Both low-dose (2 mg/day) and high-dose CPA combined with an estrogen have been associated with vitamin B12 deficiency in women in some small studies. [268] [269] [7] Vitamin B12 deficiency in turn has been associated with depression, anxiety, irritability, and fatigue due to depletion of central monoamine neurotransmitters. [270] [271] For this reason, it has been suggested that low vitamin B12 levels might be involved in the side effect of depression that has sometimes been associated with CPA. [24] Serum vitamin B12 monitoring and supplementation (e.g., 100 to 200 μg/day orally) as necessary may be recommended during CPA therapy. [7] [268] [269]
CPA has been associated rarely with retinal vascular disorder, retinal vein thrombosis, and optic neuritis. [272] A case report of symptomatic epidural lipomatosis in association with CPA therapy has been published. [273] A published case report of lymphocytic pneumonitis in associated with CPA also exists. [4] There is a case report of severe stretch marks in association with CPA therapy. [274]
Belisle and Love (1986) directly compared Diane (ethinylestradiol 50 μg/day and CPA 2 mg/day) alone versus the combination of Diane and CPA 100 mg/day (Androcur) in 158 women with hirsutism. [5] They reported no differences in mean incidences of side effects including menometrorrhagia (9.9%), acne (6.5%), decreased libido (9.5%), edema (9.3%), nausea (17.5%), vomiting (4.8%), headache (20.3%), and depression (12.7%). [5] Conversely, the incidences of fatigue and amenorrhea were significantly greater in the Diane plus Androcur group relative to the Diane alone group (6.7% vs. 2.5% and 5.4–32.6% vs. 0–4.2%, respectively), the incidence of breast tenderness was significantly lower in the Diane plus Androcur group than in the Diane alone group (3.6–26.3% vs. 12.5–46.4%), and the percent gain in body weight relative to baseline was significantly greater in the Diane plus Androcur group than in the Diane alone group (6.3% vs. 1.1% at 12 months). [5]
CPA at relatively low doses, for instance 10–20 mg/day, has been reported in small studies to cause few to no side effects in men. [275] Conversely, CPA at higher doses, for instance 100 mg/day or greater, has been reported to produce a variety of side effects in men including decreased libido, erectile dysfunction, gynecomastia, tiredness, weakness, decreased efficiency, weight gain, skin dryness, skin peeling, and decreased body hair (e.g., trunk and pubic region). [275]
Side effect | High-dose [c] (n = 602) (%) | Low-dose [d] (n = 226) (%) | |
---|---|---|---|
Fatigue | 22.0 | 13.0 | |
Weight gain (>2 kg or >4.4 lbs) | 18.5 | 5.5 | |
Decreased libido | 10.0 | 6.0 | |
Breast discomfort | 9.2 | 15.0 | |
Nausea | 9.0 | 3.9 | |
Headaches | 7.3 | 10.4 | |
Depression | 5.1 | 2.0 | |
Irregular uterine bleeding | 3.5 | 7.2 | |
Sleep disturbance | 3.5 | – | |
Thrombophlebitis | 1.0 | 3.0 | |
Chloasma | 0.9 | – | |
Constipation | 0.5 | – | |
Thrombosis | 0.15 | 0.9 | |
Heavy legs or cramps | – | 4.6 | |
Footnotes:
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Abrupt withdrawal of CPA can be harmful, and the package insert from Schering AG recommends the daily dose be reduced by no more than 50 mg at intervals of several weeks. The concern is the manner in which CPA affects the adrenal glands. Due to its glucocorticoid activity, high levels of CPA may reduce ACTH, resulting in adrenal insufficiency if discontinued abruptly. In addition, although CPA reduces androgen production in the gonads, it can increase the production of adrenal androgens, in some cases resulting in an overall rise in testosterone levels. [276] Thus, the sudden withdrawal of CPA could result in undesirable androgenic effects.[ citation needed ] This is a particular concern because androgens, especially DHT, suppress adrenal function, further reducing corticosteroid production. [277]
Suppression of adrenal function and reduced response to adrenocorticotropic hormone (ACTH) have been reported with CPA treatment. As a result, adrenal insufficiency and hence low cortisol and aldosterone levels and ACTH responsiveness can occur upon discontinuation of CPA. Low aldosterone levels may lead to hyponatremia (sodium loss) and hyperkalemia (excess potassium). Patients taking CPA should have their cortisol levels and electrolytes monitored, and if hyperkalemia develops, should reduce the consumption of foods with high potassium content or discontinue the medication.
