Day 1.
You take the first pill. Actually, you take the third pill, from the 28 tablet blistercard, because it is Tuesday.
The small peach tab contains 0.15 mcg levonorgestrel (a progestin) and 0.03 mg ethinyl estradiol (an estrogen). Most people would call this a birth control pill. You suppose in this application, that name is accidentally accurate. You are taking this pill as part of a IVF regimen — as the first step in a routine of drugs that aspires to end in a successful live birth. That is broadly a type of birth control, but it is not what people mean when they say birth control. You have taken this pill as that kind of birth control, in the past.
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It is 19 years ago. You walk into the health clinic at your college for your first pap smear and your first breast exam. You are afraid. It hurts, because everything hurt in those days. It’s awkward, because you do not know that you are supposed to draw the room’s curtain to cover yourself, and the flustered nurse sees you start to undress and pulls it with an exclamation of surprise. The nurse is kind but not polite. She asks, with motherly rudeness, whether you’d had “breast implants from Russia??” because you have large boobs and an ugly scar that spans the length of your chest. No, you say, I had a surgery when I was a child. Pectus excavatum surgery, you recite. You did not know that people got breast implants in Russia, or whether Russian cosmetic surgeons are worse at hiding scars. You know your surgeon was doing his best, and that he did excellently. The foot-long scar that splits your chest forever sits perfectly at the band of your bra, like he told you it would — although he didn’t say bra, he said bathing suit so a seven-year-old would understand. He was kind and polite. And he was right.
No one has ever seen this scar, except a handful of doctors, your parents, the class of first-graders you flashed it to when you went back to school after your surgery recovery, and now this nurse. Her shock is sort of like the shock that was on their faces. You had forgotten, for 10 years, that your body is shocking to people. You will now remember to warn all future breast examiners, clinical and otherwise, before you show them your self.
After that appointment, you felt a little hurt and a little sad, but you succeeded in achieving a prescription. You wanted a contraceptive, even though you weren’t having sex yet. You thought you might. And you thought it might be good for you, besides. You’ve been offered this pill before, but you decided not to take it, in the past.
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It is 21 years ago. You are staring into your blue-eye pediatrician; her face is neutral and neither kind or unkind. She is asking you questions she hasn’t asked before, because you are alone. It’s right that you’re alone, because if you are with your father she will not ask these questions. You should be asked these questions. It is right that you went in alone. You know this then, and you hold on the thought firmly, because you are nervous and feel alone.
She asks if you’re having sex. You are not having sex, and you say so. You know that the question she is asking is not about sex, exactly. You know she means are you having penetrative vaginal sex with a male partner who could get you pregnant. You are not doing that, so you say no. You are the founder of your school’s Gay-Straight-Alliance, so you know that “having sex” means a lot of things. She does not ask are you engaging in high-risk behavior and she does not ask are you touching the fluids of other people and she does not ask is anyone hurting you or touching you in ways that make you uncomfortable and she does not ask are you okay.
She asks if you’re menstruating. You hesitate—you think you are. At 16 almost 17, you have menstruated twice for sure. You do not know that brown spotting counts and you have only seen red blood twice in your life. You know that you are not normal, because every single person in your life who menstruates did it before you. You know that your red blood happens sometimes, but it is not 28 days between—it’s 40, or 60, or 70—long enough that you forget it’s ever going to happen, and you never have a pad. You have forgotten by then that you are a person who menstruates and you are reminded every time in surprise. You are not very organized.
You summarize this, and she writes something down. Maybe she writes amenorrhea or dysmenorrhea or maybe she just writes irregular periods. You are a borderline case, so she does not diagnose you. The modern criterion for primary amenorrhea is no menstrual period by age 15 or 16. You would have met that criterion last year, but this year you do not. She is balancing risks in her mind: because you have bled, you probably do not have a genetic or chromosomal disorder or a structural issue of the reproductive tract. Because you have developed breasts and body hair, you probably do not have severe hormone disorder requiring urgent treatment. She does not screen you for endocrine disorder. Fifteen years later, an endocrinologist will take your history and shake his head. He’ll diagnose you with polycystic ovarian syndrome, and say anyone who started menstruating that late and that irregular is an obvious diagnosis. Nineteen years later, a gynecologist will take your blood and prescribe a medication for hypothyroidism. Twenty years later, a radiologist will review your brain scan and pass your pituitary as normal. Twenty years later, a genetic counselor will call you and report good news, only minor findings, a small detail.
The blue-eyed doctor does not do these things, but she is not negligent. If she had done tests, taken blood, done scans, and diagnosed me, she would have offered me a hormone-regulating pill. This peach pill.
She skips straight to it. She offers the pill. She says—do you want to start birth control pills? It might make your periods more regular. Lots of people take them to make their hormones normal, even if they aren’t having sex and don’t need birth control. I can explain to your father that it’s for hormonal reasons.
You understand what she says, and you understand that she is being careful and complete, trying to think through your situation, and help you. Your parents will not care or react negatively like the doctor is afraid of. You spare a second of pity for people whose parents would. You’ve met people like that, who hate the idea of this pill so much that they would rather not give their daughters treatment for medical conditions.
