Puberty - it starts in utero

Aromatase is active in the brain, even as it is being formed.

Previously, I wrote a newsletter describing the role of aromatase in maintaining primate pregnancy:

Azole antifungal aromatase inhibitors - verifications and updates

There, I reported on the research of Eugene Albrecht and his colleagues, which examined baboon reproduction function, following in utero exposure to aromatase inhibitors. When baby baboons developed in a uterine environment with suppressed estradiol levels, their puberty onset was delayed, menstrual cycles prolonged and hormone levels altered. But if the moms were given replacement estradiol, their offspring turned out normal. They proposed that fetal ovarian development and timely onset of puberty in the primate is programmed by fetal exposure to sufficient placental estrogen.

Mean maternal peripheral serum estradiol levels between Days 85 and 175 of gestation in baboons with a female fetus that were untreated or treated with letrozole (115 μg/kg BW/day; s.c.) or letrozole and estradiol benzoate (115 μg/kg BW/day and 50 μg increasing to 150 μg/kg BW/day, respectively; s.c.) on Days 100–175 of gestation (term = Day 184).

Age (mo) at onset of puberty in female baboons born to mothers untreated (n = 9) or treated in utero with letrozole (n = 5) or letrozole plus estradiol benzoate (n = 6). Black circles = baboons that were delivered spontaneously; gray circles = baboons that were delivered by Cesarean section. *Mean (± SE) age of puberty onset in letrozole-treated animals differs from that in animals untreated (P < 0.01) or treated with letrozole plus estrogen (P < 0.05; ANOVA and Student-Newman-Keuls multiple statistic). Bars = 95% confidence limits for the mean age to onset of puberty.

To understand why this happens, it is important to know that the intermittent or pulsatile release of gonadotropin-releasing hormone (GnRH) from the hypothalamus into the hypophysial portal circulation is necessary for driving gonadotropin secretion from the anterior pituitary; therefore it is crucial for gonadal development and maturation, puberty, and fertility in adulthood.

ED Albrecht, GJ Pepe laboratories

Aromatase in Mice Brains

So how does aromatase inhibition during fetal development lead to changes reproductive cycles years later at adolescence? The onset of puberty is associated with the increase in pulsatile frequency of gonadotropin-releasing hormone (GnRH) neurons. Delving further, we see that the pulses are generated by inputs from neurons releasing the peptide, kisspeptin. These neurons are actively secreting before humans and other mammals are born, but they then remain dormant until just before puberty. Interestingly, the kisspeptin neurons that are talking to GnRH neurons in the embryonic hypothalamus, already express steroid hormone receptors and thus, are likely to be influenced by gonadal steroids even at that early time/stage.

A recent paper describes fertility research in the murine experimental model. They teased out the embryonic brain components that lead to the male vs female pattern of GnRH secretion.

Simple schematic of the KNDy neuron model of the GnRH pulse generator. Small green and red filled circles indicate neurokinin B and dynorphin auto-synaptic release, respectively, within the arcuate nucleus. The temporal dynamics of the release of these two neuropeptides at this location are unknown. GnRH, gonadotropin-releasing hormone; MMB, mammillary body; OC, optic chiasm - Tony Plant ResearchGate

Whether neurosteroids are locally produced in the brain and impinge onto reproductive neural circuitry is insufficiently understood. To address this question, we analyzed aromatase expression, a key enzyme in estradiol synthesis, in mouse embryos and identified a network comprising ∼6000 neurons in the brain. By birth, this network has become sexually dimorphic in a cluster of aromatase neurons in the arcuate nucleus adjacent to kisspeptin neurons. We demonstrate that male aromatase neurons convert testosterone to estradiol to regulate kisspeptin neuron activity. - P Wartenberg et al.

Therefore, if a mother is exposed to aromatase inhibitors during the pregnancy and her placental-fetal estradiol levels fall, the neuronal circuitry controlling the reproductive hormone regulation in the fetus gets messed up. And this effect shows up at each developmental stage, throughout the subsequent whole life cycle of the progeny.

Whew. Talk about long term consequences …

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REFERENCES

GJ Pepe et al. Regulation of Baboon Fetal Ovarian Development by Placental Estrogen: Onset of Puberty Is Delayed in Offspring Deprived of Estrogen In Utero BIOLOGY OF REPRODUCTION (2013) 89(6):132, 1–8
https://europepmc.org/article/PMC/4076353

T Plant. The neurobiological mechanism underlying hypothalamic GnRH pulse generation: the role of kisspeptin neurons in the arcuate nucleus. https://www.researchgate.net/publication/339084273_The_neurobiological_mechanism_underlying_hypothalamic_GnRH_pulse_generation_the_role_of_kisspeptin_neurons_in_the_arcuate_nucleus

Locally produced neurosteroids regulate the emerging reproductive neural circuitry in the embryonic mouse brain (2021, October 14). https://medicalxpress.com/news/2021-10-locally-neurosteroids-emerging-reproductive-neural.html

P Wartenberg et al. Sexually dimorphic neurosteroid synthesis regulates neuronal activity in the murine brain. Journal of Neuroscience 24 September 2021, JN-RM-0885-21; DOI: https://doi.org/10.1523/JNEUROSCI.0885-21.2021

D Kumar et al. Murine Arcuate Nucleus Kisspeptin Neurons Communicate
with GnRH Neurons In Utero . https://www.jneurosci.org/content/jneuro/34/10/3756.full.pdf

"Azole Aromatase Inhibitors and their Clinical Implications" https://www.researchgate.net/publication/308312438_Azole_Aromatase_Inhibitors_and_their_Clinical_Implications

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