Reoccurrence of EMS is very likely after surgery, so GnRH-a plays a very important role in postoperative drug therapy. However, GnRH-a treatment can have serious side effects. Adverse reactions mainly include peri-menopausal symptoms and osteoporosis caused by low estrogen. After GnRH-a treatment, the symptoms of low estrogen are obvious, resulting in serious peri-menopausal symptoms such as hot flashes, vaginal dryness, lack of libido, emotional instability, and sleep disorders. Long-term use (more than 6 months) can lead to a decrease in bone-mineral density. Because of low estrogen levels, the average bone-mass loss can reach 4–6% [12]. One study [13, 14] found that there were obvious complaints of hot flashes, fatigue, and insomnia after one month of treatment with GnRH-a alone. After using GnRH-a, the bone mass of patients decreased at a rate of 1%/month, and about 20% of patients had obvious bone pain after 3 months of treatment. Related study [15] has confirmed that GnRH-a treatment generally does not cause significant bone loss within 3 months, and has little effect on the long-term quality of life of patients. However, the bone-mineral density of patients treated for more than 3 months significantly decreased, and after one year of treatment, the bone-mineral density of patients cannot be completely restored to pre-treatment levels.

Many studies [16, 17] have indicated that GnRH-a treatment may have a lasting and far-reaching effect on bone metabolism in patients. However, in many cases, in order to improve the curative effect and reduce reoccurrence of EMS, when GnRH-a is used for 6 months longer, the treatment regimen is often supplemented with low-dose estrogen and progesterone after the 3rd month (i.e., “add-back therapy”). Exogenous estradiol can control ectopic lesions without the concurrent changes in the level of bone metabolism.

According to the guidelines for diagnosis and treatment of EMS of the Endometriosis Cooperative Group of the Obstetrics and Gynecology Branch of the Chinese Medical Association [21], add-back (sometimes deferred to as reverse addition) there are several main strategies:

The first strategy is the administration of estrogen + progesterone. A combination of estrogen and progesterone (either estradiol valerate 0.5–1.5 mg/d; conjugated estrogen 0.3–0.45 mg/d; estradiol patch with daily release of 25–50 µg; or estradiol gel 1.25 g/d smeared percutaneously) and progesterone (5 mg/d) or medroxyprogesterone acetate (2–4 mg/d) is administered continuously. Alternatively, a compound preparation of estrogen spirosterone tablets can be administered (1/day).

A second strategy is the administration of norethisterone acetate (1.25–2.5 mg/d), which is a synthetic progesterone that also binds to estrogen receptors.

The third strategy is to administer a continuous regimen of tibolone (1.25–2.5 mg/d), which is a synthetic progesterone that metabolizes into compounds that have both progestogenic and estrogenic properties.

The dose of add-back treatment should be individualized, and the level of estrogen should be monitored if possible.

It is not clear when add-back therapy for GnRH-a therapy should begin. There are mainly three viewpoints: (1) when GnRH-a starts. Barbieri [22] proposed that low-dose estrogen be used to prevent damage to other systems, and to improve patients’ compliance. In addition, progesterone, plays a role in preventing estrogen from promoting intimal overgrowth. In view of the fact that the side effects of GnRH-a may affect patients from the beginning of treatment, some scholars think that the treatment can be added from the beginning of the use of GnRH-a [23, 24]. (2) Add-back therapy can begin in the second month (second injection) of GnRH-a treatment (within 1–2 weeks after the use of GnRH-a). Because of the “ignition effect” of GnRH-a, the level of estrogen increases temporarily then drops and remains stable at a low level (close to menopausal levels) after 2 weeks. Accordingly, menopausal symptoms are generally more obvious from the second month and can be alleviated by add-back treatment. (3) Add-back therapy should begin after 3 courses of GnRH-a treatment. Related studies have found that obvious complaints of hot flashes, fatigue, and insomnia can occur after one month of treatment with GnRH-a alone, and about 20% of the patients will have obvious bone pain after 3 months of treatment [13, 14]. Bone mass is lost at a rate of 1% per month after the use of GnRH-a. Therefore, low-dose estrogen and progesterone should be supplemented after 3 months because the patients will have obvious bone-mass loss and even bone pain after 3 months, and this bone-mass loss is often irreversible [25]. By adding estrogen, estradiol can be maintained at a level that can control ectopic endometrial lesions without affecting bone metabolism.

Although the start-up time for add-back therapy is still inconclusive, individual choices can be made according to the clinical conditions of patients. However, the prevalent point of view is that add-back therapy must be started after 3 courses of GnRH-a.

As mentioned earlier, although sex-hormone-based add-back therapy solves most of the problems of peri-menopausal symptoms and bone-mass loss caused by GnRH-a treatment, sex hormone use may increase the risk of hormone-dependent tumors such as endometrial cancer and breast cancer [24, 26]. For patients with sex-hormone-dependent tumors, there must be caveats for the use of sex-hormone-based add-back therapy, so this scheme cannot always be adopted. As a second point, clinically, not all patients are willing to accept this kind of sex-hormone therapy. Third, gynecologists and obstetricians of non-endocrinological gynecology are often not familiar with the add-back therapy using sex hormones. The above three cases can be summarized as unable to use, unwilling to use, and will not use this kind of sex-hormone-based add-back therapy.