Antiandrogens, also known as androgen antagonists or testosterone blockers, are a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. They act by blocking the androgen receptor (AR) and/or inhibiting or suppressing androgen production. They can be thought of as the functional opposites of AR agonists, for instance androgens and anabolic steroids (AAS) like testosterone, DHT, and nandrolone and selective androgen receptor modulators (SARMs) like enobosarm. Antiandrogens are one of three types of sex hormone antagonists, the others being antiestrogens and antiprogestogens.
A progestogen, also referred to as a progestagen, gestagen, or gestogen, is a type of medication which produces effects similar to those of the natural female sex hormone progesterone in the body. A progestin is a synthetic progestogen. Progestogens are used most commonly in hormonal birth control and menopausal hormone therapy. They can also be used in the treatment of gynecological conditions, to support fertility and pregnancy, to lower sex hormone levels for various purposes, and for other indications. Progestogens are used alone or in combination with estrogens. They are available in a wide variety of formulations and for use by many different routes of administration. Examples of progestogens include natural or bioidentical progesterone as well as progestins such as medroxyprogesterone acetate and norethisterone.
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC). To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration. Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings. Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women, as a puberty blocker and component of feminizing hormone therapy for transgender girls and women, to treat gonadotropin-independent early puberty in boys, and to prevent overly long-lasting erections in men. It is taken by mouth.
Flutamide, sold under the brand name Eulexin among others, is a nonsteroidal antiandrogen (NSAA) which is used primarily to treat prostate cancer. It is also used in the treatment of androgen-dependent conditions like acne, excessive hair growth, and high androgen levels in women. It is taken by mouth, usually three times per day.
Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. It is taken by mouth.
Feminizing hormone therapy, also known as transfeminine hormone therapy, is hormone therapy and sex reassignment therapy to change the secondary sex characteristics of transgender people from masculine or androgynous to feminine. It is a common type of transgender hormone therapy and is used to treat transgender women and non-binary transfeminine individuals. Some, in particular intersex people, but also some non-transgender people, take this form of therapy according to their personal needs and preferences.
Chlormadinone acetate (CMA), sold under the brand names Belara, Gynorelle, Lutéran, and Prostal among others, is a progestin and antiandrogen medication which is used in birth control pills to prevent pregnancy, as a component of menopausal hormone therapy, in the treatment of gynecological disorders, and in the treatment of androgen-dependent conditions like enlarged prostate and prostate cancer in men and acne and hirsutism in women. It is available both at a low dose in combination with an estrogen in birth control pills and, in a few countries like France and Japan, at low, moderate, and high doses alone for various indications. It is taken by mouth.
Estradiol undecylate, also known as estradiol undecanoate and formerly sold under the brand names Delestrec and Progynon Depot 100 among others, is an estrogen medication which has been used in the treatment of prostate cancer in men. It has also been used as a part of hormone therapy for transgender women. Although estradiol undecylate has been used in the past, it was discontinued. The medication has been given by injection into muscle usually once a month.
An antigonadotropin is a drug which suppresses the activity and/or downstream effects of one or both of the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). This results in an inhibition of the hypothalamic-pituitary-gonadal (HPG) axis, and thus a decrease in the levels of the androgen, estrogen, and progestogen sex steroids in the body. Antigonadotropins also inhibit ovulation in women and spermatogenesis in men. They are used for a variety of purposes, including for the hormonal birth control, treatment of hormonally-sensitive cancers, to delay precocious puberty and puberty in transgender youth, as a form of chemical castration to reduce the sex drives of individuals with hypersexuality or pedophilia, and to treat estrogen-associated conditions in women such as menorrhagia and endometriosis, among others. High-dose antigonadotropin therapy has been referred to as medical castration.
