Many patients who consult with the team at the Endocrinology Department at the Hospital das Clínicas of the University of São Paulo’s School of Medicine (HC-FMUSP) have dramatic stories to tell. Due to hormonal imbalances occurring between the eighth and twelfth week of gestation, when sex is determined, many have lived as men although they are women – or vice versa. How a man or woman comes to be defined is not a simple matter. Most men have 44 body chromosomes and two different sex chromosomes (XY), but there are also men who have two identical sex chromosomes, XX. Most women have two identical X chromosomes, but there are also women who have two different sex chromosomes (XY), like men.
Working in this area since 1975, endocrinologist Berenice Bilharinho de Mendonça collected these stories as a researcher and established a reference center for diagnosis, treatment, surgery, and psychological support for patients with sexual development disorders, who are seen in clinics run by Elaine Frade Costa, Tania Bachega and Sorahia Domenice.
The 67-year-old physician changed her work routine in 2017. She now spends two afternoons a week in an office at the Institute of Advanced Studies (IEA) on USP’s campus in São Paulo with the goal of writing about genetically-linked sexual dysfunction to reach as many people as possible. Mendonça’s dream is to collaborate with creators of a television soap opera, the script for which she has already started to envision.
What are you going to be doing at IEA?
My plan is to write manuals to help guide health professionals, family members and even the children with atypical genitalia, who are neither completely male nor completely female owing to an error in their development. I am planning to write a book about sexual orientation for children with this problem and to visit different universities to discuss our experience on this topic. I am also going to use social media for this purpose. We need to learn how to normalize the handling of sexual development disorders, if nothing else because they are relatively common in the population. One in every 2500 live births involves a defect in external genitalia. My dream is to have a character – a child with atypical genitalia – on a television soap opera to reach a large audience and challenge the stigma associated with this by modeling a more natural approach to the problem, treating it like a heart or facial malformation, for example.
What kind of plot would the soap opera have?
One idea is to have a couple who have prenatal testing done to determine the baby’s sex, and they discover that he is XY. So, he’s a boy. Then the mother has an ultrasound and sees female genitalia. People who are completely androgen insensitive (these are male hormones), even though they have X and Y chromosomes, are women, and they have a completely female body, almost without body hair, since they have no male hormones. The only reason these women don’t menstruate is that they don’t have a uterus – during development, the testicles produce a hormone that turns the uterus inward — but they have a closed vagina, allowing for sexual activity after vaginal dilation. The program could portray the life of a woman in this situation, who can’t get pregnant but who can have a normal sexual relationship and adopt a child. In the 1988 Olympic Games, the Spanish runner Maria Patiño lost the medal she had won because at the time, athletes were given a karyotype test (chromosome set), and the result indicated that she was XY, like a man, even though she was a woman, feminine in every way, and derived no benefit from the male hormone testosterone. The medal was returned to her several years later.
One character on the current soap opera at 9 pm on TV Globo, A força do querer [The power of desire], is going to come out as transsexual. In March, a four-part series on Fantástico dealt with transgender people. And the GNT channel has a weekly show with stories of normal people who are trans. Although these are not the same scenarios you run into at work, does the fact that they deal with Disorders of Sexual Development (DSD) help to bring attention to sexual disorders in general, like those with a genetic basis?
This character in the soap opera, given the description, is a transsexual man, who was born and registered as a female but who identifies as a male since childhood. My research is related to genetic and organic changes related to sexual development. Transsexualism is considered a psychological DSD. I would like to see a character with atypical genitalia who is treated appropriately, a situation that the media rarely depicts.
What is life like for people with DSD?
In general, patients with DSD live normal lives, but they must deal with very specific types of situations. We once worked with a patient who was completely androgen-insensitive, but her karyotype was XY. She had already had her testicles removed, which in these cases don’t function and are internal, not external as in males. She had a normal relationship with her boyfriend, including sexual activity. She told her boyfriend that she could not have children because her uterus had not developed normally. But she didn’t say anything about her karyotype, which denotes a person’s set of chromosomes, because she was XY, while most women are XX. When they decided to live together, she decided to tell her boyfriend that she was XY, and he said that he couldn’t tell the difference. She is a woman, and testosterone has no effect. Some patients are terrified of their karyotype; one asked me to burn the result, as if that would change anything. The karyotype alone means absolutely nothing. Most men are 46,XY [44 autosomal chromosomes and two sex chromosomes, X and Y], and women are 46,XX. But one in 25,000 women is 46,XY and one in 25,000 men is 46,XX.
