak is greater than the LH surge. During and after puberty, the LH surge predominates. In cases of central precocious puberty, basal serum LH concentration is usually ≥ 0.3 IU / L and LH concentration after stimulation is ≥ 5 IU / L (1, 10). Estrogenic impregnation is assessed on pelvic ultrasound scans, which may show an estrogenized appearance of the uterus (length ≥ 35 mm) (11). Central MRI focusing on the hypothalamic region is required in most cases of CPP (1, 12). Gonadotropin-releasing hormone agonists (GnRHa) are the standard treatment for progressive CPP (9, 12). Such treatment results in the regression or stabilization of pubertal symptoms, and decreases in growth velocity and bone age advancement. The factors affecting height outcome include initial patient characteristics and treatment duration. After the cessation of GnRHa therapy, generally at an age of about 11 years, biological and clinical signs of puberty reappear within months, with most girls achieving menarche, with menstrual ovulation cycles, during the following year (9, 13, 14). PP associated with the presence of a hypothalamic lesion may progress to gonadotropin deficiency. The available data indicate that long-term GnRHa treatment does not seem to cause or aggravate obesity or have repercussions for body composition, bone mineral density, fertility and metabolic or cancer comorbidities. General health status is not different as compared to women with normal puberty (14, 15). However, data concerning psychosocial outcomes are scarce (15, 16) and studies of this aspect are required.

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THURSDAY 25 JUNE 11.00 – 12.00

Anorexia nervosa in adolescence: psycho-social, clinical and therapeutic aspects

S Guillaume

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Anorexia nervosa (AN) is characterized by an intense fear of becoming fat despite an obvious thinness and extreme behaviors for weight loss, such as food restriction with or without self-induced vomiting or use of laxatives. The result is a massive weight loss and / or pathological thinness. The 12-month prevalence of AN among young females is approximately 0.4%. The presence of AN dramatically affects quality of life both of people with AN and their relatives, and people with eating disorders have particularly high utilization rate of health services. This results in high health care costs. AN is multifactorial disorder currently conceptualized as a biopsychosocial model. There is a strong genetic component, since the heritability is about 60%. These genetic factors are likely to predispose to vulnerability via endophenotype such as perfectionist traits, lack of cognitive flexibility, facilitating the secretion of opioids during fasting, disturbance of weight homeostasis leading to impossible to regain the lost weight, slowing gastric activity … These factors will be expressed in a specific environmental context and will lead to emergence of disorders, adolescence being a period of particular vulnerability. The main environmental factors favouring the emergence of disorders include the idealization of thinness and performance of our Western societies, a focused education on the ideal of thinness and food rigidity or the presence of trauma including early trauma. Management of AN is difficult and few treatments have shown efficacy. In accordance with French and international guidelines, cares are usually multidisciplinary. They aim to restore normal weight, a suitable and relaxed behavior with food, improve social and interpersonal relationships, as well as self-perception of patients. Despite these support, approximately one third of patients will not cure their disease. This creates an excess mortality in AN. Studies with follow-up over 10 years show that approximately 10% of patients die from the consequences of their disease (22). Thus AN is the psychiatric disorder with the highest mortality rates. From people who will cure, the recover process will take several months to years. During this lecture, I will particularly emphasize on 3 neuroendocrines issues regarding AN: 1) Until the last revision diagnostics criteria, one of necessary criteria for the diagnosis of AN was amenorrhea. Amenorrhea was removed as a diagnostic criterion for AN in DSM-5. The rationale for this including studies suggesting amenorrhea reflects nutritional state rather than illness severity and that this requirement is irrelevant diagnosis in men and for females Taking oral contraceptives will be reviewed. 2) Starvation is known to induce disturbances in neuromodulators, neuropeptides and peripheral peptides involved in the regulation of feeding behavior and energy homeostasis. However, even if such changes are secondary phenomena that disappear with weight regain, recent evidence suggests that they can contribute to the maintenance of aberrant eating behavior but also to central features of anorexia as hyperactivity. Also in healthy subjects and in animals, these modulators of appetite also impact the rewarding aspects, not homeostatic emotional and cognitive food intake. The impact of these different modulator appetite on the neurobiology of AN will be addressed using the example of leptin. 3) It is now well established that patients suffering from AN exhibit impaired bone remodeling, which is characterized by a decrease in bone formation and a concomitant increase in bone resorption? Adolescence is a key period for the acquisition of bone mass with nearly 95% is already acquired in a 15 years old girls. Thus, the earliest is the age of disease onset, the more severe bone deficit is with an increased incidence of fractures in adolescent patients. To date, there is no consensus on the management of bone loss in patients with AN, even if it appears that the weight restoration is considered the prerequisite for an increase in long-term bone mass. The pharmacological approaches published or currently under consideration will be developed.

