HORMONAL THERAPY IN WOMEN OF REPRODUCTIVE AGE WITH ENDOMETRIOSIS: AN UPDATE

Abstract

Medical therapy of endometriosis is under continuous reevaluation. Hereby we updated the drugs currently available or under investigation for the hormonal treatment of endometriosis.

INTRODUCTION

Endometriosis is a progressive severe gynecological disorder defined as the presence of functional endometrial-type mucosa (endometrium glands and stroma) outside the uterine cavity, in other areas of the pelvis, and sometimes even in the great abdomen cavity. Although a benign proliferative disease, endometriosis shares common characteristics with neoplastic processes (inflammatory state, invasion of adjacent tissues, induction of angiogenesis, and resistance to apoptosis) (1).

Endometriosis is an estrogen-dependent chronic multifactorial disease involving mechanical, molecular, genetic, immunological and environmental causes. More recently, hereditary factors were estimated to account for 50% of endometriosis and familial clustering of endometriosis was demonstrated in humans (2).

Endometriosis occurs most commonly in fertile women and occasionally in women without an endometrium (3), in men (4) and unexpected, even before menarche (5). Endometriosis is a disease that affects an estimated 5%–10% of women of reproductive age with a prevalence peak between 25 and 35 years of age. It is associated with a wide spectrum of pain symptoms (dysmenorrhea, dyspareunia, periovulatory pain, chronic pelvic pain without any relation to menstrual cycle, dyschezia, dysuria, pain due to nerve root compromise) and infertility. Endometriosis - related pain is attributed to the increase of inflammatory cells and pro-inflammatory cytokines in endometrial lesions, and peripheral sensory neuronal dysfunction mediated by estrogens (6).

Infertility in endometriosis has multiple mechanisms, including the production of inflammatory mediators with damage to oocytes and sperm, reducing anti-müllerian hormone with an impact on follicular reserve, underlying adhesions, ovarian cysts and changes in tubal anatomy (7). This disorder affects women’s health and quality of life, with consequences for personal, romantic, family and workplace relationships (8).

Although the exact pathogenesis is still a subject of research, the most prevalent theory is retrograde menstruation, according to which endometrial glands and stroma are attached and implanted in the peritoneal cavity. Other theories as celomic metaplasia, stem cell origin and lymphatic or hematogenous spread were considered. To date, none of these theories has been proven beyond doubt.

Hormonal therapy

Although the scientific community is trying to find an algorithm of treatment for endometriosis that can be universally applied, to date, there is no ideal drug that can prevent, inhibit, or stop the development of endometriosis (9). Almost all of the currently available treatment options for endometriosis suppress ovarian function and are not curative.

Endometriotic lesions are associated with hormonal imbalance, including increased estrogen synthesis, and progesterone resistance. Endometriotic lesions over-express β-estrogen receptor, steroidogenic acute regulatory protein and P450 aromatase. On the other hand, a general reduction in the levels of progesterone receptors (the lack of progesterone receptor B and very low levels of progesterone receptor A) has been observed (10).

Therefore, classical pharmacological therapies are primarily aimed at the suppression of endogenous estrogen production. The hypothesis postulated by Barbieri supports the idea that endometriosis is effectively reduced in terms of endometrial growth and pain reduction by taking into account a threshold for serum estradiol of 30–50 pg/mL (11).

Treatment of endometriosis includes medical and surgical options. Medical therapy is often the first line of management for women with endometriosis in order to control pain, stop the development of endometriotic lesions and improve fertility. In the selected cases, surgical removal of endometrial lesions is recommended.

There are two basic lines of medical treatment, hormonal and analgesic. Some women with endometriosis turn to alternative therapies to alleviate their symptoms or improve their chances of becoming pregnant.

Although several hormonal therapies are available, no consensus has been established as to which medication is the best option for long-term prevention of recurrence. The blockade of estrogen secretion and estrogen receptors activity and the activation of progesteron receptors are the main target of hormonal therapies. The available treatments are limited by side effects of prolonged hypoestrogenism and high rates of recurrence after therapy is discontinued.

Current hormonal treatments for endometriosis include:

Combined hormonal contraceptives,

Progesterone,

Gonadotropin releasing hormone agonists,

Gonadotropin releasing hormone antagonists,

Aromatase inhibitors,

Selective estrogen receptor modulators and

Selective progesterone receptor modulators.

Each drug class has its own limitations such as a short-term effect on the symptoms of endometriosis, side-effects and quite an important cost of treatment (12,13). The optimal method for treatment of endometriosis is an individualized decision that should be made on patient-specific basis: the clinical manifestations, severity, extent and location of the endometrial implants, treatment response and tolerance, patient’s age, and personal decision regarding fertility (14).