What is a male like when he is XX, with two sex chromosomes that are identical?
He has a penis, testicles, a scrotum and a phallic urethra – it’s all normal. But he also has gynecomastia, that is, he develops breast tissue during puberty, and he is infertile. One patient who was XX took five karyotype exams because he didn’t believe the results. The man asks himself how he could have a female karyotype if he’s a man. We have to change the language in these instances. I have a patient who is a young girl — 46,XX – who has ovaries, a uterus, and externally looks like a boy without testicles but with a phallic urethra. We changed her situation through reconstructive surgery of the female genitalia, and today she is a girl who is living normally.
How do you explain situations like these to parents?
Parents get clear about the situation when I show them a drawing of sexual development during gestation. What makes us a man or a woman, from the perspective of external genitalia, is the presence or absence of the masculine hormone, testosterone, which is converted into dihydrotestosterone in peripheral tissue, which in a male fetus will cause the internal genital folds to fuse and form the body of the urethra and the external genital fold, the scrotum. The genital tubercle becomes a clitoris in a female and the penis in a male. It is a physical and anatomical process that occurs between the eighth and twelfth week of gestation. If a woman is pregnant with a girl and produces or is given a higher than normal dose of the masculine hormone at this time, the girl will be born with masculine genitalia, which is the result of the androgens. To the contrary, if a male in utero takes in a lot of progesterone [a hormone found at higher levels in the female body] to prevent miscarriage, hypospadias may occur, which means that the urethral opening is on the underside of the penis. Progesterone competes with testosterone through the action of the enzyme 5-alpha reductase, which will lead to a decrease in the production of dihydrotestosterone, responsible for giving the external genitalia a masculine appearance. The result is that the urethra will open in the perineum, like a female urethra, or in the midsection of the penis. In all high-risk pregnancies, gynecologists give a lot of progesterone to prevent the loss of the fetus, which can cause hypospadias.
Do physicians still frequently misdiagnose these conditions?
Yes, and in many ways. Diagnostic errors, mistakes in behavior and guidelines for the parents. Poorly trained physicians try to get the information out quickly to alleviate the discomfort their ignorance generates, but often external appearance is not the best criterion to define a child’s sex. A child who seems very masculine tends to be considered a boy, even though he might not be. Another problem is that many health programs do not pay for the necessary exams, including the karyotyping of newborns although the law requires it. That is why I always guide students and colleagues in this way: “If you are not sure, do not take on the responsibility of assigning a sex to a newborn without running the required exams.” In addition to karyotyping, measuring hormone levels and conducting an ultrasound of the pelvic region to identify internal genitalia and gonads may be necessary to arrive at a precise determination of sex. Some doctors have already been sued for assigning the wrong sex to a newborn because a formal sex change involves a cost, you must start legal proceedings and go before a judge, in addition to causing emotional stress for the parents and the family. Doctors need to be honest if they are unsure and refer the parents to a specialized hospital. And this isn’t an issue only for the physician: the whole team must speak the same language: “This child was born with a change in sexual development. To determine the sex, we need to run a few tests. For now, we will use “baby” to address the child.” If someone asks for the child’s name, you can say the family is still deciding.
The term used today is atypical genitalia, but it seems that terminology for this situation has always been problematic.
That’s correct, because there is a lot of discrimination involved. It used to be that the term hermaphrodite or pseudo-hermaphrodite was used for children born with malformed genitals. These individuals are masculine or feminine, but their genitalia are neither completely male nor completely female owing to an error in development, just as there are people born with heart defects or other kinds of problems. Now we use the term ambiguous or atypical or different genitalia. For the questionnaires I use for parents here at the hospital, the most commonly used term is genital malformation.