You think about it for a second, but only just a second. You do not want more regular periods. More regular periods means more periods, and periods suck. You hate bleeding, and you hate buying pads. If you could do it less, because your body is reluctant: that’s great. You decline the pill, for now.
It’s been a long appointment. She’s given you a lot of time. But you’ve covered topics that are so personal, so intense—you think. Well. Might as well ask.
There’s one thing. I cry all the time. That’s how you say it. You don’t say what you practiced, about depression. You freeze up. Her eyes are blue.
She turns back from finishing her charting, looks at you. She is trying to evaluate what this means. She asks if you think about hurting yourself, killing yourself. You lie. You say no, no. I’m fine. I just cry all the time. In the shower. At every movie. Every day. You do not say, I cry because I cannot bear the pain of getting out of the shower and being a person again. You do not say, every movie has people, and the people are human, and the human condition is so sad. You do not say, I would do anything to relieve this feeling, anything.
She tells you emotional swings are very normal when you are menstruating for the first time, and they will get better. She makes some other suggestions, that you don’t remember, because your brain has already turned off. You know that whatever is in you is not normal. It cannot be normal. Everyone would be dead.
You have no memory of leaving that appointment, or what you said to anyone about it.
But you do remember, a few years later, in college. That birth control pills might fix you. So you take them.
You are not afraid of them. You have researched them before.
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It is 24 years ago. You are a child, arguing with a man on the internet, about this pill.
You are in a children’s book fan forum, the Dancing Lawn, for fans of the Narnia books. This was the first forum you signed up for to talk to strangers, except for Neopets. The Harry Potter forums felt too big, too many strangers. You picked a children’s book that felt smaller, safer. Everyone on this forum is nice.
This thread is about women, but the poster you are talking to is a man. The man you are arguing with has said that birth control pills should be banned because they are chemical pollutants. You feel he is wrong, but that he is arguing in good faith. He has linked an article about the estrogenicity of waterways and fish feminization. He has said that birth control is not a medical necessity, and the environmental damage is rea. He is polite, and does not speak cruelly. His language is careful, meticulous, multisyllabic, and you think he is intelligent but he has misunderstood the article. You research, you compose, you edit, you post.
You fail to convince him that women are more important than fish. You fail to convince him that lots of medications pollute waterways, so why ban this one. You fail to convince him that the risk of exposure to synthetic estrogens in drinking water on human health is negligible. You fail to convince him that oral contraceptives are far less significant to estrogenicity of the water supply than livestock and plant sources. You fail to convince him that estrogen is a medical necessity for treatment of many people with hormonal dysfunction. You don’t know yet that you’re a person with hormonal dysfunction.
He parries your arguments. He is polite, and wrong. You don’t understand why he is not getting it. You percolate on the debate for a long time, not because it angers you, but because you can’t figure out how to make him see.
You see now. You were a child then, and you are an adult now. He was an adult then, but he was like a child. He heard someone say — the water is poison, it will make you like a woman — and he was afraid. So he wrote a calm measured message in a forum for children’s books that the government should listen to him, and arrange the world around his fear, so that he would not be scared, no matter the consequences to anyone else.
At the time, you thought he could be reasoned with, you thought you could learn the adult art of argument by convincing him of your humanity. Now you have known men, and you know: nah. He was just a fearful child and to him, you will never be as human as the imaginary fish he fears are gay.
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Levonorgestrel is a synthetic progestogen medication that resembles the shape of the endogenous (naturally-occuring) steroid hormone progesterone. All bodies make steroids, and all bodies male and female make progesterone—except rare case of enzyme deficiencies that mess with hormone production.
All steroid hormones in the body come from cholesterol, whose four little rings of carbon-hydrogen are fat-ish. They are not fat, but they are fatty enough. Fatty hormones can slip through the fat wall of your cells without a carrier. They head to the cell’s center, the nucleus, and bind receptors to turn genes on and off. Your DNA is not your destiny. In a million cells, in a million moments, your DNA is getting switched on and off.
There are several switches: a switch for salt (the mineralocorticoid receptor MR) a switch for sugar (the glucocorticoid receptor GR) and three switches for sex (the estrogen receptor ER, the androgen receptor AR, the progestogen receptor PR). All human bodies have and use all the switches, to tune the DNA in different organs at different times. In childhood, in puberty, in adulthood, in sickness, in health. All of them.
Image from Saha S, Dey S and Nath S (2021) Steroid Hormone Receptors: Links With Cell Cycle Machinery and Breast Cancer Progression. Front. Oncol. 11:620214. doi: 10.3389/fonc.2021.620214
The molecules that flip the switches are hormones. They all look the same, more or less. They are made by enzymes: machines that change cholesterol just a little bit. Add an atom here, bite off a piece there. An assembly line of changes takes place in your cells, all the time, to manufacture these different switch-flippers.