Combined hormonal contraceptives (CHCs), available for multiple routes of administration (oral, transdermal and vaginal), administered cyclically or continuously, have been the first-line hormonal option so far.

CHCs block endogenous ovarian estradiol production and ovulation and create a progesterone-dominant hormonal environment that down-regulates the local estrogen-receptor response and prevents the proliferation of endometriotic lesions. Use of hormonal therapy was associated with significantly reduced nerve fiber density in endometriotic lesions (15), and inhibition of angiogenesis, an essential part in the pathogenesis of endometriosis. Several randomized controlled trials have shown that CHCs can improve pain symptoms in the majority of patients, sometimes significantly reduce the volume of menstrual flow, are well tolerated and not expensive (16,17).

The most commonly used estrogen/progestin products were administered on a 28-day (21+7 placebo) cyclic regimen. Today it is recommended the extended-cycle administration of combined oral contraceptives as initial treatment. Extended estrogen/progestin regimens may involve 12 weeks of administration, thus reducing the number of withdrawal bleeds. Extended-cycle regimens suppress ovarian function more reliably than 28-day cyclic regimens, with greater improvement of symptoms (18). The most common side effects associated with CHCs are headaches, gastrointestinal disturbances (abdominal distension, nausea), weight gain and cardiovascular changes, as well as changes in sexual desire and mood. Combinations containing lower dose of ethinyl estradiol (20 μg) as compared to high dose (30 μg) have a lower risk of venous thromboembolism and are currently recommended.

Progesterone, progestogens/gestagens (all natural metabolites of progesterone, lying downstream of progesterone in terms of biosynthesis) and progestins (synthetic progestogens with similar effects to those of the natural hormone progesterone) are also used in the management of symptomatic endometriosis. Available in different forms (oral, injectable, transdermal patches, vaginal rings, intrauterine devices, subcutaneous implants) they have demonstrated benefits in reducing pain and suppressing the extent of endometriotic lesion. Even though they are different in their structure and action profile, they are useful in endometriosis through several mechanisms: induce anovulation, reduce the expression of aromatase, reduce the expression and enzyme activity of 17ß-HSD1 (hydroxysteroid dehydrogenase, which catalyzes the conversion of estrone to estradiol), alter estrogen receptors, inhibit angiogenesis, and decrease expression of matrix metalloproteinases needed for the growth of the endometriotic implant (19). In addition, depending on the structure and dose administered, they directly inhibit progesterone-mediated cell proliferation and the production of inflammatory cytokines (20).

Until recently it was considered that progestogen/progestin-only contraceptives, often called “mini-pill”, can be used in women who have a contraindication for CHCs. However, it has been shown that progestins play an essential role in contraception, independent of estrogens. Moreover, they can be used at any age. Based on controlled trial data, it appears that oral “mini-pill” treatment should be the first-line therapy (21).

Progestins used in the treatment of endometriosis include dienogest (2 mg or 4 mg per day), medroxyprogesterone acetate (150 mg intramuscularly every three months or oral 10 to 100 mg per day for 3–6 months), norethindrone acetate also known as norethisterone acetate (2.5 mg per day for 12 months), as well as cyproterone acetate, dydrogesterone, gestrinone, lynesterole, and megesterol acetate. As there are not enough data demonstrating the superiority of one progestin over the others, the first choice should be low-dose oral norethisterone acetate, given the extremely favorable cost-effectiveness profile. In addition, levonorgestrel-releasing intrauterine devices which contain 52 mg levonorgestrel and release 20 micrograms of hormone per day over a five-year period may be used. The main advantages of the vaginal route include avoidance of the hepatic-first pass metabolic effect, the possibility of using lower therapeutic doses and the reduced systemic side effects compared to oral administration (22). Another route of progestins delivery is the subdermal implant (etonogestrel) which offers contraceptive benefits for at least three years (23). Progestogens/ progestins have very little impact on the coagulation system and epidemiological studies have shown that there is no significant risk for thromboembolic venous or arterial disease. Based on observational data, the most frequent side effects attributed to the action of progestogens/ progestins are acne, mild hirsutism, mood change, and weight gain. However, monotherapies with progestogens/ progestins are associated with a high frequency of irregular vaginal bleeding, especially soon after beginning the treatment.

Gonadotropin - releasing hormone - agonists (GnRH agonists) are a second-line therapy, prescribed when first-line therapies are ineffective, not tolerated or contraindicated. GnRH agonists (buserelin, goserelin, leuprolide, nafarelin or triptorelin) are available in both nasal and injectable forms administered daily, monthly and three-monthly, subcutaneously or intramuscularly. GnRH agonists achieve hypoestrogenism and amenorrhea by suppressing pituitary gonadotropin secretion. They bind pituitary gonadotropin receptors and antagonize the endogenous GnRH, inhibiting the mechanism of GnRH pulsatility and consequently the synthesis of gonadotropins (24). Although within the first 5-10 days of administration GnRH agonists stimulate the pituitary releasing FSH and LH, chronic administration leads to down-regulation of pituitary GnRH receptors that results in suppression of the hypothalamic pituitary ovarian axis and secondary ovarian suppression and anovulation.