What was it like to travel from Uberaba to São Paulo and choose the field of endocrinology?
Fascinating. I studied medicine at the Federal University of the Triângulo Mineiro, but I wanted to come to São Paulo because I thought that even though my school was good, it was too small. I wanted to learn more. I did my sixth year in São Paulo in 1972 at the State Hospital for Public Servants, and my residency at the Hospital das Clínicas at FMUSP. I chose endocrinology because I met Walter Bloise, a fantastic person and a physician specializing in pediatric endocrinology and thyroid issues who is 93 and still practicing. He had established a clinic to treat children with genital ambiguities. I was fascinated by the patient reports as well as the biochemistry itself, because the sex hormones are derived from cholesterol, but all it takes is exchanging one hydrogen for an oxygen for the function of a protein to change completely.
Forty years ago, how were tests conducted to arrive at a diagnosis?
When I was a resident, there was no hormone laboratory. We began to find a solution for this problem when Antonio Barros de Ulhôa Cintra, the first professor and for all intents and purposes the founder of endocrinology at this hospital [he was also the president of USP and president of FAPESP from 1961 to 1973], decided to set up a laboratory with Willian Nicolau. We started it in 1988, and today, we test for 56 hormones, and we run about 58,000 exams per month for all the hospital’s departments. We have two full professors in the department and in the area of endocrinology, Ana Claudia Latronico and I, and 10 sub-departments, each with its own team, and about 90 employees, professors, researchers, medical residents and post-docs.
How has your research evolved?
I did a master’s thesis on the thyroid and a doctorate on what was then known as masculine pseudo-hermaphroditism, both under the supervision of Bloise, with the doctorate co-supervised by Nicolau. Years later, in 1989 I attended a conference on sexual development disorders in Montpellier, France, and I realized that the only paper without molecular research was mine. I learned molecular biology in the lab of Antonio Carlos Bianco at the Institute of Biomedical Sciences at USP and the University of Glasgow, where I did a three-month internship. Professor Latronico, who was a postdoc at that time, went to the United States to do an internship in molecular biology at the National Institutes of Health (NIH). When she returned, we expanded the molecular biology laboratory with the support of FAPESP, which financed several research projects including our most recent thematic project on the topic, which led to the establishment of the Large-Scale Sequencing Laboratory at FMUSP (Sela). Today, we sequence panels for several genes and the whole exome with research on mutations in genes already or not yet associated with a cause of DSD, which helps a lot to diagnose and predict the evolution of illnesses and plan treatment and genetic counseling for patients. For the treatment of patients with atypical genitalia, we bring together all the teams–diagnosis, treatment, surgery and psychological support (see Pesquisa FAPESP Issues Nos. 90 and 170).
What are your group’s main scientific contributions?
We described the molecular defect of patients with atypical genitalia, some of whom have a clinical profile that differs from that described in the scientific literature. We participated in describing the first mutations in the coding genes for 5-alpha-reductase type 2 and 17-beta-hydroxysteroid dehydrogenase type 3, at the invitation of Jean Wilson of Southwestern University in Dallas in the United States. Jean Wilson helped me enormously with the work on DSD linked to a deficiency of 5-alpha-reductase type 2. We have also produced very solid work on the long-term evolution of patients with disorders of sexual development. The surgical results for genital reconstruction are improving every year, and the thesis of my student, surgeon Maria Helena Sircili, published in the Journal of Urology, demonstrates our good results. These people have a good quality of life, as we showed in two studies in 2015 published in the journal Clinical Endocrinology, conducted by Rita de Cássia Amaral, Marlene Inácio and other researchers in the group, involving 144 patients. This work also serves as a response to those who say that the sex should not be assigned to newborns with atypical genitalia until they are adults and that a third sex should be created so that they can make the choice themselves, since many adult patients are not satisfied with the sex attributed to them. Patients who defend this idea are generally XY and were raised as women in poorly run treatment programs, often with no psychological support, and they do not feel suited to the feminine sex. Our experience shows that all patients with atypical genitalia treated late in life would have preferred to have been treated in childhood, and a well-designed multidisciplinary approach to treatment produces a good quality-of-life outcome.