Progesterone is a hormone in its own right, but it is also a step along the path to make other hormones. Every switch-flipper of MR, PR, ER, GR, AR -- the hormones that manage your stress response, your blood pressure, your immune system, your masculinization or feminization -- they all started as a progestogen, probably progesterone. f you find progesterone in the chart below, you’ll see he sits in the yellow, in the middle of it all. He's a precursor to testosterone, to DHT, to estrogens, to cortisol, to aldosterone. Your body can use its enzyme machines to make it into a switch-flippers for salt, for sugar, for fat, for feminization, for masculinization. There are several enzymes below: like the green box that says 21-hydroxylase, which turns progesterone into deoxycorticosterone.
Manufacturing of the switch-flippers happens all over the body, but the home base is the adrenal gland. A tiny triangular hat that sits on top of your kidneys, the adrenal gland is the steroid hormone factory. Before the sex organs are formed, the adrenal gland does it all. Before puberty, it runs the show.
Once the testes, ovaries, breasts are online, some final steps of manufacturing moves locally: to produce high concentrations of certain switch-flippers only where they’re needed. Fat cells around your body in general also have the power to do local production; this is one reason why athletes and children with low body fat percentage often have dysmenorrhea or amenorrhea.
But back to progesterone. If you are building a body, with an assembly line for a dozen steroid hormones, it’s nice to have them all interchangeable, switching out parts as needed. If you are building a medication that people will take and get predictable results: this diversity of outcomes is not so good. We don’t want to give a pill and have it make some people more fertile, some people more masculine, some people crave salt and some people suppress immunity. We want it to work in one way, if possible (on-target effect) and minimize side effects. Ideally, it would flip only one switch, the PR switch, and not touch any of MR, GR, ER, AR at all.
Levonorgestrel is usefully close. It is a strong agonist of the progesterone receptor: it switches the PR switch well. It does not switch the ER, GR, or MR switches at all, though it does touch them. It has weak androgenic activity: every now and then it switches the AR switch a bit. In levonorgestrel’s defense — it was patented in 1960. It’s been around a long time. Newer progestins don’t switch AR even a little, but levonorgestrel is pretty good. When paired with ethinylestradiol, it works, because ethinylestradiol is anti-androgenic. It turns off the AR switches that levonorgestrel just turned on. So the overall change is nil. A well-formulated medication that has stood the test of time, if what you need to do to make a person healthy is to switch on their PR switches.
Why switch on a progesterone receptor? What does it do? SO MANY THINGS. In the brain, bone, breast, pancreas, penis, testes, ovaries, uterus. There are hundreds of things it does that we know, and many we don’t know. So here we need to narrow. Why am I taking this pill? What is the on-target function, during the early phase of IVF?
Controlling the PR receptor grabs hold of the ovarian cycle (and the menstrual cycle, and the uterine cycle). The timing of egg production is governed by a half-dozen hormones rising and falling: LH and FSH from the pituitary, GnRH from the hypothalamus, estradiol and progesterone. Failures in any of these, or aberrations, can cause infertility. It might be possible to figure out which one is causing the problem, but the standard regimen of IVF (after ruling out physical issues or other hormones) takes on the task like so: if there’s a fault in some hormone’s natural production, fine, we’ll just control all the hormones to work how we want, this one time.
So instead of peeing on ovulation indicator sticks & testing your cervical mucus, you take charge and stimulate your own damn receptors. For now, that means taking a little peach pill every day at the same time and waiting. Hopefully, the little peach pill keeps my ovaries from going astray: lets the follicles pause, develop slowly, sync up, for stimulation later.
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It is 1 year ago. You’ve started the IVF process on paper a year ago now, and done a dozen tests. The genetic screening was optional, and it cost money. You did it, ‘cause sure. You like data. And you’re pretty sure from commercial genetic testing that you have nothing really bad. And if you did, you’d like to know.
Your genetic counselor has good news. You are carriers for only two bad things, and your partner has neither. One is CYP21A2:c844G>T. It is a mutation in the 21-hydroxylase enzyme, the that turns progesterone into other hormones, for flipping MR and GR switches. Your genetic counselor explains that one copy is not so bad; half your enzymes are still good, so you still get enough switches flipped. You’re not normal, but you’re close enough.
People with two copies of this mutation have congenital adrenal hyperplasia: a collection of symptoms in varying degrees. The body makes more progesterone, but can’t turn it into the hormones for MR and CR flipping. The adrenal gland gets large as it tries to make hormones it can’t manufacture. Without the MR and CR hormones, the body can’t properly manage blood pressure, blood sugar, energy, stress, illness. Extra progesterone takes the only path it can, to be made into testosterone and other androgens. So external genitalia is masculinized and enlarged, no matter what your chromosomes; voices deepen, facial hair grows. Childhood growth starts early and ends quick with short final heights. Acne is severe; periods are irregular. Fertility in females is reduced. You see parts of you and your foremothers in these words. You wonder.
Generally, carriers like you don’t have any symptoms at all. One good copy of the enzyme is enough. Some people do have two bad copies, and sometime the two are bad for different reasons. Different mutations. We haven’t identified all the mutations yet. Your other enzyme copy is good though. Probably. Normal enough.