GnRH agonists affect only the hypothalamo-pituitary-gonadal axis, but not extraglandular sites of estrogen biosynthesis. Therefore, estrogen production occurs in the adipose tissue, the skin and local endometriotic lesions during these treatments.

The use of GnRH agonists is generally restricted to a 6-month course. Long-term use of GnRH agonists for more than 6 months is associated with hypoestrogenic side-effects, sometimes felt to be intolerable by the patient, such as vasomotor symptoms, vaginal dryness, mood changes, sleep disturbance, abnormalities in lipid profile and a substantial reduction in bone mineral density that could increase the risk of osteoporosis (25).

Therefore it is mandatory to start GnRH agonist with “add-back therapy” consisting of low doses of hormone taken concurrently with GnRH agonists. Norethindrone acetate is the only FDA approved add-back therapy, but low dose estrogen and a combination of estrogen and progesterone have also been used (26). The combination of GnRH agonists and norethindrone acetate is only approved for 12 months, as data beyond that duration are not available. With add-back therapy, patients receive enough hormones to prevent somatic and psychological complaints, as well as to protect bone health while maintaining the efficacy of GnRH agonists.

In addition, antiresorptive drugs like Raloxifene (60 mg daily, p.o.) have been used to preserve the bone tissue during GnRH agonist treatment in pre-menopausal women with severe endometriosis. It is possible that antiresorptive drugs could be used as an ‘add-back therapy’ in women treated with GnRH agonists (27).

Gonadotropin-releasing hormone antagonists (GnRH antagonists) have shown promising results. GnRH antagonists are available as peptide forms (Ganirelix, Cetrorelix) that require subcutaneous injections or implantation of long-acting depots and oral nonpeptide forms (Elagolix, Abarelix, Ozarelix, TAK-385) (28). The mechanism of action of GnRH antagonists is competitive receptor occupancy, which results in the blockade of GnRH receptor dimerization required for receptor activation, thus suppressing pituitary gonadotropin in a dose-dependent manner (minimal at low doses and near-complete at high doses). The main advantage during GnRH antagonist treatment is preserving basic estrogen production, serum estradiol oscillating around a mean concentration of 50 pg/mL, thus limiting the side effects associated with hypoestrogenism. Both oral and injectable forms of GnRH antagonists are effective in reducing endometriosis-associated pain and all patients reported a pain-free period. Sequential weekly administration of cetrorelix in a 3 mg dosage once a week over 8 weeks could be a feasible medical treatment for endometriosis-associated pain (29). Elagolix has been approved for the management of moderate to severe pain associated with endometriosis. If low Elagolix doses are used, ovulation is not consistently inhibited, and patients should use non-hormonal contraceptive systems. If high Elagolix doses are used to control severe pain for long periods of time, add-back therapy should be added, similar to that prescribed when using GnRH agonists (30).

Aromatase inhibitors (AIs), another therapeutic option for patients with endometriosis, inhibit local estrogen production in endometriotic implants, ovary, and adipose tissue. Aromatase, an enzyme from the cytochrome P450 superfamily, is responsible for the last step of estrogen biosynthesis that converts testosterone and androstenedione to estradiol and estrone, respectively. Several studies reported that aromatase is more abundant in endometriotic tissues than in the normal endometrium. Its activity, absent in normal endometrium, is overexpressed in endometriosis, leading to an increased local estrogen concentration (31). In turn, estrogens of extrauterine endometrial tissue stimulate synthesis of PGE2, which is a potent inducer of aromatase activity in the endometrium (32). AIs block estrogen synthesis in the ovaries (ovarian granulosa cells) and especially in extra-ovarian tissues (adipose cells). Therefore, it is considered that AIs are likely to maintain low estrogen levels in extra-ovarian sites. Many studies demonstrated that AIs decrease the endometriosis-associated pain, reduce the size of extrauterine endometrial lesions, and improve patients’ quality of life. Monotherapy with AIs given to premenopausal women increase FSH levels through feedback of the hypothalamo-pituitary-gonadal axis, sometimes leading to the development of ovarian cysts. Long-term use of AIs is associated with an increased risk of osteoporosis and bone fractures secondary to hypoestrogenism. For this reason, ESHRE guidelines recommend concomitant use of AIs and oral contraceptives, progestins, or GnRH agonists for women of reproductive age with endometriosis. Therefore, AIs should be reserved only for women who are refractory to other treatments. Other side effects of the AIs include vaginal dryness, hot flushes, headache, numbness in lower extremities and arthralgia (33).