Cyproterone acetate (CPA), sold alone under the brand name Androcur or with ethinylestradiol under the brand names Diane or Diane-35 among others, is an antiandrogen and progestin medication used in the treatment of androgen-dependent conditions such as acne, excessive body hair growth, early puberty, and prostate cancer, as a component of feminizing hormone therapy for transgender individuals, and in birth control pills. It is formulated and used both alone and in combination with an estrogen. CPA is taken by mouth one to three times per day.
Cyproterone, also known by its developmental code name SH-80881, is a steroidal antiandrogen which was studied in the 1960s and 1970s but was never introduced for medical use. It is a precursor of cyproterone acetate (CPA), an antiandrogen, progestin, and antigonadotropin which was introduced instead of cyproterone and is widely used as a medication. Cyproterone and CPA were among the first antiandrogens to be developed.
Ethinylestradiol sulfonate (EES), sold under the brand names Deposiston and Turisteron among others, is an estrogen medication which has been used in birth control pills for women and in the treatment of prostate cancer in men. It has also been investigated in the treatment of breast cancer in women. The medication was combined with norethisterone acetate in birth control pills. EES is taken by mouth once per week.
A steroidal antiandrogen (SAA) is an antiandrogen with a steroidal chemical structure. They are typically antagonists of the androgen receptor (AR) and act both by blocking the effects of androgens like testosterone and dihydrotestosterone (DHT) and by suppressing gonadal androgen production. SAAs lower concentrations of testosterone through simulation of the negative feedback inhibition of the hypothalamus. SAAs are used in the treatment of androgen-dependent conditions in men and women, and are also used in veterinary medicine for the same purpose. They are the converse of nonsteroidal antiandrogens (NSAAs), which are antiandrogens that are not steroids and are structurally unrelated to testosterone.
The medical uses of bicalutamide, a nonsteroidal antiandrogen (NSAA), include the treatment of androgen-dependent conditions and hormone therapy to block the effects of androgens. Indications for bicalutamide include the treatment of prostate cancer in men, skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss in women, high testosterone levels in women, hormone therapy in transgender women, as a puberty blocker to prevent puberty in transgender girls and to treat early puberty in boys, and the treatment of long-lasting erections in men. It may also have some value in the treatment of paraphilias and hypersexuality in men.
The side effects of bicalutamide, a nonsteroidal antiandrogen (NSAA), including its frequent and rare side effects, have been well-studied and characterized. The most common side effects of bicalutamide monotherapy in men include breast tenderness, breast growth, feminization, demasculinization, and hot flashes. Less common side effects of bicalutamide monotherapy in men include sexual dysfunction, depression, fatigue, weakness, and anemia. Bicalutamide is well tolerated and has few side effects in women. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.
Comparison of the nonsteroidal antiandrogen (NSAA) bicalutamide with other antiandrogens reveals differences between the medications in terms of efficacy, tolerability, safety, and other parameters. Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide shows improved potency, efficacy, tolerability, and safety, and has largely replaced these medications in clinical practice. Compared to the second-generation NSAAs, enzalutamide and apalutamide, bicalutamide has inferior potency and efficacy but similar tolerability and safety and a lower propensity for drug interactions.
The pharmacology of estradiol, an estrogen medication and naturally occurring steroid hormone, concerns its pharmacodynamics, pharmacokinetics, and various routes of administration.
The pharmacology of cyproterone acetate (CPA) concerns the pharmacology of the steroidal antiandrogen and progestin medication cyproterone acetate.
Estradiol valerate/cyproterone acetate (EV/CPA), sold under the brand names Climen and Femilar among others, is a combination product of estradiol valerate (EV), an estrogen, and cyproterone acetate (CPA), a progestogen, which is used in menopausal hormone therapy and as a birth control pill to prevent pregnancy. It is taken by mouth. Climen, which is used in menopausal hormone therapy, is a sequential preparation that contains 2 mg estradiol valerate and 1 mg CPA. It was the first product for use in menopausal hormone therapy containing CPA to be marketed and is available in more than 40 countries. Femilar, which is an estradiol-containing birth control pill, contains 1 to 2 mg estradiol valerate and 1 to 2 mg CPA, and has been approved for use in Finland since 1993.
