At around fifteen weeks into a pregnancy, curious mothers-to-be can go to a doctor’s office, be rubbed with a bit of lubricating jelly, and have an ultrasound. Sometimes during this process, technically known as a fetal anatomy survey, a technician will point out a teeny, tiny penis. But while this process has become a hallmark of early parenthood, it’s only now that scientists are beginning to understand how exactly this fetal penis forms.
An international team of scientists determined that proper development of the fetal penis doesn’t just require testosterone provided by the testes. There’s a second process of penis development that involves other hormones, which coincides with the known testes-based first.
The discovery announced this week brings forth a deeper understanding of the human body, and also stands to benefit the number of children born with congenital abnormalities.
“Our results demonstrate that masculinization of the male fetus depends not only on the testes, but on other tissues, especially the placenta,” the team announced in a statement released along the with study on Thursday. “They also suggest an explanation for why disorders of placenta insufficiency can lead to hypospadias and other abnormalities of growth of the male external genitalia.” (Hypospadias is a congenital disorder of the urethra and the second-most common birth abnormality of the male reproductive system. It’s estimated that about 5 out of ever 1,000 boys born a year have this condition)
Prior to this study, scientists identified this second process involved in penis development, but the details of how it actually worked have been unclear. That’s what this study focuses on: The team examined human fetal tissues collected from electively terminated fetuses, that ranged from 10 to 21 weeks of gestation. Using mass spectrometric tools, they measured levels of different steroids in fetal plasma and tissue, and analyzed gene expression levels of the enzymes involved in hormone synthesis
When testes release testosterone, the hormone is converged into a androgen sex steroid called DHT by the genital tubercle — DHT’s role here is to prompt the genital tubercle to become a penis instead of a female clitoris. This study determined that during that newly pinpointed second process, another steroid called androsterone is converted in DHT as well.
Because androsterone is made from progresterone, the scientists believe that the sources of the hormone is the placenta. Importantly, the placenta produces just two steroid hormones — one of which is progesterone. It’s job is to maintain the lining of the uterus during pregnancy.
Furthermore, the scientists determined that levels of androsterone are much higher in male fetuses and than female fetuses. While it remains unclear why there’s a sex difference, the team does not that the male genital tubercle appears to be able to convert both testosterone and androsterone into DHT — key because DHT plays a vital role in the development of the penis and the prostrate gland.
This is “evidence indicating that androsterone is the major backdoor androgen involved in human masculinization and that it is produced in nongonadal tissues.”
For a penis to grow, a fetus needs both its testes and the placenta, whose overall job is to maintain a healthy pregnancy.
Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway. The fetal testes are essential for canonical androgen production, but little is known about the synthesis of backdoor androgens, despite their known critical role in masculinization. In this study, we have measured plasma and tissue levels of endogenous steroids in second trimester human fetuses using multidimensional and high-resolution mass spectrometry. Results show that androsterone is the principal backdoor androgen in the male fetal circulation and that DHT is undetectable (<1 ng/mL), while in female fetuses, there are significantly lower levels of androsterone and testosterone. In the male, intermediates in the backdoor pathway are found primarily in the placenta and fetal liver, with significant androsterone levels also in the fetal adrenal. Backdoor intermediates, including androsterone, are only present at very low levels in the fetal testes. This is consistent with transcript levels of enzymes involved in the alternate pathway (steroid 5α-reductase type 1 [SRD5A1], aldo-keto reductase type 1C2 [AKR1C2], aldo-keto reductase type 1C4 [AKR1C4], cytochrome P450 17A1 [CYP17A1]), as measured by quantitative PCR (qPCR). These data identify androsterone as the predominant backdoor androgen in the human fetus and show that circulating levels are sex dependent, but also that there is little de novo synthesis in the testis. Instead, the data indicate that placental progesterone acts as substrate for synthesis of backdoor androgens, which occurs across several tissues. Masculinization of the human fetus depends, therefore, on testosterone and androsterone synthesis by both the fetal testes and nongonadal tissues, leading to DHT formation at the genital tubercle. Our findings also provide a solid basis to explain why placental insufficiency is associated with disorders of sex development in humans.