There are two types of aromatase inhibitors, nonsteroidal and steroidal. Nonsteroidal inhibitors (anastrozole, letrozole) inhibit estrogen synthesis via reversible competition, while steroidal inhibitors which resemble the structure of androstenedione (exemestane) irreversibly inhibit the enzyme by binding covalently to the binding site of aromatase. AIs can be administered orally, in various doses, such as 1 mg daily for anastrazole and 2.5 mg daily for letrozole (34).

An important step in the treatment of endometriosis has been the discovery of tissue-specific steroid receptor modulators (SRMs) that elicit agonistic or antagonistic effects in a cell- and tissue-dependent manner.

Selective estrogen receptor modulators (SERMs). Selective estrogen receptor modulators (SERMs) bind to nuclear α- or β- estrogen receptors and exert estrogen or antiestrogen actions depending on the tissue type. The majority of findings were obtained in animal models and the effectiveness of SERMs in human endometriosis has still to be evaluated. In experimental models SERMs show a direct effect on endometrial blood vessels and suppress endometrial prostaglandin production without the systemic effects of estrogen deprivation.

Raloxifene, used for the treatment of postmenopausal osteoporosis, was tested in a rat model of endometriosis and was shown to have an estrogen-antagonist effect on the rat uterine tissue, producing implants regression (35).

Bazedoxifene antagonizes estrogen-induced uterine endometrial stimulation in a mice model of endometriosis. In a murine model, alone or combined with conjugated estrogen, it reduced estrogen receptor expression in the endometrium and the size of endometriotic lesions. Recently, Flores et al. have evaluated in premenopausal women the effects of Bazedoxifene paired with conjugated estrogens on reproductive hormones and uterine/ovarian appearance. After one daily administration of Bazedoxifene/conjugated estrogens (20 mg/0.45 mg) for 12 weeks all subjects demonstrated an LH surge without endometrial alterations or abnormal ovarian folliculogenesis (36).

Selective progesterone receptor modulators (SPRMs). SPRMs represent a class of nuclear progesterone receptor ligands which act as agonists, antagonists, or combined agonists / antagonists, depending on the progesterone-sensitive tissue. SPRMs are steroid derived compounds including various drugs such as mifepristone, ulipristal acetate, asoprisnil, opanpristone, lonaprisan, telapristone acetate, PRA-910, ZK 136799 and vilaprisan. They can be administered orally, via intrauterine systems or as vaginal rings.

Mifepristone (RU486) is the first and the most studied SPRM. Mifepristone is a synthetic orally active steroid with potent antiglucocorticoid, antiprogestogen and weak anti-androgen activity. It acts as a competitive receptor antagonist at the progesterone receptor in the presence of progesterone, and as a partial agonist in the absence of progesterone. Used mostly for the induction of medical abortions, it has proven effective in the treatment of dysmenorrhea and dyspareunia, with side effects of amenorrhea and hot flushes (37). It is considered to be inappropriate for long-term application as a result of the antiglucocorticoid properties and hypoadrenal state it generates. A minimum dose of 50 mg mifepristone for six months demonstrated a significant regression of endometriotic lesions and a decrease in clinical symptoms.

Asoprisnil (CBD 2914) is a SPRM which displays mixed progesterone agonist/antagonist activity and endometrial selectivity. Asoprisnil can suppress both the menstrual cycle and endometrial growth in nonhuman primates. All doses of asoprisnil (5, 10 and 25 mg/day) for 12 weeks reduced non-menstrual pelvic pain, while the effect on bleeding pattern was dose-dependent (38).

Ulipristal acetate (anti-progestin CDB 2914) contributes to the regress and atrophy of endometriotic lesions in rats through its proapoptotic effects. In addition, treatment with ulipristal reduced cellular proliferation and decreased Ki-67 expression. Its feasibility for the treatment of human endometriosis has still to be determined (39).

Lonaprisan is a highly selective SPRM that did not show a drug-related change in liver enzyme activity. However, in clinical trials, it was found to form a cocktail of active metabolites and, therefore, the compound was considered suboptimal for endometriosis (40).

Tanaproget is a SPRM which down-regulated endometrial matrix metalloproteinase expression in vitro and regressed experimental endometriosis in vivo. Clinical studies should be performed to test the safety and effectivity of these drugs in patients with endometriosis.

In conclusion, none of the hormonal therapies used up to date has been free of side effects, resistance to long-term therapy and high rate of recurrence after discontinuation. The future trend will be to define new drugs to use for a prolonged period of time and safe. Considering endometriosis a chronic disease, the ideal drug should not be contraceptive, should not interfere with spontaneous ovulation, should suppress the growth of already existing lesions and prevent the development of new ones and it should be efficacious for all endometriosis phenotypes.

Conflict of interest

The authors declare that they have no conflict of interest.