The Menopause Transition: Signs, Symptoms, and Management

Abstract and Introduction

Abstract

Context: Menopause, the permanent cessation of menses, reflects oocyte depletion and loss of gonadal steroids. It is preceded by a transition state, the perimenopause, which is characterized by the gradual loss of oocytes, altered responsiveness to gonadal steroid feedback, wide hormonal fluctuations, and irregular menstrual patterns. The goal of this mini-review is to discuss the basic pathophysiology of the menopausal transition and the hormonal and nonhormonal management of clinicopathology attributed to it.

Evidence Acquisition: A Medline search of epidemiologic, population-based studies, and studies of reproductive physiology was conducted. A total of 758 publications were screened.

Evidence Synthesis: The reproductive hormonal milieu of the menopausal transition precipitates bothersome vasomotor symptoms, mood disruption, temporary cognitive dysfunction, genitourinary symptoms, and other disease processes that reduce the quality of life of affected women. The endocrine tumult of the menopause transition also exposes racial and socioeconomic disparities in the onset, severity, and frequency of symptoms. Hormone therapy (HT) treatment can be effective for perimenopausal symptoms but its use has been stymied by concerns about health risks observed in postmenopausal HT users who are older than 60 and/or women who have been postmenopausal for greater than 10 years.

Conclusions: The menopause transition is a disruptive process that can last for over a decade and causes symptoms in a majority of women. It is important for clinicians to recognize early signs and symptoms of the transition and be prepared to offer treatment to mitigate these symptoms. Many safe and effective options, including HT, are available.

Introduction

The transition from reproductive to postreproductive life in women is called the menopausal transition and marks a significant milestone in the female life cycle. While the fundamental process of menopause is related directly to ovarian aging, all aspects of the hypothalamic-pituitary-ovarian-uterine axis are altered with time. Chronological and ovarian aging are 2 intertwined, concurrent processes that influence the pace of the process and its duration. Over recent decades, several worldwide studies of the menopausal transition have provided us with a chronology of reproductive and hormonal events that accompany the process. This chronology of ovarian aging has proven to be clinically useful in explaining the symptom experience of women undergoing the menopausal transition and has helped inform clinical practice.

The menopausal transition is roughly divided into 2 phases, which were initially based solely on menstrual patterns, but these patterns appears to have endocrine correlations. The early transition is characterized by a small increase in the prevalence of common menopausal symptoms, but perturbation of menstrual cycles is minimal, with women having at least 1 menstrual cycle within the past 3 months. During this time, a variety of compensatory endocrine mechanisms, such as elevated follicle-stimulating hormone (FSH), work to maintain cyclicity on a background of increasingly low numbers of remaining ovarian follicles. The analogy of subclinical hypothyroidism is apt, as it, too, is a situation in which trophic hormone secretion rises as the thyroid gland struggles to maintain adequate output of T₃ and T₄. By the time a woman attains the late transition, she has substantial evidence of estrogen deficiency, i.e., the ovarian failure can no longer be compensated for by changes in ovarian and pituitary hormone production. This phase is associated with an uptick in symptoms and reflects a time when bone mineral loss begins to be detectable.^[1] This mini-review provides an overview of the basic endocrine physiology of the transition, its common clinical manifestations, and an approach to clinical management.

Table 1. FDA-Approved Nonestrogen Therapies
Medication	Route	Brands	Dose	Clinical considerations
Paroxetine	Oral	Brisdelle	7.5 mg daily	The only FDA-approved, nonhormonal therapy for vasomotor symptoms
DHEA	Vaginal	Prasterone	6.5 mg daily	Treating genitourinary symptoms of menopause (GSM)
Ospemifene	Oral	Osphena	60 mg daily	Serum estrogen receptor antagonist at breast and endometrium; use for GSM
Off-label alternatives
Serotonin-norepinephrine reuptake inhibitors	Oral	Venlafaxine	37.5–150 mg daily	Improves vasomotor symptoms
Gabapentin	Oral	Neurontin	900 mg nightly	Improves vasomotor symptoms; take at night for side effects of dizziness and drowsiness
Clonidine	Oral, Patch	Catapres	0.1–0.4 mg daily	Consider for patients with hypertension
Neurokinin B (NK3) receptor antagonist	Oral	MLE4901, Fezolinetant	40 mg twice daily, 90 mg twice daily	Completed phase 2 trial with significant improvement in vasomotor symptoms, few side effects

Table 2. Estrogen Hormone Therapy
Estrogen	Route	Brands	Dose	Clinical considerations
17 β-estradiol	Patch	Vivelle, Climara, Alora, Estraderm, Menostar	1–2 patches per week	Preferred route since may mitigate thromboembolic risk, mimics biologic estradiol
	Oral	Estrace	1–2 mg daily	Preferred oral medication since it mimics biologic estradiol
	Topical	Estrasorb, Estrogel	Daily	Absorption may vary, may rub onto clothes/people
	Vaginal	Estrace, E-string, Vagifem, Imvexxy	Daily × 2 weeks then twice weekly; Ring every 3 months	Preferred route for treating only genitourinary symptoms of menopause (GSM).
Conjugated equine estrogen (CEE)	Oral	Premarin	0.3–1.25 mg daily
	Vaginal	Premarin	Daily × 2 weeks then twice weekly	Preferred route for treating only GSM
Synthetic CEE	Oral	Cenestin	0.3–1.25 mg daily
Esterified estrogen	Oral	Menest	0.3–1.25 mg daily
Ethinyl estradiol	Oral	Estinyl	0.2–0.05 mg up to 3-times daily

Table 3. Estrogen + Progestin Hormone Therapy
Estrogen	Progestin	Route	Brands	Dose	Clinical considerations
17 β-estradiol	Progesterone	Oral	Bijuva	1 mg/100 mg daily	Only combined formulation that mimics both biologic estradiol and progesterone
	Norethindrone acetate	Patch	Combipatch	Twice a week
		Oral	Activella	0.5 mg/0.1 mg daily
	Levonorgestrel	Patch	Climara-Pro	Weekly
	Norgestimate	Oral	Ortho Prefest	1 mg for 3 days, 1 mg/0.09 mg for 3 days
	Drosperinone	Oral	Angelique	1 mg/0.5 mg daily
Conjugated equine estrogen	Medroxyprogesterone acetate	Oral	Premarin, Prempro	0.625 mg with 5 mg × 2 weeks or 2.5–5 mg daily
	Bazedoxifene*	Oral	Duavee	0.45 mg/20 mg daily	*A serum estrogen receptor modulator, not a progestin. Removes side effects associated with progestin and antagonizes endometrium
Ethinyl estradiol	Norethindrone acetate	Oral	FemHRT	5 mcg/1 mg daily