Ethinylestradiol/cyproterone acetate (EE/CPA), also known as co-cyprindiol and sold under the brand names Diane and Diane-35 among others, is a combination of ethinylestradiol (EE), an estrogen, and cyproterone acetate (CPA), a progestin and antiandrogen, which is used as a birth control pill to prevent pregnancy in women. It is also used to treat androgen-dependent conditions in women such as acne, seborrhea, excessive facial/body hair growth, scalp hair loss, and high androgen levels associated with ovaries with cysts. The medication is taken by mouth once daily for 21 days, followed by a 7-day free interval.
No quantitative data on these adverse events are available, even in the product prescribing information and data sheets.
The only advantage of cyproterone acetate on pure antiandrogens seems to be the low incidence of hot flushes; [...] However, hepatotoxicity associated with long term daily doses of 300 mg daily and the unacceptably high incidence of cardiovascular side effects (10%) should restrict its use to patients who are intolerant of pure antiandrogen compound. In contrast to steroidal compound nonsteroidal compounds let sexual potency to be retained, [...]
Although during CPA therapy the activity of androgens at the breast is blocked, thereby leading to unopposed oestrogenic stimulation at the breast, circulating oestrogen levels decline due to the reduction in the levels of circulating androgens available for aromatisation and also the decrease in serum LH levels. CPA is therefore associated with a relatively low incidence of gynaecomastia (4-9%) [14,29,30].
When compared to flutamide, [cyproterone acetate] has significant intrinsic androgenic and estrogenic activities. [...] The effects of flutamide and the steroidal derivatives, cyproterone acetate, chlormadinone acetate, megestrol acetate and medroxyprogesterone acetate were compared in vivo in female nude mice bearing androgen-sensitive Shionogi tumors. All steroidal compounds stimulated tumor growth while flutamide had no stimulatory effect [51]. Thus, CPA due to its intrinsic properties stimulates androgen-sensitive parameters and cancer growth. Cyproterone acetate added to castration has never been shown in any controlled study to prolong disease-free survival or overall survival in prostate cancer when compared with castration alone [152-155].
[CPA] induces relevant effects on the coagulative system. A recent meta-analysis relating to total androgenic blockade has shown that cyproterone acetate when combined with castration reduces the long-term efficacy of androgen-suppressive treatments. In fact, it causes an increase in treatment-related mortality, mainly due to cardiovascular complications (No authors, 2000).
Recently, a publication of the Medicines Control Agency (MCA)/Committee on Safety of Medicines (CSM)[5] drew attention to spontaneous reports of serious and dose-related hepatic toxicity after the prolonged use of CPA. [...] 96 hepatotoxic events (33 fatal) have been observed, of which 91 were in males and 5 in females. The hepatic reactions included hepatitis, cholestatic jaundice and hepatic failure. The majority of patients were treated with high dosages of CPA (300 mg/day) for cancer of the prostate.
Although few case reports have been published, the Committee on Safety of Medicines had received 19 reports in the UK of adverse hepatic reactions associated with cyproterone acetate by November 1988 (personal communication, Committee on Safety of Medicines). Five of these cases were fatal.
High dose cyproterone (50mg, 100mg; Androcur, Androcur-100) is used predominantly for advanced prostate carcinoma. For the year ending June 2003, 59,000 prescriptions were dispensed for the 50mg or 100mg tablets and 97% of patients prescribed these tablets were male. [...] Over the years, ADRAC has received 105 reports implicating high-dose cyproterone. The most common adverse reactions are related to the liver with 32 reports. Other more commonly reported reactions include fatigue, dyspnoea, asthenia, confusion, depression and deep vein thrombosis. [...] All except one of the hepatic reactions involved male patients being treated for prostate cancer, whose ages ranged from 56 to 92 (median: 77) years. Time to onset of liver dysfunction ranged from 4 days to 4 years (median: 4-5 months); only 4 cases had a time to onset under a month.