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THURSDAY 25 JUNE 15:30 – 16:30

Abnormal menstrual bleeding for quantity and/or duration during pubertal maturation in adolescence

G. Creatsas

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Menstrual disorders is a common problem in young girls during the first two gynecological years. Amenorrhea, oligomenorrhea and dysfunctional uterine bleeding (DUB) are the most common conditions related to abnormal menstrual bleeding. Amenorrhea may be due to anatomical anomalies or endocrinological problems. Oligomenorrhea is related to the polycystic ovarian syndrome. Abnormal uterine bleeding (AUB) is usually due to organic causes, while dysfunctional uterine bleeding (DUB) is a painless, excessive and irregular bleeding not attributable to any structural or systemic disease. In about 95% of the cases, DUB is due to the late maturation of the hypothalamic- pituitary- ovarian axis. The pathophysiology of the disease is related to the lack of maturation of the positive feed back, which results in excess estrogen secretion, abnormal endometrial hyperplasia and profused bleeding. The disease is classified as mild, moderate or sever. In mild and moderate DUB cases the use of combined oral contraceptives (COCs) and especially the new generation 17β estradiol COCs or the cyclic use of progestagenic compounds are the treatment of choice. Severe cases need hospitalization. All cases should be treated by experts, in Pediatric and Adolescent Gynecological Centers, also taking care for any psychological problems of the girl and considering their future fertility. In this presentation, we also include five cases of young girls with abnormal menstrual.

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TUESDAY 23 JUNE 17.30 – 18.30

Delayed Puberty – Impact on Fertility

Martin H. Birkhaeuser, MD

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In Europe, mean age at menarche is 13.4 years (SD 1.1). It ranges from 11.2 to 15.6 years (-2SD to +2DS). According to the two most used definitions of delayed puberty (=pubertas tarda), the spontaneous onset of puberty occurs in this condition – More than two standard deviations later than the normal mean age of onset of puberty, – Or, alternatively, later than the 97th percentiles for the Tanner stage in question. In gynaecological endocrinology, the usual definition corresponds for practical reasons to the absence of onset of puberty until the age of 16. Delayed puberty is a rare condition, occurring in only approximately 2.5% of the population. Further diagnostic evaluation should be done if puberty does not start up to the age of 14.5 years (mean + 3 standard deviations). The major differential diagnosis is constitutional delay of growth and puberty. In this case, a normal fertility can be expected. The incidence of non-constitutional pubertal anomalies is 31% for hypogonadotropic hypogonadismus (including functional hypothalamic causes), 43% for hypergona-dotropic hypogonadismus and 26% for eugonadotropic hypogonadism. In hypothalamic as well as in hypophyseal hypogonadotropic hypogonadism, the gonads are usually normal and follicular maturation can be successfully induced Fertility in later life is therefore possible. Hypergonadotropic hypogonadismus present before or at puberty is mostly linked to congenital agenesis or dysgenesis of the ovaries with or without an abnormal karyotipe. In these cases, later fertility has been reported only exceptionally, e.g., in Turner mosaicism. If the eugonadotropic forms are linked to an anatomical malformation, such as a Rokitansky-Kuster-Hauser-Syndrome, later fertility depends on the operability of the malformation. If the uterus is missing, but eggs can be obtained, fertility is possible through a foster mother. However, this possibility is illegal in many countries. Other eugonadotropic forms, e.g. testicular feminization are compulsory infertile. In summary, delayed puberty is a rare and highly heterogeneous condition. Fertility in later life depends on its aetiology. Precise diagnostic work-up is therefore essential to be able to inform the affected girl and its parents about her fertility in later life.

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FRIDAY 26 JUNE 09.30 – 10.30

Mullerian duct abnormalities: the Mayer- Rokitansky syndrome and its surgical management, reconstruction of vagina aplasia in young women

G. Creatsas

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Mullerian anomalies with obstruction are usually found during adolescence. Diagnosis is difficult, since the vagina is narrow or absent and most girls have not yet started sexual relationships. Primary amenorrhea, dysmenorrhea, as well as a pelvic inflammatory disease or/and purulent discharge are the prominent symptoms. We have reported 22 cases of Mullerian anomalies with obstruction during adolescence and their reproductive outcome. Patients with this kind of uterine anomalies are oftenly diagnosed during adolescence due to the periodic pelvic. Uterine or vaginal masses may be due to hematocolpos or/and hematometra. Primary amenorrhea may also found if the normal vaginal canal is suppressed by a contralateral hematocolpos, in cases of a complete vaginal septum. The clinical history, the gynecological examination, the magnetic resonance imaging and the laparoscopy confirm the diagnosis. Hysteroscopy may be also needed to explore the anatomy of the uterine cavity. The urinary tract system should be checked in all cases for coexisted congenital anomalies. Vaginal aplasia is also diagnosed during adolescence. Primary amenorrhea is the prominent symptom due to the absence of the uterus, in cases of the Mayer Rokitansky Kunster Hauser (MRKH) syndrome. We have treated 240 cases with MRKH syndrome following our technique (Creatsas vaginoplasty) with mean operation time 28 minutes and a satisfied sexual life up to 94.5%. The management depends on the type of the lesion and includes surgical procedures as: the opening of the genital canal, reconstruction of the genital anomalies or/and the Creatsas vaginoplasty.