Clinically, in addition to sex-hormone-based add-back therapy for peri-menopausal symptoms caused by GnRH-a treatment, some plant preparations (such as black cohosh isopropanol extract) or proprietary Chinese medicine (Kuntai capsule, Xiangshao granules, etc.) can play a significant role in relieving peri-menopausal symptoms caused by GnRH-a therapy [15, 27, 28], but only for the relief of symptoms. The short-term application of non-hormonal therapy for GnRH-a within 3 months is called “combined regulation”.

Studies have confirmed [29, 30] that postoperative use of GnRH-a in EMS patients leads to peri-menopausal symptoms, seriously affecting the quality of life of patients and compliance to continue treatment. Black cohosh preparation or proprietary Chinese medicine (such as Kuntai capsule or Xiangshao granules) can effectively improve the symptoms of the natural peri-menopausal period, as do sex hormones, but have limited effect on liver and kidney function and blood-lipid metabolism, and have no obvious estrogen-like effects. These plant-based preparations may be a safe and effective choice for patients who require careful use or prohibition of estrogen.

Black cohosh is a plant of the genus Ranunculaceae (Actaea racemose or Cimicifuga racemose), growing in eastern North America, that can effectively relieve the symptoms of peri-menopausal women. The extract of black cohosh has no estrogen or progesterone activity, and it does not belong to the phytoestrogen class of plant substances [31]. The mechanism of action is not clear. It may be a neurotransmitter regulator that acts directly on 5-hydroxytryptamine(5-HT) receptors, or through direct action on µ-opioid receptors in the brains of postmenopausal women, but has no significant effect on serum FSH, LH, estradiol (E2), or prolactin (PRL) [32]. Therefore, black cohosh preparation is also effective on non-physiological peri-menopausal symptoms caused by drugs, and does not antagonize the inhibitory effect of GnRH-a on pituitary gonadotropin secretion. This indicates that black cohosh may be an effective preparation when combined with GnRH-a in the treatment of EMS.

The Kuntai capsule, a proprietary Chinese medical preparation, contains six kinds of Traditional Chinese Medicine ingredients, such as Radix Rehmanniae, Coptis chinensis, Radix Paeoniae Alba, Ejiao, Scutellaria baicalensis, and Poria cocos, which are thought to nourish yin and reduce fire, calm nerves and relieve annoyance, regulate yin and yang, and cure both symptoms and root causes. Kuntai capsule treatment appears to improve various peri-menopausal symptoms and improve the quality of life of patients [33, 34]. However, whether the Kuntai capsule is as effective and as safe as tibolone in relieving peri-menopausal symptoms caused by GnRH-a is not clear, and needs to be confirmed by further study.

The Xiangshao granule is a compound preparation composed of 10 kinds of traditional Chinese medicine [35]. The study [35] has confirmed that Xiangshao granules can relieve the symptoms of peri-menopausal women. However, at present, the relevant studies [36, 37] with Xiangshao granules have been based on the treatment of healthy, natural menopausal and peri-menopausal women. Study has confirmed that [38] Xiangshao granules have no effect on serum hormone levels, and that Xiangshao granules have no estrogenic effect on the uterus and vagina. In addition, clinical trials conducted by Wu et al. [39]. showed that treatment with Xiangshao granules improved the symptoms of the peri-menopausal period, but did not show any estrogenic effect. Therefore, Xiangshao granules apparently have no estrogen or progesterone activity, and does not belong to the phytoestrogen class. The main characteristic of Traditional Chinese Medicine prescriptions is the integrated regulation of multi-components, multiple targets, and multiple links. At present, the mechanism of action of the Xiangshao granule is considered to be as follows [40]: (1) it regulates $\gamma$-aminobutyric acid nerve-conduction pathways. This contributes to sedation, hypnosis, and anti-anxiety; (2) it can regulate the activity of serotonin and has the effects of anti-anxiety, anti-depression, and improving sleep quality; and (3) it inhibits the expression of µ-opioid receptors in the hypothalamus and hippocampus. Treatment with Xiangshao granules can relieve the peri-menopausal symptoms of autonomic nervous dysfunction such as hot flashes, night sweats, and anxiety. However, some scholars have speculated that the occurrence of hot flashes in the peri-menopausal period is due to the change of neurotransmitters, which leads to the imbalance of the thermoregulation center. Central monoamine receptors include serotonin receptors (5-HTR), adrenergic receptors (AR), and dopamine receptors (DR). Recent data have suggested that Xiangshao granules may act on neurotransmitter pathways to relieve peri-menopausal hot flashes [38]. Both Xiangshao granules and estradiol can effectively relieve the symptoms of peri-menopausal period, but whether they play a role through neurotransmitters such as 5-HT needs to be confirmed by further research.

In the past few years, serious attention has been paid to the long-term safety of estrogen and progesterone therapy, especially regarding the impact on breast tissue. A series of clinical and observational studies has shown that such treatments increase the risk of breast cancer [41, 42, 43]. Some studies have shown that treatment with Xiangshao granules will not lead to adverse effects on breast tissue, yet is still effective for climacteric symptoms [44, 45].