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SATURDAY 27 JUNE 12.00 – 13.00

Pregnancy in Adolescents

Joseph G. Schenker MD

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Teenage pregnancy have been problem for many years. Several issues are associated with teenage pregnancy: social, economic, cultural, educational and political. About 16 million girls aged 15 to 19 and some 1 million girls under 15 give birth every year—most in low- and middle-income countries. The 2014 -WHO Statistics indicate that the average global birth rate among 15 to 19 year olds is 49 per 1000 girls. Complications during pregnancy and childbirth are the second cause of death for 15-19 year-old girls globally. Every year, some 3 million girls aged 15 to 19 undergo unsafe abortions. Babies born to adolescent mothers face a substantially higher risk of dying than those born to women aged 20 to 24. Adolescent pregnancy remains a major contributor to maternal and child mortality, and to the cycle of ill-health and poverty. The causes are several: Some girls do not know how to avoid getting pregnant. Sex education is lacking in many countries. They may feel too inhibited or ashamed to seek contraception services. Contraceptives may be too expensive or not widely or legally available. Even when contraceptives are widely available, sexually active adolescent girls are less likely to use them than adults. Girls may be unable to refuse unwanted sex or resist coerced sex, which tends to be unprotected. Adolescent pregnancies are more likely in poor, uneducated and rural communities. In some countries, becoming pregnant outside marriage is not uncommon. The highest rate of teenage pregnancy in the world -143 per 1,000 girls aged 15–19 years is in sub-Saharan Africa. Women in Africa, in general, get married at much earlier ages than women elsewhere leading to earlier pregnancies. In sub-Saharan Africa, more than one in six teenage girls between the ages of 15 to 19 gave birth annually. The world data showed that teen pregnancy rates have fallen especially in Europe and USA among all racial and ethnic groups.. Successful reduction in teenage pregnancy is achieved where an open, tolerant, pragmatic attitude to sexuality is adopted with effective programmers of sex education and confidential contraceptive advice. The evidence clearly indicates that more and better contraceptive use has been the main factor driving the long-term decline in teen pregnancy. Adolescent pregnancy is associated with higher rates of illness and death for both the mother and infant. Unintended pregnancies can have serious negative health consequences for teens and babies. Teenage girls have a higher risk of pregnancy complications and are less likely to obtain prenatal care. Pregnant teens are at much higher risk of having serious medical complications such as: Placenta previa, pregnancy-induced hypertension , premature delivery, anemia and toxemia. Infants born to teens are 2 – 6 times more likely to have low birth weight than those born to mothers age 20 or older. Prematurity plays the greatest role in low birth weight, but intrauterine growth retardation is also a factor. Teen mothers are more likely to have unhealthy habits that place the infant at greater risk for inadequate growth, infection, or chemical dependence. The younger a mother is below age 20, the greater the risk of her infant dying during the first year of life. The more widely used contraceptive methods such as the birth control pill, condoms and the diaphragm, have one big problem: The rates of adolescent who continue to use them after starting are low. In many countries contraceptive advice or treatment can be provided to a competent young person aged under 16 years, without parental consent or knowledge. The condition is that teenage could understand the advice. The combined oral contraceptive pill effectiveness depends upon taking the pill as instructed. Teenagers are particularly at risk because of missed pills. The rates of women who continue to use them after starting are low Long-acting, reversible contraceptive (LARC) methods, which include intrauterine devices (IUDs) and implants, have been shown to be acceptable to teens with higher continuation rates than shorter-acting methods. Intrauterine devices are safe to use among adolescents, may be inserted without technical difficulty, expulsion is uncommon in most adolescents. Adolescents should be routinely screened for STIs at the time of IUD insertion. Emergency contraception is an important tool for helping adolescents prevent pregnancy after they have had sex without contraception or experienced sexual assault. In some countries Emergency Contraception which is Safe for Over-the-Counter Sale to females without limitation of age. Unnecessary age restrictions, including requiring prescriptions for adolescents women merely result in more unintended pregnancies and more abortions, and endanger the health of more young people. Compared to older women, the adolescent decision to have an abortion is more likely to be pressured by parents, peer group, or sexual partner and is therefore more difficult and hazardous. Surgical and medical methods of abortion are applied. Emotional effects following abortion are more common and include: Regret, guilt or shame, anger, depression and anxiety, sleep problem, eating disorders and suicidal thoughts

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